Cardiac visceral fat as anatomic substrate and functional trigger for the development of atrial fibrillation| JOURNAL OF GERONTOLOGY AND GERIATRICS

Abstract

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.

THERAPEUTIC PERSPECTIVES

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.

In an AF rabbit model associated with heart failure, eicosapentaenoic acid has been shown to increase adiponectin and decrease proinflammatory adipokines, such as TNF-α, in the atrium and EAT ^{35 36}.

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.

CONCLUSIONS

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.

Figures and tables

Figure 1.Role of epicardial adipose tissue in the pathogenesis of atrial fibrillation. Epicardial adipose tissue (EAT) may contribute to the anatomical substrate for the development of atrial fibrillation. In fact, EAT produces and secretes 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 may alter the atrial electrophysiological properties. EAT contains ganglionated plexus and sympathetic fibers. Furthermore, it is a source of endogenous catecholamines. All these factors may contribute to an increased sympathetic tone and to a sympatho-vagal imbalance, thus promoting atrial arrhythmias.

References

1. Karamichalakis N, Letsas KP, Vlachos K. Managing atrial fibrillation in the very alderly patient: challenges and solutions. Vasc Health Risk Manag. 2015; 11:555-62. DOI
2. Pulignano G, Del Sindaco D, Tinti MD. Atrial fibrillation management in older heart failure patients: a complex clinical problem. Heart Int 2016. 2016; 11:e41-9. DOI
3. Kirchhof P, Benussi S, Kotecha D. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur J Cardio-Thoracic Surg. 2016; 50:e1-e88. DOI
4. Pauchal G, Mahmood M, Lip G.. Revisiting the risks of incident atrial fibrillation: a narrative review. Part 1. Kardiol Pol. 2019; 77:430-6. DOI
5. Cacciatore F, Abete P, de Santis D. Mortality and blood pressure in elderly people with and without cognitive impairment. Gerontology. 2005; 51:53-61. DOI
6. Della-Morte D, Palmirotta R, Rehni AK. Pharmacogenomics and pharmacogenetics of thiazolidinediones: role in diabetes and cardiovascular risk factors. Pharmacogenomics. 2014; 15:2063-82. DOI
7. Pauchal G, Mahmood M, Lip G.. Revisiting the risks of incident atrial fibrillation: a narrative review. Part 2. Kardiol Pol. 2019; 77:515-24. DOI
8. Parisi V, Leosco D, Ferro G. The lipid theory in the pathogenesis of calcific aortic stenosis. Nutr Metab Cardiovasc Dis. 2015; 25:519-25. DOI
9. Parisi V, Paolillo S, Rengo G. Sleep-disordered breathing and epicardial adipose tissue in patients with heart failure. Nutr Metab Cardiovasc Dis. 2018; 28:126-32. DOI
10. Romanov A, Martinek M, Purefellner H. Incidence of atrial fibrillation detected by continuous rhythm monitoring after acute myocardial infarction in patients with preserved left ventricular ejection fraction: results of the ARREST study. Europeace. 2018; 20:263-70. DOI
11. Selthofer-Relatic K, Bosnjak I.. Myocardial fat as a part of cardiac visceral adipose tissue: physiological and pathophysiological view. J Endocrinol Invest. 2015; 38:933-9. DOI
12. Parisi V, Rengo G, Perrone-Filardi P. Increased epicardial adipose tissue volume correlates with cardiac sympathetic denervation in patients with heart failure. Circ Res. 2016; 118:1244-53. DOI
13. Ferrara N, Abete P, Corbi G. Insulin-induced changes in beta-adrenergic response: an experimental study in the isolated rat papillary muscle. Am J Hypertens. 2005; 18:348-53. DOI
14. Cacciatore F, Abete P, Mazzella F. Six-minute walking test but not ejection fraction predicts mortality in elderly patients undergoing cardiac rehabilitation following coronary artery bypass grafting. Eur J Prev Cardiol. 2012; 19:1401-9. DOI
15. Ungar A, Galizia G, Morrione A. Two-year morbidity and mortality in elderly patients with syncope. Age Ageing. 2011; 40:696-702. DOI
16. Ungar A, Mussi C, Ceccofiglio A. Etiology of syncope and unexplained falls in elderly adults with dementia: syncope and dementia (SYD) study. J Am Geriatr Soc. 2016; 64:1567-73. DOI
17. Curcio F, Ferro G, Basile C. Biomarkers in sarcopenia: multifactorial approach. Exp Gerontol. 2016; 85:1-8. DOI
18. Martone AM, Bianchi L, Abete P. The incidence of sarcopenia among hospitalized older patients: results from the Glisten study. J Cachexia Sarcopenia Muscle. 2017; 8:907-14. DOI
