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Background: The Brugada pattern manifests as a spontaneous variability of the electrocardiographic marker, suggesting a variability of the underlying electrical substrate.Objective: The purpose of this study was to investigate the response of the epicardial substrate of Brugada syndrome (BrS) to programmed ventricular stimulation and to Na blocker infusion.Methods: We investigated 6 patients (all male; mean age 54 ± 14 years) with BrS and recurrent ventricular fibrillation. Five had no type 1 BrS electrocardiogram pattern at admission. They underwent combined epicardial-endocardial mapping using multielectrode catheters. Changes in epicardial electrograms were evaluated during single endocardial extrastimulation and after low-dose ajmaline infusion (0.5 mg/kg in 5 minutes).Results: All patients had a region in the anterior epicardial right ventricle with prolonged multicomponent electrograms. Single extrastimulation prolonged late epicardial components by 59 ± 31 ms and in 4 patients abolished epicardial components at some sites, without reactivation by surrounding activated sites. These localized blocks occurred at an initial coupling interval of 335 ± 58 ms and then expanded to other sites, being observed in up to 40% of epicardial sites. Ajmaline infusion prolonged electrogram duration in all and produced localized blocks in 62% of sites in the same patients as during extrastimulation. Epicardial conduction recovery after ajmaline occurred intermittently and at discontinuous sites and produced beat-to-beat changes in local repolarization, resulting in an area of marked electrical disparity. These changes were consistent with models based on microstructural alterations under critical propagation conditions.Conclusion: In BrS, localized functional conduction blocks occur at multiple epicardial sites and with variable patterns, without being reactivated from the surrounding sites. [ABSTRACT FROM AUTHOR]

This international multidisciplinary document intends to provide clinicians with evidence-based practical patient-centered recommendations for evaluating patients and decedents with (aborted) sudden cardiac arrest and their families. The document includes a framework for the investigation of the family allowing steps to be taken, should an inherited condition be found, to minimize further events in affected relatives. Integral to the process is counseling of the patients and families, not only because of the emotionally charged subject, but because finding (or not finding) the cause of the arrest may influence management of family members. The formation of multidisciplinary teams is essential to provide a complete service to the patients and their families, and the varied expertise of the writing committee was formulated to reflect this need. The document sections were divided up and drafted by the writing committee members according to their expertise. The recommendations represent the consensus opinion of the entire writing committee, graded by Class of Recommendation and Level of Evidence. The recommendations were opened for public comment and reviewed by the relevant scientific and clinical document committees of the Asia Pacific Heart Rhythm Society (APHRS) and the Heart Rhythm Society (HRS); the document underwent external review and endorsement by the partner and collaborating societies. While the recommendations are for optimal care, it is recognized that not all resources will be available to all clinicians. Nevertheless, this document articulates the evaluation that the clinician should aspire to provide for patients with sudden cardiac arrest, decedents with sudden unexplained death, and their families. [ABSTRACT FROM AUTHOR]

Early repolarization indicates a distinct electrocardiographic phenotype affecting the junction between the QRS complex and the ST segment in inferolateral leads (inferolateral J-wave syndromes). It has been considered a benign electrocardiographic variant for decades, but recent clinical studies have demonstrated its arrhythmogenicity in a small subset, supported by experimental studies showing transmural dispersion of repolarization. Here we review the current knowledge and the issues of risk stratification that limit clinical management. In addition, we report on new mapping data of patients refractory to pharmacologic treatment using high-density electrogram mapping at the time of inscription of J wave. These data demonstrate that distinct substrates, delayed depolarization, and abnormal early repolarization underlie inferolateral J-wave syndromes, with significant implications. Finally, based on these data, we propose a new simplified mechanistic classification of sudden cardiac deaths without apparent structural heart disease. [ABSTRACT FROM AUTHOR]

Background: L-type calcium channel (LTCC) mutations have been associated with Brugada syndrome (BrS), short QT (SQT) syndrome, and Timothy syndrome (LQT8). Little is known about the extent to which LTCC mutations contribute to the J-wave syndromes associated with sudden cardiac death. Objective: The purpose of this study was to identify mutations in the α1, β2, and α2δ subunits of LTCC (Cav1.2) among 205 probands diagnosed with BrS, idiopathic ventricular fibrillation (IVF), and early repolarization syndrome (ERS). CACNA1C, CACNB2b, and CACNA2D1 genes of 162 probands with BrS and BrS+SQT, 19 with IVF, and 24 with ERS were screened by direct sequencing. Methods/Results: Overall, 23 distinct mutations were identified. A total of 12.3%, 5.2%, and 16% of BrS/BrS+SQT, IVF, and ERS probands displayed mutations in α1, β2, and α2δ subunits of LTCC, respectively. When rare polymorphisms were included, the yield increased to 17.9%, 21%, and 29.1% for BrS/BrS+SQT, IVF, and ERS probands, respectively. Functional expression of two CACNA1C mutations associated with BrS and BrS+SQT led to loss of function in calcium channel current. BrS probands displaying a normal QTc had additional variations known to prolong the QT interval. Conclusion: The study results indicate that mutations in the LTCCs are detected in a high percentage of probands with J-wave syndromes associated with inherited cardiac arrhythmias, suggesting that genetic screening of Cav genes may be a valuable diagnostic tool in identifying individuals at risk. These results are the first to identify CACNA2D1 as a novel BrS susceptibility gene and CACNA1C, CACNB2, and CACNA2D1 as possible novel ERS susceptibility genes. [ABSTRACT FROM AUTHOR]

