Share This Article:

Novel therapies for treating atrial fibrillation

Abstract Full-Text HTML XML Download Download as PDF (Size:193KB) PP. 242-259
DOI: 10.4236/wjcd.2012.24040    4,230 Downloads   7,250 Views  


Atrial fibrillation is the most common cardiac arrhythmia and is a major risk factor for stroke, heart failure, and death. Current treatments focus on anti-coagulation as well as rate-control and rhythm-control strategies. Frequent INR checks associated with warfarin along with several adverse side effects of anti-arrhythmics have propelled investigations into novel treatments for atrial fibrillation. Research is focused not only on pioneering new pharmacological antico- agulation and anti-arrhythmic agents but also on improving surgical techniques in hopes of treating the arrhythmia. Here, we first briefly discuss the current treatment options, both pharmacological and non-pharmacological, for atrial fibrillation. We then present a focused review of recent animal and human investigations that examine the use of novel an-ticoagulation agents, mechanisms of new anti-arrhythmics, analyze potential triggers of atrial fibrillation, and highlight the role of genetics in atrial fibrillation.

Conflicts of Interest

The authors declare no conflicts of interest.

Cite this paper

Parikh, R. and Kadowitz, P. (2012) Novel therapies for treating atrial fibrillation. World Journal of Cardiovascular Diseases, 2, 242-259. doi: 10.4236/wjcd.2012.24040.


[1] Miyasaka, Y., Barnes, M.E., Gersh, B.J., Cha, S.S., Bailey, K.R., Abhayaratna, W.P., et al. (2006) Secular trends in incidence of atrial fibrillation in Olmsted county, Minnesota, 1980 to 2000, and implications on the projections for future prevalence. Circulation, 114,119-125. doi:10.1161/CIRCULATIONAHA.105.595140
[2] Lloyd-Jones, D.M., Wang, T.J., Leip, E.P., Larson, M.G., Levy, D., Vasan, R.S., et al. (2004) Lifetime risk for development of atrial fibrillation: The Framingham heart study. Circulation, 110, 1042-1046. doi:10.1161/01.CIR.0000140263.20897.42
[3] Stewart, S., Hart, C.L., Hole, D.J. and McMurray, J.J. (2002) A population-based study of the long-term risks associated with atrial fibrillation: 20-year follow-up of the renfrew/paisley study. American Journal of Medicine, 113, 359-364. doi:10.1016/S0002-9343(02)01236-6
[4] Kannel, W.B., Wolf, P.A., Benjamin, E.J. and Levy, D. (1998) Prevalence, incidence, prognosis, and predisposing conditions for atrial fibrillation: Population-based estimates. American Journal of Cardiology, 82, 2N-9N. doi:10.1016/S0002-9149(98)00583-9
[5] Wattigney, W.A., Mensah, G.A. and Croft, J.B. (2003) Increasing trends in hospitalization for atrial fibrillation in the United States, 1985 through 1999: Implications for primary prevention. Circulation, 108, 711-716. doi:10.1161/01.CIR.0000083722.42033.0A
[6] Benjamin, E.J., Levy, D., Vaziri, S.M., D’Agostino, R.B., Belanger, A.J. and Wolf, P.A. (1994) Independent risk factors for atrial fibrillation in a population-based cohort. The Framingham heart study. JAMA, 271, 840-844. doi:10.1001/jama.1994.03510350050036
[7] Psaty, B.M., Manolio, T.A., Kuller, L.H., Kronmal, R.A., Cushman, M., Fried, L.P., et al. (1997) Incidence of and risk factors for atrial fibrillation in older adults. Circulation, 96, 2455-2461. doi:10.1161/01.CIR.96.7.2455
[8] Natale, A., Raviele, A., Arentz, T., Calkins, H., Chen, S.A., Haissaquerre, M., et al. (2007) Venice chart international consensus document on atrial fibrillation ablation. Journal of Cardiovascular Electrophysiology, 18, 560-580. doi:10.1111/j.1540-8167.2007.00816.x
[9] Pappone, C., Santinelli, V., Manguso, F., Vicedomini, G., Gugliotta, F., Augello, G., et al. (2004) Pulmonary vein denervation enhances long-term benefit after circumferential ablation for paroxysmal atrial fibrillation. Circulation, 109,327-334. doi:10.1161/01.CIR.0000112641.16340.C7
[10] Fuster, V., Ryden, L.E., Cannom, D.S., Crijns, H.K., Curtis, A.B., Ellenbogen, K.A., et al. (2006) ACC/AHA/ ESC 2006 Guidelines for the management of patients with atrial fibrillation a report of the American College of Cardiology/American Heart Association task force on practice guidelines and the European society of cardiology committee for practice guidelines (writing committee to revise the 2001 guidelines for the management of patients with atrial fibrillation). Journal of the American College of Cardi
[11] Gage, B.F., Waterman, A.D., Shannon, W., Boechler, M., Rich, M.W. and Radford, M.J. (2001) Validation of clinical classification schemes for predicting stroke: Results from the National Registry of Atrial Fibrillation. JAMA, 285, 2864-2870. doi:10.1001/jama.285.22.2864
[12] Man-Son-Hing, M., Laupacis, A., O’Connor, A.M., Biggs, J., Drake, E., Yetisir, E., et al. (1999) A patient decision aid regarding antithrombotic therapy for stroke prevention in atrial fibrillation: A randomized controlled trial. JAMA, 282, 737. doi:10.1001/jama.282.8.737
[13] ACTIVE Investigators, Connolly, S.J., Pogue, J., Hart, R.G., Hohnloser, S.H., Pfeffer, M., Chrolavicius, S., et al. (2009) Effect of clopidogrel added to aspirin in patients with atrial fibrillation. The New England Journal of Medicine, 360, 2066. doi:10.1056/NEJMoa0901301
[14] Cairns, J.A. (1991) Stroke prevention in atrial fibrillation study. Final results. Circulation, 84, 527. doi:10.1161/01.CIR.84.2.933
[15] Hart, R.G., Pearce, L.A. and Aguilar, M.I. (2007) Meta-analysis: Antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Annals of Internal Medicine, 146, 857.
