Martin Stephen Green

BACKGROUND: Early repolarization syndrome (ERS) is diagnosed in survivors of unexplained cardiac arrest (UCA) who exhibit a distinct ECG pattern of early repolarization (ER), defined as J-point elevation ≥0.1 mV in ≥2 contiguous inferolateral leads. UCA survivors without ER or another identifiable cause are classified as idiopathic ventricular fibrillation (IVF). This study evaluated long-term outcomes in ERS compared with IVF. METHODS: This retrospective cohort study analyzed patients from the CASPER (Cardiac Arrest Survivors with Preserved Ejection Fraction Registry) who survived UCA and had structurally normal hearts with an Implantable Cardioverter Defibrillator. Of 709 patients, 186 with explanatory diagnoses and no ER pattern were excluded. The remaining 523 were categorized as ERS (n=48), IVF (n=463), or UCA with ER plus an additional diagnosis (Dx+ER, n=12). Patients were followed for the primary outcome of appropriate Implantable Cardioverter Defibrillator therapy, and logistic regression identified predictors of arrhythmia recurrence. RESULTS: Corrected QT interval intervals were significantly shorter in ERS than in IVF (412±25 ms versus 431±41 ms; P P =0.09), with incidence rates of 3.0 and 1.5 per 100 person-years, respectively. Four deaths occurred (0.8%), with no significant difference between groups ( P =0.39). In Dx+ER, appropriate Implantable Cardioverter Defibrillator therapies occurred in 42% of patients (incidence rate, 4.5 per 100 person-years). Arrhythmia-free survival was lower in ERS than in IVF ( P =0.03). After adjusting for age, sex, and ethnicity, ER was an independent predictor of arrhythmia recurrence (odds ratio, 2.59 [95% CI, 1.33–4.85]; P =0.004). CONCLUSIONS: ERS is associated with shorter corrected QT interval intervals and reduced arrhythmia-free survival compared with IVF, with an incidence rate of 3.0 per 100 person-years. These findings underscore the importance of careful ECG review in patients with apparent UCA, to detect ER and undertake individualized risk assessment in affected individuals.

BACKGROUND: The safety, yield, and prognosis of a type 1 procainamide-induced Brugada pattern are incompletely understood and may differ from those of other sodium channel blockers with greater potencies. METHODS: The safety of procainamide infusion and yield of a type 1 Brugada pattern were assessed according to indication in consecutive patients from the Canadian Hearts in Rhythm Organization registry. Outcomes were evaluated in patients with a standard or high-lead procainamide-induced Brugada pattern (without previous cardiac arrest) and compared with those with a spontaneous type 1 pattern. RESULTS: In 947 consecutive patients undergoing procainamide infusion for the diagnosis or exclusion of Brugada syndrome, 2 patients (0.2%) experienced asymptomatic ventricular arrhythmias related to procainamide, which resolved upon discontinuation of the infusion. The yield of a type 1 pattern was 7.2% in 390 patients with unexplained cardiac arrest, 22.2% in 135 patients with a family history of Brugada syndrome, and 6.9% in 116 patients with a family history of unexplained cardiac arrest or sudden death. Test yield was 46.6% in 189 patients with a non-specific type 2 or 3 Brugada pattern and 92% in those with an intermittent spontaneous type 1 pattern (ie, implied sensitivity of 92%). Estimated specificity was very high. In 137 patients with a procainamide-induced type 1 Brugada pattern (with no previous cardiac arrest) followed for a mean of 5.9±4.5 years, no patients met the primary composite arrhythmic end point (0%). In 105 spontaneous type 1 patients, one patient (1%) met the primary end point after receiving appropriate shocks for ventricular fibrillation. Thirteen percent had a primary prevention implantable cardioverter defibrillator implanted at baseline (one appropriate shock), with an additional 7% undergoing implantable cardioverter defibrillator implantation during follow-up, predominantly for syncope with a suspected arrhythmic mechanism. No patient who underwent implantable cardioverter defibrillator implantation during follow-up subsequently received appropriate therapy. CONCLUSIONS: Procainamide infusion is extremely safe for the diagnosis and exclusion of Brugada syndrome, with yield dependent on pretest probability and indication for testing. Estimated sensitivity and specificity appear to be high. Patients with an asymptomatic procainamide-induced type 1 Brugada pattern are at very low risk of malignant ventricular arrhythmias.

