Moti Haim

Elevated Serum Triglyceride Levels and Long-Term Mortality in Patients With Coronary Heart Disease: The Bezafibrate Infarction Prevention (BIP) Registry

BACKGROUND The association between elevated blood triglyceride levels and subsequent mortality risk in patients with established coronary heart disease (CHD) has been investigated rarely. The aim of the present study was to investigate this association. METHODS AND RESULTS We evaluated mortality over a mean follow-up time of 5. 1 years among 9033 male and 2499 female CHD patients who were screened for participation in the Bezafibrate Infarction Prevention (BIP) Study. A stepwise increase in mortality with increasing serum triglyceride levels was observed in patients with desirable or elevated serum total cholesterol levels and in patients with either desirable or abnormally low HDL cholesterol levels. Multivariate adjustment for factors other than HDL cholesterol yielded a slightly increased adjusted mortality risk with a 1-natural-log-unit elevation of triglyceride levels in men (hazard ratio [HR] 1.14, 95% CI 1.00 to 1.30) and women (HR 1.37, 95% CI 1.04 to 1.88). Excess covariate-adjusted risk was noted among patients with elevated total and LDL cholesterol and in women with HDL cholesterol levels >45 mg/dL. After additional adjustment for HDL cholesterol, the risk of mortality with a 1-natural-log-unit elevation of triglycerides declined in men (HR 1.09, 95% CI 0.94 to 1.26) and in women (HR 1.10, 95% CI 0.80 to 1.50). A trend for increased mortality risk remained in patients with elevated total and LDL cholesterol and in women with HDL cholesterol >45 mg/dL. CONCLUSIONS Elevated triglyceride levels were associated with a small, independent increased mortality risk in CHD patients. This risk may be increased among subgroups of patients with elevated total cholesterol and LDL cholesterol levels.

Prospective Study of Serum Homocysteine and Risk of Ischemic Stroke Among Patients With Preexisting Coronary Heart Disease

Background and Purpose— Substantial evidence is accumulating suggesting that hyperhomocysteinemia may be a risk factor for ischemic stroke. Results of prospective studies are, however, conflicting, and the role of hyperhomocysteinemia in patients with preexisting atherosclerotic vascular disease is not clear. Our aim was to assess prospectively the risk of incident ischemic stroke conferred by serum total homocysteine among patients with preexisting stable coronary heart disease (CHD). Methods— We obtained baseline fasting serum samples from patients with chronic CHD enrolled in the Bezafibrate Infarction Prevention (n=3090) secondary prevention study cohort. With a nested case-control design, we measured baseline total homocysteine concentration by a high-performance liquid chromatography–based method in sera (n=160) of matched case-control pairs: patients who developed ischemic stroke during a mean follow-up of 8.2 years (cases) and age- and sex-matched controls without subsequent cardiovascular events. Results— An increase of 1 natural log unit in homocysteine concentration was associated with a >3-fold increase in relative odds of incident ischemic stroke (3.3; 95% CI, 1.2 to 10.2). Homocysteine concentrations at the highest quartile (>17.4 &mgr;mol/L) were associated with significantly higher odds of ischemic stroke compared with the lowest quartile in matched-pair analysis (3.1; 95% CI, 1.1 to 9.8) and after multivariable adjustments (4.6; 95% CI, 1.3 to 18.9). Adding fibrinogen or soluble intercellular adhesion molecule-1 concentrations, markers of inflammation, to the model did not attenuate this association. The linear trends across the quartiles were significant for all models (P <0.05). Conclusions— Serum total homocysteine concentration is a strong predictor for incident ischemic stroke among patients at increased risk because of chronic CHD. The graded association observed is independent of traditional risk factors or inflammatory markers and indicates the importance of serum homocysteine levels in patients with preexisting vascular disease.

