RESUMO
INTRODUCTION: When performing linear ablation, creating contiguous and transmural lesions are technically challenging due to the difficulty in finding electrical conduction gaps. We hypothesized that high-density mapping could identify the gaps. METHODS AND RESULTS: This study included consecutive patients who underwent conduction gap mapping of de novo lesions (41 patients, 55 lines) and previous lesions (25 patients, 34 lines). We analyzed the utility of bipolar and unipolar conduction gap mapping and retrospectively assessed the voltage and morphology of the bipolar electrograms at the gap sites. Bipolar and unipolar propagation maps were classified into three types: the propagation wavefront traveled through the linear ablation lesions (direct leak), the wavefront jumped to an opposite site across the line and returned to the line (jump and return leak), and others (indefinite leak). In the jump and return leak maps, the site where it returned suggested a conduction gap site. Bipolar propagation maps identified 30 (54.5%) conduction gaps and unipolar maps identified 40 (72.7%) gaps at de novo linear ablation lesions (P = .01), and 32 (94.1%) gaps and 33 (97.1%) gaps, respectively, at previous lesions (P = .56). Bipolar voltage mapping did not add any further efficacy in detecting conduction gaps, and the morphology of the electrograms recorded at the gap sites was not related to the types of propagation maps. CONCLUSION: Conduction gaps of linear ablation lesions can be visualized by high-density mapping with a high probability. Unipolar propagation, when used with bipolar mapping, may help detect conduction gap sites.
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Fibrilação Atrial , Ablação por Cateter , Fibrilação Atrial/cirurgia , Mapeamento Potencial de Superfície Corporal , Átrios do Coração/cirurgia , Sistema de Condução Cardíaco/cirurgia , Humanos , Estudos RetrospectivosRESUMO
BACKGROUND: A lower cut-off of the oesophageal temperature (ET) during catheter ablation of atrial fibrillation (AF) should be safer, but its durability may become in question. We evaluated an ET cut-off of 38°C with an output of 25W on the posterior wall. METHODS: In 636 consecutive patients (age: 60±10years, male: 542, paroxysmal AF: 405, CHADS2 score: 0.7±0.9), an ET probe was utilised in 303 patients (259 pulmonary vein isolations [PVIs] and 44 simultaneous isolations of the posterior wall and all PVs box isolations [BOXIs]). When the ET increased to >38°C, the radiofrequency delivery was switched off and the ablation point was tagged as an "EsoTag" by the CARTO™ system (Biosense Webster, Irvine, CA, USA). We analysed the characteristics of the ablation lesions at the EsoTags with respect to the dormant conduction, gaps in the redo-session, and ablation outcome. RESULTS: EsoTags were identified in 94.6% of the left PVIs and all BOXIs, and dormant conduction at the EsoTags was identified in 12.0% and 6.8%, respectively. In 10,796 ablation points, the ablation at the EsoTags that were associated with dormant conduction had a significantly shorter duration, smaller force-time integral, and smaller Δimpedance. The duration of an ET of >38°C was significantly and positively correlated with the body mass index and negatively with the left atrial appendage flow velocity. During the redo-sessions in a 10.5±6.0months of follow-up (PVI: 14.7%, BOXI: 11.4%), reconnections at the EsoTags with dormant conduction were observed only in two patients after the PVI. The AF survival rate did not significantly differ in the presence of dormant conduction at the EsoTags (83.1% vs. 75.0%, p=0.696). There were no patients hospitalised for gastroparesis. CONCLUSIONS: Atrial fibrillation ablation utilising an oesophageal temperature cut-off of 38°C might be safe and durable.
