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Background: There is a paucity of data on long-term outcomes after Fontan palliation in patients with a dominant morphological univentricular right (uRV) vs left (uLV) ventricle. Objectives: The purpose of this study was to compare the incidence of atrial arrhythmias, thromboembolic events, cardiac transplantation, and death following Fontan palliation in patients with uRV vs uLV. Methods: The Alliance for Adult Research in Congenital Cardiology conducted a multicenter retrospective cohort study on patients with total cavopulmonary connection Fontan palliation across 12 centers in North America. All components of the composite outcome, that is, atrial arrhythmias, thromboembolic events, cardiac transplantation, and death, were reviewed and classified by a blinded adjudicating committee. Time-to-event analyses were performed that accounted for competing risks. Results: A total of 384 patients were followed for 10.5 ± 5.9 years. The composite outcome occurred in 3.7 vs 1.7 cases per 100 person-years for uRV (N = 171) vs uLV (N = 213), respectively (P < 0.001). In multivariable analyses, uRV conferred a >2-fold higher risk of the composite outcome (HR: 2.17, 95% CI: 1.45-3.45, P < 0.001). In secondary analyses of components of the primary outcome, uRV was significantly associated with a greater risk of cardiac transplantation or death (HR: 9.09, 95% CI: 2.17-38.46, P < 0.001) and atrial arrhythmias (HR: 2.17, 95% CI: 1.20-4.00, P = 0.010) but not thromboembolic events (HR: 1.64, 95% CI: 0.86-3.16, P = 0.131). Conclusions: Fontan patients with uRV vs uLV morphology have a higher incidence of adverse cardiovascular events, including atrial arrhythmia, cardiac transplantation, and all-cause mortality.
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Introduction: Sudden Unexpected Death in Epilepsy (SUDEP) is the leading epilepsy-related cause of death, affecting approximately 1 per 1,000 individuals with epilepsy per year. Genetic variants that affect autonomic function, such as genes associated with cardiac arrhythmias, may predispose people with epilepsy to greater risk of both sudden cardiac death and SUDEP. Advances in next generation sequencing allow for the exploration of gene variants as potential biomarkers. Methods: Genetic testing for the presence of cardiac arrhythmia and epilepsy gene variants was performed via genetic panels in 39 cases of SUDEP identified via autopsy by the Ontario Forensic Pathology Service. Variants were summarized by in-silico evidence for pathogenicity from 4 algorithms (SIFT, PolyPhen-2, PROVEAN, Mutation Taster) and allele frequencies in the general population (GnomAD). A maximum credible population allele frequency of 0.00004 was calculated based on epilepsy prevalence and SUDEP incidence to assess whether a variant was compatible with a pathogenic interpretation. Results: Median age at the time of death was 33.3 years (range: 2, 60). Fifty-nine percent (n=23) were male. Gene panels detected 62 unique variants in 45 genes: 19 on the arrhythmia panel and 26 on the epilepsy panel. At least one variant was identified in 28 (72%) of decedents. Missense mutations comprised 57 (92%) of the observed variants. At least three in silico models predicted 12 (46%) cardiac arrhythmia panel missense variants and 20 (65%) epilepsy panel missense variants were pathogenic. Population allele frequencies were <0.00004 for 11 (42%) of the cardiac variants and 10 (32%) of the epilepsy variants. Together, these metrics identified 13 SUDEP variants of interest. Discussion: Nearly three-quarters of decedents in this SUDEP cohort carried variants in comprehensive epilepsy or cardiac arrhythmia gene panels, with more than a third having variants in both panels. The proportion of decedents with cardiac variants aligns with recent studies of the disproportionate cardiac burden the epilepsy community faces compared to the general population and suggests a possible cardiac contribution to epilepsy mortality. These results identified 13 priority targets for future functional studies of these genes potential role in sudden death and demonstrates the necessity for further exploration of potential genetic contributions to SUDEP.
