Inherited Arrhythmias:
Special Considerations for the Pediatric Population

K Brockmeier and N Sreeram

Pediatric Cardiology, University of Cologne, D-50924 Köln, Germany

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1.  The Brugada Syndrome

Sudden cardiac death accounts for approximately 20% of the sudden deaths in the pediatric age group. It is increasingly recognized that inherited arrhythmia syndromes contribute to a significant proportion of these deaths. The two inherited arrhythmia syndromes which have received prominence in the last 2 decades are the congenital long QT syndrome and the Brugada syndrome.

Mutations in the SCN5A gene reduce sodium current density in the right ventricular epicardium. The selective loss of the action potential dome in the epicardium creates a dispersion of repolarization across the right ventricular wall. This results in the inscription of the classical ST segment elevation in the right precordial leads of the 12 lead electrocardiogram. The dispersion of repolarization also produces a vulnerable window during which localized reentry mechanisms could trigger potentially fatal ventricular arrhythmias.

In addition to the well documented transient nature of the ECG changes typical of Brugada syndrome, additional limitations are encountered in ECG interpretation in children. There are no standardized data for optimal lead position in children to record the classical ECG changes associated with Brugada syndrome. The shape of the chest may also influence the ECG pattern, as attested to by the finding of right bundle branch block and ST segment elevation in patients with pectus excavatum. Isolated incomplete right bundle branch block is a common finding in childhood.

The role of cardiac arrhythmias as the precipitating event in the sudden infant death syndrome (SIDS) has long been a matter for debate. In recent years, it has been shown that both the congenital long QT syndrome and the Brugada syndrome are associated with SIDS. The true incidence of manifest Brugada syndrome in the pediatric population is unknown, although isolated cases of sudden death and familial sudden death in infancy or childhood have been attributed to the syndrome. Given the possibility of transient normalization of the electrocardiogram in the Brugada syndrome, the relative paucity of data concerning its association with SIDS, and the natural history of the disease, with the majority of patients manifesting symptoms of the disease in adult life, it is impossible to recommend routine neonatal ECG screening as a means of prospectively identifying the Brugada syndrome. Where there is a clear family history of sudden and unexplained death, at any age, then ECG screening of healthy neonates would be justified.

An interesting observation has been that the sodium channel function is temperature-dependent, and there are reports of ventricular arrhythmias caused by fever in patients with Brugada syndrome. As febrile convulsions are a relatively common occurrence, this raises the interesting question of whether every child presenting with a febrile convulsion would require a standard electrocardiogram as part of the diagnostic workup. Certainly, if syncope has also been documented, this seems to be mandatory.

Several attempts at risk stratification have been made, primarily in the adult population. The criteria used for assessing risk have, among others, included the presence of symptoms (syncope, sudden death or near-miss death), a classical electrocardiogram with ST elevation in the right precordial leads and a right bundle branch block pattern at rest, a positive family history of sudden and unexplained death, the results of invasive electrophysiologic testing, unmasking of the classical ECG with the use of sodium channel blockers (intravenous administration of ajmaline or flecainide), and genetic testing for SCN5A mutations. To date, the most reliable indicators for risk of sudden death appear to be a combination of symptoms (syncope or near miss death) and a classical ”Brugada” ECG at rest. Unmasking the typical ST segment elevation with the use of sodium channel blockers, or a positive genetic test for SCN5A mutation may confirm carriage of the disease, but are not necessarily associated with an increased risk of sudden death, in the absence of symptoms. The role of invasive electrophysiological testing in risk assessment remains unclear, and no data are available in children. In symptomatic patients, even in the absence of inducibility of ventricular tachycardia, implantation of an ICD is recommended in adults. If this analogy is followed in children, invasive studies to assess risk of sudden death may be entirely avoided, except in very special circumstances.

Interestingly, there are reports of recurrent monomorphic ventricular tachycardia in association with the Brugada syndrome, particularly in young patients. Whether such arrhythmic substrates may be appropriately treated by catheter ablation procedures remains to be tested.

Up to 30% of patients with Brugada syndrome may have a mutation of the SCN5A gene. A second locus on chromosome 3 has also been associated with the disease. Genetic testing is clearly indicated when there is a strongly positive family history, as the disease is inherited in a dominant fashion. However it is time-consuming (weeks or months), there are a limited number of centers which can carry out testing, the yield (30%) is relatively low, and finally, in the absence of symptoms, gene carriage does not appear to be a risk factor for sudden death for the individual patient, even when the family history is strongly positive for sudden death.

