Increased vulnerability to atrial fibrillation in transgenic mice with selective atrial fibrosis caused by overexpression of TGF-beta1.
Journal: 2004/December - Circulation Research
ISSN: 1524-4571
Abstract:
Studies on patients and large animal models suggest the importance of atrial fibrosis in the development of atrial fibrillation (AF). To investigate whether increased fibrosis is sufficient to produce a substrate for AF, we have studied cardiac electrophysiology (EP) and inducibility of atrial arrhythmias in MHC-TGFcys33ser transgenic mice (Tx), which have increased fibrosis in the atrium but not in the ventricles. In anesthetized mice, wild-type (Wt) and Tx did not show significant differences in surface ECG parameters. With transesophageal atrial pacing, no significant differences were observed in EP parameters, except for a significant decrease in corrected sinus node recovery time in Tx mice. Burst pacing induced AF in 14 of 29 Tx mice, whereas AF was not induced in Wt littermates (P<0.01). In Langendorff perfused hearts, atrial conduction was studied using a 16-electrode array. Epicardial conduction velocity was significantly decreased in the Tx RA compared with the Wt RA. In the Tx LA, conduction velocity was not significantly different from Wt, but conduction was more heterogeneous. Action potential characteristics recorded with intracellular microelectrodes did not reveal differences between Wt and Tx mice in either atrium. Thus, in this transgenic mouse model, selective atrial fibrosis is sufficient to increase AF inducibility.
Relations:
Content
Citations
(125)
References
(31)
Clinical trials
(1)
Conditions
(3)
Chemicals
(2)
Organisms
(3)
Processes
(1)
Anatomy
(2)
Affiliates
(2)
Similar articles
Articles by the same authors
Discussion board
Circ Res 94(11): 1458-1465

Increased Vulnerability to Atrial Fibrillation in Transgenic Mice With Selective Atrial Fibrosis Caused by Overexpression of TGF-<em>β</em>1

From Krannert Institute of Cardiology (S.V., S.K.E., D.O.), Indiana University School of Medicine, Indianapolis, Ind; Cardiac Electrophysiology (T.S., T.E., J.E.O.), Division of Cardiology and the Cardiovascular Research Institute, University of California San Francisco, San Francisco, Calif; Herman B. Wells Center for Pediatric Research (M.R.-v.d.L., H.O.N., H.N., L.J.F.), Indiana University School of Medicine, Indianapolis, Ind.
Correspondence to Jeffrey E. Olgin, University of California San Francisco, 500 Parnasus Ave, MU East 4/Box 1354, San Francisco, CA 94143-1354. E-mail ude.fscu.enicidem@niglo
Both authors contributed equally to this study.

Abstract

Studies on patients and large animal models suggest the importance of atrial fibrosis in the development of atrial fibrillation (AF). To investigate whether increased fibrosis is sufficient to produce a substrate for AF, we have studied cardiac electrophysiology (EP) and inducibility of atrial arrhythmias in MHC-TGFcysser transgenic mice (Tx), which have increased fibrosis in the atrium but not in the ventricles. In anesthetized mice, wild-type (Wt) and Tx did not show significant differences in surface ECG parameters. With transesophageal atrial pacing, no significant differences were observed in EP parameters, except for a significant decrease in corrected sinus node recovery time in Tx mice. Burst pacing induced AF in 14 of 29 Tx mice, whereas AF was not induced in Wt littermates (P<0.01). In Langendorff perfused hearts, atrial conduction was studied using a 16-electrode array. Epicardial conduction velocity was significantly decreased in the Tx RA compared with the Wt RA. In the Tx LA, conduction velocity was not significantly different from Wt, but conduction was more heterogeneous. Action potential characteristics recorded with intracellular microelectrodes did not reveal differences between Wt and Tx mice in either atrium. Thus, in this transgenic mouse model, selective atrial fibrosis is sufficient to increase AF inducibility.

Keywords: atrial fibrillation, fibrosis, growth factors
Abstract

Atrial fibrillation (AF) is a commonly occurring arrhythmia, present in ≈5% of people older than age 65 years. Clinically, increased vulnerability to AF is also associated with underlying heart disease, such as congestive heart failure (CHF) and mitral valve disease.1 Increased inducibility of AF has been observed in animal models of aging,23 CHF,4 atrial tachycardia-induced cardiomyopathy,56 and chronic atrial dilatation caused by mitral regurgitation.7

Theoretical models have implicated atrial interstitial fibrosis as a substrate for AF.89 Atrial interstitial fibrosis increases with age in humans and has been observed in patients with AF1011 and in animal models of aging,23 mitral regurgitation,7 and CHF.4 With the unknown cause of atrial fibrosis in humans and the presence of compounding factors in animal models, the contribution of atrial fibrosis to AF substrate formation remains unclear. Studies to date have been limited by lack of animal models of selective atrial fibrosis to study the effects of fibrosis without the presence of heart failure or other underlying heart disease.

