Abed_et_al-2013-Obesity_Reviews

Obesity Comorbidity

Obesity and atrial fibrillation

H. S. Abed and G. A. Wittert

Department of Medicine, University of

Adelaide, Royal Adelaide Hospital, Adelaide,

South Australia, Australia

Received 17 March 2013; revised 3 May

2013; accepted 24 May 2013

Address for correspondence: Professor GA

Wittert, Discipline of Medicine, University of

Adelaide, 6/33 Eleanor Harrald Building,

Royal Adelaide Hospital, Adelaide, SA 5000,

Australia.

E-mail: [email protected]

SummaryAtrial fibrillation (AF) is an increasing public health problem, often described asthe epidemic of the new millennium. The rising health economic impact of AF, itsassociation with poor quality of life and independent probability of increasedmortality, has recently been highlighted. Although population ageing is regardedas an important contributor to this epidemic, obesity and its associated cardio-metabolic comorbidities may represent the principal driving factor behind thecurrent and projected AF epidemic. Obesity-related risk factors, such as hyper-tension, vascular disease, obstructive sleep apnea and pericardial fat, are thoughtto result in atrial electro-structural dysfunction. In addition, insulin resistance, itsassociated abnormalities in nutrient utilization and intermediary metabolicby-products are associated with structural and functional abnormalities, ulti-mately promoting AF. Recent elucidation of molecular pathways, including thoseresponsible for atrial fibrosis, have provided mechanistic insights and the potentialfor targeted pharmacotherapy. In this article, we review the evidence for anobesity-related atrial electromechanical dysfunction, the mechanisms behind thisand its impact on AF therapeutic outcomes. In light of the recently describedmechanisms, we illustrate proposed management approaches and avenues forfurther investigations.

Keywords: Atrial fibrillation, fibrosis, obesity, pericardial fat.

obesity reviews (2013) 14, 929–938

Epidemiology of atrial fibrillation and obesity

Obesity is a worldwide public health crisis (1). Obesity,particularly when the excess fat is ectopically located(visceral, liver, pericardial, intra-myocellular) may be asso-ciated with increased cardiovascular risk factors, e.g. dys-lipidemia, insulin resistance and disordered of glucosemetabolism, sleep disordered breathing, a systemic inflam-matory state and arterial hypertension (2–7). Even afteraccounting for these risk factors, obesity is associated withan excess risk for ischaemic heart disease (8), diastolicdysfunction, cardiac failure (9) and atrial fibrillation(AF) (10).

The degree of adiposity is generally described by thebody mass index (BMI), calculated as the body weight inkilograms divided by the square of the height in meters

(kg m-2), and categorized by the World Health Organiza-tion (WHO). Traditionally, a BMI > 25 and �30 describesoverweight or pre-obesity. A BMI > 30 describes obesitywith a further categorization of �40 as morbid obesity.There are some variations in the overweight category, withlower cut-offs, pertinent to certain ethnicities, namelypeople of Asian heritage.

AF has been described as the epidemic of the new mil-lennium (11); it is anticipated that there will be 12–15million affected individuals in the United States by 2050with direct economic costs estimated at $6 billion annually(12). In the United Kingdom, AF accounts for 2.7% of totalnational health expenditure, 50% of which is attributableto hospitalization alone (13). Recently, novel risk factorsfor AF have been proposed. Excessive sporting activity hasbeen hypothesized to promote excess vagal activity and

obesity reviews doi: 10.1111/obr.12056

929© 2013 The Authorsobesity reviews © 2013 International Association for the Study of Obesity 14, 929–938, November 2013

abnormalities of atrial refractoriness in addition to a pro-pensity towards atrial dilation (14,15). Parental AF hasbeen shown to increase the corresponding risk in the off-spring, independent of shared environmental influences(16). Familial potassium channel variants may provide thegenetic basis in some families (17).

Although population ageing is regarded as an importantcontributor to this epidemic, obesity may account for asubstantial proportion of the increasing prevalence (18).Several epidemiological studies have demonstrated an inde-pendent association between obesity and AF (10,18–24)(Table 1). In addition, this impact of obesity on the AFepidemic does not appear to be restricted to older agegroups. A recent nationwide Danish cohort study has iden-tified obesity as an independent predictor of AF in fertileand otherwise healthy young women (25).

Mechanisms by which obesity may lead toatrial fibrillation

Obesity may predispose to AF through indirect pathways,e.g. the effects of hypertension or sleep disordered breath-ing, direct influences such as the effects of inflammatorycytokines or disordered myocardial energy metabolism, or

because of the interaction with other factors such asincreased levels of thyroid hormone or peri-atrial fat. Theextent to which any of these mechanisms operate entirelyby themselves or because of their combined effects remainsuncertain.

Hypertension

Obesity, sleep disordered breathing, excessive alcohol con-sumption and the metabolic syndrome are all associatedwith systemic arterial hypertension. Hypertension has beenshown in various animal models to promote atrial myocar-dial dilation and underlying ultra-structural changes,specifically myocyte hypertrophy, myolysis, collagen fibrildeposition and increased cellular apoptotic markers andfunctional abnormalities characterized by slowing and het-erogeneity of conduction velocity (26), factors known to beassociated with AF (27). Human atrial mapping studieshave demonstrated areas of regional low myocardial volt-ages, delayed activation times and greater AF inducibility(28). In addition, obesity and systemic hypertension havebeen associated with autonomic dysfunction (29), abnor-mal renin-angiotensin axis activation (30) and intravascu-lar volume overexpansion (31), factors that predispose

Table 1 Studies summarizing the association between obesity and AF

Author Study design Population Key findings

Wanahita,2008 (18)

Meta-analysis of cohortstudies

123,249 general populationand post-cardiac surgerypatients

Relative risk of AF development increase was 1.49 (95% CI1.36–1.64) in obese general population compared to non-obese. Nosignificant difference in post-cardiac surgical patients.

Wang, 2004(21)

Prospective observationalcohort

5,282, community-basedpopulation

4% (95% CI 1.0%–7.0%) increase in new AF risk with eachincremental BMI unit increase in men and women. This relationshipwas diminished following statistical adjustment to LA diameter.

Tsang, 2008(75)

Longitudinal cohort study 3,248, community-basedpopulation

BMI predicted the progression of AF from paroxysmal to permanent(HR 1.04 [95% CI 1.03–1.06]). LA volume had an incremental effecton BMI-associated risk.

