cardiovascular disease essay introduction

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Cardiovascular Disease (CVD)

1. introduction.

Globally, around 17.3 million people died from cardiovascular diseases in 2008. In 2016, circulatory diseases were the most common cause of death, accounting for 32.4% of all deaths. In 2008 and 2010, these diseases caused 157,000 and 316,000 deaths in Portugal, respectively. Cardiovascular diseases are a growing concern in developed countries due to increased exposure to risk factors, population aging, and improved life quality. The understanding of the multifactorial aspect of cardiovascular disease is important, as it is the basis for effective disease prevention and management. The multiple risk factors may vary according to age, sex, and socioeconomic factors. The development of risk prediction equations considering all these factors could provide an adequate method for evaluating global cardiovascular risk. The mortality from diabetes-related diseases also has a tendency to increase. It is currently estimated that diabetes was responsible for nine million deaths in 2007. From 2006 to 2016, there was a 26.7% increase in diabetes cases (from 923,000 to 1,169,000 cases). It is predicted that in 2030 diabetes will affect 439 million inhabitants worldwide, representing a 46.2% increase in the incidence of the disease. The management of risk factors for cardiovascular diseases resulting from type 2 diabetes is fundamental. Published data reported that the risk for developing cardiovascular disease is two to four times higher in diabetic patients compared to the population of non-diabetic individuals.

1.1 Overview of Cardiovascular Disease

Cardiovascular disease is among the leading causes of death and disability in developed nations. The onset of CVD is generally later in life with risk increasing with advanced age. Changes in lifestyle—most notably smoking—over the past several decades have resulted in shifts in the patterns of cardiovascular disease and have resulted in significant reductions in CVD-related morbidity and mortality. Although established CVD risk factors have been well characterized, numerous new and emerging risk factors have been linked with the development and progression of atherothrombosis. Nationally and internationally accepted guidelines have been established stratifying individuals into varying categories of CVD not only based on their risk factors but also on 10-year risk (in low, intermediate, or high risk categories) for developing future CVD events. Discussion in this edition of "CVD" section describes these issues in further detail and provides an overview of future strategies for preventing, detecting, and managing CVD. Cardiovascular disease, or CVD, is a class of diseases that involve the heart or blood vessels (arteries and veins) and collectively are the leading cause of death and disability in developed nations. Among the most problematic CVD conditions are coronary artery disease (CAD), stroke, and peripheral arterial disease (PAD), which all have similar atherothrombotic pathophysiologies. Myocardial infarction (MI or heart attack), cerebrovascular accident (CVA or stroke), and critical limb ischemia (CLI) are major ischemic complications of these conditions and have detrimental effects on the myocardium, brain, and legs, respectively. Data from the World Health Organization Global Burden of Disease Project analyses have indicated that more than 30% of all deaths worldwide are due to CVD, with CAD alone resulting in more than 7 million deaths each year.

1.2 Risk Factors for Cardiovascular Disease

Non-modifiable risk factors are age, sex, race, and heredity. Modifiable risk factors are of great interest to many people for the simple reason that they can be prevented. Below are listed modifiable risk factors for CVD. Smoking greatly increases your risk for CVD. Smoking can cause fatal conditions resulting in heart attack, stroke, and sudden death. It is important to recognize these facts. High blood pressure greatly increases your risk for CVD. High blood pressure is often considered a silent killer because it builds up in your body over time without showing any symptoms. High blood cholesterol greatly increases your risk for CVD. The higher the cholesterol in your body, the higher your risk is for CVD. High cholesterol can be controlled through diet, maintaining a healthy weight, and physical activity. Physical inactivity increases your risk for CVD. The Surgeon General recommends that individuals participate in moderate-intensity exercise for a minimum of thirty minutes on most days of the week to improve and maintain overall health. Researchers have found that moderate-intensity exercise performed regularly can lead to many positive changes in the body, including decreases in the risk of developing heart disease, reduction in levels of LDL cholesterol and an increase in HDL cholesterol, modest reduction in blood pressure, improvements in other risk factors for CVD, and weight maintenance. Diabetes more than doubles your risk for heart disease. Your dietary pattern can help reduce your risk for heart disease. Eating a diet with all of the nutrients that are included in a healthful dietary pattern, such as low sodium, low calories, and healthy eating, are all good tactics to help reduce your risk for heart disease. Obese individuals have an increased risk for heart disease even if they have no other factors.

1.3 Importance of Preventing Cardiovascular Disease

Imagine the following situation: researchers find a condition that affects a large portion of the population, is highly incapacitating, and kills a significant number of victims. The problem is that this condition could be prevented through behavioral changes such as diet and exercise. Would the population change their attitudes in favor of these good practices? According to the World Health Organization, non-communicable diseases kill three-quarters of the Brazilian population, and among them, the larger portion of deaths is caused by cardiovascular diseases. This result manifests itself from a combination of biological vulnerability, promoted by socioeconomic adversities, and modifiable risk factors. This result highlights the importance of investing in the implementation of national plans to treat and prevent the natural evolution of diseases. The main risk factors for cardiovascular diseases include tobacco use, physical inactivity, unhealthy diets, and harmful use of alcohol. All of these factors can be prevented and/or controlled by the people, who society needs to stimulate these types of actions. However, without proper guidance, it is difficult for the population to get on track. There is a whole movement around the combat and prevention of cardiovascular diseases, and the guidelines of the Brazilian Society of Cardiology are present in this wave. Through prevention campaigns and the dissemination of scientific information, we seek to emphasize to society the importance of maintaining healthy habits, which could be reflected in a longer and better quality of life.

2. Types of Cardiovascular Disease

The major types of cardiovascular disease are heart disease and stroke. Heart disease is actually a group of conditions that affect the structure and functions of the heart. From aortic aneurysm to asystole, from giant cell myocarditis to hypertrophic cardiomyopathy, there's a variety of heart conditions affecting people. Heart disease is typically the medical condition that people think of as cardiac disease, and it - like many of the other cardiac diseases - affects the heart's ability to pump blood to the rest of the body. An aneurysm is typically the result of weakness in the muscle wall, and the aortic aneurysm is characteristic of the aorta, which is the largest blood vessel in the body. Aneurysms can also be found in the heart, both in the vessels and in the heart muscle. When the weak spot in the blood vessel ruptures, blood leaks out of the hole and into the surrounding tissues. Many people don't realize that an aneurysm is a very serious condition that can cause life-threatening situations. Most people are actually aware of the aorta because of a condition called an abdominal aortic aneurysm, which is characterized by a bulging section in the aorta. It's particularly dangerous if it bursts because it causes internal bleeding and could be fatal. However, the heart can also be affected by this condition, both in the vessels in the heart itself.

2.1 Coronary Artery Disease

Coronary artery disease is the most common form of heart disease and the leading cause of death in the Netherlands. It is primarily caused by atherosclerosis: plaque buildup in the arteries that carry blood and oxygen to the heart. The disease can lead to chronic stable angina pectoris, unstable coronary syndromes, sudden death, and other complications. Coronary atherosclerosis is a gradual process that begins in childhood and increases with age. Preventing this disease is important because once it has occurred, it is a chronic and progressive condition. Risk factors: Angina pectoris or coronary artery disease (in more than 50% of the cases) is an uncomfortable (or painful) feeling caused by myocardial ischemia due to a discrepancy between supply and demand. Acute coronary syndromes are acute exacerbations, which range from unstable angina pectoris to myocardial infarction causing permanent damage to the heart. Approximately 30% of patients with chest pain and angina pectoris and 10% of patients with suspected myocardial infarction have normal coronary arteries or atherosclerotic lesions that are hemodynamically irrelevant. Cardiac disorders such as aortic stenosis and fibrillation, hypertrophic obstructive cardiomyopathy, and ASD with right ventricular failure that increases oxygen demand can also lead to angina pectoris. Patients with cardiac syndrome X have a form of microvascular angina. Other causes of chest pain and ischemia are pulmonary hypertension, vasoconstrictive diseases, anemia, and heavy physical labor. Patients with angina pectoris who do not have obstructive coronary artery disease have a good prognosis. The burden of illness in patients with preserved ejection fraction heart failure is high due to cardiovascular causes and can be attributed to symptoms and signs of the disease.

2.2 Heart Failure

Heart failure is more common in men than women, but there are more women with heart failure. A higher percentage of men than women didn't know that CHF is a serious disease. 30.7% of women and 27.3% of men (p= ns) reported no one ever told them that they had heart disease. The principal differences are in ischemic heart disease in men and atrial fibrillation in women. Congestive heart failure (CHF) is a frequent cause of disease-related hospitalization and the most common reason for hospital admissions in Medicare-covered patients after age 65. Increased awareness of and adherence to clinical practice guidelines in the prevention of ischemic heart disease (IHD) could result in a significant impact on CHF admissions. CHF admissions included 100-200 discharges each year among 100 physicians and four nurse practitioners with diagnoses relevant to inpatient CHF care at a single quaternary care hospital. This has led, with increasing frequency, to hospital CHF status tracking of the Medicare population in the United States in order to translate into process-of-care improvement and ultimately as a proxy for outcomes involving CHF. Congestive heart failure admissions in the United States have risen steadily from 27% to 46% in the year between 1990 and 2006. CHF affects approximately 5.1 million people each year. CHF is associated with substantial morbidity, multiple co-morbidities, an increased risk of adverse events, and impaired quality of life. Its prevalence is expected to increase even more over the next two decades. Congestive heart failure (CHF) affects a growing number of patients, is more frequent, and represents a substantial healthcare expenditure each year. Heart failure (HF) is a complex syndrome that frequently presents to a cardiac or primary care physician in a hospital-based practice. Proper healthcare delivery has the potential for substantial benefit to patients and their families, with an additional benefit to the healthcare system. Admissions for CHF to the hospital are predictable outcome measures related to morbidity and mortality. Congestive heart failure (CHF) is a clinical syndrome, the hallmark of which is dyspnea, such as cough and orthopnea effusion, and the hallmark of which is edema. This is exemplified by the heart's inability to pump and/or circulate blood efficiently. This results in the retention of fluid as a consequence of fluid overload. CHF also has multiple etiologies, including hypertension, ischemic heart disease, valvular, myogenic, and myocardial infiltration that result in a complex functional disorder with certain background diseases. Attention must be paid to monitor and identify the fluid status in CHF, to rationalize the three CHF manifestations, usually involving centralized monitoring by the patient owing to shortness of breath. The response to an acute exacerbation can cause the patient to demonstrate non-adherence to drug therapy and non-adherence to diet or both. Shortness of breath due to abnormal fluid retention in the CHF-related clinic is typically the most prominent reason for urgent care visits. Even careful documenting treatment recommendations based on clinical status and monitoring in the emergency department, this clinic has been an unmet medical need that affected patients prioritize and produce sometimes conflicting goals for optimal treatment to be achieved. The central problem in the management of CHF is to identify the developing stage of fluid retention, to intervene early, or ideally to prevent its appearance. That is before life-threatening hypervolemia becomes symptomatic.

Cerebral vessel dysfunction can also lead to stroke, a condition that affects around 5% of diabetic people. Studies have shown that hyperglycemia, not only at the time of the stroke but also in the post-ischemic periods, exacerbates the functioning of cerebral vessels, reducing the efficacy of thrombolytic approaches. It diminishes the efficiency of endovascular repair and increases the likelihood of injury from re-occlusion. Acute hyperglycemia can also increase perivascular and parenchymal edema associated with reperfusion of ischemic brain, forcing harmful mechanical distension. Therefore, it is important to maintain blood glucose levels after a stroke at target levels and avoid hyperglycemia, not necessarily hypoglycemia. It should be done not only by improving the glucose regulatory mediators but also promptly through treatment with acute neuroprotective agents in the post-stroke hyperglycemic population, with the objective of preventing further vascular complications. Stroke, therefore, has a significant degree of epithelial barrier dysfunction. Cerebral edema is a life-threatening complication of stroke, which once it occurs, further exacerbates itself. In the most common ischemic pathology, it is assumed that the endothelial barrier function in the cerebral vessels is compromised by ischemia causing activation of endothelium and macrophages and microglial inflammation, ultimately leading to changes in TJ structure and function. However, the role of TJs in BBB disruption is still controversial. Neural glial cell-derived neurotrophic factor (GDNF) is initially neuroprotective and promoting and could reverse this effect. Moreover, given that hyperglycemia can reduce endogenous GDNF levels, causing synaptic and cognitive dysfunction, increasing GDNF activity could facilitate recovery from stroke, especially in the presence of hyperglycemia, also helping to restore the integrity of TJs.

3. Treatment and Management of Cardiovascular Disease

Although many of the CVD risk factors cannot be directly controlled by the individual, such as age, sex, and genetic markers, some are modifiable by making lifestyle changes. A healthy lifestyle is one of the most effective means to decrease the risk of getting CVD. This includes, among other things, maintaining a normal weight, not smoking, practicing regular physical activity, and eating a wholesome diet with a moderate salt intake. While lifestyle changes are important, the use of pharmacologic treatments is also common among people who either require or are recommended to take medication for CVD-related disease. The goal of drug therapy is to prevent or control the disease and reduce the need for hospitalization or surgical procedures. Furthermore, if a person already has CVD and experiences difficulties following recommendations for diet, physical activity, and sedentary behavior changes, drug therapy may be considered as an option. There are a large number of drugs that are used in treating and preventing CVD, while many of these are recommended in specific diseases, such as dyslipidemia, hypertension, atrial fibrillation, venous thromboembolism, and heart failure. Pharmacologic options should be part of an overall treatment plan that involves assessment of CVD risk factors, particularly those of atherosclerotic cardiovascular disease (ASCVD) risk, and lifestyle counseling in all people with CVD or those at risk for ASCVD. Medications do not work similarly in all people, especially among different ethnic groups, and the risk for adverse effects may differ between different drugs or patient populations. Therefore, physicians are encouraged to be aware of potential benefits and risks of the different drugs used to prevent CVD events in different patient populations.

3.1 Medications for Cardiovascular Disease

Medications are used along with lifestyle modifications to control heart disease, stroke, and heart attack. When lifestyle changes alone are not effective, medications may be used to lower blood pressure, prevent the buildup of plaque on the inside of blood vessels, prevent blood clots, and lower cholesterol levels. If you are prescribed medications for your heart disease, stroke, high blood pressure, high cholesterol, diabetes, or other conditions that increase the risk of developing cardiovascular disease (CVD), you may not need to take all of them at once, but it is important to track each one. Furthermore, it is important that you take your heart and stroke-related medications as prescribed by your healthcare provider. Do not discontinue any medications yourself, even if you feel that they are not working for you. It is necessary for you to inform your healthcare provider if you are having any problems with any medications that have been prescribed, so that he or she can help determine if the problem is a result of the medicine or if other underlying factors may be causing the undesirable symptoms. It is important to understand that not everyone who takes medications will experience the same positive or negative effects. While most individuals will respond positively to treatment, some will not respond at all. As well, some people may experience adverse effects, while others will have no adverse effects. Studies have shown that those who are at the highest risk of developing CVD tend to receive the most benefit in terms of reduction in heart attacks and strokes as a result of moderate or high doses of the drug(s). On the whole, some individuals may tell you that they do not want to take their medications due to the perceived risk of side effects. Therefore, it is important for you to discuss this matter with your healthcare provider if you have any concerns about the medications that have been prescribed for you.

3.2 Lifestyle Modifications for Cardiovascular Health

Despite amazing technological advances during the last few decades in cardiology, both in risk factor control and life-prolonging treatments for patients with CVD, certain conventional interventions like smoking cessation, assiduous dietary therapy, dyslipidemia, hypertension, and diabetes are still either actually or putatively the most efficient for the primary and secondary prevention of CVD. The best choice among them for a specific purpose reflects the multifactor etiopathogenesis of atherosclerosis and its associated complications, primarily due to a setback of endothelial function. The potential of these interventions is supported by a wealth of scientific data that confirm all their advantages. Their presentation should not only facilitate the proper selection among these interventions based on individual morphotype, genetic, and clinical characteristics, but also promote the habit of using all of them as necessary to enhance heart health. For instance, while the abrupt cessation of smoking leads to a significant improvement in endothelium-dependent vasodilation in habitual and elderly smokers, regardless of gender, this beneficial effect is substantially compromised by acute tobacco smoking and the ingestion of only endothelium-dependent vasodilators (nitrates) long after cessation. Additionally, the timely use of a nitrate-poor cocktail of tobacco effects is also less effective than nitrates in contributing to nitric oxide, which is essential for its protective effect on the endothelial complexion. This can be seen in the theme entitled "becoming a norm in erythrocytes after cessation," as with other therapies. Indeed, smoking cessation ends the platelet-dependent smoking in the formation of thrombin, primarily through the tax exemption of both phospholipids and adhesive heterocycles, and by interacting with the alpha4 integrins of the adhesive molecule, which is soluble to the endothelium.

3.3 Surgical Interventions for Cardiovascular Disease

Cardiovascular disease (CVD), also known as coronary heart disease (CHD), is caused by the build-up of fatty deposits (atheroma) around the inside of the walls of the coronary arteries. These fatty deposits cause the arteries to narrow, reducing blood flow to the heart muscle. If the blood flow is reduced too much, this can cause a complete blockage resulting in the death of the heart muscle – this is called a heart attack and can be life-threatening. Some people experience less acute symptoms from CHD. This is called angina and can be painful and occur when doing physical activity. Symptoms include chest pain and shortness of breath. Some people have symptomless CHD. Those with untreated, poor control of their CHD such as high blood pressure, high cholesterol, smoking, and diabetes can be at greater risk of having a heart attack. There are a number of lifestyle changes and medications that can be used to control CHD, such as statins, aspirin, and beta-blockers. There are a number of established surgical interventions for CHD. These include angioplasty (balloon surgery), heart bypass surgery, and atherectomy. Coronary angioplasty is a minimally invasive procedure that widens narrowed or blocked coronary arteries. Coronary angioplasty helps improve symptoms and quality of life in those who have CHD. Atherectomy is used in those who have specifically fatty plaque with or without calcium and have not benefited from coronary angioplasty. Bypass surgery or coronary artery bypass graft (CABG) is a surgical procedure that improves symptoms and quality of life in those with complex CHD. The survival benefit of bypass surgery was most predominant in those with severe CHD. The aim of this review is to assess the effectiveness of bypassing (a connection made during surgery to go around a blocked coronary artery) the left anterior descending artery to improve blood flow.

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DOI: 10.1007/978-3-319-89315-0_1
Corpus ID: 86646836

Cardiovascular Disease: An Introduction

Published in Vasculopathies 19 February 2019
Vasculopathies

11 Citations

Biomarkers of oxidative stress tethered to cardiovascular diseases, updates in the management of coronary artery disease: a review article, the interplay between sleep disorders and cardiovascular diseases: a systematic review, bio-actives from natural products with potential cardioprotective properties: isolation, identification, and pharmacological actions of apigenin, quercetin, and silibinin, profiling system-wide variations and similarities between rheumatic heart disease and acute rheumatic fever-a pilot analysis., blood flow restriction training in cardiovascular disease patients, copy number variations: the potential association genetic cause in severe cardiovascular diseases with unknown aetiology, study title: a systematic review of rcts to examine the risk of adverse cardiovascular events with nicotine use, predictors of psychological distress among post-operative cardiac patients: a narrative review, precision and advanced nano-phytopharmaceuticals for therapeutic applications, 195 references, inflammation and cardiovascular disease mechanisms., reducing the global burden of cardiovascular disease, part 2: prevention and treatment of cardiovascular disease, vasculopathy in the setting of cardiorenal syndrome: roles of protein-bound uremic toxins., inflammation and cardiovascular disease: from pathogenesis to therapeutic target, oxidative stress in cardiovascular disease, hba1c for type 2 diabetes diagnosis in africans and african americans: personalized medicine now, reducing the global burden of cardiovascular disease, part 1: the epidemiology and risk factors., cardiovascular disease in patients with chronic inflammation: mechanisms underlying premature cardiovascular events in rheumatologic conditions., endothelial cell-cardiomyocyte crosstalk in diabetic cardiomyopathy., cardiac endothelium-myocyte interaction: clinical opportunities for new heart failure therapies regardless of ejection fraction., related papers.

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The Importance of Heart Diseases

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Cardiovascular Disease: An Introduction

First Online: 19 February 2019

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cardiovascular disease essay introduction

Marc Thiriet 2

Part of the book series: Biomathematical and Biomechanical Modeling of the Circulatory and Ventilatory Systems ((BBMCVS,volume 8))

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Wo aber Gefahr ist, wächst das Rettende auch! [Where there is danger, that which will save us also grows] (F. Hölderlin, Patmos [1803])

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Cardiovascular disease (CVD) is a collective term designating all types of affliction affecting the blood circulatory system, including the heart and vasculature, which, respectively, displaces and conveys the blood. This multifactorial disorder encompasses numerous congenital and acquired maladies. CVD represents the leading noncommunicable cause of death in Europe (∼50% of all deaths; ∼30% of all deaths worldwide) [ 29 ]. In 2008, nine million people died of noncommunicable diseases prematurely before the age of 60 years; approximately eight million of these premature deaths occurred in low- and middle-income countries [ 30 ].

Cardiovascular disease encompasses atherosclerosis with its subtypes (coronary [CoAD], cerebral [CeAD], and peripheral artery disease [PAD]) with two major complications, myocardial infarction and ischemic stroke (more common than hemorrhagic stroke; Sect. 1.1.5 and Vol. 13, Chap. 5. Atherosclerosis), heart failure (HF), cardiac valvulopathies and arrhythmias, rheumatic heart disease (damage of the myocardium and cardiac valves caused by streptococci bacteria), congenital heart disease, and deep vein thrombosis with its own complication, pulmonary embolism.

Rare cardiovascular maladies are classified into [ 31 ]:

Rare afflictions of the systemic (class I ) and pulmonary circulation (class II )

Rare cardiomyopathies (class III )

Rare congenital cardiovascular disorders (class IV )

Rare cardiac arrhythmias (class V )

Cardiac tumors and cardiovascular affections related to cancer (class V I )

Cardiovascular sickness in pregnancy (class V II )

Other types of rare cardiovascular illness (class V III )

Etiology Footnote 1 of a given malady refers to the cause, set of causes, or manner of causation of a disease. CVD is multicausal, with clinical (dyslipoproteinemia and hypertension) and behavioral factors (sedentarity, overnutrition, smoking, and a stressful life). Deficiency or excess of trace elements in soil may contribute to CVD [ 32 ]. A major cause of CVD is atherosclerosis.

Diagnosis Footnote 2 of many diseases, in addition to assessment of prognosis, is facilitated by the utilization of specific markers that can be proteins and nucleic acids, such as short microRNAs and long a priori nonprotein-coding RNA implicated in the regulation of metabolism, control of blood circulation, and inflammation.

Epidemiological studies are aimed at extracting individual, Footnote 3 environmental (indoor and outdoor air pollution, second-hand smoke), and societal risk factors, ranking them to the determined predominant factors according to their impact, morbidity, and mortality rate. These studies also aimed to propose strategies to reduce CVD burden and for the prevention of early adverse events. In a health system that brings research into practice, the aim is to reduce risk factors and determine appropriate treatments [ 33 ].

1.1 Vasculopathies and Vasculitides

Vasculopathy corresponds to any disease affecting the blood vessels that can be caused by degenerative, metabolic (e.g., diabetic vasculopathy), and inflammatory disorders in addition to thromboembolic maladies.

Vasculitis , or angiitis , is more specific, as it is defined by a focal or widespread inflammation of the vascular wall, whatever the blood vessel type (i.e., arteries, arterioles, capillaries, venules, and veins), size (i.e., large, medium, or small), number, and location.

Ethnicity and gender can affect vascular physiological and pathophysiological mechanisms. Data obtained in a general population, such as correlation between a risk factor and a given disease or complication associated with a given gene mutation, may not be representative of features of a homogeneous subpopulation. Sex differences in incidence, prevalence, morbidity, and mortality from CVD, which include sex-specific disorders and sex-dependent symptom presentation and evolution of pathophysiological processes common to both genders (e.g., hypertension and atherosclerosis), represent a source of health disparity [ 34 ]. Sex and racial differences in pharmacodynamics and -kinetics affect therapy efficiency [ 35 ].

1.1.1 Ethnic Differences

Ethnicity is a source of health inequalities. People from certain ethnicities suffer from premature CVD. In particular, ethnic heritage influences the occurrence rates of hypertension and diabetes.

According to the American Heart Association and National Institute of Health, 40% of African American men and women have a coronary disease (versus 30 and 24% of European-American men and women, respectively) due to genetic differences between ethnic groups rather than by life conditions and diet. Moreover, African American women with coronary disease are at a twofold higher risk for myocardial infarction than European American women. In the USA:

African Americans are at a higher risk for hypertension.

North American Latinos have higher rates of obesity and diabetes.

The coronary artery disease rate is highest in the South Asian population.

The stroke rate is the highest in individuals of African-Caribbean descent, the prevalence of diabetes in these two ethnic groups being much higher than in the White population.

In the UK [ 36 ]:

The incidence of myocardial infarction is higher in South Asians than in non-South Asians for both sexes.

The incidence of stroke in black people is higher than in White people, whatever the sex.

The prevalence of CoAD is highest in Indian and Pakistani men.

The revascularization rate is higher in the White ethnic group than in the black and Asian ethnic groups.

Individuals from different ethnic groups tend to store fat in different regions of the body.

The prevalence of overweight and obesity in young children is highest in the Black ethnic group.

The prevalence of diabetes is much higher in Black Caribbean, Indian, Pakistani, and Bangladeshi men.

However, these inequalities can be related not only to genetic differences but also to distinct cultural and social practices. The influence of ethnicity can be difficult to distinguish from that of the socioeconomic status. Moreover, a genetic diversity can exist within racial and ethnic groups.

1.1.2 Gender Influence

Hormonal in addition to genetic and environmental factors contribute to sex differences in CVD. The organism environment influences hormonal secretion, which, in turn, affects the brain function, hormones acting on the genome of neural cells that contain their cognate receptors. For example, the ventromedial and ventrolateral and arcuate nuclei contain estrogen-sensitive neurons, the ventromedial nucleus responding more rapidly than the arcuate nucleus [ 37 ].

In addition, hormonal secretion by the adrenal gland and gonads (testis and ovary) is controlled not only by temperature (heat or cold), threat, and sexual excitement, which prime adaptive responses, but also by circadian oscillators entrained by environmental signals (light and dark).

Repeated psychosocial stress can provoke neuronal loss in the hippocampus, which receives heavy input from the dentate gyrus mossy fiber system [ 37 ]. Adrenal steroids, which protect in the short term, operate in conjunction with neural excitatory amino acids, causing damage and allostatic load in the long term, when the adaptive response is not managed efficiently and persists. Gonadal hormones can also produce both protection and damage according to their concentration and duration of exposure.

Sex is mainly determined by the X and Y chromosomes, which create a sex-specific expression pattern. Men possess a single copy of each type (XY genotype) and women two copies of the X chromosome (XX genotype), one of the X chromosome being silenced during embryogenesis (X-chromosome inactivation).

In general, premenopausal women are at a lower CVD risk than men of a similar age. Men develop hypertension at younger ages than women. The sex-determining region Y (SRY locus) of the Y chromosome regulates the transcription of tyrosine hydroxylase (TH; or Tyr 3-monooxygenase), the rate-limiting enzyme in the synthesis of catecholamines such as noradrenaline, and yields a gender-dependent difference in sympathetic activity, predisposing men to hypertension to a greater extent than women [ 34 ].

The Y chromosome also includes genes involved in inflammation and innate immunity linked to macrophage activation [ 34 ]. On the other hand, the X chromosome affects expression of genes associated with apoptosis, lipid oxidation, and generation of reactive oxygen species (ROS) by the mitochondrion.

In individuals from European countries, some chromosomal loci related to lipid metabolism exhibit sex-specific effects, in particular the HMGCR and NCAN genes encoding 3-hydroxy 3-methylglutaryl coenzyme-A reductase and neurocan (or chondroitin sulfate proteoglycan CSPG3), respectively [ 34 ].

A sex-specific single-nucleotide polymorphism in the locus of the CPS1 gene encoding mitochondrial carbamoyl–phosphate synthase-1, which is involved in hepatic nitrogen urea metabolism and synthesis of arginine, a precursor of nitric oxide (NO), has a greater effect in women than in men [ 34 ].

The gene encoding the androgen receptor resides on the X chromosome and displays a polymorphism linked to a highly variable number of CAG repeats. Variants in this gene have a greater impact in men than in women [ 34 ]. Genetic variants also affect enzymes involved in synthesis, conversion, and degradation of sex steroids.

Estrogens (e.g., estradiol [E 2 ]) and androgens (e.g., testosterone and dihydrotestosterone [DHT; or androstanolone]) govern multiple processes in both women and men [ 38 ].

1.1.2.1 Estrogen Signaling

Estradiol is synthesized primarily in the granulosa cells of ovaries and Sertoli cells in males. It tethers to various types of cytosolic ERα and ERβ (i.e., ligand-activated transcription factors NR3a1–NR3a2) in cardiomyocytes (CMCs) and vascular smooth muscle (vSMCs) and endothelial cells (ECs) in addition to plasmalemmal estrogen receptor GPER1 (or GPR30) in vascular endotheliocytes and smooth myocytes, renal intercalated and tubular cells, and cells of the hypothalamic–pituitary–adrenal axis [ 38 ].

Membrane-initiated rapid (nongenomic) signaling launched by sex steroid hormones produced by the adrenal cortex, ovary, and testis involves estrogen receptors in the plasma membrane. In addition to the membrane estrogen receptor GPER1, sex steroid receptors such as NR3a1 and NR3a2 can localize to the plasma membrane; NR3a1 can be identified in caveolae associated with proteic complexes), its palmitoylation (Cys447) being required for its translocation to the plasma membrane [ 39 ]. NR3a1 and NR3a2 are necessary and sufficient for rapid estrogen-triggered signaling. At the plasma membrane, caveolin-1 serves as a scaffold for other signaling molecules (e.g., trimeric G protein, Src, PI3K, GFR, and MNAR) Footnote 4 that are activated by the E 2 –NR3a1 couple in caveolae, which facilitates the fast generation of early signals (e.g., Ca 2+ influx). Footnote 5 Other NR3a1 move to the nucleus chaperoned by heat shock protein HSP90 owing to a nuclear localization sequence or to mitochondria. Nuclear NR3a1 is mandatory for the development of the female reproductive tract and mammary gland.

NR3a2 prevents adverse cardiac remodeling (hypertrophy and fibrosis). The E 2 –NR3a2 couple stimulates PI3K and primes transcription of the RCAN gene that encodes the regulator of calcineurin (PP3) [ 39 ]. Footnote 6 In addition, the E 2 –NR3a2 couple launches synthesis of the natriuretic peptides ANP and BNP, which hampers adverse cardiac hypertrophy via ERK kinases in the CMC. On the other hand, atherogenic 27-hydroxycholesterol serves as an endogenous selective estrogen receptor modulator (SERM), which abounds in the diseased arterial wall. It competitively precludes E 2 –NR3a binding and hence both the rapid (i.e., NO-mediated vasodilation) and delayed transcriptional E 2 actions [ 39 ].

Estrogens are also synthesized in the central nervous system from cholesterol or converted from aromatizable androgens in presynaptic terminals [ 38 ]. Estrogens can then diffuse. Both NR3a1 and NR3a2 are produced in nuclei in the forebrain and brainstem that regulate cardiac frequency and blood pressure (solitary tract [NTS] and parabrachial nuclei [PBN] and rostral ventrolateral medulla [RVLM]), enhancing sympathetic nervous system-mediated baroreflex. They regulate the local renin–angiotensin axis (RAA), these brain nuclei possessing renin, angiotensinogen, angiotensin convertases ACE1 and ACE2, and angiotensin Agt2 receptors (e.g., AT 1 and AT 2 ). Angiotensin-2 and aldosterone stimulate ROS production in the brain by NAD(P)H oxidase, thereby raising sympathetic nerve activity. In the subfornical organ (SFO), estrogens via NR3a1 and NR3a2 prevent intracellular ROS formation. Estradiol reduces both Agt2- and aldosterone-induced hypertension in male and ovariectomized female rodents [ 38 ].

However, NR3a1 and NR3a2 regulate blood pressure differently. In male rats, injection of E 2 into the paraventricular nucleus (PVN) does not affect cardiac frequency and blood pressure. In female mice, activated CNS NR3a1 protects against Agt2-induced hypertension, whereas PVN NR3a2 and RVLM NR3a2 protect against aldosterone-induced hypertension. In female and male mice, activated CNS NR3a2 preserves resting blood pressure via RVLM Ca V channels [ 38 ]. Therefore, at least in female and male rodents, specific NR3a subtypes mediate E 2 -mediated protection in different nuclei.

Nitric oxide synthase NOS1 is produced to a greater extent in the SFO and PVN of female mice than in these nuclei in male mice [ 38 ]. In addition, estrogens rapidly stimulate NO production by NOS3 via NR3a1 in the vascular endothelium, whatever the gender.

Estrogens signal to the kidney when salt sensitivity increases in menopausal women, likely because estrogens support NO action and lower the AT 1 / AT 2 ratio, hence preserving renal Na + handling [ 38 ]. In premenopausal women, salt loading during estrogen peaks alleviates filtration fraction and causes a sustained renal vasodilation. In postmenopausal women, salt loading raises the filtration fraction. In addition, NR3a1 mediates regulation of the renal ACE1/ACE2 ratio by estrogens, ACE2 converting vasoconstrictive, prohypertrophic, and proproliferative angiotensin-2 into Agt (1–7) .

GPER1 on arterial and venous endotheliocytes and smooth myocytes counters endothelin-1– and prostanoid-primed vasoconstriction and lessens superoxide production, hence protecting against hypertension [ 38 ]. Furthermore, GPER1 activates NOS3 in the vascular endothelium. It also attenuates vascular smooth muscle cell (vSMC) proliferation and vascular inflammation.

Estrogens operate on low-density lipoproteins (LDLs) and the LDL receptor (LDLR) to improve lipidemia. Estradiol upregulates LDLR production and stimulates sterol 27-hydroxylase CyP27a1 activity, which hampers LDL formation. In addition, estrogens promote synthesis of the apolipoprotein ApoA1 in the liver and of ApoE [ 38 ]. They also boost ABCa1 production, facilitating reverse cholesterol transport, but hinder ScaRb1 expression, hence prolonging the duration of circulating high-density lipoproteins (HDLs).

Many leukocytes infiltrating atherosclerotic plaques, such as macrophages, B and T lymphocytes, and mastocytes possess sex hormone receptors; estrogens can thus influence inflammation [ 38 ]. Estrogens exert the anti-inflammatory M2 phenotype in macrophages; reduce LDL oxidation, endothelial activation, and adhesion of neutrophils and monocytes to the endothelium; and impede NOx activity and hence ROS production.

Estradiol that dampens inflammation can reduce formation of tumor-necrosis factor superfamily member TNFSF1 and prevent its secretion [ 38 ]. Moreover, it activates NR3a2 and subsequently Iκ Bα which represses NFκB-boosted inflammation.

Estrogen supports angiogenesis in PAD owing to NOS3 [ 38 ]. Proangiogenic estrogens favor mobilization of endothelial progenitor cells and incorporation into neovascularization sites owing to NOS3 stimulation and MMP9 activity in the bone marrow.

Relatively high concentrations of circulating female sex hormones protect against abdominal aortic aneurysm (AAA) development, as these hormones reduce inflammation and matrix metallopeptidase activity in the aortic wall [ 38 ]. In female animals, a higher concentration of plasminogen activator inhibitor PAI1, which precludes MMP2 and MMP9 production, protects against AAA development. Estrogens also lower MMP2 and MMP9 concentrations in addition to immunocyte infiltration in AAA and hence slow dilation rate with respect to ovariectomized rodents. In addition, NO production stimulated by estrogens protect against AAA. Aortas from female mice contain larger NR3a1 amounts and lower matrix metalloproteinase (MMP) activity.

On the other hand, in humans, AAA samples contain larger concentrations of 3-hydroxyanthranilic acid (3HAA), indoleamine (2,3)-dioxygenase (IDO), and kynureninase than adjacent aortic segments. Indoleamine dioxygenase is the first and rate-limiting enzyme in the kynurenine pathway of tryptophan metabolism that creates 3HAA. Acute infusion of angiotensin-2 favors abdominal aortic aneurysm development in APOE −∕− mice, but not in APOE −∕− and Ido −∕− mice, in which elastic lamina degradation and aortic expansion decay [ 40 ]. Angiotensin-2 activates interferon-γ which launches expression of IDO and kynureninase, thereby raising production in medial smooth myocytes and subsequently its concentration in the aortic wall and plasma of 3HAA, which upregulates synthesis of MMP2 via NFκB.

The risk of cerebral aneurysms is augmented in postmenopausal women, whereas estrogen replacement protects against intracranial aneurysms, protection ensured by estrogens being mediated by NR3a2 and cerebral vascular NO production [ 38 ]. Footnote 7

1.1.2.2 Androgen Signaling

Testosterone is synthesized in testicular Leydig cells and ovarian theca cells. It is converted to the more potent 5α-DHT by 5α-reductase.

Both androgen types connect to another ligand-activated transcription factor, androgen receptor (AR or NR3c4), which is detected in endotheliocytes and smooth myocytes, platelets, and macrophages. Two variants (ARa–ARb) lodge in most organs with varying expression levels according to the tissue type [ 38 ]. Testosterone is also converted to E 2 by aromatase, in particular in the brain.

Androgen signaling is linked to metabolism, cell proliferation, differentiation, and apoptosis, and protein secretion, whatever the gender. Androgens can trigger alternative rapid (nongenomic) signaling after binding to membrane-associated or cytosolic AR that releases intracellular Ca 2+ and activates kinases (e.g., MAPK, PKA, PKB, and PKC) [ 38 ]. Membrane-associated ARs in aortic endotheliocytes interact with Src and caveolin-1.

Postmenopausal women experience more rapid age-related hypertension than age-matched men [ 38 ]. Hypoandrogenism may be linked to hypertension in older men, suggesting that a normal androgen concentration is antihypertensive. Testosterone rapidly activates NOS3 in vascular endotheliocytes via the PI3K–PKB pathway. On the other hand, in young, obese, hypoandrogenic male rats, 10-week testosterone supplementation improves body weight and lipid profiles but increases blood pressure. Androgens can elevate blood pressure via ruptured abdominal aortic aneurysm (RAAA) constituents in the kidney. They can contribute to Agt2-induced hypertension in male animals via renal inflammation, renal lymphocyte infiltration being greater in male than in female mice [ 38 ].

Although NR3a diminishes the formation of adhesion molecules in endotheliocytes exposed to atherogenic factors, NR3c4 stimulates vcam1 production in male-derived endotheliocytes due to a higher NR3c4 concentration (not in cells of female origin).

In men, androgen deficiency is linked to endothelial dysfunction. On the other hand, in women, hyperandrogenemia favors atherogenesis and arterial calcification [ 38 ].

In both sexes experiencing hypoxia caused by occlusive peripheral artery disease, androgens promote angiogenesis via NR3c4, the upregulated formation of vascular endothelial growth factor (VEGF) and its receptors in endotheliocytes, and VEGF-primed phosphorylation of PKB and NOS3 [ 38 ]. Administration of DHT augments male-derived (but not female) endotheliocyte migration, proliferation, and tubulogenesis.

In male animals, relatively high concentrations of androgens, which upregulate expression of RAAA components, favor macrophage recruitment and extracellular matrix degradation via MMPs, and hence AAA formation, the castration of male mice limiting Agt2-induced AAA genesis and expansion to levels observed in intact female mice [ 38 ]. Male rodents can also be predisposed to AAA by androgens via elevated MMP activity.

1.1.2.3 Enzymes of Steroid Hormone Metabolism

Steroids are lipophilic, low-molecular-weight compounds derived from cholesterol. In fluids, they are usually found in either a conjugated form (i.e., linked to a hydrophilic moiety, such as sulfate or glucuronide derivatives) or bound to proteins. In the plasma, unconjugated steroids are mainly bound to carrier proteins, albumin (20–50%), serpin-A6 (or corticosteroid-binding globulin [CBG]), and sex hormone-binding globulin (SHBG) [ 42 ].

Mitochondria of steroidogenic cells of the adrenal gland, gonads, placenta during gestation, and brain are essential sites for steroid hormone synthesis. The adrenal gland synthesizes androgens and corticosteroids (mineralo- and glucocorticoids), ovary estrogens and progestins, and testis (mainly androgens). In men, the adipose tissue contains aromatase, a source of androgen-derived estrogens.

Once they are released into the bloodstream, these endocrine messengers act on target cells, including those of the central nervous system. The latter also form neurosteroids with auto- and paracrine effects. They diffuse easily through the plasma membrane. Circulating steroids are processed in target cells, which can form active metabolites.

Removal of part of the cholesterol side chain generates C21-steroids of the pregnane series (progestins and corticosteroids), total removal of C19-steroids of the androstane series (e.g., androgens), and loss of the 19-methyl group the estrane series (e.g., estrogens) [ 42 ].

Steroids are characterized by the presence or absence of functional groups (mainly hydroxy, keto(oxo), and aldehyde) at certain positions of the carbon skeleton (particularly at positions 3, 5, 11, 17, 18, 20, and 21) [ 42 ]. These functional groups characterized by their type, number, position, and orientation engender a large number of stereoisomers (i.e., molecules having the same chemical formula but distinct three-dimensional conformation).

Enzymes involved in steroid synthesis include (Tables 1.1 and 1.2 ) [ 42 ]:

Mitochondrial desmolases (or lyases), which remove parts of the cholesterol side chain via sequential hydroxylation of adjacent carbon atoms using molecular oxygen, reduced nicotinamide adenine dinucleotide phosphate (NADPH), and cytochrome P450

Membrane-bound mitochondrial or microsomal hydroxylases , which also require cytochrome-P450, O 2 , and NADPH

Cytosolic and microsomal hydroxysteroid dehydrogenase , these oxidoreductases depending on NADP(H) or NAD(H)

Membrane-bound aromatase that involves a sequence of hydroxylation and loss of the C19 methyl group, its substrate being 4-androstenedione or testosterone

Mitochondria contain the cholesterol desmolase CyP11a1, which catalyzes cholesterol side-chain cleavage to yield pregnenolone, a C21 compound, in addition to its electron transfer partners, ferredoxin and ferredoxin reductase [ 43 ].

Pregnenolone can be converted either to progesterone, which leads to glucocorticoids, androgens, and estrogens, or to 17α-hydroxypregnenolone, which also forms androgens and estrogens. In the adrenal gland, androgen formation is limited to dehydroepiandrosterone and androstenedione, whereas in Leydig cells of the testis, 17β-hydroxysteroid dehydrogenase (17HSDH) produces testosterone [ 43 ]. In granulosa cells of the ovary, estrogen synthesis requires the aromatase complex that uses the substrate androstenedione and testosterone to create estrone and estradiol, respectively.

Hydroxylation of progesterone at carbon 21 yields 11-deoxycorticosterone (DOC) and additional hydroxylation at carbon 11 corticosterone , a major glucocorticoid in mammalian species that do not produce cortisol. The main glucocorticoid secreted by human adrenal glands, cortisol , is formed of 17α-hydroxyprogesterone via the intermediate 11-deoxycortisol.

Further hydroxylation and redox at carbon 18 give rise to aldosterone.

Several other steroidogenic enzymes, such as 3β-hydroxysteroid dehydrogenase, 11β-hydroxylase, and aldosterone synthase, also reside in mitochondria.

Cholesterol ingress into the mitochondrion is regulated by the steroidogenic acute regulatory protein, StAR, the action of which requires the machinery of the outer mitochondrial membrane, which comprises translocator protein (Tspo), Footnote 8 voltage-dependent anion channel VDAC1, Tspo-associated acylCoA-binding domain-containing protein ACBD3, and protein kinase-A regulatory subunit PKA r1 α [ 43 ].

The main site of catabolism is the liver. It involves various reaction types:

Reduction of a double bond at C4 and a reduction of an oxo(keto) group at C3 to a secondary alcoholic group

Reduction of an oxo group at C20 to a secondary alcoholic group

Oxidation of a 17β-hydroxyl group

Further hydroxylations at various positions

Conjugation of a sulfate group (SO \(_4^{2-}\) ) Footnote 9 and/or glucuronosyl groups (glucuronidation), which yields steroid sulfates and glucuronides, by Mg 2+ -dependent steroid sulfokinases and glucuronyl transferase, respectively, thereby forming hydrophilic molecules that can be more easily excreted by the kidney

Corticosteroid 11β-dehydrogenase HSD11β2 converts cortisol into its inactive metabolite cortisone.

Four human aldo–keto reductases (AKR1c1–AKR1c4), also named hydroxysteroid (HSDHs) and dihydrodiol dehydrogenases (DHDHs), are involved in the metabolism of steroids in addition to drugs. These enzymes catalyze the conversion of aldehydes and ketones into their corresponding alcohols using NADH and/or NADPH as cofactors (Table 1.3 ) [ 45 ]. In humans, the aldo–keto reductase superfamily also includes aldehyde (AKR1a1) and aldose reductase (AKR1b1) and aldose reductase-like proteins AKR1b10 of the small intestine and AKR1b15, δ(4–3)-ketosteroid 5β-reductase AKR1d1, aldo–keto reductase-1C-like proteins AKR1cL1 and AKR1cL2 (or testis-specific AKR1e2), and aflatoxin aldehyde reductases AKR7a2 and AKR7a3 [ 46 ].

AKR1c1 converts progesterone to inactive 20α-dihydroxyprogesterone, AKR1c2, and liver-specific AKR1c4 dihydrotestosterone to less active 3α-diol, and AKR1c3 catalyzes reduction of prostaglandins PGd 2 and PGh 2 , and oxidation of (9α, 11β)PGf 2 to PGd 2 in addition to preferentially transforming androstenedione to testosterone [ 45 ]. AKR1c1, AKR1c2, and AKR1c3 reduce cytotoxic aldehydes derived from lipid peroxidation into less toxic metabolites.

The liver is the primary site of metabolism of steroid hormones containing a Δ 4 -3 functionality, such as testosterone and progesterone, which are converted into tetrahydrosteroids that are then eliminated. Steroid hormones are conjugated in two-phase reactions, reduction by 5α- or 5β-steroid reductases to form the respective dihydrosteroids, and, in the subsequent step, the 3-oxo group of dihydrosteroids is reduced by ketosteroid reductases to form tetrahydrosteroids. In humans, the four members of the AKR1C subset (AKR1c1–AKR1c4) reduce 5α- and 5β-dihydrosteroids [ 48 ].

The AKR1C isozymes are thus involved in the metabolism of testosterone and progesterone. They are pluripotent, but with a cell-specific expression pattern and distinct substrate preference. All four isozymes are produced in the liver. AKR1c1 to AKR1c3 are highly expressed in the mammary gland and prostate but distinctly expressed in the lung, mammary gland, prostate, and testis, whereas AKR1c4 is specific to the liver [ 48 ].

In particular, AKR1c3 is detected in stromal, endothelial, and uroepithelial cells, in addition to adenocarcinoma cells in the prostate [ 47 ]. Prostate epitheliocytes produce higher concentrations of AKR1c1 to AKR1c3 than stromal cells, the synthesis rate augmenting in prostate cancers. In the mammary gland, AKR1c3 creates a pro-estrogenic state, as it converts androstenedione to testosterone, which, upon aromatization by CyP19 aromatase, yields 17β-estradiol, and transforms active progesterone to inactive 20α-hydroxyprogesterone, thereby altering the estrogen/progesterone ratio [ 47 ].

The AKR1C enzymes catalyze ketosteroid reduction at the 3-, 17-, or 20-position to varying degrees according to the substrate. The 5β-pathway is linked to 5β-steroid reductase AKR1d1. 5β-Pregnane (3,20)-dione is a potent ligand for the pregnane X receptor (PXR or NR1i2) and constitutive androstane receptor (CAR or NR1i3). Activated hepatic NR1i3 stimulates cytochrome-P450 CyP3a4, which processes approximately 50% of consumed drugs [ 48 ].

In addition, 5β-reduced pregnanes are neuroactive steroids (synthesized in the brain) that are implicated in vasodilation [ 49 ]. They are implicated not only in the regulation of steroid receptors, exerting their action on gene expression via nuclear steroid hormone receptors, but also of ligand-gated ion channels, thereby influencing neuronal excitability. They inhibit or stimulate neurotransmission, as they act as allosteric modulators of the GABA A receptor.

Unsaturated fatty acids (FAs) are potent competitive inhibitors of the AKR enzymes. The sensitivity of AKRs for FAs varies, and the most potent inhibitors for AKR1c1, AKR1c2, and AKR1c4 are docosahexaenoic, palmitoleic, and linoleic acid, respectively [ 45 ]. FAs have the strongest inhibitory potency for 3α-hydroxysteroid dehydrogenase AKR1c3.

Sulfate conjugation is involved in the transformation of steroid and thyroid hormones, catecholamines, cholesterol, and bile acids, in addition to the detoxification of dietary and environmental xenobiotics. Cytosolic sulfotransferases (SulTs) transfer the sulfonate group from phosphoadenosine phosphosulfate (PAPS) to acceptor substrates. In humans, 13 SulT isoforms constitute four subsets [ 50 ]. The SULT1 subfamily encompasses SulT1a1 to SulT1a3, SulT1b1, SulT1c2 to SulT1c4, and SulT1e1, and the SULT2 subfamily SulT2a1, SulT2b1a, and SulT2b1b, whereas other subfamilies contain a single element, SulT4a1 and SulT6b1, respectively.

Splice variants encode distinct SulT1c3 isoforms (SulT1c3a, SulT1c3c, and SulT1C3d) [ 50 ]. Although SulT1c3a has a weaker activity and is specific for hydroxyl-chlorinated biphenyls, SulT1c3d has a broader substrate specificity, sulfating bile acids, thyroid hormones, pyrenes, and hydroxyl biphenyls.

1.1.3 Vasculitis (Angiitis)

Vasculitides are defined by the presence of inflammatory leukocytes in vascular walls caused by various immunological processes and possibly triggered by infectious agents. Vasculitis targets arterial and venous walls of any size in any organ, but frequently in the skin.

Vasculitides can be classified according to the size of blood vessels or histological examination (e.g., lymphocytic, leukocytoclastic, and granulomatous [nodular]).

Giant cell (GGA) and young women (Takayasu [TA]) arteritis Footnote 10 and autoinflammatory Behçet disease (BD) Footnote 11 affect large vessels. Complications include inflammatory obstructions and aneurysms.

Livedoid vasculitis , also named segmental hyalinizing vasculopathy and livedo reticularis, most commonly affects women with thromboses and ulcerations of the lower extremities.

Eosinophilic granulomatosis with polyangiitis (EGPA), previously called Churg–Strauss syndrome, mainly affects small and medium-sized blood vessels of men and women between 30 and 45 years of age. It commonly targets the lung and skin but also the heart, kidney, bowel, and nerves.

Granulomatosis with polyangiitis , previously named Wegener’s granulomatosis, mainly affects blood vessels in the nose, sinuses, ears, lungs, and kidneys of middle-aged or elderly individuals.

1.1.4 Vascular Wall Disorders

Wall disorders in large arteries and veins appear not only in the presence of risk factors, such as smoking, long periods without bodily motion, hypertension (Chap. 3 ), diabetes (Chap. 4 ), Footnote 12 obesity (Chap. 5 ), and a family history of vasculopathies, but also most often in a context that encompasses aging (Vol. 9, Chap. 3. Aging), one of the most important cardiovascular event predictors, injury, ciliopathies (Vol. 9, Chap. 1. Ciliopathies), replication stress, air pollution, and sleep disorders (Vol. 9, Chap. 4. Anomalies of the Respiratory Tract), among other factors.

1.1.4.1 Hemostasis and Thrombosis

The intact and healthy vascular endothelium maintains an anticoagulant surface. Thrombomodulin is an integral membrane protein on the wetted surface of endotheliocytes that serves as a cofactor for thrombin. Once it is bound to thrombin, the anticoagulant serine peptidase protein-C is rapidly activated [ 52 ]. Activation of protein-C by the thrombin–thrombomodulin complex depends on Ca 2+ ion. This complex also prevents thrombin activation of the clotting factor- V . Thrombomodulin thus has two distinct anticoagulant functions: (1) to impede the ability of thrombin to clot fibrinogen and to activate F V and (2) to accelerate activation of the anticoagulant protein-C [ 52 ]. Heparan sulfate proteoglycans on the endotheliocyte surface stimulate activation of the serine peptidase inhibitor antithrombin, or serpin-C1, which inactivates thrombin and factor- X a [ 53 ].

In addition, the endothelium produces the antiplatelet aggregation factors prostacyclin and nitric oxide. Some types of activated platelets also generate NO, thereby stimulating the sGC–PKG axis and limiting their own adhesion and aggregation [ 54 ]. PKG phosphorylates vasodilator-stimulated phosphoprotein (VASP), preventing integrin-α 2B β 3 activation, which stabilizes initial platelet rolling, adhesion, and recruitment to the site of the injury. PKG also represses integrin-α 2B β 3 activation via IP 3 R-associated cyclic guanosine monophosphate (cGMP) kinase substrate (IRAG) and inhibition of thromboxane receptor activation.

When any segment of the vasculature is damaged, the subendothelial matrix is exposed to blood. Matrix components launch hemostasis, initiating formation of a blood clot composed primarily of platelets and fibrin within seconds. Hemostasis stops bleeding from a damaged blood vessel, thereby avoiding hemorrhage, a normal blood flow being maintained elsewhere in the circulatory circuit. This first stage of wound healing involves blood coagulation, blood, a suspension of cells in plasma, in which molecules are suspended, changing from a liquid to gel, that is, by the local formation of a hemostatic plug.

