Electrophysiologic characteristics of cells spanning the left ventricular wall of human heart: Evidence for presence of M cells

Objectives.The present work was designed to provide an initial characterization of M cells in the normal human heart.Background.Recent studies have uncovered a unique population of cells in the midmyocardial region of the canine ventricle. These cells, named M cells, were found to possess electrophysiologic features and a pharmacologic responsiveness different from those of other myocardial cells. Although well characterized in the dog, their presence or absence in the human heart is unknown.Methods.Standard microelectrode techniques were used to map slices of ventricular free wall obtained from normal human hearts (n = 4). Preparations were paced at cycle lengths ranging from 1 to 10 s.Results.We identified three cell subtypes: endocardial, subepicardial (M cells) and epicardial cells. The principal features differentiating M cells from the other cell subtypes were their longer action potential duration, more accentuated action potential duration rate relations and greater maximal rate of increase in action potential upstroke (Vmax). Our findings suggest that M cells represent ∼ 30% of the cellular mass of the left ventricular wall. Concordance between changes in their repolarization and changes in QTU interval provide support for the role of M cells in the generation of the electrocardiographic (ECG) U wave.Conclusions.This study provides evidence for the existence of M cells in the human heart that contribute to heterogeneity of repolarization within the ventricular wall. Our findings provide strong support for the hypothesis that M cells contribute importantly to the manifestation of the U wave on the ECG

Response to intravenous ajmaline: a retrospective analysis of 677 ajmaline challenges.

International audienceAIMS: The diagnostic type I ECG in Brugada syndrome (BS) is often concealed and fluctuates between the diagnostic and non-diagnostic pattern. Challenge with intravenous ajmaline is used to unmask the diagnostic Brugada ECG. The aim of this study was to evaluate the safety of the test and to identify predictors for the response to an intravenous ajmaline challenge. METHODS AND RESULTS: In four tertiary referral centres, 677 consecutive patients underwent an intravenous ajmaline challenge for diagnosis or exclusion of BS in accordance with the recommendations of the Brugada consensus conferences. Two hundred and sixty-two ajmaline challenges (39%) were positive. Male gender, familial BS, sudden cardiac arrest (SCA), first-degree AV-block, basal saddleback type ECG, and basal right bundle branch block were identified as predictors for a positive ajmaline challenge. A predictor for negative ajmaline test was the absence of ST-segment elevation at baseline. Six of 12 patients who had experienced SCA, and five of 25 patients with a familial sudden death exhibited a positive response to ajmaline. Only one patient (0.15%) developed sustained ventricular tachyarrhythmias (ventricular fibrillation) during ajmaline challenge, which was terminated by a single external defibrillator shock. CONCLUSION: Ajmaline challenge is a safe procedure to unmask the electrocardiographic pattern of BS. Electrocardiographic and clinical parameters were identified to predict patients' response to ajmaline. The results of this study guide the clinician in which setting an ajmaline challenge is an appropriate diagnostic step

Multilevel behavioral simulation of VCSEL-based optoelectronic modules

International audienceThe assembly within a single optoelectronic interconnect module of different components, including vertical-cavity semiconductor lasers and photodiode arrays, optical fibers, and electronics implying electrical, optical, mechanical, and thermal interactions, introduces new constraints in the conception phase and necessitates a new and different approach for modeling and simulation. A promising solution, when conceiving optoelectronic microelectromechanical systems, is obtained by simulation with the multilevel language VHDL-AMS based on system component parameters and standards

Type of SCN5A mutation determines clinical severity and degree of conduction slowing in loss-of-function sodium channelopathies

