The value of basic research insights into atrial fibrillation mechanisms as a guide to therapeutic innovation: A critical analysis

Cardiovascular Research

Volumn 109, Issue 4, 2016, Pages 467-479

  Heijman, Jordi ^a   Algalarrondo, Vincent ^b,c   Voigt, Niels ^d   Melka, Jonathan ^b,c   Wehrens, Xander H T ^e   Dobrev, Dobromir ^d   Nattel, Stanley ^b,c,d  

^a MAASTRICHT UNIVERSITY   (Netherlands)

^b MONTREAL HEART INSTITUTE   (Canada)

^c MCGILL UNIVERSITY   (Canada)

^d UNIVERSITY HOSPITAL ESSEN   (Germany)

^e BAYLOR COLLEGE OF MEDICINE   (United States)

Author keywords

Ablation; Antiarrhythmic drugs; Atrial fibrillation; Cellular electrophysiology; Ectopic activity; Imaging; Re entry

Indexed keywords

AMIODARONE; ANTIARRHYTHMIC AGENT; CALCIUM ION; ION CHANNEL; POTASSIUM CHANNEL BLOCKING AGENT; SODIUM CHANNEL BLOCKING AGENT;

ABLATION THERAPY; ACTION POTENTIAL; ARRHYTHMOGENESIS; ATRIAL FIBRILLATION; AUTONOMIC NERVOUS SYSTEM; BASIC RESEARCH; CALCIUM METABOLISM; CONCEPTUAL FRAMEWORK; ELECTRODE; ELECTROPHYSIOLOGY; HEART ARRHYTHMIA; HEART ATRIUM; HUMAN; MOLECULAR BIOLOGY; NONHUMAN; PATHOGENESIS; PRIORITY JOURNAL; REVIEW; ANIMAL; DISEASE COURSE; DRUG EFFECTS; HEART MUSCLE CONDUCTION SYSTEM; PATHOPHYSIOLOGY; PROCEDURES; RESEARCH;

ANIMALS; ANTI-ARRHYTHMIA AGENTS; ATRIAL FIBRILLATION; DISEASE PROGRESSION; ELECTROPHYSIOLOGY; HEART CONDUCTION SYSTEM; HUMANS; RESEARCH;

EID: 84964258764     PISSN: 00086363     EISSN: 17553245     Source Type: Journal    
DOI: 10.1093/cvr/cvv275     Document Type: Review

References (130)

