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AIMS: Calmodulinopathy due to mutations in any of the three CALM genes (CALM1-3) causes life-threatening arrhythmia syndromes, especially in young individuals. The International Calmodulinopathy Registry (ICalmR) aims to define and link the increasing complexity of the clinical presentation to the underlying molecular mechanisms. METHODS AND RESULTS: The ICalmR is an international, collaborative, observational study, assembling and analysing clinical and genetic data on CALM-positive patients. The ICalmR has enrolled 140 subjects (median age 10.8 years [interquartile range 5-19]), 97 index cases and 43 family members. CALM-LQTS and CALM-CPVT are the prevalent phenotypes. Primary neurological manifestations, unrelated to post-anoxic sequelae, manifested in 20 patients. Calmodulinopathy remains associated with a high arrhythmic event rate (symptomatic patients, n = 103, 74%). However, compared with the original 2019 cohort, there was a reduced frequency and severity of all cardiac events (61% vs. 85%; P = .001) and sudden death (9% vs. 27%; P = .008). Data on therapy do not allow definitive recommendations. Cardiac structural abnormalities, either cardiomyopathy or congenital heart defects, are present in 30% of patients, mainly CALM-LQTS, and lethal cases of heart failure have occurred. The number of familial cases and of families with strikingly different phenotypes is increasing. CONCLUSION: Calmodulinopathy has pleiotropic presentations, from channelopathy to syndromic forms. Clinical severity ranges from the early onset of life-threatening arrhythmias to the absence of symptoms, and the percentage of milder and familial forms is increasing. There are no hard data to guide therapy, and current management includes pharmacological and surgical antiadrenergic interventions with sodium channel blockers often accompanied by an implantable cardioverter-defibrillator.
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Calmodulina , Síndrome do QT Longo , Taquicardia Ventricular , Criança , Humanos , Calmodulina/genética , Morte Súbita Cardíaca/etiologia , Síndrome do QT Longo/diagnóstico , Síndrome do QT Longo/genética , Mutação/genética , Sistema de Registros , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/genéticaRESUMO
BACKGROUND: Symptomatic children with catecholaminergic polymorphic ventricular tachycardia (CPVT) are at risk for recurrent arrhythmic events. ß-Blockers decrease this risk, but studies comparing individual ß-blockers in sizeable cohorts are lacking. We aimed to assess the association between risk for arrhythmic events and type of ß-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 ß-blocker initiation and age at start of ß-blocker therapy <18 years), treated with a ß-blocker were included. Cox regression analyses with time-dependent covariates for ß-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 ß-blocker (predominantly nadolol [n=140] or propranolol [n=70]) and 111 (33.7%) used a ß1-selective ß-blocker (predominantly atenolol [n=51], metoprolol [n=33], or bisoprolol [n=19]) as initial ß-blocker. Baseline characteristics did not differ. The HRs for both the primary and secondary outcomes were higher for ß1-selective compared with nonselective ß-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: ß1-selective ß-blockers were associated with a significantly higher risk for arrhythmic events in symptomatic children with CPVT compared with nonselective ß-blockers, specifically nadolol. Nadolol, or propranolol if nadolol is unavailable, should be the preferred ß-blocker for treating symptomatic children with CPVT.
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Antagonistas Adrenérgicos beta/uso terapêutico , Taquicardia Ventricular/tratamento farmacológico , Adolescente , Antagonistas Adrenérgicos beta/farmacologia , Criança , Estudos de Coortes , Feminino , Humanos , MasculinoRESUMO
Oral propranolol therapy is commonly used for the prevention of tachyarrhythmias in infancy and childhood. Propranolol is commercially produced in four concentrations allowing varying volumes to be administered. However, quite often an alternative strength of propranolol liquid is issued without clear change in instructions or warning. This may lead to parents inadvertently administering the wrong dose.
