The clinical profile and pathophysiology of atrial fibrillation: relationships among clinical features, epidemiology, and mechanisms.

Atrial fibrillation (AF) is the most common arrhythmia (estimated lifetime risk, 22%-26%). The aim of this article is to review the clinical epidemiological features of AF and to relate them to underlying mechanisms. Long-established risk factors for AF include aging, male sex, hypertension, valve disease, left ventricular dysfunction, obesity, and alcohol consumption. Emerging risk factors include prehypertension, increased pulse pressure, obstructive sleep apnea, high-level physical training, diastolic dysfunction, predisposing gene variants, hypertrophic cardiomyopathy, and congenital heart disease. Potential risk factors are coronary artery disease, kidney disease, systemic inflammation, pericardial fat, and tobacco use. AF has substantial population health consequences, including impaired quality of life, increased hospitalization rates, stroke occurrence, and increased medical costs. The pathophysiology of AF centers around 4 general types of disturbances that promote ectopic firing and reentrant mechanisms, and include the following: (1) ion channel dysfunction, (2) Ca(2+)-handling abnormalities, (3) structural remodeling, and (4) autonomic neural dysregulation. Aging, hypertension, valve disease, heart failure, myocardial infarction, obesity, smoking, diabetes mellitus, thyroid dysfunction, and endurance exercise training all cause structural remodeling. Heart failure and prior atrial infarction also cause Ca(2+)-handling abnormalities that lead to focal ectopic firing via delayed afterdepolarizations/triggered activity. Neural dysregulation is central to atrial arrhythmogenesis associated with endurance exercise training and occlusive coronary artery disease. Monogenic causes of AF typically promote the arrhythmia via ion channel dysfunction, but the mechanisms of the more common polygenic risk factors are still poorly understood and under intense investigation. Better recognition of the clinical epidemiology of AF, as well as an improved appreciation of the underlying mechanisms, is needed to develop improved methods for AF prevention and management.

[1]  T. Arentz,et al.  Cellular damage, platelet activation, and inflammatory response after pulmonary vein isolation: a randomized study comparing radiofrequency ablation with cryoablation. , 2012, Heart rhythm.

[2]  D. Fitzmaurice,et al.  Patterns of Warfarin Use in Subgroups of Patients with Atrial Fibrillation: A Cross-Sectional Analysis of 430 General Practices in the United Kingdom , 2013, PloS one.

[3]  L. Køber,et al.  Prognostic importance of atrial fibrillation in asymptomatic aortic stenosis: the Simvastatin and Ezetimibe in Aortic Stenosis study. , 2013, International journal of cardiology.

[4]  J. Halperin,et al.  Subclinical atrial fibrillation and the risk of stroke. , 2012, The New England journal of medicine.

[5]  Na Li,et al.  Cellular and Molecular Mechanisms of Atrial Arrhythmogenesis in Patients With Paroxysmal Atrial Fibrillation , 2014, Circulation.

[6]  R. D'Agostino,et al.  Low serum thyrotropin concentrations as a risk factor for atrial fibrillation in older persons. , 1994, The New England journal of medicine.

[7]  A. Camm,et al.  Rhythm Control versus Rate Control for Atrial Fibrillation and Heart Failure , 2009 .

[8]  M. Pfeffer,et al.  Atrial fibrillation and risk of clinical events in chronic heart failure with and without left ventricular systolic dysfunction: results from the Candesartan in Heart failure-Assessment of Reduction in Mortality and morbidity (CHARM) program. , 2006, Journal of the American College of Cardiology.

[9]  J. Somerville Grown-Up Congenital Heart Disease-Medical Demands Look Back, Look Forward 2000* , 2001, The Thoracic and cardiovascular surgeon.

[10]  W. Maisel,et al.  Atrial fibrillation in heart failure: epidemiology, pathophysiology, and rationale for therapy. , 2003, The American journal of cardiology.

[11]  H. Crijns,et al.  Rate control is more cost-effective than rhythm control for patients with persistent atrial fibrillation--results from the RAte Control versus Electrical cardioversion (RACE) study. , 2004, European heart journal.

[12]  Gregory Y H Lip,et al.  Quality of life in patients with atrial fibrillation: a systematic review. , 2006, The American journal of medicine.

[13]  G. Lip,et al.  The emerging role of biomarkers in atrial fibrillation. , 2013, The Canadian journal of cardiology.

[14]  Xu-Fang Yu Association of atrial fibrillation and obstructive sleep apnea , 2011 .

[15]  M. Chung,et al.  Therapy Insight: interactions between atrial fibrillation and obstructive sleep apnea , 2005, Nature Clinical Practice Cardiovascular Medicine.

[16]  S Nattel,et al.  Promotion of atrial fibrillation by heart failure in dogs: atrial remodeling of a different sort. , 1999, Circulation.

[17]  T. Rabben,et al.  Sleep-disordered breathing: a novel predictor of atrial fibrillation after coronary artery bypass surgery. , 1996, Coronary artery disease.

[18]  P. Vestergaard,et al.  Overweight and obesity as risk factors for atrial fibrillation or flutter: the Danish Diet, Cancer, and Health Study. , 2005, The American journal of medicine.

[19]  M. Houmsse,et al.  Supraventricular tachycardia causing heart failure , 2011, Current opinion in cardiology.