Miyasaka,2006 (19)

Retrospective incidencetrends to construct futureprevalence estimates

4,618, community-basedpopulation

12.6% increase in age- and sex-adjusted incidence of AF. Obesityis anticipated to account for 60% of this trend.

Rosengren,2009 (22)

Observational cohort study 6,903 men from thecommunity

Body surface area (and height) at age 20 and subsequent increaseare each significant predictors of AF development

Tedrow, 2010(10)

Observational cohort study 34,309 women from thecommunity

Risk of AF increased with dynamic weight gain to overweight (HR1.22 95% CI 1.02–1.45) and obese (HR 1.65 95% CI 1.36–2.0)

Zacharias,2005 (24)

Retrospective analysis 8,051 cardiac surgerypatients

For post-operative AF, OR of 1.18 (95% CI 1.18–1.40) foroverweight and 2.39 (95% CI 1.81–3.17) for severe obesity,compared to normal weight patients

Watanabe,2008 (23)

Prospective cohort 28,449 community-dwellingpatients

The presence of the metabolic syndrome (NCEP-ATPIII) resulted ina 1.78 HR of AF development with obesity and hypertension beingthe strongest component predictors

Gami, 2007(20)

Retrospective cohort 3,542 community-dwellingpatients

BMI was an independent predictor of new-onset AF; every unit BMIkg m-2, HR 1.07 (95% CI 1.05–1.10) in patients <65 years of age

AF, atrial fibrillation; BMI, body mass index; CI, confidence interval; HR, hazard ratio; LA, left atrium; NCEP-ATP III, National cholesterol educationprogram adult treatment panel III; OR, odds ratio.

930 Obesity and atrial fibrillation H. S. Abed & G. A. Wittert obesity reviews

© 2013 The Authorsobesity reviews © 2013 International Association for the Study of Obesity14, 929–938, November 2013

to AF through abnormal automaticity, atrial stretch andfibrosis (32).

Sleep disordered breathing

The relationship between AF and sleep disordered breath-ing is complex. While hypertension may represent animportant intermediary, an independent association hasbeen demonstrated between obstructive sleep apnea (OSA)and AF (33). The severity of OSA as reflected by the degreeof oxygen desaturation and the apnea-hypopnea index(AHI) is positively correlated with incident AF (20). Apartfrom the association with hypertension and abnormalitiesof glucose metabolism, other potential mechanisms includesystemic inflammation, extremes in hypoxemia, cyclic sym-pathetic tone surges and variations in intra-thoracic pres-sure with alterations in atrial wall stresses (34). In addition,recent work has shown that with worsening AHI (OSAseverity), there is greater inter- and intra-atrial electrome-chanical delay (35). Acute apneic episodes have beenshown to induce acute left atrial (LA) stretch-induced dila-tion and diastolic dysfunction (36).

Hyperglycaemia and diabetes mellitus

Previous observations have identified diabetes mellitus(DM) as an independent risk factor for the development ofAF (37,38). The basis of this, however, remained unclearwith frequently co-existing confounders such as hyperten-sion and atherosclerotic coronary disease. Rodent modelsof diabetes have shown atrial myocardial conduction veloc-ity slowing and increased dispersion, with no effect ontissue refractoriness (39,40), thus creating a vulnerability tore-entrant arrhythmogenesis. Structurally, diabetic rat atriahave been shown to have a significantly greater depositionof advanced glycation end products (AGES) and theirreceptors (RAGES), in addition to the pro-fibrotic mediatorconnective tissue growth factor (CTGF) (41). In addition,patients with DM and AF have been shown to haveelevated serum levels of AGES and RAGES (42).

Inflammation

Obesity, particularly when the excess fat is ectopicallylocated, is accompanied by a systemic inflammatory state(43). Even in the absence of obesity, intermittent hypoxia,such as occurs in OSA, is associated with inflammation,which may resolve, or at least improve substantially, withthe effective use of continuous positive airway pressure(44). In addition to the proposed role of systemic inflam-mation increasing the risk of AF in obesity, recent interesthas focused on the role of atrial myocardial inflammation(45) and the inflammatory impact of the contiguous peri-cardial fat (46,47). Local inflammatory infiltrates within

the myocardial–epicardial fat interface or within the atrialmuscle secondary to lipid accumulation may induce atrialstructural change and abnormal electrical conduction (48).The importance of inflammation was recently emphasizedin a neutrophil myeloperoxidase (MPO) gene knock-outmouse model (49). The study demonstrated that in com-parison to wild-type mice, MPO-deficient mice were sig-nificantly more protected from micro-architectural atrialtissue damage in the form of fibrosis, conduction inhomo-geneity and AF. In humans, colchicine (an inhibitor ofneutrophil chemotaxis) has been effectively used for theprevention of post-operative AF (50).

Adiposity and the heart

In addition to the systemic effects of obesity and theirrelationship to AF, local fat stores may also be of patho-physiological importance (47,51,52). Although intra-myocardial levels of triglycerides have been known toinfluence myocardial structure and function (53,54), it isonly recently that a relationship to atrial arrhythmias hasbeen recognized (55).

Epicardial fat located between the epicardium and theparietal pericardium has been observed in several studies torepresent a metabolically active depot with cardiometa-bolic risk comparable to other visceral fat stores (4). Func-tionally, epicardial fat shows a greater insulin-inducedtriglyceride turn-over rate as compared to other fat depotsand shows a similar fatty acid profile as other peri visceralfat depots (56,57). In addition to the common embryolo-gical origin and a common coronary microcirculation,both pericardial and intra-abdominal visceral fat depotsappear to affect contiguous organ structures throughvarious common cytokine networks influencing pro- andanti-fibrogenesis (5). Moreover, epicardial fat and intra-visceral lipid content (myocardial and hepatic lipidosisquantified by magnetic resonance spectroscopy) appear topromote collagen deposition and fibrosis (58,59) and isamenable to dietary intervention for weight loss (60,61).

Observational studies have shown incident AF to bepositively correlated with pericardial fat volume, as quan-tified on computed tomography (51). Data from the Fra-mingham cohort show that pericardial fat, but not visceralor intra-thoracic fat, is an independent predictor for AF(2). Moreover, there appears to be a graded relationshipwith a higher pericardial fat burden in persistent AFpatients compared to paroxysmal AF patients independentof BMI (62). Beyond predicting the chronicity and severityof AF, greater burdens of pericardial fat are associatedwith poorer outcomes following radiofrequency LA cath-eter ablation. Although a definite paracrine mechanismremains unproven, local fatty acid metabolites, inflamma-tory mediators and intra-myocardial lipidosis may beinvolved in the pathogenesis of myocardial structural and

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© 2013 The Authorsobesity reviews © 2013 International Association for the Study of Obesity 14, 929–938, November 2013

functional abnormalities predisposing to AF (56,63,64). Afurther local mechanism of potential clinical significance isthe close anatomic association between cardiac ganglion-ated autonomic plexuses and pericardial fat (65). It hasbeen suggested that local mediators from pericardial fatmay influence myocardial autonomic signalling, alteringdispersion of electrical refractoriness and heart rate turbu-lence, factors known to increase the risk of AF (65).

