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Endothelial dysfunction and cardiovascular disease

An article from the e-journal of the ESC Council for Cardiology Practice

In atherogenesis, Endothelial Dysfunction (ED) is the earliest measurable functional abnormality of the vessel wall. ED is closely related to the risk factors of atherosclerosis, to their intensity and duration. The involvement of ED in cardiovascular disease is also supported by its relation to cardiovascular events.



 

A healthy endothelium plays a central role in cardiovascular control. Therefore, (ED) may have a particularly significant role in the pathogenesis of atherosclerosis (1).

ED is a consequence of the harmful effects of the risk factors of atherosclerosis on the vessel wall and is more or less important depending upon the number of risk factors, their intensity and their duration. ED has been demonstrated in subjects with hypercholesterolemia, diabetes, hypertension, and in patients who smoke, and patients with atherosclerotic disease (coronary, peripheral arterial) (2, 3).

It was also shown that ED is an early event in type I and II diabetes and that it is related to the development and progression of diabetic vascular complications. In one of our studies on type I diabetic patients it was shown that ED (demonstrated by flow mediated endothelium dependent dilation) is inversely related to the extent of microalbuminuria (4).

Furthermore, the involvement of risk factors in ED is also supported by results of interventional studies that showed regression of ED with the treatment of risk factors. Improvement of ED may be achieved by eliminating risk factors, by substituting natural protective endothelial substances with L-arginine, by administrating inhibitors of endothelium-derived contracting factors (eg, ACE inhibitors, angiotensin II receptor antagonists), by administrating cytoprotective agents (eg, free-radical scavengers such as superoxide dismutase, lipid-lowering drugs and by having the patient follow a diet and do physical exercise (3). In patients with polymetabolic syndrome, we also observed improvement of ED through physical training. In growth hormone deficient patients, improvement of EF was registered with growth hormone replacement therapy (5).

These data show that the treatment of risk factors may help to restore a vascular function and that ED is reversible. ED promotes the progression of atherosclerosis and probably plays an important role in the development of thrombotic complications in the late stages of the disease.

As it has been shown that ED is a key underlying factor in the atherosclerotic process, markers of endothelial abnormalities have been sought. Different tests require the measurement of several different aspects of endothelial dysfunction such as endothelium-dependent vasomotion, as well as circulating markers of endothelial function.
Most of the functional methods for in vivo endothelial testing examine the ability of the endothelium to cause vasodilation in response to pharmacological and physiological stimuli that increase the endothelial release of NO.

Endothelial function may be tested noninvasively in the peripheral conduit arteries using high-resolution external vascular ultrasound. In this method, arterial diameter is measured in response to an increase in shear stress, which causes endothelium-dependent dilation, after the administration of sublingual nitroglycerine, an endothelium-independent dilation.

The brachial arterial dilator response to increased blood flow during reactive hyperemia has been shown to be caused mainly by an endothelial release of NO, to correlate significantly with endothelial function, as well as with the extent and severity of atherosclerosis.

Furthermore, endothelial injury may result in the release of various factors that can be detected in the circulation and that can be potentially used as markers of endothelial dysfunction. Circulatory markers of endothelial dysfunction most often used are: endothelin-1, von Willebrand factor, tPA and PAI-1 and adhesion molecules (VCAM, ICAM, P-selectin). With these tests, it is possible to follow the dose - response of harmful effects of risk factors, and the effects of preventive procedures on vessel wall function.

Determination of ED also has important clinical implications. It was shown that ED is significantly and directly correlated with the occurrence of cardiac events and that cardiac events increased as ED worsens (6).

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.

References


1.Drexler H, Hornig B. Endothelial dysfunction in human disease. J Mol Cell Cardiol 1999; 31: 51-60.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10072715&dopt=Abstract

2.Poredoš P, Orehek M, Tratnik E. Smoking is associated with dose-related increase of intima-media thickness and endothelial dysfunction. Angiology 1997; 50: 201-7.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10088799&dopt=Abstract

3.Mombouli JV, Vanhoutte PM. Endothelial dysfunction: from physiology to therapy. J Mol Cell Cardiol 1999; 31: 61-74.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10072716&dopt=Abstract

4.Poredoš P, Kek A. Relation of blunted dilation of the brachial artery in insulin-dependent diabetes mellitus to microalbuminuria. Am J Cardiol 2000; 86: 364-7.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=&DB=PubMed

5.Pfeifer M, Vrhovec R, Žižek B, Prezelj J, Poredoš P, Clyton RN. Growth hormone (GH) treatment reverses early atherosclerotic changes in GH-deficient adults. J Clin Endocrinol Metabol 1999; 84: 453-7.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10022400&dopt=Abstract

6.Schachinger V, Britten MB, Zeiher AM. Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation 2000; 101: 1899-906.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10779454&dopt=Abstract

VolumeNumber:

Vol1 N°16

Notes to editor


Prof. P. Poredos
Ljubljana, Slovenia
Vice-chair of the ESC working group on Peripheral Circulation

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.