Heart failure with preserved ejection fraction (HFpEF) has emerged as the most common form of heart failure, yet there are currently no treatment strategies that have been proven to improve prognosis. A primary reason for the lack of effective therapeutic approaches to treat this increasingly prevalent condition is the limited understanding of HFpEF pathophysiology. The studies proposed in this application are designed to address this problem by testing the central hypothesis that impairments in left ventricular (LV) compliance and diastolic reserve that characterize HFpEF arise as a consequence of myocardial adaptations to repetitive mechanical stretch-induced myocyte injury. This hypothesis is supported by the applicant's published and preliminary data from a novel swine model demonstrating that exposure to repetitive intermittent episodes of stretch-induced injury produces a pattern of LV remodeling exhibited by many HFpEF patients, with elevated chamber stiffness, myocyte cellular hypertrophy, capillary rarefaction, and increased interstitial fibrosis. These changes occur in the absence of an overt increase in LV mass and appear to serve an adaptive purpose by preventing mechanical stretch-induced injury that occurs following hemodynamic overload in the normal heart. The present proposal will investigate the mechanisms underlying the adaptive reduction in LV compliance and determine whether it has the adverse consequence of impairing diastolic reserve, leading to elevations in LV filling pressure and pulmonary congestion upon exertion or with plasma volume expansion, the hallmark hemodynamic characteristics of HFpEF. Using an integrated research approach that combines invasive assessment of hemodynamic performance during exercise and following pharmacologic volume overload, serial investigation of LV remodeling with pressure-volume analyses and three-dimensional cardiac imaging, and ex vivo mechanical analysis of myocardial tissue and isolated cardiomyocytes, the proposed studies will address three Specific Aims:
Aim 1 will evaluate the pathophysiologic consequences of repetitive pressure overload (RPO)-induced reductions in myocardial compliance on resting and exercise hemodynamics in chronically instrumented swine;
Aim 2 will identify the cellular mechanisms responsible for the reduction in LV diastolic compliance caused by RPO-induced intermittent myocardial stretch;
and Aim 3 will determine the mechanistic role of calpain-mediated myocyte apoptosis in the pathophysiology of RPO-induced reductions in myocardial compliance. Collectively, these experiments in a translational large animal model will establish a novel paradigm centered upon the role of mechanical stretch-induced myocyte injury as a primary event in the initiation of LV remodeling in HFpEF. The results are expected to significantly advance our mechanistic understanding of HFpEF pathophysiology and facilitate the development of novel strategies to reduce the unacceptably high morbidity and mortality associated with this increasingly prevalent disease. !
Heart failure with preserved ejection fraction (HFpEF) has emerged as the most common form of heart failure, but our poor understanding of how it develops has made it difficult to devise effective treatments. The studies proposed in this application will test the novel hypothesis that HFpEF arises as a consequence of heart muscle cell death and adaptive stiffening of remaining heart cells that occurs after the heart is subjected to mechanical stretch induced by intermittent elevations in blood pressure. The identification of intermittent stretch-induced heart muscle stiffening as an important mechanism underlying the development of HFpEF would serve as the impetus for future work involving strategies to increase heart muscle compliance in patients and could ultimately enhance our ability to treat this increasingly prevalent disease.
