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Homocysteine and heart failure: a review of investigations from the Framingham Heart Study

  • Johan Sundström and Ramachandran S. Vasan
Published/Copyright: September 30, 2005

Abstract

High plasma homocysteine levels are associated with a moderately increased risk of cardiovascular disease, particularly of atherosclerotic events. We review the association of plasma homocysteine with heart failure, with a specific focus on a series of previously published investigations from the community-based Framingham Heart Study that evaluated the relations of plasma homocysteine levels with overt heart failure, and with its key antecedents, echocardiographic left ventricular (LV) mass and hypertension. In the Framingham sample, higher plasma homocysteine levels were associated with increased risk of new-onset heart failure in both men and women, with a more continuous and graded relation being observed in women. A positive relation between homocysteine and LV mass was observed in women, but not in men; this may underlie the stronger relations of homocysteine to heart failure risk in women. Plasma homocysteine was not associated with hypertension incidence prospectively in either sex. The relations of increased homocysteine to heart failure (in both sexes) and to greater LV mass (in women) noted in the Framingham sample should be confirmed in other community-based samples. Secondary analyses of heart failure outcomes in ongoing randomized clinical trials may provide insights into whether lowering of plasma homocysteine levels is associated with a reduction in LV mass and/or a reduction of heart failure risk.


Corresponding author: Ramachandran S. Vasan, MD, The Framingham Study, 73 Mt. Wayte Ave, Framingham, MA 01702-5803, USA Phone: +1-508-935-3450, Fax: +1-508-626-1262,

References

1. American Heart Association. 2002 Heart and Stroke Statistical Update. Dallas, TX: American Heart Association, 2001.Search in Google Scholar

2. McMurray JJ, Petrie MC, Murdoch DR, Davie AP. Clinical epidemiology of heart failure: public and private health burden. Eur Heart J 1998; 19(Suppl P):9–16.Search in Google Scholar

3. Levy D, Larson MG, Vasan RS, Kannel WB, Ho KK. The progression from hypertension to congestive heart failure. J Am Med Assoc 1996; 275:1557–62.10.1001/jama.1996.03530440037034Search in Google Scholar

4. Aurigemma GP, Gottdiener JS, Shemanski L, Gardin J, Kitzman D. Predictive value of systolic and diastolic function for incident congestive heart failure in the elderly: the cardiovascular health study. J Am Coll Cardiol 2001; 37:1042–8.10.1016/S0735-1097(01)01110-XSearch in Google Scholar

5. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. J Am Med Assoc 2002;288:2015–22.10.1001/jama.288.16.2015Search in Google Scholar

6. Bostom AG, Selhub J. Homocysteine and arteriosclerosis: subclinical and clinical disease associations. Circulation 1999; 99:2361–3.10.1161/01.CIR.99.18.2361Search in Google Scholar

7. Eikelboom JW, Lonn E, Genest J, Jr, Hankey G, Yusuf S. Homocyst(e)ine and cardiovascular disease: a critical review of the epidemiologic evidence. Ann Intern Med 1999; 131:363–75.10.7326/0003-4819-131-5-199909070-00008Search in Google Scholar

8. Chen P, Poddar R, Tipa EV, Dibello PM, Moravec CD, Robinson K, et al. Homocysteine metabolism in cardiovascular cells and tissues: implications for hyperhomocysteinemia and cardiovascular disease. Adv Enzyme Regul 1999; 39:93–109.10.1016/S0065-2571(98)00029-6Search in Google Scholar

9. Joseph J, Washington A, Joseph L, Koehler L, Fink LM, Hauer-Jensen M, et al. Hyperhomocysteinemia leads to adverse cardiac remodeling in hypertensive rats. Am J Physiol Heart Circ Physiol 2002; 283:H2567–74.10.1152/ajpheart.00475.2002Search in Google Scholar

10. Miller A, Mujumdar V, Palmer L, Bower JD, Tyagi SC. Reversal of endocardial endothelial dysfunction by folic acid in homocysteinemic hypertensive rats. Am J Hypertens 2002; 15:157–63.10.1016/S0895-7061(01)02286-5Search in Google Scholar

11. Joseph J, Joseph L, Shekhawat NS, Devi S, Wang J, Melchert RB, et al. Hyperhomocysteinemia leads to pathological ventricular hypertrophy in normotensive rats. Am J Physiol Heart Circ Physiol 2003; 285:H679–86.10.1152/ajpheart.00145.2003Search in Google Scholar PubMed