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Genetic missense variants in TNNI3K, encoding troponin-I interacting kinase, have been associated with dilated cardiomyopathy (DCM) and observed in families with supraventricular tachycardias (SVT). Previously, a family harboring the TNNI3K-c.1615A > G (p.Thr539Ala) variant presented with congenital junctional ectopic tachycardia (CJET), an arrhythmia that arises from the atrioventricular (AV) node and His bundle. However, this was a relatively small four-generational family with limited genetic testing (N = 3). We here describe a multigenerational family with CJET harboring a novel ultra-rare TNNI3K variant: TNNI3K-c.1729C > T (p.Leu577Phe). Of all 18 variant carriers, 13 individuals presented with CJET, resulting in a genetic penetrance of 72%. In addition, CJET is reported in another small family harboring TNNI3K-c.2225C > T (p.Pro742Leu). Similar to the previously published CJET family, both TNNI3K variants demonstrate a substantial reduction of kinase activity. Our study contributes novel evidence supporting the involvement of TNNI3K genetic variants as significant contributors to CJET, shedding light on potential mechanisms underlying this cardiac arrhythmia.
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Linhagem , Proteínas Serina-Treonina Quinases , Taquicardia Ectópica de Junção , Humanos , Feminino , Masculino , Adulto , Taquicardia Ectópica de Junção/genética , Taquicardia Ectópica de Junção/fisiopatologia , Proteínas Serina-Treonina Quinases/genética , Pessoa de Meia-Idade , Predisposição Genética para Doença , Mutação de Sentido Incorreto/genética , Adolescente , Criança , Adulto JovemRESUMO
BACKGROUND: Fenestrating a Fontan baffle has been associated with improved perioperative outcomes in patients with univentricular hearts. However, longer-term potential adverse effects remain debated. We sought to assess the impact of a fenestrated Fontan baffle on adverse cardiovascular events including all-cause mortality, cardiac transplantation, atrial arrhythmias, and thromboemboli. METHODS: A multicentre North American retrospective cohort study was conducted on patients with total cavopulmonary connection Fontan baffle, with and without fenestration. All components of the composite outcome were independently adjudicated. Potential static and time-varying confounders were taken into consideration, along with competing risks. RESULTS: A total of 407 patients were followed for 10.4 (7.1-14.4) years; 70.0% had fenestration of their Fontan baffle. The fenestration spontaneously closed or was deliberately sealed in 79.9% of patients a median of 2.0 years after Fontan completion. In multivariable analysis in which a persistent fenestration was modelled as a time-dependent variable, an open fenestration did not confer a higher risk of the composite outcome (hazard ratio, 1.18; 95% confidence interval, 0.71-1.97; P = 0.521). In secondary analyses, an open fenestration was not significantly associated with components of the primary outcome: that is, mortality or transplantation, atrial arrhythmias, or thromboemboli. However, sensitivity analyses to assess the possible range of error resulting from imprecise dates for spontaneous fenestration closures could not rule out significant associations between an open fenestration and atrial arrhythmias or thromboemboli. CONCLUSIONS: In this multicentre study, no significant association was identified between an open fenestration in the Fontan baffle and major adverse cardiovascular events.
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AIMS: Echocardiographic assessment of adolescent athletes for arrhythmogenic cardiomyopathy (ACM) can be challenging owing to right ventricular (RV) exercise-related remodelling, particularly RV outflow tract (RVOT) dilation. The aim of this study is to evaluate the role of RV 2-D speckle tracking echocardiography (STE) in comparing healthy adolescent athletes with and without RVOT dilation to patients with ACM. METHODS AND RESULTS: A total of 391 adolescent athletes, mean age 14.5 ± 1.7 years, evaluated at three sports academies between 2014 and 2019 were included, and compared to previously reported ACM patients (n = 38 definite and n = 39 borderline). Peak systolic RV free wall (RVFW-Sl), global and segmental strain (Sl), and corresponding strain rates (SRl) were calculated. The participants meeting the major modified Task Force Criteria (mTFC) for RVOT dilation were defined as mTFC+ (n = 58, 14.8%), and the rest as mTFC- (n = 333, 85.2%). Mean RVFW-Sl was -27.6 ± 3.4% overall, -28.2 ± 4.1% in the mTFC+ group and - 27.5 ± 3.3% in the mTFC- group. mTFC+ athletes had normal RV-FW-Sl when compared to definite (-29% vs -19%, p < 0.001) and borderline ACM (-29% vs -21%, p < 0.001) cohorts. In addition, all mean global and regional Sl and SRl values were no worse in the mTFC+ group compared to the mTFC- (p values range < 0.0001 to 0.1, inferiority margin of 2% and 0.1 s-1 respectively). CONCLUSIONS: In athletes with RVOT dilation meeting the major mTFC, STE evaluation of the RV can demostrate normal function and differentiate physiological remodelling from pathological changes found in ACM, improving screening in grey-area cases.
