Abstract 10746: Repair of the Injured Adult Heart Involves c-Kit+ Cardiac Stem Cells and New Myocyte Formation Regionally Greatest in the Apex and Epicardium
Cardiac injury induces persistent sympathetic activity that can cause myocyte death. We induced diffuse cardiac injury by high catecholamines and studied if repair involved regionally specific new myocyte generation via c-kit+ cardiac progenitor cells.
Methods: Cardiomyopathy was induced in adult felines by infusion of L-isoproterenol (ISO; 1100 ug/kg/hr) from minipumps (10 days). Animals were studied at Day 10 (injury), 17 (early recovery) and 38 (late recovery). Bromodeoxyuridine (BrdU; to identify proliferative cells) was infused via minipumps 7 days prior to euthanasia (at Day 10, 17 or 38), or during ISO injury (pulse) with animals examined after recovery (Day 38; chase).
Results: ISO injury reduced cardiac function. % collagen increased after ISO. 7 days post ISO (Day 17), EF recovered toward BSL. At Day 10 (injury) there was a large increase in BrdU+ nuclei in the LV but few BrdU+ myocytes. A significantly larger number of c-kit+ and c-kit+BrdU+ nuclei were found at Day 10 compared with control, and were greatest in the Apex (c-kit+ 0.336±0.038, p<0.001; c-kit+BrdU+ 0.088±0.011, p<0.001) and Epicardium (c-kit+ 0.431±0.023, p<0.001; c-kit+BrdU+ 0.250±0.023, P<0.001) compared with the Middle, Base, Mid-Myocardium, and Endocardium, respectively. At Day 17, the % of BrdU+ myocytes significantly increased. The regional location of this new myocyte formation during the greatest endogenous regeneration, was found to be significantly increased in the Apex (0.216 ± 0.040%, p<0.001) and Epicardium of the heart (0.203 ± 0.048%, p<0.001) compared with other regions in the heart. We also observed that the BrdU+ myocytes at Day 38 (chase) when BrdU was infused during injury (pulse), were also significantly greater in the Apex and Epicardium. c-kit+ cardiac stem cells have significantly greater proliferation during the injury phase (Day 10), in the Apex and Epicardium, and at Day 38 (chase), a greater % are expressing GATA4 and α-sarcomeric actin.
Conclusion: Diffuse catecholamine injury induces regionally variable repair, including activation of cKit+ progenitors and BrdU+ new cardiac myocytes. Pulse-chase studies suggest that BrdU+ myocytes were derived from non-myocyte BrdU+ cardiac precursors which are concentrated in the cardiac apex and epicardium.
- © 2013 by American Heart Association, Inc.