Abstract 3222: When the L-type Ca2+ Current is Increased After Myocardial Infarction Determines if the Effects Will be Beneficial or Detrimental
Introduction: Myocardial infarction (MI) causes death of cardiac tissue which depresses cardiac pump performance. Increased myocyte [Ca2+] and contractility is required in surviving myocytes to maintain pump function, but this [Ca2+] also induces cardiac hypertrophy, arrhythmias and cell death. We tested if persistent increases in L-type Ca2+ Current (I Ca, L) after MI would improve or further depress cardiac dysfunction.
Methods: Double transgenic mouse lines with inducible (Tet-off system) and cardiac myocyte specific (αMHC promoter) overexpression of the β2a subunit of the L-type Ca2+ channel were used to increase ICa, L. Animals were divided into 3 groups: β2a gene on before and after MI (β2a-ON); β2a gene off before MI and then on after MI (β2a-OFF/ON) and wild type (WT) mice. In-vivo cardiac function was measured with the Visual Sonics Velvo 770 system. Myocytes were isolated and ICa, L was measured in WT and β2a hearts before and after MI.
Results: Ventricular myocytes (VMs) isolated from β2a-ON mice had increased ICa, L (WT vs. β2a: 13.7±0.7 vs. 24.3±2.6 pA/pF) and contractility (WT vs. β2a: 8.0±0.5% vs.11.9±1.1%) before MI. Ejection fraction (EF) was also greater (WT vs. β2a-ON: 68.9±1.3 % vs. 73.8±1.2%). Acute I/R resulted in greater infarct area (% of area at risk) in β2a-ON (83.7±14.4%) versus WT mice (45.3±6.14 %). 6 weeks after MI, EF was significantly lower in β2a-ON (27.8±8.0%) compared with WT mice (40.3±2.9%). There was no difference in ICa, L, EF, or infarct size either before or 6 weeks post MI in β2a-OFF/ON versus WT mice. When the β2a gene was turned on after 6 weeks post MI (β2a-OFF/ON), ICa,L increased in β2a-OFF/ON VMs (WT vs. β2a: 11.2±0.8 vs. 21.3±2.8 pA/pF) and EF was significantly improved in β2a-OFF/ON (48.01±5.63%) versus WT mice (33.85±3.70%).
Conclusions: Increasing Ca2+ influx before MI exacerbate infarct expansion and depress cardiac dysfunction. Increasing Ca2+ influx after MI did not induce infarct expansion and improved cardiac pump function by enhancement of individual myocyte contractility. Increasing contractility immediately after infarction exacerbates injury and causes more severe heart failure.
This research has received full or partial funding support from the American Heart Association, Great Rivers Affiliate (Delaware, Kentucky, Ohio, Pennsylvania & West Virginia).