A Cardiac Sodium Channel Mutation Associated with Epinephrine-Induced Marked QT-ProlongationMohamad N. El Moheb MD1, Marwan M. Refaat MD21Division of Trauma Emergency Surgery and Surgical Critical Care, Massachusetts General Hospital, Boston, Massachusetts - USA2Division of Cardiology, Department of Internal Medicine, American University of Beirut Medical Center Beirut, LebanonRunning Title: SCN5A mutation associated with epinephrine-induced LQTSWords (excluding references): 746Disclosures: NoneFunding: NoneKeywords: Long QT Syndrome, Genetics, Variants, Cardiac Arrhythmias, Cardiovascular DiseasesCorrespondence: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, LebanonFax: +961-1-370814Clinic: +961-1-350000/+961-1-374374 Extension 5800Office: +961-1-350000/+961-1-374374 Extension 5353 or Extension 5366 (Direct)Email: [email protected] hereditary long QT syndrome (LQTS) is an important cause of polymorphous ventricular tachycardia (torsades de pointes) and sudden cardiac death in otherwise young and healthy individuals. Clinically, this condition is caused by delayed ventricular repolarization and manifests as an abnormally prolonged QT interval on the electrocardiogram (ECG). The most common subtypes of LQTS are LQT1, LQT2, and LQT3 (1-10). The life-threatening arrhythmias occur most frequently during exercise in LQT1, upon auditory stimulation or emotional stress in LQT2, and at rest or during sleep in LQT3 (11). Patients with LQT1 have a mutation in the KCNQ1 gene which codes for the subunit of the slow outward potassium current channel (IKs) while patients with LQT3 have a mutation in the SCN5A gene, which codes for the cardiac voltage-dependent sodium channel (INa) (12). LQT1-affected individuals are more vulnerable to β-adrenergic modulation than LQT3-affected individuals. Exercise and epinephrine-infusion ECG tests are therefore useful in differentiating between the LQTS subtypes and optimizing therapeutic strategies in order to prevent sudden cardiac death. While beta-blockers have been established as the standard of care for the treatment of the LQT1 and LQT2 subtypes, their use in LQT3 remains controversial (13, 14). A new missense mutation has been recently identified in the SCN5A-encoding INA channels and was found to be associated with sinus node dysfunction and epinephrine-induced QT prolongation (1). This atypical phenotype of LQT3 has so far been observed in only one patient. Whether other mutations exist that can cause a similar manifestation has yet to determined.In the current issue of the Journal of Cardiovascular Electrophysiology, Nakajima et al. describe a family with LQT3 that exhibited epinephrine-induced marked QT prolongation. The SCN5A V1667I mutation was found to be responsible for this atypical phenotype which resulted in prolongation of the QT interval in the proband as well as in family members carrying the mutation. The SCN5A V1667I mutation is a gain of function mutation located in domain IV-segment 5 (DIV-S5) of the sodium channel encoding SCN5A gene. To elucidate the pathophysiology of the disease, the authors transfected a human kidney cell line (tsA-201) to induce expression of wild-type and mutated sodium channels and measured the membrane sodium currents (INA). They showed that SCN5A V1667I mutation was associated with larger INA peak density, depolarizing shift in steady-state inactivation (SSI) leading to increased window current, and accelerated recovery from depolarization. Additionally, an increased hump in the INA of V1667I mutant cells (V1667I-INA) was observed during a ramp pulse protocol consistent with increased window current. There was no difference in fast inactivation rate and steady-state activation between the V1667I-INA and wild-type INA(WT-INA). The authors further examined the effects of protein kinase A (PKA) activation on V1667I-INA to mimic the effect of epinephrine. PKA activation resulted in a less significant hyperpolarizing shift in SSI in V1667I-INA compared to WT-INA leading to increased window current. Additionally, V1667I mutation was found to be associated with accelerated recovery from depolarization, and increased hump during ramp pulse protocol in the setting of PKA activation. Chen et al. have also reported the case of an individual with a mutation in SCN5A who exhibited marked QT-prolongation after epinephrine infusion (1). However, contrary to the SCN5A V1667I mutation described by Nakajima et al, the SCN5A V2016M defect was a loss of function mutation causing a decrease in INA peak density. The clinical manifestations of the SCN5A mutations described by Chen et al. and Nakajima et al. are more comparable to individuals with the LQT1 subtype than those with the LQT3 subtype. Therefore, it should be considered whether certain patients with SCN5A would benefit from beta-blocker therapy.Overall, the authors should be commended on their efforts to describe for the first time a family with the SCN5A V1667I mutation and show that this mutation is associated with epinephrine-induced marked QT prolongation. The authors have also provided important insight into the electrophysiological properties of the mutant channels and the structure-function relationship of SCN5A. Further studies are needed to elucidate the precise molecular mechanisms of PKA activation on WT-INa and V1667I-INa. The results of this study have important clinical implications. The efficacy of beta-blockers for the treatment of LQTS has so far only been proven for the LQT1 and LQT2 subtypes, with conflicting results for the LQT3 subtype (13, 14). Given the marked QT prolongation in response to epinephrine infusion in carriers of the SCN5A V1667I mutation, certain LQT3 patients may benefit from beta-blocker therapy. Future studies should clarify whether beta-blockers are effective in these patients.

