Atrial fibrillation

Article metrics

Abstract

Atrial fibrillation (AF) is the most common sustained cardiac rhythm disorder, and increases in prevalence with increasing age and the number of cardiovascular comorbidities. AF is characterized by a rapid and irregular heartbeat that can be asymptomatic or lead to symptoms such as palpitations, dyspnoea and dizziness. The condition can also be associated with serious complications, including an increased risk of stroke. Important recent developments in the clinical epidemiology and management of AF have informed our approach to this arrhythmia. This Primer provides a comprehensive overview of AF, including its epidemiology, mechanisms and pathophysiology, diagnosis, screening, prevention and management. Management strategies, including stroke prevention, rate control and rhythm control, are considered. We also address quality of life issues and provide an outlook on future developments and ongoing clinical trials in managing this common arrhythmia.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Electrical conduction during sinus rhythm and atrial fibrillation.
Figure 2: Mechanisms that can maintain atrial fibrillation.
Figure 3: Afterdepolarization-mediated ectopic activity.
Figure 4: Re-entry and models of arrhythmia development.
Figure 5: Typical electrocardiograms in normal sinus rhythm and in atrial fibrillation and flutter.
Figure 6: Risk stratification and decision making in thromboprophylaxis.
Figure 7: Using the SAMe-TT2R2 score to aid decision making between a non-vitamin K antagonist oral anticoagulant and a vitamin K antagonist.
Figure 8: Selection of oral anticoagulant drugs.
Figure 9: Management of atrial fibrillation.
Figure 10: Atrial fibrillation ablation.

References

  1. 1

    Lip, G. Y., Brechin, C. M. & Lane, D. A. The global burden of atrial fibrillation and stroke: a systematic review of the epidemiology of atrial fibrillation in regions outside North America and Europe. Chest 142, 1489–1498 (2012). An important systematic review of the global burden of AF.

  2. 2

    Lloyd-Jones, D. M. et al. Lifetime risk for development of atrial fibrillation: the Framingham Heart Study. Circulation 110, 1042–1046 (2004).

  3. 3

    Heeringa, J. et al. Prevalence, incidence and lifetime risk of atrial fibrillation: the Rotterdam study. Eur. Heart J. 27, 949–953 (2006).

  4. 4

    Chugh, S. S. et al. Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study. Circulation 129, 837–847 (2014).

  5. 5

    Colilla, S. et al. Estimates of current and future incidence and prevalence of atrial fibrillation in the U.S. adult population. Am. J. Cardiol. 112, 1142–1147 (2013).

  6. 6

    Krijthe, B. P. et al. Projections on the number of individuals with atrial fibrillation in the European Union, from 2000 to 2060. Eur. Heart J. 34, 2746–2751 (2013). A study on the probable burden of AF in Europe.

  7. 7

    Kaushal, S. S., DasGupta, D. J., Prashar, B. S. & Bhardwaj, A. K. Electrocardiographic manifestations of healthy residents of a tribal Himalayan village. J. Assoc. Physicians India 43, 15–16 (1995).

  8. 8

    Go, A. S. et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) study. JAMA 285, 2370–2375 (2001).

  9. 9

    Sturm, J. W., Davis, S. M., O’Sullivan, J. G., Vedadhaghi, M. E. & Donnan, G. A. The Avoid Stroke as Soon as Possible (ASAP) general practice stroke audit. Med. J. Aust. 176, 312–316 (2002).

  10. 10

    Ball, J., Carrington, M. J., McMurray, J. J. & Stewart, S. Atrial fibrillation: profile and burden of an evolving epidemic in the 21st century. Int. J. Cardiol. 167, 1807–1824 (2013).

  11. 11

    Hernandez, M. B., Asher, C. R., Hernandez, A. V. & Novaro, G. M. African American race and prevalence of atrial fibrillation: a meta-analysis. Cardiol. Res. Pract. 2012, 275624 (2012).

  12. 12

    Dewland, T. A., Olgin, J. E., Vittinghoff, E. & Marcus, G. M. Incident atrial fibrillation among Asians, Hispanics, blacks, and whites. Circulation 128, 2470–2477 (2013).

  13. 13

    Alonso, A. et al. Incidence of atrial fibrillation in whites and African-Americans: the Atherosclerosis Risk in Communities (ARIC) study. Am. Heart J. 158, 111–117 (2009).

  14. 14

    Lip, G. Y. et al. Atrial fibrillation amongst the Indo-Asian general practice population. West Birmingham Atrial Fibrillation Project. Int. J. Cardiol. 65, 187–192 (1998).

  15. 15

    Rodriguez, C. J. et al. Atrial fibrillation incidence and risk factors in relation to race-ethnicity and the population attributable fraction of atrial fibrillation risk factors: the Multi-Ethnic Study of Atherosclerosis. Ann. Epidemiol. 25, 71–76.e1 (2015).

  16. 16

    Rahman, F., Kwan, G. F. & Benjamin, E. J. Global epidemiology of atrial fibrillation. Nat. Rev. Cardiol. 11, 639–654 (2014).

  17. 17

    Oldgren, J. et al. Variations in cause and management of atrial fibrillation in a prospective registry of 15,400 emergency department patients in 46 countries: the RE-LY Atrial Fibrillation Registry. Circulation 129, 1568–1576 (2014). A contemporary registry of AF management.

  18. 18

    Iung, B. & Vahanian, A. Epidemiology of valvular heart disease in the adult. Nat. Rev. Cardiol. 8, 162–172 (2011).

  19. 19

    Gladstone, D. J. et al. Atrial fibrillation in patients with cryptogenic stroke. N. Engl. J. Med. 370, 2467–2477 (2014).

  20. 20

    Wolf, P. A., Abbott, R. D. & Kannel, W. B. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 22, 983–988 (1991).

  21. 21

    Wang, T. J. et al. Temporal relations of atrial fibrillation and congestive heart failure and their joint influence on mortality: the Framingham Heart Study. Circulation 107, 2920–2925 (2003).

  22. 22

    Kalantarian, S., Stern, T. A., Mansour, M. & Ruskin, J. N. Cognitive impairment associated with atrial fibrillation: a meta-analysis. Ann. Intern. Med. 158, 338–346 (2013).

  23. 23

    Benjamin, E. J. et al. Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation 98, 946–952 (1998).

  24. 24

    Schnabel, R. B. et al. Development of a risk score for atrial fibrillation (Framingham Heart Study): a community-based cohort study. Lancet 373, 739–745 (2009). The risk score derived from the Framingham Study for predicting the development of AF.

  25. 25

    Alonso, A. et al. Simple risk model predicts incidence of atrial fibrillation in a racially and geographically diverse population: the CHARGE-AF consortium. J. Am. Heart Assoc. 2, e000102 (2013).

  26. 26

    Haïssaguerre, M. et al. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N. Engl. J. Med. 339, 659–666 (1998). The principal paper showing pulmonary vein foci as a source of paroxysmal AF.

  27. 27

    Lin, W.-S. et al. Catheter ablation of paroxysmal atrial fibrillation initiated by non-pulmonary vein ectopy. Circulation 107, 3176–3183 (2003).

  28. 28

    Nattel, S. New ideas about atrial fibrillation 50 years on. Nature 415, 219–226 (2002).

  29. 29

    Wakili, R., Voigt, N., Kääb, S., Dobrev, D. & Nattel, S. Recent advances in the molecular pathophysiology of atrial fibrillation. J. Clin. Invest. 121, 2955–2968 (2011).

  30. 30

    Heijman, J., Voigt, N., Nattel, S. & Dobrev, D. Cellular and molecular electrophysiology of atrial fibrillation initiation, maintenance, and progression. Circ. Res. 114, 1483–1499 (2014). A comprehensive overview of AF electrophysiology.

  31. 31

    Yeh, Y.-H. et al. Calcium-handling abnormalities underlying atrial arrhythmogenesis and contractile dysfunction in dogs with congestive heart failure. Circ. Arrhythm. Electrophysiol. 1, 93–102 (2008).

