title: Myocardial atrophy and chronic mechanical unloading of the failing human heart: implications for cardiac assist device-induced myocardial recovery.
abstract: BACKGROUND
  In animal models of heterotopic transplantation, mechanical unloading of the normal, nonhypertrophic heart results in atrophy. Primarily on the basis of these animal data, the notion that chronic left ventricular assist device (LVAD)-induced unloading will result in atrophy has dominated the clinical heart failure field, and anti-atrophic drugs have been used to enhance the cardiac recovery potential observed in some LVAD patients. However, whether unloading-induced atrophy in experimental normal heart models applies to failing and hypertrophic myocardium in heart failure patients unloaded by continuous-flow LVADs has not been studied.
  
  
  OBJECTIVE
  The study examined whether mechanical unloading by continuous-flow LVAD leads to myocardial atrophy.
  
  
  METHODS
  We prospectively examined myocardial tissue and hemodynamic and echocardiographic data from 44 LVAD patients and 18 untransplanted normal donors.
  
  
  RESULTS
  Cardiomyocyte size (cross-sectional area) decreased after LVAD unloading from 1,238 ± 81 μm(2) to 1,011 ± 68 μm(2) (p = 0.001), but not beyond that of normal donor hearts (682 ± 56 μm(2)). Electron microscopy ultrastructural evaluation, cardiomyocyte glycogen content, and echocardiographic assessment of myocardial mass and left ventricular function also did not suggest myocardial atrophy. Consistent with these findings, t-tubule morphology, cytoplasmic penetration, and distance from the ryanodine receptor were not indicative of ongoing atrophic remodeling during LVAD unloading. Molecular analysis revealed no up-regulation of proatrophic genes and proteins of the ubiquitin proteasome system.
  