19. Aronis KN, Wang N, Phillips CL. Associations of obesity and body fat distribution with incident atrial fibrillation in the biracial health aging and body composition cohort of older adults. Am Heart J. 2015; 170:498-505.e2. DOI
20. Ungar A, Galizia G, Morrione A. Two-year morbidity and mortality in elderly patients with syncope. Age Ageing. 2011; 40:696-702. DOI
21. Wong CX, Sun MT, Odutayo A. Associations of epicardial, abdominal, and overall adiposity with atrial fibrillation. Circ Arrhythm Electrophysiol. 2016; 9:1-15. DOI
22. Wong CX, Ganesan AN, Selvanayagam JB. Epicardial fat and atrial fibrillation: current evidence, potential mechanisms, clinical implications, and future directions. Eur Heart J. 2017; 38:1294-302. DOI
23. Gaeta M, Bandera F, Tassinari F.. Is epicardial fat depot associated with atrial fibrillation? A systematic review and meta-analysis. Europace. 2017; 19:747-52. DOI
24. Goudis CA, Vasileiadis IE, Liu T.. Epicardial adipose tissue and atrial fibrillation: pathophysiological mechanisms, clinical implications and potential therapies. Curr Med Res Opin. 2018; 34:1933-43. DOI
25. Parisi V, Rengo G, Pagano G. Epicardial adipose tissue has an increased thickness and is a source of inflammatory mediators in patients with calcific aortic stenosis. Int J Cardiol. 2015; 186:167-9. DOI
26. Iacobellis G, Barbaro G.. The double role of epicardial adipose tissue as pro- and anti-inflammatory organ. Horm Metab Res. 2008; 40:442-5. DOI
27. Wang Q, Xi W, Yin L. Human epicardial adipose tissue cTGF expression is an independent risk factor for atrial fibrillation and highly associated with atrial fibrosis. Sci Rep. 2018; 8:3585. DOI
28. Bernasochi GB, Boon WC, Curl CL. Pericardial adipose and aromatase: a new translational target for aging, obesity and arrhythmogenesis?. J Mol Cell Cardiol. 2017; 111:96-101. DOI
29. Silaghi A, Piercecchi-Marti Grino M. Epicardial adipose tissue extent: relationship with age, body fat distribution, and coronaropathy. Obesity (Silver Spring). 2008; 16:2424-30. DOI
30. Hatem SN, Redheuil A, Gandjbakhch E.. Cardiac adipose tissue and atrial fibrillation: the perils of adiposity. Cardiovasc Res. 2016; 109:502-9. DOI
31. Schotten U, Verheule S, Kirchof P. Pathophysiological mechanisms of atrial fibrillation: a translational appraisal. Physiol Rev. 2011; 91:265-325. DOI
32. Maeda M, Oba K, Yamaguchi S. Usefulness of epicardial adipose tissue volume to predict recurrent atrial fibrillation after radiofrequency catheter ablation. Am J Cardiol. 2018; 122:1694-700. DOI
33. Masuda M, Mizuno H, Enchi Y. Abundant epicardial adipose tissue surrounding the left atrium predicts early rather than late recurrence of atrial fibrillation after catheter ablation. J Interv Card Electrophysiol. 2015; 44:31-7. DOI
34. Sepehri Shamloo A, Dagres N, Dinov B. Is epicardial fat tissue associated with atrial fibrillation recurrence after ablation? A systematic review and meta-analysis. Int J Cardiol Heart Vasc. 2019; 22:132-8. DOI
35. Kitamura K, Shibata R, Tsuji Y. Eicosapentaenoic acid prevents atrial fibrillation associated with heart failure in a rabbit model. Am J Physiol Heart Circ Physiol. 2011; 300:H1814-21. DOI
36. Walker ME, Matthan NR, Goldbaum A.. Dietary patterns influence epicardial adipose tissue fatty acid composition and inflammatory gene expression in the Ossabaw pig. J Nutr Biochem. 2019; 70:138-46. DOI
37. Oh S, Choi EK, Zhang Y. Botulinum toxin injection in epicardial autonomic ganglia temporarily suppresses vagally mediated atrial fibrillation. Circ Arrhythm Electrophysiol. 2011; 4:560-5. DOI
38. Pokushalov E, Kozlov B, Romanov A. Long-term suppression of atrial fibrillation by botulinum toxin injection into epicardial fat pads in patients undergoing cardiac surgery: one-year follow-up of a randomized pilot study. Circ Arrhythm Electrophysiol. 2015; 8:1334-41. DOI
39. Parisi V, Petraglia L, D’Esposito V. Statin therapy modulates thickness and inflammatory profile of human epicardial adipose tissue. Int J Cardiol. 2019; 274:326-30. DOI
40. Rezaei Y, Gholami-Fesharaki M, Dehghani MR. Statin antiarrhythmic effect on atrial fibrillation in statin-naive patients undergoing cardiac surgery: a meta-analysis of randomized controlled trials. J Cardiovasc Pharmacol Ther. 2016; 21:167-76. DOI
41. Venteclef N, Guglielmi V, Balse E. Human epicardial adipose tissue induces fibrosis of the atrial myocardium through the secretion of adipo-fibrokines. Eur Heart J. 2015; 36:795-805. DOI