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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Impact of Pre-ablation Weight Loss on the Success of Catheter Ablation for Atrial FibrillationAbdul Hafiz Al Tannir BS, Marwan M. Refaat MDDepartment of Internal Medicine, Division of Cardiology, American University of Beirut Medical Center, Beirut, LebanonRunning Title: Pre-ablation Weight Loss and Success of AF AblationDisclosures: NoneFunding: NoneKeywords: Cardiac Arrhythmias, Cardiovascular Diseases, Heart Diseases, Weight Loss, Catheter Ablation, Atrial FibrillationWords: 621 (excluding references)Correspondence: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: +961-1-759616 or +961-1-355500 or +961-1-350000/+961-1-374374 Extension 5800Office: +961-1-350000/+961-1-374374 Extension 5353 or Extension 5366 (Direct)Email: [email protected] the United States, the prevalence of obese individuals has risen 3-fold since 1960, with 1 in every 3 persons being obese. The effect of weight changes on the progression on atrial fibrillation is well-established but the effect of pre-ablation weight loss on the recurrence of atrial fibrillation is not well-studied. Atrial fibrillation is the most frequently encountered cardiac arrhythmia [1]; it currently affects around 2.7 million people in the United States of America and is estimated that 6-12 million people will suffer from this condition by 2050 [2, 3]. Pulmonary vein isolation is the primary target for cardiac ablation; it can be achieved either by radiofrequency (RF) or cryoballoon ablation (CBA) [4, 5]. The FIRE and ICE trial conducted by Kuck et al showed that CBA therapy was associated with significantly fewer recurrence, rehospitalization, and cardioversion rates [6]. Several studies suggest the preferred use of CBA in treating atrial fibrillation in obese patients due to the increased surface area for ablation [4].Obesity has adverse effects on the structure and hemodynamics of the heart and it is a well-established risk factor for the development of atrial fibrillation [3]. A prospective cohort study performed by Pathak et al showed that progressive weight loss in obese and overweight patients resulted in dose-dependent effects on freedom from atrial fibrillation (FFAF) [7]. Similarly, Middeldrop et al, concluded that obesity is associated with the progression of the disease while weight loss is associated with reversal of the progression [8]. Limited data is available regarding the effect of weight loss on the recurrence of atrial fibrillation post-ablation. Current guidelines recommend lifestyle modifications, including a healthy diet and exercise, for overweight and obese patients before ablation [8, 9].The study of Peigh et al. is a retrospective cohort study from 2012-2017; 607 patients met the inclusion criteria. The aim of the study is to assess the impact of patient-directed weight loss 1 year before CBA on FFAP 15 months after ablation. The authors addressed an important topic that is poorly understood. Obese patients have a significantly lower FFAF rate 40-50% than the overall population 60-80%. The study selectively included patients undergoing CBA therapy. The follow-up time was 1-year post-ablation. The study concluded that, with the exception of non-obese patients with persistent atrial fibrillation, weight loss is associated with a significantly increased FFAF while weight gain led to a decrease in FFAF. A similar study assessed the impacted of physician-mediated risk control in patients undergoing RF ablation for atrial fibrillation [10]. A total of 149 patients were included in the prospective cohort study. The study showed a positive association between physician-directed weight loss (≥ 10%) and FFAF in symptomatic obese patients. The study performed by Peigh et al, included though a larger subject group (607) than LEGACY (141); however, the LEGACY is a prospective cohort study that is more suitable to monitor the fluctuation in patients’ variables before ablation.This study was well conducted but has the limitations of retrospective studies; a prospective cohort study would better monitor the variations in patients’ variables pre-ablation. In addition, as the authors stated, asymptomatic atrial fibrillation episodes may go unnoticed.Patients with atrial fibrillation, particularly those who are obese, should be advised to lose weight prior to catheter ablation. Lifestyle modifications should not be limited to patients undergoing ablation; the effect of weight loss on disease progression is well-established. Due to the overgrowing prevalence of atrial fibrillation and obesity worldwide, more studies are encouraged to better understand the ideal lifestyle management in patients. Larger prospective cohort studies should be conducted in order to validate the results. There is also an ongoing randomized clinical trial BAROS (Bariatric Atrial Return of Sinus Trial) [NCT 04050969] which will provide more data on this topic.

