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Background: Multiple studies have demonstrated strong associations between cardiorespiratory fitness and lower cardiovascular disease mortality. In contrast, little is known about associations of fitness with nonfatal cardiovascular events., Methods and Results: Linking individual participant data from the Cooper Center Longitudinal Study with Medicare claims files, we studied 20642 participants (21% women) with fitness measured at the mean age of 49 years and who survived to receive Medicare coverage from 1999 to 2009. Fitness was categorized into age- and sex-specific quintiles (Q) according to Balke protocol treadmill time with Q1 as low fitness. Fitness was also estimated in metabolic equivalents according to treadmill time. Associations between midlife fitness and hospitalizations for heart failure and acute myocardial infarction after the age of 65 years were assessed by applying a proportional hazards model to the multivariate failure time data. After 133514 person-years of Medicare follow-up, we observed 1051 hospitalizations for heart failure and 832 hospitalizations for acute myocardial infarction. Compared with high fitness (Q4-5), low fitness (Q1) was associated with a higher rate of heart failure hospitalization (14.3% versus 4.2%) and hospitalization for myocardial infarction (9.7% versus 4.5%). After multivariable adjustment for baseline age, blood pressure, diabetes mellitus, body mass index, smoking status, and total cholesterol, a 1 unit greater fitness level in metabolic equivalents achieved in midlife was associated with ≈20% lower risk for heart failure hospitalization after the age of 65 years (men: hazard ratio [95% confidence intervals], 0.79 [0.75-0.83]; P<0.001 and women: 0.81 [0.68-0.96]; P=0.01) but just a 10% lower risk for acute myocardial infarction in men (0.91 [0.87-0.95]; P<0.001) and no association in women (0.97 [0.83-1.13]; P=0.68)., Conclusions: Fitness in healthy, middle-aged adults is more strongly associated with heart failure hospitalization than acute myocardial infarction outcomes decades later in older age.

Aims: First-degree atrioventricular block (AVB) has traditionally been considered a benign electrocardiographic finding in healthy individuals. However, the clinical significance of first-degree AVB has not been evaluated in patients with stable coronary heart disease. We investigated whether first-degree AVB is associated with heart failure (HF) and mortality in a prospective cohort study of outpatients with stable coronary artery disease (CAD)., Methods and Results: We measured the P-R interval in 938 patients with stable CAD and classified them into those with (P-R interval ≥ 220 ms) and without (P-R interval <220 ms) first-degree AVB. Hazard ratios (HRs) and 95% confidence intervals were calculated for HF hospitalization and all-cause mortality. During 5 years of follow-up, there were 123 hospitalizations for HF and 285 deaths. Compared with patients who had normal atrioventricular conduction, those with first-degree AVB were at increased risk for HF hospitalization (age-adjusted HR 2.33: 95% CI 1.49-3.65; P= 0.0002), mortality [age-adjusted HR 1.58; 95% CI (1.13-2.20); P = 0.008], cardiovascular (CV) mortality [age-adjusted HR 2.33; 95% CI (1.28-4.22); P= 0.005], and the combined endpoint of HF hospitalization or CV mortality (age-adjusted HR 2.43: 95% CI 1.64-3.61; P ≤ 0.0001). These associations persisted after multivariable adjustment for heart rate, medication use, ischaemic burden, and QRS duration. Adjustment for left ventricular systolic and diastolic function partially attenuated the effect, but first-degree AVB remained associated with the combined endpoint of HF or CV death (HR 1.61, CI 1.02-2.54; P= 0.04)., Conclusion: In a large cohort of patients with stable coronary artery disease, first-degree AVB is associated with HF and death.

Heart failure (HF) is a common public health problem, and many new cases are now recognized to occur in patients with preserved left ventricular ejection fraction. beta Blockers improve the outcomes of patients with known left ventricular systolic dysfunction, but whether beta blockers provide similar protection among patients with left ventricular diastolic dysfunction is unclear. We studied the association between use of beta blockers and subsequent hospitalization for HF in patients with diastolic dysfunction and stable coronary heart disease. We evaluated medication use and performed echocardiography at baseline in a prospective cohort of 911 outpatients with known coronary heart disease from the Heart and Soul Study. Hospitalizations for HF were assessed by blinded review of the medical records during an average follow-up of 5.2 years. Of the 911 participants, 118 (13%) had diastolic dysfunction, of whom 2 were lost to follow-up. Of the 116 remaining patients, 19 (25%) of the 77 using beta blockers were hospitalized for HF compared to 16 (41%) of the 39 not using beta blockers (age-adjusted hazard ratio 0.51, 95% confidence interval 0.26 to 1.00; p = 0.05). This association remained after additional adjustment for gender, smoking, history of myocardial infarction, diabetes, and creatinine (hazard ratio 0.46, 95% confidence interval 0.23 to 0.93; p = 0.03). The results were similar after excluding 31 participants with a history of self-reported HF (hazard ratio 0.33, 95% confidence interval 0.13 to 0.86; p = 0.02) and 24 participants with concurrent systolic dysfunction (hazard ratio 0.36, 95% confidence interval 0.14 to 0.89; p = 0.03). In conclusion, the use of beta blockers is associated with a decreased risk of hospitalization for HF in patients with diastolic dysfunction and stable coronary heart disease., (Published by Elsevier Inc.)

