Current opinions about the role of mild hyperhomocysteinaemia as a risk factor of cardiovascular diseases

Česká verzia

Authors: J. Šimon
Authors place of work: Centrum preventivní kardiologie II. interní kliniky LF UK v Plzni
Published in the journal: Kardiol Rev Int Med 2009, 11(3): 129-133
Category: Nontraditional risk factors cardiovascular disease

Summary

Based on the available evidence, hyperhomocysteinaemia is an unquestionable and important risk factor in nearly all atherosclerotic and thrombotic vascular diseases. It is one of the newly classifi ed and researched factors that have been included in the latest Guidelines on cardiovascular diseases prevention in clinical practice. Pathophysiological mechanisms, by which hyperhomocysteinaemia impacts on the process of atherogenesis and thrombogenesis, have largely been explained in experimental and clinical studies. Hyperhomocysteinaemia is highly prevalent in the Czech population, similar to other populations with relatively low dietary folate intake. Replacement of folate alone or in combination with vitamin B₁₂ and pyridoxine represents an inexpensive treatment option for mild hyperhomocysteinaemia and enables near normalization of homocystein levels. Hyperhomocysteinaemia used to be perceived as a causal risk factor and, based on observational studies, substitution with folate and other vitamins involved in methionine cycle had been recommended for many years as primary and secondary prevention of cardiovascular diseases. It was thus rather surprising that a randomised double blind placebo controlled study (NORVIT) confi rmed that substitution with folate and other B-group vitamins, used in secondary prevention, signifi cantly decreased homocysteine levels but had no effect on atherosclerotic vascular disease morbidity and mortality. These results challenged the hypothesis on causality of this risk factor. Consequently, hyperhomocysteinaemia is currently perceived more as a marker than the cause of the disease. Since further pharmacological studies of the effects of vitamin B intervention on mortality and morbidity are currently taking place, we need to wait for defi nitive evidence for causality of this risk factor before vitamin substitution is included in the Guidelines on cardiovascular disease prevention. Routine homocysteine levels’ testing is not currently recommended; it is indicated for the atherothrombotic processes for which clinical explanation of ethiopathogenesis is lacking following standard clinical and biochemical tests.

Keywors:
homocysteine – methionine cycle – vitamin B group – cardiovascular risk

Zdroje

1. du Vigneaud VE. A trail of research in sulfur chemistry and metabolism, and related fields. Ithaca: Cornell University Press 1952.

2. Robinson K, Mayer E, Jacobsen DW. Homocysteine and coronary artery disease. Cleve Clin J Med 1994; 61: 438–450.

3. Carson NA, Neill DW. Metabolic abnormalities detected in a survey of mentally backward individuals in Northern Ireland. Arch Dis Child 1962; 32: 505–513.

4. Meisel C, Cascorbi I, Gerloff T et al. Identification of six methylenetetrahydrofolate reductase (MTHFR) genotypes resulting from common polymorphisms: impact on plasma homocysteine levels and development of coronary artery disease. Atherosclerosis 2001; 154: 651–655.

5. Nygård O, Vollset SE, Refsum HM. Total plasma homocysteine and cardiovascular risk profile. The Hordaland Homocysteine Study. JAMA 1995; 274: 1526–1533.

6. Frosst P, Blom HJ, Milos R et al. A candidate genetic risk factor for vascular disease: a common mutation in methylentetrahydrofolate reductase. Nat Genet 1995; 10: 111–113.

7. Mayer O jr, Šimon J, Rosolová H et al. The effect of homocysteine on the coronary risk. Cor Vasa 1999; 41: 16–19.

8. Jacques PF, Rosenberg IH, Rogers G et al. Serum total homocysteine concentrations in adolescent and adult Americans: results from the third National Health and Nutrition Examination Survey (NHANES III). Am J Clin Nut 1993; 3: 482–489.

9. Graham IM, Daly EL, Refsum HM et al. Plasma homocysteine as a risk factor for vascular disease. JAMA 1997; 277: 1775–1781.

10. Mallinow MR, Ducimetiere P, Luc G et al. Plasma homocysteine levels and graded risk for myocardial infarction: finding in two populations at contrasting risk for coronary heart disease. Atherosclerosis 1996; 126: 27–34.

11. Krajčovičová-Kudláčková M, Blažíček P, Kopcova J et al. Homocysteine levels in vegetarians versus omnivores. Ann Nutr Metab 2000; 44: 135–138.

12. Chaveau P, Chadefaux B, Coude M et al. Hyperhomocysteinemia, a risk factor for atherosclerosis in chronic uremic patients. Kidney Int 1993; 43 (Suppl 41): 72–77.

