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(Circulation. 2008;117:1583-1593.)
© 2008 American Heart Association, Inc.

Molecular Cardiology

Survivin Determines Cardiac Function by Controlling Total Cardiomyocyte Number

Bodo Levkau, MD^*; Michael Schäfers, MD^*; Jeremias Wohlschlaeger, MD; Karin von Wnuck Lipinski, PhD; Petra Keul, BS; Sven Hermann, MD; Naomasa Kawaguchi, MD; Paulus Kirchhof, MD; Larissa Fabritz, MD; Jörg Stypmann, MD; Lars Stegger, MD; Ulrich Flögel, PhD; Jürgen Schrader, MD; Jens W. Fischer, PhD; Patrick Hsieh, MD, PhD; Yen-Ling Ou, BS; Felix Mehrhof, MD; Klaus Tiemann, MD; Alexander Ghanem, MD; Marek Matus, PhD; Joachim Neumann, MD; Gerd Heusch, MD; Kurt W. Schmid, MD; Edward M. Conway, MD, PhD; Hideo A. Baba, MD

From the Institut für Pathophysiologie (B.L., K.v.W.L., P. Keul, G.H.) and Institut für Pathologie (J.W., N.K., K.W.S., H.A.B.), Universitätsklinikum Essen, Essen Germany; Klinik und Poliklinik für Nuklearmedizin (M.S., S.H., L.S.) and Medizinische Klinik und Poliklinik C (P. Kirchhof, L.F., J. Stypmann), Universitätsklinikum Münster, Münster, Germany; Institut für Herz und Kreislaufphysiologie (U.F., J. Schroder) and Institut für Pharmakologie und Klinische Pharmakologie (J.W.F.), Universität Düsseldorf, Düsseldorf, Germany; Institute of Clinical Medicine and Center of Micro/Nano Science and Technology, National Cheng Kung University, Tainan City, Taiwan (P.H., Y.-L.O.); Medizinische Klinik mit Schwerpunkt Kardiologie, Universitätsklinikum Charité, Berlin, Germany (F.M.); Medizinische Klinik und Poliklinik II, Universitätsklinikum Bonn, Bonn, Germany (K.T., A.G.); Institut für Pharmakologie und Toxikologie, Universitätsklinikum Münster, Münster, Germany (M.M.); Institut für Pharmakologie und Toxikologie, Universität Halle Wittenberg, Wittenberg, Germany (J.N.); and Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, University of Leuven, Leuven, Belgium (E.M.C.).

Correspondence to Bodo Levkau, Institute of Pathophysiology, University Hospital Essen, Hufelandstrasse 55, 45122 Essen, Germany. E-mail levkau{at}uni-essen.de

Received August 15, 2007; accepted December 28, 2007.

Background— Survivin inhibits apoptosis and regulates cell division in many organs, but its function in the heart is unknown.

Methods and Results— We show that cardiac-specific deletion of survivin resulted in premature cardiac death. The underlying cause was a dramatic reduction in total cardiomyocyte numbers as determined by a stereological method for quantification of cells per organ. The resulting increased hemodynamic load per cell led to progressive heart failure as assessed by echocardiography, magnetic resonance imaging, positron emission tomography, and invasive catheterization. The reduction in total cardiomyocyte number in -myosin heavy chain (MHC)–survivin^–/– mice was due to an 50% lower mitotic rate without increased apoptosis. This occurred at the expense of DNA accumulation because survivin-deficient cardiomyocytes displayed marked DNA polyploidy indicative of consecutive rounds of DNA replication without cell division. Survivin small interfering RNA knockdown in neonatal rat cardiomyocytes also led to polyploidization and cell cycle arrest without apoptosis. Adenoviral overexpression of survivin in cardiomyocytes inhibited doxorubicin-induced apoptosis, induced DNA synthesis, and promoted cell cycle progression. The phenotype of the MHC-survivin^–/– mice also allowed us to determine the minimum cardiomyocyte number sufficient for normal cardiac function. In human cardiomyopathy, survivin was potently induced in the failing heart and downregulated again after hemodynamic support by a left ventricular assist device. Its expression positively correlated with the mean cardiomyocyte DNA content.

Conclusions— We suggest that the ontogenetically determined cardiomyocyte number may be an independent factor in the susceptibility to cardiac diseases. Through its profound impact on both cardiomyocyte replication and apoptosis, survivin may emerge as a promising new target for myocardial regeneration.

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