Novel variants in TECRL leading to catecholaminergic polymorphic ventricular tachycardia.

Pathogenic and likely pathogenic variants in the TECRL gene are known to be associated with recessive catecholaminergic polymorphic ventricular tachycardia 3, which can include prolonged QT intervals (MIM#614021). We report a case of cardiac arrest in a previously healthy adolescent male in the community. The patient was found to have a novel maternally inherited likely pathogenic variant in TECRL (c.915T>G [p.Tyr305Ter]) and an additional 19-kb duplication encompassing multiple exons of TECRL (chr4:65165944-65185287, dup [4q13.1]) not identified in the mother. Genetic results were revealed via rapid whole-genome sequencing, which allowed appropriate treatment and prognostication.

Unmasking quantum effects in the surface thermodynamics of fluid nanodrops.

The focus of our study is an in-depth investigation of the quantum effects associated with the surface tension and other thermodynamic properties of nanoscopic liquid drops. The behavior of drops of quantum Lennard-Jones fluids is investigated with path-integral Monte Carlo simulations, and the test-area method is used to determine the surface tension of the spherical vapor-liquid interface. As the thermal de Broglie wavelength, λB, becomes more significant, the average density of the liquid drop decreases, with the drop becoming mechanically unstable at large wavelengths. As a consequence, the surface tension is found to decrease monotonically with λB, vanishing altogether for dominant quantum interactions. Quantum effects can be significant, leading to values that are notably lower than the classical thermodynamic limit, particularly for smaller drops. For planar interfaces (with infinite periodicity in the direction parallel to the interface), quantum effects are much less significant with the same values of λB but are, nevertheless, consequential for values representative of hydrogen or helium-4 at low temperatures corresponding to vapor-liquid coexistence. Large quantum effects are found for small drops of molecules with quantum interactions corresponding to water, ethane, methanol, and carbon dioxide, even at ambient conditions. The notable decrease in the density and tension has important consequences in reducing the Gibbs free-energy barrier of a nucleating cluster, enhancing the nucleation kinetics of liquid drops and of bubble formation. This implies that drops would form at a much greater rate than is predicted by classical nucleation theory.

Pharmacological Management of Cardiac Arrhythmias in the Fetal and Neonatal Periods: A Scientific Statement From the American Heart Association: Endorsed by the Pediatric & Congenital Electrophysiology Society (PACES).

Disorders of the cardiac rhythm may occur in both the fetus and neonate. Because of the immature myocardium, the hemodynamic consequences of either bradyarrhythmias or tachyarrhythmias may be far more significant than in mature physiological states. Treatment options are limited in the fetus and neonate because of limited vascular access, patient size, and the significant risk/benefit ratio of any intervention. In addition, exposure of the fetus or neonate to either persistent arrhythmias or antiarrhythmic medications may have yet-to-be-determined long-term developmental consequences. This scientific statement discusses the mechanism of arrhythmias, pharmacological treatment options, and distinct aspects of pharmacokinetics for the fetus and neonate. From the available current data, subjects of apparent consistency/consensus are presented, as well as future directions for research in terms of aspects of care for which evidence has not been established.

Transcatheter Leadless Pacing in Children: A PACES Collaborative Study in the Real-World Setting.

