Showing papers by "William E. Kraus published in 2015"

Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction

Abstract: Exome sequence analysis of nearly 10,000 people was carried out to identify alleles associated with early-onset myocardial infarction; mutations in low-density lipoprotein receptor (LDLR) or apolipoprotein A-V (APOA5) were associated with disease risk, identifying the key roles of low-density lipoprotein cholesterol and metabolism of triglyceride-rich lipoproteins. Sekar Kathiresan and colleagues use exome sequencing of nearly 10,000 people to probe the contribution of multiple rare mutations within a gene to risk for myocardial infarction at a population level. They find that mutations in low-density lipoprotein receptor (LDLR) or apolipoprotein A-V (APOA5) are associated with disease risk. When compared with non-carriers, LDLR mutation carriers had higher plasma levels of LDL cholesterol, whereas APOA5 mutation carriers had higher plasma levels of triglycerides. As well as confirming that APOA5 is a myocardial infarction gene, this work informs the design and conduct of rare-variant association studies for complex diseases. Myocardial infarction (MI), a leading cause of death around the world, displays a complex pattern of inheritance1,2. When MI occurs early in life, genetic inheritance is a major component to risk1. Previously, rare mutations in low-density lipoprotein (LDL) genes have been shown to contribute to MI risk in individual families3,4,5,6,7,8, whereas common variants at more than 45 loci have been associated with MI risk in the population9,10,11,12,13,14,15. Here we evaluate how rare mutations contribute to early-onset MI risk in the population. We sequenced the protein-coding regions of 9,793 genomes from patients with MI at an early age (≤50 years in males and ≤60 years in females) along with MI-free controls. We identified two genes in which rare coding-sequence mutations were more frequent in MI cases versus controls at exome-wide significance. At low-density lipoprotein receptor (LDLR), carriers of rare non-synonymous mutations were at 4.2-fold increased risk for MI; carriers of null alleles at LDLR were at even higher risk (13-fold difference). Approximately 2% of early MI cases harbour a rare, damaging mutation in LDLR; this estimate is similar to one made more than 40 years ago using an analysis of total cholesterol16. Among controls, about 1 in 217 carried an LDLR coding-sequence mutation and had plasma LDL cholesterol > 190 mg dl−1. At apolipoprotein A-V (APOA5), carriers of rare non-synonymous mutations were at 2.2-fold increased risk for MI. When compared with non-carriers, LDLR mutation carriers had higher plasma LDL cholesterol, whereas APOA5 mutation carriers had higher plasma triglycerides. Recent evidence has connected MI risk with coding-sequence mutations at two genes functionally related to APOA5, namely lipoprotein lipase15,17 and apolipoprotein C-III (refs 18, 19). Combined, these observations suggest that, as well as LDL cholesterol, disordered metabolism of triglyceride-rich lipoproteins contributes to MI risk.

A 2-Year Randomized Controlled Trial of Human Caloric Restriction: Feasibility and Effects on Predictors of Health Span and Longevity

Abstract: BACKGROUND Caloric restriction (CR), energy intake reduced below ad libitum (AL) intake, increases life span in many species. The implications for humans can be clarified by randomized controlled trials of CR. METHODS To determine CR's feasibility, safety, and effects on predictors of longevity, disease risk factors, and quality of life in nonobese humans aged 21-51 years, 218 persons were randomized to a 2-year intervention designed to achieve 25% CR or to AL diet. Outcomes were change from baseline resting metabolic rate adjusted for weight change ("RMR residual") and core temperature (primary); plasma triiodothyronine (T3) and tumor necrosis factor-α (secondary); and exploratory physiological and psychological measures. RESULTS Body mass index averaged 25.1 (range: 21.9-28.0 kg/m(2)). Eighty-two percent of CR and 95% of AL participants completed the protocol. The CR group achieved 11.7±0.7 %CR (mean ± standard error) and maintained 10.4±0.4% weight loss. Weight change in AL was negligible. RMR residual decreased significantly more in CR than AL at 12 months (p = .04) but not 24 months (M24). Core temperature change differed little between groups. T3 decreased more in CR at M12 and M24 (p < .001), while tumor necrosis factor-α decreased significantly more only at M24 (p = .02). CR had larger decreases in cardiometabolic risk factors and in daily energy expenditure adjusted for weight change, without adverse effects on quality of life. CONCLUSIONS Sustained CR is feasible in nonobese humans. The effects of the achieved CR on correlates of human survival and disease risk factors suggest potential benefits for aging-related outcomes that could be elucidated by further human studies.

