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OBJECTIVES: The clinical efficacy and safety of a novel left atrial appendage (LAA) occluder of the SeaLA closure system in patients with nonvalvular atrial fibrillation (NVAF) were reported. BACKGROUND: Patients with NVAF are at a higher risk of stroke compared to healthy individuals. Left atrial appendage closure (LAAC) has emerged as a prominent strategy for reducing the risk of thrombosis in individuals with NVAF. METHODS: A prospective, multicenter study was conducted in NVAF patients with a high risk of stroke. RESULTS: The LAAC was successfully performed in 163 patients. The mean age was 66.93 ± 7.92 years, with a mean preoperative CHA2DS2-VASc score of 4.17 ± 1.48. One patient with residual flow >3 mm was observed at the 6-month follow-up, confirmed by TEE. During the follow-up, 2 severe pericardiac effusions were noted, and 2 ischemic strokes were observed. Four device-related thromboses were resolved after anticoagulation treatment. There was no device embolism. CONCLUSIONS: The LAAC with the SeaLA device demonstrates encouraging feasibility, safety, and efficacy outcomes.
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PURPOSE: Even though nirmatrelvir-ritonavir can improve the short-term morbidity and mortality in COVID-19 patients, the effects of this treatment on long-term major adverse cardiovascular events (MACEs), especially myocardial injury, remains undetermined. METHODS: This prospective cohort study identified hospitalized adult patients with COVID-19 between April 19, 2022, and June 9, 2022, amid the omicron wave of the pandemic. Matched nirmatrelvir-ritonavir-treated and non-treated cohorts were formed using the propensity score matching method. The primary outcome of this study was the incidence of MACEs (cardiovascular death, myocardial infarction, stroke, new-onset heart failure or heart failure hospitalization or ventricular arrhythmia) from 30 days to 16 months after the diagnosis of COVID-19. RESULTS: Two 949-patient cohorts with balanced baseline characteristics were formed by propensity score matching. Patients with nirmatrelvir-ritonavir, compared to those untreated, had a lower level of troponin I peak as well as the incidence of troponin I elevation. During the follow-up period, 59 patients in the nirmatrelvir-ritonavir group and 86 patients in the control group developed MACEs (P = 0.020). Regarding specific constituents of MACEs, the differences are mainly reflected in new-onset heart failure or heart failure hospitalization. COVID-19 clinical severity and troponin I peak were the independent predictors, while nirmatrelvir-ritonavir was the independent protective factor for the occurrence of MACEs in this population. CONCLUSION: Nirmatrelvir-ritonavir was effective in reducing myocardial injury as well as long-term adverse cardiovascular outcomes among hospitalized patients with COVID-19 amid the omicron wave of the pandemic.
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Mitochondrial dysfunction is a hallmark of heart failure. Mitochondrial transplantation has been demonstrated to be able to restore heart function, but its mechanism of action remains unresolved. Using an in-house optimized mitochondrial isolation method, we tested efficacy of mitochondria transplantation in two different heart failure models. First, using a doxorubicin-induced heart failure model, we demonstrate that mitochondrial transplantation before doxorubicin challenge protects cardiac function in vivo and prevents myocardial apoptosis, but contraction improvement relies on the metabolic compatibility between transplanted mitochondria and treated cardiomyocytes. Second, using a mutation-driven dilated cardiomyopathic human induced pluripotent stem cell-derived cardiomyocyte model, we demonstrate that mitochondrial transplantation preferentially boosts contraction in the ventricular myocytes. Last, using single-cell RNA-seq, we show that mitochondria transplantation boosts contractility in dystrophic cardiomyocytes with few transcriptomic alterations. Together, we provide evidence that mitochondria transplantation confers myocardial protection and may serve as a potential therapeutic option for heart failure.
