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Patients with catecholaminergic polymorphic ventricular tachycardia (CPVT) may experience life-threatening arrhythmic events (LTAEs) despite β-blocker treatment. Further complicating management, the role of implantable cardioverter defibrillator (ICD) in CPVT is debated. To investigate the long-term outcomes of patients with RYR2 CPVT treated with β-blockers only and the cost to benefit ratio of ICD. This prospective cohort study conducted from January 1988 to October 2020 with a mean (SD) follow-up of 9.4 (7.5) years included patients who were referred to the Molecular Cardiology Clinics of ICS Maugeri Hospital, Pavia, Italy. Participants included consecutive patients with CPVT who were carriers of a pathogenic or likely pathogenic RYR2 variant with long-term clinical follow-up. Treatment with selective and nonselective β-blocker only and ICD implant when indicated. The main outcome was the occurrence of the first LTAE while taking a β-blocker. LTAE was defined as a composite of 3 hard end points: sudden cardiac death, aborted cardiac arrest, and hemodynamically nontolerated ventricular tachycardia. The cohort included 216 patients with RYR2 CPVT (121 of 216 female [55%], median [IQR] age 14, [9-30] years). During a mean (SD) follow-up of 9.4 (7.5) years taking β-blockers only, 28 of 216 patients (13%) experienced an LTAE (annual rate, 1.9%; 95% CI, 1.3-2.7). In multivariable analysis, experiencing either an LTAE (hazard ratio [HR], 3.3; 95% CI, 1.2-8.9; P = .02) or syncope before diagnosis (HR, 4.5; 95% CI, 1.8-11.1; P = .001) and carrying a C-terminal domain variant (HR, 18.1; 95% CI, 4.1-80.8; P

Evidence for the role of the CACNA1C gene, which encodes for the α-subunit of the cardiac L-type calcium channel CaV1.2, as a cause of the BrS3 variant of Brugada syndrome (BrS) is contradictory.The purpose of this study was to define in a large BrS cohort the yield of molecular screening and to test whether appropriate patient selection could improve clinical utility.A total of 709 patients were included in this study. BrS probands (n = 563, consecutively referred) underwent CACNA1C sequencing. Two matched cohorts where defined: discovery cohort (n = 200) and confirmation cohort (n = 363). In addition, the clinical phenotypes of a matched SCN5A-positive BrS cohort (n = 146) were included for comparative genotype-phenotype correlation.In the discovery cohort, we identified 11 different rare variants in 9 patients; 10 of the variants (5%) were considered potentially causative based on their frequency in the general population. However, American College of Medical Genetics criteria were unable to classify the majority (80%) of them, which eventually were labeled as variants of unknown significance (VUS). Functional studies revealed a loss of function for 9 variants, pointing to a prevalence of CACNA1C causative variants in 4% of the discovery cohort. Genotype-phenotype correlation showed that pathogenic variants are significantly more frequent in patients with shorter QTc (12.9% vs 2.2% in patients with QTc390 ms).CACNA1C is an infrequent but definitive cause of BrS typically associated with short QT. Functional studies are highly relevant to improve variant interpretation.

Background Mexiletine has been proven effective in shortening the duration of ventricular repolarization and reducing the arrhythmic events in type 3 Long QT Syndrome (LQT3). Initial reports indicate that mexiletine might also be effective in patients with type 2 Long QT Syndrome (LQT2, caused by loss-of-functions variants on KCNH2 gene, coding for HERG potassium channel), but this issue has not been investigated in detail. Purpose We quantified the electrocardiographic (ECG) effects of mexiletine in a cohort of LQT2 patients. Methods Twelve-lead ECGs were collected before and after the administration of mexiletine to evaluate the drug's effect on the heart rate-corrected QT interval (QTc). QTc intervals were classified as being (1) at “high-risk” if >500 ms or (2) “normal” if Results We tested the maximum tolerated dose of mexiletine in 20 patients (11 males, 55%), who were 17±16 years old at diagnosis, affected by genetically established LQT2. The mean age at the beginning of mexiletine administration was 23±15 years and the mean daily dose administered was 9±2 mg/kg/day. Before mexiletine, the mean QTc interval was 527±53 ms and 10/20 (50%) patients had high-risk QTc values (i.e. QTc >500 ms). After mexiletine, the mean QTc interval shortened to 484±47 ms in the overall population (p=0.001). In the majority of patients (18/20, 90%; Figure 1) QTc interval shortened, with a mean shortening of 42±28 ms, and a high-interindividual variability (range of shortening from 86 ms to 8 ms). Just 2 (10%) patients did not show any reduction of the QTc, despite receiving the highest adult dosages of mexiletine in our cohort (up to 10 mg/kg/day). As compared to baseline conditions, after mexiletine the proportion of patients with high risk QTc values (>500 ms) decreased non-significantly from 50% to 35% (p=0.52). Furthermore, in only 6/20 (30%) patients the QTc normalized (i.e. QTc The effect of mexiletine was not influenced by gender (p=0.89) or by the functional effect of the KCNH2 mutation (trafficking-deficient vs. non-trafficking-deficient variants, p=0.41). The effect of mexiletine in LQT2 patients was inferior to the one previously observed in a cohort of 34 LQT3 patients, who had similar QTc values at baseline and received similar dosages of mexiletine, but showed a significantly higher reduction of the average QTc interval (63±37 ms in LQT3 vs. 42±28 ms in LQT2, p=0.02). Conclusions Mexiletine induces a reduction of the QTc interval in most LQT2 patients, but many patients remain with high-risk QTc values after receiving the drug. The demonstration that an average QTc shortening of 42 ms is enough to reduce arrhythmic events is necessary, before the introduction of mexiletine in clinical practice for LQT2. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Italian Ministry of Research and University Dipartimenti di Eccellenza 2018–2022 grant to the Molecular Medicine Department (University of Pavia)

