Transcription alterations of KCNQ1 associated with imprinted methylation defects in the Beckwith-Wiedemann locus.

PURPOSE: Beckwith-Wiedemann syndrome (BWS) is a developmental disorder caused by dysregulation of the imprinted gene cluster of chromosome 11p15.5 and often associated with loss of methylation (LOM) of the imprinting center 2 (IC2) located in KCNQ1 intron 10. To unravel the etiological mechanisms underlying these epimutations, we searched for genetic variants associated with IC2 LOM. METHODS: We looked for cases showing the clinical features of both BWS and long QT syndrome (LQTS), which is often associated with KCNQ1 variants. Pathogenic variants were identified by genomic analysis and targeted sequencing. Functional experiments were performed to link these pathogenic variants to the imprinting defect. RESULTS: We found three rare cases in which complete IC2 LOM is associated with maternal transmission of KCNQ1 variants, two of which were demonstrated to affect KCNQ1 transcription upstream of IC2. As a consequence of KCNQ1 haploinsufficiency, these variants also cause LQTS on both maternal and paternal transmission. CONCLUSION: These results are consistent with the hypothesis that, similar to what has been demonstrated in mouse, lack of transcription across IC2 results in failure of methylation establishment in the female germline and BWS later in development, and also suggest a new link between LQTS and BWS that is important for genetic counseling.

Zero-Fluoroscopy Ablation of Accessory Pathways in Children and Adolescents: CARTO3 Electroanatomic Mapping Combined with RF and Cryoenergy.

BACKGROUND: Fluoroscopic catheter ablation of cardiac arrhythmias in pediatric patients exposes the patients to the potential risk of radiation considering the sensitivity of this population and its longer life expectancy. We evaluated the feasibility, safety, and efficacy of accessory pathway (AP) ablation guided by CARTO3 electroanatomic mapping (EAM) system with both cryoenergy and radiofrequency (RF) energy in order to avoid x-ray exposure in pediatric patients. METHODS: We included 44 patients (mean age: 13.1 ± 3.3 years); nine of 44 presented concealed AP. An electrophysiological study with a three-dimensional EAM reconstruction was performed in every patient with a venous transfemoral direct right atrium approach or an arterial transfemoral retrograde approach to reach the mitral annulus. In two patients with left-sided AP, the ablation was performed via a patent foramen ovale. RESULTS: A total of 47 APs were present, left sided in 45% (21/47) of cases (15 lateral, one anterior, three posteroseptal, and two posterolateral) and right sided in 55% (26/47; one anterior, three anterolateral, one posterolateral, three lateral, five para-Hisian, 12 posteroseptal, and one anteroseptal). Ablation without the use of fluoroscopy was successfully performed in every patient (33 with RF and in 11 with cryoenergy). No complication occurred. At a mean follow-up of 16.0 ± 11.7 months, we observed seven recurrences, three of them successfully re-ablated without fluoroscopy. In one case cryoablation of a para-Hisian AP was ineffective in the long term. CONCLUSIONS: Three-dimensional EAM allowed a safe and effective fluoroless AP ablation procedure in a pediatric population both with RF and cryoenergy.

Permanent cardiac pacing in children: choosing the optimal pacing site: a multicenter study.

BACKGROUND: We evaluated the effects of the site of ventricular pacing on left ventricular (LV) synchrony and function in children requiring permanent pacing. METHODS AND RESULTS: One hundred seventy-eight children (aged <18 years) from 21 centers with atrioventricular block and a structurally normal heart undergoing permanent pacing were studied cross-sectionally. Median age at evaluation was 11.2 (interquartile range, 6.3-15.0) years. Median pacing duration was 5.4 (interquartile range, 3.1-8.8) years. Pacing sites were the free wall of the right ventricular (RV) outflow tract (n=8), lateral RV (n=44), RV apex (n=61), RV septum (n=29), LV apex (n=12), LV midlateral wall (n=17), and LV base (n=7). LV synchrony, pump function, and contraction efficiency were significantly affected by pacing site and were superior in children paced at the LV apex/LV midlateral wall. LV dyssynchrony correlated inversely with LV ejection fraction (R=0.80, P=0.031). Pacing from the RV outflow tract/lateral RV predicted significantly decreased LV function (LV ejection fraction <45%; odds ratio, 10.72; confidence interval, 2.07-55.60; P=0.005), whereas LV apex/LV midlateral wall pacing was associated with preserved LV function (LV ejection fraction ≥55%; odds ratio, 8.26; confidence interval, 1.46-47.62; P=0.018). Presence of maternal autoantibodies, gender, age at implantation, duration of pacing, DDD mode, and QRS duration had no significant impact on LV ejection fraction. CONCLUSIONS: The site of ventricular pacing has a major impact on LV mechanical synchrony, efficiency, and pump function in children who require lifelong pacing. Of the sites studied, LV apex/LV midlateral wall pacing has the greatest potential to prevent pacing-induced reduction of cardiac pump function.