Background: Pulmonary vein isolations (PVI) are being performed using a high-power, short duration (HPSD) strategy. The purpose of this study was to compare the clinical efficacy and safety outcomes of a HPSD vs low-power long duration (LPLD) approach to PVI in patients with paroxysmal atrial fibrillation (AF). Methods: Patients were grouped according to a HPSD (≥40 W) or LPLD (≤ 35 W) strategy. The primary endpoint was the one-year recurrence of any atrial arrhythmia lasting ≥ 30 seconds, detected using three 14-day ambulatory continuous ECG monitoring. Procedural and safety endpoints were also evaluated. The primary analysis were regression models incorporating propensity scores yielding adjusted relative risk (RR _a ) and mean difference (MD _a ) estimates. Results: Of the 398 patients included in the AWARE Trial, 173 (43%) underwent HPSD and 225 (57%) LPLD ablation. The distribution of power was 50 W in 75%, 45 W in 20% and 40 W in 5% in the HPSD group, and 35W with 25W on the posterior wall in the LPLD group. The primary outcome was not statistically significant at 30.1% vs 22.2% in HPSD and LPLD group with RR _a 0.77 (95% confidence interval [CI]) 0.55-1.10; p=0.165). The secondary outcome of repeat catheter ablation was not statistically significant at 6.9% and 9.8% (RR _a 1.59 [95% CI 0.77-3.30]; p=0.208) respectively. The incidence of any ECG documented AF during the blanking period was numerically lower in the HPSD group: 1.7% vs 8.0% (RR _a 3.95 [95% CI 1.00-15.61; p=0.049). The total procedure time was significantly shorter in the HPSD group (MD _a 97.5 minutes [95% CI 84.8-110.4)]; p<0.0001) with no difference in adjudicated serious adverse events. Conclusions: A HPSD strategy was associated with significantly shorter procedural times with similar efficacy in terms of clinical arrhythmia recurrence. Importantly, there was no signal for increased harm with a HPSD strategy. Graphical Non-standard Abbreviations and Acronyms: HPSD: High-Power Short Duration; LPLD: Low-Power Long Duration; QOL: Quality of Life; WACA: wide area circumferential ablation; PVI: Pulmonary Vein Isolation; AF: Atrial Fibrillation Clinical Perspective: What is known: -The optimal power and duration of ablation lesions to produce durable pulmonary vein isolation remain unclear. -Nonrandomized studies have suggested clinical efficacy with high-power short duration radiofrequency ablation vs low-power long duration. What this study adds: -In this large substudy of the AWARE Trial, a high-power short duration radiofrequency ablation strategy was found to be similarly effective as a low-power long duration strategy with no difference in time to first recurrence of any AF lasting ≥ 30 seconds. -Procedural were substantially reduced with high-power short duration ablation with no significant difference in overall complication rates.

Background: Diagnosis of congenital long‐QT syndrome (LQTS) is complicated by phenotypic ambiguity, with a frequent normal‐to‐borderline resting QT interval. A 3‐step algorithm based on exercise response of the corrected QT interval (QTc) was previously developed to diagnose patients with LQTS and predict subtype. This study evaluated the 3‐step algorithm in a population that is more representative of the general population with LQTS with milder phenotypes and establishes sex‐specific cutoffs beyond the resting QTc. Methods and Results: We identified 208 LQTS likely pathogenic or pathogenic KCNQ1 or KCNH2 variant carriers in the Canadian NLQTS (National Long‐QT Syndrome) Registry and 215 unaffected controls from the HiRO (Hearts in Rhythm Organization) Registry. Exercise treadmill tests were analyzed across the 5 stages of the Bruce protocol. The predictive value of exercise ECG characteristics was analyzed using receiver operating characteristic curve analysis to identify optimal cutoff values. A total of 78% of male carriers and 74% of female carriers had a resting QTc value in the normal‐to‐borderline range. The 4‐minute recovery QTc demonstrated the best predictive value for carrier status in both sexes, with better LQTS ascertainment in female patients (area under the curve, 0.90 versus 0.82), with greater sensitivity and specificity. The optimal cutoff value for the 4‐minute recovery period was 440 milliseconds for male patients and 450 milliseconds for female patients. The 1‐minute recovery QTc had the best predictive value in female patients for differentiating LQTS1 versus LQTS2 (area under the curve, 0.82), and the peak exercise QTc had a marginally better predictive value in male patients for subtype with (area under the curve, 0.71). The optimal cutoff value for the 1‐minute recovery period was 435 milliseconds for male patients and 455 milliseconds for femal patients. Conclusions: The 3‐step QT exercise algorithm is a valid tool for the diagnosis of LQTS in a general population with more frequent ambiguity in phenotype. The algorithm is a simple and reliable method for the identification and prediction of the 2 major genotypes of LQTS.