1. Nattel S. New ideas about atrial fibrillation 50 years on. Nature 2002;415:219-226.
2. Nishida K, Nattel S. Atrial fibrillation compendium: historical context and detailed translational perspective on an important clinical problem. Circ Res 2014;114: 1447-1452.
3. Andrade J, Khairy P, Dobrev D, Nattel S. The clinical profile and pathophysiology of atrial fibrillation: relationships among clinical features, epidemiology, and mechanisms. Circ Res 2014;114:1453-1468.
4. Dobrev D, Nattel S. New antiarrhythmic drugs for treatment of atrial fibrillation. Lancet 2010;375:1212-1223.
5. Heijman J, Voigt N, Dobrev D. New directions in antiarrhythmic drug therapy for atrial fibrillation. Future Cardiol 2013;9:71-88.
6. Heijman J, Voigt N, Nattel S, Dobrev D. Cellular and molecular electrophysiology of atrial fibrillation initiation, maintenance, and progression. Circ Res 2014;114: 1483-1499.
7. Camm AJ, Al-Khatib SM, Calkins H, Halperin JL, Kirchhof P, Lip GY, Nattel S, Ruskin J, Banerjee A, Blendea D, Guasch E, Needleman M, Savelieva I, Viles-Gonzalez J, Williams ES. A proposal for new clinical concepts in the management of atrial fibrillation. Am Heart J 2012;164:292-302 e291.
8. Schram G, Pourrier M, Melnyk P, Nattel S. Differential distribution of cardiac ion channel expression as a basis for regional specialization in electrical function. Circ Res 2002; 90:939-950.
9. Bartos DC, Grandi E, Ripplinger CM. Ion channels in the heart. Compr Physiol 2015;5: 1423-1464.
10. Schmidt C, Wiedmann F, Voigt N, Zhou XB, Heijman J, Lang S, Albert V, Kallenberger S, Ruhparwar A, Szabo G, Kallenbach K, Karck M, Borggrefe M, Biliczki P, Ehrlich JR, Baczko I, Lugenbiel P, Schweizer PA, Donner BC, Katus HA, Dobrev D, Thomas D. Upregulation of K2P3.1 K+ current causes action potential shortening in patients with chronic atrial fibrillation. Circulation 2015;132:82-92.
11. Glasscock E, Voigt N, McCauley MD, Sun Q, Li N, Chiang DY, Zhou XB, Molina CE, Thomas D, Schmidt C, Skapura DG, Noebels JL, Dobrev D,Wehrens XH. Expression and function of Kv1.1 potassium channels in human atria from patients with atrial fibrillation. Basic Res Cardiol 2015;110:505.
12. Qi XY, Diness JG, Brundel BJ, Zhou XB, Naud P, Wu CT, Huang H, Harada M, Aflaki M, Dobrev D, Grunnet M, Nattel S. Role of small-conductance calcium-activated potassium channels in atrial electrophysiology and fibrillation in the dog. Circulation 2014;129:430-440.
13. Simard C, Hof T, Keddache Z, Launay P, Guinamard R. The TRPM4 non-selective cation channel contributes to the mammalian atrial action potential. J Mol Cell Cardiol 2013;59:11-19.
14. Ravens U. Mechano-electric feedback and arrhythmias. Prog Biophys Mol Biol 2003;82: 255-266.
15. Heijman J, Voigt N, Ghezelbash S, Schirmer I, Dobrev D. Calcium handling abnormalities as a target for atrial fibrillation therapeutics: how close to clinical implementation J Cardiovasc Pharmacol 2015;66:515-522.
16. Comtois P, Kneller J, Nattel S. Of circles and spirals: bridging the gap between the leading circle and spiral wave concepts of cardiac reentry. Europace 2005;7(Suppl. 2):10-20.
17. Aguilar M, Nattel S. The pioneering work of George Mines on cardiac arrhythmias: groundbreaking ideas that remain influential in contemporary cardiac electrophysiology. J Physiol 2015; doi:10.1113/JP270506.
18. Voigt N, Li N, Wang Q, Wang W, Trafford AW, Abu-Taha I, Sun Q,Wieland T, Ravens U, Nattel S, Wehrens XH, Dobrev D. Enhanced sarcoplasmic reticulum Ca2+ leak and increased Na+-Ca2+ exchanger function underlie delayed afterdepolarizations in patients with chronic atrial fibrillation. Circulation 2012;125:2059-2070.
19. Voigt N, Heijman J, Wang Q, Chiang DY, Li N, Karck M, Wehrens XH, Nattel S, Dobrev D. Cellular and molecular mechanisms of atrial arrhythmogenesis in patients with paroxysmal atrial fibrillation. Circulation 2014;129:145-156.
20. Chiang DY, Kongchan N, Beavers DL, Alsina KM, Voigt N, Neilson JR, Jakob H, Martin JF, Dobrev D, Wehrens XH, Li N. Loss of microRNA-106b-25 cluster promotes atrial fibrillation by enhancing ryanodine receptor type-2 expression and calcium release. Circ Arrhythm Electrophysiol 2014;7:1214-1222.
21. Christ T, Rozmaritsa N, Engel A, Berk E, Knaut M, Metzner K, Canteras M, Ravens U, Kaumann A. Arrhythmias, elicited by catecholamines and serotonin, vanish in human chronic atrial fibrillation. Proc Natl Acad Sci USA 2014;111:11193-11198.