Primary hemostasis refers to aggregation of activated platelets, which are small anuclear cell fragments derived from megakaryocytes, and subsequent platelet plug production.

In humans, platelets form subpopulations according to the presence and absence of NOS3, which produces NO, an endogenous platelet inhibitor [ 54 ]. Approximately 20% of platelets lack NOS3 and thus fail to produce NO and have defective sGC–PKG signaling. NOS3− platelets primarily initiate adhesion to collagen or von Willebrand factor; activate integrin-α 2B β 3 , which elicits between-platelet aggregation; and secrete MMP2, which elicits recruitment of NOS3+ platelets to the forming aggregate. Conversely, platelets with intact NOS3–sGC–PKG signaling form the bulk of the aggregate (thrombus) owing to their higher PGhS1 (COx1) content and greater thromboxane-A 2 generation, the platelet aggregate being amplified by thromboxane-A 2 synthesis, and ultimately limit the aggregate size via NO.

Secondary hemostasis designates the simultaneous deposition of insoluble fibrin generated by the proteolytic coagulation cascade that forms a meshwork into and around the platelet plug, which strengthens and stabilizes the blood clot.

Hemostasis relies on the balance between procoagulant (platelets and coagulation cascade components) and anticoagulant elements (protein-C and -S, fibrinolysis, serpins).

As a blood clot in hemostasis, a pathological thrombus is the final product of blood coagulation in the absence of vascular contusion (but not intrinsic vascular injury). An elevated ratio of NOS3+ / NOS3− platelets may contribute to thrombosis.

Thromboembolism results from thrombus breakage and shedding followed by embolus carriage in the bloodstream, and subsequent obstruction of a distal vessel.

Venous walls can be injured and lose their strength, thereby being the source of thrombi that are shorn and generate emboli (Vols. 12, Chap. 4. Thrombosis and Lymphedema, and 13, Chap. 8. Venous Pathologies). Venous thrombus consists mostly of fibrin with entrapped red blood capsules. Venous thrombi can cause pulmonary embolism. Venous thromboembolism (VTE) is a collective name incorporating deep vein thrombosis (DVT) and pulmonary embolism.

Arterial thrombus subjected to a higher flow rate and shear is mainly composed of aggregated platelets. Arterial emboli most often provoke ischemia and infarction of the heart, brain (stroke), gastrointestinal tract, kidney, or leg.

Obesity and dyslipidemia are risk factors for both arterial and venous thrombosis. The classical acquired risk factors for venous thrombosis include cancer, immobilization, surgery, fractures, and pregnancy.

Neutrophils contribute to host defense, not only as they process pathogens via phagocytosis and produce toxic chemicals to kill intruders directly but also as dying neutrophils mix their DNA with toxic components from their cytosolic granules and release them in the form of neutrophil extracellular traps (NETs) that trap and neutralize microbes. Neutrophil extracellular traps are lattices of processed chromatin (i.e., neutrophil DNA and histones) linked to secreted and cytoplasmic proteins released by neutrophils during inflammation. However, inappropriate NETosis is harmful, favoring sustained and excessive inflammation and thrombosis. NETs released into the vasculature can cause platelet adhesion and activation of the extrinsic and intrinsic coagulation cascade. They also damage pulmonary epithelia and endothelia. On the other hand, two deoxyribonucleases, Dnase1 and Dnase1L3, degrade extracellular (cell-free) nuclear and mitochondrial DNA, hence circulating NETs in a partly redundant manner [ 55 ]. However, Dnase1 disrupts NETs, but does not dissolve them.

The receptor tumor necrosis factor receptor superfamily (TNFRSF)-interacting protein kinase RIPK3 is involved not only in inflammation in addition to apoptosis and necroptosis but also in hemostasis, as it amplifies platelet activation. Upon vessel injury, platelets are recruited by adenosine diphosphate (ADP), thrombin, and thromboxane-A 2 , which connect to their cognate G-protein-coupled receptors and activate integrin inside–out signaling mediated by extracellular signal-related kinases (ERKs) and launch granule secretion. RIPK3 produced in platelets interacting with G13 activates PKB and supports platelet aggregation and spreading on fibrinogen via PKB1 or PKB2 in addition to the second wave of dense granule content secretion in response to thrombin, thromboxane-A 2 , and clot retraction [ 56 ]. The G13 subtype selectively enables thrombin- and TxA 2 -induced platelet aggregation, but does not influence ADP-primed aggregation. RIPK3 operates independently of its substrate used in cell necrosis and clearance, mixed lineage kinase domain-like pseudokinase (MLKL). Therefore, RIPK3 favors arterial thrombus formation.

On the other hand, heparin, a sulfated polysaccharide, prevents blood coagulation, as it connects to antithrombin (serpin-C1) and then accelerates the interaction of antithrombin with thrombin (F II a), and activated clotting factors F V II a and F IX a to F XII a, thereby preventing completion of the coagulation cascade.

1.1.4.2 Inflammation and Angiogenesis

Inflammation of the vascular wall is initiated in response to injury, infection, and lipid peroxidation. Moreover, hypertension (Chap. 3 ), obesity (Sect. 5.3.3 ), and diabetes (Chap. 4 ) are associated with chronic inflammation. Elevated concentrations of inflammatory markers predict future cardiovascular events [ 57 ].

Hypertension is linked to both macro- and microvascular disease. It alters endothelial integrity and hence vascular permeability, facilitating inflammatory leukocyte recruitment.

In addition to vasoconstriction, angiotensin-2 causes redox stress, inflammation, endothelial dysfunction, and vascular remodeling with fibrosis. It provokes accumulation of PTPRc+ leukocytes in aortic perivascular adipose tissue and upregulates MMP2 expression in these leukocytes, MMP2 favoring Agt2-primed vascular inflammation and injury [ 58 ]. Agt2 augments the generation of ROS in the aortic media and perivascular medium and of vcam1 and CCL2, thereby eliciting perivascular infiltration of monocytes, macrophages, and T lymphocytes. It also increases the density of monocytes and activated CD4+ helper and CD8+ cytotoxic T cells in the spleen in the presence of MMP2. MMP2 is synthesized in higher amounts in CD4+ effector T H1 cells than in T H2 or naive T H0 cells. In addition, T H1 cells can stimulate MMP2 synthesis in macrophages. Within the cell, Agt2 promotes phosphorylation of EGFR in addition to ERK1 and ERK2 via heparin-binding epidermal growth factor (HBEGF) shedding in vascular smooth myocytes [ 58 ].

Matrix metallopeptidases synthesized in vascular smooth muscle and endothelial cells not only modify and remodel the extracellular matrix, degrading matrix constituents (e.g., collagen, elastin, and fibronectin), but also shed growth factors (e.g., HBEGF and matrix-bound latent transforming growth factor-β), cytokines, and chemokines, hence favoring inflammation, in addition to autacoids (e.g., big endothelin-1 and other vasoactive peptides) [ 58 ]. In particular, MMP2 cleaves (activates) CCL7 and CXCL12 and processes S100 [ 59 ].

The MMPs are regulated by tissue inhibitors of metallopeptidases (TIMPs), which impede their activity, as they bind to their catalytic site. Among the four TIMPs (TIMP1–TIMP4), TIMP2 can inhibit or activate MMPs; TIMP2 is required with MMP14 for proMMP2 activation [ 58 ]. In addition to MMP2, other MMP types may participate in Agt2 action.

On the other hand, MMP2 deficiency reduces Agt2-induced redox stress, inflammation, endothelial dysfunction, medial hypertrophy, and vascular stiffness, but not SBP elevation [ 58 ]. Both vascular and immune cell-derived MMP2 contribute to impaired vascular relaxation to acetylcholine and endothelial dysfunction. Immunocytes contribute to Agt2-induced hypertension, as Mmp2 deletion in immunocytes reduces BP [ 58 ].

Atherosclerosis (Sect. 1.1.5 and Vol. 13, Chap. 5. Atherosclerosis—Biological Aspects) can be considered as a diffuse inflammatory disease of the vasculature. Inflammation is indeed observed at all stages of atherogenesis, from initial lesions to fatty streaks, evolved plaques, and end-stage complications, that is, thromboembolism after unstable plaque rupture linked to an excess inflammatory episode [ 60 ]. Atherosclerosis is triggered by oxidized LDLs conveying cholesterol. Activated endotheliocytes express adhesion molecules for the diapedesis of circulating leukocytes, activated macrophages, lymphocytes, and smooth myocytes releasing cytokines and chemokines. The procoagulant cytokine increases the synthesis and secretion of fibrinogen, plasminogen activator inhibitor PAI1 (serpin-E1), and acute phase proteins such as C-reactive protein (CRP), thereby amplifying the inflammatory and procoagulant response [ 61 ]. Inflammatory cytokines (e.g., IL1, TNFSF1, and CRP) induce the formation of adhesion molecules, provoking a vicious cycle. C-reactive protein supports the production of tissue factor by monocytes and represses that of NO, hence contributing to the creation of a proinflammatory and prothrombotic milieu. Anti-inflammatory drugs can reduce cardiovascular risk [ 62 ].

Furthermore, systemic autoimmune rheumatic diseases (SARDs), Footnote 13 that is, a group of disorders that share chronic inflammation causing connective tissue and organ damage (rheumatoid arthritis [RA], systemic lupus erythematosus [SLE], ankylosing spondylitis, gout, psoriatic arthritis, systemic sclerosis [SSc; or scleroderma], polymyositis [PM], dermatomyositis [DM], Sjögren’s syndrome [SjS], Footnote 14 mixed connective tissue disease [MCTD], Footnote 15 and systemic vasculitis), can be associated with medium- and large-vessel vasculitides (granulomatous and microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis, and giant cell arteritis) and an increased risk of premature cardiovascular disease, in particular coronary arteritis and premature atherosclerosis [ 63 ].

Angiogenesis is not only involved in organogenesis and repair but also in inflammatory diseases (at least in RA, SLE, SSc, and vasculitides) [ 64 ]. This programmed cascade of events relies on cellular (monocytes, macrophages, and endotheliocytes) and molecular mediators and inhibitors (angiostatin, endostatin, osteonectin [SPARC], thrombospondin, and, under some circumstances, TGFβ; cytokines IL1, IL4, IL6, Ifnα, and Ifnβ; and chemokines CXCL4, CXCL9, and CXCL10).

Angiogenic factors, such as growth factors (EGF, FGF1, FGF2, HGF, IGF1, PDGF, TGFβ, and VEGF), cytokines (TNFSF1, IL1, IL6, IL13, IL15, and IL18), chemokines (CCL2, CXCL1, CXCL5, CXCL7, CXCL8, CXCL12, and CX 3 CL1), cell adhesion molecules (endoglin, integrins, selectins, pecam1, and vcam1), matrix components (collagen-1, fibronectin, laminin, and heparan sulfate proteoglycans), and other factors (angiogenin, platelet-activating factor, substance-P, prostaglandin-E 2 , and prolactin]) activate endotheliocytes.

Endotheliocytes then produce matrix metallopeptidases and plasminogen activators to degrade their basement membrane and the perivascular extracellular matrix. These cells proliferate and migrate, forming a sprout that grows, tubulates, matures, and anchors onto another vessel or builds a capillary network, the endotheliocytes producing further generations of sprouts from the primary sprout.

Mastocytes are involved in innate and acquired immunity, inflammation, allergy, and autoimmunity. They release histamine, tumor-necrosis factor TNFSF1, interleukins IL1β and IL6, chemokine CXCL8, and VEGF. Proinflammatory substance-P and IL33, two major agents of diseases, cooperate to enhance TNFSF1 synthesis and secretion from mastocytes via activation of the tachykinin (neurokinin/substance-P) receptor TacR1 (NK1R or SPR) and IL1RL1 (IL33R) [ 65 ]. Owing to this mutual excitation, IL33 potentiates SP-primed TNFSF1 production more than 100-fold in mastocytes. Mastocyte-derived tryptase can cleave extracellular IL33 into its mature active form, which then activates mastocytes, which, in turn, can release soluble IL1RL1 that modulates the effects of IL33. Substance-P also stimulates histamine secretion from mastocytes. Moreover, IL33 and SP upregulate synthesis of both TacR1 and IL1RL1 receptors. In addition, IL3 enhances SP-triggered VEGF release by mastocytes [ 66 ]. IL33 also augments the frequency and magnitude of mastocyte degranulation and chemokine production, worsening chronic inflammation, even at low concentrations. The receptors TacR1 and IL1RL1 interfere; TacR1 complexes with IL1RL1 and its coreceptor IL1RAP (IL1R accessory protein); IL33 may participate in complexing TacR1 and IL1RL1 [ 65 ]. The stem cell factor receptor (SCFR) also complexes with IL1RL1 and IL1RAP in mastocytes for cross-activation. The natural flavonoid tetramethoxyluteolin inhibits mastocytes stimulated by IL33, SP, or their combination, thereby reducing chronic inflammation.

1.1.4.3 Oxidative and Nitrosative Stresses

Accrual amounts of ROS, which are toxic by-products of aerobic metabolism, cause redox stress and alleviate the fitness level and ability to maintain homeostasis. The term oxidative stress was coined by H. Sies as “a disturbance in the prooxidant–antioxidant balance in favor of the former.” The rate of ROS production increases with aging, ROS being responsible for the accumulation of cellular and tissular deterioration over time in the postreproductive phase of life [ 67 ].

Injurious oxidative stress is characterized by a shift in the oxidative–reductive balance to a more oxidative state because of augmented ROS production by prooxidant enzymes and reduced antioxidant defense mechanisms that scavenge excess ROS.

Deleterious reductive stress is characterized by an aberrant increase in reducing equivalents, such as reduced glutathione and reduced NADPH, increased activation of antioxidant enzymes, and reduced prooxidant capacity, shifting the redox balance from an oxidative to a reduced state.

Exercise is an oxidant stimulus used in redox biology studies; free radicals produced during exercise modulated muscular and systemic adaptation to physical activity. However, exercise induces oxidative or reductive stress according to the individual [ 68 ]. Using redox markers (e.g., glutathione, F2-isoprostanes, and protein carbonyls) in plasma, red blood capsules, and urine samples before and 2 days after exercise, concentrations of the oxidant markers, F2-isoprostanes and protein carbonyls, increase or decrease, whereas the amount of glutathione amount declines or rises, respectively. Footnote 16

The term redox stress , which is associated with the oxidation–reduction reaction disorder, combines oxidative and reductive stress. Both contribute to the pathogenesis of CVD; hence, redox stress is the preferred term.

Loss of function of glutathione peroxidase GPOx1 causes both oxidative and reductive stress. Reductive stress provokes S glutathionylation of the cytoplasmic protein Tyr phosphatase PTPn1 (SHP2) and vascular remodeling [ 69 ].

1.1.4.3.1 Reactive Oxygen and Nitrogen Species

All layers of the vascular wall produce ROS and reactive nitrogen species (RNS; Vol. 11, Chap. 7. Reactive Oxygen and Nitrogen Species) that include superoxide anion radical (O \(_2^{{\bullet }-}\) ), hydrogen peroxide (H 2 O 2 ), hydroxyl radical (OH • ), nitric oxide (NO • ), and peroxynitrite (ONOO − ).

Superoxide can be converted by superoxide dismutase (SOD) into hydrogen peroxide. Hydroxyl radical is formed from oxidation of glutathione, ascorbic acid, NADPH, hydroquinone, catechol, and riboflavin by hydrogen peroxide and H 2 O 2 catalysis [ 70 ]; glutathione can scavenge it [ 71 ]. Oxy- and methemoglobin can generate hydroxyl radicals from hydrogen peroxide [ 72 ].

Superoxide reacts rapidly with anti-inflammatory, anticoagulant, and vasodilatory NO, forming the oxidant peroxynitrite. The latter oxidizes tetrahydrobiopterin, a NOS cofactor, lowering NO availability and provoking endothelial dysfunction.

Among ROS and RNS, hydroxyl radical and peroxynitrite are not considered signaling molecules; these highly reactive agents contribute to redox stress and tissular damage.

1.1.4.3.2 ROS and RNS Sources

The main sources of vascular ROS comprise:

NAD(P)H oxidases (NOx1–NOx2 and NOx4–NOx5)

Mitochondrial electron transport chain (ETC) involved in oxidative phosphorylation, mainly ETC complex- I and - III (i.e., NADH–ubiquinone and ubiquinone–cytochrome-C reductase)

Uncoupled nitric oxide synthase and to a lesser extent

Xanthine oxidase

Prostaglandin-G/H synthases (cyclooxygenases)

Lipoxygenases

The endothelial cytochrome-P450 epoxygenase CyP2c9, which produces vasodilatory epoxyeicosatrienoic acids (11,12)EETs [ 73 ]

Myeloperoxidase Footnote 17

1.1.4.3.2.1 Mitochondrial Electron Transport Chain

In the heart, ROS are produced primarily by mitochondrial ETC and mitochondrial and extramitochondrial enzymes, such as NOxs. Superoxide produced in the mitochondrial matrix is rapidly dismutated by SOD2 to hydrogen peroxide, which diffuses out of the mitochondrion.

1.1.4.3.2.2 NAD(P)H Oxidases

Enzymes of the NOX set synthesize O \(_2^{{\bullet }-}\) , except NOx4, which predominantly produces H 2 O 2 . They localize to caveolae and membrane rafts, endoplasmic reticulum, endosomes, and mitochondria.

Constitutively active canonical NOx1 in addition to NOx2 function in a complex formed by their regulators and binding partners:

NOx1: P22PhOx–NoxO1–NoxA1–Rac1/2

NOx2: P22PhOx–NOxO2–NOxA2–P40PhOx–Rac1/2

NOx4 remains constitutively active in the presence of oxygen. Calcium-dependent NOx5 is regulated by cytosolic calcium concentration. Although NOx2 and NOx4 produce ROS in CMCs and fibroblasts, NOx1, NOx4, and NOx5 operate in the vascular smooth myocytes [ 71 ].

The NOx complexes produce O \(_2^{{\bullet }-}\) on the extracytoplasmic face of cellular membranes, that is, plasma membrane-bound NOxs outside the cell and intracellular NOxs in the lumen of organelles [ 74 ].

The NOx4 subtypes in the outer mitochondrial membrane and mitochondrial ETC are major ROS sources in diabetes. NOx4 is involved in migration and differentiation of vascular smooth myocytes, cardiac cells, fibroblasts, and stem cells. Upon TGFβ exposure, NOx4 oxidizes (inhibits) the phosphatase DUSP1 (MAPK phosphatase MKP1), inactivating P38MAPK, which phosphorylates SRF, which binds to MRTF, activating smooth muscle α-actin (Actα2) and promoting vSMC differentiation [ 71 ]. In addition, NOx4 activates RhoA.

1.1.4.3.2.3 Xanthine Oxidoreductase (Dehydrogenase/Oxidase)

Xanthine dehydrogenase (XDH) and oxidase (XOx) are interconvertible forms encoded by a single gene, the XDH (XOR) gene. Whereas XOx uses hypoxanthine or xanthine as substrate and O 2 as cofactor (electron acceptor) to produce superoxide and uric acid, XDH acts on the same substrates but utilizes NAD + as cofactor (electron receptor) to produce NADH [ 75 ]. Hypoxia, inflammation, apoptosis, and ROS generation from other sources cause XDH conversion into XOx [ 71 ].

Xanthine oxidase participates in the cellular redox status. It is a source of oxygen radicals in granulocytes and endothelial, epithelial, and connective tissue cells. It is involved in detoxification of aldehydes. It serves as a messenger in the activation of neutrophils and T lymphocytes and the triggering of defense mechanisms rather than as a free radical generator. However, it can be implicated in cytotoxicity and tissue injury, especially in inflammation and ischemia.

1.1.4.3.2.4 Lipoxygenases

Arachidonate lipoxygenases ALOx5, ALOx12, and ALOx15 are implicated in CVD genesis. Arachidonic acid (AA) is oxidized by ALOxs into hydroperoxides, which are further reduced into hydroxides and leukotrienes. Each ALOx subtype generates different metabolites according to the target AA carbons.

Arachidonate lipoxygenases mediate Agt2-primed NOx activity in vSMCs. Synthesis of ALOx5 is upregulated by redox stress following excess ROS formation by NOx or mitochondrial ETC. It generates 5HETE and LTa 4 from AA, which serves as a substrate for several enzymes producing proinflammatory molecules LTb 4 , LTc 4 , LTd 4 , and LTe 4 , which activate endotheliocytes, macrophages, neutrophils, mastocytes, T lymphocytes, in addition to foam cells [ 71 ].

Both ALOx12 and ALOx15 are involved in inflammation and redox stress. Generated AA metabolites 12HPETE and 15HPETE and their reduced 12HETE and 15HETE are pro- and anti-inflammatory. They oxidize LDLs [ 71 ]. The metabolite 15HETE favors ROS creation by mitochondrial ETC and NOx4. Under hypoxia, 15HETE provokes endotheliocyte migration and pulmonary arterial smooth myocyte proliferation via P38MAPK activation, hence favoring pulmonary vascular remodeling and pulmonary hypertension. NOx4 is associated with ALOx12 and ALOx15 activity in diabetic hearts.

1.1.4.3.2.5 Myeloperoxidase

Myeloperoxidase (MPOx), encoded by the MPO gene, which produces a single-chain precursor, subsequently cleaved into a light and heavy chain that tetramerize. It is stored in large quantities in neutrophils, constituting a major component of neutrophil azurophilic granules, and, to a lesser extent, in monocytes and macrophages. This heme protein is synthesized during myeloid differentiation. This microbicide is an element of the host immune defense. It also influences endothelial function.

Myeloperoxidase catalyzes H 2 O 2 and halide or semihalide ions reactions that produce hypohalous acids, Footnote 18 such as hypochlorous acid (HOCl − ) and hypothiocyanous acid (HOSCN), a potent microbicide [ 71 ]. HOCl − reacts mainly with nitrogen and sulfur atoms in cysteine residues, especially glutathione, Cys oxidation inactivating or activating cellular molecules.

Myeloperoxidase is involved in redox stress and inflammation; it can serve as a marker of atherosclerotic plaque instability [ 76 ]. Glutathione sulfonamide, the product of G SH oxidation primarily by HOCL − , can serve as a marker of MPOx damage. Smoking engenders high amounts of thiocyanate (SCN − ), Footnote 19 a small ubiquitous acidic pseudohalide thiolate that reduces H 2 O 2 by MPOx and increases quantities of hypothiocyanous acid [ 71 ]. The POx–SCN–H 2 O 2 axis is an element of host defense.

Thiocyanate can act as an antioxidant, as it interacts with peroxidases and can protect cells against injurious redox damage via hypohalous acids such as HOCl and HOBr [ 77 ]. It ablates toxicity yielded by the MPOx–Cl − –H 2 O 2 axis at concentrations of 100–400 μmol/l in the nervous system and lungs, among other organs, in addition to endotheliocytes. It also detoxifies H 2 O 2 formed by the LPOx–SCN–glucose oxidase (GluOx) axis [ 77 ]. On the other hand, SCN can play a cytotoxic role. However, diseases associated with increased SCN and HOSCN amounts are also related to exposure to other toxic agents (e.g., cyanide, tobacco smoke, and cyanogenic glucosides), which can contribute to pathogenesis.

Hypothiocyanous acid reacts with thiols, oxidizing Trp and damaging protein Tyr phosphatases, causing a hyperphosphorylation state within the cell, altering MAPK signaling, and launching apoptosis. It can also oxidize LDLs and HDLs, in addition to NO [ 71 ].

1.1.4.3.2.6 Cytochrome-P450

Enzymes of the cytochrome-P450 superfamily are involved in the oxidative metabolism of various xenobiotics using molecular oxygen and electrons supplied by CyP450 oxidoreductase (POR), also called NADPH–CyP450 reductase (CPR) [ 78 ]. Footnote 20 They insert an oxygen atom into a substrate. Processing by CyP450 enzymes is inefficient as the oxidation of substrates is associated with the production of varying proportions of superoxide and/or hydrogen peroxide.

Three types of NADPH-dependent oxidations by microsomal CyP450 monooxygenases comprise [ 79 , 80 ]:

Regio- and stereo-selective olefin epoxidation of arachidonic acid (epoxygenase reaction), which produces (5,6)-, (8,9)-, (11,12)-, and (14,15)-EETs by the cytochrome-P450 epoxygenases (HETEs) Footnote 21

Arachidonic acid allylic oxidation (lipoxygenase-like reaction), which generates 5-, 8-, 9-, 11-, 12-, 15-hydroxyeicosatetraenoic acids (HETEs)

ω- and (ω-1)-Hydroxylation (at or near the terminal carbons [C16–C20]), which forms 16- (ω-4) to 20HETEs (ω) by AA ω- and (ω-1)-hydroxylases CyP1a1, CyP1a2, CyP4a11, and CyP4a22

Four EET regioisomers, (5,6)-, (8,9)-, (11,12)-, and (14,15)-EETs, operate as auto- and paracrine messengers. The prime vasodilation of EETs is via smooth myocytic large-conductance Ca 2+ -activated K + channel (big potassium [BK]) [ 81 ]. Footnote 22 Activation by EETs of endothelial TRP channels and resulting Ca 2+ influx is an alternative endothelial-derived hyperpolarizing factor. They also have an anti-inflammatory effect on blood vessels and promote angiogenesis via an EPHb4-coupled PI3K–PKB pathway or sphingosine kinase SphK1 [ 81 ]. They convert eicosapentaenoic acid into vasoactive epoxy derivatives and endocannabinoids, whereas soluble epoxide hydrolase (sEH) transforms EETs to dihydroxyeicosatrienoic acids (DHETs), attenuating many EET effects.

1.1.4.3.2.7 Heme Oxygenases

Membrane-bound heme oxygenases HOx1 and HOx2 catalyze the rate-limiting step of heme catabolism using molecular oxygen and electrons supplied by CyP450 oxidoreductase, converting heme to CO, biliverdin, and ferrous iron. Heme is a potent hydrophobic prooxidant that intercalates in membranes and mediates peroxidation of membrane phospholipids [ 78 ].

The HOx1 subtype is constitutively expressed in the liver, spleen, and bone marrow and is inducible in most organs by redox stress, heat shock, nutrient depletion, disrupted intracellular calcium homeostasis, exposure to cytotoxins, and proinflammatory stimuli [ 78 ]. It synthesizes the second messenger CO, a gaseous vasodilator, thereby protecting hepatic microcirculation subjected to redox stress, among other vascular beds. The HOx2 isoform resides in the brain, liver, spleen, and testis.

Heme oxygenase HOx1 protects against redox stress, as it competes with CyP450 for binding to their common redox partner, CyP450 oxidoreductase, diminishing CyP450 action and associated ROS production [ 78 ]. Induction of HOx1 slows down the microsomal production rate by CyP1a2 of hydrogen peroxide and hydroxyl radical. In addition, oxidative injury caused by CyP2e1 is partly prevented by HOx1.

1.1.4.3.2.8 Crosstalk

Crosstalk exists among ROS sources. Hydrogen peroxide can activate NOx and induce xanthine dehydrogenase transformation into xanthine oxidase. Peroxynitrite induces superoxide production [ 71 ]. In addition, mitochondrial ETC and NOx can interact for mutual induction, elaborating an oxidative cycle. Hyperglycemia favors this interference.

Production of ROS partners depends on vessel location. Vascular smooth muscle and endothelial, immune, and other hematopoietic types of cells have different expression patterns for ROS-related proteins.

1.1.4.3.3 Redox Signaling

At low concentrations, certain ROS, such as superoxide and hydrogen peroxide, are signaling mediators involved in redox signaling (or redox control).

Intracellular signaling effectors stimulated by ROS encompass the MAPK module with ERK1, ERK2, and ERK4, protein Tyr kinases Src and Syk, and different redox-sensitive isoenzymes of the PKC set in addition to redox-sensitive transcription factors, such as AP1, ETS, HIF1, NFκB, and P53 [ 74 , 83 ].

Hydrogen peroxide has a longer half-life than superoxide, and unlike superoxide, it can cross lipidic membranes by diffusion or transfer through aquaporins to initiate intracellular signaling [ 89 ]. Superoxide penetrates the cell through anion chloride channel ClC3 [ 74 ].

Superoxide and hydrogen peroxide can provoke cell growth, proliferation, and via oxidative activation of signaling molecules (e.g., PKB, Src, PLC, and MAPK) or inactivation of protein Tyr phosphatases [ 74 ].

At low concentrations, ROS regulate vascular smooth myocyte proliferation in addition to its contraction–relaxation state [ 84 ].

1.1.4.3.4 Antioxidant Defense

Organisms use enzymatic and non-enzymatic antioxidant defense to prevent overload of highly reactive very short half-life free radicals. Redox-sensitive proteins are confined to signaling nanodomains in cells of the cardiovascular apparatus. Antioxidant protection consists of four sequential levels: preventive, chain-breaking, repairing, and adaptive [ 83 ]. (1) The first level of antioxidant defense involves enzymes, such as superoxide dismutases (SOD1–SOD3), glutathione peroxidases (GPOx1–GPOx8), and catalase. Extracellular SOD is produced by vSMCs (but not ECs). (2) The second level of defense, which involves vitamins C and E and probably carotenoids, prevents accumulation of secondary radicals produced in chain reactions such as lipid peroxidation. (3) The third level of defense corresponds to enzymatic prevention of the formation and removal of secondary radicals.

Adaptation to stress relies on stress response linked to protein cysteine reduction–oxidation and launched by the transcription factors NFκB NFE2L2. ROS upregulate the formation of NFE2L2, which increases synthesis of numerous antioxidant enzymes.

Upon redox stress, MAP3K5 operates in a ROS-induced cellular response. ROS mediate angiotensin-2-induced MAP3K5 activation. In unstressed cells, MAP3K5 homo-oligomerizes and forms the inactive MAP3K5–TRdx signalosome. Upon ROS stimulation, this signalosome liberates its inhibitor TRdx and forms a fully activated complex with TRAF2 and TRAF6 [ 85 ].

Antioxidants include superoxide dismutases, catalase, glutathione peroxidases (GPOxs), and the thioredoxin–thioredoxin reductase couple, which counterbalance ROS production (Table 1.4 ). Glutathione peroxidase, catalase, and peroxiredoxins catabolize hydrogen peroxide.

Removal of hydrogen peroxide prevents formation of the highly reactive hydroxyl radical, which can be formed by the reaction of hydrogen peroxide with Fe 2+ (Fenton’s reaction). In various intracellular antioxidant reactions such as H 2 O 2 removal, the reduced form of glutathione (G SH ) is oxidized into glutathione disulfide (G SS G), which can then be excreted from cells or reconverted to G SH by NADPH-dependent glutathione disulfide reductase.

1.1.4.3.4.1 Superoxide Dismutases

Extracellular (SOD3), cytosolic copper- and zinc-(SOD1), and mitochondrial manganese-containing superoxide dismutase (SOD2) process O \(_2^{{\bullet }-}\) into the messenger hydrogen peroxide and molecular oxygen, thereby preventing peroxynitrite formation (Table 1.5 ). Dismutation of O \(_2^{{\bullet }-}\) into H 2 O 2 by SOD involves the reduction and re-oxidation of a redox active transition catalytic metallic ion, such as copper (SOD with its oxidized [SOD \(^{\mathrm {MI}^{\mathrm {ox}}}\) ] and reduced metal ion [SOD \(^{\mathrm {MI}^{\mathrm {red}}}\) ]: SOD \(^{\mathrm {Cu}^{2+}}\) and SOD \(^{\mathrm {Cu}^+}\) , respectively) and manganese (SOD \(^{\mathrm {Mn}^{3+}}\) and SOD \(^{\mathrm {Mn}^{2+}}\) ) [ 74 ]. Footnote 23

1.1.4.3.4.2 Catalase

Catalase lodges principally in peroxisomes, H 2 O 2 being generated by peroxisomal β-oxidation of long-chain FAs. Heme-containing homotetrameric catalase does not usually lodge in mitochondria, except in the heart, where it resides in the mitochondrial matrix. Red blood capsules, in addition to the liver and kidney, have the highest catalase activity, the brain, heart, and skeletal muscle having a low catalase activity.

It neutralizes hydrogen peroxide, thereby preventing accumulation of hydroxyl radicals. Catalase degrades H 2 O 2 using two different mechanisms [ 86 ]. In dismutation, the oxyferryl heme is reduced back to the ferric form by another H 2 O 2 molecule, H 2 O 2 being both oxidant and reductant ( catalatic reaction ). Alternatively, catalase can use other electron donors ( peroxidatic mechanism ).

1.1.4.3.4.3 Peroxiredoxins

Ubiquitous homodimeric peroxiredoxins are nonheme peroxidases that detoxify low- and high-molecular-mass peroxides (ROOH, where R can be a hydrogen atom or a complex phospholipid). Most PRdxs use thioredoxin as a donor of reducing equivalents (of hydrogen), although PRdx6 functions as a reduced glutathione-dependent peroxidase. Glutaredoxins and cyclophilins are additional electron donors for peroxiredoxins.

Peroxiredoxins lodge in different subcellular compartments, such as the mitochondrion (e.g., PRdx3 and PRdx5) and cytosol (e.g., PRdx1, PRdx2, and PRdx6), PRdx4 residing predominantly in the endoplasmic reticulum and PRdx5 also in the cytosol and peroxisomes [ 87 ].

Peroxiredoxins are regulated by phosphorylation in response to extracellular signals, redox state, and oligomerization. They contain one or a pair of active cysteines sensitive to oxidation by H 2 O 2 , which reacts with the thiolate deprotonated form of cysteine. Peroxiredoxins are classified into three sets: typical (PRdx1–PRdx4) and atypical 2-Cys (PRdx5) and 1-Cys forms (PRdx6). They also reduce ONOO − and lipid peroxides.

Antioxidant sestrins can regenerate oxidized peroxiredoxins, scavenge ROS, and hamper expression of NOx4, especially in glomerular mesangiocytes, and TORC1-induced ROS [ 88 ].

1.1.4.3.4.4 Glutathione Peroxidases

Glutathione peroxidase GPOx1 is one of the most abundant members of the GPOX family, which includes epithelial GPOx2, highly expressed in the intestine, and secreted GPOx3, among other subtypes. GPOx1 lodges in the cytosol, mitochondrion, and peroxisome.

The intracellular antioxidant selenocysteine-containing enzyme GPOx1 reduces hydrogen peroxide to water, thereby limiting its accumulation and subsequent harmful oxidative effect on nucleic acids, proteins, and membrane lipids and preventing carcinogenesis and the development of cardiovascular disease [ 89 ].

GPOx1 can also reduce lipid hydroperoxides and other soluble hydroperoxides after their release from membrane lipids [ 89 ]. It also reduces phospholipid and monoacylglycerol hydroperoxides, such as linoleoyl lysophosphatidylcholine hydroperoxide, but not tri- or diacylglycerol hydroperoxides. These other types of membrane-associated phospholipids are reduced by GPOx4 [ 89 ]. GPOx1 may also act as a peroxynitrite reductase.

Expression of GPOx1 is regulated by transcriptional, post-transcriptional, translational, and post-translational mechanisms [ 89 ]. Estradiol and ROS contribute to GPOx1 transcription control. Selenium stabilizes mRNA, avoiding nonsense-mediated decay. Translation involves Sec insertion sequence (SecIS)-binding proteins such as SBP2. At the post-translational level, GPOx1 can be oxidatively inactivated by excess ROS or NO, whereas the kinase Abl phosphorylates (activates) GPOx1.

1.1.4.3.5 Redox Stress

At excessive and sustained concentrations, ROS have deleterious effects. Reversible and irreversible oxidations of cellular proteins, lipids, carbohydrates, RNA, and DNA have an impact on cellular functions. Mitochondrial DNA is particularly vulnerable to ROS and RNS. Generalized oxidation causes cell dysfunction, apoptosis, or necrosis [ 90 ].

Reactive oxygen species operate in inflammation. In particular, macrophages release glutathionated peroxiredoxin-2, which acts as an alarmin (or damage-associated molecular pattern molecules [DAMPs]), which triggers innate immune response and production of TNFSF1 [ 91 ].

Reactive oxygen species function in the initiation and progression of CVD. They are involved in proinflammatory signaling within vascular endothelial cells (vECs) and vSMCs, which then synthesize cell adhesion molecules and chemokines. They also activate MMPs.

Major vascular risk factors (hypertension, dyslipidemia, diabetes, and smoking) are associated with augmented vascular ROS production. A chronic metabolic disturbance favors inflammation and redox stress, an imbalance between pro- and antioxidants and their sources and sinks. Obese sedentary individuals have greater NOx activity in skeletal muscles and blood ROS concentrations than lean active subjects [ 92 ]. Adequate diet that attenuates redox stress prevents obesity-associated disorders [ 84 ].

Mitochondrial superoxide production corresponds to 1–2% of the molecular oxygen consumed. However, excess mitochondrial O \(_2^{{\bullet }-}\) influences the perivascular neutrophil niche [ 92 ]. Lysophosphatidylcholine is implicated in mitochondrial ROS production and in endotheliocyte activation likely because of electron leakage across the mitochondrial membrane. Hydrogen peroxide derived from mitochondrial O \(_2^{{\bullet }-}\) alters the caliber of the coronary resistance artery.

Chronic production of inflammatory and vasoconstrictive prostaglandins exacerbates hypertension via both inflammation and vasoconstriction.

Oxidation and glycation of LDLs engender proinflammatory and proatherogenic adducts. On the other hand, high-density lipoproteins lessen lipoprotein oxidation and hence generation of oxidized LDLs (oxLDLs), the antioxidant effect relying on HDL-associated paraoxonase [ 90 ].

In atherosclerotic lesions, ROS stabilize HIF1α, which is produced in hypoxic regions of plaques and favors M1 macrophage phenotype and hence atherogenesis [ 92 ].

Migration of macrophages primed by oxLDLs depends on FAK, PTPN11, NOx, ROS, and ScaRb3 [ 92 ]. On the other hand, ScaRb3 activation by ROS in extracellular vesicles precludes the migration of endotheliocytes.

Growth factors (e.g., platelet-derived growth factor [PDGF] and TGFβ), cytokines (e.g., TNFSF1 and IL1β), and hemodynamic stress (shear and stretch) regulate expression and/or activity of vascular NOxs [ 83 ]. The autacoids angiotensin-2, endothelin-1, and thrombin activate NOx. Agt2 not only stimulates NOx but also upregulates expression of its subunits, provoking ROS generation by ECs, vSMCs, and adventitial fibroblasts via its AT 1 receptor. Thrombin, in addition to PDGF, TGFβ, and TNFSF1, also activates NOx in vSMCs. Endothelin-1 increases NOx activity in ECs via its ET A receptor.

Angiotensin-2 causes mitochondrial dysfunction via endothelial NOx, PKC, and ONOO − , elevates mitochondrial H 2 O 2 production, and reduces endothelial NO availability [ 93 ]. On the other hand, the amount of mitochondrial ROS is lowered by manganese-containing superoxide dismutase SOD2, and/or peroxiredoxins PRdx3, and/or PRdx5, which protects against mitochondrial oxidative damage. In vascular smooth myocytes and endotheliocytes, the mitochondrial ATP-sensitive potassium channel is implicated in Agt2-induced mitochondrial ROS production, as it increases K + influx and alkalinizes the mitochondrial matrix. Mitochondrial permeability transition pore-opening also contributes to Agt2-mediated ROS production.

In some diseases, NOx1 expression is upregulated in vascular endotheliocytes and smooth myocytes. Interaction between thrombospondin-1 with neurophilin (CD47) activates NOx1 [ 92 ]. Cyclic stretch applied on vessels induces formation of myocyte-enhancing factor MEF2b, which launches NOx1 production and vSMC phenotype switching to a proliferative state. Both NOx1 and NOx4 syntheses are upregulated by hyperglycemia, leading to ROS-induced PKC-dependent downregulation of PKG production and hence repression of the NO–sGC–cGMP–PKG signaling.

Inducible NOx2, which is produced to a greater extent in fibroblasts and immunocytes, participates in recruiting macrophages to inflammation sites to remove infectious pathogens. However, NOx2 overexpression in the endothelium favors sustained leukocyte infiltration in the vasculature and thrombosis.

Hydrogen peroxide (H 2 O 2 ) formed by constitutively active brown adipocytic NOx4 protects the vasculature via PKG [ 92 ]. In addition, adipocytic NOx4 slows obesity-linked inflammation in addition to T2DM progression. On the other hand, endoplasmic reticular stress stimulates NOx4, which produces both superoxide and hydrogen peroxide. Intermedin 1−−53 , a N-terminal fragment of adrenomedullin-2, reduces NOx4 production.

Reactive nitrogen species, that is, NO • , an endothelial function marker, and its derivatives, participate in vasculopathies. In healthy vessels, NO prevents circulating leukocyte adhesion to the wetted endothelial surface and triggers vasodilation. In addition to endotheliocytes, circulating hematopoietic cells are important sources of NO in blood [ 92 ]. Excess NO production, often due to the hyperactivity of NOS2, has harmful effects on the vasculature. In obese mice, the perivascular adipose tissue causes NOS3 uncoupling, converting it from NO producer to O \(_2^{{\bullet }-}\) generator, which exacerbates the underlying pathological condition.

In endothelial and smooth muscle cells, the oxidation state (ferric versus ferrous) of hemoproteins modulates NO signaling. In particular, the redox state of hemoglobin Hbα at the myoendothelial junction regulates NO activity. In the ferric state, Hbα has a reduced binding affinity for NO, which then diffuses between endotheliocytes and smooth myocytes [ 92 ]. In the reduced ferrous Hbα state, NO is sequestered, and the NO–sGC–cGMP–PKG axis and subsequent vasodilation of resistance arteries in both the systemic and pulmonary circulation are repressed. The flavoprotein methemoglobin reductase Footnote 24 also inhibits NO signaling via the myoendothelial junction. On the other hand, in vSMCs, methemoglobin reductase reduces soluble guanylate cyclase (sGC) heme iron from the ferric to the ferrous state, thereby enabling NO sensing and subsequent arterial dilation. In addition, cGMP is not only degraded by phosphodiesterases PDE3 and PDE5 but is also exported from the cell [ 92 ].

1.1.4.3.6 Receptor for Advanced Glycation End Products

Proinflammatory multiligand receptor for advanced glycation end products (RAGE) generates ROS via NOx activation and mitochondrial production amplification and thus operates via redox stress [ 94 ].

The RAGE resides on diverse cell types (e.g., endothelial progenitor cells, cardiac endotheliocytes, vascular smooth myocytes, cells of the nervous system, pancreatic β cells, renal mesangiocytes, osteoblasts, and inflammatory leukocytes). Its cytoplasmic domain binds to the formin diaphanous-1 that activates Rac1 and NOx in aortic smooth myocytes exposed to the RAGE ligand S100b.

The RAGE connects to proinflammatory members of the S100–calgranulin set (S100a8, S100a9, and S100a12 [calgranulin-A–calgranulin-C]), which are predominantly expressed by neutrophils, monocytes, and activated macrophages, S100a8 being a potent antioxidant, in addition to high-mobility group box-containing protein HMGB1, amyloid β-peptide and β-sheet fibrils, lysophosphatidic acid, α M β 2 -integrin (CR3), and complement component C1q [ 94 ].

Advanced glycation end products (AGEs) are products of non-enzymatic glycation and oxidation of proteins and lipids formed in vascular cells, CMCs, neurons of the central and peripheral nervous systems, alveolar pneumocytes, podocytes, and inflammatory leukocytes, among other cell types [ 94 ]. In the heart, the detoxifier glyoxalase-1 of glycation precursors such as 3-deoxyglucosone of the AGE N𝜖1-carboxymethyllysine prevents diabetes-induced redox damage, inflammation, fibrosis, and diabetic cardiomyopathy [ 95 ].

1.1.4.3.7 Lipid Peroxidation

Lipids, with their reactive double bonds, are targets of oxidation. Lipid peroxidation generates isoprostanes and malondialdehyde (MDA; Table 1.6 ).

Isoprostanes are stable prostaglandin-like compounds engendered from arachidonic acid peroxidation and subsequently released from cellular membranes into the bloodstream by phospholipases. Isoprostane concentrations in plasma and urine samples correlate with cigarette smoking, hypercholesterolemia, obesity, T2DM, and hyperhomocysteinemia [ 90 ].

Malondialdehyde is formed from peroxidation of polyunsaturated FAs. It interacts with proteins, particularly with lysine residues, building Lys–Lys crosslinks, such as in ApoB of oxLDLs [ 90 ].

1.1.4.3.8 Protein Tyrosine Nitration

Proteins are also oxidized and then associated with pathophysiological processes in addition to aging. Protein tyrosine nitration, which consists of adding a nitro group (–NO 2 ), is mediated by RNS such as peroxynitrite (ONOO − ) and nitrogen dioxide (NO \(_2^{\bullet }\) ). This reaction involves two steps: the oxidation of the phenolic ring of tyrosine to tyrosyl radical (Tyr • ) and the addition of NO \(_2^{\bullet }\) to the Tyr by a nitrating agent. Myeloperoxidase, with its transition metal center, can react with ONOO − and hence facilitate nitration [ 90 ]. Nitrotyrosine formation on enzymes, such as sarcoplasmic reticulum Ca 2+ ATPase (serca2a), manganese-containing superoxide dismutase ( Mn SOD or SOD2), prostacyclin synthase, tyrosine hydroxylase, and aldolase-A, inhibits their activity. On the other hand, nitrotyrosine in fibrinogen raises its activity and accelerates clot formation.

1.1.4.3.9 Protein Glutathionation

S Glutathionation, that is, formation of a disulfide bridge between a reactive cysteine residue and the tripeptide glutathione, mediates redox regulation of numerous cellular proteins (e.g., NOS3, ryanodine receptor, SERCA, and Na + –K + ATPase, thereby affecting their function and intracellular Na + and Ca 2+ handling [ 90 ]). S Glutathionation of hemoglobin can serve as a marker of redox stress.

1.1.4.4 Aging

Aging is associated with declining organ functioning and metabolism. It is related to chronic inflammation, the so-called inflammaging , redox stress, and arterial stiffening. Arterial redox stress contributes to arterial stiffening, as it favors elastin degradation and collagen overproduction, in addition to inflammation.

Many lipids are synthesized from precursors within the body, but some essential FAs must be ingested with food intake. For example, fish contains the essential long-chain ω3 FAs eicosapentaenoic (EPA) and docosahexaenoic acid (DHA). Vegans do not eat animal products and vegetarians neither meat nor fish; semi-vegetarians consume fish, seafood, and sometimes even poultry; lacto-vegetarians add dairy products and lacto-ovo-vegetarians eggs to their diet.

Lipids can be divided into eight categories: FAs, glycerolipids, glycerophospholipids, sphingolipids, sterol and prenol lipids, saccharolipids, and polyketides). Their concentration ranges from the attomolar to the micromolar level. Lipidomics is aimed at investigating lipid fate and signaling in addition to the effects of nutritional supplementation and its role in immune and inflammatory responses and cardiovascular and pulmonary diseases. Signaling lipids include oxylipins, especially the initiation and termination of inflammation.

Oxylipins are lipophilic messengers generated by oxygenation by cyclooxygenases (COxs; or prostaglandin-G/H synthases [PGhS]), cytochrome-P450 enzymes (CyPs), and lipoxygenases (LOxs), in addition to the non-enzymatic auto-oxidation of polyunsaturated fatty acids (PUFAs), such as the ω6-fatty acids arachidonic (AA) and linoleic acid (LA) in addition to ω3-fatty acid α-linolenic acid (α LA), the plasmatic concentrations of which change not only with diet but also during aging [ 96 ].

Oxylipins are involved in immunity and hence inflammation in addition to vasomotor tone and blood coagulation. They can also be bactericides.

Eicosanoids are oxylipins derived from AA, a component of cellular membrane phospholipids. Cyclooxygenases generate class- II (2 double bonds) prostaglandins (PGs) and thromboxanes (Txs) from arachidonic acid. Class- I and- III PGs and Txs are formed from dihomo-γ-linolenic acid (DGLA) and EPA, respectively.

Lipoxygenase products encompass:

HETEs from AA, which mediate neutrophil chemotaxis and degranulation

Hydroxyoctadecadienoic acids (HODEs) from LA

Hydroxyeicosapentaenoic acids (HEPEs) from EPA

Lipoxygenase LOx5 synthesizes leukotrienes and other metabolites, such as proinflammatory 5HETE, 5oxoETE, and LTb 4 , from AA, and 9HODE and trihydroxyoctadecenoic acids (triHOMEs) from LA. ALOx12 and ALOx15 produce 12HETE, 12oxoHETE, and proinflammatory 9HETE from AA.

The CyP enzymes generate epoxides, such as EETs from AA and epoxyoctadecamonoenic acids (EOMEs) from LA, which dilate arteries. These products are converted to dihydroxyoctadecenoic (diHOMEs) and DHETs by soluble epoxide hydrolase (sEH).

1.1.4.4.1 Aging, Inflammation, and Redox Stress

Inflammaging partly results from increased concentrations of alarmins, which activate pattern recognition receptors (PRRs). Toll-like (TLRs) and nucleotide-binding oligomerization domain-like receptors (NLRs) are expressed not only on or in innate immunocytes but also on or in cells of the neurovascular unit and blood–brain barrier [ 97 ]. Among these PRRs, TLR2, TLR4, NLRP1, and NLRP3 are activated during aging in neurons, astrocytes, microgliocytes, and possibly endotheliocytes and pericytes.

Cardiovascular disease is linked to chronic obstructive pulmonary disorder (COPD) via chronic inflammation and aging with reduced sirtuin activity and exposure to cigarette smoke [ 98 ].

Desmosine and isodesmosine are involved in elastin crosslinking and can serve as indicators of elevated elastin fiber turnover and degradation, such as in COPD and atherosclerosis complications.

Sirtuins (SIRT1–SIRT7) are NAD + -dependent protein (histone) deacetylases implicated in lifespan and health regulation. Sirtuin-1 regulates endothelial function as it deacetylates NOS3 [ 98 ]. In addition, it counters senescence, as it deacetylates P53 and STK11 (LKB1), and angiogenesis, as it deacetylates FoxO1 and notch-1 [ 98 ]. It also activates liver X receptor (NR1h2/3), which is involved in reverse cholesterol transport, hence promoting cholesterol efflux. It has an antioxidant effect. Furthermore, it inhibits NFκB [ 98 ]. On the other hand, sirtuin-1 precludes vascular smooth myocyte proliferation and atherothrombosis, as it downregulates endothelial formation of tissue factor and upregulates that of tissue inhibitor of metallopeptidase TIMP3 [ 98 ]. Prolonged moderate exercise training enhances FoxO3a expression, reduces redox stress, and raises SIRT1 activity in the heart and adipose tissue of aged rats.

Sirtuin-3 hampers cardiac hypertrophy as it controls ROS concentrations. Sirtuin-6 in endotheliocytes protects against telomere and gene damage, and Sirtuin-7 interacts with P53 and protects CMCs against apoptosis and redox and genotoxic stresses [ 98 ].

Reactive oxygen species participate in aging. However, dietary antioxidants, such as vitamins C and E, do not slow aging [ 99 ].

Mitochondria are a major ROS source and thus mediate adverse processes in aging. Supplementation with the orally active mitochondrial antioxidant MitoQ ([dimethoxy methyl dioxo-cyclohexadien decyl] triphenyl methanesulfonate), a derivative of the potent antioxidant ubiquinone conjugated to triphenylphosphonium, which accumulates within mitochondria, prevents mitochondrial redox damage. It thus attenuates the production of proliferative, proinflammatory, and profibrogenic mediators (e.g., tumor growth factor [TGFβ], connective tissue growth factor [CTGF], and PDGF) by neighboring and infiltrating cells in the liver (i.e., activated hepatic stellate cells, which form a collagen-rich matrix, Kupffer cells, and cholangiocytes, in addition to injured hepatocytes, platelets, and leukocytes), and hence redox stress, hepatocyte death, and hepatic inflammation, together with liver fibrosis and cirrhosis in mice [ 100 ]. Its administration for 4 weeks limits the reduction of elastin content and decreases aortic stiffness in 27-month-old mice, affects neither young mice nor age-related collagen synthesis and deposition, and increases proinflammatory cytokine formation [ 101 ].

1.1.4.4.2 Aging and Altered Proteostasis

Aging and age-related diseases are associated with disturbed balance of protein production, folding, and degradation, in addition to subsequent accumulation of misfolded proteins and proteic aggregates. In CMCs, altered proteostasis can participate in the development of cardiac hypertrophy, cardiomyopathies, and heart failure.

Hydrotropes are small molecules, typically amphiphilic agents, that solubilize hydrophobic molecules in aqueous solutions. The canonical energy carrier and autacoid, adenosine triphosphate (ATP), an energy source for chemical reactions at micromolar concentrations, including muscular contraction, possesses at physiological millimolar concentrations (5–10 mmol/l) the properties of a hydrotrope, as it maintains protein solubility and prevents molecular aggregation [ 102 ]. At relatively high concentrations, ATP enhances the solubility of solutes, such as nonpolar lipophilic proteins (unlike polar hydrophilic proteins) and organic substances, which are nearly insoluble in the usual aqueous solutions. Amphiphilic hydrotrope molecules have shorter hydrophobic regions and therefore do not spontaneously self-aggregate in the aqueous phase [ 103 ]. Adenosine triphosphate precludes not only formation of protein aggregates, hampering aggregation of prion and amyloid fibers from amyloid-β4 protein, but also contributes to dissolving a previously formed agglutinated mass, as it can dissolve liquid–liquid phase-separated droplets, keeping the RNA-binding protein fused in sarcoma (FUS) in a water-soluble state and preventing its accumulation into separate liquid drops [ 102 ].

