RESUMO
Ion channels are membrane proteins responsible for the passage of ions down their electrochemical gradients and across biological membranes. In this, they generate and shape action potentials and provide secondary messengers for various signaling pathways. They are often part of larger complexes containing auxiliary subunits and regulatory proteins. Channelopathies arise from mutations in the genes encoding ion channels or their associated proteins. Recent advances in cryo-electron microscopy have resulted in an explosion of ion channel structures in multiple states, generating a wealth of new information on channelopathies. Disease-associated mutations fall into different categories, interfering with ion permeation, protein folding, voltage sensing, ligand and protein binding, and allosteric modulation of channel gating. Prime examples of these are Ca2+-selective channels expressed in myocytes, for which multiple structures in distinct conformational states have recently been uncovered. We discuss the latest insights into these calcium channelopathies from a structural viewpoint.
Assuntos
Canais de Cálcio/genética , Cálcio/metabolismo , Canalopatias/genética , Contração Muscular/genética , Animais , Canais de Cálcio/metabolismo , Membrana Celular/metabolismo , Membrana Celular/patologia , Membrana Celular/ultraestrutura , Canalopatias/metabolismo , Canalopatias/patologia , Microscopia Crioeletrônica , Acoplamento Excitação-Contração/genética , Humanos , Transdução de Sinais/genéticaRESUMO
Fluorescent reporters of cardiac electrophysiology provide valuable information on heart cell and tissue function. However, motion artifacts caused by cardiac muscle contraction interfere with accurate measurement of fluorescence signals. Although drugs such as blebbistatin can be applied to stop cardiac tissue from contracting by uncoupling calcium-contraction, their usage prevents the study of excitation-contraction coupling and, as we show, impacts cellular structure. We therefore developed a robust method to remove motion computationally from images of contracting cardiac muscle and to map fluorescent reporters of cardiac electrophysiological activity onto images of undeformed tissue. When validated on cardiomyocytes derived from human induced pluripotent stem cells (iPSCs), in both monolayers and engineered tissues, the method enabled efficient and robust reduction of motion artifact. As with pharmacologic approaches using blebbistatin for motion removal, our algorithm improved the accuracy of optical mapping, as demonstrated by spatial maps of calcium transient decay. However, unlike pharmacologic motion removal, our computational approach allowed direct analysis of calcium-contraction coupling. Results revealed calcium-contraction coupling to be more uniform across cells within engineered tissues than across cells in monolayer culture. The algorithm shows promise as a robust and accurate tool for optical mapping studies of excitation-contraction coupling in heart tissue.
Assuntos
Células-Tronco Pluripotentes Induzidas , Miócitos Cardíacos , Humanos , Artefatos , Cálcio , Software , Cálcio da Dieta , CorantesRESUMO
Long QT syndrome (LQTS) is a human inherited heart condition that can cause life-threatening arrhythmia including sudden cardiac death. Mutations in the ubiquitous Ca2+-sensing protein calmodulin (CaM) are associated with LQTS, but the molecular mechanism by which these mutations lead to irregular heartbeats is not fully understood. Here, we use a multidisciplinary approach including protein biophysics, structural biology, confocal imaging, and patch-clamp electrophysiology to determine the effect of the disease-associated CaM mutation E140G on CaM structure and function. We present novel data showing that mutant-regulated CaMKIIδ kinase activity is impaired with a significant reduction in enzyme autophosphorylation rate. We report the first high-resolution crystal structure of a LQTS-associated CaM variant in complex with the CaMKIIδ peptide, which shows significant structural differences, compared to the WT complex. Furthermore, we demonstrate that the E140G mutation significantly disrupted Cav1.2 Ca2+/CaM-dependent inactivation, while cardiac ryanodine receptor (RyR2) activity remained unaffected. In addition, we show that the LQTS-associated mutation alters CaM's Ca2+-binding characteristics, secondary structure content, and interaction with key partners involved in excitation-contraction coupling (CaMKIIδ, Cav1.2, RyR2). In conclusion, LQTS-associated CaM mutation E140G severely impacts the structure-function relationship of CaM and its regulation of CaMKIIδ and Cav1.2. This provides a crucial insight into the molecular factors contributing to CaM-mediated arrhythmias with a central role for CaMKIIδ.