  32. 32

    Voigt, N. et al. Enhanced sarcoplasmic reticulum Ca2+ leak and increased Na+–Ca2+ exchanger function underlie delayed afterdepolarizations in patients with chronic atrial fibrillation. Circulation 125, 2059–2070 (2012).

  33. 33

    Voigt, N. et al. Cellular and molecular mechanisms of atrial arrhythmogenesis in patients with paroxysmal atrial fibrillation. Circulation 129, 145–156 (2014).

  34. 34

    Chen, P.-S., Chen, L. S., Fishbein, M. C., Lin, S.-F. & Nattel, S. Role of the autonomic nervous system in atrial fibrillation: pathophysiology and therapy. Circ. Res. 114, 1500–1515 (2014).

  35. 35

    Burashnikov, A. & Antzelevitch, C. Reinduction of atrial fibrillation immediately after termination of the arrhythmia is mediated by late phase 3 early afterdepolarization-induced triggered activity. Circulation 107, 2355–2360 (2003).

  36. 36

    Patterson, E., Po, S. S., Scherlag, B. J. & Lazzara, R. Triggered firing in pulmonary veins initiated by in vitro autonomic nerve stimulation. Heart Rhythm 2, 624–631 (2005).

  37. 37

    Allessie, M. A., Bonke, F. I. & Schopman, F. J. Circus movement in rabbit atrial muscle as a mechanism of tachycardia. III. The ‘leading circle’ concept: a new model of circus movement in cardiac tissue without the involvement of an anatomical obstacle. Circ. Res. 41, 9–18 (1977).

  38. 38

    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 7 (Suppl. 2), 10–20 (2005).

  39. 39

    Kneller, J. et al. Mechanisms of atrial fibrillation termination by pure sodium channel blockade in an ionically-realistic mathematical model. Circ. Res. 96, e35–e47 (2005).

  40. 40

    Narayan, S. M. et al. 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. 60, 628–636 (2012).

  41. 41

    Haissaguerre, M. et al. Driver domains in persistent atrial fibrillation. Circulation 130, 530–538 (2014).

  42. 42

    Calvo, C. J., Deo, M., Zlochiver, S., Millet, J. & Berenfeld, O. Attraction of rotors to the pulmonary veins in paroxysmal atrial fibrillation: a modeling study. Biophys. J. 106, 1811–1821 (2014).

  43. 43

    Ehrlich, J. R. et al. Cellular electrophysiology of canine pulmonary vein cardiomyocytes: action potential and ionic current properties. J. Physiol. 551, 801–813 (2003).

  44. 44

    Nattel, S. Paroxysmal atrial fibrillation and pulmonary veins: relationships between clinical forms and automatic versus re-entrant mechanisms. Can. J. Cardiol. 29, 1147–1149 (2013).

  45. 45

    Li, D., Fareh, S., Leung, T. K. & Nattel, S. Promotion of atrial fibrillation by heart failure in dogs: atrial remodeling of a different sort. Circulation 100, 87–95 (1999).

  46. 46

    Hansen, B. J. et al. 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. 36, 2390–2401 (2015).

  47. 47

    Iwasaki, Y., Nishida, K., Kato, T. & Nattel, S. Atrial fibrillation pathophysiology: implications for management. Circulation 124, 2264–2274 (2011).

  48. 48

    Nishida, K., Datino, T., Macle, L. & Nattel, S. Atrial fibrillation ablation: translating basic mechanistic insights to the patient. J. Am. Coll. Cardiol. 64, 823–831 (2014).

  49. 49

    Wijffels, M. C., Kirchhof, C. J., Dorland, R. & Allessie, M. A. Atrial fibrillation begets atrial fibrillation. A study in awake chronically instrumented goats. Circulation 92, 1954–1968 (1995). A classic paper showing how ‘AF begets AF’ in relation to arrhythmia perpetuation.

  50. 50

    Yue, L. et al. Ionic remodeling underlying action potential changes in a canine model of atrial fibrillation. Circ. Res. 81, 512–525 (1997).

  51. 51

    Qi, X. Y. et al. Cellular signaling underlying atrial tachycardia remodeling of L-type calcium current. Circ. Res. 103, 845–854 (2008).

  52. 52

    Pandit, S. V. et al. Ionic determinants of functional reentry in a 2D model of human atrial cells during simulated chronic atrial fibrillation. Biophys. J. 88, 3806–3821 (2005).

  53. 53

    Luo, X. et al. MicroRNA-26 governs profibrillatory inward-rectifier potassium current changes in atrial fibrillation. J. Clin. Invest. 123, 1939–1951 (2013).

  54. 54

    Igarashi, T. et al. Connexin gene transfer preserves conduction velocity and prevents atrial fibrillation. Circulation 125, 216–225 (2012).

  55. 55

    Bikou, O. et al. Connexin 43 gene therapy prevents persistent atrial fibrillation in a porcine model. Cardiovasc. Res. 92, 218–225 (2011).

  56. 56

    Kato, T., Iwasaki, Y. & Nattel, S. Connexins and atrial fibrillation: filling in the gaps. Circulation 125, 203–206 (2012).

  57. 57

    Burstein, B., Qi, X.-Y., Yeh, Y.-H., Calderone, A. & Nattel, S. Atrial cardiomyocyte tachycardia alters cardiac fibroblast function: a novel consideration in atrial remodeling. Cardiovasc. Res. 76, 442–452 (2007).

  58. 58

    Martins, R. P. et al. Dominant frequency increase rate predicts transition from paroxysmal to long-term persistent atrial fibrillation. Circulation 129, 1472–1482 (2014).

  59. 59

    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. 114, 1453–1468 (2014).

  60. 60

    Verheule, S. et al. Alterations in atrial electrophysiology and tissue structure in a canine model of chronic atrial dilatation due to mitral regurgitation. Circulation 107, 2615–2622 (2003).

  61. 61

    Sinno, H. et al. Atrial ischemia promotes atrial fibrillation in dogs. Circulation 107, 1930–1936 (2003).

  62. 62

    Nishida, K. et al. Mechanisms of atrial tachyarrhythmias associated with coronary artery occlusion in a chronic canine model. Circulation 123, 137–146 (2011).

  63. 63

    Lau, D. H. et al. Hypertension and atrial fibrillation: evidence of progressive atrial remodeling with electrostructural correlate in a conscious chronically instrumented ovine model. Heart Rhythm 7, 1282–1290 (2010).

  64. 64

    Abed, H. S. et al. Obesity results in progressive atrial structural and electrical remodeling: implications for atrial fibrillation. Heart Rhythm 10, 90–100 (2013).

  65. 65

    Iwasaki, Y.-K. et al. Atrial fibrillation promotion with long-term repetitive obstructive sleep apnea in a rat model. J. Am. Coll. Cardiol. 64, 2013–2023 (2014).

  66. 66

    Pathak, R. K. et al. Long-term effect of goal directed weight management in an atrial fibrillation cohort: a long-term follow-up study (LEGACY study). J. Am. Coll. Cardiol. 65, 2159–2169 (2015).

  67. 67

    Fein, A. S. et al. Treatment of obstructive sleep apnea reduces the risk of atrial fibrillation recurrence after catheter ablation. J. Am. Coll. Cardiol. 62, 300–305 (2013).

  68. 68

    Nattel, S. et al. New directions in cardiac arrhythmia management: present challenges and future solutions. Can. J. Cardiol. 30, S420–S430 (2014).

  69. 69

    Savelieva, I. & Camm, A. J. Clinical relevance of silent atrial fibrillation: prevalence, prognosis, quality of life, and management. J. Interv. Card. Electrophysiol. 4, 369–382 (2000).

  70. 70

    Lau, J. K. et al. iPhone ECG application for community screening to detect silent atrial fibrillation: a novel technology to prevent stroke. Int. J. Cardiol. 165, 193–194 (2013).

  71. 71

    January, C. T. et al. 2014 AHA/ACC/HRS Guideline 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 Heart Rhythm Society. J. Am. Coll. Cardiol. 64, e1–e76 (2014).

