Thrombomodulin gene variants are associated with increased mortality after coronary artery bypass surgery in replicated analyses.

BACKGROUND: We tested the hypothesis that genetic variation in thrombotic and inflammatory pathways is independently associated with long-term mortality after coronary artery bypass graft (CABG) surgery. METHODS AND RESULTS: Two separate cohorts of patients undergoing CABG surgery at a single institution were examined, and all-cause mortality between 30 days and 5 years after the index CABG was ascertained from the National Death Index. In a discovery cohort of 1018 patients, a panel of 90 single-nucleotide polymorphisms (SNPs) in 49 candidate genes was tested with Cox proportional hazard models to identify clinical and genomic multivariate predictors of incident death. After adjustment for multiple comparisons and clinical predictors of mortality, the homozygote minor allele of a common variant in the thrombomodulin (THBD) gene (rs1042579) was independently associated with significantly increased risk of all-cause mortality (hazard ratio, 2.26; 95% CI, 1.31 to 3.92; P=0.003). Six tag SNPs in the THBD gene, 1 of which (rs3176123) in complete linkage disequilibrium with rs1042579, were then assessed in an independent validation cohort of 930 patients. After multivariate adjustment for the clinical predictors identified in the discovery cohort and multiple testing, the homozygote minor allele of rs3176123 independently predicted all-cause mortality (hazard ratio, 3.6; 95% CI, 1.67 to 7.78; P=0.001). CONCLUSIONS: In 2 independent cardiac surgery cohorts, linked common allelic variants in the THBD gene are independently associated with increased long-term mortality risk after CABG and significantly improve the classification ability of traditional postoperative mortality prediction models.

Phobic anxiety and increased risk of mortality in coronary heart disease.

OBJECTIVES: To evaluate whether phobic anxiety is associated with increased risk of cardiac mortality in individuals with established coronary heart disease (CHD) and to examine the role of reduced heart rate variability (HRV) in mediating this risk. Previous findings suggest that phobic anxiety may pose increased risk of cardiac mortality in medically healthy cohorts. METHODS: We performed a prospective cohort study in 947 CHD patients recruited during hospitalization for coronary angiography. At baseline, supine recordings of heart rate for HRV were collected, and participants completed the Crown-Crisp phobic anxiety scale. Fatal cardiac events were identified over an average period of 3 years. RESULTS: Female CHD patients reported significantly elevated levels of phobic anxiety when compared with male patients (p < .001), and survival analysis showed an interaction between gender and phobic anxiety in the prediction of cardiac mortality (p = .058) and sudden cardiac death (p = .03). In women, phobic anxiety was associated with a 1.6-fold increased risk of cardiac mortality (hazard ratio, 1.56; 95% confidence interval, 1.15-2.11; p = .004) and a 2.0-fold increased risk of sudden cardiac death (hazard ratio, 2.02; 95% confidence interval, 1.16-3.52; p = .01) and was unassociated with increased mortality risk in men (p = .56). Phobic anxiety was weakly associated with reduced high-frequency HRV in female patients (r = -.14, p = .02), but reduced HRV did not alter the association between phobic anxiety on mortality. CONCLUSIONS: Phobic anxiety levels are high in women with CHD and may be a risk factor for cardiac-related mortality in women diagnosed with CHD. Reduced HRV measured during rest does not seem to mediate phobic anxiety-related risk.

Long-term morbidity and mortality among medically managed patients with angina and multivessel coronary artery disease.

