Prevention and endothelial therapy of coronary artery disease

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Functional integrity of endothelial cells is an indicator and a prerequisite for vascular health and counteracts the development of atherosclerosis. This concept of ‘endothelial therapy’ was developed in the late 1990s as an approach to preserve or restore endothelial cell health given that ‘the knowledge of the mechanisms involved in ‘endothelial dysfunction’ allows us to interfere specifically with pathogenic pathways at very early time points and to slow down the progression of disease’. In the present review, the principles underlying endothelial cell health will be discussed as well as the role of endothelial therapy as a preventive measure to reduce the prevalence of coronary artery disease or to delay disease progression in patients with chronic coronary artery disease. This article also highlights the importance of active participation, the need to reduce the number of future patients in view of the rising prevalence of childhood obesity, and the potential of endothelial therapy to improve survival, reduce disability and health costs, and to improve overall quality of life in patients at risk for or already diagnosed with coronary artery disease. The preventive and therapeutic approaches and considerations described herein can be applied by physicians, patients, parents, educators, health agencies, and political decision makers to help reducing the global cardiovascular disease burden in the decades to come.

Introduction

Functional integrity of endothelial cells is an indicator and a prerequisite for vascular health [1, 2, 3]. Research of the last four decades has established that endothelium-dependent vascular function is not only a modulator, but can also be a mediator of vascular disease processes [4]. Importantly, common diseases such as diabetes, dyslipidaemia, obesity, and arterial hypertension promote injury to the endothelium [4, 5, 6]. The persisting deleterious effects of the disease process result in cellular and functional changes commonly described as ‘endothelial cell dysfunction’ [5, 6]; this ‘dysfunction’ represents a complex pathophysiological entity which not only refers to abnormal vasomotion, but also includes increased release of reactive oxygen species (ROS) [7], inflammatory activation [6], as well as perturbation of anticoagulatory properties of the endothelial cell [8].

Coronary artery disease has been clinically described more than two centuries ago when on July 21, 1768, William Heberden at the Royal Society in London proposed to call the related symptoms ‘angina pectoris’ [9]. The notion of vascular health being a prerequisite of general longevity is not novel, but goes back more than 120 years. In 1892, the Canadian physician and educator Sir William Osler, who is generally considered the ‘father’ of modern medicine and modern medical ethics, concluded from his clinical practice that ‘longevity is a vascular question’, and that atherogenesis is an time-dependent process [10] (Figure 1); He had also noted that cardiovascular risk depends on genetic factors  long before James Watson and Francis Crick discovered the genetic code 60 years later [11] (Figure 1). Moreover, William Osler was already aware that cardiovascular risk is increased with certain habits and life styles, which is apparently why he recommended his patients to eat a healthy diet, to stay physically fit, and to avoid tobacco and emotional stress [12]. Interestingly, all of these are modalities and risk factors, respectively, that we still use today to estimate cardiovascular risk of a patient and that we apply to increase prevention [13]. William Osler was an authority in coronary artery disease and was the first to suggest ventricular fibrillation (‘arrest of the heart in fibrillary contraction’) and the key role of atherothrombosis of the left anterior descending coronary artery (‘it may be called the “artery of sudden death”’) in sudden cardiac death [9, 14]. He became even more concerned with the disease after his brother had died suddenly from myocardial infarction at age 61 [12]. In fact, William Osler himself experienced clinical symptoms that he described as ‘several days of substernal pressure’ and even suspected that he might be suffering from coronary artery disease as well. If he had coronary artery disease its extent or the plaque vulnerability [15, 16] must have been moderate since he lived to be 70 and died of pneumonia during the 1918–1920 ‘Spanish’ H1N1 bird flu pandemic in the UK [12]. William Osler's clinical work and his efforts in medical education and in prevention of vascular disease have been exemplary and many of what he taught in the late 19th century still stands today. More than a century later, and with the advent of tools allowing us to understand molecular biology and genetics [11], we have learned that atherosclerotic vascular disease and vascular function are highly complex entities, and that endothelial cells previously thought to only provide an ‘inner lining’ of arteries (Figure 2) play an important role in the disease process.

