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

Michael Gotzmann; Susanne Grabbe; Dominik Schöne; Marion von Frieling-Salewsky; Cristobal G Dos Remedios; Justus Strauch; Matthias Bechtel; Johannes W Dietrich; Andrea Tannapfel; Andreas Mügge; Wolfgang A Linke

doi:10.1016/j.jacbts.2018.02.002

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

JACC Basic Transl Sci. 2018 Jun 25;3(3):335-346. doi: 10.1016/j.jacbts.2018.02.002. eCollection 2018 Jun.

Affiliations

¹ Department of Cardiology, Marien Hospital Witten, Ruhr University Bochum, Bochum, Germany.
² Cardiology and Angiology, Bergmannsheil, Ruhr University Bochum, Bochum, Germany.
³ Institute of Physiology II, University of Münster, Münster, Germany.
⁴ Department of Anatomy & Histology, Bosch Institute, University of Sydney, Sydney, Australia.
⁵ Department of Cardiac and Thoracic Surgery, Bergmannsheil, Ruhr University Bochum, Bochum, Germany.
⁶ Department of Internal Medicine, Bergmannsheil, Ruhr University Bochum, Bochum, Germany.
⁷ Institute of Pathology, Ruhr University Bochum, Bochum, Germany.

Abstract

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.

Keywords: AS, aortic stenosis; AVA, aortic valve area; BNP, B-type natriuretic peptide; EF, ejection fraction; LV, left ventricular; MHC, myosin heavy chain; N2Bus, unique sequence within the cardiac-specific N2B titin domain; NYHA, New York Heart Association; Z, valvuloarterial impedance; myocardial fibrosis; myocardial stiffness paradoxical aortic stenosis; titin isoforms; titin phosphorylation.