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Cardiomiopatias , Insuficiência Cardíaca , Células-Tronco Pluripotentes Induzidas , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Cardiomiopatias/metabolismo , Mitocôndrias/metabolismo , Doxorrubicina/efeitos adversos , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/terapia , Insuficiência Cardíaca/metabolismo , Miócitos Cardíacos/metabolismoRESUMO
Background: Lipid profiles differ naturally between individuals and between populations. So far, the data relating to non-fasting lipid profiles has been derived predominantly from studies on Western population. The characteristics and clinical significance of non-fasting lipids in Chinese patients with coronary heart disease (CHD) in response to traditional Chinese diets remain poorly understood. Methods: A total of 1022 Chinese CHD patients with coronary artery luminal stenosis > 40% as diagnosed by coronary artery angiography were enrolled in the study. All patients received standard treatment for CHD, including statins. They were divided into an intermediate stenosis group (luminal stenosis 40-70%, n = 486) or a severe stenosis group (luminal stenosis > 70%, n = 536). Their blood lipid profiles were measured in the fasting state, and 4 hours after normal breakfast. All participants were followed up for five years. Major adverse cardiovascular events (MACE) including all-cause death, cardiac death, myocardial infarction, unscheduled coronary revascularization and stroke were recorded. Results: After normal breakfast intake, patients with intermediate or severe stenosis showed an apparent increase in the levels of triglyceride (TG), remnant cholesterol (RC) and Apo (apolipoprotein) A1 compared to the fasting state, but a significant reduction in the levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), Apo B and Apo E. In addition to the traditional risk factors (older age, male, diabetes and smoking) and coronary artery stenosis, the fasting levels of LDL-C and Apo B, as well as non-fasting levels of HDL-C and Apo A1, were identified as independent predictors of 5-year MACE occurrence by multivariate Cox proportional hazards analysis. Patients in the 1st tertile of the non-fasting HDL-C group ( < 0.86 mmol/L) showed a significantly higher risk of MACE than 3rd tertile ( > 1.07 mmol/L) (1st tertile: 2.786, 95% CI (confidence intervals) [1.808, 4.293], p < 0.001). Conclusions: This prospective observational study found that lipid profiles in either the fasting or non-fasting states were associated with the long-term risk of MACE in Chinese CHD patients. In addition to the fasting LDL-C level, a low non-fasting HDL-C level may also be an independent risk factors for cardiovascular events. Measurement of lipid profiles during the non-fasting state may be feasible for the management of CHD patients in routine clinical practice in China.
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BACKGROUND: Adipose tissue homeostasis is at the heart of many metabolic syndromes such as diabetes. Previously it has been demonstrated that adipose tissues from diabetic patients are senescent but whether this contributes to diabetic cardiomyopathy (DCM) remains to be elucidated. METHODS: The streptozotocin (STZ) type 1 diabetic mice were established as animal model, and adult mouse ventricular myocytes (AMVMs) isolated by langendorff perfusion as well as neonatal mouse ventricular myocytes (NMVMs) were used as cell models. Senescent associated ß galactosidase (SA-ß-gal) staining and RT-qPCR were used to identify the presence of adipose senescence in diabetic adipose tissue. Senescent adipose were removed either by surgery or by senolytic treatment. Large extracellular vesicles (LEVs) derived from adipose tissue and circulation were separated by ultracentrifugation. Cardiac systolic and diastolic function was evaluated through cardiac ultrasound. Cardiomyocytes contraction function was evaluated by the Ionoptix HTS system and live cell imaging, mitochondrial morphology and functions were evaluated by transmission electron microscope, live cell fluorescent probe and seahorse analysis. RNA-seq for AMVMs and miRNA-seq for LEVs were performed, and bioinformatic analysis combined with RT-qPCR and Western blot were used to elucidate underlying mechanism that senescent adipose derives LEVs exacerbates myocardial metabolism. RESULTS: SA-ß-gal staining and RT-qPCR identified the presence of adipose tissue senescence in STZ mice. Through surgical as well as pharmacological means we show that senescent adipose tissue participates in the pathogenesis of DCM in STZ mice by exacerbates myocardial metabolism through secretion of LEVs. Specifically, expression of miRNA-326-3p was up-regulated in LEVs isolated from senescent adipose tissue, circulation, and cardiomyocytes of STZ mice. Up-regulation of miRNA-326-3p coincided with myocardial transcriptomic changes in metabolism. Functionally, we demonstrate that miRNA-326-3p inhibited the expression of Rictor and resulted in impaired mitochondrial and contractile function in cardiomyocytes. CONCLUSION: We demonstrate for the first time that senescent adipose derived LEVs exacerbates myocardial metabolism through up-regulated miRNA-326-3p which inhibits Rictor in cardiomyocytes. Furthermore, reducing senescence burden in adipose tissue is capable of relieving myocardial metabolism disorder in diabetes mellitus.
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Diabetes Mellitus Experimental , Cardiomiopatias Diabéticas , MicroRNAs , Tecido Adiposo/metabolismo , Animais , Células Cultivadas , Diabetes Mellitus Experimental/complicações , Cardiomiopatias Diabéticas/metabolismo , Humanos , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Miócitos Cardíacos/patologiaRESUMO
BACKGROUND: Type 2 diabetes mellitus (T2DM), hypertension and atrial fibrillation (AF) are risk factors for heart failure with preserved ejection fraction (HFpEF). AIM: To examine the effects of the simultaneous control of all three conditions on new-onset HFpEF in this population. METHODS: This prospective cohort study enrolled 552 patients with T2DM, hypertension and AF, but without clinical signs or symptoms of heart failure. The participants were followed up for 5 years to examine the effects of glycaemic control (haemoglobin A1c: <7.0%, 7.0%-8.0% and >8.0%), blood pressure (BP) control (systolic BP: <120, 120-140 and >140 mmHg) or rhythm versus rate control for AF on new-onset HFpEF. RESULTS: With a follow up of 5 years, the new-onset HFpEF occurred in 62 of 552 enrolled participants. Among the different control level for diabetes, hypertension and AF, the intensive blood glucose (BG) control, poor BP control and rate control of AF had the highest risk of new-onset HFpEF, and the conservative BG control, intensive BP control and rhythm control of AF had the lowest risk of new-onset HFpEF. Multivariable Cox regression analysis showed that both poor BP control (hazard ratio (HR): 1.421, 95% confidence interval (CI): 1.013-1.992, P = 0.042) and rate control of AF (HR: 1.362, 95% CI: 1.006-1.821, P = 0.033) were independently associated with the development of new-onset HFpEF. CONCLUSION: This study demonstrated that, besides intensive BP control, conservative BG control and rhythm control of AF were crucial factors to delay the progression of HFpEF among patients with T2DM, hypertension and AF.