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Propranolol , Taquicardia , Recém-Nascido , Lactente , Humanos , Criança , Propranolol/uso terapêutico , Taquicardia/tratamento farmacológico , Antagonistas Adrenérgicos beta/uso terapêutico , Administração Oral , Resultado do TratamentoRESUMO
AIM: The aim of this study is to evaluate safety and efficacy of ASP8302, a novel positive allosteric modulator for the muscarinic M3 receptor (M3-PAM), in patients with underactive bladder (UAB). METHODS: A randomized, double-blind, placebo-controlled multicenter study was performed in adult male/female subjects with UAB, defined as incomplete bladder emptying (postvoid residual volume [PVR] > 100 ml) without significant bladder outlet obstruction and/or overactive bladder. Subjects were randomized (1:1) to receive 4-week oral once-daily administration of 100 mg ASP8302 or matching placebo. Primary endpoint was a change from baseline in PVR measured by catheterization after standardized bladder filling (PVRC2 ). Other endpoints included PVR and bladder voiding efficiency (BVE) measured in various ways, uroflowmetry, bladder diary, and questionnaires. Pressure-flow studies were performed in a subgroup. RESULTS: One hundred and thirty-five patients were randomized (ASP8302 group: 65 patients, placebo group: 70 patients). The median change in PVRC2 was -40.0 ml (ASP8302) versus -35.0 ml (placebo) and the difference between groups was -5.0 ml (p = 0.960). In males, functional and symptomatic outcomes improved, for example, maximum urine flow rate (Qmax ) and detrusor pressure at Qmax (Pdet.Qmax ) increased (mean difference in change ASP8302 vs. placebo: 3.8 ml/s, p = 0.031 and 12.7 cm H2 O, p = 0.034, respectively). Urinary incontinence episodes/24 h decreased in males with preexisting incontinence (mean difference: -0.35; p = 0.028). The incidence of adverse events was similar between study groups (ASP8302: 33.3%, placebo: 31.4%). In the included subjects, both baseline urine flow and bladder voiding pressure was low. Compared with PVR, simultaneous BVE measurements were more consistent between various methods (spontaneous vs. standardized bladder filling, catheterization vs. ultrasound [US]). CONCLUSIONS: ASP8302 was safe and well tolerated in patients with UAB identified by nonurodynamic clinical criteria, but it did not show efficacy in the primary endpoint. However, in males it showed improvement of symptoms and functional parameters. BVE (using US) is a more optimal outcome measure than PVR in UAB.
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Colinérgicos , Bexiga Inativa , Adulto , Colinérgicos/uso terapêutico , Método Duplo-Cego , Feminino , Humanos , Masculino , Receptores Muscarínicos , Resultado do Tratamento , Obstrução do Colo da Bexiga Urinária , Bexiga Urinária Hiperativa , Bexiga Inativa/complicações , Bexiga Inativa/tratamento farmacológico , Incontinência Urinária/etiologiaRESUMO
BACKGROUND: Conventional superior access for cardiac implantable electronic devices (CIEDs) is not always possible and femoral CIEDs (F-CIED) are an alternative option when leadless systems are not suitable. The long-term outcomes and extraction experiences with F-CIEDs, in particular complex F-CIED (ICD/CRT devices), remain poorly understood. METHODS: Patients referred for F-CIEDs implantation between 2002 and 2019 at two tertiary centers were included. Early complications were defined as ≤30 days following implant and late complications >30 days. RESULTS: Thirty-one patients (66% male; age 56 ± 20 years; 35% [11] patients with congenital heart disease) were implanted with F-CIEDs (10 ICD/CRT and 21 pacemakers). Early complications were observed in 6.5% of patients: two lead displacements. Late complications at 6.8 ± 4.4 years occurred in 29.0% of patients. This was higher with complex F-CIED compared to simple F-CIED (60.0% vs. 14.3%, p = .02). Late complications were predominantly generator site related (n = 8, 25.8%) including seven infections/erosions and one generator migration. Eight femoral generators and 14 leads (median duration in situ seven [range 6-11] years) were extracted without complication. CONCLUSIONS: Procedural success with F-CIEDs is high with clinically acceptable early complication rates. There is a notable risk of late complications, particularly involving the generator site of complex devices following repeat femoral procedures. Extraction of chronic F-CIED in experienced centers is feasible and safe.