[16] Singer, D.E., Albers, G.W., Dalen, J.E., Fang, M.C., Go, A.S., Halperin, J.L., et al. (2008) Antithrombotic therapy in atrial fibrillation: American College of chest physicians evidence-based clinical practice guidelines (8th Edition) Chest, 133, 546S.
[17] Hylek, E.M., Go, A.S., Chang, Y., Jensvold, N.J., Hen- ault, L.E., Selby, J.V., et al. (2003) Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation. The New England Journal of Medicine, 349, 1019. doi:10.1056/NEJMoa022913
[18] Olshansky, B., Rosenfeld, L.E., Warner, A.L., Solomon, A.J., O’Neill, G., Sharma, A., et al. (2004) The atrial fibrillation follow-up investigation of rhythm management (AFFIRM) study: Approaches to control rate in atrial fibrillation. Journal of the American College of Cardiology, 43, 1201-1208. doi:10.1016/j.jacc.2003.11.032
[19] Wyse, D.G., Waldo, A.L., DiMarco, J.P., Domanski, M.J., Rosenberg, Y., Schron, E.B., et al. (2002) A comparison of rate control and rhythm control in patients with atrial fibrillation. The New England Journal of Medicine, 347, 1825. doi:10.1056/NEJMoa021328
[20] Steinberg, J.S., Sadaniantz, A., Kron, J., Krahn, A., Denny, D.M., Daubert, J., et al. (2004) Analysis of cause- specific mortality in the atrial fibrillation follow-up investigation of rhythm management (AFFIRM) study. Circulation, 109, 1973. doi:10.1161/01.CIR.0000118472.77237.FA
[21] Van Gelder, I.C., Hagens, V.E., Bosker, H.A., Kingma, J.H., Kamp, O., Kingma, T., et al. (2002) A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. The New England Journal of Medicine, 347, 1834. doi:10.1056/NEJMoa021375
[22] Fuster, V., Rydén, L.E., Cannom, D.S., Crijns, H.J., Curtis, A.B., Ellenbogen, K.A., et al. (2006) ACC/AHA/ ESC 2006 Guidelines for the management of patients with atrial fibrillation: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for practice guidelines (Writing Committee to revise the 2001 guidelines for the management of patients with atrial fibrillation): Developed in collaboration with the Eur
[23] Connolly, S.J. (2000) Appropriate outcome measures in trials evaluating treatment of atrial fibrillation. American Heart Journal, 139, 752. doi:10.1016/S0002-8703(00)90002-4
[24] Lafuente-Lafuente, C., Mouly, S., Longas-Tejero, M.A. and Bergmann, J.F. (2006) Antiarrhythmic drugs for maintaining sinus rhythm after cardioversion of atrial fibrillation: A systematic review of randomized controlled trials. Archives of Internal Medicine, 166, 719. doi:10.1001/archinte.166.7.719
[25] Chimienti, M., Cullen, M.T.Jr. and Casadei, G. (1996) Safety of long-term flecainide and propafenone in the management of patients with symptomatic paroxysmal atrial fibrillation: Report from the flecainide and propafenone Italian study investigators. American Journal of Cardiology, 77, 60A. doi:10.1016/S0002-9149(97)89119-9
[26] Schumacher, B., Jung, W., Lewalter, T., Vahlhaus, C., Wolper, C. and Luderitz, B. (1999) Radiofrequency ablation of atrial flutter due to administration of class IC antiarrhythmic drugs for atrial fibrillation. American Journal of Cardiology, 83, 710-713. doi:10.1016/S0002-9149(98)00975-8
[27] Echt, D.S., Liebson, P.R., Mitchell, L.B., Peters, R.W., Obias- Manno, D., Barker, A.H., et al. (1991) Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. The New England Journal of Medicine, 324, 781-788. doi:10.1056/NEJM199103213241201
[28] McNamara, R.L., Tamariz, L.J., Segal, J.B. and Bass, E.B. (2003) Management of atrial fibrillation: Review of the evidence for the role of pharmacologic therapy, electrical cardioversion, and echocardiography. Annals of Internal Medicine, 139, 1018-1033.
[29] Singh, S., Zoble, R.G., Yellen, L., Brodsky, M.A., Feld, G.K., Berk, M., et al. (2000) Efficacy and safety of oral dofetilide in converting to and maintaining sinus rhythm in patients with chronic atrial fibrillation or atrial flutter: The symptomatic atrial fibrillation investigative research on dofetilide (SAFIRE-D) study. Circulation, 102, 2385- 2390. doi:10.1161/01.CIR.102.19.2385
[30] Mounsey, J.P. and DiMarco, J.P. (2000) Cardiovascular drugs. Dofetilide. Circulation, 102, 2665-2670. doi:10.1161/01.CIR.102.21.2665
[31] Castro, A., Bianconi, L. and Santini, M. (2002) New anti-arrhythmic drugs for the treatment of atrial fibrillation. Pacing and Clinical Electrophysiology, 25, 249-259. doi:10.1046/j.1460-9592.2002.00249.x
[32] Gallik, D.M., Kim, S.G., Ferrick, K.J., Roth, J.A. and Fisher, J.D. (1997) Efficacy and safety of sotalol in patients with refractory atrial fibrillation or flutter. American Heart Journal, 134, 155. doi:10.1016/S0002-8703(97)70118-2
[33] Boersma, L.V., Castella, M., van Boven, W., Berruezo, A., Yilmaz, A., Nadal, M., et al. (2012) Atrial fibrillation catheter ablation versus surgical ablation treatment (FAST): A 2-center randomized clinical trial. Circulation, 125, 23-30. doi:10.1161/CIRCULATIONAHA.111.074047
[34] Ferguson, T.B.Jr. and Cox, J.L. (1995) Surgery for atrial fibrillation. In: Zipes, D.P. and Jalife, J., Eds., Cardiac Electrophysiology: From Cell to Bedside, 2nd Editon, Saunders, Philadelphia, 1567.
[35] Cox, J.L., Canavan, T.E., Schuessler, R.B., Cain, M.E., Lindsay, B.D., Stone, C., et al. (1991) The surgical treatment of atrial fibrillation. II. Intraoperative electrophysiologic mapping and description of the electrophysiologic basis of atrial flutter and atrial fibrillation. The Journal of Thoracic and Cardiovascular Surgery, 101, 406.
