Objectives: To investigate the independent and joint associations of hyperhomocysteinemia and hypertension with incident stroke and stroke death in Chinese adults.
Methods: About 39,165 rural Chinese adults aged 35 years or older who had no history of stroke at the baseline study were prospectively followed to determine major cardiovascular events, with an average follow-up of 6.2 years. Using a nested case–control design, this report includes 179 incident stroke cases (121 stroke deaths) and 179 controls without vascular events from the original cohort matched by age, sex, community, and length of plasma storage. Baseline plasma total homocysteine (tHcy) measurements were obtained for all subjects. Logistic regression analysis was performed to investigate the independent and joint associations between H-type hypertension, defined as subjects with concomitant hypertension and elevated homocysteine (≥10 μmol/L), and risk of incident stroke and stroke death, after adjusting for important covariates.
Results: We analyzed each risk factor independently and jointly. For analysis, homocysteine was divided into three groups: low (tHcy <10 µmol/L), moderate (≥10 µmol/L tHcy <20 µmol/L), and high (tHcy≥20µmol/L). Compared to subjects in the low group, the odds ratios (95% CI) of incident stroke for those in the moderate group and the high group were 1.7 (0.8–3.7) and 3.1 (1.2–8.6), respectively. The odds ratios (95% CI) of stroke death for the moderate and high groups were 2.8 (1.1–7.4) and 5.1 (1.6–16.4), respectively. Hypertension was also independently associated with a higher risk of incident stroke and stroke death: 3.8 (2.3–6.4) and 3.2 (1.8–6.0), respectively, compared to those without hypertension. When analyzed jointly, the highest risk was found among patients with H-type hypertensive with both hyperhomocysteinemia and hypertension: 12.7 (2.8–58.0) for incident stroke and 11.7 (2.5–54.7) for stroke death.
Conclusions: This study provides strong evidence that hyperhomocysteinemia and hypertension are two independent, modifiable risk factors, which act additively to increase the risk of incident stroke and stroke death. The results strongly suggest that H-type hypertension is a major risk factor for vascular disease and mortality, and those with H-type hypertension may particularly benefit from homocysteine-lowering therapy along with anti-hypertension therapy in Chinese populations.
1. Anderson JL, Muhlestein JB, Horne BD, Carlquist JF, Bair TL, Madsen TE, et al. Plasma homocysteine predicts mortality independently of traditional risk factors and C-reactive protein in patients with angiographically defined coronary artery disease. Circulation 2000;102:1227-32.
2. Boushey CJ, Beresford SA, Omenn GS, Motulsky AG. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes. JAMA 1995;274:1049-57.
3. Nygard O, Nordrehaug JE, Refsum H, Ueland PM, Farstad M, Vollset SE. Plasma homocysteine levels and mortality in patients with coronary artery disease. N Engl J Med 1997;337:230-6.
4. Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA 2002;288:2015-22.
5. Davey Smith G, Ebrahim S. ‘Mendelian randomization’: can genetic epidemiology contribute to understanding environmental determinants of disease? Int J Epidemiol 2003;32:1-22.
6. Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ 2002;325:1202.
7. Casas JP, Bautista LE, Smeeth L, Sharma P, Hingorani AD. Homocysteine and stroke: evidence on a causal link from Mendelian randomization. Lancet 2005;365:224-32.
8. Ueland PM, Refsum H, Brattstrom L. Plasma homocysteine and vascular disease. In: Francis RB Jr, ed. Atherosclerotic Cardiovascular Disease, Hemostasis and Endothelial Function. New York, NY: Marcel Dekker Inc;. 1992:183-236.
9. Graham IM, Daly LE, Refsum HM, Robinson K, Brattström LE, Ueland PM, et al. Plasma homocysteine as a risk factor for vascular disease. The European Concerted Action Project. JAMA 1997;277:1775-81.
10. Brattstrom L, Wilcken DE, Ohrvik J, Brudin L. Common methylenetetrahydrofolate reductase gene mutation leads to hyperhomocysteinemia but not to vascular disease: the result of a meta-analysis. Circulation 1998;98:2520-6.
11. Charpiot P, Bescond A, Augier T, Chareyre C, Fraterno M, Rolland PH, et al. Hyperhomocysteinemia induces elastolysis in minipig arteries: structural consequences, arterial site specificity and effect of captopril-hydrochlorothiazide. Matrix Biol 1998;17:559-74.
12. Iso H, Moriyama Y, Sato S, Kitamura A, Tanigawa T, Yamagishi K, et al. Serum total homocysteine concentrations and risk of stroke and its subtypes in Japanese. Circulation 2004;109:2766-72.
13. Sun Y, Chien KL, Hsu HC, Su TC, Chen MF, Lee YT. Use of serum homocysteine to predict stroke, coronary heart disease and death in ethnic Chinese. 12-year prospective cohort study. Circ J 2009; 73:1423-30.
14. Verhoef P, Hennekens CH, Malinow MR, Kok FJ, Willett WC, Stampfer MJ. A prospective study of plasma homocyst(e)ine and risk of ischemic stroke. Stroke 1994;25:1924-30.
15. Fallon UB, Elwood P, Ben-Shlomo Y, Ubbink JB, Greenwood R, Smith GD. Homocysteine and ischaemic stroke in men: the Caerphilly study. J Epidemiol Community Health 2001;55:91-6.