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Fibrilação Atrial , Diabetes Mellitus Tipo 2 , Insuficiência Cardíaca , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/epidemiologia , Glicemia , Pressão Sanguínea , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/prevenção & controle , Humanos , Prognóstico , Estudos Prospectivos , Volume Sistólico/fisiologiaRESUMO
The aim of this study was to investigate the correlation between v-set and transmembrane domain-containing 1 (VSTM1) expression and incidence of major adverse cardiac events (MACE) in patients with coronary heart disease (CHD). A total of 310 patients were divided into a non-acute coronary syndrome (non-ACS) group (containing the stable angina group, and the asymptomatic coronary artery diseaseand other patients group) and an ACS group (containing unstable angina and acute myocardial infarction patients). Monocytic VSTM1 expression levels (assessed via average fluorescence intensity derived from antibody binding to VSTM1) in each group were detected and analyzed. The cut-off value of monocytic VSTM1 expression to predict the onset of ACS and MACE was confirmed. VSTM1 expression in monocytes from the ACS group was lower than that of the non-ACS group. The incidence of MACEs in the high VSTM1-expression group was much less than that of those in the low VSTM1 expression group at the 1 year follow-up stage. VSTM1 expression had an independent-inversed association with increased incidence of MACE and ACS. VSTM1 expression in monocytes may help to predict the occurrence of ACS in patients with CHD, and moreover it may provide the means to evaluate MACE prognosis during CHD patient follow-up.
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Síndrome Coronariana Aguda , Doença da Artéria Coronariana , Infarto do Miocárdio , Síndrome Coronariana Aguda/diagnóstico , Síndrome Coronariana Aguda/epidemiologia , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/epidemiologia , Humanos , Monócitos , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/epidemiologia , Prognóstico , Fatores de RiscoRESUMO
Our study was aimed to investigate the effects of lgals3a (Gal-3 encoding gene) on the development of zebrafish embryo and its underlying mechanisms. Morpholino (MO) technology was used to inhibit the expression of zebrafish lgals3a, and the effect of lgals3a gene knockdown on zebrafish embryo development and the number of monocyte macrophages was observed. Effect of lgals3a-e3i3-MO on apoptosis of zebrafish was detected by acridine orange staining. In addition, the mRNA expression levels of Wnt/ß-catenin signaling pathway-related genes were detected by RT-qPCR. Compared with control-MO group, the zebrafish embryos injected with lgals3a-e3i3-MO had obvious defects in the head, eyes, and tail, and pericardial edema. Lgals3a-e3i3-MO significantly reduced the number of mononuclear macrophages in zebrafish embryos compared with the control-MO group. The results of acridine orange staining showed that compared with the control-MO group, lgals3a-e3i3-MO promoted cardiomyocyte apoptosis in zebrafish. Furthermore, lgals3a-e3i3-MO significantly up-regulated the expression of dkk1b, wnt9a, lrp5, fzd7a, ß-catenin, Gsk-3ß, mycn, myca in the Wnt/ß-catenin pathway, and decreased the expression of lef1. These results indicate that lgals3a-e3i3-MO inhibits zebrafish embryo development, reduces the number of mononuclear macrophages, activates Wnt/ß-catenin signaling pathway and promotes cardiomyocyte apoptosis.
