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Compendium

Circulation Research Compendium on Atrial Fibrillation:


Atrial Fibrillation Compendium: Historical Context and Detailed Translational Perspective on an Important Clinical Problem
The Clinical Profile and Pathophysiology of Atrial Fibrillation: Relationships Among Clinical Features,
Epidemiology, and Mechanisms
Emerging Directions in the Genetics of Atrial Fibrillation
Cellular and Molecular Electrophysiology of Atrial Fibrillation Initiation, Maintenance, and Progression
Role of the Autonomic Nervous System in Atrial Fibrillation: Pathophysiology and Therapy
Mathematical Approaches to Understanding and Imaging Atrial Fibrillation: Significance for Mechanisms and Management
Atrial Fibrillation Therapy Now and in the Future: Drugs, Biologicals, and Ablation
Stanley Nattel, Guest Editor

The Clinical Profile and Pathophysiology of Atrial Fibrillation


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Relationships Among Clinical Features, Epidemiology, and Mechanisms


Jason Andrade, Paul Khairy, Dobromir Dobrev, Stanley Nattel

Abstract: Atrial fibrillation (AF) is the most common arrhythmia (estimated lifetime risk, 22%26%). The aim of this
article is to review the clinical epidemiological features of AF and to relate them to underlying mechanisms. Long-
established risk factors for AF include aging, male sex, hypertension, valve disease, left ventricular dysfunction,
obesity, and alcohol consumption. Emerging risk factors include prehypertension, increased pulse pressure,
obstructive sleep apnea, high-level physical training, diastolic dysfunction, predisposing gene variants, hypertrophic
cardiomyopathy, and congenital heart disease. Potential risk factors are coronary artery disease, kidney disease,
systemic inflammation, pericardial fat, and tobacco use. AF has substantial population health consequences,
including impaired quality of life, increased hospitalization rates, stroke occurrence, and increased medical
costs. The pathophysiology of AF centers around 4 general types of disturbances that promote ectopic firing and
reentrant mechanisms, and include the following: (1) ion channel dysfunction, (2) Ca2+-handling abnormalities, (3)
structural remodeling, and (4) autonomic neural dysregulation. Aging, hypertension, valve disease, heart failure,
myocardial infarction, obesity, smoking, diabetes mellitus, thyroid dysfunction, and endurance exercise training
all cause structural remodeling. Heart failure and prior atrial infarction also cause Ca2+-handling abnormalities
that lead to focal ectopic firing via delayed afterdepolarizations/triggered activity. Neural dysregulation is central
to atrial arrhythmogenesis associated with endurance exercise training and occlusive coronary artery disease.
Monogenic causes of AF typically promote the arrhythmia via ion channel dysfunction, but the mechanisms of the
more common polygenic risk factors are still poorly understood and under intense investigation. Better recognition
of the clinical epidemiology of AF, as well as an improved appreciation of the underlying mechanisms, is needed to
develop improved methods for AF prevention and management.(Circ Res. 2014;114:1453-1468.)
Key Word: heart diseases

A trial fibrillation (AF), the most prevalent sustained ar-


rhythmia, is associated with substantial morbidity, re-
ductions in functional status and quality of life (QOL), and
increased mortality because of a combination of altered hemo-
dynamics, atrioventricular dyssynchrony, progressive atrial
and ventricular mechanical dysfunction, and thromboembolic

Original received December 11, 2013; revision received January 15, 2014; accepted January 21, 2014. In February 2014, the average time from
submission to first decision for all original research papers submitted to Circulation Research was 13.8 days.
From Department of Medicine and Research Center, Montreal Heart Institute and Universit de Montral, Montreal, Quebec, Canada (J.A., P.K., S.N.);
Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada (J.A.); and Faculty of Medicine, Institute of Pharmacology,
University Duisburg-Essen, Essen, Germany (D.D.).
Correspondence to Stanley Nattel, MD, Universite de Montreal, 5000 Belanger St E, Montreal, Quebec, H1T 1C8, Canada. E-mail stanley.nattel@icm-mhi.org

2014 American Heart Association, Inc.
Circulation Research is available at http://circres.ahajournals.org DOI: 10.1161/CIRCRESAHA.114.303211

1453
1454Circulation ResearchApril 25, 2014

population has transient or paroxysmal AF, which would not


Nonstandard Abbreviations and Acronyms
be accounted for in the early epidemiological studies based on
APD action potential duration populations with permanent AF diagnosed by electrocardiogra-
CAD coronary artery disease phy.58,14 Moreover, estimates of AF prevalence based on symp-
DAD delayed afterdepolarization tomatic presentations are problematic because AF is silent in
HR hazard ratio 5% to 35% of patients.1517 As such, when factoring in patients
OAC oral anticoagulant with paroxysmal and silent AF, the projected prevalence of AF
OSA obstructive sleep apnea in the United States in 2050 increases from 5.6 million (exclud-
QOL quality of life ing paroxysmal and silent AF) to 12.1 to 15.9 million.9,13
SR sarcoplasmic reticulum Risk Factors for AF
AF is a multifaceted condition ranging from an isolated elec-
trophysiological disorder to a manifestation or consequence
complications. Rarely a primary electric disorder, AF most
of other cardiac and noncardiac pathologies. The former,
commonly represents a final common pathway for a multi-
so-called lone AF, is usually defined as paroxysmal, persistent,
tude of other predisposing cardiac and noncardiac condi-
or permanent AF in individuals <60 to 65 years of age with
tions. Clinical presentations range from asymptomatic to
no apparent cardiovascular disease. Established, emerging,
debilitating reflecting, in part, the heterogeneity in associated
and potential risk factors for AF are summarized in Table1.
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comorbidities. The goal of this article is to review the epide-