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Displasia Arritmogênica Ventricular Direita , Disfunção Ventricular Direita , Humanos , Adolescente , Criança , Dilatação , Displasia Arritmogênica Ventricular Direita/diagnóstico por imagem , Função Ventricular Direita/fisiologia , Ecocardiografia/métodos , Atletas , Remodelação Ventricular/fisiologiaRESUMO
OBJECTIVE: Anti-Ro antibody-positive mothers are frequently referred for serial echocardiography due to the fetal risk of developing heart block and endocardial fibroelastosis. Little is known why only some and not all offspring develop these cardiac manifestations of neonatal lupus (CNL). This prospective study examined associations between anti-Ro antibody titers and fetal CNL. METHODS: Antibody-positive mothers referred since 2018 for fetal echocardiography at risk of CNL (group 1; n = 240) or with CNL (group 2; n = 18) were included. Maternal antibody titers were measured with a chemiluminescent immunoassay (CIA). Additional testing on diluted serum samples was used to quantify anti-Ro 60 antibody titers above the analytical measuring range (AMR) of the standard CIA (≥1,375 chemiluminescent units [CU]). RESULTS: Among 27 total mothers with a fetal diagnosis of CNL, all displayed anti-Ro 60 antibody titers that exceeded the AMR of the CIA at least 10-fold. Of 122 mothers in group 1 who underwent additional anti-Ro 60 antibody testing, event rates of CNL (n = 9) were 0% (0 of 45) among mothers with anti-Ro 60 antibody titers from 1,375-10,000 CU, 5% (3 of 56) among mothers with titers from 10,000-50,000 CU, but 29% (6 of 21) among mothers with titers >50,000 CU (odds ratio 13.1, P = 0.0008). Of mothers in group 2 with a primary diagnosis of CNL, 0% (0 of 18 mothers) had anti-Ro 60 antibody titers <10,000 CU, 44% (8 of 18 mothers) had titers from 10,000-50,000 CU, and 56% (10 of 18 mothers) had titers >50,000 CU. CONCLUSION: CNL is associated with substantially higher anti-Ro antibody titers than are obtained using a standard CIA. Enhancing the assay measuring range allows an improved specificity of identifying pregnancies at risk of CNL.
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Doenças Fetais , Cardiopatias , Lúpus Eritematoso Sistêmico , Recém-Nascido , Feminino , Gravidez , Humanos , Estudos Prospectivos , Doenças Fetais/diagnóstico , Anticorpos Antinucleares , Bloqueio Cardíaco/diagnóstico , ImunoensaioRESUMO
The intercalated disc (ICD) is a unique membrane structure that is indispensable to normal heart function, yet its structural organization is not completely understood. Previously, we showed that the ICD-bound transmembrane protein 65 (Tmem65) was required for connexin43 (Cx43) localization and function in cultured mouse neonatal cardiomyocytes. Here, we investigate the functional and cellular effects of Tmem65 reductions on the myocardium in a mouse model by injecting CD1 mouse pups (3-7 days after birth) with recombinant adeno-associated virus 9 (rAAV9) harboring Tmem65 shRNA, which reduces Tmem65 expression by 90% in mouse ventricles compared to scrambled shRNA injection. Tmem65 knockdown (KD) results in increased mortality which is accompanied by eccentric hypertrophic cardiomyopathy within 3 weeks of injection and progression to dilated cardiomyopathy with severe cardiac fibrosis by 7 weeks post-injection. Tmem65 KD hearts display depressed hemodynamics as measured echocardiographically as well as slowed conduction in optical recording accompanied by prolonged PR intervals and QRS duration in electrocardiograms. Immunoprecipitation and super-resolution microscopy demonstrate a physical interaction between Tmem65 and sodium channel ß subunit (ß1) in mouse hearts and this interaction appears to be required for both the establishment of perinexal nanodomain structure and the localization of both voltage-gated sodium channel 1.5 (NaV1.5) and Cx43 to ICDs. Despite the loss of NaV1.5 at ICDs, whole-cell patch clamp electrophysiology did not reveal reductions in Na+ currents but did show reduced Ca2+ and K+ currents in Tmem65 KD cardiomyocytes in comparison to control cells. We conclude that disrupting Tmem65 function results in impaired ICD structure, abnormal cardiac electrophysiology, and ultimately cardiomyopathy.
