Skip main navigation

Atrial Fibrillation

Epidemiology, Pathophysiology, and Clinical Outcomes
Originally publishedhttps://doi.org/10.1161/CIRCRESAHA.117.309732Circulation Research. 2017;120:1501–1517

    Abstract

    The past 3 decades have been characterized by an exponential growth in knowledge and advances in the clinical treatment of atrial fibrillation (AF). It is now known that AF genesis requires a vulnerable atrial substrate and that the formation and composition of this substrate may vary depending on comorbid conditions, genetics, sex, and other factors. Population-based studies have identified numerous factors that modify the atrial substrate and increase AF susceptibility. To date, genetic studies have reported 17 independent signals for AF at 14 genomic regions. Studies have established that advanced age, male sex, and European ancestry are prominent AF risk factors. Other modifiable risk factors include sedentary lifestyle, smoking, obesity, diabetes mellitus, obstructive sleep apnea, and elevated blood pressure predispose to AF, and each factor has been shown to induce structural and electric remodeling of the atria. Both heart failure and myocardial infarction increase risk of AF and vice versa creating a feed-forward loop that increases mortality. Other cardiovascular outcomes attributed to AF, including stroke and thromboembolism, are well established, and epidemiology studies have championed therapeutics that mitigate these adverse outcomes. However, the role of anticoagulation for preventing dementia attributed to AF is less established. Our review is a comprehensive examination of the epidemiological data associating unmodifiable and modifiable risk factors for AF and of the pathophysiological evidence supporting the mechanistic link between each risk factor and AF genesis. Our review also critically examines the epidemiological data on clinical outcomes attributed to AF and summarizes current evidence linking each outcome with AF.

    The association of an irregular pulse and mitral stenosis was first described by Robert Adams in 1827, but it was not until the turn of the 20th century when William Einthoven invented electrocardiography that atrial fibrillation (AF) was first recorded on the ECG.1 Its pathogenesis and clinical importance gained enhanced appreciation in the 1990s when early community-based studies, including the FHS (Framingham Heart Study),24 provided critical epidemiological data on associated risk factors (RFs) and clinical outcomes. These associations empowered scientists and clinicians by focusing their attention on specific disease models. Over the past 3 decades, an explosion of research has yielded progress in the clinical treatment of AF at a time when AF is reaching epidemic proportions.

    Our review provides an overview of the pathogenesis of nonvalvular AF and a comprehensive examination of the epidemiological data associating various RFs with AF (Figure 1). For each RF, we highlight key population studies supporting its association and critically review data on how the RF may lead to the development of the AF substrate and AF genesis. Last, we review clinical outcomes associated with AF and discuss possible mechanisms linking these associations. Our review focuses on the epidemiology and pathophysiology of AF rather than its clinical treatment.

    Figure 1.

    Figure 1. Atrial fibrillation (AF) risk factors (RFs) induce structural and histopathologic changes to the atrium that are characterized by fibrosis, inflammation, and cellular and molecular changes. Such changes increase susceptibility to AF. Persistent AF further induces electric and structural remodeling that promotes perpetuation of AF. AF also may lead to the development of additional AF risk factors that further alters the atrial substrate. Finally, AF is associated with several clinical outcomes. *There are limited data supporting the association. BMI, body mass index; ERP, effective refractory period; HF, heart failure; IL, interleukin; MI, myocardial infarction; OSA, obstructive sleep apnea; SEE, systemic embolism event; TNF, tumor necrosis factor; and VTE, venous thromboembolism.

    Pathophysiology and Natural History AF

    AF is characterized by high-frequency excitation of the atrium that results in both dyssynchronous atrial contraction and irregularity of ventricular excitation. Whereas AF may occur in the absence of known structural or electrophysiological abnormalities, epidemiological association studies are increasingly identifying comorbid conditions, many of which have been shown to cause structural and histopathologic changes that form a unique AF substrate or atrial cardiomyopathy.5

    AF Initiation: Ectopic Firing

    The prevailing hypothesis of AF genesis is that rapid triggering initiates propagating reentrant waves in a vulnerable atrial substrate. The relative importance of the initiating trigger may decrease because the AF substrate progresses and AF becomes more stabilized. Haïssaguerre et al6 first identified focal ectopic firing arising from myocyte sleeves within the pulmonary veins (PVs) in patients with paroxysmal AF; ablation of these ectopic foci reduced AF burden, demonstrating their role in AF genesis (Figure 2A). It is now known that the PVs have unique electric properties and a complex fiber architecture that promote reentry and ectopic activity to initiate AF.7 Autopsy studies have identified pacemaker cells, transitional cells, and Purkinje cells within the PVs.8 The molecular basis for PV triggers has been primarily attributed to abnormal calcium Ca2+ handling. A diastolic leak of Ca2+ from the sarcoplasmic reticulum activates an inward Na+ current via Na+Ca2+ exchanger resulting in spontaneous myocyte depolarization (early or delayed afterdepolarization). Hyperphosphorylation of key regulatory proteins and enzymes, including protein kinase A, calmodulin kinase II, phospholamban, and the ryanodine receptor type 2, is important contributors to sarcoplasmic reticulum Ca2+ overload and diastolic membrane instability.9,10 A reentrant mechanism for PV triggers also has been described. Decremental conduction and repolarization heterogeneity within the PV enable localized reentry and may foster a focal driver for AF.11

    Figure 2.

    Figure 2. Rendering of left and right atria showing various mechanisms of atrial fibrillation (AF). A, Focal trigger arising from muscle sleeve of pulmonary vein (PV) propagating into left atrium and initiating AF in the vulnerable substrate. B, Fixed or moving spiral rotor, a result of functional reentry, acts as a driver for AF. C, Circus movement around anatomic structures or scar generating micro- and macro-reentrant circuits. D, Perpetual propagation of multiple simultaneous wavelets mediated by both functional and structural reentries. E, Point source with fibrillatory conduction acting as driver for persistence of AF. F, Electric dissociation between myocardial layers enabling reentry in 3-dimensional construct. CS indicates coronary sinus; IVC, inferior vena cava; LAA, left atrial appendage; LIPV, left inferior pulmonary vein; LSPV, left superior; PG, parasympathetic ganglia (yellow); RIPV, right inferior pulmonary vein; RSPV, right superior pulmonary vein; and SVC, superior vena cava.

    AF Perpetuation: Reentry

    Whereas triggers are required for AF initiation, a vulnerable atrial substrate is equally important. Structural, architectural, and electrophysiological atrial abnormalities promote the perpetuation of AF by stabilizing reentry. The mechanism of reentry in AF remains controversial with 2 dominant hypotheses, including reentrant rotors12,13 or multiple independent wavelets (Figure 2B through 2E).14 Advances in electroanatomic mapping and ablation technologies have yielded increasing evidence supporting the former mechanism.15,16 Recent data supporting a third hypothesis, the double layer hypothesis, suggest that electric dissociation of epicardial and endocardial layers also may facilitate reentry (Figure 2D).17,18

    For perpetuation of functional reentry, the propagating wavefront must complete 1 circus movement in a time period long enough for atrial tissue within that circuit to recover excitability (effective refractory period [ERP]). Thus, slow conduction velocity and a short ERP promote reentry. Both reduce wavelength size increasing the likelihood of multiple simultaneous reentrant circuits and AF perpetuation.

    Atrial substrates that promote reentry are characterized by abnormalities of the atrial cardiomyocyte, fibrotic changes, and alterations in the interstitial matrix with primarily noncollagen deposits.5 These molecular and histological changes impair normal anisotropic conduction (fibrosis and reduced cell coupling) and may shorten atrial ERP. For example, in familial AF, congenital abnormalities that lead to a gain in K+ channel function shorten ERP of atrial cardiomyocytes, whereas, in heart failure (HF), a combination of atrial fibrosis and alterations in cardiomyocyte function results in both a slowing of conduction velocity and shortening of ERP. Thus, the development of and characterization of the vulnerable atrial substrate is specific to the predisposing AF RF.

    Natural History

    For decades, the prevailing notion was that AF began with paroxysmal episodes that increased in frequency and duration causing progression to more persistent AF subtypes. This so-called AF begets AF postulate was based on early experimental data in goats, showing that tachycardia induces electrophysiological atrial remodeling resulting in persistence of AF.19 Regional heterogeneity and shortening of the atrial ERP20,21 occur within 30 minutes of tachycardia onset and are a result of adaptation to intracellular Ca2+ overload.22 In the FHS, only 10% of participants remained free of AF 2 years after incident AF, and recurrent (26%) or sustained AF (34%) was common.23 But other studies suggest that this abiding notion is not ubiquitous. In the CARAF (Canadian Registry of Atrial Fibrillation), progression of paroxysmal AF to more persistent (chronic) AF subtype was 8.6% at 1 year and 24.7% by 5 years.24 The Euro Heart Survey followed 5333 patients with AF for 1 year and found that 80% of patients with paroxysmal AF remained paroxysmal, whereas 30% of patients with persistent AF progressed to permanent.25 Studies in patients with pacemakers allow for more robust assessment of AF burden and have shown that the majority of patients (54%–76%) with paroxysmal AF remain paroxysmal.26,27 One study showed that only 24% of patients with paroxysmal AF progressed to persistent AF in 1 year and that there was a progressive pattern of increasing arrhythmia burden in these patients except in the days before the development of persistent AF supporting the mechanism of tachy-mediated atrial remodeling.27

    The most remarkable observation is that persistent AF may spontaneously switch to paroxysmal subtype,26 highlighting the complex natural history of AF, the limitations of experimental data, and the existing uncertainty in the mechanisms and factors that govern the clinical course of AF. In addition, the natural history of AF may change over time because the RFs contributing to AF onset shift in prevalence and severity (eg, less smoking and lower blood pressures, higher prevalence of obesity), and primary (eg, better hypertension control) and secondary (anticoagulation) prevention treatments evolve.28 Finally, the means for quantifying and assessing AF burden over time in various population studies is inconsistent leading to ascertainment bias and challenges in predicting the natural history of AF subtypes.

    RFs for Developing AF

    Unmodifiable RFs

    Genetics
    Epidemiology

    Near the start of the millennium, rare familial forms of AF were identified, and loci were mapped to 10q22-24,29 6q14-16,30 and 11p15-5.31 Subsequent population-based studies showed that family history of AF is associated with a 40% increased risk of first-degree relatives developing AF.32,33 The recognition of the heritability of AF in the general population has propelled the search for associated genetic loci.34

    Classic Mendelian genetics and candidate gene approaches have been used to define the familial basis of AF. To date, at least 15 AF-causing mutations in K+ channel genes or accessory subunit have been identified,34 including mutations in ABCC9 (IKATP), HCN4 (If), KCNA5 (IKur), KCND3 (IKs), KCNE1 (IKs), KCNE2 (IKs), KCNE3 (IKs), KCNE4 (IKs), KCNE5 (IKs), KCNH2 (IKr), KCNJ2 (IK1), KCNJ5 (IKAch), KCNJ8 (IKATP), KCNN3 (IAHP), and KCNQ1 (IKs). Gain-of-function mutations increase repolarizing K+ current shortening the action potential duration (APD) and atrial refractoriness. Loss-of-function mutations delay repolarization and promote Ca2+ mediated afterdepolarization that triggers AF.35,36 Six variations in Na+ channel genes have been identified, and these include SCN1B, SCN2B, SCN3B, SCN4B, SCN5A, and SCN10A.34 Gain-of-function mutations may increase AF vulnerability by increasing cellular hyperexcitability,37 whereas loss-of-function mutations shorten ERP and slow conduction.38 Other important AF-causing genetic variants include mutations in the gap junctional protein-coding gene GJA5 that diminishes cell–cell coupling and promotes reentry by slowing conduction velocity and shortening the wavelength.39

    Instead of isolating a specific AF-causing gene, genome-wide association studies seek to scan the entire genome for disease-related genetic variants in single-nucleotide polymorphisms (SNPs). The first genome-wide association study for AF identified SNP rs2200733 located on chromosome 4q25 upstream of PITX2 in an Icelandic population, which was strongly replicated in samples from Sweden, United States, and Hong Kong.40 A meta-analysis of 3 AF susceptibility loci (4q25, 1q21, and 16q22) showed that the chromosome 4q25 SNP rs2200733 was associated with 30% increased risk of recurrent atrial tachycardia after AF ablation.41 In a separate meta-analysis, this locus was associated with 38% increased risk of cardioembolic stroke.42

    In experimental mouse models, the Pitx2 gene encodes a transcription factor important for the embryonic organogenesis of the asymmetrical organs placed in the left side, including the heart.43 Moreover, Pitx2c is involved in the formation of the PV muscle sleeves,44 the most common site of triggered activity in AF. Loss of function of Pitx2c gene plays a role in the development of AF, and the differentiation, proliferation, and expansion of pulmonary myocardial cells.45,46

    In separate genome-wide association studies, the SNP rs2106261 near gene ZFHX3 identified on locus 16q22 was associated with increased AF risk. A knockdown of ZFHX3 dysregulates Ca2+, shortens the APD, and promotes arrhythmia susceptibility.47

    AFGen consortium was formed in 2008 to increase statistical power for identifying loci associated with AF.48 To date, 17 independent susceptibility signals for AF at 14 genomic regions have been identified. These include KCNN3, PRRX1, CAV1, SYNE2, C9orf3, HCN4, and MYOZ1.49,50 The identification of genes related to AF is still in an early stage but in the future may allow for the assessment of an individuals’ AF risk and the discovery of novel therapeutic targets.

    Age
    Epidemiology

    Advancing age is the most prominent RF for AF.28 Understanding the influence of age on AF risk is important for assessing how changes in life expectancy will affect the prevalence of AF.

    Although the prevalence of AF varies among different ethnic populations, epidemiological studies have consistently found a stepwise increase in the prevalence of AF with advancing age.5153 For example, a population-based multicenter cohort study reported age-specific rates in individuals aged 65 to 74 and 75 to 84 years of 3.4 (95% confidence interval [CI], 1.4–7.0) and 8.6 (95% CI, 4.6–14.9) for Chinese, 4.9 (95% CI, 3.1–7.3) and 10.6 (95% CI, 7.2–15.1) for non-Hispanic blacks, 7.3 (95% CI, 4.7–10.7) and 9.4 (95% CI, 5.9–14.4) for Hispanics, and 13.4 (95% CI, 10.6–16.7) and 19.6 (95% CI, 15.6–24.3) for non-Hispanic whites, respectively.51

    The incidence of AF also increases with advancing age. In a Scottish study, the incidence rates per 1000 person-years was 0.5 for age 45 to 54 years, 1.1 for age 55 to 64, 3.2 for age 65 to 74, 6.2 for age 75 to 84, and 7.7 for age ≥85 years.53

    The FHS examined temporal trends in AF RFs. During the past 5 decades, age was observed to be the greatest RF for AF when compared with other RFs, including male sex, body mass index (BMI), diabetes mellitus, smoking, alcohol consumption, systolic blood pressure, hypertension treatment, left ventricular hypertrophy, heart murmur, HF, and myocardial infarction (MI).28 In the most recent time period studied (1998–2007), participant age of 60 to 69, 70 to 79, and 80 to 89 years was associated with 4.98-, 7.35-, and 9.33-fold risk of AF, respectively, compared with individuals aged 50 to 59 years.28 Accordingly, a stepwise increment in age has been incorporated in AF risk prediction scores.54,55 Among AF patients, those with age <65 years also have been found to be healthier, have a different AF RF profile, and less in-hospital deaths compared with those age ≥65 years.56

    Sex Differences
    Epidemiology

    There is now greater recognition that epidemiology of AF differs between men and women.57 The age-adjusted incidence of AF is higher in men compared with women in North American and European populations. In the FHS, the AF incidence (per 1000 person-years) was 3.8 in men and 1.6 in women.28 The Olmsted County Minnesota Study58 and the Rotterdam Study59 reported the AF incidence (per 1000 person-years) in men to be 4.7 and 11.5, respectively, compared with 2.7 and 8.9 in women. A higher incidence of AF in men also is observed in Asian populations, although less data are available.60,61 Similarly, the age-adjusted prevalence of AF is higher in men than in women in North American and European populations. Among the Medicare beneficiaries of adults aged ≥65 years, the prevalence was 10.3% in men and 7.4% in women.62 The higher prevalence of AF in men is also observed globally in both high-income and low- and middle-income countries.60 However, there are less consistent data in Asian countries with some studies showing higher prevalence in men,61,63,64 whereas others showed no sex difference.52,65,66

    In North American and European populations, the lifetime risk for AF is similar between men and women despite higher AF incidence in men owing to their shorter life expectancy.57 The FHS reported that the lifetime risks to develop AF at age 40 years were 26% for men and 23% for women.67 In the Rotterdam Study, the lifetime risks at age 55 years were 23.8% for men and 22.2% for women.59 On the contrary, among Chinese adults, the lifetime risk was consistently lower in men compared with women across all age groups.52

    Underlying RFs of AF and taller stature in men largely explain higher AF incidence in men.57 The CHARGE-AF consortium reported that after adjusting for AF-related RFs, male sex was no longer an independent RF for AF.54 The population attributable risks of the RFs for AF differ by sex.57 The population attributable risk for AF of coronary disease is higher in men,2 whereas the population attributable risks of elevated systolic blood pressure57 and valvular disease2 are higher in women.