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Peixe-Zebra , beta Catenina , Laranja de Acridina/metabolismo , Laranja de Acridina/farmacologia , Animais , Embrião não Mamífero/metabolismo , Desenvolvimento Embrionário/genética , Glicogênio Sintase Quinase 3 beta/metabolismo , Glicogênio Sintase Quinase 3 beta/farmacologia , Receptores de Superfície Celular , Proteínas Wnt/genética , Proteínas Wnt/metabolismo , Proteínas Wnt/farmacologia , Via de Sinalização Wnt/genética , Proteínas de Peixe-Zebra/genética , beta Catenina/genética , beta Catenina/metabolismoRESUMO
BACKGROUND: Serum free fatty acid (FFA) concentrations are associated with coronary heart disease and diabetes mellitus (DM). Few studies focused on the relationship between serum FFA levels and coronary artery calcification (CAC). METHODS: This was a retrospective, single-centered study recruiting patients underwent FFA quantification, coronary angiography and intravascular ultrasound (IVUS). CAC severity was assessed with the maximum calcific angle (arc) of the calcified plaque scanned by IVUS. Patients with an arc ≥ 180° were classified into the severe CAC (SCAC) group, and those with an arc < 180° were classified into the non-SCAC group. Clinical characteristics, serum indices were compared between 2 groups. Logistic regression, receiver operating characteristic (ROC) curves and area under the curves (AUC) were performed. RESULTS: Totally, 426 patients with coronary artery disease were consecutively included. Serum FFA levels were significantly higher in the SCAC group than non-SCAC group (6.62 ± 2.17 vs. 5.13 ± 1.73 mmol/dl, p < 0.001). Logistic regression revealed that serum FFAs were independently associated with SCAC after adjusting for confounding factors in the whole cohort (OR 1.414, CI 1.237-1.617, p < 0.001), the non-DM group (OR 1.273, CI 1.087-1.492, p = 0.003) and the DM group (OR 1.939, CI 1.388-2.710, p < 0.001). ROC analysis revealed a serum FFA AUC of 0.695 (CI 0.641-0.750, p < 0.001) in the whole population. The diagnostic predictability was augmented (AUC = 0.775, CI 0.690-0.859, p < 0.001) in the DM group and decreased (AUC = 0.649, CI 0.580-0.718, p < 0.001) in the non-DM group. CONCLUSIONS: Serum FFA levels were independently associated with SCAC, and could have some predictive capacity for SCAC. The association was strongest in the DM group.
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Doença da Artéria Coronariana/sangue , Diabetes Mellitus/sangue , Ácidos Graxos não Esterificados/sangue , Calcificação Vascular/sangue , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Angiografia Coronária , Doença da Artéria Coronariana/diagnóstico por imagem , Diabetes Mellitus/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Índice de Gravidade de Doença , Ultrassonografia de Intervenção , Calcificação Vascular/diagnóstico por imagemRESUMO
BACKGROUND: We investigated the role of ANGPTL3 and ANGPTL4 in atherosclerosis development and determined whether plasma concentrations of ANGPTL3 and ANGPTL4 are related to the degree of coronary stenosis. METHODS: A total of 305 consecutive patients with angina who underwent diagnostic coronary angiography were enrolled in the study between August 2017 and August 2018. The levels of ANGPTL3 and ANGPTL4 were measured by using competitive ELISA kits. RESULTS: According to the degree of coronary artery stenosis, patients were classified into four types: coronary artery stenosis of < 10%, 10-50%, 50-75, and > 75%. The plasma ANGPTL3 level was higher (51.71 ± 52.67 vs. 24.65 ± 10.32 ng/mL, P < 0.001) and that of ANGPTL4 was lower (454.66 ± 269.05 vs. 875.49 ± 961.15 ng/mL, P < 0.001) in the coronary artery stenosis ≥ 10% group than in the < 10% group. ANGPTL3 and ANGPTL4 levels were significantly associated with the severity of coronary vascular stenosis. ROC curve analyses indicated that ANGPTL3 concentrations above 30.5 ng/mL can predict atherosclerosis with a sensitivity of 71.2% and specificity of 75.3%, and that ANGPTL4 levels below 497.5 ng/mL can predict atherosclerosis with a sensitivity of 63.9% and specificity of 74.5%. ANGPTL3 and ANGPTL4 were determined to be independent risk factors for coronary atherosclerosis with odds ratios (ORs) of 0.189 (95% CI 0.097-0.368, P < 0.001) and 3.625 (95% CI 1.873-7.016, P < 0.001), respectively. CONCLUSIONS: Increased ANGPTL3 or decreased ANGPTL4 shows an association with coronary atherosclerosis and, may become a predictor of coronary atherosclerosis in the future.
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Proteína 3 Semelhante a Angiopoietina/sangue , Proteína 4 Semelhante a Angiopoietina/sangue , Aterosclerose/sangue , Doença da Artéria Coronariana/sangue , Idoso , Aterosclerose/etiologia , Biomarcadores/sangue , Doença da Artéria Coronariana/etiologia , Estenose Coronária/sangue , Estenose Coronária/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Curva ROC , Sensibilidade e Especificidade , Índice de Gravidade de DoençaRESUMO
Atrial fibrillation (AF) is one of the most prevalent arrhythmias. Myocardial sleeves of the pulmonary vein are critical in the occurrence of AF. Our study aims to investigate the effect of synthetic vascular smooth muscle cells (SMCs) on gap junction proteins in cardiomyocytes. (1) Extraction of vascular SMCs from the pulmonary veins of Norway rats. TGF-ß1 was used to induce the vascular SMCs switching to the synthetic phenotype and 18-α-GA was used to inhibit gap junctions of SMCs. The contractile and synthetic phenotype vascular SMCs were cocultured with HL-1 cells; (2) Western blotting was used to detect the expression of Cx43, Cx40 and Cx45 in HL-1 cells, and RT-PCR to test microRNA 27b in vascular SMCs or in HL-1 cells; (3) Lucifer yellow dye transfer experiment was used to detect the function of gap junctions. (1) TGF- ß1 induced the vascular SMCs switching to synthetic phenotype; (2) Cx43 was significantly increased, and Cx40 and Cx45 were decreased in HL-1 cocultured with synthetic SMCs; (3) The fluorescence intensity of Lucifer yellow was higher in HL-1 cocultured with synthetic SMCs than that in the cells cocultured with contractile SMCs, which was inhibited by18-α-GA; (4) the expression of microRNA 27b was increased in HL-1 cocultured with synthetic SMCs, which was attenuated markedly by 18-α-GA. (5) the expression of ZFHX3 was decreased in HL-1 cocultured with synthetic SMCs, which was reversed by 18-α-GA. The gap junction proteins of HL-1 were regulated by pulmonary venous SMCs undergoing phenotypic transition in this study, accompanied with the up-regulation of microRNA 27b and the down-regulation of ZFHX3 in HL-1 cells, which was associated with heterocellular gap junctions between HL-1 and pulmonary venous SMCs.