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Conexina 43 , Canal de Sódio Disparado por Voltagem NAV1.5 , Camundongos , Animais , Conexina 43/genética , Conexina 43/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Canal de Sódio Disparado por Voltagem NAV1.5/metabolismo , RNA Interferente Pequeno/metabolismo , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Fatores de Transcrição/metabolismoRESUMO
BACKGROUND: Vitamin K antagonists (VKAs) are frequently prescribed to patients with congenital heart disease (CHD) for atrial arrhythmias or Fontan palliation, but there is a paucity of data regarding time spent in the therapeutic range (TTR). We sought to determine the TTR in patients with CHD and atrial arrhythmias or Fontan palliation prescribed VKAs and explore associations with thromboembolic and bleeding events. METHODS: A multicentre North American cohort study was conducted on patients with CHD who received VKAs for sustained atrial arrhythmia or Fontan palliation. TTR was calculated using the Rosendaal linear interpolation method. Generalized estimating equations were used to explore factors associated with time outside the therapeutic range. RESULTS: A total of 567 patients, aged 33 ± 17 years, 56% female, received VKAs for 11.5 ± 8.4 years for atrial arrhythmias (63.0%) or Fontan palliation (58.0%). CHD was simple, moderate, and complex in 10.8%, 20.3%, and 69.0%, respectively. Site investigators perceived good control over international normalized ratio (INR) levels in most patients (75.3%), with no or minor compliance or adherence issues (85.6%). The mean TTR was 41.9% (95% confidence interval [CI], 39.0%-44.8%). Forty-seven (8.3%) and 34 (6.0%) patients had thromboembolic and bleeding events, respectively. Thromboembolic events were associated with a higher proportion of time below the therapeutic range (31.3% vs 19.1%, P = 0.003) and bleeding complications with a higher proportion of time above the therapeutic range (32.5% vs 19.5%, P = 0.006). CONCLUSIONS: Patients with CHD who receive VKAs spend < 42% of their time with INR levels in the therapeutic range, with repercussions regarding thromboembolic and bleeding complications.
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Fibrilação Atrial , Cardiopatias Congênitas , Tromboembolia , Humanos , Feminino , Masculino , Vitamina K , Estudos de Coortes , Fibrilação Atrial/complicações , Anticoagulantes/uso terapêutico , Coeficiente Internacional Normatizado , Fibrinolíticos/uso terapêutico , Tromboembolia/epidemiologia , Tromboembolia/etiologia , Tromboembolia/prevenção & controle , Hemorragia/induzido quimicamente , Hemorragia/epidemiologia , Cardiopatias Congênitas/complicaçõesRESUMO
BACKGROUND: Arrhythmogenic right-ventricular cardiomyopathy (ARVC) is an identified cause of sport-related sudden cardiac arrest (SCA). Identifying athletes with ARVC and restricting them from exercise is believed to reduce the risk of SCA. The electrocardiogram (ECG) is considered to be an important component of screening for ARVC; however, the sensitivity of the 12-lead ECG to identify ARVC in young asymptomatic persons is unknown. METHODS: In this retrospective study, we identified 70 patients (49 ARVC-positive, based on Task Force Criteria, and 21 age-matched ARVC-negative persons from a paediatric arrhythmia database (<18 years of age); ECGs were analyzed for abnormalities, based on International Criteria for Interpretation of ECGs in Athletes, and ECG findings were adjudicated by group consensus. RESULTS: Of the 49 ARVC-positive patients (median age: 17 [interquartile range: 16-18], 65% male), 22% were found to have abnormal ECGs; the most common ECG findings were T-wave inversions. Patients with symptoms were more likely to have abnormal ECGs than asymptomatic patients (28% compared with 17%, respectively; P = 0.002). Of 16 gene-positive patients, 31% had abnormal ECGs. Patients with abnormal ECGs had larger right-ventricular end-diastolic volume indexes on magnetic resonance imaging than those with normal ECGs (P = 0.03). CONCLUSIONS: The ECG was insensitive for detecting ARVC in young (age <18 years), asymptomatic patients, and is unlikely to provide significant diagnostic value for identifying ARVC on routine preparticipation screening of adolescent athletes.