For most ATP users such as ATP-dependent enzymes, the Michaelis–Menten constant of cardiac actin-based nanomotor myosin evolves in the micromolar range (β-myosin encoded by the MYH7 gene [cardiac myosin heavy chain-7]: 40 ± 6μmol/l), whereas the nucleotide ATP is typically present in millimolar concentrations in the cytoplasm of CMCs [ 103 ]. Therefore, the discrepancy between ATP concentration needed by ATP-consuming enzymes and its intracellular level can be explained, at least partly, by its hydrotrope function.

The intracellular ATP amount declines with aging in addition to impaired mitochondrial oxidative phosphorylation.

Variant proteins containing expansions of glutamine repeats (polyQ repeats), that is, with increased polyglutamine motif length, which is encoded by the DNA nucleotide sequence CAG, can misfold and form aggregates, which can sequester proteins. Expansion of polyQ domains in huntingtin and the deubiquitinase ataxin-3 causes Huntington’s disease characterized by loss of striatal neurons and hence changes in mood and personality, defective motor coordination, and involuntary movements and type-3 spinocerebellar ataxia (SCA3), a form of neurodegeneration in the striatum and cerebellum, respectively [ 104 ]. PolyQ expansions in addition to soluble N-terminal huntingtin fragment comprising exon 1 are toxic. Autophagy that is aimed at attenuating protein toxicity removes polyQ-expanded proteins, such as abnormal huntingtin and ataxin-3.

On the other hand, some polyQ-containing proteins regulate degradation of misfolded proteins and autophagy. Ataxin-3 deubiquitinates beclin-1 that then escapes proteasomal destruction and triggers starvation-induced autophagy. Short polyQ domain enables interaction between ataxin-3 and beclin-1 [ 105 ]. On the other hand, a mutated form of huntingtin that contains an expanded polyQ region competes with ataxin-3 for beclin-1 binding, thereby increasing beclin-1 degradation and dysregulating autophagy. Huntingtin also participates in stress-activated autophagy, as it competes for binding to another autophagic regulator.

Expansion of the polyglutamine stretch in ataxin-1 (Atxn1) causes the hereditary neurodegenerative disease type-1 spinocerebellar ataxia (SCA1), hence its other alias SCA1. The ATXN family includes proteins characterized by the presence of an AXH domain implicated in protein–protein interactions. Footnote 25

The deubiquitinase Atxn3L targets the zinc finger-containing transcription factor KLF5, which promotes cell survival and proliferation in addition to tumoral growth, partly as it upregulates synthesis of fibroblast growth factor-binding protein FGFBP1 Footnote 26 and microsomal prostaglandin-E synthase PtgES1 [ 106 ]. It belongs to the DUB subset of Machado–Joseph disease (MJD) proteic domain-containing peptidases with Atxn3 (a.k.a. MJD1 and SCA3), encoded by the gene mutated in MJD, also termed type-3 spinocerebellar ataxia (SCA3), and Josephin domain-containing DUbs JosD1 and JosD2 (Table 1.7 ). Footnote 27

Aggregates formed by polyglutamine-expanded ataxin-7 sequester ubiquitin-specific peptidase USP22 that cannot then fulfill its deubiquitinating function in the SAGA complex, causing cytotoxicity and neurodegeneration [ 109 ].

1.1.4.5 Sleep Disorders

Sleep disorders and short sleep duration (≤ 5 h/night) alter neurohormonal regulation and the circadian rhythm of blood pressure with its nocturnal decrease, blunting nocturnal surge in melatonin secretion and favoring hypertension. Sleep deprivation is related not only to hypertension but also diabetes mellitus and coronary artery disease [ 110 ].

Cardiovascular and metabolic disease (i.e., hypertension, atherosclerosis, heart failure, cardiac arrhythmias, obesity, and metabolic syndrome) are linked to sleep anomalies (sleep curtailment, shift work, and sleep-disordered breathing) [ 111 ]. Sleep affects the autonomic nervous system, hemodynamics, endothelial and myocardial function, and blood coagulation.

Central sleep apnea (CSA) is caused by a lack of neural input for breathing. Breathing effort is attenuated or absent during airflow cessation, typically for 10–30 s, either intermittently or in cycles.

Breathing is controlled by central and peripheral chemoreceptors. Medullary neurons respond to CO 2 content via shifts in H + concentration and chemoreceptors of the carotid body to arterial blood O 2 and CO 2 content. Elevated chemoresponsiveness along with blunted chemosensitivity can destabilize the breathing pattern. In addition, several other homeostatic feedback mechanisms regulate breathing amplitude and frequency to maintain gas exchange, such as afferent input from Golgi tendon organs and muscle spindles from respiratory muscles [ 112 ]. Ventilatory response to hypoxia and hypercapnia and respiratory load compensation are reduced during sleep, particularly during the rapid eye movement stage.

Several CSA manifestations encompass high-altitude-induced periodic breathing, idiopathic CSA, narcotic-induced central apnea, obesity hypoventilation syndrome, and Cheyne–Stokes breathing [ 112 ]. Nighttime breathing disturbances increase the risk for adverse cardiovascular outcomes.

Obstructive sleep apnea (OSA) with breathing pauses 5–30 times per hour during sleep because of upper airway hindrance is associated with respiratory efforts. It can be linked to hypertension, arrhythmia, stroke, and heart failure. Obstructive sleep apnea is associated with obesity; the resulting sleep deprivation can favor obesity, forming a vicious cycle.

1.1.4.6 Vascular Tumors and Malformations

Vascular anomalies encompass tumors and malformations (direct connections between arteries and veins), in addition to infection, trauma, and adverse remodeling.

Vascular congenital tumors comprise infantile congenital hemangioma, especially in girls, which is usually solitary, but can be multiple, along with tufted angioma, infantile fibrosarcoma, myofibromatosis, and kaposiform hemangioepithelioma.

Vascular malformations that bypass the capillary bed generally result from embryogenic errors. However, most arteriovenous malformations are idiopathic. They arise spontaneously. They differ from those engendered by gene mutations by their location and evolution.

A classification of vascular anomalies was proposed by the International Society for the Study of Vascular Anomalies (ISSVA) that categorizes benign vascular lesions into two groups according to the predominant type of vascular channel affected and flow magnitude: (1) vascular tumors , the most common form being infantile hemangioma, and (2) vascular malformations, which are created by errors of vasculo- and angiogenesis [ 113 ]. Vascular malformations usually develop gradually, but their growth is faster than that of the body, with peak growth occurring during puberty.

Birth defects can be independent of genetic cause but rely on environmental factors. For example, cardiac and craniofacial birth defects can result from maternal fever during the first trimester of pregnancy. Neural crest cells are precursors of cells forming tissues of the heart and head (face). Hyperthermia-activated TRPV1 and TRPV4 channels Footnote 28 in neural crest cells of chick embryos provoke cardiac and craniofacial birth defects [ 114 ].

Vascular tumors encompass non-involuting (NICH) and rapidly involuting congenital (RICH) and infantile hemangiomas, tufted angiomas, kaposiform, spindle cell, and other rare hemangioendotheliomas, in addition to dermatologically acquired vascular tumors (e.g., pyogenic granuloma, targetoid, glomeruloid, and microvenular hemangioma).

Slow-flow vascular malformations include venous (e.g., blue rubber bleb nevus syndrome, familial cutaneous and mucosal venous malformation, glomuvenous malformation), capillary (e.g., telangiectasia and angiokeratoma), and lymphatic malformations (primary lymphedema, and micro- and macrocystic lymphatic malformations in addition to combined vascular malformations [capillary (C), venous (V), and/or lymphatic (L) malformations (M), that is, CVMs, CLMs, LVMs, and CLVMs]).

Telangiectasias Footnote 29 are small, permanently dilated blood vessels that engender small cutaneous red dots or linear or stellate lesions. They often progress to form papules, particularly on the face [ 113 ].

Angiokeratomas constitute a heterogeneous group of red–violaceous to black papules due to vascular dilation in the papillary dermis with epidermal hyperplasia and hyperkeratosis [ 113 ].

Angiokeratoma corporis diffusum represents a diffuse form of angiokeratoma. They are associated with deficiencies in:

Lysosomal α N acetylgalactosaminidase (NAGα), which is encoded by the NAGA gene, mutations of which causes aspartylglucosaminuria and type- I (infantile) and - II (adulthood) Schindler disease

Lysosomal α-galactosidase-A (Glα), mutations in the GLA gene engendering Fabry disease

α-Fucosidase (Fucα), mutations in the FUCA1 (or FUCA) gene causing severe infantile type- I and milder type- II fucosidosis

β-Galactosidase (Glβ) and neuraminidase (Neu1–Neu4 or sialidase-1 to -4), which provokes early and late infantile and juvenile/adult galactosialidosis , which results from mutations in the CTSA gene that encodes lysosomal cathepsin-A, which cooperates and complexes with neuraminidase-1 and β-galactosidase (hence the other CtsA name, protective protein for β-galactosidase [PPGβ])

Lysosomal β-mannosidase (Manβ), mutations in the MANBA gene causing β-mannosidosis (mutations in the MAN2B1 gene that encodes lysosomal acid α-mannosidase class 2B member 1 provoking α-mannosidosis)

Lysosomal monosialotetrahexosylganglioside GM1, mutations in the GLB1 gene that encodes acid galactosidase-β1 (Glβ1), generating GM1 gangliosidosis, GM1 ganglioside that cannot be catabolized accumulating to toxic levels

Lysosomal sialidase-1, or neuraminidase Neu1, mutations in the NEU1 gene engendering type- I (partial Neu1 deficiency) and more severe type- II sialidosis (severe reduction or even elimination of Neu1 activity)

Verrucous hemangioma is a separate entity with respect to angiokeratoma. These generally deep lesions are often linked to hyperkeratosis [ 113 ].

Fast-flow vascular malformations comprise arterial and arteriovenous malformations, arteriovenous fistulas (AVFs), and combined vascular malformations (e.g., arterial [A], venous, and lymphatic (AVMLMs) and CMAVMs).

1.1.4.7 Ectopic Vascular Calcification

Arteries are not only sites of abnormal caliber changes, either narrowing ( stenosis ; Vol. 13, Chap. 7. Arterial Stenosis—Mechanical and Clinical Aspects) or enlarging ( aneurysm ; Vol. 13, Chaps. 3. Aortopathies and 4. Aneurysms), but also of ectopic calcifications.

Vascular calcification (Vol. 10, Chap. 3. Adverse Wall Remodeling) relies on bone morphogenetic proteins (BMPs; Sect. 1.4.5.6 ), the Wnt pathway (Sect. 1.4.5.2 ), tumor-necrosis factor superfamily member TNFSF11, and receptors TNFRSF11a and TNFRSF11b, in addition to various other calcification regulators, such as inflammatory factors and oxidized lipids.

Lipoprotein-A (LPa) carries proinflammatory and procalcific phosphocholine-containing oxidized phospholipids (OxPLs) [ 115 ]. In fact, various lipoproteins contribute to the progression from sclerosis to stenosis, although LPa is the preferential OxPL carrier.

1.1.5 Atherosclerosis

Atherosclerotic cardiovascular disease (ASCVD), or simply atherosclerosis, Footnote 30 is characterized by the subendothelial retention of modified lipoproteins, immunocyte infiltration, maladaptive chronic inflammation of the arterial wall, and vSMC-mediated fibrous cap formation. Atherosclerosis progression is linked to cell death, fibrous cap thinning, plaque rupture, and thrombosis.

Accumulated intracellular cholesterol can be removed using the reverse cholesterol transport that begins from cholesterol egress from cells and subsequent elimination from the body, thereby protecting against the development and progression of atherosclerosis.

On the other hand, an imbalance between the uptake of cholesterol from oxidized or aggregated LDLs through scavenger receptors and the efflux of cholesterol to apolipoprotein-A and HDLs through ABC transporters leads to atherogenesis.

Low-density lipoproteins can be oxidized, glycated, acetylated, ethylated, and methylated. Oxidized and glycated LDLs in arterial walls initiate atherogenesis. Modifications target LDL components such as their surface protein ApoB, which mediates LDL binding to its receptor. The early stage of atherogenesis is linked to oxidized LDLs that accumulate in the subendothelial space, where they activate endotheliocytes, which then produce adhesion molecules and chemokines, recruiting inflammatory leukocytes. Attracted monocytes differentiate into macrophages that internalize oxLDLs and release cytokines and ROS, further oxidizing LDLs and attracting medial smooth myocytes into the intima. These smooth myocytes contribute to atherogenesis via apoptosis and foam cell formation. Non-enzymatic glycation of lysine residues of ApoB diminishes LDL affinity for its receptor, thereby augmenting its plasmatic lifetime and uptake of glycated LDLs (glLDLs) by vascular cells and macrophages. Furthermore, LDL glycation renders them more susceptible to oxidation (gl–oxLDLs). Upon uptake of modified LDLs via scavenger receptors and pinocytosis, macrophages in the arterial intima differentiate into foam cells.

Mitochondria produce ATP and are involved in ion transfer, ROS generation, and apoptotic signaling. Mitochondrial DNA contains 37 genes that encode subunits of ETC complex- I , - III , and - IV and ATP synthase (i.e., ETC complex- V ), in addition to corresponding ribosomal and transfer RNAs.

Mitochondrial ROS damage mitochondrial DNA, a circular molecule linked to the inner mitochondrial membrane; mitochondrial dysfunction and subsequent mitophagy precede lesion development [ 116 ]. Mitochondrial DNA damage lessens mitochondrial oxidative phosphorylation. Decreased mitochondrial oxidative phosphorylation causes thinning of the fibrous cap via vascular smooth myocyte dysfunction and apoptosis, and increased necrotic core formation due to macrophage activation.

Mitochondrial DNA is replicated by the Mt DNA replisome, which comprises the twinkle helicase, Mt DNA polymerase, and mitochondrial single-stranded DNA-binding protein.

Reduced Mt DNA number and oxidative phosphorylation increase mitophagy in plaque vSMCs, whereas overexpression of the mitochondrial DNA helicase twinkle reduces Mt DNA damage but does not affect Mt DNA copy number [ 117 ]. Twinkle protects vascular smooth myocytes and macrophages against redox stress-primed apoptosis. In macrophages, overexpression of twinkle increases Mt DNA copy number without affecting Mt DNA damage. In both cell types, possibly via increased ETC subunit synthesis, twinkle overexpression enhances oxidative phosphorylation, thickening the fibrous cap via increased vSMC proliferation and reduced apoptosis and attenuating necrotic core formation via macrophage inactivation.

Atherosclerosis is a chronic disease of the arterial wall that involves both innate and adaptive immunity, inflammation being implicated at all stages of the disease. This inflammatory disease involves accumulation of lipids in the arterial intima, infiltration and proliferation of monocytes, and their differentiation into macrophages, among other leukocytes, recruitment of medial smooth myocytes, and production and degradation of the extracellular matrix. It is characterized by hardened arterial segments with narrowed or enlarged lumens (i.e., stenoses and fusiform aneurysms).

Arteriosclerosis , the hardening (or stiffening) of normally distensible arteries was described by the German-born French pathologist J.G.C.F.M. Lobstein (1777–1835). It encompasses atherosclerosis, medial thickening, and medial and intimal calcifications (e.g., Mönckeberg medial sclerosis, the most common form of medial calcifications in the arteries of the extremities) [ 118 ].

In 2013, atherosclerosis, particularly angina pectoris and myocardial and cerebral infarction ( stroke), and other types of cardiovascular affections (e.g., arrhythmias, heart failure, and cardiac valvulopathies) caused 51% and 42% of deaths among women and men, respectively [ 29 ]. In many countries, they provoke more than twice the number of deaths as cancer. However, in at least ten countries (Belgium, Denmark, France, Israel, Luxembourg, Netherlands, Portugal, Slovenia, Spain, and San Marino), cancer engenders more deaths than CVD among men and in one country (Denmark), among women [ 29 ].

Coronary atherosclerosis , also currently named coronary artery and heart disease and ischemic heart disease, Footnote 31 and cerebrovascular disease (another collective term standing for all diseases of arteries irrigating the brain), which are the first and second leading contributors to CVD burden, account for 20 and 12% of all deaths in Europe annually, respectively [ 29 ]. Inequalities exist among countries (e.g., Russia and Ukraine versus France). Approximately 63% of ischemic and 80% of hemorrhagic strokes now occur in low- and mid-income countries [ 121 ].

Acute coronary syndrome is a collective term incorporating unstable angina, ST-elevation myocardial infarction, and non-ST-elevation myocardial infarction due to atherosclerotic plaque erosion that can evolve into rupture. The resulting intraluminal thrombosis engenders sustained myocardial ischemia and infarction owing to local partial or complete vascular occlusion or, most often, embolization and subsequent obstruction of downstream arterial segments upon shedding of platelet aggregates.

Ischemia causes simultaneous massive cell death, releasing alarmins that activate NFκB, thereby producing proinflammatory cytokines. Debris from dead cells are taken up by macrophages, which then launch inflammation, relying on interferon regulatory factor IRF3 and type- I interferons, which protect against infection and cancer, IRF3 initiating a specific gene expression program. However, excessive IRF3 activation and type- I Ifn production are deleterious. Myocardial infarction stimulates IRF3 in a distinct population of interferon-inducible cardiac macrophages [ 122 ]. Secreted type- I interferons target the IfnAR receptor in an auto- and paracrine manner. In mice, deficiency in the cytosolic DNA sensor cyclic GMP–AMP synthase (cGAS), its adaptor, STING, the cGAS–STING axis activating IRF3 via TBK1, IRF3, type- I Ifns, or IfnAR, improves cell survival. In Irf3 −∕− mice, myocardial infarction-induced type- I Ifn response is nearly completely abrogated. Therefore, a transient inhibition of the interferon-dependent innate immune response in ischemia can reduce inflammation and limit the adverse ventricular remodeling.

Limbs subjected to brief periods of ischemia protect multiple organs, in particular the lung, from ischemia–reperfusion damage. Limb remote ischemic preconditioning results from the release into the bloodstream of irisin, a myokine derived from the extracellular portion of fibronectin domain-containing protein FnDC5 in skeletal muscle, which targets mitochondria and prevents some of the deleterious effects of redox stress [ 123 ]. Interaction between irisin and mitochondrial uncoupling protein UCP2 hampers ischemia–reperfusion event-induced redox stress and preserves mitochondrial function.

1.2 Vasculopathies and Cardiac Dysfunction

Heart failure , a complication of coronary atherosclerosis, hypertension, cardiomyopathies, myocarditis, heart defects, and valvular heart disease (or heart valve disease), has an estimated prevalence in North America and Europe of up to 2%. Eighty percent of new cases occur in people older than 65 years, contributing to about 11% of deaths [ 121 ].

Rheumatic heart disease (RHD), which is most frequently detected in low-income countries (Oceania; Central, South, and Southeast Asia; sub-Saharan Africa; the Caribbean; and Middle East [e.g., Yemen]), is the fifth and sixth leading cause of CVD-related mortality and disability, respectively [ 121 ].

Cardiomyopathies are categorized into various disease spectra according to their etiology and natural history, and these determine their medical management (Sect. 7.1 ). They can result from (1) left ventricular stiffening associated with adverse wall remodeling, (2) impaired sensitivity to β-agonists and insulin, (3) depressed autonomic function with altered myocardial catecholamine concentrations, (4) endothelial dysfunction, (5) abnormal ionic currents, and (6) disturbed flow in the coronary macro- and microcirculation. The most common forms are dilated and ischemic cardiomyopathies.

Dilated cardiomyopathy (DCM) is currently defined by left ventricular or biventricular dilation and systolic dysfunction (i.e., abnormal ejection fraction) in the absence of abnormal loading conditions (e.g., hypertension and valvulopathies) or coronary atherosclerosis. It comprises a set of time-varying electrochemical and functional anomalies and can be engendered by genetic and acquired disorders. Genetic predisposition can be combined with environmental factors [ 124 ].

Inherited DCM can be transmitted by an autosomal dominant or recessive, X-linked, or matrilinear mode. The main genes implicated in DCM encompass BAG3 (BCL2-associated athanogene-3), LMNA (lamin-A/C), MYBPC3 (cardiac myosin-binding protein-C), MYH7 (myosin heavy chain), MYPN (myopalladin), PLN (phospholamban), RBM20 (RNA-binding motif protein-20), SCN5A (voltage-gated sodium channel α subunit Na V 1.5), TNNT2 (troponin-T), and TTN (titin). DCM can also have a genetic origin within the framework of neuromuscular disorders, such as Becker and Duchenne muscular dystrophy and myotonic dystrophy, may be linked to mitochondrial diseases and tafazzin [ 124 ].

On the other hand, DCM can derive from viral, bacterial, fungal, and parasitic infections in addition to systemic diseases (e.g., polymyositis, sarcoidosis, and systemic lupus erythematosus) [ 124 ]. It can arise as a complication of acromegaly, diabetes mellitus, hyper- and hypothyroidism, Addison and Cushing disease, Footnote 32 and pheochromocytoma. Dilated cardiomyopathy can be induced by excess alcohol consumption and chemotherapeutic and psychiatric drugs and by electrolyte disturbances (hypocalcemia and hypophosphatemia), overload (iron) or deficiency (carnitine, copper, selenium, thiamine, and zinc), anti-heart antibodies, and toxics (e.g., arsenic and cobalt). Peri- and postpartum cardiomyopathy (PPCM) is caused by autoimmunity, fetal microchimerism, viral infection, stress-activated cytokines, and toxic cleavage product of prolactin [ 124 ].

Hypokinetic nondilated cardiomyopathy (HNDC) is defined by left ventricular or biventricular systolic dysfunction (ejection fraction< 45%) without dilation [ 124 ].

Ischemic cardiomyopathy results from altered flow in large epicardial coronary arteries that are stenosed and/or parietal microcirculation associated with chronic inflammation. Rheumatoid arthritis, systemic lupus erythematosus, and systemic sclerosis yield an important risk background for myocardial ischemia.

Hypertrophic cardiomyopathy (HCM) is another form with abnormal and often asymmetric myocardial thickening, preserved left ventricular function, phenotypic heterogeneity, and incomplete penetrance. This autosomal dominant inherited disease can be caused by mutations of genes (> 50 genes, mainly those encoding sarcomeric constituents [e.g., MYL2]). The presence of additional risk factors, especially hypertension, exacerbates the disease penetrance and severity, as MYL2 E22K mutation does not exhibit clinical symptoms in most carriers [ 125 ].

Diabetic cardiomyopathy is characterized by reduced diastolic function and left ventricular hypertrophy. Its clinical management relies on appropriate glucose and HbA1c monitoring. However, in individuals of African ancestry, a specific variant that shortens the lifespan of red blood capsules reduces HbA1c concentration [ 126 ].

Diabetic cardiomyopathy is mainly linked to a shift to exclusive FAs as an energetic substrate for CMCs, instead of the usual sources (amino acids, carbohydrates, FAs, ketones, and lactate), due to AMPK at an early stage and then NR1c1 (PPARα) [ 127 ]. Footnote 33 On the other hand, endotheliocytes use preferentially glucose (∼85%) for ATP synthesis, the faster rate of glycolysis compensating for the greater amounts of ATP per mole of glucose yielded by mitochondrial oxidative phosphorylation and sparing oxygen for CMCs [ 127 ]. However, diabetic endotheliocytes have an aberrant metabolism. Production of GluT1 is not sensitive to hyperglycemia, and glucose egress to the CMC is not adequate. Moreover, high intracellular glucose concentration creates ROS and prevents glycolysis, glycolytic intermediates accumulating and being processed by the polyol, hexosamine, and methylglyoxal pathways, which form ROS and RNS and AGEs.

Arrhythmogenic cardiomyopathy is mainly caused by mutations in genes encoding desmosomal elements. It is characterized by progressive fibroadipose replacement of the myocardium, arrhythmias, and sudden death. Cardiac mesenchymal stromal cells have a lower expression of plakophilin, contain more lipid droplets, and differentiate into adipocytes, contributing to the adipogenic substitution in arrhythmogenic cardiomyopathy.

Arrhythmogenic atrial fibrosis characterized by excess extracellular matrix deposition and fibroblast proliferation and differentiation into collagen-secreting myofibroblasts favors atrial fibrillation (AF), the most common persistent arrhythmia. This cardiac rhythm disorder is the sixth and eighth leading cause of CVD-related mortality and disability among other CVD causes, respectively, the highest prevalence being observed in North America and lowest in the Asia-Pacific region [ 121 ]. Excess collagen can disrupt atriomyocyte bundle continuity, lessen intercellular coupling, and engender longitudinal anisotropy. Moreover, fibroblasts and myofibroblasts are electrochemically connected to CMCs, thereby modulating their electrical activity and promoting re-entry [ 128 ]. Persistent AF is maintained by re-entrant drivers (or rotors) related to extensive atrial remodeling, slowing action potential propagation, reducing cell excitability, and causing unidirectional block [ 129 ]. These rotors are confined in regions characterized with high fibrosis density.

1.2.1 Cardiac Wall Remodeling

Cardiac walls remodel after pressure and volume overload or myocardial injury. This can result in heart failure.

Heart failure is associated with impaired signaling and pathological cardiac (or ventricular) wall remodeling (Vol. 7, Chap. 3. Adverse Cardiac Remodeling). Maladaptive cardiac remodeling is characterized by structural changes in dimensions, mass, and shape and metabolic remodeling with functional alterations due to molecular, cellular, and interstitial changes in response to abnormal hemodynamic load and/or damage linked to neurohormonal activation.

Congestive heart failure is marked by atrial and ventricular wall enlargement and reduced cardiac contractility and adrenergic responsiveness. The sympathetic nervous system and renin–angiotensin–aldosterone axis are activated to compensate for reduced cardiac output but further favor heart failure progression via maladaptive wall remodeling.

Cardiac modifications comprise cell death, redox stress, inflammation, hypertrophy and/or atrophy, fibrosis, and occurrence of arrhythmias. In particular, cardiac fibrosis causes electrical and mechanical dysfunction.

Ion carriers (channels, pumps, and transporters), such as plasmalemmal (sarcolemmal) Na V 1.5 and Ca V 1.2 channels, Na + –Ca 2+ and Na + –H + exchangers, K ATP channel, sarco(endo)plasmic reticulum ryanodine-sensitive Ca 2+ channel, and SERCA pump, in addition to their regulators, in particular kinases and phosphatases, are implicated in heart failure [ 130 ]. In heart failure, regulation of intracellular sodium and activity of K + channels and Ca 2+ cycling are defective.

1.2.1.1 Cardiac Wall Hypertrophy

Adverse left ventricular and arterial and arteriolar wall hypertrophy, along with associated stiffness, results from sustained hypertension (Vol. 7, Chap. 3. “Adverse Cardiac Remodeling”). However, hypertension-induced arterial wall hypertrophy of large- and medium-caliber arteries is not necessarily associated with a decreased arterial distensibility [ 131 ]. On the other hand, aging alters distensibility independently of blood pressure.

Na + –K + ATPase (Na + pump) is a plasmalemmal αβ dimer [ 132 ]. The catalytic ouabain-resistant α1 isoform is expressed in all cell types; most cells produce a second α isoform (ouabain-sensitive α2–α3, α4 being detected in the sperm). The catalytic α subunit contains the Na + , K + , ATP, and cardiotonic steroid-binding sites. Sodium ATPase β subunit exists in three isoforms (β1–β3) that support catalytic activity of chaperoned α subunit. β1 Subunit is the most important isoform in cardiac and vascular smooth muscle cells, where it forms both α1β1 and α2β1 protomers. Footnote 34 Arterial smooth myocytes also manufacture α2 isoform, which localizes to endoplasmic reticulum–plasma membrane contact sites, the so-called plasmerosomes, and controls myogenic tone. On the other hand, α1 subunit is more uniformly distributed.

Sodium pumps are regulated by multiple factors, such as hormones (e.g., aldosterone, insulin, and catecholamines) and protein phosphorylation [ 132 ]. The cardiotonic steroids, ouabain, digoxin, and bufalin, block cation transport by Na + pump.

Both Na + and K + affinities are modulated by the transmembrane regulator phospholemman (Plm) encoded by the FXYD1 gene (FXYD domain-containing ion transport regulator-1), which also regulates activity of Na + –Ca 2+ exchanger NCX1 [ 132 ]. Unphosphorylated Plm binds to the α2β dimer and reduces affinity of α2 subunit for intracellular Na + and extracellular K + ion. Phosphorylation of cardiac and arterial Plm by PKA or PKC relieves Na + ATPase inhibition and restores high Na + affinity.

Hence, in arterial smooth myocytes, Na + pump α2 subunit is structurally and functionally linked to NCX1. This crosstalk may be influenced by other adjacent channels, pumps, and transporters, such as TRPC6 and serca2 [ 132 ].

Activation of the renin–angiotensin–aldosterone axis stimulates ROS generation, causing glutathionation of β1 subunit and Na + pump inhibition. On the other hand, Plm promotes Na + pump deglutathionation and protects against oxidation (inhibition) of Na + pump in arteries and the heart [ 132 ].

Reduced expression of smooth muscle-specific Na + pump α2-subunit elevates blood pressure and sensitivity to angiotensin-2 and dietary salt, whereas its overexpression lowers basal BP and Agt2 and NaCl sensitivity [ 132 ]. Chronic salt retention augments endogenous ouabain-like compound (EOLC), a cardio- and vasotonic steroid synthesized and secreted by the adrenal cortex and Na + pump inhibitor, thereby causing salt-dependent hypertension mediated by Na + –Ca 2+ exchanger.

Ouabain triggers signaling that relies on various effectors, such as ERK1, ERK2, PI3K c1 α , PKB, and Src, in addition to NFκB [ 132 ].

In addition, another cardiotonic steroid, marinobufagenin, can be detected in human plasma and urine [ 132 ]. Prolonged exposure to ouabain or marinobufagenin causes hypertension in normal rats (but neither digoxin nor digitoxin).

Sodium ion and water retention raises blood volume and subsequently plasmatic EOLC concentration, thereby inhibiting Na + pump. Resulting elevated cytosolic Na + concentration elevates cytosolic Ca 2+ concentration due to Ca 2+ entry through NCX, hence increasing myogenic tone and total peripheral systemic vascular resistance to blood flow.

Transaortic constriction-induced hypertrophy in mice is impeded by immunoneutralizing circulating endogenous ouabain [ 133 ]. Endogenous ouabain and its receptor, Na + pump α2-subunit, are involved in hypertension-induced cardiac hypertrophy.

In many forms of hypertension, the brain RAAA is activated via circumventricular organs such as the subfornical organ, increasing arterial sympathetic nerve activity by the central nervous system and α-adrenoceptor-mediated arterial constriction [ 132 ]. The hypothalamic component of this neurohumoral pathway involves local aldosterone production, mineralocorticoid receptor, ENaCs, local endogenous ouabain release, and Na + pump.

The cardioprotective deacetylase sirtuin-2 operates via STK11 (LKb1) and AMPK in aging-related and angiotensin-2-induced adverse cardiac hypertrophy [ 134 ]. Sirtuin-2 deacetylates STK11 (Lys48), thereby eliciting STK11 phosphorylation and subsequently launching the STK11–AMPK axis. In Sirt2 −∕− aged (24-month-old) mice and Agt2-treated mice, cardiac hypertrophy and fibrosis are magnified. Conversely, cardiac-specific SIRT2 overexpression protects against Agt2-primed cardiac hypertrophy and fibrosis and rescues cardiac function.

1.2.1.2 Cardiac Wall Fibrosis

Fibrosis is a complication of chronic inflammatory diseases. Initiation of fibrogenesis involves activation of monocytes and differentiation into profibrotic macrophages. On the other hand, TGFβ provokes proliferation of myofibroblasts.

Fibrosis is assessed by its regulators and markers MMP1–MMP3 and MMP7–MMP28 and TIMP1–TIMP4. In particular, TIMP1 inhibits MMP9 [ 135 ]. TIMP1 can be a strong predictor of death from CVD, at least in some populations, such as Iceland.

Fibroblasts transdifferentiate into activated myofibroblasts, which synthesize α-smooth muscle actin (Actα2) and secrete matrix constituents such as type- I α1-procollagen (encoded by the COL1A1 gene). Persistent myofibroblast activation distinguishes pathological fibrosis from wound healing. Myofibroblasts integrate a feedback loop that perpetuates fibrosis and extracellular matrix stiffening. Fibroblast-to-myofibroblast differentiation driven by matrix stiffness provokes mitochondrial priming in activated myofibroblasts (but not in quiescent fibroblasts). Activity of proapoptotic proteins such as BCL2L11 thus increases in myofibroblasts that become particularly susceptible to apoptosis; these agents can reverse fibrosis [ 136 ]. On the other hand, myofibroblasts depend on antiapoptotic proteins such as BCL2L1 to prevent their death.

Cardiac fibrosis is characterized by an uncontrolled accumulation of extracellular matrix by cardiofibroblasts in the interstitial and perivascular spaces.

Transcription of typical fibrosis genes, such as Comp and NOX4, which encode cartilage oligomeric matrix protein and NADPH oxidase subtype NOx4, respectively, is upregulated.

Hepatic fibrosis is characterized by the accumulation of matrix proteins, mainly fibrillar collagen-1, which confers mechanical stability. Cartilage oligomeric matrix protein (COMP), Footnote 35 or thrombospondin-5, provokes collagen-1 formation via ScaRb3 and MAP2K1/2–ERK1/2 pathway, in addition to its deposition. Also, COMP supports matrix metallopeptidases MMP2, MMP9, and MMP13, but does not prevent collagen-1 cleavage by MMP1 [ 137 ].

Cartilage oligomeric matrix protein binds with high affinity to collagen-1 and to collagen-12 at the surface of collagen-1 fibrils [ 138 ]. In fact, it tethers to the fibril-forming collagens Col1 and Col2, the nonfibrillar fibril-associated collagens with interrupted triple helices (FACIT) collagens (Col9, Col12, and Col14), along with other types of matrix proteins, such as fibronectin and matrilins, and proteoglycans. It also assists secretion of collagens [ 138 ]. Therefore, in the extracellular matrix, COMP helps the organization of a collagen fibril meshwork that yields the organ rheology, whereas within the cell, COMP enables efficient secretion of collagens into the extracellular space.

This fibrillar collagen assembly regulator is implicated in fibrosis in various organs and can thus serve as a fibrosis marker [ 139 , 140 ]. Cartilage oligomeric matrix protein is indeed synthesized in fibrotic regions, where it colocalizes with vimentin around SMAD3+ cells. Stimulation of fibroblasts with TGFβ1 increases COMP production.

Reactive oxygen species produced by NADPH oxidases regulate cell differentiation. The isozyme NOx4 is implicated in cardiac and pulmonary myofibroblast differentiation. For example, in idiopathic pulmonary fibrosis, NOx4 expression rises in fibrogenic lung fibroblasts, which contain high concentrations of the hyaluronan receptor, epican variant containing exon 6 (CD44v6), thereby mediating TGFβ1-induced fibroblast differentiation into myofibroblasts [ 141 ]. Synthesis of hyaluronan and epican is augmented in numerous fibrotic organs. The TGFβ1–CD44v6 pathway is implicated in collagen-1 and Actα synthesis in pulmonary myofibroblasts [ 142 ]. It raises early growth response EGR1 formation. Production of CD44v6 is triggered by TGFβ1 via EGR1 and activator protein AP1. The ERK–EGR1 axis promotes CD44v6 splicing. Conversely, CD44v6 sustains ERK signaling, which supports AP1 activity in pulmonary fibroblasts. Hyaluronan produced by hyaluronan synthase HAS2 is required for colocalization of CD44v6 and Tβ R1 and subsequent TGFβ1–CD44v6–ERK1–EGR1 signaling, which constitutes a positive feedback loop that links TGFβ1 to the myofibroblast phenotype [ 142 ].

Transforming growth factor (TGFβ1), a major profibrotic factor, upregulates synthesis of IL11, which serves as its profibrotic effector. Interleukin-11 produced by activated fibroblasts does indeed cause cardiac fibrosis [ 143 ]. Its receptor IL11Rα is expressed at its highest concentration in fibroblasts. In these cells, the IL11–IL11Rα couple launches alternative ERK-dependent autocrine signaling used in fibrogenic protein synthesis. Production of IL11 is also upregulated in fibroblasts from patients with idiopathic pulmonary fibrosis (100-fold).

After an acute myocardial injury, cardiofibroblasts release proinflammatory cytokines that trigger their proliferation (feedforward loop) and differentiation into myofibroblasts, which secrete high amounts of proinflammatory and fibrotic agents and matrix constituents. Adaptive collagen-based fibrotic scarring preserves myocardial structure, but prolonged activation of cardiofibroblasts causes fibrosis (Vol. 10, Chap. 3. Adverse Wall Remodeling).

Fibroblasts extend filopodia into the T-tubular lumen. Heterotrimeric collagen-6 (Col6α1–Col6α2–Col6α3 with other possible chains homologous to Col6α3 [Col6α4–Col6α6]) tetramerizes and, once it is secreted, forms microfibrils. Into T-tubules, collagen colocalizes with the dystrophin complex, which links the extracellular matrix to actin microfilaments and microtubules of the cytoskeleton, and transmits stress and strain between these two compartments [ 144 ]. Dystrophin localizes to the T-tubule periphery and serves as a mechanosensor at the Z disc. Deposition of fibrillar Col1 and Col3 stiffen, T-tubule membranes, whereas nonfibrillar Col4 and Col6 may anchor fibrillar collagens to the basement membrane of CMCs [ 145 ].

The endothelium-controlled paracrine couple constituted by neuregulin-1 and receptor protein Tyr kinase human epidermal growth factor receptor (HER) modulates cardiac performance and adaptation [ 146 ]. Neuregulin-1 operates on cardiofibroblasts and has an antifibrotic effect in the left ventricle. It attenuates myocardial hypertrophy and fibrosis in a mouse model of angiotensin-2-induced myocardial remodeling in addition to pulmonary fibrosis. Moreover, the Nrg1–HER axis also regulates the function of macrophages. Neuregulin-1 at least partly inhibits macrophages, alleviates myocardial macrophage infiltration and cytokine expression, and improves ventricular stiffness. On the other hand, in mice with myeloid cell-specific deletion of the Her4 gene, myocardial fibrosis in response to Agt2 increases. Neuregulin-1 activates HER4 on macrophages and inhibits the PI3K–PKB pathway in addition to STAT3, lessening inflammatory cytokine release.

Myofibroblasts, which are derived from the differentiation of fibroblasts, fibrocytes, and epitheliocytes, are the principal effectors of fibrosis. Establishment and maintenance of myofibroblasts rely on TGFβ1-primed promotion of a hyaluronan-rich pericellular matrix, the hyaluronan coat [ 147 ].

The heparan sulfate proteoglycan epican (CD44) is a receptor for the extracellular matrix constituent hyaluronan, which mediates cell–cell and cell–matrix interactions. It is encoded by the Cd44 gene, which consists of 19 exons. Its other ligands include collagens, osteopontin (or secreted phosphoprotein SPP1), soluble galactoside-binding lectin LGalS9, and matrix metallopeptidases. Hyaluronan has various isoforms due to a variable pattern of N- and O-linked glycosylation and the existence of multiple splice variants. Exons 1 to 5, 15 to 17, and 19, which encode the extracellular N-terminus, transmembrane domain, and the cytoplasmic region, are present in all alternatively spliced Cd44 mRNA species [ 147 ]. The presence of exons 6 to 14 varies between isoforms. Exon 18 is removed before translation in most isoforms owing to an early stop codon. In mice, exons v4 to v6 in splice variants (CD44v4, CD44v5, and CD44v6) facilitate migration of Langerhans cells (dendrocytes of the skin and mucosa) to lymph nodes [ 148 ]. In rats, exons v3 and v6 are involved in FGF-mediated mesenchymal cell proliferation during limb bud development. The standard epican isoform enhances myofibroblast differentiation, thereby favoring fibrosis [ 147 ]. On the other hand, its alternatively spliced isoform containing variant exons v7–v8, CD44v7v8, prevents myofibroblast differentiation.

Hyaluronan is degraded by hyaluronoglucosaminidases or hyaluronidases, encoded by the HYAL1 to HYAL4 genes, Hyal1 and Hyal2 being the most abundant species. Hyaluronidase-2 supports CD44v7/8 production [ 147 ]. Hyaluronidase-2 lodges in lysosomes, the acidic milieu being optimal for Hyal activity. However, Hyal2 is also a plasma membrane-anchored protein with weak enzymatic activity. Hyaluronidase-2 can be enzymatically inactive. It plays a non-enzymatic role, as it participates in regulating epican splicing, promoting CD44v7v8 production.

On the other hand, when pulmonary fibroblasts are stimulated by BMP7, which prevents or reverses differentiation of cells into myofibroblasts, Hyal2 translocates to the nucleus, where it displaces components of the splicing machinery from the spliceosome, enabling Hyal2, the spliceosomal components U1 and U2 small nuclear ribonucleoproteins, and Cd44 pre-mRNA to complex, whereas arginine- and serine-rich (RS) proteins, which mediate exon exclusion, promote profibrotic standard CD44 synthesis. Both SRSF2 and SRSF5 control Cd44 pre-mRNA splicing relevant to fibrosis. Footnote 36 Splicing regulators, argonaute-mediated histone modifications, KHDRBS1, Footnote 37 and RS-rich splicing factor SFRS10 regulate Cd44 splicing [ 147 ]. Hyal2 facilitates the inclusion of Cd44 exons 11 and 12, which support expression of the antifibrotic CD44v7v8 isoform at the cell surface [ 147 ].

1.2.2 Cardiomyocyte Remodeling

Markers of cardiac remodeling have either an increased expression, such as α-myosin heavy chain isoform (MyH6), GluT1, α-actin (ActC1), natriuretic peptide, galectin, caveolin, nitric oxide synthase (NOS1), angiotensin convertase or decreased production, such as β-MHC (MyH7), GluT4, and serca2a [ 149 ].

1.2.2.1 Energy Metabolism

Cardiac energetics is impaired because of mitochondrial dysfunction in addition to calcium handling, disturbing myocardial contractility.

In the heart, the rates of ATP production and turnover are very high owing to contraction–relaxation cycles. Under normoxia, more than 95% of ATP generated in the heart is created by oxidative phosphorylation in mitochondria and the remaining mainly from glycolysis and, to a lesser extent, from the tricarboxylic acid cycle (TCAC; also named citric acid and Krebs cycle) [ 150 ]. Approximately 70–90% of cardiac ATP is produced by fatty acid oxidation and the remaining from the oxidation of glucose and lactate, small amounts deriving from ketone bodies and certain types of amino acids. About two-thirds of the ATP generated is used by the sarcomere and the remaining by ion pumps such as endoplasmic reticulum Ca 2+ ATPase (SERCA), which determines lusitropy.

Substrates are transported across the plasma membrane into the cytosol, where they are metabolized. In oxidative pathways, the metabolic intermediates, such as pyruvate or acylCoA from glycolysis and β-oxidation, are transported across the inner mitochondrial membrane by specific carriers. Inside the mitochondrial matrix, these substrates are oxidized or carboxylated (anaplerosis) and enter the TCAC, thereby generating reducing equivalents, such as FADH 2 and NADH, which are used by the ETC to generate a proton gradient, which, in turn, is used for ATP production. The energy generated is immediately used or stored in the form of phosphocreatine.

Metabolic intermediates regulate many pathways in addition to ATP production, serving as messengers (Table 1.8 ).

The myocardial energy pool includes ATP and phosphocreatine (PCr), the latter being an ATP transporter and buffer. In the mitochondrion, the high-energy phosphate bond in ATP can be transferred to creatine by creatine kinase to form PCr, which can easily diffuse through the mitochondrial membrane into the cytosol, where it can generate ATP from ADP using cytosolic creatine kinase [ 150 ].

Glucose metabolism comprises glycolysis and accessory pathways, that is, glycogen synthesis and pentose phosphate (PPP) and hexosamine synthetic pathway (HSP). The PPP, which relies on glucose 6-phosphate dehydrogenase (G6PDH), is an NADPH source used in lipid synthesis and anaplerosis (i.e., replenishment of the TCAC intermediate pool through pathways independent of acetylCoA, as these intermediates are constantly removed from the TCAC for synthesis of amino and nucleic acids and thus need to be replaced), in addition to redox stress. The hexosamine synthetic pathway (HSP), which forms \({ }^{{\mathrm {UDP}}_{\mathrm {N}}}\) acetylglucosamine (GlcNAc), a monosaccharide donor for the O-GlcNAcylation of proteins, requires glucose together with acetylCoA and glutamine. These accessory pathways can play a greater role in heart disease genesis.

Fatty acid oxidation is impaired in cardiac hypertrophy and failure, leading to reduced ATP production. Glucose oxidation can remain unchanged in compensated hypertrophy but can decrease in heart failure [ 150 ]. Non-ATP-generating pathways of glucose metabolism (HSP, PPP, and anaplerosis) are boosted. Metabolic remodeling in HF is characterized by a declined energy production linked to progressive impaired substrate use and mitochondrial genesis and function.

1.2.2.2 Ion Carriers

Cardiomyocytic T tubules contribute to regulating ion fluxes. Bridging integrator BIn1 (or amphiphysin Amph2) is a T-tubule protein residing in the inner membrane folds that is linked to calcium motion. The cardiac-specific splice variant BIn1v13v17 (including exons 3 and 17) promotes actin polymerization. It then generates and stabilizes dense T-tubule membrane folds that create a diffusion barrier to extracellular ions [ 151 ]. Its expression is downregulated in heart failure.

Cardiofibroblasts influence myocardial function by their chemical, electrical, and mechanical interactions with CMCs. Multiple ion channels regulate their fate and activity (e.g., Ca V 1, Ca V 3, BK, SOCE, TRPA1, TRPC1, TRPC6, TRPM7, Na V 1.5, K V 4.3, K IR 2.1, and volume-sensitive [Cl vol ] and Ca 2+ -gated Cl − channel [Cl Ca or anoctamin-1]) [ 152 ]. They participate in myofibroblast differentiation.

Defective ion handling by Ca 2+ , K + , and Na + channels, pumps, and transporters in addition to connexins and nonselective channels causes cardiac arrhythmias.

1.2.2.2.1 Defective Calcium Handling

In the membrane of the endoplasmic (sarcoplasmic) reticulum, ryanodine-sensitive Ca 2+ channel and SERCA pump enable Ca 2+ release from and reuptake within this organelle. Released Ca 2+ binds to the actin-connected troponin-C and allows actin–myosin interaction.

Homotetrameric ryanodine receptor at junctions between the endoplasmic reticulum and transverse tubule is an essential component of excitation–contraction coupling via Ca 2+ -induced Ca 2+ release (CICR). Footnote 38 It is linked to regulators, such as FK506-binding protein FKBP1b, a member of the immunophilin family of cis-trans peptidyl prolyl isomerases, cAMP-dependent protein kinase PKA and its anchoring protein, AKAP6, and protein phosphatases, PP1 and PP2 [ 130 ]. Muscle-selective AKAP6 coordinates a cAMP-sensitive negative feedback loop that comprises PKA and the cAMP-selective phosphodiesterase PDE4d3, PKA phosphorylating PDE4D3 and increasing its affinity for AKAP6, enhancing recruitment of PDE4D3 and hence faster signal termination [ 155 ].

Upon depletion of ER Ca 2+ content and arrest of Ca V 1.2 gating, that is, at the end of the systole, diastole begins, RyRs are inactivated and Ca 2+ is pumped back into the ER by serca2a regulated by phospholamban and out of the cell by sarcolemmal NCX, which governs lusitropy.

Stimulation by β-adrenoceptor increases inotropy. Calcium flux regulators are phosphorylated (activated) by PKA and CamK2, both targeting Ca V 1.2 and RyR in addition to phospholamban, the latter facilitating the process.

Failing ventriculomyocytes have an impaired contractility. The Ca 2+ transient amplitude lessens, excitation–contraction coupling declines, and the rate of diastolic Ca 2+ transient decay slows down. The SR Ca 2+ content drops, serca2a activity is diminishing, and Ca 2+ extrusion is caused by NCX rising. Neurohormonal stimulation causes RyR hyperphosphorylation by PKA and RyR dephosphorylation decays due to defective association of PP1 and PP2 and presence of PDE4d3 in the RyR complex [ 130 ]. In addition, increased RyR2 phosphorylation (Ser2808) favors its dissociation from its regulator FKBP1b, which increases Ca 2+ sensitivity and reduced RyR closing, and hence diastolic ER Ca 2+ leak.

Dephosphorylation of phospholamban by PP1 inhibits serca2a; this inhibition is relieved upon its phosphorylation by PKA (Ser16) and CamK2 (Thr17). In heart failure, expression of both serca2a and Pln is altered [ 130 ]. In addition, Pln phosphorylation is reduced, repressing serca2a activity.

1.2.2.2.2 Altered Sodium Control

In heart failure, intracellular Na + concentration rises, in particular because of the late Na + influx, a fraction of Na V 1.5 channels failing to enter an inactivated state [ 130 ].

Cardiac-specific sodium–hydrogen exchanger SLC9a1 (NHE1) electroneutrally exchanges intracellular H + for extracellular Na + to regulate intracellular H + and intracellular Na + concentrations, the inward gradient produced by the Na + –K + ATPase providing a driving force for SLC9a1-mediated H + extrusion and Na + influx [ 130 ]. Its activity increases upon exposure to ROS, intracellular acidosis, angiotensin-2, endothelin, and α1-adrenoceptor. Increased SLC9a1 activity causes Ca 2+ overload through Na + –Ca 2+ exchanger.

The Na + –K + ATPase Footnote 39 actively transports Na + out and K + into the CMC. Phospholemman regulates the function of this enzyme. It is also the receptor of cardiac glycosides (e.g., digoxin and ouabain) and exerts a positive inotropic effect, as they inhibit pump activity, thereby decreasing the driving force for Na + –Ca 2+ exchange and increasing cellular content and release of Ca 2+ during depolarization [ 156 ].

1.2.2.2.3 Impaired Potassium Control

The transient outward current ( i K,to ) through K V 4.2 and K V 4.3 is involved in early repolarization. It decays in heart failure, extending action potential duration [ 130 ].

Mitochondrial K ATP channel (K IR 6.2) serves as a metabolic sensor, adjusting membrane excitability to match cellular energetic demand. It opens in response to ischemia, physical exercise, and stress hormone exposure, shortening the action potential. It can protect the heart against hypertension.

1.2.2.3 Transverse Tubules

In heart failure, loss and defects of transverse tubules (T-tubules), that is, adverse reorganization of the T-tubular structure (e.g., dilation of the tubular lumen and the occurrence of sheet-like structures), affect Ca 2+ signaling [ 145 ]. In ventriculomyocytes, excitation–contraction coupling depends on these deep invaginations of the plasma membrane at Z-line levels, where apposed cellular structures and proteic complexes reside, aimed at synchronizing Ca 2+ release from the endoplasmic reticulum and hence contraction. Disrupted Ca 2+ release reduces contractility in heart failure. Enlargement of the T-tubular lumen augments the diffusion space of extracellular ions, in particular Ca 2+ and K + , thereby favoring arrhythmia. In addition, loss of the T-tubular anchor junctophilin-2 decreases T-tubule density. Moreover, several collagen isoforms (Col1, Col3–Col4, and Col6) are involved in T-tubule expansion, whereas modest amounts of collagen normally exist within the interior of T-tubules [ 144 ].

1.2.2.4 Mitochondrion

Integral outer mitochondrial membrane FUN14 domain-containing protein FunDC1 provokes hypoxia-induced mitophagy. It interacts with kinesin light chain KLC1 (but with neither the motor subunit of kinesin-1 KIF5b nor the motor subunit of kinesin-2 KIF3a) [ 158 ]. In addition, FunDC1 binds to endoplasmic reticulum-resident inositol trisphosphate receptor IP 3 R2 and localizes to mitochondrion-associated endoplasmic reticulum membranes, which participate in apoptosis and autophagy, hence promoting communication between mitochondria and the endoplasmic reticulum, modulating Ca 2+ release, and maintaining MAERMs and mitochondrial morphology and function [ 159 ]. Overexpression of FunDC1 increases mitochondrial concentrations of IP 3 R2 and Ca 2+ ion. Ablation of the FUNDC1 gene reduces intracellular Ca 2+ concentration and suppresses formation of mitochondrial fission protein Fis1 and hence mitochondrial fission, as it impedes the binding of CREB to the Fis1 promoter. The FunDC1–CREB–Fis1 axis is repressed in patients with heart failure.

1.2.3 Altered Signaling

In normal conditions, CMCs and endotheliocytes interfere and mutually control their metabolism.

Proper functioning of the cardiovascular system relies at least partly on interactions between CMCs and endotheliocytes of the cardiac capillaries and endocardium, dysregulated communication between these two cell types being implicated in the development of cardiac structural and functional anomalies and disturbed endothelium-related signaling based on NO and neuregulin being involved in heart failure [ 160 ].

Endothelial cardioactive factors encompass angiopoietins, angiotensin-2, apelin, dickkopf-3, endothelin-1, follistatin, neuregulin-1, NO, periostin, prostaglandins such as prostacyclin, thrombospondin-1, connective tissue, fibroblast, vascular endothelial growth factor, and endothelial microRNAs (Table 1.9 ) [ 160 ]. They operate briefly or have a sustained action, and they can cooperate.

Nitric oxide and natriuretic peptides launch the synthesis of cyclic guanosine monophosphate using different effectors, sGC and particulate guanylate cyclase (pGC), respectively, and spatially distinct pools, sGC and pGC lodging in the cytosol and cortex, and hence different responses. Among phosphodiesterases hydrolyzing cGMP, PDE2 limits the subsarcolemmal cGMP pool and PDE5 the cytosolic cGMP pool [ 160 ]. Whereas cGMP produced by pGC and sGC has a positive lusitropic effect, cGMP produced by sGC blunts myocardial response to β-adrenoceptor.