    Racial Differences
    Epidemiology

    Many of the early population-based studies in AF were limited by racial diversity. However, in the last decade, there has been a determined initiative to better understand the racial and ethnic differences in AF prevalence, pathophysiology, and outcomes.

    Numerous studies demonstrated that AF is less prevalent in individuals of African when compared with European ancestry.51,6872 These data seem counterintuitive given the higher prevalence of traditional AF RFs in blacks than whites.68,73 The Candidate Gene Association Resource Study68 found that among blacks, the risk of AF was independently associated with increasing percentage of European ancestry (hazard ratio [HR], 1.13; 95% CI, 1.03–1.23). Adjusted associations showed that with every 10% increase in European ancestry, there was a 16% to 20% increased risk of AF. The data are consistent with the hypothesis that either African ancestry has protective effect against AF or European ancestry enhances AF susceptibility.

    Candidate SNP analysis performed in 2 cohorts showed that the rs10824026 SNP located on the 10q22 genetic locus accounted for 11.4% to 31.7% increased AF risk in white individuals when compared with blacks.74 Furthermore, the minor allele G of the SNP confers low AF risk49 and is more common in blacks (37.7%–37.8%) when compared with white individuals (15.5%–16.4%).74 In a separate study that combined 3 cohorts with European and black descent, an intronic SNP rs4845625 of the IL6R gene was associated with AF in white individuals (relative risk, 0.9; 95% CI, 0.85–0.95) and in blacks (relative risk, 0.86; 95% CI, 0.72–1.03 with borderline significance P=0.09).75 Finally, the SNP rs4611994 on chromosome 4 near PITX2 was associated with AF risk in blacks (HR, 1.4; 95% CI, 1.16–1.69), and this chromosomal locus is associated with AF in white individuals.40 Although traditional AF RFs are well recognized, there are increasing data that race, ethnicity, and attributed genetic ancestral variants may play a significant role in modulating AF susceptibility.

    More recently, the MESA (Multi-Ethnic Study of Atherosclerosis) reported the prevalence of AF in Hispanic and Asians residing in the United States. The age- and sex-adjusted incidence rates per 1000 person-years of AF were 6.1 in Hispanics and 3.9 in Asians when compared with 11.2 in white and 5.8 in black individuals.51 These data are comparable to The Healthcare Cost and Utilization Project that reported that Hispanics and Asians had multivariable-adjusted lower risk of AF (HR, 0.78; 95% CI, 0.77–0.79) when compared with whites.73 Both studies showed that a larger proportion of AF in nonwhites was attributed to the greater presence of traditional RFs particularly hypertension when compared with whites.

    Modifiable RFs

    Physical Activity and Sedentary Lifestyle
    Epidemiology

    The relationship between level of physical activity and risk of AF has been described as nonlinear.7678 Sedentary lifestyle is associated with higher risk of AF,79 but paradoxically extreme levels of physical activity also are associated with increased AF risk.8082

    A large retrospective cohort study of 64 561 patients showed a graded and inverse relationship between cardiorespiratory fitness as objectively assessed with treadmill testing. The incidence rate of AF in patients with lowest cardiorespiratory fitness was 18.8% when compared with 3.7% in those with highest cardiorespiratory fitness. Every 1-MET increase in cardiorespiratory fitness was associated with a dose dependent 7% reduction in AF risk.83 A meta-analysis of pooled data from 7 studies showed that sedentary lifestyle was associated with increased risk of AF (odds ratio [OR], 2.47; 95% CI, 1.25–3.7) compared with moderate or intense physical activity.82

    Interesting and seemingly contradictory male endurance athletes are at increased AF risk. In a prospective case–control study, individuals who had performed <2000 hours of lifetime-accumulated high-intensity exercise had an attenuated risk of lone AF (OR, 0.38; 95% CI, 0.12–0.98) when compared with sedentary individuals. But the AF risk in those with ≥2000 hours of high-intensity exercise was increased (OR, 3.88; 95% CI, 1.55–9.73).76 The type of exercise modulates AF risk with endurance sports, such as marathon running76 or long-distance cross-country skiing,80 conferring the highest AF risk. A meta-analysis showed that there was over a 5-fold increased risk of AF in athletes than nonathlete referents.84

    Sex differences in the association of physical activity with AF have been identified. In men, a U-shaped association of AF risk and physical activity was observed where moderate physical activity was found to confer lowest risk (OR, 0.81; 95% CI, 0.26–1.00) and intense activity conferred the highest risk (OR, 3.30; 95% CI, 1.97–4.63). In women, however, the association was inverse and linear. Increasing physical activity was associated with progressive and decreasing AF risk with ORs of 0.91 (95% CI, 0.77–0.97) and 0.72 (95% CI, 0.57–0.88) for moderate and intense activity, respectively.82

    Pathophysiology

    Sedentary lifestyle is known to increase risk of AF RFs, including hypertension,85 obesity,85 and diabetes mellitus.86 Obstructive sleep apnea (OSA) is common in obese individuals and has been associated with sedentary lifestyle.87 These conditions have been shown to independently induce structural and electric remodeling of the atrium. Physical inactivity also increases systemic inflammation,88 which may induce atrial remodeling and has been associated with AF.8993 Finally, sedentary lifestyle is associated with autonomic dysfunction and elevated sympathetic tone, which enhances afterdepolarization triggering and AF susceptibility.

    In endurance athletes, the pathogenesis of AF has been attributed to 2 primary mechanisms. First, increased vagal tone in these individuals82,94 may shorten and increase the dispersion of atrial ERP promoting PV firing and localized reentry. Second, long-term endurance training causes progressive cardiac remodeling, including left atrial enlargement, which may promote AF.9597 Atrial fibrosis and increased AF susceptibility has been observed in a rat model of prolonged, intensive exercise.98

    Smoking
    Epidemiology

    Smoking is associated with incident AF.54,99 The FHS showed that within the past 50 years, the frequency of smoking among participants with new-onset AF has decreased. Between 1998 and 2007, only 12.7% of AF-affected participants were smokers when compared with 15.6% in the previous decade.28

    The Rotterdam Study found that both former and current smoking were equally associated with increased AF risk.100 In the ARIC study (Atherosclerosis Risk in Communities Study), the multivariable-adjusted incidence of AF was 1.58× higher in ever smokers (former and current) and 2-fold higher (HR, 2.05) in current smokers when compared with nonsmokers.99 A dose–response association was observed with increasing cigarette-years.99 In the CHARGE-AF consortium, incident AF was 1.44× higher in current smokers when compared with nonsmokers.54 Smoking is an RF for AF across various races and ethnicities.54,99,101

    Finally, secondhand tobacco exposure also has been associated with risk of AF.102 Exposure during gestational development or early childhood is associated with ≈40% increased risk of AF.103

    Pathophysiology

    Smoking is thought to increase AF susceptibility through indirect and direct mechanisms. Smoking may increase myocardial ischemia by increasing systemic catecholamine and myocardial work, reducing oxygen carrying capacity, and promoting coronary vasoconstriction.104 In addition, smoking accelerates atherosclerosis through effects on lipids, endothelial function, oxidative stress, inflammation, and thrombosis.105 These effects may indirectly increase AF susceptibility by predisposing to atrial ischemia, MI, and HF. Reduced lung function and chronic obstructive pulmonary disease also increase vulnerability to AF.106

    Smoking and nicotine also have been shown to directly contribute to the AF substrate. In a case–control study of patients undergoing coronary artery bypass, the volume of atrial fibrosis in smokers was shown to be dose dependent, and in nonsmokers, nicotine was shown to induce a pattern of collagen type III expression in atrial tissue culture that was similar to that observed in smokers.107 In a dog model, nicotine induced interstitial fibrosis and increased AF susceptibility.108 The profibrotic effect of nicotine was attributed to downregulation of atrial microRNAs, miR-133, and miR-590, which in turn increased transforming growth factors-b1 and -b2 and connective tissue growth factor. Finally, nicotine prolongs the APD by blocking the inward rectifier potassium channel (Ik1 and Kirs)109 and reduces the transient outward potassium current (Ito).110 Prolongation in the APD may increase arrhythmia susceptibility, but the proarrhythmic effect of nicotine has not been confirmed.

    Obesity
    Epidemiology

    Both obesity and elevated BMI predispose to established AF RFs, including hypertension,111 diabetes mellitus,112 MI,113 left ventricular hypertrophy,114 left atrial enlargement,115 left ventricular diastolic dysfunction,116 HF,117 and OSA.2 However, when accounting for these concomitant conditions, population studies show that obesity and elevated BMI independently increase risk for AF.

    Numerous population-based studies have shown an association between elevated BMI and increased risk of AF.118120 A meta-analyses of 5 studies found that obesity confers a 49% increased risk of developing AF.121 A dose–response relationship was observed with each 1 U increase in BMI associated with a 3% to 4.7% increase in AF risk.118,122,123 Other measures of obesity, including abdominal circumference and total fat mass, have been associated with 13% to 16% increase in AF risk per 1 SD over 10-year follow-up.124 Importantly, obesity is a powerful predictor of incident AF even when regression analyses have been adjusted for OSA, which commonly coexists in such patients.123

    Pathophysiology

    Excess AF risk associated with obesity has been attributed to left atrial enlargement,118 increased left ventricular mass,114 and diastolic dysfunction.116,125,126 In a sheep model of obesity, increasing weight correlated with increased left atrial volume and pressure, ventricular mass, and pericardial fat. Histological analysis revealed that myocardial lipidosis, fibrosis, and inflammatory infiltrates increased progressively with increasing weight. These pathological changes were associated with decreased conduction velocity and increased AF.127 Whereas no change in atrial ERP was observed in the sheep model, a clinical study of 63 patients undergoing PV isolation reported that elevated BMI was associated with short atrial ERP and slower atrial conduction velocity,128 properties that promote reentry.

    Pericardial fat also has been implicated in the pathogenesis of the obesity–AF relation. Cross-sectional studies have shown that pericardial fat is associated with prevalence, severity, and recurrence of AF.129,130 A recent meta-analysis of 23 studies correlated epicardial adipose tissue with AF after adjusting for traditional RFs (OR, 1.47 per SD epicardial adipose tissue increase; 95% CI, 1.17–1.84).131 A local paracrine effect of epicardial adipose tissue mediated by inflammatory cytokines,132 growth and remodeling factors,133 angiogenic factors, and adipocytokines may lead to the development of the AF substrate.133,134 Epicardial adipose tissue location on CT imaging correlates with high dominant excitation frequency during electroanatomic mapping in patients undergoing AF ablation.135

    Diabetes Mellitus
    Epidemiology

    The FHS showed that men and women with diabetes mellitus had a 40% and 60% increased risk of AF, respectively.2 Level of blood glucose may be more predictive than actual diagnosis of diabetes mellitus in older adults.136 A meta-analysis of cohort and case–control studies found that patients with diabetes mellitus or impaired glucose homeostasis had a 34% greater risk of AF than individuals without diabetes mellitus.137 A causal association is supported by evidence that worse glycemic control and longer duration of diabetes mellitus are associated with increased AF risk.138 The estimated risk of AF increases by 3% per additional year of diabetes mellitus. The risk of AF in patients with diabetes mellitus for >10 years was 64% but only 7% in those with diabetes mellitus ≤5 years.

    Pathophysiology

    Glucose intolerance and insulin resistance seem to mediate the development of the AF substrate.139 The molecular mechanism by which insulin resistance alters cardiac structure is complex and involves impaired mitochondrial function and oxidative stress, which alter the transcription and translation processes essential for cardiac adaptation.140,141 In a rat model of diabetes mellitus, prolonged intra-atrial conduction time and diffuse interstitial fibrosis were observed, predisposing to increased arrhythmogenicity.142 In patients undergoing AF ablation, abnormal glucose metabolism was associated with prolonged atrial activation time and reduced bipolar voltages with electroanatomic mapping, a finding consistent with atrial fibrosis or scar.143 Finally, autonomic dysfunction also has been implicated.144

    Obstructive Sleep Apnea
    Epidemiology

    OSA is highly prevalent145 and has been associated with other AF RFs, including hypertension, diabetes mellitus, coronary heart disease, MI, and HF.146 The Sleep Heart Health Study found a 4-fold increase in the prevalence of AF with OSA, and one third of participants had arrhythmia during sleep.147 The Olmsted County Study similarly found that OSA and its severity strongly predicted 5-year incidence of AF (HR, 2.18; 95% CI, 1.34–3.54). In older individuals, only the magnitude of nocturnal oxygen desaturation was predictive of AF.125 Similarly, a meta-analysis of 5 of prospective studies reported that OSA was associated with about a 2-fold increased odds of postoperative AF.148 Patients with OSA have a higher recurrence of AF after cardioversion149 and catheter ablation (relative risk, 1.25; 95% CI, 1.08–1.45).150

    The impact of OSA on AF outcomes was studied in the ORBIT-AF registry.151 Patients with OSA had more severe symptoms and were at higher risk of hospitalization (HR, 1.12; 95% CI, 1.03–1.22) than those without OSA, but had similar mortality, risk of stroke, or MI. Patients with OSA who were treated with CPAP were less likely to progress to permanent AF subtype than those who were untreated (HR, 0.66; 95% CI, 0.46–0.94).

    Pathophysiology

    Electroanatomic mapping in patients undergoing AF ablation has been used to characterize the AF substrate associated with OSA.152 Observed structural changes included increased atrial size and expansive areas of low voltage or electric silence, which indicate fibrosis, loss of atrial myocardium, or electric uncoupling. Prolonged and regional disparities in atrial conduction also were seen. AF associated with OSA tends to be refractory to cardioversion and catheter ablation particularly in patients with untreated OSA, highlighting the expansive atrial remodeling associated with OSA.149 In a rat model of AF, OSA was associated with atrial conduction slowing attributed to connexin-43 downregulation and increased atrial fibrosis. Such atrial remodeling promoted the persistence of AF.153

    Several mechanisms may account for the development of AF and the AF substrate in patients with OSA. First, surges of sympathetic activity induced by hypoxia and the chemoreflex near the end of an apneic episode result in transient blood pressure rises.154 Second, vigorous inspiratory efforts during apnea accentuate the fluctuation of intrathoracic pressure increasing left atrial volume (stretch) and pressure.155 Third, an increase in oxidative stress signaling156 and systemic inflammatory mediators157 may promote atrial remodeling. Fourth, hypercapnia acutely prolongs ERP and slows conduction velocity, but with return of eucapnia delayed recovery of conduction has been associated with increased AF vulnerability.158 Fifth, negative tracheal pressure shortens atrial ERP and atrial monophasic action potential via vagal stimulation, which enhances AF inducibility.159

    High Blood Pressure
    Epidemiology

    In the FHS, the RF-adjusted OR for AF was 1.5 and 1.4 in men and women with hypertension, respectively.160 Later studies, including the FHS, found a limited association with mean arterial pressure but found that pulse pressure was highly predictive of AF risk.161 The CHARGE-AF consortium observed that both systolic and diastolic blood pressure were predictive of AF risk.54 In addition, systolic blood pressure that approaches the upper limit of normal is associated with increased AF risk in healthy, middle-aged men162 and women.163 The Women’s Health Study also showed that when an individual’s blood pressure remained elevated at follow-up visits, the risk of AF was higher when compared with those whose subsequent blood pressure recordings were lower suggesting a role for secondary prevention.163 The recent 50-year analysis of the FHS showed that although the rate of treated hypertension increased and severe hypertension became less prevalent, the population attributed risk of AF was unaffected suggesting that antihypertensive therapy does not completely eliminate the elevated AF risk associated with hypertension.28

    Pathophysiology

    Increased left atrial size is a well-established, independent predictor of AF,160,164 but other pathological features of chronic hypertension, including left ventricular hypertrophy160,164,165 and impaired diastolic dysfunction,166 are also associated with AF. Common to all is an elevated left ventricular end-diastolic pressure, which increases left atrial pressure and volume. Atrial remodeling is associated with slower and more heterogeneous atrial conduction and increased PV firing. In addition, increased left atrial mass supports multiple reentry circuits.

