Advertisement

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

Published:September 01, 2010DOI:https://doi.org/10.1016/j.jns.2010.07.013

      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.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Journal of the Neurological Sciences
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Hankey G.
        Is homocysteine a causal and treatable risk factor for stroke?.
        Lancet Neurol. 2007; 6: 751-752
        • Potter K.
        • Hankey G.J.
        • Green D.J.
        • Eikelboom J.W.
        • Arnolda L.F.
        Homocysteine or renal impairment: which is the real cardiovascular risk factor?.
        Arterioscler Thromb Vasc Biol. 2008; 28: 1158-1164
        • Toole J.F.
        • Malinow M.R.
        • Chambless L.E.
        • et al.
        Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial.
        JAMA. 2004; 291: 565-575
        • Bazzano L.A.
        • Reynolds K.
        • Holder K.N.
        • He J.
        Effect of folic acid supplementation on risk of cardiovascular diseases: a meta-analysis of randomized controlled trials.
        JAMA. 2006; 296: 2720-2726
        • Bonaa K.H.
        • Njolstad I.
        • Ueland P.M.
        • et al.
        Homocysteine lowering and cardiovascular events after acute myocardial infarction.
        N Engl J Med. 2006; 354: 1578-1588
        • Ebbing M.
        • Bleie O.
        • Ueland P.M.
        • et al.
        Mortality and cardiovascular events in patients treated with homocysteine-lowering B vitamins after coronary angiography: a randomized controlled trial.
        JAMA. 2008; 300: 795-804
        • Albert C.M.
        • Cook N.R.
        • Gaziano J.M.
        • et al.
        Effect of folic acid and B vitamins on risk of cardiovascular events and total mortality among women at high risk for cardiovascular disease: a randomized trial.
        JAMA. 2008; 299: 2027-2036
        • Lonn E.
        • Yusuf S.
        • Arnold M.J.
        • et al.
        Homocysteine lowering with folic acid and B vitamins in vascular disease.
        N Engl J Med. 2006; 354: 1567-1577
        • Wang X.
        • Qin X.
        • Demirtas H.
        • et al.
        Efficacy of folic acid supplementation in stroke prevention: a meta-analysis.
        Lancet. 2007; 369: 1876-1882
        • Hankey G.J.
        • Algra A.
        • Chen C.
        • et al.
        VITATOPS, the VITAmins TO prevent stroke trial: rationale and design of a randomised trial of B-vitamin therapy in patients with recent transient ischaemic attack or stroke (NCT00097669) (ISRCTN74743444).
        Int J Stroke. 2007; 2: 144-150
        • Bostom A.G.
        • Carpenter M.A.
        • Kusek J.W.
        • et al.
        Rationale and design of the Folic Acid for Vascular Outcome Reduction In Transplantation (FAVORIT) trial.
        Am Heart J. 2006; 152 (448): e1-e7
        • Spence J.
        Homocysteine-lowering therapy: a role in stroke prevention?.
        Neurol. 2007; 6: 830-838
        • Spence J.D.
        • Bang H.
        • Chambless L.E.
        • Stampfer M.J.
        Vitamin Intervention For Stroke Prevention trial: an efficacy analysis.
        Stroke. 2005; 36: 2404-2409
      1. Plan and operation of the Third National Health and Nutrition Examination Survey, 1988–94. Series 1: programs and collection procedures.
        Vital Health Stat 1. 1994; 1: 1-407
      2. Homocysteine-lowering trials for prevention of cardiovascular events: a review of the design and power of the large randomized trials.
        Am Heart J. 2006; 151: 282-287
        • Jacques P.F.
        • Selhub J.
        • Bostom A.G.
        • Wilson P.W.
        • Rosenberg I.H.
        The effect of folic acid fortification on plasma folate and total homocysteine concentrations.
        N Engl J Med. 1999; 340: 1449-1454
        • McCully K.S.
        Homocysteine, vitamins, and vascular disease prevention.
        Am J Clin Nutr. 2007; 86: 1563S-1568S
      3. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification.
        Am J Kidney Dis. 2002; 39(2 Suppl 1): S1-S266
        • Kasiman K.
        • Eikelboom J.W.
        • Hankey G.J.
        • et al.
        Ethnicity does not affect the homocysteine-lowering effect of B-vitamin therapy in Singaporean stroke patients.