At low NO concentrations, the NO–sGC–cGMP axis can have a positive inotropic effect via activation of PKG and PKA, which increases Ca 2+ concentration [ 160 ]. Higher NO amounts have a negative inotropic effect due to the blockage of sarcolemmal Ca 2+ channels and reduction in the sensitivity of troponin-C to Ca 2+ ion. Moreover, NO has a positive lusitropic effect. Phosphorylation of troponin-I reduces sarcomeric sensitivity to Ca 2+ and promotes cross-bridge detachment. Phosphorylation of titin by PKA and/or PKG also improves lusitropy. Furthermore, NO provokes vasodilation and hence reduces afterload.

The chronotropic effect of NO depends on its site of action, being positive upon stimulation by cGMP of a hyperpolarization-activated pacemaker current and negative at the postsynaptic level [ 160 ].

Nitric oxide is synthesized by nitric oxide synthases (NOSs), constitutive NOS1 and NOS3 binding their cofactors (FAD, FMN, and BH 4 ), dimerizing, and being stimulated by Ca 2+ –calmodulin (Table 1.10 ) [ 161 ]. NOS3 also requires proper localization to caveolae using HSP90 and caveolin and phosphorylation. In addition to constitutive NOS1 and NOS3 and inducible NOS2, constitutively active Mt NOS localizes to the inner mitochondrial membrane, where it participates in modulating the transmembrane potential.

Nitric oxide mediates parasympathetic endothelium-dependent vasodilation in the vasculature in addition to parasympathetic control of cardiac function, guanylate cyclase supporting muscarinic agonists on the cardiac frequency, atrioventricular conduction, and myocardial contractility.

Endotheliocytes secrete nitric oxide, which not only relaxes vascular smooth myocytes and prevents platelet aggregation, leukocyte–endotheliocyte adhesion, and vascular smooth myocyte proliferation but also influences CMC contractility via β-adrenergic and muscarinic acetylcholine receptors and control cardiac substrate utilization, NOS3 concentration being much higher in endotheliocytes than CMCs [ 127 ]. Footnote 40

The chronotropic and inotropic response to β-adrenergic and muscarinic agonists is preserved in isolated cardiac tissue preparations from Nos3 −∕− mice in addition to β-adrenergic stimulation and muscarinic inhibition of Ca V 1.2a current [ 163 ]. However, NO formed in CMCs attenuates inotropic and lusitropic response to stimulation in addition to basal conditions [ 161 ]. In CMCs, NOS3 links to caveolin-3 at the plasma membrane, where it can interact with Ca V 1.2a and β AR, thereby blunting inotropic response to isoproterenol stimulation. On the other hand, NO produced by NOS1 at the CMC endoplasmic reticulum nitrosylates (activates) the ryanodine receptor [ 161 ]. In addition, NOS1 associated with NOS1-activating protein (NOS1AP) regulates cardiac frequency.

In young Nos3 −∕− and Nos3 +∕+ mice, cardiac contractibility does not differ [ 164 ]. However, CMCs from old Nos3 −∕− mice exhibit a reduced inotropic response to isoproterenol with respect to age-matched Nos3 +∕+ mice. On the other hand, CMCs of Nos1 −∕− mice display a greater contraction and slower relaxation. Therefore, constitutive NOS3 in murine ventriculomyocytes does not markedly affect the muscarinic-mediated inhibition of β-adrenergic signaling and controls neither basal nor β-adrenoceptor stimulated CMC contraction. The myocardial constitutive NOS1 isozyme is responsible for the NO-mediated autocrine regulation of myocardial inotropy and lusitropy [ 164 ].

In addition, NO contributes to the metabolism regulation. It inhibits the ETC complex- I , - II , and - IV of the mitochondrial electron transport chain [ 165 ]. Acute NOS inhibition reversibly affects cardiac substrate utilization. Cardiac uptake of lactate and glucose increases whereas that of free fatty acids decreases owing to a shift to carbohydrate oxidation, acute administration of a NO donor canceling cardiac metabolic changes [ 165 ]. Hence, NO hinders glucose uptake and supports free fatty acid consumption.

Neuregulin-1, a member of the EGF superfamily, Footnote 41 operates in the cardiovascular apparatus genesis and in the postnatal heart to regulate cardiac adaptation to stress. Nrg1 is released by the endocardial and microvascular endothelia. It binds to the receptor protein Tyr kinases HER3 and HER4 receptors, which are expressed in ventriculomyocytes [ 166 ], HER4 being the most important in the heart [ 160 ]. Nrg1 activates ERK1 and ERK2 (sarcomeric organization and protein synthesis), the Src–FAK couple (focal adhesion formation), NOS (cardiac function), and the PI3K–PKB axis (CMC survival), thereby attenuating adrenergic stimulation and hence its positive inotropic effect and enhancing lusitropy [ 160 ]. The Nrg1–HER couple also influences myocardial metabolism, provoking glucose uptake via PI3K by CMCs, and excess saturated fatty acid exposure causing Nrg resistance [ 127 , 166 ].

In response to hyperglycemia and subsequent notch activation, ECs secrete inactive latent and lysosomal-stored active forms of heparanase using ATP, both heparanase forms liberating VEGFa and VEGFb bound to heparan sulfate proteoglycans (HSPG) of the CMC surface, which represent a rapidly accessible auxiliary reservoir, to facilitate fatty acid transfer by FABP4 (Sect. 2.3.2.2 ) Footnote 42 and FATPs Footnote 43 in addition to angiogenesis [ 127 ]. On the other hand, angiogenesis is impeded the hexosamine synthesis pathway. Heparanase also interacts with LPL (or lipase-D).

Reciprocally, CMCs produce the majority of LPL, which matures owing to the lipase maturation factor LMF1 and is subsequently secreted owing to AMPK and P38MAPK that phosphorylates HSP25 [ 127 ]. Afterward, LPL momentarily attaches to syndecan-1 at the CMC surface and is then detached by heparinase, transported to the luminal endothelial surface, where it tethers to HSPGs and GPIHBP1, Footnote 44 and metabolizes the triglyceride core of lipoproteins to FAs, which are transferred to CMCs [ 127 ].

Activity of FoxO increases upon insulinemia decrease. Increased activity of cardiomyocytic FoxO1 augments plasmalemmal ScaRb3 concentration via actin cytoskeleton rearrangement[ 127 ]. Endothelial FoxO1 also restricts vascular expansion.

Chronic heart failure is associated with altered β-adrenoceptor signaling and subsequent reduced cAMP formation. Long-term sympathetic stimulation desensitizes β-adrenoceptors, reduces expression of β1AR, and upregulates that of inhibitory G-protein-coupled receptor kinases (GRKs). In addition, expression of the Gi subunit increases up to about 30% in end-stage heart failure (ESHF), shifting Gs-primed adenylate cyclase stimulation to Gi-mediated inhibition of AC via β2AR [ 171 ].

Reduced ventriculomyocytic cAMP concentration and the subsequent fall in PKA activity, coupled with augmented phosphatase activity, lower the phosphorylation of key cardiac Ca 2+ -handling proteins and subsequently Ca 2+ transient amplitude and CMC contraction efficiency (negative inotropic effect).

Among GRKs, GRK5 abounds in the myocardium; its synthesis is upregulated in heart failure [ 172 ]. This regulator of cardiac GPCRs has alternative activity in the nucleus after stress, particularly during adverse hypertrophy. On the other hand, IGF1, a mediator of adaptive cardiac hypertrophy does not induce GRK5 nuclear translocation in CMCs.

Nucleoside diphosphate kinases (NDPKs) abound at the plasma membrane of CMCs in ESHF patients. Group- I NDPKs (NDPKa–NDPKd) are enzymes. NDPKb, but not NDPKa, complexes with the Gβγ dimer and can activate cardiac G proteins independently of GPCRs [ 171 ]. NDPKc can heterohexamerize with NDPKa and NDPKb. Among isozymes, synthesis of NDPKc, which enables formation of the NDPKb–NDPKc complex and interaction between NDPK isozymes and G proteins, is upregulated in ESHF patients and in rats after long-term stimulation with isoprenaline, which elicits translocation of NDPKc to the plasma membrane [ 171 ]. In CMCs, overexpressed NDPKc raises cAMP concentration and sensitizes CMCs to isoprenaline, which augments contractility. In NDPKB −∕− mice, NDPKc production remains normal, but long-term isoprenaline exposure causes contractile dysfunction and adverse cardiac remodeling. In ESHF patients, the amount of the NDPKb–NDPKc complex rises, whereas the NDPKc–Gs interaction decays, switching G-protein activation from Gs to Gi2 and contributing to a decrease in the cAMP level. Moderate changes in the Gs/ Gi ratio can determine the G-protein subunit subtypes that tether to NDPKc [ 171 ].

Upon injury and stressor exposure, various fetal signaling pathways such as the canonical Wnt–β Ctnn signaling cascade are reactivated, priming transcription of genes implicated in cardiac fibrosis, a consequence of maladaptive hypertrophy and a major cause of HF.

The plasmalemmal receptor CDO, Footnote 45 which predominantly localizes to intercalated discs, Footnote 46 controls connexin-43 location and function. CDO counters Wnt signaling, as it interacts with the LRP6 coreceptor, preventing abnormal myocardial structure and action potential propagation [ 173 ]. Abnormal Wnt signaling is linked to Cx43 upregulated expression and mislocalization to CMC lateral sides.

1.2.4 Interrelation Between the Heart and Kidney

The cardiovascular apparatus and kidney are closely interconnected, under both normal and pathological conditions. Maintenance of the vasomotor tone and blood volume depends on interactions between blood circulation and the kidney.

Chronic kidney disease (CKD) often accelerates the evolution of CVD; conversely, cardiac dysfunction causes renal dysfunction, which is a common complication of CVD.

Renal dysfunction is an independent strong cardiovascular risk factor. The prevalence of CVD in the elderly (age≥66 yr) with CKD (∼70%) is twice that of non-CKD patients (∼35%); it is associated with a poor survival rate [ 174 ]. Footnote 47

Acute or chronic dysfunction has a bidirectional nature, each dysfunctional organ (heart and kidney) sustaining disease in the other organ. This mutual adverse interaction engenders cardiorenal syndrome (CRS), which is characterized by endothelial and vSMC dysfunction and resistance to natriuretic peptides and diuretics.

Defective renal perfusion and exacerbated vasoconstriction are associated with a persistent neurohormonal activation due to overactivity of arterial baroreceptors and intrarenal sensors and hence of the sympathetic nervous system, sympathoadrenal and renin–angiotensin–aldosterone axes, adenosine, and vasopressin, dysregulated hydroelectrolytic and calcium–phosphate balance, anemia, inflammation, and redox stress.

Furthermore, protein-bound uremic toxins (PBUTs), such as indoxyl (IS) and p-cresyl sulfate (pCS), which derive from dietary amino acid metabolites by colonic microorganisms, accumulate when renal excretion declines, form large complexes with albumin, and yield renal and cardiovascular toxicity [ 174 , 177 ]. These toxins affect the proliferation, migration, and senescence of vSMCs and ECs and provoke inflammation, calcification, and redox stress.

Calcific uremic arteriolopathy (CUA), also named calcific obliterative arteriolopathy and calciphylaxis, is typically observed in CKD patients, especially women of Caucasian ethnicity and individuals at end-stage renal disease. Footnote 48 Risk factors encompass malnutrition, insulin resistance, obesity, diabetes mellitus, alcoholic steatohepatitis, secondary hyperparathyroidism (elevated parathyroid hormone concentration), deficiency in protein-C and/or -S, and elevated activity of alkaline phosphatase, in addition to some therapies [ 179 ].

The uremic milieu predisposes to metabolic toxicity, redox stress linked to elevated concentrations of ROS, inflammation via activation of the transcription factor NFκB and the TNFSF11–TNFRSF11a axis, and vasoconstriction by increased activity of endothelin-1 [ 179 ].

The resulting arteriolopathy is associated with endothelial dysfunction, a prothrombotic state, intimal hyperplasia, fibrosis, and vascular smooth myocyte apoptosis and differentiation into osteoblast-like cells that provoke medial calcification [ 179 ].

1.2.5 Ectopic Calcification

Soft-tissue calcification (Vol. 10, Chap. 3. Adverse Wall Remodeling) results from a combination of tissue injury; exposure to sensitizing factors, such as parathyroid hormone and vitamin D; and a diet rich in calcium and phosphorus. It is triggered in a context combining hypercalcemia, hyperphosphatemia, and hyperparathyroidism, whereas activity of calcification inhibitors, such as matrix γ-carboxyglutamate acid (Gla)-containing protein (MGP) and fetuin-A, decays [ 179 ]. Hyperglycemia, hyperhomocysteinemia, hyperbeta2microglobulinemia, Footnote 49 elevated levels of oxidized low-density lipoprotein–cholesterol (LDL CS ), and low levels of high-density lipoprotein–cholesterol (HDL CS ) are additional factors that can raise ROS formation and contribute to vascular calcification.

Calcific aortic valve disease (CAVD), which evolves from mild focal valve thickening without blood flow obstruction (aortic sclerosis), thickening of the valve leaflets, and formation of calcium nodules, to end-stage calcification with impaired leaflet motion (aortic stenosis), Footnote 50 is the most common indication for surgical or transcutaneous valve therapy in the world [ 185 ].

Mutations in the genes encoding notch, LDLR, and LP A , an OxPL carrier, are linked to the risk for calcification.

Oxidized phospholipids are involved in the progression of CAVD. They are carried by apolipoprotein-B100 (ApoB100 OxPL ) and apolipoprotein A (i.e., lipoprotein-A [Apo \(_{\mathrm {A}}^{\mathrm {OxPL}}\) ]). An increased Lpa concentration is also a CoAD risk factor. It is heritable; two variants (rs10455872 and rs3798220) in the LP A gene-linked 6q26-27 locus are strongly associated with increased Lpa concentration [ 186 ]. Both ApoB100 OxPL ) and Apo \(_{\mathrm {A}}^{\mathrm {OxPL}}\) are causal CAVD risk factors [ 115 ].

1.3 Autoimmune Disorders

Giant cell arteritis (GCA; or granulomatous arteritis) is an autoimmune vasculitis, which particularly targets the temporal arteries (hence its other name temporal arteritis ). Many altered genes predispose to GCA, such as those encoding class- I and - II human leukocyte antigens, which form a gene cluster on chromosome 6, and PTPN22, NLRP1, IL17A, IL33, and LRRC32 genes; familial GCA cases exist [ 187 ].

In GCA, immunocytes, especially CD4+ effector helper T cells (T H1 and T H17 ), invade large arterial walls. Adventitial microvascular endotheliocytes control access of inflammatory leukocytes to the media and intima. In GCA patients, circulating CD4+ T cells have left the quiescent state, their activation resulting from the notch–TORC1 pathway, and differentiate into vasculitogenic T H1 and T H17 cells.

In GCA patients, expression of the notch ligand jagged-1 is upregulated in these endotheliocytes owing to increased circulating concentration of VEGF (augmented vegfemia) [ 188 ]. T lymphocytes endowed with notch-1 receive aberrant activating signals from jagged-1+ adventitial endotheliocytes.

Vessel walls are involved in inflammatory (autoimmune) disorders, such as systemic rheumatoid arthritis, disseminated lupus erythematosus, and scleroderma.

Systemic rheumatoid vasculitis results from an autoimmune inflammation of small and medium-sized vessels, which is associated with inflammation of joints.

Systemic lupus erythematosus is a connective tissue autoimmune disease that affects the skin, joints, brain, kidney, and lung, among other organs, vasculopathy being a typical element.

Scleroderma , or systemic sclerosis , is a connective tissue autoimmune disease characterized by fibrosis and vasculopathy in multiple organs. Many clinical complications arise from dysfunctional microvascular beds that cause tissue ischemia in addition to medium-sized vessels that can provoke endothelial dysfunction and pulmonary arterial hypertension, among other symptoms. Raynaud’s syndrome is a form of limited systemic sclerosis.

Raynaud’s syndrome corresponds to a transient cessation of blood flow in the fingers and toes due to a vasospasm of the digital arteries in the hands and feet. It can be triggered by either cold or emotion. This vasculopathy is linked to myofibroblast proliferation and matrix deposition in the subendothelial layer, leading to obliterative thickening of the vessel walls in addition to mononuclear infiltrates. It is characterized by cyanosis and pain due to ischemia of the sensory nerves and is more common in women. The pathophysiological process underlying abnormal vascular reactivity involves the hyperactive adrenergic nervous system, α2-adrenoceptors, central stress response, serotonin, endothelin, depressed vasodilatory response to NO, prostaglandin-G/H synthase (cyclooxygenase), the cGMP–PKG signaling cascade, and redox stress [ 189 ].

1.4 Congenital Vascular Malformations

Vascular malformations are localized defects of vascular development that usually affect a limited number of vessels in a restricted area of the body. Most malformations, which are present at birth and grow proportionately with age during childhood, result from gene mutations. Inherited new lesions can appear, but they remain small. They are either sporadic with a single lesion or characterized by multifocality in familial forms [ 190 ]. Familial vascular malformations follow a paradominant inheritance. Sporadic forms are caused by somatic mutations in the same genes (Tables 1.11 and 1.12 ). Major mediators involved in anomalies of blood and lymph vessels and their pathways are given in Table 1.13 .

1.4.1 Classification of Congenital Vascular Malformations

Congenital vascular malformations (CVMs) are categorized by the Mulliken classification into high- and low-flow lesions. The Hamburg classification distinguishes vascular malformations according to their predominant histological components (lymphatic, arterial, and/or venous). Arterial and venous CVMs are composed entirely of arteries and veins, respectively. Arterial defect is related to the absence of development of an arterial segment, which is thus missing, the irrigated organ being perfused by a collateral artery, which does not wither. Venous defects form thin-walled venous lakes or grape-like clusters of lakes.

Congenital vascular malformations are also formed when arteriovenous shunts persist. They include a single pair of vessels ( arteriovenous fistulas [AVFs]), or a cluster of vessels ( arteriovenous malformations [AVMs]). Truncular lesions arise from disturbances in late embryonic angiogenesis from the normal vasculature, whereas extratruncular lesions derive from the early development stage without direct connection with the normal vasculature.

Cerebral (CeAVMs) and peripheral arteriovenous malformations (PAVM) are congenital localized defects caused by altered embryonic angiogenesis that can affect the arterial, venous, and lymphatic circuits. Most AVMs are localized. Multiple AVMs are very rare lesions but can cause numerous hemorrhagic episodes. Multifocal AVMs can be observed in autosomal dominant disorders, such as hereditary hemorrhagic telangiectasia , that is, dilation of the microvasculature (microaneurysms, or telangiectasia) with bleedings in the skin and mucosae, and capillary malformation–arteriovenous malformation syndrome (CMAVM). CMAVM is characterized by small round spots of enlarged capillaries in the dermis, most often on the face, arms, and legs.

Capillary malformations can be associated with arteriovenous malformations and fistulas. Type- I CMAVM is caused by mutations in the RASA1 gene, which encodes the RasGAP RasA1. Type- II multifocal CMAVM is engendered by mutations in the EPHB4 gene that encodes the receptor protein Tyr kinase ephrin type-B receptor EPHb4, which is involved in contact-dependent bidirectional signaling between apposed cells [ 195 ]. It is implicated in cardio- and angiogenesis and in postnatal angiogenesis and vascular remodeling. Therefore, the EPHb4–Ras–ERK pathway is a major axis for AVMs.

Ephrin binds to the erythropoietin-producing hepatocyte (EPH) receptors on the surface of the apposed cell and triggers EPH aggregation, fostering EPH transphosphorylation (transactivation). Polymerization of the receptor is first carried out by assembling monomers (6–8) into active oligomers (activation phase) that then condensate into large clusters (hundreds of monomers), which dampens signaling (inactivation phase), thereby creating a fast and transient response [ 196 ]. The polymerization–condensation model states that the coalescence of oligomers into large aggregates reduces the recruitment of free monomers, as it accelerates formation of large-scale, slowly diffusing clusters and subsequent primes receptor endocytosis and signaling termination.

Arteriovenous malformations are characterized by a reduced flow resistance. These shunts connect high- to low-pressure vascular compartment, bypassing the capillary bed. Resulting arterial steal and venous hypertension depends on the lesion type and architecture.

Cirsoid AVM , the most common type (size> 1 cm), consists of multiple dilated feeding arteries and draining veins, which have a tortuous shape, hence with multiple arteriovenous connections [ 197 ]. It is adjacent to the collecting circuit.

Angiomatous AVM (size< 1 cm) is composed of a single artery feeding multiple interconnecting distal branches and draining veins.

Aneurysmal AVM consists of a single feeding artery and a single draining vein with dilation (diameter> 1 cm), which resembles an acquired fistula.

Yakes’ AVM classification defines:

Type- I anomalies, which connect a single artery to a single vein without a vascular nidus

Type- II lesions, which link many arteries directly to veins and indirectly via arterioles and venules, which form a relatively simple network

Type- III malformations, which associate many arteries via arterioles to a dilated segment, which gives birth to a single or many veins

Type- IV anomalies that connect arteries and veins via a complicated arteriolovenular network [ 198 ]

Coronary arteries can communicate with the cardiac chambers (coronary–cameral fistulas) or veins (coronary arteriovenous malformations).

An arteriovenous fistula is an abnormal single direct passage from artery to vein. In addition to congenital fistulas, those acquired after birth are caused by infections, degeneration, trauma, or iatrogenic interventions (e.g., during angiography, biopsy, bypass grafting, and pacemaker implantation). Congenital arteriovenous malformation and acquired AVFs are rare causes of secondary hypertension.

1.4.2 Venous Malformations

Venous malformations (VMs) includes sporadic and cutaneomucosal (or mucocutaneous) VMs (CMVMs), and glomuvenous malformations (GVM) [ 190 ]. Multiple inherited venous lesions are identified in venous, glomuvenous, and cerebral cavernous malformations.

Sporadic venous malformations are bluish or violaceous, solitary or multiple, localized or diffuse, superficial or deep lesions most often on the head and neck [ 113 ]. Venous malformations evolve slowly and progressively in the absence of bleeding. Thrombi and calcifications ( phleboliths ) can occur in tortuous veins. Venous nevus , or nevus venosus, is a variant of sporadic venous malformations.

Blue rubber bleb nevus Footnote 51 is a sporadic syndrome (BRBNS; also called Bean syndrome) Footnote 52 characterized by cutaneous and gastrointestinal VMs of various numbers, sizes, and locations. It can be caused by mutations in the TEK ( Tie2) gene. Nevi in the intestine can bleed spontaneously, provoking anemia. Families follow autosomal dominant inheritance but in fact have other multifocal venous malformations.

Hemangiomatosis chondrodystrophica , also termed dyschondrodysplasia with hemangiomas, enchondromatosis with multiple cavernous hemangiomas, and Maffucci syndrome, primarily affects the bone and skin. It is characterized by multiple enchondromas (cartilage enlargements), bone deformities, and hemangiomas (tangles of abnormal blood vessels [benign tumors]). IDH is caused by mutations in the Idh1 or Idh2 gene, which encode NADP + -dependent IDH1 and IDH2, respectively.

Klippel–Trenaunay–Weber syndrome (KTWS) is a disorder pertaining to the PIK3CA gene-related overgrowth spectrum (PROS), which also includes megalencephaly capillary malformation and polymicrogyria syndrome (MCAP) and congenital lipomatous overgrowth, vascular malformations, epidermal nevi, and skeletal/spinal abnormalities (CLOVES) syndrome, hemimegalencephaly, fibroadipose hyperplasia, and epidermal nevus. It affects the development of blood vessels, engendering varicose veins and malformations of deep veins in the limbs, and causes overgrowth of soft tissues and bones. It results from mutations in the PIK3CA gene, which encodes PI3K c1 α .

1.4.2.1 Cutaneomucosal Venous Malformations

Cutaneomucosal venous malformations (in the skin and mucosae) commonly infiltrate underlying muscle and joints [ 190 ]. Although mostly sporadic (∼98% cases), CMVMs obey autosomal dominant inheritance.

They are caused by mutations in the TEK gene located in the VMCM1 locus on chromosomal locus 9p21.22 (e.g., single-nucleotide polymorphisms R849W and Y897S), which encodes the endothelial-specific receptor protein Tyr kinase TIE2 [ 190 ]. Footnote 53 These gain-of-function (GOF) mutations (e.g., C2545T in exon 15, A2690G, G2744A, C2752T, G2755T, and G2773T in exon 17, and G3300C in exon 22 [ 201 ]) increase ligand-independent autophosphorylation of TIE2 without launching endotheliocyte proliferation.

Three TIE2 ligands include angiopoietins AngPt1, AngPt2, and AngPt4 (the latter corresponding to mouse AngPt3). AngPt1 has a stronger effect than competitive AngPt2, which is considered to be a AngPt1 inhibitor. Once it is liganded, TIE2 dimerizes and cross-phosphorylates, triggering mainly the MAPK module and PI3K pathway, which activates PKB and inhibits apoptosis.

1.4.2.2 Glomuvenous Malformations

Glomuvenous malformations are usually nodular multifocal lesions located on the extremities that involve the skin and subcutis, occasionally the mucosa [ 190 ]. They are characterized by abnormally differentiated vSMCs (glomus cells) in the walls of distended veins.

These autosomal dominant disorders are caused by loss-of-function (LOF) mutations in the GLMN gene on chromosomal locus 1p21-22, which encodes glomulin , an essential protein for vasculature development. Glomulin is a ligand of the immunophilins FKBP1a and FKBP4, hence its other name, FKBP-associated protein. Glomulin synthesis is restricted to vSMCs; it is involved in their differentiation [ 190 ].

Differentiation of vSMCs also depends on TGFβ, which competes with glomulin to bind Tβ R1; glomulin thus precludes TGFβ signaling. Conversely, lack of glomulin provokes TGFβ hyperactivity.

Glomulin also interacts with HGFR; upon HGF binding, glomulin is phosphorylated and released and triggers phosphorylation of S6K, thereby influencing protein synthesis.

As it also interacts with Cul7, glomulin can also control protein degradation via ubiquitination by the CRL7 complex.

1.4.3 Capillary Malformations

Capillary malformations (CapMs) form cutaneous lesions most frequently located in the head and neck. These slow-flow vascular malformations can comprise arterioles and postcapillary venules. Except for birthmarks, capillary malformations do not have a predilection for gender [ 113 ]. They are generally sporadic, but familial cases can be observed.

Megalencephaly capillary malformation syndrome , or macrocephaly (megalocephaly) cutis marmorata telangiectatica congenita, a rare, sporadic congenital capillary malformation, associates overgrowth of organs (megalencephaly) and cutaneous capillary malformations. These malformations are most often unilateral on the lower limbs. Enlarged capillaries augment blood flow near the skin surface. They can disappear spontaneously after several months or years, but they occasionally persist throughout life. This disorder is caused by mutations in the PIK3CA gene on chromosomal locus 3q26.

PTEN hamartoma tumor syndrome (PHTS) refers to a spectrum of disorders characterized by multiple hamartomas, Footnote 54 which are often intramuscular, multifocal, and associated with ectopic lipid depots. This spectrum includes (1) Cowden and Cowden-like syndrome involving mutations in the PTEN, SDHB, SDHD, and KLLN genes, which encode PTen, succinate dehydrogenase subunits B and D, and killin, respectively; (2) Bannayan–Riley–Ruvalcaba syndrome , characterized by macrocephaly and hamartomas of the intestine (hamartomatous intestinal polyps) resulting from mutations in the PTEN gene or partial or complete deletion of this gene; and (3) Proteus and Proteus-like syndrome , Footnote 55 which is characterized by usually asymmetrical overgrowth of the bones, skin, and other organs and results from a mutation in the AKT1 (Pkb1) gene on chromosomal locus 14q32.3.

Familial multiple nevi flammei is caused by mutations in the GNAQ gene, which encodes guanine nucleotide-binding (G) protein subunit Gα q . Nevi flammei (nevus flammeus neonatorum) correspond to birthmarks. These non-elevated, sharply circumscribed patches fade progressively.

Salmon patches on the forehead, eyelids, and neck, in addition to the back, legs, and arms, also termed angel kisses , when erythematous macules typically affect the glabella, but also eyelids, nose, upper lip, and sacral region, and stork bites , when observed in the back of the neck, are picturesque names that depict very common birthmarks. A port wine stain (nevus flammeus) is a cutaneous firemark due to an abnormal aggregation of capillaries, the color of which (pink to purple macules) resembles port wine, the most common location being the face.

Nevus comedonicus is a rare type of epidermal nevus with predilection for the face and neck caused by mutations in the NEK9 gene Footnote 56 on chromosomal locus 14q24.

Nevus anemicus is a nonhereditary congenital disorder characterized by irregular hypopigmented macules that coalesce to form plaques, which are generally present at birth or develop in the first postpartum days. They localize especially on the chest. This disorder results from sustained vasoconstriction due to vascular hypersensitivity to catecholamines and not to partial aplasia of dermal blood vessels [ 113 ].

Nevus roseus is characterized by a pale red or even pink color; hence, its other name “rosé wine stain.” It remains unchanged during life [ 113 ].

Phacomatosis pigmentovascularis associates a vascular nevus and extensive pigmentary nevus. It is categorized into five groups according to the pigmentary anomaly [ 113 ]: type I corresponds to nevus flammeus and pigmented linear epidermal nevi; type II to nevus flammeus, Mongolian spots, and/or nevus anemicus; type III to nevus flammeus and spilus and/or anemicus; type- IV to nevus flammeus, Mongolian spots, and nevus spilus and/or anemicus; and type V to cutis marmorata telangiectatica congenita and Mongolian spots. This classification was later simplified into phacomatosis cesioflammea (i.e., nevus cesius [blue spot] and flammeus) and spilorosea (i.e., nevus spilus and roseus).

Capillary malformation–arteriovenous malformation syndrome (CMAVM) results from mutations in the RASA1 gene, which encodes the Ras GTPase-activating protein (RasGAP) RasA1 (also aliased as CMAVM) [ 190 ].

Sporadic and autosomal dominant angioma serpiginosum (AS) is a benign cutaneous disease characterized by a progressive dilation of the subepidermal vessels manifesting as clusters of punctate erythematous lesions, usually on the lower limbs. It can be considered a type of capillary nevus. It occurs almost exclusively in women. It results from mutations in the chromosomal locus Xp11.3–Xq12.

1.4.4 Lymphatic Malformations

Two categories of lymphatic malformations (LMs) affect the skin: lymphedema and congenital, superficial or deep, solitary or multiple lymphatic malformations. Lymphatic malformations are localized dilated lymphatic channels or pseudo-vesicles (lymphangiectasias) that are not connected to the lymphatic circuit.

Cystic lesions are macro- (formerly called cystic hygromas) or microcystic, or mixed. Microcystic lymphatic malformations are also termed lymphangioma, lymphangioma circumscriptum or simplex, verrucous hemangioma, and angiokeratoma circumscriptum [ 113 ]. Macrocystic lymphatic malformations lodge in the neck, axillas, or lateral edges of the trunk. They can be solitary or multiple, and can be interconnected.

Lymphedema , that is, chronic swelling in the body, usually in the lower extremities, due to abnormal lymphatic vessels, can be primary or secondary. Primary lymphedema comprises various types (Lmph1A–Lmph1D), which are linked to the chromosomal region 5q35, 6q16.2–q22.1, 1q42, and 4q34 [ 194 ].

Type- I A hereditary lymphedema (Lmph1A), also named primary congenital lymphedema (PCL) and Milroy disease, most commonly affects the inferior limbs, from the feet up to the knees. This autosomal dominant disorder is caused by missense mutations in the FLT4 gene, which encodes VEGFR3 [ 190 ].

Type- I B hereditary lymphedema (Lmph1B) is caused by anatomical or functional defects in the lymphatic circuit. It usually appears at birth or in early childhood but can occur later [ 194 ].

Type- I C hereditary lymphedema (Lmph1C) can be governed by autosomal dominant inheritance of heterozygous mutations in the GJC2 gene that encodes gap junction protein-γ2, or connexin Cx46.6 or Cx47 [ 194 ].

Type- I D hereditary lymphedema (Lmph1D) is engendered by heterozygous mutations in the VEGFC gene, the transmission pattern being consistent with autosomal dominant inheritance [ 194 ].

Type- II late-onset lymphedema (Lmph2), also called Meige’s disease and lymphedema praecox, develops around puberty. It involves the upper and lower limbs, face, and larynx and can provoke a persistent pleural effusion. It can result from truncating and some missense mutations in the FOXC2 gene situated in the chromosomal locus 16q24.3 [ 190 ].

Hypotrichosis–lymphedema–telangiectasia syndrome (HLTS) is characterized by lymphedema and cutaneous telangiectasias. Both autosomal dominant and recessive inheritance can be observed [ 190 ]. Dominant and recessive forms are caused by mutations in the SOX18 gene, which encodes the transcription factor Sox18, an early marker of lymphatic differentiation. Sox18 interacts with MEF2c and regulates synthesis of vcam1.

Osteoporosis lymphedema anhydrotic ectodermal dysplasia with immunodeficiency syndrome (OLEDAID) is engendered by mutations (e.g., X420W) in the IKBKG gene that encodes Iκ BKγ, which reduces NFκB activation [ 190 ]. Footnote 57

Lymphedema–cholestasis syndrome (LCS), also termed Aagenaes syndrome, is most often an autosomal recessive disorder, although an autosomal dominant mutation may be involved [ 190 ].

1.4.5 Endothelial Signaling in Vasculo- and Angiogenesis

Vasculo- (i.e., de novo blood vessel formation involving differentiation and migration of endothelial precursors), angio- (i.e., development of new blood vessels by capillary sprouting from preexisting vessels), and lymphangiogenesis construct (1) the vascular closed circuit, which is formed from arteries downstream from the heart, capillaries perfusing the body’s tissues, and veins upstream from the heart and (2) vascular walls, which are composed of vECs and mural cells (vMCs). The proper structure of blood and lymph vessels consists of a single layer of endotheliocytes surrounded by pericytes or a variable number of layers of vascular smooth myocytes separated by elastic laminae in the micro- (i.e., capillaries and upstream lymphatics) and macrovasculature, respectively. Correct organization of the vascular circuit requires the controlled activities of multiple types of messengers that regulate vessel formation, vascular branching, elongation and pruning, capillary fusion, vascular stability and anastomosis, and arterial and venous differentiation of endotheliocytes, which segregates arteries from veins.

Vascular development and maintenance are controlled by a transcriptional program that integrates both extra- and intracellular signals in endotheliocytes.

Vasculo- and angiogenesis are controlled by numerous signaling cascades in addition to hemodynamic stress. The initiation and formation of new blood vessels, that is, sprouting angiogenesis, is mainly regulated by the messengers VEGFa and notch.

Angiogenesis is orchestrated by endothelial tip cells that form the vascular front and are followed by proliferating stalk cells. Tip cells sense multiple extracellular pro- and antiangiogenic signals and migrate toward the hypoxic region.

In mice and cardiac organ culture, coronary vessels arise from angiogenic sprouts of the sinus venosus, that is, the vein returning blood to the embryonic heart [ 202 ]. Sprouting venous endotheliocytes thus dedifferentiate as they migrate over and invade the myocardium. Intramyocardial ECs then redifferentiate into arterial and capillary cells, whereas epicardial ECs redifferentiate into venous cells.

Endotheliocyte differentiation into arterial and venous cells is genetically controlled for both vessel types. It precedes the onset of blood circulation. Arterial and venous angioblasts segregate from the beginning of vasculogenesis [ 203 ]. Acquisition of arterial identity is governed by a set of messengers (e.g., notch [Sect. 1.4.5.1 ], SHh [Sect. 1.4.5.3 ], and VEGF [Sect. 1.4.5.4 ]). Acquisition of venous phenotype relies on the nuclear receptor NR2f2 that suppresses notch signaling [ 203 ]. Ephrins and their receptors (e.g., the transmembrane ligand ephrin-B2 and its cognate receptor EPHb4 [Sect. 1.4.5.5 ]) are also involved in the establishment of arterial and venous identity.

Susceptibility to certain vasculopathies differs between arteries and veins. The intracellular receptor NR2f2 is involved in regulating pathophysiological processes in adult blood vessels [ 204 ]. It acts as an antiatherogenic and -osteogenic agent that downregulates formation of inflammatory factors, upregulates that of antithrombotic agents, and represses osteogenic transcriptional program and endothelial-to-mesenchymal transition. It also regulates the TGFβ pathway, as it controls production of TGFβ2 and BMP4, which support conversion of endotheliocytes into mesenchymal stem cell-like cells and undergo osteogenic differentiation.

1.4.5.1 Notch, FoxC, SoxF, and NR2f2

The notch receptor (notch-1–notch-4) binds one of its ligands, jagged proteins (Jag1–Jag2) and delta-like ligands (DLL1–DLL3). In mouse early embryo at least, Jag1, Jag2, and DLL4 are specifically expressed in arterial endotheliocytes.

Notch cleavage releases the notch intracellular domain (notch ICD ) into the cytosol. Notch ICD associates with RBPJκ, Footnote 58 a DNA-binding protein and transcriptional repressor in the absence of notch signaling, and Mastermind (Mam), a transcriptional coactivator. Notch ICD translocates to the nucleus, where it interacts with RBPJκ and converts it to a transcriptional activator, priming synthesis of basic helix–loop–helix (bHLH) transcription factors HESs Footnote 59 and HRTs. Footnote 60 In zebrafish at least, notch signaling acts downstream of the SHh and VEGF pathways in arterial specification.

Notch-1 and notch-4 are essential for maintaining vessel identity. Notch signaling overcomes activin receptor-like kinase (ALK1) loss, as it restores EfnB2 expression in endotheliocytes. Notch signaling is also implicated in tip-to-stalk cell conversion (Vol. 5, Chap. 10. Vasculature Growth, and Vol. 10, Chap. 2. Vascular Growth and Remodeling).

In endotheliocytes of mouse and zebrafish embryos, SOXF Footnote 61 proteins act in synergy with RBPJκ [ 207 ]. They function upstream from notch signaling. Sox17 activates notch signaling, as it tethers to promoters of multiple genes involved in the notch pathway.

Three SOXF genes, SOX7, SOX17, and SOX18, encode transcription factors of the SOXF group, which are expressed in vascular endotheliocytes during blood circulation development, whereas only Sox18 is involved in lymphangiogenesis [ 208 ]. Sox7 and Sox18 cooperate in the specification of arterial and venous identity.

Single nucleotide polymorphisms at the SOX17 chromosomal locus can engender intracranial aneurysms.

High concentrations of VEGF stimulate production of delta-like ligand DLL4 by tip cells, which activates notch on adjacent endotheliocytes to confer stalk cell identity. In adult venous endotheliocytes, VEGFa inhibits formation of EPHb4, a venous marker, and stimulates that of DLL4, an arterial marker.

Whereas DLL4 is involved in initiating the arterial program, DLL1 is required for the maintenance of arterial identity. In mouse embryos, DLL1 formation is restricted to arterial endotheliocytes after embryonic day 13 [ 208 ]. VEGF controls notch signaling, which is activated by DLL1, notch regulating neuropilin-1 (Nrp1) synthesis.

Among transcription factors of the forkhead box group implicated in cardiovascular system development, members of the FOXC subgroup, FoxC1 and FoxC2, which are expressed in both arteries and veins of the mouse embryo, play an overlapping role. They contribute to regulating the formation of arterial-specific genes (e.g., Dll4 and Hrt2) and vascular remodeling of primitive blood vessels. They directly activate the Dll4 gene transcription using a FoxC-binding element (FBE), upstream of notch signaling [ 208 ].

In FOXC1 +∕− and FOXC2 −∕− mice, AVMs form and their endotheliocytes fail to express DLL4, and expression of other arterial markers (notch-1, notch-4, Jag1, HRT2, and EfnB2) declines [ 209 ]. Although FoxC1 and FoxC2 are required for DLL4 synthesis, deletion of the forkhead-binding element on the Dll4 promoter does not attenuate Dll4 gene transcription by the FoxC factors, notch1 ICD and notch4 ICD using the RBPJ-binding site. As FoxC2 and notch ICD act synergistically on the Hrt2 gene promoter, FoxC and notch ICD may also cooperate on the Dll4 gene promoter [ 209 ].

In endotheliocytes, FoxC1 and FoxC2 control expression of HRT2, the Hrt2 promoter containing two FBEs [ 208 ]. In addition, Foxc2, but not FoxC1, binds to the RBPJ (or Csl) gene promoter. Foxc2 complexes with CSL and notch ICD to launch HRT2 synthesis. Production of DLL4 and HRT2 by FoxC is enhanced by VEGF in endotheliocytes.

The genetic determinant of venous specification, NR2f2, is specifically expressed in venous endotheliocytes and acts upstream from EPHb4 in mice, impeding Nrp1 and notch formation. However, it cooperates with other factors for venous cell fate determination [ 208 ]. Furthermore, it interacts with Prox1 to launch lymphatic gene expression.

Notch regulates responsiveness of endotheliocytes to BMP2 and BMP6 via inhibitory SMAD6, which is involved in neovessel branching formation [ 210 ].

The notch- and ALK1-mediated signaling cascades interact and can partly compensate for each other. Sequestration of BMP9 and BMP10 and subsequent ALK1 inhibition and notch blockage engender a hyperfused and hypersprouting vascular plexus in a neonatal mouse retina model [ 209 ]. SMAD1/5/8 binding sites exist in the regulatory region of many notch-targeted genes (e.g., HES1 and HRT1–HRT2).

1.4.5.2 Wnt and Sox

Wnt signaling regulates multiple biological processes, such as angiogenesis, inflammation, and tumorigenesis. Wnt morphogens are secreted by cysteine-rich palmitoylated glycoproteins that play an essential role in cell fate determination, tissue homeostasis, and embryo- and fetogenesis.

Canonical Wnt signaling elicits vascular invasion into the central nervous system [ 207 ]. Messengers Wnt and norrin target the receptor frizzled, coreceptors LRP5 and LRP6, coactivators tetraspanin-12 and GPR124, and effector β-catenin. In the absence of any of these Wnt signaling mediators, vascular cerebral network formation aborts, despite the high VEGF concentration produced by the hypoxic organ.

Norrin (or Norrie disease protein), a homodimeric secreted cysteine-rich and cystine knot-like Footnote 62 growth factor produced from a precursor encoded by the NDP gene, is an atypical Wnt ligand. It activates the canonical Wnt signaling pathway via Fzd4 and LRP5, acting in cooperation with TSpan12 to activate Fzd4, independently of Wnt [ 207 ]. Norrin mimics Wnt, as it can tether and activate frizzled via assembly of a molecular platform consisting of Fzd4, its LRP5–LRP6 coreceptor complex, auxiliary TSpan12, and associated HSPG [ 211 , 212 ]. It then launches the Ctnnβ1—LEF/TCF axis. Norrin maintains the blood–retina and blood–brain barriers and regulates angiogenesis in the eye, ear (cochlea), brain, and female reproductive organs (uterus) [ 211 ]. In addition, norrin connects to secreted frizzled-related proteins (sFRPs).

In retinal arterioles, capillaries, and veins, Sox17 production depends on frizzled-4 and norrin [ 207 ]. Members of the SOXF group participate in regulating the development of the blood and lymph vasculature in addition to arterial and venous identity (i.e., vascular differentiation), remodeling, and maintenance in a functionally redundant fashion (strong, but partial redundancy), compensating for defective activity of any SOXF factor. Each SOXF factor exhibits a distinct pattern of production among the different classes of retinal blood vessels [ 207 ]. Sox7 and Sox18 have a similar temporal expression pattern. They are mainly produced in endothelia at the very early stages of endothelial differentiation, but their synthesis is differently regulated [ 203 ]. They also localize to distinct vessels in zebrafishes [ 213 ].

Both Sox7 and Sox18 are dispensable for the initial specification and positioning of the major trunk vessels. On the other hand, Sox17 is mainly formed during gastrulation [ 203 ]. All three SOXF group members are coexpressed in vascular endotheliocytes. Members of the SOXF group are reciprocally regulated in the developing blood vasculature.

In mice, Sox17 and Sox18 act redundantly in postnatal angiogenesis; Sox7 and Sox18 present an overlapping expression pattern [ 213 ]. Sox7, Sox17, and Sox18 are functionally redundant in the developing mouse retinal vasculature (cell differentiation and vessel growth) and maintenance of the mature vasculature [ 207 ]. Vascular endothelial-specific deletion of a single SOXF member gene has little or no effect on vascular architecture or differentiation because of the overlapping function of Sox7 and Sox17 and the reciprocal regulation of gene expression. Combined deletion of Sox7, Sox17, and Sox18 at the onset of retinal angiogenesis leads to a dense capillary plexus, with a nearly complete loss of radial arteries and veins, whereas the presence of a single Sox17 allele largely restores arterial identity with vSMC coverage. Indeed, Sox17 plays a major role in vSMC coverage of radial retinal arteries. In the developing retina, expression of all three SOXF genes is reduced in the absence of canonical Wnt signaling mediated by norrin and frizzled-4 but remains unaffected by reduced VEGF signaling after deletion of the NRP1 gene. In adulthood, Sox7, Sox17, and Sox18 also have redundant functions in blood vessel maintenance. At adulthood onset, vascular endothelial-specific deletion of all three SOXF genes causes massive edema, despite nearly normal vascular architecture.

The production of the endothelial adhesion G-protein-coupled receptor GPR124, also named tumor endothelial marker TEM5, Footnote 63 is upregulated in endotheliocytes during physiological and tumoral angiogenesis. Its synthesis is induced by Rac during capillary network formation [ 214 ], and it prevents endotheliocyte proliferation.

1.4.5.3 Hedgehog

Secreted sonic hedgehog signals via the transmembrane receptor patched (Ptc) and G-protein-coupled receptor smoothened (Smo) on recipient cells. It can induce arterial cell fate in zebrafish angioblasts. Zebrafish embryos lacking SHh lose arterial expression of ephrin-B2, as it generates formation of VEGF, which, in turn, activates notch [ 208 ].

In mice, defective Shh signaling does not cause severe vascular defects, although vascularization is attenuated in the developing lung and formation of the dorsal aorta and remodeling of the yolk sac vasculature are altered. Murine SHh signaling may be dispensable for arterial and venous specification.

1.4.5.4 Vascular Endothelial Growth Factor

In angiogenesis, the specification of tip and stalk cells relies on VEGF. Relatively high VEGF concentrations provoke DLL4 synthesis in tip cells, which activates notch signaling on adjacent endotheliocytes, thereby conferring stalk cell identity (Vol. 10, Chap. 2. Vascular Growth and Remodeling).

In mice, lower-molecular-weight isoforms, diffusible VEGFa 120 and intermediate VEGFa 164 are required for arterial development in the retina, rather than VEGFa 188 [ 208 ].

Neuropilin-1, a VEGFa 164 coreceptor, cooperates with VEGFR2 to trigger signaling. In mice, when Nrp1 activity is defective, arterial differentiation is impaired.

Vascular endothelial growth factor triggers the PI3K pathway and induces synthesis of notch-1 and DLL4, the VEGF–DLL4–notch–HRT2 cascade promoting arterial cell determination [ 208 ]. It modulates FoxC activity, and this modulation depends on the balance between PI3K and ERK activity. Relatively high VEGF concentrations (∼50 ng/ml) induce arterial marker genes, whereas lower VEGF concentrations (≤10 ng/ml) upregulate expression of the venous marker NR2f2; according to its level, VEGF signaling may preferentially activate either the PI3K or ERK pathway [ 208 ].

The protein Tyr phosphatase receptor, PTPRJ, is involved in arterial specification. It interacts with VEGFR2-primed signaling in endotheliocytes [ 208 ].

The calcitonin receptor-like receptor (CalRLR) is a G-protein-coupled receptor for adrenomedullin, which is coordinated with the VEGF and notch pathways in arterial differentiation in mouse embryos. CalRLR is expressed in the somite and arterial progenitors of zebrafish upon VEGF exposure, VEGF activity being regulated by SHh [ 208 ]. CalRLR supports arterial gene expression such as ephrin-B2 and notch-5.

Neuropilin-2 is expressed in venous and lymphatic endotheliocytes [ 208 ]. VEGFR3, which is initially detected in blood vessels of the early embryo, later becomes restricted to venous and then lymphatic endotheliocytes.

The VEGFR3 ligand, VEGFc, is mainly expressed in mesenchymal cells surrounding embryonic veins [ 208 ]. Prox1+ VEFR3+ lymphatic endothelial progenitors subsequently bud and migrate from veins using paracrine VEGFc–VEGFR3 signaling, initiating developmental lymphangiogenesis.

Hence, a subpopulation of venous endotheliocytes progressively synthesize the transcription factors Sox18 and Prox1 and acquire a lymphatic endothelial phenotype. Sox18 is first detected in a subpopulation of the cardinal vein and precedes the onset of Prox1 synthesis [ 208 ]. Sox18 induces Prox1 expression using two Sox18-binding sites on the Prox1 promoter. Sox18 is indispensable for induction of lymphatic differentiation but dispensable for lymphatic phenotype maintenance. Prox1 is a master regulator of lymphatic endothelial identity that elicits expression of lymphatic markers, such as VEGFR3 and lymphatic vessel endothelial hyaluronan receptor LyVE1. Moreover, Prox1 controls migration of lymphatic endotheliocytes triggered by VEGFc, as it cooperates with NR2f2 to prime synthesis of FGFR3, VEGFR3, and integrin-α 9 [ 208 ].

FoxC1 and FoxC2 may contribute to regulating lymphatic vessel development, pericyte recruitment to lymphatic vessels, and lymphatic valve formation in a paracrine manner [ 208 ].

1.4.5.5 Ephrin-B2 and Its EPHb4 Receptor

The protein Tyr kinase receptor EPHb4 and its primary transmembrane ligand ephrin-B2 (EfnB2) are exclusively expressed on venous and arterial endotheliocytes, respectively (Table 1.14 ). They support but are not mandatory for arterial and venous specification.

Expression of EfnB2 and EPHb4 is distinctively detected in the primary vascular plexus before the onset of circulation in the developing embryo [ 208 ]. Arterial–venous identity is genetically predetermined, although it is influenced by hemodynamic forces that enable remodeling and EC phenotype change.

Bidirectional signals mediated by both proteins play an important role in vascular development. EfnB2 and EPHb4 are differentially expressed in arterial and venous endotheliocytes of the mouse embryo and thus considered to be markers of arterial and venous identity during embryogenesis. EfnB2 forward signaling via EPHb4 (EfnB2–EPHb4 axis) prevents cell adhesion and migration and suppresses cell proliferation, whereas EPHb4 reverse signaling via EfnB2 (EPHB4–EfnB2 axis) elicits cell attachment and migration [ 215 ].

The EfnB2–EPHb4 is involved in embryonic vascular circuit development, vascular remodeling, in addition to neovascularization, arteriovenous differentiation, and tumoral angiogenesis in adults. In hemorrhagic (hCeAVMs) and nonhemorrhagic cerebral arteriovenous malformations (nhCeAVMs), veins and arteries are coated by EPHb4+ and EfnB2+ endotheliocytes, respectively, EPHb4 and EfnB2 content being larger in hCeAVMs than in nhCeAVMs, whereas endotheliocytes of the normal superficial temporal artery express neither EPHb4 nor EfnB2 [ 216 ].

Arterial specification relies on VEGF that induces expression of notch and DLL4, the transcription factors FoxC1 and FoxC2 regulating DLL4 synthesis [ 208 ]. Notch stimulates HRT1 and HRT2, promoting arterial differentiation.

On the other hand, the nuclear receptor NR2f2 is a determinant for venous specification, as it hampers expression of arterial specification genes, such as Nrp1 and notch [ 208 ].

A subpopulation of venous endotheliocytes progressively express the transcription factors Sox18 and Prox1, thereby acquiring lymphatic fate and differentiating into lymphatic endotheliocytes [ 208 ].

A mutual coordination of size between developing arteries and veins establishes a functional vasculature. The size of the developing dorsal aorta and cardinal vein is reciprocally balanced in mouse embryos. Gain-of-function notch mutations engender enlarged aortas and small cardinal veins, whereas LOF mutations show small aortas and large cardinal veins [ 217 ].

The dorsal aorta emerges before the cardinal vein via the assembly of endotheliocytes into the dorsal aorta primordium, a transient capillary plexus. Remodeling of this primitive structure generates the dorsal aorta. The cardinal vein appears slightly later, at a stage during which transient capillaries develop between the dorsal aorta and cardinal vein. Ephrin-B2 is specifically expressed in arterial endotheliocytes before the onset of blood circulation, but does not determine arterial specification of endotheliocytes [ 217 ]. Notch controls the proportion of endotheliocytes in the dorsal aorta and cardinal vein, as it promotes arterial specification and regulates both artery and vein size. Interdependence between arterial and venous size relies on a balanced allocation of endotheliocytes between these vessel types. Notch regulates endotheliocyte allocation, because it determines arterial specification and hence the ratio of arterial to venous endotheliocytes.

Loss of EfnB2 or EPHb4 also leads to enlarged aortas and small cardinal veins. However, endotheliocytes with venous identity mislocalize in the aorta. EfnB2–EPHb4 signaling may operate distinctly from notch, sorting arterial and venous endotheliocytes into their respective vessels.

Arterioles and venules are covered by EPHb4+ endotheliocytes. EPHb4+ capillaries of sprouts contain a significantly higher EphB4 amount than capillaries connecting arterioles and venules [ 218 ]. Hence, EPHb4 is not an arterial- or venous-specific marker in adult rat microvasculature but rather an indicator of capillary sprouting.

1.4.5.6 Transforming Growth Factor- β Group

Members of the transforming growth factor-β superfamily and among them, bone morphogenetic proteins, play an essential role in embryo- and fetogenesis and in the maintenance of organ function. Altered signaling in endotheliocytes by members of the TGFβ and BMP group causes diffuse malformations. Aortic aneurysms also arise from deregulated TGFβ/ BMP signaling.

The TGFβ signaling cascades involve:

Numerous messengers, three TGFβ subtypes (TGFβ1–TGFβ3), BMPs, growth differentiation factors (GDFs), activins, nodal, and inhibins.