12. Tsai JC, Perrella MA, Yoshizumi M, Hsieh CM, Haber E, Schlegel R, et al. Promotion of vascular smooth muscle cell growth by homocysteine: a link to atherosclerosis. Proc Natl Acad Sci USA 1994; 91:6369–73.10.1073/pnas.91.14.6369Search in Google Scholar PubMed PubMed Central

13. Vermeulen EG, Niessen HW, Bogels M, Stehouwer CD, Rauwerda JA, van Hinsbergh VW. Decreased smooth muscle cell/extracellular matrix ratio of media of femoral artery in patients with atherosclerosis and hyperhomocysteinemia. Arterioscler Thromb Vasc Biol 2001; 21:573–7.10.1161/01.ATV.21.4.573Search in Google Scholar

14. Tyagi SC. Homocysteine redox receptor and regulation of extracellular matrix components in vascular cells. Am J Physiol 1998; 274:C396–405.10.1152/ajpcell.1998.274.2.C396Search in Google Scholar

15. Lentz SR, Sobey CG, Piegors DJ, Bhopatkar MY, Faraci FM, Malinow MR, et al. Vascular dysfunction in monkeys with diet-induced hyperhomocyst(e)inemia. J Clin Invest 1996; 98:24–9.10.1172/JCI118771Search in Google Scholar

16. Chambers JC, McGregor A, Jean-Marie J, Kooner JS. Acute hyperhomocysteinaemia and endothelial dysfunction. Lancet 1998; 351:36–7.10.1016/S0140-6736(05)78090-9Search in Google Scholar

17. Mujumdar VS, Aru GM, Tyagi SC. Induction of oxidative stress by homocyst(e)ine impairs endothelial function. J Cell Biochem 2001; 82:491–500.10.1002/jcb.1175Search in Google Scholar

18. Vasan RS, Beiser A, D'Agostino RB, Levy D, Selhub J, Jacques PF, et al. Plasma homocysteine and risk for congestive heart failure in adults without prior myocardial infarction. J Am Med Assoc 2003; 289:1251.10.1001/jama.289.10.1251Search in Google Scholar

19. Sundstrom J, Sullivan L, Selhub J, Benjamin EJ, D'Agostino RB, Jacques PF, et al. Relations of plasma homocysteine to left ventricular structure and function: the Framingham Heart Study. Eur Heart J 2004; 25:523–30.10.1016/j.ehj.2004.01.008Search in Google Scholar

20. Sundstrom J, Sullivan L, D'Agostino RB, Jacques PF, Selhub J, Rosenberg IH, et al. Plasma homocysteine, hypertension incidence, and blood pressure tracking: the Framingham Heart Study. Hypertension 2003; 42:1100–5.10.1161/01.HYP.0000101690.58391.13Search in Google Scholar

21. Cooke GE, Eaton GM, Whitby G, Kennedy RA, Binkley PF, Moeschberger ML, et al. Plasma atherogenic markers in congestive heart failure and posttransplant (heart) patients. J Am Coll Cardiol 2000; 36:509–16.10.1016/S0735-1097(00)00756-7Search in Google Scholar

22. Ventura P, Panini R, Verlato C, Scarpetta G, Salvioli G. Hyperhomocysteinemia and related factors in 600 hospitalized elderly subjects. Metabolism 2001; 50:1466–71.10.1053/meta.2001.28079Search in Google Scholar PubMed

23. Herrmann M, Kindermann I, Muller S, Georg T, Kindermann M, Bohm M, et al. Relationship of plasma homocysteine with the severity of chronic heart failure. Clin Chem 2005; 51:1512–5.10.1373/clinchem.2005.049841Search in Google Scholar

24. Araki A, Sako Y. Determination of free and total homocysteine in human plasma by high-performance liquid chromatography with fluorescence detection. J Chromatogr 1987; 422:43–52.10.1016/0378-4347(87)80438-3Search in Google Scholar

25. Jacques PF, Selhub J, Bostom AG, Wilson PW, Rosenberg IH. The effect of folic acid fortification on plasma folate and total homocysteine concentrations. N Engl J Med 1999; 340:1449–54.10.1056/NEJM199905133401901Search in Google Scholar PubMed

