RESUMO
BACKGROUND: Because adult cardiomyocytes have little regenerative capacity, resident cardiac fibroblasts (CFs) synthesize extracellular matrix after myocardial infarction (MI) to form fibrosis, leading to cardiac dysfunction and heart failure. Therapies that can regenerate the myocardium and reverse fibrosis in chronic MI are lacking. The overexpression of cardiac transcription factors, including Mef2c/Gata4/Tbx5/Hand2 (MGTH), can directly reprogram CFs into induced cardiomyocytes (iCMs) and improve cardiac function under acute MI. However, the ability of in vivo cardiac reprogramming to repair chronic MI with established scars is undetermined. METHODS: We generated a novel Tcf21iCre/reporter/MGTH2A transgenic mouse system in which tamoxifen treatment could induce both MGTH and reporter expression in the resident CFs for cardiac reprogramming and fibroblast lineage tracing. We first tested the efficacy of this transgenic system in vitro and in vivo for acute MI. Next, we analyzed in vivo cardiac reprogramming and fusion events under chronic MI using Tcf21iCre/Tomato/MGTH2A and Tcf21iCre/mTmG/MGTH2A mice, respectively. Microarray and single-cell RNA sequencing were performed to determine the mechanism of cardiac repair by in vivo reprogramming. RESULTS: We confirmed the efficacy of transgenic in vitro and in vivo cardiac reprogramming for acute MI. In chronic MI, in vivo cardiac reprogramming converted ≈2% of resident CFs into iCMs, in which a majority of iCMs were generated by means of bona fide cardiac reprogramming rather than by fusion with cardiomyocytes. Cardiac reprogramming significantly improved myocardial contraction and reduced fibrosis in chronic MI. Microarray analyses revealed that the overexpression of MGTH activated cardiac program and concomitantly suppressed fibroblast and inflammatory signatures in chronic MI. Single-cell RNA sequencing demonstrated that resident CFs consisted of 7 subclusters, in which the profibrotic CF population increased under chronic MI. Cardiac reprogramming suppressed fibroblastic gene expression in chronic MI by means of conversion of profibrotic CFs to a quiescent antifibrotic state. MGTH overexpression induced antifibrotic effects partly by suppression of Meox1, a central regulator of fibroblast activation. CONCLUSIONS: These results demonstrate that cardiac reprogramming could repair chronic MI by means of myocardial regeneration and reduction of fibrosis. These findings present opportunities for the development of new therapies for chronic MI and heart failure.
Assuntos
Insuficiência Cardíaca , Infarto do Miocárdio , Camundongos , Animais , Miócitos Cardíacos/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Fibrose , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/metabolismo , Fibroblastos/metabolismo , Reprogramação CelularRESUMO
Cardiomyocytes (CMs) have little regenerative capacity. After myocardial infarction (MI), scar formation and myocardial remodeling proceed in the infarct and non-infarct areas, respectively, leading to heart failure (HF). Prolonged activation of cardiac fibroblasts (CFs) and inflammatory cells may contribute to this process; however, therapies targeting these cell types remain lacking. Cardiac reprogramming converts CFs into induced CMs, reduces fibrosis, and improves cardiac function in chronic MI through the overexpression of Mef2c/Gata4/Tbx5/Hand2 (MGTH). However, whether cardiac reprogramming reduces inflammation in infarcted hearts remains unclear. Moreover, the mechanism through which MGTH overexpression in CFs affects inflammatory cells remains unknown. Here, we showed that inflammation persists in the myocardium until three months after MI, which can be reversed with cardiac reprogramming. Single-cell RNA sequencing demonstrated that CFs expressed pro-inflammatory genes and exhibited strong intercellular communication with inflammatory cells, including macrophages, in chronic MI. Cardiac reprogramming suppressed the inflammatory profiles of CFs and reduced the relative ratios and pro-inflammatory signatures of cardiac macrophages. Moreover, fluorescence-activated cell sorting analysis (FACS) revealed that cardiac reprogramming reduced the number of chemokine receptor type 2 (CCR2)-positive inflammatory macrophages in the non-infarct areas in chronic MI, thereby restoring myocardial remodeling. Thus, cardiac reprogramming reduced the number of inflammatory macrophages to exacerbate cardiac function after MI.
