Rare Variant in MRC2 Associated With Familial Supraventricular Tachycardia and Wolff-Parkinson-White Syndrome.

BACKGROUND: Accessory pathways are a common cause of supraventricular tachycardia (SVT) and can lead to sudden cardiac death in otherwise healthy children and adults when associated with Wolff-Parkinson-White syndrome. The goal of this study was to identify genetic variants within a large family with structurally normal hearts affected by SVT and Wolff-Parkinson-White syndrome and determine causality of the gene deficit in a corresponding mouse model. METHODS: Whole exome sequencing performed on 2 distant members of a 3-generation family in which multiple members were affected by SVT or Wolff-Parkinson-White pattern (preexcitation) on ECG identified MRC2 as a candidate gene. Serial electrocardiograms, intracardiac electrophysiology studies, echocardiography, optical mapping studies, and histology were performed on both Mrc2 mutant and WT (wild-type) mice. RESULTS: A rare HET (heterozygous) missense variant c.2969A>G;p.Glu990Gly (E990G) in MRC2 was identified as the leading candidate gene variant segregating with the cardiac phenotype following an autosomal-dominant Mendelian trait segregation pattern with variable expressivity. In vivo electrophysiology studies revealed reentrant SVT in E990G mice. Optical mapping studies in E990G mice demonstrated abnormal retrograde conduction, suggesting the presence of an accessory pathway. Histological analysis of E990G mouse hearts showed a disordered ECM (extracellular matrix) in the annulus fibrosus. Finally, Mrc2 knockdown in human cardiac fibroblasts enhanced accelerated cell migration. CONCLUSIONS: This study identified a rare nonsynonymous variant in the MRC2 gene in individuals with familial reentrant SVT, Wolff-Parkinson-White ECG pattern, and structurally normal hearts. Furthermore, Mrc2 knock-in mice revealed an increased incidence of reentrant SVT and bypass tract formation in the setting of preserved cardiac structure and function.

Is this an anteroseptal accessory pathway?

The ECG of a patient during sinus rhythm shows preexcited QRS pattern, with rS pattern in lead V1, transition in lead V2, and positive inferior leads. Following the stepwise algorithms, the location of accessory pathway (AP) was identified at anteroseptal region. However, the precordial transition in lead V2 indicates mid-septal or posteroseptal AP. The mismatch suggested multiple APs and 5 APs were identified by electrophysiologic study. This case highlights the importance of detailed analysis of ECG in order to achieve adequate ablation.

Ventricular insertion site ablation of a Mahaim atriofascicular fibre in Ebstein anomaly.

Ebstein anomaly is frequently associated with accessory pathways, including Mahaim atriofascicular fibres. We herein illustrate successful Mahaim fibre ablation in Ebstein anomaly by targeting the ventricular insertion site below the tricuspid ridge.

Evaluation of T-wave memory after accessory pathway ablation in pediatric patients with Wolff-Parkinson-White syndrome.

BACKGROUND: T-wave memory (TWM) is a rare cause of T-wave inversion (TWI). Alterations in ventricular activation due to abnormal depolarization may cause repolarization abnormalities on the ECG, even if myocardial conduction returns to normal. These repolarization changes are defined as TWM. In our study, we aimed to determine the frequency of TWM development and the predictors affecting it in the pediatric population who underwent accessory pathway (AP) ablation due to Wolff-Parkinson-White (WPW) syndrome. METHODS: The data of patients with manifest AP who underwent electrophysiological studies and ablation between 2015 and 2021 were retrospectively analyzed. The study included 180 patients who were under 21 years of age and had at least one year of follow-up after ablation. Patients with structural heart disease, intermittent WPWs, recurrent ablation, other arrhythmia substrates, and those with less than one-year follow-up were excluded from the study. The ECG data of the patients before the procedure, in the first 24 h after the procedure, three months, and in the first year were recorded. The standard ablation technique was used in all patients. RESULTS: Postprocedure TWM was observed in 116 (64.4%) patients. Ninety-three patients (51.7%) had a right-sided AP, and 87 patients (48.3%) had a left-sided AP. The presence of posteroseptal AP was found to be significantly higher in the group that developed TWM. Of these patients, 107 (93.1%) patients showed improvement at the end of the first year. Preprocedural absolute QRS-T angle, postprocedural PR interval, and right posteroseptal pathway location were identified as predictors of TWM. CONCLUSION: The development of TWM is particularly associated with the right-sided pathway location, especially the right posteroseptal pathway location. The predictors of TWM are the preprocedural QRS-T angle, the postprocedural PR interval, and the presence of the right posteroseptal AP.