In 1999, Paul Myles et al. published an important paper outlining the details of a novel assessment tool to measure patients’ quality of recovery (QoR) post-anesthesia and surgery.[1] The following year, Paul Myles et al. published another article outlining the QoR-40. This study, as well as multiple other studies, further studied QoR-40’s validity, reliability, internal consistency, test-retest reliability, inter-rater reliability, and split-half coefficient.[1–3] It can be completed in a relatively short period (around five minutes).[3,4] However, its administration by the investigators provides more complete and timely data as compared to self-administration.[4] It has been translated into multiple languages and validated by these languages as well.[5] However, even though the QoR-40’s score has a maximum score of 200 with a range of 160, the minimal clinically important difference is only 4.8 units to translate into clinically relevant change. The difference between the mean QoR-40 scores post-cardiac surgery (with and without complications) was only four units while maintaining a wide standard deviation within groups.[5,6] QoR’s utility lies in its correlation with patient satisfaction as well as with another measure of patient well-being, the quality of life (QoL) score.[3] Furthermore, the QoR-40’s score three days post-cardiac surgery correlated well with the SF-36’s measure of QoL 3 months after the operation. Hence QoR-40 is helpful in assess patient’s short-term prognosis.[7] These findings hold even three years after the operation; however, the correlation level does decrease. [8]In this issue of the journal of cardiovascular electrophysiology, Wasserlauf et al. utilized the QoR-40 to measure the impact of the anesthesia used during cryoballoon ablation of paroxysmal atrial fibrillation.[9] Catheter ablation has become a common procedure for the management of paroxysmal atrial fibrillation with minor procedural complication. [10,11] Patients undergoing cryoballoon ablation for atrial fibrillation experience less pain than radiofrequency ablation. [12]Multiple sedative modalities can be utilized for cardiac catheter ablation. One modality is the use of a light anesthetic: It alerts the physician of patient discomfort, it comforts the physician and nursing staff and carries a lower risk of drug overdose. However, it does increase the patients’ intraoperative motion.[13] Other modalities include general anesthesia and deep sedation. However, it should be noted that conscious sedation does carry a risk of hypoventilation and aspiration. [14] In a previous study, no significant difference in complication rate was present following ventricular tachycardia ablation during minimal as compared to deep sedation. [15] Also, in another study, patients undergoing percutaneous epicardial access (for ventricular tachycardia or premature ventricular complex) had similar complication rates regardless of whether they did the procedure under general anesthesia or moderate/deep sedation. [16] Furthermore, in a study by Tang et al., patients who underwent non-conscious sedation during catheter ablation for atrial fibrillation had more transient anesthetic complications as compared to conscious sedation. However, these two groups did not reveal a difference in the procedure-related complication/success rates. [17] Finally, Wasserlauf et al. found moderate sedation to carry a lower procedure time without jeopardizing the complication and recurrence rate up to a median follow-up duration of 0.9 years. This paper studied patients undergoing cryoballoon ablation for paroxysmal atrial fibrillation. [18]Given the previously reported evidence supporting the use of conscious anesthesia during atrial fibrillation catheter ablation, Wasserlauf et al. set on a task to expand our knowledge of patients’ tolerance of moderate sedation during cryoballoon ablation. [9] Consequently, they studied patients undergoing cryoballoon ablation for paroxysmal atrial fibrillation under general anesthesia or moderate sedation. Within 24 hours after the procedure, patients would provide the QoR-40 and their likelihood to recommend the procedure and sedation method. The mean QoR-40 was greater than 180 in the two groups with a difference of less than 5 unites. Furthermore, the difference in the QoR-40 scores was not statistically significant. [9] These scores were better than scores observed by Myles in minor surgeries (178 ± 17) and cardiac surgeries without complications (176 ± 16). [6] Moreover, patients reported a high satisfaction rate with a high likelihood to recommend the procedures (83% and 89%) and a high likelihood to recommend the sedation method (94% and 85%) depending on the sedation method (general anesthesia and moderate sedation respectively). However, the difference was not statistically significant.