Relevance of plasma levels of free homocysteine and methionine as risk predictors for ischemic stroke in the young.

Background & Aims: The debated vascular risk potential of total homocysteine (tHcy), due to failed clinical trials designed on B vitamin supplementation, raises many possible explanations like the higher risk potential of the deleterious, free form of homocysteine (fHcy) or, the unchecked confounding effects of B-vitamins in tHcy-based association studies. Additionally, the cardiovascular risk probability of altered status of the homocysteine precursor, methionine (tMet) could shed light on the causality of association between tHcy and cardiovascular diseases. Hence, we aimed to evaluate the risk associations of elevated plasma levels of tHcy, fHcy and low levels of tMet with premature, ischemic stroke.

Methods: We recruited 171 young, ischemic stroke patients (aged ≤45 years) and 249 age- and gender-matched healthy controls. Plasma levels of fHcy, tHcy, tMet and vitamin B6 were estimated using HPLC coupled with coulometric electrochemical detection. Plasma levels of vitamin B12 and folate were estimated by radioimmunoassay.

Results: Elevated fHcy (>2.9 μmol/L) was independently and strongly associated with the risk of premature, ischemic stroke (OR = 9.62, 95% CI = 3.51-26.40). On the contrary, association between premature ischemic stroke and elevated tHcy (>15.0 μmol/L) was found to attenuate when adjusted for vitamin B6 values (OR = 0.24, 95%, CI = 0.03-1.69). Interestingly, compromised B6-status (<59.2 nmol/l) was found to confer high risk of premature ischemic stroke (OR = 170.80, 95% CI = 58.22-501.06). We could not establish any significant correlation between fHcy and B-vitamin levels (P > 0.05). Low tMet (<13.86 μmol/L) was also not significantly associated with premature, ischemic stroke (OR = 2.53, 95% CI = 0.613-10.38).

Conclusion: Our results indicate significant but not-correlated, independent associations of fHcy and vitamin B6 with risk of premature, ischemic stroke. However, the causality of these associations need prospective and large scale validations. Further, our findings highlight the crucial confounding effects of B-vitamins on risk association between tHcy and premature ischemic stroke.