INTRODUCTION: La cardiomyopathie ventriculaire droite arythmogène (CVDA) est une cause établie d'arrêt cardiaque soudain (ACS) du sportif. On croit que le fait de repérer les athlètes atteints de CVDA et de limiter leur exercice réduit le risque d'ACS. On considère que l'électrocardiogramme (ECG) est une composante importante du dépistage de la CVDA. Toutefois, on ignore la sensibilité de l'ECG à 12 dérivations pour détecter la CVDA chez les jeunes personnes asymptomatiques. MÉTHODES: Dans cette étude rétrospective, nous avons repéré 70 patients (49 personnes dont les résultats sont positifs à la CVDA selon les critères de la Task Force, et 21 personnes appariées selon l'âge dont les résultats étaient positifs à la CVDA) d'une base de données sur l'arythmie en pédiatrie (< 18 ans); nous avons analysé les ECG pour détecter les anomalies selon les Critères de consensus internationaux de l'interprétation de l'ECG chez l'athlète, et nous sommes prononcés sur les résultats des ECG par consensus. RÉSULTATS: Parmi les 49 patients dont les résultats étaient positifs à la CVDA (âge médian : 17 [intervalle interquartile : 16-18], 65 % de sexe masculin), nous avons observé que 22 % d'entre eux avaient des résultats anormaux à l'ECG; les résultats les plus fréquents à l'ECG montraient des inversions de l'onde T. Les patients symptomatiques étaient plus susceptibles d'avoir des résultats anormaux à l'ECG que les patients asymptomatiques (28 % et 17 %, respectivement; P = 0,002). Parmi les 16 patients qui avaient des résultats génétiques positifs, 31 % avaient des résultats anormaux à l'ECG. Les patients qui avaient des résultats anormaux à l'ECG avaient des indices plus grands du volume télédiastolique du ventricule droit en fin de diastole à l'imagerie par résonance magnétique que ceux qui avaient des résultats normaux à l'ECG (P = 0,03). CONCLUSIONS: L'ECG n'a pas montré la sensibilité pour détecter la CVDA chez les jeunes (< 18 ans) patients asymptomatiques et n'a pas été susceptible de fournir une valeur diagnostique significative pour détecter la CVDA au dépistage systématique préalable à l'activité sportive des athlètes adolescents.
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BACKGROUND: Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disease characterized by fibrofatty replacement of the right and left ventricle, often causing ventricular dysfunction and life-threatening arrhythmias. Variants in desmosomal genes account for up to 60% of cases. Our objective was to establish the prevalence and clinical features of ACM stemming from pathogenic variants in the nondesmosomal cadherin 2 (CDH2), a novel genetic substrate of ACM. METHODS: A cohort of 500 unrelated patients with a definite diagnosis of ACM and no disease-causing variants in the main ACM genes was assembled. Genetic screening of CDH2 was performed through next-generation or Sanger sequencing. Whenever possible, cascade screening was initiated in the families of CDH2-positive probands, and clinical evaluation was performed. RESULTS: Genetic screening of CDH2 led to the identification of 7 rare variants: 5, identified in 6 probands, were classified as pathogenic or likely pathogenic. The previously established p.D407N pathogenic variant was detected in 2 additional probands. Probands and family members with pathogenic/likely pathogenic variants in CDH2 were clinically evaluated, and along with previously published cases, altogether contributed to the identification of gene-specific features (13 cases from this cohort and 11 previously published, for a total of 9 probands and 15 family members). Ventricular arrhythmic events occurred in most CDH2-positive subjects (20/24, 83%), while the occurrence of heart failure was rare (2/24, 8.3%). Among probands, sustained ventricular tachycardia and sudden cardiac death occurred in 5/9 (56%). CONCLUSIONS: In this worldwide cohort of previously genotype-negative ACM patients, the prevalence of probands with CDH2 pathogenic/likely pathogenic variants was 1.2% (6/500). Our data show that this cohort of CDH2-ACM patients has a high incidence of ventricular arrhythmias, while evolution toward heart failure is rare.