Assuntos
Infarto do Miocárdio , Humanos , Infarto do Miocárdio/metabolismo , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Macrófagos/metabolismo , Inflamação/metabolismo , Fibroblastos/metabolismoRESUMO
BACKGROUND: The mechanisms underlying pulmonary hypertension (PH) remain largely unknown; further, why advanced vascular remodeling preferentially occurs in arterioles is yet to be answered. VEGF (vascular endothelial growth factor) regulates angiogenesis through Flk1 (fetal liver kinase 1) and Flt1 (fms-like tyrosine kinase 1) on endothelial cells (ECs), which may be related to PH pathogenesis. However, spatiotemporal expression patterns of Flk1 and Flt1 in the pulmonary vascular system and the role of endothelial Flk1 in PH development remain poorly understood. METHODS: We analyzed multiple reporter mice, including Flk1-GFP (green fluorescent protein) bacterial artificial chromosome transgenic (Tg), Flt1-DsRed bacterial artificial chromosome Tg, and Flk1-GFP/Flt1-DsRed double Tg mice, to determine the spatiotemporal expression of Flk1 and Flt1 in hypoxia-induced PH. We also used Cdh5CreERT2/Flk1f/f/Tomato (Flk1-KO [knockout]) mice to induce EC-specific Flk1 deletion and lineage tracing in chronic hypoxia. RESULTS: Flk1 was specifically expressed in the ECs of small pulmonary vessels, including arterioles. Conversely, Flt1 was more broadly expressed in the ECs of large- to small-sized vessels in adult mouse lungs. Intriguingly, Flk1+ ECs were transiently increased in hypoxia with proliferation, whereas Flt1 expression was unchanged. Flk1-KO mice did not exhibit pulmonary vascular remodeling nor PH in normoxia; however, the arteriolar ECs changed to a cuboidal shape with protrusion. In hypoxia, Flk1 deletion exacerbated EC dysfunction and reduced their number via apoptosis. Additionally, Flk1 deletion promoted medial thickening and neointimal formation in arterioles and worsened PH. Mechanistically, lineage tracing revealed that neointimal cells were derived from Flk1-KO ECs. Moreover, RNA sequencing in pulmonary ECs demonstrated that Flk1 deletion and hypoxia synergistically activated multiple pathways, including cell cycle, senescence/apoptosis, and cytokine/growth factor, concomitant with suppression of cell adhesion and angiogenesis, to promote vascular remodeling. CONCLUSIONS: Flk1 and Flt1 were differentially expressed in pulmonary ECs. Flk1 deficiency and hypoxia jointly dysregulated arteriolar ECs to promote vascular remodeling. Thus, dysfunction of Flk1+ ECs may contribute to the pathogenesis of advanced vascular remodeling in pulmonary arterioles.
Assuntos
Hipertensão Pulmonar , Remodelação Vascular , Animais , Camundongos , Células Endoteliais/metabolismo , Proteínas de Fluorescência Verde/metabolismo , Hipertensão Pulmonar/genética , Hipertensão Pulmonar/metabolismo , Hipóxia/complicações , Hipóxia/genética , Hipóxia/metabolismo , Camundongos Knockout , Camundongos Transgênicos , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
The incidence of cardiovascular diseases is increasing worldwide, and cardiac regenerative therapy has great potential as a new treatment strategy, especially for ischemic heart disease. Direct cardiac reprogramming is a promising new cardiac regenerative therapy that uses defined factors to induce transdifferentiation of endogenous cardiac fibroblasts (CFs) into induced cardiomyocyte-like cells (iCMs). In vivo reprogramming is expected to restore lost cardiac function without necessitating cardiac transplantation by converting endogenous CFs that exist abundantly in cardiac tissues directly into iCMs. Indeed, we and other groups have demonstrated that in vivo cardiac reprogramming improves cardiac contractile function and reduces scar area after acute myocardial infarction (MI). Recently, we demonstrated that in vivo cardiac reprogramming is an innovative cardiac regenerative therapy that not only regenerates the myocardium, but also reverses fibrosis by inducing the quiescence of pro-fibrotic fibroblasts, thereby improving heart failure in chronic MI. In this review, we summarize the recent progresses in in vivo cardiac reprogramming, and discuss its prospects for future clinical applications and the challenges of direct human reprogramming, which has been a longstanding issue.