Soluble Intercellular Adhesion Molecule-1 and Risk of Future Ischemic Stroke A Nested Case-Control Study From the Bezafibrate Infarction Prevention (BIP) Study Cohort

Background and Purpose— Inflammation is considered to be involved in the pathogenesis of ischemic stroke. Our purpose was to assess the role of soluble intercellular adhesion molecule-1 (sICAM-1) concentration, a marker of inflammation, in predicting future ischemic stroke among patients at risk because of chronic coronary heart disease. Methods— We obtained baseline serum samples from patients with chronic coronary heart disease enrolled in the Bezafibrate Infarction Prevention trial (n=3090), which assessed the efficacy of bezafibrate in secondary prevention. Using a prospective nested case-control design, we measured baseline sICAM-1 concentration in sera of patients who developed ischemic stroke during a mean follow-up of 8.2 years (cases, n=134) and in age- and sex-matched controls without any subsequent cardiovascular events (n=134). Results— Baseline serum concentrations of sICAM-1 were significantly higher in cases compared with controls (379 versus 350 ng/mL, P <0.05). sICAM-1 concentration at the highest quartile (>394 ng/mL) was associated with significantly higher relative odds of ischemic stroke compared with the lower concentrations after adjustment for potential confounding variables (relative odds, 2.1; 95% CI, 1.1 to 4.3). After fibrinogen and total white blood cell count were added to the multivariable model, the relative odds were 2.1 (95% CI, 1.1 to 4.2) and 2.2 (95% CI, 1.1 to 4.8), respectively. The risk associated with raised concentrations of sICAM-1 seemed to be highest for large disabling strokes of cardioembolic origin. Conclusions— Elevated concentrations of sICAM-1, a marker of inflammation, are associated with increased risk of ischemic stroke, independent of other traditional cerebrovascular risk factors and of plasma fibrinogen, among patients at increased risk because of manifest coronary heart disease.

C-Reactive Protein as a Predictor of Incident Ischemic Stroke Among Patients With Preexisting Cardiovascular Disease

Background and Purpose— C-reactive protein (CRP) has emerged as an important predictor of cardiovascular disease, but there are few prospective data on its association with risk of ischemic stroke in patients at high risk. Methods— We examined the association between CRP levels and subsequent risk of incident ischemic stroke among 2979 patients with stable coronary heart disease included in a controlled clinical trial (Bezafibrate Infarction Prevention) that assessed the efficacy of bezafibrate, a fibric acid derivative, versus placebo for secondary prevention. CRP was measured by a high-sensitivity assay in plasma samples collected before randomization and again at the second follow-up year of an overall mean follow-up of 6.2 years. Results— Risk of ischemic stroke per 1000 person-years increased from 4.1% for baseline CRP in the lowest tertile (<2.3 mg/L; n=982) to 5.9% for levels at the middle tertile (2.3 to 5.4 mg/L; n=1013) and 10.5% for CRP levels at the upper tertile (>5.4 mg/L; n=984; P<0.001). With adjustment for potential confounders, baseline CRP levels in the top versus bottom tertile were associated with a 2.16-fold increased hazard (95% CI, 1.32 to 3.53) for ischemic stroke, and CRP levels measured after 2 years were associated with a hazard ratio of 2.43 (95% CI, 1.30 to 4.57). The risk of an incident ischemic stroke did not differ between the bezafibrate group compared with the placebo group regardless of baseline CRP levels. Conclusions— These findings, based on a large prospective study, demonstrate the risk prediction for incident ischemic stroke conferred by CRP levels in patients at high risk.

Frequency, Characteristics, and Outcome of Patients Hospitalized With Acute Coronary Syndromes With Undetermined Electrocardiographic Patterns

