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.

[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.

[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.

[Antenatal diagnosis of congenital left ventricular aneurysm]. / Diagnostic anténatal d'un anévrisme congénital du ventricule gauche.

Congenital aneurysm of the left ventricle is a rare condition of unknown origin, the main differential diagnosis of which is the diverticulum. The natural history of this pathology is well known in adults and adolescents, contrary to those forms diagnosed by foetal echocardiography. Based on a case of congenital left ventricular aneurysm diagnosed ante-natally and a review of the literature, the authors propose echocardiographic prognostic factors useful for prenatal management. Thus, early antenatal diagnosis, size and progression of the aneurysm, signs of antenatal cardiac failure, are poor prognostic factors and should be discussed during parent counselling.

[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.

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.

[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.

[Andersen syndrome, ventricular arrhythmias and channelopathy (a case report)]. / Maladie d'Andersen, channelopathies et arythmies ventriculaires (à propos d'un cas).

INTRODUCTION: Recent advances in molecular genetic research have provided new insights into severe ventricular arrhythmias related to channelopathies. CASE REPORT: A case of Andersen's syndrome followed during fourteen years is reported. This rare familial periodic paralysis is characterized by its association with dysmorphic features (micrognatia) and ventricular arrhythmias. COMMENTS: Andersen's syndrome has been attributed to a mutation in the KCNJ2 gene which is involved not only in stabilizing cardiac rhythm, but also in modulating the excitability of skeletal muscle and in morphogenesis. This disease must be distinguished from hyperkalemic periodic paralysis due to a mutation in the skeletal muscle sodium channel gene (SCN4A) and from hypokalemic periodic paralysis related to dihydropyridine receptor mutation (CACNL1A3). Furthermore, it may not be confused with others rhythmic channelopathies (long QT syndromes, catecholaminergic polymorphic ventricular tachycardia and Brugada's syndrome).

[Cardiogenic shock in an infant due to rupture of an aneurysm of the sinus of Valsalva into the left ventricle]. / Choc cardiogénique d'un nourrisson révélant une rupture intraventriculaire gauche d'un anévrisme du sinus de Valsalva.

The authors report the case of a 15 month-old infant admitted to the intensive care unit for cardiogenic shock due to rupture of an aneurysm of the right anterior sinus of Valsalva into the left ventricle, associated with massive aortic regurgitation. The patient underwent a Ross procedure with resection of the aneurysm. This is a very rare condition because rupture of the aneurysm into the left ventricle has not been previously reported in a young girl to the best of the authors' knowledge. Moreover, a Ross procedure has not been previously described in this indication. The case illustrates the diagnostic difficulty associated with this pathology and underlines the necessity of thinking of this diagnosis in infants with appearances of dilated cardiomyopathy and aortic regurgitation.

[T wave abnormalities on Holter monitoring of congenital long QT syndrome: phenotypic marker of a mutation of LQT2 (HERG)]. / Anomalies de l'onde T au Holter dans le syndrome du QT long congénital: marqueur phénotypique d'une mutation dans LQT2 (HERG).

The two genes which code for the potassium channels, KCNQ1 and HERG, are responsible for the most common forms of the long QT syndrome, LQT1 and LQT2. Abnormalities of duration and morphology of the ventricular repolarisation are amongst the diagnostic criteria of this syndrome. The morphology of the T waves was studied by 24 hour Holter monitoring in 190 subjects with a long QT syndrome due to KCNQ1 (LQT1) [N = 133] or HERG (N = 57) and in 100 controls, and it was compared with the ECG T wave. The T wave was characterised according to 3 morphological features: grade 0 (G0) = normal, grade 1 (G&) = slight ST depression and grade 2 (G2) = presence of ST elevation of the descending phase of the T wave. The T wave morphology on Holter ECG was normal for most LQT1 and control subjects compared with LQT2 (92%, 96% and 19% respectively, p < 0.01). Grade 1 appearances were observed more often in LQT2 (18 vs 8% for LQT1 and 4% for controls, p < 0.01). Grade 2 appearances were only observed in the cases of LQT2 (63%). The predictive factors of G2 were young age and an anti-sense mutation of the transmembrane domaines of HERG. The authors conclude that Holter monitoring improves detection of T wave changes compared with the ECG. Grade 2 changes seem to be a phenotype marker for a HERG mutation, especially those situated in the transmembrane domaines.