Because risk factors are becoming increasingly defined and
miological and clinical features of AF and then to relate them
recognized, the term lone AF is applied to a dwindling propor-
to the pathophysiology of the arrhythmia. Other articles in this
tion of patients.
compendium deal with specific pathophysiological entities in
detail, but here we aim to provide a perspective on how differ- Age and Sex
ent pathophysiological components operate to make AF a final Age and sex are 2 of the most powerful predictors of incident
common end point of a variety of cardiac conditions. AF. The role of age is discussed in detail above. Although the
prevalence of AF doubles with each decade of age, after ad-
Incidence and Prevalence of AF
justing for age and other predisposing conditions, male sex is
AF is a major burden to healthcare systems. Multiple studies
associated with a 1.5-fold risk of developing AF.112
of predominantly European and American populations have
attempted to define precisely the contemporary incidence and Hypertension
prevalence of AF and project this information against demo- The association between hypertension (blood pressure
graphic data to estimate anticipated AF-related healthcare >140/90) and AF is well established.6,1820 Although the in-
delivery and resource allocation needs. The current evidence crease in risk is relatively modest (relative risk, 1.21.5), the
indicates that the overall prevalence of AF is in the range of high prevalence of hypertension in the general population ren-
1% to 2% of the general population.112 ders it the most significant population-attributable risk factor
Although the reported annual incidence rates for AF have for AF beyond age and sex. It is estimated that hypertension
varied widely depending on the populations studied (from is responsible for 14% of all cases of AF.20 Although overt
0.8 to 28.3 cases per 1000 person-years), time trend analyses systolic hypertension is strongly associated with incident
reveal relatively stable incidence density rates over time (eg, AF, recent studies suggest that systolic blood pressure in the
27.3 per 1000 life-years in 1993 compared with 28.3 per 1000 prehypertensive range (130139 mmHg) and widened pulse
life-years in 2007).2,4,5,1113 In contrast, the prevalence of AF pressure are also associated with increased risk (adjusted haz-
continues to rise (eg, from 41 cases per 1000 in 1993 to 85 ard ratios [HRs], 1.28 versus systolic blood pressure <120 and
cases per 1000 in 2007).2 Some of the increasing prevalence 1.26 per 20 mmHg increment, respectively).19,21 Interestingly,
may be attributable to a modest improvement in AF-related mean arterial pressure does not seem to be associated with
survival (eg, 3-year mortality rate reduction from 45% to 42% incident AF.21
in 1993 versus 2005), which is related to better detection and
treatment of underlying conditions such as hypertension, coro- Valvular Heart Disease
nary artery disease (CAD), and heart failure (HF).2 However, Valvular heart disease has been associated with a 1.8- and
the predominant demographic factor increasing the prevalence 3.4-fold increased risk for AF in men and women, respective-
rates seems to be population-aging because both the incidence ly.20 Although any valvular pathology can be related to AF,
and the prevalence of AF are age dependent (Figures1 and stenotic left-sided valvular lesions (and in particular rheumat-
2).2,4,5,1113 Incidence rates increase from <0.5 to 2, to 3 to 9, and ic heart disease) have the highest prevalence rates. Severity of
10 to 39 cases per 1000 person-years at 50, 65, and 80 years, obstruction follows a doseresponse relationship: AF preva-
respectively.112 Corresponding prevalence rates increase from lence is 9.1% of patients with mild-to-moderate aortic steno-
<0.5% to 1.0%, to 1% to 4%, and 6% to 15%, respectively.112 sis and 33.7% among those with severe stenosis.22,23 Likewise,
The lifetime risk of developing AF for individuals 40 to 55 the prevalence of AF varies with the complexity of rheumatic
years of age has been estimated to be 22% to 26%.4,9 heart disease: from 16% with isolated mitral regurgitation to
It is important to note that the above-cited epidemiologi- 29% with isolated mitral stenosis, to 52% with coexisting mi-
cal studies likely underestimate the true disease burden. It tral regurgitation and stenosis, and to 70% with mixed mitral
is estimated that between a quarter and two thirds of the AF and tricuspid valve disease.24
Andrade et al Clinical Pathophysiology of AF 1455

Figure 1. A depiction of the atrial


fibrillation (AF) prevalence distribution
found by each study published to date.
This depiction uses the sex-specific
average rates of AF prevalence, grouped
by age. The thick line represents average
AF prevalence rates by age group, as
derived from a pooled analysis of the
individual studies weighted by sample size.
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HF and Cardiomyopathy Congenital Heart Disease


AF and HF often coexist, with a prevalence of AF that increas- Atrial tachyarrhythmias are highly prevalent in congenital
es with the severity of HF symptomatology (eg, <5%10% heart disease,31 are the most common complication in adults
with New York Heart Association functional class I symp- with congenital heart disease, and are the leading cause of
toms, 10%26% in New York Heart Association class IIIII, morbidity/hospitalizations.3235 Potential contributors include
and 40%50% for New York Heart Association class IV).25 surgical incisions, natural conduction barriers (eg, valve ori-
HF is associated with a 4.5- to 5.9-fold adjusted risk for AF.20 fices, venous structures, septal defects, and crista terminalis),
The association is not limited to systolic left ventricular dys- and sequelae of chronic hemodynamic or hypoxic stress (eg,
function. Isolated diastolic dysfunction is also associated with fibrosis and hypertrophy). Whereas organized atrial macro-
an increased AF incidence, possibly reflecting shared risk fac- reentrant arrhythmias are the most common supraventricu-
tors such as advancing age and hypertension.2628 Similarly, a lar arrhythmia in patients with congenital heart disease, the
10% to 28% prevalence of AF has been reported in hypertro- prevalence of AF is rising, particularly with atrial/atrioven-
phic cardiomyopathy, with an incidence 4 to 6 that of the tricular septal defects, Ebstein anomaly, tetralogy of Fallot,
general population.29,30 univentricular hearts, and left-sided obstructive lesions.3638