BACKGROUND: Transcatheter Leadless Pacemakers (TLP) are a safe and effective option for adults with pacing indications. These devices may be an alternative in pediatric patients and patients with congenital heart disease for whom repeated sternotomies, thoracotomies, or transvenous systems are unfavorable. However, exemption of children from clinical trials has created uncertainty over the indications, efficacy, and safety of TLP in the pediatric population. The objectives of this study are to evaluate clinical indications, procedural characteristics, electrical performance, and outcomes of TLP implantation in children. METHODS: Retrospective data were collected from patients enrolled in the Pediatric and Congenital Electrophysiology Society TLP registry involving 15 centers. Patients ≤21 years of age who underwent Micra (Medtronic Inc, Minneapolis, MN) TLP implantation and had follow-up of ≥1 week were included in the study. RESULTS: The device was successfully implanted in 62 of 63 registry patients (98%) at a mean age of 15±4.1 years and included 20 (32%) patients with congenital heart disease. The mean body weight at TLP implantation was 55±19 kg and included 8 patients ≤8 years of age and ≤30 kg in weight. TLP was implanted by femoral (n=55, 87%) and internal jugular (n=8, 12.6%) venous approaches. During a mean follow-up period of 9.5±5.3 months, there were 10 (16%) complications including one cardiac perforation/pericardial effusion, one nonocclusive femoral venous thrombus, and one retrieval and replacement of TLP due to high thresholds. There were no deaths, TLP infections, or device embolizations. Electrical parameters, including capture thresholds, R wave sensing, and pacing impedances, remained stable. CONCLUSIONS: Initial results from the Pediatric and Congenital Electrophysiology Society TLP registry demonstrated a high level of successful Micra device implants via femoral and internal venous jugular approaches with stable electrical parameters and infrequent major complications. Long-term prospective data are needed to confirm the reproducibility of these initial findings.

Essentials of Paroxysmal Supraventricular Tachycardia for the Pediatrician.

Paroxysmal supraventricular tachycardia (SVT) is the most common clinical arrhythmia in young patients. With an estimated prevalence of roughly 1 in 500 children, a pediatrician may knowingly or unknowingly see several patients who are affected each year. SVT symptoms can sometimes be vague or conflated with common pediatric complaints. Different forms of SVT are predominant at different ages, sometimes complicating timely recognition and referral. Differing pathophysiology and age distribution impact risk of complications such as heart failure, or rarely, sudden death. Treatment choices continue to evolve as new medications, monitoring devices, and ablation technologies continue to mature. This review focuses on the most common types of paroxysmal SVT: atrioventricular nodal reentrant tachycardia, atrioventricular reciprocating tachycardia, and Wolff-Parkinson White syndrome. Atrial arrhythmia mechanisms are also briefly outlined. It is meant to provide practical guidelines for the diagnosis and management of patients with SVT from infancy through adolescence. [Pediatr Ann. 2021;50(3):e113-e120.].

Antiarrhythmic Treatment Duration and Tachycardia Recurrence in Infants with Supraventricular Tachycardia.

We sought to assess the effect of a shorter medication treatment course (up to 4-6 months of age) on the recurrence of infantile supraventricular tachycardia (SVT). This was a retrospective review of infants with SVT diagnosed at age 0-12 months at Rady Children's Hospital (2010-2017). Infants with structural congenital heart disease, automatic tachycardias, atrial flutter, or lack of follow-up data were excluded. Seventy-four infants met criteria. Median age at diagnosis was 6 days (IQR 0-21 days); 28.4% presented with fetal tachycardia. Median gestational age was 38.4 weeks (IQR 36-40), 30% were preterm. Median age at medication discontinuation was 6.7 months (IQR 4.6-9.8). Therapy was stopped at younger age in patients managed by pediatric electrophysiologist (vs. general pediatric cardiologist): 4.9 vs. 8.6 months (p = 0.03). Thirty-eight patients (51.4%) were treated for < 6 months; 32.4% for 6-12 months, and 16.2% for > 12 months. SVT recurrence was similar for these groups: 13.2% vs. 16.7%, and 33.3%, respectively, (p = 0.27). Most patients with recurrence required emergency care, though none had significant adverse outcomes. Infants with SVT and structurally normal cardiac anatomy, who remain recurrence free on a single agent, have no increased risk of recurrence with shorter treatment courses of 4-6 months, compared to traditional treatment duration of 6-12 months.

Transjugular liver biopsy for Fontan associated liver disease surveillance: Technique, outcomes and hemodynamic correlation.

