A Natural History Study of Timothy Syndrome.

Timothy syndrome (OMIM #601005) is a rare disease caused by variants in the gene CACNA1C . Timothy syndrome patients were first identified as having a cardiac presentation of Long QT and syndactyly of the fingers and/or toes, and an identical variant in CACNA1C , Gly406Arg. However, since this original identification, more individuals harboring diverse variants in CACNA1C have been identified and have presented with various cardiac and extra-cardiac symptoms. Furthermore, it has remained underexplored whether individuals harboring canonical Gly406Arg variants in mutually exclusive exon 8A (Timothy syndrome 1) or exon 8 (Timothy syndrome 2) have additional symptoms. Here, we describe the first Natural History Study for Timothy syndrome, providing a thorough resource describing the current understanding of disease manifestation in Timothy syndrome patients. Parents of Timothy syndrome children were queried regarding a wide-ranging set of symptoms and features via a survey. Importantly, we find that in addition to cardiac concerns, Timothy syndrome patients commonly share extra-cardiac features including neurodevelopmental impairments, hypoglycemia, and respiratory problems. Our work expands the current understanding of the disorder to better inform the care of Timothy syndrome patients.

Medical cardioversion of atrial fibrillation and flutter with class IC antiarrhythmic drugs in young patients with and without congenital heart disease.

INTRODUCTION: The use of flecainide and propafenone for medical cardioversion of atrial fibrillation (AF) and atrial flutter/intra-atrial reentrant tachycardia (IART) is well-described in adults without congenital heart disease (CHD). Data are sparse regarding their use for the same purpose in adults with CHD and in adolescent patients with anatomically normal hearts and we sought to describe the use of class IC drugs in this population and identify factors associated with decreased likelihood of success. METHODS: Single center retrospective cohort study of patients who received oral flecainide or propafenone for medical cardioversion of AF or IART from 2000 to 2022. The unit of analysis was each episode of AF/IART. We performed a time-to-sinus rhythm analysis using a Cox proportional hazards model clustering on the patient to identify factors associated with increased likelihood of success. RESULTS: We identified 45 episodes involving 41 patients. As only episodes of AF were successfully cardioverted with medical therapy, episodes of IART were excluded from our analyses. Use of flecainide was the only factor associated with increased likelihood of success. There was a statistically insignificant trend toward decreased likelihood of success in patients with CHD. CONCLUSIONS: Flecainide was more effective than propafenone. We did not detect a difference in rate of conversion to sinus rhythm between patients with and without CHD and were likely underpowered to do so, however, there was a trend toward decreased likelihood of success in patients with CHD. That said, medical therapy was effective in >50% of patients with CHD with AF.

Retroflexed catheter course reduces the risk of right free wall accessory pathway recurrence.

INTRODUCTION: Accessory atrioventricular pathways (APs) may mediate atrioventricular reciprocating tachycardia and, in some cases, have the potential to conduct atrial tachycardia rapidly, which can be life threatening. While catheter ablation can be curative, ablation of right free wall APs is associated with a high rate of recurrence, likely secondary to reduced catheter stability along the right free wall atrioventricular groove. We sought to identify characteristics associated with a lower rate of recurrence and hypothesized ablation lesions placed on the ventricular side of the atrioventricular groove using a retroflexed catheter approach would decrease rates of recurrence. METHODS AND RESULTS: Retrospective chart review of patients who underwent catheter ablation of a right free wall AP from January 1, 2008 through June 1, 2021 with >2 months follow up. Cox proportional hazards regression was used to identify relationships between predictor variables and AP recurrence. We identified 95 patients who underwent ablation of 98 right free wall APs. Median age was 13.1 years and median weight at ablation was 52.3 kg. Overall, 23/98 (23%) APs recurred. Use of a retroflexed catheter course approaching the atrioventricular groove from the ventricular aspect was associated with reduced risk of AP recurrence with (univariable hazard ratio of 0.10 [95% confidence interval: 0.01-0.78]), which remained significant in multiple two variable Cox proportional hazards models. CONCLUSION: Use of a retroflexed catheter course is associated with a reduced likelihood of AP recurrence. This approach results in improved catheter stability and should be considered for ablation of right free wall APs.

