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Objectives: The aim of this study was to identify families affected by early repolarization syndrome (ERS) and to determine the mode of transmission of the disease., Background: Early repolarization (ER) has recently been linked to idiopathic ventricular fibrillation. Familial inheritance of the disease has been suggested but not demonstrated., Methods: We screened relatives of 4 families affected by ERS. ER was defined as a distinct J-wave in at least 2 consecutive leads and a 1-mm amplitude above baseline. The Valsalva maneuver was performed in affected and unaffected family members to decrease heart rate and thus increase or reveal an ER pattern., Results: Twenty-two sudden cardiac deaths occurred in the 4 families including 10 before 35 years of age. In the 4 families, the prevalence of ER was 56%, 34%, 61%, and 33% of, respectively, 30, 82, 29, and 30 screened relatives. In these families, transmission of an ER pattern is compatible with an autosomal dominant mode of inheritance. All probands were screened for genes identified in ERS, and no mutation was found. The Valsalva maneuver was performed in 80 relatives, resulting in increased J-wave amplitude for 17 of 20 affected patients and revealing an ER pattern in 17 relatives in whom 5 are obligate transmitters of an ER pattern., Conclusions: ERS can be inherited through autosomal dominant transmission and should be considered a real inherited arrhythmia syndrome. Familial investigation can be facilitated by using the Valsalva maneuver to reveal the electrocardiographic pattern in family members. The prognosis value of this test remains to be assessed., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease so far related to mutations in the cardiac ryanodine receptor (RYR2) or the cardiac calsequestrin (CASQ2) genes. Because mutations in RYR2 or in CASQ2 are not retrieved in all CPVT cases, we searched for mutations in the physiological protein partners of RyR2 and CSQ2 in a large cohort of CPVT patients with no detected mutation in these two genes. Based on a candidate gene approach, we focused our investigations on triadin and junctin, two proteins that link RyR2 and CSQ2. Mutations in the triadin (TRDN) and in the junctin (ASPH) genes were searched in a cohort of 97 CPVT patients. We identified three mutations in triadin which cosegregated with the disease on a recessive mode of transmission in two families, but no mutation was found in junctin. Two TRDN mutations, a 4 bp deletion and a nonsense mutation, resulted in premature stop codons; the third mutation, a p.T59R missense mutation, was further studied. Expression of the p.T59R mutant in COS-7 cells resulted in intracellular retention and degradation of the mutant protein. This was confirmed after in vivo expression of the mutant triadin in triadin knock-out mice by viral transduction. In this work, we identified TRDN as a new gene responsible for an autosomal recessive form of CPVT. The mutations identified in the two families lead to the absence of the protein, thereby demonstrating the importance of triadin for the normal function of the cardiac calcium release complex in humans.

Background: Loss-of-function mutations in SCN5A, the gene encoding Na(v)1.5 Na+ channel, are associated with inherited cardiac conduction defects and Brugada syndrome, which both exhibit variable phenotypic penetrance of conduction defects. We investigated the mechanisms of this heterogeneity in a mouse model with heterozygous targeted disruption of Scn5a (Scn5a(+/-) mice) and compared our results to those obtained in patients with loss-of-function mutations in SCN5A., Methodology/principal Findings: Based on ECG, 10-week-old Scn5a(+/-) mice were divided into 2 subgroups, one displaying severe ventricular conduction defects (QRS interval>18 ms) and one a mild phenotype (QRS< or = 18 ms; QRS in wild-type littermates: 10-18 ms). Phenotypic difference persisted with aging. At 10 weeks, the Na+ channel blocker ajmaline prolonged QRS interval similarly in both groups of Scn5a(+/-) mice. In contrast, in old mice (>53 weeks), ajmaline effect was larger in the severely affected subgroup. These data matched the clinical observations on patients with SCN5A loss-of-function mutations with either severe or mild conduction defects. Ventricular tachycardia developed in 5/10 old severely affected Scn5a(+/-) mice but not in mildly affected ones. Correspondingly, symptomatic SCN5A-mutated Brugada patients had more severe conduction defects than asymptomatic patients. Old severely affected Scn5a(+/-) mice but not mildly affected ones showed extensive cardiac fibrosis. Mildly affected Scn5a(+/-) mice had similar Na(v)1.5 mRNA but higher Na(v)1.5 protein expression, and moderately larger I(Na) current than severely affected Scn5a(+/-) mice. As a consequence, action potential upstroke velocity was more decreased in severely affected Scn5a(+/-) mice than in mildly affected ones., Conclusions: Scn5a(+/-) mice show similar phenotypic heterogeneity as SCN5A-mutated patients. In Scn5a(+/-) mice, phenotype severity correlates with wild-type Na(v)1.5 protein expression.

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 BrS.

