Published online before print August 19, 2002, doi: 10.1161/01.CIR.0000029804.61510.02
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(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
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
This article has been cited by other articles:
 |
|
 |
|
  A. Kontrogianni-Konstantopoulos, M. A. Ackermann, A. L. Bowman, S. V. Yap, and R. J. Bloch Muscle Giants: Molecular Scaffolds in Sarcomerogenesis Physiol Rev, October 1, 2009; 89(4): 1217 - 1267. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. H. Ahmed and M. L. Lindsey Titin Phosphorylation: Myocardial Passive Stiffness Regulated by the Intracellular Giant Circ. Res., September 25, 2009; 105(7): 611 - 613. [Full Text] [PDF]
|
|
|
|
 |
|
 B. T. Esch, J. M. Scott, D. E.R. Warburton, R. Thompson, D. Taylor, J. C. Baron, I. Paterson, and M. J. Haykowsky Left ventricular torsion and untwisting during exercise in heart transplant recipients J. Physiol., May 15, 2009; 587(10): 2375 - 2386. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Borbely, I. Falcao-Pires, L. van Heerebeek, N. Hamdani, I. Edes, C. Gavina, A. F. Leite-Moreira, J. G.F. Bronzwaer, Z. Papp, J. van der Velden, et al. Hypophosphorylation of the Stiff N2B Titin Isoform Raises Cardiomyocyte Resting Tension in Failing Human Myocardium Circ. Res., March 27, 2009; 104(6): 780 - 786. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. A. Jaber, C. Maniu, J. Krysiak, B. P. Shapiro, D. M. Meyer, W. A. Linke, and M. M. Redfield Titin Isoforms, Extracellular Matrix, and Global Chamber Remodeling in Experimental Dilated Cardiomyopathy: Functional Implications and Mechanistic Insight Circ Heart Fail, September 1, 2008; 1(3): 192 - 199. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. L. Nelson, C. T. Robbins, Y. Wu, and H. Granzier Titin isoform switching is a major cardiac adaptive response in hibernating grizzly bears Am J Physiol Heart Circ Physiol, July 1, 2008; 295(1): H366 - H371. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. J. Moore, A. Stubbings, E. B. Swallow, M. Dusmet, P. Goldstraw, R. Porcher, J. Moxham, M. I. Polkey, and M. A. Ferenczi Passive properties of the diaphragm in COPD J Appl Physiol, November 1, 2006; 101(5): 1400 - 1405. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Reddy, J. C. Osorio, A. M. Duque, B. D. Kaufman, A. B. Phillips, J. M. Chen, J. Quaegebeur, R. S. Mosca, and S. Mital Failure of Right Ventricular Adaptation in Children With Tetralogy of Fallot Circulation, July 4, 2006; 114(1_suppl): I-37 - I-42. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. A. C. Ottenheijm, L. M. A. Heunks, T. Hafmans, P. F. M. van der Ven, C. Benoist, H. Zhou, S. Labeit, H. L. Granzier, and P. N. R. Dekhuijzen Titin and Diaphragm Dysfunction in Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., March 1, 2006; 173(5): 527 - 534. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. James, L. Martin, M. Krenz, C. Quatman, F. Jones, R. Klevitsky, J. Gulick, and J. Robbins Forced Expression of {alpha}-Myosin Heavy Chain in the Rabbit Ventricle Results in Cardioprotection Under Cardiomyopathic Conditions Circulation, May 10, 2005; 111(18): 2339 - 2346. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. C. Lim and D. B. Sawyer Modulation of Cardiac Function: Titin Springs into Action J. Gen. Physiol., February 28, 2005; 125(3): 249 - 252. [Full Text] [PDF]
|
|
|
|
|
|
