Introduction: The aim of this study was to describe our experience and outcome of ablation therapy of arrhythmias in children at a tertiary care center. Methods: Data was collected retrospectively from the hospital medical records. All children presenting to AUBMC between 2000 and 2020 who underwent cardiac ablation were included. The data collected included type of arrhythmia, ablation technique, age and weight at ablation, procedure complications, medications used, and outcome assessment. Results: We had 67 patients who underwent cardiac ablation. Of those, 60% were males with a mean age of 15 years. Structural heart disease was present in 6% of patients. Wolff-Parkinson-White syndrome (WPW) was most prevalent at 31%, followed by atrioventricular nodal reentrant tachycardia (AVNRT) at 24%, atrioventricular reentrant tachycardia (AVRT) at 19%, ventricular tachycardia (VT) at 10%, atrial fibrillation (AF) at 2%, and atrial tachycardia (AT) at 1%. The remaining 13% of patients presented with less common types of arrhythmias, including narrow complex tachycardia, retrograde dual atrioventricular nodal reentry, premature ventricular contractions (PVC), and orthodromic reciprocating tachycardia. Antiarrhythmic medications were started prior to the procedure in 59% of our population. Medication regimens post-ablation included beta blockers (68%), type 1c antiarrhythmics (25%), calcium channel blockers (3%), ivabradine (2%), and amiodarone (2%). The completed procedures showed a success rate of 93%. Conclusion: Ablation of arrhythmias in children is an effective procedure in the treatment of childhood arrhythmias. More studies are needed on cardiac ablation in children with structural heart disease in the Middle East region.

Intro: Atrial fibrillation (AF) is the most frequently diagnosed arrhythmia in practice. Current guidelines on management of AF suggest that patients should be treated with antiarrhythmic drugs (AAD) as first-line therapy, our meta-analysis aims to assess the benefit of using of Cryoablation as a first line therapy for people with atrial fibrillation. Methods: We conducted an electronic search using Medline, Embase, CINAHL and google scholar along with other clinical trial registries. Results: 2 studies out of 9,244 studies fit our eligibility criteria. A total of 521 subjects were included in both studies and 4 distinct meta-analyses were performed. In terms of recurrence CA was superior to AAD with a RR of 0.6. For serious adverse events CA was also superior to AAD with a RR of 0.66 and for treatment related SAE the results were insignificant. Conclusion: CA proved to be superior in terms of recurrence and adverse effects versus AAD.

Safety and Effect on Length of Stay of Intravenous Sotalol Initiation for Arrhythmia ManagementDiane H. Rizkallah, BS; Marwan M. Refaat, MDDivision of Cardiology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, LebanonRunning Title: Safety and Effect on LOS of IV SotalolWords: 598 (excluding the title page and references)Keywords: Heart Diseases, Cardiovascular Diseases, Cardiac Arrhythmias, Safety, Length of StayFunding: NoneDisclosures: NoneCorresponding Author:Marwan M. Refaat, MD, FACC, FAHA, FHRS, FRCPTenured Professor of MedicineTenured Professor of Biochemistry and Molecular GeneticsVan Dyck Medical Educator and Director of the Cardiovascular Fellowship ProgramDepartment of Internal Medicine, Cardiovascular Medicine/Cardiac ElectrophysiologyAmerican University of Beirut Faculty of Medicine and Medical CenterPO Box 11-0236, Riad El-Solh 1107 2020- Beirut, LebanonUS Address: 3 Dag Hammarskjold Plaza, 8th Floor, New York, NY 10017, USAOffice: +961-1-350000/+961-1-374374 Extension 5353 or Extension 5366 (Direct)Email: [email protected] is a class III antiarrhythmic drug with beta-adrenergic blocking activity, used to manage both supraventricular and ventricular arrhythmias. It is available in both oral and intravenous formulations[1]. The FDA approved intravenous Sotalol in March 2020. Sotalol is known to cause QTc prolongation with serum sotalol concentration linearly correlating with QTc length regardless of the route of administration [2,3], with women being at higher risk than men[4]. QTc interval prolongation is one of many parameters that is associated with cardiovascular mortality [5]. QTc prolongation may lead to polymorphic ventricular tachycardia/Torsade de Pointes which is a potentially lethal condition that is acquired from medications or due to an underlying channelopathy predisposing to sudden cardiac arrest[6]. Additional adverse effects of sotalol may include hypotension, bradycardia and AV block[7,8]. Nevertheless, since its approval, IV sotalol has been successfully and safely used in both adult and pediatric patient populations for the management of arrhythmias in acute and chronic settings [9,10,11,12]. Initiation of sotalol therapy with PO loading requires 5 successive oral doses over a 3-day hospital stay for monitoring, at an estimated cost of $2931.55 per day [13]. In 2020, a protocol for IV loading of sotalol was developed using data modeling. This protocol was hypothesized to allow a significant reduction in the length of hospitalization, and thus in the incurred costs[14]. However, there has not been any large-scale implementation of this protocol, nor any comparison of its safety profile and efficacy to that of the traditional oral loading protocol.This study by Liu et al. is a nonrandomized clinical trial in which 29 patients underwent IV sotalol loading. They were compared by chart review to 20 patients who underwent PO sotalol loading in the same timeframe. The indication for sotalol initiation in both cases was for primary atrial or ventricular arrhythmias. The study’s main aim was to assess the safety profile of IV sotalol loading while comparing the length of hospitalization to that required for PO sotalol loading. The same exclusion and inclusion criteria were applied to both groups. Notably, patients with significantly depressed LVEF and creatinine clearance were excluded. The study revealed that safety outcomes were similar in both groups but that IV sotalol loading led to significantly shorter hospital stays. It also found that QT or QTc in patients receiving IV sotalol was similar at the conclusion of the one-hour infusion to that at discharge.These findings support the use of IV loading for sotalol initiation, as they suggest it requires shorter hospital stays than PO loading with similar safety profiles. As shorter hospital stays translate into lower patient days, lower costs, and these results suggest IV sotalol loading is more cost-efficient than its oral counterpart. They also suggest that the maximal increase in QT or QTc length following sotalol initiation is attained by the end of IV loading, thus indicating that patients may be discharged within less than 24 hours of drug initiation.While this study offered valuable insight, its design had significant limitations. Firstly, this was not a randomized clinical trial. A comparison of baseline characteristics between the two populations studied revealed a significantly higher proportion of females in the oral group, which may have inherently skewed outcomes related to QT and QTc length.Secondly, the sample size was small, with no