Kenneth B Margulies

Hospital of the University of Pennsylvania, Filadelfia, Pennsylvania, United States

Are you Kenneth B Margulies?

Claim your profile

Publications (197)1421.38 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: -The failing human heart is characterized by metabolic abnormalities, but these defects remains incompletely understood. In animal models of HF there is a switch from a predominance of fatty acid utilization to the more oxygen-sparing carbohydrate metabolism. Recent studies have reported decreases in myocardial lipid content, but inclusion of diabetics and nondiabetics obscures the distinction of adapations to metabolic derangements from adaptations to heart failure per se. Methods and results: -We performed both unbiased and targeted myocardial lipid surveys using liquid chromatography-mass spectroscopy in non-diabetic, lean, predominantly non-ischemic advanced HF patients at the time of heart transplantation or LVAD implantation. We identified significantly decreased concentrations of the majority of myocardial lipid intermediates, including long-chain acylcarnitines, the primary subset of energetic lipid substrate for mitochondrial fatty acid oxidation. We report for the first time significantly reduced levels of intermediate and anaplerotic acyl-CoA species incorporated into Krebs cycle, while the myocardial concentration of acetyl-CoA was significantly increased in end-stage heart failure. In contrast, we observed an increased abundance of ketogenic β-hydroxybutyryl CoA, in association with increased myocardial utilization of β-hydroxybutyrate. We observed a significant increase in the expression of the gene encoding succinyl-CoA: 3oxoacid-CoA transferase (SCOT), the rate limiting enzyme for myocardial oxidation of βOHB and acetoacetate. Conclusions: -These findings indicate increased ketone utilization in the severely failing human heart independent of diabetes, support the role of ketone bodies as an alternative fuel and myocardial ketone oxidation as a key metabolic adaptation in the failing human heart.
    No preview · Article · Jan 2016 · Circulation
  • [Show abstract] [Hide abstract]
    ABSTRACT: Sudden cardiac death (SCD) is a common cause of death in the general population, occurring in 300,000 to 350,000 people in the United States alone. Currently, there are no data supporting implantable cardioverter-defibrillator therapy in orthotopic heart transplant (OHT) patients with low left ventricular ejection fraction (LVEF). In this retrospective study, we included all patients who underwent primary OHT at our institution between the years 2007 and 2013. We compared the etiology of death among OHT patients and evaluated the correlation of etiology of death and the patients’ LVEF. Our objectives were to determine whether OHT patients with LVEF less than 35% are at increased risk for sudden cardiac death compared to OHT patients with normal LVEF. To summarize our results, a total of 345 patients were included in our study (mean age 50±14 years, 68% male). The mean follow up was 1260±698 days. Forty (11.5%) patients died >6 months post-OHT. Surviving patients had higher LVEF compared to deceased patients (64±7% and 50±24%, respectively, p=<0.001). In all, 10 (25%) of the deceased patients died suddenly, 9 (23%) from sepsis, and 8 (20%) from malignancy. Among 11 deceased patients with LVEF ≤35%, 2 patients (18%) died suddenly, as compared to 9 SCDs among the 29 deceased patients (31%) with LVEF>35% (p=0.54). In conclusion, OHT patients who died were more likely to have LVEF lower than 35%, and a quarter of the deceased OHT patients died suddenly. A reduced LVEF was not associated with an increased risk of SCD.
    No preview · Article · Jan 2016

