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ScienceDirect Journal of Electrocardiology 48 (2015) 150 – 156 www.jecgonline.com

Cardiac channelopathies in pediatric patients —7-years single center experience V. Illikova, MD,⁎ P. Hlivak, MD, R. Hatala, MD Departments of Arrhythmias and Pacing and ICU, Children's Cardiac Center, Comenius University School of Medicine and National Cardiovascular Institute, Slovak Medical University School of Medicine, Bratislava, Slovakia

Abstract

Introduction: Channelopathies are associated with mutations of genes encoding proteins creating or interacting with the specialized ion channels in myocardial cell membranes, thus forming arrhythmogenic substrate predisposing the patient to sudden cardiac death. The study focuses the clinical and ECG presentation and management of children with channelopathies in Slovakia. Subject and methods: Twenty-two children with suspected channelopathy were admitted to Children's Cardiac Center Bratislava in the years 2007–2014. Genetic testing was made in 19 patients. Results: Fourteen patients were symptomatic. Long QT syndrome was genetically proven in eight and catecholaminergic polymorphic ventricular tachycardia in five patients. Twenty children are treated with beta-blockers, five in combination with mexiletine or flecainide. Nine patients received implantable cardiac defibrillator and one underwent left cardiac sympathetic denervation. Conclusion: Both clinical presentation and genetic testing must be considered in the diagnostic and therapeutic process of channelopathies. Early diagnosis allows for adequate treatment and lifestyle modification. © 2015 Elsevier Inc. All rights reserved.

Keywords:

Channelopathy; Genetic testing; Children

Introduction

LQTS

Primary genetic arrhythmias or channelopathies are associated with mutations of genes encoding proteins creating or interacting with the specialized ion channels in the myocardial cell membranes. The resulting changes in the ion channel function (decreased or increased function) form the arrhythmogenic substrate predisposing the patient with structurally normal heart to sudden cardiac death (SCD) on the basis of ventricular tachycardia (VT) or fibrillation [1,2]. Channelopathies are a heterogenous group of diseases with many different causative genes. The two most commonly occurring types in children are long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT). Less commonly it is Brugada syndrome (BrS), presenting usually in adulthood.

LQTS is characterized by QT interval prolongation, T wave abnormalities and specific type of arrhythmia— torsades de pointes (TdP), with the resulting predisposition for syncope, seizures and sudden cardiac death. TdP is a specific type of ventricular tachycardia (Fig. 1), often selflimiting with transient syncope, but it can also degenerate into ventricular fibrillation and cardiac arrest [3–5]. LQTS represents a leading cause of autopsy-negative sudden death in the young [6]. Three main genes responsible for the 3 most common types of LQTS: gene KCNQ1 in LQT1, KCNH2 in LQT2 and SCN5A in LQT3, account for approximately 75% of clinically definite LQTS, minor genes contribute an additional 5% and about 20% of LQTS remain genetically elusive [2,3,5,7]. Diagnosis of LQTS is made when modified Schwartz risk score is more than 3.5 [3,8] and/or pathogenic mutation of one of the LQTS genes is found or corrected QT interval of more than 500 ms is reproducibly measured on the native ECG. The estimated yield of the genetic testing in LQTS is about 60% [2,3,7]. Treatment options for LQTS patients include life-style modification focusing on avoidance of specific triggers of

⁎ Corresponding author at: Departments of Arrhythmias and Pacing and ICU, Children's Cardiac Center, Comenius University School of Medicine and National Cardiovascular Institute, Slovak Medical University School of Medicine, Bratislava, Slovakia. E-mail address: [email protected] http://dx.doi.org/10.1016/j.jelectrocard.2014.11.010 0022-0736/© 2015 Elsevier Inc. All rights reserved.

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Fig. 1. “Torsade de pointes” in the neonate with LQT3 syndrome documented on ECG monitor and with invasive arterial blood pressure measurement: ECG lead II—top part of the figure, invasive arterial blood pressure (ABP) measurement—the bottom of the figure. Note the ventricular premature contractions before the TdP starts and the sudden fall of ABP to zero with the beginning of TdP.

arrhythmic events and QT interval prolonging drugs, pharmacological therapy with beta-blockers (propranolol or nadolol considered as the most effective) and mexiletin (flecainide, ranolazine) in LQT3 patients, left cardiac sympathetic denervation (LCSD) and implantable cardiac defibrillator (ICD) [2,3,7].

testing were classified into 4 categories: disease-causing mutation, very likely disease-causing mutation, variant of unknown significance and negative testing with no mutation.