Atherosclerosis, a systemic inflammatory disease of large arteries [4, 17, 18], is not a modern, ‘industrial disease’, but has been with mankind for thousands of years [19••]. Yet the recognition of endothelial cells as key modulators of numerous physiological and pathophysiological processes goes back only forty years to 1973, when Ross and Glomset first reported that mechanical removal of endothelial cells accelerates vascular smooth muscle proliferation and atherosclerosis progression [20]. In the mid-1970s Moncada and Vane identified and characterized endothelial factors such as prostacyclin [21], and endothelial cell binding sites for steroid hormones [22] . G protein-coupled receptor-dependent regulation of intracellular mediators such as cyclic nucleotides [23] were identified by Buonassisi and colleagues. Research performed in the late 1970s by Robert F. Furchgott resulted in a landmark paper published in 1980 in which he reported the accidental finding of endothelium-dependent arterial dilation [24, 25]. The ‘endothelium-dependent relaxing factor’ (EDRF)  only characterized functionally in his first report  was later identified by Furchgott himself and by Louis Ignarro as the labile gas nitric oxide (NO) [26, 27, 28, 29] for which they both  together with Ferid Murad  received the 1998 Nobel Prize in Physiology or Medicine [30]. Ironically, Furchgott had been working on NO as vasoactive compound of (sodium) nitrite since the early 1950s before making his discovery [31]. Of note, nitrite was the first drug ever used in coronary artery disease patients to specifically treat the clinical symptom angina pectoris [32, 33, 34•], and has regained scientific attention in hypertension research only recently [35••]. Following the identification of EDRF/NO other endothelium-dependent vasodilators were identified [36, 37]. The first endothelium-dependent vasoconstricting factor was reported shortly thereafter by De Mey and Vanhoutte [38, 39, 40], followed by the discovery of the 21-amino acid peptide endothelin-1 by Yanagisawa, Masaki, and colleagues. Endothelin-1 is a pro-inflammatory mitogen and the most potent endothelium-derived vasoconstrictor identified so far [38, 40, 41, 42, 43]. An overview of some of endothelial factors acting on contraction and function of vascular smooth muscle and circulating blood cells is shown in Figure 3 [44]. Research in the past decade has identified ROS as important pathophysiological regulators, and more recently a role of mitochondrial respiration as a regulator of endothelial cell function has become evident [45••].

In the late 1990s, with help from Christian Haudenschild I developed the concept of ‘endothelial therapy’ as an approach to preserve or restore endothelial cell health given that ‘the knowledge of the mechanisms involved in ‘endothelial dysfunction’ allows us to interfere specifically with pathogenic pathways at very early time points and to slow down the progression of disease’ (Figure 4), which we first published in 2001 [1]. As endothelial therapeutics we summarized lifestyle interventions, including smoking cessation, obesity prevention, and physical exercise, as well cardiovascular drugs positively affecting endothelial cell function, including statins, ACE inhibitors, and angiotensin receptor antagonists. Moreover, in in agreement with the therapeutic concept, studies have shown that preserving endothelial cell function (mainly determined by endothelium-dependent vasodilator responses) is associated with improved clinical outcome and survival in patients with coronary artery disease [46, 47, 48, 49, 50, 51, 52].

In the present review, I will further extend on the concept of endothelial therapy, also highlighting that so-called ‘cardiovascular risk factors’ are all associated with abnormal endothelial cell function; thus, any treatment of modifiable risk factors would also result in improvement of endothelial cell homeostasis [1] (Figure 2). In this context it is important to note that although the underlying disease mechanisms may be different  these risk factors or disease conditions share several common denominators that propel disease progression [4]. Particularly, this concerns activation of inflammatory pathways, reduced bioactivity of NO mostly due to its inactivation by ROS [53], but also activation and/or increased production of endothelium-derived vasoconstrictors and growth factors such as angiotensin II, endothelin-1, TGF-β1, and others, as well as shifting endothelial cell function toward a pro-coagulatory state [6] (Figure 3). Thus, it is conceivable that therapeutically targeting endothelial cells will have beneficial effects on numerous cellular levels [1, 3, 4].