26. Carroll JF, Tyagi SC. Extracellular matrix remodeling in the heart of the homocysteinemic obese rabbit. Am J Hypertens 2005; 18:692–8.10.1016/j.amjhyper.2004.11.035Search in Google Scholar PubMed

27. Joseph J, Kennedy RH, Devi S, Wang J, Joseph L, Hauer-Jensen M. Protective role of mast cells in homocysteine-induced cardiac remodeling. Am J Physiol Heart Circ Physiol 2005; 288:H2541–5.10.1152/ajpheart.00806.2004Search in Google Scholar PubMed

28. Tyagi N, Moshal KS, Lominadze D, Ovechkin AV, Tyagi SC. Homocysteine-dependent cardiac remodeling and endothelial-myocyte coupling in a 2 kidney, 1 clip Goldblatt hypertension mouse model. Can J Physiol Pharmacol 2005; 83:583–94.10.1139/y05-047Search in Google Scholar PubMed

29. Walker E, Black J, Parris C, Bryda EC, Cansino S, Hunt L, et al. Effect of experimental hyperhomocysteinemia on cardiac structure and function in the rat. Ann Clin Lab Sci 2004; 34:175–80.Search in Google Scholar

30. Joseph J, Washington A, Joseph L, Kennedy RH. Hyper-homocysteinaemia-induced atrial remodelling in hypertensive rats. Clin Exp Pharmacol Physiol 2004; 31:331–7.10.1111/j.1440-1681.2004.03998.xSearch in Google Scholar PubMed

31. Bokhari SW, Bokhari ZW, Zell JA, Lee DW, Faxon DP. Plasma homocysteine levels and the left ventricular systolic function in coronary artery disease patients. Coron Artery Dis 2005; 16:153–61.10.1097/00019501-200505000-00004Search in Google Scholar PubMed

32. Cesari M, Zanchetta M, Burlina A, Pedon L, Maiolino G, Sticchi D, et al. Hyperhomocysteinemia is inversely related with left ventricular ejection fraction and predicts cardiovascular mortality in high-risk coronary artery disease hypertensives. Arterioscler Thromb Vasc Biol 2005; 25:115–21.10.1161/01.ATV.0000149674.62430.e7Search in Google Scholar PubMed

33. Herzlich BC, Lichstein E, Schulhoff N, Weinstock M, Pagala M, Ravindran K, et al. Relationship among homocyst(e)ine, vitamin B-12 and cardiac disease in the elderly: association between vitamin B-12 deficiency and decreased left ventricular ejection fraction. J Nutr 1996; 126:1249S–53S.10.1093/jn/126.suppl_4.1249SSearch in Google Scholar PubMed

34. 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; 337:230–6.10.1056/NEJM199707243370403Search in Google Scholar

35. Retterstol L, Paus B, Bohn M, Bakken A, Erikssen J, Malinow MR, et al. Plasma total homocysteine levels and prognosis in patients with previous premature myocardial infarction: a 10-year follow-up study. J Intern Med 2003; 253:284–92.10.1046/j.1365-2796.2003.01096.xSearch in Google Scholar

36. Blacher J, Demuth K, Guerin AP, Vadez C, Moatti N, Safar ME, et al. Association between plasma homocysteine concentrations and cardiac hypertrophy in end-stage renal disease. J Nephrol 1999; 12:248–55.Search in Google Scholar

37. Wocial B, Berent H, Kostrubiec M, Kuczynska K, Kuch-Wocial A, Nieweglowska N. Homocysteine, adrenergic activity and left ventricular mass in patients with essential hypertension. Blood Press 2002; 11:201–5.10.1080/08037050213758Search in Google Scholar

38. Verhoef P. Hyperhomocysteinemia and risk of vascular disease in women. Semin Thromb Hemost 2000; 26:325–34.10.1055/s-2000-8474Search in Google Scholar

39. Nygard O, Vollset SE, Refsum H, Stensvold I, Tverdal A, Nordrehaug JE, et al. Total plasma homocysteine and cardiovascular risk profile. The Hordaland Homocysteine Study. J Am Med Assoc 1995; 274:1526–33.10.1001/jama.1995.03530190040032Search in Google Scholar