7 type- I receptors ( ALK1–ALK7), ALK5 corresponding to Tβ R1, ALK3 and ALK6 to BMPR1a and BMPR1b, and ALK2, ALK4, ALK7, and ALK1 Footnote 64 to AcvR1a to AcvR1c and AcvRL1, respectively.

5 type- II receptors (Tβ R2, BMPR2, AcvR2a–AcvR2b, and AMHR2).

Coreceptors, endoglin, which resides predominantly on endotheliocytes, cryptic, and β-glycan (Tβ R3); they modulate the activity of type- I and - II receptors.

Numerous ligand–receptor combinations trigger distinct TGFβ/ BMP signaling. For example, ALK2, which primarily propagates BMP6 signal, can also function as a BMP9 receptor. Heterotetrameric receptors made up from type- I and - II receptors, which, according to targeted type- I receptor type in the endothelium, predominantly endothelial ALK1 and ubiquitous ALK5, stimulate a given SMAD signaling cascade; ALK1 signals via SMAD1, SMAD5, and SMAD8 and ALK5 via SMAD2 and SMAD3.

The transmembrane receptor ALK1 is activated by BMP9 (GDF2) and BMP10 and by TGFβ1, but weakly. Once ALK1 is liganded, cytosolic SMAD1, SMAD5, and SMAD8 are phosphorylated by the ALK1–Eng–Tβ R2 complex.

Intracellular ALK1 signaling is implicated in diseases. Endothelium-specific ALK1 promotes arterial endothelial maturation and quiescence. In mice, deletion of genes encoding ALK1, endoglin, and MAP3K7 causes embryonic lethality associated with altered morphogenesis of the vascular circuit resulting from impaired arterial endothelium differentiation [ 219 ].

Phosphorylated SMADs complex with common SMAD4 and translocates to the nucleus, where they activate or repress transcription of specific target genes. Inhibitory SMADs, Smad6 and Smad7, are linked to ALK1 and ALK5, respectively (self-regulatory loop). They compete for type- I receptor binding or recruitment of specific ubiquitin ligases or phosphatases for proteasomal degradation or dephosphorylation of receptors.

In the early stages of blood vessel formation, proangiogenic BMP2 and BMP6 prevail; they signal via ALK2 or ALK3 [ 210 ]. On the other hand, antiangiogenic BMP9 and BMP10, two major ALK1 ligands, signal via ALK1 predominantly during vascular remodeling and maturation. Both BMP9 and BMP10 impede EC proliferation and migration. Endoglin and ALK1 are active in sites of vasculo- and angiogenesis during embryogenesis. During mouse postnatal development, except in the lung endothelium, ALK1 synthesis decreases, but at a high enough concentration to keep the adult vasculature quiescent via BMP9–ALK1 signaling. In wound healing and during tumorigenesis, ALK1 production linked to angiogenesis increases.

On the one hand, the BMP9–ALK1 couple upregulates the formation of notch-related mediators, HES1 (bHLHb39), HRT1 (bHLHb31), HRT2 (bHLHb32), and Jag1, in addition to endoglin, ephrin-B2, transmembrane protein TMem100, and endothelin-1 [ 210 ]. On the other hand, it downregulates the formation of E-selectin, CXCR4, and apelin.

Intracellular transmembrane protein TMem100, which localized mainly to the endoplasmic reticulum (but not to the plasma membrane), is an embryonic endothelium-enriched protein, synthesis of which is activated by BMP9 and BMP10 via the ALK1 receptor [ 219 ]. TMem100 may assist in post-translational protein modification or intracellular sorting.

In neurons, TMem100 controls the interaction between ankyrin-like and vanilloid TRP channels TRPA1 and TRPV1, disconnecting them and promoting Ca 2+ influx [ 209 ]. Both TRPA1 and TRPV1 reside on endotheliocytes; TRPV1 contributes to regulating the vasomotor tone, whereas TRPV4 facilitates arteriogenesis.

Calcium signaling upstream from NFATc1 is defective in TMEM100 −∕− embryos [ 209 ]. In Bmp10 −∕− mice, cardiac growth is impaired without defects of angiogenesis [ 219 ]. Among ALK1 targets, ablation of TMEM100 gives rise to a phenotype similar to Alk1 mutants (but not identical) [ 209 ]. Both Alk1 −∕− and TMEM100 −∕− mice have heart defects, failed vascular remodeling, and abnormal dilation and narrowing of the dorsal aorta, in addition to detachment of the endo- and mesodermal layers in the yolk sac. When TMEM100 is ablated postnatally, AVMs form in the lung and intestine, but not injury-induced cutaneous AVMs, as in Alk1 −∕− mice.

Both TMEM100 −∕− and EC TMEM100 −∕− mice die in utero because signaling from ALK1, notch, and PKB decays or is even suppressed and hence differentiation of arterial endothelium and vascular morphogenesis are defective [ 219 ].

The notch heterodimer forms owing to calcium; hence, the transplasmalemmal gradient in Ca 2+ concentration participates in notch activation in endotheliocytes [ 209 ]. When extracellular calcium concentration is low, notch subunits dissociate, promoting its cleavage.

Notch and its ligands abound in arterial (but not venous) endothelium of mouse embryos. Notch-1, notch-4, DLL4, CSL Footnote 65 (or RBPJκ), HRT1, and HRT2 elicit arterial cell fate [ 219 ]. Altered signaling from ALK1, notch, and TMem100 affects vascular smooth myocyte recruitment or differentiation during arterial maturation. In addition, activity of PKB and presenilin-1, which interacts with the notch pathway, are repressed in TMEM100 −∕− and Alk1 −∕− mouse embryos. The PKB kinase enhances PS1-mediated notch cleavage. Reciprocally, the PS1 peptidase provokes PKB activation. Altered presenilin-1 causes apoptosis via impaired PKB activity.

Synthesis of ALK1 depends on blood flow, which promotes the association of endoglin with ALK1, thus sensitizing endotheliocytes to low BMP9 concentrations [ 210 ]. In ALK1-deficient mice, arteriovenous malformation, enlarged veins, and hyperbranching of the capillary plexus in the retina are observed. Retinal arteriovenous malformations occur predominantly in regions of higher blood flow. In addition, endotheliocytes have a migratory phenotype. Although the pericyte coverage is normal at the migration front of the retina, there is less pericyte coverage in capillaries in the central region of the capillary plexus. Endotheliocytes of AVMs express the venous marker EPHb4, but loss of the arterial marker Jag1.

Endoglin-defective endotheliocytes are unable to sense and adapt to applied wall shear stress. This homodimeric glycoprotein of the vascular endothelium binds TGFβ1 with high affinity. It contributes to the regulation of angiogenesis, which involves tip cell selection, endotheliocyte proliferation and migration, mural cell recruitment, lumen formation, anastomosis, neovessel growth, and pruning.

Endoglin is linked to Tβ R3 encoded by the TGFBR3 gene that retains TGFβ for presentation to the signaling receptors. It acts as a TGFβ coreceptor, which is particularly implicated in BMP9 signaling in endotheliocytes.

Endoglin participates in the regulation of VEGFR2 signaling. Endoglin and VEGFR2 colocalize in intracellular vesicles. Endoglin affects VEGFR2 transfer and recycling and hence the balance between endotheliocyte proliferation and migration after VEGFa stimulation, favoring PKB activation. Furthermore, PKB phosphorylation promotes venous differentiation at the expense of arteriogenesis.

Hereditary hemorrhagic telangiectasia (HHT; or Osler–Weber–Rendu syndrome) and cerebral cavernous malformation (CCM) result from lowered and elevated signaling from the TGFβ/ BMP receptor complexes and sensitivity to messengers, respectively [ 210 ].

Endoglin cooperates with the component of the CCM pathway, which inhibits angiogenesis KRIT1 Footnote 66 (or CCM1), and ALK1 (or HHT2). The CCM complex includes CCM1 (KRIT1), CCM2 (aka OSM Footnote 67 and malcavernin), and CCM3 (or PdCD10). Footnote 68

Loss-of-function mutations in the ENG and ACVRL1 genes provoke a defective regulation of processes involved in angiogenesis. Although LOF ENG mutations are linked to a mild hyperbranching phenotype, LOF ACVRL1 mutations favor tip cell potential and branching. Cells with LOF ENG mutations fail to adequately respond to migratory signals provided by the direction of blood flow [ 220 ].

1.4.6 Hereditary Hemorrhagic Telangiectasia

Hereditary hemorrhagic telangiectasia is an autosomal dominant disorder characterized by AVMs, capillary overgrowth, and fragile vessels in less than 2 in 10,000 individuals.

In AVMs, flow bypasses capillaries; blood flows directly from some arteries directly to veins; the latter then undergo higher stress and strain and thus enlarge (enlarged shunts).

Near the skin, they form telangiectasias , that is, focal dilations of postcapillary venules with excessive layers of vSMCs. Cutaneomucosal telangiectasias cause bleeding (epistaxis). AVMs occur in the lung, liver, and brain [ 190 ].

Several forms of HHT are distinguished mainly by their genetic cause rather than by differences in symptoms. Patients with type- I (HHT1) have symptoms earlier than those with type- II (HHT2) and more frequently present vascular malformations in the brain and lung. The prevalence of pulmonary AVMs is greater in HHT1 than in HHT2 [ 209 ].

Juvenile polyposis combined with HHT, that is, a syndrome characterized by both AVMs, which grow and regress during life, and polyps in the gastrointestinal tract, is caused by mutations in the Smad4 gene [ 190 ]. Two additional chromosomal loci, 5q31 and 7p14, are linked to other types, HHT3 and HHT4 [ 190 ].

Heterozygous LOF autosomal dominant mutations in the ENG Footnote 69 and Alk1 genes, which encodes two receptors of the TGFβ pathway that predominantly lodge on endotheliocytes, engender HHT1 and HHT2, respectively. Arteriovenous malformations are observed in the brain, spinal cord, lung, gastrointestinal tract, and liver.

In endotheliocytes, LOF mutations of the ENG gene, which encodes endoglin cause type-1 HHT (HHT1) favored by VEGFa, and arteriolar endotheliocytes acquire venous characteristics. Endotheliocytes overexpressing endoglin serve as tip cells, preferentially in the arterial compartment [ 220 ]. Deletion of the ENG gene alters VEGFa–VEGFR2 signaling but primes the PI3K–PKB axis.

Mutations in the ACVRL1 gene that encodes ALK1 are responsible for HHT2. Arterial endotheliocytes produce EfnB2, which participates in vascular development. Its concentration decreases in ACVRL1 −∕− mice. The ALK1 ligand BMP9 induces EfnB2 production in endotheliocytes via ALK1 and its coreceptors BMPR2 and AcvR2 [ 221 ].

BMP9 activates inhibitors of DNA binding ID1 and ID3 (bHLHb24–bHLHb25), both being required for EfnB2 formation [ 221 ]. Inhibitors of DNA binding heterodimerize with other ubiquitous or cell type-specific bHLH transcription factors, especially the class-1 bHLH transcriptional activators, E-proteins (TcFE2α [E2A or bHLHb21], TcF4 [E2-2 or bHLHb19], and TcF12 [HEB or bHLHb20]), but also effectors of ALK1 and notch signaling, HES1 (bHLHb39) and HRT1 (bHLHb31), thereby inhibiting their DNA binding. Footnote 70 Both ID1 and ID3 repress cell differentiation, but support cell proliferation [ 209 ]. In addition, IDs downstream from SMAD1 and SMAD5 promote stalk cell phenotype during angiogenesis, avoiding excessive tip cell formation.

Loss of ALK1 or EfnB2, which targets EPHb4 receptor involved in venous specification, causes arteriovenous anastomosis, whereas loss of ALK1 (but not EfnB2) upregulates VEGFR2 production and capillary sprouting. Conversely, BMP9 blocks endothelial sprouting via the ALK1–BMPR2–AcvR2 receptor complex in addition to ID1 and ID3 [ 221 ].

Several HHT markers encompass VEGF, TGFβ, soluble endoglin, angiopoietin-2, clotting factor F V III , and von Willebrand factor, in addition to microRNAs, such as miR27a, a proangiogenic microRNA, miR205, which reduces EC proliferation, migration, and tubulogenesis and inhibits SMAD1 and SMAD4, and miR210 [ 210 ].

The GJA5 gene that encodes the gap junction protein connexin-40 is targeted by the BMP9–ALK1 pathway in human aortic endotheliocytes and can explain heterogeneity and the severity of HHT2 [ 222 ]. In ACVRL1 +∕− mice that develop AVMs similar to those in HHT2 patients, GJA5 haploinsufficiency causes arterial vasodilation and rarefaction of the capillary bed. Reduced Cx40 concentration also provokes ROS production and hence vessel remodeling. Capillaries form transient arteriovenous shunts that can develop into large malformations upon stressor exposure.

Although some idiopathic AVMs are linked to elevated notch signaling (notch-1 and notch-4 in addition to Jag1 and DLL4), in HHT notch activity declines [ 209 ]. Both GOF and LOF notch signaling cause abnormal arterial and venous specification and hence fusion of arteries and veins. In adult mice, constitutively active notch-4 causes AVMs in the brain, liver, skin, and uterus, which can shrink upon removal of constitutively active notch-4. Endotheliocyte-specific constitutively active notch-1 also provokes AVMs.

In HHT patients, AVMs grow because of endotheliocyte proliferation, which enlarges the arteriovenous shunt, whereas idiopathic AVMs result from endotheliocyte hypertrophy [ 209 ]. A decayed notch signaling increases endotheliocyte proliferation and may at least partly explain vascular enlargement in HHT-related AVMs.

1.4.7 Cerebral Cavernous Malformations

Cerebral cavernous (or capillary venous) malformations consist of dilated capillary-like vessels ( cavernomas ) mixed with large saccular vessels with thickened walls in the cerebral parenchyma. Endotheliocytes lack tight junctions and are thus separated by gaps [ 190 ].

These disorders occur in a sporadic and familiar form with, in general, single and multiple lesions, respectively. They obey autosomal dominant inheritance; four chromosomal loci are implicated: (1) 7q11.22 with mutations in KRIT1 gene (Ccm1; ∼40% cases), (2) 7p13 with mutations in the Ccm2 gene (encoding malcavernin, a stabilizer of endotheliocyte junctions, also abbreviated CCM2), (3) 3q26.1 with mutations in the PDCD10 gene (Ccm3), and (4) 3q26.3–27.2 [ 190 ].

These disorders are pseudodominant diseases. Although patients are heterozygous for mutation in the Ccm genes, biallelic mutation of the Ccm genes is observed locally in lesions [ 210 ]. Biallelic Ccm mutation is also observed in lesions of patients with sporadic CCM.

Loss-of-function mutations of the KRIT1 gene, which encodes KrIT1 produced in neurons, astrocytes, various types of epitheliocytes, and in capillary and arteriolar endotheliocytes, engender hyperkeratotic cutaneous capillary venous malformations in addition to CCMs [ 190 ]. KrIT1 links to microtubules and interacts with integrin-β 1 -binding protein Itgβ1BP1, which participates in regulating cell adhesion and migration, thereby controlling EC fate. Conversely, Itgβ1BP1 can sequester KrIT1 in the nucleus. Malcavernin is able to sequester KrIT1 in the cytoplasm. PdCD10 may also be involved in the same pathway [ 190 ].

Gain-of-function mutations in any of the CCM genes exacerbate TGFβ/ BMP signaling, endothelial-to-mesenchymal transition, and ultimately cerebral cavernomas. Sustained exposure to TGFβ and subsequent KLF4-induced augmented formation of BMP2 and BMP6 dismantle cellular junctions, increase vascular permeability, and provoke hyperproliferation and acquisition of mesenchymal markers, creating AVMs and multilumen cavernomas [ 210 ].

The transcription factor KLF4 enables endothelial-to-mesenchymal transition. Both KLF2 and KLF4 are overexpressed early after ablation of any Ccm genes. Stimulation by BMPs in cultured human umbilical vein ECs upregulates KLF4 synthesis [ 210 ]. However, KLF4 can also be activated by the MAP3K3–MAP2K5–ERK5 pathway, which also stimulates the transcription factors MEF2a and MEF2c, upregulating KLF4 production. In addition, KLF4 can launch BMP6 formation, thereby establishing a positive feedback loop.

αιτιoλoγ𝜖ω: inquire into causes, reason, account for; αιτιoλoγια: giving the cause.

διαγιγνoσκω: know one from the other, distinguish, discern.

For example, abdominal obesity, diabetes mellitus, hypertension, smoking, unhealthy diet, regular alcohol consumption, lack of physical activity, and psychosocial factors, in addition to biological indices such as concentrations of total cholesterol and low-density lipoproteins, total cholesterol/high-density lipoprotein, and apolipoprotein ApoB/ApoA1 ratios.

GFR: growth factor receptor; MNAR: modulator of nongenomic action of the estrogen receptor. The coactivator of estrogen receptor-mediated transcription and corepressor of other nuclear hormone receptors (transcription factors) that facilitates NR3a1 nongenomic signaling via Src and PI3K is also called proline-, glutamate-, and leucine-rich protein PELP1. The plasmalemmal NR3a signalosome comprises G-protein subunits, receptor and nonreceptor protein Tyr kinases (e.g., Src), protein Ser/Thr kinases (PKB), lipid kinases (PI3K and PDK1), and scaffold proteins (MNAR, SHC, striatin) [ 39 ]. It interacts with several growth factor signaling components (e.g., EGFR and HGF-regulated protein Tyr kinase substrate (HRS)). It interacts with androgen (AR or NR3c4) and glucocorticoid receptor (GR or NR3c1) and thus influences nuclear receptor (NR) signaling.

Both NR3a1 and NR3a2 can activate Gα and Gβγ. Plasmalemmal NR3a monomers in the absence of sex steroids rapidly homodimerize upon estrogen exposure. These dimers can then associate with Gα and Gβγ subunits. Estradiol rapidly stimulates calcium entry via the TRPV6 channel [ 39 ].

Regulators of calcineurin RCan1, RCan2, and RCan3 are also termed calcipressin-1 to -3 in addition to modulatory (or myocyte-enriched) calcineurin-interacting proteins MCIP1 to MCIP3. The RCan protein binds to protein phosphatase PP3 in the cytoplasm, blocking its activity triggered by angiotensin-2 and other hypertrophic factors. Indeed, it prevents dephosphorylation of transcription factors of the NFAT family, sequestering them in the cytoplasm and impeding their nuclear translocation [ 39 ].

Connexin-37 forms gap junctions in myoendothelial communication between microvascular endothelial and smooth muscle cells. Its phosphorylated Tyr332 controls the gap junction-dependent spread of calcium signals. Nitric oxide precludes Tyr332 dephosphorylation by PTPn11 and hence Ca 2+ transfer induced by mechanical stimulation of endotheliocytes, but enhances Ca 2+ spreading within the endothelium, thereby boosting endothelium-dependent vasodilation in response to acetylcholine, even despite inhibition of soluble guanylate cyclase [ 41 ].

18-kDa Translocator protein, previously called peripheral-type benzodiazepine receptor, is an outer mitochondrial membrane (OMM) protein necessary for cholesterol import through the OMM upon hormonal stimulation from the cytosol to the aqueous intermembrane space of the mitochondrial envelope (intermembrane space [IMS]) and steroid production. The importing of Tspo into steroidogenic cell mitochondria is regulated by cAMP. The translocase of the outer mitochondria membrane complex (TOMM), which recognizes mitochondrial proteins for importing, does not interact with Tspo and thus is not required for Tspo importing and insertion into the OMM. Initial targeting of Tspo to mitochondria depends on the cytosolic chaperones interacting with the import receptor TOMM70, which is loosely associated with the TOMM complex, and its integration into the OMM on metaxin-1 [ 44 ].

Translocator protein interacts with voltage-dependent anion channel (VDAC) and the adenine nucleotide translocase (ANT), comprising the mitochondrial permeability transition pore (MPTP), which lodges at contact sites between the OMM and the inner mitochondrial membrane (IMM) [ 44 ]. Tspo thus participates in mitochondrial cholesterol and protein import, cell proliferation, and apoptosis.

Translocator protein clusters owing to ATP and the cytosolic chaperone HSP90 and is imported as 66-kDa heteropolymers with metaxin-1, VDAC1, and nonspecific lipid-transfer protein [ 44 ]. At the OMM–IMM interface, Tspo forms 800-kDa mitochondrial complexes with VDAC1, VDAC3, ANT, ApoA1, ApoA2, fatty acid synthase, annexin-A2, and mitofilin.

The transduceosome is composed of the cytosolic proteins star, PKA, and acylCoA-binding domain-containing protein ACBD3 (Golgi complex-associated protein GoCAP11, Golgi body-resident protein GCP60, or peripheral benzodiazepine receptor [PBR]- and PKA-associated protein PAP7), and OMM proteins Tspo and VDAC1.

A sulfonate group (sulfur trioxide moiety [SO \(_3^-\) ]) can be transferred rather than a sulfate group (sulfation). Sulfation means that esters or salts of sulfuric acid (sulfates) are formed. Sulfonation refers to attachment of the sulfonic acid group (–SO 3 H) to a carbon in an organic compound by sulfotransferases using phosphoadenosine phosphosulfate as donor. However, sulfation is also defined either by the replacement of a hydrogen atom of an organic compound with a sulfate group (–OSO 2 OH) and sulfonation by the replacement of a hydrogen atom of an organic compound with a sulfonic acid group (–SO 3 H).

Takayasu arteritis affects arteries exiting from the heart and their main branches.

Behçet disease is characterized by ulcers of the mouth and genital organs, skin lesions, and ocular anomalies.

Diabetes mellitus is characterized by an altered production or response to insulin, provoking abnormal metabolism of carbohydrates and hyperglycemia.

In type-1 diabetes mellitus (T1DM), the body lacks pancreatic insulin-producing β cells. Patients with T1DM have a three- to five-fold elevated CVD risk [ 51 ].

In type-2 diabetes mellitus (T2DM), which is more common and often develops later in life, cells fail to respond to insulin.

Diabetes insipidus is characterized by an impaired secretion of or response to vasopressin.

In autoimmune diseases, immunological tolerance of the body’s cells is lost and hence the immune system, which is aimed at identifying and destroying foreign invaders attacking target cells. A genetic susceptibility predisposes the immune system to defective immunological tolerance. The genetic marker HLAdr4 increases the risk for developing rheumatoid arthritis. An environmental trigger (e.g., viruses, smoking) initiates the disease. Angiogenesis participates in the genesis of rheumatoid arthritis and other inflammatory diseases.

Sjögren’s syndrome affects the lachrymal and salivary glands, thereby drying the mouth and eyes.

A rheumatic overlap syndrome with anti-RNP antibodies (i.e., abnormally high concentrations of antibodies against U1 small nuclear ribonucleoprotein) and characterized by arthritis and often myositis, pulmonary hypertension, and interstitial lung disease.

The reduced (G SH ) and oxidized glutathione (glutathione disulfide [G SS G]) redox couple is the traditional marker of oxidative stress. F2-isoprostanes serve as the reference marker of oxidative damage.

Myeloperoxidase abounds in granules of activated neutrophils, monocytes, and macrophages. It converts hydrogen peroxide to hydroxyl radical (OH • OH), peroxynitrite, hypochlorous acid (HOCl), and nitrogen dioxide (NO \(_2^{\bullet }\) ).

Hypohalous acids are oxoacids of halogens (e.g., bromine [Br], chlorine [Cl], fluorine [F], and iodine [I]), such as hypobromous, hypochlorous, hypofluorous, and hypoiodous acid (general formula HOX, where X is the halogen atom). Hypohalites are any salts of hypohalous acids (general formula M(OX) N ).

Many types of peroxidases utilize sodium voltage-gated channels (SCNs), such as eosinophil (EPOx), gastric (GaPOx), salivary (SPOx; or secreted lactoperoxidase [LPOx]), and thyroid peroxidase (TPOx), in addition to MPOx. These enzymes generate HOSCN via a two-electron halogenation. Thiocyanate is detected at various concentrations (0.01–3 mmol/l) in extracellular fluids (plasma, saliva, airway surface fluid, milk, tears, and gastric juice) [ 77 ]. Airway SCN is concentrated from the plasma pool via its active transport through the basolateral sodium–iodide symporter (SLC5a5 or NIS) and apical anion channels, such as the cystic fibrosis transmembrane conductance regulator (CFTR) in addition to cytokine-regulated channels SLC26a4 (pendrin), an electroneutral halide exchanger, and anoctamin-1 (transmembrane protein TMem16a), a Ca 2+ -dependent Cl − channel and halide transporter [ 77 ]. The SCN originates primarily from the diet, especially from glucosidic cyanogen-rich plants (e.g., cassava, linseed, maize, sorghum, sugar cane, and yam). It is also a product of glucosinolate metabolism in addition to N-conjugated thiocyanates and structurally related isothiocyanates (e.g., sulforaphane) [ 77 ].

Catalytic turnover requires electron transfer from NADPH to the P450 heme iron, a reaction catalyzed by the membrane-bound flavoprotein, POR.

In particular, membrane-bound, heme-containing cytochrome-P450 epoxygenases metabolize polyunsaturated FAs such as arachidonic acid to epoxide products such as (14,15)EET.

Endothelial cytochrome-P450 monooxygenases, such as CyP1a, CyP2b6, CyP2c, and CyP2j, oxidize arachidonic acid, enzymatic cleavage of molecular oxygen being followed by insertion of a single atom of oxygen into the substrate, whereas the remainder is released as water. These enzymes regulate the vasomotor tone via produced epoxy FAs such as vasodilatory (11,12)EET [ 82 ].

Oxidation and reduction correspond to a loss and gain of electrons, respectively.

Also known as NADH cytochrome-B5 reductase-3.

The alias AXH stands for A ta x in-1 and H BP1 (HBP1: high-mobility–group box transcriptional repressor-1).

Also known as 17-kDa heparin-binding growth factor-binding protein HBP17.

Deubiquitinases can be categorized into six subsets: ubiquitin-specific peptidases (USPs); ubiquitin carboxy-terminal hydrolases (UCHs); ovarian tumor peptidases (OTus); MJD peptidases; JAMM/MPN domain-associated metallopeptidases (JAMMs); and monocyte chemotactic protein-induced protein (MCPIP).

TRP: transient receptor potential.

Also telangiectasis (plural telangiectases). From Greek τ𝜖λιωμα: completion; τ𝜖λo ς : end, term, achievement; αγγ𝜖ιoν: (hollow) vessel, vein; 𝜖κτασι ς : extension, dilation.

αθηρωμα: tumor full of gruel-like matter; σκληρo: hard. The Swiss scientist A. von Haller (1708–1777) described atherosclerosis in his book “Opuscula Pathologica” published in 1755. The German physician F. Marchand (1846–1928) introduced the term atherosclerosis in 1904.

Although coronary computed angiography provides the anatomy of stenoses and evaluates the extent of the lesion, it fails to assess ischemia and thus to guide the clinical management of coronary atherosclerosis. Nevertheless, some morphological features of atherosclerotic plaques, such as low-density plaque and expansion, in addition to fractional flow reserve derived from modeling, are employed to evaluate perfusion quality downstream from lesions and the infarction risk. Myocardial perfusion single-photon emission computed tomography is used to detect myocardial ischemia [ 119 ].

Plaques with lipid-rich necrotic cores are one of the main causes of myocardial infarction. Low-density noncalcified plaque is the most relevant feature associated with ischemia in arteries with 30–69% stenoses [ 120 ]. Contrast density difference, which is defined as the maximum percentage difference in contrast attenuation between the stenosed lumen and proximal normal reference segment is used to predict ischemia, is the most relevant plaque feature associated with ischemia in stenoses equal to or larger than 70%.

Addison disease is a chronic primary adrenal insufficiency, or hypocortisolism, cortisol being a glucocorticoid synthesized in the adrenal gland. It is most often caused by an autoimmune disorder that gradually destroys the adrenal cortex. This rare hormonal disorder affects about 1 in 100,000 individuals. Cortisol participates in maintaining blood pressure and controlling inflammatory response and the metabolism of carbohydrates, lipids, and proteins, especially the effect of insulin in carbohydrate catabolism. The pituitary gland secretes adrenocorticotropic hormone (ACTH; a.k.a. adrenocorticotropin and simply corticotropin), a component of the hypothalamic–pituitary–adrenal axis, which stimulates the adrenal gland. ACTH is secreted from corticotropes in the anterior lobe of the pituitary gland (or adenohypophysis) upon stimulation by corticotropin-releasing hormone (CRH) released by the hypothalamus. Conversely, glucocorticoid hormones block release of both CRH and ACTH (negative feedback). Secondary adrenal insufficiency results from a lack of ACTH. Chronically elevated ACTH concentration results from primary adrenal insufficiency such as Addison disease.

Cushing disease results from benign ACTH-producing tumors of the pituitary gland that augments ACTH concentration, subsequently causing hypercortisolism. Surgical removal of ACTH-producing tumors of the pituitary gland engenders secondary adrenal insufficiency.

Glucose and lactate generate about 30% ATP and fatty acid oxidation about 70% [ 127 ].

Adaptive activation of AMPK ensures adequate cardiac energy supply, as it raises fatty acid delivery via its activation of lipoprotein lipase (LPL), repositioning of the fatty acid transporter ScaRb3 to the plasma membrane, and inactivating phosphorylation of acetylCoA carboxylase, inhibiting carnitine palmitoyltransferase CPT1, which carries fatty acylCoA into the mitochondrion.

Activated cardiac NR1c1 elicits transcription of genes involved in various steps of fatty acid oxidation.

Astrocytes synthesize α1 and α2 subunits and most neurons α1 and α3 subunits.

Cartilage oligomeric matrix protein is an abundant component in the extracellular matrix of load-bearing organs, such as tendons, cartilage, and pericartilage tissues. It interacts with other matrix proteins, such as collagens and fibronectin, thereby stabilizing the matrix.

SRSF5 binds to intronic splicing sites within introns 10 and 11 of Cd44 pre-mRNA and recruits small nuclear ribonucleoproteins, forming mature spliceosomes (binary U1–U2 and ternary U4–U5–U6 complexes), which prime variant exon exclusion via double-exon skipping alternative splicing [ 147 ]. SRSF2 does not bind to the intron-10 and -11 region of Cd44 pre-mRNA but connects to the U1–U2 snRNP complex, promoting U1–U2 splicing initiation and mature trisnRNP U4–U5–U6 complex binding, thereby promoting the synthesis of standard Cd44 transcripts, which are translated into CD44s protein [ 147 ]. In the nucleus, Hyal2 counteracts SRSF5 action, displacing it from the early U1–U2 spliceosome and precluding the SRSF5-mediated formation of mature spliceosome and SRSF5 binding to intron 12 of the Cd44 pre-mRNA. In addition, Hyal2 may inhibit SRSF2 production and its interaction with Cd44 pre-mRNA.

KH domain-containing, RNA-binding, signal transduction-associated protein-1 is also termed 68-kDa Src-associated in mitosis protein (SAM68). It is activated by Ras and its effectors ERK1 and ERK2 [ 147 ], and favors profibrotic CD44v5 expression.

The South American plant Ryania speciosa contains an insecticidal alkaloid, ryanodine. Ryanodine binds RyRs preferentially in the open state [ 153 ]. At nanomolar concentrations, it locks the channel in a subconductance state; at micromolar concentrations (> 100 μ mol/l), it inhibits Ca 2+ release. Among the three isoforms (RyR1–RyR3), RyR1 is widely expressed in the skeletal muscle, RyR2 is identified primarily in the heart, and RyR3 in the brain, although each isoform is found in many different cell types. The primary trigger for RyR opening is Ca 2+ ion.

Calsequestrin is a major Ca 2+ buffer in the ER lumen that oligomerizes and interacts with the membrane-associated proteins junctin and triadin to control RyR activity [ 153 ].

Calmodulin associates with RyR at its cytoplasmic face; at high Ca 2+ concentrations, it inhibits both RyR1 and RyR2; at low Ca 2+ concentrations, it activates RyR1 but inhibits RyR2 [ 153 ]. According to [ 154 ], at nanomolar free Ca 2+ concentrations, although apoCam inhibits RyR2, it potentiates RyR1 and RyR3 activity; at micromolar ones, Ca 2+ –Cam inhibits all RyR isoforms. apoCam and Ca 2+ –CaM inhibit RyR2.

The adaptor homer-1C can activate RyR1 and inhibit RyR2 [ 153 ]. In addition, RyR is inhibited by Mg 2+ and activated by ATP, cytosolic dimeric Ca 2+ -binding S100a1, and NO, thereby potentiating Ca 2+ release.

This heteromeric pump consists of α and β subunits. Several cell-specific isoforms of these subunits exist (α1–α4 and β1–β3). In the human heart, α1 to α3 are expressed together with β1 and, to a lesser extent, β2 in a region-specific manner [ 156 ]. The α1 isoform is ubiquitous and participates in pumping and signaling and in cell survival, ROS generation, and cardiac hypertrophy and fibrosis [ 157 ]. The α2 isoform contributes to regulating intracellular Ca 2+ signaling and contractility in addition to adverse hypertrophy. The α3 isoform may be involved in cardiac hypertrophy. The expression of the α subunit is often altered in cardiac hypertrophy and failure.

Nitric oxide synthesized by vascular and endocardial NOS3 participates in controlling myocardial contractility via the NO–cGMP–PDE3–cAMP–PKA–Ca 2+ channel axis [ 162 ].

On the other hand, NO reduces contractile response to adrenergic stimulation in heart failure, limits post-infarction remodeling, and protects against ischemia, at least partly via the NO–AC–cGMP–PKG–K ATP pathway [ 162 ].

Four related genes encode neuregulins (NRG1–NRG4), NRg1 being the most abundant member in the cardiovascular system. Alternative splicing at the C-terminus of the EGF domain of NRG1 leads to Nrg1α and Nrg1β variants, with distinct receptor affinity. Neuregulin-1 can be further subdivided into three types. Type- I Nrg1 is a type- I transmembrane protein, its active form being released after cleavage by adam17, adam19, or memapsin; type- II Nrg1 is also cleaved, generating an active ligand on secretion; and type- III Nrg1 is almost exclusively produced in neurons and binds to membranes.

Fatty acid-binding proteins (FABP1–FABP9) are intracellular lipid chaperones that can bind various types of hydrophobic ligands, such as saturated and unsaturated long-chain FAs and eicosanoids (e.g., leukotrienes and prostaglandins).

Fatty acid-binding proteins facilitate FA transport in the cell for lipid oxidation in the mitochondrion or peroxisome, transcriptional regulation in the nucleus, membrane synthesis and trafficking in the endoplasmic reticulum, regulation of enzyme activity, and storage as lipid droplets in the cytoplasm [ 167 ].

The plasmalemmal PM FABP belongs to a distinct family of fatty acid-handling proteins. It is detected on the extracellular surface of cardiac and skeletal myocytes, hepatocytes, adipocytes, and endotheliocytes [ 168 ]. It also lodges in the mitochondrial membrane, acting as the glutamate oxaloacetate transaminase-2 (GOT2) and aspartate aminotransferase (AspAT).

Fatty acid-binding protein FABP4, both a nuclear and cytoplasmic protein, contributes to maintaining glucose and lipid homeostasis. FABP4 is not only produced in adipocytes and macrophages but also in endotheliocytes, in which VEGFa via VEGFR2 (but not VEGFR1) and FGF2 upregulate its synthesis [ 169 ]. Inhibition of FABP4 blocks most of the VEGFa effects [ 170 ]. the DLL4–notch couple triggers FABP4 synthesis using the transcription factor FoxO1, independently of VEGFa [ 170 ]. Hence, FoxO1 is needed for the basal expression of FABP4, whereas its upregulated proangiogenic formation relies on VEGFa or notch.

In fact, three FABPs are expressed in endotheliocytes (FABP3–FABP5). FABP3 is also synthesized in CMCs, renal epitheliocytes, and neurons of the brain; FABP4 in adipocytes and macrophages; and FABP5 in the heart, skeletal muscle, lung, and skin [ 168 ]. Adipocytic, macrophagic, and dendrocytic FABPs include FABP4 and FABP5 [ 167 ].

In adipocytes, FABP4 is a carrier protein for the transport of FAs generated by lipolysis from lipid droplets. β AR–AC–PKA and NPRa/GC–PKG pathways activate (trigger phosphorylation) of hormone-sensitive lipase (HSL or lipase-E), thereby priming lipolysis; FABP4 interacts with HSL [ 167 ]. In addition, FABP4 is secreted in association with lipolysis. Its plasmatic concentration decays after a meal with a high fat content, when the insulin concentration rises [ 167 ]. Insulin-induced antilipolytic signaling does indeed suppress FABP4 secretion. Furthermore, FABP4 serves as an adipokine that promotes hepatic glucose production, reduces CMC contraction in addition to NOS3 activity in vascular endotheliocytes, and supports the proliferation and migration of vascular smooth myocytes in addition to glucose-stimulated insulin secretion in pancreatic β cells.

In endotheliocytes, FABP4 promotes angiogenesis. Intermittent hypoxia increases FABP4 formation in endotheliocytes [ 167 ]. Conversely, angiopoietin-1 impedes FoxO1-mediated FABP4 synthesis. On the other hand, FABP4 and FABP5 may be involved in endotheliocyte senescence.

In the kidney, FABP4 is expressed in endotheliocytes of the peritubular capillaries and veins in both the cortex and medulla, but not in glomerular or arterial endotheliocytes [ 167 ]. Ectopic FABP4 expression in the glomerulus is associated with renal dysfunction.

In the lung, FABP4 is detected in endotheliocytes of peribronchial blood vessels and a subset of macrophages [ 167 ]. Interleukins IL4 and IL13 raise FABP4 production in bronchial epitheliocytes, whereas interferon-γ hampers it.

Diet-derived circulating lipids comprise mostly long- (lcFAs; 12–20 carbon atoms) and, to a lesser extent, medium- (mcFAs; 6–12 carbons) and short-chain FAs (scFAs; < 8 carbons). LcFAs are transported in the bloodstream in the form of triglyceride-rich lipoproteins. Triglycerides are hydrolyzed from lipoproteins into non-esterified free fatty acids (FFAs) at the wetted endothelium surface by LPL.

Fatty acids are then carried through the vascular endothelium to be used by cells. Three sets of proteins are implicated in lcFA ingress: (1) fatty acid transporter proteins (FATP1–FATP6) of the SLC27A group, which enable cellular lcFA uptake, (2) the scavenger receptor ScaRb3 (or fatty acid translocase), and (3) intracellular fatty acid-binding proteins (FABPs) Vascular endotheliocytes are endowed with FATP3 (SLC27a3), FATP4 (SLC27a4), ScaRb3, and FABP3 to FABP5, in addition to PM FABP, whereas FATP1 (SLC27a1) is produced in the heart, muscle, brown and white adipose tissue, kidney, and brain; FATP2 (SLC27a2) in the kidney, brown adipose tissue, and liver; FATP4 also in CMCs, adipocytes, hepatocytes, and keratinocytes; FATP5 (SLC27a5) in the liver; and FATP6 (SLC27a6) in the heart [ 168 ]. They are predominately located in the plasma membrane, Golgi body, and endoplasmic reticulum.

Vascular endothelia growth factor b (VEGFb), which binds specifically to VEGFR1 and neuropilin-1, regulates this transfer, as it controls the synthesis of endothelial FATPs [ 168 ]. In particular, paracrine signaling by VEGFb from cells to endotheliocytes triggers formation of the FATP3 and FATP4 subtypes.

Adipocytes store large quantities of lipids. On the other hand, excess lipid amount in other cell types causes metabolic dysfunction, intracellular FA accumulation impairing insulin signaling and glucose uptake, causing insulin resistance.

During fasting periods, FFAs are generated by lipolysis in the white adipose tissue and carried in the bloodstream bound to albumin.

GPIHBP1: glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein-1.

CDO: cell adhesion molecule-related/downregulated by oncogenes. It belongs to the set of immunoglobulin-like cell adhesion molecules. This suppressor of Wnt signaling promotes neuronal differentiation and development of the skeletal muscle via sonic hedgehog and cell adhesion signaling [ 173 ]. Upon CDO depletion, expression of axin-2, connexin-43, and collagen-1A is upregulated.

Intercalated discs of CMCs enable their synchronous contraction and support the mechanical load, as they anchor actin and intermediate filaments. They contain gap junctions that provide electrical coupling between adjacent CMCs, which are composed of connexin-43 (Cx43).

African–Americans are at a higher risk for CKD and hypertension than Americans without African ancestry, independently of socioeconomic and traditional clinical risk factors, owing to mutations in the APOL1 gene that encodes apolipoprotein-L1, a component of dense HDL3 [ 175 ]. Circulating ApoL1 can destroy the sub-Saharan African parasite Trypanosoma brucei, which is transmitted by the tsetse fly. However, Trypanosoma brucei gambiense and rhodesiense become resistant, as they produce a protein that neutralizes ApoL1. Nevertheless, 2 APOL1 gene variants (G1–G2) engender ApoL1 with a reduced affinity for the trypanosomal protein, thereby struggling against the parasite. Although African-Americans who are homozygous for either APOL1 variant and heterozygous are protected against African trypanosomiasis (or sleeping sickness), they are at an increased risk for renal disease. In any case, individuals with APOL1 risk variants do not carry a higher risk of CVD [ 176 ].

Thiosulfate, a sulfide donor, is one of the products formed during oxidative H 2 S metabolism that is used to treat CUA patients on dialysis. Thiosulfate modulates H 2 S metabolite levels and signaling. Under hypoxia, concentrations of reduced (G SH ) and oxidized glutathione (G SS G), and of free H 2 S and acid-labile sulfide, decrease in endotheliocytes [ 178 ]. Exogenous thiosulfate significantly diminishes the G SH / G SS ratio after short episodes of hypoxia but markedly raises this ratio after sustained hypoxia. Under both normoxia and hypoxia, thiosulfate represses VEGF-primed cystathionase expression, EC proliferation, and angiogenesis.

β2-Microglobulin is a small membrane protein, a component of major histocompatibility complex (MHC) class- I molecules, and an amyloid precursor.

In humans, two types of MHC molecules, MHC I and MHC II , reside on the surface of cells, where they present peptides. Peptide binding in the endoplasmic reticulum is mediated by the chaperones tapasin and TAP-binding protein-related protein (TAPBPR) [ 180 , 181 ]. When these MHC-loaded peptides on antigen-presenting cells are antigenic, the resulting MHC I –peptide complexes, such as those on infected and cancerous cells, are recognized by effector cytotoxic CD8+ T lymphocytes, whereas MHC II –peptide complexes are detected by CD4+ T lymphocytes.

β2-Microglobulin serves as a marker for the activation of the cellular immunity, increased cell turnover, hematological cancers linked to the B-lymphocyte lineage, in addition to adverse cardiovascular outcomes in patients with carotid atherosclerosis [ 182 ]. Its concentration in blood also rises in chronic inflammation, hepatic and renal dysfunction, and some acute viral infections. After long-term dialysis, retention of this uremic toxin produces deposition of amyloid-like fibrils (dialysis-related amyloidosis).

Calcific aortic stenosis is characterized by large nodular calcific masses within the aortic cusps that protrude through the outflow surfaces into the sinuses of Valsalva, impeding normal leaflet opening [ 183 ]. Hemodynamic stress can activate latent transforming growth factor TGFβ1, a profibrotic agent that can induce calcification [ 184 ]. Signaling from Wnt and increased calcium concentration via the kallikrein–kinin axis are also involved in CAVD. The Wnt proteins interact with LDL receptors; β-catenins mediate osteoblastic transformation of valvular interstitial cells. Bone morphogenetic proteins BMP2 and BMP4 are produced by myofibroblasts and preosteoblasts adjacent to T-cell infiltrates, which form upon endothelial injury. Mutations in the transcriptional regulator notch-1 cause severe calcification owing to impaired repression of the transcription factor Runx2, an osteoblast stimulator.

A nevus is an abnormal benign tissular patch caused by a cellular overgrowth.

In 1958, W. B. Bean coined the term blue rubber nevus syndrome for its color and consistency [ 199 ], although nevi of the viscera were discovered in 1860 by M. Gascoyen [ 200 ].

TIE: protein Tyr kinase with immunoglobulin and epidermal growth factor homology domains.

αμαρτα ς : error; αμαρτημα and αμαρτια: failure, fault; the suffix “-oma” from -ωμα in medical terms meaning morbid growth, tumor (καρκινωμκ: cancer, chancre, sore, ulcer). A hamartoma is commonly a benign, focal malformation linked to disorganized tissular growth, which is made up of an abnormal mixture of cells normally found in the organ where it resides. For example, in the lung, hamartomas are composed of adipose, epithelial, and fibrous tissue and cartilage; pulmonary hamartomas are the most common benign tumors of the lung detected as solitary pulmonary nodules on medical images.

Π ρωτ𝜖υ ς : Proteus, the old God of the sea, Poseidon’s eldest son; πρωτιoν: chief rank, first place; πρωτιo ς : of the first quality. The Greek god Proteus, the ancient polymorphous creature, who can change his shape at will via manifold transformations. Proteus syndrome is an extremely variable condition involving atypical growth of the skin and skull observed in unrelated children.

NeK: never in mitosis gene-A (NIMA)-related kinase.

Iκ BKγ: inhibitor of NFκB (nuclear factor κ light chain enhancer of activated B cells) subunit-γ. The Iκ B kinase (IKK) complex is composed of three subunits IKKα, IKKβ, and IKKγ, which are encoded by conserved helix–loop–helix ubiquitous kinase (CHUK; also abbreviated as IKK1, IKKA, and IKBKA), IKBKB, and IKBKG gene, respectively.

RBPJκ: recombination signal-binding protein for immunoglobulin-κ J region, that is, suppressor of hairless (SuH) homolog. It is also called C promoter-binding factor CBF1, SuH, and LAG1 and is abbreviated CSL.

HES: hairy and enhancer of split (HES1–HES7 [bHLHb37–bHLHb43]).

HRT: HES-related transcription factor (HRT1–HRT3 [bHLHb31–bHLHb33]).

Sox: sex-determining region Y (SRY)-related high mobility group (HMG) homeobox-derived (DNA-binding domain)-containing transcription factor. In other words, Sox transcription factors contain an SRY-related HMG homeodomain that is a DNA-binding sequence.

In humans, 20 SOX genes are categorized into several groups: SOXA (SRY); SOXB1 (Sox1–Sox3); SOXB2 (Sox14 and Sox21); SOXC (Sox4 and Sox11–Sox12); SOXD (Sox5–Sox6 and Sox13); SOXE (Sox8–Sox10); SOXF (Sox7 and Sox17–Sox18); SOXG (Sox15); and SOXH (Sox30) [ 205 , 206 ]. They are expressed by multiple types of progenitor and stem cells.

The cystine knot structural motif is contained in various types of peptides and proteins, such as ion channel blockers, hemolytic agents, and antiviral and antibacterial molecules. Three types of cystine knots exist: the growth factor cystine knot (GFCK), inhibitor cystine knot (ICK), and cyclic cystine knot (CCK). Norrin belongs to the GFCK category.

Transmembrane tumor endothelial markers TEM1, TEM5, TEM7, and TEM8 abound in tumoral vessels.

Type-1 activin receptor-like kinase ALK1 is also abbreviated AcvRL1 and HHT2, as LOF mutations in the ACVRL1 gene cause type-2 hereditary hemorrhagic telangiectasia.

CSL: C promoter-binding factor CBF1, suppressor of Hairless [SuH], and LAG1.

KRIT1: Kirsten sarcoma virus Ras-revertant [KRev]-interaction trapped protein-1 [Krev1 being Rap1a].

OSM: osmosensing scaffold for MAP3K3.

PdCD10: programmed cell death protein-10.

Eng: endoglin. The ENG gene resides in chromosomal locus 9q34.

HES1 binds to its own promoter, thereby preventing its synthesis and enabling proper loss of arterial identity in endotheliocytes. On the other hand, IDs preclude HES1 autoinhibition, but do not affect regulation of other HES1 target genes [ 209 ].