[Cardiac consequences of adolescent anorexia nervosa]. / Conséquences cardiaques de l'anorexie mentale de l'adolescence.

Cardiac complications are common in adolescent anorexia nervosa and are the cause of a third of deaths. Some workers have reported prolongation of the QT interval and cases of sudden death in these patients. The aim of this study was two-fold: to assess the cardiac complications of anorexic adolescents and to determine the outcome after renutrition in the hospital setting. This was a prospective study of 48 consecutive cases (45 girls) with an average age of 14 +/- 2 years, admitted to the paedopsychiatric unit and fulfilling the DSM-IV criteria of anorexia nervosa. The digitised ECG, Holter ECG and echocardiography were recorded before and after renutrition. Anorexia nervosa was severe with a body mass index < 14 in 2/3 of cases. Over 2/3 of patients had bradycardia with a heart rate < 50/min in half the cases but normal chronotropic function on Holter monitoring. Prolongation of the QTc interval was demonstrated (QTc > 440 ms in 11/44 cases). Echocardiographic abnormalities, in particular left ventricular dysfunction (24/46) and pericardial effusion (12/46) were reversible after renutrition. There were no clinical or biological predictive factors for the occurrence of cardiac complications on admission. The authors confirm that cardiac complications of anorexia nervosa are common, usually benign and always reversible after renutrition in hospital. Therefore, most electrical abnormalities normalise with the heart rate and echocardiographic abnormalities with improvement of conditions of load.

[Antenatal atrial tachycardia. Two case reports]. / Tachycardies atriales anténatales. A propos de 2 cas.

The authors report two cases of foetal supraventricular tachycardia in healthy hearts with 1/1 atrioventricular conduction which turned out to be atrial tachycardias in the postnatal period. The first foetus had permanent tachycardia at 190/minute at 34 weeks' amenorrhea with left ventricular dysfunction at 36 weeks. In the postnatal period, treatment with digoxine and amiodarone restored sinus rhythm and normal left ventricular function. Permanent foetal tachycardia, even at a rate of less than 200 beats/minute, should suggest an arrhythmia and may lead to left ventricular dysfunction in utero. The other foetus had an aneurysm of the foramen ovale with paroxysmal tachycardias at 220/minute without cardiac dysfunction. A Holter at 1 month showed paroxysmalatrial tachycardia. Postnatal rhythm monitoring is necessary in paroxysmal foetus tachycardia, especially with prenatal aneurysm of the foramen ovale.

Homozygous SCN5A mutation in long-QT syndrome with functional two-to-one atrioventricular block.

Heterozygous mutations in genes encoding cardiac ionic channel subunits KCNQ1, HERG, SCN5A, KCNE1, and KCNE2 are causally involved in the dominant form of long-QT syndrome (LQTS) while homozygous mutations in KCNQ1 and KCNE1 cause LQTS with or without congenital deafness. In addition, two homozygous HERG mutations have been associated with severe LQTS with functional atrioventricular conduction anomalies in young children. A 2:1 atrioventricular block (AVB) with a major QTc prolongation (526 ms) was evidenced in a 5-year-old boy referred for syncope and seizure. LQTS was diagnosed and beta-blocking therapy initiated leading to normal atrioventricular conduction. Electrophysiological study provided support that location of the AVB was infra-Hisian. DNA analysis was performed in the proband and in asymptomatic family members. A novel missense mutation, V1777M, in the early C-terminal domain of SCN5A was identified. The proband was homozygous while the parents and two siblings were heterozygous carriers. Homozygote and heterozygote expression of the mutant channels in tsA201 mammalian cells resulted in a persistent inward sodium current of 3.96+/-0.83% and 1.49+/-0.47% at -30 mV, respectively, which was dramatically reduced in the presence of tetrodotoxin. This study provides the first evidence for a homozygous missense mutation in SCN5A and suggests that LQTS with functional 2:1 AVB in young children, a severe phenotype associated with bad prognosis, may be caused by homozygous or heterozygous compound mutations not only in HERG but also in SCN5A. The full text of this article is available at http://www.circresaha.org.