[36] L?nnerholm, S., Blomstr?m, P., Nilsson, L., Oxelbark, S., Jideius, L. and Blomstrom-Lundqvist, C. (2000) Effects of the maze operation on health-related quality of life in patients with atrial fibrillation. Circulation, 101, 2607. doi:10.1161/01.CIR.101.22.2607
[37] Cox, J.L., Boineau, J.P., Schuessler, R.B., Kater, K.M. and Lappas, D.G. (1993) Five-year experience with the maze procedure for atrial fibrillation. The Annals of Tho-racic Surgery, 56, 814. doi:10.1016/0003-4975(93)90338-I
[38] Gaynor, S.L., Schuessler, R.B., Bailey, M.S., Ishii, Y., Boi- neau, J.P., Gleva, M.J., et al. (2005) Surgical treatment of atrial fibrillation: Predictors of late recurrence. The Journal of Thoracic and Cardiovascular Surgery, 129, 104. doi:10.1016/j.jtcvs.2004.08.042
[39] Sandoval, N., Velasco, V.M., Orjuela, H., Caicedo, V., Santos, H., Rosas, F., et al. (1996) Concomitant mitral valve or atrial septal defect surgery and the modified Cox- maze procedure. American Journal of Cardiology, 77, 591. doi:10.1016/S0002-9149(97)89312-5
[40] Pasic, M., Musci, M., Siniawski, H., Grauhan, O., Edel-mann, B., Tedoriya, T., et al. (1999) The Cox maze iii procedure: parallel normalization of sinus node dysfunction, improvement of atrial function, and recovery of the cardiac autonomic nervous system. The Journal of Thoracic and Cardiovascular Surgery, 118, 287. doi:10.1016/S0022-5223(99)70219-9
[41] Nitta, T., Lee, R., Schuessler, R.B., Boineau, J.P. and Cox, J.L. (1999) Radial approach: A new concept in surgical treatment for atrial fibrillation I. Concept, anatomic and physiologic bases and development of a procedure. The Annals of Thoracic Surgery, 67, 27. doi:10.1016/S0003-4975(98)01364-2
[42] Nitta, T., Lee, R., Watanabe, H., Harris, K.M., Erikson, J.M., Schuessler, R.B., et al. (1999) Radial approach: A new concept in surgical treatment for atrial fibrillation. II. Electrophysiologic effects and atrial contribution to ven-tricular filling. The Annals of Thoracic Surgery, 67, 36. doi:10.1016/S0003-4975(98)01365-4
[43] Nitta, T., Ishii, Y., Ogasawara, H., Sakamoto, S., Miyagi, Y., Yamada, K., et al. (1999) Initial experience with the radial incision approach for atrial fibrillation. The Annals of Thoracic Surgery, 68, 805. doi:10.1016/S0003-4975(99)00775-4
[44] Leitch, J.W., Klein, G., Yee, R. and Guiraudon, G. (1991) Sinus node-atrioventricular node isolation: Long-term results with the “corridor” operation for atrial fibrillation. Journal of the American College of Cardiology, 17, 970. doi:10.1016/0735-1097(91)90881-9
[45] Haissaguerre, M., Jais, P., Shah, D.C., Takahashi, A., Ho- cini, M., Quiniou, G., et al. (1998) Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veings. The New England Journal of Medicine, 339, 659. doi:10.1056/NEJM199809033391003
[46] Sueda, T., Imai, K., Ishii, O., Orihashi, K., Watari, M. and Okada, K. (2001) Efficacy of pulmonary vein isolation for the elimination of chronic atrial fibrillation in cardiac valvular surgery. The Annals of Thoracic Surgery, 71, 1189. doi:10.1016/S0003-4975(00)02606-0
[47] Krul, S.P., Driessen, A.H., van Boven, W.J., Linnenbank, A.C., Geuzebroek, G.S., Jackman, W.M., et al. (2011) Thoracoscopic video-assisted pulmonary vein antrum isolation, ganglionated plexus ablation, and periprocedural confirmation of ablation lesions: First results of a hybrid surgical-electrophysiological approach for atrial fibrillation. Circulation: Arrhythmia and Electrophysiology, 4, 262.
[48] Cheema, A., Dong, J., Dalal, D., Marine, J.E., Henrikson, C.A., Spragg, D., et al. (2007) Circumferential ablation with pulmonary vein isolation in permanent atrial fibril- lation. American Journal of Cardiology, 99, 1425. doi:10.1016/j.amjcard.2006.12.073
[49] Hocini, M., Ja?s, P., Sanders, P., Takahashi, Y., Rotter, M., Rostock, T., et al. (2005) Techniques, evaluation, and consequences of linear block at the left atrial roof in paroxysmal atrial fibrillation: A prospective randomized study. Circulation, 112, 3688. doi:10.1161/CIRCULATIONAHA.105.541052
[50] Oral, H., Scharf, C., Chugh, A., Hall, B., Cheung, P., Good, E., et al. (2003) Catheter ablation for paroxysmal atrial fibrillation: Segmental pulmonary vein ostial ablation ver- sus left atrial ablation. Circulation, 108, 2355. doi:10.1161/01.CIR.0000095796.45180.88
[51] Karch, M.R., Zrenner, B., Deisenhofer, I., Schreieck, J., Ndrepepa, G., Dong, J., et al. (2005) Freedom from atrial tachyarrhythmias after catheter ablation of atrial fibrillation: a randomized comparison between 2 current ablation strategies. Circulation, 111, 2875. doi:10.1161/CIRCULATIONAHA.104.491530
[52] Pappone, C., Oral, H., Santinelli, V., Vicedomini, G., Lang, C.C., Manguso, F., et al. (2004) Atrio-esophageal fistula as a complication of percutaneous transcatheter ablation of atrial fibrillation. Circulation, 109, 2724. doi:10.1161/01.CIR.0000131866.44650.46
[53] Shah, D., Dumonceau, J.M., Burri, H., Sunthorn, H., Schroft, A., Gentil-Baron, P., et al. (2005) Acute pyloric spasm and gastric hypomotility: An extracardiac adverse effect of percutaneous radiofrequency ablation for atrial fibrillation. Journal of the American College of Cardiology, 46, 327-330. doi:10.1016/j.jacc.2005.04.030
[54] Oral, H., Knight, B.P., Ozaydin, M., Tada, H., Chugh, A., Hassan, S., et al. (2002) Clinical significance of early recurrences of atrial fibrillation after pulmonary vein isolation. Journal of the American College of Cardiology, 40, 100. doi:10.1016/S0735-1097(02)01939-3
[55] Lubitz, S.A., Fischer, A. and Fuster, V. (2008) Catheter ablation for atrial fibrillation. BMJ, 336, 819. doi:10.1136/bmj.39513.555150.BE
[56] Gerstenfeld, E.P., Callans, D.J., Dixit, S., Zado, E. and Marchlinski, F.E. (2003) Incidence and location of focal atrial fibrillation triggers in patients undergoing repeat pulmonary vein isolation: Implications for ablation strategies. Journal of Cardiovascular Electrophysiology, 14, 685. doi:10.1046/j.1540-8167.2003.03013.x
