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Anti-arrhythmic Effects of I Na, I Kr, and Combined I Kr–I CaL Blockade in an Experimental Model of Acute Stretch-Related Atrial Fibrillation

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Abstract

Introduction

Atrial dilatation is commonly associated with atrial fibrillation (AF), but the electrophysiological mechanisms and the implications for anti-arrhythmic therapy are poorly understood. In a model of acute stretch-related AF in isolated rabbit hearts, we evaluated the electrophysiological effects of three different anti-arrhythmic drugs: dofetilide, flecainide and BRL-32872 (associating I Kr and I CaL blocking properties).

Methods

After 30 min of sustained stretch-related AF, we perfused BRL 10–7 M, BRL 3.10–7 M, BRL 10–6 M, flecainide 2.4 10–6 M and dofetilide 10–7 M and iteratively measured atrial effective refractory periods (ERPs), AF inducibility and AF cycle length (AFCL) 15, 30 and 60 min after drug perfusion, respectively.

Results

After a significant shortening of the ERPs by acute atrial stretch in the five groups individually (p < 0.001, stretch vs baseline for each group individually), drug perfusion led to a strong lengthening of AFCL, a very significant prolongation of ERPs (p < 0.001 vs stretch) and a reduction of AF inducibility (p < 0.01 vs control group) for each of the five experimental groups. The relative ERP increase was comparable in all groups, whereas a significantly lower AF inducibility was observed in the BRL 10–6 M group (p < 0.05 vs other BRL concentrations).

Conclusion

In a model of acute stretch-related AF, dofetilide, flecainide and BRL-32872 terminated AF and prevented its immediate reinduction after having comparatively prolonged AFCL and ERPs. These comparative results suggest that those drugs are equally efficacious, albeit with different mechanisms, in the setting of acute atrial stretch.

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References

  1. Kannel WB, Wolf PA, Benjamin EJ, Levy D. Prevalence, incidence, prognosis, and predisposing conditions for atrial fibrillation: population-based estimates. Am J Cardiol 1998;82:2N–9.

    Article  PubMed  CAS  Google Scholar 

  2. Satoh T, Zipes DP. Unequal atrial stretch in dogs increases dispersion of refractoriness conducive to developing atrial fibrillation. J Cardiovasc Electrophysiol 1996;7:833–42.

    Article  PubMed  CAS  Google Scholar 

  3. Ravelli F, Allessie M. Effects of atrial dilatation on refractory period and vulnerability to atrial fibrillation in the isolated Langendorff-perfused rabbit heart. Circulation 1997;96:1686–95.

    PubMed  CAS  Google Scholar 

  4. Bode F, Katchman A, Woosley RL, Franz MR. Gadolinium decreases stretch-induced vulnerability to atrial fibrillation. Circulation 2000;101:2200–5.

    PubMed  CAS  Google Scholar 

  5. Verheule S, Wilson E, Banthia S, Everett TH 4th, Shanbhag S, Sih HJ, et al. Direction-dependent conduction abnormalities in a canine model of atrial fibrillation due to chronic atrial dilatation. Am J Physiol Heart Circ Physiol 2004;287:H634–44.

    Article  PubMed  Google Scholar 

  6. Verheule S, Wilson E, Everett T 4th, Shanbhag S, Golden C, Olgin J. Alterations in atrial electrophysiology and tissue structure in a canine model of chronic atrial dilatation due to mitral regurgitation. Circulation 2003;107:2615–22.

    PubMed  Google Scholar 

  7. Sih HJ, Zipes DP, Berbari EJ, Adams DE, Olgin JE. Differences in organization between acute and chronic atrial fibrillation in dogs. J Am Coll Cardiol 2000;36:924–31.

    Article  PubMed  CAS  Google Scholar 

  8. Flegel KM. When atrial fibrillation occurs with pulmonary embolism, is it the chicken or the egg? CMAJ 1999;160:1181–2.