long-term follow-up. Lastly, patients with significantly depressed GFR or LVEF, particularly prone to developing adverse effects with sotalol use, were excluded from the study. Randomized clinical trials examining the short-term and long-term safety of IV sotalol loading and the optimal length of hospitalization are needed, and such efforts are already underway.References:Batul, S. A., & Gopinathannair, R. (2017). Intravenous Sotalol - Reintroducing a Forgotten Agent to the Electrophysiology Therapeutic Arsenal. Journal of atrial fibrillation , 9 (5), 1499. https://doi.org/10.4022/jafib.1499Somberg, J. C., Preston, R. A., Ranade, V., & Molnar, J. (2010). QT prolongation and serum sotalol concentration are highly correlated following intravenous and oral sotalol. Cardiology , 116 (3), 219–225. https://doi.org/10.1159/000316050Barbey, J. T., Sale, M. E., Woosley, R. L., Shi, J., Melikian, A. P., & Hinderling, P. H. (1999). Pharmacokinetic, pharmacodynamic, and safety evaluation of an accelerated dose titration regimen of sotalol in healthy middle-aged subjects. Clinical pharmacology and therapeutics , 66 (1), 91–99. https://doi.org/10.1016/S0009-9236(99)70058-5Somberg, J. C., Preston, R. A., Ranade, V., Cvetanovic, I., & Molnar, J. (2012). Gender differences in cardiac repolarization following intravenous sotalol administration. Journal of cardiovascular pharmacology and therapeutics , 17 (1), 86–92. https://doi.org/10.1177/1074248411406505Al-Kindi SG, Refaat M, Jayyousi A, Asaad N, Al Suwaidi J, Abi Khalil C. Red Cell Distribution Width is Associated with All-Cause and Cardiovascular Mortality in Patients with Diabetes. Biomed Res Int 2017; 2017: 5843702Refaat MM, Hotait M, Tseng ZH: Utility of the Exercise Electrocardiogram Testing in Sudden Cardiac Death Risk Stratification.Ann Noninvasive Electrocardiol 2014; 19(4): 311-318.Marill, K. A., & Runge, T. (2001). Meta-analysis of the Risk of Torsades de Pointes in patients treated with intravenous racemic sotalol. Academic emergency medicine,  8 (2), 117–124. https://doi.org/10.1111/j.1553-2712.2001.tb01275.xMacNeil, D. J., Davies, R. O., & Deitchman, D. (1993). Clinical safety profile of sotalol in the treatment of arrhythmias. The American journal of cardiology , 72 (4), 44A–50A. https://doi.org/10.1016/0002-9149(93)90024-7Malloy-Walton, L. E., Von Bergen, N. H., Balaji, S., Fischbach, P. S., Garnreiter, J. M., Asaki, S. Y., Moak, J. P., Ochoa, L. A., Chang, P. M., Nguyen, H. H., Patel, A. R., Kirk, C., Sherman, A. K., Avari Silva, J. N., & Saul, J. P. (2022). IV Sotalol Use in Pediatric and Congenital Heart Patients: A Multicenter Registry Study. Journal of the American Heart Association , 11 (9), e024375. https://doi.org/10.1161/JAHA.121.024375Borquez, A. A., Aljohani, O. A., Williams, M. R., & Perry, J. C. (2020). Intravenous Sotalol in the Young: Safe and Effective Treatment With Standardized Protocols. JACC. Clinical electrophysiology , 6 (4), 425–432. https://doi.org/10.1016/j.jacep.2019.11.019Kerin, N. Z., & Jacob, S. (2011). The efficacy of sotalol in preventing postoperative atrial fibrillation: a meta-analysis. The American journal of medicine , 124 (9), 875.e1–875.e8759. https://doi.org/10.1016/j.amjmed.2011.04.025Milan, D. J., Saul, J. P., Somberg, J. C., & Molnar, J. (2017). Efficacy of Intravenous and Oral Sotalol in Pharmacologic Conversion of Atrial Fibrillation: A Systematic Review and Meta-Analysis. Cardiology , 136 (1), 52–60. https://doi.org/10.1159/000447237Varela, D. L., Burnham, T. S., T May, H., L Bair, T., Steinberg, B. A., B Muhlestein, J., L Anderson, J., U Knowlton, K., & Jared Bunch, T. (2022). Economics and outcomes of sotalol in-patient dosing approaches in patients with atrial fibrillation. Journal of cardiovascular electrophysiology , 33 (3), 333–342. https://doi.org/10.1111/jce.15342Somberg, J. C., Vinks, A. A., Dong, M., & Molnar, J. (2020). Model-Informed Development of Sotalol Loading and Dose Escalation Employing an Intravenous Infusion. Cardiology research , 11 (5), 294–304. https://doi.org/10.14740/cr1143

Pulmonary Vein Isolation-induced Vagal Nerve Injury and Gastric Motility DisordersBachir Lakkiss, MD; Marwan M. Refaat, MDDivision of Cardiology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, LebanonRunning Title: PVI-induced vagal nerve injury and gastric motility disordersWords: 665 (excluding the title page and references)Keywords: Heart Diseases, Cardiovascular Diseases, Cardiac Arrhythmias, Atrial Fibrillation, Catheter Ablation, Pulmonary Vein IsolationFunding: NoneDisclosures: NoneCorresponding Author:Marwan M. Refaat, MD, FACC, FAHA, FHRS, FRCPTenured Professor of MedicineTenured Professor of Biochemistry and Molecular GeneticsVan Dyck Medical Educator and Director of the Cardiovascular Fellowship ProgramDepartment of Internal Medicine, Cardiovascular Medicine/Cardiac ElectrophysiologyAmerican University of Beirut Faculty of Medicine and Medical CenterPO Box 11-0236, Riad El-Solh 1107 2020- Beirut, LebanonUS Address: 3 Dag Hammarskjold Plaza, 8th Floor, New York, NY 10017, USAOffice: +961-1-350000/+961-1-374374 Extension 5353 or Extension 5366 (Direct)Email: [email protected] fibrillation (AF) is the most prevalent heart rhythm abnormality worldwide. An estimated three to six million people in the United States have AF. It is expected that this number is likely to double by 2050, making AF a significant public health burden. (1) AF is a leading cause of stroke and thromboembolism and is associated with a reduced quality of life. (2) Furthermore, it is linked to an increased mortality in both men and women, with an OR for death of 1.5 in men and 1.9 in women. (3) Medical expenditures for AF are significant, ranging from an annual cost of $1,632 to $21,099, with acute care accounting for the largest cost component in addition to anticoagulation therapy, which accounted for almost one-third of these costs. (4) The four pillars of AF management include rhythm control, rate control, stroke prevention and risk factor management. (5, 6) While antiarrhythmic drugs are used in some patients for AF rhythm control, AF ablation using pulmonary vein isolation (PVI) is regarded as the major modality for rhythm control. (6)The vagal nerve provides most of the parasympathetic innervation to the abdominal organs, including the stomach, esophagus, and a significant portion of the intestines. It serves a major role in the regulation of gastric and esophageal motility, in addition to maintaining lower esophageal sphincter tone. (7-9) Due to the relatively close vicinity of the vagal nerve plexus located on the anterior surface of the esophagus and the left atrial posterior wall, the thermal energy utilized during ablation can result in uncommon but potentially fatal complications such as esophageal perforation and atrial-esophageal fistula formation. (10-12) In addition, radiofrequency ablation for AF is associated with non-fatal complications such as an increased risk of gastric motility disorders and acid reflux. (13, 14)In the current issue of the Journal of Cardiovascular Electrophysiology, Meininghaus et al. recruited 85 patients to assess the incidence of ablation-induced vagal nerve injury (VNI) using both cryoballoon and radiofrequency ablation. Although many cases of VNI induced by