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EDITORIAL COMMENTARY
Epicardial atrial fat: Not quite as idle as it looks Rishi Arora, MD, FHRS, Bradley P. Knight, MD, FHRS From the Division of Cardiology, Department of Internal Medicine, Northwestern University, Chicago, Illinois. Recent studies have invoked a role of epicardial atrial adipose tissue (EAT) in the creation of the substrate for atrial fibrillation (AF).1 Because there is no physical barrier between the EAT and adjacent myocardium, several investigators have suggested that there may be cross-talk between the 2 tissues, with paracrine processes thought to at least partially underlie the biologic interactions between EAT and its neighboring myocardium.2 The investigations that have examined the association between EAT and AF include studies that demonstrate an association between the volume of EAT and the severity/incidence of AF and whether EAT characteristics contribute to the success or failure of radiofrequency catheter ablation (RFCA) for AF. In a study from the Framingham Heart Study, pericardial fat volume on computed tomographic scan predicted AF risk independent of other measures of adiposity.3 Batal et al4 showed that computed tomography-derived posterior left atria fat thickness was independently associated with AF burden, with a 1-cm increase in this fat deposit thickness being associated with a 6-fold higher risk of AF. Other reports have reported an association of pericardial fat with long-term clinical outcomes after RFCA. Wong et al5 and Nagashima et al6 reported that pericardial fat volume was associated with AF recurrence after RFCA. In a related study, an association was reported between high dominant frequency (DF) sites and EAT locations, with evidence of greater epicardial fat volumes and higher levels of serum inflammatory markers in persistent AF compared to paroxysmal AF.7 Taken together, these studies point toward EAT being a determinant of AF substrate and therefore a potentially viable therapeutic target for rhythm control strategies in AF. In this issue of HeartRhythm, Nakatani et al8 show that high DF sites that overlap with EAT may be contributing to the maintenance of AF.5,7 In patients with persistent and long-standing persistent AF, the investigators performed DF or complex fractionated atrial electrogram (CFAE) ablation after pulmonary vein isolation. Although retrospective analysis of their data revealed that total, left atrial, or right atrial EAT volumes did not influence ablation success Address reprint requests and correspondence: Dr. Bradley P. Knight, Bluhm Cardiovascular Institute of Northwestern, Feinberg School of Medicine, Northwestern University, 251 East Huron St, Feinberg 8-503E, Chicago, IL 60611. E-mail address: [email protected].
(ie, freedom from AF at 12 months), the investigators did note that, in the LA, the overlap between the high DF sites and EAT was larger in the AF-free group than in the AFrecurrence group. Although a retrospective analysis, the study does provide further evidence of the fact that EAT may be involved in the creation of AF substrate in patients with persistent AF. Perhaps more importantly though, the study strongly argues for 1 of the following scenarios: (1) all EAT may not be involved in the maintenance of AF because close EAT–high DF overlap in AF-free patients was noted only in the left and not right atrial sites and/or (2) current electrogram (EGM)-based strategies (eg, DF, CFAE) are not accurate enough to detect the EAT regions that truly are involved in the mechanisms underlying AF maintenance. Therefore, more rigorous prospective studies that incorporate EAT imaging to guide ablation strategy are needed to better define a mechanistic role for EAT in the genesis and maintenance of AF. At the same time, more experimental insights are necessary to determine the precise mechanisms by which EAT contributes to AF substrate formation. A variety of mechanisms have been invoked by which EAT may contribute to AF substrate. These include potentially direct electrophysiologic effects of EAT as well as more “indirect” effects driven by paracrine secretion by EAT of cytokines and other signaling molecules. Inhomogeneity of repolarization and conduction within the atrial myocardium are known to promote the formation of reentry, with loss of epicardial layer continuity (eg, due to endomysial fibrosis) thought to be a major determinant of the complexity of fibrillatory conduction pathways.9 Because EAT accumulation is often associated with fatty infiltration deep into the myocardium, this may contribute to myocardium functional disorganization and the formation of local arrhythmogenic substrate. Indeed, recent data suggest that AF EGMs that overlie fibrofatty tissue in the atrium are more disorganized than AF EGMs that overlie surrounding, nonfatty myocardium.10 A key mechanism by which EAT may contribute to genesis of AF is that epicardial fat harbors large concentrations of autonomic nerves (ie, in the autonomic ganglionated plexi [GP]). In light of several studies demonstrating the role of the autonomic nervous system in the creation of AF substrate, recent years have seen the development of ablative and surgical strategies targeted at 1 or more GPs. GP ablation, alone or together with PV isolation, has been used
1547-5271/$-see front matter B 2014 Published by Elsevier Inc. on behalf of Heart Rhythm Society.