BACKGROUND: Fontan associated liver disease (FALD) is attributed to the limitations of the Fontan circulation, resulting in congestive hepatopathy. The technique and outcomes of transjugular liver biopsies (TJLB) in Fontan patients warrant definition as part of a rigorous FALD surveillance program. METHOD: Four year review of patients with Fontan physiology who underwent a TJLB during surveillance catheterizations. Biopsy site, technique, histology, angiography, hemodynamics, and complications were reviewed to assess correlation of biopsy scores with simultaneously obtained catheterization hemodynamics. RESULTS: 125 patients with a TJLB from 10/1/14 to 5/1/18. Median age 17 years (2-50.5). Technical success 100% (125/125), all samples diagnostic. 17% (21) accessed via the left internal jugular vein, secondary to right IJ occlusion or Heterotaxy syndrome. No patients had superior compartment obstruction preventing transjugular approach. 3.2% complication rate (4/125). Complications were early in the experience, including capsular perforation (2), renal hematoma (1) and hemobilia (1), all without long-term effect and all avoidable. After standardized entry/exit angiography was adopted, no further complications noted. There is a significant correlation between the newly described modified Ishak congestive hepatic fibrosis (ICHF) score with mean Fontan pressure, time from Fontan and cardiac index. CONCLUSIONS: TJLB is an alternate method for obtaining critical FALD surveillance data, with lower complication rates that traditional techniques. Vascular anomalies in Fontan physiology appear common and warrant pre-biopsy assessment. There is a significant correlation between biopsy score, time from Fontan, mean Fontan pressure and cardiac index.

Intravenous Sotalol in the Young: Safe and Effective Treatment With Standardized Protocols.

OBJECTIVES: This study assessed the safety and efficacy of novel and standardized protocols for the use of intravenous (IV) sotalol in pediatric patients. BACKGROUND: Acute arrhythmia treatments in children remain limited. IV sotalol is a new option but pediatric experience is limited. There is no standardized protocol for rapid infusion during acute arrhythmias. This study assessed a single center's initial experience with IV sotalol in young patients, describing a protocol for rapid infusion for acute treatment, and reviewed the safety and efficacy of maintenance dosing. METHODS: This is a retrospective study of all patients who received IV sotalol at Rady Children's Hospital. Demographics, arrhythmia, hemodynamics, and effects of IV sotalol were assessed. RESULTS: Thirty-seven patients received IV sotalol from December 2015 to December 2018. Group 1 (n = 26) received sotalol for acute therapy and group 2 (n = 11) received a maintenance dose of sotalol after successful cardioversion with alternate therapies. The groups had similar demographics. Group 1 included patients with atrial flutter (n = 16), patients with supraventricular tachycardia (SVT) (n = 9), and patients with atrial ectopic tachycardia (AET) (n = 1). All 9 patients with SVT (100%) converted to sinus rhythm after failure to convert using adenosine. Median administration time was 15 min, the median dose was 30 mg/m2, and mean time to cardioversion was 14 min. Group 2 median infusion time was 120 min, the median dose was 54 mg/m2/day, and all patients maintained sinus rhythm. No patients required cessation for adverse effects previously described for IV sotalol. CONCLUSIONS: IV sotalol was safe and effective for acute and maintenance therapy in young patients. In acute patients, 30 mg/m2 over 15 min converted most patients. IV sotalol adds a valuable option to IV therapies in the young.

Model-Free Rheo-AFM Probes the Viscoelasticity of Tunable DNA Soft Colloids.

Atomic force microscopy rheological measurements (Rheo-AFM) of the linear viscoelastic properties of single, charged colloids having a star-like architecture with a hard core and an extended, deformable double-stranded DNA (dsDNA) corona dispersed in aqueous saline solutions are reported. This is achieved by analyzing indentation and relaxation experiments performed on individual colloidal particles by means of a novel model-free Fourier transform method that allows a direct evaluation of the frequency-dependent linear viscoelastic moduli of the system under investigation. The method provides results that are consistent with those obtained via a conventional fitting procedure of the force-relaxation curves based on a modified Maxwell model. The outcomes show a pronounced softening of the dsDNA colloids, which is described by an exponential decay of both the Young's and the storage modulus as a function of the salt concentration within the dispersing medium. The strong softening is related to a critical reduction of the size of the dsDNA corona, down to ≈70% of its size in a salt-free solution. This can be correlated to significant topological changes of the dense star-like polyelectrolyte forming the corona, which are induced by variations in the density profile of the counterions. Similarly, a significant reduction of the stiffness is obtained by increasing the length of the dsDNA chains, which we attribute to a reduction of the DNA density in the outer region of the corona.