Ablation of accessory pathways in different anatomic locations using focal pulsed field ablation.

BACKGROUND: Ablation of accessory pathways (APs) is the cornerstone for treatment of patients with Wolff-Parkinson-White syndrome and manifestation of atrioventricular reentrant tachycardia. Pulsed field ablation (PFA) is a new type of nonthermal energy source delivered to the underlying tissue via the ablation catheter and used for ablation of arrhythmic substrates. OBJECTIVE: The purpose of this study was to determine the efficiency and long-term outcome of ablation of APs of different localizations using a focal pulsed electrical field. METHODS: Electrophysiological study was performed in patients with indication for AP ablation. An ablation catheter was used to map the position of AP insertion. Pulsed electric field was delivered through a standard ablation catheter. In left-sided APs, the first ablation attempt was within the coronary sinus (CS). Patient follow-up was scheduled 1-3 months after the ablation. Additional check-up was performed after 6 and 12 months. RESULTS: Fourteen 14 patients (3 pediatric) were treated. Termination of AP conduction was achieved in all procedures. The cohort consisted of 3 right free wall, 3 posteroseptal, and 8 left-sided APs. Ablation through CS was successfully used in 7 of 8 patients with left-sided APs. No complications were reported. Median follow-up was 5.5 months. Conduction recurrence through AP was documented in 1 patient. CONCLUSION: Focal PFA for AP shows promising results in terms of efficacy and safety. A high rate of successful termination of left-sided APs by ablation within CS may represent a new standard approach. The safety and efficacy profile of PFA seems to be transferable to the pediatric population.

[Historical developments in the diagnosis and treatment of pre-excitation syndromes (WPW)]. / Historische Entwicklung in Diagnostik und Therapie bei Präexzitationssyndromen (WPW).

In 1930, Wolff, Parkinson and White described the syndrome that bears their names. The mechanisms of supraventricular tachycardias were analyzed by brilliant electrocardiography interpretation by Pick and Langendorf. Wellens and Durrer using electrophysiologic studies analyzed the tachycardia mechanism invasively. In Germany the group by Seipel and Breithardt as well as Neuss and Schlepper studied the tachycardia mechanisms and response to antiarrhythmic drugs invasively by electrophysiological studies. Following the first successful interruption of an accessory pathway by Sealy in 1967, surgeons and electrophysiologists cooperated in Germany. Two centers, Hannover and Düsseldorf were established. Direct current (DC) ablation of accessory pathways was introduced by Morady and Scheinman. Because of side effects induced by barotrauma of DC, alternative strategies were studied. In 1987, radiofrequency ablation was introduced and thereafter established as curative therapy of accessory pathways in all locations.

Accessory pathway localization with probabilistic density maps generated by a mobile application: Assessment of a full pre-excitation net-vector method.

