Pericardial fat and atrial fibrillation: Epidemiology, mechanisms and interventions

International Journal of Cardiology 195 (2015) 98–103

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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard

Review

Pericardial fat and atrial fibrillation: Epidemiology, mechanisms and interventions Mohamed Al-Rawahi, Riccardo Proietti, George Thanassoulis ⁎ Department of Medicine, Division of Cardiology, McGill University Health Center, Canada

a r t i c l e

i n f o

Article history: Received 23 March 2015 Received in revised form 20 May 2015 Accepted 20 May 2015 Available online 21 May 2015 Keywords: Pericardial Fat Atrial Fibrillation

a b s t r a c t Atrial fibrillation (AF) is the most common cardiac arrhythmia in clinical practice and is associated with major morbidity and mortality. AF prevalence has been projected to increase in the coming decades and is expected to affect over 7.5 million Americans by the year 2050. There is growing evidence that obesity represents an important risk factor for new onset AF, with each increment in BMI associated with a 3–8% higher risk for new-onset of AF, independent of other conventional AF risk factors such as age, hypertension and heart failure. Several recent studies have also reported that obesity is also a risk factor for AF severity & chronicity. Although obesity may impact AF incidence via several mechanisms, a relation between local pericardial fat depots surrounding the heart and AF has been recently described which may have important pathophysiological implications. Pericardial fat represents one of several localized, fat depots, with unique properties due to its contiguity with cardiac structures and its shared blood supply with the heart microcirculation. Pericardial fat is also highly metabolically active and is an important source of several adipokines and cytokines. Importantly, pericardial fat appears to be more closely linked with metabolic risk than indices of systemic obesity such as BMI or waist circumference. Therefore, pericardial fat may partially explain the increased risk of AF seen in obesity and may promote AF arrhythmogenesis by local mechanisms. In this article, we review the characteristics of pericardial fat, the evidence of an association between pericardial fat and AF and the potential mechanisms for this association. We also summarize the evidence from several recent reports that have linked pericardial fat to AF prevalence, severity as well as outcome after AF ablation. We also briefly review whether interventions targeting pericardial fat could reduce AF incidence and recurrence. © 2015 Elsevier Ireland Ltd. All rights reserved.

1. Epidemiologic studies 1.1. Pericardial fat and AF: cross-sectional and prospective studies In the Framingham Offspring Cohort, Thanassoulis et al. [1], using data from over 3000 individuals with computed tomographic data on several local fat depots, observed a 40% higher odds of AF per standard deviation increase in pericardial fat volume. This association remained significant after adjustment for common AF risk factors including age, sex, myocardial infarction, heart failure, BMI and other regional fat deposits. Importantly, the authors demonstrated no similar association with other fat deposit including intrathoracic fat or abdominal visceral fat, suggesting that contiguity of adipose tissue, rather than generalized increases in fat depots, may be important in the genesis of AF. This report was among the first to demonstrate such an association and has stimulated intense interest in the role of pericardial fat and AF (Table 1).

⁎ Corresponding author at: Preventive and Genomic Cardiology, McGill University Health Center, 687 Pine Ave. W. H4.55, Montreal, QC H1A 1A1, Canada. E-mail address: [email protected] (G. Thanassoulis).

http://dx.doi.org/10.1016/j.ijcard.2015.05.129 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.