Assuntos
Canais de Cálcio Tipo L , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina , Calmodulina , Síndrome do QT Longo , Humanos , Arritmias Cardíacas/genética , Arritmias Cardíacas/fisiopatologia , Cálcio/metabolismo , Canais de Cálcio Tipo L/genética , Canais de Cálcio Tipo L/metabolismo , Calmodulina/genética , Calmodulina/metabolismo , Síndrome do QT Longo/genética , Miócitos Cardíacos/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Mutação , Estrutura Secundária de Proteína/genética , Ligação Proteica/genética , CristalografiaRESUMO
Desmin, the most abundant intermediate filament in cardiomyocytes, plays a key role in maintaining cardiomyocyte structure by interconnecting intracellular organelles, and facilitating cardiomyocyte interactions with the extracellular matrix and neighboring cardiomyocytes. As a consequence, mutations in the desmin gene (DES) can lead to desminopathies, a group of diseases characterized by variable and often severe cardiomyopathies along with skeletal muscle disorders. The basic desmin intermediate filament structure is composed of four segments separated by linkers that further assemble into dimers, tetramers and eventually unit-length filaments that compact radially to give the final form of the filament. Each step in this process is critical for proper filament formation and allow specific interactions within the cell. Mutations within the desmin gene can disrupt filament formation, as seen by aggregate formation, and thus have severe cardiac and skeletal outcomes, depending on the locus of the mutation. The focus of this review is to outline the cardiac molecular consequences of mutations located in the C-terminal part of segment 2B. This region is crucial for ensuring proper desmin filament formation and is a known hotspot for mutations that significantly impact cardiac function.
Assuntos
Cardiomiopatias , Desmina , Mutação , Desmina/genética , Desmina/metabolismo , Humanos , Cardiomiopatias/genética , Cardiomiopatias/metabolismo , Cardiomiopatias/patologia , Mutação/genética , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Filamentos Intermediários/genética , Filamentos Intermediários/metabolismo , AnimaisRESUMO
Long QT syndrome (LQTS) type 3 although less common than the first two forms, differs in that arrhythmic events are less likely triggered by adrenergic stimuli and are more often lethal. Effective pharmacological treatment is challenged by interindividual differences, mutation dependence, and adverse effects, translating into an increased use of invasive measures (implantable cardioverter-defibrillator, sympathetic denervation) in patients with LQTS type 3. Previous studies have demonstrated the therapeutic potential of polyclonal KCNQ1 antibody for LQTS type 2. Here, we sought to identify a monoclonal KCNQ1 antibody that preserves the electrophysiological properties of the polyclonal form. Using hybridoma technology, murine monoclonal antibodies were generated, and patch clamp studies were performed for functional characterization. We identified a monoclonal KCNQ1 antibody able to normalize cardiac action potential duration and to suppress arrhythmias in a pharmacological model of LQTS type 3 using human-induced pluripotent stem cell-derived cardiomyocytes.NEW & NOTEWORTHY Long QT syndrome is a leading cause of sudden cardiac death in the young. Recent research has highlighted KCNQ1 antibody therapy as a new treatment modality for long QT syndrome type 2. Here, we developed a monoclonal KCNQ1 antibody that similarly restores cardiac repolarization. Moreover, the identified monoclonal KCNQ1 antibody suppresses arrhythmias in a cellular model of long QT syndrome type 3, holding promise as a first-in-class antiarrhythmic immunotherapy.
Assuntos
Canal de Potássio KCNQ1 , Síndrome do QT Longo , Humanos , Camundongos , Animais , Canal de Potássio KCNQ1/genética , Síndrome do QT Longo/terapia , Síndrome do QT Longo/tratamento farmacológico , Arritmias Cardíacas , Miócitos Cardíacos , Imunoterapia , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêuticoRESUMO
Heart diseases are a major cause of morbidity and mortality worldwide. Understanding the molecular mechanisms underlying these diseases is essential for the development of effective diagnostic and therapeutic strategies. The FHL family consists of five members: FHL1, FHL2, FHL3, FHL4, and FHL5/Act. These members exhibit different expression patterns in various tissues including the heart. FHL family proteins are implicated in cardiac remodeling, regulation of metabolic enzymes, and cardiac biomechanical stress perception. A large number of studies have explored the link between FHL family proteins and cardiac disease, skeletal muscle disease, and ovarian metabolism, but a comprehensive and in-depth understanding of the specific molecular mechanisms targeting FHL on cardiac disease is lacking. The aim of this review is to explore the structure and function of FHL family members, to comprehensively elucidate the mechanisms by which they regulate the heart, and to explore in depth the changes in FHL family members observed in different cardiac disorders, as well as the effects of mutations in FHL proteins on heart health.