  
  CONCLUSIONS
  Structural, ultrastructural, microstructural, metabolic, molecular, and clinical functional data indicated that prolonged continuous-flow LVAD unloading does not induce hypertrophy regression to the point of atrophy and degeneration. These findings may be useful in designing future investigations that combine LVAD unloading and pharmaceutical therapies as a bridge to recovery of the failing heart.
authors.affiliation: Utah Transplantation Affiliated Hospitals (UTAH) Cardiac Transplant Program: Divisions of Cardiovascular Medicine and Cardiothoracic Surgery, University of Utah Health Sciences Center, Intermountain Medical Center, Veterans Administration Salt Lake City Health Care System, Salt Lake City, Utah; University of Utah Molecular Medicine Program, Salt Lake City, Utah.
authors.forename: Nikolaos A
authors.initials: NA
authors.lastname: Diakos
authors.affiliation: Utah Transplantation Affiliated Hospitals (UTAH) Cardiac Transplant Program: Divisions of Cardiovascular Medicine and Cardiothoracic Surgery, University of Utah Health Sciences Center, Intermountain Medical Center, Veterans Administration Salt Lake City Health Care System, Salt Lake City, Utah; University of Utah Molecular Medicine Program, Salt Lake City, Utah.
authors.forename: Craig H
authors.initials: CH
authors.lastname: Selzman
authors.affiliation: Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, Utah.
authors.forename: Frank B
authors.initials: FB
authors.lastname: Sachse
authors.affiliation: Utah Transplantation Affiliated Hospitals (UTAH) Cardiac Transplant Program: Divisions of Cardiovascular Medicine and Cardiothoracic Surgery, University of Utah Health Sciences Center, Intermountain Medical Center, Veterans Administration Salt Lake City Health Care System, Salt Lake City, Utah.
authors.forename: Josef
authors.initials: J
authors.lastname: Stehlik
authors.affiliation: Utah Transplantation Affiliated Hospitals (UTAH) Cardiac Transplant Program: Divisions of Cardiovascular Medicine and Cardiothoracic Surgery, University of Utah Health Sciences Center, Intermountain Medical Center, Veterans Administration Salt Lake City Health Care System, Salt Lake City, Utah.
authors.forename: Abdallah G
authors.initials: AG
authors.lastname: Kfoury
authors.affiliation: Utah Transplantation Affiliated Hospitals (UTAH) Cardiac Transplant Program: Divisions of Cardiovascular Medicine and Cardiothoracic Surgery, University of Utah Health Sciences Center, Intermountain Medical Center, Veterans Administration Salt Lake City Health Care System, Salt Lake City, Utah.
authors.forename: Omar
authors.initials: O
authors.lastname: Wever-Pinzon
authors.affiliation: Utah Transplantation Affiliated Hospitals (UTAH) Cardiac Transplant Program: Divisions of Cardiovascular Medicine and Cardiothoracic Surgery, University of Utah Health Sciences Center, Intermountain Medical Center, Veterans Administration Salt Lake City Health Care System, Salt Lake City, Utah.
authors.forename: Anna
authors.initials: A
authors.lastname: Catino
authors.affiliation: Utah Transplantation Affiliated Hospitals (UTAH) Cardiac Transplant Program: Divisions of Cardiovascular Medicine and Cardiothoracic Surgery, University of Utah Health Sciences Center, Intermountain Medical Center, Veterans Administration Salt Lake City Health Care System, Salt Lake City, Utah.
authors.forename: Rami
authors.initials: R
authors.lastname: Alharethi
authors.affiliation: Utah Transplantation Affiliated Hospitals (UTAH) Cardiac Transplant Program: Divisions of Cardiovascular Medicine and Cardiothoracic Surgery, University of Utah Health Sciences Center, Intermountain Medical Center, Veterans Administration Salt Lake City Health Care System, Salt Lake City, Utah.
authors.forename: Bruce B
authors.initials: BB
authors.lastname: Reid
authors.affiliation: Utah Transplantation Affiliated Hospitals (UTAH) Cardiac Transplant Program: Divisions of Cardiovascular Medicine and Cardiothoracic Surgery, University of Utah Health Sciences Center, Intermountain Medical Center, Veterans Administration Salt Lake City Health Care System, Salt Lake City, Utah; Department of Pathology, University of Utah School of Medicine/ARUP Reference Laboratory, Salt Lake City, Utah.
authors.forename: Dylan V
authors.initials: DV
authors.lastname: Miller
authors.affiliation: Department of Pathology, University of Utah School of Medicine/ARUP Reference Laboratory, Salt Lake City, Utah.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Salama
authors.affiliation: Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, Utah.
authors.forename: Alexey V
authors.initials: AV
authors.lastname: Zaitsev
authors.affiliation: Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, Utah.
authors.forename: Junko
authors.initials: J
authors.lastname: Shibayama
authors.affiliation: Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, Utah.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.affiliation: Utah Transplantation Affiliated Hospitals (UTAH) Cardiac Transplant Program: Divisions of Cardiovascular Medicine and Cardiothoracic Surgery, University of Utah Health Sciences Center, Intermountain Medical Center, Veterans Administration Salt Lake City Health Care System, Salt Lake City, Utah.
authors.forename: James C
authors.initials: JC
authors.lastname: Fang
authors.affiliation: University of Utah Molecular Medicine Program, Salt Lake City, Utah.
authors.forename: Dean Y
authors.initials: DY
authors.lastname: Li
authors.affiliation: Utah Transplantation Affiliated Hospitals (UTAH) Cardiac Transplant Program: Divisions of Cardiovascular Medicine and Cardiothoracic Surgery, University of Utah Health Sciences Center, Intermountain Medical Center, Veterans Administration Salt Lake City Health Care System, Salt Lake City, Utah; University of Utah Molecular Medicine Program, Salt Lake City, Utah. Electronic address: stavros.drakos@hsc.utah.edu.
authors.forename: Stavros G
authors.initials: SG
authors.lastname: Drakos
mesh_terms: D001284:Atrophy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015153:Blotting, Western; D009202:Cardiomyopathies / Q000209:etiology / Q000235:genetics / Q000473:pathology*; D004452:Echocardiography; D005260:Female; D005500:Follow-Up Studies; D006333:Heart Failure / Q000150:complications / Q000503:physiopathology* / Q000628:therapy; D006352:Heart Ventricles / Q000000981:diagnostic imaging / Q000503:physiopathology / Q000648:ultrastructure; D006353:Heart-Assist Devices; D006801:Humans; D008297:Male; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D008875:Middle Aged; D009200:Myocardial Contraction; D009206:Myocardium / Q000648:ultrastructure*; D011379:Prognosis; D011446:Prospective Studies; D012313:RNA / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020127:Recovery of Function / Q000502:physiology*; D025801:Ubiquitin / Q000096:biosynthesis / Q000235:genetics; D015854:Up-Regulation; D016277:Ventricular Function, Left / Q000502:physiology*; D020257:Ventricular Remodeling
chemical_list: D025801:Ubiquitin; D012313:RNA
keywords: left ventricular assist device; mechanical unloading; myocardial atrophy