Kenneth C Bedi
University of Pennsylvania
Network
Latest external collaboration on country level. Dive into details by clicking on the dots.
Publication
Featured researches published by Kenneth C Bedi.
Circulation | 2016
Kenneth C Bedi; Nathaniel W. Snyder; Jeffrey Brandimarto; Moez Karim Aziz; Clementina Mesaros; Andrew J. Worth; Linda L. Wang; Ali Javaheri; Ian A. Blair; Kenneth B. Margulies; J. Eduardo Rame
Background— The failing human heart is characterized by metabolic abnormalities, but these defects remains incompletely understood. In animal models of heart failure 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 the inclusion of diabetic and nondiabetic patients obscures the distinction of adaptations 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 nondiabetic, lean, predominantly nonischemic, advanced heart failure patients at the time of heart transplantation or left ventricular assist device 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-coenzyme A (CoA) species incorporated into the Krebs cycle, whereas the myocardial concentration of acetyl-CoA was significantly increased in end-stage heart failure. In contrast, we observed an increased abundance of ketogenic &bgr;-hydroxybutyryl-CoA, in association with increased myocardial utilization of &bgr;-hydroxybutyrate. We observed a significant increase in the expression of the gene encoding succinyl-CoA:3-oxoacid-CoA transferase, the rate-limiting enzyme for myocardial oxidation of &bgr;-hydroxybutyrate and acetoacetate. Conclusions— These findings indicate increased ketone utilization in the severely failing human heart independent of diabetes mellitus, and they support the role of ketone bodies as an alternative fuel and myocardial ketone oxidation as a key metabolic adaptation in the failing human heart.
Nature Medicine | 2018
Christina Yingxian Chen; Matthew A. Caporizzo; Kenneth C Bedi; Alexia Vite; Alexey I. Bogush; Patrick Robison; Julie Heffler; Alex K. Salomon; Neil A. Kelly; Apoorva Babu; Michael P. Morley; Kenneth B. Margulies; Benjamin L. Prosser
Detyrosinated microtubules provide mechanical resistance that can impede the motion of contracting cardiomyocytes. However, the functional effects of microtubule detyrosination in heart failure or in human hearts have not previously been studied. Here, we utilize mass spectrometry and single-myocyte mechanical assays to characterize changes to the cardiomyocyte cytoskeleton and their functional consequences in human heart failure. Proteomic analysis of left ventricle tissue reveals a consistent upregulation and stabilization of intermediate filaments and microtubules in failing human hearts. As revealed by super-resolution imaging, failing cardiomyocytes are characterized by a dense, heavily detyrosinated microtubule network, which is associated with increased myocyte stiffness and impaired contractility. Pharmacological suppression of detyrosinated microtubules lowers the viscoelasticity of failing myocytes and restores 40–50% of lost contractile function; reduction of microtubule detyrosination using a genetic approach also softens cardiomyocytes and improves contractile kinetics. Together, these data demonstrate that a modified cytoskeletal network impedes contractile function in cardiomyocytes from failing human hearts and that targeting detyrosinated microtubules could represent a new inotropic strategy for improving cardiac function.Post-translational modification of microtubules by detyrosination is prevalent in failing human cardiomyocytes and inhibits cardiomyocyte contraction, suggesting a new therapeutic strategy for improving heart function.
Journal of Heart and Lung Transplantation | 2015
J.E. Rame; Kenneth C Bedi; Nathaniel W. Snyder; Jeffrey Brandimarto; Clementina Mesaros; Edo Y. Birati; Ian A. Blair; Kenneth B. Margulies
Biophysical Journal | 2018
Matthew A. Caporizzo; Christina Yingxian Chen; Alexander Koizumi Salomon; Kenneth C Bedi; Kenneth B. Margulies; Benjamin L. Prosser
Biophysical Journal | 2018
Patrick Robison; Christina Yingxian Chen; Matthew A. Caporizzo; Kenneth C Bedi; Kenneth B. Margulies; Benjamin L. Prosser
Biophysical Journal | 2018
Christina Yingxian Chen; Matthew A. Caporizzo; Kenneth C Bedi; Michael P. Morley; Kenneth B. Margulies; Benjamin L. Prosser
Circulation Research | 2015
Kenneth C Bedi; Nathaniel W. Snyder; Ali Javaheri; Jeffery Brandimarto; Clementina Mesaaros; Ian A. Blair; Kenneth B. Margulies; J.E. Rame
Circulation | 2015
J. Eduardo Rame; Anne R. Cappola; Benjamin French; Kenneth C Bedi; Alan H.B. Wu; Kenneth B. Margulies; Thomas P. Cappola
Circulation Research | 2014
Kenneth C Bedi; Nathaniel W. Snyder; Jeff Brandimarto; Clementina Mesaros; Ian A. Blair; Kenneth B. Margulies; J.E. Rame
Circulation | 2014
Nathaniel W. Snyder; Kenneth C Bedi; Ali Javaheri; Clementina Mesaros; Kenneth B. Margulies; Ian A. Blair; J.E. Rame