Showing papers by "William E. Kraus published in 2013"
TL;DR: In this paper, the authors evaluated ST2 levels and their association with functional capacity and long-term clinical outcomes in a cohort of ambulatory patients with heart failure enrolled in the Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) study.
Abstract: Background—ST2 is involved in cardioprotective signaling in the myocardium and has been identified as a potentially promising biomarker in heart failure (HF). We evaluated ST2 levels and their association with functional capacity and long-term clinical outcomes in a cohort of ambulatory patients with HF enrolled in the Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) study—a multicenter, randomized study of exercise training in HF. Methods and Results—HF-ACTION randomized 2331 patients with left ventricular ejection fraction <0.35 and New York Heart Association class II to IV HF to either exercise training or usual care. ST2 was analyzed in a subset of 910 patients with evaluable plasma samples. Correlations and Cox models were used to assess the relationship among ST2, functional capacity, and long-term outcomes. The median baseline ST2 level was 23.7 ng/mL (interquartile range, 18.6–31.8). ST2 was modestly associated with measures of functional capacity. In univa...
103 citations
TL;DR: Evidence from animal studies and a limited number of human trials indicates that calorie restriction has the potential to both delay cardiac aging and help prevent atherosclerotic cardiovascular disease via beneficial effects on blood pressure, lipids, inflammatory processes, and potentially other mechanisms.
Abstract: PURPOSE: While the impact of caloric restriction on human health is not fully understood, there is strong evidence to support further studies of its influence on cardiovascular health. The purpose of this review was to update the state of the science by examining the relevant literature regarding calorie-restriction effects on aging and cardiovascular health and to discuss the possible role(s) of calorie restriction in preserving cardiovascular function in humans.
METHODS: For purpose of this review, we have defined calorie restriction as a reduction in energy intake well below the amount of calories that would be consumed ad libitum (>=10% in humans, >=20% in animals). We examined the relevant literature on calorie-restriction effects on longevity and cardiovascular health, with an emphasis on the state of the science regarding calorie restriction in humans. We have emphasized the importance of the preliminary and expected findings from the Comprehensive Assessment of the Long-term Effect of Reducing Intake of Energy trial.
RESULTS: Evidence from animal studies and a limited number of human trials indicates that calorie restriction has the potential to both delay cardiac aging and help prevent atherosclerotic cardiovascular disease via beneficial effects on blood pressure, lipids, inflammatory processes, and potentially other mechanisms.
CONCLUSIONS: On the basis of its known benefits to cardiometabolic health, including modest calorie restriction in a combined lifestyle program is likely to improve heart health and prevent subsequent cardiovascular events in overweight and obese individuals. Additional study is needed to further illuminate its long-term applicability for older adults and for those with significant comorbidities, such as heart failure.
94 citations
TL;DR: COPD was associated with older age, more comorbidities, reduced exercise capacity, and increased CV mortality/HF hospitalization, but not a differential response to exercise training, and β-Blocker selectivity was not associated with differences in outcome for patients with vs without COPD.
81 citations
TL;DR: RNA profiles of platelet-specific genes are novel biomarkers for identifying patients who do not respond adequately to aspirin and who are at risk for death or MI, independent of cardiovascular risk factors.
63 citations
TL;DR: Hypomethylated genes, such as COL15A1, provide evidence for concomitant epigenetic regulation and genetic susceptibility, and define a class of causal targets that sit at the intersection of genetic and epigenetic predisposition in the etiology of complex disease.
