Introduction: The NKX2.5 gene is an important cardiac developmental transcription factor, and variants in this gene are most commonly associated with CHD. However, there is an increased need to recognise associations with conduction disease and potentially dangerous ventricular arrhythmias. There is an increased risk of arrhythmia and sudden cardiac death in patients with NKX2.5 variants, an association with relatively less attention in the literature. Methods: We created a family pedigree and reconstructed familial relationships involving numerous relatives with CHD, conduction disease, and ventricular non-compaction following the sudden death of one family member. Two informative but distantly related family members had genetic testing to determine the cause of arrhythmias via arrhythmia/cardiomyopathy gene testing, and we identified obligate genetic-positive relatives based on family relationships and Mendelian inheritance pattern. Results: We identified a novel pathogenic variant in the NKX2.5 gene (c.437C > A; p. Ser146*), and segregation analysis allowed us to link family cardiac phenotypes including CHD, conduction disease, left ventricular non-compaction, and ventricular arrhythmias/sudden cardiac death. Conclusions: We report a novel NKX2.5 gene variant linking a spectrum of familial heart disease, and we also encourage recognition of the association between NKX2.5 gene and potentially dangerous ventricular arrhythmias, which will inform clinical risk stratification, screening, and management.

Abstract Aims Calmodulinopathy due to mutations in any of the three CALM genes (CALM1–3) causes life-threatening arrhythmia syndromes, especially in young individuals. The International Calmodulinopathy Registry (ICalmR) aims to define and link the increasing complexity of the clinical presentation to the underlying molecular mechanisms. Methods and results The ICalmR is an international, collaborative, observational study, assembling and analysing clinical and genetic data on CALM-positive patients. The ICalmR has enrolled 140 subjects (median age 10.8 years [interquartile range 5–19]), 97 index cases and 43 family members. CALM-LQTS and CALM-CPVT are the prevalent phenotypes. Primary neurological manifestations, unrelated to post-anoxic sequelae, manifested in 20 patients. Calmodulinopathy remains associated with a high arrhythmic event rate (symptomatic patients, n = 103, 74%). However, compared with the original 2019 cohort, there was a reduced frequency and severity of all cardiac events (61% vs. 85%; P = .001) and sudden death (9% vs. 27%; P = .008). Data on therapy do not allow definitive recommendations. Cardiac structural abnormalities, either cardiomyopathy or congenital heart defects, are present in 30% of patients, mainly CALM-LQTS, and lethal cases of heart failure have occurred. The number of familial cases and of families with strikingly different phenotypes is increasing. Conclusion Calmodulinopathy has pleiotropic presentations, from channelopathy to syndromic forms. Clinical severity ranges from the early onset of life-threatening arrhythmias to the absence of symptoms, and the percentage of milder and familial forms is increasing. There are no hard data to guide therapy, and current management includes pharmacological and surgical antiadrenergic interventions with sodium channel blockers often accompanied by an implantable cardioverter–defibrillator.

BACKGROUND:Guidelines addressing magnetic resonance imaging (MRI) in patients with cardiac implantable electronic devices (CIEDs) provide algorithms for imaging pediatric and congenital heart disease (CHD) patients. Guideline acceptance varies by institution. Guidelines also do not support routine MRI scans in patients with epicardial or abandoned leads, common in pediatric and CHD patients. OBJECTIVE:The purpose of this study was to determine the incidence of MRI-related complications in pediatric and CHD patients with CIEDs, including epicardial and/or abandoned leads. METHODS:A multicenter retrospective review included patients with CIEDs who underwent any MRI between 2007 and 2022 at congenital cardiac centers. The primary outcome was any patient adverse event or clinically significant CIED change after MRI, defined as pacing lead capture threshold increase >0.5 V with output change, P- or R- wave amplitude decrease >50% with sensitivity change, or impedance change >50%. RESULTS:Across 14 institutions, 314 patients (median age 18.8 [1.3; 31.4] years) underwent 389 MRIs. There were 288 pacemakers (74%) and 87 implantable cardioverter-defibrillators (22%); 52% contained epicardial leads, and 14 (4%) were abandoned leads only. Symptoms or CIED changes occurred in 4.9% of MRI scans (6.1% of patients). On 9 occasions (2%), warmth or pain occurred. Pacing capture threshold or lead impedance changes occurred in 1.4% and 2.0% of CIEDs post-MRI and at follow-up. CONCLUSION:Our data provide evidence that MRIs can be performed in pediatric and CHD patients with CIEDs, including non-MRI-conditional CIEDs and epicardial and/or abandoned leads, with rare minor symptoms or CIED changes but no other complications.