    Studies of animal models of hypertension have reported that early left atrial remodeling is characterized by atrial dilation with hypertrophy, reduced atrial ejection fraction, increased refractoriness, and prominent inflammatory infiltrates.167 Chronically, interstitial fibrosis and conduction slowing and heterogeneity are observed.167,168 Moreover, increased atrial apoptosis has been observed.168 Electrophysiology studies in patients with chronically treated hypertension, but without AF, have shown global conduction slowing, regionally delayed conduction in the crista terminalis, and increased AF inducibility.169

    Animal studies have suggested that the renin–angiotensin–aldosterone system (RAAS), which stimulates myocyte hypertrophy and intracellular fibrosis, also may contribute to atrial remodeling.170172 Although upstream RAAS blockage was effective in animal models for reducing AF remodeling, 2 separate meta-analyses have reported that the benefit of RAAS blockade was limited to patients with HF or left ventricular hypertrophy.173,174

    Clinical Outcomes

    Stroke

    Epidemiology

    AF is associated with increased risk of stroke and transient ischemic attack175,176; furthermore, AF-related strokes increase the risk of long-term disability or death.3

    In the FHS, the attributable risk of AF for stroke was 1.5% among 50 to 59 years olds, whereas among 80 to 89 years olds, it was 23.5%.176 Often AF is asymptomatic and consequently subclinical; however, in patients with implanted cardiac devices, including pacemaker and defibrillators, the burden of AF, including subclinical AF, may be accurately assessed. Atrial tachyarrhythmia (atrial rate >190 bpm) for longer than 6 minutes has been associated with an increased risk of clinical AF (HR, 5.56; 95% CI, 3.78–8.17) and ischemic stroke (HR, 2.50; 95% CI, 1.28–4.89).177

    The risk of stroke with AF is variable and is modulated by other RFs, including age ≥65, hypertension, diabetes mellitus, previous stroke/transient ischemic attack/thromboembolism history, vascular disease, HF, and female sex.178180 Stroke risk models incorporating these RFs have been validated.181

    Strokes in AF patients are associated with increased morbidity and mortality. In the Copenhagen Stroke Study, compared with individuals without AF, patients with AF had higher rates of in-hospital death (OR, 1.7; 95% CI, 1.2–2.5), longer hospital stay (50 verses 40 days; P<0.001), and lower rates of discharge home (versus care facility; OR, 0.60; 95% CI, 0.44–0.85).182 Moreover, the infarct was larger and more commonly involved the cerebral cortex in patients with AF. The same study also showed that the odds for silent infarcts were similar for patients with AF and non-AF (OR, 0.99; 95% CI, 0.65–1.5).182 Correspondingly, the FHS showed increased 30-day mortality in AF-associated strokes than non-AF strokes (OR, 1.84; 95% CI, 1.04–3.27). Individuals with AF had worse 1-year survival after stroke and increased risk of stroke recurrences compared with those with non-AF strokes.3

    Pathophysiology

    Thrombogenesis in AF is not fully elucidated. A confluence of factors, including blood stasis, endothelial dysfunction, and prothrombotic state, has been implicated.

    Attention has focused on the left atrial appendage (LAA). Animal models of AF demonstrate atrial contractile dysfunction from reduced myofibrillar sensitivity to Ca2+183 and intracellular Ca2+ transients.184 Clinically, reduced LAA emptying velocity on transesophageal echocardiography is associated with the presence of spontaneous echo contrast, increased LAA thrombus, and stroke.185 In vitro studies have attributed spontaneous echo contrast to erythrocytes and fibrinogen interaction under low flow and shear stress.186 The role of LAA in AF-related stroke is further supported by efficacy of LAA closure devices for reducing strokes in patients with AF.187

    Observational studies have revealed abnormalities in coagulation in patients with AF-related strokes. Increases in prothrombin fragment and thrombin–antithrombin complexes have been observed in patients with AF-related strokes188 and in those with transesophageal spontaneous echo contrast.189 Other hemostatic factors have been implicated in contributing to the hypercoagulable state, including fibrinogen, d-dimer, factor VIII, and von Willebrand factor.188,190193 However, in an adjusted model, the FHS showed that such abnormalities are ascribed to AF RFs and presence of cardiovascular disease rather than AF alone.194 Finally, inflammation may mediate endothelial dysfunction and hypercoagulability.

    Extracranial Systemic Thromboembolism

    Epidemiology

    Compared with AF-related stroke, relatively less is known about epidemiology of extracranial systemic embolism events (SEEs). Data from the Danish Atrial Fibrillation Cohort showed an association between hospital diagnosis of AF and increased relative risk of SEEs in men (relative risk, 4.0; 95% CI, 3.5–4.6) and women (relative risk, 5.7; 95% CI, 5.1–6.3). Nearly, half of SEEs occurred in patients between the ages of 70 and 79 years. The highest risk period for SEE was during the first year of incident AF, which is consistent with stroke data.195

    More contemporary data are derived from a pooled analysis of 4 AF antiplatelet and anticoagulation trials with 37 973 patients from >40 countries.196 During the mean follow-up of 2.4 years, there were 221 SEEs accounting for 11.5% of clinically apparent embolic events. The incidence rates per 100 person-years for SEE and stroke were 0.24 and 1.92, respectively. Anatomically, SEEs were more likely to involve the lower extremities (58%) and mesenteric circulation (22%), whereas involvement of splenic and renal circulation was less common. Finally, increased morbidity and mortality was associated with SEE because 64% of patients required an interventional procedure or amputation and 24% died within 30 days.

    Pathophysiology

    The mechanisms underlying thromboembolism with SEE are similar to that of AF-related strokes.

    Dementia

    Epidemiology

    Whereas dementia and AF share similar RFs, including advancing age, obesity, diabetes mellitus, and hypertension, AF is associated with an adjusted increased risk of cognitive impairment,197,198 dementia,197,199202 Alzheimer’s dementia,203 and vascular dementia202 in patients with and without a history of stroke. In patients with normal baseline cognitive function and no history of stroke, meta-analysis of 8 studies found a significantly increased risk of incident dementia in those with AF (HR, 1.42; 95% CI, 1.17–1.72).200 In patients with history of stroke, 2 meta-analyses have shown that AF is associated with ≈ 2.5-fold adjusted risk of cognitive impairment and dementia.197,199 Twenty-year follow-up of the Rotterdam Study reported AF patients <67 years of age had greatest risk of dementia. The dementia risk increased with AF duration (exposure), whereas there was no increased risk associated with AF duration in those ≥67 years of age.201

    Pathophysiology

    Multiple mechanisms may explain the association of AF and dementia. Nearly, one third of patients with AF have been observed to have silent brain infarcts on brain magnetic resonance imaging,204 and micro-thromboembolisms with covert infarction have been implicated as 1 possible mechanism. The FHS showed that over the past 3 decades, the incidence of dementia, including dementia associated with AF, has decreased.202 During this time period, there has been improved use of anticoagulation in individuals with AF supporting the hypothesis that anticoagulation may reduce AF-associated dementia. This supposition is supported by a retrospective study of patients receiving long-term warfarin showing that incident dementia was 2.4× higher in individuals with AF versus those without AF and that the dementia risk in those with AF and non-AF was significantly mitigated by increasing time in therapeutic range.205

    A second possible mechanism may involve cerebral hypoperfusion associated with AF.206,207 Interestingly, 1 study indicated that the effect of AF on cerebral perfusion was most pronounced in younger patients (<50 years) and that no difference was observed in those >65 years of age206 consistent with epidemiological data showing age-dependent dementia risk in AF patients.201

    Heart Failure

    Epidemiology

    HF is both an RF and an adverse clinical cardiovascular outcome associated with AF. The association was first recognized in the 1940s,208 and it is now established that HF and AF often coexist,2 predispose to the other,209 and share common RFs, including hypertension, diabetes mellitus, coronary disease, and valvular disease.

    HF as a RF for AF

    In major HF trials, the prevalence of AF in patients with HF ranges from 13% to 27%,210212 and the prevalence increases with increasing New York Heart Association Functional Class.213 In the FHS, HF was associated with 4.5-fold risk of AF in men and 5.9-fold risk in woman.2 Other epidemiological studies showed 2.67- to 3.37-fold risk of AF associated with HF.214,215 Incremental reductions in systolic function are associated with increasing AF risk.164 HF with preserved ejection fraction (HFpEF) also confers an increased risk of developing AF (HR adjusted for age and sex, 3.75; 95% CI, 2.19–6.40) with grade IV diastolic dysfunction as assessed with echocardiography conferring the highest risk.166

    HF as an Outcome Associated With AF

    The FHS uniquely reported the joint incidence of AF and HF and their temporal relationship. Among 931 participants with HF, 24% had previous or concurrent AF, and 17% subsequently developed AF. One fifth of participants had AF and HF detected on the same day,209 demonstrating the closely interlinked pathophysiology. The incidence of first HF in FHS participants with AF is 33 per 1000 person-years,209 which is comparable to that observed in the Danish nationwide cohort study.216 In a contemporary FHS cohort, the incidence of HF was markedly higher in participants with AF than the incidence of AF in those with antecedent HF.217 In other words, AF begets HF more than HF begets AF.

    The association of AF on HF subtype has also been reported. AF precedes HFpEF more commonly than HF with reduced ejection fraction. Among patients with prevalent AF, the adjusted HRs of incident HFpEF and HF with reduced ejection fraction were 2.34 (95% CI, 1.48–3.70) and 1.32 (95% CI, 0.83–2.10), respectively.217 The finding that AF is more predictive of HFpEF is consistent with increased incident AF in patients with HFpEF versus HF with reduced ejection fraction and suggests shared common mechanisms.166

    In the FHS, the combination of AF and HF was associated with reduced survival.209 Among patients with prevalent AF, incident HF was associated with increased all-cause mortality compared with those without HF (HR, 1.25; 95% CI, 1.04–1.51).217 In one of the largest, worldwide studies, HF was found to be the leading cause of death 1 year after new onset of AF accounting for nearly a third of all deaths.218 A meta-analysis showed a significantly higher all-cause mortality in AF patient with HF with reduced ejection fraction than those with HFpEF (relative risk, 1.23; 95% CI, 1.12–1.36) despite similar risk of stroke and HF hospitalizations.219

    Pathophysiology

    The strong association of HF and AF has been attributed to shared mechanisms that lead to neurohormonal and proinflammatory activation, which induces myocardial inflammation and fibrosis. The atrial substrate with HF is characterized by atrial fibrosis and abnormalities in Ca2+ handling. It is distinct from the electrophysiological changes associated with AF-induced atrial remodeling.220 Studies in dogs221 and humans222 indicate that HF induces an AF-susceptible atrial substrate without significantly altering atrial ERP (except at rapid rates) or ERP heterogeneity. These findings differ from the AF begets AF model with reduced atrial ERP. Histological studies in HF dogs revealed structural changes, including interstitial fibrosis with cellular hypertrophy, degeneration, and loss. These changes were associated with regions of delayed conduction and AF susceptibility. In human, extensive atrial fibrosis has been observed at autopsy in patients with dilated cardiomyopathy,223 and areas of low voltage or electric silence (scar) and fractionated or delayed potentials (slow conduction) have been identified during electrophysiology studies in patients with HF (but no AF).222 Neurohormonal activation is central to the generation of the AF substrate with HF, and the milieu of profibrotic mediators is induced through angiotensin-dependent and angiotensin-independent pathways.224 Meta-analyses demonstrate benefit of upstream RAAS inhibition in AF patients with HF, but not in AF patients with other comorbidities, highlighting the unique pathophysiology of AF with HF.174,176 Oxidized calmodulin-dependent protein kinase II has been shown to be a molecular signal that is increased by RAAS activation and is a common promoter of sinus node dysfunction, AF, and HF; thus, reducing this kinase with RAAS block may explain the benefit of upstream therapy in patients with both AF and HF.225,226

    Increased trigger activity also is associated with HF and may increase risk of AF in the vulnerable substrate by generating a rapid burst of ectopic firing or maintaining a focal driver. In dogs, HF prolongs the APD and increases the phosphorylation of key regulatory kinases and phosphatases, including calmodulin-dependent protein kinase II. The net effect of these HF-mediated changes is to enhance Ca2+ uptake into the sarcoplasmic reticulum promoting afterdepolarization initiation.183 Similarly, HF has been shown to increase calcium sparks in cardiomyocytes isolated from the PVs of rabbits.227

    Finally, tachycardia and shortening of diastolic filling time associated with irregular ventricular activation with AF further impair diastolic relaxation and promote clinical HF, which further induces atrial remodeling leading to the perpetuation of AF.

    Myocardial Infarction

    Epidemiology

    As with HF, there is a bidirectional relationship between AF and MI. Coronary heart disease is associated with an increased risk of AF,228 but AF also is associated with increased risk of MI.229 In the REGARDS cohort, AF was associated with a 2-fold increased risk of MI,230 that was greater in women (HR, 2.16; 95% CI, 1.41–3.31) versus men (HR, 1.39; 95% CI, 0.91–2.10) and blacks (HR, 2.53; 95% CI, 1.67–3.86) versus whites (HR, 1.26; 95% CI, 0.83–1.93). The Olmsted study reported similar unadjusted risk of coronary ischemic event, but after adjusting for age, the incidence was higher in men than woman.231 Among those with newly diagnosed AF, the risk of death after coronary ischemic events was higher in woman than men (HR, 2.99; 95% CI, 2.53–3.53 versus HR, 2.33; 95% CI, 1.94–2.81). Interestingly, as observed with strokes and SEEs, the event rate of coronary ischemic events was highest within the first year of incident AF (4.7%, 95% CI, 3.9–5.6) and subsequently declined to 2.5% per year.

    Pathophysiology

    The mechanisms linking AF to MI are not completely understood. First, both AF and MI have overlapping RFs that may lead to the development of AF and MI in parallel. For instance, both AF and coronary heart disease are associated with proinflammatory and prothrombotic states. Second, MI in AF may be attributed to coronary artery thromboembolism. Third, myocardial ischemia may arise from supply–demand mismatch in the setting of tachycardia associated with AF. Fourth, MI may lead to left ventricular remodeling that may predispose to AF.

    Venous Thromboembolism

    Epidemiology

    Increased BMI, obesity, and smoking are associated with venous thromboembolism (VTE)232235 and AF. Potential direct causal relationship between AF and VTE has been proposed, but needs to be studied further.236,237

    A few studies have reported increased risk of VTE in AF and vice versa. In a retrospective cohort study based on the national administrative database in Taiwan, the risks of VTE (adjusted HR, 1.74; 95% CI, 1.36–2.24) and pulmonary embolism (adjusted HR, 2.18; 95% CI, 1.51–3.15) were both higher in the AF group compared with non-AF referents.238 A Norwegian administrative database study reported that AF was associated with an increased risk of pulmonary embolism (adjusted HR, 1.83; 95% CI, 1.16–2.90) but not VTE (adjusted HR, 1.04; 95% CI, 0.64–1.68).236 In addition, the same study found that individuals with incident VTE were subsequently at a higher risk of developing incident AF (adjusted HR, 1.63; 95% CI, 1.22–2.17) compared with those without VTE.237 It should be noted that in both the Taiwanese and Norwegian cohorts, a significant proportion of individuals had preexisting RFs for VTE, including lower extremity fracture, recent surgery, cancer, and immobility.236,238 In comparison to individuals with AF or VTE alone, those with AF and VTE were older and had higher mean BMI. In the Norwegian study, the mean age and BMI were 64 years and 26.9 kg/m2 for AF alone, 57 years and 26.7 kg/m2 for VTE alone, and 68 years and 29.2 kg/m2 for AF and VTE combined.237

    Pathophysiology

    The mechanisms underlying the AF-VTE association are inexplicable. Several studies have shown that AF is associated with a hypercoagulable state attributed to elevated hemostatic factors, including fibrinogen, d-dimer, prothrombin fragment, factor VIII, and von Willebrand factor188,190193; however, many of these studies were not adjusted for coexisting cardiovascular RF. In an adjusted model, the FHS showed no significant difference in levels of fibrinogen, von Willebrand factor, or tissue-type plasminogen activator, suggesting that coexisting RFs rather than AF may explain elevated thrombotic risk.

    Mortality

    Epidemiology

    The FHS was one of the first studies to report that AF had a multivariable-adjusted association with increased risk of death.4 In addition, the study observed a significant interaction, such that AF diminished the survival advantage generally enjoyed by women; the multivariable-adjusted OR for death in men and women was 1.5 and 1.9, respectively. At 10-year follow-up, 61.5% of men with AF between 55 and 74 years of age had died compared with 30.0% of men in the same age group without AF. A similar trend was found in women with 57.6% of those with AF dying by 10-year follow-up when compared with 20.9% in those without AF. The increased risk was consistent across all decades of age from 55 to 95 years. Even in individuals without clinical evidence of cardiovascular or valvular disease at baseline, AF was associated with a 2-fold increased risk of death.4 A retrospective study of Medicare beneficiaries 65 years or older showed that death was the most frequent AF outcome with an incidence of 19.5% at 1 year and 48.8% at 5 years after initial diagnosis.239 A recent systematic review and meta-analysis of 64 studies that included 1 009 501 patients with 149 746 (14.8%) having AF found a pooled relative risk of death that was 1.6 (95% CI, 1.39–1.53), although there was marked heterogeneity.240 In 14 studies, cardiovascular mortality was assessed, and the pooled relative risk associated with AF was 2.03 (95% CI, 1.79–2.3).

    It is noteworthy that there is growing evidence that AF is associated with an increased risk of sudden cardiac death. Pooled analysis of the ARIC and Cardiovascular Health Study cohorts showed that AF was associated with more than a doubling of the risk of sudden cardiac death compared with participants without AF (HR, 2.47; 95% CI, 1.95–3.13).241 A meta-analysis of 7 studies found the relative risk of sudden cardiac death was 1.88 (95% CI, 1.36–2.6), although significant study heterogeneity was present.241 In the RE-LY trial, 37.4% of all deaths and 60.4% of cardiac deaths were attributed to either sudden cardiac death or death because of progressive HF.242 For comparison, only 9.8% of all deaths were attributed to stroke or hemorrhage.

    A meta-analysis of antithrombotic studies has shown that oral anticoagulation reduced risk of all-cause mortality with an absolute risk reduction of 1.6% when compared with control or placebo.243 In anticoagulated patients with AF, increased mortality is largely driven by cardiovascular causes rather than nonhemorrhagic stroke or systemic embolism.242,244246 Strokes comprised a small portion of deaths from AF. In the ROCKET AF trial, cardiovascular deaths occurred over 2× more often than strokes.244 Predictors of higher all-cause mortality included HF (HR, 1.51; 95% CI, 1.33–1.70) and age ≥75 (HR, 1.69; 95% CI, 1.51–1.90). Thus, further advances in anticoagulation strategies may have little effect on improving overall mortality in AF.