Assuntos
Cardiopatias , Doenças Musculares , Humanos , Proteínas Musculares/metabolismo , Doenças Musculares/genética , Cardiopatias/genética , Mutação , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas com Domínio LIM/genéticaRESUMO
Atrial fibrillation (AF) remains challenging to prevent and treat. A key feature of AF is atrial enlargement. However, not all atrial enlargement progresses to AF. Atrial enlargement in response to physiological stimuli such as exercise is typically benign and reversible. Understanding the differences in atrial function and molecular profile underpinning pathological and physiological atrial remodelling will be critical for identifying new strategies for AF. The discovery of molecular mechanisms responsible for pathological and physiological ventricular hypertrophy has uncovered new drug targets for heart failure. Studies in the atria have been limited in comparison. Here, we characterised mouse atria from (1) a pathological model (cardiomyocyte-specific transgenic (Tg) that develops dilated cardiomyopathy [DCM] and AF due to reduced protective signalling [PI3K]; DCM-dnPI3K), and (2) a physiological model (cardiomyocyte-specific Tg with an enlarged heart due to increased insulin-like growth factor 1 receptor; IGF1R). Both models presented with an increase in atrial mass, but displayed distinct functional, cellular, histological and molecular phenotypes. Atrial enlargement in the DCM-dnPI3K Tg, but not IGF1R Tg, was associated with atrial dysfunction, fibrosis and a heart failure gene expression pattern. Atrial proteomics identified protein networks related to cardiac contractility, sarcomere assembly, metabolism, mitochondria, and extracellular matrix which were differentially regulated in the models; many co-identified in atrial proteomics data sets from human AF. In summary, physiological and pathological atrial enlargement are associated with distinct features, and the proteomic dataset provides a resource to study potential new regulators of atrial biology and function, drug targets and biomarkers for AF.
Assuntos
Fibrilação Atrial , Remodelamento Atrial , Átrios do Coração , Camundongos Transgênicos , Miócitos Cardíacos , Fibrilação Atrial/fisiopatologia , Fibrilação Atrial/metabolismo , Fibrilação Atrial/genética , Animais , Átrios do Coração/metabolismo , Átrios do Coração/fisiopatologia , Átrios do Coração/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Receptor IGF Tipo 1/metabolismo , Receptor IGF Tipo 1/genética , Cardiomiopatia Dilatada/fisiopatologia , Cardiomiopatia Dilatada/genética , Cardiomiopatia Dilatada/metabolismo , Cardiomiopatia Dilatada/patologia , Modelos Animais de Doenças , Fibrose , Camundongos , Humanos , Transdução de Sinais , Fosfatidilinositol 3-Quinases/metabolismo , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologiaRESUMO
Cardiac arrhythmia is currently considered to be the direct cause of death in a majority of sudden unexplained death (SUD) cases, yet the genetic predisposition and corresponding endophenotypes contributing to SUD remain incompletely understood. In this study, we aimed to investigate the involvement of Coenzyme Q (CoQ) deficiency in SUD. First, we re-analyzed the exome sequencing data of 45 SUD and 151 sudden infant death syndrome (SIDS) cases from our previous studies, focusing on previously overlooked genetic variants in 44 human CoQ deficiency-related genes. A considerable proportion of the SUD (38%) and SIDS (37%) cases were found to harbor rare variants with likely functional effects. Subsequent burden testing, including all rare exonic and untranslated region variants identified in our case cohorts, further confirmed the existence of significant genetic burden. Based on the genetic findings, the influence of CoQ deficiency on electrophysiological and morphological properties was further examined in a mouse model. A significantly prolonged PR interval and an increased occurrence of atrioventricular block were observed in the 4-nitrobenzoate induced CoQ deficiency mouse group, suggesting that CoQ deficiency may predispose individuals to sudden death through an increased risk of cardiac arrhythmia. Overall, our findings suggest that CoQ deficiency-related genes should also be considered in the molecular autopsy of SUD.
RESUMO
The rapid growth in computational power, sensor technology, and wearable devices has provided a solid foundation for all aspects of cardiac arrhythmia care. Artificial intelligence (AI) has been instrumental in bringing about significant changes in the prevention, risk assessment, diagnosis, and treatment of arrhythmia. This review examines the current state of AI in the diagnosis and treatment of atrial fibrillation, supraventricular arrhythmia, ventricular arrhythmia, hereditary channelopathies, and cardiac pacing. Furthermore, ChatGPT, which has gained attention recently, is addressed in this paper along with its potential applications in the field of arrhythmia. Additionally, the accuracy of arrhythmia diagnosis can be improved by identifying electrode misplacement or erroneous swapping of electrode position using AI. Remote monitoring has expanded greatly due to the emergence of contactless monitoring technology as wearable devices continue to develop and flourish. Parallel advances in AI computing power, ChatGPT, availability of large data sets, and more have greatly expanded applications in arrhythmia diagnosis, risk assessment, and treatment. More precise algorithms based on big data, personalized risk assessment, telemedicine and mobile health, smart hardware and wearables, and the exploration of rare or complex types of arrhythmia are the future direction.