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Comunicação Celular , Plasticidade Celular , Conexinas/metabolismo , Junções Comunicantes/metabolismo , MicroRNAs/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos Cardíacos/metabolismo , Miócitos de Músculo Liso/metabolismo , Animais , Comunicação Celular/efeitos dos fármacos , Linhagem Celular , Plasticidade Celular/efeitos dos fármacos , Técnicas de Cocultura , Conexina 43/genética , Conexina 43/metabolismo , Conexinas/genética , Junções Comunicantes/efeitos dos fármacos , Ácido Glicirretínico/análogos & derivados , Ácido Glicirretínico/farmacologia , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Masculino , MicroRNAs/genética , Músculo Liso Vascular/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Fenótipo , Veias Pulmonares/metabolismo , Ratos , Transdução de Sinais , Fator de Crescimento Transformador beta1/farmacologia , Proteína alfa-5 de Junções ComunicantesRESUMO
Both hypertension and hyperuricemia are closely associated with the morbidity and mortality of heart failure. This study was designed to evaluate the influences of long-term xanthine oxidase inhibitor (febuxostat) prescription on left ventricular hypertrophy (LVH), left ventricular (LV) diastolic function, and new-onset heart failure with preserved ejection fraction (HFpEF) in these patients. Using a propensity score matching of 1:2 ratio, this retrospective claims database study compared febuxosatat prescription (n = 96) and non-urate-lowering therapy (n = 192) in patients with hypertensive left ventricular hypertrophy (LVH) and asymptomatic hyperuricemia. With a follow-up of 36 months, febuxostat significantly decreased the level of serum uric acid as well as generated more prominent improvement in LVH and LV diastolic function. Besides, the new-onset symptomatic HFpEF occurred in 2 of 96 patients in febuxostat group and 13 of 192 patients in non-urate-lowering group (P = 0.091). No increased risk for major adverse cardiovascular events in patients prescribed with febuxostat was noted. In conclusion, long-term febuxostat exposure was associated with protective effects in terms of LVH or LV diastolic dysfunction in patients with hypertensive LVH and asymptomatic hyperuricemia. Febuxostat also displayed a trend for reduced risk of new-onset HFpEF in this population.
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Febuxostat/administração & dosagem , Supressores da Gota/administração & dosagem , Insuficiência Cardíaca/prevenção & controle , Hipertensão/complicações , Hipertrofia Ventricular Esquerda/prevenção & controle , Hiperuricemia/tratamento farmacológico , Ácido Úrico/sangue , Disfunção Ventricular Esquerda/prevenção & controle , Idoso , Doenças Assintomáticas , Biomarcadores/sangue , Pressão Sanguínea , Bases de Dados Factuais , Diástole , Progressão da Doença , Prescrições de Medicamentos , Febuxostat/efeitos adversos , Feminino , Supressores da Gota/efeitos adversos , Fatores de Risco de Doenças Cardíacas , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Hipertensão/fisiopatologia , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Hiperuricemia/sangue , Hiperuricemia/complicações , Masculino , Pessoa de Meia-Idade , Fatores de Proteção , Estudos Retrospectivos , Medição de Risco , Volume Sistólico/efeitos dos fármacos , Fatores de Tempo , Disfunção Ventricular Esquerda/etiologia , Disfunção Ventricular Esquerda/fisiopatologia , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacosRESUMO
BACKGROUND: Myocardial ischaemia reperfusion injury (MIRI) is a difficult problem in clinical practice, and it may involve various microRNAs. This study investigated the role that endogenous microRNA-146a plays in myocardial ischaemia reperfusion and explored the possible target genes. METHODS: MIRI models were established in microRNA-146a deficient (KO) and wild type (WT) mice. MicroRNA-146a expression was evaluated in the myocardium of WT mice after reperfusion. The heart function, area of myocardium infarction and in situ apoptosis were compared between the KO and WT mice. Microarray was used to explore possible target genes of microRNA-146a, while qRT-PCR and dual luciferase reporter assays were used for verification. Western blotting was performed to detect the expression levels of the target gene and related signalling molecules. A rescue study was used for further testing. RESULTS: MicroRNA-146a was upregulated 1 h after reperfusion. MicroRNA-146a deficiency decreased heart function and increased myocardial infarction and apoptosis. Microarray detected 19 apoptosis genes upregulated in the KO mice compared with the WT mice. qRT-PCR and dual luciferase verified that Med1 was one target gene of microRNA-146a. TRAP220, encoded by Med1 in the KO mice, was upregulated, accompanied by an amplified ratio of Bax/Bcl2 and increased cleaved caspase-3. Inhibition of microRNA-146a in H9C2 cells caused increased TRAP220 expression and more apoptosis under the stimulus of hypoxia and re-oxygenation, while knockdown of the increased TRAP220 expression led to decreased cell apoptosis. CONCLUSIONS: MicroRNA-146a exerts a protective effect against MIRI, which might be partially mediated by the target gene Med1 and related to the apoptosis signalling pathway.