[57] Chen, S.A. and Tai, C.T. (2005) Catheter ablation of atrial fibrillation originating from the non-pulmonary vein foci. Journal of Cardiovascular Electrophysiology, 16, 229. doi:10.1046/j.1540-8167.2005.40665.x
[58] Di Biase, L., Burkhardt, J.D., Mohanty, P., Sanchez, J., Mohanty, S., Horton, R., et al. (2010) Left atrial appendage: An underrecognized trigger site of atrial fibrillation. Circulation, 122, 109. doi:10.1161/CIRCULATIONAHA.109.928903
[59] Van Belle, Y., Janse, P., et al. (2007) Pulmonary vein isolation using an occluding cryoballoon for circumferential ablation: Feasibility, complications, and short-term out-come. European Heart Journal, 28, 2231-2237. doi:10.1093/eurheartj/ehm227
[60] Neumann, T., Vogt, J., Schumacher, B., Dorszewski, A., Kuniss, M., Neuser, H., et al. (2008) Circumferential pulmonary vein isolation with the cryoballoon technique results from a prospective 3-center study. Journal of the American College of Cardiology, 52, 273-278. doi:10.1016/j.jacc.2008.04.021
[61] Linhart, M., Bellman, B., Mittmann-Braun, E., Schrickel, J.W., Bitzen, A., et al. (2009) Comparison of cryoballoon and radiofrequency ablation of pulmonary veins in 40 patients with paroxysmal atrial fibrillation: A case-control study. Journal of Cardiovascular Electrophysiology, 20, 1-6
[62] Tintera, J., Porod, V., Cihak, R., Micochova, H., Rolen-cova, E., Fendrych, P., et al. (2006) Assessment of pulmonary venous stenosis after radiofrequency catheter ablation for atrial fibrillation by magnetic resonance angiography: A comparison of linear and cross-sectional area measurements. European Radiology, 16, 2757-2767. doi:10.1007/s00330-006-0358-3
[63] Zhou, J.M., Liu, S.W., Lin, J.X., Nie, Z.N., Wu, H.Y., Zhou, J., et al. (2007) Thromboembolic event rate in patients with persistent or paroxysmal atrial fibrillation post circumferential pulmonary vein isolation: A single center experience in China. Chinese Medical Journal, 120, 956- 959.
[64] Curtis, A.B., Kutalek, S.P., Prior, M. and Newhouse, T.T. (2000) Prevalence and characteristics of escape rhythms after radiofrequency ablation of the atrioventricular junc- tion: Results from the registry for AV junction ablation and pacing in atrial fibrillation. Ablate and Pace Trial Investigators. American Heart Journal, 139, 122. doi:10.1016/S0002-8703(00)90318-1
[65] Scheinman, M.M. and Huang, S. (2000) The 1998 NASPE prospective catheter ablation registry. Pacing and Clinical Electrophysiology, 23, 1020. doi:10.1111/j.1540-8159.2000.tb00891.x
[66] Wood, M.A., Brown-Mahoney, C., Kay, G.N. and Ellen- bogen, K.A. (2000) Clinical outcomes after ablation and pacing therapy for atrial fibrillation: A meta-analysis. Circulation, 101, 1138. doi:10.1161/01.CIR.101.10.1138
[67] Ozcan, C., Jahangir, A., Friedman, P.A., Patel, P.J., Munger, T.M., Rea, R.F., et al. (2001) Long-term survival after ablation of the atrioventricular node and implantation of a permanent pacemaker in patients with atrial fibrillation. The New England Journal of Medicine, 344, 1043. doi:10.1056/NEJM200104053441403
[68] Ozcan, C., Jahangir, A., Friedman, P.A., Hayes, D.L., Mung- er, T.M., Rea, R.F., et al. (2002) Sudden death after radiofrequency ablation of the atrioventricular node in patients with atrial fibrillation. Journal of the American College of Cardiology, 40, 105. doi:10.1016/S0735-1097(02)01927-7
[69] Geelen, P., Brugada, J., Andries, E. and Brugada, P. (1997) Ventricular fibrillation and sudden death after radio-frequency catheter ablation of the atrioventricular junction. Pacing and Clinical Electrophysiology, 20, 343. doi:10.1111/j.1540-8159.1997.tb06179.x
[70] Marshall, H.J., Harris, Z.I., Griffith, M.J., Holder, R.L. and Gammage, M.D. (1999) Prospective randomized study of ablation and pacing versus medical therapy for paro- xysmal atrial fibrillation: Effects of pacing mode and mode-switch algorithm. Circulation, 99, 1587. doi:10.1161/01.CIR.99.12.1587
[71] Williamson, B.D., Man, K.C., Daoud, E., Niebauer, M., Strickberger, S.A. and Morady, F. (1994) Radiofrequency catheter modification of atrioventricular conduction to control the ventricular rate during atrial fibrillation. The New England Journal of Medicine, 331, 910. doi:10.1056/NEJM199410063311404
[72] Della Bella, P., Carbucicchio, C., Tondo, C. and Riva, S. (1995) Modulation of atrioventricular conduction by ablation of the “slow” atrioventricular node pathway in pa- tients with drug-refractory atrial fibrillation or flutter. Journal of the American College of Cardiology, 25, 39. doi:10.1016/0735-1097(94)00315-H
[73] Proclemer, A., Della Bella, P., Tondo, C., Facchin, D., Car- bucicchia, C., Riva, S., et al. (1999) Radiofrequency ablation of atrioventricular junction and pacemaker implantation versus modulation of atrioventricular conduction in drug refractory atrial fibrillation. Journal of the American College of Cardiology, 83, 1437. doi:10.1016/S0002-9149(99)00121-6
[74] Mant, J., Hobbs, F.D., Fletcher, K., Roalfe, A., Fitz- maurice, D., Lip, G.Y., et al. (2007) Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged study, BAFTA): A randomised controlled trial. Lancet, 370, 493-503. doi:10.1016/S0140-6736(07)61233-1
[75] Connolly, S., Pogue, J., Hart, R., Pfeffer, M., Hohnloser, S., Chrolavicius, S., et al. (2006) Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): A randomised controlled trial. Lancet, 367, 1903-1912. doi:10.1016/S0140-6736(06)68845-4
[76] Francis, C.W., Berkowitz, S.D., Comp, P.C., Liberman, J.R., Ginsberg, J.S., Paiment, G., the EXULT A Study Group, et al. (2003) Comparison of ximelagatran with warfarin for the prevention of venous thromboembolism after total knee replacement. The New England Journal of Medicine, 349, 1703-1712.