Achieving Cardiac resynchronization therapy (CRT) with Biventricular pacing(BiVP) pacing for patients with moderate-to-severe heart failure (HF), left ventricular (LV) systolic dysfunction and ventricular dyssynchrony is well established and is currently the standard of care. Multiple studies have demonstrated significant improvement in quality of life, functional status, and exercise capacity in patients with New York Heart Association (NYHA) class III and IV heart failure who underwent resynchronization therapy1,2. In addition, resynchronization therapy is associated with survival benefit3. However, one third of patients do not respond to BIVP. New modalities for resynchronization have emerged namely His bundle pacing (HBP) and left ventricular septal pacing (LVSP). In this paper, we will review the benefits and limitations of BiVP and also the role of new pacing modalities such as HBP and LVSP in patients with HF with reduced left ventricular ejection fraction (LVEF) and electrical dysynchrony.

Arrhythmia Induced Cardiomyopathy: What are Predictors of Myocardial Recovery?Acile Nahlawi BS, Marwan M. Refaat MDDepartment of Internal Medicine, Division of Cardiology, American University of Beirut Medical Center, Beirut, LebanonRunning Title: AIC and Predictors of Myocardial RecoveryDisclosures: NoneFunding: NoneKeywords: Cardiac Arrhythmias, Cardiovascular Diseases, Heart Diseases, Congestive Heart Failure, CardiomyopathyWords: 958 (excluding references)Correspondence: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: +961-1-759616 or +961-1-355500 or +961-1-350000/+961-1-374374 Extension 5800Office: +961-1-350000/+961-1-374374 Extension 5353 or Extension 5366 (Direct)Email: [email protected] cause a significant public health burden and improvement in sudden cardiac death risk stratification helped in decreasing mortality by improved pharmacotherapy as well as device implantations including implantable cardiac defibrillators and cardiac resynchronization therapy [1-4]. Arrhythmia induced cardiomyopathy (AIC) is a major cause of non-ischemic cardiomyopathy and heart failure (HF) worldwide [5]. It is characterized by an impairment of left ventricular systolic function secondary to high heart rate (tachycardia-induced), asynchrony (frequent premature ventricular contractions-induced or right ventricular pacing-induced) or an irregular rhythm (such as atrial fibrillation-induced) that serves as the trigger of AIC and this is mediated by calcium mishandling. The distinctive feature of AIC is the substantial improvement in left ventricular systolic function following arrhythmia suppression or elimination [5]. Atrial Fibrillation (AF) is concomitantly present with and potentially the cause of 10 to 50% of HF cases [6]. AIC is an important, commonly encountered and potentially reversible entity that is often under-recognized. The exact incidence and prevalence of AIC remains poorly defined in the literature [7]. In some studies, it was present in as high as 50% of patients with AF undergoing ablation, while it was reported to be present in 10% of patients with focal atrial tachycardia undergoing ablation [8]. In addition, very little attention, if any, is given to AIC in major trials on AF and HF, despite its significant implications on morbidity and mortality and the promising benefits of treatment [7]. Many aspects of AIC are yet to be understood. In fact, few studies limited by small sample size constitute our main source of knowledge on extent and predictors of ventricular recovery after treatment initiation in patients with AIC [9,10].In their multicenter retrospective study, Gopinathannair et al. aimed to assess the degree of recovery of the left ventricular systolic function after suppression/elimination of the underlying arrythmia and to evaluate factors influencing this response such as baseline patient and arrhythmia characteristics. The study sample comprised 243 patients from 3 different institutions whose charts were reviewed retrospectively (no recruitment timeframe was indicated). The patient characteristics studied included baseline left ventricular ejection fraction (LVEF), presence of structural heart disease (SHD) [ defined as significant coronary artery