[9] This result is similar to a previous study that found that 96% of patients would recommend radiofrequency ablation for atrial fibrillation.[19] What these results mean is that they support the use of moderate sedation as compared to general anesthesia, given the similar patient experience, but different procedure time, expense, and possible complications from general anesthesia. [9]This study, however, does have limitations. It was a single-center non-randomized study. The QoR-40 has sections that are heavily dependent on the medical center and staff; hence this is an important issue to consider. Furthermore, the assignment to anesthesia groups was not standardized, and the decision was dependent on physician and patient preference. Though understandable, the physician preference can be made to be dictated by a predefined set of criteria to minimize nonrandom assignment. Finally, we note that the QoR-40 scores presented by Wasserlauf et al. were the means and standard deviations. [9] When calculating the 95% confidence intervals of the difference of the mean QoR-40 scores of the two groups, we find that there is no statistically significant difference between the two groups.In conclusion, Wasserlauf et al. have added to our knowledge of cryoballoon ablation under moderate sedation which might become the more frequently adopted anesthesia strategy during AFib cryoablation.References:1. Myles PS, Hunt JO, Nightingale CE, et al. Development and psychometric testing of a quality of recovery score after general anesthesia and surgery in adults. Anesth Analg. 1999;88(1):83-90. doi:10.1097/00000539-199901000-000162. Myles PS, Weitkamp B, Jones K, Melick J, Hensen S. Validity and reliability of a postoperative quality of recovery score: The QoR-40. Br J Anaesth. 2000;84(1):11-15. doi:10.1093/oxfordjournals.bja.a0133663. Gornall BF, Myles PS, Smith CL, et al. Measurement of quality of recovery using the QoR-40: A quantitative systematic review. Br J Anaesth. 2013;111(2):161-169. doi:10.1093/bja/aet0144. Gower ST, Quigg CA, Hunt JO, Wallace SK, Myles PS. A comparison of patient self-administered and investigator-administered measurement of quality of recovery using the QoR-40. Anaesth Intensive Care. 2006;34(5):634-638. doi:10.1177/0310057x06034005145. Myles PS. Measuring quality of recovery in perioperative clinical trials. Curr Opin Anaesthesiol. 2018;31(4):396-401. doi:10.1097/ACO.00000000000006126. Myles PS. Clinically Important Difference in Quality of Recovery Scores. Anesth Analg. 2016;122(1):13-14. doi:10.1213/ANE.00000000000010607. Myles PS, Hunt JO, Fletcher H, Solly R, Woodward D, Kelly S. Relation between quality of recovery in hospital and quality of life at 3 months after cardiac surgery. Anesthesiology. 2001;95(4):862-867. doi:10.1097/00000542-200110000-000138. Myles PS, Viira D, Hunt JO. Quality of life at three years after cardiac surgery: Relationship with preoperative status and quality of recovery. Anaesth Intensive Care. 2006;34(2):176-183. doi:10.1177/0310057x06034002209. Wasserlauf, Jeremiah; Kaplan, Rachel; Walega, David; Arora, Rishi; Chicos, Alexandr; Kim, Susan; Lin, Albert; Verma, Nishant; Patil, Kaustubha; Knight, Bradley; Passman R. Patient-Reported Outcomes After Cryoballoon Ablation Are Equivalent Between Moderate Sedation And General Anesthesia. J Cardiovasc Electrophysiol. 2020.10. 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): 1689-1713.11. 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): e432-3.12. Attanasio P, Huemer M, Shokor Parwani A, et al. Pain Reactions during Pulmonary Vein Isolation under Deep Sedation: Cryothermal versus Radiofrequency Ablation. PACE - Pacing Clin Electrophysiol. 2016;39(5):452-457. doi:10.1111/pace.1284013. Defaye P, Kane A, Jacon P, Mondesert B. Cryoballoon for pulmonary vein isolation: Is it better tolerated than radiofrequency? Retrospective study comparing the use of analgesia and sedation in both ablation techniques. Arch Cardiovasc Dis. 2010;103(6-7):388-393. doi:10.1016/j.acvd.2010.06.00414. Calkins H, Kuck KH, Cappato R, et al. 2012 HRS/EHRA/ECAS Expert Consensus Statement on Catheter and Surgical Ablation of Atrial Fibrillation: Recommendations for Patient Selection, Procedural Techniques, Patient Management and Follow-up, Definitions, Endpoints, and Research Trial Design. Heart Rhythm. 2012;9(4):632-696.e21. doi:10.1016/j.hrthm.2011.12.01615. Wutzler A, Mueller A, Loehr L, et al. Minimal and deep sedation during ablation of ventricular tachycardia. Int J Cardiol. 2014;172(1):161-164. doi:10.1016/j.ijcard.2013.12.17516. Killu AM, Sugrue A, Munger TM, et al. Impact of sedation vs. general anaesthesia on percutaneous epicardial access safety and procedural outcomes. Europace. 