On Causes

Abstract

But let us inquire what are the causes of these things which happened to them. — Hippocrates 1 The idea of risk factors for vascular disease has evolved from a dichotomous to continuous hazard analysis and from the consideration of a few factors to mechanistic investigation of many interrelated risks. However, confusion still abounds regarding issues of association and causation. Originally, the simple presence of tobacco abuse, hypertension, and/or hypercholesterolemia were tallied, and the cumulative score was predictive of subsequent coronary artery disease.2 Since then, dose responses have been defined for these and other factors and it has been suggested that almost 300 factors place patients at risk; these factors include elevations in plasma homocysteine. Recent studies shed interesting light on the mechanism of this potentially causal relationship, which was first noted in 1969.3 Aside from putative effects on vessel wall dynamics, there is now direct evidence that homocysteine is atherogenic. Twenty-fold increases in plasma homocysteine achieved by dietary manipulation of apoE–/– mice increased aortic root lesion size 2-fold and produced a prolonged chronic inflammatory mural response accompanied by elevations in vascular cell adhesion molecule-1 and tumor necrosis factor-α.4 In long term follow-up, homocysteine levels elevated by dietary supplementation with methionine or homocysteine promoted lesion size and plaque fibrosis in these atherosclerosis-prone mice early in life, but without influencing ultimate plaque burden as the animals aged.5 A number of mechanisms were proposed by which homocysteine achieved this effect, including promotion of inflammation, regulation of lipoprotein metabolism, and modification of critical biochemical pathways and metabolites including nitric oxide (NO).6 See p 2569 In the present issue of Circulation , Stuhlinger et al7 advance these mechanistic insights one critical step further by defining homocystine’s effects at an enzymatic level. The group led by Lentz published …