  • No preview · Conference Paper · Dec 2015
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Stem cell therapy for myocardial infarction (MI) has been shown to improve cardiac function and reduce infarct size. Exercise training, in the form of cardiac rehabilitation, is an essential part of patient care post-MI. Hence, we tested the effects of acute and chronic aerobic exercise on stem cell retention and cardiac remodeling post-MI. Small epicardial MI's were induced in 12-month-old C57BL/6 mice via cryoinjury. Two weeks post-MI, vehicle infusion (N = 4) or GFP(+) bone marrow-derived cells (BMC) were injected (tail vein I.V.) immediately after acute exercise (N = 14) or sedentary conditions (N = 14). A subset of mice continued a 5-week intervention of chronic treadmill exercise (10-13 m/min; 45 min/day; 4 days/week; N = 7) or remained sedentary (N = 6). Exercise tolerance was assessed using a graded exercise test, and cardiac function was assessed with echocardiography. Acute exercise increased GFP(+) BMC retention in the infarcted zone of the heart by 30% versus sedentary (P < 0.05). This was not associated with alterations in myocardial function or gene expression of key cell adhesion molecules. Animals treated with chronic exercise increased exercise capacity (P < 0.05) and cardiac mass (P < 0.05) without change in left ventricular ejection fraction (LVEF), infarct size, or regional wall thickness (P = NS) compared with sedentary. While BMC's alone did not affect exercise capacity, they increased LVEF (P < 0.05) and Ki67(+) nuclei number in the border zone of the heart (P < 0.05), which was potentiated with chronic exercise training (P < 0.05). We conclude that acute exercise increases BMC retention in infarcted hearts and chronic training increases exogenous BMC-mediated effects on stimulating the cardiomyocyte cell cycle. These preclinical results suggest that exercise may help to optimize stem cell therapeutics following MI.
    Preview · Article · Oct 2015
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The standard expression quantitative trait loci (eQTL) detects polymorphisms associated with gene expression without revealing causality. We introduce a coupled Bayesian regression approach-eQTeL, which leverages epigenetic data to estimate regulatory and gene interaction potential, and identifies combination of regulatory single-nucleotide polymorphisms (SNPs) that explain the gene expression variance. On human heart data, eQTeL not only explains a significantly greater proportion of expression variance but also predicts gene expression more accurately than other methods. Based on realistic simulated data, we demonstrate that eQTeL accurately detects causal regulatory SNPs, including those with small effect sizes. Using various functional data, we show that SNPs detected by eQTeL are enriched for allele-specific protein binding and histone modifications, which potentially disrupt binding of core cardiac transcription factors and are spatially proximal to their target. eQTeL SNPs capture a substantial proportion of genetic determinants of expression variance and we estimate that 58% of these SNPs are putatively causal.
    Full-text · Article · Oct 2015 · Nature Communications
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Intracellular Na(+) concentration ([Na(+)]i) regulates Ca(2+) cycling, contractility, metabolism, and electrical stability of the heart. [Na(+)]i is elevated in heart failure, leading to arrhythmias and oxidative stress. We hypothesized that myocyte [Na(+)]i is also increased in type 2 diabetes (T2D) due to enhanced activity of the Na(+)-glucose cotransporter. To test this hypothesis, we used myocardial tissue from humans with T2D and a rat model of late-onset T2D (HIP rat). Western blot analysis showed increased Na(+)-glucose cotransporter expression in failing hearts from T2D patients compared with nondiabetic persons (by 73±13%) and in HIP rat hearts versus wild-type (WT) littermates (by 61±8%). [Na(+)]i was elevated in HIP rat myocytes both at rest (14.7±0.9 versus 11.4±0.7 mmol/L in WT) and during electrical stimulation (17.3±0.8 versus 15.0±0.7 mmol/L); however, the Na(+)/K(+)-pump function was similar in HIP and WT cells, suggesting that higher [Na(+)]i is due to enhanced Na(+) entry in diabetic hearts. Indeed, Na(+) influx was significantly larger in myocytes from HIP versus WT rats (1.77±0.11 versus 1.29±0.06 mmol/L per minute). Na(+)-glucose cotransporter inhibition with phlorizin or glucose-free solution greatly reduced Na(+) influx in HIP myocytes (to 1.20±0.16 mmol/L per minute), whereas it had no effect in WT cells. Phlorizin also significantly decreased glucose uptake in HIP myocytes (by 33±9%) but not in WT, indicating an increased reliance on the Na(+)-glucose cotransporter for glucose uptake in T2D hearts. Myocyte Na(+)-glucose cotransport is enhanced in T2D, which increases Na(+) influx and causes Na(+) overload. Higher [Na(+)]i may contribute to arrhythmogenesis and oxidative stress in diabetic hearts. © 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.
    Preview · Article · Aug 2015 · Journal of the American Heart Association
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: Worsening renal function in heart failure may be related to increased venous congestion, decreased cardiac output, or both. Diuretics are universally used in acute decompensated heart failure, but they may be ineffective and may lead to azotemia. We aimed to compare the decongestive properties of a urine output-guided diuretic adjustment and standard therapy for the management of cardiorenal syndrome in acute decompensated heart failure. Methods and results: Data were pooled from subjects randomized to the stepwise pharmacologic care algorithm (SPCA) in the CARRESS-HF trial and those who developed cardiorenal syndrome (rise in creatinine >0.3 mg/dL) in the DOSE-AHF and ROSE-AHF trials. Patients treated with SPCA (n = 94) were compared with patients treated with standard decongestive therapy (SDT) that included intravenous loop diuretic use (DOSE-AHF and ROSE-AHF; n = 107) at the time of cardiorenal syndrome and followed for net fluid balance, weight loss, and changing renal function. The SPCA group had higher degrees of jugular venous pressure (P < .0001) at the time of cardiorenal syndrome. The group that received SPCA had more weight change (-3.4 ± 5.2 lb) and more net fluid loss (1.705 ± 1.417 L) after 24 hours than the SDT group (-0.8 ± 3.4 lb and 0.892 ± 1.395 L, respectively; P < .001 for both) with a slight improvement in renal function (creatinine change -0.1 ± 0.3 vs 0.0 ± 0.3 mg/dL, respectively; P = .03). Conclusions: Compared with SDT, patients who received an intensification of medication therapy for treating persisting congestion had greater net fluid and weight loss without being associated with renal compromise.
    No preview · Article · Aug 2015 · Journal of cardiac failure

