Connexin gene transfer preserves conduction velocity and prevents atrial fibrillation
Tomonori Igarashi, J Emanuel Finet, Ayano Takeuchi, Yoshihisa Fujino, Maria Strom, Ian D Greener, David S Rosenbaum, J Kevin Donahue, Tomonori Igarashi, J Emanuel Finet, Ayano Takeuchi, Yoshihisa Fujino, Maria Strom, Ian D Greener, David S Rosenbaum, J Kevin Donahue
Abstract
Background: Several lines of evidence have suggested that maintenance of atrial fibrillation (AF) depends on reentrant mechanisms. Maintenance of reentry necessitates a sufficiently short refractory period and/or delayed conduction, and AF has been associated with both alterations. Fibrosis, cellular dysfunction, and gap junction protein alterations occur in AF and cause conduction delay. We performed this study to test the hypothesis that gap junction protein overexpression would improve conduction and prevent AF.
Methods and results: Thirty Yorkshire swine were randomized into 2 groups (sinus rhythm and AF), and each group into 3 subgroups: sham-operated control, gene therapy with adenovirus expressing connexin (Cx) 40, and gene therapy with adenovirus expressing Cx43 (n=5 per subgroup). All animals had epicardial gene painting; the AF group had burst atrial pacing. All animals underwent terminal study 7 days after gene transfer. Sinus rhythm animals had strong transgene expression but no atrial conduction changes. In AF animals, controls had reduced and lateralized Cx43 expression, and Cx43 gene transfer restored expression and cellular location to sinus rhythm control levels. In the AF group, both Cx40 and Cx43 gene transfer improved conduction and reduced AF relative to controls.
Conclusions: Connexin gene therapy preserved atrial conduction and prevented AF.
Conflict of interest statement
Disclosures:
Dr Donahue has an ownership interest in Excigen Inc. The remaining authors report no conflicts.
© 2011 American Heart Association, Inc.
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References
- Miyasaka Y, Barnes ME, Gersh BJ, Cha SS, Bailey KR, Abhayaratna WP, Seward JB, Tsang TS. Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000, and implications on the projections for future prevalence. Circulation. 2006;114:119–25.
- Corley S, Epstein A, DiMarco J, Domanski M, Geller N, Greene H, Josephson M, Kellen J, Klein R, Krahn A, Mickel M, Mitchell L, Nelson J, Rosenberg Y, Schron E, Shemanski L, Waldo A, Wyse D AFFIRM Investigators. Relationships between sinus rhythm, treatment, and survival in the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) Study. Circulation. 2004;109:1509–13.
- Camm AJ. Safety considerations in the pharmacological management of atrial fibrillation. Int J Cardiol. 2008;127:299–306.
- Cappato R, Calkins H, Chen SA, Davies W, Iesaka Y, Kalman J, Kim YH, Klein G, Natale A, Packer D, Skanes A, Ambrogi F, Biganzoli E. Updated Worldwide Survey on the Methods, Efficacy, and Safety of Catheter Ablation for Human Atrial Fibrillation. Circ Arrhythm Electrophysiol. 2010;3:32–8.
- Nattel S. Therapeutic implications of atrial fibrillation mechanisms: can mechanistic insights be used to improve AF management? Cardiovasc Res. 2002;54:347–60.
- Roberts JD, Gollob MH. Impact of genetic discoveries on the classification of lone atrial fibrillation. J Am Coll Cardiol. 2010;55:705–12.
- Atienza F, Almendral J, Moreno J, Vaidyanathan R, Talkachou A, Kalifa J, Arenal A, Villacastan J, Torrecilla E, Sanchez A, Ploutz-Snyder R, Jalife J, Berenfeld O. Activation of inward rectifier potassium channels accelerates atrial fibrillation in humans: evidence for a reentrant mechanism. Circulation. 2006;114:2434–42.
- Amit G, Kikuchi K, Greener ID, Yang L, Novack V, Donahue JK. Selective molecular potassium channel blockade prevents atrial fibrillation. Circulation. 2010;121:2263–70.
- Pederson O, Bagger H, Keller N, Marchant B, Kober L, Torp-Peterson C. Efficacy of dofetilide in the treatment of atrial fibrillation-flutter in patients with reduced left ventricular function: a Danish investigations of arrhythmia and mortality on dofetilide (diamond) substudy. Circulation. 2001;104:292–6.
- Kleber AG, Rudy Y. Basic mechanisms of cardiac impulse propagation and associated arrhythmias. Physiol Rev. 2004;84:431–88.