Clinical risk prediction score for postoperative accelerated junctional rhythm and junctional ectopic tachycardia in children with congenital heart disease.

BACKGROUND: Accelerated junctional rhythm (AJR) and junctional ectopic tachycardia (JET) are common postoperative arrhythmias associated with morbidity/mortality. Studies suggest that pre- or intraoperative treatment may improve outcomes, but patient selection remains a challenge. OBJECTIVES: The purpose of this study was to describe contemporary outcomes of postoperative AJR/JET and develop a risk prediction score to identify patients at highest risk. METHODS: This was a retrospective cohort study of children aged 0-18 years undergoing cardiac surgery (2011-2018). AJR was defined as usual complex tachycardia with ≥1:1 ventricular-atrial association and junctional rate >25th percentile of sinus rate for age but <170 bpm, whereas JET was defined as a rate >170 bpm. A risk prediction score was developed using random forest analysis and logistic regression. RESULTS: Among 6364 surgeries, AJR occurred in 215 (3.4%) and JET in 59 (0.9%). Age, heterotaxy syndrome, aortic cross-clamp time, ventricular septal defect closure, and atrioventricular canal repair were independent predictors of AJR/JET on multivariate analysis and included in the risk prediction score. The model accurately predicted the risk of AJR/JET with a C-index of 0.72 (95% confidence interval 0.70-0.75). Postoperative AJR and JET were associated with prolonged intensive care unit and hospital length of stay, but not with early mortality. CONCLUSION: We describe a novel risk prediction score to estimate the risk of postoperative AJR/JET permitting early identification of at-risk patients who may benefit from prophylactic treatment.

Ventricular arrhythmias after fibroma resection: Are patients still at risk?

BACKGROUND: Ventricular fibromas frequently present with life-threatening ventricular tachycardia (VT) or ventricular fibrillation (VF) in children. The long-term risk of sustained ventricular arrhythmias after surgical resection is unknown. OBJECTIVES: The aims of this study were to quantify the VT/VF risk after surgical resection and to examine the results of early (during index surgical hospitalization) and late (≥3 months after surgery) postoperative ventricular stimulation (V-stim) studies. METHODS: We performed a retrospective cohort study of all patients with ventricular fibromas who underwent surgical resection at our institution (2000-2020). The primary outcome was defined as recurrent VT/VF ≥3 months after index surgical resection. RESULTS: Forty-six patients with a median age at surgery of 2 years (range 0.3-18.9 years) formed our study cohort. Indications for surgery included cardiac arrest in 11 (24%), sustained VT in 16 (35%), premature ventricular contractions/nonsustained VT in 10 (22%), and hemodynamic abnormalities in 9 (20%). Of the 11 patients who presented with cardiac arrest, 4 underwent pre-resection implantable cardioverter-defibrillator (ICD) implantation, all of which were explanted at the time of surgery. An early postoperative V-stim study was performed in 26 (57%) patients, and all were negative for inducible VT/VF. Of the 13 late postoperative V-stim studies, 3 were positive: 2 underwent ICD implantation and 1 was initiated on amiodarone and underwent loop recorder implantation. At the time of last follow-up (median 1.5 years; range 0.3-16.5 years), 45 (98%) were free of clinical VT/VF and no patient with an ICD has received an appropriate shock. CONCLUSION: Surgical resection of ventricular fibromas significantly reduces the risk of life-threatening arrhythmias in children; however, a small number of patients remain vulnerable.

Radiofrequency Catheter Ablation for Pediatric Atrioventricular Nodal Reentrant Tachycardia: Impact of Age on Procedural Methods and Durable Success.