2018;20(2):329-336. doi:10.1093/europace/euw31317. Tang RB, Dong JZ, Zhao W Du, et al. Unconscious sedation/analgesia with propofol versus conscious sedation with fentanyl/midazolam for catheter ablation of atrial fibrillation: A prospective, randomized study. Chin Med J (Engl). 2007;120(22):2036-2038. doi:10.1097/00029330-200711020-0001818. Wasserlauf J, Knight BP, Li Z, et al. Moderate Sedation Reduces Lab Time Compared to General Anesthesia during Cryoballoon Ablation for AF Without Compromising Safety or Long-Term Efficacy. PACE - Pacing Clin Electrophysiol. 2016;39(12):1359-1365. doi:10.1111/pace.1296119. Ezzat VA, Chew A, McCready JW, et al. Catheter ablation of atrial fibrillation - Patient satisfaction from a single-center UK experience. J Interv Card Electrophysiol. 2013;37(3):291-303. doi:10.1007/s10840-012-9763-5

Catheter ablation is the current standard of care for the management of symptomatic atrial fibrillation (AFib) refractory to pharmacological therapy. One of the complications of this procedure is thermal injury to the esophagus due to its anatomical proximity to the posterior wall of the left atrium (1). Rarely (<1%), an atrioesophageal fistula can form connecting the lumen of damaged esophagus to the atrial chamber (2). This complication is almost always fatal and can result in exsanguination, air embolism, and sepsis (3, 4). With a growing number of catheter ablations being performed each year, the rate of atrioesophageal fistulas is only expected to rise (5). Other more frequent complications include esophageal wall erosions and ulcers (47%), and thermal injury to the vagus nerve plexus leading to esophageal dysmotility and gastroparesis (17%) (6, 7). Therefore, protecting the esophagus from thermal injuries is paramount in ablative procedures and several strategies have been devised to help mitigate this risk. Many physicians monitor the luminal esophageal temperature (LET) [ as a surrogate for intramural esophageal tissue temperature] with a single sensor or multisensor temperature probe and interrupt energy delivery when LET reaches 38°C or 39°C during radiofrequency ablation. However, this technique significantly impacts the procedural workflow due to the waiting periods for LET to return to baseline. Alternative strategies involve cooling of the esophagus with ice water or reducing the ablation lesion power, contact force and/or duration but this strategy may increase the chances for pulmonary vein reconnection (8). To that end, there has been a growing interest in mechanical devices capable of deflecting the esophagus away from the atrium protecting it from thermal injury.In the current issue of the Journal of Cardiovascular Electrophysiology, Houmsse et al. introduce a novel device capable of mobilizing the esophagus laterally to protect it from injury when performing catheter ablation for AFib. Although other devices have been developed and/or used for this purpose (such as the transesophageal echocardiography probe, endotracheal stylet, Esosure stylet and DV8 shaped balloon retractor), this is the only one to operate using vacuum suction allowing it to latch onto the esophageal wall. The device consists of four main components: outer extrusion, inner stacking plates, deflecting arm and control handle. The outer extrusion is inserted via a trochanter or a bougie into the esophagus and is the only portion of the retractor that comes in contact with the surrounding tissues. Small perforations at the distal end allow for vacuum suction to adhere to the esophagus and for a radiocontrast agent to be delivered to delineate the esophageal contour. The inner stacking plates are then introduced through the outer extrusion and are designed to allow movement of the deflecting arm in the medio-lateral plane only. The deflecting arm is connected to the distal end of the stacking plates through a pivot point and can be steered using the control handle. The authors have evaluated the effectiveness and safety of the device on canine and swine animal models by measuring the distance and direction of displacement of the esophagus, examining the cellular architecture after prolonged suction, measuring the LET, and assessing compatibility of device with electroanatomical mapping systems. A total of 68 deviations were performed on four canine models. The average rightward deflection was equal to 26.6 ± 2.5mm compared to 18.7 ± 2.3mm for the direct leftward deflection (p<0.001), and 96% of deviations did not have an esophageal trailing edge. With the exception of one study, the average distance displaced using the suction retractor was superior to other devices (9-13). The substantial distance of deflection and the minimal esophageal trailing edge significantly decreased the rise in LET from baseline (mean increase of 0.2°C vs 2.5°C without deflection). Examination