Abstract: Smooth muscle cell (SMC) proliferation is a hallmark of vascular injury and disease. Global hypomethylation occurs during SMC proliferation in culture and in vivo during neointimal formation. Regardless of the programmed or stochastic nature of hypomethylation, identifying these changes is important in understanding vascular disease, as maintenance of a cells' epigenetic profile is essential for maintaining cellular phenotype. Global hypomethylation of proliferating aortic SMCs and concomitant decrease of DNMT1 expression were identified in culture during passage. An epigenome screen identified regions of the genome that were hypomethylated during proliferation and a region containing Collagen, type XV, alpha 1 (COL15A1) was selected by ‘genomic convergence’ for characterization. COL15A1 transcript and protein levels increased with passage-dependent decreases in DNA methylation and the transcript was sensitive to treatment with 5-Aza-2′-deoxycytidine, suggesting DNA methylation-mediated gene expression. Phenotypically, knockdown of COL15A1 increased SMC migration and decreased proliferation and Col15a1 expression was induced in an atherosclerotic lesion and localized to the atherosclerotic cap. A sequence variant in COL15A1 that is significantly associated with atherosclerosis (rs4142986, P = 0.017, OR = 1.434) was methylated and methylation of the risk allele correlated with decreased gene expression and increased atherosclerosis in human aorta. In summary, hypomethylation of COL15A1 occurs during SMC proliferation and the consequent increased gene expression may impact SMC phenotype and atherosclerosis formation. Hypomethylated genes, such as COL15A1, provide evidence for concomitant epigenetic regulation and genetic susceptibility, and define a class of causal targets that sit at the intersection of genetic and epigenetic predisposition in the etiology of complex disease.
61 citations
TL;DR: In HF patients receiving optimal medical therapy, a decrease in CI <0.6 was associated with adverse clinical outcomes, suggesting an optimal HR response to exercise, even in Patients receiving optimal β-blocker therapy, may be a therapeutic target in the HF population.
Abstract: Aims The aim of this study was to assess the association between resting heart rate (HR), chronotropic index (CI), and clinical outcomes in optimally treated chronic heart failure (HF) patients on β-blocker therapy
Methods and results We performed a sub-study in 1118 patients with HF and reduced ejection fraction (EF < 35%) included in the HF-ACTION trial Patients in sinus rhythm who received a β-blocker and who performed with maximal effort on the exercise test were included Chronotropic index was calculated as an index of HR reserve achieved, by using the equation (220-age) for estimating maximum HR A sensitivity analysis using an equation developed for HF patients on β-blockers was also performed Cox proportional hazards models were fit to assess the association between CI and clinical outcomes Median (25th, 75th percentiles) follow-up was 32 (21, 44) months In a multivariable model including resting HR and CI as continuous variables, neither was associated with the primary outcome of all-cause mortality or hospitalization However, each 01 unit decrease in CI <06 was associated with 17% increased risk of all-cause mortality (hazard ratio 117, 95% confidence interval 101–136; P = 0036), and 13% increased risk of cardiovascular mortality or HF hospitalization (hazard ratio 113, 102–126; P = 0025) Overall, 666 of 1118 (60%) patients had a CI <06 Chronotropic index did not retain statistical significance when dichotomized at a value of ≤062
Conclusion In HF patients receiving optimal medical therapy, a decrease in CI <06 was associated with adverse clinical outcomes Obtaining an optimal HR response to exercise, even in patients receiving optimal β-blocker therapy, may be a therapeutic target in the HF population
59 citations
TL;DR: A microphysiological three-dimensional engineered human skeletal muscle system connected to a circulatory system that consists of a tissue-engineered blood vessel as part of a high-pressure arterial system that reproduces key mechanical behaviors of skeletal muscle in vivo is developed.
Abstract: Microphysiological systems provide a tool to simulate normal and pathological function of organs for prolonged periods. These systems must incorporate the key functions of the individual organs and enable interactions among the corresponding microphysiological units. The relative size of different microphysiological organs and their flow rates are scaled in proportion to in vivo values. We have developed a microphysiological three-dimensional engineered human skeletal muscle system connected to a circulatory system that consists of a tissue-engineered blood vessel as part of a high-pressure arterial system. The engineered human skeletal muscle tissue reproduces key mechanical behaviors of skeletal muscle in vivo. Pulsatile flow is produced using a novel computer-controlled magnetically activated ferrogel. The system is versatile and the muscle unit can be integrated with other organ systems. Periodic monitoring of biomechanical function provides a non-invasive assessment of the health of the tissue and a way to measure the response to drugs and toxins.