Background Catheter-based slow-pathway modification (SPM) is the treatment of choice for symptomatic atrioventricular nodal reentrant tachycardia (AVNRT). We sought to investigate the interactions between patient age and procedural outcomes in pediatric patients undergoing catheter-based SPM for AVNRT. Methods and Results A retrospective cohort study was performed, including consecutive patients undergoing acutely successful SPM for AVNRT from 2008 to 2017. Those with congenital heart disease, cardiomyopathy, and accessory pathways were excluded. Patients were stratified by age quartile at time of SPM. The primary outcome was AVNRT recurrence. A total of 512 patients underwent successful SPM for AVNRT. Age quartile 1 had 129 patients with a median age and weight of 8.9 years and 30.6 kg, respectively. Radiofrequency energy was used in 98% of cases. Follow-up was available in 447 (87%) patients with a median duration of 0.8 years (interquartile range, 0.2-2.5 years). AVNRT recurred in 22 patients. Multivariable Cox proportional hazard modeling identified atypical AVNRT (hazard ratio [HR], 5.83; 95% CI, 2.01-16.96; P=0.001), dual atrioventricular nodal only (HR, 4.09; 95% CI, 1.39-12.02; P=0.011), total radiofrequency lesions (HR, 1.06 per lesion; 95% CI, 1.01-1.12; P=0.032), and the use of a long sheath (HR, 3.52; 95% CI, 1.23-10.03; P=0.010) as predictors of AVNRT recurrence; quartile 1 patients were not at higher risk of recurrence (HR, 0.45; 95% CI, 0.10-1.97; P=0.29). Complete heart block requiring permanent pacing occurred in one quartile 2 patient at 14.9 years of age. Conclusions Pediatric AVNRT can be treated with radiofrequency-SPM with high procedural efficacy and minimal risk of complications, including heart block. Atypical AVNRT and dual atrioventricular nodal physiology without inducible tachycardia remain challenging substrates.

Catheter Ablation of Atrioventricular Nodal Reentrant Tachycardia in Patients With Congenital Heart Disease.

Atrioventricular (AV) nodal reentrant tachycardia represents the most common regular supraventricular arrhythmia in humans, and catheter ablation of the so called slow AV nodal pathway has been effectively performed for decades. In patients with congenital heart disease, a combination of different factors makes catheter ablation of AV nodal reentrant tachycardia substrate particularly challenging, including abnormal venous access to intracardiac structures, abnormal intracardiac anatomy, potentially deviant and often unpredictable sites of the specific conduction system, loss of traditional anatomic landmarks, and congenital cardiac surgery that may complicate the access to the AV nodal area. Published experiences have confirmed the efficacy and the relative safety of such procedures when performed by experts, but the risk of complications, in particular AV block, remains non-negligible. A thorough knowledge and understanding of anatomic and electrical specificities according to underlying phenotype are essential in addressing these complex cases. Considering the major consequences associated with AV block in patients with complex congenital heart disease, particularly those without low risk access for transvenous ventricular pacing (eg, single ventricle physiology or Eisenmenger syndrome), the individual risk-benefit ratio should be carefully evaluated. The decision to defer ablation may be the wisest approach in selected patients with either infrequent or hemodynamically tolerated arrhythmias, or when the location of the AV conduction pathways remains uncertain. This narrative review aims to synthetize existing literature on catheter ablation of AV nodal reentrant tachycardia in congenital heart disease, to present main features of common associated pathologies, and to discuss approaches to mapping and safely ablating the slow AV nodal pathway in challenging cases.

The Evolution of Pediatric and Congenital Electrophysiology as a Subspecialty.

Over the past 50 years, pediatric and congenital electrophysiology has progressed from a rare subspecialty practiced at just a handful of centers to become an essential part of nearly every congenital heart program the world over. This paper traces the evolution of the subspecialty in North America by recognizing the individuals who dedicated their careers to this field and trained subsequent generations of practitioners, thereby establishing a legacy that insures continued progress in the treatment of arrhythmias for children and patients with congenital heart disease. Data were generated from a survey of the current membership of the Pediatric and Congenital Electrophysiology Society and were supplemented by review of archived Society records. Maps depicting the locations for clinicians and training centers over time provide a graphic display of progress in this field.