of the esophageal tissue integrity following one hour of continuous suctioning revealed no change in the esophageal cellular architecture, and only minimal circular areas of hyperemia in mucosa due to the suction ports without injury to the muscularis layer. Finally, the retractor did not interfere with the electroanatomical mapping systems used (CARTO and EnSite).Despite its interesting findings, this study has several limitations that should be acknowledged. First, the study was performed on swine and canine animal models, which are known to have an anatomy close to humans; however, the safety profile of the device and its effectiveness in displacing the esophagus may not translate in humans. Second, subjects may exhibit symptoms secondary to extreme deviation of the esophagus in the absence of distortion of the cellular architecture. Clinical studies are needed to assess the safety profile and side effects of this esophageal retractor. Third, it is unclear whether these results would be reproducible under monitored anesthesia care. Finally, the fluoroscopic equipment tools lacked electronic caliper capabilities, and the measurements were performed using radiopaque rulers.Overall, the authors should be commended on their efforts to introduce and evaluate an inexpensive and innovative tool for esophageal protection during AFib ablation. This retractor addresses the limitations of other products that serve a similar purpose. In fact, the suctioning power of the product minimizes the trailing edge of the esophagus that could not be managed with other devices which left esophageal tissue in the ablation field (10, 13). In addition, the control handle offers significant flexibility in device manipulation allowing physicians to choose the site of angulation and the angle of deflection depending on the patient’s anatomy. Future studies should focus on evaluating the safety and effectiveness of this device in humans. Given the growing number of esophageal retracting devices, studies should also aim to determine the device that produces the best esophageal protection and most desirable outcomes of ablation.REFERENCES1. 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): 1689-1713.2. 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): e432-3.3. Aryana A, Arthur A, O’ Neill PG, D’Avila A. Catastrophic manifestations of air embolism in a patient with atrioesophageal fistula following minimally invasive surgical ablation of atrial fibrillation. Journal of cardiovascular electrophysiology. 2013;24(8):933-4.4. Stöckigt F, Schrickel JW, Andrié R, Lickfett L. Atrioesophageal fistula after cryoballoon pulmonary vein isolation. Journal of cardiovascular electrophysiology. 2012;23(11):1254-7.5. Oral H, Siontis KC. Prevention of Atrioesophageal Fistula After Catheter Ablation: If the Esophagus Cannot Stand the Heat (Cold), Can It Be Moved to the Sidelines? : JACC: Clinical Electrophysiology; 2017.6. 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):327-30.7. Schmidt M, Nölker G, Marschang H, Gutleben K-J, Schibgilla V, Rittger H, et al. Incidence of oesophageal wall injury post-pulmonary vein antrum isolation for treatment of patients with atrial fibrillation. Europace. 2008;10(2):205-9.8. Tran VN, Kusa S, Smietana J, Tsai W-C, Bhasin K, Teh A, et al. The relationship between oesophageal heating during left atrial posterior wall ablation and the durability of pulmonary vein isolation. Ep Europace. 2017;19(10):1664-9.9. Mateos JCP, Mateos EIP, Peña TGS, Lobo TJ, Mateos JCP, Vargas RNA, et al. Simplified method for esophagus protection during radiofrequency catheter ablation of atrial fibrillation-prospective study of 704 cases. Brazilian Journal of Cardiovascular Surgery. 2015;30(2):139-47.10. Bhardwaj R, Naniwadekar A, Whang W, Mittnacht AJ, Palaniswamy C, Koruth JS, et al. Esophageal Deviation During Atrial Fibrillation Ablation: Clinical Experience With a Dedicated Esophageal Balloon Retractor. JACC Clin Electrophysiol. 2018;4(8):1020-30.11. Herweg B, Johnson N, Postler G, Curtis AB, Barold SS, Ilercil A. Mechanical esophageal deflection during ablation of atrial fibrillation. Pacing and clinical electrophysiology. 2006;29(9):957-61.12. Palaniswamy C, Koruth JS, Mittnacht AJ, Miller MA, Choudry S, Bhardwaj R, et al. The extent of mechanical esophageal deviation to avoid esophageal heating during catheter ablation of atrial fibrillation. JACC: Clinical Electrophysiology. 2017;3(10):1146-54.13. Parikh V, Swarup V, Hantla J, Vuddanda V, Dar T, Yarlagadda B, et al. Feasibility, safety, and efficacy of a novel preshaped nitinol esophageal deviator to successfully deflect the esophagus and ablate left atrium without esophageal temperature rise during atrial fibrillation ablation: The DEFLECT GUT study. Heart Rhythm. 2018;15(9):1321-7.