New Guidelines of Pediatric Cardiac Implantable Electronic Devices: What Is Changing in Clinical Practice?

Guidelines are important tools to guide the diagnosis and treatment of patients to improve the decision-making process of health professionals. They are periodically updated according to new evidence. Four new Guidelines in 2021, 2022 and 2023 referred to pediatric pacing and defibrillation. There are some relevant changes in permanent pacing. In patients with atrioventricular block, the heart rate limit in which pacemaker implantation is recommended was decreased to reduce too-early device implantation. However, it was underlined that the heart rate criterion is not absolute, as signs or symptoms of hemodynamically not tolerated bradycardia may even occur at higher rates. In sinus node dysfunction, symptomatic bradycardia is the most relevant recommendation for pacing. Physiological pacing is increasingly used and recommended when the amount of ventricular pacing is presumed to be high. New recommendations suggest that loop recorders may guide the management of inherited arrhythmia syndromes and may be useful for severe but not frequent palpitations. Regarding defibrillator implantation, the main changes are in primary prevention recommendations. In hypertrophic cardiomyopathy, pediatric risk calculators have been included in the Guidelines. In dilated cardiomyopathy, due to the rarity of sudden cardiac death in pediatric age, low ejection fraction criteria were demoted to class II. In long QT syndrome, new criteria included severely prolonged QTc with different limits according to genotype, and some specific mutations. In arrhythmogenic cardiomyopathy, hemodynamically tolerated ventricular tachycardia and arrhythmic syncope were downgraded to class II recommendation. In conclusion, these new Guidelines aim to assess all aspects of cardiac implantable electronic devices and improve treatment strategies.

Single center experience of fluoroless AVNRT ablation guided by electroanatomic reconstruction in children and adolescents.

BACKGROUND: Anatomical considerations and risks related to x-ray exposure make atrioventricular nodal reentrant tachycardia (AVNRT) ablation in pediatric patients a concerning procedure. We aimed to evaluate the feasibility, safety, and efficacy of performing fluoroless slow-pathway cryoablation guided by the electroanatomic (EA) mapping in children and adolescents. METHODS: Twenty-one consecutive patients (mean age 13.5 ± 2.4 years) symptomatic for AVNRT were prospectively enrolled to right atrium EA mapping and electrophysiological study prior to cryoablation. Cryoablation was guided by slow-pathway potential and performed using a 4-mm-tip catheter. RESULTS: Sustained slow-fast AVNRT was inducible in all the patients with a dual AV nodal physiology in 95%. Acute success was achieved in 100% of the patients with a median of two cryo-applications. Fluoroless ablation was feasible in 19 patients, while in two subjects 50 seconds and 45 seconds of x-ray were needed due to difficult progression of the catheters along the venous system. After a mean follow-up of 25 months, AVNRT recurred in five patients. All the recurrences were successfully treated with a second procedure. In three patients, a fluoroless cryoablation with a 6-mm-tip catheter was successfully performed, while in the remaining two patients, a single pulse of 60 seconds of radiofrequency energy was applied under fluoroscopic monitoring. No complications occurred. CONCLUSIONS: Combination of EA mapping systems and cryoablation may allow to perform fluoroless slow-pathway ablation for AVNRT in children and adolescents in the majority of patients. Fluoroless slow-pathway cryoablation showed a high efficacy and safety comparable to conventional fluoroscopy guided procedures.

Interventional catheterization after total cavopulmonary connection: experience in 68 patients.

