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Abstract Background The low-density lipoprotein receptor related protein 1 (LRP1) has been implicated in Alzheimer's disease (AD) but its signalling has not been fully evaluated. There is good evidence that the cytoplasmic domain of LRP1 is involved in protein-protein interactions, important in the cell biology of LRP1. Results We carried out three yeast two-hybrid screens to identify proteins that interact with the cytoplasmic domain of LRP1. The screens included both conventional screens as well as a novel, split-ubiquitin-based screen in which an LRP1 construct was expressed and screened as a transmembrane protein. The split-ubiquitin screen was validated in a screen using full-length amyloid protein precursor (APP), which successfully identified FE65 and FE65L2, as well as novel interactors (Rab3a, Napg, and ubiquitin b). Using both a conventional screen as well as the split-ubiquitin screen, we identified NYGGF4 as a novel LRP1 interactor. The interaction between LRP1 and NYGGF4 was validated using two-hybrid assays, coprecipitation and colocalization in mammalian cells. Mutation analysis demonstrated a specific interaction of NYGGF4 with an NPXY motif that required an intact tyrosine residue. Interestingly, while we confirmed that other LRP1 interactors we identified, including JIP1B and EB-1, were also able to bind to APP, NYGGF4 was unique in that it showed specific binding with LRP1. Expression of NYGGF4 decreased significantly in patients with AD as compared to age-matched controls, and showed decreasing expression with AD disease progression. Examination of Nyggf4 expression in mice with different alleles of the human APOE4 gene showed significant differences in Nyggf4 expression. Conclusions These results implicate NYGGF4 as a novel and specific interactor of LRP1. Decreased expression of LRP1 and NYGGF4 over disease, evident with the presence of even moderate numbers of neuritic plaques, suggests that LRP1-NYGGF4 is a system altered early in disease. Genetic and functional studies have implicated both LRP1 and NYGGF4 in obesity and cardiovascular disease and the physical association of these proteins may reflect a common mechanism. This is particularly interesting in light of the dual role of ApoE in both cardiovascular risk and AD. The results support further studies on the functional relationship between NYGGF4 and LRP1.

Abstract Background Hypercholesterolemia causes atherosclerosis in medium to large sized arteries. Cholesterol is less known for affecting the microvasculature and has not been previously reported to induce microvascular pathology in the central nervous system (CNS). Results Mice with a null mutation in the low-density lipoprotein receptor (LDLR) gene as well as C57BL/6J mice fed a high cholesterol diet developed a distinct microvascular pathology in the CNS that differs from cholesterol-induced atherosclerotic disease. Microvessel diameter was increased but microvascular density and length were not consistently affected. Degenerative changes and thickened vascular basement membranes were present ultrastructurally. The observed pathology shares features with the microvascular pathology of Alzheimer's disease (AD), including the presence of string-like vessels. Brain apolipoprotein E levels which have been previously found to be elevated in LDLR-/- mice were also increased in C57BL/6J mice fed a high cholesterol diet. Conclusion In addition to its effects as an inducer of atherosclerosis in medium to large sized arteries, hypercholesterolemia also induces a microvascular pathology in the CNS that shares features of the vascular pathology found in AD. These observations suggest that high cholesterol may induce microvascular disease in a range of CNS disorders including AD.

Background Huntington's disease (HD), a neurodegenerative disorder caused by an expanded CAG repeat in the HD gene, remains without a cure. Lithium, a drug widely used for the treatment of bipolar disorder, has been shown to exert neuroprotective effects in a number of models of neurological disease, including Alzheimer's disease, spinocerebellar ataxia type 1 and fragile X syndrome but has various toxic effects at conventional therapeutic doses. Aims To examine whether treatment with NP03, a low dose lithium microemulsion, would improve the phenotype of the YAC128 mouse model of HD. Methods YAC128 mice were treated with 0, 20 or 40 μg Li/kg of lithium carbonate in the form of NP03, a microemulsion of reverse micelles, via a daily deposit on rectal mucosa for 10 months, starting at 2 months of age. The microemulsion preparation allows for an increase in cellular bioavailability of lithium. Low doses of lithium in NP03 form are sufficient to achieve the intended therapeutic levels, while mitigating the toxic side effects associated with conventional lithium preparations. Wild-type (WT) animals were treated with NP03 either at 0 or 40 μg Li/kg. Motor function was assessed using the accelerating rotarod test at 2, 4, 6, 8, 10 and 12 months of age. Striatal pathology was assessed using unbiased stereology at 12 months of age. Results Treatment with NP03 at 40 μg Li/kg resulted in significant improvements in motor function in YAC128 HD mice. Further, the deficits in striatal volume, neuronal counts and DARPP-32 expression observed in YAC128 HD animals treated with vehicle alone were prevented in YAC128 HD animals treated with NP03 at 40 μg Li/kg. The motor function, striatal volume and neuronal counts of WT animals treated with NP03 at 40 μg Li/kg were similar to those of WT animals treated with vehicle alone. Furthermore, treatment with NP03 at 40μg Li/kg resulted in significant rescue of the testicular weight loss observed in YAC128 HD. Finally, treatment with NP03 at 40 μg Li/kg resulted in improved survival in YAC128 mice compared with animals treated with vehicle alone. There were no obvious toxic side effects associated with long term lithium treatment in YAC128 or WT animals. Conclusions Our findings, demonstrating multiple positive effects of low dose lithium in the form of NP03 on behavioural and neuropathological endpoints in an animal model of HD, support its further development as a potential therapeutic agent in HD. [ABSTRACT FROM PUBLISHER]

