Increasing Cardiac Contractility after Myocardial Infarction Exacerbates Cardiac Injury and Pump Dysfunction

Abstract

Myocardial infarction (MI) induces cardiac remodeling and leads to poor cardiac pump function. Increasing the contractility of the surviving myocytes is one therapy thought to improve the function of failing heart. However, the excess sympathetic activity in heart failure coupled with increased inotropic therapy could induce cell death and exacerbate cardiac dysfunction. In this study we tested the effects of increasing Ca2+ influx through the L-type Ca2+ channel (LTCC) in the post MI heart on myocyte contractility, cardiac function and remodeling.Methods: Double transgenic mouse lines with inducible (Tet-off) and cardiac myocyte specific (αMHC promoter) expression of the β2a subunit of the L-type Ca2+ channel were used. MI was produced by permanent ligation of the left anterior descending coronary artery. In-vivo cardiac function was measured with the Visual Sonics Velvo 770 system. Myocytes were isolated and LTCC Current (ICa-L) and fractional shortening (FS) were measured in wild type (WT) and β2a hearts before, and 3 weeks after MI. Results: Echo measurements showed decreased heart function in both groups after MI, but β2a mice had significantly lower ejection fraction (EF) and larger left ventricular internal diameter (LVID) than WT mice (EF: 24.7% vs.42.6%; LVID: 5.2 mm vs. 4.2 mm). ICa-L and FS were greater in uninfarcted myocytes from β2a vs WT mice (ICa-L 24.5±1.7 vs.13.7±1.8 pA/pF FS: 12.31±1.15% vs. 9.0±0.5%). 3 weeks after MI, ICa-L and FS in myocytes from both groups were decreased, but β2a myocytes still had significantly higher ICa-L and FS than in WT myocytes (β2a vs. Control: 18.37±1.90 vs.11.57±0.77 pA/pF and 12.05±0.74% vs. 7.16±0.99%). Conclusions: Increasing Ca2+ influx through the LTCC in the post MI heart increases myocyte contractility but depresses cardiac pump function, possibly by increasing myocyte death.