Personal ViewHomocysteine-lowering therapy: a role in stroke prevention?
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.
Section snippets
Genetic risk
Support for a causal role for total homocysteine in the risk of stroke26, 27 has come from genetic approaches. Perhaps the most common single nucleotide polymorphism leading to increased concentrations of total homocysteine is the C→T mutation of the methylenetetrahydrofolate reductase (MTHFR) gene. Casas and colleagues26 did two large-scale meta-analyses to assess the link between homocysteine and stroke. In the first, they aimed to determine the extent to which the MTHFR C677T polymorphism is
Pathophysiological mechanisms
There are many mechanisms by which increased total homocysteine could contribute to vascular disease. The strongest evidence for this link comes from studies of animal models and indicates that the principal mechanisms involve impaired endothelial function, increased oxidative stress, alterations of lipid metabolism, and induction of thrombosis.
Raised plasma total homocysteine concentrations have been associated with increased coagulation of the blood,29, 30, 31, 32 increased cholesterol
Raised homocysteine and cerebral infarction
Whereas almost all myocardial infarctions are due to plaque rupture in a coronary artery, with in-situ thrombosis that is secondary to the plaque rupture, there are many more mechanisms that lead to cerebral infarction. Indeed, cerebral infarction is rarely due to carotid artery occlusion. A major difference between the causal factors for myocardial infarction and stroke is the richer collateral circulation to the brain. Whereas complete occlusion of a left main coronary artery would rarely be
Homocysteine as a marker of vascular disease
Some researchers suggest that rather than having a causal role in vascular disease, homocysteine might be just a marker of disease. This hypothesis is based on an apparent rise in homocysteine concentrations between samples obtained after admission to hospital with stroke and samples obtained after discharge from hospital. However, this increase is more likely to be explained by the timing of blood sample collection after acute stroke. The apparent rise in total homocysteine after an acute
Vitamin therapy and surrogate outcomes
Studies of the effects of vitamin therapy on surrogate outcomes such as endothelial function or carotid plaque progression lend support to the notion that homocysteine concentrations are linked to risk of vascular events. Lowering of homocysteine by vitamin72 or acetylcysteine therapy improves endothelial function in patients with vascular disease or with renal failure.52, 53, 54 In patients whose carotid plaque was progressing despite treatment of traditional risk factors, my colleagues and I
Large-scale clinical studies
Scepticism about the role of homocysteine in vascular events is understandable given the mixed results of clinical studies and the results of several randomised controlled trials in which vitamin therapy to reduce homocysteine concentrations was not associated with a reduction in the incidence of myocardial infarction or stroke. Although clinical trials undoubtedly rank at the top of the hierarchy of evidence, it must be understood that they are a blunt instrument, and interpretation of their
Unrecognised importance of vitamin B12
Because stroke is more steeply related to age than is myocardial infarction,91 the issue of vitamin B12 deficiency, which is much more common in elderly individuals, could have an important role in the differential effect of vitamin therapy on stroke versus myocardial infarction. Indeed, patients in VISP and HOPE-2, where stroke reduction was found with vitamin therapy, were older than those in the two angioplasty trials or in NORVIT. Dietary factors are also crucial in determining circulating
Other therapies for lowering homocysteine
Although routine therapy with folate, vitamin B6, and vitamin B12 is effective in lowering concentrations of total homocysteine in most patients, some patients have high total homocysteine despite vitamin therapy. Reasons for this lack of effect include renal failure and probably genetically based differences in homocysteine metabolism.8 Such patients can benefit from addition of betaine (trimethylglycine)104 or choline (in the form of phosphatidylcholine),105 which affect other metabolic
Conclusions
The results of three randomised controlled trials23, 24, 25 of vitamin therapy for reduction of vascular events, all of which failed to show benefit of vitamin therapy for their primary outcome, have justifiably caused many to conclude that vitamin therapy to lower homocysteine is ineffective in preventing vascular disease. Several recent reviews reflect this doubt, which amounts almost to a consensus.88, 111, 112, 113 Although recommendation of widespread homocysteine-lowering therapy for the
References (113)
- et al.
The identification of homocystine in the urine
Biochem Biophys Res Commun
(1962) - et al.
Major lifestyle determinants of plasma total homocysteine distribution: the Hordaland Homocysteine Study
Am J Clin Nutr
(1998) - et al.
TDAG51 is induced by homocysteine, promotes detachment-mediated programmed cell death, and contributes to the development of atherosclerosis in hyperhomocysteinemia
J Biol Chem
(2003) - et al.
Homocysteine and stroke: evidence on a causal link from mendelian randomisation
Lancet
(2005) - et al.
Predominant role of sterol response element binding proteins (SREBP) lipogenic pathways in hepatic steatosis in the murine intragastric ethanol feeding model
J Hepatol
(2006) - et al.
Homocysteine induces programmed cell death in human vascular endothelial cells through activation of the unfolded protein response
J Biol Chem
(2001) - et al.
Acute hyperhomocysteinaemia and endothelial dysfunction
Lancet
(1998) - et al.
TDAG51 is induced by homocysteine, promotes detachment-mediated programmed cell death, and contributes to the cevelopment of atherosclerosis in hyperhomocysteinemia
J Biol Chem
(2003) - et al.
Thrombophilia testing in patients with venous thrombosis
Eur J Vasc Endovasc Surg
(2005) - et al.
Effects of homocysteine thiol group on fibrin networks: another possible mechanism of harm
Thromb Res
(2002)