Homocysteine and atherothrombosis

Abstract

Atherosclerosis with or without thrombosis superimposed is the most frequent cause of ischemic heart disease (IHD), peripheral arterial disease, and a main cause of stroke. Conflicting results have been reported in genetic, observational, and experimental studies on the relationship between homocysteine and these atherothrombotic diseases. Although cardiovascular complications are common in homocystinuric patients (severe hyperhomocysteinemia), IHD, the most frequent manifestation of atherothrombosis in the general population, appears to be rare. On the basis of findings in individuals with hyperhomocysteinemia of genetic origin, there is in fact no clear evidence for a causal role of homocysteine in the pathogenesis of atherothrombotic disease, and the positive association between plasma homocysteine and IHD observed in many, but not all epidemiologic studies does not prove causality. To infer causality from observational studies, there should be a temporal, consistent, strong, independent, graded (dose-response effect), and duration-dependent relationship between exposure and outcomes, and a biologically plausible mechanism should exist. The relationship between plasma homocysteine levels and IHD does not fulfill these criteria beyond reasonable doubt. In the general population, plasma homocysteine levels are to a great extent determined by dietary habits, and plasma homocysteine could be a marker, or a consequence, of atherothrombosis and/or risk-associated behavior (e.g., a diet low in fruits and vegetables) rather than a cause of atherothrombosis. Experimentally, hyperhomocysteinemia is not in itself atherogenic in normal animals with relatively low plasma cholesterol levels. The homocysteine theory of atherosclerosis should be tested more thoroughly in hypercholesterolemic animals that develop atherosclerosis spontaneously to determine whether elevated plasma homocysteine levels are harmful under atherogenic conditions. A causal role of homocysteine in atherothrombotic disease remains to be established.

Impact of Elevated Plasma Total Homocysteine Concentration on Coronary Atherosclerosis in Chinese Patients With Acute Myocardial Infarction Undergoing Primary Coronary Intervention

“…Moreover, plasma tHcy levels were strongly related to the accumulation of coronary atherosclerosis. Accordingly, this investigation supports the idea 29) that elevated plasma tHcy concentration is an aftermath, rather than a cause, of coronary atherosclerotic disease.…”

“…Previous researchers have claimed that atherosclerosis is a lipid-driven disease and that hHcy cannot in itself initiate the process. 29) Creatinine levels are well known to increase when the atherosclerotic process impairs renal function. This investigation revealed a strong effect of creatinine on the plasma tHcy level.…”

Does the oxidation of methionine in thrombomodulin contribute to the hypercoaguable state of smokers and diabetics?

“…The molecular cause of thrombosis in individuals with hyperhomocysteinemia is unclear [139][140][141][142][143]. Oxidative stress is known to be present in individuals with elevated levels of homocysteine [144,145].…”

Homocysteine Disulphides and Vascular Disease

“…Mild to moderate elevations of blood homocysteine have been associated with high risk of coronary heart disease and other vascular alterations [2][3][4]. Even though a causal role of homocysteine in cardiovascular disease remains to be established [5][6][7], it is believed that homocysteine excess may damage vascular tissue, so that blood ho-mocysteine is currently considered as an independent index of vascular risk [8][9][10]. Mechanisms underlying homocysteine-associated vascular injury are under investigation [11,12].…”