Bioengineered human myobundles mimic clinical responses of skeletal muscle to drugs

Abstract: Existing in vitro models of human skeletal muscle cannot recapitulate the organization and function of native muscle, limiting their use in physiological and pharmacological studies. Here, we demonstrate engineering of electrically and chemically responsive, contractile human muscle tissues ('myobundles') using primary myogenic cells. These biomimetic constructs exhibit aligned architecture, multinucleated and striated myofibers, and a Pax7(+) cell pool. They contract spontaneously and respond to electrical stimuli with twitch and tetanic contractions. Positive correlation between contractile force and GCaMP6-reported calcium responses enables non-invasive tracking of myobundle function and drug response. During culture, myobundles maintain functional acetylcholine receptors and structurally and functionally mature, evidenced by increased myofiber diameter and improved calcium handling and contractile strength. In response to diversely acting drugs, myobundles undergo dose-dependent hypertrophy or toxic myopathy similar to clinical outcomes. Human myobundles provide an enabling platform for predictive drug and toxicology screening and development of novel therapeutics for muscle-related disorders.

A novel multi-tissue RNA diagnostic of healthy ageing relates to cognitive health status

Abstract: Diagnostics of the human ageing process may help predict future healthcare needs or guide preventative measures for tackling diseases of older age. We take a transcriptomics approach to build the first reproducible multi-tissue RNA expression signature by gene-chip profiling tissue from sedentary normal subjects who reached 65 years of age in good health. One hundred and fifty probe-sets form an accurate classifier of young versus older muscle tissue and this healthy ageing RNA classifier performed consistently in independent cohorts of human muscle, skin and brain tissue (n = 594, AUC = 0.83–0.96) and thus represents a biomarker for biological age. Using the Uppsala Longitudinal Study of Adult Men birth-cohort (n = 108) we demonstrate that the RNA classifier is insensitive to confounding lifestyle biomarkers, while greater gene score at age 70 years is independently associated with better renal function at age 82 years and longevity. The gene score is ‘up-regulated’ in healthy human hippocampus with age, and when applied to blood RNA profiles from two large independent age-matched dementia case–control data sets (n = 717) the healthy controls have significantly greater gene scores than those with cognitive impairment. Alone, or when combined with our previously described prototype Alzheimer disease (AD) RNA ‘disease signature’, the healthy ageing RNA classifier is diagnostic for AD. We identify a novel and statistically robust multi-tissue RNA signature of human healthy ageing that can act as a diagnostic of future health, using only a peripheral blood sample. This RNA signature has great potential to assist research aimed at finding treatments for and/or management of AD and other ageing-related conditions.

Exercise Training as Therapy for Heart Failure Current Status and Future Directions

