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INTRODUCTION: The aim of the current study was to elucidated the reliable atrial fibrillation (AF) drivers identified by CARTOFINDER using OctaRay catheter. METHODS AND RESULTS: The reliability of focal and rotational activations identified by CARTOFINDER using OctaRay catheter was assessed by the sequential recordings in each site of both atrium before and after pulmonary vein isolation (PVI) in 10 persistent AF patients. The outcome measures were the reproducibility rate during the sequential recordings and the stability rate between pre- and post-PVI as reliable focal and rotational activations. The study results were compared with those under use of PentaRay catheter (N = 18). Total 68928 points of 360 sites in OctaRay group and 24 177 points of 311 sites in PentaRay were assessed. More focal activation sites were identified in OctaRay group than PentaRay group (7.9% vs. 5.7%, p < .001), although the reproducibility rate and the stability rate were significantly lower in OctaRay group (45.3% vs. 58.9%, p < .001; 11.2% vs. 28.4%, p < .001). Meanwhile, the prevalence of reproducible focal activation sites among overall points was comparable (3.6% vs. 3.3%, p = .08). Regarding rotational activation, more rotational activation sites were identified in OctaRay group (5.1% vs. 0.2%, p < .001), and the reproducibility rate and the stability rate were significantly higher in OctaRay group (45.2% and 12.5% vs. 0.0%, p < .001). Both reliable focal and rotational activation sites were characterized by significantly shorter AF-cycle length (CL) and higher repetition of focal and rotational activations during the recordings compared with the sites of non or unreliable focal and rotational activations. CONCLUSION: In CARTOFINDER, OctaRay catheter could identify reliable focal activation with high resolution and reliable rotational activation compared with PentaRay catheter. The repetitive focal and rotational activations with short AF-CL could be the potential target during ablation.
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Fibrilação Atrial , Ablação por Cateter , Veias Pulmonares , Humanos , Frequência Cardíaca , Reprodutibilidade dos Testes , Ablação por Cateter/efeitos adversos , Ablação por Cateter/métodos , Técnicas Eletrofisiológicas Cardíacas/métodos , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/cirurgia , Fibrilação Atrial/etiologia , Catéteres , Veias Pulmonares/cirurgia , Resultado do TratamentoRESUMO
AIMS: More than one-third of type 2 long QT syndrome (LQT2) patients carry KCNH2 non-missense variants that can result in haploinsufficiency (HI), leading to mechanistic loss-of-function. However, their clinical phenotypes have not been fully investigated. The remaining two-thirds of patients harbour missense variants, and past studies uncovered that most of these variants cause trafficking deficiency, resulting in different functional changes: either HI or dominant-negative (DN) effects. In this study, we examined the impact of altered molecular mechanisms on clinical outcomes in LQT2 patients. METHODS AND RESULTS: We included 429 LQT2 patients (234 probands) carrying a rare KCNH2 variant from our patient cohort undergoing genetic testing. Non-missense variants showed shorter corrected QT (QTc) and less arrhythmic events (AEs) than missense variants. We found that 40% of missense variants in this study were previously reported as HI or DN. Non-missense and HI-groups had similar phenotypes, while both exhibited shorter QTc and less AEs than the DN-group. Based on previous work, we predicted the functional change of the unreported variants-whether they cause HI or DN via altered functional domains-and stratified them as predicted HI (pHI)- or pDN-group. The pHI-group including non-missense variants exhibited milder phenotypes compared to the pDN-group. Multivariable Cox model showed that the functional change was an independent risk of AEs (P = 0.005). CONCLUSION: Stratification based on molecular biological studies enables us to better predict clinical outcomes in the patients with LQT2.