Background: The transient outward current Ito is of critical importance in regulating myocardial electrical properties during the very early phase of the action potential. The auxiliary β subunit KCNE2 recently was shown to modulate Ito. Objective: The purpose of this study was to examine the contributions of KCNE2 and its two published variants (M54T, I57T) to Ito. Methods: The functional interaction between Kv4.3 (α subunit of human Ito) and wild-type (WT), M54T, and I57T KCNE2, expressed in a heterologous cell line, was studied using patch-clamp techniques. Results: Compared to expression of Kv4.3 alone, co-expression of WT KCNE2 significantly reduced peak current density, slowed the rate of inactivation, and caused a positive shift of voltage dependence of steady-state inactivation curve. These modifications rendered Kv4.3 channels more similar to native cardiac Ito. Both M54T and I57T variants significantly increased Ito current density and slowed the inactivation rate compared with WT KCNE2. Moreover, both variants accelerated the recovery from inactivation. Conclusion: The study results suggest that KCNE2 plays a critical role in the normal function of the native Ito channel complex in human heart and that M54T and I57T variants lead to a gain of function of Ito, which may contribute to generating potential arrhythmogeneity and pathogenesis for inherited fatal rhythm disorders. [Copyright &y& Elsevier]

Background: Cardiac contractility modulation signals are associated with acutely improved hemodynamics, but chronic clinical impact is not defined. Objectives: The purpose of this randomized, double-blind, pilot study was to determine the feasibility of safely and effectively delivering cardiac contractility modulation signals in patients with heart failure. Methods: Forty-nine subjects with ejection fraction <35%, normal QRS duration (105 ± 15 ms), and New York Heart Association (NYHA) class III or IV heart failure despite medical therapy received a cardiac contractility modulation pulse generator. Patients were randomized to have their devices programmed to deliver cardiac contractility modulation signals (n = 25, treatment group) or to remain off (n = 24, control group) for 6 months. Evaluations included NYHA class, 6-minute walk, cardiopulmonary stress test, Minnesota Living with Heart Failure Questionnaire, and Holter monitoring. Results: Although most baseline features were balanced between groups, ejection fraction (31.4% ± 7.4% vs 24.9% ± 6.5%, P = .003), end-diastolic dimension (52.1 ± 21.4 mm vs 62.5 ± 6.2 mm, P = .01), peak VO2 (16.0 ± 2.9 mL O2/kg/min vs 14.3 ± 2.8 mL O2/kg/min, P = .02), and anaerobic threshold (12.3 ± 2.5 mL O2/kg/min vs 10.6 ± 2.4 mL O2/kg/min, P = .01) were worse in the treatment group than in the control group. Nevertheless, one death occurred in the control group, and more patients in the treatment group were free of hospitalization for any cause at 6 months (84% vs 62%). No change in ectopy was observed. Compared with baseline, 6-minute walk (13.4 m), peak VO2 (0.2 mL O2/kg/min), and anaerobic threshold (0.8 mL O2/kg/min) increased more in the treatment group than in control. None of these differences were statistically significant (small sample size). NYHA and Minnesota Living with Heart Failure Questionnaire changed similarly in the two groups. Conclusion: Despite a sicker population in the treatment group, no specific safety concerns emerged with chronic cardiac contractility modulation signal administration. Further study is required to definitively define the safety and efficacy of cardiac contractility modulation signals. [Copyright &y& Elsevier]

Early repolarization indicates a distinct electrocardiographic phenotype affecting the junction between the QRS complex and the ST segment in inferolateral leads (inferolateral J-wave syndromes). It has been considered a benign electrocardiographic variant for decades, but recent clinical studies have demonstrated its arrhythmogenicity in a small subset, supported by experimental studies showing transmural dispersion of repolarization. Here we review the current knowledge and the issues of risk stratification that limit clinical management. In addition, we report on new mapping data of patients refractory to pharmacologic treatment using high-density electrogram mapping at the time of inscription of J wave. These data demonstrate that distinct substrates, delayed depolarization, and abnormal early repolarization underlie inferolateral J-wave syndromes, with significant implications. Finally, based on these data, we propose a new simplified mechanistic classification of sudden cardiac deaths without apparent structural heart disease. [ABSTRACT FROM AUTHOR]