Surgical ventricular reconstruction in mice: elucidating potential targets for combined molecular/surgical intervention.

Abstract

We hypothesize that persistent alterations in molecular signaling may drive recurrent pathologic remodeling even after the reduction of mechanical stress achieved via surgical ventricular reconstruction. We developed a murine model of surgical ventricular reconstruction that would facilitate molecular analysis of the postreconstruction myocardium and allow future exploitation of genetic models. C57/B6 mice underwent coronary artery ligation. For surgical ventricular reconstruction at 4 weeks after myocardial infarction, a purse-string suture (7-0 polypropylene) achieved at least partial exclusion of the apical aneurysm. Serial echocardiography was correlated to measurements of apoptosis and to Western blot analysis of key signaling cascades. An immediate 21.7% +/- 2.6% improvement in fractional shortening was seen in the remaining myocardium after surgical ventricular reconstruction. Reduction in left ventricular volume and improved function persisted at 1 week, but recurrent dilatation at 4 weeks (left ventricular end-diastolic volume of 63.5 +/- 2.5 vs 42.1 +/- 5.4 microL immediately after reconstruction; P < .05) was associated with a loss of functional improvement (fractional shortening 41.2% +/- 2% vs 46% +/- 0.9%; P < .01). At 1 week after surgical ventricular reconstruction, there was a transient reduction in myocardial apoptosis. A steady reduction in cardioprotective myocardial Akt activation, however, was not affected by ventricular reconstruction. This murine model recapitulates both the immediate benefits of surgical ventricular reconstruction and the longer-term recurrence of dilated cardiomyopathy seen previously in some animal models and human studies. Early analysis has begun to implicate persistent signaling changes in the postinfarction myocardium that may be responsible for recurrent dilatation after surgical ventricular reconstruction and that may become targets for combined surgical and molecular interventions.