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(Circulation Research. 2009;104:780.)
© 2009 American Heart Association, Inc.

Cellular Biology

Hypophosphorylation of the Stiff N2B Titin Isoform Raises Cardiomyocyte Resting Tension in Failing Human Myocardium

Attila Borbély^*, Ines Falcao-Pires^*, Loek van Heerebeek, Nazha Hamdani, István Édes, Cristina Gavina, Adelino F. Leite-Moreira, Jean G.F. Bronzwaer, Zoltán Papp, Jolanda van der Velden, Ger J.M. Stienen, Walter J. Paulus

From the Department of Physiology (A.B., I.F-P, L.v.H., N.H., J.v.d.V, G.J.M.S., W.J.P.) and Cardiology (J.G.F.B.), Institute for Cardiovascular Research, VU University Medical Center Amsterdam, The Netherlands; Institute of Cardiology (A.B., I.É., Z.P.), University of Debrecen Medical and Health Science Center, Debrecen, Hungary; and Department of Physiology (I.F-P., C.G., A.F.L-M.), Faculty of Medicine, University of Porto, Portugal.

Correspondence to Prof Dr Walter J. Paulus, MD, PhD, Laboratory of Physiology, VU University Medical Center Amsterdam, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands. E-mail wj.paulus{at}vumc.nl

High diastolic stiffness of failing myocardium results from interstitial fibrosis and elevated resting tension (F_passive) of cardiomyocytes. A shift in titin isoform expression from N2BA to N2B isoform, lower overall phosphorylation of titin, and a shift in titin phosphorylation from N2B to N2BA isoform can raise F_passive of cardiomyocytes. In left ventricular biopsies of heart failure (HF) patients, aortic stenosis (AS) patients, and controls (CON), we therefore related F_passive of isolated cardiomyocytes to expression of titin isoforms and to phosphorylation of titin and titin isoforms. Biopsies were procured by transvascular technique (44 HF, 3 CON), perioperatively (25 AS, 4 CON), or from explanted hearts (4 HF, 8 CON). None had coronary artery disease. Isolated, permeabilized cardiomyocytes were stretched to 2.2-µm sarcomere length to measure F_passive. Expression and phosphorylation of titin isoforms were analyzed using gel electrophoresis with ProQ Diamond and SYPRO Ruby stains and reported as ratio of titin (N2BA/N2B) or of phosphorylated titin (P-N2BA/P-N2B) isoforms. F_passive was higher in HF (6.1±0.4 kN/m²) than in CON (2.3±0.3 kN/m²; P<0.01) or in AS (2.2±0.2 kN/m²; P<0.001). Titin isoform expression differed between HF (N2BA/N2B=0.73±0.06) and CON (N2BA/N2B=0.39±0.05; P<0.001) and was comparable in HF and AS (N2BA/N2B=0.59±0.06). Overall titin phosphorylation was also comparable in HF and AS, but relative phosphorylation of the stiff N2B titin isoform was significantly lower in HF (P-N2BA/P-N2B=0.77±0.05) than in AS (P-N2BA/P-N2B=0.54±0.05; P<0.01). Relative hypophosphorylation of the stiff N2B titin isoform is a novel mechanism responsible for raised F_passive of human HF cardiomyocytes.

Key Words: myocardium • heart failure • diastole • titin

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