In human vascular diseases, endothelial dysfunction is a systemic pathological state of the endothelium (the inner lining of blood vessels) and can be broadly defined as an imbalance between vasodilating and vasoconstricting substances produced by (or acting on) the endothelium. Normal functions of endothelial cells include mediation of coagulation, platelet adhesion, immune function and control of volume and electrolyte content of the intravascular and extravascular spaces.
Endothelial dysfunction can result from and/or contribute to several disease processes, as occurs in hypertension, hypercholesterolaemia, diabetes, septic shock, and Behcet's disease, and it can also result from environmental factors, such as from smoking tobacco products and exposure to air pollution. Endothelial dysfunction is more prevalent in shift workers, a group known to have a higher risk for cardiovascular diseases. Most of these studies on human participants have involved the percentage flow-mediated dilation (FMD%) index as the study outcome, which must have proper statistical consideration to be interpreted correctly. Endothelial dysfunction is a major physiopathological mechanism that leads towards coronary artery disease, and other atherosclerotic diseases.
The epidemiology of endothelial dysfunction is unknown, as %FMD varies with baseline artery diameter. This can make cross-sectional comparisons of FMD% difficult. Endothelial dysfunction was found in approximately half of women with chest pain, in the absence of overt blockages in large coronary arteries. This endothelial dysfunction cannot be predicted by typical risk factors for atherosclerosis (e.g., obesity, cholesterol, smoking) and hormones.
Endothelial Dysfunction and Atherosclerosis Link
Endothelial dysfunction is thought to be a key event in the development of atherosclerosis and has been reported to predate clinically obvious vascular pathology by many years. However, the problem with this assertion in terms of the flow-mediated response indicator of endothelial dysfunction is that a morphological characteristic of atherosclerosis (baseline artery size) is inherent in the calculation of percentage flow-mediated dilation. Endothelial dysfunction is associated with reduced anticoagulant properties as well as increased adhesion molecule expression, chemokine and other cytokine release, as well as reactive oxygen species production from the endothelium. This leads to inflammation and myofibroblast migration and proliferation inside the vessel all of which play important roles in the development of atherosclerosis.
In fact, endothelial dysfunction has been shown to be of prognostic significance in predicting independently vascular events including stroke and myocardial infarction. However, again so has baseline artery size which happens to be part of the calculation of percentage flow-mediated dilation (%FMD). Endothelial function testing might have potential prognostic value for the early detection of cardiovascular disease; clinical trials in the recent years have demonstrated the feasibility of translating this measurement to the clinical practice. However, the baseline artery size component of percentage flow-mediated dilation may also be just as prognostic and is easier to measure reliabily than flow-mediated dilation.
Nitric Oxide bioavailability reduction in Endothelial Dysfunction
Nitric Oxide (NO) reduction is considered the hallmark of endothelial dysfunction  A key and quantifiable feature of endothelial dysfunction is the inability of arteries and arterioles to dilate fully in response to an appropriate stimulus that stimulates release of vasodilators from the endothelium like NO. Endothelial dysfunction is commonly associated with decreased NO bioavailability, which is due to impaired NO production by the endothelium and/or increased inactivation of NO by reactive oxygen species.
This can be tested by a variety of methods including iontophoresis of acetylcholine, direct administration of various vasoactive agents to segments of blood vessels, localised heating of the skin and temporary arterial occlusion by inflating a blood pressure cuff to high pressures. Testing can also take place in the coronary arteries themselves but this is invasive and not normally conducted unless there is a clinical reason for intracoronary catheterisation.
Of all the current tests employed in the research setting, flow-mediated dilation is the most widely used non-invasive test for assessing endothelial function. This technique measures endothelial function by inducing reactive hyperemia via temporary arterial occlusion and measuring the resultant relative increase in blood vessel diameter via ultrasound. Measurement of endothelial function by Peripheral arterial tonometry or endopat, is also mediated by a NO response. As people with endothelial dysfunction have low NO bioavailability, their blood vessels have a decreased capacity to dilate in response to certain stimuli, compared to those with normal endothelial function. In order to properly perform a test for endothelial dysfunction, patients must avoid having certain medications and food at least 12 hours prior to the test; temperature must be controlled (at room temperature) , and ideally should be performed at the same time in the same patient due to circadian rhythms.
