Naokata Sumitomo

Current topics in catecholaminergic polymorphic ventricular tachycardia

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is induced by emotions or exercise in patients without organic heart disease and may be polymorphic or bidirectional in nature. The prognosis of CPVT is not good, and therefore prevention of sudden death is of utmost importance. Genetic variants of CPVT include RyR2, CASQ2, CALM2, TRD, and possibly KCNJ2 and ANK2 gene mutations. Hypotheses that suggest the causes of CPVT include weakened binding of FKBP12.6 and RyR2, a store overload‐induced Ca2+ release (SOICR), unzipping of intramolecular domain interactions in RyR2, and molecular and functional abnormalities caused by mutations in the CASQ2 gene. The incidence of an RyR2 anomaly in CPVTs is about 35–79%, whereas anomalies in the CASQ2 gene account for 3–5% CPVTs. The ping‐pong theory, suggesting that reciprocating delayed after depolarization induces bigeminy of the right and left bundle branches, may explain the pathogenesis of bidirectional ventricular tachycardia. Flecainide, carvedilol, left sympathetic nerve denervation, and catheter ablation of the PVC may serve as new therapeutic strategies for CPVT while gene‐therapy may be applied to some types of CPVT in the future. Although, not all sudden cardiac deaths in CPVT patients are currently preventable, new medical and interventional therapies may improve CPVT prognosis.

Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) Associated With Ryanodine Receptor (RyR2) Gene Mutations – Long-Term Prognosis After Initiation of Medical Treatment –

BACKGROUND The long-term prognosis of cardiac ryanodine receptor (RyR2) positive catecholaminergic polymorphic ventricular tachycardia (CPVT) patients after initiation of medical therapy has not been well investigated. This study aimed to assess the recurrence of fatal cardiac event after initiation of medical therapy inRyR2-positive CPVT patients. METHODSANDRESULTS Thirty-fourRyR2-positive CPVT patients with a history of cardiac events were enrolled. All patients had medical treatment initiated after the first symptom or diagnosis. Exercise stress tests (ESTs) were performed to evaluate the efficacy of the medical therapy. Even after the initiation of medical therapy, high-risk ventricular arrhythmias (VAs), including premature ventricular contraction couplets, bigeminy, and ventricular tachycardia, were still induced in the majority of patients (80.6%). During 7.4 years of follow-up after the diagnosis, 7 of the 34 (20.6%) patients developed fatal cardiac events. Among those 7 patients, 6 (85.7%) were not compliant with either exercise restriction or medication therapy at the time of the events. CONCLUSIONS Even after initiation of medical treatment, high-risk VAs were induced during EST in mostRyR2-positive CPVT patients. Most fatal recurrent cardiac events occurred in patients who were noncompliant with exercise restriction and/or medical therapy. Medical management including strict exercise restriction should be emphasized to prevent recurrent cardiac event in mostRyR2-positive CPVT patients. (Circ J 2016; 80: 1907-1915).

Sick sinus syndrome with HCN4 mutations shows early onset and frequent association with atrial fibrillation and left ventricular noncompaction

BACKGROUND Familial sick sinus syndrome (SSS) is often attributable to mutations in genes encoding the cardiac Na channel SCN5A and pacemaker channel HCN4. We previously found that SSS with SCN5A mutations shows early onset of manifestations and male predominance. Despite recent reports on the complications of atrial fibrillation (AF) and left ventricular noncompaction (LVNC) in patients with SSS caused by HCN4 mutations, their overall clinical spectrum remains unknown. OBJECTIVE The purpose of this study was to investigate the clinical and demographic features of SSS patients carrying HCN4 mutations. METHODS We genetically screened 38 unrelated SSS families and functionally analyzed the mutant SCN5A and HCN4 channels by patch clamping. We also evaluated the clinical features of familial SSS by a meta-analysis of 48 SSS probands with mutations in HCN4 (n = 16) and SCN5A (n = 32), including previously reported cases, and 538 sporadic SSS cases. RESULTS We identified two HCN4 and three SCN5A loss-of-function mutations in our familial SSS cohort. Meta-analysis of HCN4 mutation carriers showed a significantly younger age at diagnosis (39.1 ± 21.7 years) than in sporadic SSS (74.3 ± 0.4 years; P <.001), but a significantly older age than in SCN5A mutation carriers (20.0 ± 17.6 years; P = .003). Moreover, HCN4 mutation carriers were more frequently associated with AF (43.8%) and LVNC (50%) and with older age at pacemaker implantation (43.5 ± 22.1 years) than were SCN5A mutation carriers (17.8 ± 16.5 years; P <.001). CONCLUSION SSS with HCN4 mutations may form a distinct SSS subgroup characterized by early clinical manifestation after adolescence and frequent association with AF and LVNC.

