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A study was conducted to evaluate the relationship between marine omega-3 fatty acid blood levels and telomeric aging in patients with coronary heart disease. Results indicated that an inverse relationship exists between the two.

The case of a 35-year-old man with advanced acquired immunodeficiency syndrome (AIDS) is used to highlight the challenges clinicians face in the diagnosis of acute pulmonary embolism. The case illustrates the importance of 'thinking outside the box' in order to avoid missing this diagnosis, particularly in patients whose underlying diseases might otherwise suggest alternative explanations for presenting symptoms.

Introduction: Quantitative Myasthenia Gravis (QMG) and Myasthenia Gravis Activities of Daily Living (MG-ADL) scales were compared using the data from the Thymectomy Trial in Non-Thymomatous Myasthenia Gravis Patients Receiving Prednisone Therapy (MGTX) study.Methods: Correlation between QMG and MG-ADL raw and change-from-baseline scores was calculated every 3 months for 60 months based on treatment groups and minimal manifestation status (MMS).Results: QMG and MG-ADL change-from-baseline scores correlated significantly, with increasing strength of correlation over time, in both treatment groups. QMG and MG-ADL raw scores correlated significantly in both treatment groups, with increasing correlation only in the prednisone-alone group. Correlation between raw scores was weaker in patients who were in MMS, demonstrating a "floor effect" on the MG-ADL scale. Raw QMG scores could be modeled assuming a normal distribution, whereas raw MG-ADL scores could not be modeled this way.Discussion: The floor effect and skewed distribution of the MG-ADL measure should be taken into account in the design of myasthenia gravis clinical trials. [ABSTRACT FROM AUTHOR]

Introduction: The Myasthenia Gravis Patient Registry (MGR) is a voluntary, patient-submitted database dedicated to improve understanding of care/burden of myasthenia gravis (MG).Methods: In this study we present analyses of baseline records through July 2017 (n = 1140) containing data on the MG-Activities of Daily Living (MG-ADL) and the MG 15-item Quality of Life (MG-QOL15) instruments, two validated scales assessing quality of life in MG patients at sign-up into the MGR.Results: Most registrants reported moderate to severe impairment of health-related quality of life, with a median MG-ADL score of 6 and a median MG-QOL15 score of 21. Seventy-one percent of the patients had received pyridostigmine. Corticosteroids, mycophenolate mofetil, and azathioprine were the most common immunomodulators/immunosuppressants, with 85% of participants having ever using one of these agents. Forty-seven registrants reported receiving intravenous immunoglobulin, and 30% received plasma exchange. Twelve percent reported other treatments, and 40% were unsure whether they received less common therapies. Forty percent had undergone thymectomy.Discussion: The MGR data correlate well with other MG cohorts. Many MG patients remain negatively impacted despite treatment. [ABSTRACT FROM AUTHOR]

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]

Background: Short telomere length independently predicts mortality in patients with coronary heart disease. Whether 5-year change in telomere length predicts subsequent mortality in patients with coronary heart disease has not been evaluated. Methods: In a prospective cohort study of 608 individuals with stable coronary artery disease, we measured leukocyte telomere length at baseline and after five years of follow-up. We divided the sample into tertiles of telomere change: shortened, maintained or lengthened. We used Cox survival models to evaluate 5-year change in telomere length as a predictor of mortality. Results: During an average of 4.2 years follow-up, there were 149 deaths. Change in telomere length was inversely predictive of all-cause mortality. Using the continuous variable of telomere length change, each standard deviation (325 base pair) greater increase in telomere length was associated with a 24% reduction in mortality (HR 0.76, 95% CI 0.61–0.94; p = 0.01), adjusted for age, sex, waist to hip ratio, exercise capacity, LV ejection fraction, serum creatinine, and year 5 telomere length. Mortality occurred in 39% (79/203) of patients who experienced telomere shortening, 22% (45/203) of patients whose telomere length was maintained, and 12% (25/202) of patients who experienced telomere lengthening (p<0.001). As compared with patients whose telomere length was maintained, those who experienced telomere lengthening were 56% less likely to die (HR 0.44, 95% CI, 0.23–0.87). Conclusions: In patients with coronary heart disease, an increase in leukocyte telomere length over 5 years is associated with decreased mortality. [ABSTRACT FROM AUTHOR]

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disorder, with an overall prevalence of at least 1:500 in the adult population although only a fraction of affected patients come to clinical recognition. It is also the most common cause of sudden cardiac death in young adults and a major cause of morbidity caused by chronic heart failure symptoms. However, more than half a century since the original description of the disease, there is no currently approved therapy for the treatment of patients with HCM, and to date there have been only 5 randomized studies of medical therapies in HCM. As such, unmet medical need in HCM has been highlighted by the National Heart, Lung, and Blood Institute (NHLBI) as a research priority. Encouragingly, the infrastructure needed to conduct rigorous clinical trials in HCM has recently emerged because of the heightened awareness and understanding of the disease, development of clinical centers of excellence, and advances in diagnostic imaging. In this article, we will discuss the complex pathophysiology of HCM, review the current therapeutic landscape, describe new mechanistic insights into the central role of the late sodium current in HCM, and introduce the scientiic rationale and execution of the Impact of Late Sodium Current Inhibition on Exercise Capacity in Subjects with Symptomatic Hypertrophic Cardiomyopathy (LIBERTY-HCM) trial, the largest randomized, double-blind, placebo controlled clinical trial, now underway, designed to evaluate the effect of a novel pharmacological approach in patients with symptomatic HCM. [ABSTRACT FROM AUTHOR]