Non-anastomotic failure of woven Dacron tube grafts in the thoracic aorta in young adults.

BACKGROUND: Dacron tube grafts have been used in the surgical management of cardiovascular disease since the 1970s. Complications at the site of the anastomosis have been well described. Non-anastomotic failure is far less common. We present a series of four patients who presented with complications of non-anastomotic failure of woven Dacron tube grafts. METHODS: A retrospective chart review of four patients who presented to our institution between March 2014 and March 2017 with clinical complications of a Dacron tube graft was conducted. RESULTS: All four patients underwent a staged surgical repair for an interrupted aortic arch between the years of 1988 and 2001. All four patients underwent revision of their original interposition graft (Gore-Tex, W.L. Gore & Associates, Flagstaff, AZ) with implantation of a Hemashield woven Dacron tube graft (Maquet, Rastatt, Germany). From 13 to 22 years postimplant of the Dacron tube graft, all patients presented with symptoms or clinical evidence of primary graft failure. Two patients underwent urgent surgical intervention and did not survive. One patient underwent attempted surgical intervention, which was aborted in the setting of profuse bleeding, and ultimately had an endovascular rescue of the tube graft with a Zenith Alpha endograft (Cook Medical, Bloomington, IN). One patient underwent elective endovascular intervention prior to onset of symptoms. CONCLUSION: Non-anastomotic failure of woven Dacron tube grafts can occur in the thoracic aorta in young adults and may be managed with endovascular techniques.

Pulmonary reinterventions after complete unifocalization and repair in infants and young children with tetralogy of Fallot with major aortopulmonary collaterals.

BACKGROUND: Our institutional approach to tetralogy of Fallot (TOF) with major aortopulmonary collaterals (MAPCAs) emphasizes unifocalization and augmentation of the reconstructed pulmonary arterial (PA) circulation and complete intracardiac repair in infancy, usually in a single procedure. This approach yields a high rate of complete repair with excellent survival and low right ventricular (RV) pressure. However, little is known about remodeling of the unifocalized and reconstructed pulmonary circulation or about reinterventions on the reconstructed PAs or the RV outflow tract conduit. METHODS: We reviewed patients who underwent complete repair of TOF with MAPCAs at our center at <2 years of age, either as a single-stage procedure or after previous procedures. Outcomes included freedom from conduit or PA intervention after repair, which were assessed by Cox regression and Kaplan-Meier analysis. RESULTS: The study cohort included 272 patients. There were 6 early deaths and a median of follow-up of 3.6 years after complete repair. Reinterventions on the pulmonary circulation were performed in 134 patients, including conduit interventions in 101 patients, branch PA interventions in 101, and closure of residual MAPCAs in 9. The first conduit reintervention consisted of surgical conduit replacement in 77 patients, transcatheter pulmonary valve replacement with a Melody valve in 14, and angioplasty or bare metal stenting in 10. Surgical PA reinterventions were performed in 46 patients and transcatheter reinterventions in 75 (both in 20). Most PA reinterventions involved a single lung, and most transcatheter reinterventions a single vessel. Freedom from conduit replacement or transcatheter pulmonary valve replacement was 70 ± 3% at 5 years and was shorter in patients with smaller initial conduit size. Freedom from any PA reintervention was 64 ± 3% at 5 years, with the greatest rate during the first year. On multivariable analysis, factors associated with longer freedom from any PA reintervention included lower postrepair RV:aortic pressure ratio and larger original conduit size. CONCLUSIONS: We were able to obtain follow-up data for the majority of patients, which demonstrated freedom from PA reintervention for two thirds of patients. The time course of and risk factors for conduit reintervention in this cohort appeared similar to previously reported findings in patients who received RV-PA conduits in early childhood for other anomalies. Relative to the severity of baseline pulmonary vascular anatomy in TOF with MAPCAs, reinterventions on the reconstructed PAs were uncommon after repair according to our approach, and major reinterventions were rare. Nevertheless, PA reinterventions are an important aspect of the overall management strategy.