Nichols M, Townsend N, Scarborough P, Rayner M (2014) Cardiovascular disease in Europe 2014: epidemiological update. Eur Heart J 35:2950–2959

Article Google Scholar

Mendis S, Puska P, Norrving B (Eds) (2011) Global atlas on cardiovascular disease prevention and control. Policies, strategies and interventions. World Health Organization in collaboration with the World Heart Federation and World Stroke Organization, Geneva

Google Scholar

Podolec P (2013) Classification of rare cardiovascular diseases. J Rare Cardiovasc Dis 1:49–60

Masironi R (1979) Geochemistry and cardiovascular diseases. Proc R Soc Lond Ser B Ser B Biol Sci 288:193–203

Article ADS Google Scholar

Leong DP, Joseph PG, McKee M, Anand SS, Teo KK, Schwalm JD, Yusuf S (2017) Reducing the global burden of cardiovascular disease. II. Prevention and treatment of cardiovascular disease. Circ Res 121:695–710

Winham SJ, de Andrade M, Miller VM (2015) Genetics of cardiovascular disease: importance of sex and ethnicity. Atherosclerosis 241:219–228

Schaefer BM, Caracciolo V, Frishman WH, Charney P (2003) Gender, ethnicity and genetics in cardiovascular disease. Part 1: basic principles. Heart Dis 5:129–143

Scarborough P, Bhatnagar P, Kaur A, Smolina K, Wickramasinghe K, Rayner M (2010) Ethnic differences in cardiovascular disease. British Heart Foundation Statistics Database ( www.heartstats.org )

McEwen BS (2006) Endocrine effects on the brain and their relationship to behavior (Sect. diversity of steroid hormone actions on the brain). In: Siegel GJ, Agranoff BW, Albers RW, Price DL (eds) Basic neurochemistry: molecular, cellular and medical aspects. Elsevier/Academic Press, Burlington, MA

Boese AC, Kim SC, Yin KJ, Lee JP, Hamblin MH (2017) Sex differences in vascular physiology and pathophysiology: estrogen and androgen signaling in health and disease. Am J Physiol Heart Circ Physiol 313:H524–H545

Levin ER (2009) Plasma membrane estrogen receptors. Trends Endocrinol Metab 20:477–482

Wang Q, Ding Y, Song P, Zhu H, Okon I, Ding YN, Chen HZ, Liu DP, Zou MH (2017) Tryptophan-derived 3-hydroxyanthranilic acid contributes to angiotensin II-induced abdominal aortic aneurysm formation in mice in vivo. Circulation 136:2271–2283

Pogoda K, Mannell H, Blodow S, Schneider H, Schubert KM, Qiu J, Schmidt A, Imhof A, Beck H, Tanase LI, Pfeifer A, Pohl U, Kameritsch P (2017) No augments endothelial reactivity by reducing myoendothelial calcium signal spreading. A novel role for Cx37 (connexin 37) and the protein tyrosine phosphatase SHP-2. Arterioscler Thromb Vasc Biol 37:2280–2290

Steimer T (2017) Steroid hormone metabolism. Geneva Foundation for Medical Education and Research ( www.gfmer.ch )

Miller WL (2013) Steroid hormone synthesis in mitochondria. Mol Cell Endocrinol 379:62–73

Rone M, Liu J, Blonder J, Ye X, Veenstra TD, Young JC, Papadopoulos V (2009) Targeting and insertion of the cholesterol-binding translocator protein into the outer mitochondrial membrane. Biochemistry 48:6909–6920

Hara A, Endo S, Matsunaga T, Soda M, Yashiro K, El-Kabbani O (2017) Long-chain fatty acids inhibit human members of the aldo–keto reductase 1C subfamily. J Biochem 162:371–379

Hyndman D, Penning TM (2016) AKR superfamily. Perelman School of Medicine, University of Pennsylvania ( www.med.upenn.edu/akr )

Penning TM, Byrns MC (2009) Steroid hormone transforming aldo–keto reductases and cancer. Ann N Y Acad Sci 1155:33–42

Jin Y, Mesaros AC, Blair IA, Penning TM (2011) Stereospecific reduction of 5β-reduced steroids by human ketosteroid reductases of the AKR (aldo–keto reductase) superfamily: role of AKR1C1–AKR1C4 in the metabolism of testosterone and progesterone via the 5β-reductase pathway. Biochem J 437:10.1042

Lösel RM, Falkenstein E, Feuring M, Schultz A, Tillmann HC, Rossol-Haseroth K, Wehling M (2003) Nongenomic steroid action: controversies, questions, and answers. Physiol Rev 83:965–1016

Kurogi K, Shimohira T, Kouriki-Nagatomo H, Zhang G, Miller ER, Sakakibara Y, Suiko M, Liu MC (2017) Human cytosolic sulphotransferase SULT1C3: genomic analysis and functional characterization of splice variant SULT1C3a and SULT1C3d. J Biochem 162:403–414

Rawshani A, Rawshani A, Franzén S, Eliasson B, Svensson AM, Miftaraj M, McGuire DK, Sattar N, Rosengren A, Gudbjörnsdottir S (2017) Range of risk factor levels. Control, mortality, and cardiovascular outcomes in type 1 diabetes mellitus. Circulation 135:1522–1531

Esmon CT, Esmon NL, Harris KW (1982) Complex formation between thrombin and thrombomodulin inhibits both thrombin-catalyzed fibrin formation and factor V activation. J Biol Chem 257:7944–7947

Gale AJ (2011) Current understanding of hemostasis. Toxicol Pathol 39:273–280

Radziwon-Balicka A, Lesyk G, Back V, Fong T, Loredo-Calderon EL, Dong B, El-Sikhry H, El-Sherbeni AA, El-Kadi A, Ogg S, Siraki A, Seubert JM, Santos-Martinez MJ, Radomski MW, Velazquez-Martinez CA, Winship IR, Jurasz P (2017) Differential eNOS-signalling by platelet subpopulations regulates adhesion and aggregation. Cardiovasc Res 113:1719–1731

Jiménez-Alcázar M, Rangaswamy C, Panda R, Bitterling J, Simsek YJ, Long AT, Bilyy R, Krenn V, Renné C, Renné T, Kluge S, Panzer U, Mizuta R, Mannherz HG, Kitamura D, Herrmann M, Napirei M, Fuchs TA (2017) Host DNases prevent vascular occlusion by neutrophil extracellular traps. Science 358:1202–1206

Zhang Y, Zhang J, Yan R, Tian J, Zhang Y, Zhang J, Chen M, Cui Q, Zhao L, Hu R, Jiang M, Li Z, Ruan C, He S, Dai K (2017) Receptor-interacting protein kinase 3 promotes platelet activation and thrombosis. Proc Natl Acad Sci USA 114:2964–2969

Ruparelia N, Chai JT, Fisher EA, Choudhury RP (2017) Inflammatory processes in cardiovascular disease: a route to targeted therapies. Nat Rev Cardiol 14:133–144

Barhoumi T, Fraulob-Aquino JC, Mian MOR, Ouerd S, Idris-Khodja N, Huo KG, Rehman A, Caillon A, Dancose-Giambattisto B, Ebrahimian T, Lehoux S, Paradis P, Schiffrin EL (2017) Matrix metalloproteinase-2 knockout prevents angiotensin II-induced vascular injury. Cardiovasc Res 113:1753–1762

de Jager SCA, Hoefer IE (2017) Beyond the matrix: MMP2 as critical regulator of inflammation-mediated vascular dysfunction. Cardiovasc Res 113:1705–1707

Libby P (2006) Inflammation and cardiovascular disease mechanisms. Am J Clin Nutr 83:456S–460S

Willerson JT, Ridker PM (2004) Inflammation as a cardiovascular risk factor. Circulation 109:II2–II10

Golia E, Limongelli G, Natale F, Fimiani F, Maddaloni V, Pariggiano I, Bianchi R, Crisci M, D’Acierno L, Giordano R, Di Palma G, Conte M, Golino P, Russo MG, Calabrò R, Calabrò P (2014) Inflammation and cardiovascular disease: from pathogenesis to therapeutic target. Curr Atheroscler Rep 16:435

Mason JC, Libby P (2015) Cardiovascular disease in patients with chronic inflammation: mechanisms underlying premature cardiovascular events in rheumatologic conditions. Eur Heart J 36:482–489

Bodolay E, Koch AE, Kim J, Szegedi G, Szekanecz Z (2002) Angiogenesis and chemokines in rheumatoid arthritis and other systemic inflammatory rheumatic diseases. J Cell Mol Med 6:357–376

Taracanova A, Alevizos M, Karagkouni A, Weng Z, Norwitz E, Conti P, Leeman SE, Theoharides TC (2017) SP and IL-33 together markedly enhance TNF synthesis and secretion from human mast cells mediated by the interaction of their receptors. Proc Natl Acad Sci USA 114:E4002–E4009

Fattori V, Borghi SM, Verri WA (2017) Action of SP and IL-33 on mast cells. Proc Natl Acad Sci USA 114:E10034–E10035

Sohal RS, Orr WC (2012) The redox stress hypothesis of aging. Free Radic Biol Med 52:539–555

Margaritelis NV, Kyparos A, Paschalis V, Theodorou AA, Panayiotou G, Zafeiridis A, Dipla K, Nikolaidis MG, Vrabas IS (2014) Reductive stress after exercise: The issue of redox individuality. Redox Biol 2:520–528

Touyz RM, Anagnostopoulou A, de Lucca Camargo L, Montezano AC (2016) Novel biosensors reveal a shift in the redox paradigm from oxidative to reductive stress in heart disease. Circ Res 119:969–971

Florence TM (1984) The production of hydroxyl radical from hydrogen peroxide. J Inorg Biochem 22:221–230

Cervantes Gracia K, Llanas-Cornejo D, Husi H (2017) CVD and oxidative stress. J Clin Med 6:22

Puppo A, Halliwell B (1988) Formation of hydroxyl radicals from hydrogen peroxide in the presence of iron. Is haemoglobin a biological Fenton reagent? Biochem J 249:185–190

Fleming I, Michaelis UR, Bredenkötter D, Fisslthaler B, Dehghani F, Brandes RP, Busse R (2001) Endothelium-derived hyperpolarizing factor synthase (Cytochrome P450 2C9) is a functionally significant source of reactive oxygen species in coronary arteries. Circ Res 88:44–51

Fukai T, Ushio-Fukai M (2011) Superoxide dismutases: role in redox signaling, vascular function, and diseases. Antioxid Redox Signal 15:1583–1606

Chung HY, Baek BS, Song SH, Kim MS, Huh JI, Shim KH, Kim KW, Lee KH (1997) Xanthine dehydrogenase/xanthine oxidase and oxidative stress. Age 20:127–140

Loria V, Dato I, Graziani F, Biasucci LM (2008) Myeloperoxidase: a new biomarker of inflammation in ischemic heart disease and acute coronary syndromes. Mediat Inflamm 2008:135625

Chandler JD, Day BJ (2012) Thiocyanate: a potentially useful therapeutic agent with host defense and antioxidant properties. Biochem Pharmacol 84:1381–1387

Reed JR, Cawley GF, Backes WL (2011) Inhibition of cytochrome P450 1A2-mediated metabolism and production of reactive oxygen species by heme oxygenase-1 in rat liver microsomes. Drug Metab Lett 5:6–16

Capdevila JH, Falck JR, Harris RC (2000) Cytochrome P450 and arachidonic acid bioactivation: molecular and functional properties of the arachidonate monooxygenase. J Lipid Res 41:163–181

Chen JK, Capdevila J, Harris RC (2001) Cytochrome P450 epoxygenase metabolism of arachidonic acid inhibits apoptosis. Mol Cell Biol 21:6322–6331

Spector AA (2009) Arachidonic acid cytochrome P450 epoxygenase pathway. J Lipid Res 50:S52–S56

Thum T, Borlak J (2004) Mechanistic role of cytochrome P450 monooxygenases in oxidized low-density lipoprotein-induced vascular injury: therapy through LOX-1 receptor antagonism? Circ Res 94:e1–e13

Lakshmi SV, Padmaja G, Kuppusamy P, Kutala VK (2009) Oxidative stress in cardiovascular disease. Indian J Biochem Biophys 46:421–440

Csányi G, Miller FJ (2014) Oxidative stress in cardiovascular disease. Int J Mol Sci 15:6002–6008

Fujino G, Noguchi T, Matsuzawa A, Yamauchi S, Saitoh M, Takeda K, Ichijo H (2007) Thioredoxin and TRAF family proteins regulate reactive oxygen species-dependent activation of ASK1 through reciprocal modulation of the N-terminal homophilic interaction of ASK1. Mol Cell Biol 27:8152–8163

Turrens JF (2010) Superoxide dismutase and catalase. In: McQueen CA (ed) Comprehensive toxicology. Elsevier, Oxford

Rhee SG1, Woo HA, Kil IS, Bae SH (2012) Peroxiredoxin functions as a peroxidase and a regulator and sensor of local peroxides. J Biol Chem 287:4403–4410

Parmigiani A, Budanov AV (2016) Sensing the environment through sestrins: implications for cellular metabolism. Int Rev Cell Mol Biol 327:1–42

Lubos E, Loscalzo J, Handy DE (2011) Glutathione peroxidase-1 in health and disease: from molecular mechanisms to therapeutic opportunities. Antioxid Redox Signal 15:1957–1997

Ho E, Karimi Galougahi K, Liu CC, Bhindi R, Figtree GA (2013) Biological markers of oxidative stress: applications to cardiovascular research and practice. Redox Biol 1:483–491

Sies H (2015) Oxidative stress: a concept in redox biology and medicine. Redox Biol 4:180–183

Galley JC, Straub AC (2017) Redox control of vascular function. Arterioscler Thromb Vasc Biol 37:e178–e184

Doughan AK, Harrison DG, Dikalov SI (2008) Molecular mechanisms of angiotensin II-mediated mitochondrial dysfunction: linking mitochondrial oxidative damage and vascular endothelial dysfunction. Circ Res 102:488–496

Daffu G, del Pozo CH, O’Shea KM, Ananthakrishnan R, Ramasamy R, Schmidt AM (2013) Radical roles for RAGE in the pathogenesis of oxidative stress in cardiovascular diseases and beyond. Int J Mol Sci 14:19891–19910

Brouwers O, de Vos-Houben JM, Niessen PM, Miyata T, van Nieuwenhoven F, Janssen BJ, Hageman G, Stehouwer CD, Schalkwijk CG (2013) Mild oxidative damage in the diabetic rat heart is attenuated by glyoxalase-1 overexpression. Int J Mol Sci 14:15724–15739

Caligiuri SPB, Parikh M, Stamenkovic A, Pierce GN, Aukema HM (2017) Dietary modulation of oxylipins in cardiovascular disease and aging. Am J Physiol Heart Circ Physiol 313:H903–H918

Wilhelm I, Nyúl-Tóth A, Kozma M, Farkas AE, Krizbai IA (2017) Role of pattern recognition receptors of the neurovascular unit in inflamm-aging. Am J Physiol Heart Circ Physiol 313:H1000–H1012

Corbi G, Bianco A, Turchiarelli V, Cellurale M, Fatica F, Daniele A, Mazzarella G, Ferrara N (2013) Potential mechanisms linking atherosclerosis and increased cardiovascular risk in COPD: focus on sirtuins. Int J Mol Sci 14:12696–12713

Hine C (2017) An antioxidant to attenuate aortic aging. Sci Transl Med 9:eaaq1235

Rehman H, Liu Q, Krishnasamy Y, Shi Z, Ramshesh VK, Haque K, Schnellmann RG, Murphy MP, Lemasters JJ, Rockey DC, Zhong Z (2016) The mitochondria-targeted antioxidant MitoQ attenuates liver fibrosis in mice. Int J Physiol Pathophysiol Pharmacol 8:14–27

Gioscia-Ryan RA, Battson ML, Cuevas LM, Eng JS, Murphy MP, Seals DR (2017) Mitochondria-targeted antioxidant therapy with MitoQ ameliorates aortic stiffening in old mice. J Appl Physiol https://doi.org/10.1152/japplphysiol.00670.2017

Patel A, Malinovska L, Saha S, Wang J, Alberti S, Krishnan Y, Hyman AA (2017) ATP as a biological hydrotrope. Science 356:753–756

Meyer T, Voigt N (2017) In search for novel functions of adenosine 5 ′ -triphosphate (ATP) in the heart. Cardiovasc Res 113:e59–e60

Martin DDO, Hayden MR (2017) Neurodegeneration: role of repeats in protein clearance. Nature 545:33–34

Ashkenazi A, Bento CF, Ricketts T, Vicinanza M, Siddiqi F, Pavel M, Squitieri F, Hardenberg MC, Imarisio S, Menzies FM, Rubinsztein DC (2017) Polyglutamine tracts regulate beclin 1-dependent autophagy. Nature 545:108–111

Ge F, Chen W, Qin J, Zhou Z, Liu R, Liu L, Tan J, Zou T, Li H, Ren G, Chen C (2015) Ataxin-3 like (ATXN3L), a member of the Josephin family of deubiquitinating enzymes, promotes breast cancer proliferation by deubiquitinating Krüppel-like factor 5 (KLF5). Oncotarget 6:21369–21378

Hoffmann R, Valencia A (2004) A gene network for navigating the literature. Nat Genet 36:664. (Information Hyperlinked over Proteins ( www.ihop-net.org )

Universal Protein Resource (UniProt) Consortium (2002–2016) European Bioinformatics Institute, Swiss Institute of Bioinformatics, and Protein Information Resource ( www.uniprot.org )

Yang H, Liu S, He WT, Zhao J, Jiang LL, Hu HY (2015) Aggregation of polyglutamine-expanded ataxin 7 protein specifically sequesters ubiquitin-specific protease 22 and deteriorates its deubiquitinating function in the Spt–Ada–Gcn5–acetyltransferase (SAGA) complex. J Biol Chem 290:21996–22004

Nagai M, Hoshide S, Kario K (2010) Sleep duration as a risk factor for cardiovascular disease—a review of the recent literature. Curr Cardiol Rev 6:54–61

Wolk R, Gami AS, Garcia-Touchard A, Somers VK (2005) Sleep and cardiovascular disease. Curr Probl Cardiol 30:625–662

Eckert DJ, Jordan AS, Merchia P, Malhotra A (2007) Central sleep apnea: pathophysiology and treatment. Chest 131:595–607

Del Pozo J, Gómez-Tellado M, López-Gutiérrez JC (2012) Vascular malformations in childhood. Actas Dermo-Sifiliográphicas 103:661–678

Hutson MR, Keyte AL, Hernández-Morales M, Gibbs E, Kupchinsky ZA, Argyridis I, Erwin KN, Pegram K, Kneifel M, Rosenberg PB, Matak P, Xie L, Grandl J, Davis EE, Katsanis N, Liu C, Benner EJ (2017) Temperature-activated ion channels in neural crest cells confer maternal fever-associated birth defects. Sci Signal 10:eaal4055

Kamstrup PR, Hung MY, Witztum JL, Tsimikas S, Nordestgaard BG (2017) Oxidized phospholipids and risk of calcific aortic valve disease. The Copenhagen General Population Study. Arterioscler Thromb Vasc Biol 37:1570–1578

Forrester SJ, Griendling KK (2017) Mitochondrial respiration and atherosclerosis. R-E-S-P-I-R-E. Find out what it means to Mφ (and VSMC). Arterioscler Thromb Vasc Biol 37:2229–2230

Yu EPK, Reinhold J, Yu H, Starks L, Uryga AK, Foote K, Finigan A, Figg N, Pung YF, Logan A, Murphy MP, Bennett M (2017) Mitochondrial respiration is reduced in atherosclerosis, promoting necrotic core formation and reducing relative fibrous cap thickness. Arterioscler Thromb Vasc Biol 37:2322–2332

Lanzer P, Boehm M, Sorribas V, Thiriet M, Janzen J, Zeller T, St Hilaire C, Shanahan C (2014) Medial vascular calcification revisited: review and perspectives. Eur Heart J 35:1515–1525

Leipsic J, Blanke P, Norgaard BL (2017) Defining the relationship between atherosclerotic plaque, ischaemia, and risk—the story unfolds. Eur Heart J Cardiovasc Imaging 18:508–509

Diaz-Zamudio M, Fuchs TA, Slomka P, Otaki Y, Arsanjani R, Gransar H, Germano G, Berman DS, Kaufmann PA, Dey D (2017) Quantitative plaque features from coronary computed tomography angiography to identify regional ischemia by myocardial perfusion imaging. Eur Heart J Cardiovasc Imaging 18:499–507

Joseph P, Leong D, McKee M, Anand SS, Schwalm JD, Teo K, Mente A, Yusuf S (2017) Reducing the global burden of cardiovascular disease. I. the epidemiology and risk factors. Circ Res 121:677–694

King KR, Aguirre AD, Ye YX, Sun Y, Roh JD, Ng RP, Kohler RH, Arlauckas SP, Iwamoto Y, Savol A, Sadreyev RI, Kelly M, Fitzgibbons TP, Fitzgerald KA, Mitchison T, Libby P, Nahrendorf M, Weissleder R (2017) IRF3 and type I interferons fuel a fatal response to myocardial infarction. Nat Med 23:1481–1487

Chen K, Xu Z, Liu Y, Wang Z, Li Y, Xu X, Chen C, Xia T, Liao Q, Yao Y, Zeng C, He D, Yang Y, Tan T, Yi J, Zhou J, Zhu H, Ma J, Zeng C (2017) Irisin protects mitochondria function during pulmonary ischemia/reperfusion injury. Sci Transl Med 9:eaao6298

Pinto YM, Elliott PM, Arbustini E, Adler Y, Anastasakis A, Böhm M, Duboc D, Gimeno J, de Groote P, Imazio M, Heymans S, Klingel K, Komajda M, Limongelli G, Linhart A, Mogensen J, Moon J, Pieper PG, Seferovic PM, Schueler S, Zamorano JL, Caforio AL, Charron P (2016) Proposal for a revised definition of dilated cardiomyopathy, hypokinetic non-dilated cardiomyopathy, and its implications for clinical practice: a position statement of the ESC Working Group on Myocardial and Pericardial Diseases. Eur Heart J 37:1850–1858

Claes GR, van Tienen FH, Lindsey P, Krapels IP, Helderman-van den Enden AT, Hoos MB, Barrois YE, Janssen JW, Paulussen AD, Sels JW, Kuijpers SH, van Tintelen JP, van den Berg MP, Heesen WF, Garcia-Pavia P, Perrot A, Christiaans I, Salemink S, Marcelis CL, Smeets HJ, Brunner HG, Volders PG, van den Wijngaard A (2016) Hypertrophic remodelling in cardiac regulatory myosin light chain (MYL2) founder mutation carriers. Eur Heart J 37:1815–1822

Paterson AD (2017) HbA1c for type 2 diabetes diagnosis in Africans and African Americans: Personalized medicine NOW! PLoS Med 14:e1002384

Wan A, Rodrigues B (2016) Endothelial cell–cardiomyocyte crosstalk in diabetic cardiomyopathy. Cardiovasc Res 111:172–183

Nattel S (2016) How does fibrosis promote atrial fibrillation persistence: in silico findings, clinical observations, and experimental data. Cardiovasc Res 110:295–297

Zahid S, Cochet H, Boyle PM, Schwarz EL, Whyte KN, Vigmond EJ, Dubois R, Hocini M, Haïssaguerre M, Jaïs P, Trayanova NA (2016) Patient-derived models link re-entrant driver localization in atrial fibrillation to fibrosis spatial pattern. Cardiovasc Res 110:443–454

Doshi D, Marx SO (2009) Ion channels, transporters, and pumps as targets for heart failure. J Cardiovasc Pharmacol 54:273–278

Laurent S (1995) Arterial wall hypertrophy and stiffness in essential hypertensive patients. Hypertension 26:355–362

Blaustein MP, Chen L, Hamlyn JM, Leenen FH, Lingrel JB, Wier WG, Zhang J (2016) Pivotal role of α2 Na + pumps and their high affinity ouabain binding site in cardiovascular health and disease. J Physiol 594:6079–6103

Blaustein MP (2017) How does pressure overload cause cardiac hypertrophy and dysfunction? High-ouabain affinity cardiac Na + pumps are crucial. Am J Physiol Heart Circ Physiol 313:H919–H930

Tang X, Chen XF, Wang NY, Wang XM, Liang ST, Zheng W, Lu YB, Zhao X, Hao DL, Zhang ZQ, Zou MH, Liu DP, Chen HZ (2017) SIRT2 acts as a cardioprotective deacetylase in pathological cardiac hypertrophy. Circulation 136:2051–2067

LaRocca G, Aspelund T, Greve AM, Eiriksdottir G, Acharya T, Thorgeirsson G, Harris TB, Launer LJ, Gudnason V, Arai AE (2017) Fibrosis as measured by the biomarker, tissue inhibitor metalloproteinase-1, predicts mortality in Age Gene Environment Susceptibility-Reykjavik (AGES–Reykjavik) Study. Eur Heart J 38:3423–3430

Lagares D, Santos A, Grasberger PE, Liu F, Probst CK, Rahimi RA, Sakai N, Kuehl T, Ryan J, Bhola P, Montero J, Kapoor M, Baron M, Varelas X, Tschumperlin DJ, Letai A, Tager AM (2017) Targeted apoptosis of myofibroblasts with the BH3 mimetic ABT-263 reverses established fibrosis. Sci Transl Med 9:eaal3765

Magdaleno F, Arriazu E, Ruiz de Galarreta M, Chen Y, Ge X, Conde de la Rosa L, Nieto N (2016) Cartilage oligomeric matrix protein participates in the pathogenesis of liver fibrosis. J Hepatol 65:963–971

Schulz JN, Nüchel J, Niehoff A, Bloch W, Schönborn K, Hayashi S, Kamper M, Brinckmann J, Plomann M, Paulsson M, Krieg T, Zaucke F, Eckes B (2016) COMP-assisted collagen secretion—a novel intracellular function required for fibrosis. J Cell Sci 129:706–716

Vuga LJ, Milosevic J, Pandit K, Ben-Yehudah A, Chu Y, Richards T, Sciurba J, Myerburg M, Zhang Y, Parwani AV, Gibson KF, Kaminski N (2013) Cartilage oligomeric matrix protein in idiopathic pulmonary fibrosis. PLoS One 8:e83120

Zachou K, Gabeta S, Shums Z, Gatselis NK, Koukoulis GK, Norman GL, Dalekos GN (2017) COMP serum levels: a new non-invasive biomarker of liver fibrosis in patients with chronic viral hepatitis. Eur J Intern Med 38:83–88

Ghatak S, Hascall VC, Markwald RR, Feghali-Bostwick C, Artlett CM, Gooz M, Bogatkevich GS, Atanelishvili I, Silver RM, Wood J, Thannickal VJ, Misra S (2017) Transforming growth factor β1 (TGFβ1)-induced CD44V6–NOX4 signaling in pathogenesis of idiopathic pulmonary fibrosis. J Biol Chem 292:10490–10519

Ghatak S, Markwald RR, Hascall VC, Dowling W, Lottes RG, Baatz JE, Beeson G, Beeson CC, Perrella MA, Thannickal VJ, Misra S (2017) Transforming growth factor β1 (TGFβ1) regulates CD44V6 expression and activity through extracellular signal-regulated kinase (ERK)-induced EGR1 in pulmonary fibrogenic fibroblasts. J Biol Chem 292:10465–10489

Schafer S, Viswanathan S, Widjaja AA, Lim WW, Moreno-Moral A, DeLaughter DM, Ng B, Patone G, Chow K, Khin E, Tan J, Chothani SP, Ye L, Rackham OJL, Ko NSJ, Sahib NE, Pua CJ, Zhen NTG, Xie C, Wang M, Maatz H, Lim S, Saar K, Blachut S, Petretto E, Schmidt S, Putoczki T, Guimarāes-Camboa N, Wakimoto H, van Heesch S, Sigmundsson K, Lim SL, Soon JL, Chao VTT, Chua YL, Tan TE, Evans SM, Loh YJ, Jamal MH, Ong KK, Chua KC, Ong BH, Chakaramakkil MJ, Seidman JG, Seidman CE, Hubner N, Sin KYK, Cook SA (2017) IL-11 is a crucial determinant of cardiovascular fibrosis. Nature 552:110–115

ADS Google Scholar

Crossman DJ, Shen X, Jüllig M, Munro M, Hou Y, Middleditch M, Shrestha D, Lal ALS, dos Remedios CG, Baddeley D, Ruygrok PN, Soeller C (2017) Increased collagen within the transverse tubules in human heart failure. Cardiovasc Res 113:879–891

Louch WE, Nattel S (2017) T-tubular collagen: a new player in mechanosensing and disease? Cardiovasc Res 113:839–840

Vermeulen Z, Hervent AS, Dugaucquier L, Vandekerckhove L, Rombouts M, Beyens M, Schrijvers DM, De Meyer GRY, Maudsley S, de Keulenaer GW, Segers VFM (2017) Inhibitory actions of the NRG-1/ErbB4 pathway in macrophages during tissue fibrosis in the heart, skin, and lung. Am J Physiol Heart Circ Physiol 313:H934–H945

Midgley AC, Oltean S, Hascall V, Woods EL, Steadman R, Phillips AO, Meran S (2017) Nuclear hyaluronidase 2 drives alternative splicing of CD44 pre-mRNA to determine profibrotic or antifibrotic cell phenotype. Sci Signal 10:eaao1822

Wibulswas A, Croft D, Bacarese-Hamilton I, McIntyre P, Genot E, Kramer IM (2000) The CD44v7/8 epitope as a target to restrain proliferation of fibroblast-like synoviocytes in rheumatoid arthritis. Am J Pathol 157:2037–2044

Azevedo PS, Polegato BF, Minicucci MF, Paiva SA, Zornoff LA (2016) Cardiac remodeling: concepts, clinical impact, pathophysiological mechanisms and pharmacologic treatment. Arquivos Brasileiros de Cardiologica 106:62–69

Doenst T, Nguyen TD, Abel ED (2013) Cardiac metabolism in heart failure: implications beyond ATP production. Circ Res 113:709–724

Hong T, Yang H, Zhang SS, Cho HC, Kalashnikova M, Sun B, Zhang H, Bhargava A, Grabe M, Olgin J, Gorelik J, Marbán E, Jan LY, Shaw RM (2014) Cardiac BIN1 folds T-tubule membrane, controlling ion flux and limiting arrhythmia. Nat Med 20:624–632

Ross GR, Jahangir A (2016) Functional alterations of ion channels from cardiac fibroblasts in heart diseases. J Patient-Centered Res Rev 3:207–216

Van Petegem F (2012) Ryanodine receptors: structure and function. J Biol Chem 287:31624–31632

Prosser BL, Hernández-Ochoa EO, Schneider MF (2011) S100A1 and calmodulin regulation of ryanodine receptor in striated muscle. Cell Calcium 50:323–331

Carlisle Michel JJ, Dodge KL, Wong W, Mayer NC, Langeberg LK, Scott JD (2004) PKA-phosphorylation of PDE4D3 facilitates recruitment of the mAKAP signalling complex. Biochem J 381:587–592

Schwinger RH, Bundgaard H, Müller-Ehmsen J, Kjeldsen K (2003) The Na,K-ATPase in the failing human heart. Cardiovasc Res 57:913–920

Liu L, Wu J, Kennedy DJ (2016) Regulation of cardiac remodeling by cardiac Na + /K + ATPase isoforms. Front Physiol 7:382

Seog DH, Kim SJ (2017) Kinesin-1, amyloid precursor protein (APP)-vesicle transport motor interacts with FUN14 domain containing 1 (FUNDC1) via the tetratricopeptide repeat domain of KLC1. Alzheimers Dement 13:P658

Wu S, Lu Q, Wang Q, Ding Y, Ma Z, Mao X, Huang K, Xie Z, Zou MH (2017) Binding of FUN14 domain containing 1 to inositol 1,4,5-trisphosphate receptor in mitochondrion-associated endoplasmic reticulum membranes maintains mitochondrial dynamics and function in hearts in vivo. Circulation 136:2248–2266

Lim SL, Lam CSP, Segers VFM, Brutsaert DL, de Keulenaer GW (2015) Cardiac endothelium–myocyte interaction: clinical opportunities for new heart failure therapies regardless of ejection fraction. Eur Heart J 36:2050–2060

Liu VWT, Huang PL (2008) Cardiovascular roles of nitric oxide: a review of insights from nitric oxide synthase gene disrupted mice. Cardiovasc Res 77:19–29

Rastaldo R, Pagliaro P, Cappello S, Penna C, Mancardi D, Westerhof N, Losano G (2007) Nitric oxide and cardiac function. Life Sci 81:779–793

Vandecasteele G, Eschenhagen T, Scholz H, Stein B, Verde I, Fischmeister R (1999) Muscarinic and β-adrenergic regulation of heart rate, force of contraction and calcium current is preserved in mice lacking endothelial nitric oxide synthase. Nat Med 5:331–334

Martin SR, Emanuel K, Sears CE, Zhang YH, Casadei B (2006) Are myocardial eNOS and nNOS involved in the β-adrenergic and muscarinic regulation of inotropy? A systematic investigation. Cardiovasc Res 70:97–106

Recchia FA, McConnell PI, Loke KE, Xu X, Ochoa M, Hintze TH (1999) Nitric oxide controls cardiac substrate utilization in the conscious dog. Cardiovasc Res 44:325–332

Odiete O, Hill MF, Sawyer DB (2012) Neuregulin in cardiovascular development and disease. Circ Res 111:1376–1385

Furuhashi M, Saitoh S, Shimamoto K, Miura T (2014) Fatty acid-binding protein 4 (FABP4): pathophysiological insights and potent clinical biomarker of metabolic and cardiovascular diseases. Clin Med Insights Cardiol 8:23–33

Hagberg C, Mehlem A, Falkevall A, Muhl L, Eriksson U (2013) Endothelial fatty acid transport: role of vascular endothelial growth factor B. Physiology 28:125–134

Elmasri H, Karaaslan C, Teper Y, Ghelfi E, Weng M, Ince TA, Kozakewich H, Bischoff J, Cataltepe S (2009) Fatty acid binding protein 4 is a target of VEGF and a regulator of cell proliferation in endothelial cells. FASEB J 23:3865–3873

Harjes U, Bridges E, McIntyre A, Fielding BA, Harris AL (2014) Fatty acid-binding protein 4, a point of convergence for angiogenic and metabolic signaling pathways in endothelial cells. J Biol Chem 289:23168–23176

Abu-Taha IH, Heijman J, Hippe HJ, Wolf NM, El-Armouche A, Nikolaev VO, Schäfer M, Würtz CM, Neef S, Voigt N, Baczkó I, Varró A, Müller M, Meder B, Katus HA, Spiger K, Vettel C, Lehmann LH, Backs J, Skolnik EY, Lutz S, Dobrev D, Wieland T (2017) Nucleoside diphosphate kinase-C suppresses cAMP formation in human heart failure. Circulation 135:881–897

Traynham CJ, Cannavo A, Zhou Y, Vouga A, Woodall BP, Hullmann JE, Ibetti J, Gold JI, Chuprun JK, Gao E, Koch WJ (2015) Differential role of G protein-coupled receptor kinase 5 in physiological versus pathological cardiac hypertrophy. Circ Res 117:1001–1012

Jeong MH, Kim HJ, Pyun JH, Choi KS, Lee DI, Solhjoo S, O’Rourke B, Tomaselli GF, Jeong DS, Cho H, Kang JS (2017) Cdon deficiency causes cardiac remodeling through hyperactivation of WNT/β-catenin signaling. Proc Natl Acad Sci USA 114:E1345–E1354

Lekawanvijit S, Kompa AR, Krum H (2016) Protein-bound uremic toxins: a long overlooked culprit in cardiorenal syndrome. Am J Physiol Ren Physiol 311:F52–F62

Bajaj A, Susztak K, Damrauer SM (2017) APOL1 and cardiovascular disease. A story in evolution. Arterioscler Thromb Vasc Biol 37:1587–1589

Chen TK, Appel LJ, Grams ME, Tin A, Choi MJ, Lipkowitz MS, Winkler CA, Estrella MM (2017) APOL1 risk variants and cardiovascular disease. Results from the AASK (African American Study of Kidney Disease and Hypertension). Arterioscler Thromb Vasc Biol 37:1765–1769

Guo J, Lu L, Hua Y, Huang K, Wang I, Huang L, Fu Q, Chen A, Chan P, Fan H, Liu ZM, Wang BH (2017) Vasculopathy in the setting of cardiorenal syndrome: toles of protein-bound uremic toxins. Am J Physiol Heart Circ Physiol 313:H1–H13

Leskova A, Pardue S, Glawe JD, Kevil CG, Shen X (2017) Role of thiosulfate in hydrogen sulfide-dependent redox signaling in endothelial cells. Am J Physiol Heart Circ Physiol 313:H256–H264

Sowers KM, Hayden MR (2010) Calcific uremic arteriolopathy. Pathophysiology, reactive oxygen species and therapeutic approaches. Oxidative Med Cell Longev 3:109–121

Thomas C, Tampé R (2017) Structure of the TAPBPR–MHC I complex defines the mechanism of peptide loading and editing. Science 358:1060–1064

Jiang J, Natarajan K, Boyd LF, Morozov GI, Mage MG, Margulies DH (2017) Crystal structure of a TAPBPR–MHC I complex reveals the mechanism of peptide editing in antigen presentation. Science 358:1064–1068

Zumrutdal A (2015) Role of β2-microglobulin in uremic patients may be greater than originally suspected. World J Nephrol 4:98–104

Rajamannan NM, Evans FJ, Aikawa E, Grande-Allen KJ, Demer LL, Heistad DD, Simmons CA, Masters KS, Mathieu P, O’Brien KD, Schoen FJ, Towler DA, Yoganathan AP, Otto CM (2011) Calcific aortic valve disease: not simply a degenerative process—a review and agenda for research from the National Heart and Lung and Blood Institute Aortic Stenosis Working Group. Executive summary: calcific aortic valve disease-2011 update. Circulation 124:1783–1791

Lerman DA, Prasad S, Alotti N (2015) Calcific aortic valve disease: molecular mechanisms and therapeutic approaches. Eur Cardiol 10:108–112

Best PJM, Rajamannan NM (2017) OxPL—elusive risk factor in calcific aortic valve disease or another piece of the puzzle? Arterioscler Thromb Vasc Biol 37:1425–1427

Clarke R, Peden JF, Hopewell JC, Kyriakou T, Goel A, Heath SC, Parish S, Barlera S, Franzosi MG, Rust S, Bennett D, Silveira A, Malarstig A, Green FR, Lathrop M, Gigante B, Leander K, de Faire U, Seedorf U, Hamsten A, Collins R, Watkins H, Farrall M; PROCARDIS Consortium (2009) Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N Engl J Med 361:2518–2528

Carmona FD, Martín J, González-Gay MA (2016) New insights into the pathogenesis of giant cell arteritis and hopes for the clinic. Expert Rev Clin Immunol 12:57–66

Wen Z, Shen Y, Berry G, Shahram F, Li Y, Watanabe R, Liao YJ, Goronzy JJ, Weyand CM (2017) The microvascular niche instructs T cells in large vessel vasculitis via the VEGF–Jagged1–Notch pathway. Sci Transl Med 9:eaal3322

Brozovich FV, Nicholson CJ, Degen CV, Gao YZ, Aggarwal M, Morgan KG (2016) Mechanisms of vascular smooth muscle contraction and the basis for pharmacologic treatment of smooth muscle disorders. Pharmacol Rev 68:476–532

Brouillard P, Vikkula M (2007) Genetic causes of vascular malformations. Hum Mol Genet 16:R140–R149

Online Mendelian Inheritance in Man—An Online Catalog of Human Genes and Genetic Disorders (1966–2016) McKusick–Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine ( www.omim.org )

Amyere M, Revencu N, Helaers R, Pairet E, Baselga E, Cordisco MR, Chung WK, Dubois J, Lacour JP, Martorell L, Mazereeuw-Hautier J, Pyeritz RE, Amor DJ, Bisdorff A, Blei F, Bombei H, Dompmartin A, Brooks DG, Dupont J, González-Enseñat MA, Frieden IJ, Gérard M, Kvarnung M, Hanson-Kahn AK, Hudgins L, Léauté-Labrèze C, McCuaig C, Metry D, Parent P, Paul C, Petit F, Phan A, Quéré I, Salhi A, Turner AM, Vabres P, Vicente A, Wargon O, Watanabe S, Weibel L, Wilson A, Willing M, Mulliken JB, Boon LM, Vikkula M (2017) Germline loss-of-function mutations in EPHB4 cause a second form of capillary malformation–arteriovenous malformation (CM–AVM2) deregulating RAS–MAPK signaling. Circulation 136:1037–1048

Ojosnegros S, Cutrale F, Rodríguez D, Otterstrom JJ, Chiu CL, Hortigüela V, Tarantino C, Seriola A, Mieruszynski S, Martínez E, Lakadamyali M, Raya A, Fraser SE (2017) Eph–ephrin signaling modulated by polymerization and condensation of receptors. Proc Natl Acad Sci USA 114:13188–13193

Cura M, Elmerhi F, Suri R, Bugnone A, Dalsaso T (2010) Vascular malformations and arteriovenous fistulas of the kidney. Acta Radiol 51:144–149

Frey S, Haine A, Kammer R, von Tengg-Kobligk H, Obrist D, Baumgartner I (2017) Hemodynamic characterization of peripheral arterio-venous malformations. Ann Biomed Eng 45:1449–1461

Bean WB (1958) Blue rubber-bleb nevi of the skin and gastrointestinal tract. In: Bean WB (ed) Vascular spiders and related lesions of the skin. Charles C Thomas, Springfield, IL

Gascoyen M (1860) Case of naevus involving the parotid gland and causing death from suffocation: naevi of the viscera. Trans Pathol Soc Lond 11:267

Brahami N, Aribi M, Sari BE, Kien PKV, Touitou I, Lefranc G, Barat Houari-M (2013) Lack of TEK gene mutation in patients with cutaneomucosal venous malformations from the North-Western region of Algeria. Gen Res Int 2013:784789

Red-Horse K, Ueno H, Weissman IL, Krasnow MA (2010) Coronary arteries form by developmental reprogramming of venous cells. Nature 464:549–553

Cermenati S, Moleri S, Cimbro S, Corti P, Del Giacco L, Amodeo R, Dejana E, Koopman P, Cotelli F, Beltrame M (2008) Sox18 and Sox7 play redundant roles in vascular development. Blood 111:2657–2666

Cui X, Lu YW, Lee V, Kim D, Dorsey T, Wang Q, Lee Y, Vincent P, Schwarz J, Dai G (2015) Venous endothelial marker COUP-TFII regulates the distinct pathologic potentials of adult arteries and veins. Sci Report 5:16193

Sarkar A, Hochedlinger K (2013) The Sox family of transcription factors: versatile regulators of stem and progenitor cell fate. Cell Stem Cell 12:15–30

Kamachi Y, Kondoh H (2013) Sox proteins: regulators of cell fate specification and differentiation. Development 140:4129–4144

Zhou Y, Williams J, Smallwood PM, Nathans J (2015) Sox7, Sox17, and Sox18 cooperatively regulate vascular development in the mouse retina. PLoS One 10:e0143650

Kume T (2010) Specification of arterial, venous, and lymphatic endothelial cells during embryonic development. Histol Histopathol 25:637–646

Peacock HM, Caolo V, Jones EAV (2016) Arteriovenous malformations in hereditary haemorrhagic telangiectasia: looking beyond ALK1–NOTCH interactions. Cardiovasc Res 109:196–203

Cunha SI, Magnusson PU, Dejana E, Lampugnani MG (2017) Deregulated TGF-β/BMP signaling in vascular malformations. Circ Res 121:981–999

Chang TH, Hsieh FL, Zebisch M, Harlos K, Elegheert J, Jones EY (2015) Structure and functional properties of Norrin mimic Wnt for signalling with Frizzled4, Lrp5/6, and proteoglycan. eLife 4:e06554

Ke J, Harikumar KG, Erice C, Chen C, Gu X, Wang L, Parker N, Cheng Z, Xu W, Williams BO, Melcher K, Miller LJ, Xu HE (2013) Structure and function of Norrin in assembly and activation of a Frizzled 4–Lrp5/6 complex. Genes Dev 27:2305–2319

Pendeville H, Winandy M, Manfroid I, Nivelles O, Motte P, Pasque V, Peers B, Struman I, Martial JA, Voz ML (2008) Zebrafish Sox7 and Sox18 function together to control arterial-venous identity. Dev Biol 317:405–416

Vallon M, Rohde F, Janssen KP, Essler M (2010) Tumor endothelial marker 5 expression in endothelial cells during capillary morphogenesis is induced by the small GTPase Rac and mediates contact inhibition of cell proliferation. Exp Cell Res 316:412–421

Hamada K, Oike Y, Ito Y, Maekawa H, Miyata K, Shimomura T, Suda T (2003) Distinct roles of Ephrin-B2 forward and EphB4 reverse signaling in endothelial cells. Arterioscler Thromb Vasc Biol 23:190–197

Bai J, Wang YJ, Liu L, Zhao YL (2014) Ephrin B2 and EphB4 selectively mark arterial and venous vessels in cerebral arteriovenous malformation. J Int Med Res 42:405–415

Kim YH, Hu H, Guevara-Gallardo S, Lam MT, Fong SY, Wang RA (2008) Artery and vein size is balanced by Notch and ephrin B2/EphB4 during angiogenesis. Development 135:3755–3764

Taylor AC1, Murfee WL, Peirce SM (2007) EphB4 expression along adult rat microvascular networks: EphB4 is more than a venous specific marker. Microcirculation 14:253–267

Somekawa S, Imagawa K, Hayashi H, Sakabe M, Ioka T, Sato GE, Inada K, Iwamoto T, Mori T, Uemura S, Nakagawa O, Saito Y (2012) Tmem100, an ALK1 receptor signaling-dependent gene essential for arterial endothelium differentiation and vascular morphogenesis. Proc Natl Acad Sci USA 109:12064–12069

Jin Y, Muhl L, Burmakin M, Wang Y, Duchez AC, Betsholtz C, Arthur HM, Jakobsson L (2017) Endoglin prevents vascular malformation by regulating flow-induced cell migration and specification through VEGFR2 signalling. Nat Cell Biol 19:639–652

Kim JH, Peacock MR, George SC, Hughes CCW (2012) BMP9 induces EphrinB2 expression in endothelial cells through an Alk1–BMPRII/ActRII–ID1/ID3-dependent pathway: implications for hereditary hemorrhagic telangiectasia type II. Angiogenesis 15:497–509

Gkatzis K, Thalgott J, Dos Santos-Luis D, Martin S, Lamandé N, Carette MF, Disch F, Snijder RJ, Westermann CJ, Mager JJ, Oh SP, Miquerol L, Arthur HM, Mummery CL, Lebrin F (2016) Interaction between ALK1 signaling and connexin40 in the development of arteriovenous malformations. Arterioscler Thromb Vasc Biol 36:707–717

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Thiriet, M. (2018). Cardiovascular Disease: An Introduction. In: Vasculopathies. Biomathematical and Biomechanical Modeling of the Circulatory and Ventilatory Systems, vol 8. Springer, Cham. https://doi.org/10.1007/978-3-319-89315-0_1

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Heart Disease - Free Essay Examples and Topic Ideas

Heart disease refers to a range of conditions that affect the heart’s ability to function properly. These conditions may include issues with the heart’s blood vessels, valves, or rhythm. Heart disease is a leading cause of death worldwide, and common risk factors include a poor diet, lack of exercise, smoking, and high blood pressure or cholesterol. Symptoms of heart disease may include chest pain, shortness of breath, fatigue, and palpitations. Treatment options range from medications and lifestyle changes to surgery or other medical procedures, depending on the severity of the condition.

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Congestive Heart Failure Etiology and Treatment Introduction Congestive heart failure (CHF) is a “progressive and debilitating disease” that is characterized by the congestion of body tissues (Nair & Peate, 2013, p. 237). Five percent of all medical admissions in hospitals are due to CHF. When an individual has this disease, his or her heart is not able to pump adequate blood […]
Lecithin, Trimethylamine Oxide, and Heart Diseases Lecithin is a dietary phospholipid that is associated cardiovascular diseases. Trimethylamine oxide is a metabolite of lecithin that causes heart diseases.
Sampling Methods in Nursing Study on Heart Failure In systematic sampling, the arrangement of the people was done in the order of their increase in age and selection using the same order.
Heart Disease in African Americans: Intervention According to the tests carried out among the target denizens of the population, 78% of the African Americans were in the risk area due to their unhealthy lifestyles, particularly improper dieting.
Types of Cardiac Arrhythmia Resulting From Centrifugal Acceleration In the context of an airplane, these factors tend to reproduce the weight of the unit mass of the persons in the jet.
Heart Disease: Nutrition Assessment As such, it is important for the patients to increase their consumption of whole grains, vegetables, legumes and fruits that are rich in trans-fatty acids and saturated fatty acids.
Analysis of Coronary Heart Disease In such a manner, the delivery of blood with oxygen and nutrients to the whole body is timely and undisrupted, which guarantees the healthy functioning of the whole physiological system.
Hypertension and Congestive Heart Failure In conclusion, the patient experiences a range of issues related to hypertension, which is likely to cause left-sided congestive heart failure since it is the most common in the population.
Heart Diseases in Florida: Cardiology The Centers for Disease Control in Florida encourages the management of heart ailments and dementia in all the regions and Districts of Florida.
Heart Attack: Cellular Functions and Problems The story describes the symptoms and processes in the body of a man who suffered a heart attack. A heart attack directly impacts the cellular processes in the organism.
Coronary Heart Disease Caused by Stress It is essential to study the degree of influence of stress on the development of coronary heart disease since, in this way, it will be possible to prevent it more successfully.
Obesity and Coronary Heart Disease As shown in Table 1, the researchers have collected data about the rate of obesity and CHD in the chosen group.
COPD, Valvular Disease, and CHF: Risk of Heart Disease Under these conditions, it is possible to analyze the case regarding the high risks of chronic obstructive pulmonary disease, valvular disease, and congestive heart failure.
Epidemiology of Heart Disease Among Canadians At the end of the study, the connection between heart disease epidemiological evidence, community strategies, and internal and external impacts will be revealed to contribute to a better application of knowledge.
Vitamin E for Prevention of Heart Diseases As experiments on the benefits of vitamin E show, ‘swimming’ is not always the key to a completely healthy life, in which the risk of a heart attack is reduced to a minimum.
Heart Failure and Chronic Obstructive Pulmonary Disease Respiratory: The patient is diagnosed with COPD and continues to smoke up to two packs a day. Psychosocial: The patient is conscious and able to communicate with the staff, informing them of his state of […]
Congestive Heart Failure Treatment Innovations The relevance of the problem of this disease for health care is conditioned by the prevalence of pathology and the high economic costs of its treatment.
Plan for Management of Patient with Schizophrenia and Heart Disease About 1% of the world’s population suffers from schizophrenia About 0. 7% of the UK population suffers from schizophrenia Schizophrenia can manifest any time from early adulthood onwards, but rarely when a person is below […]
Preventing Heart Failure: Case Study In addition to the signs of heart failure, Mrs. The use of oxygen through nasal cannulas reduces the load on the heart, and it is rational.
Importance of Dashboard in Heart Failure Preventing Thorough testing of the heart failure dashboard is essential to ensure its successful work and contribute to the reduction of the risk of hospitalization for heart failure.
Nutrition in Relation to Heart Diseases in African Americans While the causes of such an occurrence are varied, dietary and nutrition-based difficulties are one of the factors that can increase the risk of cardiovascular diseases among African Americans.
Analysis of Heart Failure: Diagnosis and Treatment The current paper examines the two types of HF – systolic and diastolic – and explains the differences between the varieties based on the case study.
Video Consultations Between Patients and Clinicians in Diabetes, Cancer, and Heart Failure Services For example, during one of my interactions with the patient, I was asked whether the hospital had the policy to avoid face-to-face interaction during the pandemic with the help of video examinations.
Diets to Prevent Heart Disease, Cancer, and Diabetes In order to prevent heart disease, cancer, and diabetes, people are required to adhere to strict routines, including in terms of diet. Additionally, people wanting to prevent heart disease, cancer, and diabetes also need to […]
Reducing Risks of Heart Diseases In recent years, the health of US citizens has been especially alarming: obesity and heart disease top the list of the most common causes of death, and the situation needs to be changed radically.
Critiquing Research: Fatigue in the Presence of Coronary Heart Disease Fatigue is a common and debilitating symptom linked to a number of acute and chronic conditions such as chronic heart failure and acute myocardial infarction. Fatigue has not been analyzed in regards to patients with stable coronary heart disease (CHD), despite the fact that it might factor into new onsets or progression of CHD. Therefore, […]
Hypertension and Risk of Heart Failure Therefore, it is essential to reduce the circulating volume with the help of diuretics, a low-sodium diet, and ACE inhibitors that block the activation of the RAAS.
Cardiomyopathy Types, Treatment, and Consequences Cardiomyopathy is a disease associated with a gradual increase in the volume of the left ventricle and, as a consequence, resulting in the formation of heart failure.
Impact of Cognitive Dysfunctions on Patients With Heart Failure Based on the statement, which has been the initial assumption, impaired cognitive functions correlate with a lack of participation in the treatment of heart failure. The frame in which the structural concepts of the research […]
American Heart Association on Coronary Artery Disease Coronary artery disease is a type of disease during which plaque accumulates in the blood vessels, restricting blood flow to the heart.
Heart Failure: Prevent Readmissions and Noncompliance With Chronic Management The Heart failure (HF) is a rising healthcare burden which is common among many admitted patients. The project will introduce preventive interventions and measures for HF.
Congestive Heart Failure: Diagnosis and Treatment Congestive Heart Failure is a condition characterized by decreasing pumping capacity of the heart muscles of a person resulting in the congestion of the body.
Heart Disease: Population Affected- Brooklyn Brooklyn leads in morbidity of heart diseases in comparison to the rest of New York and the United States in general.
IoT-Based Heart Attack Detection and Alert System The patient’s chest pain complaint mirrored against the prevailing hypertensive state, the elevated cholesterol levels, the chronic tobacco smoking, a high sodium diet, and inadequate physical activity.
Heart Failure: Diagnosis and Pharmacologic Treatment In addition, due attention should be paid to effective strategies for the prevention of symptoms and treatment of concomitant diseases to improve the quality of life of patients with heart failure.
The Different Types of Heart Failure Right-sided heart failure occurs when the right chamber of the heart has not enough power to pump blood to the lungs. The role of a nurse is to assess and educate a patient with heart […]
Pathophysiology of Congestive Heart Failure Cardiac output and stroke volume is lowered due to vasoconstriction. It causes pressure overload, which leads to congestion.
Congestive Heart Failure (CHF): Causes, Treatment and Prevention Congestive Heart Failure is a condition that occurs when the heart is unable to pump enough blood to meet the needs of the entire body.
Aspirin and Heart Attacks Relations Research studies have demonstrated aspirin is the recommended drug for secondary prevention of heart attack and other cardiovascular diseases. 2Research studies have demonstrated that aspirin is effective in the secondary prevention of cardiovascular diseases.
Health Issues of Heart Failure and Pediatric Diabetes As for the population, which is intended to participate in the research, I am convinced that there is the need to specify the patients who should be examined and monitored.
Systolic and Diastolic Heart Failure Second, the high sinus rhythm indicates the man’s irregular heartbeat, which is the result of the emergence of the specified event, and it is referred to as cardiac arrhythmias.
Chronic Obstructive Pulmonary Disease, Hypertension, and Heart Failure: The Case Study The most likely cause of the symptom is fluid accumulation and congestion in the pulmonary system due to the failed heart that reduces the kidneys’ perfusion, thus causing an increase in the production of renin.
Prevention of Heart Failure Hospital Readmissions This paper describes on improving patient’s health literacy and providing specialized nursing care will prevent heart failure hospital readmissions.
Readmission in Hypertension and Heart Failure Patients In research, the independent variables are presented by CHF interventions, mortality rates, and population size, whereas the dependent variable is the possible results of their use for people with PH.
Heart Disease Among Hispanic and Latino Population Hispanics and Latinos have the highest propensity for heart related diseases in the society. They are at a very high risk of developing diabetes, obesity, and hypertension.
The Role of Education in the Treatment of Congestive Heart Failure Home treatment plan is critical for the treatment and management of congestive heart failure, which is experienced by Mr.P. Hence, comprehensive education is central to the treatment and management of the congestive heart failure in […]
Hospital Readmission and Health Related Quality of Life in Patients With Heart Failure The article analyzes the treatment of patients and the bettering of care. And the third is the discharge itself and the plans that organize its carrying out.
Cardiology: Women and Heart Diseases Myocardial infarctions, also referred to as heart attacks, are some of the most dangerous cardiovascular diseases making a significant contribution to the mortality of the American population and imposing a great financial burden on the […]
Heart Disease and Stroke in Sarasota County Adults in Sarasota County must be informed of healthy lifestyles that reduce the risk of contracting cardiovascular diseases such as heart disease and stroke.
Chronic Heart Failure: Symptoms and Self-Management Finally, the other cause of CHF includes endocarditis or myocarditis, a condition that affects the heart valves or the muscles of the heart.
Coronary Heart Disease: Review One of the major concerns worth considering is the issue of aspirin failure. In summary, aspirin failure is a symbol of increased risk to coronary heart diseases.
Risk Factors Involving People with Ischaemic Heart Disease: In-Depth Interview In the following account of research on ischaemic heart disease, the researcher conducts qualitative research and qualitative analysis of the data obtained to determine the cause of the disease.
Left-Sided Heart Failure and Nursing Intervention Thus left-sided heart failure or left ventricular failure refers to a condition where the left part of the heart is unable to propel adequate oxygenated blood from the pulmonary transmission to the body through the […]
Congestive Heart Failure – One of the Most Devastating Diseases Based on the guideline, the study will be focused on all aspects in the management of CHF. This is a very efficient theory in addressing nursing issues and more precisely the management of CHF.
Home Health Care vs. Telemonitoring: Reducing Hospital Readmissions for Patients With Heart Failure In the United States, chronic heart failure is regarded as the number one cause of both the hospitalization and readmission of patients.
Coronary Heart Disease Aggravated by Type 2 Diabetes and Age In the case, the patient shows multiple signs associated with the coronary heart disease, which is associated with shortness of breath, irregular heartbeats, faster heartbeats, fatigue, and hypertension. A possible backward failure in the right […]
Heart Disease in New York State For those residing in New York, one of the most populous and metropolitan states in the United States, the cardiovascular disease presents one of the most serious threats.
Why the Elders Delay Responding to Heart Failure Symptoms The paper would discuss the reasons the elderly delay in responding to the symptoms of heart failure. It incorporates the history of the problem and seeks to use the current technology to solve the problem.
Heart Disease and Low Carbohydrate Diets My opinion about the connection between heart diseases and low-carb diets is based on the article written by Sacks and his team for the Journal of the American Medical Association in 2014 where the authors […]
Heart Disease: Cell Death During Myocardial Infarction This process is known as the non-reversible cell injury because of the changes in the cell structure and functions when the cell membrane is damaged, and the cell dies.
Intervention of Heart Diseases in Children The resources that are necessary for the program include the human resources: the governing body of the school, several teachers and parents willing to promote the program, health consultants.
Remote Care Costs for Congestive Heart Failure Various aspects of the article including the significance of the chosen problem, methods, and approaches, the reliability of results and the articles structure will be discussed and evaluated.
Identification and Assessment of Heart Disease Heart diseases have always been of primary concern for the population of the United States of America. The identification of heart diseases in the elderly can be rather a challenge due to the variety of […]
Heart Disease Among Hispanic & Latino Population One of the causes of the rise in the case of heart diseases in Westminster is the literacy rate of the Hispanic/Latinos in the county.
Heart Failure: Prevention of the Disease Heart failure is now occurring in younger people and it is vital to make them cautious and have a healthy lifestyle to prevent the disease. The purpose of the leaflet is to draw people’s attention […]
Prevention of Heart Disease and Stroke in Collier County According to the statistical data, presented by the Health Planning Council of Southwest Florida, these health problems are among the leading causes of death in this particular community. This strategy is helpful for understanding various […]
Understanding Cardiomyopathy in the Elderly There are different types of cardiomyopathy diseases, but the one that prevails among the elderly is restrictive cardiomyopathy, according to the National Institutes of Health. Dilated cardiomyopathy is most prevalent in Africa, mainly due to […]
Cardiomyopathy in the Elderly Patients Lack of flexibility of the ventricles due to stiffening affects the ventricle’s role of pumping blood out of the heart to other parts of the body or lungs.
Pharmacokinetics and Pharmacodynamics: Coronary Heart Disease Consequently, an increase in the doze of the drug followed, which was quite a predictable step for the healthcare specialist to take, and a sharp rise in Tina’s blood pressure ensued.
Congestive Heart Failure Case Management Program A multidisciplinary strategy can be observed and applied to the outpatient’s supervision of the CHF conditions with the attempt to facilitate the functionality and to bring down the statistics of readmission of the CHF patients […]
Therapeutic Properties of Fish Oil: Reduction of Heart Diseases The sudden reduction in deaths resulting from cardiac diseases led to the increased interest in the potential anti-arrhythmic properties of fish oil. The researchers hypothesized that the use of fish oil causes a significant reduction […]
Cardiomegaly: Symptoms, Types, Diagnosis, Treating The enlargement is caused by the extra job that the heart has to do to pump blood to the whole body. Mild cardiomegaly is described as a slight increase in the size of the heart.
Heart Attack: Causes and Prevention There is actually a way to escape the effect of this much dreaded disease and yet every year it claims the lives of thousands of people in the United States alone.
Social Determinants of the Heart Disease Cardiovascular diseases are injuries of the heart, blood vessels and the system of the blood vessels, the major reason for this is the accumulation of fats in blood vessels which interferes with the normal rate […]
Heart Hemodynamics and Cardiomyopathy The heart is the main organ responsible for the transport of blood, which in turn is carrying nutrients and other essential things that are needed in order for the body to function perfectly.
Cardiovascular Physiology: Interval Training in a Mouse Model of Diabetic Cardiomyopathy The abstract does not describe the study and the results accurately. The authors did not give enough details of the study in the abstract.
Heart Attack: Health Education and Intervention Methodologies According to the National Heart Lung and Blood Institute, “A heart attack occurs when blood flow to a section of the heart muscle becomes blocked.
Breathlessness as an Element of Congestive or Chronic Heart Failure It was done in order to preserve the focus of the analysis on the factor of breathlessness itself. The article allows nurses and other medical specialists to gain a more in-depth understanding of breathlessness among […]
The Syndrome of Chronic Heart Failure Chronic heart failure is a syndrome of various diseases of the cardiovascular system, leading to a decrease in the pumping function of the heart, chronic hyperactivation of neurohormonal systems.
Obstructive Sleep Apnea and Heart Diseases In children with Down syndrome, incidence rates of hypertension and sleepiness are high, and the problem is compounded in the presence of OSA.
Measures to Avoid Re-Hospitalization of Patients With Congestive Heart Failure The idea of this project is to print out a supplement for the hospital’s 28-page guide in English and Spanish, which will have the essential recommendations and references to page numbers.
Patient Education: Congestive Heart Failure These statistics suggest that hospitals have a substantial number of patients with CHF, and adjusting their practice and guidelines to suit the requirements of these patients is a necessity.
Heart Diseases: History, Risks and Prevention This may be attributed to the fact that most of the risk factors are as a result of our day to day activities.
Nutrition for People With Hearth Disease Studies have shown that the soluble fiber lowers cholesterol and decreases dietary fat absorption in the intestines. 13 mm Hg and in diastolic blood pressure of 1.
Congestive Heart Failure and Coronary Artery Disease The overall result of this is the development of a clump of fatty material covered by a smooth muscle and fibrous tissue on the inside of the artery; this is known as an atherosclerotic plaque.
Alcohol Consumption and Cardiovascular Diseases This is necessary to examine the relationship between individual experience of disease and consumption, and, in the population, is essential to the calculation of attributable risk.
Heart Diseases and Their Pathophysiology The primary pacemaker of the heart is the sinus node, a group of specialized cells located in the sulcus terminalis of the high right atrium, between the superior vena cava and the base of the […]
Chronic Diseases: Heart Failure and Cancer The first article examines the role of genetic testing of molecular markers that determine the occurrence and progression of cancer in individuals. The article recommends oncology nurses to keep abreast of advances in genomics for […]
Heart and Lung Diseases: Health History and Assessment J’s case that may lead to a heart attack include the following: Past heart attack. The patient was already administered to the intensive care unit with a decompensated heart failure.
Heart Attack: Health Information Patient Handout Heart attacks can be listed among the most dangerous health issues due to their ability to stop the work of the heart muscle.
Heart Disease, Risk Factors and Emotional Support As such, the objective of the study was to determine the effects of anger, anxiety, and depression on the development of cardiovascular diseases.
Chronic Heart Failure: Symptoms, Diagnosis, and Treatment The diagnosis of the condition is made when signs and symptoms of congestion along with reduced tissue perfusion are documented in the presence of abnormal systolic or diastolic cardiac function. When it comes to the […]
Heart Disease Reverse: Dr. Esselstyn’s Impact Esselstyn’s approach to improving the condition of a human heart and to reduce the number of heart attacks will be analyzed to develop several independent assertions about heart disease and rules to avoid coronary disease […]
Heart Disease: Causal Effects of Cardiovascular Risk Factors The process of cause and effect can be described as a relationship between issues where one is the outcome of the other.
Can Aspirin Prevent a Person From Having a Heart Attack? Regardless of the effectiveness of aspirin, there is a significant drawback related to its influence on a human organism: in order to guarantee its regularity and continuity, it is recommended to avoid making pauses in […]
Heart Failure: Health and Physical Assessment DJ has a bad sleeping pattern, and no remitting factors were found. DJ has no medication intolerances.
Heart Failure: Risk Factors and Treatment A comprehension of the risk aspects for heart failure is crucial for the generation of effective interventions that seek to prevent the occurrence of the condition.
Heart Failure: Cardiology and Treatment The patients suffering from the left-sided heart failure persistently wake up several times at night because of the shortness of breath and gain weight significantly.
Heart Failure Among Older Adult Males The purpose of this paper is to evaluate the problem of heart failure in adult males of 65 years of age and older, identify risk factors, pathophysiology, typical lab, and diagnostic health data, and goals […]
Heart Disease Prevention in Postmenopausal Women The article “Coronary Heart Disease Mortality and Hormone Therapy Before and After the Women’s Health Initiative” offers new insights that can be used to prevent cardiovascular diseases in postmenopausal women. The HRT approach can be […]
Coronary Heart Attack and Health Determinants Smoking predisposes one to the risk of contracting coronary heart attack especially if the victim is an active user of the substance.
What Influences Physical Activity in People With Heart Failure When the literature on related research was reviewed, it was noted that all of the previous research that had been done on the issue of physical activities for people with heart failure conditions had centered […]
Coronary Heart Diseases in African Americans: Intervention Plan The lack of patients and community involvement in the development of prevention strategies hinders the fight against coronary heart diseases in African Americans.
Obesity, Diabetes and Heart Disease Chronic diseases such as obesity, diabetes and heart disease have become endemic and as such calls into question what processes can be implemented among members of the local population so as to prevent the spread […]
Core Functions of Public Health in the Context of Smoking and Heart Disease In the relation to our problem, heart attacks and smoking, it is important to gather the information devoted to the number of people who suffered from heart attacks and indicate the percentage rate of those […]
Medical, Social and Diet Changes and Heart Disease in Middle-Aged Men The questions seek to establish the relationship between the potential causes of heart disease and the occurrence of the disease in the surveyed population.
Congestive Heart Failure in Older Adults The research will narrow down to the readmission and admission rates for the period between January 2010 and March 2011 as well as the relevant data that will facilitate the development of a case management […]
Resource Identification, Evaluation and Selection: Congestive Heart Failure Below is modification of search terms that were most resourceful Heart failure OR congestive heart failure Congestive heart failure AND re-admission Heart failure+ causes and symptoms Congestive heart failure AND edema Congestive heart failure AND […]
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JRSM Cardiovasc Dis
v.6; Jan-Dec 2017