The purpose of this study was to determine the effect of atrial fibrosis on the AF vulnerability. We have studied a transgenic mouse model with cardiac overexpression of a constitutively active form of transforming growth factor (TGF)-β1, MHC-TGFcysser.12 This model has been previously demonstrated to have elevated TGF-β1 activity in the atria and ventricles. Cardiac development and morphology appear normal, except for increased interstitial fibrosis in the atrial myocardium. Ventricular size and histology is normal.12 We have used this model to study the impact of selective atrial fibrosis on cardiac electrophysiology and the substrate of atrial arrhythmias.

Footnotes

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circres.ahajournals.org/cgi/content/full/94/11/1458

Footnotes

References

  • 1. Levy SFactors predisposing to the development of atrial fibrillation. Pacing Clin Electrophysiol. 1997;20:2670–2674.[PubMed][Google Scholar]
  • 2. Hayashi H, Wang C, Miyauchi Y, Omichi C, Pak HN, Zhou S, Ohara T, Mandel WJ, Lin SF, Fishbein MC, Chen PS, Karagueuzian HSAging-related increase to inducible atrial fibrillation in the rat model. J Cardiovasc Electrophysiol. 2002;13:801–808.[PubMed][Google Scholar]
  • 3. Anyukhovsky EP, Sosunov EA, Plotnikov A, Gainullin RZ, Jhang JS, Marboe CC, Rosen MRCellular electrophysiologic properties of old canine atria provide a substrate for arrhythmogenesis. Cardiovasc Res. 2002;54:462–469.[PubMed][Google Scholar]
  • 4. Li D, Fareh S, Leung TK, Nattel SPromotion of atrial fibrillation by heart failure in dogs: atrial remodeling of a different sort. Circulation. 1999;100:87–95.[PubMed][Google Scholar]
  • 5. Morillo CA, Klein GJ, Jones DL, Guiraudon CM. Chronic rapid atrial pacing. Structural, functional, and electrophysiological characteristics of a new model of sustained atrial fibrillation. Circulation. 1995;91:1588–1595.[PubMed]
  • 6. Wijffels MC, Kirchhof CJ, Dorland R, Allessie MA. Atrial fibrillation begets atrial fibrillation. A study in awake chronically instrumented goats. Circulation. 1995;92:1954–1968.[PubMed]
  • 7. Verheule S, Wilson E, Everett TT, Shanbhag S, Golden C, Olgin JAlterations in atrial electrophysiology and tissue structure in a canine model of chronic atrial dilatation due to mitral regurgitation. Circulation. 2003;107:2615–2622.[Google Scholar]
  • 8. Spach MS, Josephson MEInitiating reentry: the role of nonuniform anisotropy in small circuits. J Cardiovasc Electrophysiol. 1994;5:182–209.[PubMed][Google Scholar]
  • 9. Spach MS, Boineau JPMicrofibrosis produces electrical load variations due to loss of side-to-side cell connections: a major mechanism of structural heart disease arrhythmias. Pacing Clin Electrophysiol. 1997;20:397–413.[PubMed][Google Scholar]
  • 10. Frustaci A, Chimenti C, Bellocci F, Morgante E, Russo MA, Maseri AHistological substrate of atrial biopsies in patients with lone atrial fibrillation. Circulation. 1997;96:1180–1184.[PubMed][Google Scholar]
  • 11. Kostin S, Klein G, Szalay Z, Hein S, Bauer EP, Schaper JStructural correlate of atrial fibrillation in human patients. Cardiovasc Res. 2002;54:361–379.[PubMed][Google Scholar]
  • 12. Nakajima H, Nakajima HO, Salcher O, Dittie AS, Dembowsky K, Jing S, Field LJAtrial but not ventricular fibrosis in mice expressing a mutant transforming growth factor-beta(1) transgene in the heart. Circ Res. 2000;86:571–579.[PubMed][Google Scholar]
  • 13. Verheule S, van Batenburg CA, Coenjaerts FE, Kirchhoff S, Willecke K, Jongsma HJCardiac conduction abnormalities in mice lacking the gap junction protein connexin40. J Cardiovasc Electrophysiol. 1999;10:1380–1389.[PubMed][Google Scholar]
  • 14. Lammers WJ, Schalij MJ, Kirchhof CJ, Allessie MAQuantification of spatial inhomogeneity in conduction and initiation of reentrant atrial arrhythmias. Am J Physiol. 1990;259:H1254–63.[PubMed][Google Scholar]