22. Greiser M, Kerfant BG, Williams GS, Voigt N, Harks E, Dibb KM, Giese A, Meszaros J, Verheule S, Ravens U, Allessie MA, Gammie JS, van der Velden J, Lederer WJ, Dobrev D, Schotten U. Tachycardia-induced silencing of subcellular Ca2+ signaling in atrial myocytes. J Clin Invest 2014;124:4759-4772.
23. King JH, Wickramarachchi C, Kua K, Du Y, Jeevaratnam K, Matthews HR, Grace AA, Huang CL, Fraser JA. Loss of Nav1.5 expression and function in murine atria containing the RyR2-P2328S gain-of-function mutation. Cardiovasc Res 2013;99:751-759.
24. Liu MB, de Lange E, Garfinkel A, Weiss JN, Qu Z. Delayed afterdepolarizations generate both triggers and a vulnerable substrate promoting reentry in cardiac tissue. Heart Rhythm 2015;12:2115-2124.
25. Pandit SV, Berenfeld O, Anumonwo JM, Zaritski RM, Kneller J, Nattel S, Jalife J. Ionic determinants of functional reentry in a 2-D model of human atrial cells during simulated chronic atrial fibrillation. Biophys J 2005;88:3806-3821.
26. Nishida K, Michael G, Dobrev D, Nattel S. Animal models for atrial fibrillation: clinical insights and scientific opportunities. Europace 2010;12:160-172.
27. Kato T, Iwasaki YK, Nattel S. Connexins and atrial fibrillation: filling in the gaps. Circulation 2012;125:203-206.
28. Nattel S, Burstein B, Dobrev D. Atrial remodeling and atrial fibrillation: mechanisms and implications. Circ Arrhythm Electrophysiol 2008;1:62-73.
29. Dzeshka MS, Lip GY, Snezhitskiy V, Shantsila E. Cardiac fibrosis in patients with atrial fibrillation: mechanisms and clinical implications. J Am Coll Cardiol 2015;66:943-959.
30. Burstein B, Libby E, Calderone A, Nattel S. Differential behaviors of atrial versus ventricular fibroblasts: a potential role for platelet-derived growth factor in atrialventricular remodeling differences. Circulation 2008;117:1630-1641.
31. Li N, Chiang DY,Wang S,Wang Q, Sun L, Voigt N, Respress JL, Ather S, Skapura DG, Jordan VK, Horrigan FT, SchmitzW, Muller FU, Valderrabano M, Nattel S, Dobrev D, Wehrens XH. Ryanodine receptor-mediated calcium leak drives progressive development of an atrial fibrillation substrate in a transgenic mouse model. Circulation 2014; 129:1276-1285.
32. Harada M, Luo X, Qi XY, Tadevosyan A, Maguy A, Ordog B, Ledoux J, Kato T, Naud P, Voigt N, Shi Y, Kamiya K, Murohara T, Kodama I, Tardif JC, Schotten U, Van Wagoner DR, Dobrev D, Nattel S. Transient receptor potential canonical-3 channel-dependent fibroblast regulation in atrial fibrillation. Circulation 2012;126: 2051-2064.
33. Kalifa J, Zaitsev A, Warren M, Berenfeld O, Nattel S, Jalife J. High atrial pressure-induced stretch during atrial fibrillation reveals high frequency periodic sources in the pulmonary vein region of the sheep heart (Abstract). Pacing Clin Electrophysiol 2003;26:950.
34. Chen PS, Chen LS, Fishbein MC, Lin SF, Nattel S. Role of the autonomic nervous system in atrial fibrillation: pathophysiology and therapy. Circ Res 2014;114:1500-1515.
35. Nattel S, Hadjis T, Talajic M. The treatment of atrial fibrillation. An evaluation of drug therapy, electrical modalities and therapeutic considerations. Drugs 1994;48: 345-371.
36. Anderson JL, Stewart JR, Perry BA, Van Hamersveld DD, Johnson TA, Conard GJ, Chang SF, Kvam DC, Pitt B. Oral flecainide acetate for the treatment of ventricular arrhythmias. N Engl J Med 1981;305:473-477.
37. Banitt EH, Bronn WR, Coyne WE, Schmid JR. Antiarrhythmics. 2. Synthesis and antiarrhythmic activity of N-(piperidylalkyl)trifluoroethoxybenzamides. J Med Chem 1977;20:821-826.
38. Campbell TJ, Vaughan Williams EM. Voltage-and time-dependent depression of maximum rate of depolarisation of guinea-pig ventricular action potentials by two new antiarrhythmic drugs, flecainide and lorcainide. Cardiovasc Res 1983;17:251-258.
39. Goy JJ, Maendly R, Grbic M, Finci L, Sigwart U. Cardioversion with flecainide in patients with atrial fibrillation of recent onset. Eur J Clin Pharmacol 1985;27:737-738.
40. Wang Z, Page P, Nattel S. Mechanism of flecainide's antiarrhythmic action in experimental atrial fibrillation. Circ Res 1992;71:271-287.
41. Rensma PL, Allessie MA, Lammers WJ, Bonke FI, Schalij MJ. Length of excitation wave and susceptibility to reentrant atrial arrhythmias in normal conscious dogs. Circ Res 1988;62:395-410.