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Desfibriladores Implantáveis , Cardiopatias Congênitas , Marca-Passo Artificial , Adulto , Idoso , Eletrônica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
BACKGROUND: Genetic variants in calsequestrin-2 (CASQ2) cause an autosomal recessive form of catecholaminergic polymorphic ventricular tachycardia (CPVT), although isolated reports have identified arrhythmic phenotypes among heterozygotes. Improved insight into the inheritance patterns, arrhythmic risks, and molecular mechanisms of CASQ2-CPVT was sought through an international multicenter collaboration. METHODS: Genotype-phenotype segregation in CASQ2-CPVT families was assessed, and the impact of genotype on arrhythmic risk was evaluated using Cox regression models. Putative dominant CASQ2 missense variants and the established recessive CASQ2-p.R33Q variant were evaluated using oligomerization assays and their locations mapped to a recent CASQ2 filament structure. RESULTS: A total of 112 individuals, including 36 CPVT probands (24 homozygotes/compound heterozygotes and 12 heterozygotes) and 76 family members possessing at least 1 presumed pathogenic CASQ2 variant, were identified. Among CASQ2 homozygotes and compound heterozygotes, clinical penetrance was 97.1% and 26 of 34 (76.5%) individuals had experienced a potentially fatal arrhythmic event with a median age of onset of 7 years (95% CI, 6-11). Fifty-one of 66 CASQ2 heterozygous family members had undergone clinical evaluation, and 17 of 51 (33.3%) met diagnostic criteria for CPVT. Relative to CASQ2 heterozygotes, CASQ2 homozygote/compound heterozygote genotype status in probands was associated with a 3.2-fold (95% CI, 1.3-8.0; P=0.013) increased hazard of a composite of cardiac syncope, aborted cardiac arrest, and sudden cardiac death, but a 38.8-fold (95% CI, 5.6-269.1; P<0.001) increased hazard in genotype-positive family members. In vitro turbidity assays revealed that p.R33Q and all 6 candidate dominant CASQ2 missense variants evaluated exhibited filamentation defects, but only p.R33Q convincingly failed to dimerize. Structural analysis revealed that 3 of these 6 putative dominant negative missense variants localized to an electronegative pocket considered critical for back-to-back binding of dimers. CONCLUSIONS: This international multicenter study of CASQ2-CPVT redefines its heritability and confirms that pathogenic heterozygous CASQ2 variants may manifest with a CPVT phenotype, indicating a need to clinically screen these individuals. A dominant mode of inheritance appears intrinsic to certain missense variants because of their location and function within the CASQ2 filament structure.
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Calsequestrina/genética , Heterozigoto , Homozigoto , Mutação de Sentido Incorreto , Taquicardia Ventricular/genética , Feminino , Humanos , Masculino , Fatores de RiscoRESUMO
PURPOSE: Biallelic hypomorphic variants in PPA2, encoding the mitochondrial inorganic pyrophosphatase 2 protein, have been recently identified in individuals presenting with sudden cardiac death, occasionally triggered by alcohol intake or a viral infection. Here we report 20 new families harboring PPA2 variants. METHODS: Synthesis of clinical and molecular data concerning 34 individuals harboring five previously reported PPA2 variants and 12 novel variants, 11 of which were functionally characterized. RESULTS: Among the 34 individuals, only 6 remain alive. Twenty-three died before the age of 2 years while five died between 14 and 16 years. Within these 28 cases, 15 died of sudden cardiac arrest and 13 of acute heart failure. One case was diagnosed prenatally with cardiomyopathy. Four teenagers drank alcohol before sudden cardiac arrest. Progressive neurological signs were observed in 2/6 surviving individuals. For 11 variants, recombinant PPA2 enzyme activities were significantly decreased and sensitive to temperature, compared to wild-type PPA2 enzyme activity. CONCLUSION: We expand the clinical and mutational spectrum associated with PPA2 dysfunction. Heart failure and sudden cardiac arrest occur at various ages with inter- and intrafamilial phenotypic variability, and presentation can include progressive neurological disease. Alcohol intake can trigger cardiac arrest and should be strictly avoided.