disease, prior myocardial infarction, hemodynamically significant valvular heart disease, or other structural cardiomyopathies] and medications used. As for the arrhythmia characteristics, they included arrhythmia duration and arrhythmia type. The authors used echocardiography as the imaging modality to determine extent of ventricular function recovery by comparing myocardial function before and after treatment of the culprit arrhythmia. The echocardiographic parameters that were assessed included LVEF, LV end-diastolic and end-systolic diameters, left atrial dimension, valvular abnormalities, right ventricular systolic pressures, and pulmonary arterial pressures.In contrast to reported literature on the topic, Gopinathannair et al. found that none of the studied patient and arrhythmia characteristics had a significant effect on the recovery of ventricular function. Their results showed that initiation of aggressive arrhythmia treatment is warranted in patients with suspected AIC, regardless of arrhythmia duration, arrhythmia type, severity of baseline LVEF, and underlying structural heart disease. This was concluded based on the consistent substantial improvement in LVEF after arrhythmia suppression/elimination, mainly through rhythm control, across all different subgroups. In fact, the extent of LVEF improvement was similar whether comparing the group with known arrhythmia duration [KN] to that with unknown arrhythmia duration [UKN] (21.2±9 % vs 19.4±11 %, p-value =0.16) or comparing the group with longest arrhythmia duration to the rest (21.5±7.5 % vs 21.0 ± 9.2%, p-value=0.77). On the other hand, greatest improvement was seen in the group with lowest initial LVEF (24±17 vs 19±7%; p-value <0.0001), making low index LVEF the only predictor of LVEF recovery after arrhythmia treatment in patients with AIC. However, the LVEF in these patients did not reach complete normalization; they had lower post-treatment LVEF compared to other groups (45±14 vs 54±8%; p<0.0001), a finding consistent with the available literature. Also similar to previous studies, the authors found that patients with PVCs experienced smaller extent of recovery compared to other arrhythmia types. The authors concluded by stressing the importance of suspecting AIC in patients having cardiomyopathy with a persistent arrhythmia and initiating aggressive arrhythmia treatment regardless of initial patient and arrhythmia characteristics.As for the limitations of the study by Gopinathannair et al., there are few to mention. First, the study had a retrospective design and therefore findings only serve to generate hypotheses that need further testing and validation. Second, there is a lack of a control group to exclude interference of confounding factors. Although the use of Angiotensin-Converting Enzyme inhibitors (ACEi)/ Angiotension receptor blockers (ARB) did not independently predict LVEF improvement in multivariate analysis, it could still be a confounder given the lower rates of ACEi/ARB use in the cohort. Third, the timeframe of the study and the period of follow-up were not clearly defined. Fourth, there is lack of blinding of echocardiographic analyses which can potentially lead to inter- and intra-observer variability. Finally, the sample population was not diverse as it consisted in its majority of Caucasians.The Gopinathannair et al. study demonstrated several points of strength. Among these are its multicenter nature and its relatively larger sample size compared to similar studies, giving its findings more weight. Moreover, the authors appropriately and clearly defined their inclusion and exclusion criteria. Furthermore, no funding was needed for the study which potentially frees it from direct or indirect influences on its design, execution and interpretation. Finally, the study has successfully improved our understanding of predictors of ventricular recovery in patients with AIC and showed that patients with AIC who had the longest duration of arrhythmia still had LV systolic function improvement with arrhythmia suppression/elimination. This study paves the way for prospective studies and randomized clinical trials to validate the generated hypotheses and corroborate the observational findings.