Accessory pathway ablation in Ebstein anomaly: A challenging substrate.

BACKGROUND: Catheter ablation of accessory pathways (APs) in Ebstein anomaly (EA) has been associated with a high recurrence risk. OBJECTIVE: The purpose of this study was to compare outcomes of AP ablation in EA in an early (1990-2004) vs a recent (2005-2019) era and identify variables associated with recurrence. METHODS: A retrospective review of all catheter ablations for supraventricular tachycardia in EA at our institution was performed. RESULTS: We identified 76 patients with median (25th-75th quartiles) age 9 (2.6-13.3) years. Of these patients, 52 had AP alone, 12 had atrial flutter, 3 had atrioventricular nodal reentrant tachycardia, and 9 had AP plus at least 1 additional arrhythmia. Of the 61 patients with APs, a total of 78 separate APs were identified: 40 right-sided, 37 septal, and 1 left-sided. Acute success for AP first procedure was 89% and did not differ between early and recent eras (89% vs 88%; P = .48). However, 19 patients (31%) required repeat procedures (average 1.4 per patient) due to AP recurrence or ablation failure at first attempt. In comparison to early era, recent era ablations had significantly lower recurrence rates at 1 year (62% vs 19%; P = .005). At median follow-up of 2.5 (0.2-7) years, ultimate AP elimination after all procedures was 93%. Younger age at time of electrophysiological study (<2 vs 12-47 years: hazard ratio [HR] 7.3; P = .003) and ablation era (early era vs recent era: HR 3.65; P = .009) predicted recurrence. CONCLUSION: Outcomes for AP ablation in patients with EA have improved, but there is still a relatedly high recurrence risk requiring repeat procedures.

Risk Factors for Left Ventricular Dysfunction Following Surgical Management of Cardiac Fibroma.

BACKGROUND: Surgical resection of cardiac fibromas in children reduces hemodynamic and arrhythmia burden; however, little is known about postoperative left ventricular (LV) function. We aimed to evaluate factors associated with postoperative LV dysfunction. METHODS: In this retrospective observational cohort study, imaging data were reviewed from 41 patients who had undergone surgical resection of a cardiac fibroma. Tumor volume was indexed to body surface area (tumor volume index). Right ventricular tumors were excluded from analysis of postoperative ventricular function. Postoperative regional wall motion abnormality score was defined as number of wall segments with regional wall motion abnormality, and LV dysfunction was defined as LV ejection fraction <50%. Cardiovascular magnetic resonance-derived strain was low if <5%ile by previously published normative data. RESULTS: Of 41 patients who underwent resection at a median age of 2.1 years (range, 0.5-19), 37 fibromas were in the LV, (29 free wall and 8 septal), and 4 in the right ventricle. Preoperative median tumor volume index was 66 mL/m2 (range, 11-376). Of 37 patients with LV tumors, younger patients had larger tumor volume index and higher grades of preoperative mitral regurgitation (P<0.001). Larger tumor volume index correlated with higher postoperative regional wall motion abnormality score (P<0.001). By paired pre- and post-operative cardiovascular magnetic resonance (n=14), LV end-diastolic volume increased (mean 76 versus 101 mL/m2, P=0.011), with decreased LV ejection fraction (mean 60% versus 55%, P=0.014), a higher prevalence of low global circumferential strain (36% versus 64%, P=0.045), and decreased cardiac index (mean 4.8 versus 3.9 L/[min·m2], P=0.039). More than mild preoperative mitral regurgitation was the only independent predictor of predischarge LV dysfunction (odds ratio, 22 [95% CI, 2.8-179], P=0.008). CONCLUSIONS: Surgical resection of LV fibroma is associated with regional wall motion abnormality, increased LV volume, and reduced systolic function. Children with significant preoperative mitral regurgitation are at highest risk for LV dysfunction and warrant ongoing close surveillance.