Figure 2. A comparison is made of


the atrial fibrillation (AF) incidence
rates from published studies. In cases
in which the studies report on sex-
specific incidence by age group, the age
group average is used for purposes of
comparison. The thick line represents
average AF incidence rates by age group,
as derived from a pooled analysis of the
individual studies weighted by sample size.
1456Circulation ResearchApril 25, 2014

Table 1. AF Risk Factors (body mass index, >30 kg/m2) individuals are at increased AF
Estimated
risk (HR, 1.391.75 and 1.992.35, respectively).44,45 For each
Risk Factor Increased Risk Comments unit increase in body mass index, the corrected risk of incident
AF increases 3% to 7%.44
Established
Age 2 Per decade Pericardial Fat
Male sex 1.5 In addition to sharing blood supply with the cardiac microcir-
Hypertension 1.21.5 BP >140/90 mmHg culation, pericardial fat is metabolically active and produces
Valvular heart disease 1.83.4
cytokines with inflammatory properties. The presence, thick-
ness, and volume of pericardial fat have been independently
LV systolic dysfunction 4.55.9
associated with the prevalence and severity of AF (ie, symp-
Obesity 1.392.35
tom burden, AF chronicity, AF subtype, and AF burden).4648
Alcohol consumption 1.341.46 Heavy alcohol use (36 g/d)
Emerging Sleep Apnea
Prehypertension 1.28 Systolic BP 130139 mmHg
Obstructive sleep apnea (OSA), characterized by periodic re-
vs <120 mmHg duction or cessation of breathing during sleep, often coexists
Increased pulse pressure 1.26 Per 20-mmHg increment
with AF. Patients with OSA have a 4-fold increased risk of
developing AF, with an adjusted odds estimate controlled for
Obstructive sleep apnea 2.85.6
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concomitant risk factors ranging from 2.8 to 5.6.4951 Patients


Physical activity 2.87 Cumulative lifetime practice
with AF have a high prevalence of OSA (32%49%), ap-
>1500 h
proximately double that of the general cardiology population
Diastolic dysfunction 3.335.26
(adjusted odds ratio, 2.19).52,53 OSA is also associated with
Familial and genetic 1.85 AF in 1 parent recurrent AF after cardioversion and ablation.5359 Although it
Hypertrophic cardiomyopathy 46 remains unclear whether OSA is independently and pathoge-
Congenital heart disease N/A netically linked to AF or merely reflects a shared risk factor
Potential profile, the observation that continuous positive pressure ven-
Coronary artery disease N/A Data inconclusive tilation reduces the risk of recurrent AF supports a causal role
of OSA in AF pathogenesis.53,55,56,59
Chronic kidney disease 1.33.2 Graded risk
Inflammation 1.471.77 Independent predictive Chronic Kidney Disease
valueunclear AF is more prevalent in patients with chronic renal dysfunc-
Pericardial fat 1.285.30 Risk related to thickness and tion, even after accounting for associated factors (coronary
volume of pericardial fat heart disease, HF, hypertension, left ventricular hypertrophy,
Tobacco use 1.512.05 and systemic inflammation). AF risk increases with severity
AF indicates atrial fibrillation; BP, blood pressure; LV, left ventricular; and N/A, of renal dysfunction (eg, HR of 1.31.6 and 1.63.2 with an
not available. estimated glomerular filtration rate of 3059 and <30 mL/min
per 1.73 m2, respectively, versus estimated glomerular filtra-
A strong correlation between older age and congenital heart tion rate 60 mL/min per 1.73 m2).60,61 Incident AF is associ-
diseaserelated AF has been demonstrated; however, substan- ated with an increased incidence of end-stage renal disease
tial AF onset rates appear in patients with congenital heart (adjusted HR, 1.671.77).60,62
disease decades before their onset in the general population.9 Alcohol
For example, a multicenter study of patients with tetralogy The relationship between ethanol consumption and AF has long
of Fallot quantified a 7.4% AF prevalence that increased to been known, with acute AF paroxysms associated with binge
>30% beyond age 55 years.39 Left-sided hemodynamic chang- drinking (holiday heart syndrome). Although moderate alcohol
es (eg, reduced left ventricular ejection fraction and increased intake does not seem to increase risk, heavy alcohol consump-
left atrial dimensions) are important AF risk determinants.39 tion (36 g/d) is associated with an adjusted HR of 1.34 to 1.46
In contrast, right atrial enlargement is more closely linked to for new-onset AF.6365 It has been postulated that the consump-
atrial macroreentry. tion of and subsequent withdrawal from alcohol result in a hy-
peradrenergic state, impaired vagal tone, and changes in atrial
Coronary Artery Disease
conduction properties, the sum of which predispose to AF.6365
AF is a common complication of acute myocardial infarc-
tion.40,41 Although the prevalence of AF in patients with stable Smoking
CAD does not seem to be substantially higher than in popula- Tobacco use has recently been linked to AF development (HR,
tions without CAD, recent work indicates that patients with 1.512.05), with a doseresponse effect (greatest risk in the
AF have an increased prevalence of both nonobstructive and highest tertile, >675 cigarette-years).66,67 Continued tobacco use
obstructive CAD compared with those without AF.42,43 is also associated with AF recurrence after catheter ablation.68
Obesity Diabetes Mellitus
In comparison to people with a normal body mass index (<25 Diabetes mellitus has been associated with a 1.4- to 1.6-fold
kg/m2), overweight (body mass index, 2530 kg/m2) and obese increased risk of AF.6971 Although a shared risk factor profile
Andrade et al Clinical Pathophysiology of AF 1457

exists (diabetes mellitus being associated with systemic in- Similarly, the prognosis associated with AF depends on
flammation, autonomic dysfunction, obesity, OSA, CAD, and whether the arrhythmia is isolated or is a consequence of oth-
HF), a longer duration of treated diabetes mellitus and worse er pathologies. On the whole, AF is associated with impaired
glycemic control has been independently associated with in- QOL, increased mortality, thromboembolic events, left ven-
creased risk of AF.69,72 tricular dysfunction, and HF.