    Conclusions

    Over the past 50 years, the FHS and other epidemiological studies have yielded a breadth of data associating various RFs with risk of AF and providing insight into their mechanistic link to AF genesis. However, many questions remain. Will genetic studies improve AF risk assessment, identify novel therapeutic targets, and help guide treatment strategies for both primary and secondary prevention of AF? By what degree does RF modification alter the atrial substrate, AF burden, and clinical outcomes? What are the target goals for RF modification and how will genetics alter these targets? Ongoing and future epidemiological, translational, and clinical studies may provide insight into these unanswered questions and improve clinical outcomes in patients with AF.

    Nonstandard Abbreviations and Acronyms

    AF

    atrial fibrillation

    APD

    action potential duration

    ARIC

    Atherosclerosis Risk in Communities Study

    BMI

    body mass index

    CARAF

    Canadian Registry of Atrial Fibrillation

    CI

    confidence interval

    ERP

    effective refractory period

    FHS

    Framingham Heart Study

    HF

    heart failure

    HFpEF

    heart failure with preserved ejection fraction

    HR

    hazard ratio

    LAA

    left atrial appendage

    MESA

    Multi-Ethnic Study of Atherosclerosis

    MI

    myocardial infarction

    OR

    odds ratio

    OSA

    obstructive sleep apnea

    PV

    pulmonary vein

    RAAS

    renin–angiotensin–aldosterone system

    RF

    risk factor

    SEE

    systemic embolism events

    SNP

    single-nucleotide polymorphism

    VTE

    venous thromboembolism

    Footnotes

    Correspondence to Laila Staerk, MD, Department of Cardiology, Copenhagen University Hospital Gentofte, Kildegaardsvej 28, Hellerup 2900, Denmark. E-mail ; or Robert H. Helm, MD, Section of Cardiovascular Medicine, Department of Medicine, Boston University School of Medicine, 72 E Concord St, Boston, MA 02118. E-mail