Before discussing endothelial therapy approaches (early vs. late, Figure 5) I will review how disease etiologies or even normal physiological processes such as aging or menopause affect functions of endothelial cells and how treatment or active, selected interventions can improve or even largely normalize endothelial cell homeostasis (Figure 2). Also, it is important to keep in mind that even if some causes cannot be modified (such as aging, menopause, end-stage renal disease, congestive heart failure, advanced peripheral vascular disease, etc.) outcome can be positively influenced by choosing the appropriate intervention which aims at maintaining functional integrity of the endothelial cell (Figure 5). Summarized below are the most common causes of endothelial cell injury and increased cardiovascular risk. All conditions are characterized by an increase in ROS formation (also known as ‘oxidative stress’ leading to inactivation of NO [53] and formation of the toxic peroxynitrite [54]) and activation of pathways creating a pro-inflammatory milieu. They can be regarded as the ‘common disease denominators’ and also reflect the degree of endothelial cell injury [4].

Arterial hypertension currently affects more than one billion individuals worldwide, and numbers continue to increase due to the current obesity and diabetes epidemic as well as aging of the world population [55, 56]. In fact, arterial hypertension is particularly prevalent in the elderly, in both men and postmenopausal women. Arterial hypertension is associated with reduced endothelium-dependent vasodilation [57], activation of the endothelin system [43], enhanced endothelial vasoconstrictor prostanoid formation, and inflammatory activation [58]. Most recently, inflammation has been recognized as a causal factor that contributes to maintaining hypertension and that inhibiting inflammatory pathways can interfere with development of hypertension and abnormal endothelial cell functions associated with the disease [59, 60•, 61, 62, 63, 64•]. This also suggests that anti-inflammatory approaches could provide means to possibly treat high blood pressure and to reduce endothelial injury associated with it.

Obesity and diabetes mellitus (as well as insulin resistance as a state of ‘pre-diabetes’) are closely interlinked and individually associated with an increased cardiovascular risk [55, 65]. This not only explains why obese patients, often presenting with diabetes and arterial hypertension, are at a higher risk than individuals with normal body weight [55]. It is conceivable that simultaneous insults of several deleterious factors will multiply the injury of endothelial cells. Obesity is associated with endothelial cell dysfunction leading to increased coronary vascular tone [66, 67]. Of note, treatment of obesity often not only ameliorates but may even normalize obesity-associated diabetes or arterial hypertension, thereby also reducing endothelial cell injury [65]. Endothelial injury in obesity is characterized by impaired endothelium-dependent vasodilation [67], increased vasoconstrictor activity of endogenous endothelin-1 [68, 69], enhanced activity of endothelial vasoconstrictor prostanoids [70, 71], as well as inflammatory activation [72, 73] and sympathetic activation [74]. Over the past 15 years obesity has developed into a worldwide health problem affecting not only adults, but increasingly so children [65]. A case report of an infant fed a high caloric diet illustrates the devastating early effect of obesity on premature development of vascular disease, which in this case was present already at 24 months of age [75]. As a matter of fact, childhood obesity sets the stage for disease later in life [65] which is not only limited to cardiovascular disease but also to a number of other disease conditions (reviewed in [65]) (Figure 6). Obese children may nowadays present with diseases usually seen only in adults, such as arterial hypertension and diabetes [65, 76, 77, 78, 79, 80]. More recent research has revealed that obesity shares several abnormalities with vascular aging, including endothelial cell injury and vascular stiffening (reviewed in [65]); we have thus proposed that vascular injury due to childhood obesity in fact represents ‘premature vascular aging’ [4, 65, 81, 82]. Another, still much under-appreciated aspect is the effect of pregnancy and parental health on childhood health development. While Claudio Napoli and colleagues have identified maternal blood cholesterol as a determinant of ‘fatty streak’ formation in the fetal aorta [83], a recent important study addressed the question how the mode of conception may affect vascular disease, that is, comparing vascular health development in children that were naturally conceived with pregnancies due to assisted reproductive technologies (‘in vitro fertilization’). Surprisingly, Scherrer and colleagues found that in vitro fertilization results in systemic and pulmonary dysfunction as well as early atherosclerosis as measured by increased carotid intima–media thickness [84••, 85]. Also, several recent studies suggest that children of obese mothers may carry a higher risk to also develop obesity, and that bariatric surgery of obese women before becoming pregnant reduces their children's risk for obesity [86, 87, 88]. In view of the high number of obese women with child-bearing potential due to the obesity pandemic this may directly affect the prevalence of childhood obesity and the diseases associated with it (Figure 6). As will be discussed below, measures to preserve endothelial health therefore not only apply to adult patients with obesity and diabetes, but also to children where they should be vigorously applied in order to prevent children becoming future patients [89]. Intervention as early as possible is crucial to prevent disease development and protect children from becoming future patients (Figure 6) [65, 89, 90, 91].