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Subunidade 1 do Complexo Mediador/genética , MicroRNAs/genética , Infarto do Miocárdio/genética , Traumatismo por Reperfusão Miocárdica/genética , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Animais , Apoptose/genética , Caspase 3/genética , Caspase 3/metabolismo , Linhagem Celular , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Testes de Função Cardíaca , Masculino , Subunidade 1 do Complexo Mediador/antagonistas & inibidores , Subunidade 1 do Complexo Mediador/metabolismo , Camundongos , Camundongos Knockout , MicroRNAs/metabolismo , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/patologia , Miócitos Cardíacos/patologia , Análise de Sequência com Séries de Oligonucleotídeos , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismoRESUMO
BACKGROUND: Left atrial appendage (LAA) is gaining increasing attention in patients with atrial fibrillation (AF) in the context of cardioembolic stroke. Galectin-3 (Gal-3) is a mediator of profibrotic pathways and is associated with an increased incidence of heart failure. However, the role of Gal-3 in LAA remodelling and thrombus formation in AF has not been evaluated. METHODS: This prospective study included 153 consecutive patients with paroxysmal (n=58), persistent (n=55) or permanent (n=40) nonvalvular AF. The serum level of Gal-3 was measured by enzyme-linked immunosorbent assay. The morphology and function of LAA were determined by transoesophageal echocardiography. RESULTS: Left atrial appendage thrombus was observed in 22 patients (2 in paroxysmal AF, 11 in persistent AF and 9 in permanent AF). Significant differences among patients with different types of AF were found in terms of LAA morphology (orifice diameter and depth) and function (flow velocity and tissue Doppler contracting velocity) as well as serum levels of Gal-3. Furthermore, patients with persistent or permanent AF had higher levels of Gal-3. High Gal-3 level was closely related to LAA flow velocity and occurrence of LAA thrombus. Multivariate logistic regression analysis revealed that Gal-3 was an independent determinant of LAA thrombus in patients with AF. Receiver operating characteristic (ROC) curves related to LAA thrombus formation established a cut-off point for Gal-3 >18.95ng/ml. CONCLUSIONS: Cardiac rhythm disturbances caused by AF may lead to morphologic and functional remodelling of LAA. The serum level of Gal-3 was significantly correlated with LAA remodelling in patients with AF. High levels of Gal-3 were also a predicator for LAA thrombus formation.
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Apêndice Atrial , Fibrilação Atrial , Remodelamento Atrial , Ecocardiografia Transesofagiana , Galectina 3/sangue , Trombose , Idoso , Apêndice Atrial/diagnóstico por imagem , Apêndice Atrial/metabolismo , Apêndice Atrial/fisiopatologia , Fibrilação Atrial/sangue , Fibrilação Atrial/complicações , Fibrilação Atrial/diagnóstico por imagem , Fibrilação Atrial/fisiopatologia , Proteínas Sanguíneas , Feminino , Galectinas , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Trombose/sangue , Trombose/diagnóstico por imagem , Trombose/etiologia , Trombose/fisiopatologiaRESUMO
Liver-X-receptors (LXRs) are ligand-activated transcription factors belonging to the nuclear receptor superfamily. The two popular homologous receptor subtypes, LXRα and LXRß, exhibit differential expression patterns, thereby probably playing different roles in different contexts. This study aimed to evaluate the different roles of the two LXR subtypes and the mechanisms underlying their protection of cardiomyocytes against high-glucose stress. Silencing of LXRα, but not LXRß impaired normal LXR-mediated cardioprotective effects against high glucose-induced oxidative stress, apoptosis, and inflammation. Mechanistically, silencing of small ubiquitin-like modifier (SUMO)1 or SUMO2/3 did not affect LXR-mediated cardioprotective effects; however, these were impaired in response to nuclear receptor corepressor (NCoR) silencing. Together, these findings indicate that LXRα, but not LXRß, protects against high glucose-induced cardiomyocyte injury, probably via the NCoR-dependent transrepression of downstream target genes.