INTRODUCTION: Precise electrocardiographic localization of accessory pathways (AP) can be challenging. Seminal AP localization studies were limited by complexity of algorithms and sample size. We aimed to create a nonalgorithmic method for AP localization based on color-coded maps of AP distribution generated by a web-based application. METHODS: APs were categorized into 19 regions/types based on invasive electrophysiologic mapping. Preexcited QRS complexes were categorized into 6 types based on polarity and notch/slur. For each QRS type in each lead the distribution of APs was visualized on a gradient map. The principle of common set was used to combine the single lead maps to create the distribution map for AP with any combination of QRS types in several leads. For the validation phase, a separate cohort of APs was obtained. RESULTS: A total of 800 patients with overt APs were studied. The application used the exploratory data set of 553 consecutive APs and the corresponding QRS complexes to generate AP localization maps for any possible combination of QRS types in 12 leads. Optimized approach (on average 3 steps) for evaluation of preexcited electrcardiogram was developed. The area of maximum probability of AP localization was pinpointed by providing the QRS type for the subsequent leads. The exploratory data set was validated with the separate cohort of APs (n = 256); p = .23 for difference in AP distribution. CONCLUSIONS: In the largest data set of APs to-date, a novel probabilistic and semi-automatic approach to electrocardiographic localization of APs was highly predictive for anatomic localization.

Risk assessment in patients with symptomatic and asymptomatic pre-excitation.

AIMS: Controversy remains as to whether the exercise stress test (EST) is sufficient for risk evaluation in patients with pre-excitation. This study aims to clarify the usefulness of EST in risk stratification in both asymptomatic and symptomatic patients presenting with pre-excitation. METHODS AND RESULTS: This prospective study includes consecutive asymptomatic and symptomatic patients with pre-excitation referred for risk assessment. All participants performed an incremental EST (bicycle) prior to an electrophysiology study (EPS). Primary data from the EST included loss of pre-excitation during exercise, and primary data from the EPS included the measurement of accessory pathway effective refractory period (APERP), shortest pre-excited RR interval (SPERRI), and inducible arrhythmia with the use of a beta-adrenergic receptor agonist if deemed necessary. One hundred and sixty-four patients (59 asymptomatic, 105 symptomatic) completed an EST and EPS. Forty-five patients (27%) demonstrated low-risk findings on EST, of which 19 were asymptomatic and 26 were symptomatic. Six patients with low-risk EST findings had SPERRI/APERP ≤ 250 ms at EPS, and two of them were asymptomatic. The sensitivity, specificity, positive predictive value, negative predictive value (NPV), and accuracy of low-risk EST for excluding patients with SPERRI/APERP ≤ 250 ms were 40, 91, 87, 51, and 60%, respectively. The number of patients with inducible arrhythmia at EPS was similar in the asymptomatic (36, 69%) and symptomatic (73, 61%) groups. CONCLUSION: Sudden loss of pre-excitation during EST has a low NPV in excluding high-risk APs. The EPS with the use of isoproterenol should be considered to accurately assess the risk of patients with pre-excitation regardless of symptoms (ClinicalTrials.gov Identifier: NCT03301935).

Utility of Intracoronary Acetylcholine Provocation Testing in Inducing Atrial Fibrillation with Preexcitation Followed by Ventricular Fibrillation in a Patient with Wolff-Parkinson-White Syndrome: A Case Report.

A 20-year-old man was resuscitated after ventricular fibrillation (VF). Electrocardiography revealed Wolff-Parkinson-White (WPW) syndrome. Intracoronary acetylcholine provocation testing was performed to induce VF secondary to the coronary vasospasm. The administration of acetylcholine to the coronary artery induced atrial fibrillation (AF) with pre-excitation, followed by VF without coronary vasospasm. Electrophysiological studies revealed an accessory pathway managed by catheter ablation. Subsequent intracoronary acetylcholine provocation testing (ACH test) induced the occurrence of AF without preexcitation. To our knowledge, this case report is the first to demonstrate the utility of the ACH test in confirming WPW syndrome as a cause of VF.

[History of surgical treatment of cardiac arrhythmias in Germany : Surgical treatment of ventricular tachycardia and supraventricular tachycardia, especially pre-excitation syndromes (WPW)]. / Geschichte der chirurgischen Behandlung von Herzrhythmusstörungen in Deutschland : Chirurgische Therapie ventrikulärer Tachykardien sowie supraventrikulärer Tachykardien, insbesondere Präexzitationssyndromen (WPW).

