The impact of circulating total homocysteine levels on long-term cardiovascular mortality in patients with acute coronary syndromes

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Abstract

Background

To evaluate the possible independent impact of circulating total homocysteine (tHcy) levels on long-term cardiovascular mortality, in patients with either ST-segment elevation myocardial infarction (STEMI), or non-ST-segment elevation acute coronary syndromes (NSTE-ACS).

Methods

A total of 458 STEMI and 476 NSTE-ACS patients who presented consecutively, within the first 12 and 24 h of index pain respectively were studied. Each cohort was divided according to tertiles of circulating tHcy levels upon presentation. Early (30 days) and late (31 days through 5 years) cardiovascular mortality was the predefined study endpoint.

Results

There was no difference in the risk of 30-day cardiovascular death among the tertiles of tHcy in patients with STEMI (7.2%, 8.5% and 12.4% for the first, second and third tertiles respectively; ptrend = 0.3) or NSTE-ACS (3.1%, 3.8% and 5.7% for the first, second and third tertiles respectively; ptrend = 0.5). Patients in the upper tHcy tertile were at significantly higher unadjusted risk of late (from 31 days trough 5 years) cardiovascular death than those in the other two tertiles in STEMI (23.4%, 27.9% and 41.8% for the first, second and third tertiles respectively; ptrend < 0.001), and NSTE-ACS (24.7%, 28.1% and 45.6% for the first, second and third tertiles respectively; ptrend < 0.001) cohorts. However, after adjustment for baseline differences, there was no significant difference in the risk of late cardiovascular death among tHcy tertiles in either cohort. When circulating tHcy levels were treated as a continuous variable, they were significantly associated with late cardiovascular death (p < 0.001 for both cohorts) by univariate Cox regression analysis, but not by multivariate Cox regression analysis (p = 0.8, and p = 1 for STEMI and NSTE-ACS cohorts, respectively).

Conclusions

Based on the present data circulating tHcy levels determined upon admission do not serve as an independent predictor of long-term cardiovascular mortality in patients with either STEMI or NSTE-ACS.

Introduction

Previous studies have evaluated the impact of circulating total homocysteine (tHcy) on clinical outcome in patients with stable or unstable coronary artery disease [1], [2], [3], [4], [5], [6], [7]. This amino acid is the derivative of methionine demethylation. Significantly elevated circulating tHcy levels (> 100 μmol/l) observed in patients with homocystinuria, a genetically inherited enzyme defect of Hcy metabolism, have been shown to be associated with aggressive and premature vascular disease [8], [9], [10]. Thus, it has been presumed that moderately elevated circulating tHcy levels might also have some prognostic implication in several manifestations within the wide spectrum of coronary artery disease.

Yet the place and significance of circulating tHcy levels in the setting of acute coronary syndromes have not been definitively clarified. On the contrary, it seems that the limited existing data are rather controversial [3], [4], [5], [6], [7]. Since the possible pathophysiologic mechanisms remain obscure, the critical question is whether the observed relation might be accounted to the reported association of tHcy levels with known cardiovascular disease risk factors that possibly act as confounders [11], [12], [13].

The present study was designed to attempt a further elucidation of the aforementioned controversy. We prospectively evaluated the possible association of admission circulating tHcy levels with late clinical outcome during a five-year follow-up period after an acute coronary syndrome.

Section snippets

Study population

Consecutive eligible patients with ST-segment elevation myocardial infarction (STEMI) or non-ST-segment elevation acute coronary syndromes (NSTE-ACS) who were admitted to our institute from September 1998 through December 2000 were recruited. Patients with STEMI were required to have: 1) continuous chest pain upon presentation, refractory to nitrates, and lasting ≥ 30 min; 2) ST-segment elevation of ≥ 2 mm in ≥ 2 contiguous precordial leads, or ≥ 1 mm in ≥ 2 contiguous limb leads; 3) presentation in

Baseline characteristics

During the recruiting period, 458 patients with STEMI and 476 with NSTE-ACS were included in the study. Baseline characteristics within the tertiles of tHcy, for each cohort, are presented in Table 1, Table 2. Patients in the upper tHcy tertile were significantly older and had more unfavorable risk profile than those in the other two tertiles; this observation was true for both cohorts. In particular, the frequency of prior angina, myocardial infarction, heart failure, peripheral artery

Discussion

The primary outcome of the present study is that circulating tHcy levels upon admission seem to lack independent value in the prediction of long-term cardiovascular mortality within a five-year follow up period after an acute coronary syndrome. Despite the significant relation demonstrated for both STEMI and NSTE-ACS patients, by means of univariate analysis, statistically non-significant results were produced when tHcy levels were included along with all other univariate predictors in the

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