Homocysteine-lowering therapy: a role in stroke prevention?

Summary

On the basis of the results of several recent clinical trials, many researchers have concluded that vitamin therapy designed to lower total homocysteine concentrations is not effective in reducing the risk of cardiovascular events. However, whereas almost all myocardial infarctions are due to plaque rupture, stroke has many more pathophysiological mechanisms, and thrombosis—which is increased by raised total homocysteine concentrations—has an important role in many of these processes. Thus, stroke and myocardial infarction could respond differently to vitamin therapy. A detailed assessment of the results of the recent HOPE-2 trial and a reanalysis of the VISP trial restricted to patients capable of responding to vitamin therapy suggest that higher doses of vitamin B12 and perhaps new approaches to lowering total homocysteine besides routine vitamin therapy with folate, vitamin B6, and vitamin B12 could reduce the risk of stroke. Thus, therapy to lower homocysteine could still help to prevent stroke, if not other vascular outcomes.

Introduction

Unravelling the risk factors for stroke remains an important challenge. An increased understanding of the underlying mechanisms will help us to identify ways in which we can reduce the incidence of stroke. One potential risk factor is increased plasma concentrations of homocysteine, a sulphur-containing amino acid that is formed during methionine metabolism and can be regulated by the vitamins folic acid, B6, and B12. The vascular effects of raised homocysteine concentrations were first noted in 1962 in patients with the hereditary metabolic disorder homocystinuria and very high concentrations of total homocysteine (the sum of homocysteine, homocysteine–homocysteine, and homocysteine–cysteine disulfide),¹ resulting from a homozygous deficiency of cystathionine synthase.2, 3 In 1969, McCully⁴ suggested that even moderate increases of total homocysteine could accelerate atherosclerosis. Later, a third of patients with premature atherosclerosis were reported to have raised concentrations of total homocysteine⁵ and 42% of patients with premature vascular disease had hyperhomocysteinaemia, both of which were attributed to heterozygous homocysteinuria.⁶ Many causes of raised total homocysteine have since become apparent: about a dozen genetic defects,7, 8, 9 renal failure,¹⁰ vitamin deficiencies,¹¹ increasing age,¹² and a number of drugs including methotrexate, anticonvulsants, proton pump inhibitors, and fibrates13, 14 are associated with increases in total homocysteine. Moreover, animal models15, 16 and studies of the biochemical pathways involving homocysteine suggest that increases in total homocysteine could aggravate vascular disease17, 18, 19, 20 and support a causal role for total homocysteine in vascular disease. A high total homocysteine concentration has been shown in large cohort studies to be an independent, graded predictor of cardiovascular events, including cerebral infarction, myocardial infarction, and cardiovascular death.21, 22 However, recent clinical trials23, 24, 25 have been interpreted as showing that homocysteine is not causal in vascular disease because vitamin therapy to reduce homocysteine concentrations did not reduce the incidence of myocardial infarction or stroke.

Here, I summarise and assess pathophysiological, genetic, and clinical evidence that homocysteine is involved in vascular disease, especially with respect to cerebral infarction. Moreover, a closer look at the results from recent clinical trials with respect to stroke calls into question the initial interpretation that homocysteine is not causal in vascular disease and suggests that there could indeed be an effect of vitamin therapy to lower total homocysteine, at least for cerebral infarction. This reassessment of the evidence from clinical trials raises the important issues of variations in individual responses to vitamin therapy and the need for higher doses of vitamin B12 than have been used in clinical trials to date, especially since stroke mainly affects elderly individuals, who are more likely to be deficient in vitamin B12.