[77] Albers, G.W., Diener, H.C., Frison, L., Grind, M., Nevinson, M., Partridge, S., et al. (2005) Ximelagatran vs warfarin for stroke prevention in patients with nonvalvular atrial fibrillation: A randomized trial. JAMA, 293, 690- 698. doi:10.1001/jama.293.6.690
[78] Eriksson, B.I., Dahl, O.E., Huo, M.H., Kurth, A.A., Hantel, S., Harmansson, K., et al. (2010) Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II*). A randomised, double- blind, non-inferiority trial. Haematologica, 95, 721-729.
[79] Eriksson, B.I., Dahl, O.E., Rosencher, N., Kurth, A.A., van Dijk, C.N., Frostick, S.P., et al. (2007) Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: The RE-MODEL randomized trial. Journal of Thrombosis and Haemostasis, 5, 2178-2185. doi:10.1111/j.1538-7836.2007.02748.x
[80] Ezekowitz, M.D., Reilly, P.A., Nehmiz, G., Simmers, T.A., Nagarakanti, R., Parcham-Azad, K., et al. (2007) Dabi- gatran with or without concomitant aspirin compared with warfarin alone in patients with nonvalvular atrial fibrillation (PETRO Study). American Journal of Cardiology, 100, 1419-1426. doi:10.1016/j.amjcard.2007.06.034
[81] Connolly, S.J., Ezekowitz, M.D., Yusuf, S., Eikelboom, J., Oldgren, J., Parekh, A., et al. (2009) RE-LY Steering Committee and investigators dabigatran versus warfarin in patients with atrial fibrillation. The New England Journal of Medicine, 361, 1139-1151. doi:10.1056/NEJMoa0905561
[82] Eriksson, B.I., Borris, L.C., Friedman, R.J., Haas, S., Huis- man, M.V., Kakkar, A.K., et al. (2008) Rivaroxaban ver- sus enoxaparin for thromboprophylaxis after hip arthroplasty. The New England Journal of Medicine, 358, 2765- 2775. doi:10.1056/NEJMoa0800374
[83] Becker, R., Berkowtiz, S.D., Breithardt, G., Califf, R.M., Fox, K., Hacke, W., et al. ROCKET AF Study Investigators (2010) Rivaroxaban-once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation: Rationale and design of the ROCKET AF study. American Heart Journal, 159, 340-347.
[84] Patel, M.R., Mahaffey, K.W., Garg, J., Pan, G., Singer, D.E., Hacke, W., et al. (2011) Rivaroxaban versus war- farin in nonvalvular atrial fibrillation. The New England Journal of Medicine, 365, 883. doi:10.1056/NEJMoa1009638
[85] Lassen, M.R., Raskob, G.E., Gallus, A., Pineo, G., Chen, D. and Portman, R.J. (2009) Apixaban or enoxaparin for thromboprophylaxis after knee replacement. The New England Journal of Medicine, 361, 594-604. doi:10.1056/NEJMoa0810773
[86] Lopes, R.D., Alexander, J.H., Al-Khatib, S.M., Ansell, J., Diaz, R., Easton, J.D., et al. (2010) Apixaban for reducetion in stroke and other thromboembolic events in atrial fibrillation (ARISTOTLE) trial: Design and rationale. American Heart Journal, 159, 331-339. doi:10.1016/j.ahj.2009.07.035
[87] Eikelboom, J.W., O’Donnell, M., Yusuf, S., Diaz, R., Flaker, G., Hart, R., et al. (2010) Rationale and design of AVERROES: Apixaban versus acetylsalicylic acid to prevent stroke in atrial fibrillation patients who have failed or are unsuitable for vitamin K antagonist treatment. American Heart Journal, 159, 348-353.