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Cardiomiopatias , Morte Súbita Cardíaca , Adolescente , Alelos , Cardiomiopatias/genética , Pré-Escolar , Morte Súbita Cardíaca/etiologia , Humanos , Pirofosfatase Inorgânica/genética , Pirofosfatase Inorgânica/metabolismo , Proteínas Mitocondriais/genética , MutaçãoRESUMO
AIMS: Sudden cardiac death (SCD) is the most common mode of death in paediatric hypertrophic cardiomyopathy (HCM). This study describes the implant and programming strategies with clinical outcomes following implantable cardioverter-defibrillator (ICD) insertion in a well-characterized national paediatric HCM cohort. METHODS AND RESULTS: Data from 90 patients undergoing ICD insertion at a median age 13 (±3.5) for primary (n = 67, 74%) or secondary prevention (n = 23, 26%) were collected from a retrospective, longitudinal multi-centre cohort of children (<16 years) with HCM from the UK. Seventy-six (84%) had an endovascular system [14 (18%) dual coil], 3 (3%) epicardial, and 11 (12%) subcutaneous system. Defibrillation threshold (DFT) testing was performed at implant in 68 (76%). Inadequate DFT in four led to implant adjustment in three patients. Over a median follow-up of 54 months (interquartile range 28-111), 25 (28%) patients had 53 appropriate therapies [ICD shock n = 45, anti-tachycardia pacing (ATP) n = 8], incidence rate 4.7 per 100 patient years (95% CI 2.9-7.6). Eight inappropriate therapies occurred in 7 (8%) patients (ICD shock n = 4, ATP n = 4), incidence rate 1.1/100 patient years (95% CI 0.4-2.5). Three patients (3%) died following arrhythmic events, despite a functioning device. Other device complications were seen in 28 patients (31%), including lead-related complications (n = 15) and infection (n = 10). No clinical, device, or programming characteristics predicted time to inappropriate therapy or lead complication. CONCLUSION: In a large national cohort of paediatric HCM patients with an ICD, device and programming strategies varied widely. No particular strategy was associated with inappropriate therapies, missed/delayed therapies, or lead complications.
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Cardiomiopatia Hipertrófica , Desfibriladores Implantáveis , Adolescente , Cardiomiopatia Hipertrófica/diagnóstico , Cardiomiopatia Hipertrófica/terapia , Criança , Estudos de Coortes , Morte Súbita Cardíaca/epidemiologia , Morte Súbita Cardíaca/prevenção & controle , Humanos , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento , Reino UnidoRESUMO
BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a genetic disorder causing life-threatening arrhythmias whenever sympathetic activity increases. ß-Βlockers are the mainstay of therapy; when they fail, implantable cardioverter-defibrillators (ICDs) are used but often cause multiple shocks. Preliminary results with flecainide appear encouraging. We proposed left cardiac sympathetic denervation (LCSD) as useful additional therapy, but evidence remains anecdotal. METHODS AND RESULTS: We report 63 patients with CPVT who underwent LCSD as secondary (n=54) or primary (n=9) prevention. The median post-LCSD follow-up was 37 months. The 9 asymptomatic patients remained free of major cardiac events. Of the 54 patients with prior major cardiac events either on (n=38) or off (n=16) optimal medical therapy, 13 (24%) had at least 1 recurrence: 0 patients had an aborted cardiac arrest, 2 patients had syncope only, 10 patients had ≥1 appropriate ICD discharges, and 1 patient died suddenly. The 1- and 2-year cumulative event-free survival rates were 87% and 81%. The percentage of patients with major cardiac events despite optimal medical therapy (n=38) was reduced from 100% to 32% (P<0.001) after LCSD, and among 29 patients with a presurgical ICD, the rate of shocks dropped by 93% from 3.6 to 0.6 shocks per person per year (P<0.001). Patients with an incomplete LCSD (n=7) were more likely to experience major cardiac events after LCSD (71% versus 17%; P<0.01) than those with a complete LCSD. CONCLUSIONS: LCSD is an effective antifibrillatory intervention for patients with CPVT. Whenever syncope occurs despite optimal medical therapy, LCSD could be considered the next step rather than an ICD and could complement ICDs in patients with recurrent shocks.
