Abstract 19709: Increasing Ca2+ Influx After Myocardial Infarction Improves Myocyte Contractility but Depresses Cardiac Pump Function by Increasing Myocyte Death
Introduction: Myocardial infarction (MI) causes death of cardiac tissue and depresses cardiac pump performance. Increasing the contractility of the surviving myocytes is one therapy thought to improve the function of the failing heart. However inotropic therapy involving sympathetic agonists can induce cell death and induce arrhythmias. We tested if increasing myocyte contractility without activating sympathetic signaling, by increasing Ca influx (ICa-L), would improve post MI heart function.
Methods: Double transgenic mouse lines with inducible (Tet-off system) and cardiac myocyte specific overexpression of the β2a subunit of the L-type Ca2+ channel were used to increase ICa-L. ICa-L, and myocyte fractional shortening (FS) and in vivo cardiac function were measured in wild type (WT) and β2a hearts before, and 3 weeks after MI. Apoptosis (TUNEL), fibrosis (Masson's Trichrome staining) and myocyte proliferation (Ki67 staining, a nuclear marker of cellular replication), were measured.
Results: ICa-L and FS (% resting myocyte length) were significantly greater in myocytes from either sham- or MI- β2a vs. WT mice (sham β2a vs. WT: ICa-L 24.5±1.7 vs.13.7±1.8 pA/pF; FS: 12.3±1.2% vs. 9.0±0.5%; MI β2a vs. WT: 18.4±1.9 vs.11.6±0.8 pA/pF and 12.0±0.7% vs. 7.2±1.0%). Ejection fraction was greater in β2a mice before MI (β2a vs. WT: 72.7±1.2% vs. 67.6±1.3%), however it was significantly lower in β2a (24.7±9.2%) vs. WT (42.6%±5.2) mice after MI. TUNEL + cell number was greater in β2a after acute (β2a vs. WT: 85361 vs. 53511 in border and 3407 vs. 1984 labeled/106 nuclei in remote zone) or 3-week old MI (959 vs. 647 in border and 1415 vs. 709 labeled/106 nuclei in remote zone). Fibrosis was significantly greater in β2a vs. WT mice 3 weeks after MI (0.98 vs. 0.63%). Ki67 labeling was greater in β2a vs. WT hearts after acute (4223 vs. 2621 labeled/106) or 3 weeks MI (1974 vs. 1542 labeled/106).
Conclusions: These results show that increasing Ca2+ influx through the L-type Ca channel can enhance myocyte contractility in the post MI heart without requiring sympathetic activity. However, this approach induces depressed cardiac pump function because the induced rate of myocyte death (from ongoing apoptosis) exceeds the rate of new myocyte formation.
- © 2010 by American Heart Association, Inc.