Background Type 1 Long QT Syndrome (LQT1) is an arrhythmogenic disorder, caused by loss-of-function mutations on KCNQ1 gene, coding for Kv7.1 potassium channel. Although LQT1 is described as the most benign form of LQTS, patients still experience arrhythmic events and there is an unmet need for personalized risk stratification. Attempts have been made to correlate the location of mutations with outcome, but the results are unequivocal. Purpose We provide in the present study a new mutation site-specific risk profile obtained from a large cohort of LQT1 patients. Methods We gathered data on 963 patients with the diagnosis of LQT1 and divided the Kv7.1 channel into 5 functional regions: the N-terminus (NT), the voltage sensor (VS, including transmembrane segments S1 to S4), the cytoplasmic loops (CL), the pore (PO, including the transmembrane segments S5, S6 and the S5-S6 extracellular linker), the C-terminus (CT). Results We studied 963 LQT1 patients: 518 (54%) females; average age 20±17 years; mean QTc at baseline ECG 465±38ms. During a mean follow-up of 8±7 years, 172 (18%) patients experienced arrhythmic events: 31 (3%) experienced one or more cardiac arrests, while 141 (15%) experienced one or more syncopal spells. We identified 188 different variants in the KCNQ1 gene, with the following distribution: 15 (8%) in the NT, 33 (18%) in the VS, 27 (14%) in the CL, 43 (23%) in the PO, 70 (37%) in the CT. The frequency of pathogenic variants per number of amino acids (a.a.) was higher in the CL region, as compared to the other domains (1 mutation every 1.4 a.a.). The duration of QTc interval was significantly longer for patients with mutations in the PO region (473±40 ms) and in the CL region (468±38 ms) as compared to the other regions (p Importantly, in a multivariate analysis PO and CL regions were associated with a higher probability of experiencing arrhythmic events (OR 2.89, 95% CI 1.95–4.29, p=0.019 and OR 1.61, 95% CI 1.0–2.49, p=0.05, respectively. Figure) than the other regions. Interestingly, the risk was independent from QTc interval duration. Conclusions Mutations affecting the PO and the CL region of the Kv7.1. channel are associated with a higher probability of experiencing arrhythmic events. This finding is clinically relevant, because it will allow for a more personalized, mutation site-specific risk stratification. Mutation site and arrhythmic events Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Italian Ministry of Research and University Dipartimenti di Eccellenza 2018–2022 grant to the Molecular Medicine Department (University of Pavia)

Background Manual electrocardiographic (ECG) screening tools for the use of subcutaneous cardiac defibrillator (S-ICD) have been associated with high ineligibility rates in Brugada syndrome patients (BrS). Although recent works identified ECG parameters for S-ICD eligibility in general population, automated screening tool (AST) for S-ICD eligibility have not even been assessed in large series of patients with BrS. Purpose This study evaluates the AST-derived eligibility rates for an S-ICD in patients with BrS, and ECG parameters associated with S-ICD eligibility. Methods Screening for S-ICD eligibility was performed using AST in 194 consecutive patients with BrS. Eligibility was defined when at least one of the three vectors was acceptable both in supine and standing position. Twelve-lead ECGs were registered during the screening. ECG parameters associated with AST eligibility were identified using multivariable logistical regression. Results Our study population consisted of 194 patients, with male preponderance (n=165/194; 85%); and were 43±12 years old at the time of screening. Majority of patients presented a spontaneous type 1 pattern during screening (n=128/194; 66%), with an average pattern height of 3±3 mm. Remarkably, 93% of patients passed the screening with AST. No differences in eligibility rates in terms of gender (93% males vs. 93% females eligible; p=1) and age (48±9 years non-eligible vs. 42±12 eligible; p=0.07) existed. Notably, our eligibility rate was 2.5 times higher than rates reported in literature when using manual screening tools (p=0.023). Independent 12-lead ECG parameters (Table) associated with AST eligibility were duration of S wave Conclusions Most BrS patients (93%) are eligible for S-ICD when AST is used. S wave Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): The Italian Ministry of Research and University Dipartimenti di Eccellenza 2018–2022 grant to the Molecular Medicine Department (University of Pavia)

Background Inconsistent data support the role of CACNA1C as a disease-causing gene responsible for Brugada syndrome (BrS). As of today, the only gene consistently linked with BrS is SCN5A. Several CACNA1c genetic variants have been reported in association wirh BrS; however, due to the limited evidence, CACNA1C is not suggested for routine genetic screening for BrS. Purpose In this study, we carried out a systematic screening of CACNA1C gene, including a functional evaluation of the identified variants, in order to determine the yield of screening in a large series of BrS probands and to address the hypothesis that an appropriate clinical selection of patients would substantially improve the yield of genetic testing. Methods and results Overall 564 consecutive patients, referred for BrS genetic testing, were sequenced for CACNA1C gene. Patients were divided in two groups: discovery cohort (n=200 patients) and confirmation cohort (n=363 patients). Furthermore, analysis of the clinical phenotypes of a matched SCN5A positive BrS cohort (n=146) was included for phenotype characterization. In the discovery cohort we identified 11 different genetic variants of whom 2 (18%) were considered as potentially causative based on ACMG guidelines. However, a large proportion (81%) was classified as variants of unknown significance (VUS). Functional evaluation of the identified variants, including pathogenic and VUS, was assessed by patch-clamp and immunofluorescence studies. Re-evaluation of the variants, including functional studies results, indicated an increase of pathogenic or likely pathogenic variants (81%) getting a yield of screening of 5% in the discovery cohort. Results from the confirmation cohort confirmed a low rate of CACNA1C carriers with a yield of screening of 2.2%. Analysing the clinical phenotype of all CACNA1C carriers showed a significantly shorter QTc [371 ms ± 16 ms vs. 399±18 ms; p=0.000004]. Furthermore, the prevalence of CACNA1C variants was highest (12.9%) among patients with a QTc in the lowest quartile (QTc Conclusion We confirmed that CACNA1C variants are not a common cause of BrS, with a yield of screening of 2–5%. However, pathogenic variants are more frequent (12.5%) in patients with a shorter QTc, suggesting a genetic testing strategy in this subgroup of BrS patients. Furthermore, our data highlights the impact of robust functional studies to improve variant classification and reduce uncertainties. Funding Acknowledgement Type of funding source: None