    References

    • 1. Lip GY, Beevers DG. ABC of atrial fibrillation. History, epidemiology, and importance of atrial fibrillation.BMJ. 1995; 311:1361–1363.CrossrefMedlineGoogle Scholar
    • 2. Benjamin EJ, Levy D, Vaziri SM, D’Agostino RB, Belanger AJ, Wolf PA. Independent risk factors for atrial fibrillation in a population-based cohort. The Framingham Heart Study.JAMA. 1994; 271:840–844.CrossrefMedlineGoogle Scholar
    • 3. Lin HJ, Wolf PA, Kelly-Hayes M, Beiser AS, Kase CS, Benjamin EJ, D’Agostino RB. Stroke severity in atrial fibrillation. The Framingham Study.Stroke. 1996; 27:1760–1764.LinkGoogle Scholar
    • 4. Benjamin EJ, Wolf PA, D’Agostino RB, Silbershatz H, Kannel WB, Levy D. Impact of atrial fibrillation on the risk of death: the Framingham Heart Study.Circulation. 1998; 98:946–952.LinkGoogle Scholar
    • 5. Goette A, Kalman JM, Aguinaga L, et al; Document Reviewers. EHRA/HRS/APHRS/SOLAECE expert consensus on atrial cardiomyopathies: definition, characterization, and clinical implication.Europace. 2016; 18:1455–1490. doi: 10.1093/europace/euw161.CrossrefMedlineGoogle Scholar
    • 6. Haïssaguerre M, Jaïs P, Shah DC, Takahashi A, Hocini M, Quiniou G, Garrigue S, Le Mouroux A, Le Métayer P, Clémenty J. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins.N Engl J Med. 1998; 339:659–666. doi: 10.1056/NEJM199809033391003.CrossrefMedlineGoogle Scholar
    • 7. Hocini M, Ho SY, Kawara T, Linnenbank AC, Potse M, Shah D, Jaïs P, Janse MJ, Haïssaguerre M, De Bakker JM. Electrical conduction in canine pulmonary veins: electrophysiological and anatomic correlation.Circulation. 2002; 105:2442–2448.LinkGoogle Scholar
    • 8. Perez-Lugones A, McMahon JT, Ratliff NB, Saliba WI, Schweikert RA, Marrouche NF, Saad EB, Navia JL, McCarthy PM, Tchou P, Gillinov AM, Natale A. Evidence of specialized conduction cells in human pulmonary veins of patients with atrial fibrillation.J Cardiovasc Electrophysiol. 2003; 14:803–809.CrossrefMedlineGoogle Scholar
    • 9. El-Armouche A, Boknik P, Eschenhagen T, Carrier L, Knaut M, Ravens U, Dobrev D. Molecular determinants of altered Ca2+ handling in human chronic atrial fibrillation.Circulation. 2006; 114:670–680. doi: 10.1161/CIRCULATIONAHA.106.636845.LinkGoogle Scholar
    • 10. Vest JA, Wehrens XH, Reiken SR, Lehnart SE, Dobrev D, Chandra P, Danilo P, Ravens U, Rosen MR, Marks AR. Defective cardiac ryanodine receptor regulation during atrial fibrillation.Circulation. 2005; 111:2025–2032. doi: 10.1161/01.CIR.0000162461.67140.4C.LinkGoogle Scholar
    • 11. Arora R, Verheule S, Scott L, Navarrete A, Katari V, Wilson E, Vaz D, Olgin JE. Arrhythmogenic substrate of the pulmonary veins assessed by high-resolution optical mapping.Circulation. 2003; 107:1816–1821. doi: 10.1161/01.CIR.0000058461.86339.7E.LinkGoogle Scholar
    • 12. Schuessler RB, Grayson TM, Bromberg BI, Cox JL, Boineau JP. Cholinergically mediated tachyarrhythmias induced by a single extrastimulus in the isolated canine right atrium.Circ Res. 1992; 71:1254–1267.LinkGoogle Scholar
    • 13. Mandapati R, Skanes A, Chen J, Berenfeld O, Jalife J. Stable microreentrant sources as a mechanism of atrial fibrillation in the isolated sheep heart.Circulation. 2000; 101:194–199.LinkGoogle Scholar
    • 14. Moe GK, Abildskov JA. Atrial fibrillation as a self-sustaining arrhythmia independent of focal discharge.Am Heart J. 1959; 58:59–70.CrossrefMedlineGoogle Scholar
    • 15. Pappone C, Rosanio S, Oreto G, Tocchi M, Gugliotta F, Vicedomini G, Salvati A, Dicandia C, Mazzone P, Santinelli V, Gulletta S, Chierchia S. Circumferential radiofrequency ablation of pulmonary vein ostia: a new anatomic approach for curing atrial fibrillation.Circulation. 2000; 102:2619–2628.LinkGoogle Scholar
    • 16. Miller JM, Kowal RC, Swarup V, Daubert JP, Daoud EG, Day JD, Ellenbogen KA, Hummel JD, Baykaner T, Krummen DE, Narayan SM, Reddy VY, Shivkumar K, Steinberg JS, Wheelan KR. Initial independent outcomes from focal impulse and rotor modulation ablation for atrial fibrillation: multicenter FIRM registry.J Cardiovasc Electrophysiol. 2014; 25:921–929. doi: 10.1111/jce.12474.CrossrefMedlineGoogle Scholar
    • 17. Allessie MA, de Groot NM, Houben RP, Schotten U, Boersma E, Smeets JL, Crijns HJ. Electropathological substrate of long-standing persistent atrial fibrillation in patients with structural heart disease: longitudinal dissociation.Circ Arrhythm Electrophysiol. 2010; 3:606–615. doi: 10.1161/CIRCEP.109.910125.LinkGoogle Scholar
    • 18. Eckstein J, Maesen B, Linz D, Zeemering S, van Hunnik A, Verheule S, Allessie M, Schotten U. Time course and mechanisms of endo-epicardial electrical dissociation during atrial fibrillation in the goat.Cardiovasc Res. 2011; 89:816–824. doi: 10.1093/cvr/cvq336.CrossrefMedlineGoogle Scholar
    • 19. Wijffels MC, Kirchhof CJ, Dorland R, Allessie MA. Atrial fibrillation begets atrial fibrillation. A study in awake chronically instrumented goats.Circulation. 1995; 92:1954–1968.LinkGoogle Scholar
    • 20. Morillo CA, Klein GJ, Jones DL, Guiraudon CM. Chronic rapid atrial pacing. Structural, functional, and electrophysiological characteristics of a new model of sustained atrial fibrillation.Circulation. 1995; 91:1588–1595.LinkGoogle Scholar
    • 21. Fareh S, Villemaire C, Nattel S. Importance of refractoriness heterogeneity in the enhanced vulnerability to atrial fibrillation induction caused by tachycardia-induced atrial electrical remodeling.Circulation. 1998; 98:2202–2209.LinkGoogle Scholar
    • 22. Goette A, Honeycutt C, Langberg JJ. Electrical remodeling in atrial fibrillation. Time course and mechanisms.Circulation. 1996; 94:2968–2974.LinkGoogle Scholar
    • 23. Lubitz SA, Moser C, Sullivan L, et al. Atrial fibrillation patterns and risks of subsequent stroke, heart failure, or death in the community.J Am Heart Assoc. 2013; 2:e000126. doi: 10.1161/JAHA.113.000126.LinkGoogle Scholar
    • 24. Kerr CR, Humphries KH, Talajic M, Klein GJ, Connolly SJ, Green M, Boone J, Sheldon R, Dorian P, Newman D. Progression to chronic atrial fibrillation after the initial diagnosis of paroxysmal atrial fibrillation: results from the Canadian Registry of Atrial Fibrillation.Am Heart J. 2005; 149:489–496. doi: 10.1016/j.ahj.2004.09.053.CrossrefMedlineGoogle Scholar
    • 25. Nieuwlaat R, Prins MH, Le Heuzey JY, Vardas PE, Aliot E, Santini M, Cobbe SM, Widdershoven JW, Baur LH, Lévy S, Crijns HJ. Prognosis, disease progression, and treatment of atrial fibrillation patients during 1 year: follow-up of the Euro Heart Survey on atrial fibrillation.Eur Heart J. 2008; 29:1181–1189. doi: 10.1093/eurheartj/ehn139.CrossrefMedlineGoogle Scholar
    • 26. Veasey RA, Sugihara C, Sandhu K, Dhillon G, Freemantle N, Furniss SS, Sulke AN. The natural history of atrial fibrillation in patients with permanent pacemakers: is atrial fibrillation a progressive disease?J Interv Card Electrophysiol. 2015; 44:23–30. doi: 10.1007/s10840-015-0029-x.CrossrefMedlineGoogle Scholar
    • 27. Saksena S, Hettrick DA, Koehler JL, Grammatico A, Padeletti L. Progression of paroxysmal atrial fibrillation to persistent atrial fibrillation in patients with bradyarrhythmias.Am Heart J. 2007; 154:884–892. doi: 10.1016/j.ahj.2007.06.045.CrossrefMedlineGoogle Scholar
    • 28. Schnabel RB, Yin X, Gona P, Larson MG, Beiser AS, McManus DD, Newton-Cheh C, Lubitz SA, Magnani JW, Ellinor PT, Seshadri S, Wolf PA, Vasan RS, Benjamin EJ, Levy D. 50 year trends in atrial fibrillation prevalence, incidence, risk factors, and mortality in the Framingham Heart Study: a cohort study.Lancet. 2015; 386:154–162. doi: 10.1016/S0140-6736(14)61774-8.CrossrefMedlineGoogle Scholar
    • 29. Brugada R, Tapscott T, Czernuszewicz GZ, Marian AJ, Iglesias A, Mont L, Brugada J, Girona J, Domingo A, Bachinski LL, Roberts R. Identification of a genetic locus for familial atrial fibrillation.N Engl J Med. 1997; 336:905–911. doi: 10.1056/NEJM199703273361302.CrossrefMedlineGoogle Scholar
    • 30. Ellinor PT, Shin JT, Moore RK, Yoerger DM, MacRae CA. Locus for atrial fibrillation maps to chromosome 6q14-16.Circulation. 2003; 107:2880–2883. doi: 10.1161/01.CIR.0000077910.80718.49.LinkGoogle Scholar
    • 31. Chen YH, Xu SJ, Bendahhou S, et al. KCNQ1 gain-of-function mutation in familial atrial fibrillation.Science. 2003; 299:251–254. doi: 10.1126/science.1077771.CrossrefMedlineGoogle Scholar
    • 32. Fox CS, Parise H, D’Agostino RB, Lloyd-Jones DM, Vasan RS, Wang TJ, Levy D, Wolf PA, Benjamin EJ. Parental atrial fibrillation as a risk factor for atrial fibrillation in offspring.JAMA. 2004; 291:2851–2855. doi: 10.1001/jama.291.23.2851.CrossrefMedlineGoogle Scholar
    • 33. Arnar DO, Thorvaldsson S, Manolio TA, Thorgeirsson G, Kristjansson K, Hakonarson H, Stefansson K. Familial aggregation of atrial fibrillation in Iceland.Eur Heart J. 2006; 27:708–712. doi: 10.1093/eurheartj/ehi727.CrossrefMedlineGoogle Scholar
    • 34. Christophersen IE, Ellinor PT. Genetics of atrial fibrillation: from families to genomes.J Hum Genet. 2016; 61:61–70. doi: 10.1038/jhg.2015.44.CrossrefMedlineGoogle Scholar
    • 35. Zellerhoff S, Pistulli R, Mönnig G, Hinterseer M, Beckmann BM, Köbe J, Steinbeck G, Kääb S, Haverkamp W, Fabritz L, Gradaus R, Breithardt G, Schulze-Bahr E, Böcker D, Kirchhof P. Atrial Arrhythmias in long-QT syndrome under daily life conditions: a nested case control study.J Cardiovasc Electrophysiol. 2009; 20:401–407. doi: 10.1111/j.1540-8167.2008.01339.x.CrossrefMedlineGoogle Scholar
    • 36. Olson TM, Alekseev AE, Liu XK, Park S, Zingman LV, Bienengraeber M, Sattiraju S, Ballew JD, Jahangir A, Terzic A. Kv1.5 channelopathy due to KCNA5 loss-of-function mutation causes human atrial fibrillation.Hum Mol Genet. 2006; 15:2185–2191. doi: 10.1093/hmg/ddl143.CrossrefMedlineGoogle Scholar
    • 37. Li Q, Huang H, Liu G, Lam K, Rutberg J, Green MS, Birnie DH, Lemery R, Chahine M, Gollob MH. Gain-of-function mutation of Nav1.5 in atrial fibrillation enhances cellular excitability and lowers the threshold for action potential firing.Biochem Biophys Res Commun. 2009; 380:132–137. doi: 10.1016/j.bbrc.2009.01.052.CrossrefMedlineGoogle Scholar
    • 38. Savio-Galimberti E, Weeke P, Muhammad R, Blair M, Ansari S, Short L, Atack TC, Kor K, Vanoye CG, Olesen MS, LuCamp , Yang T, George AL, Roden DM, Darbar D. SCN10A/Nav1.8 modulation of peak and late sodium currents in patients with early onset atrial fibrillation.Cardiovasc Res. 2014; 104:355–363. doi: 10.1093/cvr/cvu170.CrossrefMedlineGoogle Scholar
    • 39. Gollob MH, Jones DL, Krahn AD, et al. Somatic mutations in the connexin 40 gene (GJA5) in atrial fibrillation.N Engl J Med. 2006; 354:2677–2688. doi: 10.1056/NEJMoa052800.CrossrefMedlineGoogle Scholar
    • 40. Gudbjartsson DF, Arnar DO, Helgadottir A, et al. Variants conferring risk of atrial fibrillation on chromosome 4q25.Nature. 2007; 448:353–357. doi: 10.1038/nature06007.CrossrefMedlineGoogle Scholar
    • 41. Shoemaker MB, Bollmann A, Lubitz SA, et al. Common genetic variants and response to atrial fibrillation ablation.Circ Arrhythm Electrophysiol. 2015; 8:296–302. doi: 10.1161/CIRCEP.114.001909.LinkGoogle Scholar
    • 42. Cao YY, Ma F, Wang Y, Wang DW, Ding H. Rs2200733 and rs10033464 on chromosome 4q25 confer risk of cardioembolic stroke: an updated meta-analysis.Mol Biol Rep. 2013; 40:5977–5985. doi: 10.1007/s11033-013-2707-z.CrossrefMedlineGoogle Scholar
    • 43. Logan M, Pagán-Westphal SM, Smith DM, Paganessi L, Tabin CJ. The transcription factor Pitx2 mediates situs-specific morphogenesis in response to left-right asymmetric signals.Cell. 1998; 94:307–317.CrossrefMedlineGoogle Scholar
    • 44. Mommersteeg MT, Brown NA, Prall OW, de Gier-de Vries C, Harvey RP, Moorman AF, Christoffels VM. Pitx2c and Nkx2-5 are required for the formation and identity of the pulmonary myocardium.Circ Res. 2007; 101:902–909. doi: 10.1161/CIRCRESAHA.107.161182.LinkGoogle Scholar
    • 45. Aguirre LA, Alonso ME, Badía-Careaga C, Rollán I, Arias C, Fernández-Miñán A, López-Jiménez E, Aránega A, Gómez-Skarmeta JL, Franco D, Manzanares M. Long-range regulatory interactions at the 4q25 atrial fibrillation risk locus involve PITX2c and ENPEP.BMC Biol. 2015; 13:26. doi: 10.1186/s12915-015-0138-0.CrossrefMedlineGoogle Scholar
    • 46. Chinchilla A, Daimi H, Lozano-Velasco E, Dominguez JN, Caballero R, Delpón E, Tamargo J, Cinca J, Hove-Madsen L, Aranega AE, Franco D. PITX2 insufficiency leads to atrial electrical and structural remodeling linked to arrhythmogenesis.Circ Cardiovasc Genet. 2011; 4:269–279. doi: 10.1161/CIRCGENETICS.110.958116.LinkGoogle Scholar
    • 47. Kao YH, Hsu JC, Chen YC, Lin YK, Lkhagva B, Chen SA, Chen YJ. ZFHX3 knockdown increases arrhythmogenesis and dysregulates calcium homeostasis in HL-1 atrial myocytes.Int J Cardiol. 2016; 210:85–92. doi: 10.1016/j.ijcard.2016.02.091.CrossrefMedlineGoogle Scholar
    • 48. AFGen Consortium. https://www.afgen.org. Accessed April 10, 2017.Google Scholar
    • 49. Ellinor PT, Lunetta KL, Albert CM, et al. Meta-analysis identifies six new susceptibility loci for atrial fibrillation.Nat Genet. 2012; 44:670–675. doi: 10.1038/ng.2261.CrossrefMedlineGoogle Scholar
    • 50. Tucker NR, Ellinor PT. Emerging directions in the genetics of atrial fibrillation.Circ Res. 2014; 114:1469–1482. doi: 10.1161/CIRCRESAHA.114.302225.LinkGoogle Scholar
    • 51. Rodriguez CJ, Soliman EZ, Alonso A, Swett K, Okin PM, Goff DC, Heckbert SR. 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. 2015; 25:71–76, 76.e1. doi: 10.1016/j.annepidem.2014.11.024.CrossrefMedlineGoogle Scholar
    • 52. Guo Y, Tian Y, Wang H, Si Q, Wang Y, Lip GY. Prevalence, incidence, and lifetime risk of atrial fibrillation in China: new insights into the global burden of atrial fibrillation.Chest. 2015; 147:109–119. doi: 10.1378/chest.14-0321.CrossrefMedlineGoogle Scholar
    • 53. Murphy NF, Simpson CR, Jhund PS, Stewart S, Kirkpatrick M, Chalmers J, MacIntyre K, McMurray JJ. A national survey of the prevalence, incidence, primary care burden and treatment of atrial fibrillation in Scotland.Heart. 2007; 93:606–612. doi: 10.1136/hrt.2006.107573.CrossrefMedlineGoogle Scholar
    • 54. Alonso A, Krijthe BP, Aspelund T, 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. 2013; 2:e000102. doi: 10.1161/JAHA.112.000102.LinkGoogle Scholar
    • 55. Schnabel RB, Sullivan LM, Levy D, et al. Development of a risk score for atrial fibrillation (Framingham Heart Study): a community-based cohort study.Lancet. 2009; 373:739–745. doi: 10.1016/S0140-6736(09)60443-8.CrossrefMedlineGoogle Scholar
    • 56. Naderi S, Wang Y, Miller AL, Rodriguez F, Chung MK, Radford MJ, Foody JM. The impact of age on the epidemiology of atrial fibrillation hospitalizations.Am J Med. 2014; 127:158.e1–158.e7. doi: 10.1016/j.amjmed.2013.10.005.CrossrefMedlineGoogle Scholar
    • 57. Ko D, Rahman F, Schnabel RB, Yin X, Benjamin EJ, Christophersen IE. Atrial fibrillation in women: epidemiology, pathophysiology, presentation, and prognosis.Nat Rev Cardiol. 2016; 13:321–332.CrossrefMedlineGoogle Scholar
    • 58. Miyasaka Y, Barnes ME, Gersh BJ, Cha SS, Bailey KR, Abhayaratna WP, Seward JB, Tsang TS. Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000, and implications on the projections for future prevalence.Circulation. 2006; 114:119–125. doi: 10.1161/CIRCULATIONAHA.105.595140.LinkGoogle Scholar
    • 59. Heeringa J, van der Kuip DA, Hofman A, Kors JA, van Herpen G, Stricker BH, Stijnen T, Lip GY, Witteman JC. Prevalence, incidence and lifetime risk of atrial fibrillation: the Rotterdam study.Eur Heart J. 2006; 27:949–953. doi: 10.1093/eurheartj/ehi825.CrossrefMedlineGoogle Scholar
    • 60. Chugh SS, Havmoeller R, Narayanan K, Singh D, Rienstra M, Benjamin EJ, Gillum RF, Kim YH, McAnulty JH, Zheng ZJ, Forouzanfar MH, Naghavi M, Mensah GA, Ezzati M, Murray CJ. Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study.Circulation. 2014; 129:837–847. doi: 10.1161/CIRCULATIONAHA.113.005119.LinkGoogle Scholar
    • 61. Chien KL, Su TC, Hsu HC, Chang WT, Chen PC, Chen MF, Lee YT. Atrial fibrillation prevalence, incidence and risk of stroke and all-cause death among Chinese.Int J Cardiol. 2010; 139:173–180. doi: 10.1016/j.ijcard.2008.10.045.CrossrefMedlineGoogle Scholar
    • 62. Piccini JP, Hammill BG, Sinner MF, Jensen PN, Hernandez AF, Heckbert SR, Benjamin EJ, Curtis LH. Incidence and prevalence of atrial fibrillation and associated mortality among Medicare beneficiaries, 1993-2007.Circ Cardiovasc Qual Outcomes. 2012; 5:85–93. doi: 10.1161/CIRCOUTCOMES.111.962688.LinkGoogle Scholar
    • 63. Iguchi Y, Kimura K, Aoki J, Kobayashi K, Terasawa Y, Sakai K, Shibazaki K. Prevalence of atrial fibrillation in community-dwelling Japanese aged 40 years or older in Japan: analysis of 41,436 non-employee residents in Kurashiki-city.Circ J. 2008; 72:909–913.CrossrefMedlineGoogle Scholar