Idiopathic ventricular arrhythmias (VA) is defined as premature ventricular complexes (PVCs) or ventricular tachycardias (VT) that occur in the absence of structural heart disease. Endocardial radiofrequency (RF) ablation is often curative for idiopathic VA. The success of the procedure depends on the ability to localize the abnormal foci accurately. These arrhythmias typical originate from the right ventricular outflow tract (RVOT), specifically from the superior septal aspect, but can also originate from the left ventricular outflow tract (LVOT) and the coronary cusps.1 The QRS electrocardiogram (ECG) characteristics have been helpful in patients with VAs, patient with accessory pathways and patients who have pacemakers.2 VAs originating from the RVOT have typical ECG findings with a left bundle branch block (LBBB) morphology and an inferior axis.3In the current issue of the Journal of Cardiovascular Electrophysiology, Hisazaki et al. describe five patients with idiopathic VA suggestive of RVOT origin and who required ablation in the left-sided outflow tract (OT) in addition to the initial ablation in the RVOT for cure to be achieved. Patients exhibited monomorphic, LBBB QRS pattern with an inferior axis on ECG, consistent with the morphology of VAs originating from the RVOT. Interestingly, all patients had a common distinct ECG pattern: qs or rs (r ≤ 5 mm) pattern in lead I, Q wave ratio[aVL/aVR]>1, and dominant S-waves in leads V1 and V2. Mapping of the right ventricle demonstrated early local activation time during the VA in the posterior portion of the RVOT, matching the QRS morphology obtained during pacemapping. Despite RF energy delivery to the RV, the VAs recurred shortly after ablation in four patients and had no effect at all in one patient. A change in the QRS morphology was noted on the ECG that had never been observed before the procedure. The new patterns were suggestive of left-sided OT origin: the second VAs exhibited an increase in the Q wave ratio [aVL/aVR] and R wave amplitude in lead V1, decrease in the S wave amplitude in lead V1, and a counterclockwise rotation of the precordial R-wave transition. Early activation of the second VA could not be found in the RVOT, and the earliest activation time after mapping the LV was found to be relatively late. Real-time intracardiac echocardiography and 3D mapping systems were used to determine the location immediately contralateral to the initial ablation site in the RVOT. Energy was then delivered to that site which successfully eliminated the second VA. The authors postulated that the second VAs shared the same origins as the first VAs, and the change in QRS morphology is likely attributed to a change in the exit point or in the pathway from the origin to the exit point. The authors further explained that the VAs originated from an intramural area of the superior basal LV surrounded by the RVOT, LVOT and the transitional zone from the great cardiac vein to the anterior interventricular vein (GCV-AIV).A limitation of this study is that GCV-AIV ablation was not attempted; however, the authors’ approach is safer and was successful in eliminating VA. Another limitation is that left-sided OT mapping was not initially performed. Nevertheless, given the ECG characteristics, local activation time, and mapping, it was appropriate to attempt a RVOT site ablation.Overall, the authors should be commended for their effort to describe in detail patients with idiopathic VAs that required ablation in the left-sided OT following ablation in the RVOT. Although change in QRS morphology after ablation has been previously described, the authors were the first to describe the ECG patterns of these patients.4–7 The results of this study have important clinical implications. First, the authors have demonstrated the importance of anatomical approach from the left-sided OT for cure to be achieved. Second, insight into the location of the origin of the VA may be helpful to physicians managing patients with VAs from the RVOT. Finally, continuous monitoring of the ECG during ablation for a change in QRS morphology should be considered to identify patients who will require further ablation. We have summarized in Table 1 important ECG characteristics indicative VA of specific origins, based on the findings of this study and previous studies in the literature.3,8–15