Background The amelioration of behavioural and neuropathological deficits in mice expressing caspase 6 resistant (C6R) mutant huntingtin (mhtt), despite the presence of an expanded polyglutamine track, highlights proteolysis of htt at the 586aa caspase 6 (casp6) site as a key mechanism in the pathology of HD. In order to determine whether C6R mhtt acts as a dominant negative inhibitor of casp6 activation, we crossed C6R mice to the YAC128 HD mouse model. If the neuroprotection observed in C6R mice reflects a dominant negative effect, then similar protection and amelioration of HD related phenotypes may be expected in mice expressing both casp6 cleavable and casp6 resistant mhtt. Results Neuropathological analysis of YAC128/C6R brains reveals a significant decrease in brain weight (p<0.01) and striatal volume (p<0.01) in the YAC128/C6R mice, similar to what is observed in the YAC128 mice (brain weight p<0.05; striatal volume p<0.05). In contrast, and similar to previous findings, C6R brains demonstrated preserved brain weight and striatal volume. Furthermore, the 586aa mhtt fragment is observed in YAC128/C6R brain tissue. Behavioural testing reveals that the YAC128/C6R mice perform similar to YAC128 mice in the open field. Body weight in significantly increased in the YAC128/C6R mice compared with YAC128 due to the increased levels of htt in these mice. Conclusion These data suggest that the lack of an HD phenotype in the C6R mice is due to the absence of the 586aa mhtt fragment and provide additional evidence that the 586aa mhtt fragment plays a critical role in the pathogenesis of HD. This work supports efforts towards casp6 inhibition as a therapeutic treatment for HD. [ABSTRACT FROM PUBLISHER]

Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) may cause sudden cardiac death (SCD) despite medical therapy. Therefore, implantable cardioverter-defibrillators (ICDs) are commonly advised. However, there is limited data on the outcomes of ICD use in children., Objective: The purpose of this study was to compare the risk of arrhythmic events in pediatric patients with CPVT with and without an ICD., Methods: We compared the risk of SCD in patients with RYR2 (ryanodine receptor 2) variants and phenotype-positive symptomatic CPVT patients with and without an ICD who were younger than 19 years and had no history of sudden cardiac arrest at phenotype diagnosis. The primary outcome was SCD; secondary outcomes were composite end points of SCD, sudden cardiac arrest, or appropriate ICD shocks with or without arrhythmic syncope., Results: The study included 235 patients, 73 with an ICD (31.1%) and 162 without an ICD (68.9%). Over a median follow-up of 8.0 years (interquartile range 4.3-13.4 years), SCD occurred in 7 patients (3.0%), of whom 4 (57.1%) were noncompliant with medications and none had an ICD. Patients with ICD had a higher risk of both secondary composite outcomes (without syncope: hazard ratio 5.85; 95% confidence interval 3.40-10.09; P < .0001; with syncope: hazard ratio 2.55; 95% confidence interval 1.50-4.34; P = .0005). Thirty-one patients with ICD (42.5%) experienced appropriate shocks, 18 (24.7%) inappropriate shocks, and 21 (28.8%) device-related complications., Conclusion: SCD events occurred only in patients without an ICD and mostly in those not on optimal medical therapy. Patients with an ICD had a high risk of appropriate and inappropriate shocks, which may be reduced with appropriate device programming. Severe ICD complications were common, and risks vs benefits of ICDs need to be considered., Competing Interests: Disclosures All authors have no conflicts to disclose., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: In severely affected patients with catecholaminergic polymorphic ventricular tachycardia, beta-blockers are often insufficiently protective. The purpose of this study was to evaluate whether flecainide is associated with a lower incidence of arrhythmic events (AEs) when added to beta-blockers in a large cohort of patients with catecholaminergic polymorphic ventricular tachycardia., Methods: From 2 international registries, this multicenter case cross-over study included patients with a clinical or genetic diagnosis of catecholaminergic polymorphic ventricular tachycardia in whom flecainide was added to beta-blocker therapy. The study period was defined as the period in which background therapy (ie, beta-blocker type [beta1-selective or nonselective]), left cardiac sympathetic denervation, and implantable cardioverter defibrillator treatment status, remained unchanged within individual patients and was divided into pre-flecainide and on-flecainide periods. The primary end point was AEs, defined as sudden cardiac death, sudden cardiac arrest, appropriate implantable cardioverter defibrillator shock, and arrhythmic syncope. The association of flecainide with AE rates was assessed using a generalized linear mixed model assuming negative binomial distribution and random effects for patients., Results: A total of 247 patients (123 [50%] females; median age at start of flecainide, 18 years [interquartile range, 14-29]; median flecainide dose, 2.2 mg/kg per day [interquartile range, 1.7-3.1]) were included. At baseline, all patients used a beta-blocker, 70 (28%) had an implantable cardioverter defibrillator, and 21 (9%) had a left cardiac sympathetic denervation. During a median pre-flecainide follow-up of 2.1 years (interquartile range, 0.4-7.2), 41 patients (17%) experienced 58 AEs (annual event rate, 5.6%). During a median on-flecainide follow-up of 2.9 years (interquartile range, 1.0-6.0), 23 patients (9%) experienced 38 AEs (annual event rate, 4.0%). There were significantly fewer AEs after initiation of flecainide (incidence rate ratio, 0.55 [95% CI, 0.38-0.83]; P =0.007). Among patients who were symptomatic before diagnosis or during the pre-flecainide period (n=167), flecainide was associated with significantly fewer AEs (incidence rate ratio, 0.49 [95% CI, 0.31-0.77]; P =0.002). Among patients with ≥1 AE on beta-blocker therapy (n=41), adding flecainide was also associated with significantly fewer AEs (incidence rate ratio, 0.25 [95% CI, 0.14-0.45]; P <0.001)., Conclusions: For patients with catecholaminergic polymorphic ventricular tachycardia, adding flecainide to beta-blocker therapy was associated with a lower incidence of AEs in the overall cohort, in symptomatic patients, and particularly in patients with breakthrough AEs while on beta-blocker therapy., Competing Interests: Disclosures A.W. is a consultant for ARMGO and LQT Therapeutics. S.S. is a consultant for Cardurion. M.J.A. is a consultant for Abbott, Boston Scientific, Bristol Myers Squibb, Daiichi Sankyo, Invitae, Medtronic, Tenaya Therapeutics, and UpToDate. M.J.A. and the Mayo Clinic are involved in an equity/royalty relationship with AliveCor, Anumana, Thryv Therapeutics, and Pfizer. However, none of these entities were involved in this study. S.P.E. is a consultant for UptoDate and has a relationship with Pfizer. S.C.Y. is a consultant for Boston Scientific and has received research grants from Medtronic and Biotronik. The other authors report no conflicts.

