Abstract 16743: Targeting Renin Activity in Heart Failure: Precision Therapy With Aliskiren Improves Systolic Function and Prolongs Survival in Female Experimental Dilated Cardiomyopathy

Introduction: Patients with heart failure (HF) are treated according to general therapy guidelines, without precise consideration for the individual’s sex and biomarker profile. Renin activation has been implicated in the pathophysiology of HF progression, but studies of the direct renin inhibitor aliskiren in general HF patients have not shown benefits. Mice with experimental dilated cardiomyopathy (DCM) develop progressive HF with reduced ejection fraction that progresses through all stages (A-D) of human HF. Female DCM mice specifically show an elevation of plasma renin activity with a decline in systolic function, severe HF and enhanced mortality (median survival 103 days). We used aliskiren to determine whether renin activity is critical for HF outcomes. Methods and Results: Untreated female DCM mice were compared to female DCM littermate mice given aliskiren (100 mg/kg orally, drinking water) starting at 50 days, Stage B HF (n=20-27/group). When evaluated at 90-100 days, Stage C-D HF, aliskiren suppressed renin activity to normal levels ( P <0.001) and improved cardiac function (ejection fraction, %: 15±1 vs. 11±1, P <0.05; cardiac output, mL/min: 7.5±0.7 vs. 4.6±0.5, P <0.01) compared to untreated DCM littermates. Aliskiren also reduced the development of systemic edema (extracellular water, g: 0.36±0.06 vs. 1.25±0.35, P <0.0001). Treatment with aliskiren delayed loss of body fat and lean muscle mass consistent with cardiac cachexia and sarcopenia. The strongest predictors of survival were fat mass ( r p =0.61, P <0.0001), free water ( r p =-0.55, P <0.0001), and cardiac output ( r p =0.53, P <0.001). Overall, aliskiren treatment resulted in a 7% improvement in median survival ( P <0.05). Conclusion: In females with experimental DCM, targeted treatment of elevated plasma renin activity with aliskiren slowed the development of edema, decreased cachexia, enhanced systolic function, reduced the progression of HF and prolonged survival. These data suggest that more complete biomarker analysis of HF patients may enhance the precision of HF treatment to better address sex-related and individual differences, in order to improve outcomes.