Programmatic Approach to Management of Tetralogy of Fallot With Major Aortopulmonary Collateral Arteries: A 15-Year Experience With 458 Patients.

BACKGROUND: Tetralogy of Fallot with major aortopulmonary collateral arteries is a complex and heterogeneous condition. Our institutional approach to this lesion emphasizes early complete repair with the incorporation of all lung segments and extensive lobar and segmental pulmonary artery reconstruction. METHODS AND RESULTS: We reviewed all patients who underwent surgical intervention for tetralogy of Fallot and major aortopulmonary collateral arteries at Lucile Packard Children's Hospital Stanford (LPCHS) since November 2001. A total of 458 patients underwent surgery, 291 (64%) of whom underwent their initial procedure at LPCHS. Patients were followed for a median of 2.7 years (mean 4.3 years) after the first LPCHS surgery, with an estimated survival of 85% at 5 years after first surgical intervention. Factors associated with worse survival included first LPCHS surgery type other than complete repair and Alagille syndrome. Of the overall cohort, 402 patients achieved complete unifocalization and repair, either as a single-stage procedure (n=186), after initial palliation at our center (n=74), or after surgery elsewhere followed by repair/revision at LPCHS (n=142). The median right ventricle:aortic pressure ratio after repair was 0.35. Estimated survival after repair was 92.5% at 10 years and was shorter in patients with chromosomal anomalies, older age, a greater number of collaterals unifocalized, and higher postrepair right ventricle pressure. CONCLUSIONS: Using an approach that emphasizes early complete unifocalization and repair with incorporation of all pulmonary vascular supply, we have achieved excellent results in patients with both native and previously operated tetralogy of Fallot and major aortopulmonary collateral arteries.

Rapid modification of the insect elicitor N-linolenoyl-glutamate via a lipoxygenase-mediated mechanism on Nicotiana attenuata leaves.

BACKGROUND: Some plants distinguish mechanical wounding from herbivore attack by recognizing specific constituents of larval oral secretions (OS) which are introduced into plant wounds during feeding. Fatty acid-amino acid conjugates (FACs) are major constituents of Manduca sexta OS and strong elicitors of herbivore-induced defense responses in Nicotiana attenuata plants. RESULTS: The metabolism of one of the major FACs in M. sexta OS, N-linolenoyl-glutamic acid (18:3-Glu), was analyzed on N. attenuata wounded leaf surfaces. Between 50 to 70% of the 18:3-Glu in the OS or of synthetic 18:3-Glu were metabolized within 30 seconds of application to leaf wounds. This heat-labile process did not result in free alpha-linolenic acid (18:3) and glutamate but in the biogenesis of metabolites both more and less polar than 18:3-Glu. Identification of the major modified forms of this FAC showed that they corresponded to 13-hydroxy-18:3-Glu, 13-hydroperoxy-18:3-Glu and 13-oxo-13:2-Glu. The formation of these metabolites occurred on the wounded leaf surface and it was dependent on lipoxygenase (LOX) activity; plants silenced in the expression of NaLOX2 and NaLOX3 genes showed more than 50% reduced rates of 18:3-Glu conversion and accumulated smaller amounts of the oxygenated derivatives compared to wild-type plants. Similar to 18:3-Glu, 13-oxo-13:2-Glu activated the enhanced accumulation of jasmonic acid (JA) in N. attenuata leaves whereas 13-hydroxy-18:3-Glu did not. Moreover, compared to 18:3-Glu elicitation, 13-oxo-13:2-Glu induced the differential emission of two monoterpene volatiles (beta-pinene and an unidentified monoterpene) in irlox2 plants. CONCLUSIONS: The metabolism of one of the major elicitors of herbivore-specific responses in N. attenuata plants, 18:3-Glu, results in the formation of oxidized forms of this FAC by a LOX-dependent mechanism. One of these derivatives, 13-oxo-13:2-Glu, is an active elicitor of JA biosynthesis and differential monoterpene emission.