- Davis LM, Kanter HL, Beyer EC, Saffitz JE. Distinct gap junction protein phenotypes in cardiac tissues with disparate conduction properties. J Am Coll Cardiol. 1994;24:1124–32.
- Kikuchi K, McDonald AD, Sasano T, Donahue JK. Targeted modification of atrial electrophysiology by homogeneous transmural atrial gene transfer. Circulation. 2005;111:264–70.
- Sasano T, McDonald AD, Kikuchi K, Donahue JK. Molecular ablation of ventricular tachycardia after myocardial infarction. Nat Med. 2006;12:1256–8.
- Bauer A, McDonald AD, Donahue JK. Pathophysiological findings in a model of persistent atrial fibrillation and severe congestive heart failure. Cardiovasc Res. 2004;61:764–70.
- Bauer A, McDonald AD, Nasir K, Peller L, Rade JJ, Miller JM, Heldman AW, Donahue JK. Inhibitory G protein overexpression provides physiologically relevant heart rate control in persistent atrial fibrillation. Circulation. 2004;110:3115–20.
- Burstein B, Comtois P, Michael G, Nishida K, Villeneuve L, Yeh YH, Nattel S. Changes in connexin expression and the atrial fibrillation substrate in congestive heart failure. Circ Res. 2009;105:1213–22.
- Kostin S, Klein G, Szalay Z, Hein S, Bauer EP, Schaper J. Structural correlate of atrial fibrillation in human patients. Cardiovasc Res. 2002;54:361–79.
- Schotten U, Ausma J, Stellbrink C, Sabatschus I, Vogel M, Frechen D, Schoendube F, Hanrath P, Allessie M. Cellular mechanisms of depressed atrial contractility in patients with chronic atrial fibrillation. Circulation. 2001;103:691–8.
- Ausma J, Wijffels M, Thone F, Wouters L, Allessie M, Borgers M. Structural changes of atrial myocardium due to sustained atrial fibrillation in the goat. Circulation. 1997;96:3157–63.
- van der Velden H, Ausma J, Rook M, Hellemons A, van Veen T, Allessie M, Jongsma H. Gap junctional remodeling in relation to stabilization of atrial fibrillation in the goat. Cardiovasc Res. 2000;46:476–86.
- van der Velden H, van Kempen M, Wijffels M, van Zijverden M, Groenewegen W, Allessie M, Jongsma H. Altered pattern of connexin40 distribution in persistent atrial fibrillation in the goat. J Cardiovasc Electrophys. 1998;9:596–607.
- Ryu K, Li L, Khrestian CM, Matsumoto N, Sahadevan J, Ruehr ML, Van Wagoner DR, Efimov IR, Waldo AL. Effects of sterile pericarditis on connexins 40 and 43 in the atria: correlation with abnormal conduction and atrial arrhythmias. Am J Physiol Heart Circ Physiol. 2007;293:H1231–H1241.
- Gaspo R, Bosch RF, Talajic M, Nattel S. Functional mechanisms underlying tachycardia-induced sustained atrial fibrillation in a chronic dog model. Circulation. 1997;96:4027–35.
- Elvan A, Wylie K, Zipes DP. Pacing-induced chronic atrial fibrillation impairs sinus node function in dogs. Electrophysiological remodeling. Circulation. 1996;94:2953–60.
- Li D, Fareh S, Leung T, Nattel S. Promotion of atrial fibrillation by heart failure in dogs: atrial remodeling of a different sort. Circulation. 1999;100:87–95.
- Gollob MH, Jones DL, Krahn AD, Danis L, Gong XQ, Shao Q, Liu X, Veinot JP, Tang AS, Stewart AF, Tesson F, Klein GJ, Yee R, Skanes AC, Guiraudon GM, Ebihara L, Bai D. Somatic mutations in the connexin 40 gene (GJA5) in atrial fibrillation. N Engl J Med. 2006;354:2677–88.
- Thibodeau IL, Xu J, Li Q, Liu G, Lam K, Veinot JP, Birnie DH, Jones DL, Krahn AD, Lemery R, Nicholson BJ, Gollob MH. Paradigm of genetic mosaicism and lone atrial fibrillation: physiological characterization of a connexin 43-deletion mutant identified from atrial tissue. Circulation. 2010;122:236–44.
- Rucker-Martin C, Milliez P, Tan S, Decrouy X, Recouvreur M, Vranckx R, Delcayre C, Renaud JF, Dunia I, Segretain D, Hatem SN. Chronic hemodynamic overload of the atria is an important factor for gap junction remodeling in human and rat hearts. Cardiovasc Res. 2006;72:69–79.