  • No preview · Article · Aug 2015 · Journal of Cardiac Failure
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: RNA sequencing (RNA-Seq) allows an unbiased survey of the entire transcriptome in a high-throughput manner. A major application of RNA-Seq is to detect differential isoform expression across experimental conditions, which is of great biological interest due to its direct relevance to protein function and disease pathogenesis. Detection of differential isoform expression is challenging because of uncertainty in isoform expression estimation owing to ambiguous reads and variability in precision of the estimates across samples. It is desirable to have a method that can account for these issues and is flexible enough to allow adjustment for covariates. In this paper, we present MetaDiff, a random-effects meta-regression model that naturally fits for the above purposes. Through extensive simulations and analysis of an RNA-Seq dataset on human heart failure, we show that the random-effects meta-regression approach is computationally fast, reliable, and can improve the power of differential expression analysis while controlling for false positives due to the effect of covariates or confounding variables. In contrast, several existing methods either fail to control false discovery rate or have reduced power in the presence of covariates or confounding variables. The source code, compiled JAR package and documentation of MetaDiff are freely available at https://github.com/jiach/MetaDiff. Our results indicate that random-effects meta-regression offers a flexible framework for differential expression analysis of isoforms, particularly when gene expression is influenced by other variables.
    Preview · Article · Jul 2015 · BMC Bioinformatics
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Oxidative stress may contribute to heart failure (HF) progression. Inhibiting xanthine oxidase in hyperuricemic HF patients may improve outcomes. We randomly assigned 253 patients with symptomatic HF, left ventricular ejection fraction ≤40%, and serum uric acid levels ≥9.5 mg/dL to receive allopurinol (target dose, 600 mg daily) or placebo in a double-blind, multicenter trial. The primary composite end point at 24 weeks was based on survival, worsening HF, and patient global assessment. Secondary end points included change in quality of life, submaximal exercise capacity, and left ventricular ejection fraction. Uric acid levels were significantly reduced with allopurinol in comparison with placebo (treatment difference, -4.2 [-4.9, -3.5] mg/dL and -3.5 [-4.2, -2.7] mg/dL at 12 and 24 weeks, respectively, both P<0.0001). At 24 weeks, there was no significant difference in clinical status between the allopurinol- and placebo-treated patients (worsened 45% versus 46%, unchanged 42% versus 34%, improved 13% versus 19%, respectively; P=0.68). At 12 and 24 weeks, there was no significant difference in change in Kansas City Cardiomyopathy Questionnaire scores or 6-minute walk distances between the 2 groups. At 24 weeks, left ventricular ejection fraction did not change in either group or between groups. Rash occurred more frequently with allopurinol (10% versus 2%, P=0.01), but there was no difference in serious adverse event rates between the groups (20% versus 15%, P=0.36). In high-risk HF patients with reduced ejection fraction and elevated uric acid levels, xanthine oxidase inhibition with allopurinol failed to improve clinical status, exercise capacity, quality of life, or left ventricular ejection fraction at 24 weeks. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00987415. © 2015 American Heart Association, Inc.
    Full-text · Article · May 2015 · Circulation
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: This study evaluates the ability of label-free fluorescence lifetime imaging (FLIm) to complement intravascular ultrasound (IVUS) for concurrent visualization of human coronary vessel composition, structure, and pathology. Co-registered FLIm and IVUS data from 16 coronary segments were correlated to eight distinct pathological features including thin-cap fibroatheroma (TCFA). The sensitivity, specificity, and positive predictive value for combined FLIm-IVUS (89, 99, 89 %) were better than FLIm (70, 98, 88 %) and IVUS (45, 94, 62 %) alone in distinguishing between pathologies. FLIm can assess compositional changes in luminal surface through variations in fluorescence lifetime values (<3.5 ns for lipid-rich areas; >4 ns for collagen-rich areas) enabling detection of macrophages in fibrous caps (sensitivity, 86 %) and distinguishing between relatively stable thick-cap fibroatheromas and rupture-prone TCFA (sensitivity, 80 %) amongst other features. Current results demonstrate the potential of FLIm-IVUS as a new intravascular method for improved evaluation of plaques that may subsequently aid in guiding coronary intervention. Electronic supplementary material The online version of this article (doi:10.1007/s12265-015-9627-3) contains supplementary material, which is available to authorized users.
    Full-text · Article · May 2015 · Journal of Cardiovascular Translational Research