Assuntos
Insuficiência Cardíaca , Infarto do Miocárdio , Humanos , Reprogramação Celular/genética , Miocárdio , Miócitos Cardíacos , Infarto do Miocárdio/terapia , FibroblastosRESUMO
BACKGROUND: Identifying predictive factors for coronavirus disease 2019 (COVID-19) is crucial for risk stratification and intervention. Kidney dysfunction contributes to the severity of various infectious diseases. However, the association between on-admission kidney dysfunction and the clinical outcome in COVID-19 patients is unclear. METHODS: This study was a multicenter retrospective observational cohort study of COVID-19 patients, diagnosed by polymerase chain reaction. We retrospectively analyzed 500 COVID-19 patients (mean age: 51 ± 19 years) admitted to eight hospitals in Japan. Kidney dysfunction was defined as a reduced estimated glomerular filtration rate (< 60 mL/min/1.73 m2) or proteinuria (≥ 1 + dipstick proteinuria) on admission. The primary composite outcome included in-hospital death, extracorporeal membrane oxygenation, mechanical ventilation (invasive and noninvasive methods), and intensive care unit (ICU) admission. RESULTS: Overall, 171 (34.2%) patients presented with on-admission kidney dysfunction, and the primary composite outcome was observed in 60 (12.0%) patients. Patients with kidney dysfunction showed higher rates of in-hospital death (12.3 vs. 1.2%), mechanical ventilation (13.5 vs. 4.0%), and ICU admission (18.1 vs. 5.2%) than those without it. Categorical and multivariate regression analyses revealed that kidney dysfunction was substantially associated with the primary composite outcome. Thus, on-admission kidney dysfunction was common in COVID-19 patients. Furthermore, it correlated significantly and positively with COVID-19 severity and mortality. CONCLUSIONS: On-admission kidney dysfunction was associated with disease severity and poor short-term prognosis in patients with COVID-19. Thus, on-admission kidney dysfunction has the potential to stratify risks in COVID-19 patients.
Assuntos
COVID-19 , Insuficiência Renal Crônica , Adulto , Idoso , COVID-19/epidemiologia , COVID-19/terapia , Mortalidade Hospitalar , Humanos , Unidades de Terapia Intensiva , Japão/epidemiologia , Pessoa de Meia-Idade , Proteinúria , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/terapia , Estudos Retrospectivos , Fatores de Risco , SARS-CoV-2RESUMO
Adult hearts have limited regenerative capacity. Hence, after acute myocardial infarction (MI), dead myocardial tissues are digested by immune cells and replaced by fibrosis, leading to ventricular remodeling and heart failure at the chronic stage. Direct reprogramming of the cardiac fibroblasts (CFs) into induced cardiomyocytes (iCMs) with cardiac transcription factors, including Gata4, Mef2c, and Tbx5 (GMT), may have significant potential for cardiac repair. Sendai virus (SeV) vectors expressing GMT have been reported to reprogram the mouse cardiac fibroblasts into iCMs without any risk of insertional mutagenesis. In vivo reprogramming improved the cardiac function after acute MI in immunodeficient mice. However, it is unknown whether the newly generated iCMs could exist in infarct hearts for a prolonged period and SeV-GMT can improve cardiac function after MI at the chronic stage in immunocompetent mice. Here, we show that SeV vectors efficiently infect CFs in vivo and reprogram them into iCMs, which existed for at least four weeks after MI, in fibroblast-linage tracing mice. Moreover, SeV-GMT improved cardiac function and reduced fibrosis and collagen I expression at 12 weeks after MI in immunocompetent mice. Thus, direct cardiac reprogramming with SeV vectors could be a promising therapy for MI.
Assuntos
Reprogramação Celular , Vetores Genéticos , Infarto do Miocárdio/terapia , Vírus Sendai/genética , Animais , Doença Crônica , Colágeno Tipo I/metabolismo , Fibroblastos , Fibrose , Masculino , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Miocárdio/citologia , Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Fatores de Transcrição/genéticaRESUMO
Taste buds are complex sensory organs embedded in the epithelium of fungiform papillae (FP) and circumvallate papillae (CV). The sweet, bitter, and umami tastes are sensed by type II taste cells that express taste receptors (Tas1rs and Tas2rs) coupled with the taste G-protein α-gustducin. Recent studies revealed that the taste response profiles of α-gustducin-expressing cells are different between FP and CV, but which genes could generate such distinctive cell characteristics are still largely unknown. We performed a comprehensive transcriptome analysis on α-gustducin-expressing cells in mouse FP and CV by single-cell RNA sequencing combined with fluorescence-activated cell sorting. Transcriptome profiles of the α-gustducin-expressing cells showed various expression patterns of taste receptors. Our clustering analysis defined the specific cell populations derived from FP or CV based on their distinct gene expression. Immunohistochemistry confirmed the specific expression of galectin-3, encoded by Lgals3, which was recognized as a differentially expressed gene in the transcriptome analysis. Our work provides fundamental knowledge toward understanding the genetic heterogeneity of type II cells, potentially revealing differential characterization of FP and CV taste bud cells.