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Fibrilação Atrial , Temperatura Corporal , Ablação por Cateter , Esôfago/fisiopatologia , Idoso , Fibrilação Atrial/fisiopatologia , Fibrilação Atrial/cirurgia , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Differences in the methodologies for evaluating atrial fibrillation (AF) ablation outcomes should be evaluated. In the present study, we compared the AF ablation outcomes among periodic clinic electrocardiography (ECG), 24-h Holter ECG, and telemonitoring ECG to evaluate the differences among these methods. In addition, we evaluated the AF-free survival rate for each method with different durations of the blanking period. A total of 30 AF patients were followed up for 6 months after initial catheter ablation, with clinic ECG on every clinic visit, monthly 24-h Holter ECG, and telemonitoring ECG twice daily and upon symptoms. AF relapse was defined as AF or atrial tachycardia detected with any of the methods. Two patients dropped out of the study, and 28 patients were followed up for 8.8 ± 2.7 months. Patients underwent 3.6 ± 0.8 clinic ECG, 5.1 ± 0.8 Holter ECG, and 273 ± 68 telemonitoring ECG examinations. During the first, second, third, fourth, fifth, and sixth months of follow-up, Holter ECG detected relapses in 11.1, 8.3, 11.5, 15.4, 4.2, and 4.8 % of patients and telemonitoring ECG detected relapses in 32.1, 25.0, 25.0, 17.9, 28.6, and 17.9 % of patients, respectively. When no duration was set for the blanking period, the AF-free survival rate was significantly lower with telemonitoring ECG (46.4 %) than with Holter ECG (78.6 %, P = 0.013) or clinic ECG (85.7 %, P = 0.002). In addition, when the duration of the blanking period was set to 3 months, the AF-free survival rate was significantly lower with telemonitoring ECG than with clinic ECG (92.9 vs. 71.4 %, P = 0.041). The AF ablation outcomes with twice-daily telemonitoring ECG might differ from those with clinic ECG when the duration of the blanking period is 0-3 months. A follow-up based solely on clinic ECG might underestimate AF recurrence.
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Fibrilação Atrial/cirurgia , Ablação por Cateter/efeitos adversos , Eletrocardiografia Ambulatorial/métodos , Idoso , Feminino , Seguimentos , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Veias Pulmonares/cirurgia , Recidiva , Taxa de Sobrevida , Telemedicina , Fatores de Tempo , Resultado do TratamentoRESUMO
The precise assemblage of several types of cardiac precursors controls heart organogenesis. The cardiac precursors show dynamic movement during early development and then form the complicated heart structure. However, cardiomyocyte movements inside the newly organized mammalian heart remain unclear. We previously established the method of ex vivo time-lapse imaging of the murine heart to study cardiomyocyte behavior by using the Fucci (fluorescent ubiquitination-based cell cycle indicator) system, which can effectively label individual G1, S/G2/M, and G1/S-transition phase nuclei in living cardiomyocytes as red, green, and yellow, respectively. Global analysis of gene expression in Fucci green positive ventricular cardiomyocytes confirmed that cell cycle regulatory genes expressed in G1/S, S, G2/M, and M phase transitions were upregulated. Interestingly, pathway analysis revealed that many genes related to the cell cycle were significantly upregulated in the Fucci green positive ventricular cardiomyocytes, while only a small number of genes related to cell motility were upregulated. Time-lapse imaging showed that murine proliferating cardiomyocytes did not exhibit dynamic movement inside the heart, but stayed on site after entering the cell cycle.
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Coração Fetal/citologia , Miocárdio/citologia , Miócitos Cardíacos/citologia , Miócitos Cardíacos/fisiologia , Animais , Pontos de Checagem do Ciclo Celular/genética , Movimento Celular , Proliferação de Células , Feminino , Coração Fetal/embriologia , Regulação da Expressão Gênica no Desenvolvimento , Genes Reporter , Coração/crescimento & desenvolvimento , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Miocárdio/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , GravidezRESUMO
Heterogeneity among both primed and naive pluripotent stem cell lines remains a major unresolved problem. Here we show that expressing the maternal-specific linker histone H1FOO fused to a destabilizing domain (H1FOO-DD), together with OCT4, SOX2, KLF4, and LMYC, in human somatic cells improves the quality of reprogramming to both primed and naive pluripotency. H1FOO-DD expression was associated with altered chromatin accessibility around pluripotency genes and with suppression of the innate immune response. Notably, H1FOO-DD generates naive induced pluripotent stem cells with lower variation in transcriptome and methylome among clones and a more uniform and superior differentiation potency. Furthermore, we elucidated that upregulation of FKBP1A, driven by these five factors, plays a key role in H1FOO-DD-mediated reprogramming.
