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Plasma concentrations of total homocysteine predict mortality risk^1,2

¹ From the Oregon Regional Primate Research Center, the Division of Cardiology, Oregon Health Sciences University, Beaverton, and Providence St Vincent, The Heart Institute, Portland, OR.

² Address reprint requests to MR Malinow, Oregon Regional Primate Research Center, Division of Cardiology, Oregon Health Sciences University, 505 NW 185th Avenue, Beaverton, OR 97006-3448. E-mail: malinowr{at}ohsu.edu.

See corresponding article on page130.

In this issue of the Journal, investigators from Norway, who are well known throughout the world for their contributions to the field of blood homocysteine, have added another important finding (1). In a prospective study of 2127 men and 2639 women aged 65–67 y in 1992–1993 from Hordaland County, Norway, 162 men and 97 women died during a median 4.1 y of follow-up. The association between mortality and plasma total homocysteine (tHcy), distributed by quintiles with use of those with a concentration <9.0 µmol/L as the referent group, was highly significant for both nonvascular and cardiovascular causes of death. An increase in tHcy of 5 µmol/L was associated with a 49% increase in all-cause mortality, a 50% increase in cardiovascular mortality, a 26% increase in cancer mortality, and a 104% increase in noncancer, noncardiovascular mortality. Thus, plasma tHcy was a strong predictor of both cardiovascular and noncardiovascular mortality. The strongest association was between tHcy and noncancer, noncardiovascular mortality. The present observation confirms the prognostic value of elevated plasma tHcy for total mortality reported in Israel (2) and the United States (3, 4). Consequently, as Vollset et al (1) suggested, in addition to investigations of the mechanisms of the relation between tHcy and atherosclerosis and thrombosis, future studies should focus on tHcy and pathologies other than vascular diseases.

The association between elevated concentrations of plasma tHcy and mortality emphasizes the desirability of conducting widespread screening of plasma tHcy concentrations in middle-aged and elderly persons to help identify potential candidates for treatment. Because folic acid is the cornerstone in the treatment of elevated tHcy concentrations, it is likely that an inexpensive and usually well-tolerated vitamin therapy could prevent many deaths (5). However, pharmacologic doses of folic acid increased tHcy in 20% of subjects in a study of 304 men and women (6). Although the significance of this paradoxical tHcy response needs further study, repeated testing may be necessary to determine the effects of folic acid supplementation on tHcy. The questions of potential therapy raised by the above observations may be partly answered when the results of ongoing, secondary-prevention clinical trials are known (7), yet data from these observations suggest that primary prevention trials should also be considered.

REFERENCES

1. Vollset SE, Refsum H, Tverdal A, et al. Plasma total homocysteine and cardiovascular and noncardiovascular mortality: the Hordaland Homocysteine Study. Am J Clin Nutr 2001;74:130–6.[Abstract/Free Full Text]
2. Kark JD, Selhub J, Adler B, et al. Nonfasting plasma total homocysteine level and mortality in middle-aged and elderly men and women in Jerusalem. Ann Intern Med 1999;131:321–30.[Abstract/Free Full Text]
3. Bostom AG, Silbershatz H, Rosenberg IH, et al. Nonfasting plasma total homocysteine levels and all-cause and cardiovascular disease mortality in elderly Framingham men and women. Arch Intern Med 1999;159:1077–80.[Abstract/Free Full Text]
4. Zhao X-Q, Kosinski A, Malinow MR, Superko HR, King SB. Association of total plasma homocyst(e)ine levels and 8-years mortality following PTCA or CABG in EAST. Circulation 2000;102 (abstr 3380).
5. Boushey CJ, Beresford SAA, Omenn GS, Motulsky AG. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. JAMA 1005;274:1049–57.
6. Malinow MR, Duell PB, Williams MA, et al. Short-term folic acid supplementation is associated with variable and paradoxical responses in plasma homocyst(e)ine concentrations. Lipids (in press).
7. Clarke R, Armitaje J. Vitamin supplements and cardiovascular risk: review of the randomized trials of homocysteine-lowering vitamin supplements. Semin Thromb Hemost 2000;26:341–8.[Medline]

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