Several subsequent reports have now confirmed and extended these findings across broad patient groups. Using cardiac MRI derived fat volumes; Wong et al. [2] included 110 AF patients undergoing first time AF ablation and compared these to a 20 patient control group without AF. Patient with AF had greater pericardial fat volumes than the control group (299.9 cm3 vs. 168.8 cm3, P b 0.001). Similar results were also observed by Al-Chekakie et al. [3], who included 273 patients undergoing cardiac computed tomography prior to AF ablation. Patients with AF had significantly more pericardial fat compared with patients in sinus rhythm (p b 0.001). Pericardial fat volume was significantly larger in paroxysmal AF compared with the sinus rhythm group (93.9 ± 39.1 ml vs. 76.1 ± 36.3 ml, P = 0.02). They further showed that for every 10 mL increase in pericardial fat volume, there was a concomitant 13% increase in the odds of AF. This association was independent of age, hypertension, sex, left atrial enlargement, valvular heart disease, left ventricular ejection fraction, diabetes mellitus, and body mass index. Tereshchenko et al. [4] studied 90 patients in sinus rhythm – divided in 3 groups at risk of AF as determined by the ARIC AF risk score – and 12 patients in paroxysmal AF using a special cardiac MRI sequence to quantify intraatrial fat area. They concluded that intraatrial fat monotonically increased with increased AF risk in the various groups and

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Table 1 Studies summarizing the association between pericardial fat and AF. Author

Study design

Imaging modality

Population

Key findings

G. Thanassoulis [1] (2010)

Retrospective study

CT

O. Batal [6] (2010)

Retrospective study

Cardiac CT

Control 3161 AF 54 Control 73 AF 96

M. Al Chekakie [3] (2010)

Prospective study

CT

C. Wong [2] (2011)

Prospective study

Cardiac MRI

Nagashima [9] (2011)

Prospective study

Cardiac CT

Pericardial fat was associated with AF prevalence. Each increment in the SD of pericardial fat volume was associated with a 28% increase in the prevalence of AF. Pericardial fat thickness at LA-ESO was a significant predictor of AF burden even after adjusting for age, body mass index, and LA area (odds ratio, 5.30; 95% C.I., 1.39 to 20.24; P = 0.015). Pericardial fat volume is highly associated with paroxysmal and persistent AF. For every 10-ml increase in pericardial fat volume, the odds of AF increase by 13%. Pericardial fat volume is associated with the presence of AF (299.9 cm3 AF vs. 168.8 cm3 Control, P b 0.001) the severity of AF, left atrial volumes, and poorer outcomes after AF ablation. Pericardial fat volume increased with AF burden (paroxysmal AF 158.3 ±

Control 76 AF 197 Control 20 AF 110 Control 37 AF 40

M. Greif [8] (2013)

Retrospective study

CT

Control 934 AF 354

T. Chao [10] (2013)

Prospective study

TTE

Control 0 AF 283

T. Mazurek [28] (2014)

Retrospective study

FDG-PET CT

G. Drossos [12] (2014)

Prospective study

CT

Control 21 AF 21 Control 55 AF 28

H. Kanazawa [7] (2014)

Prospective study

CT-EPS

T. Kim [11] 2014

Prospective study

CT

47.2 cm3 vs. persistent AF 226.4 ± 93.3 cm3) Pericardial fat volume might be useful for predicting AF recurrence after catheter ablation. Patients without AF had significant lower pericardial fat volumes compared to patients with AF (255.7 ± 127.2 vs. 284.8 ± 139.2 ml, P b 0.001). Pericardial fat increased with AF severity. Pericardial thickness serves as a useful parameter in predicting recurrences after AF ablations. A cutoff value of 6 mm for PAF and 6.9 mm for non-PAF could help us to identify patients at risk of recurrences. Inflammatory activity of pericardial fat is higher in patients with AF than control. Patients with postoperative AF had significantly more pericardial fat compared with sinus rhythm patients (195 ± 80 ml postoperative AF group vs. 126 ± 47 ml sinus rhythm group, P = 0.0001) Total pericardial fat volume correlated with AF burden (paroxysmal AF 134.1

Control 120 AF 120

Control 0 AF 665 patients

could serve as an objective risk factor for the probability of developing AF in patients in pre-clinical AF. Recently, an analysis of 3467 participants of the Heinz Nixdorf Recall study without known cardiovascular disease, confirmed a strong association between pericardial fat with AF (adjusted OR 1.38, 95% CI 1.11–1.72; p = 0.003) that was attenuated by further adjustment for LA size suggesting that LA size may be an important confounder in epidemiologic studies [5].

