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

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 Ca 2+ signals from engrafted eCMs expressing a genetically encoded Ca 2+ 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. Connexin 43 for the heart Cell-based therapies are thought to have great potential for the treatment of cardiovascular diseases. Current clinical trials aim to restore contractile force by the transplantation of autologous skeletal muscle or bone marrow cells in the failing heart, but this approach has so far met with only limited success. Work in mice with experimentally induced myocardial infarcts has now produced the finding that engraftment of fetal cardiomyocytes provides potent protection against ventricular arrhythmia, a common cause of death in patients following heart attack. The implanted cells are activated by the normal cardiac action potential and the engraftment of these electrically coupled cells establishes pathways of increased conduction into the infarct. In addition, connexin 43, a protein found at 'gap junctions' between neighbouring cells, has been implicated in this protection. Surprisingly, expressing this protein in skeletal muscle cells now confers properties similar to the fetal cardiomyocytes. These results suggest a new approach to cell-based therapy for cardiac dysfunction. Tachycardia can be prevented by engrafting embryonic cardiomyocytes into mice. A protein resident at