Atrial fibrillation (AF) is the most common cardiac arrhythmia and often occurs with heart failure (HF) [1]. AF prevalence increases with increasing severity of HF: for instance its prevalence ranges from 5 percent in patients with New York Heart Association (NYHA) functional class I HF to 40 percent in patients with NYHA class IV HF [2]. Its presence with HF plays a significant prognostic role and increases morbidity and mortality. Heart Failure with reduced ejection fraction (HFrEF) is associated with cardiac arrhythmias [3]. HFrEF is also one of the indications for Cardiac resynchronization therapy (CRT) placement [4]. Therefore, many patients undergoing CRT implantation will concomitantly have HF and AF. As the benefit from CRT in HF patients has been established, the data on patients with both HF and AF is limited, because patients with atrial arrhythmias were excluded from most of the major CRT trials, such as CARE-HF and COMPANION [5]. However, a number of observational studies and small randomized clinical trials suggest a benefit from CRT in AF and HF patients such as a CRT-mediated ejection fraction (EF) increase [6, 7]. Other studies showed a high non-response rate in patients with AF as compared to those in sinus rhythm (SR) [8]. Thus, it is important to determine whether CRT has a beneficial role in these patients to decide on adding an atrial lead at the time of CRT implantation especially in patients with longstanding-persistent AF.In their published study, Ziegelhoeffer et al. investigated the outcomes of CRT placement with an atrial lead in patients with HF and AF. This was done by conducting a retrospective analysis of all patients with AF who received CRT for HF at the Kerckhoff Heart Center since June 2004 and were observed until July 2018- completing a 5-year follow-up. The authors identified 328 patients and divided them into 3 subgroups: paroxysmal (px) AF, persistent (ps) AF, and longstanding-persistent (lp) AF, with all patients receiving the same standard operative management. During the observation period, the authors analyzed the rhythm course of the patients, cardiac parameters (NYHA class, MR, LVEF, left atrial diameter) and performed a subgroup analysis for patients who received an atrial lead. The study showed that all groups had a high rate of sinus rate (SR) conversion and rhythm maintenance at 1 and 5 years. Specifically, the patients who received an atrial lead among the lp AF group were shown to have a stable EF, less pronounced  left ventricular end-systolic diameter (LVESD) and  left ventricular end diastolic diameter (LVEDD) and lower mitral regurgitation (MR) rates at one year follow-up as compared to the group without atrial lead placement. Moreover, the results of the lp group were similar to the ps-AF group, although the latter had a lower number of participants (n=4) without initial implantation of the atrial lead. The authors attributed the improvement in cardiac function and SR conversion to CRT and the implantation of an additional atrial lead.Although some studies showed that CRT therapy reduced secondary MR in HF [9, 10], this study additionally suggests that CRT with an atrial lead was associated with improved myocardial function and improvement of interventricular conduction delay triggering cardiac remodeling in patients with HF and AF. Although the results showed better cardiac function in the subgroup analysis of the patients with an additional atrial lead, these results were reported as percentages with no level of significance specified, hence statistical significance of the difference in the described parameters (such as LVESD, LVEDD) could not be determined. Further investigation via prospective studies is needed with larger sample size in the future to further support the results of the study especially that it was done in a single center and had a relatively small sample size.References:1. Chung MK, Refaat M, Shen WK, et al. Atrial Fibrillation: JACC Council Perspectives. J Am Coll Cardiol. Apr 2020; 75 (14): 1689-1713.2. Maisel, W.H. and L.W. Stevenson, Atrial fibrillation in heart failure: epidemiology, pathophysiology, and rationale for therapy. Am J Cardiol, 2003. 91 (6a): p. 2d-8d.3. AlJaroudi WA, Refaat MM, Habib RH, et al. 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):924-31.4. Yancy, C.W., et al., 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol, 2013. 62 (16): p. e147-239.5. Cleland, J.G., et al., The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med, 2005.352 (15): p. 1539-49.6. Leclercq, C., et al., Comparative effects of permanent biventricular and right-univentricular pacing in heart failure patients with chronic atrial fibrillation. Eur Heart J, 2002. 23 (22): p. 1780-7.7. Upadhyay, G.A., et al., Cardiac resynchronization in patients with atrial fibrillation: a meta-analysis of prospective cohort studies. J Am Coll Cardiol, 2008. 52 (15): p. 1239-46.8. Wilton, S.B., et al., Outcomes of cardiac resynchronization therapy in patients with versus those without atrial fibrillation: a systematic review and meta-analysis. Heart Rhythm, 2011. 8 (7): p. 1088-94.9. van Bommel, R.J., et al., Cardiac resynchronization therapy as a therapeutic option in patients with moderate-severe functional mitral regurgitation and high operative risk. Circulation, 2011.124 (8): p. 912-9.10. Breithardt, O.A., et al., Acute effects of cardiac resynchronization therapy on functional mitral regurgitation in advanced systolic heart failure. J Am Coll Cardiol, 2003. 41 (5): p. 765-70.

