Abstract 18677: New Myocytes Generated after Cardiac Injury are Derived from a Proliferative Non-Myocyte Pool
Pathological cardiac injury induces persistent sympathetic activity that can cause myocyte death. We tested the hypothesis that the cardiac injury induced by high catecholamines (CATs) elicited cardiac repair mechanisms including new myocyte generation.
Methods: Cardiomyopathy was induced in adult felines by infusion of L-isoproterenol (ISO; 1100 ug/kg/hr) from Alzet minipumps for 10 days. Animals were studied at Day 10 (injury), Day 17 (early recovery) and Day 38 (late recovery) following ISO minipump implantation. Ejection fraction (EF) was assessed by 2D echocardiography. Bromodeoxyuridine (BrdU; to identify proliferative cells) was infused via minipumps (50 mg/ml) either 7 days prior to euthanasia (heart explant at Day 10, 17 or 38) or during ISO injury (pulse) with animals examined after some recovery (Day 38; chase).
Results: ISO transiently increased EF and then caused depressed function [Baseline (BSL) EF: 73.3 ± 1.1% N=19 vs. ISO Day 10: 59.1 ± 2.1% N=19 (p<0.001)]. % collagen content in the left ventricle (LV) was increased [Control (CON): 3.5 ± 0.6% N=7 vs. ISO Day 10: 13.2 ± 1.7% N=7 (p<0.001)]. 7 days post ISO (Day 17), EF recovered toward BSL and there were no further changes in collagen content or LV dilation. At Day 10 (injury phase) there was a large increase in the # of BrdU+ nuclei in the LV [% BrdU+ nuclei: CON: 2.5 ± 0.4% N=7 vs. ISO Day 10: 18.6 ± 2.9% N=7 (p<0.001)]. However, very few BrdU+ myocyte nuclei were observed. At Day 17 the # of BrdU+ nuclei in the LV [4.7 ± 0.6% N=6] decreased. However, % BrdU+ myocyte nuclei increased significantly [LV: CON: 0.007 ± 0.004% N=7 vs. ISO Day 10: 0.007 ± 0.003% N=7, ISO Day 17: 0.080 ± 0.028% N=6 (p<0.05)]. Our most provocative finding was that we observed significantly more BrdU+ myocytes at Day 38 (chase) when BrdU was infused during injury (pulse) [0.041 ± 0.009% N=4 (p<0.01)] than when it was infused just before sacrifice [0.0057 ± 0.0057% N=4].
Conclusion: Catecholamine injury induces an increase in proliferative non-myocytes in the heart. More importantly, when catecholamines are reduced, these data suggest that the BrdU+ myocytes found at Day 38 were derived from non-myocyte BrdU+ cardiac precursors that were labeled during the injury phase, when very few BrdU+ myocytes were observed.
- Cardiac regeneration
- Regenerative medicine stem cells
- Heart failure
- Stem/progenitor cells
- © 2010 by American Heart Association, Inc.