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Background: Even before the onset of age-related diseases, obesity might be a contributing factor to the cumulative burden of oxidative stress and chronic inflammation throughout the life course. Obesity may therefore contribute to accelerated shortening of telomeres. Consequently, obese persons are more likely to have shorter telomeres, but the association between body mass index (BMI) and leukocyte telomere length (TL) might differ across the life span and between ethnicities and sexes. Objective: A collaborative cross-sectionalmeta-analysis of observational studies was conducted to investigate the associations between BMI and TL across the life span. Design: Eighty-seven distinct study samples were included in the meta-analysis capturing data from 146,114 individuals. Studyspecific age- and sex-adjusted regression coefficients were combined by using a random-effects model in which absolute [base pairs (bp)] and relative telomere to single-copy gene ratio (T/S ratio) TLs were regressed against BMI. Stratified analysis was performed by 3 age categories (“young”: 18–60 y; “middle”: 61–75 y; and “old”: >75 y), sex, and ethnicity. Results: Each unit increase in BMI corresponded to a−3.99 bp (95% CI: −5.17, −2.81 bp) difference in TL in the total pooled sample; among young adults, each unit increase in BMI corresponded to a −7.67 bp (95% CI:−10.03,−5.31 bp) difference. Each unit increase in BMI corresponded to a −1.58 × 10−3 unit T/S ratio (0.16% decrease; 95% CI: −2.14 × 10−3, −1.01 × 10−3) difference in ageand sex-adjusted relative TL in the total pooled sample; among young adults, each unit increase in BMI corresponded to a −2.58 × 10−3 unit T/S ratio (0.26% decrease; 95% CI: −3.92 × 10−3, −1.25 × 10−3). The associations were predominantly for the white pooled population. No sex differences were observed. Conclusions: A higher BMI is associated with shorter telomeres, especially in younger individuals. The presently observed difference is not negligible. Meta-analyses of longitudinal studies evaluating change in body weight alongside change in TL are warranted. [ABSTRACT FROM AUTHOR]

Objectives The aim of this study was to describe current practice regarding completeness of revascularization in patients with multivessel disease undergoing percutaneous coronary intervention (PCI) and to investigate the association of incomplete revascularization (IR) with death, repeat revascularization, and myocardial infarction (MI) in a large nationwide registry. Background The benefits of multivessel PCI are controversial. Methods Between 2006 and 2010 we identified 23,342 patients with multivessel disease in the SCAAR (Swedish Coronary Angiography and Angioplasty Registry) and merged data with official Swedish health data registries. IR was defined as any nontreated significant (60%) stenosis in a coronary artery supplying >10% of the myocardium. Results Patients with IR (n = 15,165) were older, had more extensive coronary disease, and more often had ST-segment elevation MI at presentation than those with complete revascularization (CR) (n = 8,177). All-cause 1-year mortality, MI, and repeat revascularization were higher in IR than CR: 7.1% versus 3.8%, 10.4% versus 6.0%, and 20.5% versus 8.5%, respectively. Propensity score methodology was used in the adjusted analyses. Adjusted hazard ratio (HR) for the composite of death, MI, or repeat revascularization at 1 year was higher in IR than CR: 2.12 (95% confidence interval [CI]: 1.98 to 2.28; p < 0.0001). Adjusted HR for death and the combination of death/MI were 1.29 (95% CI: 1.12 to 1.49; p = 0.0005) and 1.42 (95% CI: 1.30 to 1.56; p < 0.0001), respectively. Conclusions Incomplete revascularization at the time of hospital discharge in patients with multivessel disease undergoing PCI is associated with a high risk of recurrent 1-year adverse cardiac events. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Leptin is an adipokine with both protective and harmful effects on the cardiovascular (CV) system. Prior studies evaluating the association between leptin and CV outcomes have yielded conflicting results. Thus, we sought to investigate the relationship between leptin and CV events and mortality in patients with chronic stable coronary artery disease (CAD). Methods: We performed a prospective cohort study of 981 outpatients with stable CAD. Leptin levels were measured in fasting venous samples at baseline. We used proportional hazards models to evaluate the association of baseline leptin with subsequent CV events (myocardial infarction, stroke, transient ischemic attack) and death. Results: During a mean follow-up of 6.2±2.1 years, there were 304 deaths, 112 myocardial infarctions, and 52 strokes/TIAs. In models adjusted for age, sex, and race, low leptin was associated with a 30% increased risk of the combined outcome (HR 1.30, CI 1.05–1.59, p =0.01). After further adjustment for obesity, traditional CV risk factors and biomarkers, low leptin remained associated with a 37% increased risk of events (HR 1.37, CI 1.06–1.76, p =0.02). Conclusions: Low leptin is associated with increased CV events and mortality in patients with stable coronary artery disease. This association is independent of known factors affecting leptin levels, including gender and obesity. [Copyright &y& Elsevier]

