Whole blood folate, homocysteine in serum, and risk of first acute myocardial infarction
Introduction
High level of total homocysteine (tHcy) (hyperhomocysteinemia) is a risk factor for cardiovascular disease (CAD) [1]. The level of extracellular homocysteine is determined by genetic [2] and environmental factors as well as by gene–environment interaction [3]. The intake of the vitamin, folate, is the best known exogenous determinant of the tHcy level [4]. Some recent population studies have demonstrated that cigarette smoking is also significantly associated with hyperhomocysteinemia [5], [6].
Because patients with severe hyperhomocysteinemia due to inherited deficiency of several different enzymes in the metabolism of homocysteine and folate all may present with premature cardiovascular disease, homocysteine itself has long been assumed to be the atherogenic agent. However, recent findings of increased risk of CAD associated with low levels of folate and vitamin B6, even after adjustment for tHcy, suggest an independent effect of these vitamins on atherogenesis, tHcy merely functioning as a marker [7]. The results from some [8], [9], but not all [10], [11], [12] studies support the idea that there is an association between folate status and risk of CAD. It has been reported that the association between folate status and risk of CAD can be influenced by the intake of alcohol [8].
A number of hypotheses to explain the atherogenic effect associated with hyperhomocysteinemia have been introduced. It has been suggested that tHcy may influence the oxidation of circulating low density lipoprotein (LDL), acting as a prooxidant [13]. A positive correlation between the tHcy level and total or LDL cholesterol level has been reported in some, but not in all studies [2], [14], [15], [16]. Low levels of high density lipoprotein cholesterol (HDL-C) and its major protein component, apolipoprotein A-I (apo A-I), in serum may be better predictors of CAD than total cholesterol [17]. A relation between the levels of tHcy and HDL-C or apo A-I has not been reported, although it has been searched for [2].
The aim of the present study was to uncover any relation between the levels of folate in whole blood and of tHcy, total cholesterol, HDL-C, and apo A-I in serum, and risk of myocardial infarction (MI), and to test for correlations between the variables. A questionnaire was used to evaluate the possible effects of the life style factors, current cigarette smoking and intake of alcohol.
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Patients and controls
A total of 107 cases and 103 controls were recruited during 1996. Eligible subjects were men and postmenopausal women of Norwegian origin, aged between 45 and 75 years, without a history of MI or other serious disease (cancer, diabetes, alcoholism, drug abuse, or major psychiatric disease) which might affect their dietary patterns. Subjects with weight changes more than 5 kg during the last year and persons taking lipid-lowering drugs were excluded from the study. Informed consent was obtained
Comparison of means between biochemical variables in cases versus controls
Significant differences between cases and controls were observed for the levels of folate, tHcy, HDL-C, apo A-I, and triglycerides. For total cholesterol, a non-significant higher mean value in controls compared to cases was observed (Table 1).
Correlation between biochemical variables
Highly significant inverse correlations were seen between the levels of whole blood folate and tHcy (P=0.003), between tHcy and HDL-C (P=0.003), and between tHcy and apo A-I (P=0.000) in the combined population of cases and controls (Pearson’s correlation
Low whole blood folate and high tHcy as risk factors for first MI
Our findings of a highly significant association between folate status and the occurrence of first MI are in line with the results of some [7], [8], [9], but not all [10], [11], [12] previous studies of folate status in CAD patients. However, not all of these studies are fully comparable.
In the study of Siri et al. [11], the discrepancy can possibly be explained by the different study design. In that study, all cases had established coronary stenosis, so that previous symptoms of coronary
Conclusion
The present study demonstrates significant differences between MI cases and controls with respect to the levels of whole blood folate and tHcy. The findings could to a great extent be attributed to the presence of the strong risk factor, cigarette smoking, which was associated with low level of whole blood folate and high level of tHcy. In MI cases, but not in controls, the level of tHcy was inversely associated with the levels of HDL-C and apo A-I in serum. Further research should include
Acknowledgements
The study was supported by grants from The Norwegian Council on Cardiovascular Diseases. We will thank Jan I. Pedersen at the Institute of Nutritional Sciences, University of Oslo, for his contribution to this study, which was also supported by Throne Holst’s Foundation for Nutrition Research, The Norwegian Association of Margarine Products, DeNoFa Fabrikker A/S, and Tine Norwegian Dairies. We are indebted to Ragnhild Lekven, Hege Møklebust and Kjerstin Trygg for performing the dietary
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