RESUMO
BACKGROUND: Beyond therapeutic implications, PCSK9 (proprotein convertase subtilisin/kexin 9) has emerged as a promising cardiovascular biomarker. The exact role of PCSK9 in the setting of acute ST-elevation myocardial infarction (STEMI) is incompletely understood. We aimed to investigate the association of PCSK9 with ischemia-reperfusion injury, visualized by cardiac magnetic resonance imaging, in patients with STEMI revascularized by primary percutaneous coronary intervention (PCI). METHODS: In this prespecified substudy from the prospective MARINA-STEMI (NCT04113356) registry, we included 205 patients with STEMI. PCSK9 concentrations were measured from venous blood samples by an immunoassay 24 and 48 hours after PCI. The primary end point was defined as presence of intramyocardial hemorrhage according to cardiac magnetic resonance T2* mapping. Secondary imaging end points were the presence of microvascular obstruction (MVO) and infarct size. The clinical end point was the occurrence of major adverse cardiac events. RESULTS: We observed a significant increase in PCSK9 levels from 24 to 48 hours (268-304 ng/mL; P<0.001) after PCI. PCSK9 24 hours after PCI did not show any relation to intramyocardial hemorrhage, MVO, and infarct size (all P>0.05). PCSK9 concentrations 48 hours post-STEMI were higher in patients with intramyocardial hemorrhage (333 versus 287 ng/mL; P=0.004), MVO (320 versus 292 ng/mL; P=0.020), and large infarct size (323 versus 296 ng/mL; P=0.013). Furthermore, patients with increased PCSK9 levels >361 ng/mL at 48 hours were more likely to experience major adverse cardiac events (15% versus 8%; P=0.002) during a median follow-up of 12 months. CONCLUSIONS: In patients with STEMI, a significant increase in PCSK9 was observed from 24 to 48 hours after PCI. While PCSK9 levels after 24 hours were not related to myocardial or microvascular injury, PCSK9 after 48 hours was significantly associated with intramyocardial hemorrhage, MVO, and infarct size as well as worse subsequent clinical outcomes. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier; NCT04113356.
Assuntos
Biomarcadores , Traumatismo por Reperfusão Miocárdica , Intervenção Coronária Percutânea , Pró-Proteína Convertase 9 , Sistema de Registros , Infarto do Miocárdio com Supradesnível do Segmento ST , Humanos , Infarto do Miocárdio com Supradesnível do Segmento ST/sangue , Infarto do Miocárdio com Supradesnível do Segmento ST/terapia , Infarto do Miocárdio com Supradesnível do Segmento ST/cirurgia , Masculino , Pró-Proteína Convertase 9/sangue , Feminino , Pessoa de Meia-Idade , Intervenção Coronária Percutânea/efeitos adversos , Traumatismo por Reperfusão Miocárdica/sangue , Traumatismo por Reperfusão Miocárdica/etiologia , Traumatismo por Reperfusão Miocárdica/diagnóstico por imagem , Biomarcadores/sangue , Estudos Prospectivos , Idoso , Imagem Cinética por Ressonância Magnética/métodos , Fatores de Tempo , Resultado do TratamentoRESUMO
Objectives. The aim of this study was to investigate the expression of long non-coding RNA (lncRNA) brain and reproductive organ-expressed protein (BRE) antisense RNA 1 (BRE-AS1) in patients with acute myocardial infarction (AMI) and its effect on ischemia/reperfusion (I/R)-induced oxidative stress and apoptosis of cardiomyocytes. Methods. Serum BRE-AS1 levels in patients with AMI was detected using quantitative real-time polymerase chain reaction (qRT-PCR). The diagnostic and prognostic values of BRE-AS1 were evaluated. H9c2 cells were treated with hypoxia/reoxygenation to establish an in vitro myocardial infarction cell model. The levels of inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and IL-6 were detected by enzyme-linked immunosorbent assay (ELISA). Levels of lactate dehydrogenase (LDH), malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) were determined by commercial kits. Cell counting kit-8 (CCK-8) and flow cytometry were used to evaluate the cell viability and cell apoptosis. Results. The expression of BRE-AS1 in serum of patients with AMI is upregulated, which shows the clinical diagnostic value for AMI. In the I/R injury cell model, the knockout of BRE-AS1 can significantly alleviate the increase in TNF-α, IL-1ß, and IL-6 levels, inhibit the production of LDH and MDA, increase the activities of SOD and GSH-Px, promote the cell viability and suppress cell apoptosis. Conclusions. Abnormally elevated BRE-AS1 has a high diagnostic value for AMI as well as a prognostic value for major adverse cardiovascular events (MACEs). The elevation of BRE-AS1 promoted oxidative stress injury and cell apoptosis in vitro.