Obesity is an independent risk factor for recurrent events among patients with established coronary heart disease (CHD). The goal of the present study was to identify potential mechanisms underlying this association. We measured the waist-to-hip ratio and body mass index in 979 outpatients with stable CHD and followed them for a mean of 4.9 years. We used proportional hazards models to evaluate the extent to which the association of obesity with subsequent heart failure (HF) hospitalization or cardiovascular (CV) events (myocardial infarction, stroke, or CHD death) was explained by baseline co-morbidities, cardiac disease severity, inflammation, insulin resistance, neurohormones and adipokines. Of the 979 participants, 128 (13%) were hospitalized for HF and 152 (16%) developed a CV event. Each standard deviation (SD) increase in the waist-to-hip ratio was associated with a 30% increased risk of HF hospitalization (unadjusted hazard ratio [HR] 1.3, 95% confidence interval [CI] 1.1 to 1.6). This association was not attenuated after adjustment for potential mediators (HR 1.6, 95% CI 1.2 to 2.1). Likewise, each SD increase in the waist-to-hip ratio was associated with a 20% greater risk of CV events (unadjusted HR 1.2, 95% CI 1.0 to 1.4), and this remained unchanged after adjustment for potential mediators (adjusted HR 1.3, 95% CI 1.0 to 1.5). The body mass index was not associated with the risk of HF or CV events. In conclusion, abdominal obesity is an independent predictor of HF hospitalization and recurrent CV events in patients with stable CHD. This association does not appear to be mediated by co-morbid conditions, cardiac disease severity, insulin resistance, inflammation, neurohormones, or adipokines.

Objectives: We sought to determine which transthoracic echocardiographic (TTE) measurements most strongly predict heart failure (HF) and to develop an index for risk stratification in outpatients with coronary artery disease (CAD)., Background: Many TTE measurements have been shown to be predictive of HF, and they might be useful if aggregated into a risk-prediction index., Methods: We performed TTE in 1,024 outpatients with stable CAD enrolled in the Heart and Soul study and followed them for 4.4 years. With Cox proportional hazard models, we evaluated the association of 15 TTE measurements with subsequent HF hospital stay. Those measurements that independently predicted HF were combined into an index. Variables were defined as normal or abnormal on the basis of dichotomous cutoffs determined from the American Society of Echocardiography. Abnormal variables in each measurement were assigned points on the basis of strength of association with HF., Results: Of the 15 variables, 5 measurements were independent predictors of HF: left ventricular mass index (LVMI), left atrial volume index (LAVI), mitral regurgitation (MR), left ventricular outflow tract velocity-time integral (VTI(LVOT)), and diastolic dysfunction (DD). In multivariate analysis, each of the 5 measurements independently predicted HF: LVMI >90 g/m(2) (hazard ratio [HR]: 4.1; 95% confidence interval [CI]: 2.3 to 7.2, p < 0.0001); pseudo-normal or restrictive DD (HR: 2.9; 95% CI: 1.8 to 4.5, p < 0.0001); VTI(LVOT) <22 mm (HR: 2.2; 95% CI: 1.4 to 3.5, p = 0.0004); mild, moderate, or severe MR (HR: 1.8; 95% CI: 1.2 to 2.8, p = 0.009); and LAVI >29 ml/m(2) (HR: 1.6; 95% CI: 1.0 to 2.5, p < 0.06). Combining these measurements, the Heart Failure Index ranged from 0 to 8, representing risk as follows: 3 points for LVMI, 2 points for DD, and 1 point for VTI(LVOT), MR, and LAVI. Among participants with 0 to 2 points: 4% had HF hospital stays (reference); 3 to 4 points: 10% (HR: 2.4; 95% CI: 1.3 to 4.4, p = 0.003); 5 to 6 points: 24% (HR: 6.2; 95% CI: 3.6 to 10.6, p < 0.0001); 7 to 8 points: 48% (HR: 13.7; 95% CI: 7.2 to 25.9, p < 0.0001)., Conclusions: We identified 5 TTE measurements that independently predict HF in patients with stable CAD and combined them as an index that might be useful for risk stratification and serial observations.