Congenital heart disease (CHD) is linked to an increased incidence of neurodevelopmental impairments in young patients. Given the number of published studies on this topic, a synthesis of the literature is timely and needed. We performed a systematic review and meta-analysis of the medical literature to assess the evidence linking CHD to incidence of autism spectrum disorder (ASD). A systematic review of studies on CHD and ASD in PubMed, Cochrane and Institute for Scientific Information (ISI) from 1965 to May 2021 was conducted. Quantitative estimates of association between CHD and ASD were extracted from eligible studies for the meta-analysis. Pooled estimates were obtained using a random effect models fit by a generalised linear mixed model. We screened 2709 articles and 24 articles were included in this review. Among the 24 studies, there was a total of 348,771 subjects (12,114 CHD, 9829 ASD and 326,828 controls). Seven of 24 studies were eligible for the meta-analysis, which included information on a total of 250,611 subjects (3984 CHD, 9829 ASD, and 236,798 controls). The summary estimate indicated that having CHD is associated with almost double the odds of ASD compared with patients without CHD (OR 1.99, 95% CI 1.77-2.24, p < 0.01). Early developmental delay, perinatal factors, and genetics were potential risk factors and etiologies for the onset of ASD symptoms in CHD patients. Having CHD is associated with an increased risk of presenting with a diagnosis or symptoms suggestive of ASD., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Sudden cardiac death (SCD) is a rare and devastating event in children and remains a leading cause of death in young athletes. Channelopathies and cardiomyopathies, in particular long QT syndrome (LQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT), hypertrophic cardiomyopathy (HCM), and arrhythmogenic cardiomyopathy (ACM) are associated with exercise-related SCD. Implantable cardioverter-defibrillators (ICDs) are often placed for secondary prevention for athletes with cardiomyopathy or channelopathy. There remains concern regarding the safety of return to participation with an ICD in place. Guidelines have historically recommended that patients with inherited heart rhythm disorders be restricted from competitive sports participation. Increasing evidence suggests a lower risk of exercise-related cardiac events in young athletes with inherited heart rhythm disorders. In this review, we highlight current knowledge, evolving guidelines, and present a multidisciplinary approach involving shared decision-making and appropriate planning for safe sports participation of children with inherited heart rhythm disorders., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Katyal, Li, Franciosi and Sanatani.)

Background: Our objective was to examine the clinical presentation, echocardiographic findings, and outcomes of newborns presenting with left ventricle (LV) dysfunction in the first 48 hours of life without perinatal asphyxia or structural heart disease. We hypothesize that LV dysfunction may occur due to maladaptation to extrauterine life., Methods: This is a retrospective cohort analysis including infants born in a quaternary perinatal centre. Late preterm and term neonates who were diagnosed with left ventricular dysfunction at less than 48 hours of life were identified using an echocardiography clinical laboratory's database and extracorporeal life support database. LV dysfunction was defined as m-mode fractional shortening (FS) <28% or ejection fraction (EF) <50% on echocardiography or reduced function reported by a cardiologist. Data extracted included patient & maternal demographics, echocardiogram parameters, clinical status, and medications. The primary outcome measure was time to recovery of LV function based on echocardiography., Results: Of the 69 patients identified, 19 patients were included in the final analysis. The mean gestational age was 38 weeks. Thirteen (68%) infants did not have an underlying cause identified despite extensive work-up. Four (21%) infants had exposure to maternal illicit drug use during pregnancy. Three infants died, and all infants without identifiable etiologies had recovery of LV function within 14 days of life., Conclusions: LV dysfunction can occur during the abrupt transition from fetal to neonatal circulation and can be associated with maternal illicit drug use., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-22-301/coif). The authors have no conflicts of interest to declare., (2023 Translational Pediatrics. All rights reserved.)