CPVT CPVT is characterized by normal resting ECG and adrenergic-mediated ventricular tachycardia: monomorphic premature ventricular contractions (PVCs) progressing to specific bidirectional and polymorphic PVCs and ventricular tachycardia with physical activity and emotional stress. Adrenergic-mediated supraventricular tachycardia is also commonly occurring in this disease. CPVT is associated with mutations of gene for ryanodine receptor RYR2 in about 60% of patients, KCNJ2 (protein Kir2.1) in 10% and gene for calsequestrin CASQ2 in about 5% [9]. The estimated yield of the genetic testing is around 40%. Treatment options include life-style modification with avoidance of physical activity, beta-blockers, verapamil and flecainide, ICD and LSCD [2,7]. Our study focuses on the clinical and ECG presentation and management of children with channelopathies in Slovakia.

Subject and methods Twenty-two children aged from neonatal to eighteen years with suspected primary genetic arrhythmia were admitted to Children's Cardiac Center Bratislava in between 2007 to July 2014. In patients with suspected LQTS, QT interval was measured and corrected for heart rate using Bazzet's formula and the risk score was measured according to modified Schwartz diagnostic criteria [8]. In patients with suspected CPVT, exercise testing and 24 hours ECG Holter monitoring were made to document specific arrhythmias during exercise and/or emotional stress. Genetic testing has been performed in patients with intermediate or high risk of LQTS according to Schwartz score (1.5 and more) and in all patients with suspected CPVT. It has been made in the diagnostic genetic center GeneDx, US, from samples of isolated DNA, which were processed in the local genetic laboratory. Results of genetic

Fig. 2. X-ray AP (a) and lateral (b) scan: ICD implanted in 2-year-old girl: ICD placed abdominally under m. rectus abdominis l.dx, subcutaneous defibrillation electrode (lengths of electrode 41 cm, defibrillation coil 25 cm) tunneled subcutaneously in the intercostal space all the way to the spine.

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Table 1 Characteristics of the patients: age at presentation, symptoms, QTc, Schwartz score, genetic results, and treatment. Pts Age

Symptoms

QTc (ms) SchS Mutation

LQT type

Therapy

1 2 3 4 5

Newb 2.5 y 15 y 10 y 9y

Aborted SCD Extremely frequent syncope Aborted SCD Recurrent syncope Recurrent syncope

500–650 500–650 440–550 460–510 500–530

7.5 8 5 5 5

LQT3 LQT3 LQT2 LQT1 LQT1 + LQT2

ICD ICD ICD ICD BBs

6 7

Newb Asymptomatic, sinus bradycardia 2 mo Asymptomatic, sinus bradycardia

500–580 440–540

3.5 3.5

8 9 10 11 12 13 14 15 16 17 18 19 20 21 22

2y 9y 18 y 14 y 13 y 13 y 11 y 4y 3y 10 y 9y 6y 6y 14 y 10 y

440–470 480–560 620–670 470–530 440–540 500–530 440–490 500–560 500–550 NA NA NA NA NA NA

2.5 5 7 4 6 4 3.5 4 4 NA NA NA NA NA NA

Asymptom., aborted SCD in the mother Aborted SCD Aborted SCD SCD Syncope Asymptomatic Asymptomatic Asymptom., aborted SCD in the mother Asymptom., aborted SCD in the mother Asymptomatic, BrS in the father Aborted SCD Recurrent syncope Recurrent syncope Palpitations, chest pain Aborted SCD

SCN5A R1623Q SCN5A p.Pro1332Leu KCNH2 p.Arg176Trp KCNQ1 p.Asp611Asn KCNQ1 p.Gly314Ser + KCNH2p.Arg176Trp KCNQ1 p.Val254Met KCNQ1 p.Gly229Asp + VUSSCN5A p.Ser216Leu SCN5A VUS p.Ser216Leu Not finished Not made Not made Not finished Not finished Not finished Not finished Not finished Not made RYR2 RYR2 p.Val4771Ile RYR2 p.Val4771Ile KCNJ2 p.Arg67Gln RYR2 p.Arg420Gln

+ + + +

BBs + mexiletin BBs + mexiletin + LCSD BBs BBs

LQT1 BBs LQT1 (+LQT3?) BBs LQT3? ? ? ? ? ? ? ? ? Susp BrS CPVT CPVT CPVT CPVT CPVT

BBs ICD + ICD + NA BBs BBs BBs BBs BBs Sine BBs + BBs + BBs + BBs + BBs +

BBs BBs

ICD Flecainide + ICD Flecainide Flecainide ICD

Pts—patients, SchS—Schwartz score, newb—newborn, mo—months, y—years, SCD—sudden cardiac death, NA—not addressed, BBs—beta-blockers, LCSD—left cardiac sympathetic denervation.