PVI have been documented previously, this is one of the first studies to utilize electrophysiologic measurements of gastric motility (EGG) using cutaneous electrodes to record the electrical activity of the stomach two days prior to and two days after the procedure. (15-17) Moreover, the authors have used endoscopy to detect lesions such as erosions, ulcers, and perforations in the esophagus one week prior to and within two days of the procedure.The findings from this study add to our understanding of one of the complications of PVI in patients with AF (13, 14). One of the key outcomes the researchers observed was the perceived direct link between VNI and preexisting esophageal vulnerability. The authors have found that patients who had preexisting esophagitis had an elevated risk of developing VNI. In addition, the authors identified that in patients in whom EGG showed VNI, the elevated risk of ablation-induced endoscopic pathology was present in the post-procedure endoscopy. Furthermore, another significant finding was the detection of VNI on EGG in approximately one-third of PVI patients, irrespective of energy source, whether high power short duration, or moderate power moderate duration. These findings did not corroborate other studies, which showed that titration of the duration of the ablation energy could prevent VNI in patients undergoing AF ablation. (18)Overall, the authors should be commended for their tremendous efforts in attempting to understand the intricate pathophysiology and the association of esophageal lesions, atrial-esophageal fistula formation, and vagal nerve injury following PVI using EGG. Certainly, the results of this study have tremendous clinical implications. EGG could have a very important role in the prevention of atrial-esophageal fistula formation in the future. The article had a few limitations, mainly that the results were from a single-center study. Further studies incorporating additional patients from different medical centers should be conducted to better understand the complex pathophysiology of vagal nerve injury and gastric motility disorders following PVI. Advances in esophageal protection technologies will help in decreasing esophageal lesions during PVI. (19-20)References1. Miyasaka Y, Barnes ME, Gersh BJ, Cha SS, Bailey KR, Abhayaratna WP, et al. Secular Trends in Incidence of Atrial Fibrillation in Olmsted County, Minnesota, 1980 to 2000, and Implications on the Projections for Future Prevalence. Circulation. 2006;114(2):119-25. doi: doi:10.1161/CIRCULATIONAHA.105.595140.2. Jalloul Y, Refaat MM. IL-6 Rapidly Induces Reversible Atrial Electrical Remodeling by Downregulation of Cardiac Connexins. J Am Heart Assoc. 2019;8(16):e013638. Epub 2019/08/20. doi: 10.1161/jaha.119.013638. PubMed PMID: 31423871; PubMed Central PMCID: PMCPMC6759896.3. Benjamin EJ, Wolf PA, D’Agostino RB, Silbershatz H, Kannel WB, Levy D. Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation. 1998;98(10):946-52. Epub 1998/09/16. doi: 10.1161/01.cir.98.10.946. PubMed PMID: 9737513.4. Wodchis WP, Bhatia RS, Leblanc K, Meshkat N, Morra D. A review of the cost of atrial fibrillation. Value Health. 2012;15(2):240-8. Epub 2012/03/22. doi: 10.1016/j.jval.2011.09.009. PubMed PMID: 22433754.5. Lakkis B, Refaat MM. Is esophageal temperature management needed during cryoballoon ablation for atrial fibrillation? Journal of Cardiovascular Electrophysiology. 2022;33(12):2567-8. doi: https://doi.org/10.1111/jce.15725.6. Chung MK, Refaat M, Shen W-K, Kutyifa V, Cha Y-M, Di Biase L, et al. Atrial Fibrillation: JACC Council Perspectives. Journal of the American College of Cardiology. 2020;75(14):1689-713. doi: https://doi.org/10.1016/j.jacc.2020.02.025.7. Richards WG, Sugarbaker DJ. Neuronal control of esophageal function. Chest Surg Clin N Am. 1995;5(1):157-71. Epub 1995/02/01. PubMed PMID: 7743145.8. Hsu M, Safadi AO, Lui F. Physiology, Stomach. StatPearls. Treasure Island (FL): StatPearls PublishingCopyright © 2022, StatPearls Publishing LLC.; 2022.9. Goyal RK, Chaudhury A. Physiology of normal esophageal motility. J Clin Gastroenterol. 2008;42(5):610-9. Epub 2008/03/28. doi: 10.1097/MCG.0b013e31816b444d. PubMed PMID: 18364578; PubMed Central PMCID: PMCPMC2728598.10. Kapur S, Barbhaiya C, Deneke T, Michaud GF. Esophageal Injury and Atrioesophageal Fistula Caused by Ablation for Atrial Fibrillation. Circulation. 2017;136(13):1247-55. doi: doi:10.1161/CIRCULATIONAHA.117.025827.11. D’Avila A, Ptaszek LM, Yu PB, Walker JD, Wright C, Noseworthy PA, et al. Images in cardiovascular medicine. Left atrial-esophageal fistula after pulmonary vein isolation: a cautionary tale. Circulation. 2007;115(17):e432-3. Epub 2007/05/02. doi: 10.1161/circulationaha.106.680181. PubMed PMID: 17470703.12. Sánchez-Quintana D, Cabrera JA, Climent V, Farré J, Mendonça MCd, Ho SY. Anatomic Relations Between the Esophagus and Left Atrium and Relevance for Ablation of Atrial Fibrillation. Circulation. 2005;112(10):1400-5. doi: doi:10.1161/CIRCULATIONAHA.105.551291.13. Shah D, Dumonceau J-M, Burri H, Sunthorn H, Schroft A, Gentil-Baron P, et al. Acute Pyloric Spasm and Gastric Hypomotility: An Extracardiac Adverse Effect of Percutaneous Radiofrequency Ablation for Atrial Fibrillation. Journal of the American College of Cardiology. 2005;46(2):327-30. doi: https://doi.org/10.1016/j.jacc.2005.04.030.14. Park S-Y, Camilleri M, Packer D, Monahan K. Upper gastrointestinal complications following ablation therapy for atrial fibrillation. Neurogastroenterology & Motility. 2017;29(11):e13109. doi: https://doi.org/10.1111/nmo.13109.15. Choi SW, Kang SH, Kwon OS, Park HW, Lee S, Koo BS, et al. A case of severe gastroparesis: indigestion and weight loss after catheter ablation of atrial fibrillation. Pacing Clin Electrophysiol. 2012;35(3):e59-61. Epub 2010/10/05. doi: 10.1111/j.1540-8159.2010.02912.x. PubMed PMID: 20883511.16. Lakkireddy D, Reddy YM, Atkins D, Rajasingh J, Kanmanthareddy A, Olyaee M, et al. Effect of atrial fibrillation ablation on gastric motility: the atrial fibrillation gut study. Circ Arrhythm Electrophysiol. 2015;8(3):531-6. Epub 2015/03/17. doi: 10.1161/circep.114.002508. PubMed PMID: 25772541.17. Kuwahara T, Takahashi A, Takahashi Y, Kobori A, Miyazaki S, Takei A, et al. Clinical characteristics and management of periesophageal vagal nerve injury complicating left atrial ablation of atrial fibrillation: lessons from eleven cases. J Cardiovasc Electrophysiol. 2013;24(8):847-51. Epub 2013/04/05. doi: 10.1111/jce.12130. PubMed PMID: 23551640.18. KUWAHARA T, TAKAHASHI A, KOBORI A, MIYAZAKI S, TAKAHASHI Y, TAKEI A, et al. Safe and Effective Ablation of Atrial Fibrillation: Importance of Esophageal Temperature Monitoring to Avoid Periesophageal Nerve Injury as a Complication of Pulmonary Vein Isolation. Journal of Cardiovascular Electrophysiology. 2009;20(1):1-6. doi: https://doi.org/10.1111/j.1540-8167.2008.01280.x.19. D’Avila A, Ptaszek LM, Yu PB, Walker JD, Wright C, Noseworthy PA, Myers A, Refaat M, Ruskin JN: Left Atrial-Esophageal Fistula After Pulmonary Vein Isolation. Circulation May 2007; 115(17): e432-3.20. El Moheb MN, Refaat MM. Protecting the Esophagus During Catheter Ablation: Evaluation of a Novel Vacuum Suction-Based Retractor. J Cardiovasc Electrophysiol Jul 2020; 31 (7): 1670-1671.

