Does Lowering Homocysteine
Prevent Cardiovascular Disease?

Stephen Barrett, M.D.

In 1969, a connection between homocysteine (a sulfur-containing amino acid) and cardiovascular disease was proposed when it was observed that people with a rare hereditary condition called homocystinuria are prone to develop severe cardiovascular disease in their teens and twenties. In this condition, an enzyme deficiency causes homocysteine to accumulate in the blood and to be excreted in the urine. Abnormal homocysteine elevation also occurs among people whose diet contains inadequate amounts of folic acid, vitamin B6, or vitamin B12. Regardless of the cause of the elevation, supplementation with one or more of these vitamins can lower plasma homocysteine levels.

Studies done in the 1980s and 1990s linked elevated blood levels of homocysteine to increased risk of premature coronary artery disease, stroke, and venous blood clots, even among people with normal cholesterol levels [1-8]. These studies led to speculations that high homocysteine levels could contribute to atherosclerosis in at least three ways: (a) a direct toxic effect that damages the cells lining the inside of the arteries, (b) interference with clotting factors, and (c) oxidation of low-density lipoproteins (LDL). Lowering the serum concentration of homocysteine has been proven to reduce the risk of adverse cardiovascular events among people with homocystinuria. Without clinical trials, however, it was impossible to know whether abnormal homocysteine levels among the general population cause atherosclerosis or are merely a "marker"—a non-causative finding that often occurs in people with atherosclerosis.

Unfortunately, large controlled studies have found that treatment with B-vitamins does not reduce the incidence of cardiovascular events despite significant lowering of homocysteine levels [10-14]. In fact, a 7-year study of women with kidney disease secondary to diabetes found that those who took the B-vitamin supplemnent more heart attacks and strokes than those who did not [15].

Enough study has been done to conclude with reasonable certainty that taking B-vitamins to lower homocysteine levels will not lower the incidence or heart attacks or strokes except for people with homocystinurea. Nor is it advisable to do routine screening for homocysteine levels [16].

References

  1. Verhoef P and others. Plasma total homocysteine, B vitamins, and risk of coronary atherosclerosis. Arteriosclerosis, Thrombosis, and Vascular Biology 17:989-995, 1997.
  2. Ridker PM and others. Homocysteine and risk of cardiovascular disease among postmenopausal women. JAMA 281:1817-1821, 1999.
  3. Loralie J and others. Hyperhomocyst(e)inemia and the increased Rrisk of venous thromboembolism. Archives of Internal Medicine 160:961-964, 2000.
  4. Tanne D and others. Prospective study of serum homocysteine and risk of ischemic stroke among patients with preexisting coronary heart disease. Stroke 34:632-636, 2003.
  5. Kang SS and others. Hyperhomocyst(e)inemia as a risk factor for occlusive vascular disease. Annual Review of Nutrition 12:279-298, 1992.Rimm EB and others. Folate and Vitamin B6 from diet and supplements in relation to risk of coronary heart disease among women. JAMA 279:359-364, 1998.
  6. Malinow MR and others. Homocyst(e)ine, diet, and cardiovascular diseases: A statement for healthcare professionals from the nutrition committee, American Heart Association. Circulation 99:178-182, 1999.
  7. Eikelboom JW and others. Homocyst(e)ine and cardiovascular disease: A critical review of the epidemiologic evidence. Annals of Internal Medicine 131:363-375, 1999.
  8. Hackam DG and others. What level of plasma homocyst(e)ine should be treated? Effects of vitamin therapy on progression of carotid atherosclerosis in patients with homocyst(e)ine levels above and below 14 micromol/L. American Journal of Hypertension 13:105-100, 2000.
  9. Schnyder G and others. Homocysteine-lowering therapy with folic acid, vitamin B12, and vitamin B6 on clinical outcome after percutaneous coronary intervention. The Swiss Heart Study: A randomized controlled trial. JAMA 288:973-979, 2002.
  10. Toole JF and others. 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 291:565-575, 2004.
  11. Bønaa KH and others. Homocysteine lowering and cardiovascular events after acute myocardial infarction. New England Journal of Medicine 354:1578-1588, 2006.
  12. Albert CM and others. 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 299:2027-2036, 2008
  13. Ebbing M and others. Mortality and cardiovascular events in patients treated with homocysteine-lowering B vitamins after coronary angiography: a randomized controlled trial. JAMA 300:795-804, 2008.
  14. SEARCH Collaborative Group. Effects of homocysteine-lowering with folic acid plus vitamin B12 vs placebo on mortality and major morbidity in myocardialinfarction survivors: A randomized trial. JAMA 303:2486-2494, 2010.
  15. House AA and others. Effect of B-vitamin on progression of diabetic nephropathy: A controlled trial. JAMA 303:603-1309, 2010.
  16. Lonn E. Homocysteine-lowering B vitamin therapy in cardiovascular prevention—Wrong again? JAMA 299:2086-2087, 2008.

This article was revised on June 26, 2010.

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