Abstract
Myocardial dysfunction is strongly associated with a higher rate of ventricular arrhythmia and sudden death. Clinical studies indicate that intramyocardial injection of autologous cells to augment contractile function may modify the arrhythmogenic substrate. The aim of this study was to assess the effects of epicardial injections of autologous dermal fibroblasts in infarcted pigs on the incidence of spontaneous and induced ventricular tachycardia. In eight pigs, myocardial infarction was induced, and the skin was excised for fibroblast isolation, culture, and labeling with bromodeoxyuridine (BrdU). After 3 weeks, animals received epicardial injection of the autologous fibroblasts (n = 4) or saline (n = 4) across the scarred and border zone regions, with continuous ECG monitoring for the following 4 weeks. Electrophysiologic study with programmed stimulation was performed before injections and at sacrifice, and histological analysis was performed. ECG monitoring showed that the fibroblast group had a lower total number of ectopic ventricular complexes per day when compared to the control group (58 ± 119 versus 478 ± 1,308 respectively; p = 0.013) and fewer episodes of non-sustained ventricular arrhythmia per day (0 episodes versus 31 ± 148 respectively; p = 0.001). Inducibility during programmed ventricular stimulation was no different between the groups. Histological analysis disclosed the presence of viable BrdU-labeled cells in injected areas. This study showed that fibroblasts can be safely transplanted in an infarcted heart and survive for at least 4 weeks. Fibroblast injection did not increase the inducibility of ventricular tachycardia, and reduced the incidence of spontaneous ventricular tachycardia.
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Chachques, J. C., Shafy, A., Duarte, F., Cattadori, B., Goussef, N., Shen, L., et al. (2002). From dynamic to cellular cardiomyoplasty. Journal of Cardiac Surgery, 17(3), 194–200.
Dib, N., Diethrich, E. B., Campbell, A., Goodwin, N., Robinson, B., Gilbert, J., et al. (2002). Endoventricular transplantation of allogenic skeletal myoblasts in a porcine model of myocardial infarction. Journal of Endovascular Therapy, 9(3), 313–319.
Ghostine, S., Carrion, C., Souza, L. C., Richard, P., Bruneval, P., Vilquin, J. T., et al. (2002). Long-term efficacy of myoblast transplantation on regional structure and function after myocardial infarction. Circulation, 106(12 Suppl 1), I131–I136.
Menasche, P. (2003). Cell transplantation in myocardium. The Annals of Thoracic Surgery, 75(6 Suppl), S20–S28.
Menasche, P. (2005). Stem cells for clinical use in cardiovascular medicine: current limitations and future perspectives. Thrombosis and Haemostasis, 94(4), 697–701.
Menasche, P., Hagege, A. A., Scorsin, M., Pouzet, B., Desnos, M., Duboc, D., et al. (2001). Myoblast transplantation for heart failure. Lancet, 357(9252), 279–280.
Menasche, P., Hagege, A. A., Vilquin, J. T., Desnos, M., Abergel, E., Pouzet, B., et al. (2003). Autologous skeletal myoblast transplantation for severe postinfarction left ventricular dysfunction. Journal of the American College of Cardiology, 41(7), 1078–1083.
Menasche, P., Alfieri, O., Janssens, S., McKenna, W., Reichenspurner, H., Trinquart, L., et al. (2008). The Myoblast Autologous Grafting in Ischemic Cardiomyopathy (MAGIC) trial: first randomized placebo-controlled study of myoblast transplantation. Circulation, 117(9), 1189–1200.
Smith, R. R., Barile, L., Messina, E., & Marban, E. (2008). Stem cells in the heart: what’s the buzz all about? Part 2: arrhythmic risks and clinical studies. Heart Rhythm, 5(6), 880–887.
Yankelson, L., Feld, Y., Bressler-Stramer, T., Itzhaki, I., Huber, I., Gepstein, A., et al. (2008). Cell therapy for modification of the myocardial electrophysiological substrate. Circulation, 117(6), 720–731.
Menasche, P. (2009). Stem cell therapy for heart failure: are arrhythmias a real safety concern? Circulation, 119(20), 2735–2740.