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Reprogramação Celular , Histonas , Células-Tronco Pluripotentes Induzidas , Fator 4 Semelhante a Kruppel , Reprogramação Celular/genética , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Histonas/metabolismo , Diferenciação Celular/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição SOXB1/metabolismo , Fatores de Transcrição SOXB1/genética , Cromatina/metabolismo , Células-Tronco Pluripotentes/metabolismo , Células-Tronco Pluripotentes/citologia , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , TranscriptomaRESUMO
Naive human induced pluripotent stem cells (iPSCs) can be generated by reprogramming somatic cells with Sendai virus (SeV) vectors. However, only dermal fibroblasts have been successfully reprogrammed this way, and the process requires culture on feeder cells. Moreover, SeV vectors are highly persistent and inhibit subsequent differentiation of iPSCs. Here, we report a modified SeV vector system to generate transgene-free naive human iPSCs with superior differentiation potential. The modified method can be applied not only to fibroblasts but also to other somatic cell types. SeV vectors disappear quickly at early passages, and this approach enables the generation of naive iPSCs in a feeder-free culture. The naive iPSCs generated by this method show better differentiation to trilineage and extra-embryonic trophectoderm than those derived by conventional methods. This method can expand the application of iPSCs to research on early human development and regenerative medicine.
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Células-Tronco Pluripotentes Induzidas , Humanos , Reprogramação Celular/genética , Vírus Sendai/genética , Vetores Genéticos , Diferenciação Celular/genéticaRESUMO
Failure of the right ventricle plays a critical role in any type of heart failure. However, the mechanism remains unclear, and there is no specific therapy. Here, we show that the right ventricle predominantly expresses alternative complement pathway-related genes, including Cfd and C3aR1. Complement 3 (C3)-knockout attenuates right ventricular dysfunction and fibrosis in a mouse model of right ventricular failure. C3a is produced from C3 by the C3 convertase complex, which includes the essential component complement factor D (Cfd). Cfd-knockout mice also show attenuation of right ventricular failure. Moreover, the plasma concentration of CFD correlates with the severity of right ventricular failure in patients with chronic right ventricular failure. A C3a receptor (C3aR) antagonist dramatically improves right ventricular dysfunction in mice. In summary, we demonstrate the crucial role of the C3-Cfd-C3aR axis in right ventricular failure and highlight potential therapeutic targets for right ventricular failure.
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Insuficiência Cardíaca , Disfunção Ventricular Direita , Animais , Complemento C3/genética , Convertases de Complemento C3-C5 , Fator D do Complemento , Insuficiência Cardíaca/genética , Camundongos , Camundongos Knockout , Remodelação VentricularRESUMO
Advances in deep learning technology have enabled complex task solutions. The accuracy of image classification tasks has improved owing to the establishment of convolutional neural networks (CNN). Cellular senescence is a hallmark of ageing and is important for the pathogenesis of ageing-related diseases. Furthermore, it is a potential therapeutic target. Specific molecular markers are used to identify senescent cells. Moreover senescent cells show unique morphology, which can be identified. We develop a successful morphology-based CNN system to identify senescent cells and a quantitative scoring system to evaluate the state of endothelial cells by senescence probability output from pre-trained CNN optimised for the classification of cellular senescence, Deep Learning-Based Senescence Scoring System by Morphology (Deep-SeSMo). Deep-SeSMo correctly evaluates the effects of well-known anti-senescent reagents. We screen for drugs that control cellular senescence using a kinase inhibitor library by Deep-SeSMo-based drug screening and identify four anti-senescent drugs. RNA sequence analysis reveals that these compounds commonly suppress senescent phenotypes through inhibition of the inflammatory response pathway. Thus, morphology-based CNN system can be a powerful tool for anti-senescent drug screening.