Background: Patients after ablation for tachyarrhythmias may continue to experience palpitations in the setting of sinus rhythm. The objective of our study was to investigate if patients who have undergone ablation for tachyarrhythmia have palpitations and other somatic complaints more frequently than healthy controls., Methods: Paediatric patients after ablation for tachyarrhythmia at BC Children's Hospital from 2009 to 2020 and healthy controls were invited to participate in a survey about palpitations. Demographics, palpitation symptoms, frequency, duration, and need for medical attention were collected and compared between patients and controls., Results: We received responses from 111 patients (response rate of 27.5%; mean age = 20.0 ± 4.6 years, 52% male) and 62 controls (age = 19.8 ± 5.7 years, 40% male). Sixty-two (56%) patients experienced palpitations beyond the initial 4 weeks after ablation, of whom 77% (n = 48/62) reported their palpitations feeling different. Tachyarrhythmia recurrence rate after ablation was 7.2%. There was no difference in the prevalence of palpitations experienced between patients and controls ( P  = 0.74). Patients after ablation sought medical attention more often for their palpitations ( P  = 0.003) and chest symptoms ( P  = 0.001) compared to controls., Conclusion: The prevalence of palpitations did not differ in ablation patients compared to healthy controls. Patients reported that their palpitations felt different after ablation and were more likely to seek medical attention for their palpitations. Paediatric patients with tachyarrhythmias may have heightened awareness due to their history. Clinicians can incorporate this into procedural counselling to reduce patient concern and need for medical attention., (© 2022 Published by Elsevier Inc. on behalf of the Canadian Cardiovascular Society.)

Background: Physical activity (PA) is important for cardiovascular health as well as social and emotional well-being of children. Patients with long QT syndrome (LQTS) often face PA restrictions and are often prescribed beta-blockers for disease management. The aim of this study was to determine if PA levels were lower in patients with LQTS compared with healthy controls., Methods: Participants with LQTS from an inherited arrhythmia clinic completed the Physical Activity Questionnaire for Children and Adolescents (PAQ-C/A) and an exercise stress test. PAQ score (a general measure of PA for youth, unitless) and endurance time were compared with healthy controls., Results: Twenty-three patients with LQTS completed the PAQ and had an exercise stress test within a year of having completed the PAQ. No difference was observed in PAQ scores between LQTS and control groups (LQTS: 2.3 ± 0.15 vs controls: 2.3 ± 0.18; P  = 0.78). There was no effect of age on PA in patients with LQTS ( P > 0.05), whereas PA significantly decreased in controls with age (eg, 11-12 vs 17-20 years: 3.2 ± 0.07 vs 1.5 ± 0.08, P  = 0.005). Endurance time and heart rate at peak exercise were significantly lower in patients with LQTS compared with controls (11 ± 0.5 vs 15 ± 0.5 minutes, P < 0.0001; 169 ± 5 vs 198 ± 2 beats per minute, P < 0.0001)., Conclusions: Despite guideline recommendations restricting PA, risk of sudden cardiac death, and use of beta-blockers, our cohort of patients with LQTS reported similar PA levels as healthy controls., (© 2021 The Authors.)

Sudden cardiac arrest in the young is a rare event with a range of potential causes including cardiomyopathies, ion channelopathies, and autonomic nervous system dysfunction. Investigations into the cause involve a multidisciplinary team, including cardiologists, geneticists, and psychologists. In addition to a detailed medical history, family history and circumstances surrounding the event are important in determining the cause. Clinical investigations including an electrocardiogram are fundamental in diagnosis and should be interpreted cautiously because some children may have atypical presentations and an evolving phenotype. The potential for misdiagnosis exists that could lead to incorrect long-term management strategies. If an inherited condition is suspected, genetic testing of the patient and cascade screening of family members is recommended with genetic counselling and psychological support. Medical management is left to the treating physician acknowledging that a clear diagnosis cannot be made in approximately half of cases. Secondary prevention implantable defibrillators are widely deployed but can be associated with complications in young patients. A plan for safe return to activity is recommended along with a proper transition of care into adulthood. Broad screening of the general population for arrhythmia syndromes is not recommended; preventative measures include screening paediatric patients for risk factors by their primary care physician. Several milestone events or activities that take place in youth could be used as opportunities to promote safety. Further work into risk stratification of this paediatric population through patient registries and greater awareness of cardiopulmonary resuscitation and automated external defibrillator use in saving lives is warranted., (© 2022 The Author(s).)

