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Pronounced association of elevated serum homocysteine with stroke in subgroups of individuals: A nationwide study

https://doi.org/10.1016/j.jns.2010.07.013Get rights and content

Abstract

Background

Although the original homocysteine hypothesis for atherothrombotic disease is falling out of favor, prior studies did not comprehensively adjust for confounders or explore specific subgroups of patients who may benefit from serum homocysteine-lowering. We aimed to determine (1) if elevated total homocysteine (tHcy) affects odds of prevalent stroke after adjusting for a broad array of pertinent covariates and (2) whether particular vascular risk factors amplify the effect of high homocysteine on prevalent stroke.

Methods

The independent and interactive effects of elevated tHcy (≥10 μmol/L) on likelihood of prevalent stroke was assessed in the National Health and Nutrition Examination Survey, a nationally representative cross-sectional sample of the US population conducted from 1999 to 2004 (n = 12,683).

Results

After adjusting for 17 covariates, those with elevated tHcy were more likely to have prevalent stroke vs. those without elevated tHcy (OR 1.52, 95% CI 1.01–2.29; p = 0.045). Individuals with a combination of elevated tHcy and hypertension were substantially more likely to have prevalent stroke compared to individuals without either condition (OR 12.02, 95% CI 6.36–22.73 for men and OR 17.34, 95% CI 10.49–28.64 for women). The association of tHcy with prevalent stroke was strongest in younger individuals and declined linearly with increasing age.

Conclusions

Elevated tHcy independently increases odds of prevalent stroke. Younger individuals and those with concomitant hypertension may particularly benefit from tHcy-lowering.

Introduction

Ambiguity surrounds the role of elevated total plasma homocysteine (tHcy) as a causal and treatable risk factor for vascular disease [1]. Recent data suggest that tHcy does not independently affect vascular risk [2] and clinical trials have failed to show a benefit of tHcy-lowering on risk of vascular events, including stroke [3], [4], [5], [6], [7]. On the other hand, the Heart Outcomes Prevention Evaluation (HOPE) 2 trial, showed a 25% reduction in stroke with multivitamin therapy [8] and a meta-analysis found an 18% relative risk reduction in stroke [9]. Other trials are ongoing [10], [11].

The lack of benefit of vitamin therapy on stroke risk reduction among individuals with elevated tHcy could be due to a multitude of factors, including inadequate adjustments for confounders, insufficient tHcy lowering, inadequate differences in tHcy levels in the treatment and control arms, particularly after folate fortification of grains, heterogeneity of stroke mechanisms, and a real lack of effect/association [12], [13]. Perhaps, as suggested by an efficacy analysis of the Vitamin Intervention for Stroke Prevention (VISP) study [13], certain subgroups of individuals may benefit more from tHcy-lowering than others. The heterogeneity of patient populations and study design, and lack of individual patient level data, may limit the extent to which meta-analyses can investigate these issues properly.

The aims of this study were: (1) to assess the association of elevated tHcy with prevalent stroke by systematically accounting for covariates in a racially/ethnically diverse, nationally representative population; (2) to investigate the link between elevated tHcy and stroke risk factors; and (3) to determine if the combination of elevated tHcy with stroke risk factors amplifies the odds of prevalent stroke.

Section snippets

Study population

The National Health and Nutrition Examination Survey (NHANES) are cross-sectional samples of the US civilian non-institutionalized population conducted by the National Center for Health Statistics (NCHS). The protocols for conduct were approved by the NCHS institutional review board; informed consent was obtained from all participants. The sampling plan followed a complex, stratified, multistage, probability cluster design, with over-sampling of non-Hispanic blacks, Mexican Americans and the

Results

When compared to individuals without prevalent stroke, those with prevalent stroke were more likely to be women, older, have elevated tHcy, hypertension, DM, hypercholesterolemia, history of smoking, history of heavy alcohol use, higher BMI, higher creatinine, higher CRP, and be physically inactive and less educated (Table 1).

In women, there was a positive association of elevated tHcy with hypertension, history of smoking, and hypercholesterolemia (all p < 0.001). In men, there was a positive

Discussion

Our analysis of this nationally representative sample of the US population revealed that: (1) elevated tHcy was an independent marker of prevalent stroke; (2) elevated tHcy and hypertension had a multiplicative effect on the odds of prevalent stroke, and (3) the effect of elevated tHcy on prevalent stroke was highest in younger individuals and diminished linearly with increasing age.

A recent study, using a surrogate marker of cerebrovascular disease, suggested that elevated tHcy is a marker for

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