Homocysteine and Heart Disease

Homocysteine is an amino acid that, when elevated in humans has been demonstrated to be associated with coronary artery disease and stroke. The association between elevated homocysteine levels and CAD was first noted by Dr.Kilmer McCully1 in the 1960's, when he encountered two children with homocystinuria, who, despite being very young, had advance atherosclerosis.

Since then several studies have demonstrated an increase in mortality from myocardial infarction2 and stroke3 in patients with elevated homocysteine levels. Levels above 14 mml/L are considered to be elevated and the risk appears to increase with higher homocysteine levels.

Interestingly , homocysteine levels are only weakly related to the extent of coronary artery disease, but they are linked to a higher mortality rate from myocardial infarction and stroke. The current thinking on the pathogenesis of myocardial infarction is that the acute event is frequently due to rupture or erosion of an atherosclerotic plaque with associated thrombus formation4. There is increasing evidence that homocysteine may affect the coagulation system and the resistance of the endothelium to thrombosis5 and that it may interfere with the vasodilator and antithrombotic functions of nitric oxide.

Nygard et.al6 published a study) that looked at mortality from acute MI, in patients who already had proven CAD. Their findings were quite dramatic. After a median follow-up of 4.6 years, they found a strong, graded dose-response relation between the total homocysteine level and overall mortality. At four years, Kaplan-Meier estimates of mortality were 3.8 percent for patients with total homocysteine levels below 9 µmol per liter, 8.6 percent for those with levels of 9 to 14.9 µmol per liter, and 24.7 percent for those with levels of 15 µmol per liter or higher.

If elevated homocysteine levels are associated with increased mortality from MI and stroke, how do we modify the levels? Well, homocysteine in blood is a product of how much methionine is eaten, mainly in protein (with about three times more methionine in animal than plant protein), and how much is metabolized. Metabolism of homocysteine is by pathways which re-methylate it (requiring vitamin B12 and folic acid)7, or by a trans-sulphuration pathway which requires vitamin B6.

It follows from this that diets high in the B vitamins (B6 and B12) and folic acid will help to reduce the level of homocysteine8 and accordingly reduce the increased risk of death from acute MI. So decreasing the amount of animal protein in the diet and eating lots of fruits and vegetables is probably a good idea. This advice is not dissimilar to that which we have been giving our patients for years. Therefore it seems that management of homocysteine levels is just another good reason to follow a healthy diet.

- John Hickey

References:
  1. Kilmer McCully: pioneer of the homocysteine theory. Lancet Volume 352, Number 9137 24 October 1998
     
  2. NJ Wald, HC Watt, MR Law et al. Homocysteine and ischaemic heart disease. Archives of Internal Medicine 1998 158: 862-7.
     
  3. Perry IJ, Refsum H, Morris RW, Ebrahim SB, Ueland PM, Shaper AG. Prospective study of serum homocysteine concentration and risk of stroke in middle-aged British men. Lancet 1995;346:1395-8.
     
  4. Fuster V. Mechanisms leading to myocardial infarction: insights from studies of vascular biology. Circulation 1994;90:2126-46. [Erratum, Circulation 1995;91:256.]
     
  5. Malinow MR. Homocyst(e)ine and arterial occlusive diseases. J Intern Med 1994;236:603-17.
     
  6. Ottar Nygard, Jan Erik Nordrehaug, Helga Refsum, Per Magne Ueland, Mikael Farstad, Stein Emil Vollset. Plasma Homocysteine Levels and Mortality in Patients with Coronary Artery Disease. New England Journal of Medicine, July 24, 1997, Vol. 337, No. 4
     
  7. J Selhub, PF Jacques, et al. Vitamin status and intake as primary determinants of homocysteinaemia in an elderly population. JAMA 1993 270: 2693-8.
     
  8. EB Rimm, WC Willett, FB Hu et al. Folate and vitamin B6 from diet and supplements in relation to risk of coronary heart disease among women. JAMA 1998 279: 359-64.

Thanks to Michael O'Brien for reviewing the draft copy of this article.

You can search for abstracts of the above references by following this link: PubMed

This page last updated May 28, 1999

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