Abstract: Despite a variety of pharmacological and device therapies for persons with chronic heart failure (HF), prognosis and quality of life (QOL) remain poor. The need for new effective strategies to improve outcomes for patients with HF is underscored by persistently high mortality, morbidity, healthcare use, and costs associated with HF, with >1 million US HF hospitalizations at an estimated direct and indirect cost in the US of $40 billion in 2012.1 Exercise intolerance is a primary symptom in patients with chronic HF, both those with preserved ejection fraction (HFpEF) and reduced ejection fraction (HFrEF), and is a strong determinant of prognosis and of reduced QOL.2 Exercise training improves exercise intolerance and QOL in patients with chronic stable HFrEF, and has become an accepted adjunct therapy for these patients (Class B level of evidence) based on a fairly extensive evidence base of randomized trials, mostly small.3 The National Heart, Lung, and Blood Institute–funded Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) trial compared an individualized, supervised, and home-based aerobic exercise program plus guideline-based pharmacological and device therapy with guideline-based therapy alone in persons with HFrEF. The exercise arm showed a modest reduction in cardiovascular hospitalizations and mortality and improved QOL.4,5 However, problems with adherence in the exercise arm probably dampened the potential benefit. This landmark study leaves several unanswered key questions, including the role of exercise dose; the relative benefit of different types of aerobic exercise, including high-intensity interval training (HIIT), and resistance, training relative to aerobic training; combination of exercise training with other therapies; optimization of adherence; benefit for older patients with HF, those with HFpEF or multiple comorbidities, and those with acute decompensated HF. The National Heart, Lung, and Blood Institute convened a working group of experts on June 11, …

The National Physical Activity Plan: a call to action from the American Heart Association: a science advisory from the American Heart Association.

Abstract: The health benefits of regular physical activity and the relation between physical inactivity and chronic disease morbidity and mortality are well established. Also clear is the fact that efforts to increase physical activity at the population level will require collective action by government, nongovernment, for-profit, and nonprofit entities working together at the local, state, and national levels. The US National Physical Activity Plan (NPAP), developed by the National Physical Activity Plan Alliance, of which the American Heart Association (AHA) is a member, is designed to facilitate this collective action, to help organizations from all sectors of society work together to increase physical activity in all segments of the American population. The purposes of this advisory are to summarize the data that describe the health benefits of regular physical activity and the public health burden of low levels of physical activity, to describe the NPAP and the role it will play in increasing population levels of physical activity, and to encourage readers of Circulation to join the AHA’s efforts to promote its implementation. As summarized in Table 1, there is substantial evidence supporting the benefits of regular physical activity to prevent a wide variety of disease conditions and to enhance quality of life. Interestingly, there is less of an appreciation of noncardiovascular benefits of lifestyle physical activity and structured exercise, and this is an area of great opportunity for educating the public and healthcare practitioners. View this table: Table 1. The Health Benefits of Regular Physical Activity Physical inactivity is rapidly becoming a major global concern and is the fourth leading cause of death worldwide.2,3 As noted by Kohl and colleagues, “In view of the prevalence, global reach, and health effect of physical inactivity, the issue should be appropriately described as pandemic, with far-reaching health, economic, environmental, and social consequences.”4 According …

Physiology of Sedentary Behavior and Its Relationship to Health Outcomes

Abstract: AB Purpose: This article reports on the findings and recommendations of the "Physiology of Sedentary Behavior and Its Relationship to Health Outcomes" group, a part of a larger workshop entitled Sedentary Behavior: Identifying Research Priorities sponsored by the National Heart, Lung, and Blood Institute and by the National Institute on Aging, which aimed to establish sedentary behavior research priorities. Methods: The discussion within our workshop led to the formation of critical physiological research objectives related to sedentary behaviors, that is, if appropriately researched, would greatly affect our overall understanding of human health and longevity. Results and Conclusions: Primary questions are related to physiological "health outcomes" including the influence of physical activity versus sedentary behavior on the function of a number of critical physiological systems (aerobic capacity, skeletal muscle metabolism and function, telomeres/genetic stability, and cognitive function). The group also derived important recommendations related to the "central and peripheral mechanisms" that govern sedentary behavior and how energy balance has a role in mediating these processes. General recommendations for future sedentary physiology research efforts indicate that studies of sedentary behavior, including that of sitting time only, should focus on the physiological effect of a "lack of human movement" in contradistinction to the effects of physical movement and that new models or strategies for studying sedentary behavior-induced adaptations and links to disease development are needed to elucidate underlying mechanism(s)

Impact of combined resistance and aerobic exercise training on branched-chain amino acid turnover, glycine metabolism and insulin sensitivity in overweight humans.

