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(Circulation. 2004;110:155-162.)
© 2004 American Heart Association, Inc.

Original Articles

Altered Titin Expression, Myocardial Stiffness, and Left Ventricular Function in Patients With Dilated Cardiomyopathy

Sherif F. Nagueh, MD; Gopi Shah, MD; Yiming Wu, MD, PhD; Guillermo Torre-Amione, MD, PhD; Nicholas M.P. King, BSc; Sunshine Lahmers, DVM; Christian C. Witt, PhD; Katy Becker; Siegfried Labeit, MD; Henk L. Granzier, PhD

From the Section of Cardiology (S.F.N., G.S., G.T.-A., K.B.), Department of Medicine, Baylor College of Medicine, Houston, Texas; Department of Veterinary and Comparative Anatomy (Y.W., N.M.P.K., S. Lahmers, C.C.W., S. Labeit, H.L.G.), Pharmacology and Physiology, Washington State University, Pullman, Wash; and Institut für Anästhesiologie und Operative Intensivmedizin (C.C.W., S. Labeit), Universitätsklinikum Mannheim, Mannheim, Germany.

Correspondence and reprint requests to Dr Sherif F. Nagueh, Section of Cardiology, Baylor College of Medicine, 6550 Fannin, SM-1256, Houston, TX 77030-2717 (e-mail sherifn{at}bcm.tmc.edu), or Dr Henk L. Granzier, Wegner Hall, Rm 205, Washington State University, Pullman, WA 99164 (e-mail granzier@wsunix.wsu.edu).

Received April 18, 2004; de novo received May 14, 2004; revision received May 19, 2004; accepted May 20, 2004.

Background— The role of the giant protein titin in patients with heart failure is not well established. We investigated titin expression in patients with end-stage heart failure resulting from nonischemic dilated cardiomyopathy, in particular as it relates to left ventricular (LV) myocardial stiffness and LV function.

Methods and Results— SDS-agarose gels revealed small N2B (stiff) and large N2BA (compliant) cardiac titin isoforms with a mean N2BA:N2B expression ratio that was significantly (P<0.003) increased in 20 heart failure patients versus 6 controls. However, total titin was unchanged. The coexpression ratio was highest in a subsample of patients with an impaired LV relaxation pattern (n=7), intermediate in those with pseudonormal filling (n=6), and lowest in the group with restrictive filling (n=7). Mechanical measurements on LV muscle strips dissected from these hearts (n=8) revealed that passive muscle stiffness was significantly reduced in patients with a high N2BA:N2B expression ratio. Clinical correlations support the relevance of these changes for LV function (assessed by invasive hemodynamics and Doppler echocardiography). A positive correlation between the N2BA:N2B titin isoform ratio and deceleration time of mitral E velocity, A wave transit time, and end diastolic volume/pressure ratio was found. These changes affect exercise tolerance, as indicated by the positive correlation between the N2BA:N2B isoform ratio and peak O₂ consumption (n=10). Upregulated N2BA expression was accompanied by increased expression levels of titin-binding proteins (cardiac ankyrin repeat protein, ankrd2, and diabetes ankyrin repeat protein) that bind to the N2A element of N2BA titin (studied in 13 patients).

Conclusions— Total titin content was unchanged in end-stage failing hearts and the more compliant N2BA isoform comprised a greater percentage of titin in these hearts. Changes in titin isoform expression in heart failure patients with dilated cardiomyopathy significantly impact diastolic filling by lowering myocardial stiffness. Upregulation of titin-binding proteins indicates that the importance of altered titin expression might extend to cell signaling and regulation of gene expression.

Key Words: heart failure • diastole • echocardiography • mechanics • myocardium

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