dial infarction. The case report form also included details regarding the demographic, clinical, and ECG characteristics of the patient, diagnostic and treatment modalities, in-hospital complications, and discharge status. Patient follow-up was available at 30 days for 90% of the patients. Patients with ACS were divided into 2 groups based on their initial ECG pattern as interpreted by the attending admitting physician: undetermined ECG or determined ECG patterns (including ST elevation or non-ST elevation). We compared the clinical charac- teristics, clinical course while in-hospital, treatment, and the in-hospital and 30-day outcomes between the 2 groups. The chi-square and Studentst tests were used to determine the significance of differences be- tween variables and means, respectively. Unadjusted and multivariate adjusted odds ratios (with 95% con- fidence intervals (CI)) of in-hospital and 30-day mor- tality were calculated using logistic regression analy- sis. ECG patterns (undetermined vs determined), age, gender, prior myocardial infarction, Killip class, dia- betes, and hypertension were included in the multi- variate model. Continuous variables are presented as mean SD. SAS software (SAS Institute, Cary, North Carolina) was used for statistical analysis. Of the 10,484 patients enrolled in the Euro Heart Survey of ACS, 686 patients (6.5%) were admitted with an undetermined ECG pattern; the remaining 9,798 patients (93.5%) had determined ECG patterns. The rhythm on the initial electrocardiogram among the undetermined group was atrial fibrillation in 86 patients (12.5%), paced rhythm in 60 (8.7%), ventric- ular or supraventricular tachycardia in 14 (2%), ad- vanced atrioventricular block in 11 (1.6%), junctional rhythm in 7 (1%), and sinus rhythm in 467 (68.1%). One hundred fifty-five patients (22.6%) had left bun- dle branch block of uncertain duration, and 81 (11.8%) presumably had new left bundle branch block. In 41 patients (6%), the initial ECG description was missing in the case report, although it was avail- able to the physician who categorized it as being an undetermined ECG pattern. Fifty-one percent of the patients with an undeter- mined ECG pattern were hospitalized in coronary care units, 25.4% in cardiology departments, and 20.4% in internal medicine departments, compared with 63%, 21.9%, and 13.4%, respectively, in the determined ECG pattern group (p 0.001 for comparison be- tween the 2 groups). Thus, patients with undetermined ECG patterns were less likely to be hospitalized in coronary care units and more likely to be hospitalized in internal medicine wards compared with the deter-

Prospective Study of Chlamydia pneumoniae IgG and IgA Seropositivity and Risk of Incident Ischemic Stroke

Background and Purpose:Chlamydia pneumoniae infection or exposure to C. pneumoniae was implicated as a risk factor for ischemic stroke. Our aim was to evaluate prospectively the association between the presence of antibodies to C. pneumoniae (IgG and IgA) and the risk of incident ischemic stroke among patients with pre-existing vascular disease. Methods: Sera were collected from 3,090 coronary heart disease patients enrolled in a secondary prevention trial. We measured baseline antibodies (IgG and IgA) in the sera of patients who developed subsequent ischemic strokes (cases, n = 134) during follow-up (mean 8.2 years), and in 134 age- and gender-matched pairs without subsequent stroke or myocardial infarction. Results: The crude relative odds (95%CI) of incident ischemic strokes in seropositive patients at baseline (>1.1 relative value units) were 1.29 (95%CI, 0.69–2.47) for IgG and 1.31 (95% CI, 0.69–2.55) for IgA by matched-pair analyses, and 1.42 (95%CI, 0.69–2.98) for IgG and 1.57 (95%CI, 0.76–3.35) for IgA after adjustments for conventional risk factors and the inflammatory marker, soluble intercellular adhesion molecule-1. We explored the possibility that the risk of ischemic stroke may increase in parallel to increasing antibody titers, but did not demonstrate any significant association. Conclusions: Serological evidence for prior infection with C. pneumoniae did not emerge as an independent risk factor for incident ischemic stroke among patients at high risk due to pre-existing vascular disease.

The prognosis of a first Q-wave versus non–Q-wave myocardial infarction in the reperfusion era

PURPOSE To compare the prognosis of patients with a first Q-wave versus non-Q-wave myocardial infarction (MI) in the reperfusion era. METHODS Patients with a first MI were compared according to type of infarct-Q-wave (n = 1,786) versus non-Q-wave (n = 722)-and by treatment with thrombolysis. RESULTS Patients with non-Q-wave MI were more likely to be female and to have undergone previous coronary revascularization. Their 30-day mortality rate was 7%, as compared with a rate of 9% among patients with Q-wave infarction (adjusted odds ratio [OR] = 0.6, 95% confidence interval [CI]: 0.4 to 0.9). However, the subsequent 30-day to 1-year mortality rates were similar in patients with Q-wave or non-Q-wave MI. Patients who were not treated with thrombolysis and who had a non-Q-wave MI had a lower 30-day mortality rate (OR = 0.6, 95% CI: 0.3 to 0.9) but a similar 30-day to 1-year mortality rate (hazard ratio [HR] = 1.5, 95% CI: 0.9 to 2.5) as compared with their counterparts who developed Q-wave infarction. Among thrombolysis-treated patients, 30-day (OR = 0.8, 95% CI: 0.4 to 1.5) as well as 30-day to 1-year (HR = 1.2, 95% CI: 0.5 to 3.0) mortality rates were similar between patients who developed either Q-wave or non-Q-wave MI. CONCLUSIONS Patients who received thrombolysis had similar early and late mortality rates after the index infarction regardless of whether they had a Q-wave or non-Q-wave MI. Conversely, among patients who were not treated with thrombolysis, patients with a non-Q-wave MI had lower early mortality rates but similar long-term mortality rates as those with Q-wave MI.