[88] Camm, A.J., Pratt, C.M., Schwartz, P.J., Al-Khalidi, H.R., Spyt, M.J., Holroyde, M.J., et al. (2004) Mortality in patients with recent myocardial infarction: A randomized, placebo-controlled trial of azimilide using heart rate variability for risk stratification. Circulation, 109, 990- 996. doi:10.1161/01.CIR.0000117090.01718.2A
[89] Kerr, C.R., Connolly, S.J., Kowey, P., Page, R.L., Pritchett, E.L., Ruda, M.Y., et al., A-STAR Investigators (2006) Efficacy of azimilide for the maintenance of sinus rhythm in patients with paroxysmal atrial fibrillation in the presence and absence of structural heart disease. American Journal of Cardiology, 98, 215-218. doi:10.1016/j.amjcard.2006.01.084
[90] Lombardi, F., Borggrefe, M., Ruzyllo, W., Luderitz, B., A-COMET-II Investigators (2006) Azimilide vs. placebo and sotalol for persistent atrial fibrillation: The A-COMET- II (Azimilide-CardiOversionMaintEnance Trial-II) trial. European Heart Journal, 27, 2224-2231. doi:10.1093/eurheartj/ehl209
[91] Page, R.L., Pritchett, E.L., Connolly, S., Wilkinson, W.E., For the SVA-4 Investigators (2008) Azimilide for the treatment of atrial fibrillation, atrial flutter, and paro- xysmal supraventricular tachycardia: Results of a ran-domized trial and insights on the concordance of symptoms and recurrent arrhythmias. Journal of Cardiovascular Electrophysiology, 19, 172-177. doi:10.1111/j.1540-8167.2007.00985.x
[92] Hohnloser, S.H., Dorian, P., Straub, M., Beckmann, K. and Kowey, P. (2004) Safety and efficacy of intravenously administered tedisamil for rapid conversion of recent-onset atrial fibrillation or atrial flutter. Journal of the American College of Cardiology, 44, 99-104. doi:10.1016/j.jacc.2004.03.047
[93] Morita, N., Tanaka, K., Yodogawa, K., Hayashi, M., Aku- tsu, K., Yamamoto, T., et al. (2007) Effect of nifekalant for acute conversion of atrial flutter: The possible termination mechanism of typical atrial flutter. Pacing and Clinical Electrophysiology, 30, 1242-1253. doi:10.1111/j.1540-8159.2007.00846.x
[94] Wegener, F.T., Ehrlich, J.R. and Hohnloser, S.H. (2006) Dronedarone: An emerging agent with rhythm- and rate- controlling effects. Journal of Cardiovascular Electro- physiology, 17, 17-20. doi:10.1111/j.1540-8167.2006.00583.x
[95] Singh, B.N., Connolly, S.J., Crijns, H.J., Roy, D., Kowey, P.R., Capucci, A., et al., EURIDIS ADONIS Investigators (2007) Dronedarone for maintenance of sinus rhythm in atrial fibrillation or flutter. The New England Journal of Medicine, 357, 987-999. doi:10.1056/NEJMoa054686
[96] Davy, J.M., Herold, M., Radzik, D. and Timmermans, A.J.M. (2006) Effect of dronedarone on exercise in patients with permanent atrial fibrillation (Abstract). European Heart Journal, 27, 885.
[97] Connolly, S.J., Camm, A.J., Halperin, J.L., Joyner, C., Alings, M., Amerena, J., et al. (2011) Dronedarone in high- risk permanent atrial fibrillation. The New England Journal of Medicine, 365, 2268-2276. doi:10.1056/NEJMoa1109867
[98] Hohnloser, S.H., Connolly, S.J., Crijns, H.J., Page, R.L., Seiz, W. and Torp-Petersen, C. (2008) Rationale and design of ATHENA: A placebo-controlled, double-blind, parallel arm Trial to assess the efficacy of dronedarone 400 mg bid for the prevention of cardiovascular Hospitalization or death from any cause in patients with atrial fibrillation/atrial flutter. Journal of Cardiovascular Electrophysiology, 19, 69-73.
[99] Gautier, P., Serre, M., Cosnier-Pucheu, S., Djandjighian, L., Roccon, A., Herbert, J.M., et al. (2005) In vivo and in vitro antiarrhythmic effects of SSR149744C in animal models of atrial fibrillation and ventricular arrhythmias. Journal of Cardiovascular Pharmacology, 45, 125-135. doi:10.1097/01.fjc.0000151899.03379.76
[100] Kowey, P.R., Aliot, E.M., Capucci, A., Connolly, S.J., Crijns, H.J., Hohnloser, S.H., et al. (2007) Placebo-controlled double-blind dose-ranging study of the efficacy and safety of SSR149744C in patients with recent atrial fibrillation/flutter (Abstract). Heart Rhythm, 4, S72.
[101] Arya, A., Silberbauer, J., Sulke, N. and Camm, A.J. (2006) A phase 2 pilot study of the efficacy of AT-2042 in subjects with paroxysmal atrial fibrillation and implanted pacemakers (Abstract). Heart Rhythm, 3, S164. doi:10.1016/j.hrthm.2006.02.488
[102] Nakashima, H., Gerlach, U., Schmidt, D. and Nattel, S. (2004) In vivo electrophysiological effects of a selective slow delayed-rectifier potassium channel blocker in anes- thetized dogs: Potential insights into class III actions. Cardiovascular Research, 61, 651-652. doi:10.1016/j.cardiores.2003.12.016
[103] Blaauw, Y., Gogelein, H., Tieleman, R.G., van Hunnik, A., Schotten, U. and Allessie, M.A. (2004) “Early” class III drugs for the treatment of atrial fibrillation: Efficacy and atrial selectivity of AVE0118 in remodeled atria of the goat. Circulation, 110, 1717-1724. doi:10.1161/01.CIR.0000143050.22291.2E
[104] Wettwer, E. (2007) Is there a functional correlate of Kv1.5 in the ventricle of canine heart and what would it mean for the use of I(Kur) blockers? British Journal of Pharmacology, 152, 835-837. doi:10.1038/sj.bjp.0707463
[105] Roy, D., Rowe, B.H., Stiell, I.G., Coutu, B., Ip, J.H., Phaneuf, D., et al., CRAFT Investigators (2004) A rando- mized, controlled trial of RSD1235, a novel antiarrhythmic agent, in the treatment of recent onset atrial fibrillation. Journal of the American College of Cardiology, 44, 2355- 2361. doi:10.1016/j.jacc.2004.09.021