Pediatric and adult congenital heart disease (ACHD) patients encounter physical and emotional barriers. Cardiac implantable electronic devices (CIEDs), including pacemakers and implantable cardiac defibrillators (ICD) often compound these issues. Patient fear associated with damaging the CIED system can lead to avoidance of physical activity and reduced quality of life (QOL). CIED personal protective equipment (PPE) is a potential treatment for decreasing this fear. We sought to determine the effects of CIED PPE use in the pediatric and ACHD population. Patients 5 years or older with a CIED at a single pediatric and ACHD heart rhythm center received a CIED protector and customized athletic shirt. QOL was assessed using the PedsQL TM 4.0 SF15 prior to and after 6–12 months. Of the 77 patients enrolled, 26 completed repeat assessment. The mean age at enrollment was 15.6 years (range 5–36) with a mean device age of 2.2 years (< 1–10 years). Pacemakers were present in 77

A case report of a 7 day old neonate and a 16 month old infant both of whom presented with sustained tachyarrhythmia that was identified as fascicular ventricular tachycardia, a.k.a. verapamil sensitive ventricular tachycardia. This is a rare but well described tachycardia in the pediatric population. Fascicular VT is known to be both highly sensitive to verapamil and poorly responsive to other first-line tachyarrhythmia treatments. This is of clinical importance as verapamil is considered contraindicated in this age group given numerous reports of hemodynamic collapse or profound atrioventricular block following intravenous administration. Both of our cases described here failed initial non-calcium channel blockade treatment and ultimately were successfully treated with IV verapamil. We describe the rare case in which verapamil should be considered in treatment of a pediatric ventricular tachyarrhythmia. Our cases further exemplify that verapamil can be effectively used in the neonatal and infant population provided there is appropriate hemodynamic support available.

BACKGROUND Electronic gaming has recently been reported as a precipitant of life-threatening cardiac arrhythmia in susceptible in-dividuals. OBJECTIVE The purpose of this study was to describe the popula-tion at risk, the nature of cardiac events, and the type of game linked to cardiac arrhythmia associated with electronic gaming. METHODS A multisite international case series of suspected or proven cardiac arrhythmia during electronic gaming in children and a systematic review of the literature were performed. RESULTS Twenty-two patients (18 in the case series and 4 via sys-tematic review; aged 7-16 years; 19 males [86%]) were identified as having experienced suspected or proven ventricular arrhythmia during electronic gaming; 6 (27%) had experienced cardiac arrest, and 4 (18%) died suddenly. A proarrhythmic cardiac diagnosis was known in 7 (31%) patients before their gaming event and was estab-lished afterward in 12 (54%). Ten patients (45%) had catecholamin-ergic polymorphic ventricular tachycardia, 4 (18%) had long QT syndrome, 2 (9%) were post-congenital cardiac surgery, 2 (9%) had "idiopathic" ventricular fibrillation, and 1 (after Kawasaki disease) had coronary ischemia. In 3 patients (14%), including 2 who died, the diagnosis remains unknown. In 13 (59%) patients for whom the electronic game details were known, 8 (62%) were war games. CONCLUSION Electronic gaming can precipitate lethal cardiac ar-rhythmias in susceptible children. The incidence appears to be low, but syncope in this setting should be investigated thoroughly. In children with proarrhythmic cardiac conditions, electronic war games in particular are a potent arrhythmic trigger.

Background: Prolongation of the ECG derived QT interval predicts increased risk for sudden life-threatening arrhythmias. Many medicines are known to prolong the QT interval though current data demonstrate that progesterone given to premenopausal females <18 years shortens the QT interval by six msec. This effect may be used to treat individuals with abnormal prolongation of the QT interval. Hormone progestin is used to treat a number of conditions in post-menarche females >18 years old. The effects of this treatment on the corrected QT (QTc) in this population are unknown. Objective: To describe the effect of exogenous progestin on the QTc in adolescent females. Methods: In post-menarcheal females, <18 years old, using no medications with known ECG effects, we compared QTc in milliseconds (ms) on ECG evaluations in those taking exogenous progestin vs those who are not. Descriptive statistics were used to compare the groups. Results: There were 40 controls and 21 treated participants. The age range was 10 - 17 years. There were no differences between the groups with regard to race, height, weight, BMI, or blood pressure. In the controls, the mean QTc was 403 +/-19 milliseconds (ms) vs. 397 +/-15 ms in those treated (p=0.22). Those on progestin therapy had a shorter QTc by the same magnitude difference (six ms) as the hormonal naive group in the adult literature. Conclusions: We report no adverse effects of progestin associated with QTc prolongation and a trend suggesting a decreased QTc in a population of post menarcheal-adolescent females.