Background/Introduction Arrhythmogenic cardiomyopathy (ACM) is one of the most arrhythmogenic conditions known to man. ACM is caused by desmosomal mutations in most cases, resulting in progressive replacement of the myocardium by adipose and fibrous tissue. It comes as no surprise that ACM is one of the leading causes of sudden cardiac death (SCD). Nonetheless, the characteristics of arrhythmic manifestations have not dissected after the release of most recent criteria. Purpose This study investigates different types of ventricular tachyarrhythmias which had occurred at first arrhythmic event in patients with ACM. Methods We investigated 91 consecutive patients with documented evidence of sustained ventricular tachyarrhythmias from 291 ACM patients followed at our center up to this date. Diagnosis of ACM was made using 2010 Task Force Criteria, and patients were defined as having an advanced disease if they had more than 4 TFC points at diagnosis. Presenting ventricular tachyarrhythmias were divided into (1) life-threatening arrhythmic event (LAE; ventricular fibrillation or hemodynamically unstable polymorphic ventricular tachycardia) and (2) hemodynamically stable monomorphic ventricular tachycardia (MMVT). Right ventricular (RV) involvement was defined as a presence of RV wall motion abnormalities and RV dilation at transthoracic echocardiography or cardiac magnetic resonance. Results Our study population was constituted of a predictably higher number of males (n=68; 75%), with an average age at the first arrhythmic event of 38±15 years of age. At first documented arrhythmia, majority of patients studied experienced a stable MMVT (n=53; 58%), while 38 patients experienced an LAE (n=38; 42%). The patients suffering an LAE as first arrhythmic event were slightly younger than the patients who experienced a stable MMVT (35±14 years vs. 40±15 years; p=0.076) but there were no statistically significant gender differences (28/38 males with LAE vs. 40/53 males with stable MMVT; p= n.s.). Interestingly, patients who presented with stable MMVT were more likely to have an advanced disease at diagnosis (OR=6.52; 95% CI 2.02–20.99; p=0.002). This is supported by the fact that RV involvement was significantly more common in patients presenting with stable MMVT (OR=4.38; 95% CI 1.26–15.26; p=0.021). Additionally, patients with stable MMVT were more commonly carriers of variants on PKP2 gene (OR=3.6; 95% CI 1.1–11.91; p=0.021). Conclusions Our data suggest that two types of arrhythmia reflect the two different stages of the disease. The early stage of the ACM is characterized by LAE in absence of RV structural involvement; while, stable MMVT is typical of PKP2 carriers and advanced stage of ACM with RV involvement. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): The Italian Ministry of Research and University Dipartimenti di Eccellenza 2018–2022 grant to the Molecular Medicine Department (University of Pavia)

Background Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a leading cause of sudden cardiac death, but its progression over time and predictors of arrhythmias are still being defined. Objectives This study sought to describe the clinical course of ARVC and occurrence of life-threatening arrhythmic events (LAE) and cardiovascular mortality; identify risk factors associated with increased LAE risk; and define the response to therapy. Methods We determined the clinical course of 301 consecutive patients with ARVC using the Kaplan-Meier method adjusted to avoid the bias of delayed entry. Predictors of LAE over 5.8 years of follow-up were determined with Cox multivariable analysis. Treatment efficacy was assessed comparing LAE rates during matched time intervals. Results A first LAE occurred in 1.5 per 100 person-years between birth and age 20 years, in 4.0 per 100 person-years between ages 21 and 40 years, and in 2.4 per 100 person-years between ages 41 and 60 years. Cumulative probability of a first LAE at follow-up was 14% at 5 years, 23% at 10 years, and 30% at 15 years. Higher risk of LAE was predicted by atrial fibrillation (hazard ratio [HR]: 4.38; p = 0.002), syncope (HR: 3.36; p Conclusions The high risk of life-threatening arrhythmias in patients with ARVC spans from adolescence to advanced age, reaching its peak between ages 21 and 40 years. Atrial fibrillation, syncope, participation in strenuous exercise after the diagnosis of ARVC, hemodynamically tolerated sustained monomorphic ventricular tachycardia, and male sex predicted lethal arrhythmias at follow-up. The lack of efficacy of antiarrhythmic therapy and the life-saving role of the implantable cardioverter-defibrillator highlight the importance of risk stratification for patient management.

Background A conclusive estimate of the eligibility rate for the use of subcutaneous implantable cardioverter defibrillators (S-ICD) in patients with Brugada Syndrome (BrS) is lacking. Objective We aimed to: 1) evaluate the eligibility for S-ICD in patients with BrS using a novel automated tool; 2) investigate predictors of ineligibility for S-ICD, based on baseline 12-lead electrocardiogram. Methods Automated screening for S-ICD was performed in 118 consecutive BrS patients using the programmer provided by the S-ICD producer. The system automatically assessed the acceptability of each of the three sense vectors used by the S-ICD for the detection of cardiac rhythm. Eligibility was defined when at least one vector was acceptable both in supine and standing position. Results The clinical characteristics of 118 BrS patients were as follow: age 43±11 years; 89% males; 2% with aborted cardiac arrest; 14% with a history of syncope; 81% with spontaneous type 1 ECG pattern; 21% with a familial history of sudden cardiac death; 24% with an SCN5A mutation. No patients had an indication for pacing. Only 8/118 (7%) patients were ineligible for S-ICD. Of note, 5/8 (63%) patients who failed the screening exhibited a slurred S wave of ≥80 ms duration in the peripheral lead aVF on the 12-lead baseline electrocardiogram, vs. 4/110 (4%) of those who passed the screening (sensitivity of S wave in aVF for screening failure 63%, specificity 97%; p ECG predictor of S-ICD screening Conclusion Up to 93% of BrS patients are eligible for S-ICD when the automated screening tool is used. The presence of a slurred S wave in lead aVF on the 12-lead electrocardiogram is a powerful predictor of screening failure.