Is Esophageal Temperature Management Needed During Cryoballoon Ablation for Atrial Fibrillation?Bachir Lakkis MD, Marwan M. Refaat, MDDivision of Cardiology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, LebanonRunning Title: Is Esophageal Temperature Management Needed During CBA for AF?Words: (excluding the title page and references): 462Keywords: Catheter Ablation, Atrial Fibrillation, Heart Diseases, Cardiovascular Diseases, Cardiac ArrhythmiasFunding: NoneDisclosures: NoneCorresponding Author:Marwan M. Refaat, MD, FACC, FAHA, FHRS, FASE, FESC, FACP, FAAMATenured Professor of MedicineDirector, Cardiovascular Fellowship ProgramDepartment of Internal Medicine, Cardiovascular Medicine/Cardiac ElectrophysiologyDepartment of Biochemistry and Molecular GeneticsAmerican University of Beirut Faculty of Medicine and Medical CenterPO Box 11-0236, Riad El-Solh 1107 2020- Beirut, LebanonUS Address: 3 Dag Hammarskjold Plaza, 8th Floor, New York, NY 10017, USAOffice: +961-1-350000/+961-1-374374 Extension 5353 or Extension 5366 (Direct)Atrial fibrillation (AF) is one of the most frequently occurring arrhythmias globally. Risk factors such as aging, hypertension, cardiac and pulmonary diseases, alcohol consumption, smoking, obesity and obstructive sleep apnea play an important role in the development of AF.(1-2) AF is a leading cause of ischemic stroke worldwide and is associated with increased mortality. (3) AF management depends on four pillars: risk factor management, anticoagulation depending on the CHA₂DS₂-VASc score, rate control and rhythm control. (4) The application of thermal energy in ablation, such as in cryoablation, can cause rare complications such as an esophageal injury, esophageal perforation and atrial-esophageal fistula. (5,6). Numerous technologies have been developed to avoid this problem and include esophageal temperature surveillance, using reduced temperatures, real time visualization of the esophagus in addition to making use of an esophageal cooling device. (7-9)In the current issue of the Journal of Cardiovascular Electrophysiology, Sink et al. have conducted a single-center pilot study to assess the utilization of an esophageal warming device to avoid the development of esophageal thermal injury (ETI) while utilizing cryoballoon ablation (CBA). Alternative studies have shown that using a cooling device has been beneficial in reducing the risk of ETI formation for patients undergoing RFA. (10,11) Thus, the authors have enrolled 42 patients undergoing CBA with AF refractory to medical therapy and have randomized them into 2 groups. In the first group, 23 patients undergoing CBA used an esophageal warming device such as esophageal heat-exchange tube (WRM) while the other 19 patients undergoing CBA used traditional luminal esophageal temperature (LET) to monitor the esophageal temperatures. The authors have conducted upper endoscopy monitoring of the esophagus the next day and subsequently, classified ETI into 4 grades. They have observed in the WRM group a paradoxical increase in ETI in comparison to the other group which used LET. Moreover, the authors have perceived a direct link between ETI formation, total freeze time and colder temperature usage. However, this study has several limitations, including the small population size. Furthermore, the study results are based on a single device employment which is EnsoETM® device (Attune Medical, Chicago, IL). Therefore, the effects of using other warming devices are not known.Overall, the authors should be praised on their efforts for conducting the first pilot study to evaluate the effects of using an esophageal warming device for patients undergoing CBA and for providing cardinal insight into the safety of utilizing such a device. In addition, the results of this study have tremendous clinical implications. Certainly, patients undergoing CBA might benefit from using higher temperature (above -51 °) and lower freezing time (<300 seconds) to avert developing ETI. Further studies incorporating more patients should be conducted to elucidate whether using an esophageal warming device is associated with a beneficial or a detrimental effect.References1. Kornej J, Börschel CS, Benjamin EJ, Schnabel RB. Epidemiology of Atrial Fibrillation in the 21st Century. Circulation Research. 2020;127(1):4-20. doi: doi:10.1161/CIRCRESAHA.120.316340.2. Maan A, Mansour M, Anter E, Patel VV, Cheng A, Refaat MM, Ruskin JN, Heist EK. Obstructive Sleep Apnea and Atrial Fibrillation: Pathophysiology and Implications for Treatment. Crit Pathw Cardiol Jun 2015; 14 (2): 81-5.3. Migdady I, Russman A, Buletko AB. Atrial Fibrillation and Ischemic Stroke: A Clinical Review. Semin Neurol. 2021;41(04):348-64.4. Chung MK, Refaat M, Shen WK, Kutyifa V, Cha YM, Di Biase L, Baranchuk A, Lampert R, Natale A, Fisher J, Lakkireddy DR. Atrial Fibrillation: JACC Council Perspectives. J Am Coll Cardiol. Apr 2020; 75 (14): 1689-1713.5. Kapur S, Barbhaiya C, Deneke T, Michaud GF. Esophageal Injury and Atrioesophageal Fistula Caused by Ablation for Atrial Fibrillation. Circulation. 2017;136(13):1247-55. doi: doi:10.1161/CIRCULATIONAHA.117.025827.6. D’Avila A, Ptaszek LM, Yu PB, Walker JD, Wright C, Noseworthy PA, Myers A, Refaat M, Ruskin JN: Left Atrial-Esophageal Fistula After Pulmonary Vein Isolation. Circulation May 2007; 115(17): e432-3.7. Dagres N, Anastasiou-Nana M. Prevention of atrial-esophageal fistula after catheter ablation of atrial fibrillation. Curr Opin Cardiol. 2011 Jan;26(1):1-5. doi: 10.1097/HCO.0b013e328341387d. PMID: 21099683.8. Leung LW, Gallagher MM, Santangeli P, Tschabrunn C, Guerra JM, Campos B, Hayat J, Atem F, Mickelsen S, Kulstad E. Esophageal cooling for protection during left atrial ablation: a systematic review and meta-analysis. J Interv Card Electrophysiol. 2020 Nov;59(2):347-355. doi: 10.1007/s10840-019-00661-5. Epub 2019 Nov 22. PMID: 31758504; PMCID: PMC7591442.9. Arruda, M.S., Armaganijian, L., Base, L.D., Rashidi, R. and Natale, A. (2009), Feasibility and Safety of Using an Esophageal Protective System to Eliminate Esophageal Thermal Injury: Implications on Atrial-Esophageal Fistula Following AF Ablation. Journal of Cardiovascular Electrophysiology, 20: 1272-1278. https://doi.org/10.1111/j.1540-8167.2009.01536.x10. Leung LW, Gallagher MM, Santangeli P, Tschabrunn C, Guerra JM, Campos B, Hayat J, Atem F, Mickelsen S, Kulstad E. Esophageal cooling for protection during left atrial ablation: a systematic review and meta-analysis. J Interv Card Electrophysiol. 2020 Nov;59(2):347-355. doi: 10.1007/s10840-019-00661-5. Epub 2019 Nov 22. PMID: 31758504; PMCID: PMC7591442.11. Tschabrunn CM, Attalla S, Salas J, Frankel DS, Hyman MC, Simon E, Sharkoski T, Callans DJ, Supple GE, Nazarian S, Lin D, Schaller RD, Dixit S, Marchlinski FE, Santangeli P. Active esophageal cooling for the prevention of thermal injury during atrial fibrillation ablation: a randomized controlled pilot study. J Interv Card Electrophysiol. 2022 Jan;63(1):197-205. doi: 10.1007/s10840-021-00960-w. Epub 2021 Feb 23. PMID: 33620619.