Genetic testing is recommended in specific inherited heart diseases but its role remains unclear and it is not currently recommended in unexplained cardiac arrest (UCA). We sought to assess the yield and clinical utility of genetic testing in UCA using whole-exome sequencing (WES). Survivors of UCA requiring external defibrillation were included from the Cardiac Arrest Survivor with Preserved Ejection fraction Registry. Whole-exome sequencing was performed, followed by assessment of rare variants in previously reported cardiovascular disease genes. A total of 228 UCA survivors (mean age at arrest 39 ± 13 years) were included. The majority were males (66%) and of European ancestry (81%). Following advanced clinical testing at baseline, the likely aetiology of cardiac arrest was determined in 21/228 (9%) cases. Whole-exome sequencing identified a pathogenic or likely pathogenic (P/LP) variant in 23/228 (10%) of UCA survivors overall, increasing the proportion of ‘explained’ cases from 9% only following phenotyping to 18% when combining phenotyping with WES. Notably, 13 (57%) of the 23 P/LP variants identified were located in genes associated with cardiomyopathy, in the absence of a diagnosis of cardiomyopathy at the time of arrest. Genetic testing identifies a disease-causing variant in 10% of apparent UCA survivors. The majority of disease-causing variants was located in cardiomyopathy-associated genes, highlighting the arrhythmogenic potential of such variants in the absence of an overt cardiomyopathy diagnosis. The present study supports the use of genetic testing including assessment of arrhythmia and cardiomyopathy genes in survivors of UCA. Study flowchart and summary results. ARVC, arrhythmogenic right ventricular cardiomyopathy; BrS, Brugada syndrome; CPVT, catecholaminergic polymorphic ventricular tachycardia; CRDS, RYR2 Ca²⁺ release deficiency syndrome; DCM, dilated cardiomyopathy; ECG, electrocardiogram; HCM, hypertrophic cardiomyopathy; LQTS, long QT syndrome; LV, left ventricular; MRI, magnetic resonance imaging; MVP, mitral valve prolapse; SQTS, short QT syndrome; UCM, unclassified cardiomyopathy; WES, whole-exome sequencing.

Background: Following an unexplained cardiac arrest, clinical genetic testing is increasingly becoming standard of care. Periodic review of variant classification is required, as reinterpretation can change the diagnosis, prognosis, and management of patients and their relatives. Methods: This study aimed to develop and validate a standardized algorithm to facilitate clinical application of the 2015 American College of Medical Genetics and Association for Molecular Pathology guidelines for the interpretation of genetic variants. The algorithm was applied to genetic results in the Cardiac Arrest Survivors With Preserved Ejection Fraction Registry, to assess the rate of variant reclassification over time. Variant classifications were then compared with the classifications of 2 commercial laboratories to determine the rate and identify sources of variant interpretation discordance. Results: Thirty-one percent of participants (40 of 131) had at least 1 genetic variant with a clinically significant reclassification over time. Variants of uncertain significance were more likely to be downgraded (73%) to benign than upgraded to pathogenic (27%; P =0.03). For the second part of the study, 50% (70 of 139) of variants had discrepant interpretations (excluding benign variants), provided by at least 1 team. Conclusions: Periodic review of genetic variant classification is a key component of follow-up care given rapidly changing information in the field. There is potential for clinical care gaps with discrepant variant interpretations, based on the interpretation and application of current guidelines. The development of gene- and disease-specific guidelines and algorithms may provide an opportunity to further standardize variant interpretation reporting in the future. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00292032.

The term idiopathic ventricular fibrillation (IVF) describes survivors of unexplained cardiac arrest (UCA) without a specific diagnosis after clinical and genetic testing. Previous reports have described a subset of IVF individuals with ventricular arrhythmia initiated by short-coupled trigger premature ventricular contractions (PVCs) for which the term short-coupled ventricular fibrillation (SCVF) has been proposed. The aim of this article is to establish the phenotype and frequency of SCVF in a large cohort of UCA survivors. We performed a multicentre study including consecutive UCA survivors from the CASPER registry. Short-coupled ventricular fibrillation was defined as otherwise unexplained ventricular fibrillation initiated by a trigger PVC with a coupling interval of P < 0.001). The median time to recurrent ventricular arrhythmia in SCVF was 31 months. Recurrent ventricular fibrillation resulted in quinidine administration in 12/24 SCVF (50%) with excellent arrhythmia control. Short-coupled ventricular fibrillation is a distinct primary arrhythmia syndrome accounting for at least 6.6% of UCA. As documentation of ventricular fibrillation onset is necessary for the diagnosis, most cases are diagnosed at the time of recurrent arrhythmia, thus the true prevalence of SCVF remains still unknown. Quinidine is effective in SCVF and should be considered as first-line treatment for patients with recurrent episodes. Short-coupled ventricular fibrillation (SCVF) is a distinct primary electrical disorder accounting for at least 6.6% of otherwise idiopathic VF. Quinidine is highly effective for SCVF.