Cardiac visceral fat as anatomic substrate and functional trigger for the development of atrial fibrillation
Atrial Fibrillation (AF) is the most frequent sustained cardiac arrhythmia. It is well known that several risk factors are
associated with AF, such as hypertension, diabetes mellitus and metabolic syndrome, smoking, alcohol, coronary
artery disease (CAD), obstructive sleep apnea, myocardial infarction (MI), heart failure (HF) and obesity. Furthermore,
several pieces of evidence suggest the implication of epicardial adipose tissue (EAT) in the onset of AF. EAT
is the visceral fat depot of the heart, located between the visceral pericardium and the myocardium. In physiologic
conditions, EAT represents a source of antiatherogenic and anti-inflammatory adipokines, shows thermogenic
properties, provides energy, and acts as an immune barrier.
However, in pathologic conditions, EAT may contribute to the anatomical cardiac substrate for the development of
AF. In fact, EAT can produce and secrete pro-inflammatory cytokines, activin A, matrix metalloproteinases-MMPs,
and reactive oxygen species, that are all factors potentially contributing to atrial collagen deposition, fibrosis, and
scar formation. Furthermore, EAT may penetrate the myocardium and generate atrial fatty infiltrates that in turn may
alter the atrial electrophysiological properties.
This review aims to analyze the main mechanisms underlying the role of EAT in the pathogenesis of AF, and the
potential therapeutic strategies targeting the cardiac visceral fat.
PATHOPHYSIOLOGY OF ATRIAL FIBRILLATION IN PATIENTS WITH AND WITHOUT HEART DISEASE
Atrial Fibrillation (AF) is the most frequent sustained cardiac arrhythmia affecting 2.5% of the population worldwide; its prevalence increases with age: 2.3% in people above 40 years, 5.9% after 65 years, and 10% in people above 80 years 1.
The most common symptoms are dyspnea, fatigue, palpitations and angina but, especially in the elderly population, AF can be asymptomatic and diagnosed only for the occurrence of thromboembolic complications 2 3.
Several risk factors are associated with AF: 1) hypertension: the relationship between blood pressure has already been widely demonstrated in the Framingham Heart Study, in which patients with a systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 95 mmHg were more prone to develop AF 4 5; 2) diabetes mellitus and metabolic syndrome: it is known that diabetic cardiomyopathy is associated with changes in sympathetic tone which, in turn, predispose to AF 4 6; 3) smoking: smoke-linked mechanisms, such as oxidative stress and myocardial fibrosis are the direct culprits of AF 4; 4) alcohol: alcohol-related cardiac structural changes, such as dilated cardiomyopathy and electromechanical delay predispose to AF 7; 5) coronary artery disease (CAD): patients with CAD have concomitant conditions predisposing to AF, such as diabetes, hypertension 8; 6) obstructive sleep apnea: changes in intrathoracic pressure cause alterations of cardiac transmural pressure which, in turn, predisposes to AF 9; 7) myocardial infarction (MI): possible mechanisms of post-MI AF include ischemia of the atrial myocardium or the sinus node, myocardial remodeling 10; 8) heart failure (HF): HF related mechanisms predisposing to AF are diastolic dysfunction, electromechanical remodeling of the left atrium, hydrosaline retention and increased sympathetic tone 11-18.
Another very important risk factor for the development of AF is obesity. It is known that obesity is a chronic metabolic disease associated with several conditions such as cardiovascular diseases and type 2 diabetes. Body fat mass is distributed in several depots, localized into two main compartments: subcutaneous (SAT) and visceral (VAT) adipose tissue. The aforementioned deposits predominantly contain white adipose tissue (WAT). WAT is involved in the process of energy production (white adipocytes store excess lipids in the form of triglycerides (TG) and release free fatty acids (FFA) in periods of body energy demand), it synthesizes and releases adipokines which regulate metabolic homeostasis. Moreover, WAT is involved in hormone and cytokines secretion, insulin resistance and vascular diseases.