Myocardial energetics and fuel utilization

From a population standpoint, increasing plasma free fattyacids levels have been shown to predict a greater risk new-onset AF in multivariable models adjusted for BMI, pres-ence of diabetes mellitus, alcohol use, hypertension andcongestive cardiac failure (66).

Mechanistically, in contrast to skeletal muscle whereglucose is the primary energy source, cardiac myocytes inthe adult primarily utilize fatty acid oxidation for energyproduction. The non-ischaemic myocardium adapts to anincreased supply of fatty acids by increasing fatty acidb-oxidation (52). Because of substrate competition, the rateof glycolysis is uncoupled from the rate of glucose oxida-tion and pyruvate accumulates, leading to intracellularacidosis particularly during ischaemia (67).

Under conditions of energy stress, myocardial efficiencycan be increased by oxidizing glucose instead of fatty acids;under such circumstances, the capacity to oxidize fattyacids will be limited (67). Where the uptake of fatty acids isalso increased, the only disposal mechanism of the fattyacids is the intracellular formation of triglyceride. Thisleads to the accumulation of lipid metabolites such as cera-mides, which at least in skeletal muscle induces insulinresistance. In addition, saturated fatty acids such as pal-mitic acid also induce insulin resistance by activating proin-flammatory pathways involving nuclear factor kappa band mammalian target of rapamycin (68). The activationof these pathways may also contribute to cardiomyocyteapoptosis, tissue fibrosis and diastolic dysfunction (59,69).Moreover, proof-of-concept studies have illustrated theamenability for reversal of these mechanical and structuralchanges with caloric restriction in obese patients with dia-betes (70).

Atrial remodelling

Role of atrial size

Studies have consistently identified LA size as an indepen-dent predictor of AF onset (38,71). In addition to size, LAfunction or the incremental value of total LA emptyingcapacity has been shown to predict the risk of AF (72).

Abnormalities in LA size are often clinically observed inoverweight and obese patients (73). Longitudinal 10-year

follow-up data examining the relationship between weightchange, hypertension and LA size showed obesity to be amore potent predictor of LA enlargement than hyperten-sion (74). This relationship persisted following indexing ofLA volume to height, indicating an effect of adiposity per seon atrial dilation, disproportionate to the effect of increas-ing body size alone.

In a 21-year cohort study of 3,248 patients with parox-ysmal AF from Olmstead County, independent of age andgender, BMI and LA volume were shown to predict theprogression of disease to permanent AF, with worseningdegrees of obesity conferring a greater risk. Furthermore,LA volume was incremental to BMI in predicting thisrisk (75). In view of the observations from the OlmsteadCounty data (75) and the close relationship betweenobesity and LA size, LA dilation may mediate the effect ofobesity in promoting AF. Recent prospective data evaluat-ing 796 women have reinforced the role of LA enlargementin the obesity–AF relationship (76).

Atrial fibrosis and the atrial fibrillation substrate

Pre-clinical and clinical works have demonstrated atrialfibrosis as a common structural finding in AF (77). Broadly,fibrosis may take two forms: interstitial collagen depositionand replacement fibrosis, secondary to myolysis and cellloss (78). As compared to patients without AF, atrial tissuefrom patients with AF has significantly more abundantcollagen bundles and lympho-mononuclear cellular infil-trates (77). These microscopic changes appear to localize atthe pulmonary vein–atrial junction, a known location forAF triggers and arrhythmia maintenance (79). Moreover,specific gap junction proteins essential for myocellularelectrical coupling appear lateralized or proportionatelyreduced (80), and effect creating functional conductionslowing through anisotropy. Clinically, the degree of pro-fibrotic remodelling has been shown to correlate withworse AF therapeutic procedural outcomes (81).

Atrial remodelling has been used to describe the complexinteraction between dynamic structural and functionalchanges occurring as a consequence of an external insult.These maladaptive changes may become self-perpetuating,thereby promoting further atrial structural, functional andelectrical abnormalities (Fig. 1), an effect that allows thearrhythmia to entrench itself.

Fibrogenesis appears to result from a variety of insults onthe thin delicate atrial tissue, involving multiple interrelatedbiochemical autocrine, paracrine and endocrine pathwaysresulting in an extracellular matrix to functional myocytemismatch (78). The presence of scar is central to the con-duction abnormalities with wavefront propagation inter-ruption, inhomogeneity of tissue conduction properties andphysical barriers for the formation of re-entrant circuitsand assumption of triggered activity (82). In addition, there



is evidence that fibroblasts, the functional units of tissuefibrosis, can assume electrical activity and, accordingly,contribute to the so-called stretch-induced electromecha-nical feedback (83). Therefore, the process of fibrosismay be more than merely a passive structural barrier toconduction.

The phenotypic transition of a fibroblast to an activemyofibroblast is modulation by a variety of mediators suchas transforming growth factor beta (TGF-b) (84,85), angi-otensin II (86), platelet derived growth factor (87,88),endothelin-1 (ET-1) (89–91) and aldosterone (92). Thesesignalling systems have been the focus of much investiga-tion given the potential for targeted pharmacologicalmodulation of the fibrosis functional unit. Table 2 showsseveral putative mediators of atrial fibrosis.

Therapeutic implications

Factors that need to be considered in the management ofAF include the risk of thromboembolism, rate control,reversion to sinus rhythm and management of underlyingcardiovascular abnormalities. Therapeutic options need tobe discussed with patients and their preferences considered.Irrespective thereof, it is essential that risk factors such ashyperthyroidism, hypertension, OSA, obesity, abnormali-ties of glucose metabolism, caffeine and alcohol use areidentified and managed.