Results Symptoms Fourteen of 22 patients (pts) were symptomatic with sudden cardiac death in one and aborted sudden cardiac death in six pts, syncope in six and chest pain and palpitations in one patient; in twelve patients LQTS and in four CPVT was supposed. Eight patients were asymptomatic with ECG features suggesting channelopathy in four pts (prolonged QT interval in two older children and sinus bradycardia with prolonged QT interval in two infants) or family history of primary genetic arrhythmia in other four pts (LQTS in three and Brugada syndrome in one patient). Clinical diagnosis Corrected QT interval (QTc) in suspected LQTS pts was minimum 440–620 ms and maximum 470–670 ms, with Schwartz scores of 2.5–8 points. All but one CPVT patient had bidirectional PVCs or VT documented on 12 lead ECG, ECG Holter monitor or induced with exercise testing. Genetic testing and results Genetic testing has been performed in 19 patients with 13 results until now: LQTS was diagnosed in eight pts, five symptomatic, and CPVT in five pts, all of them symptomatic. In one patient with supposed LQT or Brugada syndrome, CPVT was diagnosed. In genetically confirmed LQTS patients there were KCNQ1 gene mutations in three, KCNH2 in two and SCN5A in four patients (two children have more than one mutation).

In genetically confirmed CPVT pts there were four RYR2 mutations, two in identical twins with frequent syncope and seizures and two in boys resuscitated from SCD (three of these children were diagnosed and treated as epilepsy for few years); and one KCNJ2 mutation in a girl with less severe symptoms of palpitations and chest pain. Mutations were diagnosed as disease-causing in six of eight LQTS patients and as variant of unknown significance (VUS) in two pts: girl whose mother was resuscitated from SCD had VUS in SCN5A gene and 15-year-old hockey-player resuscitated from SCD had VUS in KCNH2 gene, which was re-classified as mutation very likely disease-causing a year later. From five symptomatic LQTS patients the smallest two had LQT3 (both with frequent life-threatening TdPs) and three older children had LQT1 (syncope), LQT2 (aborted SCD) and one girl with recurrent syncope had mutation in both KCNQ1 and KCNH2 genes. In the three asymptomatic patients two infants with sinus bradycardia had LQT1 (one plus VUS in SCN5A gene) and a 2-year-old girl with mother resuscitated from SCD had VUS in SCN5A gene. Genetic testing has not been finished in six pts, one after aborted SCD, one after syncope and four asymptomatic. Three pts have not been tested: a girl resuscitated from SCD with clearly prolonged QT interval, a 14-year-old girl with suspected LQTS who died before therapy was started and genetic testing performed and one boy with supposed BrS with positive family history (parents refused genetic testing). Treatment Twenty children are treated with beta-blockers, all but one with propranolol (one CPVT patient with metoprolol), two of

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Fig. 3. ECG Holter monitor in 2-year-old girl with LQT3. Strict relation of ventricular ectopy and TdPs to sympathetic discharges: hundreds of TdPs during awake hours, absolute disappearance during sleep (8 pm to 8 am). a: relation of VE beats/hour to sympathetic discharges. b: self-terminating TdP run.

them in combination with mexiletine (LQT3 pts) and three in combination with flecainide (CPVT pts). Nine patients have ICD implanted, six after aborted SCD and three after syncope on beta-blockers, 4 genotyped LQTS, 2 supposed LQTS and 3 CPVT patients. A 2-year-old girl with adrenergic-mediated frequent torsades de pointes (hundreds per day) underwent left cardiac sympathetic denervation. None of the treated patients died; three patients with CPVT have brain damage with developmental delay as the consequence of cardiopulmonary resuscitation or prolonged syncope and seizures. Appropriate shock was delivered in four and inappropriate in three of nine patients with ICD. In the two smallest children (4-month-old and 2-year-old) ICD was implanted abdominally via partial

low sternotomy, pace-sense electrode placed epicardially on the right ventricular apex and subcutaneous defibrillation electrode tunneled along the intercostal space (Fig. 2a,b). Patient characteristics are summarized in Table 1.

Discussion and limitations of the study Primary genetic arrhythmias are uncommon diseases presenting with syncope, seizures or SCD. LQTS and CPVT are among the most common channelopathies in children and this is reflected also in our series of patients with 8 genetically confirmed LQTS and 5 CPVT patients.

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Fig. 4. Morphology of T wave and T wave alternans. Broad based peaked assymmetrical T wave in limb leads, especially lead II.

To illustrate the various difficulties in the process of diagnosis and management of channelopathies we describe below selected real clinical scenarios.