42. Kneller J, Kalifa J, Zou R, Zaitsev AV, Warren M, Berenfeld O, Vigmond EJ, Leon LJ, Nattel S, Jalife J. Mechanisms of atrial fibrillation termination by pure sodium channel blockade in an ionically-realistic mathematical model. Circ Res 2005;96:e35-e47.
43. Hondeghem LM, Katzung BG. Time-and voltage-dependent interactions of antiarrhythmic drugs with cardiac sodium channels. Biochim Biophys Acta 1977;472: 373-398.
44. Starmer CF, Grant AO, Strauss HC. Mechanisms of use-dependent block of sodium channels in excitable membranes by local anesthetics. Biophys J 1984;46:15-27.
45. Nattel S, De Blasio E,Wang W-Q, Beatch GN. RSD1235: a novel antiarrhythmic agent with a unique electrophysiological profile that terminates AF in dogs. Eur Heart J 2001; 22(Suppl):448. (Abstract).
46. Roy D, Rowe BH, Stiell IG, Coutu B, Ip JH, Phaneuf D, Lee J, Vidaillet H, Dickinson G, Grant S, Ezrin AM, BeatchGN, CRAFT Investigators. A randomized, controlled trial of RSD1235, a novel anti-arrhythmic agent, in the treatment of recent onset atrial fibrillation. J Am Coll Cardiol 2004;44:2355-2361.
47. Comtois P, Sakabe M, Vigmond EJ, Munoz M, Texier A, Shiroshita-Takeshita A, Nattel S. Mechanisms of atrial fibrillation termination by rapidly unbinding Na+ channel blockers: insights from mathematical models and experimental correlates. Am J Physiol Heart Circ Physiol 2008;295:H1489-H1504.
48. Aguilar M, Nattel S. The past, present and potential future of sodium channel block as an atrial fibrillation suppressing strategy. J Cardiovasc Pharmacol 2015;66:432-440.
49. Singh BN, Vaughan Williams EM. A third class of anti-arrhythmic action. Effects on atrial and ventricular intracellular potentials, and other pharmacological actions on cardiac muscle, of MJ 1999 and AH 3474. Br J Pharmacol 1970;39:675-687.
50. Prakash R, Parmley WW, Allen HN, Matloff JM. Effect of Sotalol on clinical arrhythmias. Am J Cardiol 1972;29:397-400.
51. Singh BN, Vaughan Williams EM. The effect of amiodarone, a new anti-anginal drug, on cardiac muscle. Br J Pharmacol 1970;39:657-667.
52. Hester JB, Gibson JK, Cimini MG, Emmert DE, Locker PK, Perricone SC, Skaletzky LL, Sykes JK, West BE. N-[(omega-amino-1-hydroxyalkyl)phenyl]methanesulfonamide derivatives with class III antiarrhythmic activity. J Med Chem 1991;34:308-315.
53. Nattel S. Experimental evidence for proarrhythmic mechanisms of antiarrhythmic drugs. Cardiovasc Res 1998;37:567-577.
54. Wang ZG, Pelletier LC, Talajic M, Nattel S. Effects of flecainide and quinidine on human atrial action potentials. Role of rate-dependence and comparison with guinea pig, rabbit, and dog tissues. Circulation 1990;82:274-283.
55. Rosenbaum MB, Chiale PA, Halpern MS, Nau GJ, Przybylski J, Levi RJ, Lazzari JO, Elizari MV. Clinical efficacy of amiodarone as an antiarrhythmic agent. Am J Cardiol 1976;38:934-944.
56. Mason JW, Hondeghem LM, Katzung BG. Amiodarone blocks inactivated cardiac sodium channels. Pflugers Arch 1983;396:79-81.
57. Nattel S, Talajic M, Quantz M, DeRoode M. Frequency-dependent effects of amiodarone on atrioventricular nodal function and slow-channel action potentials: evidence for calcium channel-blocking activity. Circulation 1987;76:442-449.
58. Nattel S, Talajic M. Recent advances in understanding the pharmacology of amiodarone. Drugs 1988;36:121-131.
59. Roy D, Talajic M, Dorian P, Connolly S, Eisenberg MJ, Green M, Kus T, Lambert J, Dubuc M, Gagne P, Nattel S, Thibault B. Amiodarone to prevent recurrence of atrial fibrillation. Canadian Trial of Atrial Fibrillation Investigators. N Engl J Med 2000;342: 913-920.
60. Ehrlich JR, Nattel S. Novel approaches for pharmacological management of atrial fibrillation. Drugs 2009;69:757-774.
61. Hohnloser SH, Crijns HJ, van Eickels M, Gaudin C, Page RL, Torp-Pedersen C, Connolly SJ; ATHENA Investigators. Effect of dronedarone on cardiovascular events in atrial fibrillation. N Engl J Med 2009;360:668-678.
62. Køber L, Torp-Pedersen C, McMurray JJ, Gøtzsche O, Lévy S, Crijns H, Amlie J, Carlsen J; Dronedarone Study Group. Increased mortality after dronedarone therapy for severe heart failure. N Engl J Med 2008;358:2678-2687.