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Forma Celular , Senescência Celular , Aprendizado Profundo , Avaliação Pré-Clínica de Medicamentos , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Peróxido de Hidrogênio/toxicidade , Redes Neurais de Computação , beta-Galactosidase/metabolismoRESUMO
OBJECTIVES: This study sought to isolate arrhythmogenic Marshall bundles (MBs) by radiofrequency (RF) catheter ablation. BACKGROUND: The vein of Marshall (VOM) is surrounded by a muscular bundle called the MB. The MB is 1 of the arrhythmogenic sources of atrial fibrillation (AF) and electrically connects to either the left atrial (LA) myocardium or coronary sinus (CS) musculature. By eliminating such electric connections using RF catheter ablation, the MB might be electrically isolated. METHODS: This retrospective study included 20 patients (64 ± 10 years old, 5 women) who underwent an MB isolation for nonparoxysmal AF. After pulmonary vein isolation, we performed venography of the VOM and inserted a 2-F electrode catheter into the VOM. RF applications were delivered to eliminate the MB electrograms from both the LA and CS when the MB was considered arrhythmogenic. RESULTS: MB isolation was achieved in 14 patients (70%). Of them, complete or partial MB isolation was accomplished in 7 patients (35%) each. The average number of RF applications in the LA (35 W, 30 s) and CS (25 W, 30 s) was 15 ± 14 and 4 ± 3, respectively. No severe adverse events were observed. During a follow-up of 23 ± 11 months, 18 patients (90%) maintained sinus rhythm. CONCLUSIONS: RF applications targeting recordings from an electrode catheter in the VOM were feasible, and the MB could be electrically isolated. Elimination of the MB potentials would be a clear endpoint for patients with an arrhythmogenic MB.
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Fibrilação Atrial , Ablação por Cateter , Veias Pulmonares , Fibrilação Atrial/cirurgia , Criança , Feminino , Átrios do Coração , Humanos , Veias Pulmonares/diagnóstico por imagem , Veias Pulmonares/cirurgia , Estudos RetrospectivosRESUMO
Supercentenarians (those aged ≥110 years) are approaching the current human longevity limit by preventing or surviving major illness. Identifying specific biomarkers conducive to exceptional survival might provide insights into counter-regulatory mechanisms against aging-related disease. Here, we report associations between cardiovascular disease-related biomarkers and survival to the highest ages using a unique dataset of 1,427 oldest individuals from three longitudinal cohort studies, including 36 supercentenarians, 572 semi-supercentenarians (105-109 years), 288 centenarians (100-104 years), and 531 very old people (85-99 years). During follow-up, 1,000 participants (70.1%) died. Overall, N-terminal pro-B-type natriuretic peptide (NT-proBNP), interleukin-6, cystatin C and cholinesterase are associated with all-cause mortality independent of traditional cardiovascular risk factors and plasma albumin. Of these, low NT-proBNP levels are statistically associated with a survival advantage to supercentenarian age. Only low albumin is associated with high mortality across age groups. These findings expand our knowledge on the biology of human longevity.
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Envelhecimento/sangue , Biomarcadores/sangue , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Albumina Sérica/análise , Inquéritos e Questionários/estatística & dados numéricos , Idoso de 80 Anos ou mais , Envelhecimento/fisiologia , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/diagnóstico , Feminino , Humanos , Longevidade/fisiologia , Estudos Longitudinais , Masculino , Análise Multivariada , Valor Preditivo dos Testes , Estudos Prospectivos , Fatores de Risco , Análise de SobrevidaRESUMO
INTRODUCTION: We aimed to study the prevalence and types of sleep apnea (SA) as well as their clinical characteristics in atrial fibrillation (AF) ablation candidates in Japan. METHODS: Before catheter ablation, 197 consecutive AF patients (age: 60⯱â¯9â¯years, body mass index; 25.0⯱â¯3.0) were evaluated with portable polygraphy. We compared the clinical characteristics, according to the severity of SA as well as its types, as defined by the presence of obstruction and the mixed vs. central apnea indices. RESULTS: The mean apnea-hypopnea index (AHI) was 17.7⯱â¯11.9, with 135 AF patients having an AHI ≥10 (68.5%). Patients with an AHI ≥10 had a significantly higher body mass index, plasma brain natriuretic peptide (BNP) level, prevalence of hypertension, and larger left atrial size. Among patients with an AHI ≥10, the incidence of obstructive-dominant SA was 60.9% and that of central-dominant SA was 7.6%. The prevalence of hypertension was significantly higher in obstructive-dominant SA patients (obstructive vs. central: 48.3% vs. 20.0%, Pâ¯=â¯0.038). The obstructive apnea index correlated with plasma BNP level and age, but the central and mixed apnea indices did not. CONCLUSIONS: The prevalence of SA was common in AF ablation candidates, even without an obesity epidemic, and the SA type was predominantly obstructive. Portable polygraphy was useful for detecting undiagnosed SA patients in AF ablation candidates.
