Abstract
This study was conducted to investigate the role of different homocysteine metabolism-related vitamin (HMRV) levels in the correlation between hyperhomocysteinemia (HHCY) and ischemic stroke (IS) subtypes. Three hundred and forty-eight IS patients manifesting different vascular subtypes were subclassified on the basis of HMRV deficiencies. Correlation between HHCY and IS subtypes was investigated in all the subgroups. In this study, HHCY was significantly correlated with the IS subtypes in large artery atherosclerosis (OR 1.126, 95%CI: 1.051 ~ 1.206, P = 0.001) and small artery occlusion (OR 1.105, 95%CI: 1.023 ~ 1.193, P = 0.012). Subgroup analysis revealed a correlation between HHCY and IS subgroup (OR 1.201, 1.178, 95%CI: 1.081 ~ 1.334, 1.058 ~ 1.313, P = 0.001, P = 0.003, respectively) in HMRV deficiency, but not significantly with the IS subgroup in normal HMRV levels. Serum vitamin B12 concentrations are inversely correlated with both IS subtypes in HMRV deficiency subgroups (OR 0.992, 0.995, 95%CI: 0.987 ~ 0.996, 0.991 ~ 0.999, P < 0.001, P = 0.007, respectively), which may contribute to HHCY incidence in these populations. The correlation between HHCY and IS subtypes is affected by HMRV levels in this case-control study. Our findings are helpful to understand the inconsistency in prior homocysteine studies. Serum vitamin B12 levels may play a critical role in HHCY incidence in this Chinese population.
Cerebrovascular disease has emerged as the leading cause of disability and mortality in both urban and rural areas of China (Neurology branch of Chinese Medical Association 2015). Ischemic stroke (IS) constitutes 60% to 80% of all cerebrovascular disease (Neurology branch of Chinese Medical Association 2014). Among a variety of risk factors, hyperhomocysteinemia (HHCY) has been closely correlated with IS due to intracranial small-vessel disease and extracranial large-artery disease (Selhub et al. 1995; Eikelboom et al. 2000; Alvarez et al. 2012; Jeon et al. 2014). However, the failure to lower homocysteine (HCY) via homocysteine metabolism-related vitamin (HMRV, including folic acid and vitamin B12 but not vitamin B6 in this study) supplementation to reduce stroke morbidity questions the role of HCY as a risk factor for stroke (Lonn et al. 2006; Hankey et al. 2010). Theoretically, HMRV supplementation merely lowers the incidence of stroke induced by HHCY resulting from HMRV deficiency, whereas HHCY-induced stroke concomitant with normal HMRV levels may be refractory to treatment. The correlation between HCY varying with HMRV levels and IS subtypes is still unclear. In this study, we investigated the impact of variation in HMRV levels on the correlation between HHCY and IS subtypes in 348 acute IS patients with large and small vessel diseases. We sought to determine the factors underlying the conflicting results associated with lowering HCY by HMRV supplementation to reduce stroke incidence.
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References
Adams HP Jr, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, Marsh EE 3rd (1993) Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of org 10172 in acute stroke treatment. Stroke 24:35–41
Alvarez B, Yugueros X, Fernandez E, Luccini F, Gene A, Matas M (2012) Relationship between plasma homocysteine and the morphological and immunohistochemical study of carotid plaques in patients with carotid stenosis over 70%. Ann Vasc Surg 26:500–505
Catena C, Colussi G, Nait F, Capobianco F, Sechi LA (2015) Elevated homocysteine levels are associated with the metabolic syndrome and cardiovascular events in hypertensive patients. Am J Hypertens 28:943–950
Cavalieri M, Schmidt R, Chen C et al (2012) B vitamins and magnetic resonance imaging-detected ischemic brain lesions in patients with recent transient ischemic attack or stroke: the VITAmins TO prevent stroke (VITATOPS) MRI-substudy. Stroke 43:3266–3270
Ducloux D, Chalopin JM (1999) Homocysteine in cerebral macroangiopathy and microangiopathy. Lancet 354:1029–1030
