Homocysteine, B Vitamins, and Atherosclerosis
To the Editor:
The conclusion by Folsom et al1 that raised homocysteine concentrations in the blood may be a consequence, not a cause, of coronary artery disease has serious clinical implications. As McCully2 pointed out in his recent editorial, arteriosclerosis in hyperhomocysteinemia may result from 3 different enzymatic abnormalities: deficiency of cystathionine synthase, which is a pyridoxal phosphate–dependent enzyme; deficiency of methyltetrahydrofolate homocysteine methyl transferase, which is a cobalamin-dependent enzyme; and deficiency of methylene tetrahydrofolate reductase, which is a folate-dependent enzyme. The last enzymatic abnormality explains the origin of arteriosclerosis observed in vitamin B6–deficient monkeys and choline-deficient rats, 2 important animal models in which hyperhomocysteinemia also leads to atherogenesis.2
Although I agree with Folsom et al1 that randomized trials are needed to better clarify the interrelationships of homocysteine, B vitamins, and atherosclerosis, the findings of a significant inverse relation between dietary intake of folate and vitamin B6 and mortality and morbidity from cardiovascular disease during a 14-year period in the Nurses’ Health Study, recently reported by Rimm et al,3 encourage the view that, with intervention through supplementation, fortification, improved dietary intake of folate and vitamin B6, and food processing and distribution methods, the decline in US cardiovascular mortality and morbidity will continue.2 As my mentor, the late Dr Paul D. White, taught me, atherosclerosis begins in early childhood. Therefore, the simplest dietary precautions, adopted early in life, can substantially lower the risk of coronary artery disease.4 After being ignored for many years since the publication of the original animal work of McCully and Wilson,5 homocysteine has finally reemerged as a risk factor for the development of human atherosclerosis.6 Let us not wait for the results of the randomized trials, some of which are under way, suggested by Folsom et al1 before we take decisive actions in the modern-day management of patients with coronary artery disease.
- Copyright © 1999 by American Heart Association
Folsom AR, Nieto J, McGovern PG, Tsai MY, Malino MR, Eckfeldt JH, Hess DL, Davis CE. Prospective study of coronary heart disease incidence in relation to fasting total homocysteine, related genetic polymorphisms, and B vitamins: the Atherosclerosis Risk In Communities (ARIC) study. Circulation. 1998;98:204–210.
McCully KS. Homocysteine, folate, vitamin B6, and cardiovascular disease. JAMA. 1998;279:392–393.
Rimm EB, Willett WC, Hu FB, Sampson L, Colditz GA, Manson JE, Hennekens C, Stamfer MJ. Folate and vitamin B6 from diet and supplements in relation to risk of coronary heart disease among women. JAMA. 1998;279:359–364.
Cramer DA. Homocysteine vs cholesterol: competing views, or a unifying explanation of arteriosclerotic cardiovascular disease? Lab Med. 1998;29:410–417.
McCully KS, Wilson RB. Homocysteine theory of arteriosclerosis. Atherosclerosis. 1975;22:215–227.
Cheng TO. Homocysteinaemia and coronary atherosclerosis. Heart. 1997;77:390–391.
Despite much evidence implicating homocysteine in atherosclerosis, ours is one of several prospective studies reporting no association between total homocysteine (tHcy) and coronary heart disease (CHD) incidence.R1 We, like Rimm et al,R2 observed an independent inverse association between vitamin B6 (serum pyridoxal 5′-phosphate) and CHD incidence. Although our results for tHcy were null, we agree with Dr Cheng that tHcy could still prove to be important in CHD. We also believe there are few reasons not to fortify cereals and advocate that everyone eat diets that could provide the recommended daily allowances for folate and vitamins B6 and B12. However, we disagree with Dr Cheng’s view that clinicians should “not wait for the results of the randomized trials” if he means widespread screening for elevated tHcy and aggressive prescription of vitamin supplements.
Epidemiological and clinical observations occasionally lead to incorrect conclusions about causality of complex diseases like CHD. Take as examples recent experience with beta-carotene and estrogen and medroxyprogesterone acetate replacement, for which there was considerable epidemiological evidence to suggest both may prevent CHD events, but clinical trials proved to be ineffective.R3 R4 Randomized clinical trials eliminate confounding (eg, other lifestyle characteristics incompletely accounted for in statistical analysis, such as diet or access to and attitudes regarding health care) and provide a truer picture of cause and effect than observational studies.
The basic and observational epidemiological data on tHcy, B6, and folate, though intriguing, do not prove a causal role of tHcy for the majority of patients who develop CHD. We believe that until there are clinical trial data supporting tHcy lowering, screening for elevated tHcy and widespread prescription of folate and vitamins B6 and B12 are not warranted. Clinicians could consider measuring tHcy in selected high-risk patients, ie, those with atherosclerotic diseases or a strong family history, and prescribing vitamin supplementation if tHcy is elevated, because tHcy may be more prognostic in high-risk patients.R5 Such a treatment is not supported by clinical trials, and this arbitrary decision should clearly accompany the simultaneous treatment of other traditional risk factors, like LDL lowering, hypertension control, and smoking cessation.
Folsom AR, Nieto FJ, McGovern PG, Tsai MY, Malinow MR, Eckfeldt JH, Davis CE. Prospective study of coronary heart disease incidence in relation to fasting total homocysteine, related genetic polymorphisms, and B vitamins: the Atherosclerosis Risk In Communities (ARIC) study. Circulation. 1998;98:204–210.
Rimm EB, Willett WC, Hu FB, Sampson L, Colditz GA, Manson JE, Hennekens C, Stampfer MJ. Folate and vitamin B6 from diet and supplements in relation to risk of coronary heart disease among women. JAMA. 1998;279:359–364.
Hennekens CH, Buring JE, Manson JE, Stampfer M, Rosner B, Cook NR, Belanger C, LaMotte F, Gaziano JM, Ridker PM, Willett W, Peto R. Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease. N Engl J Med. 1996;334:1145–1149.
Hulley S, Grady D, Brush T, Furberg C, Herrington D, Riggs B, Vittinghoff E. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA. 1998;280:605–613.
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;337:230–236.