The history of surgical treatment of ventricular tachycardias (VT) is short, lasting from 1978 until 1993. "Indirect procedures" with infarct scar resection were performed without electrophysiologic studies, whereas "direct procedures" consisted of either complete endocardial incisions ("encircling endocardial ventriculotomy") or large endocardial resections ("endocardial peel-off" technique) after precise epicardial and endocardial mapping procedures. In Germany, the first to report on intra-operative electrophysiologic mapping for VT treatment were Ostermeyer, Breithardt and Seipel in 1979. In 1981, the Hannover group (Frank, Klein) published their first results of surgical treatment of VT. In 1984, Ostermeyer et al. demonstrated that a partial endocardial incision resulted in more beneficial results with less myocardial damage (8% versus 46%) than applying a complete encircling incision. In 1987, the Düsseldorf group reported treatment results of 93 patients. After 5 years, 77% had no VT recurrence, while total mortality after 1 year was 11% and after 5 years 30%. In 1992, the Hannover group reported results of 147 patients after endocardial resection for VT. Total mortality after 3 years was 27%; recurrence of VT events occurred in 18% of the surviving cohort.The history of surgical procedures for supraventricular tachycardia (SVT), in particular Wolff-Parkinson-White (WPW) syndrome, is even shorter than that of surgery for VT. As early as 1969, Sealy, Gallagher and Cox reported the first cases of surgical intervention for WPW syndrome via endocardial access in cardioplegic arrest. In 1984, Guiraudon and Klein reported on a new procedure with epicardial access to the accessory bundle without cardioplegia in laterally localised conduction pathways. In Germany, too, the groups in Düsseldorf (Ostermeyer, Seipel, Breithardt, Borggrefe) from 1980 and the Hannover group (Frank, Klein and Kallfelz) from 1981 performed surgical procedures for WPW syndrome. In 1987, Borggrefe reported on 18 patients with WPW syndrome and atrial fibrillation who had undergone surgery. After 2 years, 14 of 18 patients had no recurrences of tachycardia; in 1989, Frank, Klein and Kallfelz (Hannover) reported on 10 children (2-14 years) operated on using the cryoablation technique. Between 1984 and 1992, a total of 120 patients with SVT, mostly WPW syndrome, were operated on in Hannover; after 42 months, 12 patients had a recurrence of SVT. Two patients died during the reoperation.

[Short history of the DC-Catheter-Ablation]. / Kurze Geschichte der Katheterablation mit DC-Schocks.

Direct current (DC) catheter ablation in 5 patients aiming to interrupt rapid atrioventricular (AV) conduction with atrial fibrillation and subsequent pacemaker implantation was first published by M. M. Scheinman et al. (San Francisco, CA, USA) in 1982. In Germany, L. Seipel, G. Breithardt, and M. Borggrefe reported their first experience with DC catheter ablation in 1984, followed by the group in Bonn (M. Manz and B. Lüderitz) in 1985. The first international DC catheter ablation registry, which also included four German centers, reported DC catheter ablation results of 127 patients in 24 centers in 1984. Complete AV block was achieved in 71% patients. In 1992, the Hannover group (H­J. Trappe, H. Klein and J. Huang) reported results of DC catheter ablation of AV conduction performed between 1983 and 1990 in 100 patients (86% with rapid atrial fibrillation, 14% with AV-node reentry tachycardias). The first successful DC catheter ablation in a patient with Wolff-Parkinson-White (WPW) syndrome was reported in 1985 by F. Morady et al. (San Francisco, CA, USA). In 1987, M. Borggrefe et al. were the first to report a switch from DC catheter ablation to a high-frequency (HF) catheter ablation procedure in a patient with WPW syndrome. The use of DC catheter ablation to treat ventricular tachycardia (VT) was described by G. O. Hartzler (Kansas City, MO, USA) in 3 patients in 1983. M. Borggrefe et al. (1989) reported on 24 patients who underwent DC catheter ablation for VT. Of those, 17 patients did not have VT recurrence within the following 14 months. In 1994, the Hannover group (H-J Trappe, H. Klein) published their 5­year long-term results of DC catheter ablation of VT in 51 patients. VT recurrence occurred in 57% patients and overall mortality was also high (16%). A comparison of DC catheter ablation with HF catheter ablation for recurrent VT was reported in 1994 by G. Gonska et al. (Göttingen, Germany). After 2 years follow-up, success rates were not found to be significantly different.