Background: Congenital heart disease, the most common congenital anomaly, often presents in neonates. Because of perceived risks, health care providers may consider deferring immunizations in this population. We sought to understand the perceived risk of immunizations in those providing health care to children with particular heart conditions., Methods: A survey, which included 6 hypothetical scenarios assessing immunization recommendations, was distributed internationally to relevant health care providers, and responses were compared between the different scenarios., Results: Majority of responses (n = 142) were from paediatric cardiologists (n = 98; 69%) and nurse practitioners (n = 27; 19%) located in the United States (n = 77; 54%) or Canada (n = 53; 37%) working in academic teaching hospitals (n = 133; 93.7%). Most favoured vaccinations (n = 107; 75.4%) and less likely to proceed with the first immunization in infants with structural heart disease compared with channelopathy (risk ratio: 0.80, confidence interval: 0.73-0.87; P  < 0.001). Only 40% would proceed with immunization as normal in an infant with manifest Brugada type I electrocardiogram. Special precautions after the immunization included longer duration of observation (19%) and administering prophylactic antipyretic medication (92%)., Conclusions: Respondents were 20% more likely to defer immunizations in the presence of treatable structural heart disease as compared with channelopathy despite the lack of evidence supporting deferring immunizations in children with structural heart disease. Most were cautious in their response to the scenario involving Brugada syndrome, indicating awareness of the risk of haemodynamic instability in the event of a fever. The majority of respondents still strongly recommend immunizations in this population as the benefits outweigh the potential for adverse events., (© 2022 The Author(s).)

Background: Several medication choices are available for acute and prophylactic treatment of refractory supraventricular tachycardia (SVT) in infants. There are almost no controlled trials, and medication choices are not necessarily evidence based. Our objective was to report the effectiveness of management strategies for infant SVT., Methods: A registry of infants admitted to hospital with re-entrant SVT and no haemodynamically significant heart disease were prospectively followed at 11 international tertiary care centres. In addition, a systematic review of studies on infant re-entrant SVT in MEDLINE and EMBASE was conducted. Data on demographics, symptoms, acute and maintenance treatments, and outcomes were collected., Results: A total of 2534 infants were included: n = 108 from the registry (median age, 9 days [0-324 days], 70.8% male) and n = 2426 from the literature review (median age, 14 days; 62.3% male). Propranolol was the most prevalent acute (61.4%) and maintenance treatment (53.8%) in the Registry, whereas digoxin was used sparingly (4.0% and 3.8%, respectively). Propranolol and digoxin were used frequently in the literature acutely (31% and 33.2%) and for maintenance (17.8% and 10.1%) ( P < 0.001). No differences in acute or prophylactic effectiveness between medications were observed. Recurrence was higher in the Registry (25.0%) vs literature (13.4%) ( P  < 0.001), and 22 (0.9%) deaths were reported in the literature vs none in the Registry., Conclusion: This was the largest cohort of infants with SVT analysed to date. Digoxin monotherapy use was rare amongst contemporary paediatric cardiologists. There was limited evidence to support one medication over another. Overall, recurrence and mortality rates on antiarrhythmic treatment were low., (© 2021 The Author(s).)

Background: Symptomatic children with catecholaminergic polymorphic ventricular tachycardia (CPVT) are at risk for recurrent arrhythmic events. β-Blockers decrease this risk, but studies comparing individual β-blockers in sizeable cohorts are lacking. We aimed to assess the association between risk for arrhythmic events and type of β-blocker in a large cohort of symptomatic children with CPVT., Methods: From 2 international registries of patients with CPVT, RYR2 variant-carrying symptomatic children (defined as syncope or sudden cardiac arrest before β-blocker initiation and age at start of β-blocker therapy <18 years), treated with a β-blocker were included. Cox regression analyses with time-dependent covariates for β-blockers and potential confounders were used to assess the hazard ratio (HR). The primary outcome was the first occurrence of sudden cardiac death, sudden cardiac arrest, appropriate implantable cardioverter-defibrillator shock, or syncope. The secondary outcome was the first occurrence of any of the primary outcomes except syncope., Results: We included 329 patients (median age at diagnosis, 12 [interquartile range, 7-15] years, 35% females). Ninety-nine (30.1%) patients experienced the primary outcome and 74 (22.5%) experienced the secondary outcome during a median follow-up of 6.7 (interquartile range, 2.8-12.5) years. Two-hundred sixteen patients (66.0%) used a nonselective β-blocker (predominantly nadolol [n=140] or propranolol [n=70]) and 111 (33.7%) used a β1-selective β-blocker (predominantly atenolol [n=51], metoprolol [n=33], or bisoprolol [n=19]) as initial β-blocker. Baseline characteristics did not differ. The HRs for both the primary and secondary outcomes were higher for β1-selective compared with nonselective β-blockers (HR, 2.04 [95% CI, 1.31-3.17]; and HR, 1.99 [95% CI, 1.20-3.30], respectively). When assessed separately, the HR for the primary outcome was higher for atenolol (HR, 2.68 [95% CI, 1.44-4.99]), bisoprolol (HR, 3.24 [95% CI, 1.47-7.18]), and metoprolol (HR, 2.18 [95% CI, 1.08-4.40]) compared with nadolol, but did not differ from propranolol. The HR of the secondary outcome was only higher in atenolol compared with nadolol (HR, 2.68 [95% CI, 1.30-5.55])., Conclusions: β1-selective β-blockers were associated with a significantly higher risk for arrhythmic events in symptomatic children with CPVT compared with nonselective β-blockers, specifically nadolol. Nadolol, or propranolol if nadolol is unavailable, should be the preferred β-blocker for treating symptomatic children with CPVT.

