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(Circulation. 2002;106:1384.)
© 2002 American Heart Association, Inc.

Basic Science Reports

Changes in Titin Isoform Expression in Pacing-Induced Cardiac Failure Give Rise to Increased Passive Muscle Stiffness

Yiming Wu, MD, PhD; Stephen P. Bell, BA; Karoly Trombitas, PhD; Christian C. Witt, PhD; Siegfried Labeit, MD; Martin M. LeWinter, MD; Henk Granzier, PhD

From the Department VCAPP, Washington State University, Pullman (Y.W., K.T., H.G.); the Cardiology Unit, University of Vermont, Burlington (S.P.B., M.M.L.); and Anästhesiologie und Operative Intensivmedizin, Universitätsklinikum Mannheim, Germany (C.C.W., S.L.).

Correspondence to Henk Granzier, PhD, Department VCAPP, Washington State University, Wegner Hall 205, PO Box 645520, Pullman, WA 99164-6520. E-mail granzier{at}wsunix.wsu.edu

Background— Titin contains a molecular spring segment that underlies passive myocardial stiffness. Myocardium coexpresses titin isoforms with molecular spring length variants and, consequently, distinct stiffness characteristics: the stiff N2B isoform (short spring) and more compliant N2BA isoform (long spring). We tested whether changes in titin isoform expression occur in the diastolic dysfunction that accompanies heart failure.

Methods and Results— We used the tachycardia-induced dilated cardiomyopathy canine model (4-week pacing) and found that control myocardium coexpresses the N2B and N2BA isoforms at similar levels, whereas in dilated cardiomyopathy the expression ratio had shifted, without affecting the amount of total titin, toward more prominent N2B expression. This shift was accompanied by elevated titin-based passive muscle stiffness. Pacing also resulted in significant upregulation of obscurin, an 800-kDa elastic protein with several signaling domains.

Conclusions— Coexpression of titin isoforms with distinct mechanical properties allows modulation of passive stiffness via adjustment of the isoform expression ratio. The canine pacing-induced heart failure model uses this mechanism to increase myocardial stiffness. Thus, changes in titin isoform expression may play a role in diastolic dysfunction in heart failure.

Key Words: diastole • elasticity • cardiomyopathy • heart failure • myocardium

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