[106] Roy, D., Pratt, C.M., Torp-Pedersen, C., Wyse, D.G., Toft, E., Juul-Moller, S., et al., for the Atrial Arrhythmia Conversion Trial Investigators (2008) Vernakalant hydro- chloride for rapid conversion of atrial fibrillation: A phase 3, randomized, placebo-controlled trial. Circulation, 117, 1518-1525. doi:10.1161/CIRCULATIONAHA.107.723866
[107] Rivard, L., Shiroshita-Takeshita, A., Maltais, C., Ford, J., Pinnock, R., Madge, D., et al. (2005) Electrophysiological and atrial antiarrhythmic effects of a novel IKur/ Kv1.5 blocker in dogs (Abstract). Heart Rhythm, 2, S180. doi:10.1016/j.hrthm.2005.02.561
[108] Shiroshita-Takeshita, A., Ford, J., Madge, D., Pinnock, R. and Nattel, S. (2006) Electrophysiological and atrial an- tiarrhythmic effects of a novel IKur/Kv1.5 anti-arrhy- thmic drug therapy for AF 663 (Abstract). Heart Rhythm, 3, S183. doi:10.1016/j.hrthm.2006.02.549
[109] Carlsson, L., Chartier, D. and Nattel, S. (2006) Characterization of the in vivo and in vitro electrophysiological effects of the novel antiarrhythmic agent AZD7009 in atrial and ventricular tissue of the dog. Journal of Cardiovascular Pharmacology, 47, 123-132. doi:10.1097/01.fjc.0000196242.04384.c3
[110] De Haan, S., Greiser, M., Harks, E., Blaauw, Y., van Hunnik, A., Verheule, S., et al. (2006) AVE0118, blocker of the transient outward current (I(to)) and ultrarapid delayed rectifier current (I(Kur)), fully restores atrial contractility after cardioversion of atrial fibrillation in the goat. Circulation, 114, 1234-1242. doi:10.1161/CIRCULATIONAHA.106.630905
[111] Lofberg, L., Jacobson, I. and Carlsson, L. (2006) Electrophysiological and antiarrhythmic effects of the novel antiarrhythmic agent AZD7009: A comparison with azimi- lide and AVE0118 in the acutely dilated right atrium of the rabbit in vitro. Europace, 8, 549-557. doi:10.1093/europace/eul061
[112] Crijns, H.J., Van Gelder, I.C., Walfridsson, H., Kulakow- ski, P., Ronaszeki, A., Dedek, V., et al. (2006) Safe and effective conversion of persistent atrial fibrillation to sinus rhythm by intravenous AZD7009. Heart Rhythm, 3, 1321-1331. doi:10.1016/j.hrthm.2006.06.035
[113] Okishige, K., Fukunami, M., Kumagai, K., Atarashi, H., Inoue, H. and Pilsicainide Suppression Trial for Persistent Atrial Fibrillation II Investigators (2006) Pharmacologi- cal conversion of persistent atrial fibrillation into sinus rhythm with oral pilsicainide: Pilsicainide suppression trial for persistent atrial fibrillation II. Circulation Journal, 70, 657-661. doi:10.1253/circj.70.657
[114] Antzelevitch, C., Belardinelli, L., Zygmunt, A.C., Burash- nikov, A., Di Diego, J.M., Fish, J.M., et al. (2004) Electrophysiological effects of ranolazine, a novel antianginal agent with antiarrhythmic properties. Circulation, 110, 904-910. doi:10.1161/01.CIR.0000139333.83620.5D
[115] Burashnikov, A., Di Diego, J.M., Zygmunt, A.C., Belar- dinelli, L. and Antzelevitch, C. (2007) Atrium-selective so-dium channel block as a strategy for suppression of atrial fibrillation: Differences in sodium channel inactivation between atria and ventricles and the role of ranolazine. Circulation, 116, 1449-1457. doi:10.1161/CIRCULATIONAHA.107.704890
[116] Schlotthauer, K. and Bers, D.M. (2000) Sarcoplasmic reticulum Ca(2t) release causes myocyte depolarization. Underlying mechanism and threshold for triggered action potentials. Circulation Research, 87, 774-780. doi:10.1161/01.RES.87.9.774
[117] Chen, Y.J., Chen, S.A., Chen, Y.C., Yeh, H.I., Chang, M.S. and Lin, C.I. (2002) Electrophysiology of single cardiomyocytes isolated from rabbit pulmonary veins: Implication in initiation of focal atrial fibrillation. Basic Research in Cardiology, 97, 26-34. doi:10.1007/s395-002-8384-6
[118] Vest, J.A., Wehrens, X.H., Reiken, S.R., Lehnart, S.E., Dobrev, D., Chandra, P., et al. (2005) Defective cardiac ryanodine receptor regulation during atrial fibrillation. Circulation, 111, 2025-2032. doi:10.1161/01.CIR.0000162461.67140.4C
[119] Bers, D.M. (2004) Macromolecular complexes regulating cardiac ryanodine receptor function. Journal of Molecular and Cellular Cardiology, 37, 417-429. doi:10.1016/j.yjmcc.2004.05.026
[120] Kumagai, K., Nakashima, H., Gondo, N. and Saku, K. (2003) Antiarrhythmic effects of JVT-519, a novel cardi-protective drug, on atrial fibrillation/flutter in a canine sterile pericarditis model. Journal of Cardiovascular Electrophysiology, 14, 880-884. doi:10.1046/j.1540-8167.2003.03050.x
[121] Chen, Y.J., Chen, Y.C., Wongcharoen, W., Lin, C.I. and Chen, S.A. (2007) Effect of K201, a novel antiarrhythmic drug on calcium handling and arrhythmogenic activity of pulmonary vein cardiomyocytes. British Journal of Pharcology, 153, 915-925. doi:10.1038/sj.bjp.0707564
[122] Firouzi, M., Ramanna, H., Kok, B., Jongsma, H.J., Ko-eleman, B.P., Doevendans, P.A., et al. (2004) Association of human connexin40 gene polymorphisms with atrial vulnerability as a risk factor for idiopathic atrial fibrillation. Circulation Research, 95, 29-33. doi:10.1161/01.RES.0000141134.64811.0a
[123] Aonuma, S., Kohama, Y., Makino, T. and Fujisawa, T. (1982) Studies on heart XXI. Amino acid sequence of antiarrhythmic peptide (AAP) isolated from atria. Journal of Pharmacobio-Dynamics, 5, 40-48. doi:10.1248/bpb1978.5.40
[124] Weng, S., Lauven, M., Schaefer, T., Polontchouk, L., Gro- ver, R. and Dhein, S. (2002) Pharmacological modification of gap junction coupling by an antiarrhythmic peptide via protein kinase C activation. The FASEB Journal, 16, 1114-1116.