Importance: Calcium-release deficiency syndrome (CRDS), which is caused by loss-of-function variants in cardiac ryanodine receptor 2 (RyR2), is an emerging cause of ventricular fibrillation. However, the lack of complex polymorphic/bidirectional ventricular tachyarrhythmias during exercise stress testing (EST) may distinguish it from catecholaminergic polymorphic ventricular tachycardia (CPVT). Recently, in the first clinical series describing the condition, mouse and human studies showed that the long-burst, long-pause, short-coupled ventricular extra stimulus (LBLPS) electrophysiology protocol reliably induced CRDS ventricular arrhythmias. Data from larger populations with CRDS and its associated spectrum of disease are lacking., Objective: To further insight into CRDS through international collaboration., Design, Setting, and Participants: In this multicenter observational cohort study, probands with unexplained life-threatening arrhythmic events and an ultrarare RyR2 variant were identified. Variants were expressed in HEK293 cells and subjected to caffeine stimulation to determine their functional impact. Data were collected from September 1, 2012, to March 6, 2021, and analyzed from August 9, 2015, to March 6, 2021., Main Outcomes and Measures: The functional association of RyR2 variants found in putative cases of CRDS and the associated clinical phenotype(s)., Results: Of 10 RyR2 variants found in 10 probands, 6 were loss-of-function, consistent with CRDS (p.E4451del, p.F4499C, p.V4606E, p.R4608Q, p.R4608W, and p.Q2275H) (in 4 [67%] male and 2 [33%] female probands; median age at presentation, 22 [IQR, 8-34] years). In 5 probands with a documented trigger, 3 were catecholamine driven. During EST, 3 probands with CRDS had no arrhythmias, 1 had a monomorphic couplet, and 2 could not undergo EST (deceased). Relatives of the decedents carrying the RyR2 variant did not have EST results consistent with CPVT. After screening 3 families, 13 relatives were diagnosed with CRDS, including 3 with previous arrhythmic events (23%). None had complex ventricular tachyarrhythmias during EST. Among the 19 confirmed cases with CRDS, 10 had at least 1 life-threatening event at presentation and/or during a median follow-up of 7 (IQR, 6-18) years. Two of the 3 device-detected ventricular fibrillation episodes were induced by a spontaneous LBLPS-like sequence. β-Blockers were used in 16 of 17 surviving patients (94%). Three of 16 individuals who were reportedly adherent to β-blocker therapy (19%) had breakthrough events., Conclusions and Relevance: The results of this study suggest that calcium-release deficiency syndrome due to RyR2 loss-of-function variants mechanistically and phenotypically differs from CPVT. Ventricular fibrillation may be precipitated by a spontaneous LBLPS-like sequence of ectopy; however, CRDS remains difficult to recognize clinically. These data highlight the need for better diagnostic tools and treatments for this emerging condition.

Background: Children with catecholaminergic polymorphic ventricular tachycardia (CPVT) are at risk for sudden death, and a risk stratification tool does not exist., Objective: The purpose of this study was to determine whether proband status, age at symptom onset, and/or sex are independent predictors of cardiac events., Methods: A multicenter, ambispective, cohort of pediatric CPVT patients was categorized by sex, proband status, and age at symptom onset (D1: first decade of life [symptom onset <10 years] or D2: second decade of life [symptom onset 10-18 years, inclusive]). Demographics, therapy, genetics, and outcomes were compared between groups., Results: A total of 133 patients were included and stratified into 58 D1 and 75 D2 patients (68 female and 65 male; 106 probands and 27 relatives). Localization of RYR2 variants to hotspots differed based on proband status and age at symptom onset. The cardiac event rate was 33% (n = 44/133), inclusive of a 3% (n = 4/133) mortality rate, over a median of 6 years (interquartile range 3-11) after time of symptom onset. Proband status, rather than age at of symptom onset or sex, was an independent predictor of time to first cardiac event (P = .008; hazard ratio = 4.4). The 5-, 10- and 15-year event-free survival rates for probands were 77%, 56%, and 46%, respectively, and for relatives were 96%, 91%, and 86%, respectively. Event risk after diagnosis was 48% (32/67) in patients on β-blocker or flecainide alone vs 10% (5/48) in patients on β-blocker plus flecainide and/or left cardiac sympathetic denervation (P <.001)., Conclusion: Proband status, but not age at symptom onset or male sex, independently predicted an earlier onset of cardiac events. A larger sample size would enable a comprehensive investigation of other risk factors., (Copyright © 2021 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Mitochondrial dysfunction and bioenergetics failure are common pathological hallmarks in Huntington's disease (HD) and aging. In the present study, we used the YAC128 murine model of HD to examine the effects of mutant huntingtin on mitochondrial parameters related to aging in brain and skeletal muscle. We have conducted a cross-sectional natural history study of mitochondrial DNA changes in the YAC128 mouse. Here, we first show that the mitochondrial volume fraction appears to increase in the axons and dendrite regions adjacent to the striatal neuron cell bodies in old mice. Mitochondrial DNA copy number (mtDNAcn) was used as a proxy measure for mitochondrial biogenesis and function. We observed that the mtDNAcn changes significantly with age and genotype in a tissue-specific manner. We found a positive correlation between aging and the mtDNAcn in striatum and skeletal muscle but not in cortex. Notably, the YAC128 mice had lower mtDNAcn in cortex and skeletal muscle. We further show that mtDNA deletions are present in striatal and skeletal muscle tissue in both young and aged YAC128 and WT mice. Tracking gene expression levels cross-sectionally in mice allowed us to identify contributions of age and genotype to transcriptional variance in mitochondria-related genes. These findings provide insights into the role of mitochondrial dynamics in HD pathogenesis in both brain and skeletal muscle, and suggest that mtDNAcn in skeletal muscle tissue may be a potential biomarker that should be investigated further in human HD., (© 2021. The Author(s).)

