Elsevier

Atherosclerosis

Volume 151, Issue 2, August 2000, Pages 423-431
Atherosclerosis

Plasma total homocysteine levels in postmenopausal women with unstable coronary artery disease

https://doi.org/10.1016/S0021-9150(99)00416-5Get rights and content

Abstract

An elevated plasma total homocysteine (tHcy) level is considered a risk factor for coronary artery disease (CAD), but the relationship between plasma tHcy and well-defined CAD in women is still unclear. Plasma tHcy concentrations and the covariates serum folate, vitamin B12, and creatinine were analysed in 157 angiographically examined postmenopausal women with unstable CAD and in 101 healthy controls. At coronary angiography, 16% had normal vessels and 84% had coronary atherosclerosis. Mean plasma tHcy concentration (μmol/l, 95% confidence interval) did not differ in patients compared to controls (13.1 (12.3–13.8) vs. 12.5 (11.6–13.5)) or in patients with or without coronary atherosclerosis (13.3 (12.4–14.1) vs. 12.0 (10.8–13.2)). A trend to an increasing plasma tHcy with increasing degree of coronary atherosclerosis was attenuated after adjustment for age and the previous mentioned covariates. Odds ratio for the risk of coronary artery disease and coronary atherosclerosis in hyperhomocysteinemic patients (≥90th percentile in controls) was approximately 3. However, the confidence interval included unity in half of the groups and the significance was therefore difficult to judge. Receiver operating characteristics showed age to be the only variable with a significant discriminatory ability regarding the presence of coronary atherosclerosis (area 0.77). Mild hyperhomocysteinemia seems not to be related to the risk of unstable CAD in postmenopausal women. The trend towards higher plasma tHcy with increasing degree of coronary atherosclerosis may be a marker of the disease. In future studies adjustment for age and the other three covariates should be considered.

Introduction

In homocysteinurias, severely increased plasma total homocysteine concentration (tHcy) causes vascular injury, arteriosclerosis and venous thrombosis [1]. Numerous studies, both retrospective and prospective, have shown that mildly elevated plasma tHcy concentration is associated with increased risk of myocardial infarction and coronary atherosclerosis [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16]. It also seems to be a strong predictor of mortality in patients with coronary artery disease (CAD) [17], [18]. The association between modestly increased plasma tHcy concentration and other atherosclerotic and thromboembolic cardiovascular disease is also well documented [19], [20], [21]. However, there are also negative reports [22], [23], [24], [25], [26] and it is still unclear whether mild hyperhomocysteinemia is causally linked to the development of cardiovascular disease. In most of the above mentioned studies both men and women participated, but women were often in a minority. Furthermore, coronary angiography was often not performed, adding uncertainty to the diagnosis of CAD, considering that 20–40% of women with chest pain of typical angina character do not have signs of coronary atherosclerosis at coronary angiography [27]. Only a few of the studies regarding the association of plasma tHcy and CAD in women involve patients, who were catheterized [7], [11], [14], [16], [17], [25], [26].

Receiver operating characteristics (ROC) provide a simple, direct, yet comprehensive representation of the clinical or diagnostic accuracy of a test, i.e. its fundamental ability to discriminate between two alternative states of health or conditions. The shape and position of the plot is a quantitative graphic picture of accuracy and the area under the curve quantitates accuracy and provides a measure of the discriminatory performance useful for the comparison of the accuracies among two or more tests [28]. ROC have been used, for instance, when analyzing lipids [29], [30], [31], [32], [33] and in tests for peripheral artery disease [34], but to our knowledge none of the previous studies on homocysteine have used ROC for the analysis of the results.

We measured concentrations of plasma tHcy and its important determinants, serum folate, serum vitamin B12 and serum creatinine in postmenopausal women with unstable CAD and in age-matched female controls. All the patients underwent coronary angiography. Mean plasma concentrations were compared, the association to unstable CAD of plasma tHcy was evaluated in a logistic regression model and the discriminatory ability of the different variables regarding the presence of coronary atherosclerosis was tested using ROC. The primary objective of the study was to see whether patients with or without angiographic coronary atherosclerosis differ with regard to plasma tHcy concentration. A secondary objective of the study was the confirmation of previous studies, i.e. that plasma tHcy concentration is higher in patients with CAD than in control subjects.

The study was performed in postmenopausal women because the incidence of CAD in premenopausal women is very low and also to avoid the possible variations in menstrual cycle.

Section snippets

Patients

During a 2 year period all postmenopausal women (≥12 months since last menstruation) with a history of unstable CAD entering the coronary care unit were requested to participate in the study if they fullfilled the diagnostic criteria. These were new or increasing angina during the previous 2 months or ongoing chest pain suggesting ischemia, in conjunction with transient or persistent ST-depression and/or T-wave inversion of at least 0.1 mV in at least two adjacent leads. Most of the

Characteristics of study population

One hundred and fifty seven patients and 101 healthy controls were included in the study. The results at coronary angiography and baseline characteristics are given in Table 1. Women with angina-like chest pain and normal coronary vessels were significantly younger than the rest of the study population. Serum myocardial enzyme level above reference value was found in 43%, and more frequently in patients with significant stenosis than in patients with normal vessels (50 vs. 24%, P<0.05). No

Discussion

The results of the present study of plasma tHcy in female patients with signs and symptoms of unstable CAD and female age-matched healthy control subjects, do not support the hypothesis that mild hyperhomocysteinemia is a risk factor for CAD in postmenopausal women. There was no difference in plasma tHcy concentration between patients and controls, and no significant difference between patients with or without coronary atherosclerosis. In the highest percentile for plasma tHcy concentration

Acknowledgements

Participating investigators: S Ekdahl, I Nyman (Eksjö); O Svensson, JE Karlsson, K Malmberg (Jönköping); F Landgren, B Holmberg, S Ryden (Kalmar); NE Nielsen, E Swahn, KG Säfström, E Karlsson, A Björkholm, G Wiklund, J Malmstedt (Linköping); P Ahlström, BO Ryden (Motala), J Fridén (Norrköping); B Hedbäck, J Perk (Oskarshamn); O Lind, PÅ Johansson (Värnamo); LE Larsson, B Sinnerstad (Västervik). The skilful assistance of research nurse Elisabeth Logander and laboratory technician Gunnel Almroth

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