[125] Haugan, K., Olsen, K.B., Hartvig, L., Petersen, J.S., Holstein-Rathlou, N.H., Hennan, J.K. et al. (2005) The antiarrhythmic peptide analog ZP123 prevents atrial conduction slowing during metabolic stress. Journal of Cardiovascular Electrophysiology, 16, 537-545. doi:10.1111/j.1540-8167.2005.40687.x
[126] Guerra, J.M., Everett, T.H. 4th, Lee, K.W., Wilson, E. and Olgin, J.E. (2006) Effects of the gap junction modifier rotigaptide (ZP123) on atrial conduction and vulnerability to atrial fibrillation. Circulation, 114, 110-118. doi:10.1161/CIRCULATIONAHA.105.606251
[127] Shiroshita-Takeshita, A., Sakabe, M., Haugan, K., Hen- nan, J.K. and Nattel, S. (2007) Model-dependent effects of the gap junction conduction-enhancing antiarrhythmic peptide rotigaptide (ZP123) on experimental atrial fibrillation in dogs. Circulation, 115, 310-318. doi:10.1161/CIRCULATIONAHA.106.665547
[128] Rossman, E.I., Liu, K., Morgan, G.A., Swillo, R.E., Bute- ra, J., Gruver, M., et al. (2007) Effects of the gap junction modifier, GAP-134, on conduction and atrial fibrillation/flutter inducibility in dogs (Abstract 1837). Circulation, 114.
[129] Lee, K.W., Everett, T.H., Rahmutula, D., Guerra, J.M., Wilson, E., Ding, C., et al. (2006) Pirfenidone prevents the development of a vulnerable substrate for atrial fibrillation in a canine model of heart failure. Circulation, 114, 1703-1712. doi:10.1161/CIRCULATIONAHA.106.624320
[130] Schauerte, P., Scherlag, B.J., Pitha, J., Scherlag, M.A., Reynolds, D., Lazzara, R., et al. (2000) Catheter ablation of cardiac autonomic nerves for prevention of vagal atrial fibrillation. Circulation, 102, 2774-2780. doi:10.1161/01.CIR.102.22.2774
[131] Smeets, J.L.R.M., Allessie, M.A., Lammers, W.J., Bonke, F.L. and Hollen, J. (1986) The wavelength of the cardiac impulse and reentrant arrhythmias in isolated rabbit atri- um: The role of heart rate, autonomic transmitters, tempera- ture, and potassium. Circulation Research, 58, 96-108. doi:10.1161/01.RES.58.1.96
[132] Allessie, M.A. (1998) Atrialelectrophysiologic remodeling: another vicious circle? Journal of Cardiovascular Electrophysiology, 9, 1378-1393. doi:10.1111/j.1540-8167.1998.tb00114.x
[133] Scanavacca, M., Cristiano, P., Hachul, D., Lara, S., Hardy, C., Darrieux, F., et al. (2006) Selective atrial vagal denervation guided by evoked vagal reflex to treat patients with paroxysmal atrial fibrillation. Circulation, 114, 876-885. doi:10.1161/CIRCULATIONAHA.106.633560
[134] Pappone, C., Santinelli, V., Manguso, F., Vicedomini, G., Gugliotta, F., Augello, G., et al. (2004) Pulmonary vein denervation enhances long-term benefit after circumferential ablation for paroxysmal atrial fibrillation. Circulation, 109, 327-334. doi:10.1161/01.CIR.0000112641.16340.C7
[135] Nakagawa, H., Scherlag, B.J., Wu, R., Po, S., Lockwood, D., Yokoyama, K., et al. (2004) Addition of selective ablation of autonomic ganglia to pulmonary vein antrum isolation for treatment of paroxysmal and persistent atrial fibrillation. Circulation, 110, III-459.
[136] Fox, C.S., Parise, H., D’Agostino, R.B.Sr., Lloyd-Jones, D.M., Vasan, R.S., Wang, T.J., et al. (2004) Parental atrial fibrillation as a risk factor for atrial fibrillation in offspring. JAMA, 291, 2851-2855. doi:10.1001/jama.291.23.2851
[137] Arnar, D.O., Thorvaldsson, S., Manolio, T.A., Thorgeirs- son, G., Kristjansson, K., Hakonarson, H., et al. (2006) Familial aggregation of atrial fibrillation in Iceland. European Heart Journal, 27, 708-712. doi:10.1093/eurheartj/ehi727
[138] Darbar, D., Herron, K.J., Ballew, J.D., Jahangir, A., Gersh, B.J., Shen, W.K., et al. (2003) Familial atrial fibrillation is a genetically heterogeneous disorder. Journal of the American College of Cardiology, 41, 2185-2192. doi:10.1016/S0735-1097(03)00465-0
[139] Ellinor, P.T., Yoerger, D.M., Ruskin, J.N. and MacRae, C.A. (2005) Familial aggregation in lone atrial fibrillation. Human Genetics, 118, 179-184. doi:10.1007/s00439-005-0034-8
[140] Christophersen, I.E., Ravn, L.S., Budtz-Joergensen, E., Skytthe, A., Haunsoe, S., Svendsen, J.H., et al. (2009) Familial aggregation of atrial fibrillation: A study in danish twins. Circulation: Arrhythmia and Electrophysiology, 2, 378-383.
[141] Chen, Y.H., Xu, S.J., Bendahhou, S., Wang, X.L., Wang, Y., Xu, W.Y., Jin, H.W., et al. (2003) Kcnq1 gain-of- function mutation in familial atrial fibrillation. Science, 299, 251-254. doi:10.1126/science.1077771
[142] Yang, Y., Xia, M., Jin, Q., Bendahhou, S., Shi, J., Chen, Y., et al. (2004) Identification of a kcne2 gain-of-function mutation in patients with familial atrial fibrillation. The American Journal of Human Genetics, 75, 899-905. doi:10.1086/425342
[143] Gollob, M.H., Jones, D.L., Krahn, A.D., Danis, L., Gong, X.Q., Shao, Q., Liu, X., et al. (2006) Somatic mutations in the connexin 40 gene (gja5) in atrial fibrillation. The New England Journal of Medicine, 354, 2677-2688. doi:10.1056/NEJMoa052800
[144] Hodgson-Zingman, D.M., Karst, M.L., Zingman, L.V., et al. (2008) Atrial natriuretic peptide frameshift mutation in familial atrial fibrillation. The New England Journal of Medicine, 359, 158-165. doi:10.1056/NEJMoa0706300
[145] Benjamin, E.J., Chen, P.S., Bild, D.E., Mascette, A.M., Albert, C.M., Alonso, A., et al. (2009) Prevention of atrial fibrillation: Report from a national heart, lung, and blood institute workshop. Circulation, 119, 606-618. doi:10.1161/CIRCULATIONAHA.108.825380

comments powered by Disqus

Copyright © 2019 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.