Implantation of an Induced Pluripotent Stem Cell Derived Cardiomyocyte Tissue Engineered Patch Improves Left Ventricular Function and Electro-Mechanical Coupling in Rats with Heart Failure

Background: Chronic Heart Failure (CHF) is the leading cause of hospital readmissions and mortality in the US. Here we report the effects of surgically delivering a human bioengineered patch of human induced pluripotent stem cells derived cardiomyocytes (hiPSC-CMs) and fibroblasts on left ventricular (LV) function in rats with CHF. We evaluate improvements in LV systolic and diastolic function, electromechanical coupling and gene expression after patch implantation. Methods: Adult male Sprague-Dawley rats underwent left coronary artery ligation and were randomized to Sham (N=8), CHF (N=8-21), and CHF+hiPSC-CM patch (N=20-24). Heterogeneous hiPSC-CMs were seeded and co-cultured onto a vicryl matrix embedded with human dermal fibroblasts. Echocardiography was performed at 3 and 6 weeks post-randomization. Hemodynamic pressure measurements were performed at 6 weeks post-ligation with Millar solid state micromanometer pressure catheters. Open chest Electrophysiologic (EP) mapping was performed at 6 weeks post ligation. Gene expression was evaluated through qRT-PCR. Results: 48 hours into culture hiPSC-CMs patches displayed synchronized and spontaneous contractions which developed in robustness over time. At maximal robustness, contractions were visualized across the full thickness of the construct. Contractions were recorded at 36 + 5 beats BPM. Three weeks after patch implantation (6 weeks post ligation) the hiPSC-CM patch decreased (P<0.05) LV EDP (45%), Tau (29%), E/e’ (23%) and increased (P<0.05), e’/a’ (36%) with trending improvements in EF (14%) and e’ (20%). EP studies show electro-mechanical coupling between the patch and the native myocardium with normal activation through the patch and increases (P<0.05) voltage amplitude in CHF versus hiPSC-CM patch treated rats (1±0.5 mV vs 6±1.5mV). Rats treated with the hiPSC-CM patch showed significant (P<0.05) fold expression of Cx43 (3.3), ANG-1 (13.63), VEGF (3.8), βMYH7 (6.4) and IGF-1 (22.9) versus control. Conclusion: Cardiac patch implantation with hiPSC derived cardiomyocytes is an effective and feasible method of treating CHF with improvements in systolic function, diastolic function, and electro-mechanical coupling in rats with CHF.