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The treatment for ischemic mitral regurgitation (MR) involves a combination of medical management and, in certain cases, surgical intervention. The approach depends on the severity of the condition, underlying causes, and the patient's overall health. A 76-year-old male with heart failure refractory to medical management because of ischemic MR was considered for a mitral valve repair surgery with a posterior mitral leaflet augmentation technique. Following the repair of the mitral valve and the cessation of the initial cardiopulmonary bypass (CPB), a prolapse of the posterior mitral leaflet, which had not been detected before the surgery, was revealed by intraoperative transesophageal echocardiography (TEE). A thorough inspection of the repaired mitral valve after cardiac arrest during the second CPB unveiled a loose suture at the edge of the valve and an inverted pericardium, indicating that the patch had flipped upward. Although complications of this type following the augmentation of the mitral posterior leaflet are rare, we promptly detected it using TEE, which incorporates three-dimensional imaging.
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BACKGROUND: Exercise intolerance is an independent predictor of poor prognosis in diabetes. The underlying mechanism of the association between hyperglycemia and exercise intolerance remains undefined. We recently demonstrated that the interaction between ARRDC4 (arrestin domain-containing protein 4) and GLUT1 (glucose transporter 1) regulates cardiac metabolism. METHODS: To determine whether this mechanism broadly impacts diabetic complications, we investigated the role of ARRDC4 in the pathogenesis of diabetic cardiac/skeletal myopathy using cellular and animal models. RESULTS: High glucose promoted translocation of MondoA into the nucleus, which upregulated Arrdc4 transcriptional expression, increased lysosomal GLUT1 trafficking, and blocked glucose transport in cardiomyocytes, forming a feedback mechanism. This role of ARRDC4 was confirmed in human muscular cells from type 2 diabetic patients. Prolonged hyperglycemia upregulated myocardial Arrdc4 expression in multiple types of mouse models of diabetes. We analyzed hyperglycemia-induced cardiac and skeletal muscle abnormalities in insulin-deficient mice. Hyperglycemia increased advanced glycation end-products and elicited oxidative and endoplasmic reticulum stress leading to apoptosis in the heart and peripheral muscle. Deletion of Arrdc4 augmented tissue glucose transport and mitochondrial respiration, protecting the heart and muscle from tissue damage. Stress hemodynamic analysis and treadmill exhaustion test uncovered that Arrdc4-knockout mice had greater cardiac inotropic/chronotropic reserve with higher exercise endurance than wild-type animals under diabetes. While multiple organs were involved in the mechanism, cardiac-specific overexpression using an adenoassociated virus suggests that high levels of myocardial ARRDC4 have the potential to contribute to exercise intolerance by interfering with cardiac metabolism through its interaction with GLUT1 in diabetes. Importantly, the ARRDC4 mutation mouse line exhibited greater exercise tolerance, showing the potential therapeutic impact on diabetic cardiomyopathy by disrupting the interaction between ARRDC4 and GLUT1. CONCLUSIONS: ARRDC4 regulates hyperglycemia-induced toxicities toward cardiac and skeletal muscle, revealing a new molecular framework that connects hyperglycemia to cardiac/skeletal myopathy to exercise intolerance.