    PubMed  CAS  Google Scholar 

  9. Klein HO, Bakst A, Kaplinsky E. Pulmonary embolism and atrial fibrillation. Am J Cardiol 1988;61:498–9.

    Article  PubMed  CAS  Google Scholar 

  10. O’Toole L, McLean KA, Channer KS. Pulmonary embolism presenting with atrial fibrillation. Lancet 1993;342:1050.

    Article  PubMed  CAS  Google Scholar 

  11. Kalifa J, Jalife J, Zaitsev AV, Bagwe S, Warren M, Moreno J, et al. Intra-atrial pressure increases rate and organization of waves emanating from the superior pulmonary veins during atrial fibrillation. Circulation 2003;108:668–71.

    Article  PubMed  Google Scholar 

  12. Kim D, Fu C. Activation of a nonselective cation channel by swelling in atrial cells. J Membr Biol 1993;135:27–37.

    PubMed  CAS  Google Scholar 

  13. Kim D. Novel cation-selective mechanosensitive ion channel in the atrial cell membrane. Circ Res 1993;72:225–31.

    PubMed  CAS  Google Scholar 

  14. Kim D. A mechanosensitive K+ channel in heart cells. Activation by arachidonic acid. J Gen Physiol 1992;100:1021–40.

    Article  PubMed  CAS  Google Scholar 

  15. Bode F, Sachs F, Franz MR. Tarantula peptide inhibits atrial fibrillation. Nature 2001;409:35–6.

    Article  PubMed  CAS  Google Scholar 

  16. Zarse M, Stellbrink C, Athanatou E, Robert J, Schotten U, Hanrath P. Verapamil prevents stretch-induced shortening of atrial effective refractory period in Langendorff-perfused rabbit heart. J Cardiovasc Electrophysiol 2001;12:85–92.

    Article  PubMed  CAS  Google Scholar 

  17. Eijsbouts SC, Houben RP, Blaauw Y, Schotten U, Allessie MA. Synergistic action of atrial dilation and sodium channel blockade on conduction in rabbit atria. J Cardiovasc Electrophysiol 2004;15:1453–61.

    Article  PubMed  Google Scholar 

  18. Bril A, Faivre JF, Forest MC, Cheval B, Gout B, Linee P, et al. Electrophysiological effect of BRL-32872, a novel antiarrhythmic agent with potassium and calcium channel blocking properties, in guinea pig cardiac isolated preparations. J Pharmacol Exp Ther 1995;273:1264–72.

    PubMed  CAS  Google Scholar 

  19. Zarse M, Deharo JC, Mast F, Allessie MA. Importance of right and left atrial dilation and linear ablation for perpetuation of sustained atrial fibrillation. J Cardiovasc Electrophysiol 2002;13:164–71.

    Article  PubMed  Google Scholar 

  20. Hu H, Sachs F. Stretch-activated ion channels in the heart. J Mol Cell Cardiol 1997;29:1511–23.

    Article  PubMed  CAS  Google Scholar 

  21. Kamkin A, Kiseleva I, Wagner KD, Bohm J, Theres H, Gunther J, et al. Characterization of stretch-activated ion currents in isolated atrial myocytes from human hearts. Pflugers Arch 2003;446:339–46.

    PubMed  CAS  Google Scholar 

  22. Suchyna TM, Johnson JH, Hamer K, Leykam JF, Gage DA, Clemo HF, et al. Identification of a peptide toxin from Grammostola spatulata spider venom that blocks cation-selective stretch-activated channels. J Gen Physiol 2000;115:583–98.

    Article  PubMed  CAS  Google Scholar 

  23. Bril A, Forest MC, Cheval B, Faivre JF. Combined potassium and calcium channel antagonistic activities as a basis for neutral frequency dependent increase in action potential duration: comparison between BRL-32872 and azimilide. Cardiovasc Res 1998;37:130–40.

    Article  PubMed  CAS  Google Scholar 

  24. Samie FH, Mandapati R, Gray RA, Watanabe Y, Zuur C, Beaumont J, et al. A mechanism of transition from ventricular fibrillation to tachycardia: effect of calcium channel blockade on the dynamics of rotating waves. Circ Res 2000;86:684–91.

    PubMed  CAS  Google Scholar 

  25. Benardeau A, Fareh S, Nattel S. Effects of verapamil on atrial fibrillation and its electrophysiological determinants in dogs. Cardiovasc Res 2001;50:85–96.