http://dx.doi.org/10.1016/j.hrthm.2014.10.040
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in both paroxysmal and persistent AF with variable success.11,12 Lately, some investigations have suggested that atrial GP sites may correlate with regions of CFAEs,13 with AF EGMs that overlie atrial GP sites demonstrating greater organization with autonomic blockade than AF EGMs elsewhere.10,14 This suggests that AF EGM characteristics may help in the accurate detection of EAT regions that are rich in autonomic nerves. Indeed, it is tempting to speculate that in the current study, the increased overlap noted between high DF sites and EAT in AF-free patients may be partially due to the richer autonomic nerve content of the EAT in these patients. Further investigations are needed to test this hypothesis. In addition to the direct and the autonomic effects of EAT on atrial electrophysiology, EAT may contribute to AF substrate by being actively involved in lipid and energy homeostasis.2 Adipose tissue produces a variety of bioactive adipokines that are thought to affect the functioning of neighboring myocardium in the setting of coronary artery disease, obesity, and diabetes, thereby contributing to the pathogenesis of these diseases. Several of these EATexpressed adipokines are also thought to have a role in the formation of a vulnerable AF substrate. For example, during AF there is increased activity of several matrix metalloproteinases, notably MMP-2 and MMP-7, which likely contributes to accumulation of interstitial fibrosis.15 Therefore, 1 explanation for the relationship between EAT abundance and arrhythmia severity could be that EAT-secreted adipokines contribute to structural remodeling of atrium, such as fibrosis. In addition, EAT may be contributing to AF by secreting inflammatory cytokines and by increasing oxidative stress.16 In summary, it is becoming quite clear that EAT is a “dynamic” organ that is intricately involved with the molecular ion channel and structural regulation of arrhythmogenic substrate in the fibrillating atrium. Although it is likely that EAT is a viable therapeutic target in AF, our current state of knowledge does not allow for effective therapeutic targeting of EAT in patients with AF. A better understanding of the molecular mechanisms underlying EAT–myocardial interaction would help guide the development of safe and effective therapeutic approaches, including more targeted ablation approaches, in patients with AF.
Heart Rhythm, Vol 0, No 0, Month 2014
References 1. Iacobellis G, Corradi D, Sharma AM. Epicardial adipose tissue: anatomic, biomolecular and clinical relationships with the heart. Nat Clin Pract Cardiovasc Med 2005;2:536–543. 2. Hatem SN, Sanders P. Epicardial adipose tissue and atrial fibrillation. Cardiovasc Res 2014;102:205–213. 3. Thanassoulis G, Massaro JM, O’Donnell CJ, Hoffmann U, Levy D, Ellinor PT, Wang TJ, Schnabel RB, Vasan RS, Fox CS, Benjamin EJ. Pericardial fat is associated with prevalent atrial fibrillation: the Framingham Heart Study. Circ Arrhythm Electrophysiol 2010;3:345–350. 4. Batal O, Schoenhagen P, Shao M, Ayyad AE, Van Wagoner DR, Halliburton SS, Tchou PJ, Chung MK. Left atrial epicardial adiposity and atrial fibrillation. Circ Arrhythm Electrophysiol 2010;3:230–236. 5. Wong CX, Abed HS, Molaee P, et al. Pericardial fat is associated with atrial fibrillation severity and ablation outcome. J Am Coll Cardiol 2011;57: 1745–1751. 6. Nagashima K, Okumura Y, Watanabe I, Nakai T, Ohkubo K, Kofune T, Kofune M, Mano H, Sonoda K, Hirayama A. Association between epicardial adipose tissue volumes on 3-dimensional reconstructed CT images and recurrence of atrial fibrillation after catheter ablation. Circ J 2011;75:2559–2565. 7. Nagashima K, Okumura Y, Watanabe I, Nakai T, Ohkubo K, Kofune M, Mano H, Sonoda K, Hiro T, Nikaido M, Hirayama A. Does location of epicardial adipose tissue correspond to endocardial high dominant frequency or complex fractionated atrial electrogram sites during atrial fibrillation? Circ Arrhythm Electrophysiol 2012;5:676–683. 8. Nakatani et al. 9. Eckstein J, Zeemering S, Linz D, Maesen B, Verheule S, van Hunnik A, Crijns H, Allessie MA, Schotten U. Transmural conduction is the predominant mechanism of breakthrough during atrial fibrillation: evidence from simultaneous endoepicardial high-density activation mapping. Circ Arrhythm Electrophysiol 2013;6:334–341. 