Rate control may be achieved by the use of beta blockers,calcium channel blockers, digoxin or AV-node radiofre-quency catheter ablation with pacemaker implantation.Rhythm control is often undertaken through one or a com-

bination of direct current cardioversion, anti-arrhythmicmedication and radiofrequency LA catheter ablation. Inview of the increasing uptake of the latter invasive thera-peutic modality, recent findings have emphasized the role ofobesity on ablation outcomes (Table 3). Although obesityhas been shown to predict poor outcomes followingcatheter ablation (93), SF-36 scoring for quality of life(QoL) assessment suggests at least equal benefit as com-pared to non-obese patients, when sinus rhythm is achieved(94,95). This is despite the fact that the presence of bothobesity and AF confer a worse baseline QoL score as com-pared to non-obese patients with AF, suggesting that thepatient group with worse outcomes is also the very groupthat derives the greatest absolute benefit from this invasivecatheter procedure. In addition, although obese patientshave been shown to require longer procedural times,greater fluoroscopic radiation dosage (96) and a BMI-related risk of recurrence post-LA ablation (97) as com-pared to their normal weight counterparts, BMI was shownto have no influence on overall procedure-related compli-cations. Recent data, however, suggest that morbidly obese(BMI > 40 kg m-2) women may be a subgroup especiallyvulnerable to procedural complications (98). These obser-vations again highlight the importance of conjunctivemanagement of obesity and cardiometabolic risk whenconsidering an invasive approach for rhythm control.

Emerging therapeutic strategies

In view of the increasingly important role of obesityin the genesis, maintenance and progression of AF, the

Figure 1 Current proposed mechanismsinvolved in atrial remodelling in the genesis ofatrial fibrillation.



management of obesity and its associated cardiometaboliccomorbidities must be viewed as integral to the effectivemanagement and potential prevention of the arrhythmia.AF may represent end-organ damage as a result of variousatrial metabolic stresses. In addition to cardiometabolicrisk identification and management, it is prudent that phy-sicians emphasize the role of alcohol intake in the preva-lence of AF and the importance of avoiding extreme orendurance physical activity when embarking on weightreduction (99). In light of the current understanding of theobesity–AF relationship, cardiometabolic risk factor man-agement with particular emphasis on weight loss mustbe integrated within current AF management pathways.Recent work has shown the feasibility of delivering safeand effective office-based weight management in over-weight and obese patients, utilizing a modified very lowcalorie diet coupled with the treatment of hypertension,sleep disordered breathing, insulin resistance, hyperlipi-

demia and alcohol intake (100). Effective weight and riskfactor management was associated with a reduction insubjective and objective measures of AF burden andsymptom severity, in addition to favourable changes in LAsize and left ventricular hypertrophy. Importantly, therewas a trend towards a reduction in the need for an AFablation procedure, a procedure primarily undertaken forsymptom control.

In addition to traditional cardiometabolic risk factormanagement, pharmacotherapeutic strategies targetingmolecular pathways early in the evolution of the electro-structural atrial substrate must be elucidated and incorpo-rated within this paradigm. Central to our understandingof specific biochemical pathways involved in weight gainand the outcomes of selective interruption is the ethical useof animal models (101). Briefly, models may be groupedinto two categories. Genetically manipulated models suchas the Zucker rat recessive for leptin receptor are used

Table 2 Putative pro-fibrotic markers involved in atrial structural and electrical remodeling

Factor Characteristic Role in AF Role in obesity

Transforming growthfactor-b (TGF-b)

Three isoforms; TGF-b1, -b2, -b3 withintracellular transduction via ROSand Smad proteins for pro-fibroticgene transcription

Central role in myocardial fibrosis,especially in pressure-overloadedhearts

TGF-b modulates insulin genetranscription and promotes mitochondriapoor white adipose tissue. Levelsincreased in human adipose tissue frommorbidly obesity.

Platelet-derivedgrowth factor

Dimeric forms; A-A, B-B and A-Bdimers. Functions in cell proliferation,growth and migration ofmesenchymal and smooth musclecells as well as angiogenesis.

Receptors abundant in atrialtissue > ventricular tissue. Regulatesfibroblast mitogenesis.

Receptors over-expressed on atrial tissuein response to increased afterloadconditions

Angiotensin II a2-Globulin hormone with vasomotorand pro-fibrotic actions. Modulator ofaldosterone and inductive effect onTGF-b.

Results of a meta-analysis suggestedbenefit of angiotensin-axis active agentsin reducing incident AF; however, not allstudies have shown benefit

Angiotensin II-aldosteronesystem-induced hypertension isenhanced in obesity. Angiotensin IIblockade reduces insulin resistancethrough GLUT-4 dependent pathways.

Connective tissuegrowth factor (CTGF)

Matrix-associated protein involved inphenotypic commitment ofmesenchymal cells to fibroblasts.Modulated by endothelin and TGF-b.

Endothelin-1 up regulates CTGFexpression in atrial myocardium and thein-vitro pro-fibrotic effects of ET-1 wereabolished by CTGF gene silencing. Inaddition, CTGF expression has beenshown to be under angiotensin II control.

Hyperglycaemia and hyperinsulinaemiapromote pro-fibrotic activity of CTGF

Endothelins (ET) Three subtypes cleaved byconverting enzyme, from parentprotein. Vasoconstricting andpro-fibrotic properties. Three mainreceptors ETA, ETB1 and ETB2.

Endothelins have been shown to inducemyocellular hypertrophy, reducedconnexin-43 expression, altered electricalrefractoriness, conduction slowing andinhomogeneous conduction. Greateratrial expression relative to ventricular.Levels increased in conditions of atrialstretch. Tissue levels correlated withatrial size and AF persistence. Endothelinligand and receptor levels correlated withprogressive weight gain.

Serum levels elevated in obesity andassociated with impaired vasomotorresponses in obese subjects. Plays a rolein sleep apnea-related systemichypertension.

AF, atrial fibrillation; ETA, endothelin receptor type A; ETB1, endothelin receptor type B1; ETB2, endothelin receptor type B2; GLUT4, glucosetransporter type 4; ROS, reactive oxygen species.



to study a monogenetic impact of an obesity-implicatedpathway. Polygenetic obesity may be studied through selec-tive breeding of New Zealand Obese Mouse. Another cat-egory is the over-fed obese animal model (102). Suchmodels generally employ a high energy ad libitum dietsometimes combined with limited energy exertion. Thesemodels are often utilized in studying the impact of a remoteorgan system during dynamic weight gain and the finaloutcome of attained obesity rather than specific mechanis-tic pathways.

Recent pre-clinical work has identified the role ofendothelin signalling in the obesity–AF syndromecomplex with an over-expression of the receptor proteinand ligand in the atrial tissue of an obese ovine model(55). Although further proof-of-concept studies areneeded, substrate modifying therapies may be of particu-lar benefit in halting disease progression early in the atrialremodelling process.