Thyroid Dysfunction Symptoms and QOL


The risk of AF is closely associated with underlying thyroid The QOL in individuals with AF is significantly impaired
function. Although overt hyperthyroidism has long been as- across areas of physical and social functioning, mental and
sociated with an increased risk of AF (3- to 6-fold increased general health, as well as metrics of illness intrusiveness, ac-
incidence versus those with normal thyroid function), an ap- tivity limitation, and symptom status.104108 In addition, AF is
parent linear relationship between thyroid function and AF associated with a significantly reduced exercise capacity.106
risk has been noted with the risk of AF increasing with de- Even in the perceived absence of symptoms, patients with
creasing levels of thyroid-stimulating hormone (relative risk AF express reduced global life satisfaction.104 These impair-
1.1 with high normal euthyroidism to 1.2 with subclinical ments are comparable or worse than those in patients with
hyperthyroidism, to 1.4 with subclinical hyperthyroidism and HF or coronary heart disease (postcoronary angioplasty and
suppressed thyroid-stimulating hormone compared with those postmyocardial infarction cohorts).104 Although studies have
with normal thyroid function).7376 This is postulated to reflect demonstrated significantly improved QOL after therapeutic
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increases in -adrenergic tone, as well as the direct effects intervention, in general there does not seem to be a significant
of thyroid hormone on pulmonary vein cardiomyocytes (in- difference between a management strategy aiming to control
creased automaticity and enhanced triggered activity).77 ventricular rate and a strategy of rhythm control (ie, inter-
ventions to convert AF and maintain sinus rhythm).107,109,110
Physical Activity/Exercise This is despite the observations that (1) restoration of sinus
Regular moderate physical activity beneficially affects multi- rhythm increases scores for physical functioning, vitality,
ple cardiovascular risk factors and may decrease the incidence mental health, and role-emotional104,106,108,111,112 and (2) AF
of AF.7880 Conversely, excessive or vigorous sports practices recurrences have a significant and negative effect on global
(eg, endurance or high-performance athletes) are linked to a well-being,104,106,108,111,112 thus suggesting that the lack of ob-
higher AF prevalence. A cumulative lifetime practice >1500 served QOL benefit may reflect deficiencies of the contem-
hours is associated with a 3-fold risk of developing AF (HR, porary rhythm-control toolset rather than the strategy itself.
2.87) and greater AF recurrence rates after catheter ablation
(multivariate HR, 1.81).8083 In this population, AF paroxysms Mortality
are >3 as likely to occur in vagal contexts (postprandial, Incident AF is associated with age-adjusted 1-year mortal-
sleep, at rest) compared with healthy controls (57% versus ity rates of 23% to 27%, significantly greater (HR, 1.41) than
18% in nonhigh-performance athletes).84 patients without AF.2,113,114 Although AF has been associated
with increased mortality in diverse populations, it remains un-
Inflammation clear whether well-controlled AF independently predicts death
Multiple studies have noted an association between circulating or whether residual confounding may be at play.2,18,42,113119 In
inflammatory markers (C-reactive protein and interleukins) particular, increases in mortality rates are highest with an in-
and AF severity (chronicity, type, and burden).85,86 Although patient diagnosis of AF, suggesting that a portion of the excess
elevated inflammatory markers predict incident AF and recur- mortality may reflect underlying comorbidities.2 Moreover,
rence after cardioversion, sinus rhythm restoration alone re- despite improved treatment strategies, the AF-related mor-
duces inflammatory markers.8789 Despite these observations, tality has remained relatively static. Although observational
the inclusion of inflammatory biomarkers (C-reactive protein studies have suggested that a long-term strategy of rhythm
and fibrinogen) does not improve predictive ability beyond control may be associated with improved long-term mortal-
well-established clinical risk factors.90 ity (HR 0.89 at 5 years and 0.77 at 8 years of follow-up), to
date only anticoagulation therapy has been definitively shown
Familial and Genetic to improve survival.120,121 Large-scale randomized trials have
Genetic contributions are increasingly recognized. A family his- not shown mortality benefits of rhythm-control over rate-con-
tory of AF in a first-degree relative independently increases AF trol therapy.122124 It has been suggested that failure to improve
risk 2-fold.9193 Although polygenic inheritance is more com- outcomes may have been because of inefficacy of available
mon, monogenic inheritance has been described for a variety rhythm-control therapies or application too late in the natural
of genes, principally affecting ion channels.9498 Genetic link- history of the disease.125 Ongoing trials including the Catheter
age analyses have identified a range of potentially pathogenic ABlation vs ANti-Arrhythmic drug therapy for atrial fibrillation
loci.94,95,99102 In particular, multiple susceptibility signals have (CABANA) trial and the Early treatment of Atrial fibrillation
been identified at the chromosome 4q25 locus, which is thought for Stroke prevention Trial (EAST) should address this issue.125
to alter the expression of transcription factor PITX2.102,103
Stroke and Thromboembolism
Associated Morbidity and Mortality AF is associated with a 3- to 5-fold increased risk of
The clinical consequences of AF can be highly variable, from stroke,5,15,20,126 accounting for 20% of all strokes.17
incapacitating symptoms to an asymptomatic dysrhythmia. Importantly, the annual stroke risk increases significantly by
1458Circulation ResearchApril 25, 2014

