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The controversy over homocysteine and cardiovascular risk
P M Ueland1, H Refsum, S A Beresford
1LOCUS for Homocysteine and Related Vitamins, Armauer Hansens hus, University of Bergen, Norway. per.ueland@ikb.uib.no
Insights
Elevated total homocysteine (tHcy) is linked to cardiovascular disease (CVD). While some studies question this link, evidence suggests tHcy is a risk factor, especially in kidney disease. Further research is needed.
Area of Science:
- Cardiovascular Science
- Metabolic Disease Research
- Genetic Epidemiology
Background:
- Elevated plasma total homocysteine (tHcy) is a recognized risk factor for occlusive cardiovascular disease (CVD).
- Evidence includes premature vascular disease in homocystinuria, associations with clinical and preclinical atherosclerosis, and B vitamin intervention studies.
- Potential mechanisms involve interference with nitric oxide-dependent vasodilation.
Purpose of the Study:
- To evaluate the role of total homocysteine (tHcy) as a causal risk factor for cardiovascular disease (CVD).
- To address conflicting evidence regarding the association between tHcy and CVD.
- To highlight the need for placebo-controlled intervention studies with clinical endpoints.
Main Methods:
- Review of observational studies linking tHcy to CVD and preclinical atherosclerosis.
- Analysis of studies on tHcy in relation to traditional risk factors, renal function, and genetic polymorphisms (e.g., MTHFR C677T).
- Consideration of evidence from tHcy-lowering B vitamin intervention trials.
Main Results:
- Some prospective studies show weak or no association between tHcy and CVD.
- Confounding by traditional risk factors and association with renal function are noted.
- Evidence suggests tHcy may be a proximate risk factor, interacting with traditional factors and predicting outcomes in renal failure.
Conclusions:
- Despite some contradictory findings, growing evidence supports tHcy as a significant CVD risk factor.
- The role of tHcy is particularly relevant in patients with chronic kidney disease.
- Placebo-controlled intervention trials with B vitamins are crucial for definitive conclusions on causality.
Abstract:
Elevated plasma total homocysteine (tHcy) is a risk factor for occlusive cardiovascular disease (CVD). This concept is based on the observations of premature vascular disease in patients with homocystinuria, the relation between tHcy and both clinical CVD as well as preclinical atherosclerotic disease, the relation between tHcy in children and CVD in their parents or relatives, and reduction in CVD or surrogate endpoints after tHcy-lowering intervention with B vitamins. Plausible mechanisms include the in vivo interference with nitric oxide-dependent reactive vasodilatation. Some observations have raised questions about tHcy as a risk factor. 1) Some prospective studies showed a weak relation or no relation between tHcy and CVD. 2) Several traditional risk factors are associated with tHcy and may confound the relation between tHcy and CVD. 3) tHcy is related to renal function, and hyperhomocysteinemia may reflect early nephrosclerosis. 4) The C677T transition of the methylenetetrahydrofolate reductase gene causes a moderate increase in tHcy but no or only minor increased CVD risk. However, the strength of some of these arguments can be questioned because there is increasing evidence that tHcy is a proximate risk factor provoking the acute event, it strongly interacts with traditional risk factors, and it may predict CVD or death in patients with chronic renal failure. Furthermore, the studies of the C677T polymorphism lack statistical power, and the TT genotype may even modulate CVD risk independently of homocysteine. Thus, only placebo-controlled intervention studies with tHcy-lowering B vitamins and clinical endpoints can provide additional valid arguments for the debate over whether tHcy is a causal CVD risk factor.