N. Fukuda, Y. Wu, P. Nair, and H. L. Granzier Phosphorylation of Titin Modulates Passive Stiffness of Cardiac Muscle in a Titin Isoform-dependent Manner J. Gen. Physiol., February 28, 2005; 125(3): 257 - 271. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Sarkar, S. Caamano, and J. M. Fernandez The Elasticity of Individual Titin PEVK Exons Measured by Single Molecule Atomic Force Microscopy J. Biol. Chem., February 25, 2005; 280(8): 6261 - 6264. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Borbely, J. van der Velden, Z. Papp, J. G.F. Bronzwaer, I. Edes, G. J.M. Stienen, and W. J. Paulus Cardiomyocyte Stiffness in Diastolic Heart Failure Circulation, February 15, 2005; 111(6): 774 - 781. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Makarenko, C.A. Opitz, M.C. Leake, C. Neagoe, M. Kulke, J.K. Gwathmey, F. del Monte, R.J. Hajjar, and W.A. Linke Passive Stiffness Changes Caused by Upregulation of Compliant Titin Isoforms in Human Dilated Cardiomyopathy Hearts Circ. Res., October 1, 2004; 95(7): 708 - 716. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. M. LeWinter Titin Isoforms in Heart Failure: Are There Benefits to Supersizing? Circulation, July 13, 2004; 110(2): 109 - 111. [Full Text] [PDF]
|
|
|
|
|
|
S. F. Nagueh, G. Shah, Y. Wu, G. Torre-Amione, N. M.P. King, S. Lahmers, C. C. Witt, K. Becker, S. Labeit, and H. L. Granzier Altered Titin Expression, Myocardial Stiffness, and Left Ventricular Function in Patients With Dilated Cardiomyopathy Circulation, July 13, 2004; 110(2): 155 - 162. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. A. Kass, J. G.F. Bronzwaer, and W. J. Paulus What Mechanisms Underlie Diastolic Dysfunction in Heart Failure? Circ. Res., June 25, 2004; 94(12): 1533 - 1542. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. H. Cingolani, X.-P. Yang, Y.-H. Liu, M. Villanueva, N.-E. Rhaleb, and O. A. Carretero Reduction of Cardiac Fibrosis Decreases Systolic Performance Without Affecting Diastolic Function in Hypertensive Rats Hypertension, May 1, 2004; 43(5): 1067 - 1073. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. S. Walker and P. P. de Tombe Titin and the Developing Heart Circ. Res., April 16, 2004; 94(7): 860 - 862. [Full Text] [PDF]
|
|
|
|
|
|
C. A. Opitz, M. C. Leake, I. Makarenko, V. Benes, and W. A. Linke Developmentally Regulated Switching of Titin Size Alters Myofibrillar Stiffness in the Perinatal Heart Circ. Res., April 16, 2004; 94(7): 967 - 975. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Lahmers, Y. Wu, D. R. Call, S. Labeit, and H. Granzier Developmental Control of Titin Isoform Expression and Passive Stiffness in Fetal and Neonatal Myocardium Circ. Res., March 5, 2004; 94(4): 505 - 513. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. L. Granzier and S. Labeit The Giant Protein Titin: A Major Player in Myocardial Mechanics, Signaling, and Disease Circ. Res., February 20, 2004; 94(3): 284 - 295. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. L. Granzier, Y. Wu, K. Trombitas, C. Witt, S. Labeit, S. Bell, and M. LeWinter Variable Titin-Based Stiffness Adjustment in Heart Disease Circulation, July 29, 2003; 108 (4): e23 - e23. [Full Text] [PDF]
|
|
|
|
 |
|
 C. M. Warren, M. C. Jordan, K. P. Roos, P. R. Krzesinski, and M. L. Greaser Titin isoform expression in normal and hypertensive myocardium Cardiovasc Res, July 1, 2003; 59(1): 86 - 94. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. A. Linke, S. Hein, W. H. Gaasch, and J. Schaper Titin Stiffness in Heart Disease * Response Circulation, March 25, 2003; 107 (11): e73 - e73. [Full Text] [PDF]
|
|
|
|
 |
|
 F. Huq, E. K. Heist, and R. J. Hajjar Titin--Springing Back to Youth? Sci. Aging Knowl. Environ., December 11, 2002; 2002(49): pe20 - 20. [Abstract] [Full Text]
|
|
|
|
|
|
S. Hein, W. H. Gaasch, and J. Schaper Giant Molecule Titin and Myocardial Stiffness Circulation, September 10, 2002; 106(11): 1302 - 1304. [Full Text] [PDF]
|
|