The identification of nearly a dozen ion channel genes involved in the genesis of human atrial and ventricular arrhythmias has been critical for the diagnosis and treatment of fatal cardiovascular diseases. In contrast, very little is known about the genetic and molecular mechanisms underlying human sinus node dysfunction (SND). Here, we report a genetic and molecular mechanism for human SND. We mapped two families with highly penetrant and severe SND to the human ANK2 (ankyrin-B/AnkB) locus. Mice heterozygous for AnkB phenocopy human SND displayed severe bradycardia and rate variability. AnkB is essential for normal membrane organization of sinoatrial node cell channels and transporters, and AnkB is required for physiological cardiac pacing. Finally, dysfunction in AnkB-based trafficking pathways causes abnormal sinoatrial node (SAN) electrical activity and SND. Together, our findings associate abnormal channel targeting with human SND and highlight the critical role of local membrane organization for sinoatrial node excitability.

The place of antiarrhythmic drugs in the preventive treatment of the cardiac arrhythmias was recently revalued because of the improvement of the radiofrequency catheter ablation techniques and the growing place of the implantable cardioverter defibrillator. The choice of the antiarrhythmic treatment must always be based on the type of arrhythmia, the presence of a structural cardiopathy and the potential side effects of the antiarrhythmic drug.

The identification of the first gene locus of hereditary arrhythmias was made over 10 years ago. In the last few years, considerable progress has been made and the number of culprit genes for cardiac arrhythmias has rapidly increased. This has been the fruit of close collaboration between clinicians, geneticists and physiologists. This work has demonstrated the heterogenous nature of genetics of diseases. It has led to a better understanding of underlying physiopathological mechanisms by the study of the relationship between gene and clinical abnormalities. In addition, analysis of phenotypes and genotypes has improved our knowledge of the clinical presentation of diseases and opened up new therapeutic approaches. These new diagnostic methods have enabled preventive measures to be taken to avoid potentially serious arrhythmias. The genetics of cardiac arrhythmias is still in its infancy: many culprit genes remain undetected and their identification should led to considerable progress in the understanding of the physiopathology of arrhythmias and their treatment.

Degenerative conduction defects are usually considered to be exaggerated ageing affecting the conduction pathways. For several years familial forms have been described, and a first locus on chromosome 19 and then a first gene, SCN5A on chromosome 3 (coding for the sodium channel alpha subunit), have been identified. Mutations of this gene can lead not only to congenital conduction defects but also to progressive forms of conduction defects similar to Lenègre disease. A third locus on chromosome 16 at 16q23-24 has been identified, as have other families not linked to the loci described previously. Although it now seems clear that conduction defects can have a genetic component, the frequency of the familial forms remains to be determined. Important progress could be made in the understanding of this disease if other implicated genes were identified. It would then become possible to elucidate the different pathophysiological mechanisms responsible for conduction defects.

Objectives: This study sought to determine whether abnormal ventricular repolarization is implicated in cardiac arrhythmias of German shepherd dogs with inherited sudden death., Background: Moïse et al. (9) have identified German shepherd dogs that display pause-dependent lethal ventricular arrhythmias., Methods: Ventricular repolarization was studied both in vivo using electrocardiogram recordings on conscious dogs and in vitro with a standard microelectrode technique performed on endomyocardial biopsies and Purkinje fibers. Pharmacological manipulation was used to evaluate the role of potassium channels., Results: In control conditions, electrocardiogram parameters were similar in both groups of dogs, except for the PR interval (18% longer in affected dogs, p < 0.05). Injection of d,l-sotalol (2 mg/kg) prolonged QT interval more in affected dogs (+14%, n = 9) than it did in unaffected dogs (+6%, n = 6, p < 0.05) and increased the severity of arrhythmias in affected dogs. In vitro, in control conditions, action potential duration (APD90) of endomyocardial biopsies and Purkinje fibers were significantly longer in affected dogs (respectively 209 +/- 3 ms, n = 30 and 352 +/- 15 ms, n = 17) than they were in unaffected dogs (197 +/- 4 ms, n = 25 and 300 +/- 9 ms, n = 30) at a pacing cycle length (PCL) of 1,000 ms. This difference increased with PCL. The kinetics of adaptation of APD90 to a change in PCL was faster in affected dogs. D,l-sotalol (10(-5) and 10(-4)M) increased APD90 in both groups of dogs, but this increase was greater in affected dogs, with the occurrence of triggered activity on Purkinje fibers. E-4031 (10(-7) and 10(-6) M), an I(Kr)-blocker, increased APD90 similarly in both groups of dogs. Chromanol 293B (10(-6) and 10(-5)M), an I(Ks)-blocker, increased significantly APD90 in unaffected dogs but had no effect in affected dogs., Conclusions: These results support the hypothesis of an abnormal cardiac repolarization in affected dogs. The effects of 293B suggest that I(Ks) may be involved in this anomaly.