Assuntos
Glucose/farmacologia , Receptores X do Fígado/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Animais , Apoptose/efeitos dos fármacos , Benzoatos/farmacologia , Benzilaminas/farmacologia , Células Cultivadas , Inflamação/induzido quimicamente , Inflamação/metabolismo , Receptores X do Fígado/agonistas , Receptores X do Fígado/genética , Miócitos Cardíacos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , RatosRESUMO
BACKGROUND: The prognostic impact of long-term glycemic variability on clinical outcomes in patients with heart failure (HF) and type 2 diabetes mellitus (T2DM) remains unclear. We determined and compared hemoglobin A1c (HbA1c) variability and clinical outcomes for patients with HF with preserved ejection fraction (HFpEF), HF with mid-range ejection fraction (HFmrEF) and HF with reduced ejection fraction (HFrEF) in a prospective longitudinal study. METHODS: Patients with HF and T2DM, undergone 3 or more HbA1c determinations during the first 18 months, were then followed for 42 months. The primary outcome was death from any cause. Secondary outcome was composite endpoints with death and HF hospitalization. Cox proportional hazards models were used to compare outcomes for patients with HFpEF, HFmrEF and HFrEF. RESULTS: Of 902 patients enrolled, 32.2% had HFpEF, 14.5% HFmrEF, and 53.3% HFrEF. During 42 months of follow-up, 270 (29.9%) patients died and 545 (60.4%) patients experienced composite endpoints of death and HF readmission. The risk of all-cause death or composite endpoints was lower for HFpEF than HFrEF. Moreover, higher HbA1c variability was associated with higher all-cause mortality or composite endpoints and HbA1c variability was an independent predictor of all-cause mortality or composite endpoints, regardless of EF. CONCLUSIONS: This prospective longitudinal study showed that the all-cause death and composite events was lower for HFpEF than HFrEF. HbA1c variability was independently and similarly predictive of death or combined endpoints in the three HF phenotypes.
Assuntos
Diabetes Mellitus Tipo 2/sangue , Hemoglobinas Glicadas/metabolismo , Insuficiência Cardíaca/fisiopatologia , Idoso , Biomarcadores/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/mortalidade , Diabetes Mellitus Tipo 2/terapia , Feminino , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/terapia , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Readmissão do Paciente , Prognóstico , Estudos Prospectivos , Fatores de Risco , Volume Sistólico , Fatores de Tempo , Função Ventricular EsquerdaRESUMO
BACKGROUND/AIMS: MicroRNA-9 (miR-9) is involved in inflammatory reaction in atherosclerosis; however, its function and regulatory mechanisms remain unclear. We aimed to uncover the exact roles of miR-9 and downstream signaling pathways using in vitro human atherosclerosis models. METHODS: We used oxidized low-density lipoprotein (oxLDL)-stimulated human THP-1 derived macrophages, oxLDL-stimulated human primary peripheral blood monocytes and lipopolysaccharides (LPS) or Alum-stimulated human THP-1 derived macrophages as in vitro atherosclerosis inflammation models. Transient transfection of over-expression vectors, small interference RNAs (siRNAs) or antisense oligonucleotides was used to regulate intracellular protein or miR-9 levels. Cell responses and signal transduction were detected by multiple assays including Western blotting, enzyme-linked immunosorbent assay (ELISA) and luciferase reporter assay. RESULTS: MiR-9 inhibited while anti-miR-9 antisense oligonucleotides induced interleukin-1 beta (IL-1ß) and NLRP3 inflammasome activation in all in vitro models. Janus kinase 1 (JAK1) and matrix metalloproteinase 13 (MMP-13) were identified as the target genes of miR-9. In oxLDL-stimulated human THP-1 derived macrophages, knockdown of JAK1 by siRNA blocked the phosphorylation of signal transducer and activator of transcription 1 (STAT1) and mimicked the effects of miR-9. In the same model, JAK1 knockdown blocked the phosphorylation of NF-κB p65 in the nuclei and the phosphorylation of NF-κB IκBα in the cytoplasm. CONCLUSIONS: Our study demonstrated that miR-9 could inhibit activation of the NLRP3 inflammasome and attenuate atherosclerosis-related inflammation, likely through the JAK1/STAT1 signaling pathway. Therefore, miR-9 may serve as a potential therapeutic target for atherosclerosis.