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Tolerância ao Exercício , Transportador de Glucose Tipo 1 , Camundongos Knockout , Animais , Humanos , Masculino , Camundongos , Células Cultivadas , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/genética , Cardiomiopatias Diabéticas/metabolismo , Cardiomiopatias Diabéticas/genética , Cardiomiopatias Diabéticas/fisiopatologia , Cardiomiopatias Diabéticas/etiologia , Transportador de Glucose Tipo 1/genética , Transportador de Glucose Tipo 1/metabolismo , Hiperglicemia/metabolismo , Hiperglicemia/genética , Camundongos Endogâmicos C57BL , Músculo Esquelético/metabolismo , Miócitos Cardíacos/metabolismoRESUMO
BACKGROUND: Arterial catheterisation in children can be challenging and time-consuming. We aimed to compare the success rates of ultrasound-guided arterial catheterisation utilising the short-axis out-of-plane approach with dynamic needle tip positioning in the radial, dorsalis pedis, and posterior tibial arteries in paediatric patients. We also examined the factors influencing the catheterisation success using dynamic needle tip positioning. METHODS: Paediatric patients (aged <3 yr) undergoing cardiac surgery were randomly assigned to three groups based on puncture sites: radial artery (Group R), dorsalis pedis artery (Group D), and posterior tibial artery (Group P). The first-attempt and overall success rates of arterial catheterisation were compared, followed by multiple logistic regression analysis (dependent variable: first-attempt success; independent variables: body weight, diameter and depth of the artery, targeted artery, and trisomy 21). RESULTS: The study included 270 subjects (n=90 per group). There was no significant difference in the first-attempt (Group R: 82%, Group D: 76%, and Group P: 81%) and overall success rates (Group R: 94%, Group D: 93%, and Group P: 91%) among the three groups. The diameter of the artery (per 0.1 mm) (odds ratio: 1.32, 95% confidence interval: 1.09-1.60) and trisomy 21 (odds ratio: 0.43, 95% confidence interval: 0.20-0.92) were independent predictors of first-attempt success or failure. CONCLUSION: The first-attempt and overall success rates of arterial catheterisation of the dorsalis pedis and posterior tibial arteries were not inferior to those in the radial artery when using dynamic needle tip positioning. These two lower extremity peripheral arteries present viable alternative catheterisation sites in paediatric patients. CLINICAL TRIAL REGISTRATION: UMIN000042847.
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Síndrome de Down , Artérias da Tíbia , Humanos , Criança , Artérias da Tíbia/diagnóstico por imagem , Artéria Radial/diagnóstico por imagem , Extremidade Inferior , Ultrassonografia de IntervençãoRESUMO
Underlying molecular mechanisms for the development of diabetic cardiomyopathy remain to be determined. Long-term exposure to hyperglycemia causes oxidative stress, which leads to cardiomyocyte dysfunction. Previous studies established the importance of thioredoxin-interacting protein (Txnip) in cellular redox homeostasis and glucose metabolism. Txnip is a highly glucose-responsive molecule that interacts with the catalytic center of reduced thioredoxin and inhibits the antioxidant function of thioredoxin. Here, we show that the molecular interaction between Txnip and thioredoxin plays a pivotal role in the regulation of redox balance in the diabetic myocardium. High glucose increased Txnip expression, decreased thioredoxin activities, and caused oxidative stress in cells. The Txnip-thioredoxin complex was detected in cells with overexpressing wild-type Txnip but not Txnip cysteine 247 to serine (C247S) mutant that disrupts the intermolecular disulfide bridge. Then, diabetes was induced in cardiomyocyte-specific Txnip C247S knock-in mice and their littermate control animals by injections of streptozotocin (STZ). Prolonged hyperglycemia upregulated myocardial Txnip expression in both genotypes. The absence of Txnip's inhibition of thioredoxin in Txnip C247S mutant hearts promoted mitochondrial antioxidative capacities in cardiomyocytes, thereby protecting the heart from oxidative damage by diabetes. Stress hemodynamic analysis uncovered that Txnip C247S knock-in hearts have a greater left ventricular contractile reserve than wild-type hearts under STZ-induced diabetic conditions. These results provide novel evidence that Txnip serves as a regulator of hyperglycemia-induced cardiomyocyte toxicities through direct inhibition of thioredoxin and identify the single cysteine residue in Txnip as a therapeutic target for diabetic injuries.NEW & NORTEWORTHY Thioredoxin-interacting protein (Txnip) has been of great interest as a molecular mechanism to mediate diabetic organ damage. Here, we provide novel evidence that a single mutation of Txnip confers a defense mechanism against myocardial oxidative stress in streptozotocin-induced diabetic mice. The results demonstrate the importance of Txnip as a cysteine-containing redox protein that regulates antioxidant thioredoxin via disulfide bond-switching mechanism and identify the cysteine in Txnip as a therapeutic target for diabetic cardiomyopathy.