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Síndrome do QT Longo , Humanos , Canal de Potássio ERG1/genética , Síndrome do QT Longo/diagnóstico , Síndrome do QT Longo/genética , Mutação de Sentido Incorreto , Testes Genéticos , Arritmias CardíacasRESUMO
BACKGROUND: This study assessed the prognostic importance of B-type natriuretic peptide (BNP) concentrations for clinical events after catheter ablation for atrial fibrillation (AF).MethodsâandâResults: We enrolled 1,750 consecutive patients undergoing initial AF ablation whose baseline BNP data were available from a large-scale multicenter observational cohort (TRANQUILIZE-AF Registry). The prognostic impact of BNP concentration on clinical outcomes, including recurrent tachyarrhythmias and a composite of heart failure (HF) hospitalization or cardiac death, was evaluated. Median baseline BNP was 94.2 pg/mL. During a median follow-up of 2.4 years, low BNP (<38.3 pg/mL) was associated with lower rates of recurrent atrial tachyarrhythmias than BNP concentrations ≥38.3 pg/mL (19.9% vs. 30.6% at 3 years; P<0.001) and HF (0.8% vs. 5.3% at 3 years; P<0.001). Multivariable Cox regression analyses revealed that low BNP was independently associated with lower risks of arrhythmia recurrence (hazard ratio [HR] 0.63; 95% confidence interval [CI] 0.47-0.82; P<0.001) and HF (HR 0.17; 95% CI 0.04-0.71; P=0.002). The favorable impact of low BNP on arrhythmia recurrence was prominent in patients with paroxysmal, but not non-paroxysmal, AF, particularly among those with long-standing AF. CONCLUSIONS: Low BNP concentrations had a favorable impact on clinical outcomes after AF ablation. The heterogeneous impact of baseline BNP concentrations on arrhythmia recurrence for the subgroups of patients divided by AF type warrants future larger studies with longer follow-up periods.
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Fibrilação Atrial , Ablação por Cateter , Insuficiência Cardíaca , Humanos , Prognóstico , Fibrilação Atrial/cirurgia , Peptídeo Natriurético Encefálico , Resultado do Tratamento , Biomarcadores , Ablação por Cateter/efeitos adversos , Ablação por Cateter/métodos , Insuficiência Cardíaca/cirurgia , Taquicardia , RecidivaRESUMO
BACKGROUND: ExTRa Mapping™ has developed to visualize rotational activation as atrial fibrillation (AF) drivers. The current study was sought to evaluate the instability of AF drivers by ExTRa Mapping™. METHODS: Variation of nonpassively activated ratio (%NP) among three-time repetitive recordings before and after pulmonary vein isolation (PVI) in left atrium was assessed in 26 persistent AF patients. The recoding time was set at 5 or 8 s for the respective patients. The outcome measures included %NP at each recording, mean value of the three-time recordings, and the instability index, which was defined as maximum difference per mean %NP × 100 (%). RESULTS: Total 683 sites 2049 recordings were assessed. Mean %NP was 33.3(23.3-42.7)%, and higher in sites with severe (≥50%) and patchy low voltage area than those without, but not in those with severe complex fractionated atrial electrogram area. There was significant correlation between actual and mean %NP (R = 0.86, P < .001), but maximum difference among the repetitive recordings was 16(10-24)%. The instability index of %NP was 55.9(30.9-83.6)%, and significantly lower at the recordings of 8 s compared with 5 s (50.6[28.6-78.4]% vs. 60.4[35.0-90.0]%, P = .004). Furthermore, it was higher at sites with lower reliability of the recordings. After PVI, mean %NP significantly decreased (28.7[18.3-36.7]% vs. 37.7[28.7-45.7]%, P < .001), but the instability index significantly increased compared with those before PVI (60.0[35.0-92.7]% vs. 48.9[29.1-75.0]%, P = .001). CONCLUSION: Rotational activation as AF drivers assessed by ExTRa Mapping™ is unstable, and repetitive and longer recording is required for the reliable assessment even after PVI.
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Fibrilação Atrial , Ablação por Cateter , Veias Pulmonares , Ablação por Cateter/efeitos adversos , Técnicas Eletrofisiológicas Cardíacas , Humanos , Veias Pulmonares/cirurgia , Recidiva , Reprodutibilidade dos Testes , Resultado do TratamentoRESUMO
It is still controversial whether catheter ablation for atrial fibrillation (AF) could improve clinical outcomes in general AF population. Among 4398 patients with diagnosis of AF in the outpatient department of Kyoto University Hospital between January 2005 and March 2015, we identified 537 pairs of patients who received first-time catheter ablation (ablation group) or conservative management (conservative group), matched for age, gender, AF duration, AF type, AF symptoms, and previous heart failure (HF). The primary outcome measure was a composite of cardiovascular death, HF hospitalization, ischemic stroke, or major bleeding. Most baseline characteristics were well balanced between the 2 groups, except for the higher prevalence of low body weight, history of malignancy, and severe chronic kidney disease in the conservative group. Median follow-up duration was 5.3 years. The cumulative 5-year incidence of the primary outcome measure was significantly lower in the ablation group than in the conservative group (5.2% versus 15.6%, log-rank P < 0.001). Even after adjusting for the imbalances in the baseline characteristics, the lower risk of the ablation group relative to the conservative group for the primary outcome measure remained highly significant (HR 0.32, 95% CI 0.21-0.47, P < 0.001). Ablation compared with conservative management was also associated with significantly lower risks for the individual components of the primary outcome. In this matched analysis in AF patients, ablation as compared with conservative management was associated with better long-term clinical outcomes, although we could not deny the possibility of selection bias and unmeasured confounding.
