High prevalence of ventricular repolarization abnormalities in people carrying TGFßR2 mutations.

Mutations in the TGFßR2 gene have been associated with a life threatening risk of aortic dissection but no arrhythmic death has been previously reported. Two young females carrying a TGFßR2 mutation, initially diagnosed as Marfan syndrome or Loeys Dietz syndrome, presented sudden death with autopsy ruling out dissection. The ECGs of the 2 Sudden Cardiac Deaths revealed profound ventricular repolarization abnormalities with a sinusoidal T-U morphology associated with normal left ventricular ejection fraction. These data strongly suggest sudden cardiac arrhythmic deaths and prompted us to systematically study the repolarization pattern in the patients with TGFßR2 mutations. ECG findings from 58 mutation carriers patients (TGFßR2 group) were compared with those of 46 non-affected first degree relatives (control group). TGFßR2 mutation was associated with ventricular repolarization abnormalities in 47% of patients (p < 0.001 vs. controls), including a 19.6 ms (95%CI 8.7; 30.5) QTc interval prolongation compared to the non-affected first degree relatives (p < 0.001), higher prevalence of abnormal U waves (16% vs. 2%), and sinusoidal T-U morphology (10% vs. 0%). TGFßR2 mutations can be associated with abnormal ventricular repolarization pattern, longer QT interval than non-carrier relatives and an increased risk for sudden death.

Beckwith-Wiedemann syndrome and long QT syndrome due to familial-balanced translocation t(11;17)(p15.5;q21.3) involving the KCNQ1 gene.

We report a child with Beckwith-Wiedemann syndrome (BWS) as the consequence of an apparently balanced, maternally inherited reciprocal translocation t(11;17)(p15.5;q21.3). His mother and aunt, who inherited the translocation from their father, did not have BWS. At birth, long QT syndrome (LQTS) was diagnosed in this child and, secondarily, among apparently healthy family members carrying the translocation. By FISH analysis, the breakpoint in 11p15.5 interrupts the KCNQ1 gene between exons 2 and 10 and causes a loss of methylation of the IC2 (and thus BWS) on the maternally inherited der(11) chromosome. To explain the presence of LQTS segregating with the t(11;17) translocation in this family, we hypothesize that the translocation that interrupts KCNQ1 allow translation of an abnormal short allele that interferes in a dominant negative way with the normal isoform 1 of KCNQ1 in the heart (where this allele is not subject to parental imprint). This appears to be the first report of BWS with congenital LQTS, which should be considered as a rare but serious complication to be searched systematically in patients with BWS due to 11p15 rearrangements.

[Management of atrial fibrillation in France: the observational FACTUEL study]. / Fibrillation atriale, description de la prise en charge par les cardiologues, étude observationnelle. Résultats de l'étude Factuel.

OBJECTIVES: To describe the management of patients with atrial fibrillation (AF) and to study consistency with guidelines on management of AF. PATIENTS AND METHODS: Observational study on a random sample of cardiologists from a French national database. Each cardiologist had to recruit the first five patients meeting inclusion criteria (patients diagnosed with AF between January 2004 and one month before inclusion and accepting the collection of their medical data). RESULTS: Between December 2006 and January 2207, 1789 patients aged 71 on average have been recruited by 481 cardiologists. Fifty-one percent were diagnosed with paroxysmal, 15% with persistent and 33% with permanent AF. Restoration of sinus rhythm was preferred in forms considered as paroxysmal or persistent forms whereas control of the ventricular rate was more frequent in AF considered as permanent. Overall, therapeutic guidelines are applied in practice, despite a frequent use of amiodarone in patients with no associated heart disease. Prevention of thromboembolism was observed in 88% of the patients. CONCLUSIONS: FACTUEL is the biggest observational study on AF ever conducted in France. The therapeutic strategies used by the cardiologists are consistent with the objectives of preventing thromboembolism and controlling heart rhythm and/or rate. In most cases, the treatment used is consistent with the therapeutic guidelines.

Arrhythmic sudden death in children.