10. Koduri H, Ng J, Cokic I, Aistrup GL, Gordon D, Wasserstrom JA, Kadish AH, Lee R, Passman R, Knight BP, Goldberger JJ, Arora R. Contribution of fibrosis and the autonomic nervous system to atrial fibrillation electrograms in heart failure. Circ Arrhythm Electrophysiol 2012;5:640–649. 11. Pokushalov E, Romanov A, Artyomenko S, Turov A, Shugayev P, Shirokova N, Katritsis DG. Ganglionated plexi ablation for longstanding persistent atrial fibrillation. Europace 2010;12:342–346. 12. Pokushalov DG E1, Romanov A, Shugayev P, Artyomenko S, Shirokova N, Turov A, Katritsis DG. Selective ganglionated plexi ablation for paroxysmal atrial fibrillation. Heart Rhythm 2009;6:1257–1264. 13. Katritsis D, Giazitzoglou E, Sougiannis D, Voridis E, Po SS. Complex fractionated atrial electrograms at anatomic sites of ganglionated plexi in atrial fibrillation. Europace 2009;11:308–315. 14. Arora R. Recent insights into the role of the autonomic nervous system in the creation of substrate for atrial fibrillation: implications for therapies targeting the atrial autonomic nervous system. Circ Arrhythm Electrophysiol 2012;5:850–859. 15. Boixel C, Fontaine V, Rücker-Martin C, Milliez P, Louedec L, Michel JB, Jacob MP, Hatem SN. Fibrosis of the left atria during progression of heart failure is associated with increased matrix metalloproteinases in the rat. J Am Coll Cardiol 2003;42:336–344. 16. Chung SN MK1, Martin DO, Sprecher D, Wazni O, Kanderian A, Carnes CA, Bauer JA, Tchou PJ, Niebauer MJ, Natale A, Van Wagoner DR. C-reactive protein elevation in patients with atrial arrhythmias: inflammatory mechanisms and persistence of atrial fibrillation. Circulation 2001;104:2886–2891.
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EDITORIAL COMMENTARY
Epicardial atrial fat: Not quite as idle as it looks Rishi Arora, MD, FHRS, Bradley P. Knight, MD, FHRS From the Division of Cardiology, Department of Internal Medicine, Northwestern University, Chicago, Illinois. Recent studies have invoked a role of epicardial atrial adipose tissue (EAT) in the creation of the substrate for atrial fibrillation (AF).1 Because there is no physical barrier between the EAT and adjacent myocardium, several investigators have suggested that there may be cross-talk between the 2 tissues, with paracrine processes thought to at least partially underlie the biologic interactions between EAT and its neighboring myocardium.2 The investigations that have examined the association between EAT and AF include studies that demonstrate an association between the volume of EAT and the severity/incidence of AF and whether EAT characteristics contribute to the success or failure of radiofrequency catheter ablation (RFCA) for AF. In a study from the Framingham Heart Study, pericardial fat volume on computed tomographic scan predicted AF risk independent of other measures of adiposity.3 Batal et al4 showed that computed tomography-derived posterior left atria fat thickness was independently associated with AF burden, with a 1-cm increase in this fat deposit thickness being associated with a 6-fold higher risk of AF. Other reports have reported an association of pericardial fat with long-term clinical outcomes after RFCA. Wong et al5 and Nagashima et al6 reported that pericardial fat volume was associated with AF recurrence after RFCA. In a related study, an association was reported between high dominant frequency (DF) sites and EAT locations, with evidence of greater epicardial fat volumes and higher levels of serum inflammatory markers in persistent AF compared to paroxysmal AF.7 Taken together, these studies point toward EAT being a determinant of AF substrate and therefore a potentially viable therapeutic target for rhythm control strategies in AF. In this issue of HeartRhythm, Nakatani et al8 show that high DF sites that overlap with EAT may be contributing to the maintenance of AF.5,7 In patients with persistent and long-standing persistent AF, the investigators performed DF or complex fractionated atrial electrogram (CFAE) ablation after pulmonary vein isolation. Although retrospective analysis of their data revealed that total, left atrial, or right atrial EAT volumes did not influence ablation success Address reprint requests and correspondence: Dr. Bradley P. Knight, Bluhm Cardiovascular Institute of Northwestern, Feinberg School of Medicine, Northwestern University, 251 East Huron St, Feinberg 8-503E, Chicago, IL 60611. E-mail address: [email protected].