13. Dierkes J, Westphal S, Luley C. Serum homocysteine increases after therapy with fenofibrate or bezafibrate. Lancet 1999; 354: 219–220.

14. Jonkers IJ, de Man FH, Onkenhout W et al. Implication of fibrate therapy for homocysteine. Lancet 1999; 354: 1208.

15. Westphal S, Dierkes J, Luley C. Effect of fenofibrate and gemfibrozil on plasma homocysteine. Lancet 2001; 358: 39–40.

16. Mayer O jr, Šimon J, Holubec L et al. The fenofibrate‑induced hyperhomocysteinemia may be prevented by folate co-administration. Eur J Clin Pharm 2003; 59: 367–371.

17. Meade T, Zuhrie R, Cook C et al. Bezafibrate in men with lower remity arterial disease: randomised controlled trial. BMJ 2002; 325: 1139–1141.

18. Ericsson CG, Nilsson J, Grip L et al. Effect of bezafibrate treatment over five years on coronary plaques causing 20% to 50% diameter narrowing. The Bezafibrate Coronary Atherosclerosis Intervention Trial (BECAIT). Am J Cardiol 1997; 80: 1125–1129.

19. Kanani MP, Sinkey CA, Browning RL et al. Role of oxidant stress in endothelial dysfunction produced by experimental hyperhomocysteinemia in humans. Circulation 1999; 100: 1161–1168.

20. Zeng X, Dai J, Remick DG et al. Homocysteine mediated expression and secretion of monocyte chemoattractant protein‑1 and interleukin‑8 in human monocytes. Circ Res 2003; 93: 311–320.

21. Wang G, Siow YL, O K. Homocysteine induces monocyte chemoattractant protein‑1 expression by activating NF-kappaB in THP-1 macrophages. Am J Physiol Heart Circ Physiol 2001; 280: H2840–H2847.

22. Silverman MD, Tumuluri RJ, Davis M et al. Homocysteine upregulates vascular cell adhesion molecule‑1 expression in cultured human aortic endothelial cells and enhances monocyte adhesion. Arterioscler Thromb Vasc Biol 2002; 22: 587–592.

23. Stangl V, Gunther C, Jarrin A et al. Homocysteine inhibits TNF‑alpha‑induced endothelial adhesion molecule expression and monocyte adhesion via nuclear factor-kappaB dependent pathway. Biochem Biophys Res Commun 2001; 280: 1093–100.

24. Homocysteine Lowering Trialists‘ Collaboration. Lowering blood homocysteine with folic acid based supplements: meta‑analysis of randomised trials. BMJ 1998; 316: 894–898.

25. Boushey CJ, Beresford SA, Omenn GS et al. A quantitative assesment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes. JAMA 1995; 274: 1049–1057.

26. Bostom AG, Silbershatz H, Rosenberg IH et al. Nonfasting plasma total homocysteine levels and all‑cause and cardivascular disease mortality in elderly Framingham men and women. Arch Intern Med 1999; 159: 1077–1080.

27. Clarke B. Homocysteine‑lowering trials for prevention of heart disease and stroke. Semin Vasc Med 2005; 5: 215–222.

28. Casais P, Alberto MF, Salviú MJ et al. Pilot study of homocysteine and cysteine in patients with thrombosis in different vascular sites. Epidemiology and response to folate. Thromb Res 2009; 123: 592–596.

29. Bønaa KH, Njølstad I, Ueland PH et al. Homocysteine lowering and cardiovascular events after acute myocardial infarction (NORVIT Trial). N Engl J Med 2006; 354: 1578–1588.

30. Galan P, Biancon SB, Blacher J et al. The SU.FOL.OOM3 Study: a secondary prevention trial testing the impact of supplementation with folate and B‑vitamins and/or Omega‑3 PUFA on fatal and non fatal cardiovascular events, design of a randomised trial of vitamin B, methods and participants characteristics. Trials 2008; 9: 9–35.

31. VITATOPS Trial Study Group. Hankey GJ, Algra A,Chen C, Wong MC 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 (NCT00097 669) (ISRCTN74743444). Int J Stroke 2007; 2: 144–150.

32. Khandanpour N, Willis G, Meyer FJ et al. Peripheral arterial disease and methylene tatrahydrofolate reductase (MTHFR) C677T mutations: A case‑control study and meta‑analysis. J Vasc Surg 2009; 49: 711–718.

33. Selhub J. Public health signifcance of elevated homocysteine. Food Nutr Bull 2008; 29 (Suppl 2): S116–S125.

34. Pfeiffer CM, Caudilli SP, Gunter EW et al. Biochemical indicators of B-vitamin status in the US population after folic acid fortification: results from the National Health and Nutrition Examination Survey 1999–2000. Am J Clin Nutr 2005; 82: 442–450.