63. Connolly SJ, Camm AJ, Halperin JL, Joyner C, Alings M, Amerena J, Atar D, AvezumÁ, Blomström P, Borggrefe M, Budaj A, Chen SA, Ching CK, Commerford P, Dans A, Davy JM, Delacrétaz E, Di Pasquale G, Diaz R, Dorian P, Flaker G, Golitsyn S, Gonzalez-Hermosillo A, Granger CB, Heidbüchel H, Kautzner J, Kim JS, Lanas F, Lewis BS, Merino JL, Morillo C, Murin J, Narasimhan C, Paolasso E, Parkhomenko A, Peters NS, Sim KH, Stiles MK, Tanomsup S, Toivonen L, Tomcsányi J, Torp-Pedersen C, Tse HF, Vardas P, Vinereanu D, Xavier D, Zhu J, Zhu JR, Baret-Cormel L, Weinling E, Staiger C, Yusuf S, Chrolavicius S, Afzal R, Hohnloser SH; PALLAS Investigators. Dronedarone in high-risk permanent atrial fibrillation. N Engl J Med 2011;365:2268-2276.
64. Nattel S. Dronedarone in atrial fibrillation-Jekyll and Hyde N Engl J Med 2011;365: 2321-2322.
65. Nattel S, Carlsson L. Innovative approaches to anti-arrhythmic drug therapy. Nat Rev Drug Discov 2006;5:1034-1049.
66. Nattel S, Bourne G, Talajic M. Insights into mechanisms of antiarrhythmic drug action from experimental models of atrial fibrillation. J Cardiovasc Electrophysiol 1997;8: 469-480.
67. Nattel S,Waters D. What is an antiarrhythmic drug From clinical trials to fundamental concepts. Am J Cardiol 1990;66:96-99.
68. Sicilian Gambit Group. The search for novel antiarrhythmic strategies. Sicilian Gambit. Eur Heart J 1998;19:1178-1196.
69. Savelieva I, Kakouros N, Kourliouros A, Camm AJ. Upstream therapies for management of atrial fibrillation: review of clinical evidence and implications for European Society of Cardiology guidelines. Part II: secondary prevention. Europace 2011;13: 610-625.
70. Savelieva I, Kakouros N, Kourliouros A, Camm AJ. Upstream therapies for management of atrial fibrillation: review of clinical evidence and implications for European Society of Cardiology guidelines. Part I: primary prevention. Europace 2011;13:308-328.
71. Abed HS, Samuel CS, Lau DH, Kelly DJ, Royce SG, Alasady M, Mahajan R, Kuklik P, Zhang Y, Brooks AG, Nelson AJ, Worthley SG, Abhayaratna WP, Kalman JM, Wittert GA, Sanders P. Obesity results in progressive atrial structural and electrical remodeling: implications for atrial fibrillation. Heart Rhythm 2013;10:90-100.
72. Iwasaki YK, Kato T, Xiong F, Shi YF, Naud P, Maguy A, Mizuno K, Tardif JC, Comtois P, Nattel S. Atrial fibrillation promotion with long-term repetitive obstructive sleep apnea in a rat model. J Am Coll Cardiol 2014;64:2013-2023.
73. Abed HS, Wittert GA, Leong DP, Shirazi MG, Bahrami B, Middeldorp ME, Lorimer MF, Lau DH, Antic NA, Brooks AG, Abhayaratna WP, Kalman JM, Sanders P. Effect of weight reduction and cardiometabolic risk factor management on symptom burden and severity in patients with atrial fibrillation: a randomized clinical trial. JAMA 2013; 310:2050-2060.
74. Naruse Y, Tada H, Satoh M, Yanagihara M, Tsuneoka H, Hirata Y, Ito Y, Kuroki K, Machino T, Yamasaki H, Igarashi M, Sekiguchi Y, Sato A, Aonuma K. Concomitant obstructive sleep apnea increases the recurrence of atrial fibrillation following radiofrequency catheter ablation of atrial fibrillation: clinical impact of continuous positive airway pressure therapy. Heart Rhythm 2013;10:331-337.
75. Benjamin EJ, Chen PS, Bild DE, Mascette AM, Albert CM, Alonso A, Calkins H, Connolly SJ, Curtis AB, Darbar D, Ellinor PT, Go AS, Goldschlager NF, Heckbert SR, Jalife J, Kerr CR, Levy D, Lloyd-Jones DM, Massie BM, Nattel S, Olgin JE, Packer DL, Po SS, Tsang TS, VanWagoner DR, Waldo AL, Wyse DG. Prevention of atrial fibrillation: report from a national heart, lung, and blood institute workshop. Circulation 2009;119:606-618.
76. Nishida K, Datino T, Macle L, Nattel S. Atrial fibrillation ablation: translating basic mechanistic insights to the patient. J Am Coll Cardiol 2014;64:823-831.
77. Cox JL, Schuessler RB, D'Agostino HJ Jr, Stone CM, Chang BC, Cain ME, Corr PB, Boineau JP. The surgical treatment of atrial fibrillation. III. Development of a definitive surgical procedure. J Thorac Cardiovasc Surg 1991;101:569-583.
78. Jais P, Haissaguerre M, Shah DC, Chouairi S, Gencel L, Hocini M, Clementy J. A focal source of atrial fibrillation treated by discrete radiofrequency ablation. Circulation 1997;95:572-576.
79. Nattel S. Paroxysmal atrial fibrillation and pulmonary veins: relationships between clinical forms and automatic versus re-entrant mechanisms. Can J Cardiol 2013;29: 1147-1149.
80. Arentz T, Macle L, Kalusche D, Hocini M, Jais P, Shah D, Haissaguerre M. "Dormant" pulmonary vein conduction revealed by adenosine after ostial radiofrequency catheter ablation. J Cardiovasc Electrophysiol 2004;15:1041-1047.