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Is there a need for a novel algorithm for accessory pathways localization?Malek Nayfeh MD, Marwan M. Refaat MDDivision of Cardiology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, LebanonRunning Title: Is there a need for a novel algorithm for WPW localization?Words: 572 (excluding the title page and references)Keywords: accessory pathways, Wolff-Parkinson-white, WPW, cardiac arrhythmias, cardiovascular diseases, heart diseases, Inferior Lead DiscordanceFunding: NoneDisclosures: NoneCorresponding Author:Marwan M. Refaat, MD, FACC, FAHA, FHRS, FASE, FESC, FACP, FRCPAssociate Professor of MedicineDirector, Cardiovascular Fellowship ProgramDepartment of Internal Medicine, Cardiovascular Medicine/Cardiac ElectrophysiologyDepartment of Biochemistry and Molecular GeneticsAmerican University of Beirut Faculty of Medicine and Medical CenterPO Box 11-0236, Riad El-Solh 1107 2020- Beirut, LebanonUS Address: 3 Dag Hammarskjold Plaza, 8th Floor, New York, NY 10017, USAOffice: +961-1-350000/+961-1-374374 Extension 5353 or Extension 5366 (Direct)Wolff Parkinson White Syndrome (WPW) affects between 0.1% and 0.2% of the population, causes morbidity due to supraventricular tachycardia (SVT) and can lead to sudden cardiac arrest [1-3]. The management involves localizing the accessory pathway, and then ablating it, by using either radiofrequency (RF) ablation or cryoablation. The electrocardiogram has been useful over the last decades in the localization of accessory pathways, premature ventricular contractions site of origin and pacing sites [4]. Regarding localization of the pathway, following a large study of RF ablation, Fitzpatrick et al described eight anatomical locations of different pathways using fluoroscopic landmarks: Right anteroseptal (RAS), right midseptal (RMS), right posteroseptal (RPS), right anterolateral (RAL), right posterolateral (RPL), left anterolateral (LAL), left posterolateral (LPL) and left posteroseptal (LPS) [5]. Other algorithms such as the Arruda algorithm or the D’Avila algorithm are also used by clinicians [6, 7]. Most of the accessory pathways’ localization algorithms involve assessment of the delta wave vector (Figure 1), some focus more on QRS morphology (Figure 2), and others combine both methods (Figure 3) [8-12]. By using these algorithms, differentiating between right sided and left sided accessory pathways does not generally pose a problem. However, determining the exact location of right and left sided pathways appears to be more challenging.The study of Bera et al. is a retrospective cohort. Twenty-two patients met the inclusion criteria. The aim was to assess the value of inferior lead discordance (meaning a positive QRS in lead II and a negative QRS in lead III) as a predictor of right anterior (RA) and RAL pathway. The authors included participants who had undergone RF ablation and were found to have right sided pathways. They then separated them in two groups based on if they had RA and RAL pathway (group 1) vs other pathways (group 2). The study found that all patients who had RA and RAL pathway had an ECG showing ILD, while 17 out of 18 patients who were in the other locations did not have an ECG with ILD. The sensitivity and specificity of ILD for predicting RAL location are 100% and 95% respectively.The findings in this study are highly relevant because they represent a clear and simple way of localizing RA/RAL pathways. Other algorithms are also extremely helpful but have their limitations especially if they rely on the delta wave polarity and the electrocardiogram is not fully pre-excited. Another advantage to the algorithm used in this study is that it focuses on limb leads, instead of pericardial leads, which are highly susceptible to variability due to possible displacement.This was a well conducted study, but has some limitations, most notably the small sample size of 22, with only 4 being RA and RAL pathways. There are many algorithms that help cardiologists and cardiac electrophysiologists in localizing accessory pathways before ablation, however, none has specifically focused on RA and RAL pathways. With the advances in artificial intelligence and machine learning, more algorithms using them might be developed in the future.Figure LegendsFigure 1: Examples of algorithms that rely on delta wave polarity such as Fitzpatrick (top) [5], Chiang (bottom left) [8] and Arruda (bottom right) [6]Figure 2: Example of algorithms that rely on QRS morphology such as D’Avilla (top left) [7], Taguchi (top right) [9] and St George’s (bottom) [10].Figure 3: Examples of algorithms that rely both on delta waves and QRS morphology, such as Pambrun (top) [11] and Baek (bottom) [12].References:1. Refaat MM, Hotait M, Tseng ZH (2014). Utility of the Exercise Electrocardiogram Testing in Sudden Cardiac Death Risk Stratification. Ann Noninvasive Electrocardiol, 19(4): 311-318.2. Lu, C. W., Wu, M. H., Chen, H. C., Kao, F. Y., & Huang, S. K. (2014). Epidemiological profile of Wolff-Parkinson-White syndrome in a general population younger than 50 years of age in an era of radiofrequency catheter ablation. International journal of cardiology, 174(3), 530–534. https://doi.org/10.1016/j.ijcard.2014.04.1343. Arai, A., & Kron, J. (1990). Current management of the Wolff-Parkinson-White syndrome. The Western journal of medicine, 152(4), 383–391.4. Refaat M, Mansour M, Singh JP, Ruskin JN, Heist EK (2011). Electrocardiographic Characteristics in Right Ventricular Versus Biventricular Pacing in Patients With Paced Right Bundle Branch Block QRS Pattern. J Electrocardiol, 44 (2): 289-95.5. Fitzpatrick, A. P., Gonzales, R. P., Lesh, M. D., Modin, G. W., Lee, R. J., & Scheinman, M. M. (1994). New algorithm for the localization of accessory atrioventricular connections using a baseline electrocardiogram. Journal of the American College of Cardiology, 23(1), 107–116. https://doi.org/10.1016/0735-1097(94)90508-86. Arruda, M. S., McClelland, J. H., Wang, X., Beckman, K. J., Widman, L. E., Gonzalez, M. D., Nakagawa, H., Lazzara, R., & Jackman, W. M. (1998). Development and validation of an ECG algorithm for identifying accessory pathway ablation site in Wolff-Parkinson-White syndrome. Journal of cardiovascular electrophysiology, 9(1), 2–12. https://doi.org/10.1111/j.1540-8167.1998.tb00861.x7. d’Avila, A., Brugada, J., Skeberis, V., Andries, E., Sosa, E., & Brugada, P. (1995). A fast and reliable algorithm to localize accessory pathways based on the polarity of the QRS complex on the surface ECG during sinus rhythm. Pacing and clinical electrophysiology : PACE, 18(9 Pt 1), 1615–1627. https://doi.org/10.1111/j.1540-8159.1995.tb06983.x8. Chiang, C. E., Chen, S. A., Teo, W. S., Tsai, D. S., Wu, T. J., Cheng, C. C., Chiou, C. W., Tai, C. T., Lee, S. H., & Chen, C. Y. (1995). An accurate stepwise electrocardiographic algorithm for localization of accessory pathways in patients with Wolff-Parkinson-White syndrome from a comprehensive analysis of delta waves and R/S ratio during sinus rhythm. The American journal of cardiology, 76(1), 40–46. https://doi.org/10.1016/s0002-9149(99)80798-x9. Taguchi, N., Yoshida, N., Inden, Y., Yamamoto, T., Miyata, S., Fujita, M., Yokoi, K., Kyo, S., Shimano, M., Hirai, M., &amp; Murohara, T. (2013, December 22). A simple algorithm for localizing accessory pathways in patients with Wolff-Parkinson-White syndrome using only the R/S ratio. Journal of Arrhythmia. Retrieved February 10, 2022, from https://www.sciencedirect.com/science/article/pii/S188042761300165810. Xie, B., Heald, S. C., Bashir, Y., Katritsis, D., Murgatroyd, F. D., Camm, A. J., Rowland, E., & Ward, D. E. (1994). Localization of accessory pathways from the 12-lead electrocardiogram using a new algorithm. The American journal of cardiology, 74(2), 161–165. https://doi.org/10.1016/0002-9149(94)90090-611. Pambrun, T., El Bouazzaoui, R., Combes, N., Combes, S., Sousa, P., Le Bloa, M., Massoullié, G., Cheniti, G., Martin, R., Pillois, X., Duchateau, J., Sacher, F., Hocini, M., Jaïs, P., Derval, N., Bortone, A., Boveda, S., Denis, A., Haïssaguerre, M., & Albenque, J. P. (2018). Maximal Pre-Excitation Based Algorithm for Localization of Manifest Accessory Pathways in Adults. JACC. Clinical electrophysiology, 4(8), 1052–1061. https://doi.org/10.1016/j.jacep.2018.03.01812. Baek, S. M., Song, M. K., Uhm, J. S., Kim, G. B., & Bae, E. J. (2020). New algorithm for accessory pathway localization focused on screening septal pathways in pediatric patients with Wolff-Parkinson-White syndrome. Heart rhythm, 17(12), 2172–2179. https://doi.org/10.1016/j.hrthm.2020.07.016.