[20]  M. Abrahamowicz,et al.  Comparative effectiveness of rhythm control vs rate control drug treatment effect on mortality in patients with atrial fibrillation. , 2012, Archives of internal medicine.

[21]  Leif Hove-Madsen,et al.  PITX2 Insufficiency Leads to Atrial Electrical and Structural Remodeling Linked to Arrhythmogenesis , 2011, Circulation. Cardiovascular genetics.

[22]  D. Levy,et al.  Independent risk factors for atrial fibrillation in a population-based cohort. The Framingham Heart Study. , 1994, JAMA.

[23]  J. Brugada,et al.  Long-lasting sport practice and lone atrial fibrillation. , 2002, European heart journal.

[24]  Niels Voigt,et al.  Recent advances in the molecular pathophysiology of atrial fibrillation. , 2011, The Journal of clinical investigation.

[25]  S. Nattel,et al.  Atrial Ischemia Promotes Atrial Fibrillation in Dogs , 2003, Circulation.

[26]  Yuan Zhang,et al.  Obesity results in progressive atrial structural and electrical remodeling: implications for atrial fibrillation. , 2013, Heart rhythm.

[27]  A. L. Waldo Rhythm Control versus Rate Control for Atrial Fibrillation and Heart Failure , 2009 .

[28]  Shih‐Ann Chen,et al.  Effects of thyroid hormone on the arrhythmogenic activity of pulmonary vein cardiomyocytes. , 2002, Journal of the American College of Cardiology.

[29]  A. Waldo,et al.  Chronic atrial fibrillation: Incidence, prevalence, and prediction of stroke using the Congestive heart failure, Hypertension, Age >75, Diabetes mellitus, and prior Stroke or transient ischemic attack (CHADS2) risk stratification scheme , 2009 .

[30]  N. Frasure-smith,et al.  Quality of life and functional capacity in patients with atrial fibrillation and congestive heart failure. , 2013, Journal of the American College of Cardiology.

[31]  Younhee Kang Relation of atrial arrhythmia-related symptoms to health-related quality of life in patients with newly diagnosed atrial fibrillation: a community hospital-based cohort. , 2006, Heart & lung : the journal of critical care.

[32]  M. Frenneaux,et al.  Atrial fibrillation in hypertrophic cardiomyopathy: a longitudinal study. , 1990, Journal of the American College of Cardiology.

[33]  J. Plumb,et al.  Risks of stroke and mortality associated with suboptimal anticoagulation in atrial fibrillation patients , 2011, Thrombosis and Haemostasis.

[34]  Vesa Virtanen,et al.  SCN5A Mutation Associated with Cardiac Conduction Defect and Atrial Arrhythmias , 2006, Journal of cardiovascular electrophysiology.

[35]  D. Singer,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. , 2001, JAMA.

[36]  Cynthia A. Carnes,et al.  C-Reactive Protein Elevation in Patients With Atrial Arrhythmias: Inflammatory Mechanisms and Persistence of Atrial Fibrillation , 2001, Circulation.

[37]  G. Mensah,et al.  Increasing Trends in Hospitalization for Atrial Fibrillation in the United States, 1985 Through 1999: Implications for Primary Prevention , 2003, Circulation.

[38]  Stanley Nattel,et al.  Atrial fibrillation pathophysiology: implications for management. , 2011, Circulation.

[39]  G. Marcus,et al.  Incident Atrial Fibrillation and Risk of End-Stage Renal Disease in Adults With Chronic Kidney Disease , 2013, Circulation.

[40]  V. Boyko,et al.  Significance of paroxysmal atrial fibrillation complicating acute myocardial infarction in the thrombolytic era. SPRINT and Thrombolytic Survey Groups. , 1998, Circulation.

[41]  G. Naccarelli,et al.  Acute treatment of atrial fibrillation: spontaneous conversion rates and cost of care. , 1999, The American journal of cardiology.

[42]  Dhaval Shah,et al.  Treatment of obstructive sleep apnea reduces the risk of atrial fibrillation recurrence after catheter ablation. , 2012, Journal of the American College of Cardiology.

[43]  M. Aguilar,et al.  Meta-analysis: Antithrombotic Therapy to Prevent Stroke in Patients Who Have Nonvalvular Atrial Fibrillation , 2007, Annals of Internal Medicine.

[44]  S. Nattel,et al.  Abstract 1343: Atrial Cardiomyocyte Tachycardia Alters Cardiac Fibroblast Function: A Novel Consideration in Atrial Remodeling , 2007 .

[45]  Jeroen J. Bax,et al.  Relationship between obstructive coronary artery disease and abnormal stress testing in patients with paroxysmal or persistent atrial fibrillation , 2010, The International Journal of Cardiovascular Imaging.

[46]  Wenjun Xie,et al.  Calcium Leak Through Ryanodine Receptors Leads to Atrial Fibrillation in 3 Mouse Models of Catecholaminergic Polymorphic Ventricular Tachycardia , 2012, Circulation research.

[47]  Juan F Granada,et al.  A population-based study of mortality among patients with atrial fibrillation or flutter. , 2002, The American journal of medicine.

[48]  S. Nattel,et al.  MicroRNA29: A Mechanistic Contributor and Potential Biomarker in Atrial Fibrillation , 2013, Circulation.