    Article  PubMed  CAS  Google Scholar 

  26. Tse HF, Wang Q, Yu CM, Ayers GM, Lau CP. Effect of verapamil on prevention of atrial fibrillation in patients implanted with an implantable atrial defibrillator. Clin Cardiol 2001;24:503–5.

    Article  PubMed  CAS  Google Scholar 

  27. Hassan SA, Oral H, Scharf C, Chugh A, Pelosi F, Knight BP, et al. Rate-dependent effect of verapamil on atrial refractoriness. J Am Coll Cardiol 2003;41:446–51.

    Article  PubMed  CAS  Google Scholar 

  28. Feld GK, Cha Y. Electrophysiologic effects of the new class III antiarrhythmic drug dofetilide in an experimental canine model of pacing-induced atrial fibrillation. J Cardiovasc Pharmacol Ther 1997;2:195–203.

    Article  PubMed  CAS  Google Scholar 

  29. Pallandi RT, Lovell NH, Campbell TJ. Class III Antiarrhythmic effects of dofetilide in rabbit atrial myocardium. J Cardiovasc Pharmacol Ther 1996;1:229–34.

    PubMed  CAS  Google Scholar 

  30. Kneller J, Kalifa J, Zou R, Zaitsev AV, Warren M, Berenfeld O, et al. Mechanisms of atrial fibrillation termination by pure sodium channel blockade in an ionically-realistic mathematical model. Circ Res 2005;96:e35–47.

    Article  PubMed  CAS  Google Scholar 

  31. Wijffels MC, Dorland R, Mast F, Allessie MA. Widening of the excitable gap during pharmacological cardioversion of atrial fibrillation in the goat: effects of cibenzoline, hydroquinidine, flecainide, and d-sotalol. Circulation 2000;102:260–7.

    PubMed  CAS  Google Scholar 

  32. Youm JB, Han J, Kim N, Zhang YH, Kim E, Joo H, et al. Role of stretch-activated channels on the stretch-induced changes of rat atrial myocytes. Prog Biophys Mol Biol 2006;90:186–206.

    Article  PubMed  CAS  Google Scholar 

  33. Li D, Benardeau A, Nattel S. Contrasting efficacy of dofetilide in differing experimental models of atrial fibrillation. Circulation 2000;102:104–12.

    PubMed  CAS  Google Scholar 

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Acknowledgements

Smithkline Beecham supported this work. Jérôme Kalifa was supported by the ADEREM (Marseilles).

Author information

Author notes

  1. B. Gout

    Present address: G.S.R., 35 rue bernard de Vantadour, 31300, Toulouse, France

  2. A. Bril

    Present address: Institut de Researches Servier, 11 rue des Moulineaux, 92510, SURESNES, France

Authors and Affiliations

  1. Centre de Résonance Magnétique Biologique et Médicale, UMR CNRS 6612, Faculté de Médecine, 27 Bd Jean Moulin, 13005, Marseille, France

    J. Kalifa, M. Bernard & P. Cozzone

  2. Département de Cardiologie, Hôpital Timone Adultes, 264 Rue Saint Pierre, 13385, Marseille Cedex 05, France

    J. Kalifa, D. Cozma, P. Laurent, T. Chalvidan, J. C. Deharo & P. Djiane

  3. Inserm E0324 CHU La Milétrie - BP 5772, rue de la Milétrie, Poitiers Cedex, 86022, France

    J. M. Maixent

  4. Laboratoire GlaxoSmithKline, Unité de Biologie Cardiovasculaire, Saint-Grégoire, France

    B. Gout & A. Bril

  5. Bioproject Biotech, 4 rue du Chesnay Beauregard BP 96205, 35762, Saint-Grégoire Cedex, France

    A. Bril

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  1. J. Kalifa
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Correspondence to J. Kalifa.

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Kalifa, J., Bernard, M., Gout, B. et al. Anti-arrhythmic Effects of I Na, I Kr, and Combined I Kr–I CaL Blockade in an Experimental Model of Acute Stretch-Related Atrial Fibrillation. Cardiovasc Drugs Ther 21, 47–53 (2007). https://doi.org/10.1007/s10557-007-6001-y

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  • DOI: https://doi.org/10.1007/s10557-007-6001-y

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