BACKGROUND: There are little data regarding outcomes in patients with angina and severe coronary artery disease (CAD) treated with medical management. Using the Duke Databank of Cardiovascular Disease, we describe the prevalence and long-term outcomes of patients with angina and multivessel CAD treated medically after catheterization. METHODS: Patients undergoing catheterization for angina (chest pain without recent revascularization or myocardial infarction) with severe CAD (>or=75% stenosis in >or=2 epicardial vessels) were identified (n = 8,555). One and five year outcomes in the 32% (n = 2,776) of patients who did not receive revascularization in the 30 days after catheterization were described. Predictors of 1-year death, cardiac rehospitalization, and late revascularization in this population were identified. RESULTS: The population had a median age of 66, were mostly male, had significant comorbidities, and most had prior revascularization. Outcomes were poor at 1 and 5 years: death (11% and 37%), cardiac rehospitalization (29% and 61%), and late revascularization (10% and 27%). The cumulative rate of death, myocardial infarction, late revascularization, or cardiac rehospitalization occurred in 38% at 1 year and 76% at 5 years. Prior coronary artery bypass grafting was the only variable independently associated with protection from death, cardiac rehospitalization, and late revascularization. CONCLUSIONS: Medical management after catheterization is a common in patients with severe CAD and angina. Of patients treated with medical management, one third will have a recurrent cardiac event within the first year highlighting the poor outcomes and high utilization of resources by this patient population.

Phobic anxiety, depression, and risk of ventricular arrhythmias in patients with coronary heart disease.

OBJECTIVE: Findings of an association between phobic anxiety and elevated risks of sudden cardiac death suggest that phobic anxiety may be related to increased risk of ventricular arrhythmias. The purpose of this study was to examine whether phobic anxiety is associated with ventricular arrhythmias in patients with documented coronary artery disease (CAD). METHODS: Phobic anxiety level was measured using the Crown-Crisp phobic anxiety scale in 940 patients (660 men, 280 women) hospitalized for diagnostic cardiac catheterization between April 1999 and June 2002. Depressive symptomatology was assessed using the Beck Depression Inventory. Patients were followed for a median follow-up period of 3 years, and the occurrence of ventricular arrhythmias was determined through review of medical records. RESULTS: Ventricular arrhythmias occurred in 97 patients and were significantly related to higher phobic anxiety after statistical adjustment for established medical and demographic determinants of arrhythmias (odds ratio = 1.40; p = .012). Depressive symptomatology was significantly correlated with phobic anxiety (r = 0.44, p < .001) and was also related to ventricular arrhythmias (odds ratio = 1.40; p = .006). The composite of depression and phobic anxiety predicted ventricular arrhythmias with a larger effect size than either depression or phobic anxiety score alone (odds ratio = 1.6, 95% confidence interval, 1.2-2.1, p = .002). CONCLUSIONS: Both phobic anxiety and depressive symptomatology predict ventricular arrhythmias in patients with CAD and may share a common factor predictive of ventricular arrhythmias.

Effects of decreased preoperative endotoxin core antibody levels on long-term mortality after coronary artery bypass graft surgery.

HYPOTHESIS: Decreased preoperative levels of antiendotoxin core antibody (EndoCAb) in patients undergoing cardiac surgery with cardiopulmonary bypass are associated with increased long-term mortality. DESIGN: Observational study. SETTING: Academic medical center. PATIENTS: A total of 474 patients undergoing coronary artery bypass graft surgery with cardiopulmonary bypass. INTERVENTIONS: Preoperative serum IgM EndoCAb levels were determined, and established preoperative risk factors were assessed. Patients were assigned a risk score using a validated method. MAIN OUTCOME MEASURES: The primary end point was mortality. Statistical analysis used the Cox proportional hazards regression model with log EndoCAb as the predictor of interest and Parsonnet additive risk score as a covariate. Kaplan-Meier survival curves were generated to visually compare groups with high vs low EndoCAb levels. RESULTS: Forty-six deaths occurred in 5 years. Annual follow-up rates during the 5 years were 100%, 94%, 93%, 98%, and 98% for the 1-, 2-, 3-, 4-, and 5-year periods, respectively. Parsonnet additive risk score (hazard ratio, 1.07; 95% confidence interval [CI], 1.04-1.11; P < .001) and log EndoCAb (hazard ratio, 0.73; 95% CI, 0.53-0.99; P = .04) were independent predictors of long-term mortality in the final model. Kaplan-Meier analysis revealed that the preoperative EndoCAb level was significantly associated with mortality up to 5 years (P = .01 by log-rank test). CONCLUSION: Lower preoperative serum EndoCAb level is a significant predictor of long-term mortality independent of other known risk factors.

Low serum magnesium level predicts major adverse cardiac events after coronary artery bypass graft surgery.