Lead age as a predictor for failure in pediatrics and congenital heart disease.

BACKGROUND: Pediatric and congenital heart disease (CHD) patients have a high rate of transvenous (TV) lead failure. OBJECTIVE: To determine whether TV lead age can aid risk assessment for lead failure to guide the decision of whether a lead should be replaced or reused at the time of a generator change. METHODS: Retrospective cohort study of patients <21 years old undergoing TV device implant from 2000 to 2014 at our institution. Patient, device, and lead variables were collected. Leads were compared in groups based on how many generator changes were completed. RESULTS: A total of 393 leads in 257 patients met inclusion criteria, 60 leads failed (15%). Failed leads were more likely to have not yet undergone generator change (p = .048). CHD (p = .045), Tendril lead type (p = .02) and silicone insulation (p = .02) were associated with failure. In multivariate analysis, younger leads (p = .022), number of generator changes (p = .003), CHD (p = .005) and silicone insulation (p = .004) remained significant while Tendril lead type did not (p = .052). Survival curves show an early decline around 4 years. CONCLUSIONS: Lead failure rate in pediatric and CHD patients is high. Leads that have not yet undergone a generator change were more likely to fail in this cohort. The strategy of serial replacement based on lead age needs further research to justify in this population.

Risk Factors for Early Recurrence Following Ablation for Accessory Pathways: The Role of Consolidation Lesions.

BACKGROUND: Atrioventricular reentrant tachycardia is common in children. Catheter ablation is increasingly used as a first-line therapy with a high acute success rate, but recurrence during follow-up remains a concern. The aim of this study was to identify risk factors for recurrence after accessory pathway (AP) ablation. METHODS: Retrospective cohort study including patients who underwent AP ablation between 2013 and 2018. Cox proportional hazards model was used to examine the association between patient and procedural characteristics and recurrence during follow-up. RESULTS: From 558 AP ablation procedure, 542 (97%) were acutely successful. During a median follow-up of 0.4 (interquartile range, 0.1-1.4) years, there were 42 (8%) patients with documented recurrence. On univariate analysis, early recurrence was associated with younger age, congenital heart disease, multiple AP, AP location (right sided and posteroseptal versus left sided), cryoablation (versus radiofrequency), empirical ablation, the lack of full power radiofrequency lesions (<50 W), radiofrequency consolidation time <90 seconds and the use of fluoroscopy without a 3-dimensional electroanatomic mapping system. On multivariable analysis, only multiple AP (hazard ratio, 2.78 [95% CI, 1.063-4.74]) and radiofrequency consolidation time < 90 seconds (hazard ratio, 4.38 [95% CI, 1.92-9.51]) remained significantly associated with early recurrence; this association remained true when analyzed in subgroups by pathway location for right and left free wall AP. CONCLUSIONS: In our institutional experience, radiofrequency consolidation time <90 seconds after ablation of AP was associated with an increased risk of early recurrence.

Difference in the prevalence of intracardiac thrombus on the first presentation of atrial fibrillation versus flutter in the pediatric and congenital heart disease population.