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Displasia Arritmogênica Ventricular Direita/genética , Caderinas/genética , Adolescente , Adulto , Displasia Arritmogênica Ventricular Direita/diagnóstico , Displasia Arritmogênica Ventricular Direita/epidemiologia , Caderinas/química , Feminino , Frequência do Gene , Variação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Prevalência , Domínios Proteicos/genética , Adulto JovemRESUMO
BACKGROUND: Right ventricular (RV) enlargement is common in endurance athletes. It is usually considered to be physiological, but it is possible that this remodelling is adverse, manifesting as a variant of arrhythmogenic right ventricular cardiomyopathy (ARVC), termed "exercise-induced ARVC." A novel biomarker (anti-desmoglein-2 [anti-DSG2] antibody) has been shown to indicate ARVC with high sensitivity and specificity and may be an immune response to breakdown of RV desmosomes. It is not known if this antibody is present in endurance athletes with RV enlargement but without clinical ARVC. METHODS: Middle-aged, healthy endurance athletes with RV enlargement on cardiac magnetic resonance imaging had serum tested for the presence of the anti-DSG2 antibody. All athletes also underwent Holter monitoring, a signal-averaged electrocardiogram, and an exercise questionnaire. RESULTS: A total of 30 athletes (20 men, 10 women, average age 53 ± 6 years) were enrolled in this study with median RV end-diastolic volume indexes of 117.1 mL/m2 (men) and 103.5 mL/m2 (women). Athletes demonstrated other characteristics of endurance training, including depolarization abnormalities (abnormal signal-averaged electrocardiogram, 19 of 30) and incomplete right bundle branch block (8 of 30). No athlete met criteria for definite or probable ARVC. None of the athletes tested positive for anti-DSG2 antibody. CONCLUSIONS: Among middle-aged endurance athletes with RV enlargement, the anti-DSG2 antibody, a suggested ARVC biomarker, is absent in all and is highly specific in this cohort (95% confidence interval, 88%-100%). Despite significant RV remodelling, these athletes did not express a previously characterized pathologic biomarker known to be sensitive for ARVC. Physiological exercise remodelling and pathologic ARVC remodelling are likely separate processes.
INTRODUCTION: L'augmentation du volume du ventricule droit (VD) est fréquente chez les sportifs d'endurance. On considère habituellement que ce remodelage est physiologique, mais il est possible qu'il soit indésirable, c'est-à-dire qu'il révèle une variante de la cardiomyopathie arythmogène du ventricule droit (CAVD), appelée « CAVD induite par l'exercice ¼. Il a été démontré qu'un nouveau biomarqueur (l'anticorps anti-desmogléine 2 [anti-DSG2]) présente une sensibilité et une spécificité élevées pour dépister la CAVD et qu'il peut être une réponse immunitaire à la dégradation des desmosomes du VD. On ne sait pas si cet anticorps est présent chez les sportifs d'endurance qui ont une augmentation du volume du VD, sans CAVD clinique. MÉTHODES: Les sportifs d'endurance d'âge moyen en bonne santé qui ont une augmentation du volume du VD à l'imagerie cardiaque par résonance magnétique ont subi une épreuve pour vérifier la présence de l'anticorps anti-DSG2 dans le sérum. Tous les athlètes ont également eu une surveillance par la méthode de Holter, un électrocardiogramme à signaux moyennés et un questionnaire sur l'exercice. RÉSULTATS: Nous avons inscrit à cette étude un total de 30 athlètes (20 hommes, 10 femmes, âge moyen de 53 ± 6 ans) dont les indices volumiques télédiastoliques médians du VD des hommes étaient de 117,1 ml/m2 et des femmes, de 103,5 ml/m2. Les athlètes ont démontré d'autres caractéristiques de l'entraînement en endurance, notamment des anomalies de la dépolarisation (électrocardiogramme à signaux moyennés anormal, 19 sur 30) et un bloc de branche droit incomplet (8 sur 30). Aucun athlète n'a répondu aux critères de CAVD définie ou probable. Aucun des athlètes n'a eu de résultats positifs au test de dépistage des anticorps anti-DSG2. CONCLUSIONS: Chez tous les sportifs d'endurance d'âge moyen qui ont une augmentation du volume du VD, l'anticorps anti-DSG2, un biomarqueur proposé pour dépister la CAVD, est absent et est hautement spécifique dans cette cohorte (intervalle de confiance à 95 %, 88 %-100 %). En dépit d'un remodelage important du VD, les athlètes n'ont pas exprimé le biomarqueur pathologique, auparavant caractérisé, connu pour être sensible au dépistage de la CAVD. Le remodelage physiologique induit par l'exercice et le remodelage pathologique associé à la CAVD sont des processus probablement distincts.