Clinical Features of Long QT Syndrome in Children

gested if the fetal heart rate is less than the 3rd percentile.11 In addition to a low baseline heart rate, nonreactive heart rate patterns are also suggestive in LQTS fetuses and may be explained by lower-than-normal right sympathetic cardiac activity or a blunted response to a sympathetic drive, as seen postnatally.8 LQTS with 2:1 AVB is commonly observed during the fetal and neonatal periods,9,10 but rarely observed in childhood and adulthood. In neonates with LQT2 and LQT3, 2:1 AVB was observed in 55% and 83% of the patients, respectively (Figure 1).10 AVB may be caused by functional block of the ventricle, because of prolongation of the ventricular refractory period, and in the majority of patients the atrioventricular conduction returns with a significant decrease in the QTc interval during the follow-up period.8 That may explain the rare occurrence of AVB in older children and adults with LQTS.

Linking the heart and the brain: Neurodevelopmental disorders in patients with catecholaminergic polymorphic ventricular tachycardia

BACKGROUND Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an uncommon inherited arrhythmia disorder characterized by adrenergically evoked ventricular arrhythmias. Mutations in the cardiac calcium release channel/ryanodine receptor gene (RYR2) are identified in the majority of patients with CPVT. RyR2 is also the major RyR isoform expressed in the brain. OBJECTIVE The purpose of this study was to estimate the prevalence of intellectual disability (ID) and other neurodevelopmental disorders (NDDs) in RYR2-associated CPVT (CPVT1) and to study the characteristics of these patients. METHODS We reviewed the medical records of all CPVT1 patients from 12 international centers and analyzed the characteristics of all CPVT1 patients with concomitant NDDs. We functionally characterized the mutations to assess their response to caffeine activation. We did not correct for potential confounders. RESULTS Among 421 CPVT1 patients, we identified 34 patients with ID (8%; 95% confidence interval 6%-11%). Median age at diagnosis was 9.3 years (interquartile range 7.0-14.5). Parents for 24 of 34 patients were available for genetic testing, and 13 of 24 (54%) had a de novo mutation. Severity of ID ranged from mild to severe and was accompanied by other NDDs in 9 patients (26%). Functionally, the ID-associated mutations showed a markedly enhanced response of RyR2 to activation by caffeine. Seventeen patients (50%) also had supraventricular arrhythmias. During median follow-up of 8.4 years (interquartile range 1.8-12.4), 15 patients (45%) experienced an arrhythmic event despite adequate therapy. CONCLUSION Our study indicates that ID is more prevalent among CPVT1 patients (8%) than in the general population (1%-3%). This subgroup of CPVT1 patients reveals a malignant cardiac phenotype with marked supraventricular and ventricular arrhythmias.

Standard Values and Characteristics of Electrocardiographic Findings in Children and Adolescents

BACKGROUND Reference values and the characteristics of the electrocardiographic (ECG) findings using a large number of subjects are lacking for children and adolescents.Methods and Results:A total of 56,753 digitally stored ECGs of participants in a school-based ECG screening system were obtained between 2006 and 2009 in Kagoshima, Japan. Each ECG was manually reviewed by 2 pediatric cardiologists and only ECGs with sinus rhythm were included. A final total of 48,401 ECGs from 16,773 1st (6 years old, 50% girls), 18,126 7th (12 years old, 51% girls), and 13,502 10th graders (15 years old, 52% girls) were selected. ECG variables showed differences in age and sex. However, the effects of age and sex on ECG variables such as the PQ interval, QRS voltage, and STJ segment were also different. The 98th percentile values of well-known surrogate parameters for ventricular hypertrophy in the present study were much higher than the conventional criteria. CONCLUSIONS The present study of a large number of pediatric subjects showed that the effects of age and sex on ECG parameters are different, and that criteria for ventricular hypertrophy should be newly determined by age and sex. We have developed reference data for STJ segment elevation for children and adolescents. These findings are useful for creating guidelines and recommendations for interpretation of pediatric ECG.