Conflict of interest statement

No conflict of interest statement.

References

1. Christakis NA, Fowler JH. The spread of obesity in a largesocial network over 32 years. N Engl J Med 2007; 357: 370–379.2. Fox CS, Gona P, Hoffmann U et al. Pericardial fat, intratho-racic fat, and measures of left ventricular structure and function:the Framingham Heart Study. Circulation 2009; 119: 1586–1591.3. Jain SH, Massaro JM, Hoffmann U et al. Cross-sectional asso-ciations between abdominal and thoracic adipose tissue compart-ments and adiponectin and resistin in the Framingham HeartStudy. Diabetes Care 2009; 32: 903–908.4. Mahabadi AA, Massaro JM, Rosito GA et al. Association ofpericardial fat, intrathoracic fat, and visceral abdominal fat withcardiovascular disease burden: the Framingham Heart Study. EurHeart J 2009; 30: 850–856.5. Rosito GA, Massaro JM, Hoffmann U et al. Pericardial fat,visceral abdominal fat, cardiovascular disease risk factors, and

Table 3 Summary of studies examining the relationship between obesity and therapeutic outcomes for AF

Author Study design Population Key findings

Jongnarangsin,2008 (103)

Retrospective,observational

324 patients undergoing ablation forparoxysmal or chronic AF

OSA was strongest predictor of recurrent AF in multivariateanalysis, OR 3.04 (95% CI 1.11–8.32). BMI was not associated withAF recurrence. No differences in procedural complications seenacross BMI groups.

Chilukuri, 2010(104)

Prospective,descriptive

109 patients undergoing ablation forparoxysmal or non-paroxysmal AF

Clinical procedural success in patients without OSA compared topatients with OSA, P = 0.04. On multivariate analysis, BMI was theindependent predictor of procedural failure, OR 1.11 (95% CI1.00–1.21).

Kanagala, 2003(105)


118 patients with paroxysmal ornon-paroxysmal AF undergoing DCcardioversion

Recurrence rate of AF higher in the OSA non-treated group (82%)compared to the OSA treated group (42%), P = 0.01.

Liu, 2007(106)

Meta-analysis ofclinical trials

420 pooled patients undergoing DCcardioversion for paroxysmal ornon-paroxysmal AF

Baseline C-reactive protein levels higher in patients with AFrecurrence, 0.35 units (95% CI 0.01–0.69)

Mohanty,2012 (93)


1,496 patients with paroxysmal ornon-paroxysmal AF undergoingcatheter ablation

Recurrence of AF following ablation in the metabolic syndromegroup was greater (39%) than in the group without (32%),P = 0.005. Patients with metabolic syndrome showed improvementin mental and physical domains of QoL, whereas patients withoutmetabolic syndrome only showed improvement in the mentaldomain.

Mainigi, 2006(107)

Case–control studyinto late recurrence(>12 months)post-ablation

246 patients undergoingradiofrequency ablation ofparoxysmal and non-paroxysmal AF

Patients with late recurrence were more likely to weigh >90 kg,P = 0.01

Wong, 2010(62)

Retrospective,observational

110 patients with paroxysmal ornon-paroxysmal AF undergoingradiofrequency ablation

Cardiac MRI quantified pericardial fat was predictive of AFrecurrence following catheter ablation (P = 0.035)

Guijain, 2013(97)

Meta-analysis ofobservational studies

6 observational studies pooling2,658 patients

RR of recurrence post-ablation for overweight 0.27 (95% CI0.96–1.68), P = 0.09 and for obesity 1.38 (95% CI 1.01–1.98),P = 0.045

AF, atrial fibrillation; BMI, body mass index; CI, confidence interval; DC, direct current; MRI, magnetic resonance imaging; OR, odds ratio; OSA,obstructive sleep apnea; QoL, quality of life; RR, relative risk.



vascular calcification in a community-based sample: the Framing-ham Heart Study. Circulation 2008; 117: 605–613.6. Tadros TM, Massaro JM, Rosito GA et al. Pericardialfat volume correlates with inflammatory markers: the Framing-ham Heart Study. Obesity (Silver Spring) 2010; 18: 1039–1045.7. Thanassoulis G, Massaro JM, Hoffmann U et al. Prevalence,distribution, and risk factor correlates of high pericardial andintrathoracic fat depots in the Framingham heart study. Circ Car-diovasc Imaging 2010; 3: 559–566.8. Eckel RH. Obesity and heart disease: a statement for healthcareprofessionals from the Nutrition Committee, American HeartAssociation. Circulation 1997; 96: 3248–3250.9. Kenchaiah S, Evans JC, Levy D et al. Obesity and the risk ofheart failure. N Engl J Med 2002; 347: 305–313.10. Tedrow UB, Conen D, Ridker PM, et al. The long- and short-term impact of elevated body mass index on the risk of new atrialfibrillation the WHS (women’s health study). J Am Coll Cardiol2010; 55: 2319–2327.11. Braunwald E. Shattuck lecture–cardiovascular medicine at theturn of the millennium: triumphs, concerns, and opportunities. NEngl J Med 1997; 337: 1360–1369.12. Coyne KS, Paramore C, Grandy S, Mercader M, Reynolds M,Zimetbaum P. Assessing the direct costs of treating nonvalvularatrial fibrillation in the United States. Value Health 2006; 9: 348–356.13. Stewart S, Murphy NF, Walker A, McGuire A, McMurray JJ.Cost of an emerging epidemic: an economic analysis of atrialfibrillation in the UK. Heart 2004; 90: 286–292.14. Karjalainen J, Kujala UM, Kaprio J, Sarna S, Viitasalo M.Lone atrial fibrillation in vigorously exercising middle aged men:case-control study. BMJ 1998; 316: 1784–1785.15. Mont L, Elosua R, Brugada J. Endurance sport practice as arisk factor for atrial fibrillation and atrial flutter. Europace 2009;11: 11–17.16. Fox CS, Parise H, D′Agostino RB, Sr., et al. Parental atrialfibrillation as a risk factor for atrial fibrillation in offspring. JAMA2004; 291: 2851–2855.17. Mann SA, Otway R, Guo G, et al. Epistatic effects of potas-sium channel variation on cardiac repolarization and atrial fibril-lation risk. J Am Coll Cardiol 2012; 59: 1017–1025.18. 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: 310–315.19. Miyasaka Y, Barnes ME, Gersh BJ, et al. Secular trends inincidence of atrial fibrillation in Olmsted County, Minnesota,1980 to 2000, and implications on the projections for futureprevalence. Circulation 2006; 114: 119–125.20. Gami AS, Hodge DO, Herges RM, et al. Obstructive sleepapnea, obesity, and the risk of incident atrial fibrillation. J Am CollCardiol 2007; 49: 565–571.21. Wang TJ, Parise H, Levy D, et al. Obesity and the risk ofnew-onset atrial fibrillation. JAMA 2004; 292: 2471–2477.22. Rosengren A, Hauptman PJ, Lappas G, Olsson L, WilhelmsenL, Swedberg K. Big men and atrial fibrillation: effects of body sizeand weight gain on risk of atrial fibrillation in men. Eur Heart J2009; 30: 1113–1120.23. Watanabe H, Tanabe N, Watanabe T, et al. Metabolicsyndrome and risk of development of atrial fibrillation: theNiigata preventive medicine study. Circulation 2008; 117: 1255–1260.24. Zacharias A, Schwann TA, Riordan CJ, Durham SJ, Shah AS,Habib RH. Obesity and risk of new-onset atrial fibrillation aftercardiac surgery. Circulation 2005; 112: 3247–3255.

