Alterations in Titin Properties and Myocardial Fibrosis Correlate With Clinical Phenotypes in Hemodynamic Subgroups of Severe Aortic Stenosis

Visual Abstract
Highlights • The extent of myocardial fibrosis and the degree of isoform-expression and phosphorylation changes in cardiomyocyte titin were unknown in different hemodynamic subgroups of AS, including “paradoxical” low-flow, low-gradient AS with preserved ejection fraction. • Hemodynamic subtypes of AS were found to exhibit increased cardiac fibrosis, titin-isoform transition toward more compliant N2BA variants, and both total and site-specific titin (N2Bus) hypophosphorylation compared with donor heart controls. • A significant shift toward N2BA titin appeared in “paradoxical” AS, whereas alterations in total-titin phosphorylation and cardiac fibrosis were similar in all hemodynamic subtypes of AS, suggesting increased myocardial passive stiffness. • The unfavorable prognosis of “paradoxical” AS could be explained by the pronounced myocardial remodeling, which is no less severe than in other AS subtypes.
Summary Titin-isoform expression, titin phosphorylation, and myocardial fibrosis were studied in 30 patients with severe symptomatic aortic stenosis (AS). Patients were grouped into “classical” high-gradient, normal-flow AS with preserved ejection fraction (EF); “paradoxical” low-flow, low-gradient AS with preserved EF; and AS with reduced EF. Nonfailing donor hearts served as controls. AS was associated with increased fibrosis, titin-isoform switch toward compliant N2BA, and both total and site-specific titin hypophosphorylation compared with control hearts. All AS subtypes revealed titin and matrix alterations. The extent of myocardial remodeling in “paradoxical” AS was no less severe than in other AS subtypes, thus explaining the unfavorable prognosis.