Assuntos
Arritmias Cardíacas , Inteligência Artificial , Humanos , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/terapia , Medição de RiscoRESUMO
Limb-girdle muscular dystrophy type R25 (LGMDR25) is caused by recessive mutations in BVES encoding a cAMP-binding protein, characterized by progressive muscular dystrophy with deteriorating muscle function and impaired cardiac conduction in patients. There is currently no therapeutic treatment for LGMDR25 patients. Here we report the efficacy and safety of recombinant adeno-associated virus 9 (AAV9)-mediated systemic delivery of human BVES driven by a muscle-specific promoter MHCK7 (AAV9.BVES) in BVES-knockout (BVES-KO) mice. AAV9.BVES efficiently transduced the cardiac and skeletal muscle tissues when intraperitoneally injected into neonatal BVES-KO mice. AAV9.BVES dramatically improved body weight gain, muscle mass, muscle strength, and exercise performance in BVES-KO mice regardless of sex. AAV9.BVES also significantly ameliorated the histopathological features of muscular dystrophy. The heart rate reduction was also normalized in BVES-KO mice under exercise-induced stress following systemic AAV9.BVES delivery. Moreover, intravenous AAV9.BVES administration into adult BVES-KO mice after the disease onset also resulted in substantial improvement in body weight, muscle mass, muscle contractility, and stress-induced heart rhythm abnormality. No obvious toxicity was detected. Taken together, these results provide the proof-of-concept evidence to support the AAV9.BVES gene therapy for LGMDR25.
Assuntos
Distrofia Muscular do Cíngulo dos Membros , Distrofias Musculares , Camundongos , Animais , Humanos , Dependovirus/genética , Distrofia Muscular do Cíngulo dos Membros/genética , Músculo Esquelético/metabolismo , Proteínas/metabolismo , Camundongos Knockout , Proteínas Musculares/genética , Moléculas de Adesão Celular/metabolismoRESUMO
Background: Celiac Disease (CD) is characterized by small intestine involvement. However, cardiac manifestations may also be seen in the clinical course. The significance of the QRS prolongation and the presence of QRS fragmentation (fQRS) has been previously studied in many chronic inflammatory disorders as an independent predictor of cardiac manifestations. The study aimed to evaluate the QRS duration and presence of fQRS in patients with CD. Methods: 164 patients with CD and 162 healthy controls were included in the present study. QRS duration and presence of fQRS were calculated from the 12-lead electrocardiogram and compared between groups. The association between these parameters and disease duration was also evaluated. Results: QRS duration was found to be higher in the CD group compared to the control group (83 (76.8-93) vs. 91 (84-94), p<0.001). The presence of fQRS was demonstrated to be higher in the CD group (n=68 (41.5%) vs n=42 (25.9%), p=0.003). Notably, QRS duration was positively correlated with disease duration (Spearman's Rho= 0.47, p<0.001). In addition, disease duration was significantly higher in the fQRS (+) group (60 (23,5-144) vs. 28,5 (15-71,5), p=0.002). Conclusion: This study revealed that QRS prolongation and the presence of fQRS were higher in patients with CD. The presence of these findings may be an indicator of early subclinical cardiac involvement, especially in those with long disease duration. Thus, patients with these ECG findings can be considered for further cardiac evaluation.
Assuntos
Doença Celíaca , Eletrocardiografia , Humanos , Doença Celíaca/fisiopatologia , Doença Celíaca/complicações , Feminino , Masculino , Adulto , Pessoa de Meia-Idade , Estudos de Casos e Controles , Adulto Jovem , AdolescenteRESUMO
Background: Inflammatory Bowel Disease (IBD) is mostly characterized by gastrointestinal tract involvement, however can also be accompanied with cardiac manifestations. QRS prolongation and the presence of QRS fragmentation (fQRS) have been previously evaluated in many chronic inflammatory diseases, as an independent predictor of cardiac events. In this study, we aimed to evaluate the QRS duration and fQRS in patients with IBD. Methods: The presented study was designed as a single-center retrospective cohort study. The study population consisted of 217 patients with IBD and 195 healthy controls. QRS duration and presence of fQRS were evaluated using a 12-lead electrocardiogram. These parameters were compared between groups. Results: QRS duration was demonstrated to be higher in the IBD group compared to the control group (92 (86-98) vs. 82 (75-90), p<0.001). The presence of fQRS was significantly higher in the IBD group (n=101 (47%) vs n=59 (30%), p=0.006). In addition, a positive correlation was demonstrated between QRS duration and disease duration (Spearman's Rho= 0.4, p<0.001). Notably, disease and QRS duration were significantly higher in the fQRS (+) group (102 (56.5-154) vs. 55 (24.3-118.3), <0.001; 94 (86-100) vs. 92 (84-96), 0.016; respectively). Conclusion: Our results demonstrated that QRS prolongation and the presence of fQRS (+) were more common in IBD patients, and associated with longer disease duration. These findings may indicate subclinical cardiac involvement in IBD. Therefore, IBD patients, especially those with long-standing disease, should be followed more closely in terms of cardiac manifestations.