Progress in molecular biology has advanced our medical knowledge. The identification of genetic abnormalities has been transformed into the new approach of "inverse genetic s" which is based on close collaboration between clinicians, geneticians, molecular biologists and physiologists. In monogenic affections of unknown mechanism, the scientific method of determining the culprit gene is based essentially on precise phenotypic identification of all members of a large family and on DNA studies. The following steps consist in localising the gene with polymorphic genetic probes and then demonstrate the causal mutations and, finally, reexpress the normal and abnormal genes to study their function and thereby confirm the mutation. This approach has recently been applied to cardiac arrhythmias. Genes responsible for atrioventricular conduction defects, Wolff-Parkinson-White syndromes associated with hypertrophic cardiomyopathy and arrhythmogenic right ventricular dysplasia have been localised in the human genome showing that these syndromes are often very variable. The greatest progress has been achieved in the congenital long QT syndrome. Four genes have been localised on chromosomes 3, 1, 7 and 11, and three have already been identified which has allowed study of their function and genotype-phenotype analysis.

An early after/depolarization (EAD) is an abnormality of the repolarization process of an action potential which causes an interruption or a retardation of normal repolarization. Two types were described: phase 3 EADs occur at a takeoff potential of approximately-60 mV and phase 2 EADs occur at the end of a prolonged plateau at a takeoff potential of between-10 and-30 mV. EADs can result from an increase in inward current, a reduction of outward current or both. EADs show cycle-length dependence: as cycle length increases and repolarization lengthens, EADs occur, and their magnitude increases, at a critical cycle length, can trigger the action potential of these EADs. The autonomic nervous system can also modulate EADs and trigger activity. In cesium-intoxicated Purkinje fibers, beta-adrenergic stimulation increases EAD magnitude and the occurrence of triggered activity. Cholinergic stimulation decreases EAD magnitude and suppresses triggered activity occurring after beta-adrenergic stimulation. Alpha 1-adrenergic stimulation has no effect on phase 3 EADs but induces phase 2 EADs. In normal Tyrode's solution (0 cesium), phenylephrine prolongs action potential and induces EADs. This effect seems to depend on alpha 1 A stimulation. These electrogenic abnormalities are supposed to be responsible for long QT and torsades de pointes. As our experimental data have shown that both the rate of stimulation and the autonomic nervous system could modulate EADs and trigger activity, we can speculate on the therapeutic implications of such modulations and the role of pacing as well as alpha- and beta-adrenergic antagonists.

To study the cellular mechanisms of arrhythmias occurring in cardiac hypertrophy, we performed standard microelectrode studies on papillary muscles isolated from control (group N) and hypertrophied ferrets right ventricles. Different stages of hypertrophy, induced by pulmonary banding, were studied: 10-22 days (group H1), 4-6 weeks (H2), and 5 1/2-6 months (H3). During the development of hypertrophy, under beta-adrenergic stimulation, triggered activity (TA) induced by delayed afterdepolarizations appeared in 2 of 5 muscles in group H1 and 8 of 8 in group H2. This arrhythmia was absent in N muscles, as well as in H3, despite a pronounced prolongation of the action potentials at 50% (100 +/- 9.3 msec in group H3 vs 67 +/- 5.7 msec in H2; P less than 0.01) and 90% of repolarization (225 +/- 8.7 in H3 vs 185 +/- 7.4 msec in H2; P less than 0.02). The presence of TA was associated with an increase in the intracellular calcium activity (144 +/- 60 nM in H2 vs 47 +/- 9 nM in N; P less than 0.05). TA properties were as follows. Triggering frequency increased as beta-adrenergic stimulation increased, as pacing cycle length (PCL) decreased, and as duration of the prestimulative pause increased. The duration of salvos of TA increased as duration of the prestimulative pauses increased (NS). The coupling interval of the first triggered beat decreased as PCL decreased (P less than 0.001). The minimal cycle length of salvos of TA was not modified by these parameters. It is concluded that delayed afterdepolarizations-induced TA may occur under beta-adrenergic stimulation during the first stages of ventricular hypertrophy.(ABSTRACT TRUNCATED AT 250 WORDS)

Since the early 1980's, in parallel to development of "physiological" cardiac stimulation, modalities and objectives for cardiac stimulation have been modified radically. Among the many methods of stimulation available, in practice the physician may choose from four main types: (1) single-chamber ventricular stimulation; (2) single-chamber atrial stimulation; (3) two-chamber stimulation; (4) variable rate stimulation. Three main elements determine choice of the method of stimulation: the patient's physical condition, his heart condition (nature and type of cardiopathy and hemodynamic profile) and of course, electrophysiological data and cardiac rhythm encountered. The object of this paper is to schematically describe this choice.