Sudden death (SD) in childhood is rare, representing only 10% of paediatric mortality after one year of age. The individual risk is estimated between 1 in 20.000 and 1 in 50.000 per year. In case of a negative autopsy for cardiac morphologic anomalies, the most presumable cause remains a genetically-determined malignant primary ventricular arrhythmia. Rhythmic sudden cardiac death can be categorized as a complication of a cardiomyopathy (dilated or hypertrophic), or as a primary channelopathy without any structural heart disease. Primary ventricular arrhythmias include long QT syndrome, Brugada syndrome, short QT syndrome and Polymorphic Ventricular Tachycardia. The diagnosis of such syndromes relies upon specific ECG anomalies, personal history of family members, eventually echocardiography and drug challenge. For some of these diseases, morbid genes have been identified thus rendering possible the management of pre symptomatic or undiagnosed family members within specialized multidisciplinary teams. In case of sudden arrhythmic death in children, the parents and siblings must be examined Rescued sudden death exposes to a high risk of recurrence. In such patients, the automatic implantable defibrillator has dramatically improved survival.

[The Jervell and Lange-Nielsen syndrome. Natural history, molecular basis and clinical outcome]. / Syndrome de Jervell et Lange-Nielsen. Histoire naturelle, bases moléculaires et devenir clinique.

UNLABELLED: Data on the Jervell and Lange-Nielsen syndrome (JLN), the long QT syndrome (LQTS) variant associated with deafness and caused by homozygous or compound heterozygous mutations on the KCNQ1 or on the KCNE1 genes encoding the IKs current, are still largely based on case reports. We analyzed data from 186 JLN patients obtained from the literature (31%) and from individual physicians (69%). Most patients (86%) had cardiac events and 50% were symptomatic already by age 3. Their QTc was markedly prolonged (557 +/- 65 ms). Most of the arrhythmic events (95%) were triggered by emotions or exercise. Females are at lower risk for cardiac arrest and sudden death (CA/SD). A QTc>550 ms and history of syncope during the first year of life are independent predictors of subsequent CA/SD. Most mutations (90.5%) are on the KCNQ1 gene; mutations on the KCNE1 gene are associated with a more benign course. beta-blockers have only partial efficacy as 51% of the patients had events despite therapy and 29% had CA/SD. CONCLUSIONS: JLN syndrome is a most severe variant of LQTS, with a very early onset, major QTc prolongation, and is not well responsive to beta-blockers. Subgroups at relatively lower risk for CA/SD are identifiable and include females, patients with a QTc pound550 ms, without events in the first year of life, and with mutations on KCNE1. Early therapy with ICDs has to be considered.

Permanent junctional reciprocating tachycardia in children: a multicentre study on clinical profile and outcome.

OBJECTIVES: To investigate the clinical profile, natural history, and optimal management of persistent or permanent junctional reciprocating tachycardia (PJRT) in children. METHODS AND RESULTS: 85 patients meeting the ECG criteria for PJRT were enrolled in a retrospective multicentre study. Age at diagnosis varied from birth to 20 years (median 3 months). Follow up ranged from 0.1 to 26.0 (median 8.2) years. At the time of referral, 24 of 85 patients (28%) had congestive heart failure that was resolved with medical treatment in all patients. Eighty three patients received drug treatment initially. Amiodarone and verapamil were the most effective with a success rate of 84-94% alone or in association with digoxin. Radiofrequency ablation of the accessory pathway was performed in 18 patients. There was a trend for a relation between age at ablation and the result of the procedure, failures being more common in younger patients (three of six procedures in younger and 15 of 18 in older children were successful; p = 0.14). Two patients with persistent left ventricular dysfunction on echocardiography but with no symptoms of congestive heart failure died suddenly one month and three years after diagnosis. PJRT resolved spontaneously in 19 patients (22%). Age at diagnosis of PJRT was not a predictor of spontaneous resolution. CONCLUSIONS: PJRT is a potentially lethal arrhythmia in children with tachycardia induced cardiomyopathy. Spontaneous resolution of tachycardia is not uncommon. Antiarrhythmic treatment is often effective. Radiofrequency ablation should be performed in older children or when rate is not controlled, especially in patients with persistent left ventricular dysfunction.

Catecholaminergic polymorphic ventricular tachycardia: RYR2 mutations, bradycardia, and follow up of the patients.