16. Boushey CJ, Beresford SA, Omenn GS, Motulsky AG. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes. J Am Med Assoc 1995;274:1049-57.
17. Moller J, Nielsen GM, Tvedegaard KC, Andersen NT, Jorgensen PE. A meta-analysis of cerebrovascular disease and hyperhomocysteinaemia. Scand J Clin Lab Invest 2000;60:491-9.
18. Collaboration HS. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. J Am Med Assoc 2002;288:2015-22.
19. Zhang W, Sun K, Chen J, Liao Y, Qin Q, Ma A, et al. High plasma homocysteine levels contribute to the risk of stroke recurrence and all-cause mortality in a large prospective stroke population. Clin Sci (Lond) 2010;118:187-94.
20. Jones DW, Chambless LE, Folsom AR, Heiss G, Hutchinson RG, Sharrett AR, et al. Risk factors for coronary heart disease in African Americans: the atherosclerosis risk in communities study, 1987-1997. Arch Intern Med 2002;162:2565-71.
21. Kuller LH, Arnold AM, Psaty BM, Robbins JA, O’Leary DH, Tracy RP, et al. 10-year follow-up of subclinical cardiovascular disease and risk of coronary heart disease in the Cardiovascular Health Study. Arch Intern Med 2006;166:71-8.
22. Seshadri S, Beiser A, Kelly-Hayes M, Kase CS, Au R, Kannel WB, et al. The lifetime risk of stroke: estimates from the Framingham Study. Stroke 2006;37:345-50.
23. Stegmayr B, Asplund K, Kuulasmaa K, Rajakangas AM, Thorvaldsen P, Tuomilehto J. Stroke incidence and mortality correlated to stroke risk factors in the WHO MONICA Project. An ecological study of 18 populations. Stroke 1997;28:1367-74.
24. He J, Klag MJ, Wu Z, Whelton PK. Stroke in the People’s Republic of China. II. Meta-analysis of hypertension and risk of stroke. Stroke 1995;26:2228-32.
25. Malinow MR, Bostom AG, Krauss RM. Homocyst(e)ine, diet, and cardiovascular diseases: a statement for healthcare professionals from the Nutrition Committee, American Heart Association. Circulation 1999;99:178-82.
26. Sacco RL, Adams R, Albers G, Alberts MJ, Benavente O, Furie K, et al. Guidelines for prevention of stroke in patients with ischemic stroke or transient ischemic attack: a statement for healthcare professionals from the American Heart Association/American Stroke Association Council on Stroke: co-sponsored by the Council on Cardiovascular Radiology and Intervention: the American Academy of Neurology affirms the value of this guideline. Circulation 2006;113:e409-49.
27. Qin X, Huo Y. H-Type hypertension, stroke and diabetes in China: Opportunities for primary prevention. J Diabetes 2015 Sep 1. doi: 10.1111/1753-0407.12333.
28 He Y, Li Y, Chen Y, Feng L, Nie Z. Homocysteine level and risk of different stroke types: a meta-analysis of prospective observational studies. Nutr Metab Cardiovasc Dis. 2014;24:1158-65.
29. Schnyder G, Roffi M, Pin R, Flammer Y, Lange H, Eberli FR, et al. Decreased rate of coronary restenosis after lowering of plasma homocysteine levels. N Engl J Med 2001;345:1593-600.
30. Perry HM Jr, Davis BR, Price TR, Applegate WB, Fields WS, Guralnik JM, et al. Effect of treating isolated systolic hypertension on the risk of developing various types and subtypes of stroke: the Systolic Hypertension in the Elderly Program (SHEP). JAMA 2000;284:465-71.
31. Ye DS, Li Y, Li DY, Qian WH, Yu H, Xia Y, et al. The epidemiologic study of the relationship between plasma homocysteine and hypertension. J Clin Cardiol. 2005;21:536-8.
32. van Guldener C, Nanayakkara PW, Stehouwer CD. Homocysteine and blood pressure. Curr Hypertens Rep 2003;5:26-31.
33. Papandreou D, Rousso I, Makedou A, Arvanitidou M, Mavromichalis I. Association of blood pressure, obesity and serum homocysteine levels in healthy children. Acta Paediatr 2007;96:1819-23.
34. Han L, Wu Q, Wang C, Hao Y, Zhao J, Zhang L, et al. Homocysteine, ischemic stroke, and coronary heart disease in hypertensive patients: a population-based, prospective cohort study. Stroke 2015;46:1777-86.
35. Selhub J, Jacques PF, Wilson PW, Rush D, Rosenberg IH. Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. JAMA 1993;270:2693-8.
36. Hao L, Ma J, Zhu J, Stampfer MJ, Tian Y, Willett WC, et al. High prevalence of hyperhomocysteinemia in Chinese adults is associated with low folate, vitamin B-12, and vitamin B-6 status. J Nutr 2007;137:407-13.
37. Committee of Guidelines for Hypertension Prevention and Control. Guidelines for Hypertension Prevention and Control in China 2005. Beijing: People’s Medical Publishing House, 2015: 1-47.
38. Wang X, Qin X, Demirtas H, Li J, Mao G, Huo Y, et al. Efficacy of folic acid supplementation in stroke prevention: a meta-analysis. Lancet 2007;369:1876-82.
39. Rosamond W, Flegal K, Furie K, Go A, Greenlund K, Haase N, et al. Heart disease and stroke statistics--2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2008;117:e25-146.