Introduction The reuse of cardiac implantable electronic devices may help increase access to these therapies in low- and middle-income countries (LMICs). No published data exist regarding the views of patients and family members in LMICs regarding this practice. Methods and Results A paper questionnaire eliciting attitudes regarding pacemaker reuse was administered to ambulatory adult patients and patients’ family members at outpatient clinics at Centro Nacional Cardiologia in Managua, Nicaragua, Indus Hospital in Karachi, Pakistan, Hospital Carlos Andrade Marín and Hospital Eugenio Espejo in Quito, Ecuador, and American University of Beirut Medical Center in Beirut, Lebanon. There were 945 responses (Nicaragua – 100; Pakistan – 493; Ecuador – 252; Lebanon – 100). A majority of respondents agreed or strongly agreed that they would be willing to accept a reused pacemaker if risks were similar to a new device (707, 75%), if there were a higher risk of device failure compared to a new device (584, 70%), or if there were a higher risk of infection compared to a new device (458, 56%). A large majority would be willing to donate their own pacemaker at the time of their death (884, 96%) or the device of a family member (805, 93%). Respondents who were unable to afford a new device were more likely to be willing to accept a reused device (79% vs. 63%, P<0.001). Conclusions Patients and their family members support the concept of pacemaker reuse for patients who cannot afford new devices.

Toward Better Risk Stratification of Asymptomatic Brugada Syndrome Patients? Najla Beydoun MD1 , Charbel Gharios MD2 , Marwan M. Refaat MD3 1 Department of Anesthesiology and Perioperative Medicine, Tufts Medical Center, Boston, MA2 Cardiovascular Imaging Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA3 Department of Internal Medicine, Division of Cardiology, and Department of Biochemistry and Molecular Genetics, American University of Beirut Faculty of Medicine and Medical Center, Beirut, LebanonShort Title: Risk Stratification in Asymptomatic BrSWord Counts: 602

Brugada syndrome masked by complete left bundle branch blockAbbas Hoteit MD, Marwan M. Refaat, MDDivision of Cardiology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, LebanonRunning Title: Brugada Syndrome masked by LBBBWords: 741 (excluding the title page and references)Keywords: Brugada syndrome, Left bundle branch block, Cardiovascular Diseases, Heart Diseases, Cardiac ArrhythmiasFunding: NoneDisclosures: NoneCorresponding Author:Marwan M. Refaat, MD, FACC, FAHA, FHRS, FASE, FESC, FACP, FAAMAAssociate Professor of MedicineDirector, Cardiovascular Fellowship ProgramDepartment of Internal Medicine, Cardiovascular Medicine/Cardiac ElectrophysiologyDepartment of Biochemistry and Molecular GeneticsAmerican University of Beirut Faculty of Medicine and Medical CenterPO Box 11-0236, Riad El-Solh 1107 2020- Beirut, LebanonUS Address: 3 Dag Hammarskjold Plaza, 8th Floor, New York, NY 10017, USAOffice: +961-1-350000/+961-1-374374 Extension 5353 or Extension 5366 (Direct)Brugada syndrome is a genetic disorder that affects the electrical activity of the heart. It is characterized by ST-segment elevations in the right precordial leads and right bundle branch morphology on ECG.1 These ECG changes are present in the absence of other causes of ST elevation or right bundle branch block morphology such as structural heart disease, ischemia, pacing or electrolyte disturbances.2 Clinical presentation varies between patients; it can range from asymptomatic changes seen on ECG to syncope, ventricular arrhythmias, and sudden cardiac death. 3So far, three types of ECG repolarization patterns have been identified (type 1, type 2, and type 3).4 Type 1 pattern is diagnostic of Brugada syndrome whereas types 2 and 3 are considered suggestive.5 According to the 2016 consensus conference of J-wave syndromes, the diagnosis of Brugada syndrome can only be made by finding a type 1 repolarization pattern. A type 1 pattern can either be spontaneous or unmasked by fever or medications. If it has been unmasked by either, then further evidence of patient clinical history, family history, or genetic testing should be present to fulfill a score of 3.5 or higher according to the Shanghai Scoring System.6 7 The Shanghai Scoring System does not include imaging; hence, even if changes in the right ventricle are found on cardiac MRI, they play no role in the diagnosis. 7In patients presenting with a non-type 1 pattern, a sodium channel blocker challenge is frequently used to unmask the type 1 pattern. Unmasking this pattern allows for diagnosis of Brugada syndrome which has a big impact on prognosis and management options. In some patients, an initial flecainide challenge test may be negative due to the variable sensitivity of this test. Some studies have shown that repeating the test may increase sensitivity, but, with increased risk of adverse drug effects. Prasad et al. showed that in patients with high clinical suspicion, family history of sudden cardiac death could serve as an indicator to repeat the flecainide test.5 8 9Several possible risk factors, that might predispose individuals to have a more severe presentation, have been identified. These include male gender, history of syncope, spontaneous type 1 pattern, family history of Brugada syndrome, and loss-of-function mutations in the SCN5A gene (which codes the alpha subunit of the cardiac sodium channel).10 Patients with SCN5A mutations tend to have earlier onset of symptoms, more noticeable electrophysiological defects (such as sick sinus syndrome and AV blocks), and increased risk of major arrhythmic events especially in Asian and Caucasian populations.11 High-risk patients are susceptible to sudden cardiac death; therefore, risk