Project Summary: In the last 30 years there has been a dramatic increase in our understanding of the genetic and non-genetic mechanisms that contribute to the development of cardiomyopathy in humans. Despite this increased mechanistic understanding, the risk of heart failure and sudden death remains high in this patient population. While multiple small molecule agents reduce the morbidity and mortality of patients with cardiomyopathy, many patients still progress to end stage disease. In addition, these small molecule agents act in a non-cell type specific manner and their utilization is often limited by side effects. Likewise, pharmacological therapy to prevent sudden death in individuals with cardiomyopathy remains lacking, and many patients still require an implantable cardiac defibrillator (ICD). Therefore, new strategies are required to reduce disease progression and sudden death in patients with cardiomyopathy. Preventing the degradation of circulating natriuretic peptides by the chemical inhibition of neprilysin has proven to be very beneficial in patients with dilated cardiomyopathy. The combination of the neprilysin inhibitor, sacubitril, and the angiotensin receptor blocker, valsartan, not only reduced mortality secondary to heart failure but also significantly reduced sudden death in the dilated cardiomyopathy population. However, in the landmark clinical trial PARADIGM-HF, many trial participants developed symptomatic hypotension (14%), renal failure (3.3%), or hyperkalemia (16.1%) from sacubitril/valsartan (LCZ696). In an effort to understand why alterations in NP signaling impact cardiomyopathy remodeling and sudden death, we studied murine models deficient in either atrial natriuretic peptide (ANP) or B-type natriuretic peptide (BNP). We found that reduced levels of either ANP or BNP led to increased stress induced sudden death and ventricular arrhythmias. Mechanistically, we discovered that the phosphorylation of the transcription factor CREB1 was regulated by NP signaling, and a reduction in CREB1 signaling sensitized the heart to stress induced ventricular arrhythmias. We have now discovered that NP-PKG1 signaling can activate protein inhibitor of activated STAT 1 (PIAS1), which regulates the levels of the key cardiomyocyte calcium regulatory protein SERCA2a. We hypothesize that cardiomyocyte selective targeting of key natriuretic peptide regulated pathways will improve myocardial function and reduce ventricular arrhythmia susceptibility in cardiomyopathy while avoiding systemic side effects. Aim 1: Define how cardiomyocyte specific modulation of PKG1 activity modifies cardiomyopathy progression and arrhythmia susceptibility. Aim 2: Determine the role of PIAS1 in regulating cardiomyopathy progression and ventricular arrhythmias. Aim 3: Define how CREB1 signaling modifies cardiomyopathy remodeling and ventricular arrhythmias. At the conclusion of these high impact studies, we will have defined how cardiomyocyte selective modulation of natriuretic peptide signaling pathways modifies cardiac remodeling and arrhythmogenesis in preclinical cardiomyopathy models, setting the stage for future therapeutic strategies in humans.

Narrative: Despite tremendous progress in treating patients with heart failure and cardiomyopathy, these diseases remain a leading cause of death across the US population. This proposal will study how natriuretic peptide signaling pathways regulate cardiomyocyte biology and test if cardiomyocyte selective targeting of these pathways can improve cardiac remodeling and reduce arrhythmia susceptibility in preclinical models of cardiomyopathy.