Brown adipose tissue (BAT) is located in cervical-supraclavicular, perirenal, paravertebral regions and around the major vessels such as aorta. It is involved in the process of energy dissipation by thermogenesis, which occurs through the uncoupling protein-1 (UCP-1), present in the inner membrane of mitochondria, acting through the uncoupled respiration.
Numerous studies have reported the association between obesity and AF, and several hypotheses have been formulated to explain this correlation: patients with increased BMI present with increased left atrial size 19; obesity is associated to a chronic low-grade systemic inflammation contributing to AF development 19, as well as to other pathological conditions potentially associated to cardiovascular complications 20; in obese patients, shorter refractory periods in both left atrial and pulmonary veins have been identified; obesity is associated with atrial inflammation and atrial contractile dysfunction which, in turn, lead to structural remodeling and electrophysiological abnormalities, thus contributing to an arrhythmogenic atrial substrate 21.
ASSOCIATION BETWEEN EPICARDIAL ADIPOSE TISSUE (EAT) AND AF (FIG. 1)
There is accumulating evidence linking EAT to AF. EAT, the visceral fat depot of the heart, is located between the visceral pericardium and the myocardium with absence of fascial boundaries. Cardiac visceral fat is more represented in the atrio-ventricular, inter-ventricular furrows and on the lateral wall of the right ventricle. Therefore, this tissue is anatomically different from the pericardial fat (located inside the parietal pericardium) and from the paracardial fat (located outside the parietal pericardium) 22. From an embryological point of view, EAT derives from the splanchno-pleural mesoderm, while the paracardial fat from the primitive thoracic mesenchyme; their vascularization is also different: EAT is served by the coronary arteries, while the paracardial fat by the branches of the internal mammary artery.
EAT has several functions: it provides mechanical support to coronary arteries, protecting them from tensions and twists. In physiologic conditions, it represents a source of antiatherogenic and anti-inflammatory adipokines, has thermogenic properties, provides energy, acts as an immune barrier and is a source of fatty acids 22.
The quantification of EAT occurs through different imaging methods, such as echocardiography, computerized tomography, magnetic resonance 23. The visualization of EAT by ultrasonography takes place in parasternal long-axis view at the level of the fold of Rindfleish, between the free wall of the right ventricle and the anterior surface of the ascending aorta. There are several pieces of evidence showing a correlation between increased EAT thickness and AF.
Several pathogenetic mechanisms have been proposed on the implication of EAT in the onset of AF: since the proximity of EAT to the underlying myocardium, it can infiltrate the myocardium, thus creating circuits that alter the propagation of the depolarizing wave and generating the return phenomena 24; EAT produces several adipokines that promote myocardial fibrosis: activin A (a member of TGF-β superfamily) and matrix metalloproteinases-MMPs (such as MMP1, MMP2, MMP7, MMP8, MMP9 more abundantly represented than in subcutaneus adipose tissue). Activin A induces synthesis of collagen types I, III and VI, thus promoting a fibrotic effect on atrial myocardium; EAT secretes several inflammatory factors (PCR, IL-6, IL-8, IL-1b, TFN-a) 25 that have local pro-inflammatory effects on atrial myocardium and promote arrythmogenesis 22 26. EAT is a source of reactive oxygen species (ROS) and their production is greater in human EAT than in SAT. In animal models, atrial remodeling is attenuated by inhibition of ROS 22. Ganglionated plexuses have been identified in EAT. In this regard, it is known that the autonomic nervous system is implicated in the initiation of AF and the activation of ganglionated plexuses can cause both parasympathetic and sympathetic stimulation, resulting in shortening of action potential duration that, in turn, plays an important role in the genesis of AF 22. EAT influences triggers, which are areas located near the pulmonary veins having spontaneous, rapid and repetitive electrical activity that can promote AF 22. Inflammatory cells, like macrophages, have been found in EAT: these cells produce cytokines, like connective tissue growth factor (cTGF) that, in turn, stimulate myocardial fibroblasts to produce type I and II collagen 27. Aromatase is an enzymatic protein whose function is to convert androgens into estrogens. It is abundantly expressed in subcutaneous and visceral adipose tissue. Aromatase is also expressed in the myocardium and in EAT, thus indicating the ability of these tissues to synthesize locally estrogens which, in turn, play an important role in modulating electromechanical properties, with consequent susceptibility to atrial arrhythmias. In experimental models, EAT levels of aromatase have been shown to be higher in aged than in young animals 28 29.