BACKGROUND: Total cavopulmonary connection (TCPC) is performed in patients having a single ventricle to allow the passive flow of systemic venous blood to the lungs. Interventional catheterization is needed to treat residual defects or complications. AIMS: We discuss our results concerning 68 patients who had had TCPC from January 1995 to December 2010. METHODS: Initial and follow-up catheterization data were reviewed retrospectively. Mid-term results were evaluated by means of angiography and/or CT scan. RESULTS: Mean age at TCPC was 5 years (2.5-18); mean interval between TCPC and catheterization was 5.6 years (1.5-15). Sixty-nine catheterizations were performed in 53 patients. Eleven patients (21%) had low venous pressure, did not display a right-to-left shunt, and did not need any intervention. Fifteen patients (28%) had low venous pressure and only needed the closure of the fenestration. The remaining 27 patients (51%) needed the following interventions: embolization of venous vessels prompting right-to-left shunt (n = 15), stenting or reconnection of pulmonary arteries (n = 5), stenting or recanalization of systemic veins (n = 11), other procedures (n = 5). In 3 patients the fenestration could not be closed due to high venous pressure. After the interventions oxygen saturation increased from 90.5%± 4.8% to 94.7% ± 3.6% (P = 0.002). CONCLUSIONS: Our data show that 49% of patients with TCPC are in good condition late after surgery. However, half of these patients continue to need interventions generally aimed at suppressing stenoses at various levels of TCPC or at occluding vessels prompting right-to-left shunt. This population should enter a multicenter program aimed at identifying patients at risk.

Selective site pacing in paediatric patients: how to recreate a new loop in the right atrium to follow body growth.

In children, intracardiac loops are created to avoid a lead's fracture due to rapid body growth. Selective site pacing needs the insertion of two 4.1 Fr lumenless leads that do not allow direct manoeuvrability and should be extracted when tension on the lead occurs. We describe an easy, safe, and inexpensive technique to reposition the leads and generate new intracardiac loops.

Prevalence of the congenital long-QT syndrome.

BACKGROUND: The prevalence of genetic arrhythmogenic diseases is unknown. For the long-QT syndrome (LQTS), figures ranging from 1:20 000 to 1:5000 were published, but none was based on actual data. Our objective was to define the prevalence of LQTS. METHODS AND RESULTS: In 18 maternity hospitals, an ECG was performed in 44 596 infants 15 to 25 days old (43 080 whites). In infants with a corrected QT interval (QTc) >450 ms, the ECG was repeated within 1 to 2 weeks. Genetic analysis, by screening 7 LQTS genes, was performed in 28 of 31 (90%) and in 14 of 28 infants (50%) with, respectively, a QTc >470 ms or between 461 and 470 ms. A QTc of 451 to 460, 461 to 470, and >470 ms was observed in 177 (0.41%), 28 (0.06%), and 31 infants (0.07%). Among genotyped infants, disease-causing mutations were found in 12 of 28 (43%) with a QTc >470 ms and in 4 of 14 (29%) with a QTc of 461 to 470 ms. One genotype-negative infant (QTc 482 ms) was diagnosed as affected by LQTS on clinical grounds. Among family members of genotype-positive infants, 51% were found to carry disease-causing mutations. In total, 17 of 43 080 white infants were affected by LQTS, demonstrating a prevalence of at least 1:2534 apparently healthy live births (95% confidence interval, 1:1583 to 1:4350). CONCLUSIONS: This study provides the first data-based estimate of the prevalence of LQTS among whites. On the basis of the nongenotyped infants with QTc between 451 and 470 ms, we advance the hypothesis that this prevalence might be close to 1:2000. ECG-guided molecular screening can identify most infants affected by LQTS and unmask affected relatives, thus allowing effective preventive measures.

Selective-site pacing in paediatric patients: use of the SelectSecure System and risk of vein occlusion.

