Longitudinal arrhythmogenic remodelling in a mouse model of longstanding pressure overload
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Introduction. Sudden arrhythmogenic cardiac death is a major cause of mortality in patients with congestive heart failure due to adverse electrical remodelling. To establish whether abnormal conduction is responsible for arrhythmogenic remodelling in progressed stages of heart failure, we have monitored functional, structural and electrical remodelling in a murine model of heart failure, induced by longstanding pressure overload.
Methods. Mice were subjected to transverse aortic constriction (TAC; n=18) or sham operated (n=19) and monitored biweekly by echocardiography and electrocardiography. At the 16-week endpoint, electrical mapping was performed to measure epicardial conduction velocity and susceptibility to arrhythmias. Finally, tissue sections were stained for Cx43 and fibrosis.
Results. In TAC mice, fractional shortening decreased gradually and was significantly lower compared with sham at 16 weeks. Left ventricular hypertrophy was significant after six weeks. TAC mice developed PQ prolongation after 12 weeks, QT prolongation after 16 weeks and QRS prolongation after two weeks. Right ventricular conduction velocity was slowed parallel to fibre orientation. In 8/18 TAC hearts, polymorphic ventricular tachyarrhythmias were provoked and none in sham hearts. TAC mice had more interstitial fibrosis than sham. Immunohistology showed that Cx43 levels were similar but highly heterogeneous in TAC mice. All parameters were comparable in TAC mice with and without arrhythmias, except for Cx43 heterogeneity, which was significantly higher in arrhythmogenic TAC mice.
Conclusion. Chronic pressure overload resulted in rapid structural and electrical remodelling. Arrhythmias were related to heterogeneous expression of Cx43. This may lead to functional block and unstable reentry, giving rise to polymorphic ventricular tachyarrhythmias. (Neth Heart J 2010;18:509-15.)
- 1.Rosamond W, Flegal K, Furie K, Go A, Greenlund K, Haase N, et al. Heart disease and stroke statistics--2008 update: A report from the american heart association statistics committee and stroke statistics subcommittee. Circulation. 2008;117:e25-146.Google Scholar
- 2.Coumel P. The management of clinical arrhythmias. An overview on invasive versus non-invasive electrophysiology. Eur Heart J. 1987;8:92-9.Google Scholar
- 3.Kleber AG, Rudy Y. Basic mechanisms of cardiac impulse propagation and associated arrhythmias. Physiol Rev. 2004;84:431-88.Google Scholar
- 4.Anastasiou-Nana MI, Nanas JN, Karagounis LA, Tsagalou EP, Alexopoulos GE, Toumanidis S, et al. Relation of dispersion of qrs and qt in patients with advanced congestive heart failure to cardiac and sudden death mortality. Am J Cardiol. 2000;85:1212-7.Google Scholar
- 5.Iuliano S, Fisher SG, Karasik PE, Fletcher RD, Singh SN. Qrs duration and mortality in patients with congestive heart failure. Am Heart J. 2002;143:1085-91.Google Scholar
- 6.Marionneau C, Brunet S, Flagg TP, Pilgram TK, Demolombe S, Nerbonne JM. Distinct cellular and molecular mechanisms underlie functional remodeling of repolarizing k+ currents with left ventricular hypertrophy. Circ Res. 2008;102:1406-15.Google Scholar
- 7.Liao Y, Ishikura F, Beppu S, Asakura M, Takashima S, Asanuma H, et al. Echocardiographic assessment of lv hypertrophy and function in aortic-banded mice: Necropsy validation. Am J Physiol Heart Circ Physiol. 2002;282:H1703-1708.Google Scholar
- 8.Barrick CJ, Rojas M, Schoonhoven R, Smyth SS, Threadgill DW. Cardiac response to pressure overload in 129s1/svimj and c57bl/6j mice: Temporal- and background-dependent development of concentric left ventricular hypertrophy. Am J Physiol Heart Circ Physiol. 2007;292:H2119-2130.Google Scholar
- 9.Qu J, Volpicelli FM, Garcia LI, Sandeep N, Zhang J, Marquez-Rosado L, et al. Gap junction remodeling and spironolactone-dependent reverse remodeling in the hypertrophied Heart. Circ Res. 2009;104:365-71.Google Scholar
- 10.Wiegerinck RF, Verkerk AO, Belterman CN, van Veen TA, Baartscheer A, Opthof T, et al. Larger cell size in rabbits with heart failure increases myocardial conduction velocity and qrs duration. Circulation. 2006;113:806-13.Google Scholar
- 11.Allessie MA, Bonke FI, Schopman FJ. Circus movement in rabbit atrial muscle as a mechanism of tachycardia. Iii. The "Leading circle" Concept: A new model of circus movement in cardiac tissue without the involvement of an anatomical obstacle. Circ Res. 1977;41:9-18.Google Scholar
- 12.van Veen TA, Stein M, Royer A, Le Quang K, Charpentier F, Colledge WH, et al. Impaired impulse propagation in scn5a-knockout mice. Combined contribution of excitability, connexin expression, and tissue architecture in relation to aging. Circulation. 2005;112:1927-35.Google Scholar
- 13.Kitamura H, Ohnishi Y, Yoshida A, Okajima K, Azumi H, Ishida A, et al. Heterogeneous loss of connexin43 protein in nonischemic dilated cardiomyopathy with ventricular tachycardia. J Cardiovasc Electrophysiol. 2002;13:865-70.Google Scholar
- 14.Cabo C, Yao JA, Boyden PA, Chen S, Hussain W, Duffy HS, et al. Heterogeneous gap junction remodeling in reentrant circuits in the epicardial border zone of the healing canine infarct. Cardiovasc Res. 2006;72:241-9.Google Scholar
- 15.Peters NS, Coromilas J, Severs NJ, Wit AL. Disturbed connexin43 gap junction distribution correlates with the location of reentrant circuits in the epicardial border zone of healing canine infarcts that cause ventricular tachycardia. Circulation. 1997;95:988-96.Google Scholar
- 16.Gutstein DE, Morley GE, Vaidya D, Liu F, Chen FL, Stuhlmann H, et al. Heterogeneous expression of gap junction channels in the heart leads to conduction defects and ventricular dysfunction. Circulation. 2001;104:1194-9.Google Scholar
- 17.Boulaksil M, Winckels SK, Engelen MA, Stein M, van Veen TA, Jansen JA, et al. Heterogeneous connexin43 distribution in heart failure is associated with dispersed conduction and enhanced susceptibility to ventricular arrhythmias. Eur J Heart Fail. 2010;12:913-21.Google Scholar