        Stroke. 2009; 40: 2209-2211
        • Lim U.
        • Cassano P.A.
        Homocysteine and blood pressure in the Third National Health and Nutrition Examination Survey, 1988-1994.
        Am J Epidemiol. 2002; 156: 1105-1113
        • Giles W.H.
        • Croft J.B.
        • Greenlund K.J.
        • Ford E.S.
        • Kittner S.J.
        Total homocyst(e)ine concentration and the likelihood of nonfatal stroke: results from the Third National Health and Nutrition Examination Survey, 1988-1994.
        Stroke. 1998; 29: 2473-2477
        • Evers S.
        • Koch H.G.
        • Grotemeyer K.H.
        • Lange B.
        • Deufel T.
        • Ringelstein E.B.
        Features, symptoms, and neurophysiological findings in stroke associated with hyperhomocysteinemia.
        Arch Neurol. 1997; 54: 1276-1282
        • Mizrahi E.H.
        • Noy S.
        • Sela B.A.
        • Fleissig Y.
        • Arad M.
        • Adunsky A.
        Further evidence of interrelation between homocysteine and hypertension in stroke patients: a cross-sectional study.
        Isr Med Assoc J. 2003; 5: 791-794
        • Al-Delaimy W.K.
        • Rexrode K.M.
        • Hu F.B.
        • et al.
        Folate intake and risk of stroke among women.
        Stroke. 2004; 35: 1259-1263
        • He K.
        • Merchant A.
        • Rimm E.B.
        • et al.
        Folate, vitamin B6, and B12 intakes in relation to risk of stroke among men.
        Stroke. 2004; 35: 169-174
        • Van Guelpen B.
        • Hultdin J.
        • Johansson I.
        • et al.
        Folate, vitamin B12, and risk of ischemic and hemorrhagic stroke: a prospective, nested case-referent study of plasma concentrations and dietary intake.
        Stroke. 2005; 36: 1426-1431
        • Bazzano L.A.
        • He J.
        • Ogden L.G.
        • et al.
        Dietary intake of folate and risk of stroke in US men and women: NHANES I Epidemiologic Follow-up Study. National Health and Nutrition Examination Survey.
        Stroke. 2002; 33: 1183-1188
        • Weng L.C.
        • Yeh W.T.
        • Bai C.H.
        • et al.
        Is ischemic stroke risk related to folate status or other nutrients correlated with folate intake?.
        Stroke. 2008; 39: 3152-3158
        • Saposnik G.
        • Ray J.G.
        • Sheridan P.
        • McQueen M.
        • Lonn E.
        Homocysteine-lowering therapy and stroke risk, severity, and disability: additional findings from the HOPE 2 trial.
        Stroke. 2009; 40: 1365-1372
        • Spence J.D.
        • Cordy P.
        • Kortas C.
        • Freeman D.
        Effect of usual doses of folate supplementation on elevated plasma homocyst(e)ine in hemodialysis patients: no difference between 1 and 5 mg daily.
        Am J Nephrol. 1999; 19: 405-410
        • Engstad T.
        • Bonaa K.H.
        • Viitanen M.
        Validity of self-reported stroke: The Tromso Study.
        Stroke. 2000; 31: 1602-1607
        • O'Mahony P.G.
        • Dobson R.
        • Rodgers H.
        • James O.F.
        • Thomson R.G.
        Validation of a population screening questionnaire to assess prevalence of stroke.
        Stroke. 1995; 26: 1334-1337
        • Li Z.
        • Sun L.
        • Zhang H.
        • et al.
        Elevated plasma homocysteine was associated with hemorrhagic and ischemic stroke, but methylenetetrahydrofolate reductase gene C677T polymorphism was a risk factor for thrombotic stroke: a Multicenter Case-Control Study in China.
        Stroke. 2003; 34: 2085-2090
        • Ay H.
        • Arsava E.M.
        • Tokgozoglu S.L.
        • Ozer N.
        • Saribas O.
        Hyperhomocysteinemia is associated with the presence of left atrial thrombus in stroke patients with nonvalvular atrial fibrillation.
        Stroke. 2003; 34: 909-912
        • Loffredo L.
        • Violi F.
        • Fimognari F.L.
        • et al.
        The association between hyperhomocysteinemia and ischemic stroke in patients with non-valvular atrial fibrillation.
        Haematologica. 2005; 90: 1205-1211
        • Poli D.
        • Antonucci E.
        • Cecchi E.
        • et al.
        Culprit factors for the failure of well-conducted warfarin therapy to prevent ischemic events in patients with atrial fibrillation: the role of homocysteine.
        Stroke. 2005; 36: 2159-2163