Experimental and clinical approaches for treating heart failure (HF) have traditionally focused on interrupting processes involved with its development, and in particular, understanding and preventing the transition from adaptive to maladaptive left ventricular hypertrophy (LVH). This application argues for an alternative paradigm that focuses on myocardial recovery rather than injury. In models of pressure-relief and pharmacologic LVH regression in mice, we have demonstrated that myocardial recovery, including from failing hearts, is associated with structural and genomic patterns that are distinct from factors associated with LVH development. Mechanistically, although nuclear factor kappa B (NF-:B) is known to be involved in promoting LVH, we have shown that this transcription factor can independently regulate many recovery genes and processes, including the balance of survival and apoptotic signals. Our global hypothesis is that myocardial recovery can be independently studied and targeted for therapy. The objective of this application is to define when and how the heart can recover from a decompensated state. We will use NF-:B as a molecular tool to characterize mechanisms necessary for reverse remodeling. We will achieve our objective by pursuing the following aims: (1) Characterize the cellular and genomic response following relief of pressure overload by expanding our existing model to create a detailed pathologic and genomic framework for reverse remodeling of both the compensated and decompensated heart, including determining when recovery is no longer feasible. (2) Determine the effect of NF-:B inactivation on myocardial recovery by generating and functionally testing the effect of pressure-relief on conditional, cardiac-specific NF-:B knockout mice. (3) Determine the mechanistic role of NF-:B in myocardial recovery by evaluating the functional phase-dependent influence of NF-:B to promote survival or death pathways following pressure relief. This proposal is innovative in that it focuses on the recovery arm of LVH and HF. We expect to generate a molecular program of myocardial mass regression that will significantly contribute to the overall understanding of hypertrophy and heart failure. We envision a novel therapeutic paradigm that targets the system of myocardial repair as well as injury. Ultimately, these results will have a relevant and positive impact on treatment algorithms for the large number of HF patients.
Heart failure is a growing epidemic in our society that contributes to significant morbidity and mortality. Whereas most current therapies are aimed at preventing or halting progression of detrimental heart remodeling, we propose an alternative approach that would try to reverse existing disease. We envision an innovative treatment paradigm that would link preventive and regressive therapy to favorably impact outcomes in this devastating disease.
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