25. Karasoy D, Bo Jensen T, Hansen ML, et al. Obesity is a riskfactor for atrial fibrillation among fertile young women: a nation-wide cohort study. Europace 2013; 15: 781–786.26. Kistler PM, Sanders P, Dodic M, et al. Atrial electrical andstructural abnormalities in an ovine model of chronic blood pres-sure elevation after prenatal corticosteroid exposure: implicationsfor development of atrial fibrillation. Eur Heart J 2006; 27: 3045–3056.27. Kim SJ, Choisy SC, Barman P, et al. Atrial remodeling and thesubstrate for atrial fibrillation in rat hearts with elevated afterload.Circ Arrhythm Electrophysiol 2011; 4: 761–769.28. Medi C, Kalman JM, Spence SJ, et al. Atrial electrical andstructural changes associated with longstanding hypertension inhumans: implications for the substrate for atrial fibrillation.J Cardiovasc Electrophysiol 2011; 22: 1317–1324.29. Lambert E, Sari CI, Dawood T, et al. Sympathetic nervoussystem activity is associated with obesity-induced subclinical organdamage in young adults. Hypertension 2010; 56: 351–358.30. Sarzani R, Salvi F, Dessi-Fulgheri P, Rappelli A. Renin-angiotensin system, natriuretic peptides, obesity, metabolicsyndrome, and hypertension: an integrated view in humans.J Hypertens 2008; 26: 831–843.31. Messerli FH. Cardiovascular effects of obesity and hyperten-sion. Lancet 1982; 1: 1165–1168.32. Coronel R, Langerveld J, Boersma LV, et al. Left atrial pres-sure reduction for mitral stenosis reverses left atrial direction-dependent conduction abnormalities. Cardiovasc Res 2010; 85:711–718.33. Gami AS, Pressman G, Caples SM, et al. Association of atrialfibrillation and obstructive sleep apnea. Circulation 2004; 110:364–367.34. Latina JM, Estes NA, 3rd, Garlitski AC. The Relationshipbetween Obstructive Sleep Apnea and Atrial Fibrillation: AComplex Interplay. Pulm Med 2013; 2013: 621736.35. Yagmur J, Yetkin O, Cansel M, et al. Assessment of atrialelectromechanical delay and influential factors in patients withobstructive sleep apnea. Sleep Breath 2012; 16: 83–88.36. Iwasaki YK, Shi Y, Benito B, et al. Determinants of atrialfibrillation in an animal model of obesity and acute obstructivesleep apnea. Heart Rhythm 2012; 9: 1409–1416 e1.37. Movahed MR, Hashemzadeh M, Jamal MM. Diabetes melli-tus is a strong, independent risk for atrial fibrillation and flutter inaddition to other cardiovascular disease. Int J Cardiol 2005; 105:315–318.38. Kannel WB, Wolf PA, Benjamin EJ, Levy D. Prevalence,incidence, prognosis, and predisposing conditions for atrial fibril-lation: population-based estimates. Am J Cardiol 1998; 82:2N-9N.39. Watanabe M, Yokoshiki H, Mitsuyama H, Mizukami K,Ono T, Tsutsui H. Conduction and refractory disorders in thediabetic atrium. Am J Physiol Heart Circ Physiol 2012; 303:H86–H95.40. Kato T, Yamashita T, Sekiguchi A, et al. What are arrhyth-mogenic substrates in diabetic rat atria? J Cardiovasc Electro-physiol 2006; 17: 890–894.41. Kato T, Yamashita T, Sekiguchi A, et al. AGEs-RAGE systemmediates atrial structural remodeling in the diabetic rat. J Cardio-vasc Electrophysiol 2008; 19: 415–420.42. Raposeiras-Roubin S, Rodino-Janeiro BK, Grigorian-Shamagian L, et al. Evidence for a role of advanced glycation endproducts in atrial fibrillation. Int J Cardiol 2012; 157: 397–402.43. Aviles RJ, Martin DO, Apperson-Hansen C et al. Inflamma-tion as a risk factor for atrial fibrillation. Circulation 2003; 108:3006–3010.