AIMS: Few data are available about selective-site pacing in children. A 4.1 Fr lead is now available: it has to be introduced through an 8.4 Fr steerable catheter, and it raises concerns as to the long-term patency of the subclavian vein. The aim of this study was to systematically evaluate the patency of the subclavian vein in children who had selective-site pacing by the SelectSecure Lead System (SSLS) for atrioventricular block and look for possible local early and late complications. METHODS AND RESULTS: From June 2006 to January 2010, we implanted 20 patients. Mean age at implantation was 9 years (range 3-16), mean weight 31 kg (range 13-57). All patients received a dual-chamber pacemaker (PM). The patency of the subclavian vein was evaluated by ultrasound 1, 3, and every 6 months after the PM implantation. We also looked for oedema, swelling, changes in temperature or colour of the skin, and visible superficial circulation. Forty leads were implanted in 20 patients. After a median follow-up of 19 months (range 6-44), no clinical signs or symptoms of vein occlusion were detected in the whole population. None of the patients had an alteration of blood flow at Doppler examination. CONCLUSION: The SSLS is a promising and safe system for permanent intracardiac pacing in paediatric patients. We show that it does not increase the risk of venous thrombosis. Until a venography study with a larger population and longer follow-up regarding venous patency and overall complications using SSLS will be performed, our results although promising have to be considered preliminary data.

Gram-positive occult bacteremia in patients with pacemaker and mechanical valve prosthesis: a difficult therapeutic challenge.

AIMS: In pacemaker patients with Gram-positive occult bacteremia, it is reasonable to remove the whole stimulation system, but therapeutic decision is sometimes very challenging. METHODS AND RESULTS: A young patient at 6 years of age underwent dual-chamber pacemaker implantation due to complete atrioventricular block after mitral valve replacement. He felt well until November 2008, when he suffered from febrile illness with blood cultures disclosing methicillin-resistant staphylococcus aureus strain. Repeated antibiotic courses were effective only in obtaining temporary remissions. Consecutive transoesophageal echocardiography examinations were inconclusive. A labelled leucocyte scintigraphy, showing increased captation along leads, was very helpful and critical in guiding our decision to extract leads. CONCLUSION: In equivocal cases, or when the hazard of extraction procedure is presumably high, every accessory diagnostic tool (like scintigraphy with labelled leucocytes) is helpful in establishing a definitive diagnosis and in strengthening a somewhat difficult decision.

Selective-site pacing in paediatric patients: a new application of the Select Secure system.

AIMS: The aim of this study was to evaluate the feasibility and reliability of selective-site pacing by means of a new lead system in a paediatric population. This lead system is composed of a 4.1 Fr, active-fixation lead and a steerable catheter that allows easy positioning in selective sites. METHODS AND RESULTS: Thirty young patients (mean age 9.0 +/- 4.5 years, range 2-16 years) received a single- (10) or dual- (20) chamber pacemaker. The 3830 lead was implanted successfully in the targeted chambers in all patients. The selective RV sites of pacing in 26 of the patients were: 18 mid-septum, 5 outflow tract, 1 low-septum, and 2 LEVO-RV-Apex. In all patients, an intracardiac loop was left in order to avoid stretching of the lead with growth. Mean follow-up duration was 11 +/- 10 months. Atrial sensing and pacing thresholds were 3.2 +/- 1.7 mV and 0.8 +/- 0.6 V at 0.5 ms at implantation and 3.4 +/- 2.1 mV and 0.6 +/- 0.3 V at 0.5 ms at follow-up. Ventricular sensing and pacing thresholds were 12.1 +/- 4.9 and 0.7 +/- 0.4 V at 0.5 ms on implantation and 12.7 +/- 6.1 mV and 0.8 +/- 0.5 V at 0.5 ms at follow-up (P = NS). No adverse events were reported. CONCLUSION: Select Secure is a promising system for selective-site pacing in children.

Interventional catheterisation of stenotic or occluded systemic veins in children with or without congenital heart diseases: early results and intermediate follow-up.

AIMS: Limited data exists on midterm results concerning paediatric interventions on stenotic or occluded systemic veins following indwelling lines, cardiac surgery, or catheterisations. The purpose of this study was to report our acute and intermediate results concerning patients with (Group A) and without (Group B) congenital heart diseases (CHD) over a 10-year period. METHODS AND RESULTS: From January 2000 to December 2010, 32 patients (23 in Group A and nine in Group B, respectively) underwent 39 interventional catheterisations aimed to dilate or recanalise occluded iliofemoral veins, inferior or superior venae cavae. Initial and follow-up catheterisation data were reviewed retrospectively. Midterm results were evaluated by means of echography, angiography, and CT scan in all 15 and 17 patients, respectively. Median age and weight of all patients at catheterisation were five years (range 0.1-18) and 15 kg (range 2-60), respectively. Fifty-two stents were implanted in 29 patients (32 vessels). In 25 patients 28 vessels were occluded and required recanalisation. There were no major complications. In all but three patients it was possible to treat the lesion. There were two procedural complications (5.1%): one acute stent occlusion and one local dissection. At a median follow-up of 2.5 years (range 1-10) we observed six complications of stenting (11.5%): two fractures, two occlusions and two restenoses. CONCLUSIONS: Interventional catheterisation of stenotic or occluded systemic veins grants good immediate results at a low rate of complication. Stent dilatation or recanalisation may open the vessel for use during future procedures. However, long-term results are yet to be established.