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Gerenciamento Clínico , Simpatectomia , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/cirurgia , Adolescente , Criança , Feminino , Seguimentos , Humanos , Masculino , Simpatectomia/métodos , Taquicardia Ventricular/fisiopatologia , Resultado do TratamentoRESUMO
ASP8302 is an orally administered positive allosteric modulator of the muscarinic M3 receptor. Two Phase 1 studies were conducted, a first-in-human study in Europe and a Japanese phase 1 study. Both were randomized, participant- and investigator-blinded, placebo-controlled, single and multiple ascending oral doses, parallel group, clinical studies in healthy volunteers. Both studies evaluated safety and pharmacokinetics and also included salivary secretion and pupil diameter as pharmacodynamic assessments. There were no deaths, serious adverse events, or treatment-emergent adverse events reported leading to study discontinuation. There were no clinically relevant findings in any of the laboratory, vital signs, electrocardiogram assessments, or photosensitivity testing following multiple administration of up to 150 mg or up to 140 mg once daily for 14 days in the European first-in-human and Japanese Phase 1 study, respectively. The pharmacokinetics of ASP8302 were approximately linear over the dose range studied. There was no evidence of drug accumulation upon repeated dosing. In both studies, ASP8302 showed a dose-dependent pharmacodynamic effect on saliva production at doses from 100 mg onward, which was maintained during repeated dosing. No effect was observed on pupil diameter. These data supported progression of ASP8302 into Phase 2 clinical trials for further clinical development.
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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.
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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. ß-Blockers were used in 16 of 17 surviving patients (94%). Three of 16 individuals who were reportedly adherent to ß-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.
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Morte Súbita Cardíaca/prevenção & controle , Mutação , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Taquicardia Ventricular/genética , Adolescente , Adulto , Criança , Morte Súbita Cardíaca/epidemiologia , Eletrocardiografia , Feminino , Seguimentos , Saúde Global , Humanos , Masculino , Morbidade/tendências , Fenótipo , Estudos Prospectivos , Estudos Retrospectivos , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Taquicardia Ventricular/epidemiologia , Taquicardia Ventricular/metabolismo , Adulto JovemRESUMO
OBJECTIVES: This study set out to examine outcomes from pediatric supraventricular tachycardia ablations over a 20-year period. This study sought to examine success rates and repeat ablations over time and to evaluate whether modalities such as 3-dimensional (3D) mapping, contact force, and cryotherapy have improved outcomes. BACKGROUND: Ablation of supraventricular tachycardia in pediatric patients is commonly performed in most congenital heart centers with excellent long-term results. METHODS: Data were retrieved from the NICOR (National Institute of Clinical Outcomes Research) database in the United Kingdom. Outcomes over time were evaluated, and procedure-related details were compared. RESULTS: There were 7,069 ablations performed from January 1, 1999, to December 31, 2018, at 10 centers. Overall, ablation success rates were 92% for accessory pathways, 97% for atrioventricular node re-entry tachycardia, and 89% for atrial tachycardia. There was an improvement in procedural success rates over time (p < 0.01). The use of 3D mapping did not alter success or need for repeat ablation but was associated with a higher proportion of lower fluoroscopy cases; 55% of 3D mapping cases used <5 min of fluoroscopy (p < 0.01). Patients needing a repeat ablation were 341 (12%) for accessory pathways, 128 (7%) for atrioventricular node re-entry tachycardia, and 35 (7%) for atrial tachycardia. Overall, the risk of complete heart block was low (n = 12, <0.01%). The use of cryotherapy was associated with an increased risk of needing a repeat ablation. CONCLUSIONS: Overall success rates from pediatric ablations are excellent and compare favorably to other registries. Introduction of newer technologies have likely made procedures safer and reduced radiation exposure, but they have not changed success rates or the need for a repeat procedure.