stratification helps in patient selection for Implantable Cardioverter Defibrillator placement.12 13In their article, Eduardo et al. presented the case of a 48-year-old lady who was initially diagnosed with Brugada syndrome after having a type 1 pattern on ECG. During follow-up, the patient’s ECG changed and showed a complete left bundle branch block instead of the typical type 1 pattern. Molecular studies showed the novel SCN5A p.1449Y>H variant and subsequent functional analysis showed a nonfunctional mutated membrane channel. SCN5A mutation can cause Brugada syndrome and conduction system abnormality as described in this lady. This variant generated minimal sodium currents. Such major decrease in current magnitude is associated with high penetrance as seen in the cases in this study. Although, during close follow-up, these patients did not have severe symptoms.14 What is most significant is that the authors presented a patient with Brugada syndrome who subsequently developed findings of complete left bundle branch block on ECG, making the diagnosis challenging due to masking of the type 1 pattern. This opens further discussion about diagnosis of the syndrome and potential maneuvers or procedures that would help unmask type 1 pattern under heart block. Since diagnosis can only be made by witnessing this pattern, this presents us a possibility where a diagnosis would be missed in such patients. SCN5A is the most common gene associated with this syndrome, accounting for around 20%. However, patient presentation varies widely with different mutations affecting channel function differently. In this case, the p.1449Y>H variant showed high penetrance and channel dysfunction despite relatively non-severe symptoms in patients affected. However, further observation is warranted to assess progression of the disease and the incidence of major arrhythmogenic events with aging and subsequent fibrosis. Further research is required to investigate the role of genetic studies in risk stratification and projecting patient clinical course depending on the presence of specific gene mutations/variants.References:Refaat MM, Hotait M, Scheinman MM. Brugada Syndrome. Card Electrophysiol Clin Mar 2016; 8(1): 239-45.Refaat M, Mansour M, Singh JP, Ruskin JN, Heist EK. Electrocardiographic Characteristics in Right Ventricular Versus Biventricular Pacing in Patients With Paced Right Bundle Branch Block QRS Pattern. J Electrocardiol Mar-Apr 2011; 44 (2): 289-95.Tse G, Liu T, Li KH, et al. Electrophysiological mechanisms of Brugada syndrome: insights from pre-clinical and clinical studies. Front Physiol 2016; 7: 467.Wilde, A. a. M.; Antzelevitch, C.; Borggrefe, M.; Brugada, J.; Brugada, R.; Brugada, P.; Corrado, D.; Hauer, R. N. W.; Kass, R. S.; Nademanee, K.; Priori, S. G. (November 2002). ”Proposed diagnostic criteria for the Brugada syndrome”. European Heart Journal . 23  (21): 1648–1654.Prasad S, Namboodiri N, Thajudheen A, Singh G, Prabhu MA, Abhilash SP, Mohanan Nair KK, Rashid A, Ajit Kumar VK, Tharakan JA. Flecainide challenge test: Predictors of unmasking of type 1 Brugada ECG pattern among those with non-type 1 Brugada ECG pattern. Indian Pacing Electrophysiol J. 2016 Mar-Apr;16(2):53-58. doi: 10.1016/j.ipej.2016.06.001. Epub 2016 Jun 20. PMID: 27676161; PMCID: PMC5031807.Antzelevitch C, Yan GX, Ackerman MJ, et al. J-wave syndromes expert consensus conference report: emerging concepts and gaps in knowledge.Heart Rhythm 2016;13:e295-324.Vutthikraivit W, Rattanawong P, Putthapiban P, Sukhumthammarat W, Vathesatogkit P, Ngarmukos T, Thakkinstian A. Worldwide Prevalence of Brugada Syndrome: A Systematic Review and Meta-Analysis. Acta Cardiol Sin. 2018 May;34(3):267-277. doi: 10.6515/ACS.201805_34(3).20180302B. Erratum in: Acta Cardiol Sin. 2019 Mar;35(2):192. PMID: 29844648; PMCID: PMC5968343.Gasparini M, Priori SG, Mantica M, Napolitano C, Galimberti P, Ceriotti C, Simonini S. Flecainide test in Brugada syndrome: a reproducible but risky tool. Pacing Clin Electrophysiol. 2003 Jan;26(1P2):338-41. doi: 10.1046/j.1460-9592.2003.00045.x. PMID: 12687841.Dubner S, Azocar D, Gallino S, Cerantonio AR, Muryan S, Medrano J, Bruno C. Single oral flecainide dose to unmask type 1 Brugada syndrome electrocardiographic pattern. Ann Noninvasive Electrocardiol. 2013 May;18(3):256-61. doi: 10.1111/anec.12052. PMID: 23714084; PMCID: PMC6932426.Bayoumy A, Gong MQ, Christien Li KH, Wong SH, Wu WK, Li GP, Bazoukis G, Letsas KP, Wong WT, Xia YL, Liu T, Tse G; International Health Informatics Study (IHIS) Network. Spontaneous type 1 pattern, ventricular arrhythmias and sudden cardiac death in Brugada Syndrome: an updated systematic review and meta-analysis. J Geriatr Cardiol. 2017 Oct;14(10):639-643. doi: 10.11909/j.issn.1671-5411.2017.10.010. PMID: 29238365; PMCID: PMC5721199.Chen C, Tan Z, Zhu W, Fu L, Kong Q, Xiong Q, Yu J, Hong K. Brugada syndrome with SCN5A mutations exhibits more pronounced electrophysiological defects and more severe prognosis: A meta-analysis. Clin Genet. 2020 Jan;97(1):198-208. doi: 10.1111/cge.13552. Epub 2019 May 6. PMID: 30963536.Probst, V., Veltmann, C., Eckardt, L., Meregalli, P. G., Gaita, F., Tan, H. L., Wilde, A. A. (2010). Long‐term prognosis of patients diagnosed with Brugada syndrome: Results from the FINGER Brugada Syndrome Registry. Circulation , 121 (5), 635–643. https://doi.org/10.1161/circulationaha.109.887026.Rattanawong P, Chenbhanich J, Mekraksakit P, Vutthikraivit W, Chongsathidkiet P, Limpruttidham N, Prasitlumkum N, Chung EH. SCN5A mutation status increases the risk of major arrhythmic events in Asian populations with Brugada syndrome: systematic review and meta-analysis. Ann Noninvasive Electrocardiol. 2019 Jan;24(1):e12589. doi: 10.1111/anec.12589. Epub 2018 Aug 20. PMID: 30126015; PMCID: PMC6931443.