Background Quinidine at high-dose is used in patients with Brugada Syndrome (BrS), but its efficacy to prevent life-threatening arrhythmic events (LAE) in BrS is unproven and its use is limited by side effects. Objective We assessed whether low-dose quinidine in BrS patients reduces: 1) the occurrence of a first LAE; 2) the arrhythmic burden in the high-risk group of cardiac arrest survivors. Methods We first compared the clinical course of 53 BrS patients treated with quinidine to that of 441 untreated controls, matched by sex, age, and symptoms. Furthermore, we calculated the annual incidence of LAEs off- and on-quinidine in 123 BrS patients who had survived a cardiac arrest. Results First, we compared the clinical course of 53 BrS patients treated with quinidine (i.e. “cases”: 89% males, median age 40 years) to that of 441 untreated, clinically-matched BrS patients (i.e. “controls”: 91% males, median age 41 years) present in our database of patients with inherited arrhythmias. Cases received quinidine (median dose of 450 mg per day) for 5.0±3.7 years. Quinidine was interrupted in only 3/53 cases (6%) for side effects and it conferred a nonsignificant reduction of the risk of a first LAE in cases versus controls (HR 0.74, 95% CI 0.22–2.48, P=0.62). Secondly, we calculated the annual recurrence of LAE off- and on-quinidine in 123 BrS cardiac arrest survivors, 27 of whom were treated with quinidine for 7.0±3.5 years. The annual rate of recurrent LAEs decreased significantly from 14.7% while off-quinidine to 3.9% while on-quinidine (P=0.03). Notably, recurrent life-threatening arrhythmic events were recorded in 4/27 (15%) symptomatic patients while on-quinidine. Conclusion We demonstrated for the first time in the long-term that low-dose quinidine reduces the recurrence of life-threatening arrhythmias in symptomatic BrS patients, with few side effects. Remarkably, about one-fifth of symptomatic patients experience life-threatening arrhythmias while on-treatment, suggesting that quinidine cannot replace implantable defibrillators in high-risk subjects.

BACKGROUND Andersen-Tawil Syndrome type 1 (ATS1) is a rare arrhythmogenic disorder, caused by loss-of-function mutations in the KCNJ2 gene. We present here the largest cohort of patients with ATS1 with outcome data reported. OBJECTIVES This study sought to define the risk of life-threatening arrhythmic events (LAE), identify predictors of such events, and define the efficacy of antiarrhythmic therapy in patients with ATS1. METHODS Clinical and genetic data from consecutive patients with ATS1 from 23 centers were entered in a database implemented at ICS Maugeri in Pavia, Italy, and pooled for analysis. RESULTS We enrolled 118 patients with ATS1 from 57 families (age 23 +/- 17 years at enrollment). Over a median follow-up of 6.2 years (interquartile range: 2.7 to 16.5 years), 17 patients experienced a first LAE, with a cumulative probability of 7.9% at 5 years. An increased risk of LAE was associated with a history of syncope (hazard ratio [HR]: 4.54; p = 0.02), with the documentation of sustained ventricular tachycardia (HR 9.34; p = 0.001) and with the administration of amiodarone (HR: 268; p < 0.001). The rate of LAE without therapy (1.24 per 100 person-years [py]) was not reduced by beta-blockers alone (1.37 per 100 py; p = 1.00), or in combination with Class Ic antiarrhythmic drugs (1.46 per 100 py, p = 1.00). CONCLUSIONS Our data demonstrate that the clinical course of patients with ATS1 is characterized by a high rate of LAE. A history of unexplained syncope or of documented sustained ventricular tachycardia is associated with a higher risk of LAE. Amiodarone is proarrhythmic and should be avoided in patients with ATS1. (C) 2020 Published by Elsevier on behalf of the American College of Cardiology Foundation.

Background:Quinidine at high dose is suggested as antiarrhythmic treatment in patients with Brugada Syndrome (BrS), but its efficacy to prevent life-threatening arrhythmic events (LAE) in this population is unproven and its use limited by frequent side effects. We assessed whether low-dose quinidine in patients with BrS reduces the following: (1) the occurrence of LAEs at follow-up, as compared to no therapy, in a population of both high-risk survivors of LAE and lower risk patients asymptomatic for LAEs and (2) the arrhythmic burden in the high-risk group of cardiac arrest survivors.Methods:We compared the clinical course of 53 patients with BrS treated with quinidine to that of 441 untreated controls, matched by sex, age, symptoms, and the duration of observation. Furthermore, we calculated the annual incidence of LAE off-quinidine and on-quinidine in 123 patients with BrS who were cardiac arrest survivors.Results:Fifty-three patients with BrS (89% males, median age 39.8 years) received quinidine (439±115 mg/d) for 5.0±3.7 years. Therapy was stopped in 3 cases (6%) for side effects. Quinidine reduced by 26% the risk of experiencing an LAE in cases versus controls (hazard ratio, 0.74; 95% CI, 0.22–2.48;P=0.62). Furthermore, in 27 of 123 patients with BrS symptomatic for LAEs who were treated for 7.0±3.5 years, the annual rate of LAEs decreased from 14.7% while off-quinidine to 3.9% while on-quinidine (P=0.03). Of note, recurrent LAEs were recorded in 4 (15%) cardiac arrest survivors while on-quinidine.Conclusions:We demonstrated for the first time in the long-term that low-dose quinidine reduces recurrent LAEs in patients with BrS who had already survived an LAE, with few side effects. Remarkably, 15% of patients symptomatic for LAEs experience recurrent life-threatening arrhythmias while on-treatment, suggesting that quinidine cannot replace implantable defibrillators in high-risk subjects.

The clinical course of Brugada syndrome (BrS) in children and adolescents is incompletely defined due to the rarity of the phenotype in the first decades of life. In 2007, Probst et al. [(1)][1] reported the outcome of 30 pediatric patients with 3 years of follow-up, who experienced a 3% annual

Introduction The 2013 HRS/EHRA/APHRS consensus statement recommends the use of V1 and V2 leads recorded in the second and third intercostal spaces (High-ICS) for diagnosis of Brugada syndrome (BrS) creating a new category of patients discovered only with modified leads. The clinical presentation and the arrhythmic risk in these patients are ill defined. This study was aimed at assessing the role of High-ICS in the analysis of BrS and the clinical profile of the patients diagnosed only when ECG leads are moved to upper intercostal spaces. Methods and results We searched our Brugada syndrome registry and identified 300 subjects (age 36 ± 13 years), without a diagnostic coved ST-segment elevation in conventional V1 -V3 leads, both at baseline and after provocative drug challenge. Sixty-four subjects (21.3%, mean age at last follow-up 42 ± 11 years) were diagnosed with High-ICS. Diagnosis was possible at baseline only in 4 subjects while in 60 it was made after drug challenge with sodium channel blockers. Three subjects (4.7%) with spontaneous abnormal ECG experienced cardiac events with an annual event rate (0.11%) superimposable to that of the low risk category of BrS diagnosed in standard leads. Conclusion This study demonstrates that the use of new diagnostic criteria for BrS allows increasing the diagnostic yield by 20% and that the arrhythmic risk is low when BrS can be established only in High-ICS. We also show that the prognostic value of spontaneous ECG pattern is confirmed in this subgroup.