Abstract: Aims/hypotheses Obesity is associated with decreased insulin sensitivity (IS) and elevated plasma branched-chain amino acids (BCAAs). The purpose of this study was to investigate the relationship between BCAA metabolism and IS in overweight (OW) individuals during exercise intervention.

Metabolomic Quantitative Trait Loci (mQTL) Mapping Implicates the Ubiquitin Proteasome System in Cardiovascular Disease Pathogenesis.

Abstract: Levels of certain circulating short-chain dicarboxylacylcarnitine (SCDA), long-chain dicarboxylacylcarnitine (LCDA) and medium chain acylcarnitine (MCA) metabolites are heritable and predict cardiovascular disease (CVD) events. Little is known about the biological pathways that influence levels of most of these metabolites. Here, we analyzed genetics, epigenetics, and transcriptomics with metabolomics in samples from a large CVD cohort to identify novel genetic markers for CVD and to better understand the role of metabolites in CVD pathogenesis. Using genomewide association in the CATHGEN cohort (N = 1490), we observed associations of several metabolites with genetic loci. Our strongest findings were for SCDA metabolite levels with variants in genes that regulate components of endoplasmic reticulum (ER) stress (USP3, HERC1, STIM1, SEL1L, FBXO25, SUGT1) These findings were validated in a second cohort of CATHGEN subjects (N = 2022, combined p = 8.4x10-6–2.3x10-10). Importantly, variants in these genes independently predicted CVD events. Association of genomewide methylation profiles with SCDA metabolites identified two ER stress genes as differentially methylated (BRSK2 and HOOK2). Expression quantitative trait loci (eQTL) pathway analyses driven by gene variants and SCDA metabolites corroborated perturbations in ER stress and highlighted the ubiquitin proteasome system (UPS) arm. Moreover, culture of human kidney cells in the presence of levels of fatty acids found in individuals with cardiometabolic disease, induced accumulation of SCDA metabolites in parallel with increases in the ER stress marker BiP. Thus, our integrative strategy implicates the UPS arm of the ER stress pathway in CVD pathogenesis, and identifies novel genetic loci associated with CVD event risk.

The Effects of Aerobic, Resistance and Combination Training on Insulin Sensitivity and secretion in Overweight Adults from STRRIDE AT/RT: A Randomized Trial

Abstract: Most health organizations recommend a combination of aerobic training (AT) and resistance training (RT), yet few studies have compared their acute (within 24 h of the last exercise bout) and sustai...

A Guide for a Cardiovascular Genomics Biorepository: the CATHGEN Experience

Abstract: The CATHeterization GENetics (CATHGEN) biorepository was assembled in four phases. First, project start-up began in 2000. Second, between 2001 and 2010, we collected clinical data and biological samples from 9334 individuals undergoing cardiac catheterization. Samples were matched at the individual level to clinical data collected at the time of catheterization and stored in the Duke Databank for Cardiovascular Diseases (DDCD). Clinical data included the following: subject demographics (birth date, race, gender, etc.); cardiometabolic history including symptoms; coronary anatomy and cardiac function at catheterization; and fasting chemistry data. Third, as part of the DDCD regular follow-up protocol, yearly evaluations included interim information: vital status (verified via National Death Index search and supplemented by Social Security Death Index search), myocardial infarction (MI), stroke, rehospitalization, coronary revascularization procedures, medication use, and lifestyle habits including smoking. Fourth, samples were used to generate molecular data. CATHGEN offers the opportunity to discover biomarkers and explore mechanisms of cardiovascular disease.