Assuntos
Galectina 3/metabolismo , Regulação da Expressão Gênica/genética , Papilas Gustativas/metabolismo , Língua/metabolismo , Transducina/metabolismo , Animais , Diferenciação Celular/genética , Feminino , Galectina 3/genética , Perfilação da Expressão Gênica , Ontologia Genética , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , RNA-Seq , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Análise de Célula Única , Percepção Gustatória/genética , Transducina/genéticaRESUMO
BACKGROUND: It remains unclear whether intrarenal venous flow (IRVF) patterns in patients with heart failure (HF) could change over the clinical course, and whether the changes could have a clinical impact. Thus, this study aimed to clarify these characteristics as well as to identify the relation between changes in the IRVF pattern and renal impairment progression. METHODS AND RESULTS: Patients with HF with repetitive IRVF evaluations were enrolled. Doppler waveforms of IRVF were classified into the following 3 flow patterns: continuous, biphasic discontinuous, and monophasic discontinuous. Primary end points included death from cardiovascular diseases and unplanned hospitalization for HF. Finally, 108 patients with adequate images were enrolled. The IRVF in 35 patients (32.4%) shifted to another pattern at the follow-up examinations. The median brain natriuretic peptide level in the continuous flow pattern at follow-up was significantly decreased (183 to 60 pg/mL, P < .001), whereas that of the discontinuous flow pattern at follow-up was increased (from 339 to 366 pg/mL, Pâ¯=â¯.042) and the estimated glomerular filtration rate was decreased (from 55 to 50 mL/min/1.73 m2, P = .013). A multivariable Cox proportional hazard model analysis revealed that the discontinuous pattern at follow-up (P < .001) and brain natriuretic peptide (Pâ¯=â¯.021) were significantly associated with the end points, independent of age, estimated glomerular filtration rate, and serum sodium level. CONCLUSIONS: The IRVF pattern could be changed depending on the status of congestion. Persistent or worsened renal congestion, represented by discontinuous flow patterns, during the clinical courses indicated a poor prognosis accompanied by renal impairment in patients with HF.
Assuntos
Insuficiência Cardíaca , Taxa de Filtração Glomerular , Insuficiência Cardíaca/diagnóstico por imagem , Humanos , Rim/diagnóstico por imagem , Peptídeo Natriurético Encefálico , PrognósticoRESUMO
A 50-year-old man with decompensated aortic stenosis displayed significantly reduced ejection fraction, an ascending aortic aneurysm (55 mm in diameter), and bilateral giant bullae, and was evaluated as having extremely high surgical risk. Therefore, as a bridge to definitive treatment, he simultaneously underwent transcatheter aortic valve replacement (TAVR) and upper left lung lobectomy. His heart function recovered 6 months later and he underwent surgical aortic valve replacement (SAVR) and graft replacement of the ascending aorta. TAVR may serve as a bridge procedure before SAVR for aortic stenosis in younger patients with high surgical risk.
Assuntos
Estenose da Valva Aórtica , Implante de Prótese de Valva Cardíaca , Substituição da Valva Aórtica Transcateter , Valva Aórtica/diagnóstico por imagem , Valva Aórtica/cirurgia , Estenose da Valva Aórtica/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Resultado do TratamentoRESUMO
Taste disorders are common adverse effects of cancer chemotherapy that can reduce quality of life and impair nutritional status. However, the molecular mechanisms underlying chemotherapy-induced taste disorders remain largely unknown. Furthermore, there are no effective preventive measures for chemotherapy-induced taste disorders. We investigated the effects of a combination of three anticancer drugs (TPF: docetaxel, cisplatin and 5-fluorouracil) on the structure and function of mouse taste tissues and examined whether the drinking of ice-cold water after TPF administration would attenuate these effects. TPF administration significantly increased the number of cells expressing apoptotic and proliferative markers. Furthermore, TPF administration significantly reduced the number of cells expressing taste cell markers and the magnitudes of the responses of taste nerves to tastants. The above results suggest that anticancer drug-induced taste dysfunction may be due to a reduction in the number of taste cells expressing taste-related molecules. The suppressive effects of TPF on taste cell marker expression and taste perception were reduced by the drinking of ice-cold water. We speculate that oral cryotherapy with an ice cube might be useful for prophylaxis against anticancer drug-induced taste disorders in humans.
