Myotonic dystrophy type 1 mimics and exacerbates Brugada phenotype induced by Nav1.5 sodium channel loss of function mutation.

International audienceBACKGROUND: Myotonic dystrophy type 1 (DM1), a muscular dystrophy due to CTG-expansion in the DMPK gene, can cause cardiac conduction disorders and sudden death. These cardiac manifestations are similar to those observed in loss-of-function SCN5A mutations, which are also responsible for Brugada syndrome (BrS). OBJECTIVE: To investigate DM1 effects on the clinical expression of a loss-of-function SCN5A mutation causing BrS. METHODS: We performed complete clinical evaluation, including ajmaline test, in one family combining DM1 and BrS. We screened the known BrS susceptibility genes. We characterized an SCN5A mutation using whole-cell patch-clamp experiments associated to cell surface biotinylation. RESULTS: The proband, a 15-year old female, was a survivor of out-of-hospital cardiac arrest with ventricular fibrillation. She combined a DMPK CTG-expansion from the father's side and an SCN5A mutation (S910L) from the mother's side. S910L is a trafficking defective mutant inducing a dominant negative effect when transfected with wild-type Nav1.5. This loss-of-function SCN5A mutation caused a Brugada phenotype during the mother's ajmaline test. Surprisingly in the father, a DM1 patient without SCN5A mutation, ajmaline also unmasked a Brugada phenotype. Furthermore, association of both genetic abnormalities in the proband exacerbated the response to ajmaline with a massive conduction defect. CONCLUSIONS: Our study is the first to describe the deleterious effect of DM1 on the clinical expression of a loss-of-function SCN5A mutation and to show a provoked BrS phenotype in a DM1 patient. The modification of the electrocardiographic pattern by ajmaline supports the hypothesis of a link between DM1 and Nav1.5 loss-of-function

The Spectrum of Idiopathic Ventricular Fibrillation and J-Wave Syndromes: Novel Mapping Insights

KEY POINTS Idiopathic ventricular fibrillation (IVF) is defined as unexplained sudden cardiac death due to ven-tricular fibrillation (VF) without any identifiable structural or electrical cause after extensive investigations (no phenotype). Recent data show that the use of high-density electrophysiologic mapping may ultimately offer sub-clinical diagnoses of cardiac disease in about 90% of individuals with IVF. Two major conditions underlie the occurrence of VF: the presence of either depolarization abnormalities due to micro-structural myocardial alteration or Purkinje abnormalities manifesting as triggering ectopy or reentry in the peripheral network. J-wave syndromes are defined as a distinct electrocardiographic phenotype (slurring/notch) affecting the junction between the QRS complex and the ST segment in inferolateral leads. Recent data provide evidence for heterogeneous substrates, related to either delayed depolarization due to microstructural alterations or early repolarization abnormalities. IVF and J-wave syndromes are the result of a wide spectrum of pathophysiologic processes. The individual phenotypic characterization is essential given its implications in therapy, genetic testing, and risk stratification

Heart Rhythm

BACKGROUND Beyond pulmonary vein (PV) isolation, anatomic isthmus transection is an adjunctive strategy for persistent atrial fibrillation. Data on the durability of multiple lines of block remain scarce.OBJECTIVE The purpose of this study was to evaluate the impact of gaps within such a lesion set.METHODS We followed 291 consecutive patients who underwent (1) vein of Marshall ethanol infusion, (2) PV isolation, and (3) mitral, cavotricuspid, and dome isthmus transection. Dome transec-tion relied on 2 distinct strategies over time: a single roof line with touch-ups applied in case of gap demonstrated by conventional ma-neuvers (first leg), and an alternative floor line if the roof line ex-hibited a gap during high-density mapping with careful electrogram reannotation (second leg).RESULTS Twelve-month sinus rhythm maintenance was 70% after 1 procedure and 94% after 1 or 2 procedures. Event-free survival af-ter the first procedure was lower in case of residual gaps within the lesion set (log-rank, P = .004). Delayed gaps were found in 94% of a second procedure performed in the 69 patients relapsing despite a complete lesion set with PV gaps increasing the risk of recurrence of atrial fibrillation (67% vs 34%; P = .02) and anatomic isthmus gaps supporting a majority of atrial tachycardias (60%). Between the first leg and the second leg, a significant decrease was found in roof lines considered blocked during the first procedure (99% vs 78%; P , .001) and in delayed dome gaps observed during a second procedure (68% vs 43%; P = .05).CONCLUSION Gaps are arrhythmogenic and can be reduced by optimized ablation and assessment of lines of block. Closing these gaps improves sinus rhythm maintenance