Psychosocial Factors, Exercise Adherence, and Outcomes in Heart Failure Patients Insights From Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION)

Abstract: Background— Psychosocial factors may influence adherence with exercise training for heart failure (HF) patients. We aimed to describe the association between social support and barriers to participation with exercise adherence and clinical outcomes. Methods and Results— Of patients enrolled in Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION), 2279 (97.8%) completed surveys to assess social support and barriers to exercise, resulting in the perceived social support score (PSSS) and barriers to exercise score (BTES). Higher PSSS indicated higher levels of social support, whereas higher BTES indicated more barriers to exercise. Exercise time at 3 and 12 months correlated with PSSS ( r = 0.09 and r = 0.13, respectively) and BTES ( r =−0.11 and r =−0.12, respectively), with higher exercise time associated with higher PSSS and lower BTES (All P <0.005). For cardiovascular death or HF hospitalization, there was a significant interaction between the randomization group and BTES ( P =0.035), which corresponded to a borderline association between increasing BTES and cardiovascular death or HF hospitalization in the exercise group (hazard ratio 1.25, 95% confidence interval 0.99, 1.59), but no association in the usual care group (hazard ratio 0.83, 95% confidence interval 0.66, 1.06). Conclusions— Poor social support and high barriers to exercise were associated with lower exercise time. PSSS did not impact the effect of exercise training on outcomes. However, for cardiovascular death or HF hospitalization, exercise training had a greater impact on patients with lower BTES. Given that exercise training improves outcomes in HF patients, assessment of perceived barriers may facilitate individualized approaches to implement exercise training therapy in clinical practice. Clinical Trial Registration— URL: . Unique identifier: [NCT00047437][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00047437&atom=%2Fcirchf%2F8%2F6%2F1044.atom

Self-efficacy for exercise, more than disease-related factors, is associated with objectively assessed exercise time and sedentary behaviour in rheumatoid arthritis.

Abstract: Objectives: Until recently, reports of physical activity in rheumatoid arthritis (RA) were limited to self-report methods and/or leisure-time physical activity. Our objectives were to assess, determine correlates of, and compare to well-matched controls both exercise and sedentary time in a typical clinical cohort of RA.Method: Persons with established RA (seropositive or radiographic erosions; n = 41) without diabetes or cardiovascular disease underwent assessments of traditional and disease-specific correlates of physical activity and 7 days of triaxial accelerometry. Twenty-seven age, gender, and body mass index (BMI)-matched controls were assessed.Results: For persons with RA, objectively measured median (25th–75th percentile) exercise time was 3 (1–11) min/day; only 10% (n = 4) of participants exercised for ≥ 30 min/day. Time spent in sedentary activities was 92% (89–95%). Exercise time was not related to pain but was inversely related to disease activity (r = –0.3, p < 0.05) and disability (r = –0.3...

Gene by stress genome-wide interaction analysis and path analysis identify EBF1 as a cardiovascular and metabolic risk gene.

Abstract: We performed gene–environment interaction genome-wide association analysis (G × E GWAS) to identify SNPs whose effects on metabolic traits are modified by chronic psychosocial stress in the Multi-Ethnic Study of Atherosclerosis (MESA). In Whites, the G × E GWAS for hip circumference identified five SNPs within the Early B-cell Factor 1 (EBF1) gene, all of which were in strong linkage disequilibrium. The gene-by-stress interaction (SNP × STRESS) term P-values were genome-wide significant (Ps=7.14E−09 to 2.33E−08, uncorrected; Ps=1.99E−07 to 5.18E−07, corrected for genomic control). The SNP-only (without interaction) model P-values (Ps=0.011–0.022) were not significant at the conventional genome-wide significance level. Further analysis of related phenotypes identified gene-by-stress interaction effects for waist circumference, body mass index (BMI), fasting glucose, type II diabetes status, and common carotid intimal–medial thickness (CCIMT), supporting a proposed model of gene-by-stress interaction that connects cardiovascular disease (CVD) risk factor endophenotypes such as central obesity and increased blood glucose or diabetes to CVD itself. Structural equation path analysis suggested that the path from chronic psychosocial stress to CCIMT via hip circumference and fasting glucose was larger (estimate=0.26, P=0.033, 95% CI=0.02–0.49) in the EBF1 rs4704963 CT/CC genotypes group than the same path in the TT group (estimate=0.004, P=0.34, 95% CI=−0.004–0.012). We replicated the association of the EBF1 SNPs and hip circumference in the Framingham Offspring Cohort (gene-by-stress term P-values=0.007–0.012) as well as identified similar path relationships. This observed and replicated interaction between psychosocial stress and variation in the EBF1 gene may provide a biological hypothesis for the complex relationship between psychosocial stress, central obesity, diabetes, and cardiovascular disease.

