Protein Kinase Inhibitors in Heart Failure: Mechanistic Insights and Therapeutic Prospects

Heart failure (HF) is a complex clinical syndrome marked by impaired contractility, adverse remodeling, and dysregulated intracellular signaling. Protein kinases are central regulators of cardiac function, modulating calcium handling, gene transcription, hypertrophy, and apoptosis through phosphorylation of target proteins. In HF, chronic activation of kinases such as protein kinase A, protein kinase C, calcium/calmodulin-dependent kinase II, mitogen-activated protein kinases, protein kinase B, and Rho-associated protein kinase contributes to progressive cardiac dysfunction. Preclinical studies have demonstrated that selective inhibition of these kinases can reverse maladaptive remodeling, improve contractile performance, and attenuate neurohormonal activation. However, clinical translation remains limited, and most approved kinase inhibitors are oncologic agents associated with cardiotoxicity. This review explores the mechanistic roles of key kinases in HF pathogenesis, the therapeutic potential of kinase inhibitors, and the current landscape of clinical and translational research.