Primary prevention of cardiovascular disease: A review of contemporary guidance and literature

Jack stewart.

1 Department of Cardiology, Ashford & St Peter’s NHS Foundation Trust, London, UK; Institute of Cardiovascular Research, Biological Sciences, University of London, Surrey, UK

Gavin Manmathan

2 Department of Cardiology, Ashford & St Peter’s NHS Foundation Trust, London, UK

Peter Wilkinson

Cardiovascular disease is a significant and ever-growing problem in the United Kingdom, accounting for nearly one-third of all deaths and leading to significant morbidity. It is also of particular and pressing interest as developing countries experience a change in lifestyle which introduces novel risk factors for cardiovascular disease, leading to a boom in cardiovascular disease risk throughout the developing world. The burden of cardiovascular disease can be ameliorated by careful risk reduction and, as such, primary prevention is an important priority for all developers of health policy. Strong consensus exists between international guidelines regarding the necessity of smoking cessation, weight optimisation and the importance of exercise, whilst guidelines vary slightly in their approach to hypertension and considerably regarding their approach to optimal lipid profile which remains a contentious issue. Previously fashionable ideas such as the polypill appear devoid of in-vivo efficacy, but there remain areas of future interest such as the benefit of serum urate reduction and utility of reduction of homocysteine levels.

Introduction

Cardiovascular disease (CVD) is an umbrella term for a number of linked pathologies, commonly defined as coronary heart disease (CHD), cerebrovascular disease, peripheral arterial disease, rheumatic and congenital heart diseases and venous thromboembolism. Globally CVD accounts for 31% of mortality, the majority of this in the form of CHD and cerebrovascular accident. 1

In England CVD accounts for nearly 34% of all deaths, whilst the figure is approximately 40% in the European Union. 2 The rate of CVD worldwide is predicted to increase as the prevalence of risk factors for CVD rises in previously low-risk countries. Currently 80% of CVD mortality occurs in developing nations 3 and CVD is expected to be the major cause of mortality in most developing nations by 2020, overtaking infectious disease. 4 Not only is CVD a leading cause of mortality, but it is the leading cause of loss of disability-adjusted life years globally. 3

The World Health Organisation (WHO) estimate that over 75% of premature CVD is preventable and risk factor amelioration can help reduce the growing CVD burden on both individuals and healthcare providers. 5 Whilst age is a known risk factor for the development of CVD, autopsy evidence suggests that the process of developing CVD in later years is not inevitable, 6 thus risk reduction is crucial.

The INTERHEART study elucidated the effect of CVD risk factors including dyslipidaemia, smoking, hypertension, diabetes, abdominal obesity, whilst it demonstrated the protective effects of consumption of fruits and vegetables, and regular physical activity. These risk factors were consistent throughout all populations and socioeconomic levels studied, helping to establish the viability of uniform approaches to CVD primary prevention worldwide. 7

In this review we look at the main components of primary prevention of CVD as discussed in current best practice guidelines in the United Kingdom, Europe and America and attempt to provide a summary of primary prevention guidelines in CVD for clinicians.

We looked specifically at the current National Institute for Health and Care Excellence (NICE) guidelines. 8 – 10 European Society of Cardiology (ESC) guidelines, 3 , 11 , 12 as well as guidelines from the American Heart Association (AHA) and American College of Cardiologists (ACC) 13 – 15 or, in the case of hypertension, guidelines referred to by the ACC. 16 We highlighted areas targeted by these guidelines and performed a review of current literature. A literature search was performed using the search terms ‘Primary prevention in Cardiovascular Disease’, then a combination of ‘diet’, ‘hypertension’, ‘lipids’, ‘exercise’, ‘smoking’, ‘alcohol’ ‘polypill’, ‘weight’, ‘blood glucose’ and the term ‘cardiovascular disease prevention’. Data, guidelines and their scientific underpinning were extracted from the above and compared.

Here we discuss the main areas targeted for primary prevention of CVD, looking at current guidelines, the data which supports them and any variation in guideline recommendations.

Lifestyle modifications

Exercise is universally recognised as having a positive impact on the majority of health outcomes and its effect on CVD is no different. Mortality and morbidity directly due to exercise remains minimal even up to very intense levels of exercise and in the overwhelming majority the benefits outweigh the risks. 17

NICE recommend 150 minutes of moderate intensity aerobic activity per week, or 75 minutes of vigorous aerobic activity. This can be defined either subjectively or in terms of relative changes in metabolic rate. They also advise muscle strengthening activities on two or more days per week. 8 NICE give only a consensus recommendation regarding the utility of exercise as primary prevention, however guidelines from the AHA and ESC give class 1 A recommendations with almost identical prescriptions, referring to a solid and consensual body of evidence. 11 , 13

The guidelines all state that any form of exercise provides CVD risk reduction, with those newly starting exercise achieving greatest benefit and any subsequent increases providing significant but diminishing returns. Persuading the population to exercise as suggested remains difficult despite the obvious benefits, but the evidence is clear that any increase in physical activity reduces risk of CVD. 18

Diet is thought to play a significant role in CVD risk but the body of evidence regarding its use is not clear, nor are the guidelines overwhelmingly consensual.

The AHA recommend the Dietary Approaches to Stop Hypertension (DASH) diet which is low in sugars and saturated fats, high in vegetables, fruits and whole grains. This has been shown to as a method to lower blood pressure (BP) and low-density lipoprotein cholesterol (LDL-C) which are independent risk factors for CVD, but they do not attempt to show a direct reduction in CVD risk. 13

NICE recommend reducing saturated fat intake, increasing monounsaturated fatty acids and five portions of fruit and vegetables per day. They also suggest a high fibre diet and two portions of fish per week. They do acknowledge that they lack evidence that these changes will impact directly on CVD risk, but rather that they have benefits on other areas of health. Notably, the majority of the studies referenced came from pre-1990s when dietary patterns were substantially different, and almost all their data were underpowered concerning CVD risk. 19

The ESC recommends switching from saturated to polyunsaturated fatty acids, an increase in fibre, fruit, vegetable and fish intake as well as abstinence from alcohol and adherence to a Mediterranean type diet. These have all been shown to offer significant reductions in CVD risk. 11

There is also clear evidence that industrially produced transfats are causally linked to CHD 20 and these are specifically proscribed in ESC and NICE guidelines.

The disparity between the recommendations is multi-factorial. For example, NICE guidelines on fibre intake look only at randomised controlled trials (RCTs) from the 1980s cf. the ESC which refers to meta-analyses of data up to the 2010s.

Regarding the advice on saturated fats, the ESC guidelines use modelling data to extrapolate a CVD risk reduction from reduction in LDL-C rather than epidemiological evidence or RCTs, whilst AHA guidelines do not comment specifically on CVD risk. This is an area where NICE guidelines would benefit from an update of its evidence base and greater use of prospective or epidemiological data to justify its recommendations.

In summary, there does seem to be good evidence for recommending diets high in fibre, fruit and vegetable intake and low in simple sugars and salt. Adherence to a Mediterranean style diet also appears to be cardioprotective.

Smoking has long been known as the major risk factor for CVD. 21 European data indicate that smoking doubles the 10 year CVD mortality rate 3 whilst 30% of US CVD mortality is attributable to smoking. 13 Not only is it deleterious but this effect is dose related with no safe lower limit seen. 22 Passive smoking is similarly harmful as workplace exposure increases CVD risk by 30% and UK public health initiatives including smoking bans are associated with a significant fall in CVD events. 11

Stopping smoking is the single most cost-effective intervention in CVD prevention, and some benefits are seen within months of cessation. 11 , 13 All guidelines recommend cessation, with short and long-term benefits seen irrespective of length or intensity of smoking habit.

Pharmacologically, the use of nicotine replacement therapy (NRT), buproprion (a norepinephrine dopamine reuptake inhibitor) and particularly varenicline (a partial nicotine receptor agonist) are universally recommended. The two former both improve abstinence rates by 50–70%, whilst varenicline doubles abstinence. 23 , 24

Medication choice should be patient led, with a particular note to side-effect profiles. NRT previously held warnings regarding its use in those with CVD but evidence suggests that the benefits of smoking cessation outweigh the risks. 25 Also recommended is physician intervention as a cost-effective method of reducing smoking, 26 notably effective in secondary prevention post myocardial infarction (MI). 15

E-Cigarettes are still controversial with regards to CVD risk. Whilst the reduction in toxic products within cigarette smoke is undoubtedly beneficial, animal models of nicotine exposure still display CVD effects with increased atherosclerotic plaques found in mice models. 27 Long-term data are awaited to determine the effect upon humans.

Having a body mass index (BMI) > 25 is a risk factor for CVD with lowest all-cause mortality seen at BMI 20–25 but, due to increased all-cause mortality with BMI < 20, 28 reductions below this level are not routinely recommended. No guidelines recommend specific intervention regarding weight, but advise maintenance of a healthy weight for reduction of CVD risk. BMI is a good predictor of CVD risk, particularly at higher levels, but there is good evidence that, at all levels of BMI, visceral adiposity and liver fat are significant drivers of risk. 29 This helps to explain the heterogeneity in the CVD risk profile seen in the overweight as it varies depending on the location of adipose deposition. There are moves to suggest that, alongside reduction in BMI, reduction in waist circumference as a proxy for reductions in visceral fat should become an important target for amelioration of CVD risk.

Alcohol consumption is a controversial subject given the known sequelae of regular and excess alcohol use. The difficulty exists as historically the evidence suggested a J-shaped curve when it comes to risk, where abstinence is associated with an increase in CVD compared to light drinkers, with low levels of alcohol consumption associated with a lower level of CHD. 30 Besides the understood physiological effects of alcohol, interfering with platelet aggregation, evidence from the INTERHEART study would appear to substantiate these claims, showing reductions in risk for those with moderate and light use of alcohol. 31 A recent large mendelian analysis by Holmes et al. 32 has, however, shown that within a genetic subset for alcohol dehydrogenase, reductions in alcohol intake are associated with reduction in CVD risk across the spectrum of alcohol intake. This would suggest that reductions in alcohol intake, even for moderate drinkers, are associated with a reduction in CVD risk. It is on this basis that the ESC guidelines recommend no safe level of alcohol intake. 11 NICE guidelines 8 were produced prior to this data being released and continue with advice on moderate intake, advising not more than four units per day for men and three for women, despite these being arbitrary figures. The ACC also advise moderation along the same lines, with one to two drinks per day for men, and one drink per day for women. 33 As yet there does not seem to be a consensus of opinion regarding safe levels, but high levels are evidently deleterious.

Medical treatment

Lipid-lowering therapy.

Interventions to ameliorate lipid levels have long been used in primary prevention and sub-fractions of serum lipids have been studied to differentiate their individual effects on CVD risk profile.

LDL-C is the best understood atherogenic sub-fraction with a strong correlation between LDL-C levels and CVD risk: reducing LDL-C by 1.0 mmol/L causes a corresponding 20–25% risk reduction in CVD mortality and non-fatal MI. 11

It has been hypothesised that raised high-density lipoprotein cholesterol (HDL-C) levels are cardioprotective but the causal link remains unproven. This controversy is borne out by the adverse CVD profile of HDL raising drugs such as torcetrapib, as well as recent mendelian randomisation analysis suggesting no intrinsic benefit from naturally higher levels of HDL-C. 11

Apolipoprotein B (ApoB) seems a similar predictor of CVD risk to LDL, whilst serum triglycerides lack the strength of data of LDL but remain an independent risk factor for CVD. 11

3-Hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors, commonly referred to as statins, have been used since the 1980s to reduce LDL-C levels. Their side-effect and risk profile is well recognised, with a reported 5–10% experiencing significant side-effects, commonly in the form of myalgia, arthralgia and temporary gastrointestinal upset. 34

The AHA recommend statins for primary prevention in all patients with a serum LDL-C > 4.9 mmol/L regardless of risk profile, 14 whilst the ESC recommend statins in high-risk patients or those with cholesterol levels raised to > 4.9 mmol/L. 11 They are more circumspect about their general use, but do recommend them as ideal first-line monotherapy without suggesting dosing levels.

QRISK2 is a risk stratifying method which determines 10-year risk profile using multiple physiological and comorbidity data including serum cholesterol ratios. NICE guidelines advise atorvastatin 20 mg to be offered as primary prevention in patients < 85 years with a QRISK2 score of > 10%. It also notes that patients > 85 years are likely to benefit from a similar CVD risk reduction despite a lack of confirmatory data. NICE does not use specific cholesterol levels nor ratios as individual markers of risk, though does suggest specialist referral if total lipid levels > 9 mmol/L or non-HDL > 7.5 mmol/L. Satisfactory lipid levels remain an area of controversy, with no guidelines defining a normal range. 8

Statins are one of the most commonly prescribed medications worldwide, thus the data behind their use is plentiful, with atorvastatin shown to significantly reduce LDL-C and be the most cost-effective throughout all risk profiles. NICE states that treatment remains cost effective for those with a QRISK2 < 10%, but due to the reported side-effect profile NICE suggests 10% risk of CVD as a cut-off for statins as primary prevention. 8

The controversy regarding the above is twofold. Firstly, a 2013 paper by Abramson et al. claimed that their reanalysis of the data showed no reduction in mortality or morbidity in the low-risk population, 35 thus causing iatrogenic harm in the form of intolerable side-effects – reported in 5–10% of patients. Secondly, the corollary of this guideline would be the almost ubiquitous prescription of statins in otherwise well patients. A male aged 65 years would obtain a risk of 10% despite optimal BMI, optimal cholesterol and no comorbidities, the same being true for a 70-year-old female. 36 Given the current side-effect recommendations there is reluctance amongst the medical profession to engage in blanket therapy for a theoretical gain on a population-wide basis. Reanalysis from Collins et al., however, suggested that the side-effect profile is significantly misreported and therefore the risk–benefit ratio shifts back in favour of statins. 37 Their analysis attributes a 1% of risk of diabetes, 1% risk of muscle pain or weakness, 0.1% risk of haemorrhagic stroke and 0.05% risk of myopathy over five years of statin therapy – a significant reduction in side-effect rate.

Whilst controversy remains, the evidence is compelling for use in those with significant CVD risks and may be appropriate in more moderate risk profiles, but prescription requires careful tailoring to individual patients. A summary of guideline recommendations for LDL reduction can be seen in Table 1 .

Guidelines for LDL reduction.

Guideline	NICE	ACC	ESC
Level at which to attempt LDL reduction	QRISK2 score > 10% if < 85 yrs	>4.9 mmol/L irrespective of risk	>4.9 mmol/L if high risk of CVD
Recommended pharmacotherapy	Atorvastatin 20 mg	Statin – no preferred version	Statin – no preferred version

LDL: low-density lipoprotein; CVD: cardiovascular disease.

Non-statin therapies are also used, commonly in patients whose lipid profiles are not optimised by statin monotherapy. Commonly used drugs include bile acid sequestrants, fibrates and nicotinic acid, but these drugs are not recommended as monotherapy due to side-effects and a lack of reduction in CVD events. 11 Further reductions in serum LDL can be achieved with combination therapies. No guideline recommends specific combinations but they do suggest combination with other lipid-lowering drugs in resistant cases or in those not tolerant of statins.

New therapies are forthcoming, with phase III data from proprotein convertase subtilisin–kexin type 9 (PCSK9) monoclonal antibodies such as alirocumab providing increasingly effective lipid-lowering therapies. They can be used either as monotherapies or as add-ons to statins with a significant impact on CVD events. 38 Both alirocumab and evolocumab have recently been recommended by NICE for CVD prevention in those with primary hypercholesterolaemia, mixed dyslipidaemia or in whom statins are not sufficient to control cholesterol. 39 Their use is likely to become more widespread with further phase III and IV clinical trial data and eventual reduction in cost.

Anti-hypertensive therapies

Hypertension is an independent risk factor for the development of CVD. The effect of increasing BP > 115/75 mmHg is consistent and exponential, where each 20 mmHg increase in systolic blood pressure (SBP) or a 10 mmHg increase in diastolic BP doubles the risk of a cardiovascular event. 40

Previous meta-analyses have shown a reduction in CVD risk over a wider range of BPs suggesting that there is no lower limit to the benefit of BP reduction, and no obvious cut-off at which further reductions become harmful. 41 , 42

Contemporary meta-analyses indicate that the benefits of lowering BP from a baseline < 140 may be equivocal or even detrimental. 43 Combining this evidence would suggest that BP reductions in hypertensives reduce mortality, but for normotensive or pre-hypertensive patients there is little evidence for early treatment.

Given that hypertension acts as an independent risk factor for CVD, and synergistically with other risk factors, it is the consensus opinion that the threshold for treatment of hypertension in those at risk of CVD should be lower. 44

Regarding timing of intervention and precise target ranges there is some variability between guidelines which can be seen broadly in Table 2 .

Guidelines for commencement of anti-hypertensives and target BP.

Guideline	NICE	ACC recommended guidelines	ESC
Commencement of treatment – no comorbidities	>160/100 mmHg	>150/90 mmHg if ≥60 yrs	>160/100 mmHg – after lifestyle modification attempted
Commencement of treatment – no comorbidities	>160/100 mmHg	>140/90 mmHg if <60 yrs	>160/100 mmHg – after lifestyle modification attempted
Target	<140/90 mmHg if <80 yrs	<150/90 mmHg if ≥60 yrs	<140/90 mmHg if < 60 yrs
Target	<150/90 mmHg if >80 yrs	<140/90 mmHg if < 60 yrs	SBP 140–150 mmHg if > 60 yrs
Commencement of treatment if CKD/ DM/ risk of CVD	>140/90 mmHg	>140/90 mmHg	>140/90 mmHg
Target	<140/90 mmHg	<140/90 mmHg	<140/90 mmHg

CKD: chronic kidney disease; DM: diabetes mellitus; CVD: cardiovascular disease.

The ESC and NICE guidelines note that the majority of data showed greatest benefit for those with BP > 160/100 mmHg, and whilst there may be benefit at lower levels 45 the evidence was not yet considered strong enough to give direct recommendations. 12

Strong evidence suggests that the reduction in BP is more important than the individual drug class used, 46 compounded by the fact that the majority of people with hypertension require more than one antihypertensive drug for optimal control. 47

The recommended pharmacotherapy can be seen in Table 3 .

Recommended anti-hypertensive therapy.

Guideline	NICE	ACC recommended guidelines	ESC
First line anti-hypertensive therapy	If <55 yrs – ACEi/ARB If > 55 yrs/Afrocaribbean descent – CCB or thiazide	ACEI/ARB, thiazide, CCBs If black – thiazide or CCB	ACEi, thiazide, CCB, ARB, beta blocker
Additional notes		Use 2 drugs if goal BP not reached within one month

ACEi: angiotensin converting enzyme inhibitor; ARB: angiotensin receptor blocker; CCB: calcium channel blocker; BP: blood pressure.

NICE justify the changes in treatment for Afro-Caribbean patients due to differences in plasma renin concentrations between ethnic groups and a tendency towards lower cardiac output with increased peripheral resistance in Afro-Caribbean hypertensives. 48 The ACC recommended guidelines note that the ALLHAT trial showed improved outcomes in Afro-Caribbean patients treated with thiazides, whilst calcium channel blocker (CCBs) improved all outcomes other than heart failure. 49

A small discrepancy exists with the ESC guidelines. Their use of beta blockers stems from a meta-analysis suggesting that the class cause an equal reduction in CVD mortality, though the ESC do acknowledge conflicting data which suggests inferiority and an increased side-effect profile. 12

Whilst risk of CVD increases with BP, the majority of population events occur within the upper range of normal, therefore NICE public health guidelines 10 suggest that a population-wide drop in BP would lead to a significant reduction in CVD events. As this group does not receive antihypertensive treatment, they recommend population measures to reduce salt intake. Salt intake is well associated with BP, with a strong causal link between increased intake and rise in BP. The reverse is also true: studies looking at reduction in salt intake show consistent reductions in BP, particularly in hypertensive individuals, 50 and there is evidence of CVD event reduction. 51 Given the above, all three guidelines recommend reduction in salt intake on an individual and population level regardless of BP.

Specific daily targets vary, largely due to the responsibilities of each organisation: AHA 2.4 g, ESC 5–6 g and NICE 6 g reducing to 3 g by 2025. 10 , 11 , 13 NICE also has a greater public health remit than the ESC and AHA and recommends national-level interventions such as population education, pricing changes on higher-salt products, and national legislation if necessary to aid reduction in salt intake (NICE PH25). All agree, however, that lower salt intake leads to BP reduction and concomitant CVD risk reduction. 52

Blood glucose

Glucose control is pertinent in the diabetic populations but is non-significantly associated with CVD risk in non-diabetics. On average diabetes mellitus (DM) risk of CVD, whilst those with impaired fasting glucose (IFG) are known to be at significant risk of CVD as well as progression to DM. 53 In DM serum glucose reduction is shown to reduce CVD, with lowest risk at normal blood sugars. 54 More intense glucose reductions were deleterious, with particular CVD risk from certain thiazolidinediones and dipeptidyl peptidase-4 inhibitors. 55 Recent trials from the sodium/glucose transporter 2 inhibitor class of oral hypoglycaemics such as empagliflozin have been shown to significantly reduce all-cause mortality by 32%, as well as CVD death by 28% and HF by 35% in comparison with standard care. 56 It appears that these effects were not mediated by reduction in glucose, rather cardio-renal haemodynamic effects, but the substantial benefits demonstrated would recommend its early use in diabetic patients. Current guidelines need to be updated with further data on these medications.

Anti-platelet therapy

Anti-platelet therapy is a significant contributor to secondary prevention but should be avoided in primary prevention in those without comorbidities due to increased bleeding risk with no evidence of CVD risk reduction. In patients with DM the advice is conflicting: ESC guidelines maintain that the bleeding risk exceeds the benefits of aspiring therapy, whilst the American College of Chest Physicians recommend aspirin therapy in patients with DM and 10-year CVD event risk of ≥ 10%. 57

Further areas of research

Other areas include the polypill, uric acid and homocysteine. The use of a polypill – a combination pill for CVD risk reduction – has impressive theoretical benefits, but meta-analyses on in-vivo data have not demonstrated significant improvement in CVD risk. 58

Lowering serum uric acid levels may improve CVD risk, as it is known that both patients with gout or hyperuricaemia receiving urate-lowering therapies have improved CVD and all cause-mortality 59 , 60 ; however more research is needed to clarify if these benefits translate to population-wide risk reduction. Homocysteine is a known atherogen, but lowering therapies have not demonstrated a reduced CVD. 61

The objective of CVD prevention is to reduce the occurrence of major cardiovascular events thereby reducing premature disability and morbidity whilst prolonging survival and quality of life.

The American, European and British guidelines demonstrate numerous methods to reduce CVD risk profile with strong consensus regarding smoking and exercise, whilst the fine details may vary slightly for other factors. Pharmaceutical options have developed over the years whilst lifestyle advice remains largely unchanged.

Primary prevention continues to evolve and with greater availability of long-term data comes improved understanding of the means by which we can reduce CVD risk. It is an endeavour that must be continued if we are to reduce the burden of a preventable disease.

Acknowledgements

The authors thank Ms Nicola F Raeside and Ms Katherine A Addy.

Declaration of conflicting interests

The author(s) declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Ethical approval

Dr Jack Stewart.

Contributorship

The main text was written by Dr. Jack Stewart, draft revision was performed by Dr Gavin Manmathan and the review was supervised and guided by Dr Peter Wilkinson.

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Exploring the heart-brain and brain-heart axis: Insights from a bidirectional Mendelian randomization study on brain cortical structure and cardiovascular disease

Affiliations.

1 State Key Laboratory of Cardiovascular Disease, Heart Failure Center, National Center for Cardiovascular Diseases, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
2 Department of Urology, West China Hospital, Sichuan University, Chengdu 610041, China.
3 State Key Laboratory of Cardiovascular Disease, Heart Failure Center, National Center for Cardiovascular Diseases, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Electronic address: [email protected].
4 State Key Laboratory of Cardiovascular Disease, Heart Failure Center, National Center for Cardiovascular Diseases, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Key Laboratory of Clinical Research for Cardiovascular Medications, National Health Committee, 10037 Beijing, China. Electronic address: [email protected].
PMID: 39142612
DOI: 10.1016/j.nbd.2024.106636

Introduction: The bidirectional relationship between the brain cortex and cardiovascular diseases (CVDs) remains inadequately explored.

Methods: This study employed bidirectional Mendelian randomization (MR) analysis to investigate the interaction between nine phenotypes, namely hypertension, heart failure, atrial fibrillation (AF), and coronary heart disease (CHD), and brain cortex measurements, including total surface area (SA), average thickness (TH), and the SA and TH of 34 regions based on the Desikan-Killiany atlas. The nine traits were obtained from sources such as the UK Biobank and FinnGen, etc., while MRI-derived traits of cortical structure were sourced from the ENIGMA Consortium. The primary estimate was obtained using the inverse-variance weighted approach. False discovery rate adjustment was applied to p-values (q-values) in the analyses for regional cortical structure.

Results: A total of 1260 two-sample MR analyses were conducted. Existing CHD demonstrated an influence on the SA of the banks of the superior temporal sulcus (bankssts) (q = 0.018) and the superior frontal lobe (q = 0.018), while hypertension was associated with changes in the TH of the lateral occipital region (q = 0.02). Regarding the effects of the brain cortex on CVD incidence, total SA was significantly associated with the risk of CHD. Additionally, 15 regions and four areas exhibited significant effects on blood pressure and AF risk, respectively (q < 0.05). These regions were primarily located in the frontal, temporal, and cingulate areas, which are responsible for cognitive function and mood regulation.

Conclusion: The detection of cortical changes through MRI could aid in screening for potential neuropsychiatric disorders in individuals with established CVD. Moreover, abnormalities in cortical structure may predict future CVD risk, offering new insights for prevention and treatment strategies.

Keywords: Bidirectional Mendelian randomization study; Brain cortical structure; Brain-heart axis; Cardiovascular diseases; Heart-brain axis.

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Insulin resistance, a risk factor for alzheimer’s disease: pathological mechanisms and a new proposal for a preventive therapeutic approach, 1. introduction, 2. insulin, brain and insulin resistance, 3. glucose metabolism and dysregulation of brain energetics, 4. aβ, tau, apolipoprotein e and ir, 5. mitochondria, oxidative stress, ir and neuroinflammation, 6. vascular damage, 7. potential therapeutic approach, 7.1. metformin, 7.2. pparɣ agonists, 7.3. glucagon-like peptide-1 receptor agonists, 7.4. sodium-glucose cotransporter 2 inhibitors, 7.5. phosphodiesterase 5 inhibitors, 7.6. berberine, 7.7. quercetin, 7.8. l-arginine, 7.9. klotho protein as therapeutic target of neurodegenerative diseases, 7.10. inhaled insulin, 8. conclusions, author contributions, institutional review board statement, informed consent statement, data availability statement, conflicts of interest.

