1. Introduction
Atrial fibrillation (AF), as a sustained and growing epidemic, is the most common arrhythmia among adults, leading to an increase in mortality and morbidity [
1]. The pathophysiology of AF is caused by asynchronous excitation of the atria, leading to irregularities in both the atrial and ventricular contractions [
2]. Age [
2] and various comorbidities including obesity [
3], type 2 diabetes [
4] obstructive sleep apnea [
5], and alcohol consumption [
6] are recognized as risk factors.
Obesity, which refers to the distribution of total body fat and is measured using body mass index (BMI), is a well-established risk factor for AF [
7]. Excessive body fat, particularly metabolically active visceral fat, increases inflammatory and oxidative stress on the heart, leading to atrial enlargement and electrical instability, predisposing to AF [
8,
9,
10,
11]. Obesity-related expansion of epicardial adipose tissue (EAT), a visceral fat deposit located between the myocardium and epicardium, causes microvascular dysfunction and fibrosis of the underlying myocardium, resulting in atrial myopathy that can lead to AF [
12]. Epicardial fat thickness is associated with metabolic syndromes and an increased risk of cardiovascular diseases [
13]. In-vivo and ex-vivo studies suggest that the accumulation of EAT can also potentially impact the left ventricle (LV) diastolic function [
14,
15,
16]. Moreover, pericardial adipose tissue (PAT), which refers to fat deposits outside the epicardium, causes cardiovascular dysfunction [
17]. An increment in PAT has been linked to a rise in the incidence, severity, and recurrence of AF seen in obesity [
18]. The impact of the fat around the heart and AF remains unclear. Thus, quantifying EAT and PAT are important parameters that can help identify patients who may be at risk for cardiovascular events.
Different imaging modalities can measure cardiac fat deposits, such as cardiac computed tomography (CCT), which was proposed as a gold standard for quantifying the EAT volume. However, due to the significant amount of ionizing radiation, CCT poses a potential health risk to the patient [
19]. This limitation was surmounted by the introduction of cardiac magnetic resonance imaging (MRI), which can measure cardiac function, morphology, perfusion, and myocardial tissue in a single exam with minimal, if any, impact on patients’ health. In the current study, therefore, we aim to assess the factors that influence EAT and PAT fat in AF using cardiac MRI.
The study’s hypotheses are: (1) an increase in BMI and subsequent obesity will be associated with increased cardiac fat deposition; (2) an increase in cardiac fat will have a functional impact on the heart, i.e., LV deterioration; and (3) there will be an increased incidence of AF recurrence in patients with higher cardiac fat deposits. The specific objectives of the study are: (1) to characterize parameters that influence cardiac fat; (2) to assess the effect of cardiac fat on the functional parameters of the heart; and (3) to assess the role of cardiac fat in AF recurrence.
4. Discussion
Our findings indicate that obesity and its subsequent deposition of cardiac fat significantly impacts both the anatomical and functional characteristics of the heart, predisposing to atrial fibrillation. All cardiac fat parameters, including EAT, PAT, and total cardiac fat area, are substantially associated with an increase in BMI. Moreover, an increase in BMI was also associated with a decrease in functionality, as indicated by reduced cardiac indices in obese patients.
Our findings demonstrate that BMI is significantly associated with EAT, PAT, and total cardiac fat area, making obesity pivotal in atrial fibrillation. In the context of cardiovascular diseases, including AF, EAT has been shown to have a direct relationship with obesity and BMI [
21,
22]. The relationship stems from the shared embryological origin of EAT with the epicardial layer of the myocardium, resulting in no connective tissue layer separating the two [
22]. Therefore, excessive deposition of EAT causes direct fibrofatty infiltration and the release of inflammatory mediators such as interleukin-1-beta, interleukin-6, tumor necrosis factor-alpha, and monocyte chemoattractant protein-1 that, via paracrine mechanism, cause atrial fibrosis and AF [
21].
Furthermore, EAT contains abundant ganglionated plexi that might contribute to the recurrence of AF [
23,
24,
25,
26]. In our study, overweight and obese AF patients showed higher recurrence compared to normal. EAT inflammatory activity has been reported as being higher in patients with AF than in controls, and it was shown to be greater in the left main artery than in the subcutaneous or visceral thoracic tissue [
23]. An increased EAT could affect the ganglia function and impact the atrial substrate remodeling, and thereby, the maintenance of AF [
25]. The association of the regional distribution of fat was not evaluated in the current study. However, regional EAT increment may be associated with AF nesting [
25]. The latter remains an important question to address in future studies.