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Fibrilação Atrial , Ablação por Cateter , Insuficiência Cardíaca , Acidente Vascular Cerebral , Fibrilação Atrial/epidemiologia , Fibrilação Atrial/cirurgia , Ablação por Cateter/efeitos adversos , Tratamento Conservador/efeitos adversos , Humanos , Resultado do TratamentoRESUMO
BACKGROUND: The incidence of subsequent need for permanent pacemaker implantation (PMI) after radiofrequency catheter ablation (RFCA) for atrial fibrillation (AF) in real world patients with and without pre-existing bradycardia has not yet been fully evaluated. MethodsâandâResults: A total of 1,131 consecutive patients undergoing first-time RFCA for AF who had no previous or planned device implantation, were enrolled in the present study. Of 799 paroxysmal AF (PAF) patients, 121 (15.1%) had sinus node dysfunction (SND). Of 332 non-PAF patients, 73 (22.0%) had slow ventricular response (VR), defined as heart rate <80 beats/min at rest without any rate-control drugs. The 5-year cumulative incidence of PMI after RFCA in PAF patients with and without SND was 14.8% and 1.7%, respectively (P<0.001). The 5-year cumulative incidence of PMI after RFCA in non-PAF patients with and without slow VR was 14.8% and 4.7%, respectively (P<0.001). SND and female gender in PAF patients, as well as slow VR and age ≥75 years in non-PAF patients, were independent and additive predictors of PMI. The 5-year cumulative incidence of PMI was 26.3% in female PAF patients with SND and 33.3% in elderly non-PAF patients with slow VR. CONCLUSIONS: PMI was avoided in >85% of patients undergoing RFCA for PAF with pre-existing SND, although care should be taken for female patients. Decision-making regarding RFCA for non-PAF patients with slow VR, especially in the elderly, should be cautious.
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Fibrilação Atrial/terapia , Bradicardia/terapia , Ablação por Cateter , Marca-Passo Artificial/estatística & dados numéricos , Síndrome do Nó Sinusal/terapia , Fatores Etários , Idoso , Feminino , Frequência Cardíaca , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Fatores SexuaisRESUMO
BACKGROUND: The concealed nodoventricular/nodofascicular (NV/NF) pathway is mostly a bystander, retrograde bypass tract connecting the right ventricle/right bundle branch (RBB) and slow pathway that is observed in patients with atrioventricular nodal reentrant tachycardia (AVNRT). However, its prevalence and characteristics in response to pacing maneuvers have not been fully evaluated. OBJECTIVE: This study investigated the prevalence and characteristics of AVNRT with a bystander NV/NF pathway. METHODS: We retrospectively reviewed 153 consecutive patients undergoing catheter ablation of AVNRT. After exclusion of 52 patients with inadequate electrophysiologic data, 101 patients composed the study population. RESULTS: Three patients (3.0%) had bystander concealed NV/NF pathways, all of which were connected to the slow pathway. The tachycardia was typical slow pathway/fast pathway AVNRT in 2 patients and atypical fast pathway/slow pathway AVNRT in 1 patient. In all cases, His-refractory ventricular extra-stimuli (VES) reset the AVNRTs with delay through the NV/NF pathways. Ventricular overdrive pacing (VOP) in the early phase also reset the AVNRT with delay. Earlier VES and middle phase of VOP did not reset the tachycardia, and further earlier VES and late phase of VOP reset the tachycardia with advance through the RBB-His conduction. CONCLUSION: A bystander NV/NF pathway was not rare in patients with AVNRT. The VES and VOP for the AVNRTs with the bystander NV/NF pathways were characterized by the 2-phase resetting phenomenon: initial transient resetting with delay through the NV/NF pathway, and late resetting with advance through the RBB-His conduction.