A document by Youssef Jalloul. Click on the document to view its contents.

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.

Sudden Cardiac Death (SCD) remains a global threat.1The most common causes of SCD are ischemic heart diseases and structural cardiomyopathies in the elderly. Additional causes can be arrhythmogenic, respiratory, metabolic, or even toxigenic.2,3,4 Despite the novel diagnostic tools and our deeper understanding of pathologies and genetic associations, there remains a subset of patients for whom a trigger is not identifiable. When associated with a pattern of Ventricular Fibrillation, the diagnosis of exclusion is deemed Idiopathic Ventricular Fibrillation (IVF).2,5 IVF accounts for 5% of all SCDs6 – and up to 23% in the young male subgroup5 – and has a high range of recurrence rates (11-45%).7,8,9 There are still knowledge gaps in the initial assessment, follow-up approach, risk stratification and subsequent management for IVF.1,10,11 While subsets of IVF presentations have been better characterized into channelopathies, such as Brugada’s syndrome (BrS), Long QT Syndrome (LQTS), Early Repolarization Syndrome (ERS), Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT), much remains to be discovered.12,13 Implantable Cardioverter Device (ICD) placement as secondary prevention for IVF is the standard of care. This is warranted in the setting of high recurrence rates of arrhythmias (11-43%). Multiple studies have shown potential complications from ICDs and a significant number of cases experiencing inappropriate shock after ICD placement.14In their article, Stampe et al. aim to further understand clinical presentation and assessment, and risk factors for recurrent ventricular arrhythmias in IVF patients. Using a single-centered retrospective study, they followed a total of 84 Danish patients who were initially diagnosed with IVF and received a secondary ICD placement between December 2007 and June 2019. Median follow-up time was 5.2 years (ICR=2-7.6). To ensure detection of many possible underlying etiologies ranging from structural, ischemic, arrhythmogenic, metabolic, or toxicologic, the researchers found that a wide array of diagnostic tools were necessary: standard electrocardiograms (ECGs), high-precordial leads ECGs, standing ECGs, Holter monitoring, sodium-channel blocker provocation tests, exercise stress tests, echocardiograms, cardiac magnetic resonance imaging, coronary angiograms, cardiac computed tomography, electrophysiological studies, histological assessment, blood tests, toxicology screens, and genetic analysis.The study by Stampe et al. highlights the importance of thorough and continuous follow-up with rigorous evaluation: Three (3.6%) patients initially diagnosed with IVF were later found to have underlying cardiac abnormalities (LQTS and Dilated Cardiomyopathy) that explained their SCA. Like other studies, the burden of arrhythmia was found to be high, but unlike reported data, the overall prognosis of IVF was good. Despite the initial pattern of ventricular fibrillation in those who experienced appropriate ICD placement (29.6%), ventricular tachycardia and ventricular fibrillation had a comparable predominance. As for patients with inappropriate ICD placements, atrial fibrillation was a commonly identified pathological rhythm (16.7%). Recurrent cardiac arrest at presentation (19.8%) was a risk factor for appropriate ICD therapy (HR=2.63, CI=1.08-6.40, p=0.033). However, in contrast to previous studies, early repolarization detected on baseline ECG (12.5%), was not found to be a risk factor (p=0.842).The study by Stampe et al. has few limitations. First, the study design, a retrospective cohort, precluded standardized follow-up frequencies and