Pediatric antiarrhythmics and toxicity: A clinical review.

Antiarrhythmic medications are fundamental in the acute and chronic management of pediatric arrhythmias. Particularly in the pediatric patient population, associated antiarrhythmic toxicities represent important potential adverse effects. Emergency medicine clinicians must be skilled in the detection, workup, and management of antiarrhythmic toxicity. This is a clinical review of the indications, pharmacology, adverse effects, and toxicologic treatment of antiarrhythmics commonly used in the pediatric patient population.

Gene Therapy for Catecholaminergic Polymorphic Ventricular Tachycardia by Inhibition of Ca2+/Calmodulin-Dependent Kinase II.

BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT), an inherited cardiac arrhythmia characterized by adrenergically triggered arrhythmias, is inadequately treated by current standard of care. Ca2+/calmodulin-dependent protein kinase II (CaMKII), an adrenergically activated kinase that contributes to arrhythmogenesis in heart disease models, is a candidate therapeutic target in CPVT. However, translation of CaMKII inhibition has been limited by the need for selective CaMKII inhibition in cardiomyocytes. Here, we tested the hypothesis that CaMKII inhibition with a cardiomyocyte-targeted gene therapy strategy would suppress arrhythmia in CPVT mouse models. METHODS: We developed AAV9-GFP-AIP, an adeno-associated viral vector in which a potent CaMKII inhibitory peptide, autocamtide-2-related inhibitory peptide [AIP], is fused to green fluorescent protein (GFP) and expressed from a cardiomyocyte selective promoter. The vector was delivered systemically. Arrhythmia burden was evaluated with invasive electrophysiology testing in adult mice. AIP was also tested on induced pluripotent stem cells derived from patients with CPVT with different disease-causing mutations to determine the effectiveness of our proposed therapy on human induced pluripotent stem cell-derived cardiomyocytes and different pathogenic genotypes. RESULTS: AAV9-GFP-AIP was robustly expressed in the heart without significant expression in extracardiac tissues, including the brain. Administration of AAV9-GFP-AIP to neonatal mice with a known CPVT mutation (RYR2R176Q/+) effectively suppressed ventricular arrhythmias induced by either ß-adrenergic stimulation or programmed ventricular pacing, without significant proarrhythmic effect. Intravascular delivery of AAV9-GFP-AIP to adolescent mice transduced ≈50% of cardiomyocytes and was effective in suppressing arrhythmia in CPVT mice. Induced pluripotent stem cell-derived cardiomyocytes derived from 2 different patients with CPVT with different pathogenic mutations demonstrated increased frequency of abnormal calcium release events, which was suppressed by a cell-permeable form of AIP. CONCLUSIONS: This proof-of-concept study showed that AAV-mediated delivery of a CaMKII peptide inhibitor to the heart was effective in suppressing arrhythmias in a murine model of CPVT. CaMKII inhibition also reversed the arrhythmia phenotype in human CPVT induced pluripotent stem cell-derived cardiomyocyte models with different pathogenic mutations.

Cardiac Events During Competitive, Recreational, and Daily Activities in Children and Adolescents With Long QT Syndrome.

BACKGROUND: The 2005 Bethesda Conference Guidelines advise patients with long QT syndrome against competitive sports. We assessed cardiac event rates during competitive and recreational sports, and daily activities among treated long QT syndrome patients. METHODS AND RESULTS: Long QT syndrome patients aged ≥4 years treated with anti-adrenergic therapy were included. Demographics included mechanism of presentation, corrected QT interval pretreatment, symptom history, medication compliance, and administration of QT-prolonging medications. Corrected QT interval ≥550 ms or prior cardiac arrest defined high risk. Sports were categorized by cardiovascular demand per the 2005 Bethesda Conference Guidelines. Each was classified as recreational or competitive. One hundred seventy-two patients (90; 52% female) with median age 15.2 years (interquartile range 11.4, 19.4) were included. Evaluation was performed for family history (102; 59%), incidental finding (34; 20%), and symptoms (36; 21%). Median corrected QT interval was 474 ms (interquartile range 446, 496) and 14 patients (8%) were deemed high risk. Treatment included ß-blockers (171; 99%), implantable cardioverter-defibrillator (27; 16%), left cardiac sympathetic denervation (7; 4%), and pacemaker (3; 2%). Sports participation was recreational (66; 38%) or competitive (106; 62%), with 92 (53%) exercising against the Bethesda Conference Guidelines. There were no cardiac events in competitive athletes and no deaths. There were 13 cardiac events in 9 previously symptomatic patients during either recreational exercise or activities of daily life. CONCLUSIONS: In this cohort of appropriately managed children with long QT syndrome, cardiac event rates were low and occurred during recreational but not competitive activities. This study further supports the need for increased assessment of arrhythmia risk during exercise in this patient population.