BACKGROUND: Despite improved myocardial protection strategies and enhanced surgical techniques, mortality after coronary artery bypass graft surgery (CABG) remains essentially unchanged. This may be because of the increasing age of patients who undergo primary CABG. Magnesium is an important regulator of vascular tone, reperfusion injury, and thrombosis. Therefore, we decided to investigate the relationship between serum magnesium levels and major adverse cardiac events (MACE) after CABG. METHODS: A total of 957 patients undergoing primary CABG were prospectively recruited into the Duke Cardiovascular database and had daily serum magnesium levels measured. Low magnesium was defined as <1.8 mmol/L(-1) at any point during the first 8 days after surgery. Adverse events were defined as Q-wave infarction or death measured 1 year after surgery. A Kaplan-Meier survival analysis was performed, followed by a Cox proportional hazards model, to account for other known predictors of adverse events. RESULTS: In the low magnesium group, 12.3% of patients had adverse events, compared with 9.2% of patients in the normal magnesium group. A serum magnesium level <1.8 mmol/L(-1) decreased the event-free survival rate (2-fold increased risk of death or myocardial infarction at 1 year; hazard ratio 2.0, 95% CI 1.19-3.37). CONCLUSIONS: We demonstrated a robust relationship between low serum magnesium levels after CABG and a 2-fold increased incidence of Q-wave infarction and all-cause mortality rate as long as 1 year after surgery. This relationship is independent of known preoperative and intraoperative predictors of adverse outcomes. This study provides a rationale for a randomized controlled trial of magnesium therapy during CABG.

Patient-reported frequency of taking aspirin in a population with coronary artery disease.

Despite the established benefits of antiplatelet agents in coronary artery disease (CAD), many appropriate patients are not receiving them. We investigated the prevalence of and factors associated with aspirin use and nonuse within a large referral population with CAD. The goal was to identify an approach to increase the use of antiplatelet agents by such patients. We surveyed a subset (n = 2,694) of a large CAD referral population (n = 16,174) to determine the use of aspirin and factors associated with its use or nonuse. The subset was made up of all of the CAD referral population who were considered nonusers of aspirin and a 5% sample of those considered aspirin users. We then extrapolated survey data to the overall population to estimate how many eligible patients were not taking antiplatelet agents. In all, 1,626 (63%) of the surviving patients responded to the survey. Of these, 948 (58%) reported taking aspirin, and 678 (42%) reported no aspirin use. The extrapolated rate of aspirin use in the overall population was 85%. Of 2,367 nonusers, 998 (42%, or 6% of the overall cohort) were eligible for antiplatelet agents but were not taking such therapy. Although the rate of aspirin use in this population was higher than previously reported, an estimated 6% of eligible patients were not receiving antiplatelet therapy.

Underuse of aspirin in a referral population with documented coronary artery disease.

Despite substantial evidence that antiplatelet therapy saves lives and reduces adverse events in patients with coronary artery disease (CAD), use of the most widely available and lowest cost antiplatelet agent, aspirin, continues to be disappointingly low. In a large database of patients with known CAD, we (1) explored trends in the use of aspirin over time, (2) characterized patients most likely to take aspirin regularly, and (3) estimated the effectiveness of aspirin use by examining long-term outcomes. Using patients entered in the Duke Databank for Cardiovascular Diseases, we explored the use of aspirin from 1969 to 1999. More than 25,000 patients were sent a questionnaire that included several questions about medication use, including 1 question specifically about aspirin. Patients who failed to respond to the questionnaire received a follow-up telephone call. Aspirin use increased substantially over the most recent 4 years in the study, from 59% in 1995 to 81% in 1999. Predictors of aspirin use included younger age, male sex, being a nonsmoker, and having had a myocardial infarction or revascularization procedure. Patients who never took aspirin had a risk ratio for death of 1.85 compared with patients who regularly took aspirin. Despite the well-known beneficial effects of aspirin, too many patients without contraindications to aspirin fail to take it regularly. The health care system currently lacks effective methods to ensure that patients who have CAD have adequate follow-up concerning aspirin use.