    • 64. Yap KB, Ng TP, Ong HY. Low prevalence of atrial fibrillation in community-dwelling Chinese aged 55 years or older in Singapore: a population-based study.J Electrocardiol. 2008; 41:94–98. doi: 10.1016/j.jelectrocard.2007.03.012.CrossrefMedlineGoogle Scholar
    • 65. Li Y, Wu YF, Chen KP, Li X, Zhang X, Xie GQ, Wang FZ, Zhang S. Prevalence of atrial fibrillation in China and its risk factors.Biomed Environ Sci. 2013; 26:709–716. doi: 10.3967/0895-3988.2013.09.001.CrossrefMedlineGoogle Scholar
    • 66. Zhou Z, Hu D. An epidemiological study on the prevalence of atrial fibrillation in the Chinese population of mainland China.J Epidemiol. 2008; 18:209–216.CrossrefMedlineGoogle Scholar
    • 67. Lloyd-Jones DM, Wang TJ, Leip EP, Larson MG, Levy D, Vasan RS, D’Agostino RB, Massaro JM, Beiser A, Wolf PA, Benjamin EJ. Lifetime risk for development of atrial fibrillation: the Framingham Heart Study.Circulation. 2004; 110:1042–1046. doi: 10.1161/01.CIR.0000140263.20897.42.LinkGoogle Scholar
    • 68. Marcus GM, Alonso A, Peralta CA, et al; Candidate-Gene Association Resource (CARe) Study. European ancestry as a risk factor for atrial fibrillation in African Americans.Circulation. 2010; 122:2009–2015. doi: 10.1161/CIRCULATIONAHA.110.958306.LinkGoogle Scholar
    • 69. Sacco RL, Boden-Albala B, Abel G, Lin IF, Elkind M, Hauser WA, Paik MC, Shea S. Race-ethnic disparities in the impact of stroke risk factors: the northern Manhattan stroke study.Stroke. 2001; 32:1725–1731.LinkGoogle Scholar
    • 70. Magnani JW, Norby FL, Agarwal SK, Soliman EZ, Chen LY, Loehr LR, Alonso A. Racial differences in atrial fibrillation-related cardiovascular disease and mortality: the Atherosclerosis Risk in Communities (ARIC) Study.JAMA Cardiol. 2016; 1:433–441. doi: 10.1001/jamacardio.2016.1025.CrossrefMedlineGoogle Scholar
    • 71. Hernandez MB, Asher CR, Hernandez AV, Novaro GM. African American race and prevalence of atrial fibrillation: a meta-analysis.Cardiol Res Pract. 2012; 2012:275624. doi: 10.1155/2012/275624.CrossrefMedlineGoogle Scholar
    • 72. Lahiri MK, Fang K, Lamerato L, Khan AM, Schuger CD. Effect of race on the frequency of postoperative atrial fibrillation following coronary artery bypass grafting.Am J Cardiol. 2011; 107:383–386. doi: 10.1016/j.amjcard.2010.09.032.CrossrefMedlineGoogle Scholar
    • 73. Dewland TA, Olgin JE, Vittinghoff E, Marcus GM. Incident atrial fibrillation among Asians, Hispanics, blacks, and whites.Circulation. 2013; 128:2470–2477. doi: 10.1161/CIRCULATIONAHA.113.002449.LinkGoogle Scholar
    • 74. Roberts JD, Hu D, Heckbert SR, et al. Genetic investigation into the differential risk of atrial fibrillation among black and white individuals.JAMA Cardiol. 2016; 1:442–450. doi: 10.1001/jamacardio.2016.1185.CrossrefMedlineGoogle Scholar
    • 75. Schnabel RB, Kerr KF, Lubitz SA, et al; Candidate Gene Association Resource (CARe) Atrial Fibrillation/Electrocardiography Working Group. Large-scale candidate gene analysis in whites and African Americans identifies IL6R polymorphism in relation to atrial fibrillation: the National Heart, Lung, and Blood Institute’s Candidate Gene Association Resource (CARe) project.Circ Cardiovasc Genet. 2011; 4:557–564. doi: 10.1161/CIRCGENETICS.110.959197.LinkGoogle Scholar
    • 76. Calvo N, Ramos P, Montserrat S, et al. Emerging risk factors and the dose-response relationship between physical activity and lone atrial fibrillation: a prospective case-control study.Europace. 2016; 18:57–63. doi: 10.1093/europace/euv216.CrossrefMedlineGoogle Scholar
    • 77. Drca N, Wolk A, Jensen-Urstad M, Larsson SC. Atrial fibrillation is associated with different levels of physical activity levels at different ages in men.Heart. 2014; 100:1037–1042. doi: 10.1136/heartjnl-2013-305304.CrossrefMedlineGoogle Scholar
    • 78. Mozaffarian D, Furberg CD, Psaty BM, Siscovick D. Physical activity and incidence of atrial fibrillation in older adults: the cardiovascular health study.Circulation. 2008; 118:800–807. doi: 10.1161/CIRCULATIONAHA.108.785626.LinkGoogle Scholar
    • 79. Diouf I, Magliano DJ, Carrington MJ, Stewart S, Shaw JE. Prevalence, incidence, risk factors and treatment of atrial fibrillation in Australia: the Australian Diabetes, Obesity and Lifestyle (AusDiab) longitudinal, population cohort study.Int J Cardiol. 2016; 205:127–132. doi: 10.1016/j.ijcard.2015.12.013.CrossrefMedlineGoogle Scholar
    • 80. Andersen K, Farahmand B, Ahlbom A, Held C, Ljunghall S, Michaëlsson K, Sundström J. Risk of arrhythmias in 52 755 long-distance cross-country skiers: a cohort study.Eur Heart J. 2013; 34:3624–3631. doi: 10.1093/eurheartj/eht188.CrossrefMedlineGoogle Scholar
    • 81. Elosua R, Arquer A, Mont L, Sambola A, Molina L, García-Morán E, Brugada J, Marrugat J. Sport practice and the risk of lone atrial fibrillation: a case-control study.Int J Cardiol. 2006; 108:332–337. doi: 10.1016/j.ijcard.2005.05.020.CrossrefMedlineGoogle Scholar
    • 82. Mohanty S, Mohanty P, Tamaki M, Natale V, Gianni C, Trivedi C, Gokoglan Y, DI Biase L, Natale A. Differential association of exercise intensity with risk of atrial fibrillation in men and women: evidence from a meta-analysis.J Cardiovasc Electrophysiol. 2016; 27:1021–1029. doi: 10.1111/jce.13023.CrossrefMedlineGoogle Scholar
    • 83. Qureshi WT, Alirhayim Z, Blaha MJ, Juraschek SP, Keteyian SJ, Brawner CA, Al-Mallah MH. Cardiorespiratory fitness and risk of incident atrial fibrillation: results from the Henry Ford Exercise Testing (FIT) Project.Circulation. 2015; 131:1827–1834. doi: 10.1161/CIRCULATIONAHA.114.014833.LinkGoogle Scholar
    • 84. Abdulla J, Nielsen JR. Is the risk of atrial fibrillation higher in athletes than in the general population? A systematic review and meta-analysis.Europace. 2009; 11:1156–1159. doi: 10.1093/europace/eup197.CrossrefMedlineGoogle Scholar
    • 85. Thorp AA, Owen N, Neuhaus M, Dunstan DW. Sedentary behaviors and subsequent health outcomes in adults a systematic review of longitudinal studies, 1996-2011.Am J Prev Med. 2011; 41:207–215. doi: 10.1016/j.amepre.2011.05.004.CrossrefMedlineGoogle Scholar
    • 86. Hu FB, Leitzmann MF, Stampfer MJ, Colditz GA, Willett WC, Rimm EB. Physical activity and television watching in relation to risk for type 2 diabetes mellitus in men.Arch Intern Med. 2001; 161:1542–1548.CrossrefMedlineGoogle Scholar
    • 87. Moreno CR, Carvalho FA, Lorenzi C, Matuzaki LS, Prezotti S, Bighetti P, Louzada FM, Lorenzi-Filho G. High risk for obstructive sleep apnea in truck drivers estimated by the Berlin questionnaire: prevalence and associated factors.Chronobiol Int. 2004; 21:871–879.CrossrefMedlineGoogle Scholar
    • 88. Allison MA, Jensky NE, Marshall SJ, Bertoni AG, Cushman M. Sedentary behavior and adiposity-associated inflammation: the Multi-Ethnic Study of Atherosclerosis.Am J Prev Med. 2012; 42:8–13. doi: 10.1016/j.amepre.2011.09.023.CrossrefMedlineGoogle Scholar
    • 89. Rienstra M, Sun JX, Magnani JW, Sinner MF, Lubitz SA, Sullivan LM, Ellinor PT, Benjamin EJ. White blood cell count and risk of incident atrial fibrillation (from the Framingham Heart Study).Am J Cardiol. 2012; 109:533–537. doi: 10.1016/j.amjcard.2011.09.049.CrossrefMedlineGoogle Scholar
    • 90. Aviles RJ, Martin DO, Apperson-Hansen C, Houghtaling PL, Rautaharju P, Kronmal RA, Tracy RP, Van Wagoner DR, Psaty BM, Lauer MS, Chung MK. Inflammation as a risk factor for atrial fibrillation.Circulation. 2003; 108:3006–3010. doi: 10.1161/01.CIR.0000103131.70301.4F.LinkGoogle Scholar
    • 91. Li J, Solus J, Chen Q, Rho YH, Milne G, Stein CM, Darbar D. Role of inflammation and oxidative stress in atrial fibrillation.Heart Rhythm. 2010; 7:438–444. doi: 10.1016/j.hrthm.2009.12.009.CrossrefMedlineGoogle Scholar
    • 92. Chung MK, Martin DO, Sprecher D, Wazni O, Kanderian A, Carnes CA, Bauer JA, Tchou PJ, Niebauer MJ, Natale A, Van Wagoner DR. C-reactive protein elevation in patients with atrial arrhythmias: inflammatory mechanisms and persistence of atrial fibrillation.Circulation. 2001; 104:2886–2891.LinkGoogle Scholar
    • 93. Conen D, Ridker PM, Everett BM, Tedrow UB, Rose L, Cook NR, Buring JE, Albert CM. A multimarker approach to assess the influence of inflammation on the incidence of atrial fibrillation in women.Eur Heart J. 2010; 31:1730–1736. doi: 10.1093/eurheartj/ehq146.CrossrefMedlineGoogle Scholar
    • 94. Mont L, Sambola A, Brugada J, Vacca M, Marrugat J, Elosua R, Paré C, Azqueta M, Sanz G. Long-lasting sport practice and lone atrial fibrillation.Eur Heart J. 2002; 23:477–482. doi: 10.1053/euhj.2001.2802.CrossrefMedlineGoogle Scholar
    • 95. D’Andrea A, Riegler L, Cocchia R, et al. Left atrial volume index in highly trained athletes.Am Heart J. 2010; 159:1155–1161. doi: 10.1016/j.ahj.2010.03.036.CrossrefMedlineGoogle Scholar
    • 96. Molina L, Mont L, Marrugat J, Berruezo A, Brugada J, Bruguera J, Rebato C, Elosua R. Long-term endurance sport practice increases the incidence of lone atrial fibrillation in men: a follow-up study.Europace. 2008; 10:618–623. doi: 10.1093/europace/eun071.CrossrefMedlineGoogle Scholar
    • 97. Hoogsteen J, Hoogeveen A, Schaffers H, Wijn PF, van der Wall EE. Left atrial and ventricular dimensions in highly trained cyclists.Int J Cardiovasc Imaging. 2003; 19:211–217.CrossrefMedlineGoogle Scholar
    • 98. Benito B, Gay-Jordi G, Serrano-Mollar A, Guasch E, Shi Y, Tardif JC, Brugada J, Nattel S, Mont L. Cardiac arrhythmogenic remodeling in a rat model of long-term intensive exercise training.Circulation. 2011; 123:13–22. doi: 10.1161/CIRCULATIONAHA.110.938282.LinkGoogle Scholar
    • 99. Chamberlain AM, Agarwal SK, Folsom AR, Duval S, Soliman EZ, Ambrose M, Eberly LE, Alonso A. Smoking and incidence of atrial fibrillation: results from the Atherosclerosis Risk in Communities (ARIC) study.Heart Rhythm. 2011; 8:1160–1166. doi: 10.1016/j.hrthm.2011.03.038.CrossrefMedlineGoogle Scholar
    • 100. Heeringa J, Kors JA, Hofman A, van Rooij FJ, Witteman JC. Cigarette smoking and risk of atrial fibrillation: the Rotterdam Study.Am Heart J. 2008; 156:1163–1169. doi: 10.1016/j.ahj.2008.08.003.CrossrefMedlineGoogle Scholar
    • 101. Suzuki S, Otsuka T, Sagara K, et al. Association between smoking habits and the first-time appearance of atrial fibrillation in Japanese patients: evidence from the Shinken Database.J Cardiol. 2015; 66:73–79. doi: 10.1016/j.jjcc.2014.09.010.CrossrefMedlineGoogle Scholar
    • 102. O’Neal WT, Qureshi WT, Judd SE, McClure LA, Cushman M, Howard VJ, Howard G, Soliman EZ. Environmental tobacco smoke and atrial fibrillation: the REasons for Geographic And Racial Differences in Stroke (REGARDS) Study.J Occup Environ Med. 2015; 57:1154–1158. doi: 10.1097/JOM.0000000000000565.CrossrefMedlineGoogle Scholar
    • 103. Dixit S, Pletcher MJ, Vittinghoff E, Imburgia K, Maguire C, Whitman IR, Glantz SA, Olgin JE, Marcus GM. Secondhand smoke and atrial fibrillation: data from the Health eHeart Study.Heart Rhythm. 2016; 13:3–9. doi: 10.1016/j.hrthm.2015.08.004.CrossrefMedlineGoogle Scholar
    • 104. Moliterno DJ, Willard JE, Lange RA, Negus BH, Boehrer JD, Glamann DB, Landau C, Rossen JD, Winniford MD, Hillis LD. Coronary-artery vasoconstriction induced by cocaine, cigarette smoking, or both.N Engl J Med. 1994; 330:454–459. doi: 10.1056/NEJM199402173300702.CrossrefMedlineGoogle Scholar
    • 105. Levitzky YS, Guo CY, Rong J, Larson MG, Walter RE, Keaney JF, Sutherland PA, Vasan A, Lipinska I, Evans JC, Benjamin EJ. Relation of smoking status to a panel of inflammatory markers: the Framingham offspring.Atherosclerosis. 2008; 201:217–224. doi: 10.1016/j.atherosclerosis.2007.12.058.CrossrefMedlineGoogle Scholar
    • 106. Buch P, Friberg J, Scharling H, Lange P, Prescott E. Reduced lung function and risk of atrial fibrillation in the Copenhagen City Heart Study.Eur Respir J. 2003; 21:1012–1016.CrossrefMedlineGoogle Scholar
    • 107. Goette A, Lendeckel U, Kuchenbecker A, Bukowska A, Peters B, Klein HU, Huth C, Röcken C. Cigarette smoking induces atrial fibrosis in humans via nicotine.Heart. 2007; 93:1056–1063. doi: 10.1136/hrt.2005.087171.CrossrefMedlineGoogle Scholar
    • 108. Shan H, Zhang Y, Lu Y, Zhang Y, Pan Z, Cai B, Wang N, Li X, Feng T, Hong Y, Yang B. Downregulation of miR-133 and miR-590 contributes to nicotine-induced atrial remodelling in canines.Cardiovasc Res. 2009; 83:465–472. doi: 10.1093/cvr/cvp130.CrossrefMedlineGoogle Scholar
    • 109. Wang H, Yang B, Zhang L, Xu D, Wang Z. Direct block of inward rectifier potassium channels by nicotine.Toxicol Appl Pharmacol. 2000; 164:97–101. doi: 10.1006/taap.2000.8896.CrossrefMedlineGoogle Scholar
    • 110. Wang H, Shi H, Zhang L, Pourrier M, Yang B, Nattel S, Wang Z. Nicotine is a potent blocker of the cardiac A-type K(+) channels. Effects on cloned Kv4.3 channels and native transient outward current.Circulation. 2000; 102:1165–1171.LinkGoogle Scholar
    • 111. Stamler R, Stamler J, Riedlinger WF, Algera G, Roberts RH. Weight and blood pressure. Findings in hypertension screening of 1 million Americans.JAMA. 1978; 240:1607–1610.CrossrefMedlineGoogle Scholar
    • 112. Mokdad AH, Ford ES, Bowman BA, Dietz WH, Vinicor F, Bales VS, Marks JS. Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001.JAMA. 2003; 289:76–79.CrossrefMedlineGoogle Scholar
    • 113. Yusuf S, Hawken S, Ounpuu S, Bautista L, Franzosi MG, Commerford P, Lang CC, Rumboldt Z, Onen CL, Lisheng L, Tanomsup S, Wangai P, Razak F, Sharma AM, Anand SS; INTERHEART Study Investigators. Obesity and the risk of myocardial infarction in 27,000 participants from 52 countries: a case-control study.Lancet. 2005; 366:1640–1649. doi: 10.1016/S0140-6736(05)67663-5.CrossrefMedlineGoogle Scholar
    • 114. Lauer MS, Anderson KM, Kannel WB, Levy D. The impact of obesity on left ventricular mass and geometry. The Framingham Heart Study.JAMA. 1991; 266:231–236.CrossrefMedlineGoogle Scholar
    • 115. Gottdiener JS, Reda DJ, Williams DW, Materson BJ. Left atrial size in hypertensive men: influence of obesity, race and age. Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents.J Am Coll Cardiol. 1997; 29:651–658.CrossrefMedlineGoogle Scholar
    • 116. Powell BD, Redfield MM, Bybee KA, Freeman WK, Rihal CS. Association of obesity with left ventricular remodeling and diastolic dysfunction in patients without coronary artery disease.Am J Cardiol. 2006; 98:116–120. doi: 10.1016/j.amjcard.2006.01.063.CrossrefMedlineGoogle Scholar
    • 117. Kenchaiah S, Evans JC, Levy D, Wilson PW, Benjamin EJ, Larson MG, Kannel WB, Vasan RS. Obesity and the risk of heart failure.N Engl J Med. 2002; 347:305–313. doi: 10.1056/NEJMoa020245.CrossrefMedlineGoogle Scholar
    • 118. Wang TJ, Parise H, Levy D, D’Agostino RB, Wolf PA, Vasan RS, Benjamin EJ. Obesity and the risk of new-onset atrial fibrillation.JAMA. 2004; 292:2471–2477. doi: 10.1001/jama.292.20.2471.CrossrefMedlineGoogle Scholar
    • 119. Frost L, Hune LJ, Vestergaard P. Overweight and obesity as risk factors for atrial fibrillation or flutter: the Danish Diet, Cancer, and Health Study.Am J Med. 2005; 118:489–495. doi: 10.1016/j.amjmed.2005.01.031.CrossrefMedlineGoogle Scholar
    • 120. Murphy NF, MacIntyre K, Stewart S, Hart CL, Hole D, McMurray JJ. Long-term cardiovascular consequences of obesity: 20-year follow-up of more than 15 000 middle-aged men and women (the Renfrew-Paisley study).Eur Heart J. 2006; 27:96–106. doi: 10.1093/eurheartj/ehi506.CrossrefMedlineGoogle Scholar
    • 121. Wanahita N, Messerli FH, Bangalore S, Gami AS, Somers VK, Steinberg JS. Atrial fibrillation and obesity–results of a meta-analysis.Am Heart J. 2008; 155:310–315. doi: 10.1016/j.ahj.2007.10.004.CrossrefMedlineGoogle Scholar
    • 122. Tedrow UB, Conen D, Ridker PM, Cook NR, Koplan BA, Manson JE, Buring JE, Albert CM. 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. 2010; 55:2319–2327. doi: 10.1016/j.jacc.2010.02.029.CrossrefMedlineGoogle Scholar
    • 123. Gami AS, Hodge DO, Herges RM, Olson EJ, Nykodym J, Kara T, Somers VK. Obstructive sleep apnea, obesity, and the risk of incident atrial fibrillation.J Am Coll Cardiol. 2007; 49:565–571. doi: 10.1016/j.jacc.2006.08.060.CrossrefMedlineGoogle Scholar
    • 124. Aronis KN, Wang N, Phillips CL, Benjamin EJ, Marcus GM, Newman AB, Rodondi N, Satterfield S, Harris TB, Magnani JW; Health ABC study. Associations of obesity and body fat distribution with incident atrial fibrillation in the biracial health aging and body composition cohort of older adults.Am Heart J. 2015; 170:498.e2–505.e2. doi: 10.1016/j.ahj.2015.06.007.CrossrefGoogle Scholar
    • 125. Tsang TS, Barnes ME, Gersh BJ, Bailey KR, Seward JB. Left atrial volume as a morphophysiologic expression of left ventricular diastolic dysfunction and relation to cardiovascular risk burden.Am J Cardiol. 2002; 90:1284–1289.CrossrefMedlineGoogle Scholar
    • 126. Pritchett AM, Mahoney DW, Jacobsen SJ, Rodeheffer RJ, Karon BL, Redfield MM. Diastolic dysfunction and left atrial volume: a population-based study.J Am Coll Cardiol. 2005; 45:87–92. doi: 10.1016/j.jacc.2004.09.054.CrossrefMedlineGoogle Scholar