81. Datino T, Macle L, Qi XY, Maguy A, Comtois P, Chartier D, Guerra PG, Arenal A, Fernandez-Aviles F, Nattel S. Mechanisms by which adenosine restores conduction in dormant canine pulmonary veins. Circulation 2010;121:963-972.
82. Macle L, Khairy P, Weerasooriya R, Novak P, Verma A, Willems S, Arentz T, Deisenhofer I, Veenhuyzen G, Scaveé C, Jäs P, Puererfellner H, Levesque S, Andrade JG, Rivard L, Guerra PG, Dubuc M, Thibault B, Talajic M, Roy D, Nattel S; ADVICE trial investigators. Adenosine-guided pulmonary vein isolation for the treatment of paroxysmal atrial fibrillation: an international, multicentre, randomised superiority trial. Lancet 2015;386:672-679.
83. Verma A, Jiang CY, Betts TR, Chen J, Deisenhofer I, Mantovan R, Macle L, Morillo CA, HaverkampW,Weerasooriya R, Albenque JP, Nardi S, Menardi E, Novak P, Sanders P; STAR AF II Investigators. Approaches to catheter ablation for persistent atrial fibrillation. N Engl J Med 2015;372:1812-1822.
84. Krinskii VI. Excitation propagation in nonhomogenous medium (actions analogous to heart fibrillation). Biofizika 1966;11:676-683.
85. Sarmast F, Kolli A, Zaitsev A, Parisian K, Dhamoon AS, Guha PK, Warren M, Anumonwo JM, Taffet SM, Berenfeld O, Jalife J. Cholinergic atrial fibrillation: IK,ACh gradients determine unequal left/right atrial frequencies and rotor dynamics. Cardiovasc Res 2003;59:863-873.
86. Narayan SM, Krummen DE, Shivkumar K, Clopton P, Rappel WJ, Miller JM. Treatment of atrial fibrillation by the ablation of localized sources: CONFIRM (Conventional Ablation for Atrial Fibrillation With or Without Focal Impulse and Rotor Modulation) trial. J Am Coll Cardiol 2012;60:628-636.
87. Cuculich PS, Wang Y, Lindsay BD, Faddis MN, Schuessler RB, Damiano RJ Jr, Li L, Rudy Y. Noninvasive characterization of epicardial activation in humans with diverse atrial fibrillation patterns. Circulation 2010;122:1364-1372.
88. Haissaguerre M, Hocini M, Denis A, Shah AJ, Komatsu Y, Yamashita S, Daly M, Amraoui S, Zellerhoff S, Picat MQ, Quotb A, Jesel L, Lim H, Ploux S, Bordachar P, Attuel G, Meillet V, Ritter P, Derval N, Sacher F, Bernus O, Cochet H, Jais P, Dubois R. Driver domains in persistent atrial fibrillation. Circulation 2014;130: 530-538.
89. Eckstein J, Zeemering S, Linz D, Maesen B, Verheule S, van Hunnik A, Crijns H, Allessie MA, Schotten U. Transmural conduction is the predominant mechanism of breakthrough during atrial fibrillation: evidence from simultaneous endo-epicardial high-density activation mapping. Circ Arrhythm Electrophysiol 2013;6:334-341.
90. Hansen BJ, Zhao J, Csepe TA, Moore BT, Li N, Jayne LA, Kalyanasundaram A, Lim P, Bratasz A, Powell KA, Simonetti OP, Higgins RS, Kilic A, Mohler PJ, Janssen PM, Weiss R, Hummel JD, Fedorov VV. Atrial fibrillation driven by micro-anatomic intramural re-entry revealed by simultaneous sub-epicardial and sub-endocardial optical mapping in explanted human hearts. Eur Heart J 2015;36:2390-2401.
91. Iwasaki YK, Nishida K, Kato T, Nattel S. Atrial fibrillation pathophysiology: implications for management. Circulation 2011;124:2264-2274.
92. Lemola K, Chartier D, Yeh YH, Dubuc M, Cartier R, Armour A, Ting M, Sakabe M, Shiroshita-Takeshita A, Comtois P, Nattel S. Pulmonary vein region ablation in experimental vagal atrial fibrillation: role of pulmonary veins versus autonomic ganglia. Circulation 2008;117:470-477.
93. Katritsis DG, Giazitzoglou E, Zografos T, Pokushalov E, Po SS, Camm AJ. Rapid pulmonary vein isolation combined with autonomic ganglia modification: a randomized study. Heart Rhythm 2011;8:672-678.
94. Dobrev D, Carlsson L, Nattel S. Novel molecular targets for atrial fibrillation therapy. Nat Rev Drug Discov 2012;11:275-291.
95. Bode F, Sachs F, Franz MR. Tarantula peptide inhibits atrial fibrillation. Nature 2001; 409:35-36.
96. Pavri BB, Greenberg HE, Kraft WK, Lazarus N, Lynch JJ, Salata JJ, Bilodeau MT, Regan CP, Stump G, Fan L, Mehta A, Wagner JA, Gutstein DE, Bloomfield D. MK-0448, a specific Kv1.5 inhibitor: safety, pharmacokinetics, and pharmacodynamic electrophysiology in experimental animal models and humans. Circ Arrhythm Electrophysiol 2012;5:1193-1201.
97. Courtemanche M, Ramirez RJ, Nattel S. Ionic targets for drug therapy and atrial fibrillation-induced electrical remodeling: insights from a mathematical model. Cardiovasc Res 1999;42:477-489.