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Fibrilação Atrial/epidemiologia , Ablação por Cateter/tendências , Apneia do Sono Tipo Central/epidemiologia , Apneia Obstrutiva do Sono/epidemiologia , Idoso , Fibrilação Atrial/fisiopatologia , Fibrilação Atrial/cirurgia , Ablação por Cateter/métodos , Estudos Transversais , Feminino , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Prevalência , Apneia do Sono Tipo Central/fisiopatologia , Apneia do Sono Tipo Central/cirurgia , Apneia Obstrutiva do Sono/fisiopatologia , Apneia Obstrutiva do Sono/cirurgiaRESUMO
Background Brugada syndrome ( BS ) is known to be 9 times more prevalent in males than females. However, little is known about the development of sick sinus syndrome in female members with familial BS . Methods and Results Familial BS patients and family members, both from our institutions and collaborating sites that specialize in clinical care of BS , participated in this study. We collected information on their clinical and genetic background, along with the inheritance patterns of BS . Detailed information on each case with familial BS is described. A total of 7 families, including 25 BS patients (12 females and 13 males), were included. Seven were probands and 18 were family members. Ten out of the 12 female patients and none of the 13 male patients developed sick sinus syndrome. Sudden death or spontaneous ventricular fibrillation occurred in 7 out of 13 male patients and 2 out of 12 female patients. Conclusions Familial BS existed in which female patients developed sick sinus syndrome but male patients did not. Some of those female patients with sick sinus syndrome had unrecognized BS . Information should be collected not only regarding a family history of sudden death or BS , but also whether a pacemaker was implanted in female members.
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Síndrome de Brugada/genética , Mutação , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Adolescente , Adulto , Idoso , Síndrome de Brugada/metabolismo , Síndrome de Brugada/fisiopatologia , Criança , Análise Mutacional de DNA , Eletrocardiografia , Feminino , Testes Genéticos/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Canal de Sódio Disparado por Voltagem NAV1.5/metabolismo , Linhagem , Fenótipo , Síndrome do Nó Sinusal/genética , Síndrome do Nó Sinusal/metabolismo , Síndrome do Nó Sinusal/fisiopatologia , Adulto JovemRESUMO
BACKGROUND: We aimed to clarify the cost-effectiveness of an expensive combination therapy for atrial fibrillation (AF) using both catheter ablation and dabigatran compared with warfarin at each CHADS2 score for patients in Japan. METHODS: A Markov model was constructed to analyze costs and quality-adjusted life years associated with AF therapeutic options with a time horizon of 10 years. The target population was 60-year-old patients with paroxysmal AF. The indication for anticoagulation was determined according to the Japanese guideline. Anticoagulation-related data were derived from the RE-LY study and the AF recurrence rate was set at 2.7% per month during the first 12 months and at 0.40% per month afterwards. Stroke risk was determined according to AF recurrence, anticoagulation, and CHADS2 score. The risks for stroke recurrence and stroke death were also considered. Costs were calculated from the healthcare payer's perspective, and only direct medical costs were included. RESULTS: Warfarin was the most preferred option for patients with a CHADS2 score of 0 from a health economics aspect. Ablation under warfarin was preferred for a CHADS2 score of 1-3, while ablation under dabigatran was preferred for a CHADS2 score ≥4. The quality of life score for AF had the largest impact on the incremental cost-effectiveness ratios in the analysis between the anticoagulation arm and the anticoagulation+ablation arm for a CHADS2 score of 2. Within the range of the Japanese willingness-to-pay threshold (¥5,000,000), the ablation+warfarin arm became the best option with its probability of 81.7% for a CHADS2 score of 2; the dabigatran+ablation arm was the most preferred option with its probability of 56.1% for a CHADS2 score of 4. CONCLUSIONS: Ablation under dabigatran therapy is an expensive therapeutic option, but it might benefit patients with a low quality of life and a high CHADS2 score.