Safety of same-day discharge without anticoagulation for left-sided radiofrequency catheter ablations in pediatrics.

BACKGROUND: For left-sided radiofrequency catheter ablation (LCA) in pediatrics, significant practice variability exists regarding anticoagulation and discharge practices. Given the lack of data in pediatric patients, the risks and benefits of these practices are not well defined. OBJECTIVE: The purpose of this study was to evaluate the safety of same-day discharge and use of aspirin (ASA) in pediatric patients following LCA. METHODS: We performed a retrospective cohort study of pediatric patients who underwent LCA from 2010 to 2020 at our institution. Discharge timing and ASA usage were based on operator preference. The primary outcome was incidence of postablation anticoagulation complications reported within 1 month of the procedure. RESULTS: Three hundred seventy-six patients underwent LCA and met inclusion criteria. Median [25th, 75th percentiles] age was 13.9 [10.5, 16.2] years; 18 (4.7%) had a history of structural heart disease. The most common substrates for ablation were Wolff-Parkinson-White syndrome (183 patients [48.7%]), concealed accessory pathway (159 patients [42.3%]), and ectopic atrial tachycardia (10 patients [2.7%]). Three hundred thirty-eight patients (89.9%) were discharged on the day of LCA. Seventy-six patients (20.2%) were prescribed ASA at discharge. Of those who underwent follow-up (273 patients [72.6%]), 7 (2.7%) reported an anticoagulation complication (5 with hematoma, 2 with headache). One of these patients was prescribed ASA; none required readmission. There was no correlation between anticoagulation complications and same-day discharge or with ASA usage. CONCLUSION: Given the rare incidence of anticoagulation complications in pediatric patients undergoing LCAs, same-day discharge from the electrophysiology laboratory without anticoagulation should be considered.

The Incidence and Factors Associated with the Recurrence of Supraventricular Tachycardia in Children: 15 Years Experience from Middle-Income Country.

Limited data are available concerning supraventricular tachycardia (SVT) recurrence. Hence, this study aimed to determine the incidence, outcome, and factors associated with SVT recurrence. This retrospective, observational, population-based study was conducted among children with SVT from 2006 to 2020. The primary outcome measure was SVT recurrence. Kaplan Meier analysis was used to estimate SVT-free at 1, 5, and 10 years after diagnosis. Cox regression analysis was used to identify independent factors associated with recurrence. There were 156 patients with SVT with a median age at diagnosis of 1.9 years (Interquartile range [IQR] 11 days to 8.7 years) and follow-up for a median of 3.5 years (IQR 1.7 to 6.1 years). 35 patients (22%) had recurrent SVT at a median age of 7.8 years (IQR 4.4 to 12 years). Infants with Wolff-Parkinson-White Syndrome (WPW) had the highest recurrence (11/16, 68%), with 33% SVT-free at 5 years follow-up. The lowest recurrence rate was observed in neonatal diagnosis (2/54, 3.7%) with 98% SVT-free at 5 years follow-up. The independent factors associated with the recurrence of SVT were the diagnosis of WPW with an adjusted hazard ratio (aHR) of 5.2 (95% CI 2.4-11.2), age of more than 1 year at diagnosis (aHR 3.7 95% CI 1.4-9.7), and combine with or need second-line therapy (aHR 4.0 95% CI 1.5-10.7). One in five children with SVT experienced a recurrence, which is more likely for those with WPW, multiple maintenance therapy, and older age at first presentation. Whereas neonates with non-WPW may benefit from shorter maintenance therapy.