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare and potentially lethal inherited arrhythmia disease characterized by exercise or emotion-induced bidirectional or polymorphic ventricular tachyarrhythmias. The median age of disease onset is reported to be approximately 10 years of age. The majority of CPVT patients have pathogenic variants in the gene encoding the cardiac ryanodine receptor, or calsequestrin 2. These lead to mishandling of calcium in cardiomyocytes resulting in after-depolarizations, and ventricular arrhythmias. Disease severity is particularly pronounced in younger individuals who usually present with cardiac arrest and arrhythmic syncope. Risk stratification is imprecise and long-term prognosis on therapy is unknown despite decades of research focused on pediatric CPVT populations. The purpose of this review is to summarize contemporary data on pediatric CPVT, highlight knowledge gaps and present future research directions for the clinician-scientist to address.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is characterized by cardiac arrest during sudden exertion. However, standard exercise stress testing (EST) lacks sensitivity, leading to misdiagnosis and undertreatment. After a nondiagnostic standard gradual EST, we report 6 patients who underwent a novel burst exercise test characterized by sudden high workload at the outset of testing. In 5 of 6 patients, the burst EST induced new and more complex arrhythmias versus standard EST, which compelled medication initiation in 3 patients. We postulate that this simple EST modification better mimics a typical CPVT triggering event and could improve diagnostic sensitivity and therapeutic decision making., Competing Interests: Funding Support and Author Disclosures Dr. Roston is funded by the University of British Columbia Clinician Investigator Program and Friedman Scholars in Health Program and the George Mines Traveling Fellowship in Cardiac Electrophysiology. The study was supported by the Rare Disease Foundation “Innovative Therapies” Grant (to Drs. Roston, Santanani, and Krahn). Dr. Krahn has received support from the Sauder Family and Heart and Stroke Foundation Chair in Cardiology (Vancouver, British Columbia, Canada), the Paul Brunes Chair in Heart Rhythm Disorders (Vancouver, British Columbia, Canada), and the Paul Albrechtson Foundation (Winnipeg, Manitoba, Canada). The Hearts in Rhythm Organization (Dr. Krahn, Principal Investigator), which is funded by the Canadian Institute of Health Research (RN380020 – 406814), and the Heart and Stroke Foundation (G150008870 [Dr. Santanani, Principal Investigator]), supported the work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aim: Assess executive and socio-emotional/behavioural functioning in paediatric supraventricular tachycardia (SVT) patients., Methods: SVT patients aged 7-17 who had not undergone catheter ablation were included. Parents completed the Child Behaviour Checklist (CBCL/6-18) and the Behavior Rating Inventory of Executive Functioning (BRIEF). Participants age 11-17 years completed the Youth Self-Report (YSR/11-18) and the BRIEF Self-Report (BRIEF-SR). One-sample z test was used to compare questionnaire results to the average t-score range (M = 50, SD = 10)., Results: Thirty (18 female) children/adolescents participated (M = 12.6 years old, SD = 3.2 years) with a mean SVT onset age of 7 years (SD = 4.3 years). BRIEF and BRIEF-SR results suggested no difference in executive functioning from average. Mean t-scores of CBCL/6-18 and YSR/11-18 subscales Anxious/Depressed, Withdrawn/Depressed, Somatic Complaints, Thought Problems, Diagnostic and Statistical Manual of Mental Disorders (DSM) Affective Problems, DSM Anxiety Problems and DSM Somatic Problems were significantly elevated compared to average. YSR/11-18 subscales Social Problems, Attention Problems, Internalizing Problems, DSM ADHD Problems and DSM Oppositional Defiant Problems had elevated mean t-scores compared to average. Effect sizes were small to medium (0.2 ≤ d ≤ 0.8)., Conclusion: Paediatric patients with SVT potentially have a greater risk of developing behaviour, especially internalizing, problems compared to similarly aged children/adolescents without SVT., (©2020 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Background: Long QT syndrome (LQTS) is a dangerous arrhythmia disorder that often presents in childhood and adolescence. The exercise stress test (EST) and QT-stand test may unmask QT interval prolongation at key heart rate transition points in LQTS, but their utility in children is debated., Objective: To determine if the QT-stand test or EST can differentiate children with a low probability of LQTS from those with confirmed LQTS., Methods: This retrospective study compares the corrected QT intervals (QTc) of children (<19 years) during the QT-stand test and EST. Patients were divided into three groups for comparison: confirmed LQTS (n = 14), low probability of LQTS (n = 14), and a control population (n = 9)., Results: Using the Bazett formula, confirmed LQTS patients had longer QTc intervals than controls when supine, standing, and at 3-4 min of recovery (p ≤ .01). Patients with a low probability of LQTS had longer QTc duration upon standing (p = .018) and at 1 min of recovery (p = .016) versus controls. There were no significant QTc differences at any transition point between low probability and confirmed LQTS. Using the Fridericia formula, differences in QTc between low probability and confirmed LQTS were also absent at the transition points examined, except at 1 min into exercise, where low probability patients had shorter QTc intervals (437 vs. 460 ms, p = .029)., Conclusion: The diagnostic utility of the QT stand test and EST remains unclear in pediatric LQTS. The formula used for heart rate correction may influence accuracy, and dynamic T-U wave morphology changes may confound interpretation in low probability situations., (© 2020 Wiley Periodicals LLC.)