  72. 72

    Friberg, L. et al. High prevalence of atrial fibrillation among patients with ischemic stroke. Stroke 45, 2599–2605 (2014).

  73. 73

    Leyden, J. M. et al. Adelaide stroke incidence study: declining stroke rates but many preventable cardioembolic strokes. Stroke 44, 1226–1231 (2013).

  74. 74

    Camm, A. J. et al. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Eur. Heart J. 33, 2719–2747 (2012). European guidelines on AF.

  75. 75

    Hobbs, F. D. R. et al. A randomised controlled trial and cost-effectiveness study of systematic screening (targeted and total population screening) versus routine practice for the detection of atrial fibrillation in people aged 65 and over. The SAFE study. Health Technol. Assess. 9, http://dx.doi.org/10.3310/hta9400 (2005). The only large randomized trial of opportunistic versus systematic screening for AF.

  76. 76

    Wiesel, J., Arbesfeld, B. & Schechter, D. Comparison of the Microlife blood pressure monitor with the Omron blood pressure monitor for detecting atrial fibrillation. Am. J. Cardiol. 114, 1046–1048 (2014).

  77. 77

    McManus, D. D. et al. A novel application for the detection of an irregular pulse using an iPhone 4S in patients with atrial fibrillation. Heart Rhythm 10, 315–319 (2013).

  78. 78

    Engdahl, J., Andersson, L., Mirskaya, M. & Rosenqvist, M. Stepwise screening of atrial fibrillation in a 75-year-old population: implications for stroke prevention. Circulation 127, 930–937 (2013).

  79. 79

    Lowres, N. et al. Feasibility and cost-effectiveness of stroke prevention through community screening for atrial fibrillation using iPhone ECG in pharmacies. The SEARCH-AF study. Thromb. Haemost. 111, 1167–1176 (2014). An assessment of AF screening using iPhone technology.

  80. 80

    Tieleman, R. G. et al. Validation and clinical use of a novel diagnostic device for screening of atrial fibrillation. Europace 16, 1291–1295 (2014).

  81. 81

    Lowres, N., Neubeck, L., Redfern, J. & Freedman, S. B. Screening to identify unknown atrial fibrillation. A systematic review. Thromb. Haemost. 110, 213–222 (2013). A systematic review of screening for AF.

  82. 82

    Martinez, C., Katholing, A. & Freedman, S. B. Adverse prognosis of incidentally detected ambulatory atrial fibrillation. A cohort study. Thromb. Haemost. 112, 276–286 (2014).

  83. 83

    Kirchhof, P. et al. A roadmap to improve the quality of atrial fibrillation management: proceedings from the fifth Atrial Fibrillation Network/European Heart Rhythm Association consensus conference. Europace 18, 37–50 (2016).

  84. 84

    Ben Freedman, S. & Lowres, N. Asymptomatic atrial fibrillation: the case for screening to prevent stroke. JAMA 314, 1911–1912 (2015).

  85. 85

    Tondo, C. et al. Rhythm-symptom correlation in patients on continuous monitoring after catheter ablation of atrial fibrillation. J. Cardiovasc. Electrophysiol. 25, 154–160 (2014).

  86. 86

    Manganiello, S. et al. Symptomatic and asymptomatic long-term recurrences following transcatheter atrial fibrillation ablation. Pacing Clin. Electrophysiol. 37, 697–702 (2014).

  87. 87

    Lowres, N. et al. Self-monitoring for atrial fibrillation recurrence in the discharge period post-cardiac surgery using an iPhone electrocardiogram. Eur. J. Cardiothorac. Surg. http://dx.doi.org/10.1093/ejcts/ezv486 (2016).

  88. 88

    Kishore, A. et al. Detection of atrial fibrillation after ischemic stroke or transient ischemic attack: a systematic review and meta-analysis. Stroke 45, 520–526 (2014). A systematic review of AF detection post-stroke.

  89. 89

    Sanna, T. et al. Cryptogenic stroke and underlying atrial fibrillation. N. Engl. J. Med. 370, 2478–2486 (2014).

  90. 90

    Kamel, H. Heart-rhythm monitoring for evaluation of cryptogenic stroke. N. Engl. J. Med. 370, 2532–2533 (2014).

  91. 91

    Mittal, S. et al. Frequency, duration, and predictors of newly-diagnosed atrial fibrillation following dual-chamber pacemaker implantation in patients without a previous history of atrial fibrillation. Am. J. Cardiol. 102, 450–453 (2008).

  92. 92

    Healey, J. S. et al. Subclinical atrial fibrillation and the risk of stroke. N. Engl. J. Med. 366, 120–129 (2012). An important paper on subclinical AF detected by devices.

  93. 93

    Boriani, G. et al. Device-detected atrial fibrillation and risk for stroke: an analysis of >10,000 patients from the SOS AF project (Stroke preventiOn Strategies based on Atrial Fibrillation information from implanted devices). Eur. Heart J. 35, 508–516 (2014).

  94. 94

    Kaufman, E. S. et al. Positive predictive value of device-detected atrial high-rate episodes at different rates and durations: an analysis from ASSERT. Heart Rhythm 9, 1241–1246 (2012).

  95. 95

    DeCicco, A. E., Finkel, J. B., Greenspon, A. J. & Frisch, D. R. Clinical significance of atrial fibrillation detected by cardiac implantable electronic devices. Heart Rhythm 11, 719–724 (2014).

  96. 96

    Chen-Scarabelli, C., Scarabelli, T. M., Ellenbogen, K. A. & Halperin, J. L. Device-detected atrial fibrillation: what to do with asymptomatic patients? J. Am. Coll. Cardiol. 65, 281–294 (2015).

  97. 97

    Turakhia, M. P. et al. Atrial fibrillation burden and short-term risk of stroke: case-crossover analysis of continuously recorded heart rhythm from cardiac electronic implanted devices. Circ. Arrhythm. Electrophysiol. 8, 1040–1047 (2015).

  98. 98

    Brambatti, M. et al. Temporal relationship between subclinical atrial fibrillation and embolic events. Circulation 129, 2094–2099 (2014).

  99. 99

    Zuhlke, L. et al. Characteristics, complications, and gaps in evidence-based interventions in rheumatic heart disease: the Global Rheumatic Heart Disease Registry (the REMEDY study). Eur. Heart J. 36, 1115–1122 (2015).

  100. 100

    De Dassel, J. L., Ralph, A. P. & Carapetis, J. R. Controlling acute rheumatic fever and rheumatic heart disease in developing countries: are we getting closer? Curr. Opin. Pediatr. 27, 116–123 (2015).

  101. 101

    Watkins, D. A., Mvundura, M., Nordet, P. & Mayosi, B. M. A cost-effectiveness analysis of a program to control rheumatic fever and rheumatic heart disease in Pinar del Rio, Cuba. PLoS ONE 10, e0121363 (2015).

  102. 102

    Wanahita, N. et al. Atrial fibrillation and obesity: results of a meta-analysis. Am. Heart J. 155, 310–315 (2008).

  103. 103

    Wang, T. J. et al. Obesity and the risk of new-onset atrial fibrillation. JAMA 292, 2471–2477 (2004).

  104. 104

    Tedrow, U. B. et al. The long- and short-term impact of elevated body mass index on the risk of new atrial fibrillation: the WHS (Women's Health Study). J. Am. Coll. Cardiol. 55, 2319–2327 (2010).

  105. 105

    Andersen, K. et al. Risk of arrhythmias in 52 755 long-distance cross-country skiers: a cohort study. Eur. Heart J. 34, 3624–3631 (2013).

  106. 106

    La Gerche, A. & Schmied, C. M. Atrial fibrillation in athletes and the interplay between exercise and health. Eur. Heart J. 34, 3599–3602 (2013).

  107. 107

    Mozaffarian, D., Furberg, C. D., Psaty, B. M. & Siscovick, D. Physical activity and incidence of atrial fibrillation in older adults: the cardiovascular health study. Circulation 118, 800–807 (2008).