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Proteínas de Transporte/genética , Diabetes Mellitus Experimental/metabolismo , Cardiomiopatias Diabéticas/metabolismo , Miócitos Cardíacos/metabolismo , Estresse Oxidativo/genética , Tiorredoxinas/metabolismo , Função Ventricular Esquerda/genética , Animais , Proteínas de Transporte/metabolismo , Proteínas de Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular , Técnicas de Introdução de Genes , Glucose/farmacologia , Células HEK293 , Humanos , Preparação de Coração Isolado , Camundongos , Mutação , Miócitos Cardíacos/efeitos dos fármacos , Ratos , Tiorredoxinas/genéticaRESUMO
RATIONALE: Thioredoxin-interacting protein (Txnip) is a novel molecular target with translational potential in diverse human diseases. Txnip has several established cellular actions including binding to thioredoxin, a scavenger of reactive oxygen species (ROS). It has been long recognized from in vitro evidence that Txnip forms a disulfide bridge through cysteine 247 (C247) with reduced thioredoxin to inhibit the anti-oxidative properties of thioredoxin. However, the physiological significance of the Txnip-thioredoxin interaction remains largely undefined in vivo. OBJECTIVE: A single mutation of Txnip, C247S, abolishes the binding of Txnip with thioredoxin. Using a conditional and inducible approach with a mouse model of a mutant Txnip that does not bind thioredoxin, we tested whether the interaction of thioredoxin with Txnip is required for Txnip's pro-oxidative or cytotoxic effects in the heart. METHODS AND RESULTS: Overexpression of Txnip C247S in cells resulted in a reduction in ROS, due to an inability to inhibit thioredoxin. Hypoxia (1% O2, 24 h)-induced killing effects of Txnip were decreased by lower levels of cellular ROS in Txnip C247S-expressing cells compared with wild-type Txnip-expressing cells. Then, myocardial ischemic injuries were assessed in the animal model. Cardiomyocyte-specific Txnip C247S knock-in mice had better survival with smaller infarct size following myocardial infarction (MI) compared to control animals. The absence of Txnip's inhibition of thioredoxin promoted mitochondrial anti-oxidative capacities in cardiomyocytes, thereby protecting the heart from oxidative damage induced by MI. Furthermore, an unbiased RNA sequencing screen identified that hypoxia-inducible factor 1 signaling pathway was involved in Txnip C247S-mediated cardioprotective mechanisms. CONCLUSION: Txnip is a cysteine-containing redox protein that robustly regulates the thioredoxin system via a disulfide bond-switching mechanism in adult cardiomyocytes. Our results provide the direct in vivo evidence that regulation of redox state by Txnip is a crucial component for myocardial homeostasis under ischemic stress.
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Alelos , Substituição de Aminoácidos , Proteínas de Transporte/genética , Resistência à Doença/genética , Mutação , Infarto do Miocárdio/etiologia , Tiorredoxinas/genética , Trifosfato de Adenosina/metabolismo , Animais , Biomarcadores , Proteínas de Transporte/metabolismo , Linhagem Celular , Modelos Animais de Doenças , Suscetibilidade a Doenças , Eletrocardiografia , Expressão Gênica , Glucose/metabolismo , Hipóxia/genética , Hipóxia/metabolismo , Fator 1 Induzível por Hipóxia/metabolismo , Camundongos , Camundongos Transgênicos , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/metabolismo , Especificidade de Órgãos/genética , Oxirredução , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Tiorredoxinas/metabolismo , Ubiquitina Tiolesterase/metabolismoRESUMO
Anomalous origin of the coronary artery from the aortic arch associated with hypoplastic left heart syndrome is an extremely rare anomaly. Coronary anomalies can significantly deteriorate the clinical outcomes of hypoplastic left heart syndrome. We describe the case of a newborn with concomitant hypoplastic left heart syndrome and abnormal origin of the left coronary artery arising from the distal aortic arch.
