Exercise Capacity Recovery After Myocardial Infarction: Response to Novel Therapy



 DESCRIPTION (provided by applicant): Myocardial infarction (MI) occurs in more than a million people in the United States annually. Risk factors for MI include obesity, smoking, increased stress, diet, etc. which tend to be exacerbated in the Veteran population. Despite adequate reperfusion at the time of a MI, scar formation and the attendant left ventricular (LV) remodeling remain sequelae that contribute to poor prognoses, which include reduced LV pump function - and a slow progression to heart failure, which could impair physical activity. Time-dependent changes with respect to the cellular content, where fibroblasts become the predominant cell type within the MI region, lead to expansion and progressive thinning of the MI region. Concomitantly, the LV dilates and there is a deterioration of LV pump function in the post-MI setting. A recent study has provided evidence that a novel paradigm of localized high frequency stimulation (LHFS) using low amplitude electrical pulses within the "healed" MI region attenuated LV wall thinning (infarct expansion) and LV dilation post-MI and was associated with a relative preservation of LV ejection fraction. However, whether and to what degree this functional benefit on LV pump function translates to tangible changes in exercise capacity remains unknown. Given the past association between improved LV pump function and an increase in the capacity to perform physical exercise, the hypothesis of this project is that the effects of LHFS with respect to effects LV remodeling post-MI will directly translate to tangible improvements in exercise capacity. Furthermore, these post- MI benefits of LHFS with respect to exercise tolerance will be accompanied by fundamental effects on functional characteristics of fibroblasts in the MI region. In a porcine MI model, LHFS will be initiated within the MI region during a well-defined temporal window at which the post-MI healing response transitions from inflammation to ECM accumulation. In vitro studies will establish that the fundamental cellular basis for the effects of LHFS is phenotypic changes in fibroblasts from the MI region. Thus, through an integrated approach, this project will utilize the novel LHFS technique to interrupt MI expansion and preserve LV pump function, thus providing a means to further develop/characterize this device-based - and likely, clinically applicable - technique to improve prognoses with respect to exercise capacity after myocardial infarction.