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Antitrombinas/economia , Fibrilação Atrial/terapia , Ablação por Cateter/economia , Dabigatrana/economia , Índice de Gravidade de Doença , Varfarina/economia , Antitrombinas/uso terapêutico , Fibrilação Atrial/economia , Terapia Combinada , Análise Custo-Benefício , Dabigatrana/uso terapêutico , Humanos , Japão , Cadeias de Markov , Pessoa de Meia-Idade , Qualidade de Vida , Anos de Vida Ajustados por Qualidade de Vida , Varfarina/uso terapêuticoRESUMO
BACKGROUND: The monitoring of the effects of direct oral anticoagulants may be beneficial during emergencies and adverse events. We aimed to explore direct oral anticoagulant monitoring in "real-world" settings, in which monitoring methods are limited and loading time can be estimated based on only patient reports. METHODS: In 164 patients, plasma anti-Xa activity was assessed using a STA®-Liquid Anti-Xa reagent (Diagnostica Stago, Asnieres, France), and prothrombin time was measured using HemosIL® RecombiPlasTin 2G (Instrumentation Laboratory, Bedford, MA, USA). The loading time was calculated according to the previous dosing time reported by the patient. In the clinic setting, rivaroxaban and apixaban were administered to 103 patients with atrial fibrillation and a blood sample was tested once during a clinic visit. In the hospitalization setting, edoxaban was administered to 61 patients undergoing arthroplasty for prophylaxis of a venous thrombosis and blood samples were tested 3 and 18 h after the last intake. RESULTS: Plasma Xa activity in the clinical setting ranged widely (rivaroxaban: 1.1-424.4 ng/mL, apixaban: 15.4-469.2 ng/mL) during the 11.7 ± 7.0 h following the previous dose. The values varied over a wide range (up to a factor of 2) at the same loading time, especially around the peak period. The plasma anti-Xa activity of rivaroxaban and apixaban showed linear correlations with prothrombin time (R2 = 0.828 and 0.717, respectively). Edoxaban administration prolonged the prothrombin time by only 1.6 ± 1.1 s from the trough to the peak, to a degree that was negatively correlated with age, but not with plasma creatinine level, creatinine clearance, or body mass index. CONCLUSION: In real-world settings, plasma anti-Xa monitoring should be interpreted considering the wide variations in data, reflecting the variability in patient-reported loading time and interpatient variability.
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BACKGROUND: For perimitral atrial flutter (PMFL) developing after catheter ablation of atrial fibrillation (AF), to create a complete conduction block at the mitral isthmus (MI) is mandatory to terminate it, however, it is still challenging. METHODS: This study consisted of 80 patients (74 male, 61 ± 8.1 years) undergoing MI ablation. After a circular mapping catheter was positioned at the neck of the left atrial appendage (LAA), the MI ablation was performed on the MI line just below the LAA neck targeting the earliest activation recording site of the LAA catheter during pacing from the coronary sinus (CS). When ablation during CS pacing was not successful, an RF delivery during LAA pacing was applied targeting the earliest activation site just below the MI line. If the endocardial approach failed, an RF application inside the CS was attempted. RESULTS: With the endocardial approach, acute success was achieved in 51/80 patients (64%). Additional epicardial ablation from the CS was performed in 26/29 (90%) endocardially unsuccessful patients and conduction block at the MI was achieved in 21/26 (81%). Overall, complete conduction block at the MI was achieved in 72/80 patients (90%). At a mean follow-up of 16 ± 6 months, 20 patients (25%) had recurrence of atrial arrhythmias (AT: 12, AF: 8), and 10 (AT: 7, AF : 3) underwent a second procedure in which an LMI block line was completed in 3 (33%). PMFL was diagnosed in 6 out of 7 AT patients. No complications were observed. CONCLUSIONS: Creating linear lesions just beneath the neck of the LAA was highly successful under the guidance of a circular mapping catheter in the LAA using a steerable sheath. An RF application from the CS was needed in less than half of the cases.