- Nao T, Ohkusa T, Hisamatsu Y, Inoue N, Matsumoto T, Yamada J, Shimizu A, Yoshiga Y, Yamagata T. Comparison of expression of connexin in right atrial myocardium in patients with chronic atrial fibrillation versus those in sinus rhythm. Am J Cardiol. 2003;91:678–583.
- Gaborit N, Steenman M, Lamirault G, Le Meur N, Le Bouter S, Lande G, Leger J, Charpentier F, Christ T, Dobrev D, Escande D, Nattel S, Demolombe S. Human atrial ion channel and transporter subunit gene-expression remodeling associated with valvular heart disease and atrial fibrillation. Circulation. 2005;112:471–81.
- Wetzel U, Boldt A, Lauschke J, Weigl J, Schirdewahn P, Dorszewski A, Doll N, Hindricks G, Dhein S, Kottkamp H. Expression of connexins 40 and 43 in human left atrium in atrial fibrillation of different aetiologies. Heart. 2005;91:166–70.
- Fukaya H, Niwano S, Satoh D, Masaki Y, Niwano H, Kojima J, Moriguchi M, Izumi T. Inhomogenic effect of bepridil on atrial electrical remodeling in a canine rapid atrial stimulation model. Circ J. 2008;72:318–26.
- Elvan A, Huang XD, Pressler ML, Zipes DP. Radiofrequency catheter ablation of the atria eliminates pacing-induced sustained atrial fibrillation and reduces connexin 43 in dogs. Circulation. 1997;96:1675–85.
- Bikou O, Thomas D, Trappe K, Lugenbiel P, Kelemen K, Koch M, Soucek R, Voss F, Becker R, Katus H, Bauer A. Connexin 43 gene therapy prevents persistent atrial fibrillation in a porcine model. Cardiovasc Res. 2011 In press.
- Shiroshita-Takeshita A, Sakabe M, Haugan K, Hennan JK, Nattel S. Model-dependent effects of the gap junction conduction-enhancing antiarrhythmic peptide rotigaptide (ZP123) on experimental atrial fibrillation in dogs. Circulation. 2007;115:310–8.
- Guerra JM, Everett TH, Lee KW, Wilson E, Olgin JE. Effects of the gap junction modifier rotigaptide (ZP123) on atrial conduction and vulnerability to atrial fibrillation. Circulation. 2006;114:110–8.
- Dhein S, Hagen A, Jozwiak J, Dietze A, Garbade J, Barten M, Kostelka M, Mohr FW. Improving cardiac gap junction communication as a new antiarrhythmic mechanism: the action of antiarrhythmic peptides. Naunyn Schmiedebergs Arch Pharmacol. 2010;381:221–34.
- Thomas SA, Schuessler RB, Berul CI, Beardslee MA, Beyer EC, Mendelsohn ME, Saffitz JE. Disparate effects of deficient expression of connexin43 on atrial and ventricular conduction: evidence for chamber-specific molecular determinants of conduction. Circulation. 1998;97:686–91.
- Beauchamp P, Yamada K, Baertschi A, Green K, Kanter E, Saffitz J, Kleber A. Relative contributions of connexins 40 and 43 to atrial impulse propagation in synthetic strands of neonatal and fetal murine cardiomyocytes. Circ Res. 2006;99:1216–24.
- Leaf DE, Feig JE, Vasquez C, Riva PL, Yu C, Lader JM, Kontogeorgis A, Baron EL, Peters NS, Fisher EA, Gutstein DE, Morley GE. Connexin40 imparts conduction heterogeneity to atrial tissue. Circ Res. 2008;103:1001–8.
- Verheule S, van Batenburg CA, Coenjaerts FE, Kirchhoff S, Willecke K, Jongsma HJ. Cardiac conduction abnormalities in mice lacking the gap junction protein connexin40. J Cardiovasc Electrophysiol. 1999;10:1380–9.
- Cottrell GT, Wu Y, Burt JM. Cx40 and Cx43 expression ratio influences heteromeric/heterotypic gap junction channel properties. Am J Physiol Cell Physiol. 2002;282:C1469–C1482.
- Cottrell GT, Burt JM. Heterotypic gap junction channel formation between heteromeric and homomeric Cx40 and Cx43 connexons. Am J Physiol Cell Physiol. 2001;281:C1559–C1567.
Source: PubMed