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BACKGROUND: Early arrhythmia recurrences commonly occur after atrial fibrillation (AF) ablation because of irritability and inflammation of left atrium. We hypothesized that short-term use of Saireito would be effective in reducing frequent atrial tachyarrhythmias in the early-phase post-ablation. METHODS: One hundred patients undergoing catheter ablation for symptomatic AF were randomly assigned to either a 30-day use of Saireito or control group. The primary endpoint was total number of episodes of frequent atrial tachyarrhythmias including definite recurrent AF and frequent premature atrial contractions during the 30-day treatment period post-ablation. RESULTS: Three (6.0%) out of 50 patients treated with Saireito discontinued the drug because of adverse symptoms. The Saireito group was associated with a numerically lower number of episodes of frequent atrial tachyarrhythmias than the control group (3.1 versus 5.2 times, P = 0.17). The mean daily episodes of frequent atrial tachyarrhythmias were significantly fewer in the Saireito group during Day-6 to Day-10 (0.12/day versus 0.27/day, P = 0.03), and during Day-11 to Day-15 (0.08/day versus 0.24/day, P = 0.001). The prevalence of adverse symptoms during the 30-day treatment period was significantly higher in the Saireito group (18.0% versus 2.0%, P = 0.005). CONCLUSIONS: Thirty-day use of Saireito following AF ablation was associated with a tendency toward reduced number of episodes of frequent atrial tachyarrhythmias during the treatment period, with more pronounced effect in the first two weeks.
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Fibrilação Atrial , Ablação por Cateter , Humanos , Fibrilação Atrial/cirurgia , Fibrilação Atrial/tratamento farmacológico , Ablação por Cateter/métodos , Ablação por Cateter/efeitos adversos , Masculino , Feminino , Pessoa de Meia-Idade , Projetos Piloto , Idoso , Resultado do TratamentoRESUMO
Acute coronary syndrome (ACS) includes myocardial infarction (MI) and unstable angina (UA). MI is defined by elevated necrosis markers, preferably high-sensitivity cardiac troponins (hs-cTn). However, it takes hours for cTn to become elevated after coronary occlusion; therefore, difficulties are associated with diagnosing early post-onset MI or UA. The aim of this prospective cohort study was to examine the diagnostic ability of serum nardilysin (NRDC) for the early detection of ACS. This study consisted of two sequential cohorts, the Phase I cohort, 435 patients presenting to the emergency room (ER) with chest pain, and the Phase II cohort, 486 patients with chest pain who underwent coronary angiography. The final diagnosis was ACS in 155 out of 435 patients (35.6%) in the phase I and 418 out of 486 (86.0%) in the phase II cohort. Among 680 patients who presented within 24 h of onset, 466 patients (68.5%) were diagnosed with ACS. Serum NRDC levels were significantly higher in patients with ACS than in those without ACS. The sensitivity of NRDC in patients who presented within 6 h after the onset was higher than that of hsTnI, and the AUC of NRDC within 1 h of the onset was higher than that of hsTnI (0.718 versus 0.633). Among hsTnI-negative patients (300 of 680 patients: 44.1%), 136 of whom (45.3%) were diagnosed with ACS, the sensitivity and the NPV of NRDC were 73.5 and 65.7%, respectively. When measured in combination with hsTnI, NRDC plays auxiliary roles in the early diagnosis of ACS.
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Síndrome Coronariana Aguda , Biomarcadores , Diagnóstico Precoce , Humanos , Estudos Prospectivos , Masculino , Síndrome Coronariana Aguda/diagnóstico , Síndrome Coronariana Aguda/sangue , Feminino , Pessoa de Meia-Idade , Idoso , Biomarcadores/sangue , Metaloendopeptidases/sangue , Estudos de Coortes , Serviço Hospitalar de EmergênciaRESUMO
While 3D chromatin organization in topologically associating domains (TADs) and loops mediating regulatory element-promoter interactions is crucial for tissue-specific gene regulation, the extent of their involvement in human Mendelian disease is largely unknown. Here, we identify 7 families presenting a new cardiac entity associated with a heterozygous deletion of 2 CTCF binding sites on 4q25, inducing TAD fusion and chromatin conformation remodeling. The CTCF binding sites are located in a gene desert at 1 Mb from the Paired-like homeodomain transcription factor 2 gene (PITX2). By introducing the ortholog of the human deletion in the mouse genome, we recapitulate the patient phenotype and characterize an opposite dysregulation of PITX2 expression in the sinoatrial node (ectopic activation) and ventricle (reduction), respectively. Chromatin conformation assay performed in human induced pluripotent stem cell-derived cardiomyocytes harboring the minimal deletion identified in family#1 reveals a conformation remodeling and fusion of TADs. We conclude that TAD remodeling mediated by deletion of CTCF binding sites causes a new autosomal dominant Mendelian cardiac disorder.