Introduction: The SCN5A gene is implicated in many arrhythmogenic and cardiomyopathic processes. We identified a novel SCN5A variant in a family with significant segregation in individuals affected with progressive sinus and atrioventricular nodal disease, atrial arrhythmia, dilated cardiomyopathy, and early sudden cardiac arrest. Methods: A patient pedigree was created following the clinical evaluation of three affected individuals, two monozygotic twins and a paternal half-brother, which lead to the evaluation of a paternal half-sister (four siblings with the same father and three mothers) all of whom experienced varying degrees of atrial arrhythmias, conduction disease, and dilated cardiomyopathy in addition to a paternal history of unexplained death in his 50s with similar autopsy findings. The index male underwent sequencing of 58 genes associated with cardiomyopathies. Sanger sequencing was used to provide data for bases with insufficient coverage and for bases in some known regions of genomic segmental duplications. All clinically significant and novel variants were confirmed by independent Sanger sequencing. Results: All relatives tested were shown to have the same SCN5A variant of unknown significance (p. Asp197His) and the monozygotic twins shared a co-occurring NEXN (p. Glu575*). Segregation analysis demonstrates likely pathogenic trait for the SCN5A variant with an additional possible role for the NEXN variant in combination. Conclusions: There is compelling clinical evidence suggesting that the SCN5A variant p. Asp197His may be re-classified as likely pathogenic based on the segregation analysis of our family of interest. Molecular mechanism studies are pending.

There are minimal data on the impact of genetic counselors in subspecialty clinics, including the pediatric arrhythmia clinic. This study aimed to describe the clinical encounters of a genetic counselor integrated into a pediatric arrhythmia clinic. In the 20 months between July 2015 and February 2017, a total of 1914 scheduled patients were screened for indications relevant for assessment by a genetic counselor. Of these, the genetic counselor completed 276 patient encounters, seeing 14.4% of all patients in clinic. The most expected and common indications for genetic counselor involvement were related to suspicion for primary heritable arrhythmia conditions, though patients seen in this clinic display a wide range of cardiac problems and many additional indications for genetic evaluation were identified. Roughly 75% (211/276) of encounters were for personal history of confirmed/suspected heritable disease, including cardiac channelopathies, cardiomyopathies, ventricular arrhythmias, and congenital heart defects, and 25% (65/276) were for family history of disease, including long QT syndrome and sudden unexplained death. Overall, this study shows that about 1 in 7 patients seen in a pediatric arrhythmia clinic have indications that likely benefit from genetic counselor involvement and care. Similar service delivery models embedding genetic counselors in pediatric arrhythmia clinics should be encouraged, and this model could be emulated to increase patient access to genetic counseling services.

Clinical genetics services continue to expand into diverse medical specialties. An ever-increasing number of non-genetics providers are independently ordering genetic tests, interpreting results, and at times, making diagnoses leading to patient care recommendations. Non-genetics healthcare providers can help increase patient access to these services, but a potential pitfall occurs when these providers either do not have adequate expertise with genetic variant interpretation or do not have access to multi-disciplinary teams including genetic counselors or clinical geneticists for advanced review. In the cardiology setting, variant misinterpretation can lead to misattribution of disease risk, unnecessary treatments or management, and potentially adverse psychosocial and financial effects. To address this, case reports and series are needed to highlight variant misinterpretation and misdiagnoses, including discussion of possible solutions and best practices for avoidance. This report details a child previously diagnosed with long QT syndrome type 4 by chromosomal microarray who was then subsequently managed for this disease by cardiac providers with insufficient expertise to critically review and question the genetic testing results. The patient was eventually referred to a pediatric electrophysiology team as part of a larger multidisciplinary cardiovascular genetics program, composed of specialist genetic counselors, cardiologists, and clinical geneticists. Advanced review and clinical evaluation raised concern about the initial genetic testing result and diagnosis. Complementary testing with a different modality to confirm or disconfirm the chromosome microarray result was performed, providing evidence that the original result reflected analytic error in the laboratory as well as interpretive error by the clinical geneticist and that the patient was misdiagnosed, and treated over the course of years, for long QT syndrome. This case shows the value of multidisciplinary teams caring for patients with inherited cardiovascular diseases.