Dietary intake of n-3 polyunsaturated fatty acids is associated with a lower incidence of cardiovascular events. Mechanisms underlying this association are poorly understood but may include beneficial effects on physical conditioning and vagal tone. We investigated the association of n-3 fatty acid levels to exercise parameters in 992 subjects with stable coronary artery disease. Cross-sectional associations of heart rate recovery time, treadmill exercise capacity, and exercise time with docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) levels were evaluated in multivariable linear and logistic regression models adjusted for demographics, cardiovascular risk factors, co-morbidities, self-reported physical activity, medication use, and left ventricular function. After multivariable adjustment, n-3 fatty acid levels (DHA + EPA) were strongly associated with heart rate recovery (beta 2.1, p = 0.003), exercise capacity (beta 0.8, p <0.0001), and exercise time (beta 0.9, p <0.0001). Increasing levels of (DHA + EPA) were also associated with decreased risk of impaired heart rate recovery (odds ratio 0.8, p = 0.004) and exercise time (odds ratio 0.7, p = 0.01) and trended toward significance for exercise capacity (odds ratio 0.8, p = 0.07). These associations were not modified by demographics, body mass index, smoking, co-morbid conditions, statin use, or β-blocker use (p for interaction >0.1 for all comparisons). In conclusion, an independent association exists between n-3 fatty acid levels and important exercise parameters in patients with stable coronary artery disease. These findings support the hypothesis that n-3 fatty acids may increase vagal tone and physical conditioning. [ABSTRACT FROM AUTHOR]

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. β Blockers improve the outcomes of patients with known left ventricular systolic dysfunction, but whether β blockers provide similar protection among patients with left ventricular diastolic dysfunction is unclear. We studied the association between use of β 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 β blockers were hospitalized for HF compared to 16 (41%) of the 39 not using β 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 β blockers is associated with a decreased risk of hospitalization for HF in patients with diastolic dysfunction and stable coronary heart disease. [Copyright &y& Elsevier]

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. [Copyright &y& Elsevier]

Abstract: Objective: Dietary intake of polyunsaturated n-3 fatty acids has been associated with a reduced incidence of adverse cardiovascular events. The protective mechanisms involved are not fully understood, but may include anti-inflammatory factors. We sought to investigate the relationship between n-3 fatty acid levels in erythrocyte membranes and markers of systemic inflammation in 992 individuals with stable coronary artery disease. Methods: Cross-sectional associations of C-reactive protein (CRP) and Interleukin-6 (Il-6) with docosahexaenoic acid (DHA) and eicosapentaenoic acid (EHA) were evaluated in multivariable linear regression models adjusted for demographics, cardiovascular risk factors, medication use, exercise capacity, body-mass index, and waist-to-hip ratio. Results: After multivariable adjustment, n-3 fatty acid levels (DHA+EPA) were inversely associated with CRP and IL-6. The inverse association of n-3 fatty acids with CRP and IL-6 was not modified by demographics, body-mass index, smoking, LDL-cholesterol, or statin use (p values for interaction>0.1). Conclusions: In patients with stable coronary artery disease, an independent and inverse association exists between n-3 fatty acid levels and inflammatory biomarkers. These findings suggest that inhibition of systemic inflammation may be a mechanism by which n-3 fatty acids prevent recurrent cardiovascular events. [Copyright &y& Elsevier]

Abstract: Objective: Recent large-scale genome-wide association studies have identified a novel susceptibility locus on chromosome 9p21.3 that contributes a significant attributable risk for myocardial infarction. The phenotypic significance of this locus in patients with established coronary artery disease is unknown. We sought to compare cardiovascular structure and function in carriers and non-carriers of the risk haplotype in a cross-sectional study. Methods: We genotyped the rs1333049 single-nucleotide polymorphism in 593 Caucasian individuals with stable coronary artery disease recruited in the Heart and Soul Study. All study subjects underwent resting and stress echocardiography. Linear and logistic regression models were used to examine the association between the rs1333049 polymorphism and echocardiographic parameters of cardiovascular structure and function. Results: There was no association between rs1333049 genotype and echocardiographic phenotype (left ventricular hypertrophy, systolic dysfunction, diastolic dysfunction, inducible ischemia, exercise capacity, mitral annular calcification, and aortic plaque). Conclusions: In a cross-sectional study of individuals with stable coronary artery disease, there was no association of chromosome 9p21.3 genotype with cardiovascular structure and function. [Copyright &y& Elsevier]

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 (VTILVOT), and diastolic dysfunction (DD). In multivariate analysis, each of the 5 measurements independently predicted HF: LVMI >90 g/m2 (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); VTILVOT <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/m2 (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 VTILVOT, 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. [Copyright &y& Elsevier]

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/VTIRVOT 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/VTIRVOT 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/VTIRVOT ratio) predicts mortality, heart failure hospitalization, and adverse cardiovascular events in patients with stable coronary artery disease. [Copyright &y& Elsevier]