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The expression of pluripotency genes fluctuates in a population of embryonic stem (ES) cells and the fluctuations in the expression of some pluripotency genes correlate. However, no correlation in the fluctuation of Pou5f1, Zfp42, and Nanog expression was observed in ES cells. Correlation between Pou5f1 and Zfp42 fluctuations was demonstrated in ES cells containing a knockout in the NuRD component Mbd3. ES cells containing a triple knockout in the DNA methyltransferases Dnmt1, Dnmt3a, and Dnmt3b showed correlation between the fluctuation of Pou5f1, Zfp42, and Nanog gene expression. We suggest that an epigenetic barrier is key to preventing the propagation of fluctuating pluripotency gene expression in ES cells.
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Células-Tronco Embrionárias/metabolismo , Animais , Epigenômica , Expressão Gênica/genética , Camundongos , Proteína Homeobox Nanog/genética , Fator 3 de Transcrição de Octâmero/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Transcrição SOXB1/genéticaRESUMO
Alteration of the nuclear Ca2+ transient is an early event in cardiac remodeling. Regulation of the nuclear Ca2+ transient is partly independent of the cytosolic Ca2+ transient in cardiomyocytes. One nuclear membrane protein, emerin, is encoded by EMD, and an EMD mutation causes Emery-Dreifuss muscular dystrophy (EDMD). It remains unclear whether emerin is involved in nuclear Ca2+ homeostasis. The aim of this study is to elucidate the role of emerin in rat cardiomyocytes by means of hypertrophic stimuli and in EDMD induced pluripotent stem (iPS) cell-derived cardiomyocytes in terms of nuclear structure and the Ca2+ transient. The cardiac hypertrophic stimuli increased the nuclear area, decreased nuclear invagination, and increased the half-decay time of the nuclear Ca2+ transient in cardiomyocytes. Emd knockdown cardiomyocytes showed similar properties after hypertrophic stimuli. The EDMD-iPS cell-derived cardiomyocytes showed increased nuclear area, decreased nuclear invagination, and increased half-decay time of the nuclear Ca2+ transient. An autopsied heart from a patient with EDMD also showed increased nuclear area and decreased nuclear invagination. These data suggest that Emerin plays a crucial role in nuclear structure and in the nuclear Ca2+ transient. Thus, emerin and the nuclear Ca2+ transient are possible therapeutic targets in heart failure and EDMD.
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Cálcio/metabolismo , Cardiomegalia/genética , Proteínas de Membrana/genética , Distrofia Muscular de Emery-Dreifuss/genética , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Membrana Nuclear/metabolismo , Proteínas Nucleares/genética , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Angiotensina II/farmacologia , Compostos de Anilina/química , Animais , Remodelamento Atrial , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Citoplasma/efeitos dos fármacos , Citoplasma/metabolismo , Citoplasma/ultraestrutura , Modelos Animais de Doenças , Endotelina-1/farmacologia , Corantes Fluorescentes/química , Regulação da Expressão Gênica , Compostos Heterocíclicos com 3 Anéis/química , Humanos , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/metabolismo , Distrofia Muscular de Emery-Dreifuss/metabolismo , Distrofia Muscular de Emery-Dreifuss/patologia , Miocárdio/patologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/ultraestrutura , Membrana Nuclear/efeitos dos fármacos , Membrana Nuclear/ultraestrutura , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/metabolismo , Fenilefrina/farmacologia , Cultura Primária de Células , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Ratos , Ratos Sprague-Dawley , Remodelação Ventricular , Xantenos/químicaRESUMO
Embryonic stem cells (ESCs) are a hallmark of ideal pluripotent stem cells. Epigenetic reprogramming of induced pluripotent stem cells (iPSCs) has not been fully accomplished. iPSC generation is similar to somatic cell nuclear transfer (SCNT) in oocytes, and this procedure can be used to generate ESCs (SCNT-ESCs), which suggests the contribution of oocyte-specific constituents. Here, we show that the mammalian oocyte-specific linker histone H1foo has beneficial effects on iPSC generation. Induction of H1foo with Oct4, Sox2, and Klf4 significantly enhanced the efficiency of iPSC generation. H1foo promoted in vitro differentiation characteristics with low heterogeneity in iPSCs. H1foo enhanced the generation of germline-competent chimeric mice from iPSCs in a manner similar to that for ESCs. These findings indicate that H1foo contributes to the generation of higher-quality iPSCs.