BACKGROUND: The aim of the study was to assess underlying genetic cause(s), clinical features, and response to therapy in catecholaminergic polymorphic ventricular tachycardia (CPVT) probands. METHODS AND RESULTS: We identified 13 missense mutations in the cardiac ryanodine receptor (RYR2) in 12 probands with CPVT. Twelve were new, of which two are de novo mutations. A further 11 patients were silent gene carriers, suggesting that some mutations are associated with low penetrance. A marked resting sinus bradycardia off drugs was observed in all carriers. On beta blocker treatment, 98% of the RYR2 mutation carriers remained symptom free with a median follow up of 2 (range: 2-37) years. CONCLUSION: CPVT patients with RYR2 mutation have bradycardia regardless of the site of the mutation, which could direct molecular diagnosis in (young) patients without structural heart disease presenting with syncopal events and a slow heart rate but with normal QTc at resting ECG. Treatment with beta blockers has been very effective in our CPVT patients during initial or short term follow up. Given the risk of sudden death and the efficacy of beta blocker therapy, the identification of large numbers of RYR2 mutations thus calls for genetic screening, early diagnosis, and subsequent preventive strategies.

[Use of transesophageal pacing for documentation of older children with accessory pathway]. / Intérêt de la stimulation oeophagienne dans les syndromes de préexcitation ventriculaire du grand enfant.

INTRODUCTION: In case of an accessory pathway, children are exposed to severe cardiac events including sudden death. Radiofrequency ablation is a standardized procedure, which can be applied to a significant number of children although complications can still potentially occur. In this context, transesophageal evaluation of the accessory pathway evaluation can be discussed. MATERIALS AND METHODS: Among 140 procedures performed in 19 years, 70 were done for accessory pathway evaluation. The preexcitation was overt in 59 children older than 5 years, which form the basis in this study. RESULTS: Anterograde refractory period was determined in 88% cases and was found<220 ms in 12 cases justifying an ablation procedure. Conversely, in case of a long refractory period (>250 ms), the ablation procedure was not performed in 8 asymptomatic cases and was postponed in 11/20 mildly symptomatic children. Transesophageal electrophysiologic study seems legitimate in asymptomatic or mildly symptomatic children. CONCLUSION: This technique is probably less useful in case of an overt preexcitation and recurrent reciprocating tachycardia requiring long-term antiarrythmic treatment. In this case, endocavitary electrophysiological study eventually followed by an ablation procedure seems the best option.

[Catecholinergic ventricular tachycardia in children]. / Tachycardies ventriculaires catécholergiques chez l'enfant.

Catecholinergic ventricular tachycardia is an adrenergic induced polymorphic ventricular arrhythmia. It occurs in infancy and is responsible for syncope and sudden death in the absence of any morphological cardiac abnormality. Without treatment the mortality in catecholinergic ventricular tachycardia is very high. We report genetic and clinical data from 25 cases of catecholinergic ventricular tachycardia referred with syncope (n=19) or resuscitated sudden death during exercise (n=6). A family history from the 25 families identified 41 apparent subjects considered as being clinically affected, with an average age of 30 +/- 10 years (11 to 62 years). Analysis of the RyR2 gene showed mutations in 13 of the 25 cases and in 39 of apparent subjects. With betablocker treatment (nadolol: 1.6 +/- 0.15 mg/kg), 96% of patients remained asymptomatic over an average follow-up of between 7.5 +/- 1.5 years, although some of them continued to display polymorphic ventricular extrasystoles on exercise. Nevertheless, 12% of the cases suffered sudden death or further syncope during follow-up. An automatic defibrillator was implanted in 2 patients who had a RyR2 mutation. High dose betablockers are effective in preventing serious rhythm disturbance in children. In adolescence, implanting an automatic defibrillator should be discussed in cases with a history of syncope or resuscitated sudden death. We confirm the importance of genetic studies in these families at high risk of sudden death.

[Recent concepts of the Brugada syndrome, the long QT syndrome and adrenergic ventricular tachycardias]. / Aspects récents dans le syndrome de Brugada, le syndrome du QT long et les TV catécholergiques.