Incorporation of pharmacogenetic testing into medication therapy management

Abstract: Aim: To assess feasibility and patient satisfaction with a pharmacist-delivered medication therapy management (MTM) plus pharmacogenetic (PGx) testing service. Methods: Thirty patients from a cardiology outpatient clinic were enrolled to attend two MTM sessions, undergo PGx testing and complete pre- and post-intervention surveys. Outcome measures included duration of MTM sessions, clinical application of test results, self-reported medication adherence, patient recall of results and perceived value of testing and MTM. Results: Overall, patients were very satisfied with the MTM plus PGx testing service. About half of participants (47%) were able to accurately recall their PGx test results. Comparable to MTM without PGx testing, the first MTM session averaged 40 min and the follow-up MTM session averaged 15 min. Conclusion: PGx testing incorporated into a clinical MTM service offered by pharmacists may be a feasible delivery model and is satisfactory to patients.

The ACTN3 R577X Polymorphism Is Associated with Cardiometabolic Fitness in Healthy Young Adults

Abstract: Homozygosity for a premature stop codon (X) in the ACTN3 “sprinter” gene is common in humans despite the fact that it reduces muscle size, strength and power. Because of the close relationship between skeletal muscle function and cardiometabolic health we examined the influence of ACTN3 R577X polymorphism over cardiovascular and metabolic characteristics of young adults (n = 98 males, n = 102 females; 23 ± 4.2 years) from our Assessing Inherent Markers for Metabolic syndrome in the Young (AIMMY) study. Both males and females with the RR vs XX genotype achieved higher mean VO2 peak scores (47.8 ± 1.5 vs 43.2 ±1.8 ml/O2/min, p = 0.002) and exhibited higher resting systolic (115 ± 2 vs 105 ± mmHg, p = 0.027) and diastolic (69 ± 3 vs 59 ± 3 mmHg, p = 0.005) blood pressure suggesting a role for ACTN3 in the maintenance of vascular tone. We subsequently identified the expression of alpha-actinin 3 protein in pulmonary artery smooth muscle, which may explain the genotype-specific differences in cardiovascular adaptation to acute exercise. In addition, we utilized targeted serum metabolomics to distinguish between RR and XX genotypes, suggesting an additional role for the ACTN3 R577X polymorphism in human metabolism. Taken together, these results identify significant cardiometabolic effects associated with possessing one or more functional copies of the ACTN3 gene.

Association of Roadway Proximity with Fasting Plasma Glucose and Metabolic Risk Factors for Cardiovascular Disease in a Cross-Sectional Study of Cardiac Catheterization Patients

Abstract: BackgroundThe relationship between traffic-related air pollution (TRAP) and risk factors for cardiovascular disease needs to be better understood in order to address the adverse impact of air pollu...

Gene Expression Profiles Link Respiratory Viral Infection, Platelet Response to Aspirin, and Acute Myocardial Infarction.

Abstract: Background Influenza infection is associated with myocardial infarction (MI), suggesting that respiratory viral infection may induce biologic pathways that contribute to MI. We tested the hypotheses that 1) a validated blood gene expression signature of respiratory viral infection (viral GES) was associated with MI and 2) respiratory viral exposure changes levels of a validated platelet gene expression signature (platelet GES) of platelet function in response to aspirin that is associated with MI.

Simultaneous consideration of multiple candidate protein biomarkers for long-term risk for cardiovascular events.

