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
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Figure 1 Mechanistic hypothesis of the efficacy of skeletal myoblast transplantation on chronic ischemic mitral regurgitation (MR). (Left) Baseline configuration of left ventricle (LV) with normal mitral leaflet closure. (Middle) Chronic infero-posterior infarction: loss of viable myocardial cells induce local LV remodeling with outward bulging of the free wall, papillary muscle displacement, and increased leaflet tethering and MR. (Right) Myoblast transplantation reverses local remodeling with decreased tethering distance and improved leaflet coaptation and MR. Ao = aorta; Ant. = anterior; LA = left atrium; MI = myocardial infarction; Post. = posterior.
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Figure 2 (A) Method. T0 = Infarction and vastus lateralis biopsy; M2 = two months after infarction: time for MR to develop and time of injections; M4 = four months after infarction: sacrifice. At each time point three-dimensional (3D) and two-dimensional echo analysis were performed. (B) 3D echo analysis. 3D left ventricular volumes were obtained using endocardial borders from nine views (left). The least-squares plane of the mitral annular hinge points was established as reference frame; projecting the annulus onto this plane gave annular area. Mitral geometry was analyzed at mid-systole (time of closest leaflet-annulus approach), including papillary muscle-to-annulus tethering distance (right). MI = myocardial infarction; MR = mitral regurgitation.
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Figure 3 Mid-systolic apical two-dimensional echo images. (Left) Mild bulging of the infarcted infero-posterior wall with apical leaflet tenting relative to the annulus (dashes) in the direction of tethering (upward arrows). Mild-to-moderate MR in the more globular remodeled LV is seen below. (Right) Cell transplantation restores a more normal LV shape with less bulging of the infero-posterior wall (upward arrows) and decreases tethering distance with improved coaptation and no MR (bottom panel) despite important LV dilation. Abbreviations as in Figure 1.
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Figure 4 Efficacy of myoblast transplantation. Parallel variations in mitral regurgitation (MR) stroke volume (A) and tethering distance (B). MI = myocardial infarction.
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Figure 5 Effects of myoblast transplantation on left ventricular ejection fraction function (A) and wall motion score (WMS) (B). MI = myocardial infarction.
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Figure 6 Histology of the subpapillary muscle region. (A) Chronic infarction (after four months) in a control animal characterized by dense fibrous tissue (H&E stain, bar = 600 µm). (B) Scar area in a grafted sheep at two months after transplantation with identification of a group of well-differentiated grafted cells (black arrow) replacing fat and fibrous tissues (H&E stain, bar = 600 µm).
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Figure 7 Organized skeletal muscle cells. Treated area in a grafted sheep at two months after transplantation. (A) (x40) High density of grafted cells on traversal section and surrounded by fibrous tissue (H&E stain; bar = 100 µm). (B) (x300) Skeletal myotubes (SM) organized in parallel with multiple peripheral nuclei (*) and abundant myofilaments (H&E stain; bar = 150 µm). (C) Section of an engrafted scar area at two months after transplantation. Immunostaining for the fast isoform of the beta myosin heavy chain (My 32; bar = 200 µm). (D) To a serial section, immunostaining for the slow isoform of beta myosin heavy chain (NOQ7; bar = 200 µm).
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