Although a physiological process, aging is an important determinant of cardiovascular risk in both men and women [92, 93]. Aging is associated with numerous cardiovascular changes, including vascular stiffening, calcification, reduced endothelium-dependent vasodilation, increases in arterial blood and pulse pressure, and sympathetic activation [94••, 95••]. At the level at the endothelial cell, aging leads to a number of alterations affecting cell function, morphology, telomere shortening, and epigenetic modification (methylation) of endothelial cell genes [92, 93, 96, 97]. In the next forty years we will see an overall increase in aged populations around the world which will pose a great task to societies, politics, and health agencies [4, 56, 92]. The effects of aging on the vasculature are evident from diseases such as Hutchinson–Gilford progeria syndrome [98] or Werner syndrome which are due to mutations in the LMNA or the WRN genes [99]. Of note, endothelial cells of Werner syndrome patients are functionally abnormal [97] and patients develop premature atherosclerosis [98]. Progeria patients experience accelerated aging; the median life expectancy in Werner syndrome patients is 47 years, those with Hutchinson–Gilford progeria is 11–13 years, deaths are mostly due to myocardial infarction or stroke [100, 101]. Aging in humans is also associated with progressive calcification of the arterial tree [102], and is associated with reduced endothelium-dependent coronary blood flow [57]. While endothelial cell aging involves increased ROS formation and abnormal vasodilation among other changes [4, 92, 93], abnormal vascular function with aging may spare certain vascular beds [103]. Age-dependent vascular dysfunction may be aggravated by an inactive (‘sedentary’) lifestyle [104••] or even normalized by regular physical exercise [105].

High levels of LDL cholesterol and low levels of HDL cholesterol are independently associated with impaired endothelium-dependent vasodilation [57] and inflammation [106]. A role for increased decomposition of NO by ROS has been suggested in hypercholesterolemic patients with coronary artery disease since infusion of the NO synthase (NOS 3) substrate l-arginine in part normalized the impaired coronary vasomotion [107]. Patients with familial hypercholesterolemia (FH) are at particularly high risk, and abnormal endothelium-dependent vasomotion can be already detected in children diagnosed with FH [108]. Due to the LDL-lowering/HDL-increasing effects of endogenous estrogen in premenopausal women estrogens have been attributed anti-atherosclerotic and endothelium-protective effects [109]. Because experimental studies had shown that HDL cholesterol acts via endothelial cell NOS 3 and thereby increases NO bioactivity [110], it was believed for many years that preserving or even increasing HDL levels would ultimately benefit the clinical outcome of patients. However, a recent study by Ulf Landmesser and colleagues indicates that in patients with overt coronary artery disease HDL cholesterol loses its endothelial-protective properties (as opposed to HDL cholesterol from healthy individuals which retains its NO-activating properties) [111]. This unexpected and important finding now questions the clinical value of measuring HDL levels in CAD patients and increasing HDL cholesterol as a therapeutic goal [109].

Known as one of the major cardiovascular risk factors, exposure to cigarette smoke through a number of different toxins causes endothelial cell injury [112]. Smoking is associated with abnormal endothelium-dependent vasomotion, oxidative stress, endothelial cell inflammation [113], and release of circulating factors involved in cell injury [114]. Smoking is also responsible for many cardiovascular deaths [115]. Work by Thomas Münzel and colleagues has demonstrated that chronic cigarette smoking causes oxidative stress and impairs endothelium-dependent vasodilation [116, 117], whereas acute effects may be less pronounced [118]. Importantly, passive exposure to cigarette smoke is also associated with increased cardiovascular risk [119], and at least in experimental studies accelerates atherosclerosis, both in offspring and in animals exposed to second-hand smoke [120, 121]. These data highlight the importance of primary prevention in children who live with parents who smoke and are forced to breath smoky air at home [122]. Endothelin has also been implicated in lung cancer, for which smoking is the most important preventable cause [123, 124]. Cigarette smoke enhances inflammatory airway responses [125] and induces expression of endothelin converting enzymes [126]. Moreover, contractile responses to ET-1 in arteries from patients with coronary artery disease are much more potent in smokers than in nonsmokers [127]. Nicotine, as a constituent of cigarette smoke, also adversely affects endothelial cells by stimulating angiogenesis and thereby promotes atherosclerosis [128, 129, 130]. Thus, exaggerated angiogenesis  at least in the context of overt atherosclerosis  may also be viewed as a form of ‘endothelial cell dysfunction’.