Background: CRT devices allow the option of programming left ventricular (LV) lead pacing configuration as LV tip or ring to right ventricular (RV) lead ring to potentially improve pacing thresholds.However, anodal stimulation can result in unintentional RV pacing (anode) instead of LV pacing (cathode), which is a potential underrecognized and amenable cause of poor response to CRT.Objective: This case report illustrates how anodal stimulation was recognized during device interrogation and amended in the clinic.Methods: N/A Results: A 68 year old man with cardiomyopathy underwent CRT-D device implantation.Device interrogation was performed to assess an unusual ECG in follow up evaluation. in the setting of a poor response to CRT therapy with recurrent CHF symptoms.Bi-V pacing percentage was 99% and LV pacing polarity was set LV tip to RV ring with a V-V offset of 100ms.LV threshold testing revealed a change in morphology in a far-field channel as the pacing voltage was decreased similar to the morphology seen during RV threshold testing.A 12 lead ECG was performed during repeat testing and clearly demonstrated RV capture with high pacing amplitude and LV capture at lower amplitude.(Fig. 1) This intermittent unintentional RV pacing was resolved by reprogramming the LV pacing configuration to LV tip to LV ring.Conclusion: Morphology changes during pacing threshold testing should not be overlooked and 12 lead ECG or surface leads should be utilized to confirm the presence of anodal pacing.This important finding may have implications for clinical response to CRT.

Atrioventricular (AV) heart block without adequate escape rhythm can result in sudden cardiac arrest and death. We describe complete (third-degree) AV block in a 16-year-old boy as a late effect of vagus nerve stimulation (VNS). He experienced brief, daily, complex partial seizures, treated with lamotrigine, levetiracetam, and the placement of Model 102 VNS at age 4 years. Electroencephalography (EEG) showed generalized slow spike-and-wave discharges of Lennox-Gastaut syndrome. At age 12, his VNS was changed to Model 303 PereniaDURA/Model 103 Demipulse generator, set at an output current of 2.25 mA on a standard 30 seconds on, five minutes off paradigm. At age 16, he experienced episodes of sudden collapse followed by unconsciousness. Holter monitor showed 15-second symptomatic complete AV block without escape (Figure). The patient was taking psychotropic medication with potential cardiac side-effects: methylphenidate (tachycardia), guanfacine (first-degree AV block), and haloperidol (prolonged QT interval, torsades de pointes). Haloperidol, methylphenidate, and VNS were stopped without further symptoms. Off these medications, the VNS was resumed at reduced current (1.25 mA), with re-occurrence of symptomatic AV block. Again, the VNS was stopped and symptoms or heart block ceased. Psychotropic medication was resumed without any side-effects.

OBJECTIVE:Neurocardiogenic syncope (NCS) is the most common cause of syncope in children and adolescents. Neurocardiogenic syncope occurs secondary to cerebral hypotension because of bradycardia, hypotension, or both. Head-up tilt-table test (HUTT) is the primary diagnostic test. Near-infrared spectroscopy (NIRS) is a noninvasive technology that directly monitors trends in regional tissue oxygen saturations over a specific body region. Placing an NIRS probe over the temporal region allows an indirect measurement of cerebral perfusion. Our hypothesis is that regional tissue oxygen saturation will decrease during an NCS episode and will remain stable in patients without syncope.PATIENTS AND DESIGN:The investigators conducted a retrospective review of all HUTT utilizing cephalic NIRS performed at our institution from August 2012 to January 2013. Tests were classified as positive, negative, or psychogenic reactions. Paired t-test was used to determine statistical significance of NIRS changes and one-way analysis of variance was used to analyze baseline characteristics among the three groups.RESULTS:Twelve patients were included in the study (female = 10). The average age was 14.4 years (range: 12-17). Five tests were positive for NCS, four were negative, and three demonstrated psychogenic reactions. Patients with a positive test had a sudden, significant decrease in regional tissue oxygen saturations (P = .009) by an average of 11.3 ± 5.2% compared with baseline. The decrease in regional tissue oxygen saturation preceded symptoms, hypotension, and bradycardia in all patients. Regional tissue oxygen saturation levels remained stable in patients with a negative test or psychogenic syncope.CONCLUSIONS:NIRS monitoring during HUTT produces a reliable, positive result that precedes clinical signs and symptoms. Further, it helps distinguish NCS from psychogenic syncope.