Homocysteine lowering and cardiovascular disease risk: lost in translation

Abstract

Studies of the general population have suggested that high homocysteine levels are associated with cardiovascular morbidity and mortality. In chronic kidney disease, homocysteine levels rise, and cardiovascular risk increases with declining kidney function. While some studies in this population have found an association between elevated homocysteine and cardiovascular risk, others have noted that this association is largely attenuated by adjustment for kidney function, and several studies of patients with kidney failure have found that lower homocysteine levels predict mortality. Homocysteine levels can be lowered with folate, vitamin B6 and vitamin B12. Three large, randomized, controlled trials of patients with pre-existing cardiovascular disease and two smaller, randomized, controlled trials of patients with kidney failure failed to detect any cardiovascular benefit from homocysteine-lowering vitamins. Several more interventional trials are ongoing, but the available data thus far do not support screening for or treatment of hyperhomocysteinemia.

Figure 1)

Postulated adverse vascular effects of homocysteine. The postulated effects involve oxidative damage to vascular endothelial cells and increased proliferation of vascular smooth muscle cells after oxidative metabolism of homocysteine to homocystine and homocysteine thiolactone. Oxidative modification of low-density lipoprotein (LDL) promotes the formation of foam cells, which in turn yields another source of reactive oxygen species. Reproduced with permission from reference 1