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Células-Tronco Pluripotentes Induzidas , Humanos , Animais , Camundongos , Fator de Ligação a CCCTC/genética , Fator de Ligação a CCCTC/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Cromatina/genética , Proteínas de Ligação a DNA/metabolismo , GenomaRESUMO
Background: Long QT syndrome (LQTS) is a lethal arrhythmia syndrome, frequently caused by rare loss-of-function variants in the potassium channel encoded by KCNH2. Variant classification is difficult, often owing to lack of functional data. Moreover, variant-based risk stratification is also complicated by heterogenous clinical data and incomplete penetrance. Here, we sought to test whether variant-specific information, primarily from high-throughput functional assays, could improve both classification and cardiac event risk stratification in a large, harmonized cohort of KCNH2 missense variant heterozygotes. Methods: We quantified cell-surface trafficking of 18,796 variants in KCNH2 using a Multiplexed Assay of Variant Effect (MAVE). We recorded KCNH2 current density for 533 variants by automated patch clamping (APC). We calibrated the strength of evidence of MAVE data according to ClinGen guidelines. We deeply phenotyped 1,458 patients with KCNH2 missense variants, including QTc, cardiac event history, and mortality. We correlated variant functional data and Bayesian LQTS penetrance estimates with cohort phenotypes and assessed hazard ratios for cardiac events. Results: Variant MAVE trafficking scores and APC peak tail currents were highly correlated (Spearman Rank-order ρ = 0.69). The MAVE data were found to provide up to pathogenic very strong evidence for severe loss-of-function variants. In the cohort, both functional assays and Bayesian LQTS penetrance estimates were significantly predictive of cardiac events when independently modeled with patient sex and adjusted QT interval (QTc); however, MAVE data became non-significant when peak-tail current and penetrance estimates were also available. The area under the ROC for 20-year event outcomes based on patient-specific sex and QTc (AUC 0.80 [0.76-0.83]) was improved with prospectively available penetrance scores conditioned on MAVE (AUC 0.86 [0.83-0.89]) or attainable APC peak tail current data (AUC 0.84 [0.81-0.88]). Conclusion: High throughput KCNH2 variant MAVE data meaningfully contribute to variant classification at scale while LQTS penetrance estimates and APC peak tail current measurements meaningfully contribute to risk stratification of cardiac events in patients with heterozygous KCNH2 missense variants.
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BACKGROUND: Atrial fibrillation (AF) plays the main role in atrial functional tricuspid regurgitation (TR). However, the effectiveness of catheter ablation (CA) for atrial functional TR together with the mechanisms of improvement of atrial functional TR have not been fully evaluated. METHODS: We retrospectively investigated consecutive 2685 patients with AF who received CA from February 2004 to December 2019 in Kyoto University Hospital, Kyoto, Japan. The current study population consisted of 2331 patients with available transthoracic echocardiographic (TTE) data before CA (2110 patients without significant TR and 221 patients with significant TR). Among the 221 patients with significant TR, there were 64 patients with functional TR and follow-up TTE at 6-18 months after CA for AF, in whom we compared echocardiographic parameters from baseline to follow-up. RESULTS: Patients with significant TR were older, and more often women, and had more persistent AF than those without significant TR. Among the 64 patients with functional TR, TR severity and TR jet area significantly improved at follow-up (TR jet area: 5.8 [4.0-7.6] cm2 to 2.1 [1.1-3.1] cm2, P < 0.001). Moreover, mitral regurgitation jet area, left atrial area, mitral valve diameter, right ventricular end-diastolic area, right atrial area, and tricuspid valve diameter decreased at follow-up. CONCLUSIONS: TR severity and jet area improved after CA in patients with AF and significant TR. The improvement of TR might be associated with reverse remodeling of the right heart.