Abstract: Background— Although individual protein biomarkers are associated with cardiovascular risk, rarely have multiple proteins been considered simultaneously to identify which set of proteins best predicts risk. Methods and Results— In a nested case–control study of 273 death/myocardial infarction (MI) cases and 273 age- (within 10 years), sex-, and race-matched and event-free controls from among 2023 consecutive patients (median follow-up 2.5 years) with suspected coronary disease, plasma levels of 53 previously reported biomarkers of cardiovascular risk were determined in a core laboratory. Three penalized logistic regression models were fit using the elastic net to identify panels of proteins independently associated with death/MI: proteins alone (Model 1); proteins in a model constrained to retain clinical variables (Model 2); and proteins and clinical variables available for selection (Model 3). Model 1 identified 6 biomarkers strongly associated with death/MI: intercellular adhesion molecule-1, matrix metalloproteinase-3, N-terminal pro-B-type natriuretic peptide, interleukin-6, soluble CD40 ligand, and insulin-like growth factor binding protein-2. In Model 2, only soluble CD40 ligand remained strongly associated with death/MI when all clinical risk predictors were retained. Model 3 identified a set of 6 biomarkers (intercellular adhesion molecule-1, matrix metalloproteinase-3, N-terminal pro-B-type natriuretic peptide, interleukin-6, soluble CD40 ligand, and insulin-like growth factor binding protein-2) and 5 clinical variables (age, red-cell distribution width, diabetes mellitus, hemoglobin, and New York Heart Association class) strongly associated with death/MI. Conclusions— Simultaneously assessing the association between multiple putative protein biomarkers of cardiovascular risk and clinical outcomes is useful in identifying relevant biomarker panels for further assessment.

Epigenetic Profiling Identifies Novel Genes for Ascending Aortic Aneurysm Formation with Bicuspid Aortic Valves

Abstract: Background: Bicuspid aortic valves predispose to ascending aortic aneurysms, but the mechanisms underlying this aortopathy remain incompletely characterized. We sought to identify epigenetic pathways predisposing to aneurysm formation in bicuspid patients. Methods: Ascending aortic aneurysm tissue samples were collected at the time of aortic replacement in subjects with bicuspid and trileaflet aortic valves. Genome-wide DNA methylation status was determined on DNA from tissue using the Illumina 450K methylation chip, and gene expression was profiled on the same samples using Illumina Whole-Genome DASL arrays. Gene methylation and expression were compared between bicuspid and trileaflet individuals using an unadjusted Wilcoxon rank sum test. Results: Twenty-seven probes in 9 genes showed significant differential methylation and expression (P<5.5x10 -4 ). The top gene was protein tyrosine phosphatase, non-receptor type 22 ( PTPN22 ), which was hypermethylated (delta beta range: +15.4 to +16.0%) and underexpressed (log 2 gene expression intensity: bicuspid 5.1 vs. trileaflet 7.9, P=2x10 -5 ) in bicuspid patients, as compared to tricuspid patients. Numerous genes involved in cardiovascular development were also differentially methylated, but not differentially expressed, including ACTA2 (4 probes, delta beta range: -10.0 to -22.9%), which when mutated causes the syndrome of familial thoracic aortic aneurysms and dissections Conclusions: Using an integrated, unbiased genomic approach, we have identified novel genes associated with ascending aortic aneurysms in patients with bicuspid aortic valves, modulated through epigenetic mechanisms. The top gene was PTPN22 , which is involved in T-cell receptor signaling and associated with various immune disorders. These differences highlight novel potential mechanisms of aneurysm development in the bicuspid population.

SLCO1B1 genetic variants, long-term low-density lipoprotein cholesterol levels and clinical events in patients following cardiac catheterization

Abstract: Aim: SLCO1B1 variants are associated with intermediate outcomes that may increase risk of death/myocardial infarction (MI) in statin-treated patients. Patients & methods: In high-risk Caucasians undergoing cardiac catheterization, we tested the association between rs4149056/625T>C and rs2306283/492A>G with low-density lipoprotein cholesterol (LDL-c) over 3 years (n = 1402) and death/MI over 6 years (n = 2994), accounting for statin use or type during follow-up. Results: Carriers of the rs4149056 C allele had 6.2 ± 1.7 mg/dl higher LDL-c per C allele (p 0.6). Conclusion: Functional SLCO1B1 variants are not associated with death/MI in patients commonly treated with statins, despite higher LDL-c in carriers of the rs4149056 C allele. Original submitted 3 November 2014; Revision submitted 5 January 2015

Incremental and independent value of cardiopulmonary exercise test measures and the Seattle Heart Failure Model for prediction of risk in patients with heart failure.

