Abstract 398: Alternative Splicing of Titin Restores Diastolic Function and Improves HFpEF Associated Symptoms

Abstract

Greater than half of all heart failure (HF) patients suffer from increased diastolic stiffness and impaired relaxation of the left ventricle while their ejection fraction (EF) is preserved (HFpEF). HFpEF is a complex disease characterized by diastolic dysfunction, exercise intolerance, and concentric hypertrophic remodeling. No effective therapy exists for treating this pervasive disease due in part to our limited understanding of the underlying pathophysiology. Titin, the largest known protein and molecular spring in the heart, has emerged as a prime candidate for therapeutic targets aimed at restoring compliance to the sarcomere in order to improve diastolic function. Titin has two main cardiac isoforms; the smaller N2B isoform (~3.0 MDa) and the larger more compliant N2BA isoform (~3.3 MDa). Diastolic stiffness of the left ventricle is in large part dependent upon the N2BA:N2B isoform ratio. Modification of these two primary isoforms can be achieved post-transcriptionally through inhibiting the known titin splicing factor Rbm20. Alternative splicing of messenger RNA occurs primarily in the spring region of titin and therefore regulates the elastic property of titin through changes in contour length of the spring. The current study evaluates whether reduction of titin splicing factor Rbm20 has a beneficial effect on the diastolic function of mice with restrictive cardiomyopathy. A previously published mouse model deficient in titin’s IA junction ( Ttn ΔIAjxn ) places increased strain on the spring region of titin and acts as a mechanical analogue of the titin-based increase in passive myocardial stiffness found in HFpEF patients. This model exhibits a HFpEF-like phenotype apparent as early as 3 months in the adult mouse that becomes exaggerated with age apart from pharmacological or surgical intervention. We report for the first time a rescue of HFpEF in the mouse through inhibiting Rbm20. We demonstrate that Rbm20 reduction restores diastolic function, improves exercise tolerance and attenuates afterload induced pathologic remodeling of the left ventricle. No specific FDA approved therapies exist to treat the pathologically stiff left ventricle, therefore our findings on Rbm20 inhibition are clinically significant.