  • No preview · Article · Apr 2015 · The Journal of Heart and Lung Transplantation

  • No preview · Article · Apr 2015 · The Journal of Heart and Lung Transplantation

  • No preview · Article · Apr 2015 · The Journal of Heart and Lung Transplantation

  • No preview · Article · Apr 2015 · The Journal of Heart and Lung Transplantation
  • [Show abstract] [Hide abstract]
    ABSTRACT: The cardiac voltage-gated sodium channel, NaV1.5, drives the upstroke of the cardiac action potential and is a critical determinant of myocyte excitability. Recently, Calcium (Ca)/Calmodulin(CaM) dependent protein kinase II (CaMKII) has emerged as a critical regulator of NaV1.5 function through phosphorylation of multiple residues including S516, T594, and S571 and these phosphorylation events may be important for the genesis of acquired arrhythmias, as occur in heart failure. However, phosphorylation of full-length human NaV1.5 has not been systematically analyzed and NaV1.5 phosphorylation in human heart failure is incompletely understood. In the present study, we used label-free mass spectrometry to assess phosphorylation of human NaV1.5 purified from HEK293 cells with full coverage of phosphorylatable sites and identified 23 sites that were phosphorylated by CaMKII in vitro. We confirmed phosphorylation of S516 and S571 by LC-MS/MS and found a decrease in S516 phosphorylation in human heart failure, using a novel phospho-specific antibody. This work furthers our understanding of the phosphorylation of NaV1.5 by CaMKII under normal and disease conditions, provides novel CaMKII target sites for functional validation, and provides the first phospho-proteomic map of full-length human NaV1.5.
    No preview · Article · Mar 2015 · Journal of Proteome Research
  • [Show abstract] [Hide abstract]
    ABSTRACT: Cyclic guanosine monophosphate (cGMP) is a second messenger molecule that transduces nitric-oxide- and natriuretic-peptide-coupled signalling, stimulating phosphorylation changes by protein kinase G. Enhancing cGMP synthesis or blocking its degradation by phosphodiesterase type 5A (PDE5A) protects against cardiovascular disease. However, cGMP stimulation alone is limited by counter-adaptions including PDE upregulation. Furthermore, although PDE5A regulates nitric-oxide-generated cGMP, nitric oxide signalling is often depressed by heart disease. PDEs controlling natriuretic-peptide-coupled cGMP remain uncertain. Here we show that cGMP-selective PDE9A (refs 7, 8) is expressed in the mammalian heart, including humans, and is upregulated by hypertrophy and cardiac failure. PDE9A regulates natriuretic-peptide- rather than nitric-oxide-stimulated cGMP in heart myocytes and muscle, and its genetic or selective pharmacological inhibition protects against pathological responses to neurohormones, and sustained pressure-overload stress. PDE9A inhibition reverses pre-established heart disease independent of nitric oxide synthase (NOS) activity, whereas PDE5A inhibition requires active NOS. Transcription factor activation and phosphoproteome analyses of myocytes with each PDE selectively inhibited reveals substantial differential targeting, with phosphorylation changes from PDE5A inhibition being more sensitive to NOS activation. Thus, unlike PDE5A, PDE9A can regulate cGMP signalling independent of the nitric oxide pathway, and its role in stress-induced heart disease suggests potential as a therapeutic target.
    No preview · Article · Mar 2015 · Nature
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: -Early studies showed beneficial effects of phosphodiesterase 5 inhibitors (PDE5i) on cardiovascular function in heart failure (HF) patients, but the RELAX trial observed no improvement in exercise capacity with sildenafil treatment in subjects with HF and preserved ejection fraction (HFpEF). -A subgroup of participants in the RELAX trial (n=48) underwent comprehensive noninvasive cardiovascular assessment before and after treatment with sildenafil or placebo in a prospective ancillary study. Left ventricular (LV) contractility was assessed by peak power index (PWR/EDV) and stroke work index (SW/EDV). Systemic arterial load was assessed by arterial elastance (Ea) and right ventricular afterload by pulmonary artery systolic pressure (PASP). Endothelial function was assessed by reactive hyperemia index (RHI) following upper arm cuff occlusion. Compared to placebo (n=25), sildenafil (n=23) decreased Ea (-0.29±0.28mmHg/ml vs +0.02±0.29, p=0.008) and tended to improve RHI (+0.30±0.45 vs -0.17±0.30, p=0.054). In contrast, LV contractility was reduced by 11-16% with sildenafil compared to placebo (ΔPWR/EDV -52±70 vs +0±40 mmHg/s, p=0.006; ΔSW/EDV +0.3±5.8 vs -6.0±5.1 mmHg, p=0.04). Sildenafil had no effect on PASP. -In subjects with HFpEF, sildenafil displayed opposing effects on ventricular and vascular function. We speculate that beneficial effects of PDE5i in the systemic vasculature and endothelium were insufficient to improve clinical status, or that the deleterious effects on left ventricular function offset any salutary vascular effects, contributing to the absence of benefit observed with sildenafil in subjects with HFpEF in the RELAX trial. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00094302.
    Preview · Article · Mar 2015 · Circulation Heart Failure

