Electrical storm after cardiac resynchronization therapy in a patient with nonischemic cardiomyopathy: Signal-averaged vector-projected 187-channel electrocardiogram-based risk stratification for lethal arrhythmia

AbstractWe describe treatment of atrial flutter and electrical storm presenting as incessant ventricular tachycardia (VT) after implantation of a cardiac resynchronization therapy defibrillator (CRT-D) in a patient with dilated cardiomyopathy. No prior arrhythmic event had occurred. Our treatment strategy, including amiodarone administration, was guided in part by signal-averaged vector-projected 187-channel electrocardiogram (SAVP-ECG)-based risk stratification for ventricular arrhythmia. Corrected recovery time (RTc) dispersion and Tpeak-end dispersion were used to evaluate transmural dispersion of repolarization. RTc and Tpeak-end dispersion increased during the period of electrical storm. Values were improved 2 years after CRT-D implantation, and the amiodarone was discontinued. The VT has not recurred despite discontinuation of the antiarrhythmic agent. SAVP-ECG-based risk stratification for ventricular arrhythmia proved useful for the management of antiarrhythmic therapy

Effects of a high-fat diet on the electrical properties of porcine atria

AbstractBackgroundBecause obesity is an important risk factor for atrial fibrillation (AF), we conducted an animal study to examine the effect of a high-fat diet (HFD) on atrial properties and AF inducibility.MethodsTen 8-week-old pigs (weight, 18–23kg) were divided into two groups. For 18 weeks, five pigs were fed a HFD (HFD group) and five were fed a normal diet (control group). Maps of atrial activation and voltages during sinus rhythm were created for all pigs using the EnSite NavX system. Effective refractory period (ERP) and AF inducibility were also determined. When AF was induced, complex fractionated atrial electrogram (CFAE) mapping was performed. At 18 weeks, hearts were removed for comparing the results of histological analysis between the two groups. Body weight, lipid levels, hemodynamics, cardiac structures, and electrophysiological properties were also compared.ResultsTotal cholesterol levels were significantly higher (347 [191–434] vs. 81 [67–88]mg/dL, P=0.0088), and left atrium pressure was higher (34.5 [25.6–39.5] vs. 24.5 [21.3–27.8]mmHg, P=0.0833) in the HFD group than in the control group, although body weight only increased marginally (89 [78–101] vs. 70 [66–91]kg, P=0.3472). ERPs of the pulmonary vein (PV) were shorter (P<0.05) and AF lasted longer in the HFD group than in the control group (80 [45–1350] vs. 22 [3–30]s, P=0.0212). Neither CFAE site distribution nor histopathological characteristics differed between the two groups.ConclusionsThe shorter ERPs for the PV observed in response to the HFD increased vulnerability to AF, and these electrophysiological characteristics may underlie obesity-related AF

Sodium Channelopathy Underlying Familial Sick Sinus Syndrome With Early Onset and Predominantly Male Characteristics

Background-Sick sinus syndrome (SSS) is a common arrhythmia often associated with aging or organic heart diseases but may also occur in a familial form with a variable mode of inheritance. Despite the identifcation of causative genes, including cardiac Na channel (SCN5A), the pathogenesis and molecular epidemiology of familial SSS remain undetermined primarily because of its rarity. Methods and Results-We genetically screened 48 members of 15 SSS families for mutations in several candidate genes and determined the functional properties of mutant Na channels using whole-cell patch clamping. We identifed 6 SCN5A mutations including a compound heterozygous mutation. Heterologously expressed mutant Na channels showed loss-of-function properties of reduced or no Na current density in conjunction with gating modulations. Among 19 family members with SCN5A mutations, QT prolongation and Brugada syndrome were associated in 4 and 2 individuals, respectively. Age of onset in probands carrying SCN5A mutations was signifcantly less (mean±SE, 12.4±4.6 years; n=5) than in SCN5A-negative probands (47.0±4.6 years; n=10; P<0.001) or nonfamilial SSS (74.3±0.4 years; n=538; P<0.001). Meta-analysis of SSS probands carrying SCN5A mutations (n=29) indicated profound male predominance (79.3%) resembling Brugada syndrome but with a considerably earlier age of onset (20.9±3.4 years). Conclusions-The notable pathophysiological overlap between familial SSS and Na channelopathy indicates that familial SSS with SCN5A mutations may represent a subset of cardiac Na channelopathy with strong male predominance and early clinical manifestations

Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls.

