In our murine model, SVR improved cardiac function. These reconstructed ventricles, however, were susceptible to recurrent dilatation, and a reduction in function was observed as early as 4 weeks post reconstruction. These results are similar to the findings of Nishina et al. in a rat model of aneurysm exclusion [3
], and are reminiscent of longer-term changes documented in clinical studies of linear or patch ventricular repair [20
The complex integration of multiple signaling pathways is not yet well understood in the evolution of post-MI cardiomyopathy. However, studies have suggested a cardioprotective role for the PI3K/Akt pathway [23
]; the drop we observed in Akt phosphorylation in the post-MI myocardium may therefore play an important role in the loss and dysfunction of myocardial tissue; this drop persisted even after an improvement in ventricular geometry achieved via SVR.
Only minor differences were observed between sham control and SVR hearts in terms of the phosphorylation of MAP kinases p38 and ERK early after re-operation. MAP kinase activation is generally upregulated after ischemic insults, although the role of this activation has been studied more extensively in the progression from pressure overload-induced hypertrophy to dilated cardiomyopathy. It is not clear what role, if any, the observed reduction in phosphorylation of JNK, generally considered, like p38, a “stress-induced” kinase, might have played in sham control hearts 1 week after re-operation, although this change was not observed in SVR hearts. JNK phosphorylation was then increased in both groups by week 4.
SVR results in a reduction in ventricular volume and a decrease in chamber radius. According to LaPlace's law, these changes decrease wall stress. A reduction in wall stress reduces myocardial oxygen demand and enhances ventricular contraction [9
], and there is an increase in the extent and velocity of systolic fiber shortening. This phenomenon was reflected in the increases in FS and EF observed in our murine model. In addition, SVR is likely associated with acute and subacute changes in hemodynamic parameters, that, in turn, are likely to affect both ventricular remodeling as well as associated changes in myocyte signaling. Future studies may be necessary to sort out the various stimuli for changes in cardiac myocyte gene expression and kinase activation in order to optimize human translation of these interventions.
Furthermore, a reduction in mechanical stress may have also contributed to the reduced level of myocardial apoptosis seen early after SVR, and that may have been mediated by an increase in the Bcl-2/ Bax ratio and a preservation of BAD phosphorylation. As suggested by the schema in , persistent changes in molecular signaling, however, such as the reduction of Akt phosphorylation, may drive cardiac remodeling at the cellular level, even after SVR. Subsequent recurrence of LV dilatation could, in turn, instigate a return to pathologic levels of wall stress, and to the vicious cycle of apoptotic cell loss and further progressive LV enlargement.
Current surgical treatments for ischemic cardiomyopathy may not yield optimal long-term outcomes [2
]. This study explored changes in myocardial signaling that might induce reverse remodeling or “physiologic hypertrophy” to compliment the immediate improvement in ventricular geometry achieved by surgical reconstruction. In addition, cell-based and tissue engineering approaches may be combined with reconstruction. Numerous studies have demonstrated benefit from stem cell delivery to injured myocardium [25
], and more recent reports have also described bio-artificial matrices that may provide mechanical support to the injured myocardium and enhance myocardial regeneration [28
]. The direct access of the surgeon at the time of SVR may facilitate otherwise challenging, early applications of these approaches.
Like any small animal model, ours must be understood in light of its numerous limitations. We induced acute infarction in the setting of otherwise normal coronary anatomy and function; more complex human disease may be better mimicked through application of this model in genetic mouse models of diffuse coronary atherosclerosis. In addition, permanent coronary occlusion resulted in a large transmural infarction/aneurysm that exaggerates the typical infarctions of modern candidates for aneurysm resection. Future variations of this model, such as temporary ligation, may extend these observations toward a broader range of human clinical scenarios. The rapid progression of LV remodeling after MI in mice, and of recurrent dilatation after SVR, may require transition through larger animal models for accurate extrapolation to human translation.
If one key to recurrent LV dilatation, however, lies in the molecular biology of the cardiac myocyte, [30
], then the murine model described here may be well-suited to identify critical molecular pathways in the response of the ventricle to SVR. The relative ease with which transgenic strains can be developed in mice has already yielded a wide array of available genetic models. Interestingly, the rapid progression of recurrent dilatation in mice may provide an advantage in the early discovery process. Ongoing studies have begun to examine SVR in the context of myocardial overexpression of activated Akt in transgenic mice. Data from these and other studies may in turn provide a foundation for the development of novel, hybrid surgical interventions for failing hearts, in which genetic, molecular or cell-based therapies may be applied intra-operatively based on a more detailed appreciation of the molecular and cellular parameters of ventricular recovery after reconstruction.