± 37.6 ml vs. persistent AF 178.3 ± 47.9 mlP b 0.001) Pericardial fat volume correlated significantly with complex fractionated atrial electrogram area in patients with AF. Pericardial fat volume is a significant predictor for AF recurrence after catheter ablation for persistent AF only. (HR 1.10; 95% CI 1.05–1.16, P b 0.001).

1.2. Pericardial fat, AF disease severity and chronicity In addition to the association between pericardial fat and AF prevalence, increasing evidence suggests an association with AF burden, persistence and chronicity. Batal et al. [6] examined the association between left atrial epicardial fat and AF severity. In this study of 169 patients who underwent cardiac computed tomography for evaluation

Fig. 1. Potential mechanisms and association between pericardial fat and atrial fibrillation.

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of AF or CAD, posterior epicardial fat between the left atrium and esophagus (LA-ESO) was significantly thicker in patients with persistent AF compared to patients with no AF or with paroxysmal AF (P values 0.03, 0.011 respectively). A stepwise trend was also observed between increasing posterior LA-ESO epicardial fat thickness and increasing AF burden. Mean epicardial thickness was 0.34 cm (0.21, 0.52) among controls, 0.39 cm (0.27, 0.54) among those with paroxysmal AF at and 0.56 cm (0.40, 0.69) in those with persistent AF. This association was independent for conventional AF risk factors such as age, BMI and left atrial area. Interestingly, retrosternal fat pad thickness and anterior epicardial fat deposits were not associated with increasing AF burden further suggesting a potential local mechanism. These findings were also consistent with the study by Wong et al. [2] who also demonstrated using MRI derived fat depot volumes, a significant association between pericardial fat volume and AF chronicity (adjusted odds ratio of 3.56 (95% 1.41–9.00) P = 0.007) and AF symptom burden (adjusted regression coefficient of 1.71 (0.73 to 2.68) P = 0.001). Al Chekakie et al. [3] also reported that persistent AF patients also had a significantly larger pericardial fat volume compared with paroxysmal AF patients (115.4 ± 49.3 ml vs. 93.9 ± 39.1 ml, P = 0.001). Kanazawa et al. [7] also demonstrated a significant correlation between pericardial fat volume and AF presence in 120 patients with AF undergoing ablation. The total pericardial fat volume in paroxysmal AF was measured at 134.1 ± 37.6 ml vs. persistent AF at 178.3 ± 47.9 ml. (P b 0.001). The total area of complex fractionated atrial electrogram (CFAE) in paroxysmal AF was significantly larger than in persistent AF (20.0 ± 7.3 cm2 vs. 28.3 ± 7.8 cm2 respectively, P b 0.001). Interestingly, pericardial fat volume and CFAE areas were independently associated with persistence of AF (OR: 1.018, P = 0.018, OR: 1.144, P = 0.002, respectively). In addition, pericardial fat volume correlated significantly with the area of CFAE region, suggesting that pericardial fat may directly relate to the genesis of CFAE, resulting in the development of AF. In one of the largest studies to date examining AF burden and chronicity, Greif et al. [8] retrospectively measured pericardial fat in 1288 patients (n = 354 patients with AF) who underwent coronary artery calcium-scanning for coronary risk stratification. They noted a significantly higher pericardial fat volume with increasing burden of AF. Patients with persistent AF had significantly more pericardial fat than patients with paroxysmal AF (323.8 ± 139.2 ml vs. 261.8 ± 127.8 ml; P b 0.0001, for persistent and paroxysmal, respectively). Finally, Nagashima et al. [9] conducted a small prospective study including 40 patients with AF (24 patients with paroxysmal AF and 16 patients with persistent AF) who underwent radio-frequency catheter ablation and 37 age-matched control candidates. Pericardial fat volume measured by computed tomography was higher in AF patients independent of AF risk factors and they noted a graded increase in fat volumes that correlated with AF burden (pericardial fat volumes: 138.3 ± 45.2 cm3 vs. 158.3 ± 47.2 cm3 vs. 226.4 ± 93.3 for controls, paroxysmal and persistent AF, respectively, P b 0.01 for all the groups). 1.3. Pericardial fat and recurrence after AF ablation To date, most studies examining the AF link with pericardial fat have been cross-sectional, limiting the ability to draw firm conclusions as to whether pericardial fat promotes AF or simply develops in response to AF. However, short-term data from small studies examining recurrence post-ablation, demonstrate a prospective association suggesting that pericardial fat may promote AF. Using TTE based measures of pericardial fat, Chao et al. [10] prospectively studied 227 patients with paroxysmal AF and 56 patients with non-paroxysmal AF scheduled for AF catheter ablation. Over a 16 ± 9 month follow-up period, 95 patients (33.6%) suffered from AF recurrences. Pericardial fat thickness was consistently thicker in patients with post-ablation recurrence than those without recurrence (among