[49]  P. Kirchhof,et al.  Pathophysiological mechanisms of atrial fibrillation: a translational appraisal. , 2011, Physiological reviews.

[50]  S. Chugh,et al.  Meta-analysis of obstructive sleep apnea as predictor of atrial fibrillation recurrence after catheter ablation. , 2011, The American journal of cardiology.

[51]  P. Vestergaard,et al.  Hyperthyroidism and risk of atrial fibrillation or flutter: a population-based study. , 2004, Archives of internal medicine.

[52]  S. Nattel,et al.  Transforming growth factor-β and oxidative stress mediate tachycardia-induced cellular remodelling in cultured atrial-derived myocytes. , 2011, Cardiovascular research.

[53]  D. Levy,et al.  Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. , 1998, Circulation.

[54]  M. Allessie,et al.  Atrial fibrillation-induced atrial contractile dysfunction: a tachycardiomyopathy of a different sort. , 2002, Cardiovascular research.

[55]  Michael A Rosenberg,et al.  Echocardiographic diastolic parameters and risk of atrial fibrillation: the Cardiovascular Health Study. , 2012, European heart journal.

[56]  R. Barr,et al.  Cell size and communication: role in structural and electrical development and remodeling of the heart. , 2004, Heart rhythm.

[57]  Jeffrey L. Anderson,et al.  Sodium channel mutations and susceptibility to heart failure and atrial fibrillation. , 2005, JAMA.

[58]  Wei Huang,et al.  KCNQ1 Gain-of-Function Mutation in Familial Atrial Fibrillation , 2003, Science.

[59]  J. Ruskin,et al.  Economic burden and co‐morbidities of atrial fibrillation in a privately insured population , 2005, Current medical research and opinion.

[60]  A. Waldo Atrial Fibrillation Is Associated With Lower Cognitive Performance in the Framingham Offspring Men , 2007 .

[61]  Ning Wang,et al.  Downregulation of miR-133 and miR-590 contributes to nicotine-induced atrial remodelling in canines. , 2009, Cardiovascular research.

[62]  P. Vardas,et al.  The role of the post-cardioversion time course of hs-CRP levels in clarifying the relationship between inflammation and persistence of atrial fibrillation , 2007, Heart.

[63]  Robert J. Glynn,et al.  Influence of Systolic and Diastolic Blood Pressure on the Risk of Incident Atrial Fibrillation in Women , 2009, Circulation.

[64]  L. Kalra,et al.  Prospective cohort study to determine if trial efficacy of anticoagulation for stroke prevention in atrial fibrillation translates into clinical effectiveness , 2000, BMJ : British Medical Journal.

[65]  K. Yamagishi,et al.  Arterial oxygen desaturation during sleep and atrial fibrillation , 2006, Heart.

[66]  D. Hodge,et al.  The Natural History of Preclinical Diastolic Dysfunction: A Population Based Study , 2010 .

[67]  Matthew Reynolds,et al.  Assessing the direct costs of treating nonvalvular atrial fibrillation in the United States. , 2006, Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research.

[68]  R B Schuessler,et al.  Natural and evoked atrial flutter due to circus movement in dogs. Role of abnormal atrial pathways, slow conduction, nonuniform refractory period distribution and premature beats. , 1978, The American journal of cardiology.

[69]  Stefan Kääb,et al.  Genetics of Atrial Fibrillation: Implications for Future Research Directions and Personalized Medicine , 2010, Circulation. Arrhythmia and electrophysiology.

[70]  G. Perry,et al.  Incident atrial fibrillation and mortality in older adults with heart failure , 2005, European journal of heart failure.

[71]  S. Nattel,et al.  The multidimensional role of calcium in atrial fibrillation pathophysiology: mechanistic insights and therapeutic opportunities. , 2012, European heart journal.

[72]  Habib Gamra,et al.  Distribution and Risk Profile of Paroxysmal, Persistent, and Permanent Atrial Fibrillation in Routine Clinical Practice: Insight From the Real-Life Global Survey Evaluating Patients With Atrial Fibrillation International Registry , 2012, Circulation. Arrhythmia and electrophysiology.

[73]  S. Nattel,et al.  Atrial fibrosis: mechanisms and clinical relevance in atrial fibrillation. , 2008, Journal of the American College of Cardiology.

[74]  Colin R Simpson,et al.  A national survey of the prevalence, incidence, primary care burden and treatment of atrial fibrillation in Scotland , 2007, Heart.

[75]  Prashanthan Sanders,et al.  Pericardial fat is associated with atrial fibrillation severity and ablation outcome. , 2011, Journal of the American College of Cardiology.

[76]  A. Terzic,et al.  KATP channel mutation confers risk for vein of Marshall adrenergic atrial fibrillation , 2007, Nature Clinical Practice Cardiovascular Medicine.

[77]  Frederick T. Han,et al.  Value of magnetic resonance imaging in guiding atrial fibrillation management. , 2013, The Canadian journal of cardiology.

[78]  G. Naccarelli,et al.  Increasing prevalence of atrial fibrillation and flutter in the United States. , 2009, The American journal of cardiology.

[79]  A. Sato,et al.  Concomitant obstructive sleep apnea increases the recurrence of atrial fibrillation following radiofrequency catheter ablation of atrial fibrillation: clinical impact of continuous positive airway pressure therapy. , 2013, Heart rhythm.