40. Jacques PF, Bostom AG, Wilson PW, Rich S, Rosenberg IH, Selhub J. Determinants of plasma total homocysteine concentration in the Framingham Offspring cohort. Am J Clin Nutr 2001; 73:613–21.10.1093/ajcn/73.3.613Search in Google Scholar

41. Kahleova R, Palyzova D, Zvara K, Zvarova J, Hrach K, Novakova I, et al. Essential hypertension in adolescents: association with insulin resistance and with metabolism of homocysteine and vitamins. Am J Hypertens 2002; 15:857–64.10.1016/S0895-7061(02)02984-9Search in Google Scholar

42. Lim U, Cassano PA. Homocysteine and blood pressure in the Third National Health and Nutrition Examination Survey, 1988–1994. Am J Epidemiol 2002; 156:1105–13.10.1093/aje/kwf157Search in Google Scholar PubMed

43. Mangoni AA, Sherwood RA, Swift CG, Jackson SH. Folic acid enhances endothelial function and reduces blood pressure in smokers: a randomized controlled trial. J Intern Med 2002; 252:497–503.10.1046/j.1365-2796.2002.01059.xSearch in Google Scholar PubMed

44. van Dijk RA, Rauwerda JA, Steyn M, Twisk JW, Stehouwer CD. Long-term homocysteine-lowering treatment with folic acid plus pyridoxine is associated with decreased blood pressure but not with improved brachial artery endothelium-dependent vasodilation or carotid artery stiffness: a 2-year, randomized, placebo-controlled trial. Arterioscler Thromb Vasc Biol 2001; 21:2072–9.10.1161/hq1201.100223Search in Google Scholar PubMed

45. The sixth report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Arch Intern Med 1997;157:2413–46.10.1001/archinte.157.21.2413Search in Google Scholar

46. Yen CH, Lau YT. Vascular responses in male and female hypertensive rats with hyperhomocysteinemia. Hypertension 2002; 40:322–8.10.1161/01.HYP.0000028489.29543.58Search in Google Scholar

47. Krumholz HM, Larson M, Levy D. Sex differences in cardiac adaptation to isolated systolic hypertension. Am J Cardiol 1993; 72:310–3.10.1016/0002-9149(93)90678-6Search in Google Scholar

48. Weinberg EO, Thienelt CD, Katz SE, Bartunek J, Tajima M, Rohrbach S, et al. Gender differences in molecular remodeling in pressure overload hypertrophy. J Am Coll Cardiol 1999; 34:264–73.10.1016/S0735-1097(99)00165-5Search in Google Scholar

49. Streck EL, Zugno AI, Tagliari B, Wannmacher C, Wajner M, Wyse AT. Inhibition of Na+, K+-ATPase activity by the metabolites accumulating in homocystinuria. Metab Brain Dis 2002; 17:83–91.10.1023/A:1015594111778Search in Google Scholar

50. Rathore SS, Wang Y, Krumholz HM. Sex-based differences in the effect of digoxin for the treatment of heart failure. N Engl J Med 2002; 347:1403–11.10.1056/NEJMoa021266Search in Google Scholar

51. Hayward CS, Webb CM, Collins P. Effect of sex hormones on cardiac mass. Lancet 2001; 357:1354–6.10.1016/S0140-6736(00)04523-2Search in Google Scholar

52. Dimitrova KR, DeGroot K, Myers AK, Kim YD. Estrogen and homocysteine. Cardiovasc Res 2002; 53:577–88.10.1016/S0008-6363(01)00462-XSearch in Google Scholar

53. Selhub J, Jacques PF, Bostom AG, D'Agostino RB, Wilson PW, Belanger AJ, et al. Association between plasma homocysteine concentrations and extracranial carotid-artery stenosis. N Engl J Med 1995; 332:286–91.10.1056/NEJM199502023320502Search in Google Scholar PubMed

54. Bostom AG, Rosenberg IH, Silbershatz H, Jacques PF, Selhub J, D'Agostino RB, et al. Nonfasting plasma total homocysteine levels and stroke incidence in elderly persons: the Framingham Study. Ann Intern Med 1999; 131:352–5.10.7326/0003-4819-131-5-199909070-00006Search in Google Scholar PubMed

55. Bostom AG, Silbershatz H, Rosenberg IH, Selhub J, D'Agostino RB, Wolf PA, et al. Nonfasting plasma total homocysteine levels and all-cause and cardiovascular disease mortality in elderly Framingham men and women. Arch Intern Med 1999; 159:1077–80.10.1001/archinte.159.10.1077Search in Google Scholar