age category (from 1.5% for patients aged 5059 years to In a meta-analysis including 77668 patients, of whom 11700
>23% for those >80 years).127,128 AF-associated strokes are of- had AF, AF was associated with a 42% greater risk of de-
ten recurrent and relatively more severe, causing significantly mentia after adjustment for other known stroke-promoting
greater resource use, long-term disability, and mortality com- conditions.142 Hypothesized pathophysiological mechanisms
pared with non-AF stroke.129132 include cerebral hypoperfusion,143 microembolization,144 in-
The absolute risk of stroke associated with AF is variable flammation, and platelet dysfunction.145 Unfortunately, al-
and reflects other clinical characteristics and comorbidities. A though the Atrial fibrillation Clopidogrel Trial with Ibesartan
high risk is observed in AF associated with rheumatic valvu- for Prevention of Vascular Events (ACTIVE) trial correlated
lar disease (predominantly mitral stenosis) or prosthetic heart low Mini-Mental State Examination scores with nontherapeu-
valves. Conversely, the risk of stroke with lone AF is low tic anticoagulation, these results were not reproduced in the
and comparable with that in the general population. Because Ongoing Telmisartan Alone and in Combination with Ramipril
of this heterogeneity, risk prediction systems have been de- Global Endpoint Trial (ONTARGET) and Telmisartan
veloped to inform decision making on stroke risk and anti- Randomized Assessment Study in ACE-intolerant Subjects
thrombotic therapy. These scores were initially derived from with Cardiovascular Disease (TRANSCEND) studies.141,146
control populations in AF stroke prevention trials. The Atrial Consequently, the pathogenitic role of microemboli is uncer-
Fibrillation Investigators pooled data from several trials to tain, given the observation that antithrombotic therapy did not
form a unified stroke classification scheme that included age, modify the association between AF and cognitive decline in
hypertension, prior cerebral ischemia (either stroke or tran- these studies.
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sient ischemic attack), and diabetes mellitus, as well as CAD


and congestive HF (equivocal stroke risk factors).133 Similarly, Heart Failure
the Stroke Prevention and Atrial Fibrillation investigators Although the association between AF and HF is well es-
identified hypertension (blood pressure >160 mmHg), prior tablished, the causative relationship between the 2 has not
cerebral ischemia, recent HF (within 100 days) or left ventric- been fully elucidated. AF can cause reductions in cardiac
ular dysfunction, or the combination of age >75 years and fe- output (because of shorter diastolic filling time, loss of atri-
male sex.134 Combinations of these risk-scoring systems led to al contractile function, and elevated filling pressures) and
the development of the CHADS2 score (Table2).135 Although tachycardia-induced myocardial dysfunction.147 In turn, HF
CHADS2 is elegant in its simplicity, it is weak in identify- results in structural and electric remodeling changes that en-
ing truly low-risk individuals. The expanded CHA2DS2-VASC hance susceptibility to AF (see below).
scoring system was developed to identify low-risk patients for
whom oral anticoagulant (OAC) therapy would not be benefi- Healthcare Resource Use
cial (Table2).136 Contemporary costs of managing AF have been estimated to
account for 1.0% to 2.7% of total annual healthcare expendi-
Cognitive Dysfunction tures (United States, $6.65 billion in 2001; United Kingdom,
Independent of stroke, AF has been linked to a more rapid 459 million in 2000).148 A sizeable proportion of these ex-
decline in cognitive function, resulting in a 1.7- to 3.3-fold penses is attributed to direct costs associated with hospitaliza-
increased risk of cognitive impairment, and a 2.3-fold in- tion and acute care (40%50% if AF is the primary diagnosis;
creased risk of dementia, compared with patients in sinus 75% if AF is a comorbid diagnosis), with outpatient care
rhythm.137139 Although shared risk factors have been proposed and pharmacotherapy accounting for the remainder.148,149 On
as a potential mechanism, the association between AF and a per-patient basis, the adjusted excess annual direct and indi-
cognitive impairment persists after risk factor adjustment.140,141 rect cost of AF has been estimated to be $12349 and $14875,

Table 2. Stroke Risk Scores in Patients with Nonvalvular Atrial Fibrillation135,136


Scoring System Annual Stroke Rate
CHADS2 CHA2DS2-VASc Total Points CHADS2 CHA2DS2-VASc
CHF or LVEF <40% 1 point 1 point 0 1.9% 0%
Hypertension 1 point 1 point 1 2.8% 1.3%
Age 75 y 1 point 2 points 2 4% 2.2%
Diabetes mellitus 1 point 1 point 3 5.9% 3.2%
Stroke/TIA/ 2 points 2 points 4 8.5% 4%
thromboembolism
Vascular disease (MI, PVD) 1 point 5 12.5% 6.7%
Age 6574 y 1 point 6 18.2% 9.8%
Sex (female) 1 point 7 N/A 9.6%
8 N/A 6.7%
9 N/A 15.2%
CHF indicates congestive heart failure; LVEF, left ventricular ejection fraction; MI, myocardial infarction; N/A, not applicable;
PVD, peripheral vascular disease; and TIA, transient ischemic attack.
Andrade et al Clinical Pathophysiology of AF 1459