Assuntos
Neoplasias de Cabeça e Pescoço/dietoterapia , Gelo , Distúrbios do Paladar/dietoterapia , Água/farmacologia , Animais , Proliferação de Células/efeitos dos fármacos , Cisplatino/efeitos adversos , Modelos Animais de Doenças , Docetaxel/efeitos adversos , Fluoruracila/efeitos adversos , Neoplasias de Cabeça e Pescoço/complicações , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Camundongos , Distúrbios do Paladar/induzido quimicamente , Distúrbios do Paladar/patologia , Taxoides/efeitos adversos , Água/químicaRESUMO
The unfolded protein response (UPR) occurs when protein folding and maturation are disturbed in the endoplasmic reticulum (ER). During the UPR, a number of genes including those encoding ER-resident molecular chaperones are induced. In Arabidopsis, BiP3 has been used as a UPR marker gene whose expression is strongly induced in response to ER stress. In this study, we mutagenized Arabidopsis plants expressing ß-glucuronidase (GUS) gene under the control of BiP3 promoter and isolated a mutant that exhibits strong GUS activity without treatment with ER stress inducers. By whole genome sequencing, we identified a causal gene in the mutant as SUPPRESSOR OF SALICYLIC ACID INSENSITIVITY2 (SSI2), which encodes stearoyl-acyl carrier protein desaturase that converts stearic acids to oleic acids in the chloroplasts. In addition to GUS proteins, the ssi2 mutant accumulates endogenous BiP3 proteins without treatment by any stress reagents. Interestingly, although the degree of endogenous BiP3 protein accumulation in the ssi2 mutant was comparable to that in wild-type plants treated with the ER stress inducer tunicamycin, much less BiP3 transcripts were detected in the ssi2 mutant compared to tunicamycin-treated wild-type plants. Our finding suggests a genetic link between fatty acid metabolism in the chloroplasts and ER functions.
Assuntos
Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Arabidopsis/metabolismo , Cloroplastos/metabolismo , Ácidos Graxos Dessaturases/genética , Regulação da Expressão Gênica de Plantas , Chaperonas Moleculares/metabolismo , Mutação , Arabidopsis/genética , Arabidopsis/crescimento & desenvolvimento , Fatores de Transcrição de Zíper de Leucina Básica/genética , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Retículo Endoplasmático/metabolismo , Ácidos Graxos Dessaturases/metabolismo , Ácidos Graxos/metabolismo , Chaperonas Moleculares/genética , Fenótipo , Plantas Geneticamente Modificadas , Resposta a Proteínas não DobradasRESUMO
Venovenous extracorporeal membrane oxygenation (VV-ECMO) is used not only support gas transfer of patients suffering from respiratory failure, but also to manage hypoxic patients with critical airway obstruction during various procedures. We present a case in which we electively used VV-ECMO to facilitate tube placement and tracheal biopsy in a 67-year-old female with critical tracheal stenosis. The patient was transferred to our hospital for a surgical treatment after emergent tracheostomy for postoperative management of cerebral hemorrhage in right putamen. Her trachea was severely stenotic and just enough for a 5.5 mm tracheostomy tube. Removal of tracheostomy tube, tracheal wall biopsy and intra-tracheal tube placement were successfully performed under VV-ECMO support, drainage from inferior vena cava returned into the right ventricle (RV). RV perfusion was a very useful and effective method in VV-ECMO system, although some careful wire management was needed under fluoroscopic guidance.