  108. 108

    Larsson, S. C., Drca, N. & Wolk, A. Alcohol consumption and risk of atrial fibrillation: a prospective study and dose-response meta-analysis. J. Am. Coll. Cardiol. 64, 281–289 (2014).

  109. 109

    Samokhvalov, A. V., Irving, H. M. & Rehm, J. Alcohol consumption as a risk factor for atrial fibrillation: a systematic review and meta-analysis. Eur. J. Cardiovasc. Prev. Rehabil. 17, 706–712 (2010).

  110. 110

    Holmqvist, F. et al. Obstructive sleep apnea and atrial fibrillation: findings from ORBIT-AF. J. Am. Coll. Cardiol. Abstr. 63, A292 (2014).

  111. 111

    Stevenson, I. H. et al. Prevalence of sleep disordered breathing in paroxysmal and persistent atrial fibrillation patients with normal left ventricular function. Eur. Heart J. 29, 1662–1669 (2008).

  112. 112

    Kanagala, R. et al. Obstructive sleep apnea and the recurrence of atrial fibrillation. Circulation 107, 2589–2594 (2003).

  113. 113

    Russo, V. et al. Severe obesity and P-wave dispersion: the effect of surgically induced weight loss. Obes. Surg. 18, 90–96 (2008).

  114. 114

    Abed, H. S. et al. Effect of weight reduction and cardiometabolic risk factor management on symptom burden and severity in patients with atrial fibrillation: a randomized clinical trial. JAMA 310, 2050–2060 (2013).

  115. 115

    Reinhart, K., Baker, W. L. & Siv, M. L. Beyond the guidelines: new and novel agents for the prevention of atrial fibrillation after cardiothoracic surgery. J. Cardiovasc. Pharmacol. Ther. 16, 5–13 (2011).

  116. 116

    Fang, W. T., Li, H. J., Zhang, H. & Jiang, S. The role of statin therapy in the prevention of atrial fibrillation: a meta-analysis of randomized controlled trials. Br. J. Clin. Pharmacol. 74, 744–756 (2012).

  117. 117

    Imazio, M. et al. Colchicine for prevention of postpericardiotomy syndrome and postoperative atrial fibrillation: the COPPS-2 randomized clinical trial. JAMA 312, 1016–1023 (2014).

  118. 118

    Johnston, K. & Stephens, S. Effect of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on risk of atrial fibrillation before coronary artery bypass grafting. Ann. Pharmacother. 46, 1239–1244 (2012).

  119. 119

    Hung, C. Y. et al. Efficacy of different statins for primary prevention of atrial fibrillation in male and female patients: a nationwide population-based cohort study. Int. J. Cardiol. 168, 4367–4369 (2013).

  120. 120

    Watson, T., Shantsila, E. & Lip, G. Y. Mechanisms of thrombogenesis in atrial fibrillation: Virchow's triad revisited. Lancet 373, 155–166 (2009). An overview of pathogenesis of thrombosis in AF.

  121. 121

    Lip, G. Y. H. & Lane, D. A. Stroke prevention in atrial fibrillation: a systematic review. JAMA 313, 1950–1962 (2015). A contemporary review of stroke prevention in patients with AF.

  122. 122

    Lin, H. J. et al. Stroke severity in atrial fibrillation. The Framingham Study. Stroke 27, 1760–1764 (1996).

  123. 123

    Hart, R. G., Pearce, L. A. & Aguilar, M. I. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann. Intern. Med. 146, 857–867 (2007). A meta-analysis of trials for stroke prevention in patients with AF.

  124. 124

    Lip, G. Y. The role of aspirin for stroke prevention in atrial fibrillation. Nat. Rev. Cardiol. 8, 602–606 (2011). An overview of the role of aspirin in stroke prevention for AF.

  125. 125

    Pisters, R., Lane, D. A., Marin, F., Camm, A. J. & Lip, G. Y. Stroke and thromboembolism in atrial fibrillation. Circ. J. 76, 2289–2304 (2012).

  126. 126

    Gage, B. F. et al. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA 285, 2864–2870 (2001).

  127. 127

    Karthikeyan, G. & Eikelboom, J. W. The CHADS2 score for stroke risk stratification in atrial fibrillation — friend or foe? Thromb. Haemost. 104, 45–48 (2010).

  128. 128

    Lip, G. Y., Nieuwlaat, R., Pisters, R., Lane, D. A. & Crijns, H. J. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation. Chest 137, 263–272 (2010). The original paper validating the CHA2DS2-VASC score.

  129. 129

    Olesen, J. B. et al. Validation of risk stratification schemes for predicting stroke and thromboembolism in patients with atrial fibrillation: nationwide cohort study. BMJ 342, d124 (2011).

  130. 130

    Olesen, J. B., Torp-Pedersen, C., Hansen, M. L. & Lip, G. Y. The value of the CHA2DS2-VASc score for refining stroke risk stratification in patients with atrial fibrillation with a CHADS2 score 0–1: a nationwide cohort study. Thromb. Haemost. 107, 1172–1179 (2012).

  131. 131

    Chao, T.-F. et al. Comparisons of CHADS2 and CHA2DS2-VASc scores for stroke risk stratification in atrial fibrillation: which scoring system should be used for Asians? Heart Rhythm 13, 46–53 (2016).

  132. 132

    Siu, C.-W., Lip, G. Y. H., Lam, K.-F. & Tse, H.-F. Risk of stroke and intracranial hemorrhage in 9727 Chinese with atrial fibrillation in Hong Kong. Heart Rhythm 11, 1401–1408 (2014).

  133. 133

    Apostolakis, S. et al. Assessment of stroke risk in Middle Eastern patients with atrial fibrillation: the Gulf SAFE registry. Int. J. Cardiol. 168, 1644–1646 (2013).

  134. 134

    Chao, T.-F. et al. Age threshold for increased stroke risk among patients with atrial fibrillation. J. Am. Coll. Cardiol. 66, 1339–1347 (2015).

  135. 135

    Lip, G. Y. & Lane, D. A. Modern management of atrial fibrillation requires initial identification of ‘low-risk’ patients using the CHA2DS2-VASc score, and not focusing on ‘high-risk’ prediction. Circ. J. 78, 1843–1845 (2014).

  136. 136

    Nielsen, P. B. & Chao, T. F. The risks of risk scores for stroke risk assessment in atrial fibrillation. Thromb. Haemost. 113, 1170–1173 (2015).

  137. 137

    Chao, T. F. et al. Should atrial fibrillation patients with 1 additional risk factor of the CHA2DS2-VASc score (beyond sex) receive oral anticoagulation? J. Am. Coll. Cardiol. 65, 635–642 (2015).

  138. 138

    Lip, G. Y., Skjoth, F., Rasmussen, L. H. & Larsen, T. B. Oral anticoagulation, aspirin, or no therapy in patients with nonvalvular AF with 0 or 1 stroke risk factor based on the CHADS-VASc score. J. Am. Coll. Cardiol. 65, 1385–1394 (2015).

  139. 139

    Lip, G. Y. H., Skjøth, F., Rasmussen, L. H., Nielsen, P. B. & Larsen, T. B. Net clinical benefit for oral anticoagulation, aspirin, or no therapy in nonvalvular atrial fibrillation patients with one additional risk factor of the CHA2DS2- VASc score (beyond sex). J. Am. Coll. Cardiol. 66, 488–490 (2015).

  140. 140

    Lip, G. Y. H., Skjøth, F., Nielsen, P. B. & Larsen, T. B. Non-valvular atrial fibrillation patients with none or one additional risk factor of the CHA2DS2-VASc score. A comprehensive net clinical benefit analysis for warfarin, aspirin, or no therapy. Thromb. Haemost. 114, 826–834 (2015).

  141. 141

    Ntaios, G. et al. Leukoaraiosis and stroke recurrence risk in patients with and without atrial fibrillation. Neurology 84, 1213–1219 (2015).