50 citations
TL;DR: The authors found no evidence of increased ICD shocks in patients with HF and reduced left ventricular function who underwent exercise training, and exercise therapy should not be prohibited in ICD recipients with HF.
Abstract: Objectives The purpose of this study was to determine whether exercise training is associated with an increased risk of implantable cardioverter-defibrillator (ICD) therapy in patients with heart failure (HF). Background Few data are available regarding the safety of exercise training in patients with ICDs and HF. Methods HF-ACTION (Heart Failure and A Controlled Trial Investigating Outcomes of Exercise TraiNing) randomized 2,331 outpatients with HF and an ejection fraction (EF) ≤35% to exercise training or usual care. Cox proportional hazards modeling was used to examine the relationship between exercise training and ICD shocks. Results We identified 1,053 patients (45%) with an ICD at baseline who were randomized to exercise training (n = 546) or usual care (n = 507). Median age was 61 years old, and median EF was 24%. Over a median of 2.2 years of follow-up, 20% (n = 108) of the exercise patients had a shock versus 22% (n = 113) of the control patients. A history of sustained ventricular tachycardia/fibrillation (hazard ratio [HR]: 1.93 [95% confidence interval (CI): 1.47 to 2.54]), previous atrial fibrillation/flutter (HR: 1.63 [95% CI: 1.22 to 2.18]), exercise-induced dysrhythmia (HR: 1.67 [95% CI: 1.23 to 2.26]), lower diastolic blood pressure (HR for 5-mm Hg decrease l60: 1.35 [95% CI: 1.12 to 1.61]), and nonwhite race (HR: 1.50 [95% CI: 1.13 to 2.00]) were associated with an increased risk of ICD shocks. Exercise training was not associated with the occurrence of ICD shocks (HR: 0.90 [95% CI: 0.69 to 1.18], p = 0.45). The presence of an ICD was not associated with the primary efficacy composite endpoint of death or hospitalization (HR: 0.99 [95% CI: 0.86 to 1.14], p = 0.90). Conclusions We found no evidence of increased ICD shocks in patients with HF and reduced left ventricular function who underwent exercise training. Exercise therapy should not be prohibited in ICD recipients with HF. (Exercise Training Program to Improve Clinical Outcomes in Individuals With Congestive Heart Failure; NCT00047437 )
48 citations
TL;DR: This work examined whether the Arg389Gly polymorphism in ADRβ1 interacts with the dose requirements of beta‐blockers in patients with systolic HF.
Abstract: Aims
Beta-blockers reduce morbidity and mortality in chronic heart failure (HF) patients with reduced ejection fraction. However, there is heterogeneity in the response to these drugs, perhaps due to genetic variations in the β1-adrenergic receptor (ADRβ1). We examined whether the Arg389Gly polymorphism in ADRβ1 interacts with the dose requirements of beta-blockers in patients with systolic HF.
39 citations
TL;DR: The present study supports the efficacy of ET interventions on metabolic syndrome features in morbidly obese minority youth.
Abstract: We initiated a pilot study to investigate the effects of 8 wks of aerobic exercise training (ET) on insulin sensitivity and inflammatory markers in obese and insulin-resistant minority adolescents. Eleven morbidly obese (BMI 41.4 ± 1.8 kg/m2) minority adolescents were entered into a supervised ET intervention (~180 min/wk at 40–55%VO2PeakR [(VO2Peak − VO2Rest)/VO2Rest]). The effects of training on insulin sensitivity (SI), inflammation and other metabolic syndrome features were examined. Results: Insulin action improved in response to training, as indicated by a ~37% increase in SI (p = .018). Plasma levels of several proinflammatory cytokines were reduced in response to ET, as indicated by significant decrements in sTNF-R, CCL2, MPO, IL-6, resistin, and leptin, with no significant changes in hsCRP. ET induced reductions in BMI and percent total body fat. Conclusions: The present study supports the efficacy of ET interventions on metabolic syndrome features in morbidly obese minority youth. Nosotros inici...
