Showing papers by "Charles Antzelevitch published in 2016"

Programmed Ventricular Stimulation for Risk Stratification in the Brugada Syndrome: A Pooled Analysis

Abstract: Background—The role of programmed ventricular stimulation in identifying patients with Brugada syndrome at the highest risk for sudden death is uncertain. Methods and Results—We performed a systema...

Ranolazine for Congenital Long-QT Syndrome Type III: Experimental and Long-Term Clinical Data.

Abstract: Background— The basic defect in long-QT syndrome type III (LQT3) is an excessive inflow of sodium current during phase 3 of the action potential caused by mutations in the SCN5A gene. Most sodium channel blockers reduce the early (peak) and late components of the sodium current ( I Na and I NaL), but ranolazine preferentially reduces I NaL. We, therefore, evaluated the effects of ranolazine in LQT3 caused by the D1790G mutation in SCN5A . Methods and Results— We performed an experimental study of ranolazine in TSA201 cells expressing the D1790G mutation. We then performed a long-term clinical evaluation of ranolazine in LQT3 patients carrying the D1790G mutation. In the experimental study, I NaL was significantly higher in D1790G than in wild-type channels expressed in the TSA201 cells. Ranolazine exerted a concentration-dependent block of I NaL of the SCN5A-D1790G channel without reducing peak I Na significantly. In the clinical study, among 8 patients with LQT3 and confirmed D1790G mutation, ranolazine had no effects on the sinus rate or QRS width but shortened the QTc from 509±41 to 451±26 ms, a mean decrease of 56±52 ms (10.6%; P =0.012). The QT-shortening effect of ranolazine remained effective throughout the entire study period of 22.8±12.8 months. Ranolazine reduced the QTc at all heart rates but less so during extreme nocturnal bradycardia. A type I Brugada ECG was never noticed. Conclusions— Ranolazine blocks I NaL in experimental models of LQT3 harboring the SCN5A-D1790G mutation and shortened the QT interval of LQT3 patients. Clinical Trial Registration— URL: ; Unique identifier: [NCT01728025][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01728025&atom=%2Fcircae%2F9%2F10%2Fe004370.atom

Further Insights in the Most Common SCN5A Mutation Causing Overlapping Phenotype of Long QT Syndrome, Brugada Syndrome, and Conduction Defect

Abstract: Background Phenotypic overlap of type 3 long QT syndrome (LQT3), Brugada syndrome (BrS), cardiac conduction disease (CCD), and sinus node dysfunction (SND) is observed with SCN5A mutations. SCN5A ‐E1784K is the most common mutation associated with BrS and LQTS3. The present study examines the genotype–phenotype relationship in a large family carrying SCN5A ‐E1784K and SCN5A ‐H558R polymorphism. Methods and Results Clinical work‐up, follow‐up, and genetic analysis were performed in 35 family members. Seventeen were SCN5A ‐E1784K positive. They also displayed QTc prolongation, and either BrS, CCD, or both. One carrier exhibited SND. The presence of SCN5A ‐H558R did not significantly alter the phenotype of SCN5A ‐E1784K carriers. Fourteen SCN5A ‐E1784K patients underwent implantable cardioverter‐defibrillator (ICD) implantation; 4 developed VF and received appropriate ICD shocks after 8±3 months of follow‐up. One patient without ICD also developed VF after 6.7 years. These 5 cases carried both SCN5A ‐E1784K and SCN5A ‐H558R. Functional characterization was achieved by expressing SCN5A variants in TSA201 cells. Peak (INa,P) or late (INa,L) sodium currents were recorded using whole‐cell patch‐clamp techniques. Co‐expression of SCN5A ‐E1784K and SCN5A ‐WT reduced INa,P to 70.03% of WT, shifted steady‐state inactivation by −11.03 mV, and increased INa,L from 0.14% to 1.86% of INa,P. Similar changes were observed when SCN5A ‐E1784K was co‐expressed with SCN5A ‐H558R. Conclusions We demonstrate a strong genotype‐phenotype correlation with complete penetrance for BrS, LQTS, or CCD in the largest family harboring SCN5A ‐E1784K mutation described so far. Phenotype of LQTS is present during all decades of life, whereas CCD develops with increasing age. Phenotypic overlap may explain the high event rate in carriers.

Molecular and Functional Characterization of Rare CACNA1C Variants in Sudden Unexplained Death in the Young

Abstract: Introduction Perturbations in the CACNA1C-encoded L-type calcium channel α-subunit have been linked recently to heritable arrhythmia syndromes, including Timothy syndrome, Brugada syndrome, early repolarization syndrome, and long QT syndrome. These heritable arrhythmia syndromes may serve as a pathogenic basis for autopsy-negative sudden unexplained death in the young (SUDY). However, the contribution of CACNA1C mutations to SUDY is unknown. Objective We set out to determine the spectrum, prevalence, and pathophysiology of rare CACNA1C variants in SUDY. Methods Mutational analysis of CACNA1C was conducted in 82 SUDY cases using polymerase chain reaction, denaturing high-performance liquid chromatography, and direct sequencing. Identified variants were engineered using site-directed mutagenesis, and heterologously expressed in TSA-201 or HEK293 cells. Results Two SUDY cases (2.4%) harbored functional variants in CACNA1C. The E850del and N2091S variants involve highly conserved residues and localize to the II-III linker and C-terminus, respectively. Although observed in publically available exome databases, both variants confer abnormal CaV1.2 electrophysiological characteristics. Examination of the electrophysiological properties revealed the E850del mutation in CACNA1C led to a 95% loss-of-function in ICa, and the N2091S variant led to a 105% gain-of-function in ICa. Additionally, N2091S led to minor kinetic alterations including a −3.4 mV shift in V1/2 of activation. Conclusion This study provides molecular and functional evidence that rare CACNA1C genetic variants may contribute to the underlying pathogenic basis for some cases of SUDY in either a gain or loss-of-function mechanism.

Ionic and Cellular Mechanisms Underlying J Wave Syndromes

Abstract: Prominent J waves are encountered in a number of life-threatening cardiac arrhythmia syndromes, including the Brugada (BrS) and early repolarization (ERS) syndromes. BrS and ERS differ with respect to the magnitude and lead location of abnormal J waves and are thought to represent a continuous spectrum of phenotypic expression termed J wave syndromes. Both are associated with the development of polymorphic ventricular tachycardia (VT) and ventricular fibrillation (VF) leading to sudden cardiac death (SCD) in young adults. J wave syndromes are characterized by J-onset and ST-elevation in distinct ECG-leads. The region most affected by BrS is the anterior right ventricular outflow tract, accounting for why J-onset and ST-segment elevation are limited to the right precordial leads. The region most affected in ERS is the inferior wall of the left ventricle, accounting for why the appearance of J waves or early repolarization in the inferior ECG leads is associated with the highest risk for development of arrhythmias and SCD. Risk stratification and the approach to therapy of the J wave syndromes continue to be mired in controversy. Our objective in this chapter is to provide an integrated review of the clinical characteristics, risk stratifiers, as well as the molecular, ionic, cellular and genetic mechanisms underlying the J wave syndromes.