Impact of the permanent ventricular pacing site on left ventricular function in children: a retrospective multicentre survey.

BACKGROUND: Chronic right ventricular (RV) pacing is associated with deleterious effects on cardiac function. OBJECTIVE: In an observational multicentre study in children with isolated atrioventricular (AV) block receiving chronic ventricular pacing, the importance of the ventricular pacing site on left ventricular (LV) function was investigated. METHODS: Demographics, maternal autoantibody status and echocardiographic measurements on LV end-diastolic and end-systolic dimensions and volumes at age <18 years were retrospectively collected from patients undergoing chronic ventricular pacing (>1 year) for isolated AV block. LV fractional shortening (LVFS) and, if possible LV ejection fraction (LVEF) were calculated. Linear regression analyses were adjusted for patient characteristics. RESULTS: From 27 centres, 297 children were included, in whom pacing was applied at the RV epicardium (RVepi, n = 147), RV endocardium (RVendo, n = 113) or LV epicardium (LVepi, n = 37). LVFS was significantly affected by pacing site (p = 0.001), and not by maternal autoantibody status (p = 0.266). LVFS in LVepi (39 ± 5%) was significantly higher than in RVendo (33 ± 7%, p < 0.001) and RVepi (35 ± 8%, p = 0.001; no significant difference between RV-paced groups, p = 0.275). Subnormal LVFS (LVFS < 28%) was seen in 16/113 (14%) RVendo-paced and 21/147 (14%) RVepi-paced children, while LVFS was normal (LVFS ≥ 28%) in all LVepi-paced children (p = 0.049). These results are supported by the findings for LVEF (n = 122): LVEF was <50% in 17/69 (25%) RVendo- and in 10/35 (29%) RVepi-paced patients, while LVEF was ≥ 50% in 17/18 (94%) LVepi-paced patients. CONCLUSION: In children with isolated AV block, permanent ventricular pacing site is an important determinant of LV function, with LVFS being significantly higher with LV pacing than with RV pacing.

Cryoenergy catheter ablation: a new technique for treatment of permanent junctional reciprocating tachycardia in children.

INTRODUCTION: Permanent junctional reciprocating tachycardia (PJRT) is an infrequent form of reciprocating tachycardia, almost incessant from childhood and usually refractory to drug therapy. Radiofrequency catheter ablation currently is the first-line therapy for PJRT, but its application in the septal region may be associated with complications. In contrast, cryoenergy has several advantages, such as the ability to test the effects of ablation while the lesion is still forming, thus reducing the number of ineffective, useless, and potentially harmful lesions. The aim of this study was to investigate the potential clinical utility of percutaneous cryoenergy catheter ablation for treatment of pediatric patients with PJRT. METHODS AND RESULTS: Four patients (age 14 +/- 5 years; mean +/- SD) with a clinical diagnosis of PJRT underwent catheter cryoablation. The ablation was successfully accomplished in 4 (100%) of 4 patients. The mean +/- SD number of cryoapplications was 1.8 +/- 0.8, and from 1 to 6 cryomappings were performed for each permanent cryolesion. The successful site was in the mid-septal region (2 patients), at the coronary sinus orifice (1 patient), and in the middle cardiac vein (1 patient). No complications with cryoablation were reported, nor was there prolongation of the AH interval during cryomapping or cryoablation. No pain was reported by patients during the cryoenergy catheter ablation procedure. PJRT recurrence occurred in 1 patient who underwent a second successful cryoablation procedure. CONCLUSION: The outcomes of cryoenergy catheter ablation in these 4 patients treated for PJRT suggest that cryoablation is a safe, effective, and pain-free technique for treating pediatric patients with PJRT.