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Fibrilação Atrial , Ablação por Cateter , Insuficiência da Valva Tricúspide , Humanos , Feminino , Insuficiência da Valva Tricúspide/complicações , Insuficiência da Valva Tricúspide/diagnóstico por imagem , Insuficiência da Valva Tricúspide/cirurgia , Fibrilação Atrial/diagnóstico por imagem , Fibrilação Atrial/cirurgia , Fibrilação Atrial/complicações , Estudos Retrospectivos , Valva Tricúspide/cirurgiaRESUMO
BACKGROUND: A missense mutation in the α1c subunit of voltage-gated L-type Ca2+ channel-coding CACNA1C-E1115K, located in the Ca2+ selectivity site, causes a variety of arrhythmogenic phenotypes. OBJECTIVE: We aimed to investigate the electrophysiological features and pathophysiological mechanisms of CACNA1C-E1115K in patient-specific induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMs). METHODS: We generated iPSCs from a patient carrying heterozygous CACNA1C-E1115K with overlapping phenotypes of long QT syndrome, Brugada syndrome, and mild cardiac dysfunction. Electrophysiological properties were investigated using iPSC-CMs. We used iPSCs from a healthy individual and an isogenic iPSC line corrected using CRISPR-Cas9-mediated gene editing as controls. A mathematical E1115K-CM model was developed using a human ventricular cell model. RESULTS: Patch-clamp analysis revealed that E1115K-iPSC-CMs exhibited reduced peak Ca2+ current density and impaired Ca2+ selectivity with an increased permeability to monovalent cations. Consequently, E1115K-iPSC-CMs showed decreased action potential plateau amplitude, longer action potential duration (APD), and a higher frequency of early afterdepolarization compared with controls. In optical recordings examining the antiarrhythmic drug effect, late Na+ channel current (INaL) inhibitors (mexiletine and GS-458967) shortened APDs specifically in E1115K-iPSC-CMs. The AP-clamp using a voltage command obtained from E1115K-iPSC-CMs with lower action potential plateau amplitude and longer APD confirmed the upregulation of INaL. An in silico study recapitulated the in vitro electrophysiological properties. CONCLUSION: Our iPSC-based analysis in CACNA1C-E1115K with disrupted CaV1.2 selectivity demonstrated that the aberrant currents through the mutant channels carried by monovalent cations resulted in specific action potential changes, which increased endogenous INaL, thereby synergistically contributing to the arrhythmogenic phenotype.
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Síndrome de Brugada , Canais de Cálcio Tipo L , Células-Tronco Pluripotentes Induzidas , Síndrome do QT Longo , Humanos , Potenciais de Ação , Síndrome de Brugada/genética , Síndrome de Brugada/metabolismo , Canais de Cálcio Tipo L/genética , Canais de Cálcio Tipo L/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Síndrome do QT Longo/genética , Miócitos Cardíacos/metabolismo , FenótipoRESUMO
BACKGROUND: CaM (calmodulin) is a ubiquitously expressed, multifunctional Ca2+ sensor protein that regulates numerous proteins. Recently, CaM missense variants have been identified in patients with malignant inherited arrhythmias, such as long QT syndrome and catecholaminergic polymorphic ventricular tachycardia (CPVT). However, the exact mechanism of CaM-related CPVT in human cardiomyocytes remains unclear. In this study, we sought to investigate the arrhythmogenic mechanism of CPVT caused by a novel variant using human induced pluripotent stem cell (iPSC) models and biochemical assays. METHODS: We generated iPSCs from a patient with CPVT bearing CALM2 p.E46K. As comparisons, we used 2 control lines including an isogenic line, and another iPSC line from a patient with long QT syndrome bearing CALM2 p.N98S (also reported in CPVT). Electrophysiological properties were investigated using iPSC-cardiomyocytes. We further examined the RyR2 (ryanodine receptor 2) and Ca2+ affinities of CaM using recombinant proteins. RESULTS: We identified a novel de novo heterozygous variant, CALM2 p.E46K, in 2 unrelated patients with CPVT accompanied by neurodevelopmental disorders. The E46K-cardiomyocytes exhibited more frequent abnormal electrical excitations and Ca2+ waves than the other lines in association with increased Ca2+ leakage from the sarcoplasmic reticulum via RyR2. Furthermore, the [3H]ryanodine binding assay revealed that E46K-CaM facilitated RyR2 function especially by activating at low [Ca2+] levels. The real-time CaM-RyR2 binding analysis demonstrated that E46K-CaM had a 10-fold increased RyR2 binding affinity compared with wild-type CaM which may account for the dominant effect of the mutant CaM. Additionally, the E46K-CaM did not affect CaM-Ca2+ binding or L-type calcium channel function. Finally, antiarrhythmic agents, nadolol and flecainide, suppressed abnormal Ca2+ waves in E46K-cardiomyocytes. CONCLUSIONS: We, for the first time, established a CaM-related CPVT iPSC-CM model which recapitulated severe arrhythmogenic features resulting from E46K-CaM dominantly binding and facilitating RyR2. In addition, the findings in iPSC-based drug testing will contribute to precision medicine.