The clinical syndromes responsible for sudden death have benefited from spectacular advances in recent years. The authors propose a brief review of the genetic, electrophysiological, physiopathological and clinical characteristics of the long QT syndrome, Brugada's syndrome, adrenergic ventricular tachycardias and the short QT syndrome. The initial concept of one gene responsible for one pathology has uncovered new zones of complexity within diseases considered to be monogenetic in origin. These new findings have impacted on diagnostic and therapeutic strategies of these conditions. However, the assessment of the arrhythmic risk and the choice of treatment in individual cases still remain almost exclusively the domain of clinical judgement. Similarly, the better understanding of the mechanisms of the arrhythmias in these syndromes has opened up new specific therapeutic approaches which require validation by clinical trial.

[Practical attitude toward arrhythmia in the neonate and infant]. / Attitude pratique devant un trouble du rythme chez le nourrisson.

Arrhythmias in neonates and infants require a specific management due to the particular nature of the rhythm anomalies in children. Accurate diagnosis of the tachycardia is realised mainly by means of ECG recording and vagal manoeuvres. The nature of the tachycardia will determine management, therapy and prognosis. In neonates <3 months, supraventricular tachycardia due to Wolff-Parkinson-White syndrome represents 70% of all supraventricular tachycardias, which, after conversion by vagal manoeuvres, requires a preventive treatment by digoxine (10 y/kg/day tid). Neonatal flutter occurs in infants without structural heart disease. It has an excellent prognosis after conversion to sinus rhythm by transoesophageal pacing. Atrial tachycardia is less frequent but can induce a tachymyocardiopathy and often requires combined therapy including amiodarone. Long QT syndrome, clinically and genetically heterogeneous, is characterized by a prolongation of the QT interval (QTc > 440 ms) and a high risk of syncope and sudden death due to malignant ventricular arrhythmias. Beta-blockers significantly decrease cardiac events during follow-up. Congenital atrio-ventricular block is rare but potentially lethal in the first months of life in the absence of permanent pacing. The morbidity remains high during long term follow-up in unpaced children.

Low incidence of cardiac events with beta-blocking therapy in children with long QT syndrome.

AIMS: To evaluate the effect of beta-blockers in children with long QT syndrome (LQTS) we reviewed the outcome of 122 patients (pts). METHODS: LQTS was diagnosed in 24 neonates and in 98 pts aged 0.5-15 years. Diagnosis was made because of syncope in 51 pts, bradycardia in 10 neonates and family history in 61 pts. The longest QTc ranged from 400 to 700 ms. Thirteen pts had 2:1 atrioventricular block and/or ventricular arrhythmias. Screening for mutations was performed in 118 pts. All children were treated with beta-blockers, annually checked by exercise testing and/or 24 h ECG monitoring. RESULTS: Four pts died. Survivors were followed-up for 1-18 years (7.5 +/- 5.3 years). Five neonates and 3 older pts received a prophylactic pacemaker (1 death) so that only 111/122 pts survived and were followed-up with beta-blockers alone. None of them died and five experienced a non-fatal cardiac event. There was no cardiac event among pts who were diagnosed because of familial history and among symptomatic KCNQ1 pts who were effectively treated with beta-blockers. CONCLUSION: The outcome of children with LQTS under effective beta-blockers is favourable. Persisting arrhythmia or symptoms despite beta-blockers should aim at identifying other genotypes than KCNQ1.

[Neonatal forms of congenital long QT syndrome]. / Formes néonatales du syndrome de QT long congénital.

UNLABELLED: The neonatal congenital long QT syndrome (LQTS) is rare and of bad prognosis due to the presence of severe ventricular arrhythmia and conduction abnormalities. METHODS: we included 24 propositus newborns from our population with LQTS. Genetic study was possible in 19 cases. RESULTS: the diagnosis of LQTS was made according to a QT prolongation associated with a sinusal neonatal bradycardia (n=9) or a 2/1 AV block (n=15). The onset presentation consisted of syncope (n=2), torsades de pointes (n=7), cardiovascular collapse (n=5), cardiac arrest (n=1). The mean QTc was at 550+60 ms. During the neonatal period the treatment consisted of beta-blocking agents in all cases, associated with a definitive pacemaker implantation in 10 cases with 2/1 AV block. Three newborns with a 2/1 AV block died during the first month of life (one case due to a septecemia after implantation of a pacemaker, and two who were waiting for that implantation). All survivors remained asymptomatic during a follow-up period of 7 years. In all cases with a 2/1 AV block we identified mutations in HERG (n=8). Newborns with isolated sinusal bradycardia presented all a mutation in KCNQ1 (n=9). CONCLUSION: the LTQS with 2/1 AV block is preferably associated with mutation in HERO with a bad initial prognosis.