PURPOSE: Stringent variant interpretation guidelines can lead to high rates of variants of uncertain significance (VUS) for genetically heterogeneous disease like long QT syndrome (LQTS) and Brugada syndrome (BrS). Quantitative and disease-specific customization of American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines can address this false negative rate. METHODS: We compared rare variant frequencies from 1847 LQTS (KCNQ1/KCNH2/SCN5A) and 3335 BrS (SCN5A) cases from the International LQTS/BrS Genetics Consortia to population-specific gnomAD data and developed disease-specific criteria for ACMG/AMP evidence classes-rarity (PM2/BS1 rules) and case enrichment of individual (PS4) and domain-specific (PM1) variants. RESULTS: Rare SCN5A variant prevalence differed between European (20.8%) and Japanese (8.9%) BrS patients (p = 5.7 × 10-18) and diagnosis with spontaneous (28.7%) versus induced (15.8%) Brugada type 1 electrocardiogram (ECG) (p = 1.3 × 10-13). Ion channel transmembrane regions and specific N-terminus (KCNH2) and C-terminus (KCNQ1/KCNH2) domains were characterized by high enrichment of case variants and >95% probability of pathogenicity. Applying the customized rules, 17.4% of European BrS and 74.8% of European LQTS cases had (likely) pathogenic variants, compared with estimated diagnostic yields (case excess over gnomAD) of 19.2%/82.1%, reducing VUS prevalence to close to background rare variant frequency. CONCLUSION: Large case-control data sets enable quantitative implementation of ACMG/AMP guidelines and increased sensitivity for inherited arrhythmia genetic testing

Risk of defibrillation threshold testing in severe heart failure patient: A case of cardiac resynchronization therapy (CRT-D) with acute myocardial infarction

AbstractDefibrillation threshold (DFT) testing is usually recommended after device implantation to confirm appropriate implantable cardioverter defibrillator (ICD)/cardiac resynchronization therapy defibrillator (CRT-D) function [1,2]. However, induction of ventricular fibrillation may result in hemodynamic compromise, and cardioversion itself may cause myocardial injury [3,4]. We report on a CRT-D patient with acute myocardial infarction who died due to multiple organ failure 1 day after DFT testing. Our case emphasizes the importance of deciding whether DFT testing should be performed for patients with very severe heart failure in the acute stage of myocardial infarction

What Are the Expectations for Cardiac Resynchronization Therapy? A Validation of Two Response Definitions

Background: The definition of response to cardiac resynchronization therapy (CRT) varies across clinical trials. There are two main definitions, i.e., echocardiographic response and functional response. We assessed which definition was more reasonable. Methods: In this study of 260 patients who had undergone CRT, an echocardiographic response was defined as a reduction in a left ventricular end-systolic volume of greater than or equal to 15% or an improvement in left ventricular ejection fraction of greater than or equal to 5%. A functional response was defined as an improvement of at least one class category in the New York Heart Association functional classification. We assessed the response to CRT at 6 months after device implantation, based on each definition, and investigated the relationship between response and clinical outcomes. Results: The echocardiographic response rate was 74.2%. The functional response rate was 86.9%. Non-responder status, based on both definitions, was associated with higher all-cause mortality. Cardiac death was only associated with functional non-responder status (hazard ratio (HR) 2.65, 95% confidence interval (CI) 1.19–5.46, p = 0.0186) and heart failure hospitalization (HR 2.78, 95% CI, 1.29–5.26, p = 0.0111). Conclusion: After CRT implantation, the functional response definition of CRT response is associated with a higher response rate and better clinical outcomes than that of the echocardiographic response definition, and therefore it is reasonable to use the functional definition to assess CRT response