  • No preview · Article · Mar 2015 · Journal of the American College of Cardiology
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Regular exercise is recommended to improve outcomes in patients with heart failure. Exercise is known to decrease inflammation and thought to decrease myocardial stress; however, studies of exercise in heart failure have had mixed results on levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity C-reactive protein (hsCRP). A multi-marker analysis may help identify distinct subgroups of patients who respond to exercise. The primary study objective was to identify common and distinct patterns of change in hsCRP and NT-proBNP and quantify the influence of exercise therapy on the observed patterns of change. NT-proBNP and hsCRP were assessed in a random sample of 320 participants from the biomarker sub-study of HF-ACTION, a randomized clinical trial of exercise training versus usual care in patients with stable and chronic heart failure. Growth mixture modeling was used to identify unique biomarker patterns over 12-months. Three statistically independent and clinically meaningful biomarker patterns of NTproBNP and hsCRP were identified. Two patterns were combined and compared to the "low/stable" pattern, which was characterized by the lowest levels of NT-proBNP and hsCRP over time. Participants who were taking a loop diuretic, had hypertension or ischemic etiology were about two times as likely to be in the "elevated/worsening" biomarker pattern. Participants randomized to the exercise intervention were less likely to be in the elevated/worsening pattern of NT-proBNP and hsCRP (relative risk ratio: 0.56, CI: 0.32-0.98, p=0.04). Exercise therapy was protective for reducing the frequency of membership in the elevated/worsening biomarker pattern, indicating that exercise may be helpful in delaying the progression of heart failure. Copyright © 2015 Elsevier Inc. All rights reserved.
    Full-text · Article · Feb 2015 · Journal of Cardiac Failure

Publication Stats

5k Citations
1,421.38 Total Impact Points

Institutions

  • 2015
    • Hospital of the University of Pennsylvania
      Filadelfia, Pennsylvania, United States
  • 2006-2015
    • William Penn University
      Filadelfia, Pennsylvania, United States
    • University of Pennsylvania
      • • Perelman School of Medicine
      • • Cardiovascular Institute
      • • Department of Medicine
      Filadelfia, Pennsylvania, United States
  • 2014
    • Stanford University
      Stanford, California, United States
  • 2008
    • University of Cincinnati
      Cincinnati, Ohio, United States
  • 2003-2007
    • Cardiovascular Research Foundation
      New York, New York, United States
    • University of Pittsburgh
      Pittsburgh, Pennsylvania, United States
    • Allegheny General Hospital
      Pittsburgh, Pennsylvania, United States
  • 1997-2007
    • Temple University
      • • Department of Medicine
      • • Department of Physiology
      • • Department of Surgery
      Filadelfia, Pennsylvania, United States
  • 1990-1994
    • Mayo Clinic - Rochester
      • Department of Cardiovascular Diseases
      Рочестер, Minnesota, United States