INTRODUCTION: Guidelines recommend trans-esophageal echocardiography (TEE) for patients with atrial fibrillation (AF) or atrial flutter (AFL) for >48 h, due to risk of intracardiac thrombus formation. With growing evidence that AFL in adults with structurally normal hearts has less thrombogenic potential compared to AF, and the need for TEE questioned, we compared prevalence of intracardiac thrombus detected by TEE in pediatric and congenital heart disease (CHD) patients presenting in AF and AFL. METHODS/RESULTS: Single-center, cross-sectional analysis for unique first-time presentations of patients for either AF, AFL, or intra-atrial reentrant tachycardia (IART) between 2000 and 2019. Patients were categorized by presenting arrhythmia (AF vs. AFL/IART), with the exclusion of other forms of atrial tachycardia, hemodynamic instability, chronic anti-coagulation before TEE, and presentation for a reason other than TEE examination for thrombus. A total of 201 patients had TEE with co-diagnosis of AF or AFL. Of these, 105 patients (29 AF, 76 AFL) met inclusion criteria, with no difference in age between AF (median 24.9 years; IQR 18.6-38.3 years) and AFL/IART (23.3 years; 15.4-38.4 years). The prevalence of thrombus in the entire cohort was 9.5%, with no difference between AF (13.8%) and AFL groups (7.9%), p = .46. Patients with thrombus demonstrated no difference in age, systemic ventricular function, cardiac complexity, or CHADS2/CHA2DS2VASc score at presentation. CONCLUSIONS: The risk for intracardiac thrombus is high in the pediatric and CHD population, with no apparent distinguishing factors to warrant a change in the recommendations for TEE, with all levels of cardiac complexity being at risk for clot.

Ventricular Arrhythmia and Life-Threatening Events in Patients With Repaired Tetralogy of Fallot.

Risk stratification for malignant arrhythmias and risk of sudden cardiac death in tetralogy of Fallot (TOF) remains challenging. We aimed to ascertain factors associated with life-threatening arrhythmic events. A multicenter retrospective case-control study including 72 TOF patients with documented cardiac arrest and/or sustained ventricular tachycardia, compared with 216 controls matched for era of surgery. The mean age at event in the cases was 27.3 ± 12.5 years. The majority (57%) presented with sustained ventricular tachycardia. Fatal events occurred in 9. Random forest analysis and a decision tree demonstrated surgical era specific risk factors (< vs ≥ 1980). For both eras, arrhythmic symptoms and left ventricular dysfunction were strongly associated with malignant arrhythmias. In addition, right ventricular dysfunction and age at repair ≥ 6.5 years preceded by a shunt were associated with a higher risk group in the early era, whereas a trans-annular patch type repair was associated with a lower risk group in the recent era. For the moderate and high-risk groups, the decision tree showed a sensitivity of 88.4% and specificity of 68.1%. An "importance factor" was calculated for each predictor, creating a risk score and 4 risk categories. In conclusions, this risk stratification scheme, based on clinical history and noninvasive testing, allows categorization of TOF patients at high risk of malignant arrhythmia. A multicenter prospective evaluation of the accuracy of this scoring system is now being planned.

Value of provocative electrophysiology testing in the management of pediatric patients after congenital heart surgery.

OBJECTIVE: To determine the impact of provocative electrophysiology testing in postoperative congenital heart disease (CHD) patients on the management of supraventricular tachycardia (SVT) and clinical outcomes. METHODS: This is a retrospective study including patients <18 years of age with surgery for CHD who had postoperative SVT between 2006 and 2017. Postoperative outcomes were compared between patients with and without postoperative electrophysiology testing using the Wilcoxon rank sum test, Fisher's exact test, Kaplan-Meier method with the log-rank test, and Cox proportional hazard model. RESULTS: From 341 patients who had SVT after surgery for CHD, 65 (19%) had postoperative electrophysiology testing. There was no significant difference in baseline patient characteristics or surgical complexity between patients with and without electrophysiology testing. Patients with inducible SVT on electrophysiology testing were more likely to have recurrence of SVT prior to hospital discharge with an odds ratio 4.0 (95% confidence interval 1.3, 12.0). Patients who underwent postoperative electrophysiology testing had shorter intensive care unit (12 [6, 20] vs 16 [9, 32] days, HR 2.1 [95% CI 1.6, 2.8], P < .001) and hospital (25 [13, 38] vs 31 [18, 54] days, HR 1.8 [95% CI 1.4, 2.4], P < .001) length of stay. CONCLUSION: Postoperative electrophysiology testing was associated with improved postoperative outcomes, likely related to the ability to predict recurrence of arrhythmia and tailored antiarrhythmic management.