Abstract 8851: Intracoronary Infusion of Cardiosphere-Derived Cells (icCDCs) Improves Cardiac Function by Stimulating Myocyte Proliferation in Non-Infarcted Hibernating Myocardium with No Effect in Normal Myocardium

Abstract

Background: icCDCs have been shown to improve function and reduce fibrotic area when regionally infused into infarcted myocardium. Their ability to improve flow and function in viable dysfunctional myocardium in the absence of scar is unclear. Methods: Swine (n=12) with collateral-dependent hibernating myocardium from a chronic LAD occlusion were studied 4-months after instrumentation in the closed-chest propofol sedated state. CDCs were isolated from myocardial biopsies at the time of initial instrumentation. We assessed regional flow, LAD wall thickening (%LADWT) and global EF before and 4 weeks after icCDCs (∼40x10 6 cells) into each of the 3 major coronary arteries. Autologous (n=3) as well as non-autologous CDCs with cyclosporine treatment (200mg/day; n=3) had similar effects and results were pooled and compared to untreated swine (n=6). Histological analysis was performed to assess the frequency of Ki-67 and phospho-Histone H3 (pHH3) positive myocytes along with myocyte nuclear density and myocyte diameter. Results: Infusion of icCDCs in normal animals (icCDCs; n=5 vs. untreated; n=6) did not affect regional (%LADWT 51±1% vs. 48±3%, p-ns) or global function (EF: 70±2% vs. 70±3%, p-ns). In contrast, in hibernating myocardium, %LADWT increased from 23±6 to 51±5 % (p<0.01) and EF increased from 57±1 to 71±4 % (p<0.01) after icCDCs. There was no change in LAD coronary flow reserve (adenosine vasodilated flow/ resting flow 1.88 ± 0.20 to 2.03 ± 0.31, p-ns). icCDCs increased the number of Ki-67 and pHH3 positive myocytes (Table). This was accompanied by a prominent increase in myocyte nuclear density with reduced myocyte size suggesting the formation of new myocytes. Conclusion: We conclude that icCDCs result in a robust improvement in function in hibernating myocardium. This is not secondary to increases in myocardial perfusion but is secondary to pronounced myocyte proliferation and regeneration with newly formed myocytes in diseased but not normal myocardium.