Abstract
Introduction: The progression of dilated cardiomyopathy (DCM) mainly involves genetic mutations or ischemia at the cellular level, leading to microvascular dysfunction associated with cell death, interstitial fibrosis, and high wall stress. Radical treatment of DCM requires how to ameliorate its microcirculation and integrate cardiomyocytes created ex vivo into recipient myocardium. Hypothesis: The induced pluripotent stem cell derived cardiomyocyte sheets (iPS-sheet) has therapeutic potential by the improvement of microcirculation in a porcine DCM model. Methods: The iPS-sheets were generated from clinical grade human iPS cells. A DCM model was created by tachycardia pacing, and iPS-sheet was transplanted with immunosuppressive agents 1 month after the initiation of the pacing. We compared the therapeutic efficacy functionally and pathologically between the iPS-sheet transplant group (iPS-group) and the sham group after 1 month of transplantation. Results: On echocardiography, the iPS group showed a significant improvement in contractility compared to the sham group (LVEF 4 weeks after transplantation iPS vs. sham 49.0±6.5% vs. 36.4±3.3%, p<0.05, Figure A). Pressure-volume loop analysis revealed that a significant decrease in left ventricular end diastolic pressure and an improvement in end-systolic pressure-volume relationship in the iPS group (Figure B). Ammonia PET showed improvement in myocardial blood flow at both rest and stress in iPS group (Figure C). Histological analysis revealed that the density of CD31-positive capillaries in transplanted area was significantly greater in the iPS group than the sham group. Immunostaining revealed iPS-sheet were detected on the epicardium of the distressed myocardium (Figure D). Conclusions: The iPS sheet showed engraftment in distressed myocardium, leading to amelioration in cardiac function through improving microcirculation with angiogenesis in porcine DCM model.
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