98. Dobrev D, Friedrich A, Voigt N, Jost N,Wettwer E, Christ T, Knaut M, Ravens U. The G protein-gated potassium current IK,ACh is constitutively active in patients with chronic atrial fibrillation. Circulation 2005;112:3697-3706.
99. Zhou Q, Xiao J, Jiang D,Wang R, Vembaiyan K,Wang A, Smith CD, Xie C, ChenW, Zhang J, Tian X, Jones PP, Zhong X, Guo A, Chen H, Zhang L, Zhu W, Yang D, Li X, Chen J, Gillis AM, Duff HJ, Cheng H, Feldman AM, Song LS, Fill M, Back TG, Chen SR. Carvedilol and its new analogs suppress arrhythmogenic store overload-induced Ca2+ release. Nat Med 2011;17:1003-1009.
100. Jalalian R, Ghafari R, Ghazanfari P. Comparing the therapeutic effects of carvedilol and metoprolol on prevention of atrial fibrillation after coronary artery bypass surgery, a double-blind study. Int Cardiovasc Res J 2014;8:111-115.
101. Brundel BJ, Ausma J, van Gelder IC, Van der Want JJ, van Gilst WH, Crijns HJ, Henning RH. Activation of proteolysis by calpains and structural changes in human paroxysmal and persistent atrial fibrillation. Cardiovasc Res 2002;54:380-389.
102. Luo X, Pan Z, Shan H, Xiao J, Sun X, Wang N, Lin H, Xiao L, Maguy A, Qi XY, Li Y, Gao X, Dong D, Zhang Y, Bai Y, Ai J, Sun L, Lu H, Luo XY, Wang Z, Lu Y, Yang B, Nattel S. MicroRNA-26 governs profibrillatory inward-rectifier potassium current changes in atrial fibrillation. J Clin Invest 2013;123:1939-1951.
103. Luo X, Yang B, Nattel S. MicroRNAs and atrial fibrillation: mechanisms and translational potential. Nat Rev Cardiol 2015;12:80-90.
104. van Bragt KA, Nasrallah HM, Kuiper M, Luiken JJ, Schotten U, Verheule S. Atrial supply-demand balance in healthy adult pigs: coronary blood flow, oxygen extraction, and lactate production during acute atrial fibrillation. Cardiovasc Res 2014;101:9-19.
105. Mayr M, Yusuf S,Weir G, Chung YL, Mayr U, Yin X, Ladroue C, Madhu B, Roberts N, De Souza A, Fredericks S, Stubbs M, Griffiths JR, Jahangiri M, Xu Q, Camm AJ. Combined metabolomic and proteomic analysis of human atrial fibrillation. J Am Coll Cardiol 2008;51:585-594.
106. De Souza AI, Cardin S, Wait R, Chung YL, Vijayakumar M, Maguy A, Camm AJ, Nattel S. Proteomic and metabolomic analysis of atrial profibrillatory remodelling in congestive heart failure. J Mol Cell Cardiol 2010;49:851-863.
107. Harada M, Tadevosyan A, Qi X, Xiao J, Liu T, Voigt N, Karck M, Kamler M, Kodama I, Murohara T, Dobrev D, Nattel S. Atrial fibrillation activates AMP-dependent protein kinase and its regulation of cellular calcium handling: potential role in metabolic adaptation and prevention of progression. J Am Coll Cardiol 2015;66:47-58.
108. Lenski M, Schleider G, Kohlhaas M, Adrian L, Adam O, Tian Q, Kaestner L, Lipp P, Lehrke M, Maack C, Bohm M, Laufs U. Arrhythmia causes lipid accumulation and reduced glucose uptake. Basic Res Cardiol 2015;110:40.
109. Heijman J, Dobrev D. Irregular rhythm and atrial metabolism are key for the evolution of proarrhythmic atrial remodeling in atrial fibrillation. Basic Res Cardiol 2015;110:41.
110. Kim GE, Ross JL, Xie C, Su KN, Zaha VG, Wu X, Palmeri M, Ashraf M, Akar JG, Russell KS, Akar FG, Young LH. LKB1 deletion causes early changes in atrial channel expression and electrophysiology prior to atrial fibrillation. Cardiovasc Res 2015;108: 197-208.
111. Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N, Musi N, Hirshman MF, Goodyear LJ, Moller DE. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 2001;108:1167-1174.
112. Chang SH, Wu LS, Chiou MJ, Liu JR, Yu KH, Kuo CF, Wen MS, Chen WJ, Yeh YH, See LC. Association of metformin with lower atrial fibrillation risk among patients with type 2 diabetes mellitus: a population-based dynamic cohort and in vitro studies. Cardiovasc Diabetol 2014;13:123.
113. Shen MJ, Shinohara T, Park HW, Frick K, Ice DS, Choi EK, Han S, Maruyama M, Sharma R, Shen C, Fishbein MC, Chen LS, Lopshire JC, Zipes DP, Lin SF, Chen PS. Continuous low-level vagus nerve stimulation reduces stellate ganglion nerve activity and paroxysmal atrial tachyarrhythmias in ambulatory canines. Circulation 2011;123: 2204-2212.
114. Stavrakis S, Humphrey MB, Scherlag BJ, Hu Y, Jackman WM, Nakagawa H, Lockwood D, Lazzara R, Po SS. Low-level transcutaneous electrical vagus nerve stimulation suppresses atrial fibrillation. J Am Coll Cardiol 2015;65:867-875.
