Novel Therapies in Heart Failure with Reduced Ejection Fraction: from Soluble Guanylyl Cyclase Stimulators to Cardiac Myosin Activators

Purpose of review: In this review, our goal was to provide a brief background on the evolution of therapeutic targets for heart failure with reduced ejection fraction (HFrEF), summarize the results of recent clinical trials with diverse pharmacological targets, discuss potential limitations of these findings, and provide future perspectives. Recent findings: Despite advances in pharmacological and device therapy, HFrEF still carries a considerably high morbidity and mortality. For the past four decades, the neurohormonal model has been pivotal in the development of efficacious pharmacotherapies for HFrEF. However, recent clinical trials with sodium-glucose cotransporter 2 inhibitors (SGLT2i), soluble guanylate cyclase stimulators, and cardiac myosin activators have yielded positive results and created a new spectrum of pharmacologic targets to further improve outcomes in HFrEF. Specifically for SGLT2i, the data point to a class disease-modifying effect with mortality benefit in HFrEF, in addition to a substantial reduction in healthcare resources utilization. Summary: We are currently witnessing a paradigm shift away from neurohormonal inhibition as the sole line of disease-modifying pharmacotherapies in HFrEF, as encouraging data emerge about alternative pathophysiologic pathways. Further research is needed to identify the optimal target subpopulations for these therapies and to improve outcomes in patients with HFrEF decompensation.