Is homocysteine a relevant cardiovascular risk factor?

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Corresponding author Sanjay Kaul, MD Division of Cardiology, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA. E-mail: [email protected] Current Cardiovascular Risk Reports 2008, 2:141–149 Current Medicine Group LLC ISSN 1932-9520 Copyright © 2008 by Current Medicine Group LLC

Scientific research is searching constantly for new markers to help stage the progress and prognosis of cardiovascular disease. Over the past few decades, homocysteine has been suggested as a risk factor involved in the promotion of atherosclerosis and thrombotic vascular events. Several large observational studies have indicated a relationship between homocysteine and cardiovascular illness. However, more robust prospective trials reveal a weaker association between the two than do case-control and cross-sectional data. Recently, many randomized controlled trials have evaluated the impact of homocysteine-lowering therapy on vascular risk. The overall evidence suggests a null effect, thereby failing to validate the hypothesis that a reduction in homocysteine levels would result in clinical benefit. This review outlines the latest relevant data and illustrates why the use of homocysteine as a screening tool or a target of cardiovascular treatment cannot be recommended.

Introduction Over the past century, significant strides have been made in optimizing the diagnosis and treatment of cardiovascular disease (CVD). Recognition of genetic and metabolic indicators of vascular illness has made a major impact on risk stratification and management of CVD. Two studies reviewing more than 500,000 subjects have shown that 80% to 90% of those diagnosed with coronary heart disease (CHD) had previously displayed at least one of four classic risk factors: hypercholesterolemia, hypertension, diabetes mellitus, and smoking [1–3]. In addition to aiding in risk stratification, these markers have provided clinicians with valuable targets for therapy. However, our ability to predict risk for vascular events remains some-

what limited [3]. Accordingly, the search for alternative indicators of risk remains a worthwhile goal. Homocysteine is a natural sulfur amino acid found in the body. Serum levels usually vary from 5 to 15 Nmol/L. It is produced during the metabolism of the essential amino acid methionine. In 1969, McCully [4] first noted that children with homocystinuria, a deficiency in an enzyme responsible for methionine breakdown, were prone to a substantial increase in atherothrombotic events. The children also had significantly higher serum levels of homocysteine. Subsequently, data were published linking coronary artery disease to elevated serum homocysteine levels in the general population. On the basis of these seminal observations, homocysteine was proposed as a novel cardiovascular risk factor [5]. Several large-scale observational and randomized trials have examined the role of homocysteine as a modifiable cardiovascular risk factor. This article provides an overview of homocysteine metabolism, reviews the etiology of and p