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Anomalias dos Vasos Coronários/cirurgia , Síndrome do Coração Esquerdo Hipoplásico/cirurgia , Aorta/anormalidades , Aorta/cirurgia , Anomalias dos Vasos Coronários/patologia , Evolução Fatal , Feminino , Parada Cardíaca/etiologia , Humanos , Síndrome do Coração Esquerdo Hipoplásico/patologia , Recém-Nascido , Complicações Intraoperatórias/etiologia , Ligadura , Procedimentos de Norwood , Cuidados Paliativos , Artéria Pulmonar/cirurgiaRESUMO
BACKGROUND: Recombinant activated factor VII (rFVIIa) concentrate reduces allogeneic blood transfusions, but it may increase thromboembolic complications in complex cardiac surgery. The mixture of activated factor VII (FVIIa) and factor X (FX) (FVIIa/FX) (FVIIa:FX = 1:10) is a novel bypassing agent for hemophilia patients. We hypothesized that the combination of FX and FVIIa could improve thrombin generation (TG) in acquired multifactorial coagulation defects such as seen in cardiac surgery and conducted in vitro evaluation of FVIIa/FX in parallel with other coagulation factor concentrates using in vitro and in vivo diluted plasma samples. METHODS: Plasma samples were collected from 9 healthy volunteers and 12 cardiac surgical patients. We measured TG (Thrombinoscope) using in vitro 50% dilution plasma and in vivo dilution plasma after cardiopulmonary bypass, in parallel with thromboelastometry (ROTEM) and standard coagulation assays. In vitro additions of FVIIa/FX (0.35, 0.7, and 1.4 µg/mL, based on the FVIIa level), rFVIIa (1.4, 2.8, and 6.4 µg/mL), prothrombin complex concentrate (0.3 international unit), and 20% plasma replacement were evaluated. RESULTS: In diluted plasma, the addition of either FVIIa/FX or rFVIIa shortened the lag time and increased the peak TG, but the effect in lag time of FVIIa/FX at 0.35 µg/mL was more extensive than rFVIIa at 6.4 µg/mL. Prothrombin complex concentrate increased peak TG by increasing the prothrombin level but failed to shorten the lag time. No improvement in any of the TG variables was observed after 20% volume replacement with plasma. The addition of factor concentrates normalized prothrombin time/international normalized ratio but not with plasma replacement. In cardiac patients, similar patterns were observed on TG in post-cardiopulmonary bypass samples. FVIIa/FX shortened clotting time (CT) in a concentration-dependent manner on CT on thromboelastometry. Plasma replacement did not improve CT, but a combination of plasma and FVIIa/FX (0.35 µg/mL) more effectively shortened CT than FVIIa/FX alone. CONCLUSIONS: The combination of FVIIa and FX improved TG more efficiently than rFVIIa alone or plasma in dilutional coagulopathy models. The required FVIIa dose in FVIIa/FX was considerably lower than those reported during bypassing therapy in hemophilia patients (1.4-2.8 µg/mL). The combination of plasma could restore coagulation more efficiently compared to FVIIa/FX alone. Lesser FVIIa requirement to exert procoagulant activity may be favorable in terms of reducing systemic thromboembolic complications.