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BACKGROUND: Antibiotic stewardship (ABS) is a set of strategies to optimize antimicrobial use while reducing antibiotic resistance, improving patient outcomes, and decreasing unnecessary costs. Nurse practitioners (NPs) play an essential role in health care education and represent a valuable potential resource for ABS efforts. PURPOSE: The purpose of this study was to describe the knowledge, attitudes, and perceptions of NPs toward ABS. METHODS: A convenience sample of NPs attending the American Association of Nurse Practitioners annual conference was given a modified descriptive survey. Descriptive statistics were used to assess normality. RESULTS: A total of 194 NPs completed the questionnaire (88% female; 70% master's degree). Factors affecting the decisions of antibiotic prescriptions included patient condition (79%) and patient cost (58%). Nurse practitioners based their antibiotic decisions on the antibiogram (63%) in their setting, whereas 56% indicated they start with broad spectrum and tailor antibiotic choices after cultures are received. Nurse practitioners understood that inappropriate antibiotic use causes resistance (97%), harms the patient (97%), and optimum antibiotic use will reduce resistance (94%). Participants also recognized that strong knowledge of antibiotics was important (94%) and felt confident in using antibiotics (86%). However, 94% agreed that antibiotics are overused nationally, and only 62% thought antibiotics were overused in their setting. IMPLICATIONS FOR PRACTICE: Nurse practitioners recognize that knowledge about antibiotics is important to their career and would like more education about antibiotics and feedback about their antibiotic choices. Finding effective ways to provide this education could change practice and improve antibiotic use.
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Gestão de Antimicrobianos , Profissionais de Enfermagem , Antibacterianos/uso terapêutico , Resistência Microbiana a Medicamentos , Feminino , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Masculino , PercepçãoRESUMO
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
AIMS: Brugada syndrome (BrS) is characterized by a unique electrocardiogram (ECG) pattern and life-threatening arrhythmias. However, the Type 1 Brugada ECG pattern is often transient, and a genetic cause is only identified in <25% of patients. We sought to identify an additional biomarker for this rare condition. As myocardial inflammation may be present in BrS, we evaluated whether myocardial autoantibodies can be detected in these patients. METHODS AND RESULTS: For antibody (Ab) discovery, normal human ventricular myocardial proteins were solubilized and separated by isoelectric focusing (IEF) and molecular weight on two-dimensional (2D) gels and used to discover Abs by plating with sera from patients with BrS and control subjects. Target proteins were identified by mass spectrometry (MS). Brugada syndrome subjects were defined based on a consensus clinical scoring system. We assessed discovery and validation cohorts by 2D gels, western blots, and ELISA. We performed immunohistochemistry on myocardium from BrS subjects (vs. control). All (3/3) 2D gels exposed to sera from BrS patients demonstrated specific Abs to four proteins, confirmed by MS to be α-cardiac actin, α-skeletal actin, keratin, and connexin-43, vs. 0/8 control subjects. All (18/18) BrS subjects from our validation cohorts demonstrated the same Abs, confirmed by western blots, vs. 0/24 additional controls. ELISA optical densities for all Abs were elevated in all BrS subjects compared to controls. In myocardium obtained from BrS subjects, each protein, as well as SCN5A, demonstrated abnormal protein expression in aggregates. CONCLUSION: A biomarker profile of autoantibodies against four cardiac proteins, namely α-cardiac actin, α-skeletal actin, keratin, and connexin-43, can be identified from sera of BrS patients and is highly sensitive and specific, irrespective of genetic cause for BrS. The four involved proteins, along with the SCN5A-encoded Nav1.5 alpha subunit are expressed abnormally in the myocardium of patients with BrS.
