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PRECLINICAL STUDY

Autologous Myoblast Transplantation for Chronic Ischemic Mitral Regurgitation

Emmanuel Messas, MD, MSc^_*,,,,_*, Alain Bel, MD^_*,,,, Miguel Cortes Morichetti, MD^,,, Claire Carrion, PhD^||, Marc D. Handschumacher, BS^¶, Séverine Peyrard, BS^#, Jean Thomas Vilquin, PhD^||, Michel Desnos, MD^_*,,,, Patrice Bruneval, MD^_*,,_**, Alain Carpentier, MD, PhD, FACC^_*,,,, Philippe Menasché, MD, PhD^_*,,,, Robert A. Levine, MD^¶ and Albert A. Hagège, MD, PhD^,,

^_* Université René Descartes Paris 5, Faculté de Médecine René Descartes Paris 5, Paris, France
Institut National de la Santé et de la Récherche Médicale, Unité 633, Paris, France
Ecole de Chirurgie, Paris, France
Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France
^|| INSERM U582, Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
^¶ Cardiac Ultrasound Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
^# Clinical Investigation Center 92010-INSERM, Paris, France
^_** Department of Pathology, INSERM U 430, Paris, France

Manuscript received August 2, 2005; revised manuscript received November 1, 2005, accepted December 19, 2005.

^_* Reprint requests and correspondence: Dr. Emmanuel Messas, Cardiology Department, Hôpital Européen Georges Pompidou, INSERM U 633, Hôpital Broussais, 6 rue Didot, 75014 Paris, France. (Email: emmanuel.messas{at}nck.aphp.fr).

Presented in part as an abstract in the Scientific Sessions of the American College of Cardiology, March 2004.

OBJECTIVES: This study was designed to assess whether post-myocardial infarction (MI) in-scar transplantation of skeletal myoblasts (SM) could reduce chronic ischemic mitral regurgitation (MR) by decreasing left ventricular (LV) remodeling.

BACKGROUND: Extensive work has confirmed the relationship between ischemic MR and post-myocardial infarction (MI) remodeling of the LV.

METHODS: An infero-posterior MI was created in 13 sheep, thereby resulting in increasing MR. Two months post-MI, the animals were randomized and in-scar injected with expanded autologous SM (n = 6, mean: 251 x 10⁶ cells) or culture medium only (n = 7). Three-dimensional echocardiography was performed at baseline, before transplantation, and for two months thereafter (sacrifice), with measurements of LV end-diastolic and end-systolic volumes (ESV), ejection fraction (EF), MR stroke volume, and leaflet tethering distance; wall motion score index (WMSi) was assessed by two-dimensional echo.

RESULTS: Measurements were similar between groups at baseline and before transplantation. At sacrifice, transplantation was found to have reduced MR progression (regurgitant volume change: –1.83 ± 0.32 ml vs. 5.9 ± 0.7 ml in control group, p < 0.0001) and tethering distance (–0.41 ± 0.09 cm vs. 0.44 ± 0.12 cm in control group, p < 0.001), with significant improvement of EF (2.01 ± 0.94% vs. –4.86 ± 2.23%, p = 0.02), WMSi (–0.25 ± 0.11 vs. 0.13 ± 0.03 in controls, p < 0.01) and a trend to a lesser increase in ESV (23.3 ± 3.5 ml vs. 35.4 ± 4.2 ml in control group, p = 0.055).

CONCLUSIONS: Autologous skeletal myoblast transplantation attenuates mild-to-moderate chronic ischemic MR, which otherwise is progressive, by decreasing tethering distance and improving EF and wall motion score, thereby enhancing valve coaptation. These data shed additional light on the mechanism by which skeletal myoblast transplantation may be cardioprotective.

Abbreviations and Acronyms   ESV = end-systolic volume   FBS = fetal bovine serum   IV = intravenously   LV = left ventricle   MHC = myosin heavy chain   MI = myocardial infarction   MR = mitral regurgitation   PM = papillary muscle   SM = skeletal myoblast   3D = three-dimensional   WMS = wall motion score

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