    • 127. Abed HS, Samuel CS, Lau DH, et al. Obesity results in progressive atrial structural and electrical remodeling: implications for atrial fibrillation.Heart Rhythm. 2013; 10:90–100. doi: 10.1016/j.hrthm.2012.08.043.CrossrefMedlineGoogle Scholar
    • 128. Munger TM, Dong YX, Masaki M, et al. Electrophysiological and hemodynamic characteristics associated with obesity in patients with atrial fibrillation.J Am Coll Cardiol. 2012; 60:851–860. doi: 10.1016/j.jacc.2012.03.042.CrossrefMedlineGoogle Scholar
    • 129. Al Chekakie MO, Welles CC, Metoyer R, Ibrahim A, Shapira AR, Cytron J, Santucci P, Wilber DJ, Akar JG. Pericardial fat is independently associated with human atrial fibrillation.J Am Coll Cardiol. 2010; 56:784–788. doi: 10.1016/j.jacc.2010.03.071.CrossrefMedlineGoogle Scholar
    • 130. Thanassoulis G, Massaro JM, O’Donnell CJ, Hoffmann U, Levy D, Ellinor PT, Wang TJ, Schnabel RB, Vasan RS, Fox CS, Benjamin EJ. Pericardial fat is associated with prevalent atrial fibrillation: the Framingham Heart Study.Circ Arrhythm Electrophysiol. 2010; 3:345–350. doi: 10.1161/CIRCEP.109.912055.LinkGoogle Scholar
    • 131. Agbaedeng T, Mahajan R, Munawar D, Elliott A, Twomey D, Kurmar S, Lau D, Sanders P. Meta-analysis of effects of epicardial fat on atrial fibrillation and ablation outcome.Heart Lung Circ. 2016; 25:S150.CrossrefGoogle Scholar
    • 132. Karastergiou K, Evans I, Ogston N, Miheisi N, Nair D, Kaski JC, Jahangiri M, Mohamed-Ali V. Epicardial adipokines in obesity and coronary artery disease induce atherogenic changes in monocytes and endothelial cells.Arterioscler Thromb Vasc Biol. 2010; 30:1340–1346. doi: 10.1161/ATVBAHA.110.204719.LinkGoogle Scholar
    • 133. Greulich S, Maxhera B, Vandenplas G, de Wiza DH, Smiris K, Mueller H, Heinrichs J, Blumensatt M, Cuvelier C, Akhyari P, Ruige JB, Ouwens DM, Eckel J. Secretory products from epicardial adipose tissue of patients with type 2 diabetes mellitus induce cardiomyocyte dysfunction.Circulation. 2012; 126:2324–2334. doi: 10.1161/CIRCULATIONAHA.111.039586.LinkGoogle Scholar
    • 134. Venteclef N, Guglielmi V, Balse E, Gaborit B, Cotillard A, Atassi F, Amour J, Leprince P, Dutour A, Clément K, Hatem SN. Human epicardial adipose tissue induces fibrosis of the atrial myocardium through the secretion of adipo-fibrokines.Eur Heart J. 2015; 36:795a–805a. doi: 10.1093/eurheartj/eht099.CrossrefMedlineGoogle Scholar
    • 135. Nagashima K, Okumura Y, Watanabe I, Nakai T, Ohkubo K, Kofune M, Mano H, Sonoda K, Hiro T, Nikaido M, Hirayama A. Does location of epicardial adipose tissue correspond to endocardial high dominant frequency or complex fractionated atrial electrogram sites during atrial fibrillation?Circ Arrhythm Electrophysiol. 2012; 5:676–683. doi: 10.1161/CIRCEP.112.971200.LinkGoogle Scholar
    • 136. Psaty BM, Manolio TA, Kuller LH, Kronmal RA, Cushman M, Fried LP, White R, Furberg CD, Rautaharju PM. Incidence of and risk factors for atrial fibrillation in older adults.Circulation. 1997; 96:2455–2461.LinkGoogle Scholar
    • 137. Huxley RR, Filion KB, Konety S, Alonso A. Meta-analysis of cohort and case-control studies of type 2 diabetes mellitus and risk of atrial fibrillation.Am J Cardiol. 2011; 108:56–62. doi: 10.1016/j.amjcard.2011.03.004.CrossrefMedlineGoogle Scholar
    • 138. Dublin S, Glazer NL, Smith NL, Psaty BM, Lumley T, Wiggins KL, Page RL, Heckbert SR. Diabetes mellitus, glycemic control, and risk of atrial fibrillation.J Gen Intern Med. 2010; 25:853–858. doi: 10.1007/s11606-010-1340-y.CrossrefMedlineGoogle Scholar
    • 139. Rutter MK, Parise H, Benjamin EJ, Levy D, Larson MG, Meigs JB, Nesto RW, Wilson PW, Vasan RS. Impact of glucose intolerance and insulin resistance on cardiac structure and function: sex-related differences in the Framingham Heart Study.Circulation. 2003; 107:448–454.LinkGoogle Scholar
    • 140. Anderson EJ, Kypson AP, Rodriguez E, Anderson CA, Lehr EJ, Neufer PD. Substrate-specific derangements in mitochondrial metabolism and redox balance in the atrium of the type 2 diabetic human heart.J Am Coll Cardiol. 2009; 54:1891–1898. doi: 10.1016/j.jacc.2009.07.031.CrossrefMedlineGoogle Scholar
    • 141. Kato T, Yamashita T, Sekiguchi A, Tsuneda T, Sagara K, Takamura M, Kaneko S, Aizawa T, Fu LT. AGEs-RAGE system mediates atrial structural remodeling in the diabetic rat.J Cardiovasc Electrophysiol. 2008; 19:415–420. doi: 10.1111/j.1540-8167.2007.01037.x.CrossrefMedlineGoogle Scholar
    • 142. Kato T, Yamashita T, Sekiguchi A, Sagara K, Takamura M, Takata S, Kaneko S, Aizawa T, Fu LT. What are arrhythmogenic substrates in diabetic rat atria?J Cardiovasc Electrophysiol. 2006; 17:890–894. doi: 10.1111/j.1540-8167.2006.00528.x.CrossrefMedlineGoogle Scholar
    • 143. Chao TF, Suenari K, Chang SL, Lin YJ, Lo LW, Hu YF, Tuan TC, Tai CT, Tsao HM, Li CH, Ueng KC, Wu TJ, Chen SA. Atrial substrate properties and outcome of catheter ablation in patients with paroxysmal atrial fibrillation associated with diabetes mellitus or impaired fasting glucose.Am J Cardiol. 2010; 106:1615–1620. doi: 10.1016/j.amjcard.2010.07.038.CrossrefMedlineGoogle Scholar
    • 144. Otake H, Suzuki H, Honda T, Maruyama Y. Influences of autonomic nervous system on atrial arrhythmogenic substrates and the incidence of atrial fibrillation in diabetic heart.Int Heart J. 2009; 50:627–641.CrossrefMedlineGoogle Scholar
    • 145. Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S. The occurrence of sleep-disordered breathing among middle-aged adults.N Engl J Med. 1993; 328:1230–1235. doi: 10.1056/NEJM199304293281704.CrossrefMedlineGoogle Scholar
    • 146. Shamsuzzaman AS, Gersh BJ, Somers VK. Obstructive sleep apnea: implications for cardiac and vascular disease.JAMA. 2003; 290:1906–1914. doi: 10.1001/jama.290.14.1906.CrossrefMedlineGoogle Scholar
    • 147. Mehra R, Benjamin EJ, Shahar E, Gottlieb DJ, Nawabit R, Kirchner HL, Sahadevan J, Redline S; Sleep Heart Health Study. Association of nocturnal arrhythmias with sleep-disordered breathing: the Sleep Heart Health Study.Am J Respir Crit Care Med. 2006; 173:910–916. doi: 10.1164/rccm.200509-1442OC.CrossrefMedlineGoogle Scholar
    • 148. Qaddoura A, Kabali C, Drew D, van Oosten EM, Michael KA, Redfearn DP, Simpson CS, Baranchuk A. Obstructive sleep apnea as a predictor of atrial fibrillation after coronary artery bypass grafting: a systematic review and meta-analysis.Can J Cardiol. 2014; 30:1516–1522. doi: 10.1016/j.cjca.2014.10.014.CrossrefMedlineGoogle Scholar
    • 149. Kanagala R, Murali NS, Friedman PA, Ammash NM, Gersh BJ, Ballman KV, Shamsuzzaman AS, Somers VK. Obstructive sleep apnea and the recurrence of atrial fibrillation.Circulation. 2003; 107:2589–2594. doi: 10.1161/01.CIR.0000068337.25994.21.LinkGoogle Scholar
    • 150. Ng CY, Liu T, Shehata M, Stevens S, Chugh SS, Wang X. Meta-analysis of obstructive sleep apnea as predictor of atrial fibrillation recurrence after catheter ablation.Am J Cardiol. 2011; 108:47–51. doi: 10.1016/j.amjcard.2011.02.343.CrossrefMedlineGoogle Scholar
    • 151. Holmqvist F, Guan N, Zhu Z, Kowey PR, Allen LA, Fonarow GC, Hylek EM, Mahaffey KW, Freeman JV, Chang P, Holmes DN, Peterson ED, Piccini JP, Gersh BJ; ORBIT-AF Investigators. Impact of obstructive sleep apnea and continuous positive airway pressure therapy on outcomes in patients with atrial fibrillation-Results from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF).Am Heart J. 2015; 169:647.e2–654.e2. doi: 10.1016/j.ahj.2014.12.024.CrossrefGoogle Scholar
    • 152. Dimitri H, Ng M, Brooks AG, Kuklik P, Stiles MK, Lau DH, Antic N, Thornton A, Saint DA, McEvoy D, Antic R, Kalman JM, Sanders P. Atrial remodeling in obstructive sleep apnea: implications for atrial fibrillation.Heart Rhythm. 2012; 9:321–327. doi: 10.1016/j.hrthm.2011.10.017.CrossrefMedlineGoogle Scholar
    • 153. Iwasaki YK, Kato T, Xiong F, Shi YF, Naud P, Maguy A, Mizuno K, Tardif JC, Comtois P, Nattel S. Atrial fibrillation promotion with long-term repetitive obstructive sleep apnea in a rat model.J Am Coll Cardiol. 2014; 64:2013–2023. doi: 10.1016/j.jacc.2014.05.077.CrossrefMedlineGoogle Scholar
    • 154. Leuenberger U, Jacob E, Sweer L, Waravdekar N, Zwillich C, Sinoway L. Surges of muscle sympathetic nerve activity during obstructive apnea are linked to hypoxemia.J Appl Physiol. 1995; 79:581–588.CrossrefMedlineGoogle Scholar
    • 155. Orban M, Bruce CJ, Pressman GS, Leinveber P, Romero-Corral A, Korinek J, Konecny T, Villarraga HR, Kara T, Caples SM, Somers VK. Dynamic changes of left ventricular performance and left atrial volume induced by the mueller maneuver in healthy young adults and implications for obstructive sleep apnea, atrial fibrillation, and heart failure.Am J Cardiol. 2008; 102:1557–1561. doi: 10.1016/j.amjcard.2008.07.050.CrossrefMedlineGoogle Scholar
    • 156. Ntalapascha M, Makris D, Kyparos A, Tsilioni I, Kostikas K, Gourgoulianis K, Kouretas D, Zakynthinos E. Oxidative stress in patients with obstructive sleep apnea syndrome.Sleep Breath. 2013; 17:549–555. doi: 10.1007/s11325-012-0718-y.CrossrefMedlineGoogle Scholar
    • 157. Shamsuzzaman AS, Winnicki M, Lanfranchi P, Wolk R, Kara T, Accurso V, Somers VK. Elevated C-reactive protein in patients with obstructive sleep apnea.Circulation. 2002; 105:2462–2464.LinkGoogle Scholar
    • 158. Stevenson IH, Roberts-Thomson KC, Kistler PM, Edwards GA, Spence S, Sanders P, Kalman JM. Atrial electrophysiology is altered by acute hypercapnia but not hypoxemia: implications for promotion of atrial fibrillation in pulmonary disease and sleep apnea.Heart Rhythm. 2010; 7:1263–1270. doi: 10.1016/j.hrthm.2010.03.020.CrossrefMedlineGoogle Scholar
    • 159. Linz D, Schotten U, Neuberger HR, Böhm M, Wirth K. Negative tracheal pressure during obstructive respiratory events promotes atrial fibrillation by vagal activation.Heart Rhythm. 2011; 8:1436–1443. doi: 10.1016/j.hrthm.2011.03.053.CrossrefMedlineGoogle Scholar
    • 160. Kannel WB, Wolf PA, Benjamin EJ, Levy D. Prevalence, incidence, prognosis, and predisposing conditions for atrial fibrillation: population-based estimates.Am J Cardiol. 1998; 82:2N–9N.CrossrefMedlineGoogle Scholar
    • 161. Mitchell GF, Vasan RS, Keyes MJ, Parise H, Wang TJ, Larson MG, D’Agostino RB, Kannel WB, Levy D, Benjamin EJ. Pulse pressure and risk of new-onset atrial fibrillation.JAMA. 2007; 297:709–715. doi: 10.1001/jama.297.7.709.CrossrefMedlineGoogle Scholar
    • 162. Grundvold I, Skretteberg PT, Liestøl K, Erikssen G, Kjeldsen SE, Arnesen H, Erikssen J, Bodegard J. Upper normal blood pressures predict incident atrial fibrillation in healthy middle-aged men: a 35-year follow-up study.Hypertension. 2012; 59:198–204. doi: 10.1161/HYPERTENSIONAHA.111.179713.LinkGoogle Scholar
    • 163. Conen D, Tedrow UB, Koplan BA, Glynn RJ, Buring JE, Albert CM. Influence of systolic and diastolic blood pressure on the risk of incident atrial fibrillation in women.Circulation. 2009; 119:2146–2152. doi: 10.1161/CIRCULATIONAHA.108.830042.LinkGoogle Scholar
    • 164. Vaziri SM, Larson MG, Benjamin EJ, Levy D. Echocardiographic predictors of nonrheumatic atrial fibrillation. The Framingham Heart Study.Circulation. 1994; 89:724–730.LinkGoogle Scholar
    • 165. Verdecchia P, Reboldi G, Gattobigio R, Bentivoglio M, Borgioni C, Angeli F, Carluccio E, Sardone MG, Porcellati C. Atrial fibrillation in hypertension: predictors and outcome.Hypertension. 2003; 41:218–223.LinkGoogle Scholar
    • 166. Tsang TS, Gersh BJ, Appleton CP, Tajik AJ, Barnes ME, Bailey KR, Oh JK, Leibson C, Montgomery SC, Seward JB. Left ventricular diastolic dysfunction as a predictor of the first diagnosed nonvalvular atrial fibrillation in 840 elderly men and women.J Am Coll Cardiol. 2002; 40:1636–1644.CrossrefMedlineGoogle Scholar
    • 167. Lau DH, Mackenzie L, Kelly DJ, et al. Short-term hypertension is associated with the development of atrial fibrillation substrate: a study in an ovine hypertensive model.Heart Rhythm. 2010; 7:396–404. doi: 10.1016/j.hrthm.2009.11.031.CrossrefMedlineGoogle Scholar
    • 168. Kistler PM, Sanders P, Dodic M, Spence SJ, Samuel CS, Zhao C, Charles JA, Edwards GA, Kalman JM. Atrial electrical and structural abnormalities in an ovine model of chronic blood pressure elevation after prenatal corticosteroid exposure: implications for development of atrial fibrillation.Eur Heart J. 2006; 27:3045–3056. doi: 10.1093/eurheartj/ehl360.CrossrefMedlineGoogle Scholar
    • 169. Medi C, Kalman JM, Spence SJ, Teh AW, Lee G, Bader I, Kaye DM, Kistler PM. Atrial electrical and structural changes associated with longstanding hypertension in humans: implications for the substrate for atrial fibrillation.J Cardiovasc Electrophysiol. 2011; 22:1317–1324. doi: 10.1111/j.1540-8167.2011.02125.x.CrossrefMedlineGoogle Scholar
    • 170. Nakashima H, Kumagai K, Urata H, Gondo N, Ideishi M, Arakawa K. Angiotensin II antagonist prevents electrical remodeling in atrial fibrillation.Circulation. 2000; 101:2612–2617.LinkGoogle Scholar
    • 171. Li D, Shinagawa K, Pang L, Leung TK, Cardin S, Wang Z, Nattel S. Effects of angiotensin-converting enzyme inhibition on the development of the atrial fibrillation substrate in dogs with ventricular tachypacing-induced congestive heart failure.Circulation. 2001; 104:2608–2614.LinkGoogle Scholar
    • 172. Shi Y, Li D, Tardif JC, Nattel S. Enalapril effects on atrial remodeling and atrial fibrillation in experimental congestive heart failure.Cardiovasc Res. 2002; 54:456–461.CrossrefMedlineGoogle Scholar
    • 173. Healey JS, Baranchuk A, Crystal E, Morillo CA, Garfinkle M, Yusuf S, Connolly SJ. Prevention of atrial fibrillation with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: a meta-analysis.J Am Coll Cardiol. 2005; 45:1832–1839. doi: 10.1016/j.jacc.2004.11.070.CrossrefMedlineGoogle Scholar
    • 174. Schneider MP, Hua TA, Böhm M, Wachtell K, Kjeldsen SE, Schmieder RE. Prevention of atrial fibrillation by renin-angiotensin system inhibition a meta-analysis.J Am Coll Cardiol. 2010; 55:2299–2307. doi: 10.1016/j.jacc.2010.01.043.CrossrefMedlineGoogle Scholar
    • 175. McAllen PM, Marshall J. Cardiac dysrhythmia and transient cerebral ischaemic attacks.Lancet. 1973; 1:1212–1214.CrossrefMedlineGoogle Scholar
    • 176. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study.Stroke. 1991; 22:983–988.LinkGoogle Scholar
    • 177. Healey JS, Connolly SJ, Gold MR, Israel CW, Van Gelder IC, Capucci A, Lau CP, Fain E, Yang S, Bailleul C, Morillo CA, Carlson M, Themeles E, Kaufman ES, Hohnloser SH; ASSERT Investigators. Subclinical atrial fibrillation and the risk of stroke.N Engl J Med. 2012; 366:120–129. doi: 10.1056/NEJMoa1105575.CrossrefMedlineGoogle Scholar
    • 178. AFI. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials.Arch Intern Med. 1994; 154:1449–1457.CrossrefMedlineGoogle Scholar
    • 179. The SPAF III Writing Committee for the Stroke Prevention in Atrial Fibrillation Investigators. Patients with nonvalvular atrial fibrillation at low risk of stroke during treatment with aspirin: Stroke Prevention in Atrial Fibrillation III Study.JAMA. 1998; 279:1273–1277.CrossrefMedlineGoogle Scholar
    • 180. Hart RG, Pearce LA, McBride R, Rothbart RM, Asinger RW. 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.Stroke. 1999; 30:1223–1229.LinkGoogle Scholar
    • 181. Olesen JB, Lip GY, Hansen ML, Hansen PR, Tolstrup JS, Lindhardsen J, Selmer C, Ahlehoff O, Olsen AM, Gislason GH, Torp-Pedersen C. Validation of risk stratification schemes for predicting stroke and thromboembolism in patients with atrial fibrillation: nationwide cohort study.BMJ. 2011; 342:d124.CrossrefMedlineGoogle Scholar
    • 182. Jørgensen HS, Nakayama H, Reith J, Raaschou HO, Olsen TS. Acute stroke with atrial fibrillation. The Copenhagen Stroke Study.Stroke. 1996; 27:1765–1769.LinkGoogle Scholar
    • 183. Yeh YH, Wakili R, Qi XY, Chartier D, Boknik P, Kääb S, Ravens U, Coutu P, Dobrev D, Nattel S. Calcium-handling abnormalities underlying atrial arrhythmogenesis and contractile dysfunction in dogs with congestive heart failure.Circ Arrhythm Electrophysiol. 2008; 1:93–102. doi: 10.1161/CIRCEP.107.754788.LinkGoogle Scholar
    • 184. Kneller J, Sun H, Leblanc N, Nattel S. Remodeling of Ca(2+)-handling by atrial tachycardia: evidence for a role in loss of rate-adaptation.Cardiovasc Res. 2002; 54:416–426.CrossrefMedlineGoogle Scholar
    • 185. Goldman ME, Pearce LA, Hart RG, Zabalgoitia M, Asinger RW, Safford R, Halperin JL. Pathophysiologic correlates of thromboembolism in nonvalvular atrial fibrillation: I. Reduced flow velocity in the left atrial appendage (The Stroke Prevention in Atrial Fibrillation [SPAF-III] study).J Am Soc Echocardiogr. 1999; 12:1080–1087.CrossrefMedlineGoogle Scholar
    • 186. Merino A, Hauptman P, Badimon L, Badimon JJ, Cohen M, Fuster V, Goldman M. Echocardiographic “smoke” is produced by an interaction of erythrocytes and plasma proteins modulated by shear forces.J Am Coll Cardiol. 1992; 20:1661–1668.CrossrefMedlineGoogle Scholar