PAF patients: 6.3 ± 0.6 mm versus 5.7 ± 0.6 mm, P b 0.001, for recurrence vs. no recurrence; and among non-PAF: 7.3 ± 0.6 mm versus 6.7 ± 0.7 mm, P = 0.001, for recurrence vs. no recurrence). Pericardial fat thickness was also found to be an independent predictor of recurrence after catheter ablations. The authors also proposed that a pericardial fat thickness cutoff value of 6 mm for PAF and 6.9 mm for non-PAF identified patients at risk of recurrences. Kim et al. [11] also prospectively included 665 patients (450 patients with paroxysmal — 67.7% — and 215 patients with persistent AF — 32.3%) who underwent radio-frequency catheter ablation for AF. With a mean follow-up period of 19.3 ± 8.5 months, 176 participant out of 665 patients (26.5%) experienced clinical recurrence of AF. Pericardial fat volume was greater in persistent AF patients than in paroxysmal AF patients (108.13 ± 46.88 cm 3 vs. 100.67 ± 43.07 cm 3 , P = 0.043). Pericardial fat volume was also significantly greater in persistent AF patients with post-ablation recurrence than in those without (121.9 ± 51.6 cm 3 vs. 99.6 ± 41.7 cm 3 P = 0.001). However, they were unable to identify any such difference among recurrence post-ablation in the paroxysmal AF group (105.6 ± 43.7 cm3 vs. 99.4 ± 42.9 cm3 P = 0.212). In two smaller studies, Nagashima et al. [9] showed that pericardial fat volumes were greater in the 15 AF patients out of the 40 AF patients (37.5%) with post-ablation recurrence than in patients without recurrence (239.0 ± 90.2 cm3 vs. 153.5 ± 42.7 cm 3 , P = 0.0002). Wong et al. [2], have also shown that pericardial fat depots, as measured by MRI, were predictive of long-term AF recurrence after ablation (P = 0.035). 1.4. Pericardial fat and incidence of AF post-CABG The first and only prospective report of an association between pericardial fat and AF following CABG comes from a study by Drossos et al. [12] where they measured pericardial fat volume by CT in 83 patients with coronary artery disease scheduled for coronary bypass surgery and evaluated for in-hospital post-operative AF incidence. Twentyeight patients (33.7%) developed post-operative AF. Pericardial fat volume was the strongest independent variable associated with the development of postoperative AF (pericardial volumes: 195 ± 80 ml in postoperative AF group vs. 126 ± 47 ml in sinus rhythm group, P = 0.0001; OR 1.018, 95% confidence interval: 1.009–1.027, P = 0.0001). The pericardial fat volume cut-off for increased risk of post-operative AF, as assessed by receiver operating characteristic analysis, was 129.5 ml with a sensitivity of 86% and specificity of 56%. 2. Potential mechanisms The majority of studies reporting an association between pericardial fat and AF have adjusted for AF risk factors and general measures of obesity such as BMI, suggesting that the effect of pericardial fat is not explained by obesity or obesity-induced systemic changes and points to a local mechanism for these associations. Although the evidence remains limited, there are several potential local mechanisms that may explain the observed association between pericardial fat and AF including local inflammation, cardiac structural changes and autonomic nervous system modulation (Fig. 1). 2.1. Inflammation There is a strong association between AF and many inflammatory conditions that affect the heart such as pericarditis and myocarditis [13,14]. Atrial biopsies in patients with AF have demonstrated evidence of inflammatory cells, suggesting that inflammation plays a role in the development of AF [15–18]. In patients post-coronary artery bypass graft, the incidence of AF coincides with peak postoperative C-reactive protein levels [19], suggesting an inflammatory link in AF initiation. Moreover, CRP appears to be higher in patients