Assuntos
Obstrução das Vias Respiratórias/terapia , Gerenciamento Clínico , Oxigenação por Membrana Extracorpórea/métodos , Insuficiência Respiratória/terapia , Idoso , Obstrução das Vias Respiratórias/complicações , Obstrução das Vias Respiratórias/diagnóstico , Feminino , Humanos , Insuficiência Respiratória/diagnóstico , Insuficiência Respiratória/etiologia , Tomografia Computadorizada por Raios X , Veia Cava InferiorAssuntos
Fator de Transcrição GATA4/biossíntese , Infarto do Miocárdio/genética , Miócitos Cardíacos/metabolismo , Proteínas com Domínio T/biossíntese , Animais , Fusão Celular , Reprogramação Celular/fisiologia , Feminino , Fatores de Transcrição MEF2/biossíntese , Masculino , Camundongos , Miócitos Cardíacos/citologiaRESUMO
PURPOSE: The adequacy of pain management for individuals with cancer who receive outpatient chemotherapy is unclear. The primary objective of this study was to assess pain prevalence and intensity in such patients. The secondary objectives included assessment of pain management with the pain management index (PMI) and exploration of predictors of inadequate pain management. METHODS: Cancer patients who received outpatient chemotherapy were enrolled. Patients were required to complete questionnaires covering demographic data and including the Brief Pain Inventory and the Distress Thermometer and Impact Thermometer. The PMI score was determined twice with an interval of at least 3 weeks. RESULTS: Of the 740 patients enrolled in the study, 524 individuals (70.8%) completed all questionnaires. Totals of 282 patients (53.8%) and 264 patients (50.4%) reported pain at baseline and follow-up, respectively, with â¼14% of patients having moderate or severe pain at each assessment. Totals of 365 patients (69.7%) at baseline and 320 patients (61.1%) at follow-up reported pain or were prescribed analgesics, with the rate of inadequate pain management for these patients being 39.7 and 51.6%, respectively. Multivariable analysis for 418 patients (79.8%) who had pain or required analgesics at baseline or follow-up (or both) revealed that the most significant predictor of inadequate pain management was depressive state. CONCLUSIONS: Pain in cancer patients receiving outpatient chemotherapy is prevalent and at risk for undertreatment. Pain management should be assessed on a regular basis and is likely to be improved by screening for depression.
Assuntos
Dor do Câncer/diagnóstico , Dor do Câncer/tratamento farmacológico , Neoplasias/tratamento farmacológico , Neoplasias/fisiopatologia , Manejo da Dor/métodos , Medição da Dor/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Analgésicos/uso terapêutico , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Pacientes Ambulatoriais , Prevalência , Inquéritos e Questionários , Adulto JovemRESUMO
Purpose Human breath analysis is proposed with increasing frequency as a useful tool in clinical application. We performed this study to find the characteristic volatile organic compounds (VOCs) in the exhaled breath of patients with idiopathic pulmonary fibrosis (IPF) for discrimination from healthy subjects. Methods VOCs in the exhaled breath of 40 IPF patients and 55 healthy controls were measured using a multi-capillary column and ion mobility spectrometer. The patients were examined by pulmonary function tests, blood gas analysis, and serum biomarkers of interstitial pneumonia. Results We detected 85 VOC peaks in the exhaled breath of IPF patients and controls. IPF patients showed 5 significant VOC peaks; p-cymene, acetoin, isoprene, ethylbenzene, and an unknown compound. The VOC peak of p-cymene was significantly lower (p < 0.001), while the VOC peaks of acetoin, isoprene, ethylbenzene, and the unknown compound were significantly higher (p < 0.001 for all) compared with the peaks of controls. Comparing VOC peaks with clinical parameters, negative correlations with VC (r =-0.393, p = 0.013), %VC (r =-0.569, p < 0.001), FVC (r = -0.440, p = 0.004), %FVC (r =-0.539, p < 0.001), DLco (r =-0.394, p = 0.018), and %DLco (r =-0.413, p = 0.008) and a positive correlation with KL-6 (r = 0.432, p = 0.005) were found for p-cymene. Conclusion We found characteristic 5 VOCs in the exhaled breath of IPF patients. Among them, the VOC peaks of p-cymene were related to the clinical parameters of IPF. These VOCs may be useful biomarkers of IPF.
Assuntos
Fibrose Pulmonar Idiopática/diagnóstico , Fibrose Pulmonar Idiopática/fisiopatologia , Compostos Orgânicos Voláteis/análise , Acetoína/análise , Adulto , Idoso , Idoso de 80 Anos ou mais , Derivados de Benzeno/análise , Testes Respiratórios , Butadienos/análise , Estudos de Casos e Controles , Cimenos , Feminino , Voluntários Saudáveis , Hemiterpenos/análise , Humanos , Masculino , Pessoa de Meia-Idade , Monoterpenos/análise , Mucina-1/sangue , Oxigênio/sangue , Pressão Parcial , Pentanos/análise , Capacidade de Difusão Pulmonar , Capacidade Vital , Adulto JovemRESUMO
A 62-year-old male was transferred to our hospital complaining of palpitations. His heart rate was 185/min. Electrocardiogram showed a narrow QRS regular tachycardia and the tachycardia changed spontaneously to another narrow QRS tachycardia with two alternating cycle lengths. The arrhythmia was stopped by the administration of adenosine triphosphate. Findings from electrophysiological study suggested that there was an accessory pathway (AP) and dual atrioventricular (AV) nodal pathways. After AP ablation, any other tachyarrythmias were not induced. We supposed that the tachycardia was paroxysmal supraventricular tachycardia involving AP and anterograde conduction alternating between slow and fast AV nodal pathways.