Device therapy in pediatric and congenital heart disease patients

Device therapy is an established therapy for preventing sudden cardiac death or managing refractory congestive heart failure in adults. However, it is performed less commonly in pediatric populations. This review aimed to examine the indications and problems associated with implantable cardioverter‐defibrillator (ICD) and cardiac resynchronization therapy (CRT) device implantations in pediatric and congenital heart disease (CHD) patients.

Successful radiofrequency catheter ablation of life-threatening atrial tachycardia in an infant with asplenia syndrome

A 1-year-old infant with asplenia syndrome and congenital heart disease consisting of common atrium, common inlet left ventricle with a common atrio-ventricular (AV) valve, pulmonary atresia, and total anomalous pulmonary venous connection was admitted to our hospital for radiofrequency catheter ablation (RFCA) of supraventricular tachycardia (SVT) before total cavo-pulmonary connection. After antiarrhythmic medications were discontinued for RFCA, she suffered from SVT that resulted in the rapid deterioration of hemodynamic status. Antiarrhythmic medications and cardioversion were not effective in terminating SVT. The baseline electrocardiogram confirmed the existence of twin AV nodes; however, this SVT was revealed to be focal atrial tachycardia (AT) with enhanced automaticity. The origin of AT was not related to surgical scar. Emergent RFCA for AT was successful in our case of asplenia syndrome. AT is a life-threatening complication in a single ventricle and delayed treatment can be fatal. It is important to perform RFCA promptly when drug treatment is not effective. We suggest that the AV node is not always the target site for ablation in patients with asplenia syndrome and twin AV nodes. <Learning objective: In the case of supraventricular tachycardia with asplenia and twin atrio-ventricular (AV) nodes, atrial tachycardia (AT) as well as AV reentrant tachycardia could occur. AT is a life-threatening complication in infants with single ventricle. If drug therapy is not effective, emergent catheter ablation should be performed. AV node is not always the target site for ablation in patients with asplenia and twin AV nodes.>.

Successful demonstration of the detailed connection between the twin atrioventricular nodes and sling in a patient with asplenia syndrome

Introduction Two distinct twin atrioventricular (AV) nodes and a connecting sling could be confirmed in a number of patients with asplenia syndrome. Atrioventricular reciprocating tachycardia (AVRT) via twin AV nodes can develop in some patients, and radiofrequency catheter ablation (RFCA) to interrupt or modify 1 of the 2 AV nodes that does not perform the main conduction has been attempted in tachycardia cases. A pathologic analysis of autopsy specimens has demonstrated 2 separate AV nodes and a connecting sling. There have been several hypotheses on the anatomic and electrophysiological characteristics of the AV nodes and connecting sling; however, a detailed electrophysiological mechanism remains unknown. We report the case of a patient with AVRT via twin AV nodes after a Fontan procedure who underwent successful RFCA for 1 of the 2 separate AV nodes, and we reveal the precise connection between the AV nodes and connecting sling.

The Safety and Accuracy of the RHYTHMIA Mapping System in Pediatric Patients

BACKGROUND A new mapping system (Rhythmia) using a 64 mini-electrode small basket array (Orion) was developed that enables rapid high-density mapping in a short time. However, there are few reports about the usefulness of this system in pediatric cases. OBJECTIVE The purpose of this study was to investigate the safety and accuracy of the Rhythmia system and Orion catheter in children. METHODS Catheter ablation was performed using the Rhythmia system and Orion catheter in 23 patients younger than 20 years (body weight >20 kg) without a past medical history of cardiac disease. Mapping time, number of mapping beats, and number of mapping electrodes were compared for left atrium, right atrium and right ventricular outflow tract. RESULTS Twenty-three maps of the right atrium were acquired in 12.6 minutes (range 8.9-15.1), consisting of 709 beats (range 492-1163) and 7132 electrograms (range 4618-10,533). Twelve maps of the left atrium were acquired in 12.1 minutes (range 9.8-14.6), consisting of 565 beats (range 446-881) and 6412 electrograms (range 4912-11,402). There were no significant difference in mapping time, accepted beats, and electrograms between the 2 chambers. Manual annotation was needed in 53 of 293,185 electrograms (0.01%) due to far-field ventricular electrogram sensing and artifact. No adverse events occurred in any of the cases. CONCLUSION The Orion catheter and Rhythmia mapping system were safe and accurate for mapping various arrhythmias in pediatric patients. Detailed geometry and high-resolution activation mapping were acquired without the need for manual reannotation.