Homocysteine and the Risk of Heart Disease, Stroke, and Death
abstracts & commentary
Synopsis: These studies indicate that hyperhomocysteinemia is an independent risk factor for atherothrombotic disease, although its causal relation to atherosclerosis has not been totally proven.
Sources: Kark JD, et al. Ann Intern Med 1999;131:321-330; Selhub J, et al. Ann Intern Med 1999;131:331-339; Eikelboom JW, et al. Ann Intern Med 1999;131:363-375; Bostom AG, et al. Ann Intern Med 1999;131:352-355; Graham I. Ann Intern Med 1999;131:387-388.
In 1969, mccully noted the association between homocystinuria and premature thromboembolic disease1 and suggested that an elevated plasma homocysteine level might be a cardiovascular risk factor in the general population.2 Plasma homocysteine levels are determined both by genetic and nutritional factors. Defects in the enzymes that control homocysteine metabolism or deficiencies in vitamin cofactors (folic acid, B6, B12) can result in elevated plasma homocysteine.
Kark and associates studied a community cohort of 1788 middle-aged and elderly residents of Jerusalem and recorded 405 deaths over a decade. The mortality hazard ratio was 2.0 (95% CI, 1.3-3.0) when the highest and lowest fifths of the homocysteine distributions were compared. The difference was greater in men than in women. Ten percent of deaths were attributable to homocysteine levels greater than 14 mmol/L. The study found that elevated homocysteine levels were associated with cardiovascular and total mortality.
Selhub and colleagues used a nationally representative sample of 3563 men and 4523 women aged 12 years or older to define reference ranges for total homocysteine levels among persons who were folate and vitamin B12 replete and had normal creatinine concentrations. Reference ranges for serum homocysteine concentration increased with age. A high homocysteine concentration was defined as at least 11.4 mmol/L for men and at least 10.4 mmol/L for women. In study participants, two-thirds of cases of high homocysteine levels were associated with low serum concentrations of folate, vitamin B12, or both. However, a low vitamin concentration alone contributed little to the prevalence of high total homocysteine levels in the entire population.
Eikelboom and colleagues reviewed the epidemiologic evidence relating homocysteine to cardiovascular disease. They concluded that although the association between homocysteine and cardiovascular disease is strong, the data from prospective studies do not prove a causal relation. Therefore, the effectiveness of folate and vitamins B6 and B12 in reducing cardiovascular morbidity and mortality requires testing in randomized trials.
Bostom and colleagues examined the association between baseline nonfasting plasma homocysteine levels and incident stroke in 1947 Framingham Study participants of whom 1158 (60%) were women and 789 (40%) were men. The mean age ± SD of the cohort was 70 ± 7 years. Age, systolic blood pressure, current smoking, diabetes, and atrial fibrillation or coronary heart disease were independently predictive of total stroke occurrence. Elevated homocysteine levels also were independently associated with stroke incidence. When quartile 4 (homocysteine level 14.24-219.84 mmol/L) was compared to quartile 1 (homocysteine level 4.13-9.25 mmol/L), the relative risk was 1.82 (see Table).
Comment by John J. Caronna, MD
These studies indicate that hyperhomocysteinemia is an independent risk factor for atherothrombotic disease, although its causal relation to atherosclerosis has not been totally proved. Therefore, the practicing physician should measure plasma homocysteine concentration as well as folate and vitamin B12 levels as part of risk assessment. It appears that most people with low serum folate or vitamin B12 levels also have high homocysteine levels.
| Table-Predictors of Stroke Incidence in the Framingham Study Cohort | |
| Variable | Relative Risk-(95% CI) |
| Age, per one year increase | 1.06 (1.04-1.09) |
| Systolic BP, per 20 mmHg increase | 1.16 (1.01-1.34) |
| Smoking 1.52 | (1.03-2.24) |
| Diabetes mellitus | 1.90 (1.25-2.89) |
| Atrial fibrillation | 2.29 (1.29-404) |
| Coronary heart disease | 1.49 (1.04-2.16) |
| Homocysteine level (quartile 4 c/w quartile 1) | 1.82 (1.14-2.91) |
| Source: Modified from Bostom AG, et al. Ann Intern Med 1999;131:352. | |
In an editorial commenting on several of the articles reviewed above, Graham emphasizes that recommendations about prescribing folic acid or vitamin B12 to patients with elevated homocysteine levels must wait for the results of randomized controlled trials.3 Nevertheless, as he suggests, it is reasonable to prescribe multivitamins and folic acid supplements of 0.4-1.0 mg daily to patients at high risk for cardiovascular and cerebrovascular disease because of the interaction of high homocysteine levels and conventional risk factors. (Dr. Caronna is Vice-Chairman, Department of Neurology, Cornell University Medical Center; Professor of Clinical Neurology, New York Hospital.)
References
1. McCully KS, Wilson RB. Atherosclerosis 1975;22: 215-227.
2. McCully KS. Am J Pathol 1969;56:111-128.
3. Clarke R, Collins RJ. Cardiovasc Risk 1998;5:249-255.
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