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.

Long QT syndrome (LQTS) is characterized by prolongation of the QT interval on the electrocardiogram (ECG). Clinically, LQTS is associated with the development of Torsades de Pointes (TdP), a well-defined polymorphic ventricular tachycardia and the development of sudden cardiac death (1). The most common type is the acquired form caused mainly by drugs, it is also known as the drug induced LQTS (diLQTS) (2-5). The diLQTS is caused by certain families of drugs which can markedly prolong the QT interval on the ECG most notably antiarrhythmic drugs (class IA, class III), anti-histamines, antipsychotics, antidepressants, antibiotics, antimalarial, and antifungals (2-5). Some of these agents including the antimalarial drug hydroxycholoquine and the antibiotic azithromycin which are being used in some countries as therapies for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)(6,7). However, these drugs have been implicated in causing prolongation of the QT interval on the ECG (2-5).There is a solution for monitoring this large number of patients which consists of using mobile ECG devices instead of using the standard 12-lead ECG owing to the difficulty of using the 12-lead ECG due to its medical cost and increased risk of transmitting infection. These mobile ECG devices have been shown to be effective in interpreting the QT interval in patients who are using QT interval prolonging drugs (8, 9). However, the ECG mobile devices have been associated with decreased accuracy to interpret the QT interval at high heart rates (9). On the other hand, some of them have been linked with no accuracy to interpret the QT interval (10). This can put some patients at risk of TdP and sudden cardiac death.In this current issue of the Journal of Cardiovascular electrophysiology, Krisai P et al. reported that the limb leads underestimated the occurrence of diLQTS and subsequent TdP compared to the chest leads in the ECG device, this occurred in particular with the usage of mobile standard ECG devices which use limb leads only. To illuminate these findings, the authors have studied the ECGs of 84 patients who have met the requirements for this study, which are diLQTS and subsequent TdP. Furthermore, the patients in this study were also taking a QT interval prolonging drug. Krisai P et al. additionally reported the morphology of the T-wave in every ECG and classified them into flat, broad, notched, late peaked, biphasic and inverted. The authors showed that in 11.9% of these patients the ECG was non reliable in diagnosing diLQTS and subsequent Tdp using only limb leads due to T-wave flattening in these leads, in contrast to chest leads where the non- interpretability of the QT interval was never attributable to the T-wave morphology but to other causes. The authors further examined the QT interval duration in limb leads and chest leads and found that the QT interval in limb leads was shorter compared to that of the chest leads, but reported a high variability in these differences. Therefore, it should be taken into account when screening patients with diLQTS using only mobile ECG devices and these patients should be screened using both limb leads and chest leads. Moreover, the authors have highlighted the limitations of using ECG mobile devices as limb leads to interpret the QT interval especially in high heart rates (when Bazett’s equation overcorrects the QTc and overestimates the prevalence of the QT interval) and have advocated the usage of ECG mobile devices as chest leads instead of limb leads due to their superior ability to interpret the QT interval.The authors should be praised for their efforts in illustrating the difference in the QT interval interpretability between the chest leads and the limb leads in patients with diLQTS. The authors also pointed out the limitation of using mobile ECG devices as limb leads for the diagnosis of diLQTS and recommended their usage as chest leads by applying their leads onto the chest due to their better diagnostic accuracy for detecting the diLQTS. The study results are very relevant, it further expanded the contemporary knowledge about the limitation of the QT interval interpretability using ECG mobile device only (11). Future investigation is needed to elucidate the difference in chest and limb leads interpretability of the QT interval and to assess the ability of the mobile ECG devices to interpret the QT interval.ReferencesRefaat 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.Kannankeril P, Roden D, Darbar D. Drug-Induced Long QT Syndrome. Pharmacological Reviews. 2010;62(4):760-781.Nachimuthu S, Assar M, Schussler J. Drug-induced QT interval prolongation: mechanisms and clinical management. Therapeutic Advances in Drug Safety. 2012;3(5):241-253.Jankelson L, Karam G, Becker M, Chinitz L, Tsai M. QT prolongation, torsades de pointes, and sudden death with short courses of chloroquine or hydroxychloroquine as used in COVID-19: A systematic review. Heart Rhythm. 2020 ; S1547-5271(20)30431-8.Li M, Ramos LG. Drug-Induced QT Prolongation And Torsades de Pointes. P T . 2017;42(7):473-477.Singh A, Singh A, Shaikh A, Singh R, Misra A. Chloroquine and hydroxychloroquine in the treatment of COVID-19 with or without diabetes: A systematic search and a narrative review with a special reference to India and other developing countries. Diabetes & Metabolic Syndrome: Clinical Research & Reviews. 2020;14(3):241-246.Hashem A, Alghamdi B, Algaissi A, Alshehri F, Bukhari A, Alfaleh M et al. Therapeutic use of chloroquine and hydroxychloroquine in COVID-19 and other viral infections: A narrative review. Travel Medicine and Infectious Disease. 2020; 35:101735.Chung E, Guise K. QTC intervals can be assessed with the AliveCor heart monitor in patients on dofetilide for atrial fibrillation. J Electrocardiol. 2015;48(1):8-9.Garabelli P, Stavrakis S, Albert M et al. Comparison of QT Interval Readings in Normal Sinus Rhythm Between a Smartphone Heart Monitor and a 12-Lead ECG for Healthy Volunteers and Inpatients Receiving Sotalol or Dofetilide. Journal Cardiovasc Electrophysiol. 2016;27(7):827-832.Bekker C, Noordergraaf F, Teerenstra S, Pop G, Bemt B. Diagnostic accuracy of a single‐lead portable ECG device for measuring QTc prolongation. Annals Noninvasive Electrocardiol. 2019;25(1): e12683.Malone D, Gallo T, Beck J, Clark D. Feasibility of measuring QT intervals with a portable device. American Journal of Health-System Pharmacy. 2017;74(22):1850-1851.