44. Sharma SK, Agrawal S, Damodaran D et al. CPAP for themetabolic syndrome in patients with obstructive sleep apnea. NEngl J Med 2011; 365: 2277–2286.45. Ishii Y, Schuessler RB, Gaynor SL et al. Inflammation ofatrium after cardiac surgery is associated with inhomogeneity ofatrial conduction and atrial fibrillation. Circulation 2005; 111:2881–2888.46. Mazurek T, Zhang L, Zalewski A et al. Human epicardialadipose tissue is a source of inflammatory mediators. Circulation2003; 108: 2460–2466.47. Batal O, Schoenhagen P, Shao M et al. Left atrial epicardialadiposity and atrial fibrillation. Circ Arrhythm Electrophysiol2010; 3: 230–236.48. Shin SY, Yong HS, Lim HE et al. Total and interatrial epicar-dial adipose tissues are independently associated with left atrialremodeling in patients with atrial fibrillation. J Cardiovasc Elec-trophysiol 2011; 22: 647–655.49. Rudolph V, Andrie RP, Rudolph TK et al. Myeloperoxidaseacts as a profibrotic mediator of atrial fibrillation. Nat Med 2010;16: 470–474.50. Imazio M, Brucato A, Ferrazzi P et al. Colchicine reducespostoperative atrial fibrillation: results of the Colchicine for thePrevention of the Postpericardiotomy Syndrome (COPPS) atrialfibrillation substudy. Circulation 2011; 124: 2290–2295.51. Al Chekakie MO, Welles CC, Metoyer R, et al. Pericardial fatis independently associated with human atrial fibrillation. J AmColl Cardiol 2010; 56: 784–788.52. Thanassoulis G, Massaro JM, O’Donnell CJ, et al. Pericardialfat is associated with prevalent atrial fibrillation: the FraminghamHeart Study. Circ Arrhythm Electrophysiol 2010; 3: 345–350.53. Kankaanpaa M, Lehto HR, Parkka JP, et al. Myocardialtriglyceride content and epicardial fat mass in human obesity:relationship to left ventricular function and serum free fatty acidlevels. J Clin Endocrinol Metab 2006; 91: 4689–4695.54. Szczepaniak LS, Dobbins RL, Metzger GJ, et al. Myocardialtriglycerides and systolic function in humans: in vivo evaluation bylocalized proton spectroscopy and cardiac imaging. Magn ResonMed 2003; 49: 417–423.55. Abed HS, Samuel CS, Lau DH, et al. Obesity results in pro-gressive atrial structural and electrical remodeling: Implications foratrial fibrillation. Heart Rhythm 2013; 10: 90–100.56. Rabkin SW. Epicardial fat: properties, function and relation-ship to obesity. Obes Rev 2007; 8: 253–261.57. Marchington JM, Pond CM. Site-specific properties of peri-cardial and epicardial adipose tissue: the effects of insulin andhigh-fat feeding on lipogenesis and the incorporation of fatty acidsin vitro. Int J Obes 1990; 14: 1013–1022.58. Browning JD, Horton JD. Molecular mediators of hepaticsteatosis and liver injury. J Clin Invest 2004; 114: 147–152.59. Zhou YT, Grayburn P, Karim A, et al. Lipotoxic heart diseasein obese rats: implications for human obesity. Proc Natl Acad SciU S A 2000; 97: 1784–1789.60. Nakazato R, Rajani R, Cheng VY, et al. Weight change modu-lates epicardial fat burden: a 4-year serial study with non-contrastcomputed tomography. Atherosclerosis 2012; 220: 139–144.61. Snel M, Jonker JT, Hammer S, et al. Long-term beneficialeffect of a 16-week very low calorie diet on pericardial fat in obesetype 2 diabetes mellitus patients. Obesity (Silver Spring) 2012; 20:1572–1576.62. Wong CX, Abed HS, Molaee P, et al. Pericardial fat is asso-ciated with atrial fibrillation severity and ablation outcome. J AmColl Cardiol 2011; 57: 1745–1751.63. Sacks HS, Fain JN. Human epicardial adipose tissue: a review.Am Heart J 2007; 153: 907–917.

64. Malavazos AE, Ermetici F, Coman C, Corsi MM, MorriconeL, Ambrosi B. Influence of epicardial adipose tissue and adipocy-tokine levels on cardiac abnormalities in visceral obesity. Int JCardiol 2007; 121: 132–134.65. Nakagawa H, Scherlag BJ, Patterson E, Ikeda A, LockwoodD, Jackman WM. Pathophysiologic basis of autonomic ganglion-ated plexus ablation in patients with atrial fibrillation. HeartRhythm 2009; 6: S26–S34.66. Khawaja O, Bartz TM, Ix JH, et al. Plasma free fatty acids andrisk of atrial fibrillation (from the Cardiovascular Health Study).Am J Cardiol 2012; 110: 212–216.67. Jaswal JS, Keung W, Wang W, Ussher JR, Lopaschuk GD.Targeting fatty acid and carbohydrate oxidation–a novel therapeu-tic intervention in the ischemic and failing heart. Biochim BiophysActa 2011; 1813: 1333–1350.68. Lam YY, Hatzinikolas G, Weir JM, et al. Insulin-stimulatedglucose uptake and pathways regulating energy metabolism inskeletal muscle cells: the effects of subcutaneous and visceral fat,and long-chain saturated, n-3 and n-6 polyunsaturated fatty acids.Biochim Biophys Acta 2011; 1811: 468–475.69. Mazumder PK, O′Neill BT, Roberts MW, et al. Impairedcardiac efficiency and increased fatty acid oxidation in insulin-resistant ob/ob mouse hearts. Diabetes 2004; 53: 2366–2374.70. Hammer S, Snel M, Lamb HJ, et al. Prolonged caloric restric-tion in obese patients with type 2 diabetes mellitus decreasesmyocardial triglyceride content and improves myocardial function.J Am Coll Cardiol 2008; 52: 1006–1012.71. Vaziri SM, Larson MG, Benjamin EJ, Levy D. Echocardio-graphic predictors of nonrheumatic atrial fibrillation. The Fram-ingham Heart Study. Circulation 1994; 89: 724–730.72. Abhayaratna WP, Fatema K, Barnes ME, et al. Left atrialreservoir function as a potent marker for first atrial fibrillation orflutter in persons > or = 65 years of age. Am J Cardiol 2008; 101:1626–1629.73. Munger TM, Dong YX, Masaki M, et al. Electrophysiologicaland hemodynamic characteristics associated with obesity inpatients with atrial fibrillation. J Am Coll Cardiol 2012; 60: 851–860.74. Stritzke J, Markus MR, Duderstadt S, et al. The aging processof the heart: obesity is the main risk factor for left atrial enlarge-ment during aging the MONICA/KORA (monitoring of trends anddeterminations in cardiovascular disease/cooperative research inthe region of Augsburg) study. J Am Coll Cardiol 2009; 54:1982–1989.75. Tsang TS, Barnes ME, Miyasaka Y, et al. Obesity as a riskfactor for the progression of paroxysmal to permanent atrial fibril-lation: a longitudinal cohort study of 21 years. Eur Heart J 2008;29: 2227–2233.76. Conen D, Glynn RJ, Sandhu RK, Tedrow UB, Albert CM.Risk factors for incident atrial fibrillation with and without leftatrial enlargement in women. Int J Cardiol 2013. doi: 10.1016/j.ijcard.2012.12.060.77. Nguyen BL, Fishbein MC, Chen LS, Chen PS, Masroor S.Histopathological substrate for chronic atrial fibrillation inhumans. Heart Rhythm 2009; 6: 454–460.78. Burstein B, Nattel S. Atrial fibrosis: mechanisms and clinicalrelevance in atrial fibrillation. J Am Coll Cardiol 2008; 51: 802–809.79. Haissaguerre M, Jais P, Shah DC, et al. Spontaneous initiationof atrial fibrillation by ectopic beats originating in the pulmonaryveins. N Engl J Med 1998; 339: 659–666.80. Kostin S, Klein G, Szalay Z, Hein S, Bauer EP, Schaper J.Structural correlate of atrial fibrillation in human patients. Car-diovasc Res 2002; 54: 361–379.