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Transtornos da Coagulação Sanguínea/tratamento farmacológico , Coagulação Sanguínea/efeitos dos fármacos , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Coagulantes/farmacologia , Fator VIIa/farmacologia , Fator X/farmacologia , Hemodiluição/efeitos adversos , Transtornos da Coagulação Sanguínea/sangue , Transtornos da Coagulação Sanguínea/diagnóstico , Transtornos da Coagulação Sanguínea/etiologia , Fatores de Coagulação Sanguínea/farmacologia , Testes de Coagulação Sanguínea , Estudos de Casos e Controles , Quimioterapia Combinada , Feminino , Humanos , Masculino , Proteínas Recombinantes/farmacologia , Trombina/metabolismo , Fatores de TempoRESUMO
OBJECTIVE: Point-of-care (POC) devices allow for prothrombin time/international normalized ratio (PT/INR) testing in whole blood (WB) and timely administration of plasma or prothrombin complex concentrate during cardiopulmonary bypass surgery. This study evaluated the sensitivities of a new POC PT test, a dry-hematology method with heparin neutralization technology (DRIHEMATO PT-S [DRI PT-S]; A&T Corporation, Kanagawa, Japan), and compared it with other POC tests currently available. DESIGN: Prospective, observational study. SETTING: University hospital, single center. PARTICIPANTS: Healthy volunteers and warfarin-treated and cardiac surgical patients. MEASUREMENT AND MAIN RESULTS: In WB samples obtained from 6 healthy volunteers, PT-INR results of DRI PT-S were not affected by an in vitro addition of heparin <6.0 U/mL. In warfarin-treated samples (n = 88, PT/INR 0.98-3.87), PT-INR with DRI PT-S showed acceptable correlation with the laboratory method (r2 = 0.85, p < 0.001). In blood samples obtained from cardiac surgical patients (n = 72), heparin prolonged the PT/INR with the laboratory assay, dry-hematology method with non heparin neutralization technology (DRI PT), Coaguchek XS (Roche Diagnostics, Basel, Switzerland), and Hemochron Jr. (Accriva Diagnostics, Edison, NJ), but DRI PT-S was not affected by heparin anticoagulation. In nonheparinized samples, different methods between DRI PT-S and the laboratory method yielded acceptable correlations (r2 = 0.76, p < 0.0001). There was a moderate correlation between factor levels and the PT-INR with DRI PT-S (factor [F]II: r2 = 0.63, FVII: r2 = 0.47, FX: r2 = 0.67; p < 0.0001). CONCLUSIONS: This study demonstrated that PT/INR can be accurately assessed using the dry-hematology method in WB under therapeutic heparin levels. Currently available other POC PT/INR tests are affected by heparin, and thus they are not recommended for coagulation monitoring during cardiopulmonary bypass.
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Ponte Cardiopulmonar/métodos , Monitorização Intraoperatória/métodos , Sistemas Automatizados de Assistência Junto ao Leito , Tempo de Protrombina/métodos , Adulto , Anticoagulantes/administração & dosagem , Anticoagulantes/efeitos adversos , Ponte Cardiopulmonar/normas , Feminino , Humanos , Coeficiente Internacional Normatizado/métodos , Coeficiente Internacional Normatizado/normas , Masculino , Pessoa de Meia-Idade , Monitorização Intraoperatória/normas , Sistemas Automatizados de Assistência Junto ao Leito/normas , Estudos Prospectivos , Tempo de Protrombina/normas , Varfarina/administração & dosagem , Varfarina/efeitos adversos , Adulto JovemRESUMO
BackgroundChildren with cyanotic heart disease develop secondary erythrocytosis and thrombocytopenia via unknown mechanisms. Mature erythrocyte microRNAs may reflect clinical pathologies and cell differentiation processes pre-enucleation. This study evaluated erythrocyte microRNAs in children with cyanotic heart disease.MethodsErythrocyte microRNAs from children with cyanotic and acyanotic heart disease and without cardiac disease were quantified with Ion PGM System (n=10 per group). Differential expression was confirmed by quantitative PCR (qPCR; n=20 per group).ResultsMir-486-3p, mir-486-5p, and mir-155-5p increased in patients with cyanotic heart disease compared with those without heart disease: fold differences (95% confidence interval): mir-486-3p: 1.92 (1.14-3.23), P=0.011; mir-486-5p: 2.27 (1.41-3.65), P<0.001; and mir-155-5p: 1.44 (1.03-2.03), P=0.028. Mir-486-5p was increased, and let-7e-5p and mir-1260a were decreased in patients with acyanotic heart disease compared with those without heart disease: mir-486-5p: 1.66 (1.03-2.66), P=0.035; let-7e-5p: 0.66 (0.44-0.99), P=0.049; and mir-1260a: 0.53 (0.29-0.99), P=0.045.ConclusionSeveral microRNA levels changed in children with cyanotic and acyanotic heart disease. Mir-486-3p and -5p are associated with hematopoietic differentiation. Mir-486-3p regulates the erythroid vs. megakaryocyte lineage fate decision. Mir-155 is a hypoxia-inducible microRNA, whose overexpression inhibits megakaryocyte differentiation. Erythrocyte microRNA expression changes may contribute to erythrocytosis and thrombocytopenia in children with cyanotic heart disease.