Background Long QT syndrome type 3 (LQT3) is a lethal disease caused by gain-of-function mutations in the SCN5A gene, coding for the alpha-subunit of the sodium channel NaV1.5. Mexiletine is used to block late sodium current and to shorten QT interval in LQT3 patients. Objectives The aim of this study was to determine whether mexiletine prevents arrhythmic events (arrhythmic syncope, aborted cardiac arrest, or sudden cardiac death) in LQT3 patients. Methods The endpoint of this retrospective cohort study, which studied consecutive LQT3 patients who were referred to our center and treated with mexiletine, was to evaluate the antiarrhythmic efficacy of mexiletine by comparing the number of arrhythmic events per patient and the annual rate of arrhythmic events during observation periods of equal duration before and after the beginning of therapy with mexiletine. Results The study population comprised 34 LQT3 patients, 19 (56%) of whom were male. The median age at beginning of treatment with mexiletine was 22 years, and median QTc interval before therapy 509 ms. The median duration of oral mexiletine therapy was 36 months, at an average daily dose of 8 ± 0.5 mg/kg. Mexiletine significantly shortened QTc (by 63 ± 6 ms; p < 0.0001) and reduced the percentage of patients with arrhythmic events (from 22% to 3%; p = 0.031), the mean number of arrhythmic events per patient (from 0.43 ± 0.17 to 0.03 ± 0.03; p = 0.027), and the annual rate of arrhythmic events (from 10.3% to 0.7%; p = 0.0097). Conclusions Besides shortening QTc interval, mexiletine caused a major reduction of life-threatening arrhythmic events in LQT3 patients, thus representing an efficacious therapeutic strategy.

Long QT syndrome (LQTS) is a common inheritable arrhythmogenic disorder, often secondary to mutations in the KCNQ1, KCNH2, and SCN5A genes. The disease is characterized by a prolonged ventricular repolarization (QTc interval) that confers susceptibility to life-threatening arrhythmic events (LAEs). This study sought to create an evidence-based risk stratification scheme to personalize the quantification of the arrhythmic risk in patients with LQTS. Data from 1,710 patients with LQTS followed up for a median of 7.1 years (interquartile range [IQR]: 2.7 to 13.4 years) were analyzed to estimate the 5-year risk of LAEs based on QTc duration and genotype and to assess the antiarrhythmic efficacy of beta-blockers. The relationship between QTc duration and risk of events was investigated by comparison of linear and cubic spline models, and the linear model provided the best fit. The 5-year risk of LAEs while patients were off therapy was then calculated in a multivariable Cox model with QTc and genotype considered as independent factors. The estimated risk of LAEs increased by 15% for every 10-ms increment of QTc duration for all genotypes. Intergenotype comparison showed that the risk for patients with LQT2 and LQT3 increased by 130% and 157% at any QTc duration versus patients with LQT1. Analysis of response to beta-blockers showed that only nadolol reduced the arrhythmic risk in all genotypes significantly compared with no therapy (hazard ratio: 0.38; 95% confidence interval: 0.15 to 0.93; p = 0.03). The study provides an estimator of risk of LAEs in LQTS that allows a granular estimate of 5-year arrhythmic risk and demonstrate the superiority of nadolol in reducing the risk of LAEs in LQTS. This work was supported by the Ricerca Corrente funding scheme of the Italian Ministry of Health. Dr. Ortiz has received personal fees from Health in Code, SL. Dr. Monserrat is a shareholder in Health in Code, SL. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Sí

Background: Short QT Syndrome (SQTS) is one of the rarest and most lethal inherited arrhythmogenic syndromes. Preliminary data have shown that hydroquinidine (HQ) is effective in prolonging the duration of QT interval and in preventing the induction of ventricular arrhythmias during programmed electrical stimulation in SQTS patients. No data exist regarding the efficacy of HQ in reducing cardiac events in SQTS patients. Objective: To determine whether HQ reduces the occurrence of Life-threatening Arrhythmic Events (LAE), defined as aborted cardiac arrest and sudden cardiac death, in SQTS patients. Methods: Cohort study on consecutive SQTS patients referred to our center and treated with HQ. The endpoint was to evaluate the antiarrhythmic efficacy of HQ, by comparing the percentage of patients with LAE, the number of LAE per patient and the annual rate of LAE before and after the beginning of therapy with HQ (mean duration of therapy 6±1 years). Results: The study population was comprised of 17 SQTS patients with the following characteristics: 13 (76%) males, age at beginning of therapy with HQ 29±3 years, QTc interval before treatment 331±3 ms. Therapy with HQ was ceased in 2 cases (12%) after 1 week due to gastrointestinal intolerance, while in the remaining 15 patients HQ was administered continuously for 6±1 years, at an average dose of 528±42 mg per day (7±0.6 mg/kg/day). HQ significantly prolonged the QTc interval in all patients, by a mean of 60±6 ms (p Conclusions: We showed for the first time that HQ, besides normalizing the duration of the QT interval, is associated with a major reduction of life-threatening arrhythmic events in SQTS patients, thus representing an efficacious therapeutic approach in this group of individuals. Early discontinuation due to gastrointestinal intolerance occurred in 12% of patients.

