Homocysteine and Cardiovascular Disease

Cardiovascular disease remains by far the leading cause of premature death for men and women in the U.S., the disease itself the consequence of a variety of factors, both hereditary and environmental.

Of the major risk factors, namely, high low-density lipoprotein (LDL), cholesterol and/or low high-density lipoprotein (HDL) cholesterol, old age, male gender, premature menopause in women, hypertension, smoking, diabetes mellitus and a family history of heart attack, three are related to diet: HDL and LDL cholesterol levels, hypertension and diabetes. Much research time has been spent exploring potential dietary intervention strategies and preventative measures.

For several decades, the debate on diet and cardiovascular disease has been dominated by the classic diet-heart hypothesis that proposes an adverse effect of dietary saturated fat and cholesterol and a beneficial effect of polyunsaturated fatty acid (PUFA) intake. However, recent research suggests that the diet-heart relationship is much more complex than previously recognized. No doubt, dietary lipids play a significant role in the development and prevention of this chronic disease, however, it is becoming clear that myriad of other dietary factors work synergistically and may prove to be just as, if not more, important in maintaining the health of the heart.

Antioxidants are emerging as protective factors, as well as numerous other phytochemicals often overlooked in fruits and vegetables. Moreover, deficiencies and/or excesses in certain vitamins, minerals and trace elements appear to effect the health status of the heart. There is also increasing evidence that high levels of homocysteine, an amino acid partially regulated by folic acid and vitamin B12, may contribute to the development of cardiovascular disease.

Coronary Heart Disease (CHD) is the most common form of cardiovascular disease and involves both atherosclerosis and hypertension. A heart attack (myocardial infarction) is usually the consequence of three events: 1) the narrowing of coronary arteries by atherosclerosis, 2) the rupture of an atheromatous plaque and 3) the formation of a blood clot (thrombus) in a narrowed artery. Atherosclerosis is the accumulation of cholesterol-rich deposits along the inner walls of the arteries. It first appears in arteries as fatty streaks, slightly raised yellow areas which contain foam cells. Over time, these fatty streaks collect minerals and they enlarge to form fibrous plaques which stiffen the arteries and tighten their passage. Arteries narrowed by plaques are unable to expand normally with each heartbeat, thereby causing blood pressure to rise with each pulse and the artery walls to undergo further damage. When the body’s tissues are injured, platelets and several clotting factors known as eicosanoids are released into the blood to stimulate coagulation. Consequently, soluble fibrinogen is converted into insoluble fibrin which, along with the platelets and red blood cells, aggregates at a damaged point in the artery wall to form a thrombus. The blood clot gradually expands until it reaches a narrow artery where it is blocked from passage. Consequently, the heart is robbed of oxygen and nutrients resulting in myocardial infarction.

Evidence is rapidly accumulating which suggests that elevated blood levels of homocysteine, a sulfhydryl-containing amino acid formed by the demethylation of methionine, may increase the risk of vascular disease. Several recent studies have established that moderately elevated levels of homocysteine are associated with CHD, independent of other risk factors (1). Epidemiological studies have been invaluable in delineating this relationship; more than 20 case-controlled and cross-sectional studies of more that 2000 subjects have demonstrated that subjects with stroke, hypertension and/or atherosclerosis tend to have relatively high blood levels of homocysteine compared to individuals free of disease (2). Aronow et al. found plasma homocysteine to be an independent predictor of new coronary events in elderly persons (3). Likewise, in a recent prospective study, men with homocysteine levels above 15.8 umol/liter (the 95th percentile for controls) were found to have a 3.4 fold excess risk of myocardial infarction (4)It has been estimated that mild homocysteine elevation (>15 umol/L) occurs in 20 – 30 % of patients with atherosclerotic disease (5). Findings from other related studies indicate that the association might be linear rather than present only above a certain threshold (6,7).

Carotid artery intimal-medial wall thickening is a known predictor of CHD and has been shown to be associated with plasma homocysteine levels (8). Moreover, elevated homocysteine levels have been associated with endothelial dysfunction, or reduced arterial wall elasticity, an independent CHD risk factor. In fact, plasma homocysteine levels have been associated with most standard vascular risk factors. Whether an elevation in homocysteine is a cause or an effect of CHD remains unknown.

Several potential mechanisms for this association have been suggested including enhanced uptake of LDL in the vascular wall, promotion of arterial cell growth and alterations in vascular coagulant systems (9). In particular, homocysteine thiolactone, a reactive form of homocysteine, has been shown to alter LDL, concomitantly leading to aggregation and increased uptake of LDL by macrophages. When released from the LDL within the artery wall, homocysteine causes damage to the wall and effects vascular coagulation mechanisms (10). It has also been suggested that homocysteine may also promote vascular smooth muscle growth, at the same time inhibiting endothelial cell growth; both changes may lead to atherosclerosis (11). Finally, elevated levels of homocysteine may interfere with nitric oxide-dependent reactive vasodilation (12). Reduced arterial vasodilation is an indication of increased risk for CHD.

The relevance of the relationship between hyperhomocysteinemia and diet is gradually becoming recognized. Among the enzymes in the metabolic pathway of homocysteine, two are dependent on vitamins that must be obtained from the diet, namely vitamin B12 and folate. Intracellular homocysteine is metabolized by either the transsulforation pathway or by remethylation to methionine (13). Remethylation requires folate and vitamin B12 as cosubstrate and coenzyme, respectively.

The prevalence of hyperhomocysteinemia is between 5 and 10% in the general population, and possibly higher among the elderly (14). It has been suggested that elevated levels of homocysteine may be responsible for up to 10% of CHD events. While the most severe elevations in blood homocysteine are caused by rare enzymatic defects along the metabolic pathway, hyperhomocysteinemia may also result from deficiencies of dietary vitamin B12 and folate. In addition, it has been proposed that inadequate intake of vitamin B6 or excessive intake of methionine may also result in elevated homocysteine levels (15).

Numerous studies have found that homocysteine levels are significantly higher in subjects with the lowest plasma folate, vitamins B12 and B6 (13,16,17). Dietary intakes of folate, vitamins B12 and B6 appear to be inversely related to plasma homocysteine levels (17). Likewise, supplementation trials have shown that homocysteine levels stabilize at a low level following supplementation with 400 ug or more per day (2,18,19). Moreover, 20% of the subjects in the Framingham Heart Study had hyperhomocysteinemia and correspondingly low intakes of vitamin B6 and folate (15). Therefore, homocysteine may be an important and potentially modifiable risk factor for CHD. While these studies lend credence to the notion that homocysteine is directly involved in the pathogenesis of CHD, the evidence is still inconclusive and requires further research. Only placebo-controlled intervention studies with clinical outcomes can provide conclusive evidence for homocysteine as a causal CHD risk factor.

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