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Células-Tronco Pluripotentes Induzidas , Síndrome do QT Longo , Taquicardia Ventricular , Humanos , Calmodulina/genética , Calmodulina/metabolismo , Miócitos Cardíacos/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Taquicardia Ventricular/metabolismo , Arritmias Cardíacas , Síndrome do QT Longo/genética , Síndrome do QT Longo/metabolismo , Cálcio/metabolismo , MutaçãoRESUMO
Filling defect (FD) in left atrial appendage (LAA) is commonly observed in contrast computed tomography (CT) among patients with atrial fibrillation (AF), although its prognostic impact has not been well explored. We enrolled 1,019 consecutive patients who underwent AF ablation with baseline contrast CT images. FD in LAA was graded into 3 groups: grade 0 for complete filling (79.7%), grade 1 for incomplete filling (12.6%), and grade 2 for complete FD (7.8%). We evaluated the impact of the FD grade on the long-term clinical outcomes during the mean follow-up of 4.4 ± 2.0 years. Patients with grade 2 FD had higher prevalence of nonparoxysmal AF, higher brain natriuretic peptide level, and larger left atrial volume than those with grade 0 or 1 FD. The 5-year cumulative incidence of recurrent atrial tachyarrhythmias was higher in patients with grade 2 FD than those with grade 0 or 1 FD (74.0% vs 38.8% and 62.1%, log-rank p <0.001). The 5-year cumulative incidence of major adverse cardiovascular events (MACEs), defined as a composite of all-cause death, heart failure hospitalization, and ischemic stroke, was also significantly higher in patients with grade 2 FD (19.4% vs 5.6% and 9.5%, log-rank p <0.001). Follow-up CT images acquired in 87.1% of patients at median interval of 98 days showed significantly decreased FD (grade 1 in 4.5% and grade 2 in 2.1%, p <0.001). The residual grade 2 FD at follow-up was associated with significantly higher risk for subsequent MACEs. In conclusion, among patients with AF receiving catheter ablation, severe FD in LAA in contrast CT was associated with higher incidence of arrhythmia recurrence and MACEs during follow-up.
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Apêndice Atrial , Fibrilação Atrial , Ablação por Cateter , Apêndice Atrial/diagnóstico por imagem , Apêndice Atrial/cirurgia , Fibrilação Atrial/complicações , Ablação por Cateter/métodos , Átrios do Coração , Humanos , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: The characteristics of atrial fibrillation (AF) drivers identified by CARTOFINDER have not been thoroughly evaluated. Therefore, the current study was sought to validate the reliability of AF drivers. METHODS: The reliability of focal and rotational activation identified by CARTOFINDER during AF was assessed by the sequential recordings in each site before and after pulmonary vein isolation (PVI) in 27 persistent AF patients. The primary outcome measures were the reproducibility rate during the sequential recordings and the stability rate between pre- and post-PVI. RESULTS: Among 32,135 points in 509 sites, focal activation was identified in 1775 points (5.5%) with a repetition of 11 (6-26) times during the recording. Rotational activation was identified in 132 points (0.4%) with a repetition number of 21 (14-21) times. AF drivers had significantly higher voltage and shorter AF cycle length than non-AF driver sites. The reproducibility rate of focal activation during the sequential recordings was 57.8% and increased with the repetition number. The reproducibility rate of rotational activation was 37.4%. The prevalence and the reproducibility rate of focal activation in post-PVI were significantly lower than pre-PVI (5.3% versus 6.0%, P = 0.02; 53.4% versus 63.6%, P < 0.001). The stability rate of focal activation between pre- and post-PVI was only 28.3% but increased with the repetition number. There was no stable rotational activation between pre- and post-PVI. CONCLUSIONS: The reproducibility of AF drivers, especially focal activation, identified by CARTOFINDER is relatively favorable, but the stability between pre- and post-PVI was poor. These results depended on the repetition number during the recording.