Eikelboom JW, Hankey GJ, Anand SS, Lofthouse E, Staples N, Baker RI (2000) Association between high homocyst(e)ine and ischemic stroke due to large- and small-artery disease but not other etiologic subtypes of ischemic stroke. Stroke 31:1069–1075
Hankey GJ, Eikelboom JW, Baker RI et al (2010) B vitamins in patients with recent transient ischaemic attack or stroke in the VITAmins TO prevent stroke (VITATOPS) trial: a randomised, double-blind, parallel, placebo-controlled trial. Lancet Neurol 9:855–865
Hao L, Ma J, Zhu J, Stampfer MJ, Tian Y, Willett WC, Li Z (2007) High prevalence of hyperhomocysteinemia in Chinese adults is associated with low folate, vitamin B-12, and vitamin B-6 status. J Nutr 137:407–413
Huo Y, Li J, Qin X et al (2015) Efficacy of folic acid therapy in primary prevention of stroke among adults with hypertension in China: the CSPPT randomized clinical trial. JAMA 313:1325–1335
Jeon SB, Kang DW, Kim JS, Kwon SU (2014) Homocysteine, small-vessel disease, and atherosclerosis: an MRI study of 825 stroke patients. Neurology 83:695–701
Lonn E, Yusuf S, Arnold MJ et al (2006) Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med 354:1567–1577
Loscalzo J (2006) Homocysteine trials--clear outcomes for complex reasons. N Engl J Med 354:1629–1632
Ma YC, Zuo L, Chen JH et al (2006) Modified glomerular filtration rate estimating equation for Chinese patients with chronic kidney disease. J Am Soc Nephrol 17:2937–2944
Ma Y, Zhao X, Zhang W, Liu L, Wang Y, Fang R, Wang Y (2010) Homocysteine and ischemic stroke subtype: a relationship study in Chinese patients. Neurol Res 32:636–641
Neurology branch of Chinese Medical Association (2014) Guidelines for diagnosis and treatment of acute ischemic stroke in China 2014. Chin J Neurol 48:246–257
Neurology branch of Chinese Medical Association (2015) Guidelines for primary prevention of cerebrovascular diseases in China. Chin J Neurol 48:629–643
Oh SH, Kim NK, Kim HS, Kim WC, Kim OJ (2011) Plasma total homocysteine and the methylenetetrahydrofolate reductase 677C>T polymorphism do not contribute to the distribution of cervico-cerebral atherosclerosis in ischaemic stroke patients. Eur J Neurol 18:491–496
Pantoni L (2010) Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol 9:689–701
Pawlak R (2015) Is vitamin B12 deficiency a risk factor for cardiovascular disease in vegetarians? Am J Prev Med 48:e11–e26
Risch M, Meier DW, Sakem B, Medina Escobar P, Risch C, Nydegger U, Risch L (2015) Vitamin B12 and folate levels in healthy Swiss senior citizens: a prospective study evaluating reference intervals and decision limits. BMC Geriatr 15:82
dos Santos EF, Busanello EN, Miglioranza A et al (2009) Evidence that folic acid deficiency is a major determinant of hyperhomocysteinemia in Parkinson's disease. Metab Brain Dis 24:257–269
Selhub J, Jacques PF, Bostom AG, D'Agostino RB, Wilson PW, Belanger AJ, O'Leary DH, Wolf PA, Schaefer EJ, Rosenberg IH (1995) Association between plasma homocysteine concentrations and extracranial carotid-artery stenosis. N Engl J Med 332:286–291
Spence JD (2016) Metabolic B12 deficiency: a missed opportunity to prevent dementia and stroke. Nutr Res 36:109–116
Wang Y, Zhao X, Jiang Y et al (2015) Prevalence, knowledge, and treatment of transient ischemic attacks in China. Neurology 84:2354–2361
Weikert C, Dierkes J, Hoffmann K, Berger K, Drogan D, Klipstein-Grobusch K, Spranger J, Möhlig M, Luley C, Boeing H (2007) B vitamin plasma levels and the risk of ischemic stroke and transient ischemic attack in a German cohort. Stroke 38:2912–2918
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Wu, GH., Kong, FZ., Dong, XF. et al. Association between hyperhomocysteinemia and stroke with atherosclerosis and small artery occlusion depends on homocysteine metabolism-related vitamin levels in Chinese patients with normal renal function. Metab Brain Dis 32, 859–865 (2017). https://doi.org/10.1007/s11011-017-9978-3
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DOI: https://doi.org/10.1007/s11011-017-9978-3