NO has the following physiological effects that contribute to the inhibition of atherosclerosis: 1) NO is released and produces vasodilation after shear stress in the vessel; the vasodilation NO mediated-response in turns decreases the shear stress. If the shear stress is chronically induced it leads to the upregulation of and release of inflammatory cytokines  2) NO decreases LDL oxidation; 3) NO reduces platelet aggregation to the endothelium 4) NO Inhibits smooth muscle cell proliferation 5) NO prevents leukocyte adhesion and infiltration into the vessel.
Testing & Diagnosis
The gold standard for measuring endothelial function is angiography with acetylcholine injection, however due to the invasive and complex nature of the procedure it has never been used outside research.
A noninvasive method to measure endothelial dysfunction is % Flow Mediated Dilation (FMD) as measured by Brachial Artery Ultrasound Imaging (BAUI). Current measurements of endothelial function via FMD vary due to technical and physiological factors. A negative correlation between percent flow mediated dilation and baseline artery size is recognised as a fundamental scaling problem, leading to biased estimates of endothelial function. For research on FMD an ANCOVA approach to adjusting FMD for variation in baseline diameter is more appropriate. Another challenge of FMD is variability across centers and the requirement of highly qualified technicians to perform the procedure.
Non-invasive, FDA-approved devices for measuring Endothelial function that work by measuring Reactive Hyperemia Index (RHI) is Itamar Medical's EndoPAT, has shown an 80% sensitivity and 86% specificity to diagnose coronary artery disease when compared against the gold standard, acetylcoline angiogram. This results suggests that this peripheral test reflects the physiology of the coronary endothelium. Endopat has been tested in several clinical trials at multiple centers (including major cohort studies such as the Framingham Heart Study, the Heart SCORE study, and the Gutenberg Health Study). The results from clinical trials have shown that Endopat is useful for risk evaluation, stratification and prognosis of getting major cardiovascular events (MACE).
Since NO maintains low tone and high compliance of the small arteries at rest  a reduction of age-dependent small artery compliance is a marker for endothelial dysfunction that is associated with both functional and structural changes in the microcirculation that are predictive of subsequent morbid events  Small artery compliance or stiffness can be assessed simply and at rest and can be distinguished from large artery stiffness by use of pulsewave analysis with the CV Profilor.
Prevention and treatment
Endothelial function can be improved significantly by exercise, smoke cessation, weight loss in overweight or obese persons, and improved diet. Treatment of hypertension and hypercholesterolemia are also critical; the major pharmacological interventions to improve endothelial function in those set of patients are statins(HMGCoA-reductase inhibitor), and renin angiotensin system inhibitors, (such as ACE inhibitors and angiotensin II receptor antagonists). Some studies have found antioxidants, potassium and arginine supplementation to restore impaired endothelial function. A positive relationship exists between the consumption of trans fat (commonly found in hydrogenated products such as margarine) and the development of endothelial dysfunction. New third-generation β-blockers and 5-phosphodiesterase inhibitors may affect endothelial function. New non-invasive strategies that measure endothelial function will prove critical to assess which set of patients are improving their endothelial function. Statins have major pleiotropic anti-inflammatory and anti-hypertensive effects besides the cholesterol reduction effect. This immunomodulatory effects of statins may explain why some patients improve their endothelial function with those drugs.
Relevant endothelial function molecular mediators:
- Nitric oxide
- endothelial nitric oxide synthase
- Endothelium-derived relaxing factor
Relevant endothelial function molecular pathways:
- Integrin network
- PI3K-AKT Network
Relevant biophysical endothelial function mediators:
- Endothelial shear stress
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