  • 15. Wakimoto H, Maguire CT, Kovoor P, Hammer PE, Gehrmann J, Triedman JK, Berul CIInduction of atrial tachycardia and fibrillation in the mouse heart. Cardiovasc Res. 2001;50:463–473.[PubMed][Google Scholar]
  • 16. Kovoor P, Wickman K, Maguire CT, Pu W, Gehrmann J, Berul CI, Clapham DEEvaluation of the role of I(KACh) in atrial fibrillation using a mouse knockout model. J Am Coll Cardiol. 2001;37:2136–2143.[PubMed][Google Scholar]
  • 17. Schrickel JW, Bielik H, Yang A, Schimpf R, Shlevkov N, Burkhardt D, Meyer R, Grohe C, Fink K, Tiemann K, Luderitz B, Lewalter TInduction of atrial fibrillation in mice by rapid transesophageal atrial pacing. Basic Res Cardiol. 2002;97:452–460.[PubMed][Google Scholar]
  • 18. Hagendorff A, Schumacher B, Kirchhoff S, Luderitz B, Willecke KConduction disturbances and increased atrial vulnerability in Connexin40-deficient mice analyzed by transesophageal stimulation. Circulation. 1999;99:1508–1515.[PubMed][Google Scholar]
  • 19. Prinsze FJ, Bouman LNThe cellular basis of intrinsic sinus node recovery time. Cardiovasc Res. 1991;25:546–557.[PubMed][Google Scholar]
  • 20. Allessie MAAtrial electrophysiologic remodeling: another vicious circle? J Cardiovasc Electrophysiol. 1998;9:1378–1393.[PubMed][Google Scholar]
  • 21. 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.[PubMed]
  • 22. Winfree ATElectrical turbulence in three-dimensional heart muscle. Science. 1994;266:1003–1006.[PubMed][Google Scholar]
  • 23. Vaidya D, Morley GE, Samie FH, Jalife J. Reentry and fibrillation in the mouse heart. A challenge to the critical mass hypothesis. Circ Res. 1999;85:174–181.[PubMed]
  • 24. Spach MS, Miller WT, 3rd, Dolber PC, Kootsey JM, Sommer JR, Mosher CE., Jr The functional role of structural complexities in the propagation of depolarization in the atrium of the dogCardiac conduction disturbances due to discontinuities of effective axial resistivity. Circ Res. 1982;50:175–191.[PubMed][Google Scholar]
  • 25. Ausma J, Wijffels M, Thone F, Wouters L, Allessie M, Borgers MStructural changes of atrial myocardium due to sustained atrial fibrillation in the goat. Circulation. 1997;96:3157–3163.[PubMed][Google Scholar]
  • 26. Frustaci A, Caldarulo M, Buffon A, Bellocci F, Fenici R, Melina D. Cardiac biopsy in patients with “primary” atrial fibrillation. Histologic evidence of occult myocardial diseases. Chest. 1991;100:303–306.[PubMed]
  • 27. Li D, Shinagawa K, Pang L, Leung TK, Cardin S, Wang Z, Nattel SEffects of angiotensin-converting enzyme inhibition on the development of the atrial fibrillation substrate in dogs with ventricular tachypacing-induced congestive heart failure. Circulation. 2001;104:2608–2614.[PubMed][Google Scholar]
  • 28. Cha TJ, Ehrlich JR, Zhang L, Shi YF, Tardif JC, Leung TK, Nattel SDissociation between ionic remodeling and ability to sustain atrial fibrillation during recovery from experimental congestive heart failure. Circulation. 2004;109:412–418.[PubMed][Google Scholar]
  • 29. Shinagawa K, Shi YF, Tardif JC, Leung TK, Nattel SDynamic nature of atrial fibrillation substrate during development and reversal of heart failure in dogs. Circulation. 2002;105:2672–2678.[PubMed][Google Scholar]
  • 30. Li D, Melnyk P, Feng J, Wang Z, Petrecca K, Shrier A, Nattel SEffects of experimental heart failure on atrial cellular and ionic electrophysiology. Circulation. 2000;101:2631–2638.[PubMed][Google Scholar]
  • 31. Rubart M, Wang E, Dunn KW, Field LJTwo-photon molecular excitation imaging of Ca2+ transients in Langendorff-perfused mouse hearts. Am J Physiol Cell Physiol. 2003;284:C1654–68.[PubMed][Google Scholar]
Collaboration tool especially designed for Life Science professionals.Drag-and-drop any entity to your messages.