BACKGROUND: Patients carrying loss-of-function SCN5A mutations linked to Brugada syndrome (BrS) or progressive cardiac conduction disease (PCCD) are at risk of sudden cardiac death at a young age. The penetrance and expressivity of the disease are highly variable, and new tools for risk stratification are needed. OBJECTIVES: We aimed to establish whether the type of SCN5A mutation correlates with the clinical and electrocardiographic phenotype. METHODS: We studied BrS or PCCD probands and their relatives who carried a SCN5A mutation. Mutations were divided into 2 main groups: missense mutations (M) or mutations leading to premature truncation of the protein (T). The M group was subdivided according to available biophysical properties: M mutations with 90% (M(inactive)) peak I(Na) reduction were analyzed separately. RESULTS: The study group was composed of 147 individuals with 32 different mutations. No differences in age and sex distribution were found between the groups. Subjects carrying a T mutation had significantly more syncopes than those with an M(active) mutation (19 of 75 versus 2 of 35, P = .03). Also, mutations associated with drastic peak I(Na) reduction (T and M(inactive) mutants) had a significantly longer PR interval, compared with M(active) mutations. All other electrocardiographic parameters were comparable. After drug provocation testing, both PR and QRS intervals were significantly longer in the T and M(inactive) groups than in the M(active) group. CONCLUSION: In loss-of-function SCN5A channelopathies, patients carrying T and M(inactive) mutations develop a more severe phenotype than those with M(active) mutations. This is associated with more severe conduction disorders. This is the first time that genetic data are proposed for risk stratification in Br

Dysfunction of the Voltage-Gated K+ Channel beta 2 Subunit in a Familial Case of Brugada Syndrome

International audienceBackground-The Brugada syndrome is an inherited cardiac arrhythmia associated with high risk of sudden death. Although 20% of patients with Brugada syndrome carry mutations in SCN5A, the molecular mechanisms underlying this condition are still largely unknown. Methods and Results-We combined whole-exome sequencing and linkage analysis to identify the genetic variant likely causing Brugada syndrome in a pedigree for which SCN5A mutations had been excluded. This approach identified 6 genetic variants cosegregating with the Brugada electrocardiographic pattern within the pedigree. In silico gene prioritization pointed to 1 variant residing in KCNAB2, which encodes the voltage-gated K+ channel beta 2-subunit (Kv beta 2-R12Q). Kv beta 2 is widely expressed in the human heart and has been shown to interact with the fast transient outward K+ channel subunit Kv4.3, increasing its current density. By targeted sequencing of the KCNAB2 gene in 167 unrelated patients with Brugada syndrome, we found 2 additional rare missense variants (L13F and V114I). We then investigated the physiological effects of the 3 KCNAB2 variants by using cellular electrophysiology and biochemistry. Patch-clamp experiments performed in COS-7 cells expressing both Kv4.3 and Kv beta 2 revealed a significant increase in the current density in presence of the R12Q and L13F Kv beta 2 mutants. Although biotinylation assays showed no differences in the expression of Kv4.3, the total and submembrane expression of Kv beta 2-R12Q were significantly increased in comparison with wild-type Kv beta 2. Conclusions-Altogether, our results indicate that Kv beta 2 dysfunction can contribute to the Brugada electrocardiographic pattern

Clinical aspects and prognosis of Brugada syndrome in children

BACKGROUND: Brugada syndrome is an arrhythmogenic disease characterized by an ECG pattern of ST-segment elevation in the right precordial leads and augmented risk of sudden cardiac death. Little is known about the clinical presentation and prognosis of this disease in children. METHODS AND RESULTS: Thirty children affected by Brugada syndrome who were <16 years of age (mean, 8+/-4 years) were included. All patients displayed a type I ECG pattern before or after drug provocation challenge. Diagnosis of Brugada syndrome was made under the following circumstances: aborted sudden death (n=1), syncope of unexplained origin (n=10), symptomatic supraventricular tachycardia (n=1), suspicious ECG (n=1), and family screening for Brugada syndrome (n=17). Syncope was precipitated by fever in 5 cases. Ten of 11 symptomatic patients displayed a spontaneous type I ECG. An implantable cardioverter-defibrillator was implanted in 5 children; 4 children were treated with hydroquinidine; and 1 child received a pacemaker because of symptomatic sick sinus syndrome. During a mean follow-up of 37+/-23 months, 1 child experienced sudden cardiac death, and 2 children received an appropriate implantable cardioverter-defibrillator shock; all of them were symptomatic and had manifested a type I ECG spontaneously. One child had a cardioverter-defibrillator infection that required explantation of the defibrillator. CONCLUSIONS: In the largest population of children affected by Brugada syndrome described to date, fever represented the most important precipitating factor for arrhythmic events, and as in the adult population, the risk of arrhythmic events was higher in previously symptomatic patients and in those displaying a spontaneous type I EC