Titin-Based Mechanisms of Myocardial Stiffness and Heart Failure: From Bench to Bedside

Titin, the largest known human protein, plays a critical role in myocardial elasticity and cardiac function. Alterations in titin isoform expression, phosphorylation, and redox modifications have emerged as key contributors to heart failure with preserved ejection fraction and dilated cardiomyopathy. This study reviews recent advances in preclinical models and translational research, highlighting how modulation of titin's mechanical properties can impact heart failure outcomes. Genetic approaches targeting RNA-binding motif protein 20-mediated splicing and pharmacologic strategies enhancing titin phosphorylation through pathways like guanase 3,5-cyclic monophosphate-protein kinase G show promise in improving ventricular compliance. The potential of titin fragments as biomarkers for diagnosis and prognosis of cardiac dysfunction is also discussed. Despite technical challenges posed by titin's size and complex splicing, emerging therapies such as prime editing, antisense oligonucleotides, and kinase modulators offer new opportunities for personalized heart failure treatment. Future research focused on integrating isoform modulation, redox regulation, phosphorylation dynamics, and mechanotransduction mechanisms may enable targeted therapies to restore myocardial function. This work underscores titin's central role as both a therapeutic target and a biomarker in advancing heart failure management.