31 citations
TL;DR: Distinct trajectories and course of BMI were present in this older population, and adverse health characteristics distinguished the overweight and obese classes from the normal-weight class, but not from each other.
Abstract: ALTHOUGH increase in obesity in adults may have plateaued (1), obesity has been occurring at successively younger ages (2), and its impact remains to be fully felt in the older population (3) Obesity is a risk factor for many adverse health conditions (including diabetes, cardiovascular disease, hypertension, stroke, and certain cancers [4]), which are already more prevalent in the older population (5), functional disability (6,7), increased health service use and cost (8), and possibly reduced longevity (9) The extent to which these associations hold in the older population and how weight changes over time in persons aged 65 years and older remain unclear (10–13)
Longitudinal studies have typically used a population averaging approach, which may conceal notable differences within the population Recently, more sophisticated analytic procedures, such as generalized growth mixture models (GMM [14]), have been used to identify the presence of distinct latent-class trajectories within a population Such analyses identify classes with unique characteristics, classes that might not otherwise be noticed, and classes that may merit different types of attention Regarding examination of obesity, latent-class trajectory analyses have only been applied to data from young-to-late middle-aged samples (15–18), but the findings indicate what may be expected in older age All these studies (sample sizes from ~5,000 to 90,000 participants), used self-reported height and weight to determine body mass index (BMI: weight (kg)/height/[m2]) They followed ages 12–23 (17), 18–49 (18), 19–35 (15), and 25–59 (16), typically identifying four latent-class trajectories, from normal weight to obese, each increasing in BMI over time An exception was the study of 19- to 35-year-old persons (15), which yielded two classes, and the 25- to 59-year-old persons, where one trajectory (with small representation) showed gain and then loss In all studies except the latter, which did not look at this issue, heavier weight was associated with poorer health status or adverse outcome Overall, in these young-to-late middle age representative samples, several latent classes of increasing BMI were present In only one instance, and for only a small proportion, was decline in BMI found
Here, we examine BMI over a 10-year period in a community-representative sample of whites and blacks aged 65 and older We anticipate that multiple latent-class trajectories of BMI will be found Given conflicting prior findings, we did not predict trajectory direction (BMI increase or decrease), but we did predict that classes reflecting higher BMI would be associated with more adverse circumstances
TL;DR: To robustly identify those symptomatic patients without obstructive CAD, who can avoid subsequent cardiac testing and look elsewhere for the cause of their symptoms, a recently described whole blood gene expression score (GES) has been developed and validated in two multi-center trials.
Abstract: The determination of the underlying etiology of symptoms suggestive of obstructive coronary artery disease (CAD, "e50% stenosis in a major coronary artery) is a common clinical challenge in both primary care and cardiology clinics. Usual care in low to medium risk patients often involves a family history, risk factor assessment, and then stress testing with or without non-invasive imaging. If positive, this is often followed by invasive coronary angiography (ICA). Despite extensive adoption of this usual care paradigm, more than 60% of patients referred for angiography do not have obstructive CAD. In order to robustly identify those symptomatic patients without obstructive CAD, who can avoid subsequent cardiac testing and look elsewhere for the cause of their symptoms, a recently described whole blood gene expression score (GES: CorusAE CAD, CardioDx, Inc., Palo Alto, CA) has been developed and validated in two multi-center trials. This paper reviews the published literature and assessments by independent parties regarding the analytical and clinical validity as well as the clinical utility of the CorusAE CAD test. Abstract The determination of the underlying etiology of symptoms suggestive of obstructive coronary artery disease (CAD, "e50% stenosis in a major coronary artery) is a common clinical challenge in both primary care and cardiology clinics. Usual care in low to medium risk patients often involves a family