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Síndrome de Brugada , Arritmias Cardíacas , Autoanticorpos , Síndrome de Brugada/diagnóstico , Eletrocardiografia , Ventrículos do Coração , HumanosRESUMO
Advances in genomics have transformed our ability to identify the genetic causes of rare diseases (RDs), yet we have a limited understanding of the mechanistic roles of most genes in health and disease. When a novel RD gene is first discovered, there is minimal insight into its biological function, the pathogenic mechanisms of disease-causing variants, and how therapy might be approached. To address this gap, the Canadian Rare Diseases Models and Mechanisms (RDMM) Network was established to connect clinicians discovering new disease genes with Canadian scientists able to study equivalent genes and pathways in model organisms (MOs). The Network is built around a registry of more than 500 Canadian MO scientists, representing expertise for over 7,500 human genes. RDMM uses a committee process to identify and evaluate clinician-MO scientist collaborations and approve 25,000 Canadian dollars in catalyst funding. To date, we have made 85 clinician-MO scientist connections and funded 105 projects. These collaborations help confirm variant pathogenicity and unravel the molecular mechanisms of RD, and also test novel therapies and lead to long-term collaborations. To expand the impact and reach of this model, we made the RDMM Registry open-source, portable, and customizable, and we freely share our committee structures and processes. We are currently working with emerging networks in Europe, Australia, and Japan to link international RDMM networks and registries and enable matches across borders. We will continue to create meaningful collaborations, generate knowledge, and advance RD research locally and globally for the benefit of patients and families living with RD.
Assuntos
Modelos Animais de Doenças , Marcadores Genéticos , Doenças Raras/genética , Doenças Raras/terapia , Sistema de Registros/normas , Animais , Bases de Dados Factuais , Genômica , Humanos , Doenças Raras/epidemiologiaRESUMO
BACKGROUND: There is limited pharmacologic therapy to reduce the QT interval in hereditary long QT syndrome (LQTS). CASE SUMMARY: We describe a child with Allan-Herndon-Dudley syndrome, Lennox-Gastaut epileptic syndrome (LGS), and LQTS Type 1 (LQTS1). Rufinamide was added to his antiepileptic medications to improve seizure control and was noted to be associated with a marked improvement in electrocardiogram QT interval. To the best of our knowledge, this is the first reported case of successful pharmacologic shortening of the QT interval in LQTS1. DISCUSSION: This case report highlights the potential benefits of rufinamide, a drug associated with mild QT shortening in normal individuals, to markedly reduce and normalize QT duration in a subject with LQTS1.
RESUMO
AIMS: Pathogenic gain-of-function variants in CACAN1C cause type-8 long QT syndrome (LQT8). We sought to describe the electrocardiographic features in LQT8 and utilize molecular modelling to gain mechanistic insights into its genetic culprits. METHODS AND RESULTS: Rare variants in CACNA1C were identified from genetic testing laboratories. Treating physicians provided clinical information. Variant pathogenicity was independently assessed according to recent guidelines. Pathogenic (P) and likely pathogenic (LP) variants were mapped onto a 3D modelled structure of the Cav1.2 protein. Nine P/LP variants, identified in 23 patients from 19 families with non-syndromic LQTS were identified. Six variants, found in 79% of families, clustered to a 4-residue section in the cytosolic II-III loop region which forms a region capable of binding STAC SH3 domains. Therefore, variants may affect binding of SH3-domain containing proteins. Arrhythmic events occurred in similar proportions of patients with II-III loop variants and with other P/LP variants (53% vs. 48%, P = 0.41) despite shorter QTc intervals (477 ± 31 ms vs. 515 ± 37 ms, P = 0.03). A history of sudden death was reported only in families with II-III loop variants (60% vs. 0%, P = 0.03). The predominant T-wave morphology was a late peaking T wave with a steep descending limb. Exercise testing demonstrated QTc prolongation on standing and at 4 min recovery after exercise. CONCLUSION: The majority of P/LP variants in patients with CACNA1C-mediated LQT8 cluster in an SH3-binding domain of the cytosolic II-III loop. This represents a 'mutation hotspot' in LQT8. A late-peaking T wave with a steep descending limb and QT prolongation on exercise are commonly seen.