Myocardial infarction and subsequent reperfusion lead to the activation of apoptosis, and the final destruction of the cell. The aim of this study was to show that broad-scale inhibition of
caspases, the main executioners of apoptosis, improves functional outcome after
ischemia and reperfusion in an in vivo model. Twenty male Wistar rats were directly injected with an adenovirus, encoding the baculoviral
protein p35. Nineteen rats served as controls, and were injected with a virus only encoding
green fluorescent protein (GFP). After 3 days, 12 animals were used for Langendorff perfusion experiments, the other 27 animals were submitted to in vivo
infarction.
Myocardial infarction was induced by
ligation of the left anterior descending artery (LAD) for 30 min, and reperfusion for 24 h. Echocardiographic and hemodynamic measurements were made 24 h after
infarction.
Infarct size was assessed in all animals histologically. In both, in vivo and Langendorff perfused hearts,
myocardial infarct size was significantly reduced in the p35 group (for in vivo experiments: 0.11+/-0.03 vs 0.33+/-0.03 in the GFP group, p<0.01), as was the ratio of
infarct size to area at risk (6 vs 17%, p<0.01). Left ventricular function was similar in both groups prior to
infarction, but was significantly less compromised after
infarction in the p35 group. The left ventricular systolic pressure after
infarction was higher in the p35 group (107+/-5 vs 92+/-4 mmHg, p<0.05), as was the maximal rate of rise of left ventricular systolic pressure dp/dt (5,659+/-585 vs 4,634+/-256 mmHg s(-1), p<0.05). Adenoviral gene transfer of the
caspase inhibitor p35 leads to a significant reduction of the
myocardial infarct size after
ischemia and reperfusion. Hemodynamic variables were significantly improved by treatment with p35. Cardiac restricted inhibition of apoptosis seems to be a promising approach for ameliorating the effects of
ischemia and reperfusion.