Assuntos
Eletrocardiografia , Doenças Inflamatórias Intestinais , Humanos , Feminino , Masculino , Estudos Retrospectivos , Adulto , Doenças Inflamatórias Intestinais/fisiopatologia , Doenças Inflamatórias Intestinais/complicações , Pessoa de Meia-Idade , Idoso , Estudos de Casos e ControlesRESUMO
BACKGROUND: A growing proportion of people experience incomplete recovery months after contracting coronavirus disease 2019 (COVID-19). These COVID-19 survivors develop a condition known as post-COVID syndrome (PCS), where COVID-19 symptoms persist for > 12 weeks after acute infection. Limited studies have investigated PCS risk factors that notably include pre-existing cardiovascular diseases (CVD), which should be examined considering the most recent PCS data. This review aims to identify CVD as a risk factor for PCS development in COVID-19 survivors. METHODS: Following the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) checklist, systematic literature searches were performed in the PubMed, Scopus, and Web of Science databases from the earliest date available to June 2023. Data from observational studies in English that described the association between CVD and PCS in adults (≥ 18 years old) were included. A minimum of two authors independently performed the screening, study selection, data extraction, data synthesis, and quality assessment (Newcastle-Ottawa Scale). The protocol of this review was registered under PROSPERO (ID: CRD42023440834). RESULTS: In total, 594 studies were screened after duplicates and non-original articles had been removed. Of the 11 included studies, CVD including hypertension (six studies), heart failure (three studies), and others (two studies) were significantly associated with PCS development with different factors considered. The included studies were of moderate to high methodological quality. CONCLUSION: Our review highlighted that COVID-19 survivors with pre-existing CVD have a significantly greater risk of developing PCS symptomology than survivors without pre-existing CVD. As heart failure, hypertension and other CVD are associated with a higher risk of developing PCS, comprehensive screening and thorough examinations are essential to minimise the impact of PCS and improve patients' disease progression.
Assuntos
COVID-19 , Doenças Cardiovasculares , Humanos , COVID-19/epidemiologia , COVID-19/complicações , Doenças Cardiovasculares/epidemiologia , Fatores de Risco , Síndrome de COVID-19 Pós-Aguda , Sobreviventes/estatística & dados numéricosRESUMO
PURPOSE: Maintaining hemodynamic stability during cardiac ablation under general anesthesia is challenging. Remimazolam, a novel ultrashort-acting benzodiazepine, is characterized by maintaining comparatively stable blood pressure and does not influence the cardiac conduction system, which renders it a reasonable choice for general anesthesia for cardiac ablation. We aimed to evaluate whether remimazolam is associated with a decreased incidence of intraoperative hypotension compared with desflurane. METHODS: In this single-centre, parallel-group, prospective, single-blind, randomized clinical trial, we randomized patients (1:1) into a remimazolam group (remimazolam-based total intravenous anesthesia) or desflurane group (propofol-induced and desflurane-maintained inhalational anesthesia) during cardiac ablation procedures for arrhythmia. The primary outcome was the incidence of intraoperative hypotensive events, defined as mean arterial pressure of < 60 mm Hg at any period. RESULTS: Overall, we enrolled 96 patients between 2 August 2022 and 19 May 2023 (47 and 49 patients in the remimazolam and desflurane groups, respectively). The remimazolam group showed a significantly lower incidence of hypotensive events (14/47, 30%) than the desflurane group (29/49, 59%; relative risk [RR], 0.5; 95% confidence interval [CI], 0.31 to 0.83; P = 0.004). Remimazolam was associated with a lower requirement for bolus or continuous vasopressor infusion than desflurane was (23/47, 49% vs 43/49, 88%; RR, 0.56; 95% CI, 0.41 to 0.76; P < 0.001). No between-group differences existed in the incidence of perioperative complications such as nausea, vomiting, oxygen desaturation, delayed emergence, or pain. CONCLUSIONS: Remimazolam was a viable option for general anesthesia for cardiac ablation. Remimazolam-based total intravenous anesthesia was associated with significantly fewer hypotensive events and vasopressor requirements than desflurane-based inhalational anesthesia was, without significantly more complications. STUDY REGISTRATION: ClinicalTrials.gov (NCT05486377); first submitted 1 August 2022.