Assuntos
Ablação por Cateter , Taquicardia por Reentrada no Nó Atrioventricular , Taquicardia Ventricular , Masculino , Humanos , Pessoa de Meia-Idade , Taquicardia por Reentrada no Nó Atrioventricular/cirurgia , Nó Atrioventricular/cirurgia , EletrocardiografiaRESUMO
Background: Ventricular arrhythmia (VA) is a life-threatening condition associated with cardiac sarcoidosis (CS). Right bundle branch block (RBBB) is a common conduction disorder in CS; however, its association with VA remains unknown. Objectives: This study aimed to investigate the relationship between RBBB and VA in patients with CS. Methods: This was a post hoc analysis of ILLUMINATE-CS (Illustration of the Management and Prognosis of Japanese Patients with Cardiac Sarcoidosis), a multicenter, retrospective, and observational study that evaluated the clinical characteristics and prognosis of CS. Eligible patients were divided into two groups based on the presence or absence of RBBB at the time of diagnosis. The primary outcome was serious ventricular arrhythmia events (SVAEs), defined as a combination of sudden cardiac death and documented ventricular fibrillation, sustained ventricular tachycardia, or appropriate implantable cardioverter-defibrillator therapy. Results: Overall, 312 patients were studied, with 155 (49.7%) patients presenting with RBBB (RBBB group). Patients in the RBBB group had a higher prevalence of basal interventricular septum (IVS) thinning and prominent late gadolinium enhancement in the basal IVS on cardiac magnetic resonance imaging than those in the non-RBBB group. During a median follow-up of 3.0 years (IQR: 1.6-6.0 years), 66 patients experienced SVAE. In multivariable Cox regression analysis, the RBBB group was independently associated with a higher incidence of SVAEs (HR: 1.93 [95% CI: 1.14-3.28]; P = 0.015). Conclusions: In patients with CS, RBBB was an independent predictor of SVAEs, which might reflect the specific scar distribution that is predominant in the IVS.
RESUMO
It has not yet been established whether angiotensin II receptor blockers (ARB), statins, and multiple drugs affect the severity of COVID-19. Therefore, we herein performed an observational study on the effects of 1st- and 2nd-generation ARB, statins, and multiple drugs, on COVID-19 in patients admitted to 15 Japanese medical facilities. The results obtained showed that ARB, statins, and multiple drugs were not associated with the primary outcome (odds ratio: 1.040, 95% confidence interval: 0.688-0.571; 0.696, 0.439-1.103; 1.056, 0.941-1.185, respectively), each component of the primary outcome (in-hospital death, ventilator support, extracorporeal membrane oxygenation support, and admission to the intensive care unit), or the secondary outcomes (oxygen administration, disturbed consciousness, and hypotension, defined as systolic blood pressure ≤90 mmHg). ARB were divided into 1st- and 2nd-generations based on their approval for use (before 2000 and after 2001), with the former consisting of losartan, candesartan, and valsartan, and the latter of telmisartan, olmesartan, irbesartan, and azilsartan. The difference of ARB generation was not associated with the primary outcome (odds ratio with 2nd-generation ARB relative to 1st-generation ARB: 1.257, 95% confidence interval: 0.613-2.574). The odd ratio for a hypotension as one of the secondary outcomes with 2nd-generation ARB was 1.754 (95% confidence interval: 1.745-1.763) relative to 1st-generation ARB. These results suggest that patients taking 2nd-generation ARB may be at a higher risk of hypotension than those taking 1st-generation ARB and also that careful observations are needed. Further studies are continuously needed to support decisions to adjust medications for co-morbidities.