Short QT syndrome (SQTS) is a rare and life-threatening arrhythmogenic syndrome characterized by abbreviated repolarization. Hydroquinidine (HQ) prolongs the QT interval in SQTS patients, although whether it reduces cardiac events is currently unknown. This study investigated whether long-term treatment with HQ reduces the occurrence of life-threatening arrhythmic events (LAE) (cardiac arrest or sudden cardiac death) in SQTS patients. In this cohort study on consecutive SQTS patients, 2 analyses were performed: 1) a matched-period analysis for the occurrence of LAE in 17 SQTS patients who received long-term HQ; and 2) a comparison of the annual incidence of LAE off- and on-HQ in 16 SQTS patients who survived a cardiac arrest. A total of 17 patients (82% male, age 29 ± 3 years, QTc before treatment 331 ± 3 ms) received HQ therapy (584 ± 53 mg/day). Therapy was stopped in 2 cases (12%) due to gastrointestinal intolerance, and 15 patients continued treatment for 6 ± 1 year. QTc prolongation was observed in all patients (by 60 ± 6 ms; p < 0.001). We compared the occurrence of LAE during 6 ± 1 years before and after HQ, observing that patients on HQ experienced a reduction in both the rate of LAE from 40% to 0% (p = 0.03) and the number of LAE per patient from 0.73 ± 0.3 to 0 (p = 0.026). Furthermore, the annual rate of LAE in the 16 patients with a previous cardiac arrest dropped from 12% before HQ to 0 on therapy (p = 0.028). We demonstrated for the first time that treatment with HQ was associated with a lower incidence of LAE in SQTS patients. These data point to the importance that quinidine, that in several countries has been removed from the market, remains available worldwide for patients with SQTS. In the present study, therapy with HQ has been proven to be safe, with a relatively low rate of side effects. This work was supported by the Ricerca Corrente Funding scheme of the Italian Ministry of Health. Dr. Bellazzi is a shareholder of Biomeris; and is a stakeholder of Engenome. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Pedro Brugada, MD, served as Guest Editor for this paper. Sí

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a leading cause of sudden cardiac death, but its progression over time and predictors of arrhythmias are still being defined.This study sought to describe the clinical course of ARVC and occurrence of life-threatening arrhythmic events (LAE) and cardiovascular mortality; identify risk factors associated with increased LAE risk; and define the response to therapy.We determined the clinical course of 301 consecutive patients with ARVC using the Kaplan-Meier method adjusted to avoid the bias of delayed entry. Predictors of LAE over 5.8 years of follow-up were determined with Cox multivariable analysis. Treatment efficacy was assessed comparing LAE rates during matched time intervals.A first LAE occurred in 1.5 per 100 person-years between birth and age 20 years, in 4.0 per 100 person-years between ages 21 and 40 years, and in 2.4 per 100 person-years between ages 41 and 60 years. Cumulative probability of a first LAE at follow-up was 14% at 5 years, 23% at 10 years, and 30% at 15 years. Higher risk of LAE was predicted by atrial fibrillation (hazard ratio [HR]: 4.38; p = 0.002), syncope (HR: 3.36; p 0.001), participation in strenuous exercise after the diagnosis (HR: 2.98; p = 0.028), hemodynamically tolerated sustained monomorphic ventricular tachycardia (HR: 2.19; p = 0.023), and male sex (HR: 2.49; p = 0.012). No difference was observed in the occurrence of LAE before and after treatment with amiodarone, beta-blockers, sotalol, or ablation. A total of 81 patients received an implantable cardioverter-defibrillator, 34 were successfully defibrillated.The high risk of life-threatening arrhythmias in patients with ARVC spans from adolescence to advanced age, reaching its peak between ages 21 and 40 years. Atrial fibrillation, syncope, participation in strenuous exercise after the diagnosis of ARVC, hemodynamically tolerated sustained monomorphic ventricular tachycardia, and male sex predicted lethal arrhythmias at follow-up. The lack of efficacy of antiarrhythmic therapy and the life-saving role of the implantable cardioverter-defibrillator highlight the importance of risk stratification for patient management.

Resumen En este articulo de revision se comentan las bases geneticas de la parada cardiaca, prestando especial atencion a las canalopatias cardiacas y la miocardiopatia ventricular derecha. Revisamos el uso apropiado de las pruebas geneticas para pacientes en quienes se sospecha de arritmias cardiacas hereditarias, subrayando la importancia de la mayoria de las correlaciones genotipo-fenotipo para la estratificacion del riesgo. El articulo presenta tambien las opiniones mas recientes sobre los criterios diagnosticos y los diagramas de flujo para el tratamiento de los pacientes con enfermedades arritmogenicas hereditarias.

This review article discusses the genetic bases of cardiac arrest with a specific focus on cardiac channelopathies and right ventricular cardiomyopathy. We review the appropriate use of genetic testing in those patients suspected to have inherited cardiac arrhythmias, highlighting the importance of most genotype-phenotype correlations for risk stratification. The article also presents the most recent views on diagnostic criteria and flowcharts for treatment of patients with inherited arrhythmogenic diseases.

The 2013 HRS/EHRA/APHRS consensus statement recommends the use of V1 and V2 leads recorded in the second and third intercostal spaces (High-ICS) for diagnosis of Brugada syndrome (BrS) creating a new category of patients discovered only with modified leads. The clinical presentation and the arrhythmic risk in these patients are ill defined. This study was aimed at assessing the role of High-ICS in the analysis of BrS and the clinical profile of the patients diagnosed only when ECG leads are moved to upper intercostal spaces.We searched our Brugada syndrome registry and identified 300 subjects (age 36 ± 13 years), without a diagnostic coved ST-segment elevation in conventional V1 -V3 leads, both at baseline and after provocative drug challenge. Sixty-four subjects (21.3%, mean age at last follow-up 42 ± 11 years) were diagnosed with High-ICS. Diagnosis was possible at baseline only in 4 subjects while in 60 it was made after drug challenge with sodium channel blockers. Three subjects (4.7%) with spontaneous abnormal ECG experienced cardiac events with an annual event rate (0.11%) superimposable to that of the low risk category of BrS diagnosed in standard leads.This study demonstrates that the use of new diagnostic criteria for BrS allows increasing the diagnostic yield by 20% and that the arrhythmic risk is low when BrS can be established only in High-ICS. We also show that the prognostic value of spontaneous ECG pattern is confirmed in this subgroup.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease characterized by a structurally normal heart and high lethality beginning in early childhood. The identification of its genetic bases made possible the discovery that arrhythmias are caused by intracellular calcium dysregulation. In the 9 years since the description of the genetic substrate of the disease, we have witnessed remarkable progress in the unraveling of the molecular mechanisms underlying its arrhythmogenesis. The impact of these discoveries extends beyond the field of inherited arrhythmias and sheds new light on the arrhythmogenic mechanisms in some more prevalent diseases characterized by abnormal calcium regulation, such as heart failure. Additionally, basic research studies led to the exploration of new therapeutic strategies with potential clinical impact in the near future in reducing the still high incidence of sudden death associated with these conditions. In the current review, the authors discuss the clinical and genetic features of CPVT, highlighting pathophysiologic insights derived from experimental research and future therapeutic targets.