Assuntos
Apoptose , Mediadores da Inflamação , Infarto do Miocárdio , Miócitos Cardíacos , Estresse Oxidativo , RNA Longo não Codificante , Animais , Feminino , Humanos , Masculino , Ratos , Estudos de Casos e Controles , Linhagem Celular , Citocinas/metabolismo , Citocinas/sangue , Mediadores da Inflamação/metabolismo , Mediadores da Inflamação/sangue , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Infarto do Miocárdio/sangue , Infarto do Miocárdio/genética , Infarto do Miocárdio/diagnóstico , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/sangue , Traumatismo por Reperfusão Miocárdica/diagnóstico , Traumatismo por Reperfusão Miocárdica/genética , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , RNA Longo não Codificante/sangue , RNA Longo não Codificante/metabolismo , RNA Longo não Codificante/genética , Transdução de Sinais , Regulação para CimaRESUMO
AIMS: Adiponectin is an adipocyte-derived circulating protein that exerts cardiovascular and metabolic protection. Due to the futile degradation of endogenous adiponectin and the challenges of exogenous administration, regulatory mechanisms of adiponectin biosynthesis are of significant pharmacological interest. METHODS AND RESULTS: Here, we report that 5-diphosphoinositol 1,2,3,4,6-pentakisphosphate (5-InsP7) generated by inositol hexakisphosphate kinase 1 (IP6K1) governed circulating adiponectin levels via thiol-mediated protein quality control in the secretory pathway. IP6K1 bound to adiponectin and DsbA-L and generated 5-InsP7 to stabilize adiponectin/ERp44 and DsbA-L/Ero1-Lα interactions, driving adiponectin intracellular degradation. Depleting 5-InsP7 by either IP6K1 deletion or pharmacological inhibition blocked intracellular adiponectin degradation. Whole-body and adipocyte-specific deletion of IP6K1 boosted plasma adiponectin levels, especially its high molecular weight forms, and activated AMPK-mediated protection against myocardial ischaemia-reperfusion injury. Pharmacological inhibition of 5-InsP7 biosynthesis in wild-type but not adiponectin knockout mice attenuated myocardial ischaemia-reperfusion injury. CONCLUSION: Our findings revealed that 5-InsP7 is a physiological regulator of adiponectin biosynthesis that is amenable to pharmacological intervention for cardioprotection.
Assuntos
Adiponectina , Camundongos Endogâmicos C57BL , Camundongos Knockout , Traumatismo por Reperfusão Miocárdica , Animais , Adiponectina/metabolismo , Adiponectina/genética , Adiponectina/sangue , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/sangue , Traumatismo por Reperfusão Miocárdica/enzimologia , Fosfotransferases (Aceptor do Grupo Fosfato)/metabolismo , Fosfotransferases (Aceptor do Grupo Fosfato)/genética , Fosfatos de Inositol/metabolismo , Adipócitos/metabolismo , Adipócitos/enzimologia , Adipócitos/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Proteínas Quinases Ativadas por AMP/genética , Masculino , Camundongos , Modelos Animais de Doenças , Transdução de Sinais , Proteólise , HumanosRESUMO
Extracellular potassium concentration might modify electrophysiological properties in the border zone of ischemic myocardium. We evaluated the depolarization and repolarization characteristics across the ischemic-normal border under [K+] variation. Sixty-four-lead epicardial mapping was performed in 26 rats ([K+] 2.3-6.4 mM) in a model of acute ischemia/reperfusion. The animals with [K+] < 4.7 mM (low-normal potassium) had an ischemic zone with ST-segment elevation and activation delay, a border zone with ST-segment elevation and no activation delay, and a normal zone without electrophysiological abnormalities. The animals with [K+] >4.7 mM (normal-high potassium) had only the ischemic and normal zones and no transitional area. Activation-repolarization intervals and local conduction velocities were inversely associated with [K+] in linear regression analysis with adjustment for the zone of myocardium. The reperfusion extrasystolic burden (ESB) was greater in the low-normal as compared to normal-high potassium animals. Ventricular tachycardia/fibrillation incidence did not differ between the groups. In patch-clamp experiments, hypoxia shortened action potential duration at 5.4 mM but not at 1.3 mM of [K+]. IK(ATP) current was lower at 1.3 mM than at 5.4 mM of [K+]. We conclude that the border zone formation in low-normal [K+] was associated with attenuation of IK(ATP) response to hypoxia and increased reperfusion ESB.
Assuntos
Potenciais de Ação , Isquemia Miocárdica , Potássio , Animais , Potássio/sangue , Potássio/metabolismo , Masculino , Ratos , Isquemia Miocárdica/fisiopatologia , Isquemia Miocárdica/sangue , Isquemia Miocárdica/metabolismo , Potenciais de Ação/fisiologia , Traumatismo por Reperfusão Miocárdica/sangue , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Ratos WistarRESUMO
The majority of cardiovascular deaths are associated with acute coronary syndrome, especially ST-elevation myocardial infarction. Therapeutic reperfusion alone can contribute up to 40 percent of total infarct size following coronary artery occlusion, which is called ischemia-reperfusion injury (IRI). Its size depends on many factors, including the main risk factors of cardiovascular mortality, such as age, sex, systolic blood pressure, smoking, and total cholesterol level as well as obesity, diabetes, and physical effort. Extracellular vesicles (EVs) are membrane-coated particles released by every type of cell, which can carry content that affects the functioning of other tissues. Their role is essential in the communication between healthy and dysfunctional cells. In this article, data on the variability of the content of EVs in patients with the most prevalent cardiovascular risk factors is presented, and their influence on IRI is discussed.