Electrogram-guided Endomyocardial Biopsy Yield in Patients with Suspected Cardiac SarcoidosisAbbas Hoteit MD, Marwan M. Refaat, MDDivision of Cardiology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, LebanonRunning Title: Electrogram-guided Biopsy in Cardiac SarcoidosisWords: 819 (excluding the title page and references)Keywords: Cardiac Sarcoidosis, Heart Diseases, Cardiovascular Diseases, Cardiac ArrhythmiasFunding: NoneDisclosures: NoneCorresponding Author:Marwan M. Refaat, MD, FACC, FAHA, FHRS, FASE, FESC, FACP, FAAMAAssociate Professor of MedicineDirector, Cardiovascular Fellowship ProgramDepartment of Internal Medicine, Cardiovascular Medicine/Cardiac ElectrophysiologyDepartment of Biochemistry and Molecular GeneticsAmerican University of Beirut Faculty of Medicine and Medical CenterPO Box 11-0236, Riad El-Solh 1107 2020- Beirut, LebanonUS Address: 3 Dag Hammarskjold Plaza, 8th Floor, New York, NY 10017, USAOffice: +961-1-350000/+961-1-374374 Extension 5353 or Extension 5366 (Direct)Sarcoidosis is a multisystem disease that is characterized by T-cell mediated formation of noncaseating granulomas in affected organs. The disease commonly might involve hilar lymphadenopathy, lungs, liver, spleen, heart, and other organs. The natural course and prognosis of the disease generally depends on the extent of the disease and the organs affected where spontaneous remission occurs in around two-thirds of patient.1 Involvement of the heart is recognized in around 30% of patients and is associated with poor prognosis.2 The presentation of patients with cardiac sarcoidosis varies significantly; it can range from mild to severe disease such as heart failure and fatal arrhythmias. Patients with cardiomyopathies might require implantable cardiac defibrillators or cardiac resynchronization therapy for sudden death prevention.3,4 Cardiac sarcoidosis can either present alongside extracardiac manifestations or isolated.5Diagnosis of cardiac sarcoidosis presents a particular challenge since there is no gold standard diagnostic tool and the presentation is variable.6 There are no disease-specific biomarkers that can reliably be used for diagnosis. Clinicians typically rely on current published guidelines for diagnostic criteria of cardiac sarcoidosis such as those of Heart Rhythm Society (HRS) and the Japanese Ministry of Health and Welfare (JMHW). The revised JMHW criteria provide a diagnosis either through histological evidence on biopsy or through the fulfillment of major and minor criteria that do not include cardiac PET whereas the HRS criteria provide either a definite pathway for diagnosis through histology or a clinical pathway for diagnosis of probable cardiac sarcoidosis that includes both cardiac PET and CMR as criteria.7,8 A definitive diagnosis of cardiac sarcoidosis can be obtained if endomyocardial biopsy can show noncaseating granulomas in the context of suspected cardiac sarcoidosis and other granulomatous diseases are excluded. However, endomyocardial biopsy has a low sensitivity of 20-30% since it is limited by several factors such as technique, sampling, patchy distribution of granulomas, location of lesions, and stage of the disease at the time of biopsy.5 Areas of inflammation and scarring typically show abnormal electrogram morphology, hence, it is thought that electrogram guidance may help in increasing the yield of endomyocardial biopsies. Electrogram guidance would potentially help avoiding normal myocardium during biopsy leading to increased yield and sensitivity.9In their study, Ezzedine et al. assessed the diagnostic yield of electrogram-guided endomyocardial biopsy and investigated association between positive endomyocardial biopsy and prognosis in patients with suspected cardiac sarcoidosis.10 This retrospective observational study included seventy-nine patients between 2011 and 2019 who had suspected cardiac sarcoidosis based on clinical presentation and findings on late gadolinium-enhancement cardiac magnetic resonance and/or cardiac positron emission tomography-computed tomography with N-13 NH3 perfusion imaging and F-18 fluorodeoxyglucose. Biopsy was done in patients suspicious of cardiac sarcoidosis in patients without extracardiac sarcoidosis or those with extracardiac disease but atypical/equivocal findings of cardiac sarcoidosis on imaging and meeting criteria in HRS guidelines as per the routine practice in Mayo Clinic. Mapping of the heart was performed prior to biopsy with partial guidance based on pre-procedural cardiac imaging. In patients with no identifiable abnormalities on electrogram, biopsies were taken from areas corresponding to those with abnormalities on pre-procedural imaging. Collected specimens were processed according to protocol and assessed by a blinded specialist. These specimens were considered positive if there was a combination of non-necrotizing granulomas, interstitial fibrosis, and scatted eosinophils. The study showed that electrogram-guided endomyocardial biopsy was associated with an adequate negative predictive value but low positive predictive value. A diagnosis of probable cardiac sarcoidosis can be made in patients with extracardiac manifestations according to established guidelines whereas in patients with suspected isolated cardiac sarcoidosis this is more difficult and as such biopsies play a more major role here. This study showed that, when guided by electrograms, endomyocardial biopsies had a higher diagnostic yield (41%) than that established in literature around 20-25%. Utilizing both abnormalities seen on both electrograms and on CMR or PET showed the highest diagnostic yield in endomyocardial biopsies. This acts as an important point of consideration for further research because accurate and timely diagnosis is paramount due to the diagnostics challenges and poor prognosis seen in cardiac sarcoidosis.10Previous evidence had shown that a positive endomyocardial biopsy for sarcoidosis was associated with poor prognosis.11However, LVAD and transplantation-free survival was found to be similar regardless of status of endomyocardial biopsy in this study.10 The authors explained that this could be explained by earlier detection of disease, differences in treatment, or more subtle detection of areas of involvement through electrograms. This study was well conducted but has been limited by its nature of being a retrospective observational study. Also, mapping was mostly limited to the right ventricle which may have underestimated the diagnostic yield of biopsies. This study represents the management done in a single tertiary care center which may not represent the same practice in other institutions with different facilities. Further multicenter and prospective studies are warranted to corroborate the data here and assess diagnostic and therapeutic modalities and long-term outcomes in patients.ReferencesStatement on sarcoidosis. Joint Statement of the American Thoracic Society (ATS), the European Respiratory Society (ERS) and the World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) adopted by the ATS Board of Directors and by the ERS Executive Committee, February 1999. Am J Respir Crit Care Med Aug 1999 ;160(2):736-55.Sekhri V, Sanal S, Delorenzo LJ, Aronow WS, Maguire GP. Cardiac sarcoidosis: a comprehensive review. Arch Med Sci Aug 2011; 7(4):546-54.AlJaroudi WA, Refaat MM, Habib RH, Al-Shaar L, Singh M, Gutmann R, Bloom HL, Dudley SC, Ellinor PT, Saba SF, Shalaby AA, Weiss R, McNamara DM, Halder I, London B; for the Genetic Risk Assessment of Defibrillator Events (GRADE) Investigators. Effect of Angiotensin Converting Enzyme Inhibitors and Receptor Blockers on Appropriate Implantable Cardiac Defibrillator Shock: Insights from the GRADE Multicenter Registry. Am J Cardiol Apr 2015; 115 (7): 115(7):924-31.Refaat M, Mansour M, Singh JP, Ruskin JN, Heist EK: Electrocardiographic Characteristics in Right Ventricular Versus Biventricular Pacing in Patients With Paced Right Bundle Branch Block QRS Pattern. J Electrocardiol Mar-Apr 2011; 44 (2): 289-95.Isobe M, Tezuka D. Isolated cardiac sarcoidosis: Clinical characteristics, diagnosis and treatment. Int J Cardiol Mar 2015; 182:132-40.Ahmed AI, Abebe AT, Han Y, Alnabelsi T, Agrawal T, Kassi M, Aljizeeri A, Taylor A, Tleyjeh IM, Al-Mallah MH. The prognostic role of cardiac positron emission tomography imaging in patients with sarcoidosis: A systematic review. J Nucl Cardiol Jul 2021; doi: 10.1007/s12350-021-02681-z. Online ahead of print.Sharma A, Okada DR, Yacoub H, Chrispin J, Bokhari S. Diagnosis of cardiac sarcoidosis: an era of paradigm shift. Ann Nucl Med Feb 2020;34(2):87-93.Ha FJ, Agarwal S, Tweed K, Palmer SC, Adams HS, Thillai M, Williams L. Imaging in Suspected Cardiac Sarcoidosis: A Diagnostic Challenge. Curr Cardiol Rev 2020;16(2):90-97.Liang JJ, Hebl VB, DeSimone CV, Madhavan M, Nanda S, Kapa S, Maleszewski JJ, Edwards WD, Reeder G, Cooper LT , Asirvatham SJ. Electrogram guidance: a method to increase the precision and diagnostic yield of endomyocardial biopsy for suspected cardiac sarcoidosis and myocarditis. JACC Heart Fail Oct 2014;2(5):466-73.Ezzedine FM, Kapa S, Rosenbaum A, Blauwet L, Deshmukh AJ, AbouEzzeddine OF, Maleszewski JJ, Asirvatham SJ, Bois JP, Schirger JA, Chareonthaitawee P, Siontis KC. Electrogram-guided Endomyocardial Biopsy Yield in Patients with Suspected Cardiac Sarcoidosis and Relation to Outcome. J Cardiovasc Electrophysiol Jul 2021; In Press.Ardehali H , Howard DL, Hariri A, Qasim A, Hare JM, Baughman KL, Kasper EK. A positive endomyocardial biopsy result for sarcoid is associated with poor prognosis in patients with initially unexplained cardiomyopathy. Am Heart J Sep 2005 ;150(3):459-63.

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