Abstract 324: Genetically Mediated Increases in Myocyte Contractility after Myocardial Infarction Exacerbate Cardiac Dysfunction
Myocyte death induced by ischemia or infarction can lead to depressed cardiac pump function and + inotropic drugs are often employed as therapy. The increased myocyte [Ca2+] required to increase myocyte contractility can also induce cardiac hypertrophy, arrhythmias and cell death. Our hypothesis is that + inotropic therapies after MI, while they will increase myocyte contractility, will ultimately exacerbate pump dysfunction by increasing myocyte death.
METHODS: Double transgenic (TG) mouse lines with inducible (Tet-off system; tTA-TG) and cardiac myocyte specific (αMHC promoter) overexpression of the β2a subunit of the L-type Ca2+ channel (Cav1.2 β2a (β2a-TG)) were used. Littermates having only one or none trangene (only β2a or tTA or WT) served as controls (CTR). Myocardial infarction (MI) was produced by permanent ligation of the left anterior descending coronary artery and animals were sacrificed 6 weeks later. Ischemia/reperfusion (I/R) was produced by ligating the LAD for 30 minutes followed by reperfusion for 3 hours (I/R) and then animals were sacrificed. In-vivo cardiac function was measured with the Visual Sonics Velvo 770 system.
RESULTS: Myocytes isolated from β2a-TG mice had increased Ca2+ current (CTR: 13.7 ± 0.7pA/pF, n = 6 vs. TG: 24.3 ± 2.6pA/pF, n = 6; p < 0.05) and contractility (CTR vs. TG VM: 8.0 ± 0.5%, n = 16 vs. 11.9 ± 1.1%, n = 11). Acute I/R resulted into greater Infarct size (the infarcted area vs. total area) in β2a-TG with I/R (62.4 ± 8.4%) than in CTR mice (49.2 ± 2.5%; p < 0.05). Before MI, β2a-TG mice had greater ejection fraction (EF) (73.8 ± 1.2%) than CTRs (68.9 ± 1.3%; p < 0.05). EF was decreased after MI in all mice (β2a-TG: 42.2 ± 7.5% vs. control: 45.2 ± 5.8%, p < ns). However, in β2a-TG mice, EF continued to decrease (27.8 ± 8.0%) at 6 weeks post MI but remained stable in CTRs (40.3 ± 2.9%; p < 0.05). The 6-week post MI survival rate was significantly lower in β2a-TG mice (16.6%) than in CTRs (50.0%; p < 0.05). Infarct size 6 weeks after MI was smaller than in acute I/R, but was still greater in β2a-DTG (45.8 ± 11.8%) than in CTRs (21.7 ± 9.8%; p < 0.05).
CONCLUSION: These results suggest that increasing the contractility of myocytes after MI contributes to infarct expansion and CHF progression, possibly by increasing Ca2+ -mediated myocyte death.