respectively, with patients with AF proving 5 more costly DADs and can also contribute to early afterdepolarizations,
than non-AF individuals.150 particularly in the presence of sympathovagal activation.169 In
A rate-control strategy has been associated with lower re- addition to maintaining AF by rapid focal firing, ectopic activ-
source use and costs compared with a rhythm-control strategy ity can act on a vulnerable substrate to induce AF-sustaining
but not consistently so.151154 Among patients with paroxysmal re-entry. Re-entry requires specific conditions for initiation
AF, the frequency of recurrences is strongly linked to higher and maintenance and is favored by brief refractoriness, slow
resource use, with each recurrence averaging an additional conduction, and conduction barriers that can stabilize re-entry
$1600 dollars/y.154 circuits.165168,170 Structural remodeling, consisting primarily
Although the current clinical and economic burden of AF of atrial fibrosis,171 causes localized conduction slowing and
is substantial, AF is poised to become a public health crisis. conduction barriers that can induce unidirectional block.171173
Between 1995 and 2000,148 the cost of caring for AF nearly Fibrosis may also increase the number of fibroblasts and alter
doubled and is expected to continue to increase with aging of their properties, promoting AF by altering the electrophysi-
the population. ological behavior of cardiomyocytes coupled to fibroblasts
through cardiomyocytefibroblast interactions.173 Ion channel
Hospitalization and Acute Care dysfunction that either increases plateau outward K+ currents
AF accounts for the majority of arrhythmia-related emergency or decreases inward L-type Ca2+ current accelerates repolar-
room visits and hospital admissions (eg, 350000 hospitaliza- ization, abbreviating atrial action potential duration (APD)
tions in the United States each year),155,156 with an increasing and atrial refractoriness, and thereby facilitating re-entry.165167
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burden over time.157 Altered autonomic function can also promote AF by sev-
Costs associated with AF-related hospitalizations are sub- eral mechanisms, including vagally mediated APD shorten-
stantial. Emergency room patients in the United States with ing,165167 adrenergically mediated Ca2+ loading and DAD
a primary diagnosis of AF had an average hospital stay of promotion,167 and early afterdepolarization induction through
3.95.2 (meanSD) days, despite a spontaneous conver- combined sympathoadrenal discharge.169 In addition to en-
sion rate of 50%.158 The average cost of hospitalization was hancing cellular Ca2+ load by increasing the open probability
$66924928 (meanSD)/patient. of L-type Ca2+ channels and thereby enhancing transmem-
Stroke Prevention and Care brane Ca2+ entry, -adrenergic stimulation favors abnormal
OACs are paramount in preventing AF-associated thrombo- diastolic Ca2+ release from the sarcoplasmic reticulum (SR)
embolism. OACs (and their attendant monitoring) account Ca2+ stores, which causes DAD formation by enhancing
for a large portion of AF-related costs.148 Nevertheless, de- phosphorylation of several important Ca2+-handling proteins.
spite strong evidence of efficacy, OAC use is limited by Adrenergically induced hyperphosphorylation of phosphol-
nonprescription (50% patients do not receive OAC, despite amban removes phospholamban-induced suppression of the
an appropriate indication),159,160 nonadherence (30% 1-year cardiac SR Ca2+ uptake pump, SR Ca2+ ATPase, increasing SR
discontinuation for warfarin),161 and subtherapeutic dosing Ca2+ load. In addition, hyperphosphorylation of the ryanodine
(25%38% of warfarin-treated patients).162,163 Suboptimal receptor (the SR Ca2+ release channel) by adrenergically ac-
therapy is costly as a result of the economic burden associated tivated protein kinases (protein kinase A and C a2+/calmodu-
with excess stroke, an observation that is particularly relevant lin-dependent kinase type 2) increases ryanodine receptor 2
in the case of AF-associated strokes.148,164 Although the mean sensitivity to SR Ca2+ load and favors aberrant diastolic Ca2+
lifetime cost of stroke (including inpatient care, rehabilitation, releases.167,172 Abnormalities in Ca2+ signaling also contribute
and follow-up) is estimated at $140000/patient, the cost of to the development of AF-related ion channel dysfunction and
caring for patients with AF-associated strokes is substantially structural remodeling.172 Each of the principal mechanisms in
higher because AF-associated strokes are more severe.129,130 As blue boxes in Figure3 have been implicated in the association
a result of the increased disability associated with AF-related of AF with risk factors; all of them also occur as a result of
strokes, the nursing home costs associated with AF more AF-induced remodeling and contribute to the AF begets AF
than doubled from $73.3 million in 1995 to $167.8 million phenomenon.165,166
in 2000.148
Nature and Role of Structural Remodeling
Other articles in this compendium deal in detail with
Pathophysiological Links Between AF Risk AF-related remodeling of atrial ion channel properties,174 Ca2+
Factors and Arrhythmia Occurrence handling,174 and autonomic innervation.175 Structural remodel-
Overview of AF Pathophysiology ing is not a primary focus of any other article in the compen-
The pathophysiology of AF is complex. A general over- dium and so will be discussed in somewhat greater depth here.
view is provided here; for more information, see detailed Structural remodeling has emerged as an important motif
reviews.165167 Figure3 provides a schematic representation in AF. The term structural remodeling includes changes in
of AF pathophysiology. AF can be maintained by a rapidly atrial tissue properties (most notably fibrosis), size, and cel-
firing focus, by complex multiple-circuit re-entry, or by 1 lular ultrastructure. Atrial cardiomyocyte ultrastructure is
discrete rotors.165 Ectopic atrial foci are thought to arise via changed in AF, with alterations including myolysis, glycogen
triggered activity, most typically caused by delayed afterde- accumulation, gap junction disturbances, changes in nuclear
polarizations (DADs),168 but in some cases by early afterde- chromatin, mitochondrial disruption and redistribution, and
polarizations.169 Ca2+-handling abnormalities are central to SR alterations.176,177 Ca2+-dependent calpain activation and
1460Circulation ResearchApril 25, 2014