Tissue Doppler echocardiography in patients with long QT syndrome.

BACKGROUND: Congenital long QT syndrome (LQTS) is a well-defined clinical entity associated with a high mortality among untreated patients. Tissue Doppler (TD) echocardiography that has been recently introduced, facilitates wall motion analysis. Therefore, to further characterize myocardial velocity abnormalities associated with LQTS, using TD and conventional echocardiography, we compared control subjects and LQTS patients. METHODS AND RESULTS: Ten patients with mild LQTS and 14 control subjects were examined with standard and TD echocardiography. We studied myocardial velocities in basal and mid-segments of the septal, lateral, inferior and anterior walls. Peak velocity and time intervals were measured in each segment. We confirmed previously described M-mode abnormalities, demonstrated by an increase of the wall thickening time index. TD analysis demonstrated increased systolic and diastolic peak velocities for all segments in LQTS patients. Regional isovolumic relaxation time and systolic velocity half time (VHT) were significantly longer in LQTS group associated with a prolonged late systolic phase, resulting in a plateau morphology. CONCLUSION: We demonstrated that TD allows the characterization of myocardial velocity abnormalities in LQTS patients. TD measurements could become part of the routine clinical evaluation for patients potentially affected by the LQTS as a new phenotypic marker.

[Value of genetic testing in the management of the congenital long QT syndrome]. / Apports de la génétique dans la prise en charge du syndrome du QT long congénital.

The congenital long QT syndrome (LQTS) is a variable clinical and genetic entity characterised by prolongation of the QT interval on the ECG associated with the risk of serious ventricular arrhythmias (torsades de pointe, ventricular fibrillation) which may cause syncope and sudden death in patients with otherwise normal hearts. To date, 6 loci have been identified with the genes responsible for the forms LQT1, LQT2, LQT5 and LQT6, coding for the potassium channels (KCNQ1, HERG, KCNE1 and KCNE2, respectively) which, in the heterozygote state, are responsible for the main forms of LQTS without deafness and, in the homozygote state (KCNQ1 and KCNE1) for the recessive forms of LQTS with or without deafness. The gene for the LQT3 form codes for the cardiac sodium channel (SCN5A). The genetic variability observed in the LQTS corresponds to the diversity of cardiac ionic channels implicated in the genesis of the action potential, so making the LQTS a disease of the ionic channels or a "channelopathy". The potential severity of the prognosis justifies testing of subjects with long QT intervals on the ECG and Holter recording. In order to identify subjects with the genetic abnormality who are asymptomatic, these investigations associated with genetic testing should be made in all close members of the family of an affected person. The major problem remains the evaluation of the risk of sudden death in asymptomatic subjects with a genetic abnormality. At present, in the absence of clearly proven prognostic factors and in the knowledge that effective treatment without major secondary effects is available, all patients should be given prophylactic betablocker therapy.

[Brugada syndrome]. / Syndrome de Brugada.

The Brugada syndrome is characterised clinically by the occurrence of syncope or sudden death due to ventricular arrhythmias in patients with structurally normal hearts and electrocardiographic signs of right bundle branch block and ST elevation in the right precordial leads (V1 to V3). The transmission of the condition is autosomal dominant with variable penetration. Mutations have been identified in a gene coding for the alpha sub-unity of the sodium channel (SCN5A) on chromosome 3 in only 30% of cases. This mutation is responsible for a reduction of the density of the sodium current and explains the aggravation of the electrocardiographic anomalies by antiarrhythmic drugs which block the sodium channels. The prognosis is poor in symptomatic patients and depends on the prevention of sudden death by the implantation of an automatic defibrillator. The therapeutic decision is much more difficult in asymptomatic patients without a family history. The authors propose a decisional algorithm. The management may have to be modified in the months or years to come depending on advances in the understanding of this syndrome.

Safety of a controlled-release flecainide acetate formulation in the prevention of paroxysmal atrial fibrillation in outpatients.