[80]  A Laupacis,et al.  Prevalence, age distribution, and gender of patients with atrial fibrillation. Analysis and implications. , 1995, Archives of internal medicine.

[81]  J. Brugada,et al.  Sport practice and the risk of lone atrial fibrillation: a case-control study. , 2006, International journal of cardiology.

[82]  P A Wolf,et al.  Prevalence, incidence, prognosis, and predisposing conditions for atrial fibrillation: population-based estimates. , 1998, The American journal of cardiology.

[83]  B. Gersh,et al.  Obstructive Sleep Apnea and the Recurrence of Atrial Fibrillation , 2003, Circulation.

[84]  Douglas L. Jones,et al.  Somatic mutations in the connexin 40 gene (GJA5) in atrial fibrillation. , 2006, The New England journal of medicine.

[85]  R B D'Agostino,et al.  Impact of atrial fibrillation on mortality, stroke, and medical costs. , 1998, Archives of internal medicine.

[86]  I. V. Van Gelder,et al.  Role of inflammation in early atrial fibrillation recurrence. , 2012, Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology.

[87]  Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials. , 1994, Archives of internal medicine.

[88]  P. Zimetbaum,et al.  Healthcare Resource Utilization and Costs Associated with Recurrent Episodes of Atrial Fibrillation: The FRACTAL Registry , 2007, Journal of cardiovascular electrophysiology.

[89]  G. Oudit,et al.  S4153R is a gain-of-function mutation in the cardiac Ca(2+) release channel ryanodine receptor associated with catecholaminergic polymorphic ventricular tachycardia and paroxysmal atrial fibrillation. , 2013, The Canadian journal of cardiology.

[90]  A. Hofman,et al.  Prevalence, incidence and lifetime risk of atrial fibrillation: the Rotterdam study. , 2006, European heart journal.

[91]  D. Lin,et al.  Clinical predictors and outcomes associated with acute return of pulmonary vein conduction during pulmonary vein isolation for treatment of atrial fibrillation. , 2006, Heart rhythm.

[92]  F. Van de Werf,et al.  Endurance sports is a risk factor for atrial fibrillation after ablation for atrial flutter. , 2006, International journal of cardiology.

[93]  T. Kural,et al.  Prevalence and predictors of atrial fibrillation in rheumatic valvular heart disease. , 1996, The American journal of cardiology.

[94]  R. Califf,et al.  Atrial fibrillation in the setting of acute myocardial infarction: the GUSTO-I experience. Global Utilization of Streptokinase and TPA for Occluded Coronary Arteries. , 1997, Journal of the American College of Cardiology.

[95]  R McBride,et al.  Factors associated with ischemic stroke during aspirin therapy in atrial fibrillation: analysis of 2012 participants in the SPAF I-III clinical trials. The Stroke Prevention in Atrial Fibrillation (SPAF) Investigators. , 1999, Stroke.

[96]  J. Plumb,et al.  Initiation and persistence of warfarin or aspirin in patients with chronic atrial fibrillation in general practice: do the appropriate patients receive stroke prophylaxis? , 2008, Journal of thrombosis and haemostasis : JTH.

[97]  S. Nattel,et al.  Molecular determinants of cardiac fibroblast electrical function and therapeutic implications for atrial fibrillation. , 2011, Cardiovascular research.

[98]  S. Kalantarian,et al.  Cognitive Impairment Associated With Atrial Fibrillation , 2013, Annals of Internal Medicine.

[99]  David D Spragg,et al.  Predictive value of obstructive sleep apnoea assessed by the Berlin Questionnaire for outcomes after the catheter ablation of atrial fibrillation. , 2009, Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology.

[100]  S. Willich,et al.  The impact of atrial fibrillation on the cost of stroke: the berlin acute stroke study. , 2007, Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research.

[101]  Niels Voigt,et al.  Multiple Potential Molecular Contributors to Atrial Hypocontractility Caused by Atrial Tachycardia Remodeling in Dogs , 2010, Circulation. Arrhythmia and electrophysiology.

[102]  G. Samsa,et al.  Improving the quality of anticoagulation of patients with atrial fibrillation in managed care organizations: results of the managing anticoagulation services trial. , 2002, The American journal of medicine.

[103]  P. Khairy,et al.  Cardiac Arrhythmias In Congenital Heart Diseases , 2009, Indian pacing and electrophysiology journal.

[104]  P. Wolf,et al.  Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. , 1991, Stroke.

[105]  S. Nattel,et al.  Changes in Connexin Expression and the Atrial Fibrillation Substrate in Congestive Heart Failure , 2009, Circulation research.

[106]  A. Belanger,et al.  The Framingham study. , 1976, British medical journal.

[107]  W. Kannel,et al.  Epidemiologic features of chronic atrial fibrillation: the Framingham study. , 1982, The New England journal of medicine.

[108]  Sander Verheule,et al.  Alterations in Atrial Electrophysiology and Tissue Structure in a Canine Model of Chronic Atrial Dilatation Due to Mitral Regurgitation , 2003, Circulation.

[109]  D. Reda,et al.  Clinical ResearchHeart Rhythm DisorderQuality of Life and Exercise Performance in Patients in Sinus Rhythm Versus Persistent Atrial Fibrillation: A Veterans Affairs Cooperative Studies Program Substudy , 2006 .

