Although the endothelium is an integral structural component of the human vascular system, it was, until recently, considered merely as a passive vascular lining separating two interfaces: the blood and the interstitium. Recent advances in cardiovascular biology have confirmed that highly specialized endothelial cells not only secrete several vasoactive substances/hormones, which maintain vascular hemostasis, but also serve other essential biological functions, such as retardation of smooth muscle proliferation and the modulation of inflammatory cytokines.
In simplistic terms, inequilibrium of endothelial hormones is regarded as endothelial dysfunction (ED). However, there still remains some debate as to whether ED is a de novo phenomenon that leads to the future development of cardiovascular disorders or is an intermediary step in the development of cardiac diseases resulting from various inflammatory, autonomic, molecular and biochemical changes. ED has been consistently demonstrated in a wide range of cardiovascular disorders such as hypertension, coronary artery disease (CAD), obstructive sleep apnea and heart failure Citation[1].
Indeed, ED has an important pathophysiological role in the development of cardiovascular disorders. Therefore, it would be fair to say that an accurate assessment of ED would serve as a gauge for the primary prevention of cardiovascular diseases among ‘high risk’ populations, such as those with hypertension (and associated target-organ damage), besides risk stratifying newly diagnosed patients. In hypertension, for example, ED has been linked with complications related to hypertension and an adverse prognosis.
How do we assess endothelial function?
Due to intense focus on the endothelium, the demand for an easy, cost-effective, noninvasive, reliable, reproducible and easily available technique to assess endothelial function has grown tremendously.
Various methods have been utilized for endothelial assessment over the years. Broadly, such methods can be categorized as noninvasive and invasive. Although coronary angiography was the first method to be used to study cardiac microvascular function since the 1980s in animal and human models, its invasive nature makes it less practicable Citation[2]. Among noninvasive techniques, flow-mediated dilatation (FMD) of the brachial artery and biochemical indices of endothelial dysfunction have been extensively used, although observer bias can be a limitation. Similarly, techniques such as venous occlusion plethysmography can be used to quantify regional blood flow, and laser Doppler flowmetry to measure local perfusion in small areas of tissue.
Among the many plasma markers of ED, plasma von Willebrand factor (vWF) levels are the most commonly used, being closely correlated with FMD and adverse cardiovascular outcomes Citation[3]. Quantitative and qualitative analysis of circulating endothelial cells and endothelial progenitor cells by flow cytometry has recently attracted much interest, and may reflect the balance of endothelial injury and repair Citation[4]. Other methods such as immunomagnetic bead isolation have also been utilized for circulating endothelial cell quantification, which is broadly comparable to flow cytometry Citation[5].
More recently, attention has focused on regional myocardial blood flow and coronary flow reserve, the latter accurately correlates with ED. Both these parameters can be accurately assessed by noninvasive techniques, such as positron emission tomography, cardiac magnetic resonance and myocardial contrast echocardiography. Myocardial perfusion assessed by myocardial contrast echocardiography has been shown to predict postmyocardial infarction prognosis Citation[6]. Additionally, other noninvasive techniques, such as PET and cardiac magnetic resonance, provide an accurate estimation of coronary flow reserve.
Role of ED in the development of cardiovascular disorders
It is crucial to understand how ED contributes to the development of various cardiovascular disorders. Impaired vasomotion, oxidative stress, inflammatory changes and the antithrombotic environment associated with ED induce widespread vascular changes. These cellular and molecular changes result in peripheral arterial vasoconstriction and vascular smooth muscle proliferation, ultimately causing increased peripheral and pulmonary vascular resistance. Since blood pressure is directly related to cardiac output and peripheral vascular resistance, the hemodynamic effects of the latter contribute to hypertension. Such vascular changes at arteriolar and subarteriolar levels also provide some insight into the development of end-organ damage due to hypertension Citation[7].
Thus, it is intuitive to conclude that high blood pressure due to ED contributes to the development of other cardiovascular diseases, such as CAD and heart failure. Increased pulmonary vascular resistance could also adversely affect ventricular function Citation[8]. Additionally, the role of coagulopathy and inflammatory changes associated with ED in the causation of CAD cannot be underestimated. Molecular analyses show that subcellular inflammatory changes not only cause atherogenesis but also play a critical role in plaque stability Citation[9,10].
Prognostic implications of ED in cardiovascular disorders
Data from several studies suggest that assessment of ED could serve as a valuable tool for predicting cardiovascular outcomes in the short- and long-term. In a study of 225 hypertensive patients, for example, forearm endothelial function was predictive of future cardiovascular and cerebrovascular events Citation[11]. Furthermore, results from a substudy of the Anglo–Scandinavian Cardiac Outcomes Trial (ASCOT) also suggest that FMD and vWF strongly correlate with 10-year cardiovascular risk (both p < 0.001) Citation[3]. This study also suggested that FMD was correlated significantly with vWF. Data from a recent prospective study of 104 hypertensive patients suggest a link between vWF and adverse clinical outcome Citation[12].
Similarly, in both acute and chronic cardiac ischemic conditions, the assessment of endothelial function has been shown to be of prognostic value. In the large (n = 3043) prospective European Concerted Action on Thrombosis and disabilities (ECAT) study, patients with stable angina were followed up for 2 years Citation[13]. Subsequent analysis revealed that tissue plasminogen activator antigen, a marker of ED, was strongly predictive of future coronary events. Recent evidence suggests that markers of inflammation, such as IL-6, which are deranged in ED as well as in acute coronary syndromes, have a significant prognostic role Citation[14]. Other markers of ED, such as FMD, have also been shown to have prognostic value in patients with acute coronary syndrome Citation[15].
Finally, a strong link has been demonstrated between markers of ED and prognosis in patients with heart failure. Endothelial-dependent vasodilatation, evaluated with the use of venous occlusion plethysmography, was found to be impaired in 289 patients with heart failure and predicted a worse outcome Citation[16]. Quantitative analysis of endothelial progenitor cells, a noninvasive technique, has also been shown to have an independent association with all-cause mortality in heart failure patients Citation[17].
Therapeutic implications
Current evidence suggests that ED has a fundamental role in the causation of cardiovascular disorders. Therefore, amelioration of molecular and cellular derangements associated with ED could provide a strategy for primary and secondary prevention of cardiovascular disorders. For example, chronic overexpression of tissue angiotensin-converting enzyme in CAD disrupts the angiotensin II/bradykinin balance with a net result of ED Citation[18]. Therefore, angiotensin-converting enzyme inhibitors hold great promise as a potential therapy for ED by reducing the production of angiotensin II, which prevents vasoconstriction, reduces the production of adhesion molecules and growth factors, decreases oxidative stress and prevents apoptosis. Similarly, the statin group of drugs, which have a proven role in reducing oxidative stress, would benefit patients with ED Citation[19].
Conclusion
Endothelial dysfunction is strongly linked with the development of cardiovascular diseases. Over the last 30 years, several techniques have been utilized to assess ED, ranging from invasive intracoronary studies to noninvasive testing such as FMD. More recently, plasma indices of ED, such as vWF, have gained much attention. As ED is strongly linked with the development of cadiovascular diseases, improved understanding and clinical evaluation of endothelial function may not only assist in risk stratification of these disorders but also have important therapeutic implications.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript
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