ASSOCIATION BETWEEN EAT AND FORMS OF AF
The association between the presence of AF and the amount of EAT is well recognized 30. Recent studies have also identified a stronger relationship between the amount of EAT and the persistence of arrhythmia: from a recent meta-analysis, it is possible to establish that the EAT amount is greater in patients with paroxysmal AF and persistent AF than in healthy subjects. Therefore, these results not only demonstrate the association between EAT amount and AF, but also indicate a correlation with AF severity. The greatest amount of EAT has been found in patients with persistent AF. This finding is in line with the pathophysiological hypothesis, since it reflects the reduced role of EAT in patients with self-limiting AF in whom the triggers (vagal hypertone, gastroesophageal reflux) play an important role compared to the EAT modulator activity 23 31.
ATRIAL FIBRILLATION RECURRENCE AFTER ABLATION: RELATIONSHIP WITH EAT AMOUNT
Ablation is one of the procedures used for the treatment of symptomatic and drug-resistant AF. It consists of the introduction of a catheter in the blood vessels that is pushed up to the heart, canceling the anomalous electrical paths; more precisely this procedure prevents the departure of unwanted electrical currents from the pulmonary veins and their arrival at the atria.
Several scientific pieces of evidence have shown the correlation between EAT and recurrence of atrial fibrillation post ablation. Maeda et al studied fibrillating patients subjected to ablation and stratified the population according to the EAT volume; it was found that recurrent post-ablation AF is more frequent in the group of patients with higher EAT amount, thus demonstrating how EAT volume is an independent predictor of recurrent AF post ablation 32.
In another study, the relationship between EAT volume and early and late post-ablation AF was examined; even in this study, EAT volume resulted as an independent predictor of early but not late post-ablation AF 33. According to the findings of a recent meta-analysis, the EAT measurement, both volume and thickness measurements, seemed to be acceptable strategies for risk stratification of AF recurrence. This meta-analysis showed that total and left atrial-EAT volumes, as well as EAT thickness, were higher in patients with AF recurrence compared to those without AF recurrence after ablation 34.
Overall, these pieces of evidence indicate that the EAT volume can be used as a new imaging marker for the prediction of AF recurrence, together with the already established predictive factors: older age, female gender, classical cardiovascular risk factors, non-paroxysmal AF, left ventricular disfunction, myocardial fibrosis, atrial enlargement.
Given the recognized pathogenetic role of EAT on AF occurrence, it is plausible to hypothesize different therapeutic strategies for AF acting on EAT volume and modulating EAT pro-inflammatory profile in the future.
Botulinum toxin suppresses AF inducibility when injected into EAT in experimental models 37. Accordingly, in patients with paroxysmal AF, botulinum toxin injection into EAT during coronary artery bypass grafting provided atrial tachyarrhythmia suppression both early, as well as at 1-year follow-up 38. Interestingly, the use of statins, such as atorvastatin, is able to reduce the EAT volume and blunt inflammation 39. A recent meta-analysis reported that, in patients with sinus rhythm undergoing cardiac surgeries, perioperative statin therapy was associated with a decrease in the development of postoperative AF 40. Finally, the use of anti-activin antibodies is able to neutralize the EAT pro-fibrotic effect in animal models, thus avoiding negative atrial remodeling 41.
Current epidemiological and clinical studies demonstrate a strong association between EAT and AF. However, many pathophysiological mechanisms are still unexplored and further studies, especially in humans, are required to clarify the causative mechanisms of this association. Additional evidence is also needed regarding the specific roles of different sub-depots of EAT for AF development. Finally, it will be important to define whether EAT quantification may contribute to risk stratification and therapeutic management of AF patients.
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