Serum Homocysteine and Long-Term Risk of Myocardial Infarction and Sudden Death in Patients with Coronary Heart Disease

We have prospectively evaluated the risk of incident coronary events in association with serum total homocysteine in patients with preexisting chronic coronary heart disease. A nested case-control design was used. Total homocysteine concentration was measured in baseline fasting serum samples from patients with chronic coronary heart disease enrolled in the Bezafibrate Infarction Prevention Study (n = 3,090) who developed coronary events during 6.2 years of follow-up (n = 69). They were matched for age and gender with controls without subsequent cardiovascular events. Elevated homocysteine levels were associated with 2.5 times higher risk of subsequent coronary events and each 5 µmol/l increment was associated with a 25% higher risk.

The outcome of patients with a first non-Q wave acute myocardial infarction presenting with ST segment depression, ST segment elevation, or no ST deviations on the admission electrocardiogram

UNLABELLED We evaluated the prognosis of patients with a first non-Q wave myocardial infarction according to their admission electrocardiogram. Hospital and 1-year mortality rates in patients with ST elevation (15%, and 21% respectively) and ST depression (17%, and 27% respectively) were similar and significantly higher than in patients with no ST changes (3%, and 10% respectively). Likewise, the adjusted hospital and 1-year mortality risks of patients with ST elevation or depression were comparable but higher than the corresponding mortality risk of patients with no ST deviations. The cumulative 5-year mortality rate was highest among patients with ST segment depression (51%) compared to patients with ST elevation (34%) or no ST deviation (21%), (p<0.001 for both comparisons). The adjusted 5-year mortality risk of patients with ST depression was higher (HR: 1.83, 95% C.I., 1.17-2.83) compared to patients with baseline ST elevation (HR-1.33, 95% C.I., 0.83-2.12) or patients with no ST changes (reference group). Patients with baseline ST segment elevation and coexistent ST segment depression in other electrocardiogram leads, had a higher in-hospital mortality rate (19%) compared to counterparts without concomitant ST depression (10%) and a tendency for higher in-hospital mortality risk but not for subsequent 1- and 5-year mortality risks. CONCLUSIONS Patients with a first non-Q wave MI with ST elevation or depression on admission have similar hospital and 1-year mortality risk, but the long-term mortality risk is higher among patients with ST segment depression. Patients with ST elevation and concomitant ST segment depression are at increased risk for mortality during the index hospitalization.

C-Reactive Protein Distribution and Correlates among Men and Women with Chronic Coronary Heart Disease

Background: C-reactive protein (CRP) elevated in inflammation is associated with atherosclerotic disease. We describe the distribution of CRP and its association with coronary heart disease (CHD) risk factors in a large CHD patient group. Methods: This analysis comprises 2,723 male and 256 female CHD patients, included in the Bezafibrate Infarction Prevention (BIP) study. High sensitive CRP levels were determined in frozen plasma samples. Results: CRP distribution, was normalized upon log transformation. Levels among women were higher than in men in the entire group (4.4 vs. 3.5 mg/l) and in each age group. Co-morbidities, smoking, lower education level, and use of cardiovascular drugs, were associated with elevated CRP levels in both sexes. The correlation between CRP and body mass index (BMI), insulin and glucose was stronger among women. The explained variability in CRP level was larger in women (20%) compared to men (13%). Among women, BMI explained 10% of CRP variability, whereas the contribution of each variable among men was significantly smaller. Conclusions: Among men and women with CHD, CRP level was correlated with traditional risk factors and to a lesser degree to manifestation of CHD. BMI is the main contributor to CRP variability, explained by these factors among women.