Chronic proteinuric renal disease, mainly due to diabetes or arterial hypertension [131], is an independent cardiovascular risk factor and causes pronounced endothelial cell dysfunction [132]. In both experimental as well as in clinical renal disease abnormal endothelium-dependent vasodilation, inflammatory activation, and increased oxidative stress are caused by retention of toxins no longer filtered by the diseased kidney and posing injury to the endothelial cells [132]. The observation that even microalbuminuria as an indicator of renal filter dysfunction is independently associated with increased cardiovascular risk [133] emphasizes the importance of preserving or restoring kidney function to ensure functional integrity of endothelial cells.

Endothelium-dependent vasodilatation in premenopausal women is directly related to circulating estrogen levels, and systolic and diastolic blood pressure is lower in premenopausal women than in age-matched men (reviewed in [134]). Accordingly, premenopausal women are at lower cardiovascular risk than men, a difference that disappears after menopause when cardiovascular disease becomes the predominant disease and cause of death in women [134, 135]. Menopause is frequently associated with the onset with therapy-resistant, salt-sensitive arterial hypertension [134] and a metabolic phenotype favoring the development of obesity and diabetes [136]. As a consequence and due to the above conditions, endothelial cell function becomes abnormal in postmenopausal women, showing attenuated endothelium-dependent vasodilation, inflammation, and increased oxidative stress [134, 137, 138], contributing to elevated cardiovascular risk [135]. New research suggests that vascular health rather than endocrine factors determine the time of menopause (i.e. the loss of atheroprotective estrogen production) as heart disease may directly affect ovarian function. Thus, women who smoke or do not exercise [139] will likely experience menopause at a younger age than those who avoid cigarettes and stay physically fit. It is likely that preservation of endothelial cell function of the ovarian vasculature is involved in these protective effects. Also, women with vasomotor symptoms due to cessation of estrogen production appear to be at an increased cardiovascular risk that cannot be simply explained by other risk factors [140, 141].

Emotional stress, such as anger, anxiety or stress [142, 143] as well as other forms of impairment of psychological health, have only recently gained attention in cardiovascular health and disease prevention [142]. Perhaps the most obvious example suggesting a connection between emotional stress and coronary artery disease comes from the Vietnam and Korea wars, where young soldiers died from myocardial infarction in their twenties, and were diagnosed post mortem with advanced coronary atherosclerosis despite their young age [144, 145, 146, 147]. Emotional stress such as anger has been associated with an elevated cardiovascular risk and abnormal endothelial cell function [148, 149], which is often present in conjunction with other conditions such as arterial hypertension [148, 149]. Interestingly, even short-lasting stressors may have prolonged, unfavorable effects on endothelial cell homeostasis [150]. Similar to stress, depressive disorders have now also been recognized as an independent cardiovascular risk factor [142, 151, 152]. Both emotional stress and depression are associated with abnormal endothelial cell function [142], changes in oxidative metabolism and endothelial mediators such as endothelin-1 [153] and development of a pro-inflammatory phenotypes [151, 152]. Most recent experimental data suggest that stress-dependent pathophysiological changes such as arterial hypertension may be mediated  at least in part  by inflammatory-immunological mechanisms [154••] that also contribute to the abnormal endothelium-dependent responses in hypertension.