Background: Quantitative stress echocardiography enables calculation of left-ventricular power-to-mass ratio (LVPMR) at peak exercise, a novel measure of cardiac performance per unit mass of myocardial tissue. We hypothesized that LVPMR at peak exercise provides prognostic information beyond established echocardiographic indices such as left-ventricular ejection fraction (LVEF) and left-ventricular mass index (LVMI)., Methods: LVPMR (watts/kilogram) at peak exercise was defined as (k x heart rate x mean arterial pressure x stroke volume)/LV mass. We measured LVPMR in 918 adults with stable ambulatory coronary artery disease recruited for the Heart and Soul Study. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for all-cause mortality, cardiovascular death, nonfatal myocardial infarction, heart failure hospitalization, and combined adverse cardiovascular events. Multivariate adjustments were made for established risk factors including LVEF and LVMI. The prognostic value of LVPMR was also compared with established exercise parameters using receiver-operating characteristic curve analysis., Results: Compared with patients in the highest LVPMR quartile, those in the lowest quartile were at increased risk of all-cause mortality (adjusted HR 1.9; 95% CI 1.1-3.3), heart failure hospitalization (adjusted HR 2.9; 95% CI 1.2-6.9), and combined adverse cardiovascular events (adjusted HR 1.9; 95% CI 1.1-3.4). In comparison with the rate-pressure product and the Duke treadmill score, LVPMR did not add significant prognostic value (p > 0.1 for c-statistic comparisons)., Conclusions: In patients with stable ambulatory coronary artery disease, LVPMR at peak exercise predicts mortality, heart failure hospitalization, and adverse cardiovascular events. However, LVPMR does not add significant prognostic information beyond established exercise test parameters., (Copyright 2009 S. Karger AG, Basel.)

Background: Telomere shortening has been proposed as a marker of biological aging. Whether leukocyte telomere length is associated with mortality among patients with stable coronary artery disease (CAD) is unknown., Methods and Results: We measured leukocyte telomere length in 780 patients with stable CAD in a prospective cohort study. Participants were categorized by quartiles of telomere length. Hazard Ratios (HRs) and 95% confidence intervals were calculated for all-cause mortality, heart failure (HF) hospitalization, and cardiovascular (CV) events. After 4.4 years of follow-up there were 166 deaths. Compared with participants in the highest telomere length quartile, those in the lowest quartile were at increased risk of death (age-adjusted HR 1.8; 95% CI 1.2 to 2.9). After multivariate adjustment for clinical (HR 2.1; CI 1.3 to 3.3), inflammatory (HR 2.0; CI 1.2 to 3.2), and echocardiographic (HR 1.9; CI 1.0 to 3.5) risk factors, patients in the lowest quartile of telomere length remained at significantly increased risk of death compared to those in the highest quartile. Patients in the lowest quartile of telomere length were also at significantly increased risk of HF hospitalization (HR 2.6; CI 1.1 to 6.0) but not CV events (HR 1.7; CI 0.9 to 3.5)., Conclusions: Reduced leukocyte telomere length is associated with all-cause mortality in patients with stable CAD. The prognostic value of short telomeres in predicting death is not completely captured by existing clinical, inflammatory, and echocardiographic markers of risk.

Pulmonary vascular resistance (PVR) is an important hemodynamic variable that affects prognosis and therapy in a wide range of cardiovascular and pulmonary conditions. We sought to determine whether a noninvasive estimate of PVR predicts adverse outcomes in patients with stable coronary artery disease. Using Doppler echocardiography we measured the estimated PVR (defined as the ratio of the tricuspid regurgitant velocity [TRV] to the velocity-time integral [VTI] of the right ventricular outflow tract [RVOT]) in 795 ambulatory patients with stable coronary artery disease. Participants were categorized by quartiles of the TRV/VTI RVOT ratio. Hazard ratios (HRs) and 95% confidence intervals were calculated for all-cause mortality, heart failure hospitalization, and adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction, or stroke). After 4.3 years of follow-up there were 161 deaths, 44 deaths from cardiovascular causes, 103 heart failure hospitalizations, and 120 adverse cardiovascular events. Compared with patients in the lowest TRV/VTI RVOT quartile, those in the highest quartile were at increased risk of all-cause mortality (unadjusted HR 1.8, 95% confidence interval 1.3 to 2.5), heart failure hospitalization (unadjusted HR 2.9, 95% confidence interval 2.0 to 4.3), and adverse cardiovascular events (unadjusted HR 2.0, 95% confidence interval 1.4 to 2.9). After multivariate adjustment, patients in the highest quartile were at increased risk of heart failure hospitalizations (adjusted HR 2.5, 95% confidence interval 1.3 to 4.7). In conclusion, a noninvasive estimate of PVR (TRV/VTI RVOT ratio) predicts mortality, heart failure hospitalization, and adverse cardiovascular events in patients with stable coronary artery disease.