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with non-post-operative AF and is associated with AF duration and persistence [20–22]. Pericardial fat is highly metabolically active and has been linked to increased local release of various pro-inflammatory mediators including interleukin-1β, interleukin-6 and tumor necrosis factor-α [23]. Interestingly, these mediators are also observed at greater concentration in the left atrium as compared to other cardiac chambers, which suggests a possible role of inflammation in pericardial-mediated AF development [24,25]. Inflammatory mediators produced by the pericardial deposit at the posterior wall may promote the activation of ectopic foci in the pulmonary vein ostia causing AF [26,27]. In addition, the left atrial pericardial fat is in close proximity to pulmonary veins ostia where AF is usually triggered. This may partly explain the decrease incidence of AF after posterior pericardiectomy during cardiac surgery. To date, the best evidence suggesting a pro-inflammatory mechanism, comes from a provocative study by Mazurek et al. [28] who examined the inflammatory activity of pericardial fat using FDG-PET–computerized tomography in 21 patients with AF and in 21 control and demonstrated that pericardial fat FDG activity, a marker of active inflammation, was significantly greater in patients with AF than in controls without AF. 2.2. Cardiac structural changes Increased pericardial fat is associated with various cardiac structural changes that could affect the propensity for AF. Most importantly, increased pericardial fat has been associated with increased left atrial dimensions in cross-sectional studies independent of other AF risk factors [1,2,6]. It has been noted that as the pericardial fat increases in size, there is fatty infiltration of the ventricular myocardium and atrial septum [29] which may lead to electromechanical changes in atrial tissue due to local inflammation and resulting fibrosis promoting the development of AF. Friedman et al. [30] studied 1946 Framingham Heart Study participants and determined the relation between pericardial fat and atrial conduction as measured by P wave indices. They noted that pericardial fat was associated with P wave duration and P wave terminal force in men and women, PR interval in women, and P wave amplitude in men. Pericardial fat remained associated with P wave duration even after adjustment for intrathoracic fat and visceral fat. This suggests that pericardial fat may alter atrial conduction, promoting atrial electrical remodeling thus favoring the development of AF.

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reported that weight loss after bariatric surgery (average weight loss of 40 kg) was associated with a decrease in pericardial fat thickness. Abed et al. [36] demonstrated that weight reduction with intensive risk factor management resulted in a reduction in atrial fibrillation symptom burden and severity in obese patients. They equally randomized 150 obese patients with symptomatic atrial fibrillation to either weight management (75 patients in the intervention group) or general lifestyle advice (75 patients in the control group). The primary outcomes were changes in symptom burden and symptom severity, based on the AF Severity Scale. Secondary outcomes included total atrial fibrillation episodes and AF duration measured by 7-day Holter and left atrial area, as well as LV wall thickness, on echocardiography. The intervention group showed a significant weight reduction compared to the control group (14.3 and 3.6 kg, respectively; P b 0.001) and statistical significant decrease in atrial fibrillation symptom burden scores (11.8 and 2.6 points, P b 0.001), as well as symptom severity scores (8.4 and 1.7 points, P b 0.001), number of episodes (2.5 and no change, P = .01), and cumulative duration (692-minute decline and 419-minute increase, P = 0.002). Moreover, there was a reduction in left atrial area (3.5 and 1.9 cm2, P = 0.02). This study demonstrates that weight reduction reduces AF events, AF symptom burden and promotes beneficial cardiac structural changes (decrease in LA volume and septal thickness). However, because weight loss leads to several systemic and metabolic changes, it is impossible to ascribe any specific effect to changes in pericardial fat. Further studies relating changes in pericardial fat, after controlling for changes in other measures of obesity and fitness, are needed to demonstrate a specific benefit of reducing pericardial fat. 3.2. Drugs