Background: The etiology of sudden cardiac arrest (SCA) in individuals without known cardiovascular heart disease remains elusive in nearly half of all patients after systematic testing. We investigated the relationship between stressful life events and SCA risk in cases of explained and unexplained SCA (USCA) events., Methods: Individuals who previously experienced SCA were enrolled prospectively and divided into a USCA or explained SCA (ESCA) subgroup dependent on whether a diagnosis was ascribed after SCA. Participants completed either the 1997 Recent Life Changes Questionnaire, Student Stress Scale, or Social Re-adjustment Rating Scale for Non-Adults recalling events during the year preceding their SCA, depending on age at SCA presentation; all measure stress in life change units (LCUs). SCA group scores were compared with an age- and sex-matched control group., Results: We compared 36 SCA group participants (22 USCA, 14 ESCA, age 47 ± 15 years, age at SCA 40 ± 14 years, 50% male) with 36 control participants (age 47 ± 15 years, 50% male). There was no significant difference in LCU score between the control group and the SCA group (248 ± 181 LCU vs 252 ± 227 LCU; P > .05). The ESCA subgroup had significantly lower mean LCU scores than the USCA subgroup (163 ± 183 LCU vs 308 ± 237 LCU; P  = .030)., Conclusions: Stressful life events, especially those producing chronic stress, might predispose otherwise healthy individuals to lethal arrhythmias. Further investigation into the role of stress in SCA precipitation is warranted., (© 2020 Canadian Cardiovascular Society. Published by Elsevier Inc.)

Background: Unexplained cardiac arrest (UCA) is rare in children. Despite investigations, the etiology in up to one-half of patients remains unknown., Objective: The purpose of this study was to assess the management and outcomes of pediatric UCA survivors through the Canadian Pediatric Heart Rhythm Network., Methods: A retrospective case series of children (age 1-19 years) who presented with UCA between January 1, 2004, and November 1, 2017, was conducted. Patients with known heart disease pre-UCA were excluded. UCA details, investigations, genetic test results, treatment, implantable cardioverter-defibrillator (ICD) data, subsequent diagnoses, and family screening data were collected., Results: Forty-six patients (61% male) were survivors of sudden unexpected death and met inclusion criteria at 8 participating sites. Median age at UCA was 13.8 years (interquartile range [IQR] 9-16 years). Baseline retrievable investigations included electrocardiogram (96%), echocardiogram (85%), exercise stress test (73%), and cardiac magnetic resonance imaging (57%). The presumed etiology for the UCA was identified in 24 (52%), mainly long QT syndrome or catecholaminergic polymorphic ventricular tachycardia. Genetic testing was performed in 33 of 46 (72%), with pathogenic/likely pathogenic variants identified in 13 of 33 (39%) and variants of uncertain significance in 8 of 33 (24%). ICDs were implanted in 35 of 46 (76%). Over median follow-up of 36 months (IQR 17-57 months), 8 of 35 had arrhythmia events captured on device interrogation. Families of 26 of 46 patients(57%) underwent screening, leading to a cardiac diagnosis in 6 of 26 families., Conclusion: A cause for UCA was not identified in nearly 50% of patients despite extensive investigations, including cascade screening. A large proportion (75%) of ICD shocks occurred in patients without a diagnosis., (Copyright © 2020 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Introduction: Risk stratification tools for catecholaminergic polymorphic ventricular tachycardia (CPVT) are limited. The exercise stress test (EST) is the most important diagnostic and prognostic test. We aimed to determine whether heart rate (HR) and blood pressure (BP) response during EST were associated with the risk of arrhythmias., Materials and Methods: We studied the association between HR and BP response and ventricular arrhythmia burden on EST in 20 CPVT patients. HR reserve values <80% and ≤62% were used to define chronotropic incompetence (CI) off and on therapy, respectively. Symptoms and ventricular arrhythmia score (VAS) in all patients with respect to CI and BP during index EST off therapy and on maximal therapy were compared., Results: CI in CPVT patients off therapy was associated with a worse VAS during EST (P = .046). Patients with CI also more frequently presented with syncope and/or cardiac arrest compared to patients with a normal chronotropic response (P = .008). Once on therapy, patients with CI had similar VAS compared to patients without CI (P = .50), suggesting that treatment attenuates risk related to CI. Patients with CI also had a lower peak systolic BP (P = .041) which persisted on maximal therapy (P = .033)., Conclusion: Untreated CPVT patients with CI have more ventricular arrhythmias than those without CI. This may serve as a simple disease prognosticator that can be modified by antiarrhythmic therapy. A mechanistic link between CI and arrhythmia susceptibility remains unknown. Larger studies are needed to confirm and establish the mechanism of these findings., (© 2019 Wiley Periodicals, Inc.)