  142. 142

    Charidimou, A. et al. The Clinical Relevance of Microbleeds in Stroke study (CROMIS-2): rationale, design, and methods. Int. J. Stroke 10 (Suppl. A), 155–161 (2015).

  143. 143

    Apostolakis, S., Sullivan, R. M., Olshansky, B. & Lip, G. Y. Factors affecting quality of anticoagulation control among patients with atrial fibrillation on warfarin: the SAMe-TT2R2 score. Chest 144, 1555–1563 (2013). The original paper describing the SAMe-TT2R2 score.

  144. 144

    Proietti, M. & Lip, G. Y. H. Simple decision making between a vitamin K antagonist and non-vitamin K antagonist oral anticoagulant (NOACs): using the SAMe-TT2R2 score. Eur. Heart J. Cardiovasc. Pharmacother. 1, 150–152 (2015).

  145. 145

    Lip, G. Y., Haguenoer, K., Saint-Etienne, C. & Fauchier, L. Relationship of the SAMe-TT2R2 score to poor-quality anticoagulation, stroke, clinically relevant bleeding, and mortality in patients with atrial fibrillation. Chest 146, 719–726 (2014).

  146. 146

    Ruff, C. T. et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 383, 955–962 (2014). A meta-analysis of the NOAC trials.

  147. 147

    Connolly, S. J. et al. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N. Engl. J. Med. 360, 2066–2078 (2009).

  148. 148

    Connolly, S. J. et al. Apixaban in patients with atrial fibrillation. N. Engl. J. Med. 364, 806–817 (2011).

  149. 149

    Lip, G. Y. et al. Management of antithrombotic therapy in atrial fibrillation patients presenting with acute coronary syndrome and/or undergoing percutaneous coronary or valve interventions: a joint consensus document of the European Society of Cardiology Working Group on Thrombosis, European Heart Rhythm Association (EHRA), European Association of Percutaneous Cardiovascular Interventions (EAPCI) and European Association of Acute Cardiac Care (ACCA) endorsed by the Heart Rhythm Society (HRS) and Asia-Pacific Heart Rhythm Society (APHRS). Eur. Heart J. 35, 3155–3179 (2014). European consensus document on managing this complex group of patients.

  150. 150

    Van Gelder, I. C. et al. Lenient versus strict rate control in patients with atrial fibrillation. N. Engl. J. Med. 362, 1363–1373 (2010). A classic trial examining lenient versus strict rate control in patients with AF.

  151. 151

    Groenveld, H. F. et al. The effect of rate control on quality of life in patients with permanent atrial fibrillation: data from the RACE II (Rate Control Efficacy in Permanent Atrial Fibrillation II) study. J. Am. Coll. Cardiol. 58, 1795–1803 (2011).

  152. 152

    Farshi, R., Kistner, D., Sarma, J. S., Longmate, J. A. & Singh, B. N. Ventricular rate control in chronic atrial fibrillation during daily activity and programmed exercise: a crossover open-label study of five drug regimens. J. Am. Coll. Cardiol. 33, 304–310 (1999).

  153. 153

    Khand, A. U. et al. Carvedilol alone or in combination with digoxin for the management of atrial fibrillation in patients with heart failure? J. Am. Coll. Cardiol. 42, 1944–1951 (2003).

  154. 154

    Chao, T.-F. et al. Rate-control treatment and mortality in atrial fibrillation. Circulation 132, 1604–1612 (2015).

  155. 155

    Van Gelder, I. C., Hobbelt, A. H., Mulder, B. A. & Rienstra, M. Rate control in atrial fibrillation: many questions still unanswered. Circulation 132, 1597–1599 (2015).

  156. 156

    Danias, P. G., Caulfield, T. A., Weigner, M. J., Silverman, D. I. & Manning, W. J. Likelihood of spontaneous conversion of atrial fibrillation to sinus rhythm. J. Am. Coll. Cardiol. 31, 588–592 (1998).

  157. 157

    Crijns, H. J. et al. Contemporary real life cardioversion of atrial fibrillation: results from the multinational RHYTHM-AF study. Int. J. Cardiol. 172, 588–594 (2014).

  158. 158

    Lafuente-Lafuente, C., Valembois, L., Bergmann, J. F. & Belmin, J. Antiarrhythmics for maintaining sinus rhythm after cardioversion of atrial fibrillation. Cochrane Database Syst. Rev. 3, CD005049 (2015). A systematic review of antiarrhythmic drugs for AF cardioversion.

  159. 159

    Cadrin-Tourigny, J. et al. Efficacy of amiodarone in patients with atrial fibrillation with and without left ventricular dysfunction: a pooled analysis of AFFIRM and AF-CHF trials. J. Cardiovasc. Electrophysiol. 25, 1306–1313 (2014).

  160. 160

    Savelieva, I., Graydon, R. & Camm, A. J. Pharmacological cardioversion of atrial fibrillation with vernakalant: evidence in support of the ESC Guidelines. Europace 16, 162–173 (2014).

  161. 161

    Freemantle, N., Lafuente-Lafuente, C., Mitchell, S., Eckert, L. & Reynolds, M. Mixed treatment comparison of dronedarone, amiodarone, sotalol, flecainide, and propafenone, for the management of atrial fibrillation. Europace 13, 329–345 (2011).

  162. 162

    Opolski, G. et al. Amiodarone in restoration and maintenance of sinus rhythm in patients with chronic atrial fibrillation after unsuccessful direct-current cardioversion. Clin. Cardiol. 20, 337–340 (1997).

  163. 163

    Hohnloser, S. H., Connolly, S. J., John Camm, A., Halperin, J. L. & Radzik, D. An individual patient-based meta-analysis of the effects of dronedarone in patients with atrial fibrillation. Europace 16, 1117–1124 (2014).

  164. 164

    Hohnloser, S. H. et al. Interaction between digoxin and dronedarone in the PALLAS trial. Circ. Arrhythm. Electrophysiol. 7, 1019–1025 (2014).

  165. 165

    Lin, C. Y. et al. Factors predisposing to ventricular proarrhythmia during antiarrhythmic drug therapy for atrial fibrillation in patients with structurally normal heart. Heart Rhythm 12, 1490–1500 (2015).

  166. 166

    Steinberg, B. A. et al. Use and outcomes of antiarrhythmic therapy in patients with atrial fibrillation receiving oral anticoagulation: results from the ROCKET AF trial. Heart Rhythm 11, 925–932 (2014).

  167. 167

    Flaker, G. et al. Amiodarone, anticoagulation, and clinical events in patients with atrial fibrillation: insights from the ARISTOTLE trial. J. Am. Coll. Cardiol. 64, 1541–1550 (2014).

  168. 168

    Mohanty, S. et al. Effect of periprocedural amiodarone on procedure outcome in patients with longstanding persistent atrial fibrillation undergoing extended pulmonary vein antrum isolation: results from a randomized study (SPECULATE). Heart Rhythm 12, 477–483 (2015).

  169. 169

    Darkner, S. et al. Recurrence of arrhythmia following short-term oral AMIOdarone after CATheter ablation for atrial fibrillation: a double-blind, randomized, placebo-controlled study (AMIO-CAT trial). Eur. Heart J. 35, 3356–3364 (2014).

  170. 170

    Khitri, A. R. et al. Celivarone for maintenance of sinus rhythm and conversion of atrial fibrillation/flutter. J. Cardiovasc. Electrophysiol. 23, 462–472 (2012).

  171. 171

    Ford, J. et al. Human electrophysiological and pharmacological properties of XEN-D0101: a novel atrial-selective Kv1.5/IKur inhibitor. J. Cardiovasc. Pharmacol. 61, 408–415 (2013).

  172. 172

    Burashnikov, A. et al. Atrial-selective prolongation of refractory period with AVE0118 is due principally to inhibition of sodium channel activity. J. Cardiovasc. Pharmacol. 59, 539–546 (2012).

  173. 173

    Gupta, T., Khera, S., Kolte, D., Aronow, W. S. & Iwai, S. Antiarrhythmic properties of ranolazine: a review of the current evidence. Int. J. Cardiol. 187, 66–74 (2015).

