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Nature 450, 819-824 (6 December 2007) | doi:10.1038/nature06321; Received 15 June 2007; Accepted 28 September 2007

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Engraftment of connexin 43-expressing cells prevents post-infarct arrhythmia

Wilhelm Roell1,2,9, Thorsten Lewalter3,9, Philipp Sasse1,9, Yvonne N. Tallini6, Bum-Rak Choi7, Martin Breitbach1, Robert Doran6, Ulrich M. Becher1,3, Seong-Min Hwang8, Toktam Bostani1,2, Julia von Maltzahn4, Andreas Hofmann5, Shaun Reining6, Britta Eiberger4, Bethann Gabris8, Alexander Pfeifer5, Armin Welz2, Klaus Willecke4, Guy Salama8, Jan W. Schrickel1,3, Michael I. Kotlikoff6 & Bernd K. Fleischmann1

  1. Institute of Physiology I, Life and Brain Center,
  2. Department of Cardiac Surgery,
  3. Department of Internal Medicine II,
  4. Institute of Genetics,
  5. Institute of Pharmacology, University of Bonn, Bonn 53105, Germany
  6. Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853-6401, USA
  7. Cardiovascular Research Center, Rhode Island Hospital and Brown Medical School, Providence, Rhode Island 02903, USA
  8. Department of Cell Biology and Physiology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania 15261, USA
  9. These authors contributed equally to this work.

Correspondence to: Michael I. Kotlikoff6Bernd K. Fleischmann1 Correspondence and requests for materials should be addressed to B.K.F. (Email: bernd.fleischmann@uni-bonn.de) or M.I.K. (Email: mik7@cornell.edu).

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Ventricular tachyarrhythmias are the main cause of sudden death in patients after myocardial infarction. Here we show that transplantation of embryonic cardiomyocytes (eCMs) in myocardial infarcts protects against the induction of ventricular tachycardia (VT) in mice. Engraftment of eCMs, but not skeletal myoblasts (SMs), bone marrow cells or cardiac myofibroblasts, markedly decreased the incidence of VT induced by in vivo pacing. eCM engraftment results in improved electrical coupling between the surrounding myocardium and the infarct region, and Ca2+ signals from engrafted eCMs expressing a genetically encoded Ca2+ indicator could be entrained during sinoatrial cardiac activation in vivo. eCM grafts also increased conduction velocity and decreased the incidence of conduction block within the infarct. VT protection is critically dependent on expression of the gap-junction protein connexin 43 (Cx43; also known as Gja1): SMs genetically engineered to express Cx43 conferred a similar protection to that of eCMs against induced VT. Thus, engraftment of Cx43-expressing myocytes has the potential to reduce life-threatening post-infarct arrhythmias through the augmentation of intercellular coupling, suggesting autologous strategies for cardiac cell-based therapy.