Quo vadis: whither homocysteine research?

Four decades of research on the link between hyperhomocysteinemia and cardiovascular disease has led to a crossroads. Several negative studies on the role of homocysteine-lowering B-vitamin therapy in reducing the risk of atherothrombotic cardiovascular disease have dampened enthusiasm for this important field of research. In this review, we assess the present state of homocysteine research and suggest potential avenues that would help to clarify the purported link between the plasma homocysteine level and cardiovascular risk. We address several questions raised by the findings of various basic, epidemiological and clinical studies and attempt to construct a framework that we believe will allow us to address the fundamental unresolved issues in this controversial area, specifically focusing on the risk of coronary vascular disease and cardiac failure. This review should allow researchers to deconstruct this complex field into separate areas that, when addressed adequately, may lead to findings that elucidate the overall link between hyperhomocysteinemia and cardiovascular disease and allow the design of appropriate clinical trials.