Assuntos
Antagonistas de Receptores de Angiotensina , COVID-19 , Hipotensão , Humanos , Masculino , Feminino , Hipotensão/induzido quimicamente , Idoso , Antagonistas de Receptores de Angiotensina/efeitos adversos , Antagonistas de Receptores de Angiotensina/uso terapêutico , Pessoa de Meia-Idade , COVID-19/complicações , Japão/epidemiologia , Tratamento Farmacológico da COVID-19 , Hospitalização/estatística & dados numéricos , Idoso de 80 Anos ou mais , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , SARS-CoV-2RESUMO
BACKGROUND: Electron microscopy enables a finely detailed analysis of ultra-structural features, and hence, it generally has an added diagnostic value to light microscopy alone. However, no studies have verified the additional diagnostic value of electron microscopic examination in patients with suspected non-ischemic cardiomyopathy. METHODS: A total of 294 consecutive patients with non-ischemic cardiomyopathy who underwent endomyocardial biopsy were prospectively enrolled. Patients were divided into three groups according to left ventricular morphology assessed using echocardiography. Myocardial specimens were collected from the right ventricular septum and examined by light microscopy. Electron microscopy was performed subsequently to evaluate the additional diagnostic value. RESULTS: Altogether, 294 patients were analyzed, including 160 (55â¯%), 96 (33â¯%), and 35 (12â¯%) patients who were diagnosed with primary, secondary, and unclassified cardiomyopathy, respectively. In patients with dilated cardiomyopathy-like morphology, the detection rate of disease-specific histological findings was relatively low compared to that in patients with other cardiac morphologies. The additional diagnostic value of electron microscopy was observed in eight patients, including five with Fabry disease, one with cardiac amyloidosis, one with mitochondrial cardiomyopathy, and one with triglyceride deposit cardiomyovasculopathy. Among the 18 cardiac amyloidosis cases, electron microscopy detected amyloid fibrils in all patients, whereas light microscopy could not detect amyloid deposition in 1 patient. Among one of five patients with Fabry disease, light microscopy did not show obvious vacuolated cardiomyocytes, but zebra bodies were detected by electron microscopy, leading to the diagnosis of cardiac Fabry disease. The diagnostic value of electron microscopic examination in patients with cardiac sarcoidosis was not observed. CONCLUSIONS: The additional diagnostic value of electron microscopy was observed in patients with secondary cardiomyopathy, in whom light microscopy did not show disease-specific histological findings. Electron microscopy should be performed in cases where secondary cardiomyopathy is strongly suspected with no disease-specific findings by light microscopy.
Assuntos
Amiloidose , Cardiomiopatias , Doença de Fabry , Cardiopatias , Humanos , Miocárdio/patologia , Doença de Fabry/patologia , Elétrons , Cardiomiopatias/diagnóstico , Cardiomiopatias/patologia , Biópsia , Microscopia Eletrônica , Amiloidose/diagnósticoRESUMO
BACKGROUND: Long-term survival after surgery for severe aortic stenosis (AS) provides important information regarding the choice between surgical (SAVR) and transcatheter (TAVR) aortic valve replacement. This study investigated the long-term survival of AS patients with low or intermediate surgical risk who underwent SAVR or TAVR in our institution versus that of the Japanese general population. METHODS: From 2009 to 2019, 1276 consecutive patients underwent SAVR or TAVR for severe AS. Among them, we retrospectively investigated those with low (nâ¯=â¯383) or intermediate (nâ¯=â¯137) surgical risk treated with SAVR and those with low (nâ¯=â¯86) or intermediate (nâ¯=â¯333) surgical risk treated with TAVR. Their post-intervention survival was compared with that of an age- and gender-matched Japanese general population. RESULTS: The overall 5-year survival rate of SAVR for patients with low surgical risk (mean age, 72⯱â¯9â¯years) was not significantly different from that of the general population (90â¯% vs. 89â¯%, respectively; pâ¯=â¯0.58), whereas that of patients with intermediate surgical risk (77⯱â¯6â¯years) was significantly lower than that of the general population (77â¯% vs. 84â¯%, respectively; pâ¯=â¯0.03). After TAVR, the 5-year survival of patients with low (78⯱â¯8â¯years) or intermediate (83⯱â¯5â¯years) surgical risk was significantly lower than that of the general population (low risk, 64â¯% vs. 81â¯%, pâ¯<â¯0.01; intermediate risk, 66â¯% vs. 71â¯%, respectively, pâ¯=â¯0.01). CONCLUSIONS: Our study demonstrated that long-term survival after SAVR for AS patients with low surgical risk was as good as that of the age- and gender-matched general population, while the long-term survival after SAVR for intermediate-risk or TAVR for low- or intermediate-risk patients was lower than that of the general population. These findings suggest that SAVR is an appropriate option for AS patients with low surgical risk and good life expectancy, especially in Japan, where the life expectancy is the longest worldwide.