Our study also reveals an association between PAT and BMI in the setting of paroxysmal AF. On the other hand, Wong et al. demonstrated significant associations of PAT with AF presence, severity, and post-ablation outcomes, independent of systemic adiposity measures like BMI and BSA, suggesting that PAT may be a possible independent biomarker of AF [
27]. However, this might be attributable to the use of volume measurements compared to area measurements in our study.
Sex and age also impact cardiac fat and AF. Our findings reveal slight sex differences for EAT and PAT deposition, with male sex having a stronger correlation to PAT area than EAT. In fact, across all BMI groups, males had significantly higher PAT areas compared to females. Men tend to have higher visceral fat deposition, which includes EAT and PAT, whereas women have more subcutaneous fat deposits [
28]. Gill et al. also illustrated that PAT volume is positively associated with BMI and is significantly higher in men than in women. However, in the context of metabolic syndrome and other cardiometabolic risk measures that are similar for various cardiovascular diseases including AF, the association of PAT was found to be stronger in women compared to men [
29]. Nonetheless, sex seems to play less of a role in EAT than PAT, as in our study, there was no significant difference between the area of EAT in the hearts of normal, overweight, or obese males and their female counterparts. Conversely, Zhu et al. demonstrated higher total EAT volume in male AF patients and higher peri-atrial/total EAT ratio in post-menopausal females, alongside a greater rate of post-ablation AF recurrence [
30]. Further exploration into sex differences in cardiac fat deposition is needed.
Advancing age, a well-established AF risk factor, may affect cardiac fat dynamics [
2]. Our results demonstrate significant EAT and PAT area differences in normal-weight patients between age groups 40 and 50 years and over 60 years, suggesting that epicardial fat naturally increases with age. Indeed, previous studies have found EAT to be 22% thicker in patients aged 65 years and older, corroborating the notion of age-related increase [
22,
31]. This could be partially attributed to the hormonal changes that come with aging or to medications that manage comorbid conditions.
With respect to anatomical and functional parameters, we observed that patients’ LV mass significantly increased with obesity and was positively correlated with EAT and PAT. However, when indexed by BSA, LV mass was reduced among obese patients and had no association with cardiac fat. Our data suggest eccentric and not concentric LV changes, indicating increased preload rather than afterload, which might be consistent with increased BMI. This implies that the relationship between LV mass and cardiac fat is influenced by body size adjustment, suggesting that LV mass may be linked to larger body size rather than solely cardiac hypertrophy. This aligns with findings by Nerker et al. and Fox et al., who propose that in the context of CAD, the influence of obesity on cardiac remodeling may overcome the local consequences of both EAT and PAT [
32,
33]. The central obesity and visceral adipose tissue may raise LV afterload, eventually resulting in LV remodeling as a compensatory mechanism, which comprises an increase in LV diameter, volume, and mass [
32]. Thus, it seems that obesity’s impact on LV mass and cardiac structure may extend beyond local cardiac fat deposits.
EAT and PAT in our patient population also exhibited negative correlations with functional aspects such as LV-Cardiac Index (CI), which reflects cardiac output (CO) adjusted by BSA [
34]. Although, to our knowledge, no clear EAT/PAT-CI relationship in the setting of AF has been established, it is recognized that higher BMI is associated with an enlarged left atrium, subsequently increasing stroke volume and CO [
3]. Prolonged elevated output leads to LV enlargement and hypertrophy, eventually resulting in diastolic dysfunction and systolic impairment [
3]. Indeed, AF is known to increase the risk of heart failure along with EAT [
15,
16,
35].
Obese patients with AF tend to be younger than patients with a normal BMI, which was also the case in our patient population. The impact of age may explain our findings, given that age is a key predictor of all-cause mortality in AF [
3]. Moreover, obese patients tend to have more comorbidities, warranting stricter treatment strategies for rhythm control and anticoagulation, potentially influencing their outcomes [
3]. Thus, the roots of the obesity paradox likely stem from the complex interactions of several contributing factors, requiring further exploration in future studies. In our study, EAT did not show an association with AF recurrence. However, other studies have demonstrated that EAT can be associated with AF recurrence [
36].
Our study has certain limitations that warrant consideration. Firstly, this was a single-center investigation, and our findings may not fully represent broader populations. We were limited to the records captured by our local registry. The normal BMI group served as a control group and reference for other BMI groups. An appropriate control match was not conducted. We focused solely on area measurements of EAT and PAT and did not consider volume measurements. The automate machine learning model is only able to quantify EAT and PAT following similar patterns to those used in the training dataset. The latter limited our capacity to define and quantify regions not included in the model. Additionally, due to the constraints of our available data, we were unable to analyze the potential effects of underweight individuals (BMI < 18.5). Although BMI is acknowledged as a significant cardiovascular risk indicator, it must be noted that it is limited in predicting total adiposity due to the contribution of subcutaneous adipose mass [
37].