title: Human hibernating myocardium is jeopardized by apoptotic and autophagic cell death.
abstract: OBJECTIVE
  The aim of the present study was to objectify the loss of myocytes and the mechanism by which myocytes die in human hibernating myocardium (HHM).
  
  
  BACKGROUND
  Intracellular degeneration, reduced cellular protein synthesis, and the replacement fibrosis contribute to structural disintegration of HHM.
  
  
  METHODS
  In 14 patients, HHM was diagnosed by dobutamine echocardiography, radionuclide ventriculography, and thallium-201 scintigraphy. Functional recovery was documented by repeating the preoperative clinical investigations three months after successful coronary artery bypass graft surgery (CABG). During CABG, transmural biopsies were taken from the center of HHM regions and studied by electron microscopy, immunohistochemistry, the terminal deoxynucleotidyl transferase-mediated nick end-labeling (TUNEL) method, reverse transcription-polymerase chain reaction, and Western blotting. Control samples were taken from nondiseased human myocardium.
  
  
  RESULTS
  All patients showed significant improvement or normalization of the regional function of HHM. Ubiquitin-related autophagic cell death was evident ultrastructurally by the occurrence of autophagic vacuoles, cellular degeneration, and nuclear disassembly. Ubiquitin-protein complexes were found in 0.03 +/- 0.008% (control: 0%, p < 0.005) of all myocytes. The proteasome 20S subunit/total myocytes were reduced from 63.3 +/- 9.6% in control myocardium to 36.9 +/- 8.4% in HHM. Complement-9, indicating oncosis, was found in only one of 14 biopsies. TUNEL-positive myocytes were 0.002 +/- 0.0003%. Electron microscopy showed apoptotic cells in 3 of 14 samples. However, the bcl-2/bax ratio was significantly reduced. Moreover, caspase-3 messenger ribonucleic acid was 8.5 times upregulated, and caspase-3 was activated. Cell death was absent in controls.
  
  
  CONCLUSIONS
  In HHM, ubiquitin-related autophagic cell death and apoptosis cause a loss of myocytes. This plays an important role in progressive tissue damage and causes a reduction of the extent of functional recovery of HHM.
authors.affiliation: Department of Cardiology, Kerckhoff Clinic, Bad Nauheim, Germany. a.elsaesser@kerckhoff.mpg.de
authors.forename: Albrecht
authors.initials: A
authors.lastname: Elsässer
authors.forename: Achim M
authors.initials: AM
authors.lastname: Vogt
authors.forename: Holger
authors.initials: H
authors.lastname: Nef
authors.forename: Sawa
authors.initials: S
authors.lastname: Kostin
authors.forename: Helge
authors.initials: H
authors.lastname: Möllmann
authors.forename: Woitek
authors.initials: W
authors.lastname: Skwara
authors.forename: Christoph
authors.initials: C
authors.lastname: Bode
authors.forename: Christian
authors.initials: C
authors.lastname: Hamm
authors.forename: Jutta
authors.initials: J
authors.lastname: Schaper
mesh_terms: D000368:Aged; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D016923:Cell Death / Q000502:physiology; D017023:Coronary Angiography; D001026:Coronary Artery Bypass; D003327:Coronary Disease / Q000175:diagnosis / Q000503:physiopathology / Q000601:surgery; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008854:Microscopy, Electron; D008875:Middle Aged; D009200:Myocardial Contraction / Q000502:physiology; D017682:Myocardial Stunning / Q000175:diagnosis / Q000503:physiopathology* / Q000601:surgery; D009206:Myocardium / Q000166:cytology / Q000378:metabolism / Q000648:ultrastructure; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000648:ultrastructure; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015635:Radionuclide Ventriculography; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013794:Thallium Radioisotopes; D016896:Treatment Outcome; D015854:Up-Regulation / Q000502:physiology; D018487:Ventricular Dysfunction, Left / Q000175:diagnosis / Q000503:physiopathology / Q000601:surgery
chemical_list: D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D013794:Thallium Radioisotopes