RéSUMé: OBJECTIF: Le maintien de la stabilité hémodynamique lors d'une ablation cardiaque sous anesthésie générale est un défi. Le remimazolam, une nouvelle benzodiazépine à action ultra-courte, se caractérise par le maintien d'une tension artérielle relativement stable et son absence d'influence sur le système de conduction cardiaque, ce qui en fait un choix raisonnable pour l'anesthésie générale pour l'ablation cardiaque. Nous avons cherché à déterminer si le remimazolam est associé à une diminution de l'incidence d'hypotension peropératoire comparativement au desflurane. MéTHODE: Dans cette étude clinique randomisée, prospective, en simple aveugle, en groupes parallèles et monocentrique, nous avons randomisé des patient·es (1:1) dans un groupe remimazolam (anesthésie intraveineuse totale à base de remimazolam) et un groupe desflurane (anesthésie volatile induite par propofol et maintenue par desflurane) pendant des interventions d'ablation cardiaque pour arythmie. Le critère d'évaluation principal était l'incidence d'événements hypotensifs peropératoires, définis comme une tension artérielle moyenne de < 60 mm Hg à n'importe quelle période. RéSULTATS: Au total, nous avons recruté 96 patient·es entre le 2 août 2022 et le 19 mai 2023 (47 et 49 personnes dans les groupes remimazolam et desflurane, respectivement). Le groupe remimazolam a montré une incidence significativement plus faible d'événements hypotensifs (14/47, 30 %) que le groupe desflurane (29/49, 59 %; risque relatif [RR], 0,5; intervalle de confiance [IC] à 95 %, 0,31 à 0,83; P = 0,004). Le remimazolam a été associé à des besoins plus faibles de bolus ou de perfusion continue de vasopresseurs que le desflurane (23/47, 49 % vs 43/49, 88 %; RR, 0,56; IC 95 %, 0,41 à 0,76; P < 0,001). Il n'y avait pas de différences entre les groupes dans l'incidence des complications périopératoires telles que les nausées, les vomissements, la désaturation en oxygène, l'émergence retardée ou la douleur. CONCLUSION: Le remimazolam a constitué une option viable pour l'anesthésie générale en vue d'une ablation cardiaque. L'anesthésie intraveineuse totale à base de remimazolam a été associée à un nombre significativement plus faible d'événements d'hypotension et de besoins en vasopresseurs que l'anesthésie par inhalation à base de desflurane, sans complications significativement plus nombreuses. ENREGISTREMENT DE L'éTUDE: ClinicalTrials.gov (NCT05486377); soumis pour la première fois le 1er août 2022.
Assuntos
Anestesia Geral , Ablação por Cateter , Desflurano , Hemodinâmica , Hipotensão , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Anestesia Geral/métodos , Método Simples-Cego , Estudos Prospectivos , Idoso , Desflurano/administração & dosagem , Hemodinâmica/efeitos dos fármacos , Hipotensão/prevenção & controle , Hipotensão/induzido quimicamente , Ablação por Cateter/métodos , Benzodiazepinas/administração & dosagem , Propofol/administração & dosagem , Propofol/efeitos adversos , Anestésicos Inalatórios/administração & dosagem , Complicações Intraoperatórias/prevenção & controle , Complicações Intraoperatórias/epidemiologia , Anestésicos Intravenosos/administração & dosagem , Arritmias Cardíacas/prevenção & controle , AdultoRESUMO
The voltage-gated sodium channel Nav1.5 initiates the cardiac action potential. Alterations of its activation and inactivation properties due to mutations can cause severe, life-threatening arrhythmias. Yet despite intensive research efforts, many functional aspects of this cardiac channel remain poorly understood. For instance, Nav1.5 undergoes extensive posttranslational modification in vivo, but the functional significance of these modifications is largely unexplored, especially under pathological conditions. This is because most conventional approaches are unable to insert metabolically stable posttranslational modification mimics, thus preventing a precise elucidation of the contribution by these modifications to channel function. Here, we overcome this limitation by using protein semisynthesis of Nav1.5 in live cells and carry out complementary molecular dynamics simulations. We introduce metabolically stable phosphorylation mimics on both wild-type (WT) and two pathogenic long-QT mutant channel backgrounds and decipher functional and pharmacological effects with unique precision. We elucidate the mechanism by which phosphorylation of Y1495 impairs steady-state inactivation in WT Nav1.5. Surprisingly, we find that while the Q1476R patient mutation does not affect inactivation on its own, it enhances the impairment of steady-state inactivation caused by phosphorylation of Y1495 through enhanced unbinding of the inactivation particle. We also show that both phosphorylation and patient mutations can impact Nav1.5 sensitivity toward the clinically used antiarrhythmic drugs quinidine and ranolazine, but not flecainide. The data highlight that functional effects of Nav1.5 phosphorylation can be dramatically amplified by patient mutations. Our work is thus likely to have implications for the interpretation of mutational phenotypes and the design of future drug regimens.