Pericardial fat may modulate the activity of the intrinsic autonomic nervous system, which consists of nerves and ganglia contained entirely within the pericardium and enclosed within pericardial fat. Animal models have shown that parasympathetic nerve activity within such fat pads promotes AF pathogenesis primarily by shortening the atrial refractory period [31,32]. As a result, increased pericardial fat could locally influence these autonomic ganglia, enhancing vagal tone and increasing propensity for AF.

Few studies have investigated the effect of oral medication on pericardial fat. A 10% reduction in pericardial fat volume was observed in 27 obese subjects who lost 6% weight on orlistat. However, the effect of orlistat on pericardial fat cannot be precisely determined, as there was no placebo arm or a diet only arm [37] in this study and changes in other obesity measures could not be controlled. Interestingly, statins, including atorvastatin and simvastatin/ezetimibe have been shown to decrease pericardial fat in patients with coronary artery disease [38]. A substudy of the BELLES trial confirmed this beneficial effect of statins in 420 overweight hyperlipidemic post-menopausal women. They reported a greater reduction in pericardial fat (3%) with an intensive therapy of atorvastatin (80 mg/day) compared to pravastatin (40 mg/day), P = 0.02 at one year [39]. A recent meta-analysis and systematic review by Fauchier et al. [40] included thirty-two published studies with 71,005 patients showed the use of statins was significantly associated with a decreased risk of atrial fibrillation in patients with sinus rhythm but did not examine changes in pericardial fat measures. Interestingly, the greatest benefit for statins was seen for the prevention of postoperative atrial fibrillation and in the secondary prevention of atrial fibrillation. Whether this effect may be partially mediated by a decrease in pericardial fat or other pleiotropic effects of statin remains to be seen.

3. Interventions targeting pericardial fat

3.3. Pericardiectomy

3.1. Weight loss

The best interventional evidence that reductions in pericardial fat may reduce AF comes from the cardiac surgery literature. It has been observed that posterior pericardiectomy (PP) during cardiac surgery is associated with important reductions in postoperative AF in multiple studies [41–44]. Biancari et al. [44] preformed a meta-analysis of 6 randomized prospective controlled trials, which studied the association between PP and post-operative AF after coronary artery bypass grafting surgery. They included 763 patients (PP = 389, control = 374). They showed a significant reduction in supraventricular arrhythmia and AF in the PP group (odds ratio 0.31 and 0.33, respectively). The incidence of AF in the PP group was 10.8% (41/379) compared to 28.1% in the

2.3. Autonomic nervous system modulation

Several studies have shown that weight loss may reduce pericardial fat burden. Nakazato et al. [33] analyzed the relationship between epicardial fat volume and weight change in 374 healthy subjects in a 4-year follow-up study. They reported that pericardial fat decreased by 2% with a N 5% weight loss but increased by 23% in patients with N5% weight gain. Iacobellis et al. [34] showed a decrease in epicardial fat thickness in 20 obese subjects who underwent an aggressive 6-month long weight loss program (mean 20 kg) by adhering to a very low-calorie diet (900 kcal/day). Similarly, Willens et al. [35]

