CLINICAL RESEARCH: MYOCARDIAL ISCHEMIA/INFARCTION
Human hibernating myocardium is jeopardized by apoptotic and autophagic cell death
Albrecht Elsässer, MD*,*,
Achim M. Vogt, MD ,
Holger Nef, MD*,
Sawa Kostin, MD ,
Helge Möllmann, MD*,
Woitek Skwara, MD ,
Christoph Bode, MD||,
Christian Hamm, MD* and
Jutta Schaper, MD
* Department of Cardiology, Kerckhoff Clinic, Bad Nauheim, Germany
Department of Cardiology, Ruprecht-Carls-University, Heidelberg, Germany
Department of Experimental Cardiology, Max-Planck-Institute, Bad Nauheim, Germany
Department of Thoracic and Cardiovascular Surgery, Kerckhoff Clinic, Bad Nauheim, Germany
|| Department of Cardiology, Albert-Ludwigs-University, Freiburg, Germany
Manuscript received March 18, 2002;
revised manuscript received January 21, 2004,
accepted February 17, 2004.
* Reprint requests and correspondence: Dr. Albrecht Elsässer, Kerckhoff Clinic, Department of Cardiology, Benekestr 2-8, 61231 Bad Nauheim, Germany.
a.elsaesser{at}kerckhoff.mpg.de
OBJECTIVES: 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.
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Abbreviations and Acronyms
| | ATP | = adenosine triphosphate | | CABG | = coronary artery bypass graft surgery | | DNA | = deoxyribonucleic acid | | HHM | = human hibernating myocardium | | LV | = left ventricle/ventricular | | RNA | = ribonucleic acid | | RT-PCR | = reverse transcription-polymerase chain reaction | | SPECT | = single-photon emission computed tomography | | TUNEL | = terminal deoxynucleotidyl transferase-mediated nick end-labeling |
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