Assuntos
Reprogramação Celular , Epigênese Genética , Histonas/genética , Células-Tronco Pluripotentes Induzidas/metabolismo , Oócitos/metabolismo , Animais , Quimerismo , Embrião de Mamíferos , Feminino , Fibroblastos/citologia , Fibroblastos/metabolismo , Expressão Gênica , Histonas/metabolismo , Células-Tronco Pluripotentes Induzidas/citologia , Fator 4 Semelhante a Kruppel , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Camundongos , Camundongos Transgênicos , Fator 3 de Transcrição de Octâmero/genética , Fator 3 de Transcrição de Octâmero/metabolismo , Oócitos/citologia , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Fatores de Transcrição SOXB1/genética , Fatores de Transcrição SOXB1/metabolismoRESUMO
INTRODUCTION: Lead failures (LFs) are one of the most common complications in patients implanted with cardiovascular implantable electronic devices. LFs often cause serious secondary complications such as inappropriate ICD shocks or asystole. This study aimed to identify the clinical factors associated with the occurrence of LFs. METHODS: A total of 735 consecutive device implantations (mean age 67±15years, males 64%) performed at a single university hospital setting from 1997 to 2014 were included. The implanted devices consisted of 421 pacemakers, 250 implantable cardioverter defibrillators (ICD), 9 cardiac resynchronization therapy pacemakers (CRT-P), and 55 CRT defibrillators (CRT-D). The primary endpoint was the development of an LF. RESULTS: During a mean duration of 5.8±4.3years, 38 LFs developed in 31 patients (mean age 56±14years). LFs included 32 ICD (7 Sprint Fidelis, 2 Riata), and 6 pacing leads. Nine patients received inappropriate ICD shocks and 1 had syncope due to an LF. All patients underwent lead reinsertions with device replacements. Eight patients required opposite site implantations due to venous occlusions. The predictive factors of LFs were the age, male sex, taller body length, ICD vs. pacemaker, lesser lead number, extra-thoracic puncture of the axillary vein vs. a cut-down of the cephalic vein, use of recalled leads and patients with idiopathic ventricular fibrillation (IVF) and Brugada syndrome (BrS). CONCLUSION: LFs occurred mainly with ICD leads. A lesser age, the puncture method, lead model, and diagnosis of IVF/BrS were associated with the development of LFs.
Assuntos
Arritmias Cardíacas/terapia , Desfibriladores Implantáveis/efeitos adversos , Marca-Passo Artificial/efeitos adversos , Idoso , Remoção de Dispositivo , Falha de Equipamento , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Fatores de TempoRESUMO
Mitochondrial diseases are heterogeneous disorders, caused by mitochondrial dysfunction. Mitochondria are not regulated solely by nuclear genomic DNA but by mitochondrial DNA. It is difficult to develop effective therapies for mitochondrial disease because of the lack of mitochondrial disease models. Mitochondrial myopathy, encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is one of the major mitochondrial diseases. The aim of this study was to generate MELAS-specific induced pluripotent stem cells (iPSCs) and to demonstrate that MELAS-iPSCs can be models for mitochondrial disease. We successfully established iPSCs from the primary MELAS-fibroblasts carrying 77.7% of m.3243A>G heteroplasmy. MELAS-iPSC lines ranged from 3.6% to 99.4% of m.3243A>G heteroplasmy levels. The enzymatic activities of mitochondrial respiratory complexes indicated that MELAS-iPSC-derived fibroblasts with high heteroplasmy levels showed a deficiency of complex I activity but MELAS-iPSC-derived fibroblasts with low heteroplasmy levels showed normal complex I activity. Our data indicate that MELAS-iPSCs can be models for MELAS but we should carefully select MELAS-iPSCs with appropriate heteroplasmy levels and respiratory functions for mitochondrial disease modeling.