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control group (108/384). The number needed to treat with PP procedure was 6 to prevent one case of AF post-CABG. They also demonstrated a reduction of early and late pericardial effusion in the PP group compared to control group and hypothesized that one of the reasons of reduction in AF might be secondary to reduction in postop pericardial effusion/inflammation. An alternative explanation for this benefit might be removal of the posterior pericardial fat pad, which is in close proximity of the pulmonary vein ostia where AF is generated. By removing this potential focus, AF initiation may be reduced. Recently, Pokushalov et al. [45] demonstrated in small randomized pilot study of 60 patients that botulinum toxin injection into the epicardial fat pads prevented recurrences of atrial fibrillation in the postoperative period in patients with prior history of PAF undergoing CABG. AF recurrence was seen in 7% in botulinum toxin group as compared to 30% in the placebo saline group (with no adverse outcome in either group), which suggested a possible neural-mediated (i.e. parasympathetic) mechanism. Based on the available evidence, the American College of Chest Physicians recommends PP to reduce the incidence of AF post-coronary artery bypass graft with a grade B strength recommendation [46]. 4. Current limitations in understanding the role of pericardial fat in atrial fibrillation and future directions Although, there is mounting evidence suggesting a link between pericardial fat and atrial fibrillation, the available evidence to date cannot definitively answer whether pericardial fat is causal or is simply a marker for atrial fibrillation. Several limitations of this review also deserve mention that further limit causal inference and should be addressed in future studies. First, there is marked heterogeneity among the population selected in the various studies including patients scheduled for CABG, those undergoing cardiac CT coronary calcium scoring and others with symptomatic atrial fibrillation prior to AF ablation. Although, the consistent associations across several disparate patient groups may demonstrate that the link between AF and pericardial fat is generalizable across several types of patients, additional studies in both large hospital-based but also communitybased cohorts are needed to validate these associations. Second, methods of quantifying pericardial fat differed across studies and included TTE, cardiac CT, cardiac MRI and PET/CT. Pericardial fat measures based on these modalities and their agreement have not all been validated. It is therefore possible that the accuracy of measuring pericardial fat with some modalities may be suboptimal which could bias associations. Additional work evaluating the most accurate measurement strategies to define a gold-standard methodology would further clarify this issue. In addition, although some studies quantified the entire pericardial fat volume, others only measured a specific fat thickness compartment within the pericardium, which may be more prone to bias without appropriate standardization (and blinding to outcome). Careful description of imaging protocols with clear anatomical coordinates to allow for replication of such measures across studies would also be useful. Third, many studies were retrospective non-randomized single-center studies with small sample sizes. Although recent reports have included larger prospective cohorts, additional prospective validation will be needed. Finally, additional randomized studies (e.g. surgical pericardial fat removal), with larger sample sizes, examining clear pre-specified primary endpoints of long-term AF incidence, will be needed to better understand the causal nature of pericardial fat in AF. 5. Conclusion Pericardial fat may represent a novel risk factor for AF that may be modifiable by lifestyle change, medication or surgery. Given the high prevalence of obesity worldwide [47], that is projected to continue to rise, pericardial fat may be an important mediator of obesity-related

cardiovascular disease, including AF. The available evidence suggests that pericardial fat is associated with AF prevalence, severity and recurrence via several plausible biological mechanisms. Understanding the role of pericardial fat in AF represents an exciting area for future research and may lead to innovative novel interventions to reduce the growing burden of AF. Funding sources None. Disclosures None. References [1] G. Thanassoulis, J.M. Massaro, C.J. O'Donnell, U. Hoffmann, D. Levy, P.T. Ellinor, T.J. Wang, R.B. Schnabel, R.S. Vasan, C.S. Fox, E.J. Benjamin, Pericardial fat is associated with prevalent atrial fibrillation: the Framingham Heart Study, Circ. Arrhythm. Electrophysiol. 3 (2010) 345–350. [2] C.X. Wong, H.S. Abed, P. Molaee, A.J. Nelson, A.G. Brooks, G. Sharma, D.P. Leong, D.H. Lau, M.E. Middeldorp, K.C. Roberts-Thomson, G.A. Wittert, W.P. Abhayaratna, S.G. Worthley, P. 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