2023 Alzheimer’s disease facts and figures. Alzheimers Dement. 2023 , 19 , 1598–1695. [ CrossRef ] [ PubMed ]
Saeedi, P.; Petersohn, I.; Salpea, P.; Malanda, B.; Karuranga, S.; Unwin, N.; Colagiuri, S.; Guariguata, L.; Motala, A.A.; Ogurtsova, K.; et al. IDF Diabetes Atlas Committee. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas, 9th edition. Diabetes Res Clin Pract. 2019 , 157 , 107843. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Freeman, A.M.; Acevedo, L.A.; Pennings, N. Insulin Resistance [Updated 2023 Aug 17] ; StatPearls Publishing: Treasure Island, FL, USA, 2023. [ Google Scholar ]
Crane, P.K.; Walker, R.; Hubbard, R.A.; Li, G.; Nathan, D.M.; Zheng, H.; Haneuse, S.; Craft, S.; Montine, T.J.; Kahn, S.E.; et al. Glucose levels and risk of dementia. N. Engl. J. Med. 2013 , 369 , 540–548. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Zhao, H.; Wu, C.; Zhang, X.; Wang, L.; Sun, J.; Zhuge, F. Insulin resistance is a risk factor for mild cognitive impairment in elderly adults with T2DM. Open Life Sci. 2019 , 14 , 255–261. [ Google Scholar ] [ CrossRef ]
Ott, A.; Stolk, R.P.; van Harskamp, F.; Pols, H.A.; Hofman, A.; Breteler, M.M. Diabetes mellitus and the risk of dementia: The Rotterdam Study. Neurology 1999 , 53 , 1937–1942. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Rhea, E.M.; Banks, W.A.; Raber, J. Insulin Resistance in Peripheral Tissues and the Brain: A Tale of Two Sites. Biomedicines 2022 , 10 , 1582. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Janson, J.; Laedtke, T.; Parisi, J.E.; O’Brien, P.; Petersen, R.C.; Butler, P.C. Increased risk of type 2 diabetes in Alzheimer disease. Diabetes 2004 , 53 , 474–481. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Banks, W.A.; Jaspan, J.B.; Huang, W.; Kastin, A.J. Transport of insulin across the blood-brain barrier: Saturability at euglycemic doses of insulin. Peptides 1997 , 18 , 1423–1429. [ Google Scholar ] [ CrossRef ]
Baura, G.D.; Foster, D.M.; Porte, D.; Kahn, S.E.; Bergman, R.N.; Cobelli, C.; Schwartz, M.W. Saturable transport of insulin from plasma into the central nervous system of dogs in vivo. A mechanism for regulated insulin delivery to the brain. J. Clin. Investig. 1993 , 92 , 1824–1830. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Nguyen, V.; Thomas, P.; Pemberton, S.; Babin, A.; Noonan, C.; Weaver, R.; Banks, W.A.; Rhea, E.M. Central nervous system insulin signaling can influence the rate of insulin influx into brain. Fluids Barriers CNS 2023 , 20 , 28. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ PubMed Central ]
Sánchez-Zúñiga, M.J.; Carrillo-Esper, R.; Sánchez-Pérez, H.; González-Chávez, A.; Elizondo-Argueta, S. Brain insulin circuit. From the basics to impact on the clinic. Cir Cir. 2020 , 88 , 100–106. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Rhea, E.M.; Rask-Madsen, C.; Banks, W.A. Insulin transport across the blood–brain barrier can occur independently of the insulin receptor. J. Physiol. 2018 , 596 , 4753–4765. [ Google Scholar ] [ CrossRef ]
Devaskar, S.U.; Giddings, S.J.; Rajakumar, P.A.; Carnaghi, L.R.; Menon, R.K.; Zahm, D.S. Insulin gene expression and insulin synthesis in mammalian neuronal cells. J. Biol. Chem. 1994 , 269 , 8445–8454. [ Google Scholar ] [ CrossRef ]
Mazucanti, C.H.; Liu, Q.R.; Lang, D.; Huang, N.; O’Connell, J.F.; Camandola, S.; Egan, J.M. Release of insulin produced by the choroid plexis is regulated by serotonergic signaling. JCI Insight. 2019 , 4 , e131682. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ PubMed Central ]
Heidenreich, K.A.; Zahniser, N.R.; Berhanu, P.; Brandenburg, D.; Olefsky, J.M. Structural differences between insulin receptors in the brain and peripheral target tissues. J. Biol. Chem. 1983 , 258 , 8527–8530. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Kleinridders, A.; Ferris, H.A.; Cai, W.; Kahn, C.R. Insulin action in brain regulates systemic metabolism and brain function. Diabetes 2014 , 63 , 2232–2243. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Kwon, H.; Pessin, J.E. Insulin-Mediated PI3K and AKT Signaling. In The Liver: Biology And Pathobiology ; Wiley: Hoboken, NJ, USA, 2020; pp. 485–495. [ Google Scholar ]
Goodner, C.J.; Hom, F.G.; Berrie, M.A. Investigation of the effect of insulin upon regional brain glucose metabolism in the rat in vivo. Endocrinology 1980 , 107 , 1827–1832. [ Google Scholar ] [ CrossRef ]
Van Der Heide, L.P.; Kamal, A.; Artola, A.; Gispen, W.H.; Ramakers, G.M. Insulin modulates hippocampal activity-dependent synaptic plasticity in a N-methyl-d-aspartate receptor and phosphatidyl-inositol-3-kinase-dependent manner. J. Neurochem. 2005 , 94 , 1158–1166. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Shymko, R.M.; Dumont, E.; Meyts, P.D.; Dumont, J.E. Timing-dependence of insulin-receptor mitogenic versus metabolic signalling: A plausible model based on coincidence of hormone and effector binding. Biochem. J. 1999 , 339 , 675–683. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Cai, W.; Sakaguchi, M.; Kleinridders, A.; Gonzalez-Del Pino, G.; Dreyfuss, J.M.; O’Neill, B.T.; Kahn, C.R. Domain-dependent effects of insulin and IGF-1 receptors on signalling and gene expression. Nat. Commun. 2017 , 8 , 14892. [ Google Scholar ] [ CrossRef ]
Suzuki, R.; Lee, K.; Jing, E.; Biddinger, S.B.; McDonald, J.G.; Montine, T.J.; Kahn, C.R. Diabetes and insulin in regulation of brain cholesterol metabolism. Cell Metab. 2010 , 12 , 567–579. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Ghasemi, R.; Haeri, A.; Dargahi, L.; Mohamed, Z.; Ahmadiani, A. Insulin in the brain: Sources, localization and functions. Mol. Neurobiol. 2013 , 47 , 145–171. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Porte, D., Jr.; Seeley, R.J.; Woods, S.C.; Baskin, D.G.; Figlewicz, D.P.; Schwartz, M.W. Obesity, diabetes and the central nervous system. Diabetologia 1998 , 41 , 863–881. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Ryu, B.R.; Ko, H.W.; Jou, I.; Noh, J.S.; Gwag, B.J. Phosphatidylinositol 3-kinase-mediated regulation of neuronal apoptosis and necrosis by insulin and IGF-I. J. Neurobiol. 1999 , 39 , 536–546. [ Google Scholar ] [ CrossRef ]
Rensink, A.A.; Otte-Höller, I.; de Boer, R.; Bosch, R.R.; ten Donkelaar, H.J.; de Waal, R.M.; Kremer, B. Insulin inhibits amyloid β-induced cell death in cultured human brain pericytes. Neurobiol. Aging 2004 , 25 , 93–103. [ Google Scholar ] [ CrossRef ]
Nash, A.I. Crosstalk between insulin and dopamine signaling: A basis for the metabolic effects of antipsychotic drugs. J. Chem. Neuroanat. 2017 , 83 , 59–68. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Farris, W.; Mansourian, S.; Chang, Y.; Lindsley, L.; Eckman, E.A.; Frosch, M.P.; Guénette, S. Insulin-degrading enzyme regulates the levels of insulin, amyloid β-protein, and the β-amyloid precursor protein intracellular domain in vivo. Proc. Natl. Acad. Sci. USA 2003 , 100 , 4162–4167. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Ito, S.; Ohtsuki, S.; Murata, S.; Katsukura, Y.; Suzuki, H.; Funaki, M.; Terasaki, T. Involvement of insulin-degrading enzyme in insulin-and atrial natriuretic peptide-sensitive internalization of amyloid-β peptide in mouse brain capillary endothelial cells. J. Alzheimer’s Dis. 2014 , 38 , 185–200. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Zhao, Z.; Xiang, Z.; Haroutunian, V.; Buxbaum, J.D.; Stetka, B.; Pasinetti, G.M. Insulin degrading enzyme activity selectively decreases in the hippocampal formation of cases at high risk to develop Alzheimer’s disease. Neurobiol. Aging 2007 , 28 , 824–830. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Rhea, E.M.; Leclerc, M.; Yassine, H.N.; Capuano, A.W.; Tong, H.; Petyuk, V.A.; Macauley, S.L.; Fioramonti, X.; Carmichael, O.; Calon, F.; et al. State of the Science on Brain Insulin Resistance and Cognitive Decline Due to Alzheimer’s Disease. Aging Dis. 2023 , 15 , 1688. [ Google Scholar ] [ CrossRef ]
Leclerc, M.; Bourassa, P.; Tremblay, C.; Caron, V.; Sugère, C.; Edmond, V.; Calon, F. Cerebrovascular insulin receptors are defective in Alzheimer’s disease. Brain 2023 , 146 , 75–90. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Talbot, K.; Wang, H.Y.; Kazi, H.; Han, L.Y.; Bakshi, K.P.; Stucky, A.; Arnold, S.E. Demonstrated brain insulin resistance in Alzheimer’s disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. J. Clin. Investig. 2012 , 122 , 1316–1338. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Konishi, M.; Sakaguchi, M.; Lockhart, S.M.; Cai, W.; Li, M.E.; Homan, E.P.; Kahn, C.R. Endothelial insulin receptors differentially control insulin signaling kinetics in peripheral tissues and brain of mice. Proc. Natl. Acad. Sci. USA 2017 , 114 , E8478–E8487. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Rhea, E.M.; Banks, W.A. Role of the blood-brain barrier in central nervous system insulin resistance. Front. Neurosci. 2019 , 13 , 457034. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Starr, J.M.; Wardlaw, J.; Ferguson, K.; MacLullich, A.; Deary, I.J.; Marshall, I. Increased blood–brain barrier permeability in type II diabetes demonstrated by gadolinium magnetic resonance imaging. J. Neurol. Neurosurg. Psychiatry 2003 , 74 , 70–76. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Arnold, S.E.; Lucki, I.; Brookshire, B.R.; Carlson, G.C.; Browne, C.A.; Kazi, H.; Kim, S.F. High fat diet produces brain insulin resistance, synaptodendritic abnormalities and altered behavior in mice. Neurobiol. Dis. 2014 , 67 , 79–87. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Cui, Y.; Liang, X.; Gu, H.; Hu, Y.; Zhao, Z.; Yang, X.Y.; Qian, C.; Yang, Y.; Teng, G.J. Cerebral perfusion alterations in type 2 diabetes and its relation to insulin resistance and cognitive dysfunction. Brain Imaging Behav. 2017 , 11 , 1248–1257. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Arnold, S.E.; Arvanitakis, Z.; Macauley-Rambach, S.L.; Koenig, A.M.; Wang, H.Y.; Ahima, R.S.; Nathan, D.M. Brain insulin resistance in type 2 diabetes and Alzheimer disease: Concepts and conundrums. Nat. Rev. Neurol. 2018 , 14 , 168–181. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Watson, L.S.; Wilken-Resman, B.; Williams, A.; DiLucia, S.; Sanchez, G.; McLeod, T.L.; Sims-Robinson, C. Hyperinsulinemia alters insulin receptor presentation and internalization in brain microvascular endothelial cells. Diab. Vasc. Dis. Res. 2022 , 19 , 14791641221118626. [ Google Scholar ] [ CrossRef ]
de la Monte, S.M.; Longato, L.; Tong, M.; Wands, J.R. Insulin resistance and neurodegeneration: Roles of obesity, type 2 diabetes mellitus and non-alcoholic steatohepatitis. Curr. Opin. Investig. Drugs 2009 , 10 , 1049. [ Google Scholar ]
Sripetchwandee, J.; Chattipakorn, N.; Chattipakorn, S.C. Links between obesity-induced brain insulin resistance, brain mitochondrial dysfunction, and dementia. Front. Endocrinol. 2018 , 9 , 359824. [ Google Scholar ] [ CrossRef ]
Frisardi, V.; Solfrizzi, V.; Seripa, D.; Capurso, C.; Santamato, A.; Sancarlo, D.; Panza, F. Metabolic-cognitive syndrome: A cross-talk between metabolic syndrome and Alzheimer’s disease. Ageing Res. Rev. 2010 , 9 , 399–417. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Tong, M.; De la Monte, S.M. Mechanisms of ceramide-mediated neurodegeneration. J. Alzheimer’s Dis. 2009 , 16 , 705–714. [ Google Scholar ] [ CrossRef ]
Butterfield, D.A.; Di Domenico, F.; Barone, E. Elevated risk of type 2 diabetes for development of Alzheimer disease: A key role for oxidative stress in brain. Biochim. Et Biophys. Acta (BBA) Mol. Basis Dis. 2014 , 1842 , 1693–1706. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Whitmer, R.A. Type 2 diabetes and risk of cognitive impairment and dementia. Curr. Neurol. Neurosci. Rep. 2007 , 7 , 373–380. [ Google Scholar ] [ CrossRef ]
Ferreira, S.T.; Klein, W.L. The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease. Neurobiol Learn Mem. 2011 , 96 , 529–543. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ PubMed Central ]
Zhao, W.Q.; De Felice, F.G.; Fernandez, S.; Chen, H.; Lambert, M.P.; Quon, M.J.; Krafft, G.A.; Klein, W.L. Amyloid beta oligomers induce impairment of neuronal insulin receptors. FASEB J. 2008 , 22 , 246–260. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Hasselbach SGKnudsen, G.M.; Videbaek, C.; Pinborg, L.H.; Schmidt, J.F.; Holm, S.; Paulson, O.B. No effect of insulin on glucose blood-brain barrier transport and cerebral metabolism in humans. Diabetes 1999 , 48 , 1915–1921. [ Google Scholar ] [ CrossRef ]
Seaquist, E.R.; Damberg, G.S.; Tkac, I.; Gruetter, R. The effect of insulin on in vivo cerebral glucose concentrations and rates of glucose transport/metabolism in humans. Diabetes 2001 , 50 , 2203–2209. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Simpson, I.A.; Dwyer, D.; Malide, D.; Moley, K.H.; Travis, A.; Vannucci, S.J. The facilitative glucose transporter GLUT3: 20 years of distinction. Am. J. Physiol. Endocrinol. Metab. 2008 , 295 , E242–E253. [ Google Scholar ] [ CrossRef ]
Milstein, J.L.; Ferris, H.A. The brain as an insulin-sensitive metabolic organ. Mol. Metab. 2021 , 52 , 101234. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Simpson, I.A.; Carruthers, A.; Vannucci, S.J. Supply and demand in cerebral energy metabolism: The role of nutrient transporters. J. Cereb. Blood Flow Metab. 2007 , 27 , 1766–1791. [ Google Scholar ] [ CrossRef ]
Dienel, G.A. Fueling and imaging brain activation. ASN Neuro 2012 , 4 , AN20120021. [ Google Scholar ] [ CrossRef ]
Bentsen, M.A.; Mirzadeh, Z.; Schwartz, M.W. Revisiting how the brain senses glucose—And why. Cell Metab. 2019 , 29 , 11–17. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Bouzier-Sore, A.K.; Merle, M.; Magistretti, P.J.; Pellerin, L. Feeding active neurons:(re) emergence of a nursing role for astrocytes. J. Physiol. 2002 , 96 , 273–282. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Benomar, Y.; Naour, N.; Aubourg, A.; Bailleux, V.; Gertler, A.; Djiane, J.; Taouis, M. Insulin and leptin induce Glut4 plasma membrane translocation and glucose uptake in a human neuronal cell line by a phosphatidylinositol 3-kinase-dependent mechanism. Endocrinology 2006 , 147 , 2550–2556. [ Google Scholar ] [ CrossRef ]
Reno, C.M.; Puente, E.C.; Sheng, Z.; Daphna-Iken, D.; Bree, A.J.; Routh, V.H.; Kahn, B.B.; Fisher, S.J. Brain GLUT4 Knockout Mice Have Impaired Glucose Tolerance, Decreased Insulin Sensitivity, and Impaired Hypoglycemic Counterregulation. Diabetes 2017 , 66 , 587–597. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ PubMed Central ]
Frere, S.; Slutsky, I. Alzheimer’s disease: From firing instability to homeostasis network collapse. Neuron 2018 , 97 , 32–58. [ Google Scholar ] [ CrossRef ]
Kapogiannis, D.; Mattson, M.P. Disrupted energy metabolism and neuronal circuit dysfunction in cognitive impairment and Alzheimer’s disease. Lancet Neurol. 2011 , 10 , 187–198. [ Google Scholar ] [ CrossRef ]
Mosconi, L.; Pupi, A.; De Leon, M.J. Brain glucose hypometabolism and oxidative stress in preclinical Alzheimer’s disease. Ann. N. Y. Acad. Sci. 2008 , 1147 , 180–195. [ Google Scholar ] [ CrossRef ]
Adlimoghaddam, A.; Snow, W.M.; Stortz, G.; Perez, C.; Djordjevic, J.; Goertzen, A.L.; Albensi, B.C. Regional hypometabolism in the 3xTg mouse model of Alzheimer’s disease. Neurobiol. Dis. 2019 , 127 , 264–277. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Chadwick, W.; Maudsley, S.; Hull, W.; Havolli, E.; Boshoff, E.; Hill, M.D.; Goetghebeur, P.J.; Harrison, D.C.; Nizami, S.; Bedford, D.C.; et al. The oDGal mouse: A novel, physiologically relevant rodent model of sporadic Alzheimer’s disease. Int. J. Mol. Sci. 2023 , 24 , 6953. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Hirono, N.; Mori, E.; Ishii, K.; Ikejiri, Y.; Imamura, T.; Shimomura, T.; Hashimoto, M.; Yamashita, H.; Sasaki, M. Frontal lobe hypometabolism and depression in Alzheimer’s disease. Neurology 1998 , 50 , 380–383. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Daulatzai, M.A. Cerebral hypoperfusion and glucose hypometabolism: Key pathophysiological modulators promote neurodegeneration, cognitive impairment, and Alzheimer’s disease. J. Neurosci. Res. 2017 , 95 , 943–972. [ Google Scholar ] [ CrossRef ]
Förster, S.; Grimmer, T.; Miederer, I.; Henriksen, G.; Yousefi, B.H.; Graner, P.; Wester, H.J.; Förstl, H.; Kurz, A.; Dickerson, B.C.; et al. Regional expansion of hypometabolism in Alzheimer’s disease follows amyloid deposition with temporal delay. Biol. Psychiatry 2012 , 71 , 792–797. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Drzezga, A.; Lautenschlager, N.; Siebner, H.; Riemenschneider, M.; Willoch, F.; Minoshima, S.; Schwaiger, M.; Kurz, A. Cerebral metabolic changes accompanying conversion of mild cognitive impairment into Alzheimer’s disease: A PET follow-up study. Eur. J. Nucl. Med. Mol. Imaging 2003 , 30 , 1104–1113. [ Google Scholar ] [ PubMed ]
Small, G.W.; Ercoli, L.M.; Silverman, D.H.; Huang, S.C.; Komo, S.; Bookheimer, S.Y.; Lavretsky, H.; Miller, K.; Siddarth, P.; Rasgon, N.L.; et al. Cerebral metabolic and cognitive decline in persons at genetic risk for Alzheimer’s disease. Proc. Natl. Acad. Sci. USA 2000 , 97 , 6037–6042. [ Google Scholar ] [ CrossRef ]
Duarte, A.I.; Moreira, P.I.; Oliveira, C.R. Insulin in central nervous system: More than just a peripheral hormone. J. Aging Res. 2012 , 2012 , 384017. [ Google Scholar ] [ CrossRef ] [ PubMed ]
McNay, E.C.; Pearson-Leary, J. GluT4: A central player in hippocampal memory and brain insulin resistance. Exp. Neurol. 2020 , 323 , 113076. [ Google Scholar ] [ CrossRef ]
Raut, S.; Bhalerao, A.; Powers, M.; Gonzalez, M.; Mancuso, S.; Cucullo, L. Hypometabolism, Alzheimer’s Disease, and Possible Therapeutic Targets: An Overview. Cells 2023 , 12 , 2019. [ Google Scholar ] [ CrossRef ]
Simpson, I.A.; Chundu, K.R.; Davies-Hill, T.; Honer, W.G.; Davies, P. Decreased concentrations of GLUT1 and GLUT3 glucose transporters in the brains of patients with Alzheimer’s disease. Ann. Neurol. Off. J. Am. Neurol. Assoc. Child Neurol. Soc. 1994 , 35 , 546–551. [ Google Scholar ] [ CrossRef ]
Liu, Y.; Liu, F.; Iqbal, K.; Grundke-Iqbal, I.; Gong, C.X. Decreased glucose transporters correlate to abnormal hyperphosphorylation of tau in Alzheimer disease. FEBS Lett. 2008 , 582 , 359–364. [ Google Scholar ] [ CrossRef ]
Montagne, A.; Barnes, S.R.; Sweeney, M.D.; Halliday, M.R.; Sagare, A.P.; Zhao, Z.; Toga, A.W.; Jacobs, R.E.; Liu, C.Y.; Amezcua, L.; et al. Blood-brain barrier breakdown in the aging human hippocampus. Neuron 2015 , 85 , 296–302. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Harr, S.D.; Simonian, N.A.; Hyman, B.T. Functional alterations in Alzheimer’s disease: Decreased glucose transporter 3 immunoreactivity in the perforant pathway terminal zone. J. Neuropathol. Exp. Neurol. 1995 , 54 , 38–41. [ Google Scholar ] [ CrossRef ] [ PubMed ]
An, Y.; Varma, V.R.; Varma, S.; Casanova, R.; Dammer, E.; Pletnikova, O.; Chia, C.W.; Egan, J.M.; Ferrucci, L.; Troncoso, J.; et al. Evidence for brain glucose dysregulation in Alzheimer’s disease. Alzheimer’s Dement. 2018 , 14 , 318–329. [ Google Scholar ] [ CrossRef ]
Zhang, H.; Wei, W.; Zhao, M.; Ma, L.; Jiang, X.; Pei, H.; Cao, Y.; Li, H. Interaction between Aβ and Tau in the Pathogenesis of Alzheimer’s Disease. Int. J. Biol. Sci. 2021 , 17 , 2181–2192. [ Google Scholar ] [ CrossRef ]
Ramos-Rodriguez, J.J.; Spires-Jones, T.; Pooler, A.M.; Lechuga-Sancho, A.M.; Bacskai, B.J.; Garcia-Alloza, M. Progressive neuronal pathology and synaptic loss induced by prediabetes and type 2 diabetes in a mouse model of Alzheimer’s disease. Mol. Neurobiol. 2017 , 54 , 3428–3438. [ Google Scholar ] [ CrossRef ]
Lee, C.C.; Kuo, Y.M.; Huang, C.C.; Hsu, K.S. Insulin rescues amyloid β-induced impairment of hippocampal long-term potentiation. Neurobiol. Aging 2009 , 30 , 377–387. [ Google Scholar ] [ CrossRef ] [ PubMed ]
De Felice, F.G.; Vieira, M.N.; Bomfim, T.R.; Decker, H.; Velasco, P.T.; Lambert, M.P.; Viola, K.L.; Zhao, W.Q.; Ferreira, S.T.; Klein, W.L. Protection of synapses against Alzheimer’s-linked toxins: Insulin signaling prevents the pathogenic binding of Aβ oligomers. Proc. Natl. Acad. Sci. USA 2009 , 106 , 1971–1976. [ Google Scholar ] [ CrossRef ]
Steen, E.; Terry, B.M.; JRivera, E.; Cannon, J.L.; Neely, T.R.; Tavares, R.; Xu, X.J.; Wands, J.R.; de La Monte, S.M. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer’s disease–is this type 3 diabetes? J. Alzheimer’s Dis. 2005 , 7 , 63–80. [ Google Scholar ] [ CrossRef ]
Medeiros, R.; Baglietto-Vargas, D.; LaFerla, F.M. The role of tau in Alzheimer’s disease and related disorders. CNS Neurosci. Ther. 2011 , 17 , 514–524. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Sperber, B.R.; Leight, S.; Goedert, M.; Lee, V.M. Glycogen synthase kinase-3 beta phosphorylates tau protein at multiple sites in intact cells. Neurosci. Lett. 1995 , 197 , 149–153. [ Google Scholar ] [ CrossRef ]
Kim, J.; Basak, J.M.; Holtzman, D.M. The role of apolipoprotein E in Alzheimer’s disease. Neuron 2009 , 63 , 287–303. [ Google Scholar ] [ CrossRef ]
Xu, P.T.; Gilbert, J.R.; Qiu, H.L.; Ervin, J.; Rothrock-Christian, T.R.; Hulette, C.; Schmechel, D.E. Specific regional transcription of apolipoprotein E in human brain neurons. Am. J. Pathol. 1999 , 154 , 601–611. [ Google Scholar ] [ CrossRef ]
Mahley, R.W.; Huang, Y. Apolipoprotein e sets the stage: Response to injury triggers neuropathology. Neuron 2012 , 76 , 871–885. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Kang, S.S.; Ebbert, M.T.; Baker, K.E.; Cook, C.; Wang, X.; Sens, J.P.; Kocher, J.P.; Petrucelli, L.; Fryer, J.D. Microglial translational profiling reveals a convergent APOE pathway from aging, amyloid, and tau. J. Exp. Med. 2018 , 215 , 2235–2245. [ Google Scholar ] [ CrossRef ]
Lanfranco, M.F.; Sepulveda, J.; Kopetsky, G.; Rebeck, G.W. Expression and secretion of apoE isoforms in astrocytes and microglia during inflammation. Glia 2021 , 69 , 1478–1493. [ Google Scholar ] [ CrossRef ]
van der Lee, S.J.; Wolters, F.J.; Ikram, M.K.; Hofman, A.; Ikram, M.A.; Amin, N.; van Duijn, C.M. The effect of APOE and other common genetic variants on the onset of Alzheimer’s disease and dementia: A community-based cohort study. Lancet Neurol. 2018 , 17 , 434–444. [ Google Scholar ] [ CrossRef ]
Bales, K.R.; Dodart, J.C.; DeMattos, R.B.; Holtzman, D.M.; Paul, S.M. Apolipoprotein E, amyloid, and Alzheimer disease. Mol. Interv. 2002 , 2 , 363. [ Google Scholar ] [ CrossRef ]
Holtzman, D.M.; Fagan, A.M.; Mackey, B.; Tenkova, T.; Sartorius, L.; Paul, S.M.; Bales, K.; Hsiao Ashe, K.; Irizarry, M.C.; Hyman, B.T. Apolipoprotein E facilitates neuritic and cerebrovascular plaque formation in an Alzheimer’s disease model. Ann. Neurol. Off. J. Am. Neurol. Assoc. Child Neurol. Soc. 2000 , 47 , 739–747. [ Google Scholar ] [ CrossRef ]
Kok, E.; Haikonen, S.; Luoto, T.; Huhtala, H.; Goebeler, S.; Haapasalo, H.; Karhunen, P.J. Apolipoprotein E–dependent accumulation of Alzheimer disease–related lesions begins in middle age. Ann. Neurol. Off. J. Am. Neurol. Assoc. Child Neurol. Soc. 2009 , 65 , 650–657. [ Google Scholar ] [ CrossRef ]
Garai, K.; Verghese, P.B.; Baban, B.; Holtzman, D.M.; Frieden, C. The binding of apolipoprotein E to oligomers and fibrils of amyloid-β alters the kinetics of amyloid aggregation. Biochemistry 2014 , 53 , 6323–6331. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Tai, L.M.; Bilousova, T.; Jungbauer, L.; Roeske, S.K.; Youmans, K.L.; Yu, C.; Poon, W.W.; Cornwell, L.B.; Miller, C.A.; Vinters, H.V.; et al. Levels of soluble apolipoprotein E/amyloid-β (Aβ) complex are reduced and oligomeric Aβ increased with APOE4 and Alzheimer disease in a transgenic mouse model and human samples. J. Biol. Chem. 2013 , 288 , 5914–5926. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ PubMed Central ]
Tarasoff-Conway, J.M.; Carare, R.O.; Osorio, R.S.; Glodzik, L.; Butler, T.; Fieremans, E.; Axel, L.; Rusinek, H.; Nicholson, C.; Zlokovic, B.V.; et al. Clearance systems in the brain—Implications for Alzheimer disease. Nat. Rev. Neurol. 2015 , 11 , 457–470. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Wadhwani, A.R.; Affaneh, A.; Van Gulden, S.; Kessler, J.A. Neuronal apolipoprotein E4 increases cell death and phosphorylated tau release in alzheimer disease. Ann. Neurol. 2019 , 85 , 726–739. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Harris, F.M.; Brecht, W.J.; Xu, Q.; Mahley, R.W.; Huang, Y. Increased tau phosphorylation in apolipoprotein E4 transgenic mice is associated with activation of extracellular signal-regulated kinase: Modulation by zinc. J. Biol. Chem. 2004 , 279 , 44795–44801. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Filippini, N.; Ebmeier, K.P.; MacIntosh, B.J.; Trachtenberg, A.J.; Frisoni, G.B.; Wilcock, G.K.; Beckmann, C.F.; Smith, S.M.; Matthews, P.M.; Mackay, C.E. Differential effects of the APOE genotype on brain function across the lifespan. Neuroimage 2011 , 54 , 602–610. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Thambisetty, M.; Beason-Held, L.; An, Y.; Kraut, M.A.; Resnick, S.M. APOE ε4 genotype and longitudinal changes in cerebral blood flow in normal aging. Arch. Neurol. 2010 , 67 , 93–98. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Johnson, L.A.; Torres, E.R.; Weber Boutros, S.; Patel, E.; Akinyeke, T.; Alkayed, N.J.; Raber, J. Apolipoprotein E4 mediates insulin resistance-associated cerebrovascular dysfunction and the post-prandial response. J. Cereb. Blood Flow Metab. 2019 , 39 , 770–781. [ Google Scholar ] [ CrossRef ]
Zhao, N.; Liu, C.C.; Van Ingelgom, A.J.; Martens, Y.A.; Linares, C.; Knight, J.A.; Painter, M.M.; Sullivan, P.M.; Bu, G. Apolipoprotein E4 impairs neuronal insulin signaling by trapping insulin receptor in the endosomes. Neuron 2017 , 96 , 115–129. [ Google Scholar ] [ CrossRef ]
Simonovitch, S.; Schmukler, E.; Masliah, E.; Pinkas-Kramarski, R.; Michaelson, D.M. The effects of APOE4 on mitochondrial dynamics and proteins in vivo. J. Alzheimer’s Dis. 2019 , 70 , 861–875. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Ho, A.J.; Stein, J.L.; Hua, X.; Lee, S.; Hibar, D.P.; Leow, A.D.; Dinov, I.D.; Toga, A.W.; Saykin, A.J.; Shen, L.; et al. Alzheimer’s Disease Neuroimaging Initiative. A commonly carried allele of the obesity-related FTO gene is associated with reduced brain volume in the healthy elderly. Proc. Natl. Acad. Sci. USA 2010 , 107 , 8404–8409. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Shi, L.; Du, X.; Jiang, H.; Xie, J. Ghrelin and Neurodegenerative Disorders-a Review. Mol. Neurobiol. 2017 , 54 , 1144–1155. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Amin, A.M.; Mostafa, H.; Khonah, H.M.J. Insulin resistance in Alzheimer’s disease. The genetica and metabolomics links. Clin. Chim. Acta 2023 , 539 , 215–236. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Belosludtsev, K.N.; Belosludtseva, N.V.; Dubinin, M.V. Diabetes mellitus, mitochondrial dysfunction and Ca 2+ -dependent permeability transition pore. Int. J. Mol. Sci. 2020 , 21 , 6559. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Skelly, D.T.; Hennessy, E.; Dansereau, M.A.; Cunningham, C. A systematic analysis of the peripheral and CNS effects of systemic LPS, IL-1β, TNF-α and IL-6 challenges in C57BL/6 mice. PLoS ONE 2013 , 8 , e69123. [ Google Scholar ] [ CrossRef ]
Mootha, V.K.; Lindgren, C.M.; Eriksson, K.F.; Subramanian, A.; Sihag, S.; Lehar, J.; Puigserver, P.; Carlsson, E.; Ridderstråle, M.; Laurila, E.; et al. PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat. Genet. 2003 , 34 , 267–273. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Patti, M.E.; Butte, A.J.; Crunkhorn, S.; Cusi, K.; Berria, R.; Kashyap, S.; Miyazaki, Y.; Kohane, I.; Costello, M.; Saccone, R.; et al. Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: Potential role of PGC1 and NRF1. Proc. Natl. Acad. Sci. USA 2003 , 100 , 8466–8471. [ Google Scholar ] [ CrossRef ]
Qin, W.; Haroutunian, V.; Katsel, P.; Cardozo, C.P.; Ho, L.; Buxbaum, J.D.; Pasinetti, G.M. PGC-1α expression decreases in the Alzheimer disease brain as a function of dementia. Arch. Neurol. 2009 , 66 , 352–361. [ Google Scholar ] [ CrossRef ]
Srivastava, S.; Diaz, F.; Iommarini, L.; Aure, K.; Lombes, A.; Moraes, C.T. PGC-1alpha/beta induced expression partially compesates for respiratory chain defects in cells from patients with mitochondrial disorders. Hum. Mol. Genet. 2009 , 18 , 180512. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ PubMed Central ]
Wang, J.; Markesbery, W.R.; Lovell, M.A. Increased oxidative damage in nuclear and mitochondrial DNA in mild cognitive impairment. J. Neurochem. 2006 , 96 , 825–832. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Fournet, M.; Bonté, F.; Desmoulière, A. Glycation damage: A possible hub for major pathophysiological disorders and aging. Aging Dis. 2018 , 9 , 880. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Sirangelo, I.; Iannuzzi, C. Understanding the role of protein glycation in the amyloid aggregation process. Int. J. Mol. Sci. 2021 , 22 , 6609. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Smith, M.A.; Rudnicka-Nawrot, M.; Richey, P.L.; Praprotnik, D.; Mulvihill, P.; Miller, C.A.; Sayre, L.M.; Perry, G. Carbonyl-related posttranslational modification of neurofilament protein in the neurofibrillary pathology of Alzheimer’s disease. J. Neurochem. 1995 , 64 , 2660–2666. [ Google Scholar ] [ CrossRef ]
Rolland, S.G.; Motori, E.; Memar, N.; Hench, J.; Frank, S.; Winklhofer, K.F.; Conradt, B. Impaired complex IV activity in response to loss of LRPPRC function can be compensated by mitochondrial hyperfusion. Proc. Natl. Acad. Sci. USA 2013 , 110 , E2967–E2976. [ Google Scholar ] [ CrossRef ]
Westermann, B. Bioenergetic role of mitochondrial fusion and fission. Biochim. Et Biophys. Acta (BBA) Bioenerg. 2012 , 1817 , 1833–1838. [ Google Scholar ] [ CrossRef ]
Friedman, J.R.; Nunnari, J. Mitochondrial form and function. Nature 2014 , 505 , 335–343. [ Google Scholar ] [ CrossRef ]
Maciejczyk, M.; Żebrowska, E.; Chabowski, A. Insulin resistance and oxidative stress in the brain: What’s new? Int. J. Mol. Sci. 2019 , 20 , 874. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Verdile, G.; Keane, K.N.; Cruzat, V.F.; Medic, S.; Sabale, M.; Rowles, J.; Wijesekara, N.; Martins, R.N.; Fraser, P.E.; Newsholme, P. Inflammation and oxidative stress: The molecular connectivity between insulin resistance, obesity, and Alzheimer’s disease. Mediat. Inflamm. 2015 , 2015 , 105828. [ Google Scholar ] [ CrossRef ]
Finkel, T. Oxygen radicals and signaling. Curr. Opin. Cell Biol. 1998 , 10 , 248–253. [ Google Scholar ] [ CrossRef ]
Nemoto, S.; Takeda, K.; Yu, Z.X.; Ferrans, V.J.; Finkel, T. Role for mitochondrial oxidants as regulators of cellular metabolism. Mol. Cell. Biol. 2000 , 20 , 7311–7318. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Sena, L.A.; Chandel, N.S. Physiological roles of mitochondrial reactive oxygen species. Mol. Cell 2012 , 48 , 158–167. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Chandel, N.S.; Trzyna, W.C.; McClintock, D.S.; Schumacker, P.T. Role of oxidants in NF-κB activation and TNF-α gene transcription induced by hypoxia and endotoxin. J. Immunol. 2000 , 165 , 1013–1021. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Collins, Y.; Chouchani, E.T.; James, A.M.; Menger, K.E.; Cochemé, H.M.; Murphy, M.P. Mitochondrial redox signalling at a glance. J. Cell Sci. 2012 , 125 , 801–806. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Cross, D.A.; Alessi, D.R.; Cohen, P.; Andjelkovich, M.; Hemmings, B.A. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 1995 , 378 , 785–789. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Martin, M.; Rehani, K.; Jope, R.S.; Michalek, S.M. Toll-like receptor–mediated cytokine production is differentially regulated by glycogen synthase kinase 3. Nat. Immunol. 2005 , 6 , 777–784. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Ma, Q. Role of nrf2 in oxidative stress and toxicity. Annu. Rev. Pharmacol. Toxicol. 2013 , 53 , 401–426. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Federico, A.; Cardaioli, E.; Da Pozzo, P.; Formichi, P.; Gallus, G.N.; Radi, E. Mitochondria, oxidative stress and neurodegeneration. J. Neurol. Sci. 2012 , 322 , 254–262. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Ruegsegger, G.N.; Vanderboom, P.M.; Dasari, S.; Klaus, K.A.; Kabiraj, P.; McCarthy, C.B.; Lucchinetti, C.F.; Nair, K.S. Exercise and metformin counteract altered mitochondrial function in the insulin-resistant brain. JCI insight 2019 , 4 , e130681. [ Google Scholar ] [ CrossRef ]
Maciejczyk, M.; Żebrowska, E.; Zalewska, A.; Chabowski, A. Redox balance, antioxidant defense, and oxidative damage in the hypothalamus and cerebral cortex of rats with high fat diet-induced insulin resistance. Oxidative Med. Cell. Longev. 2018 , 2018 , 6940515. [ Google Scholar ] [ CrossRef ]
Di Filippo, M.; Chiasserini, D.; Tozzi, A.; Picconi, B.; Calabresi, P. Mitochondria and the link between neuroinflammation and neurodegeneration. J. Alzheimer’s Dis. 2010 , 20 , S369–S379. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Wilkins, H.M.; Carl, S.M.; Greenlief, A.C.; Festoff, B.W.; Swerdlow, R.H. Bioenergetic dysfunction and inflammation in Alzheimer’s disease: A possible connection. Front. Aging Neurosci. 2014 , 6 , 311. [ Google Scholar ] [ CrossRef ]
Zhou, R.; Yazdi, A.S.; Menu, P.; Tschopp, J. A role for mitochondria in NLRP3 inflammasome activation. Nature 2011 , 469 , 221–225. [ Google Scholar ] [ CrossRef ]
Sprenger, H.G.; MacVicar, T.; Bahat, A.; Fiedler, K.U.; Hermans, S.; Ehrentraut, D.; Ried, K.; Milenkovic, D.; Bonekamp, N.; Larsson, N.G.; et al. Cellular pyrimidine imbalance triggers mitochondrial DNA–dependent innate immunity. Nat. Metab. 2021 , 3 , 636–650. [ Google Scholar ] [ CrossRef ]
Zhao, W.; Beers, D.R.; Bell, S.; Wang, J.; Wen, S.; Baloh, R.H.; Appel, S.H. TDP-43 activates microglia through NF-κB and NLRP3 inflammasome. Exp. Neurol. 2015 , 273 , 24–35. [ Google Scholar ] [ CrossRef ]
Hamelin, L.; Lagarde, J.; Dorothée, G.; Leroy, C.; Labit, M.; Comley, R.A.; Clinical IMABio3 Team. Early and protective microglial activation in Alzheimer’s disease: A prospective study using 18 F-DPA-714 PET imaging. Brain 2016 , 139 , 1252–1264. [ Google Scholar ] [ CrossRef ]
Jiang, C.; Li, G.; Huang, P.; Liu, Z.; Zhao, B. The Gut Microbiota and Alzheimer’s Disease. J. Alzheimers. Dis. 2017 , 58 , 1–15. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Lazar, E.; Sherzai, A.; Adeghate, J.; Sherzai, D. Gut dysbiosis, insulin resistance and Alzheimer’s disease: Review of a novel approach to neurodegeneration. Front. Biosci. (Schol. Ed.) 2021 , 13 , 17–29. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Iturria-Medina, Y.; Sotero, R.C.; Toussaint, P.J.; Mateos-Pérez, J.M.; Evans, A.C. Early role of vascular dysregulation on late-onset Alzheimer’s disease based on multifactorial data-driven analysis. Nat. Commun. 2016 , 7 , 11934. [ Google Scholar ] [ CrossRef ]
Cuadrado-Godia, E.; Dwivedi, P.; Sharma, S.; Santiago, A.O.; Gonzalez, J.R.; Balcells, M.; Laird, J.; Turk, M.; Suri, H.S.; Nicolaides, A.; et al. Cerebral small vessel disease: A review focusing on pathophysiology, biomarkers, and machine learning strategies. J. Stroke 2018 , 20 , 302. [ Google Scholar ] [ CrossRef ]
Cortes-Canteli, M.; Iadecola, C. Alzheimer’s disease and vascular aging: JACC focus seminar. J. Am. Coll. Cardiol. 2020 , 75 , 942–951. [ Google Scholar ] [ CrossRef ]
Kawahito, S.; Kitahata, H.; Oshita, S. Problems associated with glucose toxicity: Role of hyperglycemia-induced oxidative stress. World J. Gastroenterol. 2009 , 15 , 4137. [ Google Scholar ] [ CrossRef ]
Lau, L.H.; Lew, J.; Borschmann, K.; Thijs, V.; Ekinci, E.I. Prevalence of diabetes and its effects on stroke outcomes: A meta-analysis and literature review. J. Diabetes Investig. 2019 , 10 , 780–792. [ Google Scholar ] [ CrossRef ]
Claassen, J.A.H.R.; Thiessens, D.H.J.; Panerai, R.B.; Faraci, F.M. Regulation of cerebral blood flow in humans: Physiology and clinical implications of autoregulation. Physiol. Rev. 2021 , 101 , 1487–1559. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Biffi, A.; Greenberg, S.M. Cerebral amyloid angiopathy: A systematic review. J. Clin. Neurol. 2011 , 7 , 1–9. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Abraham, H.M.; Wolfson, L.; Moscufo, N.; Guttmann, C.R.; Kaplan, R.F.; White, W.B. Cardiovascular risk factors and small vessel disease of the brain: Blood pressure, white matter lesions, and functional decline in older persons. J. Cereb. Blood Flow Metab. 2016 , 36 , 132–142. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Herman, R.; Kravos, N.A.; Jensterle, M.; Janež, A.; Dolžan, V. Metformin and Insulin Resistance: A Review of the Underlying Mechanisms behind Changes in GLUT4-Mediated Glucose Transport. Int. J. Mol. Sci. 2022 , 23 , 1264. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ PubMed Central ]
Hsu, C.C.; Wahlqvist, M.L.; Lee, M.S.; Tsai, H.N. Incidence of dementia is increased in type 2diabetes and reduced by the use of sulfonylureas and metformin. J Alzheimer’s Dis. 2011 , 24 , 485–493. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Zimmerman, S.C.; Ferguson, E.L.; Choudhary, V.; Ranatunga, D.K.; Oni-Orisan, A.; Hayes-Larson, E.; Folle, A.D.; Mayeda, E.R.; Whitmer, R.A.; Gilsanz, P.; et al. Metformin Cessation and Dementia Incidence. JAMA Netw Open. 2023 , 6 , e2339723. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ PubMed Central ]
Zheng, J.; Xu, M.; Walker, V.; Yuan, J.; Korologou-Linden, R.; Robinson, J.; Huang, P.; Burgess, S.; Au Yeung, S.L.; Luo, S.; et al. Evaluating the efficacy and mechanism of metformin targets on reducing Alzheimers disease risk in the general population: A Mendelian randomisation study. Diabetologia 2022 , 65 , 1664–1675. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ PubMed Central ]
Combs, C.K.; Johnson, D.E.; Karlo, J.C.; Cannady, S.B.; Landreth, G.E. Inflammatory mechanisms in Alzheimer’s disease: Inhibition of beta-amyloid-stimulated proinflammatory responses and neurotoxicity by PPARgamma agonists. J. Neurosci. 2000 , 20 , 558–567. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ PubMed Central ]
Delerive, P.; Fruchart, J.C.; Staels, B. Peroxisome proliferator-activated receptors ininflammation control. J. Endocrinol. 2001 , 169 , 453–459. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Seferović, P.M.; Petrie, M.C.; Filippatos, G.S.; Anker, S.D.; Rosano, G.; Bauersachs, J.; Paulus, W.J.; Komajda, M.; Cosentino, F.; De Boer, R.A.; et al. Type 2 diabetes mellitus and heart failure: A position statement from the Heart Failure Association of the European Society of Cardiology. Eur. J. Heart Fail. 2018 , 20 , 853–872. [ Google Scholar ] [ CrossRef ] [ PubMed ]
McClean, P.L.; Parthsarathy, V.; Faivre, E.; Hölscher, C. The diabetes drug liraglutide prevents degenerative processes in a mouse model of Alzheimer’s disease. J Neurosci. 2011 , 31 , 6587–6594. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ PubMed Central ]
Li, Y.; Duffy, K.B.; Ottinger, M.A.; Ray, B.; Bailey, J.A.; Holloway, H.W.; Tweedie, D.; Perry, T.; Mattson, M.P.; Kapogiannis, D.; et al. GLP-1 receptor stimulation reduces amyloid-beta peptide accumulation and cytotoxicity in cellular and animal models of Alzheimer’s disease. J. Alzheimers. Dis. 2010 , 19 , 1205–1219. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ PubMed Central ]
Nørgaard, C.H.; Friedrich, S.; Hansen, C.T.; Gerds, T.; Ballard, C.; Møller, D.V.; Knudsen, L.B.; Kvist, K.; Zinman, B.; Holm, E.; et al. Treatment with glucagon-like peptide-1 receptor agonists and incidence of dementia: Data from pooled double-blind randomized controlled trials and nationwide disease and prescription registers. Alzheimers Dement 2022 , 8 , e12268. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ PubMed Central ]
Kelsey, M.D.; Nelson, A.J.; Green, J.B.; Granger, C.B.; Peterson, E.D.; McGuire, D.K.; Pagidipati, N.J. Guidelines for Cardiovascular Risk Reduction in Patients With Type 2 Diabetes: JACCGuideline Comparison. J. Am. Coll. Cardiol. 2022 , 79 , 1849–1857. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ PubMed Central ]
Heidenreich, P.A.; Bozkurt, B.; Aguilar, D.; Allen, L.A.; Byun, J.J.; Colvin, M.M.; Deswal, A.; Drazner, M.H.; Dunlay, S.M.; Evers, L.R.; et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation 2022 , 145 , e895–e1032, Erratum in Circulation 2022 , 145 , e1033; Erratum in Circulation 2022 , 146 , e185; Erratum in Circulation 2023 , 147 , e674. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Hosokawa, Y.; Ogawa, W. SGLT2 inhibitors for genetic and acquired insulin resistance: Considerations for clinical use. J Diabetes Investig. 2020 , 11 , 1431–1433. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ PubMed Central ]
Sim, A.Y.; Choi, D.H.; Kim, J.Y.; Kim, E.R.; Goh, A.R.; Lee, Y.H.; Lee, J.E. SGLT2 and DPP4inhibitors improve Alzheimer’s disease-like pathology and cognitive function through distinct mechanisms in a T2D-AD mouse model. Biomed. Pharmacother. 2023 , 168 , 115755. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Siao, W.Z.; Lin, T.K.; Huang, J.Y.; Tsai, C.F.; Jong, G.P. The association between sodium-glucosecotransporter 2 inhibitors and incident dementia: A nationwide population-based longitudinal cohort study. Diab. Vasc. Dis. Res. 2022 , 19 , 14791641221098168. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ PubMed Central ]
Kuate Defo, A.; Bakula, V.; Pisaturo, A.; Labos, C.; Wing, S.S.; Daskalopoulou, S.S. Diabetes, antidiabetic medications and risk of dementia: A systematic umbrella review and meta-analysis. Diabetes Obes Metab. 2024 , 26 , 441–462. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Wu, C.Y.; Iskander, C.; Wang, C.; Xiong, L.Y.; Shah, B.R.; Edwards, J.D.; Kapral, M.K.; Herrmann, N.; Lanctôt, K.L.; Masellis, M.; et al. Association of Sodium-Glucose Cotransporter 2 Inhibitors with Time to Dementia: A Population-Based Cohort Study. Diabetes Care 2023 , 46 , 297–304. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Tang, H.; Shao, H.; Shaaban, C.E.; Yang, K.; Brown, J.; Anton, S.; Wu, Y.; Bress, A.; Donahoo, W.T.; DeKosky, S.T.; et al. Newer glucose-lowering drugs and risk of dementia: A systematic review and meta-analysis of observational studies. J. Am. Geriatr. Soc. 2023 , 71 , 2096–2106. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ PubMed Central ]
O’Keefe, J.H.R.; O’Keefe, E.L.; Franco, W.G. SGLT inhibitors for improving Healthspan and lifespan. Prog Cardiovasc Dis. 2023 , 81 , 2–9. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ PubMed Central ]
Antinozzi, C.; Sgrò, P.; Di Luigi, L. Advantages of Phosphodiesterase Type 5 Inhibitors in the Management of Glucose Metabolism Disorders: A Clinical and Translational Issue. Int. J. Endocrinol. 2020 , 2020 , 7078108. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ PubMed Central ]
Ayala, J.E.; Bracy, D.P.; Julien, B.M.; Rottman, J.N.; Fueger, P.T.; Wasserman, D.H. Chronic treatment with sildenafil improves energy balance and insulin action in high fat-fed conscious mice. Diabetes 2007 , 56 , 1025–1033. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Puzzo, D.; Staniszewski, A.; Deng, S.X.; Privitera, L.; Leznik, E.; Liu, S.; Zhang, H.; Feng, Y.; Palmeri, A.; Landry, D.W.; et al. Phosphodiesterase 5 inhibition improves synaptic function, memory, and amyloid-beta load in an Alzheimer’s disease mouse model. J. Neurosci. 2009 , 29 , 8075–8086. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ PubMed Central ]
García-Barroso, C.; Ricobaraza, A.; Pascual-Lucas, M.; Unceta, N.; Rico, A.J.; Goicolea, M.A.; Sallés, J.; Lanciego, J.L.; Oyarzabal, J.; Franco, R.; et al. Tadalafil crosses the blood-brain barrier and reverses cognitive dysfunction in a mouse model of AD. Neuropharmacology 2013 , 64 , 114–123. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Adesuyan, M.; Jani, Y.H.; Alsugeir, D.; Howard, R.; Ju, C.; Wei, L.; Brauer, R. Phosphodiesterase Type 5 Inhibitors in Men with Erectile Dysfunction and the Risk of Alzheimer Disease: A Cohort Study. Neurology 2024 , 102 , e209131. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ PubMed Central ]
Singh, A.; Dhaneshwar, S.; Mazumder, A. Investigating Neuroprotective Potential of Berberine, Levetiracetam and their Combination in the Management of Alzheimer’s Disease Utilizing Drug Repurposing Strategy. Curr. Rev. Clin. Exp. Pharmacol. 2023 , 18 , 182–190. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Lin, X.; Zhang, N. Berberine: Pathways to protect neurons. Phytother Res. 2018 , 32 , 1501–1510. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Wu, L.; Meng, X.J.; Xu, T.B.; Zhang, X.C.; Zhou, Y.; Tong, Z.F.; Jiang, J.H. Berberine attenuates cognitive dysfunction and hippocampal apoptosis in rats with prediabetes. Chem. Biol. Drug Des. 2024 , 103 , e14420. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Zhang, J.H.; Zhang, J.F.; Song, J.; Bai, Y.; Deng, L.; Feng, C.P.; Xu, X.Y.; Guo, H.X.; Wang, Y.; Gao, X.; et al. Effects of Berberine on Diabetes and Cognitive Impairment in an Animal Model: The Mechanisms of Action. Am. J. Chin. Med. 2021 , 49 , 1399–1415. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Baska, A.; Leis, K.; Gałązka, P. Berberine in the Treatment of Diabetes Mellitus: A Review. Endocr. Metab. Immune Disord. Drug Targets 2021 , 21 , 1379–1386. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Bellavite, P.; Fazio, S.; Affuso, F. A Descriptive Review of the Action Mechanisms of Berberine, Quercetin and Silymarin on Insulin Resistance/Hyperinsulinemia and Cardiovascular Prevention. Molecules 2023 , 28 , 4491. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ PubMed Central ]
Huang, M.; Chen, S.; Liang, Y.; Guo, Y. The Role of Berberine in the Multi-Target Treatment of Senile Dementia. Curr. Top Med. Chem. 2016 , 16 , 867–873. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Zhang, N.; Gao, Y.; Yu, S.; Sun, X.; Shen, K. Berberine attenuates Aβ42-induced neuronal damage through regulating circHDAC9/miR-142-5p axis in human neuronal cells. Life Sci. 2020 , 252 , 117637. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Moghaddam, H.K.; Baluchnejadmojarad, T.; Roghani, M.; Khaksari, M.; Norouzi, P.; Ahooie, M.; Mahboobi, F. Berberine ameliorate oxidative stress and astrogliosis in the hippocampus of STZ-induced diabetic rats. Mol. Neurobiol. 2014 , 49 , 820–826. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Chatterjee, P.; Vermunt, L.; Gordon, B.; Pedrini, S.; Boonkamp, L.; Armstrong, N.; Teunissen, C. Plasma glial fibrillary acidic protein in autosomal dominant Alzheimer’s disease: Associations with β-amyloid-PET, neurodegeneration and cognition. Alzheimer’s Dement. 2022 , 19 , 2790–2804. [ Google Scholar ] [ CrossRef ]
Durairajan, S.S.K.; Liu, L.F.; Lu, J.H.; Chen, L.L.; Yuan, Q.; Chung, S.K.; Huang, L.; Li, X.S.; Huang, J.D.; Li, M. Berberine ameliorates β-amyloid pathology, gliosis, and cognitive impairment in an Alzheimer’s disease transgenic mouse model. Neurobiol. Aging 2012 , 33 , 2903–2919. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Sun, C.; Dong, S.; Chen, W.; Li, J.; Luo, E.; Ji, J. Berberine alleviates Alzheimer’s disease by regulating the gut microenvironment, restoring the gut barrier and brain-gut axis balance. Phytomedicine 2024 , 129 , 155624. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Duc Nguyen, H. Neurotherapeutic Effects of Quercetin and Its Metabolite Compounds on Cognitive Impairment and Parkinson’s Disease: An In Silico Study. Eur. J. Drug Metabm. Pharmacokinet. 2023 , 48 , 151–169. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Khan, H.; Ullah, H.; Aschner, M.; Cheang, W.S.; Akkol, E.K. Neuroprotective Effects of Quercetin in Alzheimer’s Disease. Biomolecules 2019 , 30 , 59. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ PubMed Central ]
Wang, D.; Zhao, J.; Li, S.; Shen, G.; Hu, S. Quercetin attenuates domoic acid-induced cognitive deficits in mice. Nutr. Neurosci. 2018 , 21 , 123–131. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Nakamura, Y.; Watanabe, H.; Tanaka, A.; Nishihira, J.; Murayama, N. Effect of quercetin glycosides on cognitive functions and cerebral blood flow: A randomized, double-blind, and placebo-controlled study. Eur. Rev. Med. Pharmacol. Sci. 2022 , 26 , 8700–8712. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Zhang, P.; Kishimoto, Y.; Grammatikakis, I.; Gottimukkala, K.; Cutler, R.G.; Zhang, S.; Abdelmohsen, K.; Bohr, V.A.; Misra Sen, J.; Gorospe, M.; et al. Senolytic therapy alleviates Aβ-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer’s disease model. Nat. Neurosci. 2019 , 22 , 719–728. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ PubMed Central ]
Bellavite, P. Neuroprotective Potentials of Flavonoids: Experimental Studies and Mechanisms of Action. Antioxidants 2023 , 12 , 280. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ PubMed Central ]
de Luis, D.; Izaola, O.; de la Fuente, B.; Aller, R. Effect of L-arginine supplementation on insulin resistance and adipocitokines levels in head and neck cancer non diabetic patients after surgery. Nutr Hosp. 2014 , 30 , 870–875. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Piatti, P.; Monti, L.D.; Valsecchi, G.; Magni, F.; Setola, E.; Marchesi, F.; Galli-Kienle, M.; Pozza, G.; Alberti, K.G.M. Long-term oral L-arginine administration improves peripheral and hepatic insulin sensitivity in type 2 diabetic patients. Diabetes Care 2001 , 24 , 875–880. [ Google Scholar ] [ CrossRef ]
Fleszar, M.G.; Wiśniewski, J.; Zboch, M.; Diakowska, D.; Gamian, A.; Krzystek-Korpacka, M. Targeted metabolomic analysis of nitric oxide/L-arginine pathway metabolites in dementia: Association with pathology, severity, and structural brain changes. Sci. Rep. 2019 , 9 , 13764. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ PubMed Central ]
Virarkar, M.; Alappat, L.; Bradford, P.G.; Awad, A.B. L-arginine and nitric oxide in CNS function and neurodegenerative diseases. Crit. Rev. Food Sci. Nutr. 2013 , 53 , 1157–1167. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Geravand, S.; Karami, M.; Sahraei, H.; Rahimi, F. Protective effects of L-arginine on Alzheimer’s disease: Modulating hippocampal nitric oxide levels and memory deficits in aluminum chloride-induced rat model. Eur. J. Pharmacol. 2023 , 958 , 176030. [ Google Scholar ] [ CrossRef ] [ PubMed ]
İsmail, S.; Serpil, E.; Esma, Ö.; Durmuş, A.; Erdal, E.; Avni, B.; Savaş, K. Changes in arginine metabolism in advanced Alzheimer’s patients:mExperimental and theoretical analyses. J. Mol. Struct. 2023 , 1282 , 135254. [ Google Scholar ]
Mone, P.; Pansini, A.; Jankauskas, S.S.; Varzideh, F.; Kansakar, U.; Lombardi, A.; Trimarco, V.; Frullone, S.; Santulli, G. L-Arginine Improves Cognitive Impairment in Hypertensive Frail Older Adults. Front. Cardiovasc. Med. 2022 , 9 , 868521. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ PubMed Central ]
Kuro-O, M. The Klotho proteins in health and disease. Nat. Rev. Nephrol. 2019 , 15 , 27–44. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Prud’homme, G.J.; Kurt, M.; Wang, Q. Pathobiology of the Klotho Antiaging Protein and Therapeutic Considerations. Front. Aging 2022 , 3 , 931331. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ PubMed Central ]
Hwang, H.J.; Kim, N.; Herman, A.B.; Gorospe, M.; Lee, J.S. Factors and Pathways Modulating Endothelial Cell Senescence in Vascular Aging. Int. J. Mol. Sci. 2022 , 23 , 10135. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ PubMed Central ]
Yan, L.; Hu, X.; Wu, S.; Zhao, S. Serum Klotho and insulin resistance: Insights from a cross-sectional analysis. Medicine 2024 , 103 , e37971. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ PubMed Central ]
Silva, A.P.; Mendes, F.; Pereira, L.; Fragoso, A.; Gonçalves, R.B.; Santos, N.; Rato, F.; Neves, P.L. Klotho levels: Association with insulin resistance and albumin-to-creatinine ratio in type 2 diabetic patients. Int. Urol. Nephrol. 2017 , 49 , 1809–1814. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Cheng, Y.W.; Hung, C.C.; Fang, W.H.; Chen, W.L. Association between Soluble α-Klotho Protein and Metabolic Syndrome in the Adult Population. Biomolecules 2022 , 12 , 70. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ PubMed Central ]
Dërmaku-Sopjani, M.; Kolgec, S.; Abazi, S.; Sopjani, M. Significance of the anti-aging protein Klotho. Mol. Membr. Biol. 2013 , 30 , 369–385. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Semba, R.D.; Moghekar, A.R.; Hu, J.; Sun, K.; Turner, R.; Ferrucci, L.; O’Brien, R. Klotho in the cerebrospinal fluid of adults with and without Alzheimer’s disease. Neurosci. Lett. 2014 , 558 , 37–40. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ PubMed Central ]
Zhao, Y.; Zeng, C.Y.; Li, X.H.; Yang, T.T.; Kuang, X.; Du, J.R. Klotho overexpression improves amyloid-β clearance and cognition in the APP/PS1 mouse model of Alzheimer’s disease. Aging Cell. 2020 , 19 , e13239. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ PubMed Central ]
Pedersen, A.K.N.; Gormsen, L.C.; Nielsen, S.; Jessen, N.; Bjerre, M. Metformin Improves the Prerequisites for FGF21 Signaling in Patients with Type 2 Diabetes. J. Clin. Endocrinol. Metab. 2024 , 109 , e552–e561. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Wolf, L.; Föller, M.; Feger, M. The impact of SGLT2 inhibitors on αKlotho in renal MDCK and HK-2 cells. Front. Endocrinol. 2023 , 14 , 1069715. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ PubMed Central ]
Li, C.; Jiang, S.; Wang, H.; Wang, Y.; Han, Y.; Jiang, J. Berberine exerts protective effects on cardiac senescence by regulating the Klotho/.SIRT1 signaling pathway. Biomed Pharmacother. 2022 , 151 , 113097. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Zhu, Y.; Prata, L.G.L.; Gerdes, E.O.W.; Netto, J.M.E.; Pirtskhalava, T.; Giorgadze, N.; Tripathi, U.; Inman, C.L.; Johnson, K.O.; Xue, A.; et al. Orally-active, clinically-translatable senolytics restore α-Klotho in mice and humans. EBioMedicine 2022 , 77 , 103912. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ PubMed Central ]
Alharbi, K.S.; Afzal, O.; Altamimi, A.S.A.; Almalki, W.H.; Kazmi, I.; Al-Abbasi, F.A.; Alzarea, S.I.; Makeen, H.A.; Albratty, M. A study of the molecular mechanism of quercetin and dasatinib combination as senolytic in alleviating age-related and kidney diseases. J. Food Biochem. 2022 , 46 , e14471. [ Google Scholar ] [ CrossRef ] [ PubMed ]
Schmid, V.; Kullmann, S.; Gfrörer, W.; Hund, V.; Hallschmid, M.; Lipp, H.P.; Häring, H.U.; Preissl, H.; Fritsche, A.; Heni, M. Safety of intranasal human insulin: A review. Diabetes Obes. Metab. 2018 , 20 , 1563–1577. [ Google Scholar ] [ CrossRef ]
Salameh, T.S.; Bullock, K.M.; Hujoel, I.A.; Niehoff, M.L.; Wolden-Hanson, T.; Kim, J.; Morley, J.E.; Farr, S.A.; Banks, W.A. Central nervous system delivery of intranasal insulin: Mechanisms of uptake and effects on cognition. J. Alzheimer’s Dis. 2015 , 47 , 715–728. [ Google Scholar ] [ CrossRef ] [ PubMed ]
McNay, E.C.; Ong, C.T.; McCrimmon, R.J.; Cresswell, J.; Bogan, J.S.; Sherwin, R.S. Hippocampal memory processes are modulated by insulin and high-fat-induced insulin resistance. Neurobiol Learn Mem. 2010 , 93 , 546–553. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ PubMed Central ]
Craft, S.; Baker, L.D.; Montine, T.J.; Minoshima, S.; Watson, G.S.; Claxton, A.; Arbuckle, M.; Callaghan, M.; Tsai, E.; Plymate, S.R.; et al. Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: A pilot clinical trial. Arch. Neurol. 2012 , 69 , 29–38. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ PubMed Central ]
Formiga, F.; Pérez-Maraver, M. Type 3 diabetes mellitus. The revival of inhaled insulin? Endocrinol Nutr. 2014 , 61 , 173–175. [ Google Scholar ] [ CrossRef ] [ PubMed ]
de la Monte, S.M. Early intranasal insulin therapy halts progression of neurodegeneration: Progress in Alzheimer’s disease therapeutics. Aging Health 2012 , 8 , 61–64. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ PubMed Central ]
Reger, M.A.; Watson, G.; Green, P.S.; Baker, L.D.; Cholerton, B.; Fishel, M.A.; Plymate, S.R.; Cherrier, M.M.; Schellenberg, G.D.; Frey Ii, W.H.; et al. Intranasal insulin administration dose-dependently modulates verbal memory and plasma amyloid-beta in memory-impaired older adults. J. Alzheimer’s Dis. 2008 , 13 , 323–331. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ PubMed Central ]
Claxton, A.; Baker, L.D.; Hanson, A.; Trittschuh, E.H.; Cholerton, B.; Morgan, A.; Callaghan, M.; Arbuckle, M.; Behl, C.; Craft, S. Long-acting intranasal insulin detemir improves cognition for adults with mild cognitive impairment or early-stage Alzheimer’s disease dementia. J. Alzheimers Dis. 2015 , 44 , 897–906, Erratum in J. Alzheimers Dis . 2015 , 45 , 1269–1270. [ Google Scholar ] [ CrossRef ] [ PubMed ]
National Library of Medicine. ClinicalTrials.gov. SNIFF-Combo INI+EMPA Trial. ClinicalTrials.gov ID NCT05081219. Wake Forest University Healthy Sciences (Responsible Party). Available online: https://clinicaltrials.gov/search?lat=36.13700800000001&lng=-80.275307&locStr=Wake%20Forest%20University%20Health%20and%20Exercise%20Science%20Department,%20Winston-Salem,%20NC&distance=50&cond=Alzheimer%27s%20Disease&intr=SNIFF-Combo%20INI%2BEMPA%20 (accessed on 16 May 2024).

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Affuso, F.; Micillo, F.; Fazio, S. Insulin Resistance, a Risk Factor for Alzheimer’s Disease: Pathological Mechanisms and a New Proposal for a Preventive Therapeutic Approach. Biomedicines 2024 , 12 , 1888. https://doi.org/10.3390/biomedicines12081888

Affuso F, Micillo F, Fazio S. Insulin Resistance, a Risk Factor for Alzheimer’s Disease: Pathological Mechanisms and a New Proposal for a Preventive Therapeutic Approach. Biomedicines . 2024; 12(8):1888. https://doi.org/10.3390/biomedicines12081888

Affuso, Flora, Filomena Micillo, and Serafino Fazio. 2024. "Insulin Resistance, a Risk Factor for Alzheimer’s Disease: Pathological Mechanisms and a New Proposal for a Preventive Therapeutic Approach" Biomedicines 12, no. 8: 1888. https://doi.org/10.3390/biomedicines12081888

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The diagnosis and therapy of heart failure with preserved ejection fraction (HFpEF) are complicated by the disease's varied etiology. In the field of heart failure (HF), N-terminal pro-B-type natriuretic peptide (NT-proBNP) has become an important biomarker, providing information on diagnosis, prognosis, and treatment monitoring.
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Inflammation plays an important role in lipid peroxidation, coronary atherosclerosis, and thrombosis. 2 The circulating C-reactive protein (CRP) produced by hepatocytes responds to the inflammatory state of the body and almost any form of tissue injury, infection or inflammation, and indeed also most forms of adverse non-physiological 'stress ...
Coronary Heart Disease Essay
Coronary Heart Disease (CHD) it is also know as Coronary Artery Disease. It happens when the blood vessels delivering to the heart develop blockage or are narrowed by plaque, which reduces the flow of the blood, oxygen and nutrients supplied to the heart. If this happens the person starts to feel chest pain (also known as angina pectoris) and ...
Exploring the heart-brain and brain-heart axis: Insights from a
Introduction: The bidirectional relationship between the brain cortex and cardiovascular diseases (CVDs) remains inadequately explored. Methods: This study employed bidirectional Mendelian randomization (MR) analysis to investigate the interaction between nine phenotypes, namely hypertension, heart failure, atrial fibrillation (AF), and coronary heart disease (CHD), and brain cortex ...
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Peripheral insulin resistance (IR) is a well-documented, independent risk factor for the development of type 2 diabetes, cardiovascular disease, cancer and cellular senescence. Recently, the brain has also been identified as an insulin-responsive region, where insulin acts as regulator of the brain metabolism. Despite the clear link between IR and the brain, the exact mechanisms underlying ...

Cardiovascular Disease (CVD)

1.1 Overview of Cardiovascular Disease

1.2 Risk Factors for Cardiovascular Disease

1.3 Importance of Preventing Cardiovascular Disease

2. Types of Cardiovascular Disease

2.1 Coronary Artery Disease

2.2 Heart Failure

3. Treatment and Management of Cardiovascular Disease

3.1 Medications for Cardiovascular Disease

3.2 Lifestyle Modifications for Cardiovascular Health

3.3 Surgical Interventions for Cardiovascular Disease

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The Importance of Heart Diseases

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Cardiovascular Disease: An Introduction

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1.1 Vasculopathies and Vasculitides

1.1.1 Ethnic Differences

1.1.2 Gender Influence

1.1.2.1 Estrogen Signaling

1.1.2.2 Androgen Signaling

1.1.2.3 Enzymes of Steroid Hormone Metabolism

1.1.3 Vasculitis (Angiitis)

1.1.4 Vascular Wall Disorders

1.1.4.1 Hemostasis and Thrombosis

1.1.4.2 Inflammation and Angiogenesis

1.1.4.3 Oxidative and Nitrosative Stresses

1.1.4.3.1 Reactive Oxygen and Nitrogen Species

1.1.4.3.2 ROS and RNS Sources

1.1.4.3.2.1 Mitochondrial Electron Transport Chain

1.1.4.3.2.2 NAD(P)H Oxidases

1.1.4.3.2.3 Xanthine Oxidoreductase (Dehydrogenase/Oxidase)

1.1.4.3.2.4 Lipoxygenases

1.1.4.3.2.5 Myeloperoxidase

1.1.4.3.2.6 Cytochrome-P450

1.1.4.3.2.7 Heme Oxygenases

1.1.4.3.2.8 Crosstalk

1.1.4.3.3 Redox Signaling

1.1.4.3.4 Antioxidant Defense

1.1.4.3.4.1 Superoxide Dismutases

1.1.4.3.4.2 Catalase

1.1.4.3.4.3 Peroxiredoxins

1.1.4.3.4.4 Glutathione Peroxidases

1.1.4.3.5 Redox Stress

1.1.4.3.6 Receptor for Advanced Glycation End Products

1.1.4.3.7 Lipid Peroxidation

1.1.4.3.8 Protein Tyrosine Nitration

1.1.4.3.9 Protein Glutathionation

1.1.4.4 Aging

1.1.4.4.1 Aging, Inflammation, and Redox Stress

1.1.4.4.2 Aging and Altered Proteostasis

1.1.4.5 Sleep Disorders

1.1.4.6 Vascular Tumors and Malformations

1.1.4.7 Ectopic Vascular Calcification

1.1.5 Atherosclerosis

1.2 Vasculopathies and Cardiac Dysfunction

1.2.1 Cardiac Wall Remodeling

1.2.1.1 Cardiac Wall Hypertrophy

1.2.1.2 Cardiac Wall Fibrosis

1.2.2 Cardiomyocyte Remodeling

1.2.2.1 Energy Metabolism

1.2.2.2 Ion Carriers

1.2.2.2.1 Defective Calcium Handling

1.2.2.2.2 Altered Sodium Control

1.2.2.2.3 Impaired Potassium Control

1.2.2.3 Transverse Tubules