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Eritrócitos/metabolismo , Cardiopatias Congênitas/sangue , Cardiopatias/sangue , MicroRNAs/genética , Policitemia/sangue , Trombocitopenia/sangue , Pré-Escolar , Eritrócitos/citologia , Feminino , Cardiopatias Congênitas/complicações , Cardiopatias/complicações , Humanos , Hipóxia/sangue , Lactente , Recém-Nascido , Masculino , Policitemia/complicações , Trombocitopenia/complicaçõesRESUMO
The number of patients with chronic kidney disease (CKD) continues to increase all over the world for the past ten years. It follows that we have more CKD patients with various complications who need perioperative management in Japan. Previous studies revealed that impaired renal function in preoperative period was the independent predictor of postoperative renal dysfunction. Safe comprehensive anesthetic management is required in order not to aggravate the preoperative CKD. In this review, we will take up some recent topics and novel concept in association with noncardiac surgery for the perioperative management of CKD patients.
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Injúria Renal Aguda/prevenção & controle , Anestesiologia/métodos , Assistência Perioperatória/métodos , Complicações Pós-Operatórias/prevenção & controle , Insuficiência Renal Crônica/complicações , Acidose/etiologia , Doenças do Sistema Nervoso Autônomo/etiologia , Transtornos da Coagulação Sanguínea/etiologia , Doença das Coronárias/etiologia , Doenças do Sistema Digestório/complicações , Doenças do Sistema Digestório/cirurgia , Procedimentos Cirúrgicos do Sistema Digestório , Feminino , Taxa de Filtração Glomerular , Humanos , Masculino , Respiração com Pressão Positiva , Proteinúria , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/fisiopatologia , Índice de Gravidade de Doença , Desequilíbrio Hidroeletrolítico/etiologiaRESUMO
PURPOSE: The Risk Adjustment for Congenital Heart Surgery (RACHS-1) classification was originally designed to facilitate the prediction of in-hospital mortality for pediatric cardiac surgery patients. However, there have been few reports on clinical outcomes predicted by the RACHS-1 category, especially in an Asian population. The aim of this study was to determine whether RACHS-1 classification can predict patient outcomes. METHODS: A total of 580 pediatric cardiac surgery procedures performed from January 2005 to December 2009 were retrospectively classified into the six RACHS-1 categories. The association between RACHS-1 category and clinical outcomes, including length of catecholamine requirement, mechanical ventilation time, intensive care unit stay, and in-hospital mortality, were examined. RESULTS: The frequencies of RACHS-1 categories in the study population were: category 1, 10.7 %; category 2, 36.7 %; category 3, 42.8 %; category 4, 6.6 %; category 5, 0.0 %; category 6, 3.3 %. There was a significant linear correlation between RACHS-1 category and in-hospital mortality (r = 0.96, p < 0.001). Kaplan-Meier analysis demonstrated that length of catecholamine infusion, mechanical ventilation time, and ICU stay were significantly different (p < 0.05) in the different RACHS-1 categories, except for those between category 4 and 6 (p = 0.09). CONCLUSIONS: Based on the results of our analysis, we conclude that the RACHS-1 stratification system can predict in-hospital mortality and patient outcomes in patients undergoing pediatric cardiac surgery.