Figure 3. A general schema representing the


various mechanisms that can lead to the
perturbations underlying atrial fibrillation (AF),
including focal ectopic firing and vulnerable
substrates that can maintain re-entry. APD
indicates action potential duration; DAD, delayed
afterdepolarization; EAD, early afterdepolarization;
and ERP, effective refractory period.
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resulting proteolysis play a major role in remodeling of cell interrupting muscle continuity and creating a physical barrier
ultrastructure.177 Cell ultrastructure changes likely contrib- to conduction.189 This type of conduction barrier has been im-
ute to the atrial hypocontractility that characterizes AF,178180 plicated in local conduction disturbances and block that in-
thereby contributing to atrial dilation.179 Whether, and if so duce re-entry (Figure5).171,189,190 Second, fibrosis is associated
how, cellular ultrastructural remodeling also plays a role in the with proliferation of fibroblasts and their differentiation into a
AF-initiating or AF-maintaining substrate remains unclear. myofibroblast phenotype,173 increasing the likelihood and sig-
Atrial size is a long-recognized determinant of AF likeli- nificance of fibroblastcardiomyocyte interaction. Extensive
hood, both at the experimental181 and clinical182 levels. This cardiomyocytefibroblast electric interaction, with the induc-
relationship has been attributed to a critical mass needed to tion of re-entry and spontaneous ectopic activity, is well docu-
maintain multiple-circuit re-entry.181 More recent computa- mented in cardiomyocytefibroblast coculture systems.191,192
tional modeling suggests that larger atrial substrates have a Interactions between cardiomyocytes and fibroblasts via
greater ability to maintain a critical balance between rotor cell-coupling connexin hemichannels make fibroblasts (which
formation and rotor annihilation in the absence of rotor-sta- are inexcitable but can carry currents) act as an electric sink
bilizing properties such as functional or anatomic pinning.183 for cardiomyocyte bioelectricity.173 This results in slowing of
In addition, greater atrial enlargement likely reflects greater conduction, depolarization of cardiomyocyte resting poten-
atrial stretch, a known profibrillatory phenomenon,184 as well tial, variable effects on APD, and the induction of spontane-
as atrial damage/remodeling in general. ous phase-4 depolarization.169 Spontaneous depolarization
Ever since its pathophysiological importance in AF sub- causes focal ectopy and both conduction slowing and APD
strate development was first identified,171 atrial fibrosis has abbreviation favor the induction and maintenance of re-entry.
emerged as a significant contributor to AF in many paradigms. In addition to direct electric interactions, fibroblasts can affect
Fibrosis results from a broad range of factors related to AF- cardiomyocyte bioelectricity by secreting biologically active
inducing pathologies, including cell stretch, neurohumoral substances that cause paracrine effects.193 Whether fibroblast
activation, oxidative stress, and possibly even AF itself.184187 cardiomyocyte interactions promote arrhythmogenesis de-
For a full discussion of the complex signaling mechanisms pends on the number of fibroblasts, their size, and (for electric
that lead to atrial fibrosis, please see detailed reviews.167,185,188 interactions) the extent of electric coupling between the 2
Fibrosis can favor atrial arrhythmogenesis in several ways cell types.194,195 Thus, although fibroblasts can directly induce
(Figure4). First, fibrous tissue can physically separate atri- cardiomyocyte arrhythmic activity in cocultured in vitro sys-
al muscle fibers in the longitudinal direction (Figure4A), tems, whether this happens in vivo is still unclear. However,
Andrade et al Clinical Pathophysiology of AF 1461

