Titin Modification as a Potential Treatment for Chronic Heart Failure with Preserved Eject Fraction

Chronic heart failure with preserved ejection fraction (CHFpEF) is a multifactorial condition with various pathophysiological causes and morphological manifestations, which largely determines the use of therapeutic approaches adapted to the patient’s clinical phenotype. In recent years, CHF has been increasingly replacing chronic heart failure with a reduced ejection fraction (CHFrEF), and is an equally serious condition that reduces the quality of life of patients on a par with CHFrEF. Currently, CHFpEF affects approximately 9 % of individuals over the age of 60, and the 5-year survival rate for this form of heart failure is roughly 35 %. The contemporary pharmacological armamentarium for managing CHFpEF symptoms remains notably limited. One promising therapeutic avenue involves targeting the modification processes — and consequently the mechanical properties — of titin, a major protein of the muscle sarcomere. Active research is currently underway on the development and application of agents that influence titin modification, with ongoing preclinical and clinical trials. This review examines the structure and post-translational modification (predominantly phosphorylation) of titin. It also explores the various signaling pathways whose dysregulation is associated with CHFpEF pathogenesis, as well as data from studies investigating drugs that target these pathways in both animal models and human subjects. The review presents an analysis of domestic and international literature published between 2000 and 2026, sourced from platforms including PubMed, Elsevier, and Google Scholar. Current evidence indicates that modulating titin modification is a potentially effective strategy for treating chronic heart failure. These findings underscore the need for further investigation in this field. The ultimate goal is to identify novel pharmacological solutions and integrate them into clinical practice to enable personalized management of CHFpEF syndrome.

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