Assuntos
Regulação da Expressão Gênica/fisiologia , Canal de Sódio Disparado por Voltagem NAV1.5/metabolismo , Animais , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Modelos Moleculares , Simulação de Dinâmica Molecular , Mutação , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Oócitos , Técnicas de Patch-Clamp , Fosforilação , Conformação Proteica , Bloqueadores dos Canais de Sódio/farmacologia , Xenopus laevisRESUMO
The heart pumps blood against the mechanical afterload from arterial resistance, and increased afterload may alter cardiac electrophysiology and contribute to life-threatening arrhythmias. However, the cellular and molecular mechanisms underlying mechanoelectric coupling in cardiomyocytes remain unclear. We developed an innovative patch-clamp-in-gel technology to embed cardiomyocytes in a three-dimensional (3D) viscoelastic hydrogel that imposes an afterload during regular myocyte contraction. Here, we investigated how afterload affects action potentials, ionic currents, intracellular Ca2+ transients, and cell contraction of adult rabbit ventricular cardiomyocytes. We found that afterload prolonged action potential duration (APD), increased transient outward K+ current, decreased inward rectifier K+ current, and increased L-type Ca2+ current. Increased Ca2+ entry caused enhanced Ca2+ transients and contractility. Moreover, elevated afterload led to discordant alternans in APD and Ca2+ transient. Ca2+ alternans persisted under action potential clamp, indicating that the alternans was Ca2+ dependent. Furthermore, all these afterload effects were significantly attenuated by inhibiting nitric oxide synthase 1 (NOS1). Taken together, our data reveal a mechano-chemo-electrotransduction (MCET) mechanism that acutely transduces afterload through NOS1-nitric oxide signaling to modulate the action potential, Ca2+ transient, and contractility. The MCET pathway provides a feedback loop in excitation-Ca2+ signaling-contraction coupling, enabling autoregulation of contractility in cardiomyocytes in response to afterload. This MCET mechanism is integral to the individual cardiomyocyte (and thus the heart) to intrinsically enhance its contractility in response to the load against which it has to do work. While this MCET is largely compensatory for physiological load changes, it may also increase susceptibility to arrhythmias under excessive pathological loading.
Assuntos
Arritmias Cardíacas/fisiopatologia , Fenômenos Eletrofisiológicos , Hidrogéis , Miócitos Cardíacos/fisiologia , Potenciais de Ação/fisiologia , Animais , Fenômenos Biomecânicos , Cálcio , Sinalização do Cálcio/fisiologia , Células Cultivadas , Masculino , Contração Miocárdica/fisiologia , Óxido Nítrico Sintase Tipo I/genética , Óxido Nítrico Sintase Tipo I/metabolismo , Técnicas de Patch-Clamp , Coelhos , Transdução de Sinais , Substâncias ViscoelásticasRESUMO
Sudden unexplained death in childhood (SUDC) is an understudied problem. Whole-exome sequence data from 124 "trios" (decedent child, living parents) was used to test for excessive de novo mutations (DNMs) in genes involved in cardiac arrhythmias, epilepsy, and other disorders. Among decedents, nonsynonymous DNMs were enriched in genes associated with cardiac and seizure disorders relative to controls (odds ratio = 9.76, P = 2.15 × 10-4). We also found evidence for overtransmission of loss-of-function (LoF) or previously reported pathogenic variants in these same genes from heterozygous carrier parents (11 of 14 transmitted, P = 0.03). We identified a total of 11 SUDC proband genotypes (7 de novo, 1 transmitted parental mosaic, 2 transmitted parental heterozygous, and 1 compound heterozygous) as pathogenic and likely contributory to death, a genetic finding in 8.9% of our cohort. Two genes had recurrent missense DNMs, RYR2 and CACNA1C Both RYR2 mutations are pathogenic (P = 1.7 × 10-7) and were previously studied in mouse models. Both CACNA1C mutations lie within a 104-nt exon (P = 1.0 × 10-7) and result in slowed L-type calcium channel inactivation and lower current density. In total, six pathogenic DNMs can alter calcium-related regulation of cardiomyocyte and neuronal excitability at a submembrane junction, suggesting a pathway conferring susceptibility to sudden death. There was a trend for excess LoF mutations in LoF intolerant genes, where ≥1 nonhealthy sample in denovo-db has a similar variant (odds ratio = 6.73, P = 0.02); additional uncharacterized genetic causes of sudden death in children might be discovered with larger cohorts.
Assuntos
Arritmias Cardíacas/genética , Sinalização do Cálcio/genética , Morte Súbita , Epilepsia/genética , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Mutação/genética , Sequenciamento do ExomaRESUMO
INTRODUCTION: Pregnant women with pre-excitation syndrome are more likely to develop supraventricular tachycardia (SVT) during pregnancy and delivery, leading to an increased risk of adverse events. METHOD: This was a retrospective study of 309 pregnancies in 280 women (29 women had two pregnancies in this series) with pre-excitation syndrome who delivered at West China Second University Hospital from June 2011 to October 2021. All the 309 pregnant women with pre-excitation syndrome were divided into SVT and non-SVT groups to analyze the cardiac and obstetric complications. RESULTS: Among the included pregnant women in the past 10 years, the prevalence of pre-excitation syndrome was 0.24% (309/127725). There were 309 cases with pre-excitation syndrome in all hospitalized pregnant women. Among them, 62 (20.1%, 62/309) had a history of SVT. In the 62 cases with SVT during pregnancy, 22 (35.5%) cases had a history of SVT. Gestational diabetes mellitus was associated with SVT during pregnancy. The cesarean section rate was 88.7% in the SVT group, which was significantly higher than that in the non-SVT group (64.8%) (P < 0.001). Cases with SVT during pregnancy had more cardiac and obstetric complications. Four fetal deaths were recorded in the SVT group. Additionally, 29 women experienced two pregnancies during the study period, among whom, five received radiofrequency ablation after the first delivery and obtained better outcomes in the second pregnancy. CONCLUSION: The adverse outcomes such as cardiac complications, maternal and fetal complications (PROM, prematurity, SGA, fetal distress, etc.) in pregnant women with pre-excitation syndrome were closely related to SVT, with possible risk factors including history of SVT before pregnancy, cardiac function, heart organic abnormalities, and gestational diabetes mellitus.