diagnostic testing. Second, while the study was included many of the cofounders tested in previous studies (baseline characteristics, baseline ECG patterns, comorbidities), medication use was not included. Third, the follow-up period may have been insufficient to detect effect from some of the confounding factors. Finally, the sample size was small and it was from a single center.There are several strengths of the Stampe et al. study. Firstly, the wide range of diagnostic tests used at index presentation and during the follow-up period ensured meticulous detection of most underlying etiologies. Secondly, appropriate and well-defined inclusion and exclusion criteria were used. Thirdly, funding by independent parties ensured no influence on study design, result evaluation, and interpretation. Finally, the study has succeeded in improving our understanding of IVF. Future studies should include though a larger population size and a more diverse population.References:1.AlJaroudi WA, Refaat MM, Habib RH, Al-Shaar L, Singh M, et al. 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):924-31.2. Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017 AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: executive summary. J Am Coll Cardiol 2018;72:e91–e220.3. Refaat MM, Hotait M, London B: Genetics of Sudden Cardiac Death. Curr Cardiol Rep Jul 2015; 17(7): 6064. Priori SG, Wilde AA, Horie M, Cho Y, Behr ER, Berul C, et al. HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes: document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013. Heart Rhythm 2013;10:1932–1963.5. Priori SG, Blomström-Lundqvist C, Mazzanti A, et al. ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC). Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC). Eur Heart J 2015;36(41):2793-2867.6. Zipes DP, Wellens HJ. Sudden cardiac death. Circulation. 1998;98:2334–2351.7. Ozaydin M, Moazzami K, Kalantarian S, Lee H, Mansour M, Ruskin JN. Long-term outcome of patients with idiopathic ventricular fibrillation: a meta-analysis. J Cardiovasc Electrophysiol 2015;26:1095–1104.8. Herman AR, Cheung C, Gerull B, Simpson CS, Birnie DH, Klein GJ, et al. Outcome of apparently unexplained cardiac arrest: results from investigation and follow-up of the prospective cardiac arrest survivors with preserved ejection fraction registry. Circ Arrhythm Electrophysiol 2016;9:e003619.9. Siebermair J, Sinner MF, Beckmann BM, Laubender RP, Martens E, Sattler S, et al.Early repolarization pattern is the strongest predictor of arrhythmia recurrence in patients with idiopathic ventricular fibrillation: results from a single centre long-term follow-up over 20 years. Europace 2016;18:718-25.10. Refaat MM, Hotait M, Tseng ZH: Utility of the Exercise Electrocardiogram Testing in Sudden Cardiac Death Risk Stratification. Ann Noninvasive Electrocardiol 2014; 19(4): 311-318.11. Gray B, Ackerman MJ, Semsarian C, Behr ER. Evaluation after sudden death in the young: a global approach. Circ Arrhythm Electrophysiol 2019;12: e007453.12. Herman AR, Cheung C, Gerull B, Simpson CS, Birnie DH, Klein GJ, et al. Response to Letter Regarding Article, Outcome of apparently unexplained cardiac arrest: results from investigation and follow-up of the prospective cardiac arrest survivors with preserved ejection fraction registry”. Circ Arrhythm Electrophysiol 2016;9:e004012.13. Chen Q, Kirsch GE, Zhang D, Brugada R, Brugada J, Brugada P, Potenza D, et al. Genetic basis and molecular mechanism for idiopathic ventricular fibrillation. Nature 1998;392:293–296.14. Baranchuk A, Refaat M, Patton KK, Chung M, Krishnan K, et al. What Should You Know About Cybersecurity For Cardiac Implantable Electronic Devices? ACC EP Council Perspective. J Am Coll Cardiol Mar 2018; 71(11):1284-1288.