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.Linking individual participant data from the Cooper Center Longitudinal Study with Medicare claims files, we studied 20 642 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 133 514 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).Fitness in healthy, middle-aged adults is more strongly associated with heart failure hospitalization than acute myocardial infarction outcomes decades later in older age. [ABSTRACT FROM AUTHOR]

Background: Short telomere length (TL) is an independent predictor of mortality in patients with coronary heart disease (CHD). However, the relationship between physical fitness and TL has not been explored in these patients. Methods: In a cross sectional study of 944 outpatients with stable CHD, we performed exercise treadmill testing, assessed self-reported physical activity, and measured leukocyte TL using a quantitative PCR assay. We used generalized linear models to calculate mean TL (T/S ratio), and logistic regression models to compare the proportion of patients with short TL (defined as the lowest quartile), among participants with low, medium and high physical fitness, based on metabolic equivalent tasks achieved (METs). Results: 229 participants had low physical fitness (<5 METS), 334 had moderate physical fitness (5-7 METS), and 381 had high physical fitness (>7 METS). Mean ± T/S ratio ranged from 0.86±0.21 (534963781 base pairs) in those with low physical fitness to 0.95±0.23 (5566±3829 base pairs) in those with high physical fitness (p<.001). This association remained strong after adjustment for numerous patient characteristics, including measures of cardiac disease severity and physical inactivity (p = 0.005). Compared with participants with high physical fitness, those with low physical fitness had 2-fold greater odds of having TL in the lowest quartile (OR 2.39, 95% CI 1.60-3.55; p<.001). This association was similar after multivariable adjustment (OR 1.94, 95%CI, 1.18-3.20; p = 0.009). Self-reported physical inactivity was associated with shorter TL in unadjusted analyses, but not after multivariable adjustment. Conclusions: We found that worse objectively-assessed physical fitness is associated with shorter leukocyte telomere length in patients with CHD. The clinical implications of this association deserve further study. [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]

Background: Renalase is a soluble enzyme that metabolizes circulating catecholamines. A common missense polymorphism in the flavin-adenine dinucleotide-binding domain of human renalase (Glu37Asp) has recently been described. The association of this polymorphism with cardiac structure, function, and ischemia has not previously been reported. Methods: We genotyped the rs2296545 single-nucleotide polymorphism (Glu37Asp) in 590 Caucasian individuals and performed resting and stress echocardiography. Logistic regression was used to examine the associations of the Glu37Asp polymorphism (C allele) with cardiac hypertrophy (LV mass>100 g/m2), systolic dysfunction (LVEF<50%), diastolic dysfunction, poor treadmill exercise capacity (METS<5) and inducible ischemia. Results: Compared with the 406 participants who had GG or CG genotypes, the 184 participants with the CC genotype had increased odds of left ventricular hypertrophy (OR = 1.43; 95% CI 0.99-2.06), systolic dysfunction (OR = 1.72; 95% CI 1.01-2.94), diastolic dysfunction (OR = 1.75; 95% CI 1.05-2.93), poor exercise capacity (OR = 1.61; 95% CI 1.05-2.47), and inducible ischemia (OR = 1.49, 95% CI 0.99-2.24). The Glu37Asp (CC genotype) caused a 24-fold decrease in affinity for NADH and a 2.3-fold reduction in maximal renalase enzymatic activity. Conclusions: A functional missense polymorphism in renalase (Glu37Asp) is associated with cardiac hypertrophy, ventricular dysfunction, poor exercise capacity, and inducible ischemia in persons with stable coronary artery disease. Further studies investigating the therapeutic implications of this polymorphism should be considered. [ABSTRACT FROM AUTHOR]

Background: Leukocyte telomere length, an emerging marker of biological age, has been shown to predict cardiovascular morbidity and mortality. However, the natural history of telomere length in patients with coronary artery disease has not been studied. We sought to investigate the longitudinal trajectory of telomere length, and to identify the independent predictors of telomere shortening, in persons with coronary artery disease. Methodology/Principal Findings: In a prospective cohort study of 608 individuals with stable coronary artery disease, we measured leukocyte telomere length at baseline, and again after five years of follow-up. We used multivariable linear and logistic regression models to identify the independent predictors of leukocyte telomere trajectory. Baseline and follow-up telomere lengths were normally distributed. Mean telomere length decreased by 42 base pairs per year (p<0.001). Three distinct telomere trajectories were observed: shortening in 45%, maintenance in 32%, and lengthening in 23% of participants. The most powerful predictor of telomere shortening was baseline telomere length (OR per SD increase = 7.6; 95% CI 5.5, 10.6). Other independent predictors of telomere shortening were age (OR per 10 years = 1.6; 95% CI 1.3, 2.1), male sex (OR = 2.4; 95% CI 1.3, 4.7), and waist-to-hip ratio (OR per 0.1 increase = 1.4; 95% CI 1.0, 2.0). Conclusions/Significance: Leukocyte telomere length may increase as well as decrease in persons with coronary artery disease. Telomere length trajectory is powerfully influenced by baseline telomere length, possibly suggesting negative feedback regulation. Age, male sex, and abdominal obesity independently predict telomere shortening. The mechanisms and reversibility of telomeric aging in cardiovascular disease deserve further study. [ABSTRACT FROM AUTHOR]

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]

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]