[110]  A. Keren,et al.  Effect of Chronic Atrial Fibrillation on Regional Cerebral Blood Flow , 1980, Stroke.

[111]  E. Walsh,et al.  Arrhythmias in Adult Patients With Congenital Heart Disease , 2007, Circulation.

[112]  S. Nattel,et al.  Intra-Atrial Pressure Increases Rate and Organization of Waves Emanating From the Superior Pulmonary Veins During Atrial Fibrillation , 2003, Circulation.

[113]  P. Xiao,et al.  Blockade of angiotensin II improves hyperthyroid induced abnormal atrial electrophysiological properties , 2011, Regulatory Peptides.

[114]  M. Allessie,et al.  Structural changes of atrial myocardium due to sustained atrial fibrillation in the goat. , 1997, Circulation.

[115]  James B Seward,et al.  Left ventricular diastolic dysfunction as a predictor of the first diagnosed nonvalvular atrial fibrillation in 840 elderly men and women. , 2002, Journal of the American College of Cardiology.

[116]  Niels Voigt,et al.  Cellular and Molecular Electrophysiology of Atrial Fibrillation Initiation, Maintenance, and Progression , 2014, Circulation research.

[117]  R. Lazzara,et al.  Triggered firing in pulmonary veins initiated by in vitro autonomic nerve stimulation. , 2005, Heart rhythm.

[118]  S. Nattel,et al.  Determinants of atrial fibrillation in an animal model of obesity and acute obstructive sleep apnea. , 2012, Heart rhythm.

[119]  Paul Schoenhagen,et al.  Left Atrial Epicardial Adiposity and Atrial Fibrillation , 2010, Circulation. Arrhythmia and electrophysiology.

[120]  Y. Maruyama,et al.  Influences of autonomic nervous system on atrial arrhythmogenic substrates and the incidence of atrial fibrillation in diabetic heart. , 2009, International heart journal.

[121]  N. Poirier,et al.  Arrhythmias in adult congenital heart disease , 2006, Expert review of cardiovascular therapy.

[122]  Eric E. Smith,et al.  Variants conferring risk of atrial fibrillation on chromosome 4q25 , 2007, Nature.

[123]  Otto Kamp,et al.  Effect of rate or rhythm control on quality of life in persistent atrial fibrillation. Results from the Rate Control Versus Electrical Cardioversion (RACE) Study. , 2004, Journal of the American College of Cardiology.

[124]  Gernot Plank,et al.  Mechanistic inquiry into the role of tissue remodeling in fibrotic lesions in human atrial fibrillation. , 2013, Biophysical journal.

[125]  H. Crijns,et al.  A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. , 2002, The New England journal of medicine.

[126]  J. Olesen,et al.  The spectrum of thyroid disease and risk of new onset atrial fibrillation: a large population cohort study , 2012, BMJ : British Medical Journal.

[127]  Stanley Nattel,et al.  Atrial Remodeling and Atrial Fibrillation: Mechanisms and Implications , 2008, Circulation. Arrhythmia and electrophysiology.

[128]  S. Nattel,et al.  Gender-related differences in ion-channel and transporter subunit expression in non-diseased human hearts. , 2010, Journal of molecular and cellular cardiology.

[129]  W M O'Fallon,et al.  Ischemic stroke subtypes : a population-based study of functional outcome, survival, and recurrence. , 2000, Stroke.

[130]  D. Stott,et al.  Dementia in subjects with atrial fibrillation: hemostatic function and the role of anticoagulation , 2004, Journal of thrombosis and haemostasis : JTH.

[131]  H. Inoue,et al.  Role of anatomic architecture in sustained atrial reentry and double potentials. , 1992, American heart journal.

[132]  B. O'brien,et al.  Cost-Effectiveness of Rhythm versus Rate Control in Atrial Fibrillation , 2004, Annals of Internal Medicine.

[133]  J. Olesen,et al.  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 , 2012, Thrombosis and Haemostasis.

[134]  Susan Redline,et al.  Association of nocturnal arrhythmias with sleep-disordered breathing: The Sleep Heart Health Study. , 2006, American journal of respiratory and critical care medicine.

[135]  K. Stefánsson,et al.  Familial aggregation of atrial fibrillation in Iceland. , 2006, European heart journal.

[136]  I. Kodama,et al.  Anisotropic Conduction Properties in Canine Atria Analyzed by High-Resolution Optical Mapping: Preferential Direction of Conduction Block Changes From Longitudinal to Transverse With Increasing Age , 2002, Circulation.

[137]  T. Lumley,et al.  Risk of new-onset atrial fibrillation in relation to body mass index. , 2006, Archives of internal medicine.

[138]  Walter E. Garrey THE NATURE OF FIBRILLARY CONTRACTION OF THE HEART.—ITS RELATION TO TISSUE MASS AND FORM , 1914 .

[139]  J. Seward,et al.  Mortality trends in patients diagnosed with first atrial fibrillation: a 21-year community-based study. , 2007, Journal of the American College of Cardiology.

[140]  J. C. Hall,et al.  Genetics and molecular biology of rhythms , 1987, BioEssays : news and reviews in molecular, cellular and developmental biology.