Figure 4. Mechanisms by which fibrosis


can promote atrial arrhythmogenesis
leading to atrial fibrillation. A, Excess
extracellular matrix protein can interrupt
cardiac muscle bundle continuity in
the longitudinal direction, leading to
conduction slowing and block that help to
initiate and maintain re-entry. B, Fibroblasts
can interact with cardiomyocytes
electrically. Because fibroblasts are an
B inexcitable current sink, they can slow
conduction. In addition, because they
are less polarized than cardiomyocytes,
they can enhance phase-4 depolarization
(leading to spontaneous firing), depolarize
the cardiomyocyte resting membrane
potential, and shorten action potential
duration (APD; favoring re-entry). ECM
indicates extracellular matrix.
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the contribution of fibrosis per se to the AF substrate is fairly Ca2+ load via increased APD and phospholamban hyperphos-
well established based on the close association between fibro- phorylation, and thereby promoting DAD-related triggered
sis and AF promotion over a wide range of paradigms,185 as activity.204 CAD can promote AF via multiple mechanisms.
well as observations that under conditions in which atrial fi- Myocardial infarction often causes substantial left ventricular
brosis seems to be the only fibrosis-promoting derangement dysfunction and HF, resulting in HF-related AF promotion. In
a strong AF-supporting substrate can be demonstrated.189,196 addition, atrial ischemia has significant AF-promoting prop-
Atrial fibrosis can now be imaged quantitatively in vivo in erties. Acute atrial ischemia/injury enhances AF sustainabili-
man,197,198 and the combination of quantitative imaging and ty by causing important atrial conduction disturbances, likely
mathematical modeling promises to provide new insights into related to impaired cell-to-cell coupling.205 Healed atrial in-
the mechanisms by which fibrosis contributes to clinical AF.198 farctions/persistent ischemia favor AF occurrence by causing
Ca2+-handling abnormalities, resulting in DADs and triggered
Pathophysiological Mechanisms by Which Specific activity that underlie ectopic firing, along with structural re-
Risk Factors Promote AF modeling that creates a reentrant substrate.206 Autonomic
The recognition of AF risk factors has led to extensive research activity is required to elicit ectopic firing in the setting of
into the pathophysiological mechanisms through which risk chronic atrial coronary artery obstruction.206 Obesity causes
factors operate to make AF more likely. In turn, this research atrial structural remodeling,207 as well as left ventricular dia-
has provided central insights into key pathophysiological par- stolic dysfunction that induces acute left atrial dilation and
adigms underlying AF. stretch on volume loading.208 Acute OSA is associated with
The risk factors (other than genetic) for which mechanisms strongly negative intrathoracic pressures that increase venous
have been identified are summarized in Table3. Aging is ac- return and thereby induce AF-promoting left atrial volume
companied by atrial structural remodeling associated with loading.208 Repetitive OSA over prolonged periods induces
substantial conduction abnormalities.167,199 The precise basis atrial structural remodeling.209 Chronic nicotine exposure
for sex-dependent differences in AF risk is unclear. Men have also leads to atrial structural remodeling, possibly caused by
greater expression of important repolarizing ion channel sub- downregulation of microRNAs 133 and 590.210 Long-term en-
units, which could accelerate atrial repolarization, abbrevi- durance exercise causes a combination of structural remodel-
ate atrial refractoriness, and favor re-entry200; however, atrial ing and vagal enhancement.211 Enhanced vagal tone promotes
refractoriness does not seem to be sex dependent, and men AF by causing spatially heterogeneous abbreviations in atrial
have greater atrial dimensions that could promote AF main- refractoriness. Autonomic changes, due both to baroreflex en-
tenance.201 Hypertension causes significant atrial structural hancement and sensitization to acetylcholine resulting from
remodeling, and in particular atrial fibrosis, which seems to downregulation of regulators of G-protein signaling proteins,
underlie an enhanced susceptibility to AF.202 Cardiac valve seem to be particularly important for the AF-maintaining
disease, for which mitral regurgitation is a paradigm that has substrate caused by endurance exercise training.211 Diabetes
been studied experimentally, also promotes AF via structural mellitus promotes AF via both structural remodeling, pos-
remodeling.203 Congestive HF produces major atrial struc- sibly mediated by advanced glycosylation end products,212
tural remodeling and was the context in which the important and autonomic remodeling.213 Thyroid dysfunction seems to
contribution of structural remodeling to AF pathophysiology promote arrhythmic activity of pulmonary vein cardiomyo-
was first identified.171 In addition, HF causes substantial alter- cytes,77 to cause ion current remodeling,214 and to promote
ations in atrial cardiomyocyte Ca2+ handling, increasing cell atrial structural remodeling.214,215
1462Circulation ResearchApril 25, 2014
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Figure 5. Evidence that fibrous tissue can act as a barrier to longitudinal conduction in remodeled atrial tissue prone to atrial
fibrillation (AF). A, Masson trichrome stains (cardiomyocytes pink, collagen blue) of atrial tissue from a control dog (CTL, top), a dog
with congestive heart failure (CHF) induced by 2 weeks of ventricular tachypacing (middle), and a dog subjected to 2-week ventricular
tachypacing and then allowed to dhow full hemodynamic recovery through cessation of pacing for 4 weeks (REC, bottom). Note that fibrous
tissue separates cardiomyocytes in the longitudinal direction (yellow arrows) for the CHF and REC conditions. Both CHF and REC dogs
showed conduction abnormalities and prolonged AF. In the REC case, full hemodynamic recovery allows for normalization of other atrial
properties but leaves fibrosis unchanged, pointing to fibrosis as a sufficient condition for the AF substrate. B, Top, Optical mapping of atrial
conduction in a CTL (left) and REC (right) dog, showing clear conduction abnormalities in REC. Bottom, Results of realistic mathematical
modeling of the same preparations shown above, assuming that fibrous tissue creates a conduction barrier. There is good general
agreement between experimental observations and the modeling results, supporting the notion that fibrosis produces conduction barriers.
Data reproduced from Burstein etal189 with permission of the American Heart Association Inc. REC indicates recovered heart failure.

Genetic risk factors for AF can be separated into mono- nucleotide polymorphisms, contribute to AF susceptibility
genic (usually rare disease-causing mutations) and polygenic in a quantitative fashion, with much lower penetrance than
(generally common gene variants). The pathophysiology un- monogenic causes. It is likely that they predispose individu-
derlying most monogenic causes of AF is reasonably under- als to develop AF in association with acquired risk factors.
stood. Most monogenic AF-causing mutations occur in genes The mechanisms linking single nucleotide polymorphisms
encoding cardiac ion channels. Gain-of-function K+ channel to AF are much less clear than for monogenic causes.219 For
mutations accelerate repolarization and thereby promote atrial a detailed discussion, readers are referred to the review by
re-entry.167 Loss-of-function K+ channel mutations and other Ellinor220 in this Compendium.
long-QT syndrome mutations paradoxically also predispose
to AF, probably by inducing atrial early afterdepolarization Significance of Understanding Pathophysiological
related ectopic activity.216 Mutations altering connexin expres- Links Between Risk Factors and AF
sion or function lead to AF by altering cell-to-cell coupling Understanding the mechanisms linking risk factors to AF
and causing conduction abnormalities.167 Catecholaminergic provides better insights into the pathophysiology of the ar-
polymorphic ventricular tachycardia mutations alter cellular rhythmia. More importantly, such understanding may be the
Ca2+ handling and induce DADs; although they are typically key to improve AF prevention measures. By appreciating the
associated with ventricular arrhythmias, they can also cause fundamental mechanisms through which risk factors promote
AF,217 likely by inducing DAD-related rapid atrial ectopic fir- AF, we may be able to develop innovative therapeutic ap-
ing.218 Common gene variants, generally manifesting as single proaches that are directed toward preventing the development
Andrade et al Clinical Pathophysiology of AF 1463

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This work was supported by Canadian Institutes of Health Research brillation in patients with risk factors. Europace. 2013;15:657662.
(S. Nattel: grant Nos. 6957 and 44365), Quebec Heart and Stroke 17. Cotter PE, Martin PJ, Ring L, Warburton EA, Belham M, Pugh PJ.

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The Clinical Profile and Pathophysiology of Atrial Fibrillation: Relationships Among
Clinical Features, Epidemiology, and Mechanisms
Jason Andrade, Paul Khairy, Dobromir Dobrev and Stanley Nattel
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Circ Res. 2014;114:1453-1468


doi: 10.1161/CIRCRESAHA.114.303211
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