(ie, freedom from AF at 12 months), the investigators did note that, in the LA, the overlap between the high DF sites and EAT was larger in the AF-free group than in the AFrecurrence group. Although a retrospective analysis, the study does provide further evidence of the fact that EAT may be involved in the creation of AF substrate in patients with persistent AF. Perhaps more importantly though, the study strongly argues for 1 of the following scenarios: (1) all EAT may not be involved in the maintenance of AF because close EAT–high DF overlap in AF-free patients was noted only in the left and not right atrial sites and/or (2) current electrogram (EGM)-based strategies (eg, DF, CFAE) are not accurate enough to detect the EAT regions that truly are involved in the mechanisms underlying AF maintenance. Therefore, more rigorous prospective studies that incorporate EAT imaging to guide ablation strategy are needed to better define a mechanistic role for EAT in the genesis and maintenance of AF. At the same time, more experimental insights are necessary to determine the precise mechanisms by which EAT contributes to AF substrate formation. A variety of mechanisms have been invoked by which EAT may contribute to AF substrate. These include potentially direct electrophysiologic effects of EAT as well as more “indirect” effects driven by paracrine secretion by EAT of cytokines and other signaling molecules. Inhomogeneity of repolarization and conduction within the atrial myocardium are known to promote the formation of reentry, with loss of epicardial layer continuity (eg, due to endomysial fibrosis) thought to be a major determinant of the complexity of fibrillatory conduction pathways.9 Because EAT accumulation is often associated with fatty infiltration deep into the myocardium, this may contribute to myocardium functional disorganization and the formation of local arrhythmogenic substrate. Indeed, recent data suggest that AF EGMs that overlie fibrofatty tissue in the atrium are more disorganized than AF EGMs that overlie surrounding, nonfatty myocardium.10 A key mechanism by which EAT may contribute to genesis of AF is that epicardial fat harbors large concentrations of autonomic nerves (ie, in the autonomic ganglionated plexi [GP]). In light of several studies demonstrating the role of the autonomic nervous system in the creation of AF substrate, recent years have seen the development of ablative and surgical strategies targeted at 1 or more GPs. GP ablation, alone or together with PV isolation, has been used
1547-5271/$-see front matter B 2014 Published by Elsevier Inc. on behalf of Heart Rhythm Society.
http://dx.doi.org/10.1016/j.hrthm.2014.10.040
55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108
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in both paroxysmal and persistent AF with variable success.11,12 Lately, some investigations have suggested that atrial GP sites may correlate with regions of CFAEs,13 with AF EGMs that overlie atrial GP sites demonstrating greater organization with autonomic blockade than AF EGMs elsewhere.10,14 This suggests that AF EGM characteristics may help in the accurate detection of EAT regions that are rich in autonomic nerves. Indeed, it is tempting to speculate that in the current study, the increased overlap noted between high DF sites and EAT in AF-free patients may be partially due to the richer autonomic nerve content of the EAT in these patients. Further investigations are needed to test this hypothesis. In addition to the direct and the autonomic effects of EAT on atrial electrophysiology, EAT may contribute to AF substrate by being actively involved in lipid and energy homeostasis.2 Adipose tissue produces a variety of bioactive adipokines that are thought to affect the functioning of neighboring myocardium in the setting of coronary artery disease, obesity, and diabetes, thereby contributing to the pathogenesis of these diseases. Several of these EATexpressed adipokines are also thought to have a role in the formation of a vulnerable AF substrate. For example, during AF there is increased activity of several matrix metalloproteinases, notably MMP-2 and MMP-7, which likely contributes to accumulation of interstitial fibrosis.15 Therefore, 1 explanation for the relationship between EAT abundance and arrhythmia severity could be that EAT-secreted adipokines contribute to structural remodeling of atrium, such as fibrosis. In addition, EAT may be contributing to AF by secreting inflammatory cytokines and by increasing oxidative stress.16 In summary, it is becoming quite clear that EAT is a “dynamic” organ that is intricately involved with the molecular ion channel and structural regulation of arrhythmogenic substrate in the fibrillating atrium. Although it is likely that EAT is a viable therapeutic target in AF, our current state of knowledge does not allow for effective therapeutic targeting of EAT in patients with AF. A better understanding of the molecular mechanisms underlying EAT–myocardial interaction would help guide the development of safe and effective therapeutic approaches, including more targeted ablation approaches, in patients with AF.