Thanks to the contribution of molecular genetics, the genetic bases, the pathogenesis and genotype-phenotype correlation of diseases such as the long QT syndrome and catecholaminergic polymorphic ventricular tachycardia have been progressively unveiled and show an extremely high degree of genetic heterogeneity. Data from clinical registries are summarized together with the recommendations provided in clinical practice guidelines for management of patients with these diseases. Furthermore the evidence supporting the importance of genetic analysis for risk stratification and therapy selections is reviewed.

ObjectivesThis study intends to gain further insights into the natural history, the yield of familial and genetic screening, and the arrhythmogenic mechanisms in the largest cohort of short QT syndrome (SQTS) patients described so far.BackgroundSQTS is a rare genetic disorder associated with life-threatening arrhythmias, and its natural history is incompletely ascertained.MethodsSeventy-three SQTS patients (84% male; age, 26 ± 15 years; corrected QT interval, 329 ± 22 ms) were studied, and 62 were followed for 60 ± 41 months (median, 56 months).ResultsCardiac arrest (CA) was the most frequent presenting symptom (40% of probands; range

Sudden cardiac death is a common outcome of several cardiac disorders such as acute myocardial ischemia, myocardial infarction, and heart failure. However, ≈5% to 15% of cardiac arrest victims fail to show evidence of structural abnormalities at autopsy.1–3 In 1997, a panel of experts defined sudden death in the absence of an identifiable cause as idiopathic ventricular fibrillation (IVF): “IVF is the terminology that best acknowledges our current inability to identify a causal relationship between the clinical circumstance and the arrhythmia.”4 In the same article, the requirements for the diagnosis of IVF were identified on the basis of the clinical tools available at the time. In 1992, using the phenotypes observed in the IVF registry, we advanced the hypothesis that IVF could be the manifestation of concealed forms of arrhythmogenic disorders5 exacerbated by appropriate triggers. A few years later, the discovery of the genes of long-QT syndrome (LQTS)6–8 and the detection of incomplete penetrance9 supported this early hypothesis. Incomplete penetrance and variable expressivity in inherited arrhythmogenic disorders imply that the distinctive ECG patterns that characterize these disorders may be concealed.10 Interestingly, however, the absence of the ECG markers of the disease is not an indicator of favorable outcome, as demonstrated by the evidence that the incidence of cardiac arrest in LQTS patients with normal QTc during the first 40 years of life is ≈4%, ie, 0.1%/y.11,12 In the last 15 years, the results of mutation screening in sudden unexplained death syndrome or sudden infant death syndrome, the so-called molecular autopsy, have been reported in several studies (Table 1).13–20 Although the yield of molecular autopsy reported by different studies is highly variable, ranging from 4% to 30%, it is sufficient to prove the concept …

This review article discusses the genetic bases of cardiac arrest with a specific focus on cardiac channelopathies and right ventricular cardiomyopathy. We review the appropriate use of genetic testing in those patients suspected to have inherited cardiac arrhythmias, highlighting the importance of most genotype-phenotype correlations for risk stratification. The article also presents the most recent views on diagnostic criteria and flowcharts for treatment of patients with inherited arrhythmogenic diseases.

Inherited arrhythmogenic diseases occur in the absence of morphological abnormalities of the heart, and common symptoms are syncope and sudden death due to ventricular tachycardia/fibrillation. In this chapter, we discuss genetic abnormalities that lead to altered intracellular calcium handling and susceptibility to ventricular tachyarrhythmias. The three diseases that we will discuss are as follows: (1) catecholaminergic polymorphic ventricular tachycardia (CPVT) that results as the consequence of mutations in two different genes involved in cardiac cellular calcium control i.e., RyR2 encoding for the cardiac ryanodine receptor and CASQ2 encoding for the cardiac calsequestrin; (2) long QT syndrome type 8 (also called Timothy syndrome) resulting from gain-of-function mutations in CACNA1C gene that encodes the α subunit of the L-type calcium channel; and (3) Brugada syndrome types 3 and 4 caused by loss-of-function mutations in the CACNA1C and CACNB2 gene encoding α and β subunit of the L-type calcium channel. We review the clinical manifestations and management strategies for each of the conditions with a specific effort to present the distinguishing phenotypic manifestations of each genetic variant.

Background— Identification of mutations in cardiac ion channel genes concurs to the diagnosis of long-QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia. However, because availability of genetic screening is still limited and reimbursement policies are lacking, there is a need of evidence-based criteria to prioritize access to genetic testing for these diseases. Methods and Results— We determined the yield of genetic testing and cost per positive genotyping in 1394 consecutive probands. Among the 546 patients referred for long-QT syndrome-genes screening, those with clinical diagnosis of long-QT syndrome had the highest yield (64%) and lowest cost (US $8418) for each positive genotyping. Among 798 individuals screened for mutation on the SCN5A gene, the highest yield was obtained in patients with type 1 Brugada syndrome ECG pattern (51 of 405; 13%) corresponding to a cost of US $21441 per positive genotyping. In conclusive Brugada syndrome patients the presence of atrioventricular block (odds ratio: 3.3, CI: 1.8 to 6.1; P =0.0001) increases the yield (23%) of genotyping and reduces its cost (US $ 11700). Among 175 patients screened on RyR2 gene, those with documented bidirectional ventricular tachycardia had the highest incidence (62%) of mutations and the lowest cost (US $5263) per positive genotyping. Genetic screening of unselected family members of sudden cardiac death victims and idiopathic ventricular fibrillation survivors is largely ineffective (yield of 9%) and costly (US $71430 per 1 positive genotyping). Conclusions— Genotyping can be performed at reasonable cost in individuals with conclusive diagnosis of long-QT syndrome and catecholaminergic polymorphic ventricular tachycardia, and in patients with type I Brugada syndrome ECG with atrioventricular block. These patients should be given priority to access genetic testing.