56. Majors A, Ehrhart LA, Pezacka EH. Homocysteine as a risk factor for vascular disease: enhanced collagen production and accumulation by smooth muscle cells. Arterioscler Thromb Vasc Biol 1997; 17:2074–81.10.1161/01.ATV.17.10.2074Search in Google Scholar

57. Chao CL, Tsai HH, Lee CM, Hsu SM, Kao JT, Chien KL, et al. The graded effect of hyperhomocysteinemia on the severity and extent of coronary atherosclerosis. Atherosclerosis 1999; 147:379–86.10.1016/S0021-9150(99)00208-7Search in Google Scholar

58. Welch GN, Loscalzo J. Homocysteine and atherothrombosis. N Engl J Med 1998; 338:1042–50.10.1056/NEJM199804093381507Search in Google Scholar PubMed

59. Whincup PH, Refsum H, Perry IJ, Morris R, Walker M, Lennon L, et al. Serum total homocysteine and coronary heart disease: prospective study in middle aged men. Heart 1999; 82:448–54.10.1136/hrt.82.4.448Search in Google Scholar PubMed PubMed Central

60. Chilian WM. Coronary microcirculation in health and disease: summary of an NHLBI workshop. Circulation 1997; 95:522–8.10.1161/01.CIR.95.2.522Search in Google Scholar PubMed PubMed Central

61. Symons JD, Mullick AE, Ensunsa JL, Ma AA, Rutledge JC. Hyperhomocysteinemia evoked by folate depletion: effects on coronary and carotid arterial function. Arterioscler Thromb Vasc Biol 2002; 22:772–80.10.1161/01.ATV.0000014588.71807.0ASearch in Google Scholar PubMed

62. Loscalzo J. The oxidant stress of hyperhomocyst(e)inemia. J Clin Invest 1996; 98:5–7.10.1172/JCI118776Search in Google Scholar PubMed PubMed Central

63. Tyagi SC, Rodriguez W, Patel AM, Roberts AM, Falcone JC, Passmore JC, et al. Hyperhomocysteinemic diabetic cardiomyopathy: oxidative stress, remodeling, and endothelial-myocyte uncoupling. J Cardiovasc Pharmacol Ther 2005; 10:1–10.10.1177/107424840501000101Search in Google Scholar PubMed

64. Kennedy RH, Owings R, Shekhawat N, Joseph J. Acute negative inotropic effects of homocysteine are mediated via the endothelium. Am J Physiol Heart Circ Physiol 2004; 287:H812–7.10.1152/ajpheart.01042.2003Search in Google Scholar PubMed

Published Online: 2005-9-30
Published in Print: 2005-10-1

©2005 by Walter de Gruyter Berlin New York

Articles in the same Issue

  1. Homocysteine research – where do we stand and where are we going?
  2. Hyperhomocysteinemia and arteriosclerosis: historical perspectives
  3. Homocysteine and heart failure: a review of investigations from the Framingham Heart Study
  4. Homocysteine and vascular disease in diabetes: a double hit?
  5. Reduced adenosine receptor stimulation as a pathogenic factor in hyperhomocysteinemia
  6. Effects of homocysteine on vascular and tissue adenosine: a stake in homocysteine pathogenicity?
  7. Anti-N-homocysteinylated protein autoantibodies and cardiovascular disease
  8. Carotid narrowing degree and plasma thiol levels in carotid endarterectomy patients
  9. Impairment of homocysteine metabolism in patients with retinal vascular occlusion and non-arteritic ischemic optic neuropathy
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  12. Hyperhomocysteinemia and response of methionine cycle intermediates to vitamin treatment in renal patients
  13. Vitamin B12 deficiency is the dominant nutritional cause of hyperhomocysteinemia in a folic acid-fortified population
  14. Homocysteine, folic acid and vitamin B12 in relation to pre- and postnatal health aspects
  15. Evaluation of the technical performance of novel holotranscobalamin (holoTC) assays in a multicenter European demonstration project
  16. A laboratory algorithm with homocysteine as the primary parameter reduces the cost of investigation of folate and cobalamin deficiency
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  26. Elevated levels of asymmetric dimethylarginine (ADMA) as a marker of cardiovascular disease and mortality
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