Assuntos
Fibrilação Atrial , Ablação por Cateter , Veias Pulmonares , Humanos , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/cirurgia , Fibrilação Atrial/etiologia , Técnicas Eletrofisiológicas Cardíacas , Ablação por Cateter/efeitos adversos , Reprodutibilidade dos Testes , Frequência Cardíaca , Potenciais de Ação , Veias Pulmonares/cirurgia , Algoritmos , Resultado do Tratamento , RecidivaRESUMO
Activated clotting time (ACT) kinetics under uninterrupted oral anticoagulants (OACs) has not been fully evaluated. The present study is sought to validate ACT kinetics including stability under uninterrupted use of OACs during an ablation procedure in daily clinical practice. We prospectively enrolled consecutive 554 patients with atrial fibrillation who underwent catheter ablation procedure under uninterrupted OACs. We evaluated ACT kinetics at an interval of 15 minutes during the procedure and periprocedural complications among 5 OACs (dabigatran [N = 46], rivaroxaban [N = 125], apixaban [N = 129], edoxaban [N = 184], and warfarin [N = 70]). Compared with the dabigatran group, time to achieve target ACT was significantly longer in the rivaroxaban and apixaban groups, but not in the edoxaban and warfarin groups (8.7 vs 11.7 minutes, P < .001; 13.3 minutes, P < .001; 8.8 minutes, P = .64; 10.3 minutes, P = .19, respectively). Heparin dose to achieve target ACT was comparable except for the warfarin group, whereas, compared with the dabigatran group, time in therapeutic range of ACT within the first hour was comparable in the rivaroxaban and apixaban group but significantly lower in the edoxaban and warfarin groups (73.7 % vs 63.0%, P = .06; 67.0 %, P = .16; 59.2 %, P = .001; 58.2%, P = .004, respectively). In multiple regression analysis, low body weight, rivaroxaban, apixaban, and morning session had significant associations with time and heparin dose to achieve target ACT, and there were positive associations of dabigatran and apixaban with time in therapeutic range of ACT within the first hour. The incidence of periprocedural complications did not significantly differ among the 5 groups. Under uninterrupted OAC use in daily clinical practice, dabigatran showed faster achievement of target ACT and higher stability of ACT than other OACs.
Assuntos
Fibrilação Atrial , Ablação por Cateter , Administração Oral , Anticoagulantes/uso terapêutico , Fibrilação Atrial/complicações , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/cirurgia , Dabigatrana/uso terapêutico , Heparina/uso terapêutico , Humanos , Cinética , Piridonas/uso terapêutico , Rivaroxabana/uso terapêutico , Resultado do Tratamento , Varfarina/uso terapêuticoRESUMO
BACKGROUND: Catheter ablation for asymptomatic atrial fibrillation (AF) remains controversial. The aim of the present study was to explore the prognostic impact of catheter ablation in asymptomatic AF patients. METHODS: We performed a post-hoc analysis of 537 risk-matched pairs of AF patients receiving first-time catheter ablation or conservative management. The primary outcome measure was a composite of cardiovascular death, heart failure (HF) hospitalization, ischemic stroke, or major bleeding. The study patients were divided into asymptomatic and symptomatic patients, and were further divided according to the presence or absence of previous AF-related complications (ischemic stroke or HF hospitalization). RESULTS: Most baseline characteristics were well balanced between the catheter ablation versus conservative management groups. The median follow-up period was 5.3 years. Catheter ablation as compared to conservative management was associated with significantly lower incidence of the primary outcome measure in the asymptomatic AF patients (14.7% versus 25.4% at 8-year, log-rank P = 0.008). However, the advantage of catheter ablation was significant only in the high-risk subset of patients with the previous AF-related complications (19.2% versus 55.6% at 8-year, log-rank P = 0.006), but not in those without (13.9% and 17.3%, P = 0.08). On the other hand, among the symptomatic AF patients, catheter ablation was associated with significantly lower incidence of the primary outcome measure regardless of the previous AF-related complications. CONCLUSIONS: In the post-hoc analysis of the matched AF cohort, catheter ablation as compared with conservative management was associated with better long-term clinical outcomes among asymptomatic AF patients only when the previous AF-related complications were present.