Autologous skeletal myoblast sheet prevents cardiomyocyte ischemia and right heart dysfunction in pressure-overloaded right heart porcine model

Abstract

Abstract Introduction Severe heart failure (HF) with congenital heart disease (CHD) have demonstrated life threatening disorder despite of remarkable progress in medical therapies. Autologous skeletal myoblast sheet transplantation therapy showed clinical efficacy for left ventricular dysfunction by cytokine paracrine effects, which are expected to be sufficiently effective against right ventricular (RV) dysfunction which is often seen in end-stage of CHD patients with severe HF. Hypothesis An autologous skeletal myoblast sheet transplantation alleviates RV dysfunction in a pressure-overloaded right heart in a porcine model. Methods Five-to-six-month-old Göttingen mini-pigs underwent pulmonary artery banding with vascular occluding system. To create the porcine model of chronic pressure-overloaded right heart, vascular occluding system was gradually inflated, over a month, to make pulmonary stenosis to banding velocity >3.0 m/s measured by echocardiography (UCG), and then fixed for another month. Two months after banding, autologous skeletal myoblast sheet was placed on the epicardium of the RV free wall and followed for 2 months. Groups were as follows: control (C, n=5), sheet implantation (S, n=5). Cardiac function was measured using UCG, cardiac computed tomography (CT), and cardiac catheterization (Cath). Two months after sheet implantation, hearts were dissected for histologic analysis. Results Before sheet implantation, RV dysfunction was equal in groups; however, 2 months after sheet implantation, RV dysfunction and myocardial ischemia was significantly ameliorated in group S than group C. On CT, RV ejection fraction exacerbation were well controlled in Group S compared to Group C (S 44.9±2.2 vs C 31.9±2.1% [p=0.0042]). UCG and Cath revealed well maintained systolic and diastolic function in Group S compared to Group C (Tei index: S 0.42±0.06 vs C 0.70±0.07 [p=0.0240], Fraction Area Change: S 45.8±7.8 vs C 19.5±1.3% [p=0.0240], Isovolumic Relaxation Time; S 44.3±9.2 vs C 97.3±9.5 ms [p=0.0304]). On C11-Acetate Positron Emission Tomography, myocardial ischemia was more prominent in Group C compared to Group S (K mono-Rest/Stress: S 3.17±0.69 vs C 2.03±0.65 min-1 [p=0.0421], Myocardial Blood Flow-Rest/Stress: S 3.22±0.39 vs C 2.13±0.92 min-1 [p=0.0421]). In histologic analysis, Group S presented less progressed hypertrophic change in periodic acid-Schiff stain (S 13.5±0.9 vs C 18.0±3.0 μg [p=0.0240]), anti-fibrotic changes in picrosirius red stain (S 3.0±0.3 vs C 4.2±0.2% [p=0.0421]), more angiogenesis in CD31 expression (S 18.3±1.5 vs C 10.7±2.8 / 104 μm2 [p=0.0240]), and less production of reactive oxygen species in fluorescent immunostaining (S 5.9±1.7 vs C 18.4±1.7% [p=0.0304]). Conclusion Autologous skeletal myoblast sheet transplantation alleviates cardiomyocyte Ischemia and RV dysfunction in a porcine model of pressure-overloaded right heart. Funding Acknowledgement Type of funding source: None