In recent years, circulating microparticles have gained interest in cardiovascular medicine. Derived from endothelial cells, leukocytes, or ambient particular matter, increased concentrations of microparticles are associated with atherosclerosis, arterial hypertension, and diabetes [18, 155, 156, 157, 158••, 160]. Air pollution by car fumes, particularly diesel exhaust, has also been shown to be pro-atherosclerotic [158••] and to cause pro-inflammatory activation of endothelial cells [161]. Exposure to diesel exhaust results in increases of the vasoconstrictor response to ET-1 [162] and causes endothelin receptor dysfunction [163]. Fine particulate matter as part of air pollution has also been implicated in diseases such as hypertension and, airway diseases [159, 164] and inflammation [165]. Increases in carbon and particulate matter air pollution stimulate circulating endothelin levels [166], and endothelin receptor expression [167, 168], even in the absence of any local or systemic inflammation [169]. Car fumes have also been shown to stimulate endothelium-derived endothelin and to aggravate atherosclerosis [170, 171]. The activating effects of diesel exhaust on endothelin have also been observed in humans [172]. In the recent decade the global cell phone use has led to warnings about the potential health risks of long-term exposure to electromagnetic radiation, including risk for cardiovascular disease [173, 174]. Human endothelial cells are sensitive to cell phone radiation and respond with changes in protein expression, protein phosphorylation and cytoskeleton rearrangement [175, 176], changes that can also be observed under disease conditions. Preclinical studies in experimental animals indicate that excessive use of cell phones, that is, up to six hours per day over about 4 months, results in induction of endothelin [177]. Whether chronic cell phone use affects human health in the long term, and whether (the yet unknown) consequences of cell phone use might involve the cardiovascular system or cardiovascular disease development is not known at this time.

Crucial factors determining success of endothelial therapy are (early) recognition of conditions associated with cardiovascular risk/endothelial injury, the willingness to counteract these changes, and active participation involving health professionals on the one side, and patients and/or individuals on the other. The motivation text shown in Figure 7 (modified from a quote from John F. Kennedy's 1961 inauguration speech [178]) may help to explain the health potential of active participation in health preservation and disease prevention to patients, parents, educators, and health professionals and to understand its value. This text allows patients to realize that they can receive health as an ‘award’, and to motivate themselves to receive more healthy years as a ‘return of investment’ in the course of their life by ‘adding life to years and years to life’ [179]. Importantly, this benefit can be achieved in healthy individuals (used as a preventive measure) as well as in vascular disease patients (delaying disease progression, Figure 5) if individuals are willing to actively participate in and contribute to preserving their own (vascular) health. Importantly, with regard to physical exercise this should be applied moderately, as vigorous exercise has been shown to increase the risk of myocardial infarction, particularly in those individuals who had been previously physically inactive [180]. The motivation text may also be used to help gain and increase health awareness and that actively contributing to prevention will positively reflect on families and social environments and that serving as role models for healthy living eventually will improve overall (vascular) health of societies (Figure 4). With regard to the benefits of physical exercise on cardiovascular health it is noteworthy that recent research suggests that overall cardiovascular (and thus endothelial) health appears to also reduce the risk of other diseases, such as cancer [181••, 182].

Early endothelial therapy (although the term ‘therapy’ is usually used in the context of disease) could also be viewed as ‘preservation of endothelial cell health’ or ‘endothelial cell injury prevention’ (Figure 5, left panel). The overall goal of this approach is recognition and control of cardiovascular risk factors by nonpharmacological preventive measures such as lifestyle optimization (Mediterranean diet, physical exercise, maintaining a normal body weight [183]) in order to reduce the number of future patients, to increase quality of life, and to reduce overall health costs for societies (Figure 5). The knowledge about the possibilities and about the health advantages of early endothelial therapy should be shared by physicians, particularly family physicians, with parents, schools teachers, educators, and institutions of higher education. The preventive potential should also be recognized by health agencies, insurance companies, government agencies and political decision makers in charge of countries’ health or education, possibly providing rewards for active participation in prevention [184]. The implementation of nonpharmacological measures such as regular physical exercise [183] should become part of life on a weekly and  if possible  on a daily basis. In addition, early risk factor screening and, if necessary, early treatment remain vital components of this therapy concept to ensure and achieve the greatest possible prevention by ‘preventing today's children becoming tomorrow's patients’ [89, 185]. This of course particularly includes obesity as a disease [55], which now increasingly affects children that are presenting with abnormal endothelium-dependent vasodilation, inflammatory activation, increased vascular stiffness, and even type 2 diabetes usually observed only in the elderly (reviewed in [65]). In this context it is important to also involve obese women during pregnancy, making them aware of the increased medical risk obesity carries, advising them to exercise and to optimize their diet; this might offer one approach to interfere with the exaggerated intrauterine growth and is likely to beneficially affect future health of the child [186, 187, 188]. Similarly, prophylactic effects of physical exercise have been reported to protect pregnant women from preecclampsia [189]. The risk for preecclampsia is increased in obese mothers [190] and involves abnormal endothelial cell function and endothelin activation [191•, 192, 193]. Whereas some may view the active participation in prevention as a need for a concept change [184], the groundwork has already been laid and requires merely to convince others to participate (Figure 6). The expenses involved in applying an ‘exercise regimen’ are very low, whereas the (health) reward to be gained will be high.