  174. 174

    Dittrich, H. C. et al. COR-ART: a multicenter, randomized, double-blind, placebo-controlled dose-ranging study to evaluate single oral doses of vanoxerine for conversion of recent-onset atrial fibrillation or flutter to normal sinus rhythm. Heart Rhythm 12, 1105–1112 (2015).

  175. 175

    Kanj, M., Wazni, O. & Natale, A. Pulmonary vein antrum isolation. Heart Rhythm 4, S73–S79 (2007).

  176. 176

    Webb, S., Kanani, M., Anderson, R. H., Richardson, M. K. & Brown, N. A. Development of the human pulmonary vein and its incorporation in the morphologically left atrium. Cardiol. Young 11, 632–642 (2001).

  177. 177

    Raviele, A. et al. Venice chart international consensus document on atrial fibrillation ablation: 2011 update. J. Cardiovasc. Electrophysiol. 23, 890–923 (2012).

  178. 178

    Di Biase, L. et al. Left atrial appendage: an underrecognized trigger site of atrial fibrillation. Circulation 122, 109–118 (2010).

  179. 179

    Atienza, F. et al. Comparison of radiofrequency catheter ablation of drivers and circumferential pulmonary vein isolation in atrial fibrillation: a noninferiority randomized multicenter RADAR-AF trial. J. Am. Coll. Cardiol. 64, 2455–2467 (2014).

  180. 180

    Brooks, A. G. et al. Outcomes of long-standing persistent atrial fibrillation ablation: a systematic review. Heart Rhythm 7, 835–846 (2010). A systematic review of AF ablation.

  181. 181

    Verma, A. 1, Jiang, C. Y. et al. Approaches to catheter ablation for persistent atrial fibrillation. N. Engl. J. Med 372, 1812–1822 (2015).

  182. 182

    Natale, A. et al. Paroxysmal AF catheter ablation with a contact force sensing catheter: results of the prospective, multicenter SMART-AF trial. J. Am. Coll. Cardiol. 64, 647–656 (2014).

  183. 183

    Packer, D. L. et al. Cryoballoon ablation of pulmonary veins for paroxysmal atrial fibrillation: first results of the North American Arctic Front (STOP AF) pivotal trial. J. Am. Coll. Cardiol. 61, 1713–1723 (2013).

  184. 184

    Dukkipati, S. R. et al. Pulmonary vein isolation using a visually guided laser balloon catheter: the first 200-patient multicenter clinical experience. Circ. Arrhythm. Electrophysiol. 6, 467–472 (2013).

  185. 185

    Pappone, C. et al. Robotic magnetic navigation for atrial fibrillation ablation. J. Am. Coll. Cardiol. 47, 1390–1400 (2006).

  186. 186

    Saliba, W. et al. Atrial fibrillation ablation using a robotic catheter remote control system: initial human experience and long-term follow-up results. J. Am. Coll. Cardiol. 51, 2407–2411 (2008).

  187. 187

    Scharf, C. et al. Ablation of persistent atrial fibrillation using multielectrode catheters and duty-cycled radiofrequency energy. J. Am. Coll. Cardiol. 54, 1450–1456 (2009).

  188. 188

    Haegeli, L. M. & Calkins, H. Catheter ablation of atrial fibrillation: an update. Eur. Heart J. 35, 2454–2459 (2014).

  189. 189

    Cappato, R. et al. Updated worldwide survey on the methods, efficacy, and safety of catheter ablation for human atrial fibrillation. Circ. Arrhythm. Electrophysiol. 3, 32–38 (2010).

  190. 190

    Sorgente, A. et al. Complications of atrial fibrillation ablation: when prevention is better than cure. Europace 13, 1526–1532 (2011).

  191. 191

    Deshmukh, A. et al. In-hospital complications associated with catheter ablation of atrial fibrillation in the United States between 2000 and 2010: analysis of 93 801 procedures. Circulation 128, 2104–2112 (2013).

  192. 192

    Calkins, H. et al. 2012 HRS/EHRA/ECAS expert consensus statement on catheter and surgical ablation of atrial fibrillation: recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, endpoints, and research trial design. Europace 14, 528–606 (2012). A contemporary consensus document on AF ablation.

  193. 193

    Aliot, E., Botto, G. L., Crijns, H. J. & Kirchhof, P. Quality of life in patients with atrial fibrillation: how to assess it and how to improve it. Europace 16, 787–796 (2014).

  194. 194

    Dorian, P. et al. The impairment of health-related quality of life in patients with intermittent atrial fibrillation: implications for the assessment of investigational therapy. J. Am. Coll. Cardiol. 36, 1303–1309 (2000).

  195. 195

    Thrall, G., Lane, D., Carroll, D. & Lip, G. Y. Quality of life in patients with atrial fibrillation: a systematic review. Am J. Med 119, 448.e1–448.19 (2006). A systematic review on QOL in patients with AF.

  196. 196

    Pepine, C. J. Effects of pharmacologic therapy on health-related quality of life in elderly patients with atrial fibrillation: a systematic review of randomized and nonrandomized trials. Clin. Med. Insights Cardiol. 7, 1–20 (2013).

  197. 197

    Healey, J. S., Parkash, R., Pollak, T., Tsang, T. & Dorian, P. Canadian Cardiovascular Society atrial fibrillation guidelines 2010: etiology and initial investigations. Can. J. Cardiol. 27, 31–37 (2011).

  198. 198

    Dorian, P. et al. Interpreting changes in quality of life in atrial fibrillation: how much change is meaningful? Am. Heart J. 166, 381–387.e8 (2013).

  199. 199

    Anker, S. D. et al. The importance of patient-reported outcomes: a call for their comprehensive integration in cardiovascular clinical trials. Eur. Heart J. 35, 2001–2009 (2014).

  200. 200

    Rienstra, M. et al. Symptoms and functional status of patients with atrial fibrillation: state of the art and future research opportunities. Circulation 125, 2933–2943 (2012).

  201. 201

    Wood, M. A., Brown-Mahoney, C., Kay, G. N. & Ellenbogen, K. A. Clinical outcomes after ablation and pacing therapy for atrial fibrillation: a meta-analysis. Circulation 101, 1138–1144 (2000).

  202. 202

    Roy, D. et al. Amiodarone to prevent recurrence of atrial fibrillation. N. Engl. J. Med. 342, 913–920 (2000).

  203. 203

    Singh, S. N. et al. Quality of life and exercise performance in patients in sinus rhythm versus persistent atrial fibrillation: a Veterans Affairs Cooperative Studies Program substudy. J. Am. Coll. Cardiol. 48, 721–730 (2006).

  204. 204

    Lane, D. A., Apostolakis, S., Boos, C. J. & Lip, G. Y. Atrial fibrillation (chronic). BMJ Clin. Evid. 2011, 0217 (2011). An evidence review of drugs for rate and rhythm control in patients with AF.

  205. 205

    Ha, A. C. et al. Health-related quality of life in patients with atrial fibrillation treated with rhythm control versus rate control: insights from a prospective international registry (Registry on Cardiac Rhythm Disorders Assessing the Control of Atrial Fibrillation: RECORD-AF). Circ. Cardiovasc. Qual. Outcomes 7, 896–904 (2014).

  206. 206

    Hemels, M. E. et al. Favorable long-term outcome of Maze surgery in patients with lone atrial fibrillation. Ann. Thorac Surg. 81, 1773–1779 (2006).

  207. 207

    Bonanno, C., Paccanaro, M., La Vecchia, L., Ometto, R. & Fontanelli, A. Efficacy and safety of catheter ablation versus antiarrhythmic drugs for atrial fibrillation: a meta-analysis of randomized trials. J. Cardiovasc. Med. 11, 408–418 (2010).

  208. 208

    Jais, P. et al. Catheter ablation versus antiarrhythmic drugs for atrial fibrillation: the A4 study. Circulation 118, 2498–2505 (2008).