Life-threatening arrhythmias in LQTS tend to occur under specific circumstances in a gene-specific manner: exercise or emotional stress being the arrhythmogenic triggers in LQT1 syndrome, sudden noise in LQT2 and sleep in LQT3 syndrome [3,10]. In one of our patients with genetically confirmed LQTS we have observed an interesting phenotype-genotype mismatch. This 2-year-old girl with recurrent syncope presented with clinical and ECG features suggesting LQT1 syndrome. She had hundreds of torsades de pointes runs during awake hours, strictly related to adrenergic discharges, which were completely supressed during sleep (Fig. 3a,b). Morphology of the T wave, with delayed onset and peaked T waves suggested LQT1 syndrome (Fig. 4). Response to treatment with no effect of beta-blockers (propranolol in supramaximal doses), no effect of left cardiac sympathetic denervation but good effect of mexiletine corresponded with LQT3 syndrome. Genetic testing confirmed LQT3 syndrome with SCN5A mutation. Another case of genotype-phenotype dissociaton we have observed is an 11-year-old boy admitted after aborted SCD. He had no clear features corresponding to any specific genetic arrhythmic syndrome. However, clinical presentation with very frequent syncope (15 syncope in 2 years) triggered by emotional stimuli suggested LQTS or CPVT. Repolarization changes on repeated ECGs with inconclusive QTI prolongation could suggest possible LQTS (Fig. 5a,b). With no ventricular ectopy on repeated ECG Holter monitoring, during emotionally stressful situations or exercise testing there was no evidence for the diagnosis of CPVT. Ajmaline challenge with the coved type ST segment elevation (dose 1 mg per kg of body weight intravenously) suggested Brugada syndrome (Fig. 6a,b). Genetic testing revealed RYR2 gene mutation (CPVT). This case shows how the clinical presentation of various genetic syndromes can overlap and genetic testing is important for the correct diagnosis.

Fig. 5. Repolarization changes with time in the 11-year-old boy after aborted SCD. Both ECGs made in the supine position with identical position of the leads. a: ECG on admission: positive T wave with quite well discernible end of T wave, especially in leads I, II, aVF and left precordial leads, QTc 426 ms. b: ECG day after admission: note the change of T wave morphology mainly in lead I and left precordial leads: T wave is biphasic with barely discernible T wave end and borderline QTc of 447–459 ms. T wave is of low amplitude in leads II and aVF.

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Fig. 6. Ajmaline challenge in the 11-year-old boy after aborted SCD (the same as in Fig. 5). Precordial leads, 25 mm/sec. a: ECG before ajmaline. b: ECG after ajmaline (10 mg/kg of body weight i.v.).

Another issue we have encountered is a finding of mutation classified as variant of unknown significance in obviously symptomatic boy (junior hockey player after aborted SCD). In this case mutation was reclassified as a very likely disease-causing one year later, with subsequent testing of his family members. This observation reflects the continously evolving knowledge about the relation of specific mutations to clinical presentation. Another specific problem poses the treatment of asymptomatic infants with LQT1 syndrome and sinus bradycardia with beta-blockers (Fig. 7). Understanding of a crucial role of beta-blocker therapy by parents is of utmost importance, as well as the acceptance of the risk of possible pacemaker implantation. Point of discussion is an ICD implantation in identical twin patients with CPVT. One of them had syncope on betablockers and had ICD implanted. Should his twin with no syncope on BBs have ICD implanted as well? We suppose he carries the same risk of SCD as his twin with the same mutation, so we think he should be implanted. ICD implantation in children presents specific problem not only because of the high risk of complications and inadequate discharges, but also because of technical aspects

of implantation in small children with nonvenous electrode systems. In our experience with two small children, ICD system with subcutaneous defibrillation electrode performed well. Another observation was that CPVT patients were not infrequently misdiagnosed and treated as epilepsy, so that correct diagnosis and treatment was delayed until the occurrence of life-threatening arrhythmias and brain damage due to cardiopulmonary resuscitation or prolonged syncope and seizures. The major limitation of the presented study is obviously the limited size of our patient cohort. Conclusion Our experience with a limited cohort of patients shows that both clinical presentation and genetic testing must be considered in the diagnostic and therapeutic process. Early diagnosis of channelopathies allows for necessary lifestyle modification focusing on avoidance of specific triggers of arrhythmic events and adequate therapy. Genetic testing is important both for the optimal management of the patient and for counseling of family members.

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Fig. 7. ECG of asymptomatic infant with genetically confirmed LQT1 syndrome and sinus bradycardia. Heart rate 111 bpm, QTc 540 ms.

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Cardiac channelopathies in pediatric patients - 7-years single center experience.

Channelopathies are associated with mutations of genes encoding proteins creating or interacting with the specialized ion channels in myocardial cell ...
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