OBJECTIVES: The cardiac safety of a once-a-day 200 mg controlled-release formulation of flecainide acetate in the prevention of paroxysmal atrial fibrillation (PAF) was assessed in outpatients. MATERIAL AND METHODS: The drug was administered for 24 weeks to 227 patients diagnosed with recurrent Paf episodes. Cardiac safety was assessed primarily by the maximum change from baseline in QRS duration. Changes in left ventricular function at echocardiography, incidence of proarrhythmic effects determined from ECG and Holter recordings and cardiovascular adverse events were also taken into account to assess cardiac safety. Efficacy was documented by actuarial methods. RESULTS: Mean maximum QRS increase from baseline was 11.4% (n = 181); QRS increase was < 15% in 71.8% of the patients and > or = 25% in 18.8%. Only 4 patients had maximum QRS value > 100 ms under treatment. Left ventricular ejection fraction remained within +/- 20% of baseline for 90% of the patients, increased above 20% for 8.6% and decrease below 30% for 1.4% (n = 139). Bradycardia (13.2%; n = 129) and ventricular extrasystoles (10.6%; n = 104) were the most frequently identified proarrhythmic effects. Atrio-ventricular block (4.0%), supra-ventricular tachycardia (2.2%), bundle branch block (1.8%) and atrial fibrillation (1.3%) were the most frequent drug-related cardiac adverse events. Estimated treatment success rate was 74% (95% CI: [68%; 80%]) and the incidence of Paf episodes decreased from baseline 28.6% to 11.0% (P < 0.0001). CONCLUSIONS: We provided evidence for a good cardiac safety profile of the controlled-release formulation of flecainide acetate and confirmed the effectiveness of the drug in the prevention of PAF recurrences.

[Bidirectional ventricular tachycardias]. / Tachycardies ventriculaires bidirectionnelles.

Bidirectional tachycardias are rare arrhythmias. Nevertheless in the sixties and seventies these arrhythmias prompted much work relating to their mechanism. Discussions about the supposed supra-ventricular origin of certain bidirectional tachycardias essentially rested on presumptive arguments based on electrocardiographic analysis. All the electrophysiological investigations which could be performed in tachycardia showed a ventricular origin. The current hypotheses concerning the electrophysiological mechanism favour non-unifocal mechanisms as well as a very diverse aetiology: an automatic focus, or the triggered activities being associated with alternating conduction, or re-entry between the left hemibranches. Although the classic context is of excess digitalis with advanced cardiopathy, readily in atrial fibrillation with a poor prognosis as a corollary, the most recent description of catecholergic ventricular tachycardias with the very characteristic appearance of bidirectional tachycardias justifies updating the understanding of these unusual tachycardias.

[Homozygotous mutation of the SCN5A gene responsible for congenital long QT syndrome with 2/1 atrioventricular block]. / Mutation homozygote dans le gène SCN5A responsable d'un syndrome de QT long congénital avec bloc auriculo-ventriculaire 2/1.

Long QT syndrome is characterized by a prolongation of the QT interval on the surface ECG. This clinically and genetically heterogeneous cardiac disease is potentially lethal due to ventricular polymorphic tachyarrhythmias leading to syncope or sudden death. It is transmitted according to different mendelian modes due to mutations in several genes coding for cardiac ion channels. Heterozygous mutations in KCNQ1, HERG, SCN5A, KCNE1 and KCNE2 genes are responsible for the dominant form without deafness whereas homozygous mutations in KCNQ1 and KCNE1 are responsible for the recessive form (Jervell and Lange-Nielsen syndrome) associated with congenital deafness. We report the case of a 5 year-old boy referred for syncope with a prolongation of the QTc interval (526 ms) and a 2/1 Atrio-Ventricular (AVB) block on the surface ECG. Under beta-blocking therapy, the sinus rate decreased and the 2/1 AVB disappeared. Electrophysiological study evidenced an infra-hisian block and a unipolar ventricular endocardial pacemaker was implanted. A V1777M missense mutation was identified in the C-terminal part of SCN5A, cardiac sodium channel gene, at the homozygous state in the proband and at the heterozygous state in both parents and 2 sibblings. Only the proband had a severe phenotype with syncope and AV conduction anomalies. All other genetically affected subjects were asymptomatic. This study provides evidence for the involvement of homozygous LQT3 forms in "functional" AVB.