  209. 209

    Reynolds, M. R., Walczak, J., White, S. A., Cohen, D. J. & Wilber, D. J. Improvements in symptoms and quality of life in patients with paroxysmal atrial fibrillation treated with radiofrequency catheter ablation versus antiarrhythmic drugs. Circ. Cardiovasc. Qual. Outcomes 3, 615–623 (2010).

  210. 210

    Walfridsson, H. et al. Radiofrequency ablation as initial therapy in paroxysmal atrial fibrillation: results on health-related quality of life and symptom burden. The MANTRA-PAF trial. Europace 17, 215–221 (2015).

  211. 211

    Lip, G. Y. et al. Oral anticoagulation in atrial fibrillation: a pan-European patient survey. Eur. J. Intern. Med. 18, 202–208 (2007).

  212. 212

    Clarkesmith, D. E., Pattison, H. M., Lip, G. Y. & Lane, D. A. Educational intervention improves anticoagulation control in atrial fibrillation patients: the TREAT randomised trial. PLoS ONE 8, e74037 (2013). An RCT of an educational intervention to improve the quality of anticoagulation control with warfarin.

  213. 213

    Dantas, G. C., Thompson, B. V., Manson, J. A., Tracy, C. S. & Upshur, R. E. Patients' perspectives on taking warfarin: qualitative study in family practice. BMC Fam. Prac. 5, 15 (2004).

  214. 214

    Das, A. K., Willcoxson, P. D., Corrado, O. J. & West, R. M. The impact of long-term warfarin on the quality of life of elderly people with atrial fibrillation. Age Ageing 36, 95–97 (2007).

  215. 215

    Kirchhof, P. et al. Early and comprehensive management of atrial fibrillation: executive summary of the proceedings from the 2nd AFNET-EHRA consensus conference ‘research perspectives in AF’. Eur. Heart J. 30, 2969–2977c (2009).

  216. 216

    Nattel, S. et al. Early management of atrial fibrillation to prevent cardiovascular complications. Eur. Heart J. 35, 1448–1456 (2014).

  217. 217

    Jalife, J. & Kaur, K. Atrial remodeling, fibrosis, and atrial fibrillation. Trends Cardiovasc. Med. 25, 475–484 (2015).

  218. 218

    Kirchhof, P. et al. Personalized management of atrial fibrillation: proceedings from the fourth Atrial Fibrillation competence NETwork/European Heart Rhythm Association consensus conference. Europace 15, 1540–1556 (2013).

  219. 219

    Lee, G., Sanders, P. & Kalman, J. M. Catheter ablation of atrial arrhythmias: state of the art. Lancet 380, 1509–1519 (2012).

  220. 220

    Hakalahti, A., Biancari, F., Nielsen, J. C. & Raatikainen, M. J. P. Radiofrequency ablation versus antiarrhythmic drug therapy as first line treatment of symptomatic atrial fibrillation: systematic review and meta-analysis. Europace 17, 370–378 (2015).

  221. 221

    Kottkamp, H., Bender, R. & Berg, J. Catheter ablation of atrial fibrillation: how to modify the substrate? J. Am. Coll. Cardiol. 65, 196–206 (2015).

  222. 222

    Weerasooriya, R., Shah, A. J., Hocini, M., Jaïs, P. & Haïssaguerre, M. Contemporary challenges of catheter ablation for atrial fibrillation. Clin. Ther. 36, 1145–1150 (2014).

  223. 223

    Bax, J. J., Marsan, N. A. & Delgado, V. Non-invasive imaging in atrial fibrillation: focus on prognosis and catheter ablation. Heart 101, 94–100 (2015).

  224. 224

    US National Library of Science. Catheter ablation versus anti-arrhythmic drug therapy for atrial fibrillation trial. ClinicalTrials.gov[online], (2009).

  225. 225

    Kirchhof, P. et al. Improving outcomes in patients with atrial fibrillation: rationale and design of the Early Treatment of Atrial Fibrillation for Stroke Prevention trial. Am. Heart J. 166, 442–448 (2013).

  226. 226

    Hart, R. G. et al. Embolic strokes of undetermined source: the case for a new clinical construct. Lancet Neurol. 13, 429–438 (2014).

  227. 227

    Jacobs, V. et al. The impact of risk score (CHADS2 versus CHA2DS2-VASc) on long-term outcomes after atrial fibrillation ablation. Heart Rhythm 12, 681–686 (2015).

  228. 228

    Guo, Y. et al. Prevalence, incidence, and lifetime risk of atrial fibrillation in China: new insights into the global burden of atrial fibrillation. Chest 147, 109–119 (2015). A study on AF in China.

  229. 229

    Lau, K.-K. et al. Roles of the CHADS2 and CHA2DS2-VASc scores in post-myocardial infarction patients: Risk of new occurrence of atrial fibrillation and ischemic stroke. Cardiol. J. 21, 474–483 (2014).

  230. 230

    Melgaard, L. et al. Assessment of the CHA 2 DS 2 -VASc score in predicting ischemic stroke, thromboembolism, and death in patients with heart failure with and without atrial fibrillation. JAMA 314, 1030–1038 (2015). A large study showing how CHA2DS2VASC predicts outcomes in patients with heart failure without AF.

  231. 231

    Boriani, G. et al. Non-valvular atrial fibrillation: potential clinical implications of the heterogeneous definitions used in trials on new oral anticoagulants. J. Cardiovasc. Med. (Hagerstown) 16, 491–496 (2015).

  232. 232

    Eikelboom, J. W. et al. Dabigatran versus warfarin in patients with mechanical heart valves. N. Engl. J. Med. 369, 1206–1214 (2013).

  233. 233

    Kooiman, J. et al. Efficacy and safety of vitamin K-antagonists (VKA) for atrial fibrillation in non-dialysis dependent chronic kidney disease. PLoS ONE 9, e94420 (2014).

  234. 234

    Lega, J.-C. et al. Consistency of safety profile of new oral anticoagulants in patients with renal failure. J. Thromb. Haemost. 12, 337–343 (2014).

  235. 235

    Pathak, R. K. et al. Aggressive risk factor reduction study for atrial fibrillation and implications for the outcome of ablation. J. Am. Coll. Cardiol. 64, 2222–2231 (2014).

  236. 236

    Gami, A. S. et al. Obstructive sleep apnea, obesity, and the risk of incident atrial fibrillation. J. Am. Coll. Cardiol. 49, 565–571 (2007).

  237. 237

    Stewart, S. et al. Standard versus atrial fibrillation-specific management strategy (SAFETY) to reduce recurrent admission and prolong survival: pragmatic, multicentre, randomised controlled trial. Lancet 385, 775–784 (2015). A study on the multidisciplinary management of AF and improved outcomes.

  238. 238

    Ware, J. E. Jr& Sherbourne, C. D. The MOS 36-item Short-Form Health Survey (SF-36). I. Conceptual framework and item selection. Med. Care 30, 473–483 (1992).

  239. 239

    Ware, J. E. Jr, Kosinski, M. & Keller, S. D. A 12-Item Short-Form Health Survey: construction of scales and preliminary tests of reliability and validity. Med. Care 34, 220–233 (1996).

  240. 240

    Kosinski, M. et al. A six-item short-form survey for measuring headache impact: the HIT-6. Qual. Life Res. 12, 963–974 (2003).

  241. 241

    EuroQol Group. EuroQol — a new facility for the measurement of health-related quality of life. Health Policy 16, 199–208 (1990).

  242. 242

    Hunt, S. M., McEwen, J. & McKenna, S. P. Measuring health status: a new tool for clinicians and epidemiologists. J. R. Coll. Gen. Pract. 35, 185–188 (1985).

  243. 243

    Nelson, E. C., Landgraf, J. M., Hays, R. D., Wasson, J. H. & Kirk, J. W. The functional status of patients. How can it be measured in physicians' offices? Med. Care 28, 1111–1126 (1990).

  244. 244

    Spertus, J. et al. Development and validation of the Atrial Fibrillation Effect on QualiTy-of-Life (AFEQT) questionnaire in patients with atrial fibrillation. Circ. Arrhythm. Electrophysiol. 4, 15–25 (2011).