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Feixe Acessório Atrioventricular , Ablação por Cateter , Taquicardia por Reentrada no Nó Atrioventricular , Taquicardia Supraventricular , Criança , Fluoroscopia , Humanos , Taquicardia por Reentrada no Nó Atrioventricular/cirurgia , Taquicardia Supraventricular/epidemiologia , Taquicardia Supraventricular/cirurgiaRESUMO
RATIONALE: Myeloid-related protein-8 (MRP8) and MRP14 can form heterodimers that elicit a variety of inflammatory responses. We showed that MRP8/14 is a ligand for Toll-like receptor-4, and that mice deficient in MRP8/14 are protected against endotoxic shock-induced lethality. OBJECTIVES: To determine (1) the extent of MRP8/14 release in patients with sepsis and/or peritonitis and in healthy humans exposed to LPS and (2) the contribution of MRP8/14 to the host response in murine abdominal sepsis. METHODS: MRP8/14 was measured in 51 patients with severe sepsis, 8 subjects after intravenous injection of LPS, and 17 patients with peritonitis. Host responses to sepsis were compared in mrp14 gene-deficient (and thereby MRP8/14-deficient) and wild-type mice intraperitoneally injected with Escherichia coli. MEASUREMENTS AND MAIN RESULTS: Patients with sepsis displayed elevated circulating MRP8/14 concentrations on both Days 0 and 3, and LPS injection resulted in systemic MRP8/14 release in healthy humans. In patients with peritonitis, MRP8/14 levels in abdominal fluid were more than 15-fold higher than in plasma. MRP14-deficient mice displayed improved defense against E. coli abdominal sepsis in an early phase, as indicated by diminished dissemination of the bacteria at 6 hours. In addition, MRP14-deficient mice demonstrated decreased systemic inflammation, as reflected by lower cytokine plasma concentrations, and less severe liver damage. CONCLUSIONS: Human sepsis and endotoxemia are associated with enhanced release of MRP8/14. In abdominal sepsis, MRP8/14 likely occurs primarily at the site of the infection, facilitating bacterial dissemination at an early phase and liver injury.
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Calgranulina A/genética , Calgranulina B/genética , Expressão Gênica/genética , Peritonite/complicações , Sepse/complicações , Sepse/genética , Idoso , Animais , Modelos Animais de Doenças , Infecções por Escherichia coli/microbiologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Peritonite/microbiologia , Sepse/microbiologiaRESUMO
BACKGROUND: Risk stratification in catecholaminergic polymorphic ventricular tachycardia remains ill defined. Heart rate recovery (HRR) immediately after exercise is regulated by autonomic reflexes, particularly vagal tone, and may be associated with symptoms and ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia. Our objective was to evaluate whether HRR after maximal exercise on the exercise stress test (EST) is associated with symptoms and ventricular arrhythmias. METHODS: In this retrospective observational study, we included patients ≤65 years of age with an EST without antiarrhythmic drugs who attained at least 80% of their age- and sex-predicted maximal HR. HRR in the recovery phase was calculated as the difference in heart rate (HR) at maximal exercise and at 1 minute in the recovery phase (ΔHRR1'). RESULTS: We included 187 patients (median age, 36 years; 68 [36%] symptomatic before diagnosis). Pre-EST HR and maximal HR were equal among symptomatic and asymptomatic patients. Patients who were symptomatic before diagnosis had a greater ΔHRR1' after maximal exercise (43 [interquartile range, 25-58] versus 25 [interquartile range, 19-34] beats/min; P<0.001). Corrected for age, sex, and relatedness, patients in the upper tertile for ΔHRR1' had an odds ratio of 3.4 (95% CI, 1.6-7.4) of being symptomatic before diagnosis (P<0.001). In addition, ΔHRR1' was higher in patients with complex ventricular arrhythmias at EST off antiarrhythmic drugs (33 [interquartile range, 22-48] versus 27 [interquartile range, 20-36] beats/min; P=0.01). After diagnosis, patients with a ΔHRR1' in the upper tertile of its distribution had significantly more arrhythmic events as compared with patients in the other tertiles (P=0.045). CONCLUSIONS: Catecholaminergic polymorphic ventricular tachycardia patients with a larger HRR following exercise are more likely to be symptomatic and have complex ventricular arrhythmias during the first EST off antiarrhythmic drug.