Abstract: Background Multivariable risk scores and exercise measures are well-validated risk prediction methods. Combining information from a functional evaluation and a risk model may improve accuracy of risk predictions. We analyzed whether adding exercise measures to the Seattle Heart Failure Model (SHFM) improves risk prediction accuracy in systolic heart failure. Methods We used a sample of patients from the Heart Failure and A Controlled Trial Investigating Outcomes of Exercise TraiNing (HF-ACTION) study (http://www.clinicaltrials.gov; unique identifier: NCT00047437) to examine the addition of peak oxygen consumption, expired volume per unit time/volume of carbon dioxide slope, 6-minute walk distance, or cardiopulmonary exercise duration to the SHFM. Multivariable Cox proportional hazards models were used to test the association between the combined end point (death, left ventricular assist device, or cardiac transplantation) and the addition of exercise variables to the SHFM. Results The sample included 2,152 patients. The SHFM and all exercise measures were associated with events (all p Conclusions Exercise performance measures and the SHFM are independently useful for predicting risk in systolic heart failure. Adding cardiopulmonary exercise testing measures and 6MWD to the SHFM offers only minimal improvement in risk reassignment at clinically meaningful cut points.

Prospective relationships between body weight and physical activity: an observational analysis from the NAVIGATOR study

Abstract: Objectives While bidirectional relationships exist between body weight and physical activity, direction of causality remains uncertain and previous studies have been limited by self-reported activity or weight and small sample size. We investigated the prospective relationships between weight and physical activity. Design Observational analysis of data from the Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) study, a double-blinded randomised clinical trial of nateglinide and valsartan, respectively. Setting Multinational study of 9306 participants. Participants Participants with biochemically confirmed impaired glucose tolerance had annual measurements of both weight and step count using research grade pedometers, worn for 7 days consecutively. Along with randomisation to valsartan or placebo plus nateglinide or placebo, participants took part in a lifestyle modification programme. Outcome measures Longitudinal regression using weight as response value and physical activity as predictor value was conducted, adjusted for baseline covariates. Analysis was then repeated with physical activity as response value and weight as predictor value. Only participants with a response value preceded by at least three annual response values were included. Results Adequate data were available for 2811 (30%) of NAVIGATOR participants. Previous weight (χ 2 =16.8; p 2 =0.1; p=0.71) was inversely associated with subsequent step count, indicating lower subsequent levels of physical activity in heavier individuals. Change in step count (χ 2 =5.9; p=0.02) but not previous step count (χ 2 =0.9; p=0.34) was inversely associated with subsequent weight. However, in the context of trajectories already established for weight (χ 2 for previous weight measurements 747.3; p 2 for previous step count 432.6; p Conclusions While a prospective bidirectional relationship was observed between weight and physical activity, the magnitude of any effect was very small in the context of natural trajectories already established for these variables. Trial registration number NCT00097786.

Prognostic Significance of Depression in Blacks With Heart Failure Insights From Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training

Abstract: Background—Although studies have shown that depression is associated with worse outcomes in patients with heart failure, most studies have been in white patients. The impact of depression on outcomes in blacks with heart failure has not been studied. Methods and Results—We analyzed 747 blacks and 1420 whites enrolled in Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training, which randomized 2331 patients with ejection fraction ≤35% to usual care with or without exercise training. We examined the association between depressive symptoms assessed by the Beck Depression Inventory-II (BDI-II) at baseline and after 3 months with all-cause mortality/hospitalization. A race by baseline BDI-II interaction was observed (P=0.003) in which elevated baseline scores were associated with worse outcomes in blacks versus whites. In blacks, the association was nonlinear with a hazard ratio of 1.44 (95% confidence interval, 1.24–1.68) when comparing the 75th and 25th percentile of BDI-II (score of 15...