Assuntos
Cesárea , Diabetes Gestacional , Síndromes de Pré-Excitação , Resultado da Gravidez , Taquicardia Supraventricular , Humanos , Feminino , Gravidez , Estudos Retrospectivos , Adulto , Resultado da Gravidez/epidemiologia , Síndromes de Pré-Excitação/epidemiologia , Síndromes de Pré-Excitação/complicações , China/epidemiologia , Taquicardia Supraventricular/epidemiologia , Taquicardia Supraventricular/etiologia , Cesárea/estatística & dados numéricos , Diabetes Gestacional/epidemiologia , Complicações Cardiovasculares na Gravidez/epidemiologia , Adulto JovemRESUMO
BACKGROUND AND QUESTION: Atrial fibrillation (AF) is the most common cardiac arrhythmia in the total population, and previous studies have already reported the prevalence of AF; however, AF is of special importance in geriatric patients due to demographic changes. Therefore, the aim of this study was to determine how many geriatric patients have a history of AF (prevalence) and how often AF can be newly diagnosed during an inpatient stay (incidence). Additionally, predictive factors for the incidence of AF in geriatric patients are described. STUDY PARTICIPANTS AND METHODS: In a monocentric prospective observational study from April 2021 to April 2022, all admissions to a geriatric clinic were included in the study. Data collection was carried out using the patients' digital files. As part of the admission routine, all patients had a 12-lead ECG recorded. Additionally, a 24h long-term electrocardiogram (LTECG) was used in a subset of patients depending on the clinical need. RESULTS: A total of 1914 participants were included in the study. At the time of admission, 715 (37.4%) patients had a known history of AF. Of the remaining 1199 patients without a history of AF, AF could be newly detected in 73 cases (6.1%). Multivariate regression analysis identified age >â¯80 years (odds ratio, OR: 2.3) and heart failure (OR: 3.5) as significant risk factors for the incidence of AF (each pâ¯< 0.05). CONCLUSION: Despite an already high prevalence, AF was newly diagnosed in 6% of patients during the stay at a geriatric clinic. Heart failure and age above 80 years were significantly associated with the presence of AF. This should be taken into account when screening for AF in this patient population.
Assuntos
Fibrilação Atrial , Insuficiência Cardíaca , Idoso , Idoso de 80 Anos ou mais , Humanos , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/epidemiologia , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/complicações , Incidência , Prevalência , Fatores de Risco , Estudos ProspectivosRESUMO
BACKGROUND: Early detection of atrial fibrillation (AF) is essential to prevent stroke and other cardiac and embolic complications. We compared the diagnostic properties for AF detection of the percentage of successive RR interval differences greater than or equal to 30 ms or 3.25% of the previous RR interval (pRR30 and pRR3.25%, respectively), and asymmetric entropy descriptors of RR intervals. Previously, both pRR30 and pRR3.25% outperformed many other heart rate variability (HRV) parameters in distinguishing AF from sinus rhythm (SR) in 60 s electrocardiograms (ECGs). METHODS: The 60 s segments with RR intervals were extracted from the publicly available Physionet Long-Term Atrial Fibrillation Database (84 recording, 24 h Holter ECG). There were 31,753 60 s segments of AF and 32,073 60 s segments of SR. The diagnostic properties of all parameters were analysed with receiver operator curve analysis, a confusion matrix and logistic regression. The best model with pRR30, pRR3.25% and total entropic features (H) had the largest area under the curve (AUC)-0.98 compared to 0.959 for pRR30-and 0.972 for pRR3.25%. However, the differences in AUC between pRR30 and pRR3.25% alone and the combined model were negligible from a practical point of view. Moreover, combining pRR30 and pRR3.25% with H significantly increased the number of false-negative cases by more than threefold. CONCLUSIONS: Asymmetric entropy has some potential in differentiating AF from SR in the 60 s RR interval time series, but the addition of these parameters does not seem to make a relevant difference compared to pRR30 and especially pRR3.25%.