  245. 245

    Arribas, F. et al. Validation of the AF-QoL, a disease-specific quality of life questionnaire for patients with atrial fibrillation. Europace 12, 364–370 (2010).

  246. 246

    Badia, X., Arribas, F., Ormaetxe, J. M., Peinado, R. & de Los Terreros, M. S. Development of a questionnaire to measure health-related quality of life (HRQoL) in patients with atrial fibrillation (AF-QoL). Health Qual. Life Outcomes 5, 37 (2007).

  247. 247

    Braganca, E. O., Filho, B. L., Maria, V. H., Levy, D. & de Paola, A. A. Validating a new quality of life questionnaire for atrial fibrillation patients. Int. J. Cardiol. 143, 391–398 (2010).

  248. 248

    Yamashita, T. Koretsune Y. et al. A new method for evaluating quality of life specific to patients with atrial fibrillation: Atrial Fibrillation Quality of Life Questionnaire (AFQLQ). Jpn J. Electrocardiol. 23, 332–343 (2003).

  249. 249

    Yamashita, T. et al. Internal consistency and reproducibility of Atrial Fibrillation Quality of Life Questionnaire. Jpn J. Electrocardiol. 25, 488–494 (2005).

  250. 250

    Shields, A. M. & Lip, G. Y. H. Choosing the right drug to fit the patient when selecting oral anticoagulation for stroke prevention in atrial fibrillation. J. Intern. Med. 278, 1–18 (2015).

  251. 251

    Huxley, R. R. et al. Absolute and attributable risks of atrial fibrillation in relation to optimal and borderline risk factors: the Atherosclerosis Risk in Communities (ARIC) study. Circulation 123, 1501–1508 (2011).

  252. 252

    Watanabe, H. et al. Metabolic syndrome and risk of development of atrial fibrillation: the Niigata preventive medicine study. Circulation 117, 1255–1260 (2008).

  253. 253

    Baber, U. et al. Association of chronic kidney disease with atrial fibrillation among adults in the United States: REasons for Geographic and Racial Differences in Stroke (REGARDS) study. Circ. Arrhythm. Electrophysiol. 4, 26–32 (2011).

  254. 254

    Liao, J.-N. et al. Incidence and risk factors for new-onset atrial fibrillation among patients with end-stage renal disease undergoing renal replacement therapy. Kidney Int. 87, 1209–1215 (2015).

  255. 255

    Butt, M., Dwivedi, G., Khair, O. & Lip, G. Y. Obstructive sleep apnea and cardiovascular disease. Int. J. Cardiol. 139, 7–16 (2010).

  256. 256

    Chao, T.-F. et al. Incidence and risk of atrial fibrillation in sleep-disordered breathing without coexistent systemic disease. Circ. J. 78, 2182–2187 (2014).

  257. 257

    Chao, T.-F. et al. The association between hyperuricemia, left atrial size and new-onset atrial fibrillation. Int. J. Cardiol. 168, 4027–4032 (2013).

  258. 258

    Nyrnes, A. et al. Uric acid is associated with future atrial fibrillation: an 11-year follow-up of 6308 men and women — the Tromso study. Europace 16, 320–326 (2014).

  259. 259

    Chamberlain, A. M. et al. A clinical risk score for atrial fibrillation in a biracial prospective cohort (from the Atherosclerosis Risk in Communities [ARIC] study). Am. J. Cardiol. 107, 85–91 (2011).

Download references

Author information

Introduction (G.Y.H.L.); Epidemiology (T.P.); Mechanisms/pathophysiology (S.N.); Diagnosis, screening and prevention (S.B.F.); Management (A.N., C.G., G.Y.H.L., H.-F.T., I.V.G. and M.R.); Quality of life (D.A.L.); Outlook (L.F.); Overview of Primer (G.Y.H.L.).

Correspondence to Gregory Y. H. Lip.

Ethics declarations

Competing interests

G.Y.H.L. has had guideline membership or has been involved in reviewing the European Society of Cardiology (ESC) Guidelines on Atrial Fibrillation (2010) and Focused Update (2012), the ESC Guidelines on Heart Failure (2012), the American College of Chest Physicians Antithrombotic Therapy Guidelines for Atrial Fibrillation (2012), the National Institute for Health and Care Excellence (NICE) Guidelines on Atrial Fibrillation (2006 and 2014), the NICE Quality Standards on Atrial Fibrillation (2015), the ESC Cardio-oncology Task Force (2015) and the ESC Working Group on Thrombosis position documents (2011–present). He is the chairman of the Scientific Documents Committee for the European Heart Rhythm Association (EHRA) and a reviewer for various guidelines and position statements from the ESC, EHRA, NICE and other organizations. He has been a member of steering committees for various Phase II and III studies, Health Economics and Outcomes Research and other studies, and has been an investigator in various clinical trials in cardiovascular disease, including those on antithrombotic therapies in atrial fibrillation, acute coronary syndrome and lipids. He has been or is currently a consultant for Bayer/Janssen, Astellas, Merck, Sanofi, BMS/Pfizer, Biotronik, Medtronic, Portola, Boehringer Ingelheim, Microlife and Daiichi-Sankyo, and a speaker for Bayer, BMS/Pfizer, Medtronic, Boehringer Ingelheim, Microlife, Roche and Daiichi-Sankyo. L.F. has served as a consultant for Bayer HealthCare, Bristol-Myers Squibb/Pfizer, Boehringer Ingelheim, Medtronic and Novartis and has been on the speakers' bureau for Bayer HealthCare, Bristol-Myers Squibb/Pfizer, Boehringher Ingelheim, Boston Scientific and Medtronic. S.B.F. receives investigator-initiated research grants, personal fees and non-financial support from Bayer Pharma AG, investigator-initiated research grants and non-financial support from Boehringer Ingelheim, investigator-initiated research grants and personal fees from Bristol-Myers Squibb/Pfizer and personal fees from Servier, AstraZeneca and Gilead Sciences. These associations are not related to the submitted work. I.V.G. has had guideline membership of and been involved in reviewing the ESC Guidelines on Atrial Fibrillation (2010). She has received research grants that have been paid to the University Medical Center Groningen from Medtronic, Biotronik and St Jude Medical. A.N. has received consulting fees or honoraria from Janssen Pharmaceuticals, Biosense Webster, St Jude Medical, Medtronic and Boston Scientific. C.G. declares no competing interests. S.N. declares no competing interests. T.P. has received consultant and speaker fees from Bayer HealthCare, Pfizer and Boehringer Ingelheim. M.R. is supported by a grant from the Netherlands Organization for Scientific Research (Veni grant number 016.136.055). He declares no relationship with industry. H.-F.T. is chairman of the Clinical Trial Committee for the Asia Pacific Heart Rhythm Society. He has been or is currently a steering committee member and investigator in various clinical trials in cardiovascular disease, including those on antithrombotic therapies in atrial fibrillation, acute coronary syndrome and lipids. He has been or is currently a consultant for BayerHealthcare/Jensen J&J, MSD, Bristol-Myers Squibb/Pfizer, Boston Scientific, St Jude Medical, Medtronic, Boehringer Ingelheim and Daiichi-Sankyo, and a speaker for Bayer HealthCare/Jensen J&J, MSD, Bristol-Myers Squibb/Pfizer, Boston Scientific, St Jude Medical, Medtronic, Boehringer Ingelheim and Merck. D.A.L. has received investigator-initiated educational grants from Bayer HealthCare, Bristol-Myers Squibb and Boehringer Ingelheim and has been on the speaker bureau for Boehringer Ingelheim, Bayer HealthCare and Bristol-Myers Squibb/Pfizer. She is a steering committee member of a Bristol-Myers Squibb Phase IV trial.

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Lip, G., Fauchier, L., Freedman, S. et al. Atrial fibrillation. Nat Rev Dis Primers 2, 16016 (2016) doi:10.1038/nrdp.2016.16

Download citation

Further reading