[141]  B. Maron,et al.  Hypertrophic cardiomyopathy in Tuscany: clinical course and outcome in an unselected regional population. , 1995, Journal of the American College of Cardiology.

[142]  Dhanunjaya R. Lakkireddy,et al.  Atrial fibrillation and the risk of incident dementia: a meta-analysis. , 2012, Heart rhythm.

[143]  W. Giles,et al.  A mathematical model of electrotonic interactions between ventricular myocytes and fibroblasts. , 2007, Biophysical journal.

[144]  José Jalife,et al.  Electrotonic myofibroblast-to-myocyte coupling increases propensity to reentrant arrhythmias in two-dimensional cardiac monolayers. , 2008, Biophysical journal.

[145]  A. Laupacis,et al.  Population rates of hospitalization for atrial fibrillation/flutter in Canada. , 2004, The Canadian journal of cardiology.

[146]  Prashanthan Sanders,et al.  Hypertension and atrial fibrillation: evidence of progressive atrial remodeling with electrostructural correlate in a conscious chronically instrumented ovine model. , 2010, Heart rhythm.

[147]  A Majeed,et al.  Trends in the prevalence and management of atrial fibrillation in general practice in England and Wales, 1994–1998: analysis of data from the general practice research database , 2001, Heart.

[148]  MicheleMiragoli,et al.  Myofibroblasts Induce Ectopic Activity in Cardiac Tissue , 2007 .

[149]  D. Levy,et al.  Prevention of Atrial Fibrillation: Report From a National Heart, Lung, and Blood Institute Workshop , 2009, Circulation.

[150]  Simon Stewart,et al.  A population-based study of the long-term risks associated with atrial fibrillation: 20-year follow-up of the Renfrew/Paisley study. , 2002, The American journal of medicine.

[151]  R. Hatala,et al.  Anticoagulants for atrial fibrillation: Why is the treatment rate so low? , 2002, Clinical cardiology.

[152]  B. Nordestgaard,et al.  Does elevated C-reactive protein increase atrial fibrillation risk? A Mendelian randomization of 47,000 individuals from the general population. , 2010, Journal of the American College of Cardiology.

[153]  M. Allessie,et al.  Electrical, contractile and structural remodeling during atrial fibrillation. , 2002, Cardiovascular research.

[154]  M. Ezekowitz,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. , 2014, Circulation.

[155]  E. Warburton,et al.  Incidence of atrial fibrillation detected by implantable loop recorders in unexplained stroke , 2013, Neurology.

[156]  D. Levy,et al.  Long-term alcohol consumption and the risk of atrial fibrillation in the Framingham Study. , 2004, The American journal of cardiology.

[157]  M A Waclawiw,et al.  Atrial fibrillation is associated with an increased risk for mortality and heart failure progression in patients with asymptomatic and symptomatic left ventricular systolic dysfunction: a retrospective analysis of the SOLVD trials. Studies of Left Ventricular Dysfunction. , 1998, Journal of the American College of Cardiology.

[158]  P. Ellinor,et al.  Locus for Atrial Fibrillation Maps to Chromosome 6q14‐16 , 2003, Circulation.

[159]  M. Hochman Rate Control versus Rhythm Control for Atrial Fibrillation , 2013 .

[160]  P. Dorian,et al.  Quality of life variables in the selection of rate versus rhythm control in patients with atrial fibrillation: observations from the Canadian Trial of Atrial Fibrillation. , 2003, Cardiac electrophysiology review.

[161]  Andre Terzic,et al.  Age- and sex-related atrial electrophysiologic and structural changes. , 2004, The American journal of cardiology.

[162]  Paulus Kirchhof,et al.  Prevalence of unknown atrial fibrillation in patients with risk factors. , 2013, Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology.

[163]  D. Roden,et al.  Close bidirectional relationship between chronic kidney disease and atrial fibrillation: the Niigata preventive medicine study. , 2009, American heart journal.

[164]  W. Oertel,et al.  Evaluation of costs and outcome in cardioembolic stroke or TIA , 2009, Journal of Neurology.

[165]  J. Gardin,et al.  Prevalence of atrial fibrillation in elderly subjects (the Cardiovascular Health Study). , 1994, The American journal of cardiology.

[166]  B. Psaty,et al.  Atrial fibrillation and cognitive decline , 2013, Neurology.

[167]  J. Tolstrup,et al.  Alcohol Consumption and Risk of Atrial Fibrillation in Men and Women: The Copenhagen City Heart Study , 2005, Circulation.

[168]  Josef Coresh,et al.  Chronic Kidney Disease Is Associated With the Incidence of Atrial Fibrillation: The Atherosclerosis Risk in Communities (ARIC) Study , 2011, Circulation.

[169]  Shuichi Kaneko,et al.  AGEs‐RAGE System Mediates Atrial Structural Remodeling in the Diabetic Rat , 2008, Journal of cardiovascular electrophysiology.

[170]  J. Brugada,et al.  Identification of a genetic locus for familial atrial fibrillation. , 1997, The New England journal of medicine.

[171]  Curt D. Furberg,et al.  Physical Activity and Incidence of Atrial Fibrillation in Older Adults: The Cardiovascular Health Study , 2008, Circulation.

[172]  H. Crijns,et al.  A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation , 2002 .

