This Article Full Text Full Text (PDF) All Versions of this Article: 110/15/2102    most recent 01.CIR.0000144460.84795.E3v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Maass, A. H. Articles by Leinwand, L. A. Search for Related Content PubMed PubMed Citation Articles by Maass, A. H. Articles by Leinwand, L. A. Related Collections Structure Animal models of human disease Hypertrophy

(Circulation. 2004;110:2102-2109.)
© 2004 American Heart Association, Inc.

Arrhythmia/Electrophysiology

Hypertrophy, Fibrosis, and Sudden Cardiac Death in Response to Pathological Stimuli in Mice With Mutations in Cardiac Troponin T

Alexander H. Maass, MD; Kaori Ikeda; Silke Oberdorf-Maass; Sebastian K.G. Maier, MD; Leslie A. Leinwand, PhD

From the Department of Molecular, Cellular, and Developmental Biology (A.H.M., K.I., S.O.-M., L.A.L.), University of Colorado, Boulder, and the Department of Pharmacology (S.K.G.M.), University of Washington, Seattle. A.H.M. and S.K.G.M. are currently at the Department of Medicine, University of Würzburg, Würzburg, Germany. K.I. is currently at the Department of Pharmacology, University of Washington, Seattle. S.O.-M. is currently at the Department of Pharmacology, University of Würzburg, Würzburg, Germany.

Correspondence to Leslie A. Leinwand, PhD, Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Campus Box 347, Boulder, CO 80309-0347. E-mail leinwand{at}stripe.colorado.edu

Received November 14, 2003; de novo received February 12, 2004; revision received April 29, 2004; accepted April 30, 2004.

Background— Transgenic mouse models expressing a missense mutation (R92Q) or a splice donor site mutation (trunc) in the cardiac troponin T (cTnT) model familial hypertrophic cardiomyopathy (FHC) in humans. Although males from these strains share the unusual property of having significantly smaller ventricles and cardiac myocytes, they differ with regard to systolic function, fibrosis, and gene expression. Little is known about how these phenotypes affect the responses to additional pathological stimuli.

Methods and Results— We tested the ability of hearts of both sexes of wild-type and mutant mice to respond to defined pathological, pharmacological, hypertrophic stimuli in vivo. Hearts of mutant cTnT models of both sexes were able to undergo hypertrophy in response to at least one stimulus, but the extent differed between the 2 mutants and was sex specific. Interestingly, the trunc-mutant mouse heart was resistant to the development of fibrosis in response to pharmacological stimuli. Stimulation with 2 adrenergic agonists led to sudden cardiac death of all male but not female mutant animals, which suggests altered adrenergic responsiveness in these 2 models of FHC.

Conclusions— Hypertrophic signaling is differentially affected by distinct mutations in cTnT and is sex modified. Hearts can respond with either an augmented hypertrophic and fibrotic response or a diminished hypertrophy and resistance to fibrosis. Sudden cardiac death is related to adrenergic stress and is independent of the development of fibrosis but occurred only in male mice. These results suggest that patients with certain TnT mutations may respond to certain pathological situations with a worsened phenotype.

Key Words: cardiomyopathy • catecholamines • death, sudden • hypertrophy • remodeling

This article has been cited by other articles:

				B. M. Palmer, Y. Wang, P. Teekakirikul, J. T. Hinson, D. Fatkin, S. Strouse, P. VanBuren, C. E. Seidman, J. G. Seidman, and D. W. Maughan Myofilament mechanical performance is enhanced by R403Q myosin in mouse myocardium independent of sex Am J Physiol Heart Circ Physiol, April 1, 2008; 294(4): H1939 - H1947. [Abstract] [Full Text] [PDF]

				M. Revera, L. van der Merwe, M. Heradien, A. Goosen, V. A. Corfield, P. A. Brink, and J. C. Moolman-Smook Troponin T and {beta}-myosin mutations have distinct cardiac functional effects in hypertrophic cardiomyopathy patients without hypertrophy Cardiovasc Res, March 1, 2008; 77(4): 687 - 694. [Abstract] [Full Text] [PDF]

				J. P. Konhilas and L. A. Leinwand The Effects of Biological Sex and Diet on the Development of Heart Failure Circulation, December 4, 2007; 116(23): 2747 - 2759. [Full Text] [PDF]

				L. A. DiMichele, J. T. Doherty, M. Rojas, H. E. Beggs, L. F. Reichardt, C. P. Mack, and J. M. Taylor Myocyte-Restricted Focal Adhesion Kinase Deletion Attenuates Pressure Overload-Induced Hypertrophy Circ. Res., September 15, 2006; 99(6): 636 - 645. [Abstract] [Full Text] [PDF]

				J. P. Konhilas, P. A. Watson, A. Maass, D. M. Boucek, T. Horn, B. L. Stauffer, S. W. Luckey, P. Rosenberg, and L. A. Leinwand Exercise Can Prevent and Reverse the Severity of Hypertrophic Cardiomyopathy Circ. Res., March 3, 2006; 98(4): 540 - 548. [Abstract] [Full Text] [PDF]