Assuntos
Aterosclerose/metabolismo , Inflamassomos/metabolismo , Janus Quinase 1/metabolismo , MicroRNAs/biossíntese , Modelos Biológicos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Fator de Transcrição STAT1/metabolismo , Transdução de Sinais , Aterosclerose/induzido quimicamente , Aterosclerose/genética , Aterosclerose/patologia , Linhagem Celular Tumoral , Humanos , Inflamassomos/genética , Inflamação/induzido quimicamente , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Janus Quinase 1/genética , Lipoproteínas LDL/toxicidade , MicroRNAs/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Fator de Transcrição STAT1/genéticaRESUMO
The clinical significance of detecting early atherosclerosis is now widely recognized. Measurement methods available at present are usually not suitable for use in primary care where rapid screening for a large population is needed. The Arterial Velocity-pulse Index (AVI) and Arterial Pressure-volume Index (API) are new noninvasive arterial stiffness indices that can be rapidly measured using an oscillometric device. The purpose of this study was to determine whether high AVI and API values are predictive of early atherosclerosis prior to the onset of obstructive coronary artery disease (CAD). A total of 183 patients were enrolled and allocated to the CAD group (n = 109), early atherosclerosis (AS) group (n = 34) or an apparently healthy (non-AS) group (n = 40) based on the results of angiographic examinations. Measurements for arterial blood pressure, AVI, API and brachial-ankle pulse wave velocity (baPWV) were collected. Statistical analyses revealed that AVIs were significantly lower in the non-AS group than in the AS group and the CAD group. The inter-group differences in API were not statistically significant among the 3 patient groups. As a reference, baPWV was found to be statistically higher in the CAD group than in the non-AS group, whereas there was no significant difference between the CAD group and the AS group, or between the AS group and the non-AS group. The AVI and API were both significantly correlated with baPWV. This study demonstrated that AVI was more sensitive than baPWV and API in indicating early atherosclerosis, although elevated AVI and baPWV were both predictive of CAD.
Assuntos
Aterosclerose/diagnóstico , Rigidez Vascular , Idoso , Idoso de 80 Anos ou mais , Braço/irrigação sanguínea , Braço/fisiopatologia , Pressão Arterial , Estudos de Coortes , Angiografia Coronária , Doença da Artéria Coronariana/diagnóstico , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oscilometria , Análise de Onda de Pulso , Fluxo Sanguíneo RegionalRESUMO
The present study aimed to study lipid-lowering effect of seven traditional Chinese medicine monomers in zebrafish system. Zebrafish were fed with high fat diet to establish a hyperlipemia model, then fasted and bathed with seven traditional Chinese medicine monomers stigmasterol, triacontanol, chrysophanol, vanillic acid, shikimic acid, polydatin and oleanolic acid respectively. The oil red O staining was used to detect the blood lipids of zebrafish. Serum total cholesterol and triglyceride levels were detected to validate the lipid-lowering effect. The result showed that a zebrafish model of hyperlipemia could be established by feeding larvae zebrafish with high fat diet. Among the seven traditional Chinese medicine monomers, chrysophanol had lipid-lowering effect. Chrysophanol significantly reduced serum total cholesterol and triglyceride levels in adult zebrafish fed with high fat diet. Chrysophanol accelerated peristalsis frequency of zebrafish intestine and the excretion of high fat food. It is concluded that chrysophanol has lipid- lowering effect in zebrafish, and the mechanism of the effect may be due to the roles of chrysophanol in reducing lipid absorption from gastrointestinal tract and accelerating the excretion of food.
Assuntos
Hiperlipidemias/tratamento farmacológico , Hipolipemiantes/farmacologia , Medicina Tradicional Chinesa , Animais , Antraquinonas/farmacologia , Dieta Hiperlipídica , Álcoois Graxos/farmacologia , Glucosídeos/farmacologia , Larva , Lipídeos/sangue , Ácido Oleanólico/farmacologia , Ácido Chiquímico/farmacologia , Estigmasterol/farmacologia , Estilbenos/farmacologia , Ácido Vanílico/farmacologia , Peixe-ZebraRESUMO
The purpose of this paper was to explore a new method for screening lipid-lowering drugs in zebrafish models. The suitable drug concentrations of atorvastatin (ATV), fenofibrate (FEF) and ezetimibe (EZE) were first determined. Then, the serum cholesterol and triglyceride levels were detected in high-fat diet (HFD)-fed zebrafish. The HFD zebrafish models were constructed and the effects of drugs on them were observed by Oil red O staining and fluorescence labeling. Statistical analyses among groups were conducted using SPSS software. The lowest drug concentration (LDC) and the highest (HDC) of ATV, FEF and EZE were 0.3 µM/37.0µM, 1.2µM/3.5µM, and 6.3 µM/26.4µM, respectively, while, the intermediate (IDC) was, in order, 18.5µM, 1.8µM, 13.2µM. The cholesterol and triglyceride levels in HFD-fed zebrafish were increased after 7 weeks fat feeding (p<0.05). Moreover, the levels of triglyceride were significantly decreased after LDC of ATV and FEF treated (p<0.05), but not that of EZE. While, the cholesterol levels were reduced in three groups (p<0.05). Moreover, the 5 dpf high-fat zebrafish model was established successfully and maintained stably for 24h. ATV produced effects in a concentration-dependent manner, while only IDC and HDC of FEF and EZE made effects on this model. Intravascular cholesterol levels were significantly increased after HCD treatment and decreased after drug treated. The high-fat zebrafish model induced by HFD-fed was available and successful, besides, the Oil red O staining may be an available and rapid method for screening lipid-lowering drugs.