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From Bench to Bedside: New Approaches to Therapeutic Discovery for Heart Failure. Heart failure is a significant global health problem, which is becoming worse as the population ages, and remains one of the biggest burdens on our economy. Despite significant advances in cardiovascular medicine, management and surgery, mortality rates remain high, with almost half of patients with heart failure dying within five years of diagnosis. As a multifactorial clinical syndrome, heart failure still represents an epidemic threat, highlighting the need for deeper insights into disease mechanisms and the development of innovative therapeutic strategies for both treatment and prevention. In this review, we discuss conventional heart failure therapies and highlight new pharmacological agents targeting pathophysiological features of the failing heart, for example, non-coding RNAs, angiotensin receptor-neprilysin inhibitors, cardiac myosin activators, BGP-15 and molecules targeting GRK2 including M119, gallein and paroxetine. Finally, we address the disparity between phase II and phase III clinical trials that prevent the translation of emerging HF therapies into new and approved therapies.