history, risk factor assessment, and then stress testing with or without non-invasive imaging. If positive, this is often followed by invasive coronary angiography (ICA). Despite extensive adoption of this usual care paradigm, more than 60% of patients referred for angiography do not have obstructive CAD. In order to robustly identify those symptomatic patients without obstructive CAD, who can avoid subsequent cardiac testing and look elsewhere for the cause of their symptoms, a recently described whole blood gene expression score (GES: CorusAE CAD, CardioDx, Inc., Palo Alto, CA) has been developed and validated in two multi-center trials. This paper reviews the published literature and assessments by independent parties regarding the analytical and clinical validity as well as the clinical utility of the CorusAE CAD test. Abstract The determination of the underlying etiology of symptoms suggestive of obstructive coronary artery disease (CAD, "e50% stenosis in a major coronary artery) is a common clinical challenge in both primary care and cardiology clinics. Usual care in low to medium risk patients often involves a family history, risk factor assessment, and then stress testing with or without non-invasive imaging. If positive, this is often followed by invasive coronary angiography (ICA). Despite extensive adoption of this usual care paradigm, more than 60% of patients referred for angiography do not have obstructive CAD. In order to robustly identify those symptomatic patients without obstructive CAD, who can avoid subsequent cardiac testing and look elsewhere for the cause of their symptoms, a recently described whole blood gene expression score (GES: CorusAE CAD, CardioDx, Inc., Palo Alto, CA) has been developed and validated in two multi-center trials. This paper reviews the published literature and assessments by independent parties regarding the analytical and clinical validity as well as the clinical utility of the CorusAE CAD test.
TL;DR: There is a need for medical interventions to ameliorate incontinence or for behavioral interventions to address this issue among survivors, as cancer-specific concerns diminish over time among breast cancer survivors.
Abstract: Background. Cancer treatment -related side effects may have a negative impact on quality of life among cancer survivors and may limit participation in physical activity (PA). Hypothesis. Cancer-specific concerns will be reduced throughout a 10-month diet and exercise intervention among recently diagnosed cancer survivors. Additionally, participants reporting greater levels of PA will also report fewer cancer-specific concerns. Study design. This study is an exploratory analysis of 452 recently diagnosed, early-stage breast and prostate cancer survivors who participated in the FRESH START diet and exercise trial. Data were collected at baseline and 1-year follow-up. Results. At baseline, chief concerns among prostate cancer survivors included ability to have an erection (mean score [standard deviation] = 1.0 [1.3]) and urinary frequency (2.5 [1.4]), whereas among breast cancer survivors, eminent concerns were not feeling sexually attractive (2.0 [1.3]) and worry about cancer in other members of their famil...
TL;DR: The strength of race as an independent predictor of long-term outcomes in a contemporary chronic heart failure (HF) population and its association with exercise training response have not been well established.
01 May 2013
TL;DR: Novel strategies deployed within existing AF primary care to increase adherence to evidence-based diet, physical activity, smoking cessation, and medication recommendations for CHD and T2D risk reduction through methods of patient engagement and self-management support are tested.
Abstract: Background:Type 2 diabetes (T2D) and coronary heart disease (CHD) are prevalent chronic diseases from which military personnel are not exempt. While many genetic markers for these diseases have bee...
TL;DR: The ENLIGHTEN trial will evaluate the effectiveness of aerobic exercise and the DASH diet in improving neurocognitive functioning in CIND patients with CVD risk factors and consider potential moderators of treatment, including subclinical CVD.
TL;DR: Recombinant human acid-α glucosidase (rhGAA) significantly reduced glycogen levels in the two GSD IIIa patients' muscle cells suggesting that rhGAA could be a novel therapy for G SD III.
TL;DR: This work has measured 21 cardiovascular-related biomarkers in an extended multigenerational pedigree, the CARRIAGE family (Carolinas Region Interaction of Aging, Genes, and Environment), and four showed noteworthy evidence for linkage in multipoint analysis.