Dib, N., Menasche, P., Bartunek, J. J., Zeiher, A. M., Terzic, A., Chronos, N. A., et al. (2010). Recommendations for successful training on methods of delivery of biologics for cardiac regeneration: a report of the International Society for Cardiovascular Translational Research. JACC Cardiovascular Interventions, 3(3), 265–275.
Menasche, P. (2002). Myoblast transplantation: feasibility, safety and efficacy. Annals of Medicine, 34(5), 314–315.
Eghbali, M. (1992). Cardiac fibroblasts: function, regulation of gene expression, and phenotypic modulation. Basic Research in Cardiology, 87(Suppl 2), 183–189.
Etzion, S., Barbash, I. M., Feinberg, M. S., Zarin, P., Miller, L., Guetta, E., et al. (2002). Cellular cardiomyoplasty of cardiac fibroblasts by adenoviral delivery of MyoD ex vivo: an unlimited source of cells for myocardial repair. Circulation, 106(12 Suppl 1), I125–I130.
Gaudesius, G., Miragoli, M., Thomas, S. P., & Rohr, S. (2003). Coupling of cardiac electrical activity over extended distances by fibroblasts of cardiac origin. Circulation Research, 93(5), 421–428.
Ho, K. K., Anderson, K. M., Kannel, W. B., Grossman, W., & Levy, D. (1993). Survival after the onset of congestive heart failure in Framingham Heart Study subjects. Circulation, 88(1), 107–115.
Peters, N. S. (2005). Arrhythmias after cell transplantation for myocardial regeneration: natural history or result of the intervention? Journal of Cardiovascular Electrophysiology, 16(11), 1255–1257.
Peters, N. S., Coromilas, J., Severs, N. J., & Wit, A. L. (1997). Disturbed connexin43 gap junction distribution correlates with the location of reentrant circuits in the epicardial border zone of healing canine infarcts that cause ventricular tachycardia. Circulation, 95(4), 988–996.
Hagege, A. A., Marolleau, J. P., Vilquin, J. T., Alheritiere, A., Peyrard, S., Duboc, D., et al. (2006). Skeletal myoblast transplantation in ischemic heart failure: long-term follow-up of the first phase I cohort of patients. Circulation, 114(1 Suppl), I108–I113.
Wollert, K. C., Meyer, G. P., Lotz, J., Ringes-Lichtenberg, S., Lippolt, P., Breidenbach, C., et al. (2004). Intracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial. Lancet, 364(9429), 141–148.
Schachinger, V., Tonn, T., Dimmeler, S., & Zeiher, A. M. (2006). Bone-marrow-derived progenitor cell therapy in need of proof of concept: design of the REPAIR-AMI trial. Nature Clinical Practice, 3(Suppl 1), S23–S28.
Reinecke, H., MacDonald, G. H., Hauschka, S. D., & Murry, C. E. (2000). Electromechanical coupling between skeletal and cardiac muscle. Implications for infarct repair. The Journal of Cell Biology, 149(3), 731–740.
Long, C. S., & Brown, R. D. (2002). The cardiac fibroblast, another therapeutic target for mending the broken heart? Journal of Molecular and Cellular Cardiology, 34(10), 1273–1278.
Acknowledgements
We gratefully acknowledge the great contribution of our colleague Dr. Keith Robinson, sadly deceased. The authors thank Melissa Fowlkes and Jesse Rios for technical support. This study was sponsored by Symphony Medical, Inc. and British Heart Foundation (BHF RG/10/11/28457), with acknowledgement of the NIHR Biomedical Research Centre funding scheme.
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This study was sponsored by Symphony Medical, Inc. and British Heart Foundation (RG05/009), with acknowledgement of the NIHR Biomedical Research Centre funding scheme.
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Tondato, F., Robinson, K., Cui, J. et al. Effects on Arrhythmogenesis and Arrhythmic Threshold of Injection of Autologous Fibroblasts into Myocardial Infarcts in Adult Pigs. J. of Cardiovasc. Trans. Res. 5, 337–344 (2012). https://doi.org/10.1007/s12265-011-9316-9
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DOI: https://doi.org/10.1007/s12265-011-9316-9