Heart Rhythm, Vol 0, No 0, Month 2014
References 1. Iacobellis G, Corradi D, Sharma AM. Epicardial adipose tissue: anatomic, biomolecular and clinical relationships with the heart. Nat Clin Pract Cardiovasc Med 2005;2:536–543. 2. Hatem SN, Sanders P. Epicardial adipose tissue and atrial fibrillation. Cardiovasc Res 2014;102:205–213. 3. Thanassoulis G, Massaro JM, O’Donnell CJ, Hoffmann U, Levy D, Ellinor PT, Wang TJ, Schnabel RB, Vasan RS, Fox CS, Benjamin EJ. Pericardial fat is associated with prevalent atrial fibrillation: the Framingham Heart Study. Circ Arrhythm Electrophysiol 2010;3:345–350. 4. Batal O, Schoenhagen P, Shao M, Ayyad AE, Van Wagoner DR, Halliburton SS, Tchou PJ, Chung MK. Left atrial epicardial adiposity and atrial fibrillation. Circ Arrhythm Electrophysiol 2010;3:230–236. 5. Wong CX, Abed HS, Molaee P, et al. Pericardial fat is associated with atrial fibrillation severity and ablation outcome. J Am Coll Cardiol 2011;57: 1745–1751. 6. Nagashima K, Okumura Y, Watanabe I, Nakai T, Ohkubo K, Kofune T, Kofune M, Mano H, Sonoda K, Hirayama A. Association between epicardial adipose tissue volumes on 3-dimensional reconstructed CT images and recurrence of atrial fibrillation after catheter ablation. Circ J 2011;75:2559–2565. 7. Nagashima K, Okumura Y, Watanabe I, Nakai T, Ohkubo K, Kofune M, Mano H, Sonoda K, Hiro T, Nikaido M, Hirayama A. Does location of epicardial adipose tissue correspond to endocardial high dominant frequency or complex fractionated atrial electrogram sites during atrial fibrillation? Circ Arrhythm Electrophysiol 2012;5:676–683. 8. Nakatani et al. 9. Eckstein J, Zeemering S, Linz D, Maesen B, Verheule S, van Hunnik A, Crijns H, Allessie MA, Schotten U. Transmural conduction is the predominant mechanism of breakthrough during atrial fibrillation: evidence from simultaneous endoepicardial high-density activation mapping. Circ Arrhythm Electrophysiol 2013;6:334–341. 10. Koduri H, Ng J, Cokic I, Aistrup GL, Gordon D, Wasserstrom JA, Kadish AH, Lee R, Passman R, Knight BP, Goldberger JJ, Arora R. Contribution of fibrosis and the autonomic nervous system to atrial fibrillation electrograms in heart failure. Circ Arrhythm Electrophysiol 2012;5:640–649. 11. Pokushalov E, Romanov A, Artyomenko S, Turov A, Shugayev P, Shirokova N, Katritsis DG. Ganglionated plexi ablation for longstanding persistent atrial fibrillation. Europace 2010;12:342–346. 12. Pokushalov DG E1, Romanov A, Shugayev P, Artyomenko S, Shirokova N, Turov A, Katritsis DG. Selective ganglionated plexi ablation for paroxysmal atrial fibrillation. Heart Rhythm 2009;6:1257–1264. 13. Katritsis D, Giazitzoglou E, Sougiannis D, Voridis E, Po SS. Complex fractionated atrial electrograms at anatomic sites of ganglionated plexi in atrial fibrillation. Europace 2009;11:308–315. 14. Arora R. Recent insights into the role of the autonomic nervous system in the creation of substrate for atrial fibrillation: implications for therapies targeting the atrial autonomic nervous system. Circ Arrhythm Electrophysiol 2012;5:850–859. 15. Boixel C, Fontaine V, Rücker-Martin C, Milliez P, Louedec L, Michel JB, Jacob MP, Hatem SN. Fibrosis of the left atria during progression of heart failure is associated with increased matrix metalloproteinases in the rat. J Am Coll Cardiol 2003;42:336–344. 16. Chung SN MK1, Martin DO, Sprecher D, Wazni O, Kanderian A, Carnes CA, Bauer JA, Tchou PJ, Niebauer MJ, Natale A, Van Wagoner DR. C-reactive protein elevation in patients with atrial arrhythmias: inflammatory mechanisms and persistence of atrial fibrillation. Circulation 2001;104:2886–2891.
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