[173]  Thomas Wilke,et al.  Incidence and prevalence of atrial fibrillation: an analysis based on 8.3 million patients. , 2013, Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology.

[174]  D. Roden,et al.  Metabolic Syndrome and Risk of Development of Atrial Fibrillation: The Niigata Preventive Medicine Study , 2008, Circulation.

[175]  S. Lévesque,et al.  Clinical Research Atrial Fibrillation and Congestive Heart Failure: A Cost Analysis of Rhythm-Control vs Rate-Control Strategies , 2013 .

[176]  Vincent Jacquemet,et al.  Loading effect of fibroblast-myocyte coupling on resting potential, impulse propagation, and repolarization: insights from a microstructure model. , 2008, American journal of physiology. Heart and circulatory physiology.

[177]  P. Wenaweser,et al.  Atrial Fibrillation and Aortic Stenosis: Impact on Clinical Outcomes Among Patients Undergoing Transcatheter Aortic Valve Implantation , 2013, Circulation. Cardiovascular interventions.

[178]  Ralph B. D'Agostino,et al.  Parental Atrial Fibrillation as a Risk Factor for Atrial Fibrillation in Offspring , 2004 .

[179]  M. Chung,et al.  C reactive protein concentration and recurrence of atrial fibrillation after electrical cardioversion , 2005, Heart.

[180]  Martha J. Radford,et al.  Validation of Clinical Classification Schemes for Predicting Stroke: Results From the National Registry of Atrial Fibrillation , 2001 .

[181]  S. Nattel New ideas about atrial fibrillation 50 years on , 2002, Nature.

[182]  Thomas Lumley,et al.  Diabetes Mellitus, Glycemic Control, and Risk of Atrial Fibrillation , 2010, Journal of General Internal Medicine.

[183]  I-Min Lee,et al.  Physical Activity and the Risk of Incident Atrial Fibrillation in Women , 2008, Circulation. Cardiovascular quality and outcomes.

[184]  P. Hasselgren,et al.  The selective beta 1-blocking agent metoprolol compared with antithyroid drug and thyroxine as preoperative treatment of patients with hyperthyroidism. Results from a prospective, randomized study. , 1987, Annals of surgery.

[185]  Joseph D. Kay,et al.  Arrhythmia Burden in Adults With Surgically Repaired Tetralogy of Fallot: A Multi-Institutional Study , 2010, Circulation.

[186]  S. Hohnloser,et al.  Impact of rate versus rhythm control on quality of life in patients with persistent atrial fibrillation. Results from a prospective randomized study. , 2003, European heart journal.

[187]  P. Vestergaard,et al.  Alcohol and risk of atrial fibrillation or flutter: a cohort study. , 2004, Archives of internal medicine.

[188]  A. Camm,et al.  Quality of life in patients with silent atrial fibrillation , 2001, Heart.

[189]  G. Lip,et al.  Atrial fibrillation as a risk factor for cognitive impairment: a semi-systematic review. , 2013, QJM : monthly journal of the Association of Physicians.

[190]  Stanley Nattel,et al.  Early management of atrial fibrillation to prevent cardiovascular complications. , 2014, European heart journal.

[191]  R B D'Agostino,et al.  Probability of stroke: a risk profile from the Framingham Study. , 1991, Stroke.

[192]  W. Henry,et al.  Relation between Echocardiographically Determined Left Atrial Size and Atrial Fibrillation , 1976, Circulation.

[193]  James Elber Duverger,et al.  Arrhythmogenic left atrial cellular electrophysiology in a murine genetic long QT syndrome model. , 2011, Cardiovascular research.

[194]  M. Pfeffer,et al.  Cognitive Function and Anticoagulation Control in Patients With Atrial Fibrillation , 2010, Circulation. Cardiovascular quality and outcomes.

[195]  J. Camm,et al.  The impairment of health-related quality of life in patients with intermittent atrial fibrillation: implications for the assessment of investigational therapy. , 2000, Journal of the American College of Cardiology.

[196]  D. Levy,et al.  Relations of Biomarkers of Distinct Pathophysiological Pathways and Atrial Fibrillation Incidence in the Community , 2010, Circulation.

[197]  Stanley Nattel,et al.  Role of the Autonomic Nervous System in Atrial Fibrillation: Pathophysiology and Therapy , 2014, Circulation research.

[198]  P. Engelfriet,et al.  The spectrum of adult congenital heart disease in Europe: morbidity and mortality in a 5 year follow-up period. The Euro Heart Survey on adult congenital heart disease. , 2005, European heart journal.

[199]  Lesley H. Curtis,et al.  Incidence and Prevalence of Atrial Fibrillation and Associated Mortality Among Medicare Beneficiaries: 1993–2007 , 2012, Circulation. Cardiovascular quality and outcomes.

[200]  Maurits A. Allessie,et al.  Reverse Structural and Gap-Junctional Remodeling After Prolonged Atrial Fibrillation in the Goat , 2003, Circulation.

[201]  D. Levy,et al.  Pulse pressure and risk of new-onset atrial fibrillation. , 2007, JAMA.

[202]  Chun-Hsu Pan,et al.  Regulatory mechanisms of atrial fibrotic remodeling in atrial fibrillation , 2008, Cellular and Molecular Life Sciences.

[203]  A. Iorio,et al.  Silent lacunar infarcts in elderly patients with chronic non valvular atrial fibrillation , 1996, Aging.