    • 187. Holmes DR, Reddy VY, Turi ZG, Doshi SK, Sievert H, Buchbinder M, Mullin CM, Sick P; PROTECT AF Investigators. Percutaneous closure of the left atrial appendage versus warfarin therapy for prevention of stroke in patients with atrial fibrillation: a randomised non-inferiority trial.Lancet. 2009; 374:534–542. doi: 10.1016/S0140-6736(09)61343-X.CrossrefMedlineGoogle Scholar
    • 188. Turgut N, Akdemir O, Turgut B, Demir M, Ekuklu G, Vural O, Ozbay G, Utku U. Hypercoagulopathy in stroke patients with nonvalvular atrial fibrillation: hematologic and cardiologic investigations.Clin Appl Thromb Hemost. 2006; 12:15–20.CrossrefMedlineGoogle Scholar
    • 189. Tsai LM, Chen JH, Tsao CJ. Relation of left atrial spontaneous echo contrast with prethrombotic state in atrial fibrillation associated with systemic hypertension, idiopathic dilated cardiomyopathy, or no identifiable cause (lone).Am J Cardiol. 1998; 81:1249–1252.CrossrefMedlineGoogle Scholar
    • 190. Mondillo S, Sabatini L, Agricola E, Ammaturo T, Guerrini F, Barbati R, Pastore M, Fineschi D, Nami R. Correlation between left atrial size, prothrombotic state and markers of endothelial dysfunction in patients with lone chronic nonrheumatic atrial fibrillation.Int J Cardiol. 2000; 75:227–232.CrossrefMedlineGoogle Scholar
    • 191. Conway DS, Heeringa J, Van Der Kuip DA, Chin BS, Hofman A, Witteman JC, Lip GY. Atrial fibrillation and the prothrombotic state in the elderly: the Rotterdam Study.Stroke. 2003; 34:413–417.LinkGoogle Scholar
    • 192. Lip GY, Lowe GD, Rumley A, Dunn FG. Fibrinogen and fibrin D-dimer levels in paroxysmal atrial fibrillation: evidence for intermediate elevated levels of intravascular thrombogenesis.Am Heart J. 1996; 131:724–730.CrossrefMedlineGoogle Scholar
    • 193. Kahn SR, Solymoss S, Flegel KM. Nonvalvular atrial fibrillation: evidence for a prothrombotic state.CMAJ. 1997; 157:673–681.MedlineGoogle Scholar
    • 194. Feng D, D’Agostino RB, Silbershatz H, Lipinska I, Massaro J, Levy D, Benjamin EJ, Wolf PA, Tofler GH. Hemostatic state and atrial fibrillation (the Framingham Offspring Study).Am J Cardiol. 2001; 87:168–171.CrossrefMedlineGoogle Scholar
    • 195. Wolf PA, Kannel WB, McGee DL, Meeks SL, Bharucha NE, McNamara PM. Duration of atrial fibrillation and imminence of stroke: the Framingham study.Stroke. 1983; 14:664–667.LinkGoogle Scholar
    • 196. Bekwelem W, Connolly SJ, Halperin JL, Adabag S, Duval S, Chrolavicius S, Pogue J, Ezekowitz MD, Eikelboom JW, Wallentin LG, Yusuf S, Hirsch AT. Extracranial systemic embolic events in patients with nonvalvular atrial fibrillation: incidence, risk factors, and outcomes.Circulation. 2015; 132:796–803. doi: 10.1161/CIRCULATIONAHA.114.013243.LinkGoogle Scholar
    • 197. Kalantarian S, Ruskin JN. Cognitive impairment associated with atrial fibrillation–in response.Ann Intern Med. 2013; 158:849. doi: 10.7326/0003-4819-158-11-201306040-00016.CrossrefMedlineGoogle Scholar
    • 198. Marzona I, O’Donnell M, Teo K, Gao P, Anderson C, Bosch J, Yusuf S. Increased risk of cognitive and functional decline in patients with atrial fibrillation: results of the ONTARGET and TRANSCEND studies.CMAJ. 2012; 184:E329–E336. doi: 10.1503/cmaj.111173.CrossrefMedlineGoogle Scholar
    • 199. Kwok CS, Loke YK, Hale R, Potter JF, Myint PK. Atrial fibrillation and incidence of dementia: a systematic review and meta-analysis.Neurology. 2011; 76:914–922. doi: 10.1212/WNL.0b013e31820f2e38.CrossrefMedlineGoogle Scholar
    • 200. Santangeli P, Di Biase L, Bai R, Mohanty S, Pump A, Cereceda Brantes M, Horton R, Burkhardt JD, Lakkireddy D, Reddy YM, Casella M, Dello Russo A, Tondo C, Natale A. Atrial fibrillation and the risk of incident dementia: a meta-analysis.Heart Rhythm. 2012; 9:1761–1768. doi: 10.1016/j.hrthm.2012.07.026.CrossrefMedlineGoogle Scholar
    • 201. de Bruijn RF, Heeringa J, Wolters FJ, Franco OH, Stricker BH, Hofman A, Koudstaal PJ, Ikram MA. Association between atrial fibrillation and dementia in the general population.JAMA Neurol. 2015; 72:1288–1294. doi: 10.1001/jamaneurol.2015.2161.CrossrefMedlineGoogle Scholar
    • 202. Satizabal C, Beiser AS, Seshadri S. Incidence of dementia over three decades in the Framingham Heart Study.N Engl J Med. 2016; 375:93–94. doi: 10.1056/NEJMc1604823.CrossrefMedlineGoogle Scholar
    • 203. Dublin S, Anderson ML, Haneuse SJ, Heckbert SR, Crane PK, Breitner JC, McCormick W, Bowen JD, Teri L, McCurry SM, Larson EB. Atrial fibrillation and risk of dementia: a prospective cohort study.J Am Geriatr Soc. 2011; 59:1369–1375. doi: 10.1111/j.1532-5415.2011.03508.x.CrossrefMedlineGoogle Scholar
    • 204. Hara M, Ooie T, Yufu K, Tsunematsu Y, Kusakabe T, Ooga M, Saikawa T, Sakata T. Silent cortical strokes associated with atrial fibrillation.Clin Cardiol. 1995; 18:573–574.CrossrefMedlineGoogle Scholar
    • 205. Bunch TJ, May HT, Bair TL, Crandall BG, Cutler MJ, Day JD, Jacobs V, Mallender C, Osborn JS, Stevens SM, Weiss JP, Woller SC. Atrial fibrillation patients treated with long-term warfarin anticoagulation have higher rates of all dementia types compared with patients receiving long-term warfarin for other indications.J Am Heart Assoc. 2016; 5:e003932.LinkGoogle Scholar
    • 206. Lavy S, Stern S, Melamed E, Cooper G, Keren A, Levy P. Effect of chronic atrial fibrillation on regional cerebral blood flow.Stroke. 1980; 11:35–38.LinkGoogle Scholar
    • 207. Petersen P, Kastrup J, Videbaek R, Boysen G. Cerebral blood flow before and after cardioversion of atrial fibrillation.J Cereb Blood Flow Metab. 1989; 9:422–425. doi: 10.1038/jcbfm.1989.62.CrossrefMedlineGoogle Scholar
    • 208. Phillips E, Levine SA. Auricular fibrillation without other evidence of heart disease; a cause of reversible heart failure.Am J Med. 1949; 7:478–489.CrossrefMedlineGoogle Scholar
    • 209. Wang TJ, Larson MG, Levy D, Vasan RS, Leip EP, Wolf PA, D’Agostino RB, Murabito JM, Kannel WB, Benjamin EJ. Temporal relations of atrial fibrillation and congestive heart failure and their joint influence on mortality: the Framingham Heart Study.Circulation. 2003; 107:2920–2925. doi: 10.1161/01.CIR.0000072767.89944.6E.LinkGoogle Scholar
    • 210. Middlekauff HR, Stevenson WG, Stevenson LW. Prognostic significance of atrial fibrillation in advanced heart failure. A study of 390 patients.Circulation. 1991; 84:40–48.LinkGoogle Scholar
    • 211. Torp-Pedersen C, Møller M, Bloch-Thomsen PE, Køber L, Sandøe E, Egstrup K, Agner E, Carlsen J, Videbaek J, Marchant B, Camm AJ. Dofetilide in patients with congestive heart failure and left ventricular dysfunction. Danish Investigations of Arrhythmia and Mortality on Dofetilide Study Group.N Engl J Med. 1999; 341:857–865. doi: 10.1056/NEJM199909163411201.CrossrefMedlineGoogle Scholar
    • 212. Carson PE, Johnson GR, Dunkman WB, Fletcher RD, Farrell L, Cohn JN. The influence of atrial fibrillation on prognosis in mild to moderate heart failure. The V-HeFT Studies. The V-HeFT VA Cooperative Studies Group.Circulation. 1993; 87:VI102–VI110.MedlineGoogle Scholar
    • 213. Camm AJ, Savelieva I. Atrial fibrillation: advances and perspectives.Lead Article. 1912; 13:183.Google Scholar
    • 214. Furberg CD, Psaty BM, Manolio TA, Gardin JM, Smith VE, Rautaharju PM. Prevalence of atrial fibrillation in elderly subjects (the Cardiovascular Health Study).Am J Cardiol. 1994; 74:236–241.CrossrefMedlineGoogle Scholar
    • 215. Krahn AD, Manfreda J, Tate RB, Mathewson FA, Cuddy TE. The natural history of atrial fibrillation: incidence, risk factors, and prognosis in the Manitoba Follow-Up Study.Am J Med. 1995; 98:476–484. doi: 10.1016/S0002-9343(99)80348-9.CrossrefMedlineGoogle Scholar
    • 216. Schmidt M, Ulrichsen SP, Pedersen L, Bøtker HE, Nielsen JC, Sørensen HT. 30-year nationwide trends in incidence of atrial fibrillation in Denmark and associated 5-year risk of heart failure, stroke, and death.Int J Cardiol. 2016; 225:30–36. doi: 10.1016/j.ijcard.2016.09.071.CrossrefMedlineGoogle Scholar
    • 217. Santhanakrishnan R, Wang N, Larson MG, Magnani JW, McManus DD, Lubitz SA, Ellinor PT, Cheng S, Vasan RS, Lee DS, Wang TJ, Levy D, Benjamin EJ, Ho JE. Atrial fibrillation begets heart failure and vice versa: temporal associations and differences in preserved versus reduced ejection fraction.Circulation. 2016; 133:484–492. doi: 10.1161/CIRCULATIONAHA.115.018614.LinkGoogle Scholar
    • 218. Healey JS, Oldgren J, Ezekowitz M, et al; RE-LY Atrial Fibrillation Registry and Cohort Study Investigators. Occurrence of death and stroke in patients in 47 countries 1 year after presenting with atrial fibrillation: a cohort study.Lancet. 2016; 388:1161–1169. doi: 10.1016/S0140-6736(16)30968-0.CrossrefMedlineGoogle Scholar
    • 219. Kotecha D, Chudasama R, Lane DA, Kirchhof P, Lip GY. Atrial fibrillation and heart failure due to reduced versus preserved ejection fraction: a systematic review and meta-analysis of death and adverse outcomes.Int J Cardiol. 2016; 203:660–666. doi: 10.1016/j.ijcard.2015.10.220.CrossrefMedlineGoogle Scholar
    • 220. Li D, Melnyk P, Feng J, Wang Z, Petrecca K, Shrier A, Nattel S. Effects of experimental heart failure on atrial cellular and ionic electrophysiology.Circulation. 2000; 101:2631–2638.LinkGoogle Scholar
    • 221. Li D, Fareh S, Leung TK, Nattel S. Promotion of atrial fibrillation by heart failure in dogs: atrial remodeling of a different sort.Circulation. 1999; 100:87–95.LinkGoogle Scholar
    • 222. Sanders P, Morton JB, Davidson NC, Spence SJ, Vohra JK, Sparks PB, Kalman JM. Electrical remodeling of the atria in congestive heart failure: electrophysiological and electroanatomic mapping in humans.Circulation. 2003; 108:1461–1468. doi: 10.1161/01.CIR.0000090688.49283.67.LinkGoogle Scholar
    • 223. Ohtani K, Yutani C, Nagata S, Koretsune Y, Hori M, Kamada T. High prevalence of atrial fibrosis in patients with dilated cardiomyopathy.J Am Coll Cardiol. 1995; 25:1162–1169.CrossrefMedlineGoogle Scholar
    • 224. Cardin S, Li D, Thorin-Trescases N, Leung TK, Thorin E, Nattel S. Evolution of the atrial fibrillation substrate in experimental congestive heart failure: angiotensin-dependent and -independent pathways.Cardiovasc Res. 2003; 60:315–325.CrossrefMedlineGoogle Scholar
    • 225. Swaminathan PD, Purohit A, Soni S, et al. Oxidized CaMKII causes cardiac sinus node dysfunction in mice.J Clin Invest. 2011; 121:3277–3288. doi: 10.1172/JCI57833.CrossrefMedlineGoogle Scholar
    • 226. Purohit A, Rokita AG, Guan X, et al. Oxidized Ca(2+)/calmodulin-dependent protein kinase II triggers atrial fibrillation.Circulation. 2013; 128:1748–1757. doi: 10.1161/CIRCULATIONAHA.113.003313.LinkGoogle Scholar
    • 227. Chang SL, Chen YC, Yeh YH, Lin YK, Wu TJ, Lin CI, Chen SA, Chen YJ. Heart failure enhanced pulmonary vein arrhythmogenesis and dysregulated sodium and calcium homeostasis with increased calcium sparks.J Cardiovasc Electrophysiol. 2011; 22:1378–1386. doi: 10.1111/j.1540-8167.2011.02126.x.CrossrefMedlineGoogle Scholar
    • 228. Kannel WB, Abbott RD, Savage DD, McNamara PM. Coronary heart disease and atrial fibrillation: the Framingham Study.Am Heart J. 1983; 106:389–396.CrossrefMedlineGoogle Scholar
    • 229. Violi F, Soliman EZ, Pignatelli P, Pastori D. Atrial fibrillation and myocardial infarction: a systematic review and appraisal of pathophysiologic mechanisms.J Am Heart Assoc. 2016; 5:e003347.LinkGoogle Scholar
    • 230. Soliman EZ, Safford MM, Muntner P, Khodneva Y, Dawood FZ, Zakai NA, Thacker EL, Judd S, Howard VJ, Howard G, Herrington DM, Cushman M. Atrial fibrillation and the risk of myocardial infarction.JAMA Intern Med. 2014; 174:107–114. doi: 10.1001/jamainternmed.2013.11912.CrossrefMedlineGoogle Scholar
    • 231. Miyasaka Y, Barnes ME, Gersh BJ, Cha SS, Bailey KR, Seward JB, Iwasaka T, Tsang TS. Coronary ischemic events after first atrial fibrillation: risk and survival.Am J Med. 2007; 120:357–363. doi: 10.1016/j.amjmed.2006.06.042.CrossrefMedlineGoogle Scholar
    • 232. Holst AG, Jensen G, Prescott E. Risk factors for venous thromboembolism: results from the Copenhagen City Heart Study.Circulation. 2010; 121:1896–1903. doi: 10.1161/CIRCULATIONAHA.109.921460.LinkGoogle Scholar
    • 233. Brækkan SK, Hald EM, Mathiesen EB, Njølstad I, Wilsgaard T, Rosendaal FR, Hansen JB. Competing risk of atherosclerotic risk factors for arterial and venous thrombosis in a general population: the Tromso study.Arterioscler Thromb Vasc Biol. 2012; 32:487–491. doi: 10.1161/ATVBAHA.111.237545.LinkGoogle Scholar
    • 234. Wattanakit K, Lutsey PL, Bell EJ, Gornik H, Cushman M, Heckbert SR, Rosamond WD, Folsom AR. Association between cardiovascular disease risk factors and occurrence of venous thromboembolism. A time-dependent analysis.Thromb Haemost. 2012; 108:508–515. doi: 10.1160/TH11-10-0726.CrossrefMedlineGoogle Scholar
    • 235. Mahmoodi BK, Cushman M, Anne Næss I, et al. Association of traditional cardiovascular risk factors with venous thromboembolism: an individual participant data meta-analysis of prospective studies.Circulation. 2017; 135:7–16. doi: 10.1161/CIRCULATIONAHA.116.024507.LinkGoogle Scholar
    • 236. Enga KF, Rye-Holmboe I, Hald EM, Løchen ML, Mathiesen EB, Njølstad I, Wilsgaard T, Braekkan SK, Hansen JB. Atrial fibrillation and future risk of venous thromboembolism: the Tromsø study.J Thromb Haemost. 2015; 13:10–16. doi: 10.1111/jth.12762.CrossrefMedlineGoogle Scholar
    • 237. Hald EM, Enga KF, Løchen ML, Mathiesen EB, Njølstad I, Wilsgaard T, Braekkan SK, Hansen JB. Venous thromboembolism increases the risk of atrial fibrillation: the Tromso study.J Am Heart Assoc. 2014; 3:e000483. doi: 10.1161/JAHA.113.000483.LinkGoogle Scholar
    • 238. Wang CC, Lin CL, Wang GJ, Chang CT, Sung FC, Kao CH. Atrial fibrillation associated with increased risk of venous thromboembolism. A population-based cohort study.Thromb Haemost. 2015; 113:185–192. doi: 10.1160/TH14-05-0405.CrossrefMedlineGoogle Scholar
    • 239. Piccini JP, Hammill BG, Sinner MF, Hernandez AF, Walkey AJ, Benjamin EJ, Curtis LH, Heckbert SR. Clinical course of atrial fibrillation in older adults: the importance of cardiovascular events beyond stroke.Eur Heart J. 2014; 35:250–256. doi: 10.1093/eurheartj/eht483.CrossrefMedlineGoogle Scholar
    • 240. Odutayo A, Wong CX, Hsiao AJ, Hopewell S, Altman DG, Emdin CA. Atrial fibrillation and risks of cardiovascular disease, renal disease, and death: systematic review and meta-analysis.BMJ. 2016; 354:i4482.CrossrefMedlineGoogle Scholar
    • 241. Chen LY, Sotoodehnia N, Bůžková P, Lopez FL, Yee LM, Heckbert SR, Prineas R, Soliman EZ, Adabag S, Konety S, Folsom AR, Siscovick D, Alonso A. Atrial fibrillation and the risk of sudden cardiac death: the atherosclerosis risk in communities study and cardiovascular health study.JAMA Intern Med. 2013; 173:29–35. doi: 10.1001/2013.jamainternmed.744.CrossrefMedlineGoogle Scholar
    • 242. Marijon E, Le Heuzey JY, Connolly S, Yang S, Pogue J, Brueckmann M, Eikelboom J, Themeles E, Ezekowitz M, Wallentin L, Yusuf S; RE-LY Investigators. Causes of death and influencing factors in patients with atrial fibrillation: a competing-risk analysis from the randomized evaluation of long-term anticoagulant therapy study.Circulation. 2013; 128:2192–2201. doi: 10.1161/CIRCULATIONAHA.112.000491.LinkGoogle Scholar
    • 243. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation.Ann Intern Med. 2007; 146:857–867.CrossrefMedlineGoogle Scholar
    • 244. Pokorney SD, Piccini JP, Stevens SR, et al; ROCKET AF Steering Committee and Investigators; ROCKET AF Steering Committee Investigators. Cause of death and predictors of all-cause mortality in anticoagulated patients with nonvalvular atrial fibrillation: data from ROCKET AF.J Am Heart Assoc. 2016; 5:e002197. doi: 10.1161/JAHA.115.002197.LinkGoogle Scholar
    • 245. Larsen TB, Rasmussen LH, Skjøth F, Due KM, Callréus T, Rosenzweig M, Lip GY. Efficacy and safety of dabigatran etexilate and warfarin in “real-world” patients with atrial fibrillation: a prospective nationwide cohort study.J Am Coll Cardiol. 2013; 61:2264–2273. doi: 10.1016/j.jacc.2013.03.020.CrossrefMedlineGoogle Scholar
    • 246. Proietti M, Laroche C, Opolski G, Maggioni AP, Boriani G, Lip GY; Investigators AFGP. ‘Real-world’ atrial fibrillation management in Europe: observations from the 2-year follow-up of the EURObservational Research Programme-Atrial Fibrillation General Registry Pilot Phase [published online ahead of print May 18, 2016].Europace. doi: 10.1093/europace/euw112. https://academic.oup.com/europace/article-abstract/doi/10.1093/europace/euw112/2952333/Real-world-atrial-fibrillation-management-in?redirectedFrom=fulltext.CrossrefGoogle Scholar

    eLetters(0)

    eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate.

    Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page.