Assuntos
Exercício Físico/fisiologia , Frequência Cardíaca/fisiologia , Recuperação de Função Fisiológica/fisiologia , Taquicardia Ventricular/fisiopatologia , Adulto , Eletrocardiografia , Teste de Esforço , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taquicardia Ventricular/diagnóstico , Nervo Vago/fisiopatologia , Adulto JovemRESUMO
BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an uncommon inherited arrhythmia disorder characterized by adrenergically evoked ventricular arrhythmias. Mutations in the cardiac calcium release channel/ryanodine receptor gene (RYR2) are identified in the majority of patients with CPVT. RyR2 is also the major RyR isoform expressed in the brain. OBJECTIVE: The purpose of this study was to estimate the prevalence of intellectual disability (ID) and other neurodevelopmental disorders (NDDs) in RYR2-associated CPVT (CPVT1) and to study the characteristics of these patients. METHODS: We reviewed the medical records of all CPVT1 patients from 12 international centers and analyzed the characteristics of all CPVT1 patients with concomitant NDDs. We functionally characterized the mutations to assess their response to caffeine activation. We did not correct for potential confounders. RESULTS: Among 421 CPVT1 patients, we identified 34 patients with ID (8%; 95% confidence interval 6%-11%). Median age at diagnosis was 9.3 years (interquartile range 7.0-14.5). Parents for 24 of 34 patients were available for genetic testing, and 13 of 24 (54%) had a de novo mutation. Severity of ID ranged from mild to severe and was accompanied by other NDDs in 9 patients (26%). Functionally, the ID-associated mutations showed a markedly enhanced response of RyR2 to activation by caffeine. Seventeen patients (50%) also had supraventricular arrhythmias. During median follow-up of 8.4 years (interquartile range 1.8-12.4), 15 patients (45%) experienced an arrhythmic event despite adequate therapy. CONCLUSION: Our study indicates that ID is more prevalent among CPVT1 patients (8%) than in the general population (1%-3%). This subgroup of CPVT1 patients reveals a malignant cardiac phenotype with marked supraventricular and ventricular arrhythmias.
Assuntos
Encéfalo/diagnóstico por imagem , Miocárdio/patologia , Transtornos do Neurodesenvolvimento/etiologia , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Taquicardia Ventricular/complicações , Adolescente , Criança , Análise Mutacional de DNA , Feminino , Seguimentos , Testes Genéticos , Humanos , Imagem Cinética por Ressonância Magnética , Masculino , Mutação , Países Baixos/epidemiologia , Transtornos do Neurodesenvolvimento/diagnóstico , Transtornos do Neurodesenvolvimento/epidemiologia , Fenótipo , Prevalência , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/genética , Tomografia Computadorizada por Raios X , Reino Unido/epidemiologia , Estados Unidos/epidemiologiaRESUMO
We describe a teenage girl who presented with syncope on exertion and prolonged QT on electrocardiogram (ECG). She was found to be hypocalcaemic due to hypoparathyroidism. Following oral calcium and vitamin D supplementation, there were no further episodes of syncope with normalization of the QT segment. This case highlights the need to consider all causes of a long QT segment.
Assuntos
Hipocalcemia/diagnóstico , Hipoparatireoidismo/diagnóstico , Síndrome do QT Longo/diagnóstico , Síncope/etiologia , Adolescente , Diagnóstico Diferencial , Eletrocardiografia , Feminino , Humanos , Hipocalcemia/complicações , Hipoparatireoidismo/complicaçõesRESUMO
OBJECTIVE: Ivabradine is a selective and specific inhibitor of the I(f) current in the sinoatrial and atrioventricular nodes. It decreases heart rate and myocardial oxygen consumption at rest and during exercise. It is used in adults for management of heart failure and angina, but promising results have been obtained in postural orthostatic tachycardia syndrome (POTS). There is little experience of ivabradine in childhood, although it is used on a compassionate basis. Our aim was to review our experience of ivabradine in a retrospective evaluation of pediatric patients with POTS. METHODS: We evaluated all patients younger than 18 years for whom ivabradine had been prescribed for this indication, from February 2008 to June 2014. RESULTS: Twenty-two patients were identified (15 female). Median age was 14.5 years (11-17 years). The ivabradine dosage after up-titration was 0.1 mg/kg per dose twice daily. In 15 (68%) symptoms improved. Ivabradine was suspended in five, but only in one for worsening of symptoms. There was a reduction in heart rate on resting electrocardiogram (EKG) from a mean (standard deviation) of 82.5 (13.6) bpm to a mean of 71 (16.5) bpm (p = 0.007). No patient had increased duration of QTc (p = 0.44). One (4.5%) experienced phosphenes. CONCLUSIONS: From this initial experience, ivabradine is safe in patients younger than 18 years with POTS. We observed improvement of symptoms in 68% and phosphenes in less than 5%. Further studies are needed to assess the safety in a randomized control setting.