Abstract: Given the importance of cardiovascular disease (CVD) to public health and the demonstrated heritability of both disease status and its related risk factors, identifying the genetic variation underlying these susceptibilities is a critical step in understanding the pathogenesis of CVD and informing prevention and treatment strategies. Although one can look for genetic variation underlying susceptibility to CVD per se, it can be difficult to define the disease phenotype for such a qualitative analysis and CVD itself represents a convergence of diverse etiologic pathways. Alternatively, one can study the genetics of intermediate traits that are known risk factors for CVD, which can be measured quantitatively. Using the latter strategy, we have measured 21 cardiovascular-related biomarkers in an extended multigenerational pedigree, the CARRIAGE family (Carolinas Region Interaction of Aging, Genes, and Environment). These biomarkers belong to inflammatory and immune, connective tissue, lipid, and hemostasis pathways. Of these, 18 met our quality control standards. Using the pedigree and biomarker data, we have estimated the broad sense heritability (H2) of each biomarker (ranging from 0.09–0.56). A genome-wide panel of 6,015 SNPs was used subsequently to map these biomarkers as quantitative traits. Four showed noteworthy evidence for linkage in multipoint analysis (LOD score ≥ 2.6): paraoxonase (chromosome 8p11, 21), the chemokine RANTES (22q13.33), matrix metalloproteinase 3 (MMP3, 17p13.3), and granulocyte colony stimulating factor (GCSF, 8q22.1). Identifying the causal variation underlying each linkage score will help to unravel the genetic architecture of these quantitative traits and, by extension, the genetic architecture of cardiovascular risk.
TL;DR: The guiding hypothesis is that the magnitude of adaptation after 12 weeks will be greatest in those initially randomized to RSTS, and possible mediators of the intervention effect - physical impairment/fitness and function relationship, including vascular function, muscle mass, strength, and physiology will also be assessed.
TL;DR: A pathway-based analysis of the association results using WebGestalt revealed several enriched pathways including the regulation of the actin cytoskeleton pathway as defined by the Kyoto Encyclopedia of Genes and Genomes.
Abstract: We performed a gene–smoking interaction analysis using families from an early-onset coronary artery disease cohort (GENECARD). This analysis was focused on validating and expanding results from previous studies implicating single nucleotide polymorphisms (SNPs) on chromosome 3 in smoking-mediated coronary artery disease. We analyzed 430 SNPs on chromosome 3 and identified 16 SNPs that showed a gene–smoking interaction at P < 0.05 using association in the presence of linkage—ordered subset analysis, a method that uses permutations of the data to empirically estimate the strength of the association signal. Seven of the 16 SNPs were in the Rho-GTPase pathway indicating a 1.87-fold enrichment for this pathway. A meta-analysis of gene–smoking interactions in three independent studies revealed that rs9289231 in KALRN had a Fisher’s combined P value of 0.0017 for the interaction with smoking. In a gene-based meta-analysis KALRN had a P value of 0.026. Finally, a pathway-based analysis of the association results using WebGestalt revealed several enriched pathways including the regulation of the actin cytoskeleton pathway as defined by the Kyoto Encyclopedia of Genes and Genomes.
TL;DR: Identifying gene variants that confer improved survival in the context of clinically appreciable CAD may improve the understanding of cardioprotective mechanisms acting at the gene level and potentially impact patients clinically in the future.
Abstract: Survivorship is a trait characterized by endurance and virility in the face of hardship. It is largely considered a psychosocial attribute developed during fatal conditions, rather than a biological trait for robustness in the context of complex, age-dependent diseases like coronary artery disease (CAD). The purpose of this paper is to present the novel phenotype, survivorship in CAD as an observed survival advantage concurrent with clinically significant CAD. We present a model for characterizing survivorship in CAD and its relationships with overlapping time- and clinically-related phenotypes. We offer an optimal measurement interval for investigating survivorship in CAD. We hypothesize genetic contributions to this construct and review the literature for evidence of genetic contribution to overlapping phenotypes in support of our hypothesis. We also present preliminary evidence of genetic effects on survival in people with clinically significant CAD from a primary case-control study of symptomatic coronary disease. Identifying gene variants that confer improved survival in the context of clinically appreciable CAD may improve our understanding of cardioprotective mechanisms acting at the gene level and potentially impact patients clinically in the future. Further, characterizing other survival-variant genetic effects may improve signal-to-noise ratio in detecting gene associations for CAD.
01 Dec 2013
Journal Article•
Journal Article•