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Neurology India, Vol. 53, No. 3, July-September, 2005, pp. 301-302 Invited Comments Invited Comments Prabhakaran S The Neurological Institute, Columbia University, Stroke and Critical Care Division, 710 W 168th Street, Room 640, New York, NY - 10032 Code Number: ni05104 Related article: ni05103, ni05105 For over 30 years, there has been a belief that hyperhomocysteinemia plays a role in atherothrombosis.[1] However, not until recently has epidemiological evidence (over 100 case-control, cross-sectional, and prospective studies) shown an association between homocysteine levels and vascular disease.[2] Regarding stroke risk, the evidence is still emerging. Trends for an association of the highest quartile of homocysteine and stroke have been seen in the Framingham Study as well as British Regional Heart Study.[3],[4] In the Northern Manhattan Study, elevation greater than 15 mg/dl was associated strongly with vascular death, combined vascular outcomes, and with ischemic stroke in a tri-ethnic population. The link between moderate homocysteine elevations (10-15 mol/l) and ischemic stroke were less dramatic than for vascular death and combined vascular events.[5] The Homocysteine Collaborative Group′s meta-analysis of the data concluded that a moderate independent association existed with a 25% lower level being associated with about a 10% lower stroke and cardiac risk in asymptomatic persons.[6] The study in the current issue of Neurology India corroborates this association in Indian patients with stroke.[7] While there seems to be a strong association and perhaps a dose-dependent relationship between homocysteine and vascular disease, the leap from association to causality has been difficult. Evidence from genetic conditions known to elevate homocysteine 10-50 times than the general population (i.e. cystathionine B-synthase), would support the hypothesis that early atherosclerosis is linked to elevated homocysteine levels. However, genetic studies have also failed to show an association with vascular disease in those with some genotypes known to cause hyperhomocysteinemia.[8] In addition, biologic plausibility is still largely speculative despite emerging evidence that suggests it may cause endothelial damage via oxidative stress mechanisms, alterations of coagulation properties, and impairment of vasomotor regulation.[9] These, however, have been studies in which concentrations of homocysteine are 10 times greater than seen in most patients with moderately elevated levels. Furthermore, to satisfy Bradford Hill′s criteria for epidemiologic causality, homocysteine may need to pass one last hurdle: removing the exposure or treating it should decrease the risk of the disease. Therefore, treatment for hyperhomocysteinemia with multivitamins (folate, B12, and B6), which has been shown to reduce homocysteine levels even in individuals not vitamin deficient,[10] should lower the risk of vascular outcomes. Multivitamin therapy has been demonstrated to reduce homocysteine levels and cardiovascular risks among those with genetic causes of marked hyperhomocysteinemia.[11] Surrogate markers such as carotid plaque likewise show regression with homocysteine-lowering therapy.[12] However, in a recent large international randomized trial among stroke survivors with moderate homocysteinemia, multivitamin therapy showed no reduction in the risk of stroke recurrence.[13] Ongoing trials such as VITATOPS may help address the question regarding the benefits of homocysteine-lowering therapies.[14] For now, the preponderance of evidence from many epidemiologic, basic scientific, and genetic studies suggests that homocysteine is moderately associated with cardiovascular disease (stroke included). Given the safety and low cost of multivitamin therapy, recommendations suggest starting B12, folate, and B6 in those with elevated homocysteine and cardiovascular disease.[15] Whether reducing homocysteine will translate into a reduction in vascular or stroke risk is still an area of uncertainty. References
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