The hyperdynamic circulation associated with cirrhosis is typically characterized by high cardiac output and low systemic and pulmonary vascular resistance (PVR). Approximately 4% of cirrhotic patients develop portopulmonary hypertension, which is an important predictor of hemodynamic instability after orthotopic liver transplantation. Doppler estimation of pulmonary artery systolic pressure (PASP) is used as a screening test for the presence of portopulmonary hypertension. We tested the accuracy of a noninvasive measurement of PVR (ratio of peak tricuspid regurgitant velocity [TRV] to right ventricular outflow tract velocity time integral [VTIRVOT]) to detect increased PVR in a population before liver transplantation. We compared test characteristics of the TRV/VTIRVOT ratio to echocardiographically derived PASP for detection of invasively measured PVR >1.5 Wood units. There was no significant correlation between Doppler-derived PASP and invasively measured PVR. There was a moderate and significant correlation between TRV/VTIRVOT ratio and invasively measured PVR. Compared with Doppler-derived PASP, the TRV/VTIRVOT ratio was a more accurate test for PVR >1.5 Wood units. Using a cut-off value of TRV/VTIRVOT >0.12, the sensitivity and negative predictive value for PVR >1.5 Wood units were 100%. In conclusion, the TRV/VTIRVOT ratio is a more accurate screening test for the presence of portopulmonary hypertension than PASP in patients undergoing orthotopic liver transplantation. Routine use of this ratio may decrease the need for invasive hemodynamic assessment in this patient population. [Copyright &y& Elsevier]

Leukotrienes are potent biological mediators implicated in an increasing number of disease processes. This review outlines the basic biology of leukotrienes and discusses recent developments in our understanding of the specific role of cysteinyl-leukotrienes (cLTs) in cholestasis, hepatic inflammation, portal hypertension, and the pathogenesis of the hepatorenal syndrome (HRS). [Copyright &y& Elsevier]

Background: Incomplete revascularization (ICR) after percutaneous coronary intervention (PCI) is common and is associated with increased rates of rehospitalization, revascularization, and mortality. Adjunctive pharmacotherapy with ranolazine, an inhibitor of the late sodium current with anti-ischemic properties, may be effective in reducing recurrent events after PCI in patients with ICR. Trial Design: RIVER-PCI is a phase 3, randomized, double-blind, placebo-controlled, international event-driven clinical trial evaluating the efficacy of ranolazine in patients with a history of chronic angina and ICR after PCI. Approximately 2,600 participants with ICR post-PCI will be randomized in a 1:1 ratio to ranolazine or matched placebo within 14 days of an index PCI. The primary end point of the trial is time to the first occurrence of ischemia-driven revascularization or ischemia-driven hospitalization without revascularization. Participants will be followed up for a minimum of 1 year and until at least 720 confirmed primary end point events have occurred. Secondary end points include sudden cardiac death, cardiovascular death, myocardial infarction, and measures of quality of life and cost-effectiveness. The evaluation of long-term safety will include all-cause mortality, stroke, transient ischemic attack, and hospitalization for heart failure. Enrollment commenced in November 2011 and was completed in summer 2013. Conclusions: RIVER-PCI is a novel, large-scale, international, randomized, double-blind, placebo-controlled clinical trial evaluating the role of ranolazine in the long-term medical management of patients with ICR post-PCI. [Copyright &y& Elsevier]

Hypertrophic cardiomyopathy (HC) is the most common genetic heart disease and an important cause of sudden death and heart failure symptoms. The current prevalence for HC (1:500) is based on echocardiographic population studies in which a substantial proportion of affected subjects have not come to clinical recognition. Therefore, we sought to define the subset of patients with HC who are diagnosed in the US. A proprietary integrated claims database including medical condition International Classification of Diseases, Ninth Revision diagnostic codes for over 160 million individual patients in the US was interrogated for 2013 to identify the prevalence of clinically recognized HC. Patients with ≥1 claim for any of the HC International Classification of Diseases, Ninth Revision diagnosis codes from January to December 2013 were identified. The combined occurrence rate of HC was stratified by age and gender and multiplied by the 2013 United States population in the same age/gender categories to produce the final projected prevalence. The analysis was performed on 169,089,614 patients, of whom 59,009 unique patients were identified with ≥1 claim for HC. The projected estimated occurrence of diagnosed HC in the US in 2013 was 1:3,195 for a total of 98,958 subjects. Average age at HC diagnosis was in the fifth decade of life, with 43% of the cohort composed of women. In conclusion, leveraging a claims-based data analytic technique, about 100,000 patients are diagnosed clinically with HC in the US, an occurrence which is less than the prevalence reported in systematic population studies based on echocardiographic diagnosis. This observation supports the view that many patients with HC are undiagnosed throughout life and enhances our understanding of the burden of this genetic heart disease on the health care system. [ABSTRACT FROM AUTHOR]