81. Oakes RS, Badger TJ, Kholmovski EG, et al. Detection andquantification of left atrial structural remodeling with delayed-enhancement magnetic resonance imaging in patients with atrialfibrillation. Circulation 2009; 119: 1758–1767.82. Everett THt, Olgin JE. Atrial fibrosis and the mechanisms ofatrial fibrillation. Heart Rhythm 2007; 4: S24–S27.83. Camelliti P, Borg TK, Kohl P. Structural and functional char-acterisation of cardiac fibroblasts. Cardiovasc Res 2005; 65:40–51.84. Creemers EE, Pinto YM. Molecular mechanisms that controlinterstitial fibrosis in the pressure-overloaded heart. CardiovascRes 2011; 89: 265–272.85. Yeh YH, Kuo CT, Chan TH, et al. Transforming growthfactor-beta and oxidative stress mediate tachycardia-induced cel-lular remodelling in cultured atrial-derived myocytes. CardiovascRes 2011; 91: 62–70.86. Rosenkranz S. TGF-beta1 and angiotensin networking incardiac remodeling. Cardiovasc Res 2004; 63: 423–432.87. Burstein B, Libby E, Calderone A, Nattel S. Differential behav-iors of atrial versus ventricular fibroblasts: a potential role forplatelet-derived growth factor in atrial-ventricular remodeling dif-ferences. Circulation 2008; 117: 1630–1641.88. Liao CH, Akazawa H, Tamagawa M, et al. Cardiac mast cellscause atrial fibrillation through PDGF-A-mediated fibrosis inpressure-overloaded mouse hearts. J Clin Invest 2010; 120: 242–253.89. Yang Z, Krasnici N, Luscher TF. Endothelin-1 potentiateshuman smooth muscle cell growth to PDGF: effects of ETA andETB receptor blockade. Circulation 1999; 100: 5–8.90. Rodriguez-Vita J, Ruiz-Ortega M, Ruperez M, et al.Endothelin-1, via ETA receptor and independently of transforminggrowth factor-beta, increases the connective tissue growth factor invascular smooth muscle cells. Circ Res 2005; 97: 125–134.91. Mayyas F, Niebauer M, Zurick A, et al. Association of leftatrial endothelin-1 with atrial rhythm, size, and fibrosis in patientswith structural heart disease. Circ Arrhythm Electrophysiol 2010;3: 369–379.92. Stein M, Boulaksil M, Jansen JA, et al. Reduction of fibrosis-related arrhythmias by chronic renin-angiotensin-aldosteronesystem inhibitors in an aged mouse model. Am J Physiol HeartCirc Physiol 2010; 299: H310–H321.93. Mohanty S, Mohanty P, Di Biase L, et al. Impact of metabolicsyndrome on procedural outcomes in patients with atrial fibrilla-tion undergoing catheter ablation. J Am Coll Cardiol 2012; 59:1295–1301.94. Cha YM, Friedman PA, Asirvatham SJ, et al. Catheter abla-tion for atrial fibrillation in patients with obesity. Circulation2008; 117: 2583–2590.

95. Mohanty S, Mohanty P, Di Biase L, et al. Influence ofbody mass index on quality of life in atrial fibrillation patientsundergoing catheter ablation. Heart Rhythm 2011; 8: 1847–1852.96. Ector J, Dragusin O, Adriaenssens B, et al. Obesity is a majordeterminant of radiation dose in patients undergoing pulmonaryvein isolation for atrial fibrillation. J Am Coll Cardiol 2007; 50:234–242.97. Guijian L, Jinchuan Y, Rongzeng D, Jun Q, Jun W, WenqingZ. Impact of Body Mass Index on Atrial Fibrillation Recurrence: AMeta-analysis of Observational Studies. Pacing Clin Electro-physiol 2013; 36: 748–756.98. Shoemaker MB, Muhammad R, Farrell M, et al. Relation ofmorbid obesity and female gender to risk of procedural complica-tions in patients undergoing atrial fibrillation ablation. Am JCardiol 2013; 111: 368–373.99. Menezes AR, Lavie CJ, Dinicolantonio JJ, et al. Atrial fibril-lation in the 21st century: a current understanding of risk factorsand primary prevention strategies. Mayo Clin Proc 2013; 88:394–409.100. Abed HS, Wittert GA, Middeldorp ME, et al. Weight andRisk Factor Modification: Impact on Atrial Fibrillation. Circula-tion 2012; 126: 196–197.101. Kanasaki K, Koya D. Biology of obesity: lessons fromanimal models of obesity. J Biomed Biotechnol 2011; 2011:197636.102. McCann JP, Bergman EN, Beermann DH. Dynamic andstatic phases of severe dietary obesity in sheep: food intakes, endo-crinology and carcass and organ chemical composition. J Nutr1992; 122: 496–505.103. Jongnarangsin K, Chugh A, Good E, et al. Body massindex, obstructive sleep apnea, and outcomes of catheter ablationof atrial fibrillation. J Cardiovasc Electrophysiol 2008; 19: 668–672.104. Chilukuri K, Dalal D, Gadrey S, et al. A prospective studyevaluating the role of obesity and obstructive sleep apnea foroutcomes after catheter ablation of atrial fibrillation. J CardiovascElectrophysiol 2010; 21: 521–525.105. Kanagala R, Murali NS, Friedman PA, et al. Obstructivesleep apnea and the recurrence of atrial fibrillation. Circulation2003; 107: 2589–2594.106. Liu T, Li G, Li L, Korantzopoulos P. Association betweenC-reactive protein and recurrence of atrial fibrillation after suc-cessful electrical cardioversion: a meta-analysis. J Am Coll Cardiol2007; 49: 1642–1648.107. Mainigi SK, Sauer WH, Cooper JM, et al. Incidence andpredictors of very late recurrence of atrial fibrillation after abla-tion. J Cardiovasc Electrophysiol 2007; 18: 69–74.



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