[204]  StanleyNattel,et al.  Mechanisms of Atrial Tachyarrhythmias Associated With Coronary Artery Occlusion in a Chronic Canine Model , 2011 .

[205]  Silvia G. Priori,et al.  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 PRAC , 2006 .

[206]  Jesper Hastrup Svendsen,et al.  Familial Aggregation of Atrial Fibrillation: A Study in Danish Twins , 2009, Circulation. Arrhythmia and electrophysiology.

[207]  A L Waldo,et al.  A comparison of rate control and rhythm control in patients with atrial fibrillation. , 2002, The New England journal of medicine.

[208]  L H Kuller,et al.  Incidence of and risk factors for atrial fibrillation in older adults. , 1997, Circulation.

[209]  A S Kosinski,et al.  Prevalence and significance of atrial fibrillation in coronary artery disease (CASS Registry). , 1988, The American journal of cardiology.

[210]  G. Feld,et al.  Activation patterns in experimental canine atrial flutter produced by right atrial crush injury. , 1992, Journal of the American College of Cardiology.

[211]  A. Levy,et al.  Cost-Effectiveness of Rhythm versus Rate Control in Atrial Fibrillation , 2004, Annals of Internal Medicine.

[212]  Y. Yeh,et al.  Molecular characterization of thyroid hormone-inhibited atrial L-type calcium channel expression: implication for atrial fibrillation in hyperthyroidism , 2011, Basic Research in Cardiology.

[213]  Stanley Nattel,et al.  Calcium-Handling Abnormalities Underlying Atrial Arrhythmogenesis and Contractile Dysfunction in Dogs With Congestive Heart Failure , 2008, Circulation. Arrhythmia and electrophysiology.

[214]  Catherine R. Rahilly-Tierney,et al.  Regular Physical Activity and Risk of Atrial Fibrillation: A Systematic Review and Meta-analysis , 2013, Circulation. Arrhythmia and electrophysiology.

[215]  Stanley Nattel,et al.  Management of atrial fibrillation in the year 2033: new concepts, tools, and applications leading to personalized medicine. , 2013, The Canadian journal of cardiology.

[216]  Randall J. Lee,et al.  Markers of inflammation before and after curative ablation of atrial flutter. , 2008, Heart rhythm.

[217]  Janet Entwistle,et al.  Analysis and Implications , 2005, Menachem Begin and the Israel-Egypt Peace Process.

[218]  David J. Gladstone,et al.  Potentially Preventable Strokes in High-Risk Patients With Atrial Fibrillation Who Are Not Adequately Anticoagulated , 2009, Stroke.

[219]  S. Nattel,et al.  Atrial fibrillation promotion by endurance exercise: demonstration and mechanistic exploration in an animal model. , 2013, Journal of the American College of Cardiology.

[220]  Stanley Nattel,et al.  Substrate size as a determinant of fibrillatory activity maintenance in a mathematical model of canine atrium. , 2005, American journal of physiology. Heart and circulatory physiology.

[221]  S. Yusuf,et al.  Increased risk of cognitive and functional decline in patients with atrial fibrillation: results of the ONTARGET and TRANSCEND studies , 2012, Canadian Medical Association Journal.

[222]  N. Bursac,et al.  Cardiac fibroblast paracrine factors alter impulse conduction and ion channel expression of neonatal rat cardiomyocytes. , 2009, Cardiovascular research.

[223]  Albert Hofman,et al.  Cigarette smoking and risk of atrial fibrillation: the Rotterdam Study. , 2008, American heart journal.

[224]  J. Auer,et al.  Subclinical hyperthyroidism as a risk factor for atrial fibrillation. , 2001, American heart journal.

[225]  Udo Hoffmann,et al.  Pericardial Fat Is Associated With Prevalent Atrial Fibrillation: The Framingham Heart Study , 2010, Circulation. Arrhythmia and electrophysiology.

[226]  A. Folsom,et al.  Smoking and incidence of atrial fibrillation: results from the Atherosclerosis Risk in Communities (ARIC) study. , 2011, Heart Rhythm.

[227]  H. Ueshima,et al.  Rapid Increase in Estimated Number of Persons with Atrial Fibrillation in Japan: An Analysis from National Surveys on Cardiovascular Diseases in 1980, 1990 and 2000 , 2005, Journal of epidemiology.

[228]  Stephen S. Cha,et al.  Secular Trends in Incidence of Atrial Fibrillation in Olmsted County, Minnesota, 1980 to 2000, and Implications on the Projections for Future Prevalence , 2006, Circulation.

[229]  F A Mathewson,et al.  The natural history of atrial fibrillation: incidence, risk factors, and prognosis in the Manitoba Follow-Up Study. , 1995, The American journal of medicine.

[230]  Sander Verheule,et al.  Increased Vulnerability to Atrial Fibrillation in Transgenic Mice With Selective Atrial Fibrosis Caused by Overexpression of TGF-β1 , 2004, Circulation research.

[231]  B. Lindsay,et al.  Noninvasive Characterization of Epicardial Activation in Humans With Diverse Atrial Fibrillation Patterns , 2010, Circulation.

[232]  J. McMurray,et al.  Cost of an emerging epidemic: an economic analysis of atrial fibrillation in the UK , 2004, Heart.