115. Lampugnani P. The therapy of atrial fibrillation with the combination of hydroquinidine and reserpine. Clin Ter 1966;36:491-525.
116. de Mendonca JV. Verapamil associated with quinidine in the treatment of chronic atrial fibrillation. Arq Bras Cardiol 1978;31(Suppl. 1):87-93.
117. Burashnikov A, Sicouri S, Di Diego JM, Belardinelli L, Antzelevitch C. Synergistic effect of the combination of ranolazine and dronedarone to suppress atrial fibrillation. J Am Coll Cardiol 2010;56:1216-1224.
118. Reiffel JA, Camm AJ, Belardinelli L, Zeng D, Karwatowska-Prokopczuk E, Olmsted A, ZarebaW, Rosero S, Kowey P. The HARMONY Trial: combined ranolazine and dronedarone in the management of paroxysmal atrial fibrillation: mechanistic and therapeutic synergism. Circ Arrhythm Electrophysiol 2015;8:1048-1056.
119. Aguilar-Shardonofsky M, Vigmond EJ, Nattel S, Comtois P. In silico optimization of atrial fibrillation-selective sodium channel blocker pharmacodynamics. Biophys J 2012; 102:951-960.
120. Aguilar M, Xiong F, Qi XY, Comtois P, Nattel S. Potassium channel blockade enhances atrial fibrillation-selective antiarrhythmic effects of optimized state-dependent sodium channel blockade. Circulation 2015;132:2203-2211.
121. Paci M, Hyttinen J, Aalto-Setala K, Severi S. Computational models of ventricular-and atrial-like human induced pluripotent stem cell derived cardiomyocytes. Ann Biomed Eng 2013;41:2334-2348.
122. Zhao Y, Feric NT, Thavandiran N, Nunes SS, Radisic M. The role of tissue engineering and biomaterials in cardiac regenerative medicine. Can J Cardiol 2014;30:1307-1322.
123. Heijman J, Erfanian Abdoust P, Voigt N, Nattel S, Dobrev D. Computational models of atrial cellular electrophysiology and calcium handling, and their role in atrial fibrillation. J Physiol 2015; doi:10.1113/JP271404.
124. Michelena HI, Powell BD, Brady PA, Friedman PA, Ezekowitz MD. Gender in atrial fibrillation: Ten years later. Gend Med 2010;7:206-217.
125. Parvez B, Vaglio J, Rowan S, Muhammad R, Kucera G, Stubblefield T, Carter S, Roden D, Darbar D. Symptomatic response to antiarrhythmic drug therapy is modulated by a common single nucleotide polymorphism in atrial fibrillation. J Am Coll Cardiol 2012;60:539-545.
126. Darbar D. The role of pharmacogenetics in atrial fibrillation therapeutics-is personalized therapy in sight J Cardiovasc Pharmacol 2016;67:9-18.
127. Choi EK, Park JH, Lee JY, Nam CM, Hwang MK, Uhm JS, Joung B, Ko YG, Lee MH, Lubitz SA, Ellinor PT, Pak HN. Korean Atrial Fibrillation (AF) Network: Genetic Variants for AF Do Not Predict Ablation Success. J Am Heart Assoc 2015;4:e002046.
128. Kirchhof P, Breithardt G, Aliot E, Al Khatib S, Apostolakis S, Auricchio A, Bailleul C, Bax J, Benninger G, Blomstrom-Lundqvist C, Boersma L, Boriani G, Brandes A, Brown H, Brueckmann M, Calkins H, Casadei B, Clemens A, Crijns H, Derwand R, Dobrev D, Ezekowitz M, Fetsch T, Gerth A, Gillis A, Gulizia M, Hack G, Haegeli L, Hatem S, Georg Hausler K, Heidbuchel H, Hernandez-Brichis J, Jais P, Kappenberger L, Kautzner J, Kim S, Kuck KH, Lane D, Leute A, Lewalter T, Meyer R, Mont L, Moses G, Mueller M, Munzel F, Nabauer M, Nielsen JC, Oeff M, Oto A, Pieske B, Pisters R, Potpara T, Rasmussen L, Ravens U, Reiffel J, Richard-Lordereau I, Schafer H, Schotten U, Stegink W, Stein K, Steinbeck G, Szumowski L, Tavazzi L, Themistoclakis S, Thomitzek K, Van Gelder IC, von Stritzky B, Vincent A,Werring D, Willems S, Lip GY, Camm AJ. Personalized management of atrial fibrillation: Proceedings from the fourth Atrial Fibrillation competence NETwork/European Heart Rhythm Association consensus conference. Europace 2013;15:1540-1556.
129. Nattel S, Andrade J, Macle L, Rivard L, Dyrda K, Mondesert B, Khairy P. New directions in cardiac arrhythmia management: present challenges and future solutions. Can J Cardiol 2014;30:S420-S430.
130. Jackson N, Atar D, Borentain M, Breithardt G, van Eickels M, Endres M, Fraass U, Friede T, Hannachi H, Janmohamed S, Kreuzer J, Landray M, Lautsch D, Le Floch C, Mol P, Naci H, Samani NJ, Svensson A, Thorstensen C, Tijssen J, Vandzhura V, Zalewski A, Kirchhof P. Improving clinical trials for cardiovascular diseases: a position paper from the Cardiovascular Round Table of the European Society of Cardiology. Eur Heart J 2016;37:747-754.