Aims Recent data suggest that sub-clinical structural abnormalities may be part of the Brugada syndrome (BrS) phenotype, a disease traditionally thought to occur in the structurally normal heart. In this study, we carried out detailed assessment of cardiac morphology and function using cardiac magnetic resonance imaging (CMRI). Methods and results Thirty consecutive patients with BrS were compared with 30 sex- (26/4 male/female), body surface area- (±0.2 m2), and age-matched (±5 years) normal volunteers. CMRI exam included long- and short-axis ECG-gated breath-hold morphological T1-TSE sequences for fatty infiltration and cine-SSFP sequences for kinetic assessment. Fatty infiltration was not found in any subject. Patients with BrS compared with normal subjects showed higher incidence of mild right ventricle (RV) wall-motion abnormalities [15 (50%) vs. 5 (17%) subjects ( P = 0.006) with reduced radial fractional shortening in more than two segments], reduction of outflow tract ejection fraction (49 ± 11% vs. 55 ± 10%; P = 0.032), enlargement of the inflow tract diameter (46 ± 4 vs. 41 ± 5 mm, P < 0.001 in short-axis; 46 ± 4 vs. 42 ± 5 mm, P = 0.001 in four-chamber long-axis view) and area (22 ± 2 vs. 20 ± 3 cm2; P = 0.050), and of global RV end-systolic volume (34 ± 10 vs. 30 ± 6 mL/m2; P = 0.031) but comparable outflow tract dimensions, global RV end-diastolic volume, left ventricle parameters, and atria areas. Conclusion CMRI detects a high prevalence of mild structural changes of the RV, and suggests further pathophysiological complexity in BrS. Prospective studies to assess the long-term evolution of such abnormalities are warranted.

Short QT syndrome (SQTS) is a rare genetic disorder characterized by abnormally short QT interval and high risk of sudden cardiac death (SCD). This study addresses the issue of natural history, genetics and electrocardiographic features in the largest prospective SQTS cohort (47 individuals in 24 families). Diagnosis was made in the presence of QTc interval ≤ 350 ms w./out history of cardiac arrest (CA) or SCD without structural abnormalities. Median age at diagnosis was 27 years (range 4–56); mean QTc was 323±17 ms, 22/36 (61%) pts had abnormal T wave (n=17) and/or J point elevation (n=8) and/or QRS slurring (n=3); at a mean observation time of 30±14 years, 22 (47%) pts had cardiac events: 11 SCD, 4 resuscitated CA and 7 syncopal episodes. Median age at SCD or CA was 19 (range 0 – 48) years (4 death/CA occurred in the first year of life). The Kaplan Meyer curve shows survival-free interval before drugs. Triggers for the 15 death/CA were exercise (44%) and rest (56%). Eight pts were treated with quinidine (250 mg bid) that prolonged QTc: from 320±18 ms to 380±18 ms (pKCNH2, KCNQ1 and KCNJ2 genes was positive in 3/24 probands and 3 family members. Interestingly, genotyped pts (n=6) presented significantly shorter QTc than non-genotyped pts (303±13 ms vs. 328±14 ms, p

Effective automatic mode switching (AMS) algorithms capable of detecting a range of supraventricular tachyarrhythmias is important given evidence of atrial fibrillation (AF), atrial flutter (AFL), and atrial tachycardia (AT) post-implantation of pacemakers.The aim of the study was to assess the efficacy, defined as ability to detect a specific atrial rate and activate AMS, of five different AMS mechanisms during simulation of AF, AFL, and AT.A total of 48 subjects (35 men, 13 women; mean age: 69 +/- 8 years) implanted with DDDR pacemakers utilizing five different AMS mechanisms (mean atrial rate, rate cut-off, complex 'fallback' algorithm, retriggerable atrial refractory period, and physiological band 'beat-to-beat') were tested using an external electronic device that simulated the occurrence of supraventricular tachyarrhythmias. AF, AFL, and AT were simulated by delivering low voltage pulse trains at 350, 250 and 160 beats/min, respectively.Mean efficacy for all AMS mechanisms was 81% [range: 57% to 100%] at 350 beats/min, 81% [range: 57-100%] at 250 beats/min, and 79% [range: 57-100%] at 160 beats/min. The AMS mechanisms that yielded 100% efficacy were the rate cut-off and physiological band 'beat-to-beat.'Not all AMS algorithms are equally efficacious at detecting atrial arrhythmias and subsequently activating AMS. Our results suggest that the most efficacious AMS algorithms are those that use rate cut-off and physiological band 'beat-to-beat' to detect supraventricular tachyarrhythmias.

Transthoracic electrical cardioversion represents the most effective therapy in converting atrial fibrillation (AF) to sinus rhythm. External cardioverter-defibrillators discharge a current with monophasic and most recently biphasic waveforms. Lately, many articles support the superiority of the biphasic waveform over the monophasic one. Moreover, we have the opportunity to use different biphasic waveforms. The aim of this study was to compare the efficacy (success rate and energy delivered) of a monophasic wave and two different biphasic waves, in patients with persistent AF undergoing external electrical cardioversion. The monophasic wave was delivered by a Zoll M series NM PDMA-9, while the so-called "rectilinear" biphasic waveform was used by a Zoll M series PDM-7S and the biphasic truncated exponential wave by a Laerdal Heartstart 4000.Sixty-four patients with clinical indications to undergo external electrical cardioversion were randomized into three groups. All the groups were homogeneous for almost all characteristics, particularly atrial dimensions, body surface area, and duration of AF and therapy. Eighteen patients underwent external cardioversion with monophasic waveform (group 1), 22 patients were treated with rectilinear biphasic waveform (group II), and 24 patients with biphasic truncated waveform (group III). A cardioversion protocol, providing up to 5 shocks, with incremental energy levels was used. A blood sample was obtained 6 hours later to evaluate myocardial damage due to shock therapy for each patient.Both biphasic devices demonstrated to be more effective than the monophasic one (group I 78%, group II 95%, group III 100%). Moreover, none of them caused any significant myocardial damage, evaluated in terms of cardiac enzyme release. Nonetheless, the biphasic truncated exponential wave demonstrated an efficiency of 10 0% compared to 95 % of the rectilinear one and 78% of the monophasic one, using less energy/patient (873 +/- 101 J group I, 390 +/- 48 J group II, and 280 +/- 42 J group III), at almost the same shock attempts.Biphasic truncated exponential wave seems to be more effective at a lower energy level.