To date, the only effective therapy for preventing sudden death appears to be implantation of an ICD device. As the requirement for treatment is lifelong, this form of therapy has serious implications for children. The higher likelihood of inappropriate shocks in young children, with their adverse effect on the quality of life has also to be considered. Particularly in the Far East, where the disease appears to be endemic, the prohibitive costs of such therapy and the expert long-term follow-up also need to be considered. Pharmacologic therapy aimed at aimed at rebalancing the epicardial action potential has shown promise in isolated cases. Quinidine, which blocks the transient outward current (Ito) or isoproterenol, which boosts the calcium current, have resulted in ”normalization” of the surface ECG and proven helpful in controlling electrical storms in children. However, the mainstay of therapy at the present time is the ICD.

2.  The Congenital Long QT Syndrome

The Long QT Syndrome (LQTS) is a rather heterogeneous group of ion-channel diseases caused by numerous mutations in at least six distinct gene loci, all of them resulting in a prolongation of the myocardial repolarization. As a genetically determined disorder the clinical manifestation of the LQTS naturally starts in childhood. In 34% of the children, syncope or cardiac arrest was found before the age of 15 years. In addition, 54% of all LQTS patients who died from sudden cardiac death were less than 20 years old.

Most LQTS cases in childhood were identified by the detection of a prolonged QT interval in the ECG while evaluating unexplained cases of syncope, or by investigations of a family with an identified LQTS patient. In children more than in adults the typically applied algorithms to correct the QT interval to heart rate is problematic, particularly in younger children due to the encountered higher heart rates. A useful and reliable tool for the analysis of possible pathologic QT prolongation, QT patterns, and its circadian variation are multilead digital Holter recordings. The changes of T wave morphology and instability of ST-T pattern offers greater diagnostic value than time domain. The diagnostic determination of the disease is based on clinical findings using the criteria of the ”International LQTS Registry”.

Genetic investigations are actually diagnostic in about 50% of the patients only, therefore not very effective as a clinical screening tool. The genetically determined LQTS types (LQT1–LQT6) differ significantly in terms of the trigger for life-threatening arrhythmias and their response to treatment. In LQT1, physical stress will more likely induce Torsades de Pointes than in the other forms. In LQTS2, auditory stimuli appear to be important triggers for ventricular tachycardia. LQTS3, which is caused by a mutation in the SCN5A gene, results in arrhythmias which are more prone to occur in sleep (as also appears to be the case in the Brugada syndrome).

General approach in the LQTS treatment is life-long medication with beta blocking agents; however, in LQT3 patients with mutations in the SCN5A sodium channel gene, treatment with sodium channel blocking substances such as mexiletine may have advantages.

In order to prevent bradycardia or short-long sequences of the heart beat that might induce torsades, the use of implantable pacemakers is recommended. Stellectomy to minimize cardiac adrenergic susceptibility has been performed in several patients at higher risk, however proven effectiveness in children is lacking. Recently, the rapid technical improvement of implantable defibrillators led to a more frequent use of these devices in children with documented syncope under medication.

3.  Arrhythmogenic Right Ventricular Cardiomyopathy

This is an underestimated cause of sudden death in young patients. Studies suggest that up to 25% of young athletes dying suddenly during exercise may have ARVC. There are at least 7 genetic loci associated with the disease. Similar to the diagnostic criteria for LQTS, a combination of major and minor criteria are required to establish the diagnosis. One of the important ECG criteria is the presence of T wave inversion in the right precordial leads. This is however uninterpretable in children <12 years of age, in whom this finding may be considered normal. The pathologic substrate for malignant ventricular tachyarrhythmia is progressive fibro-fatty infiltration of the myocardium, primarily of the right ventricle. This process usually starts in the epicardial region, so biopsies may be inconclusive. Newer imaging techniques (gated MRI) may be helpful in establishing the diagnosis in patients with exercise-related syncope. In young children with exercise related syncope, in whom formal exercise testing cannot be performed, ambulatory Holter recording (including use of the implantable loop recorder) may be justified in establishing a symptom-rhythm correlation. Therapy involves a combination of antiarrhythmic agents, occasionally catheter ablation for recurrent monomorphic ventricular tachycardia originating in the right ventricle, or implantation of an ICD. Rarely, cardiac transplantation may be required in patients with malignant arrhythmias not controlled by the above measures.