The goal of late endothelial therapy is to preserve function of already injured endothelial cells, to restore their functionality in part in order to delay disease progression [1], to allow disease stabilization in patients with chronic coronary or peripheral artery disease, and ultimately, to improve overall quality of life, to reduce disability and health costs, and to increase survival (Figure 5, right panel). Late endothelial therapy can be applied to both modifiable (hypertension, obesity, diabetes, dyslipidemia, smoking, impairment of mental health) and non-modifiable conditions (aging, menopause, chronic coronary or peripheral artery disease, end-stage renal disease, heart failure). The most relevant approaches are summarized in Figure 3. As a first step, all modifiable factors must be eliminated or at least optimized (smoking cessation, normalizing body weight in obesity, psychological counseling as required). As a second step  provided that health status allows the patient to exercise, regular physical exercise should be used as an active, nonpharmacological approach as part of the daily routine [194]. It has been shown that not only patients with coronary artery disease [194] or heart failure [195] benefit from physical exercise, but that exercise also improves endothelial function and reduces cardiovascular risk in elderly individuals [196], obese individuals [197•, 198•], postmenopausal women [199], and also in hypercholesterolemic patients where exercise raises HDL levels [200]. Moreover, exercise has been proposed as a countermeasure for the aging-associated decline in vascular function [201, 202•]. It is also important to note that in diabetic patients exercise should be used rigorously as a therapeutic since it improves insulin sensitivity [203, 204]. Finally, physical exercise has been successfully used to treat patients with depression [205]. As a third step, as required, pharmacological treatment of the underlying disease conditions should aim at restoring endothelial cell homeostasis (statin treatment to reduce LDL cholesterol levels [206], antidiabetics to reduce blood glucose levels [55], antihypertensives to normalize blood pressure [207], heart failure therapy to optimize myocardial and vasomotor function [208, 209]). It should be noted that some drugs may have some favorable, endothelium-protective off-target effects, such as statins by inhibiting inflammation [206, 210, 211, 212•] and certain angiotensin antagonists also having metabolic, that is, antidiabetic effects [213]. Finally, as a fourth step where needed, medical interventions should be applied such as percutaneous revascularization in patients with atherosclerotic vascular disease to improve perfusion and shear-mediated release of endothelial vasodilators [13], or dialysis in patients with end-stage renal disease to remove toxic components from the circulation to reduce endothelial injury [214] (Figure 5).

Section snippets

Summary and conclusion

With the knowledge of the crucial role of intact endothelial cell function to counteract coronary artery disease development and progression of existing atherosclerosis which was first postulated in 1954 by Rudolf Altschul and who rightfully proposed “one is as old as one's endothelium” [215], endothelial therapy allows to directly apply means to interfere with endothelial cell injury or to even largely restore endothelial cell and thus improve cardiovascular health [181••]. It is likely that

Conflicts of interest

None.

Special note

This manuscript underwent independent peer-review and was edited by Karolina Kublickiene, MD, PhD, who handled the reviewing process and was responsible for the final editorial decision

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

I am indebted to Christian C. Haudenschild, M.D., George Washington University, Washington, D.C., who helped me to develop the concept of endothelial therapy in the late 1990s and which we first published together in 2001 [1]. I am grateful for our most stimulating scientific discussions and for his friendship. I also thank the reviewers for providing helpful suggestions. This work was supported by Swiss National Science Foundation (Nr. 108 258 and 122 504).

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