Assuntos
Vesículas Extracelulares/metabolismo , Traumatismo por Reperfusão Miocárdica/sangue , Traumatismo por Reperfusão Miocárdica/epidemiologia , Fatores Etários , Animais , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Fatores de Risco , Caracteres SexuaisRESUMO
The effect of uridine on the myocardial ischemic and reperfusion injury was investigated. A possible mechanism of its cardioprotective action was established. Two rat models were used: (1) acute myocardial ischemia induced by occlusion of the left coronary artery for 60 min; and (2) myocardial ischemia/reperfusion with 30-min ischemia and 120-min reperfusion. In both models, treatment with uridine (30 mg/kg) prevented a decrease in cell energy supply and in the activity of the antioxidant system, as well as an increase in the level of lipid hydroperoxides and diene conjugates. This led to a reduction of the necrosis zone in the myocardium and disturbances in the heart rhythm. The blocker of the mitochondrial ATP-dependent potassium (mitoKATP) channel 5-hydroxydecanoate limited the positive effects of uridine. The data indicate that the cardioprotective action of uridine may be related to the activation of the mitoKATP channel. Intravenously injected uridine was more rapidly eliminated from the blood in hypoxia than in normoxia, and the level of the mitoKATP channel activator UDP in the myocardium after uridine administration increased. The results suggest that the use of uridine can be a potentially effective approach to the management of cardiovascular diseases.
Assuntos
Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/patologia , Canais de Potássio/metabolismo , Uridina/farmacologia , Doença Aguda , Trifosfato de Adenosina/metabolismo , Animais , Antioxidantes/metabolismo , Arritmias Cardíacas/sangue , Arritmias Cardíacas/tratamento farmacológico , Arritmias Cardíacas/etiologia , Modelos Animais de Doenças , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Traumatismo por Reperfusão Miocárdica/sangue , Miocárdio/metabolismo , Ratos Wistar , Taquicardia/sangue , Taquicardia/complicações , Uridina/sangue , Uridina/uso terapêutico , Difosfato de Uridina/metabolismo , Uridina Trifosfato/metabolismo , Fibrilação Ventricular/complicações , Fibrilação Ventricular/tratamento farmacológicoRESUMO
Electroacupuncture (EA) intervention has a remarkable cardioprotection against myocardial ischemia reperfusion injury (MIRI). Recently, it has been suggested that the gut microbiota plays an important role in regulating the progression and prognosis of MIRI. The purpose of this study was to illustrate the relationship between gut microbiota and cardioprotection of EA on MIRI. We conducted a MIRI model by ligating the left anterior descending coronary artery for 30 min followed by reperfusion in male Sprague Dawley rats, which then received 7 days of EA intervention. Echocardiography was employed to evaluate left ventricular function. Fecal samples were collected for microbial analysis by 16S rDNA high-throughput sequencing. Blood samples and myocardium were collected for inflammatory cytokine detection by enzyme linked immunosorbent assay (ELISA) and Western blot. Hematoxylin & eosin (HE) staining and immunofluorescence of ileum tissue were performed for intestinal damage evaluation. After 7 days of EA intervention, the left ventricular function was improved with significantly increased ejection fraction and fractional shortening. Furthermore, we found that EA intervention reversed the changed gut microbiota induced by MIRI, including Clostridiales, RF39, S24-7, Desulfovibrio, and Allobaculum, improved the impaired gut barrier, reduced the production and circulation of lipopolysaccharide (LPS), inhibited the level of interleukin 6 (IL-6) and interleukin 12 (IL-12) in periphery and decreased the expression of Toll like receptor 4 (TLR4) and IL-6 in myocardium. EA intervention could improve the impaired gut mucosal barrier and reduce the production and circulation of LPS after MIRI through regulating gut microbiota, thus inhibiting the circulation and myocardium inflammation and finally exerted the cardioprotective effect.
Assuntos
Bactérias/metabolismo , Eletroacupuntura , Microbioma Gastrointestinal , Mediadores da Inflamação/metabolismo , Mucosa Intestinal/microbiologia , Lipopolissacarídeos/sangue , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miocárdio/metabolismo , Proteínas de Fase Aguda , Animais , Bactérias/crescimento & desenvolvimento , Proteínas de Transporte/sangue , Modelos Animais de Doenças , Disbiose , Masculino , Glicoproteínas de Membrana/sangue , Traumatismo por Reperfusão Miocárdica/sangue , Traumatismo por Reperfusão Miocárdica/microbiologia , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/patologia , Ratos Sprague-Dawley , Função Ventricular EsquerdaRESUMO
Complete vascular occlusion to distant tissue prior to an ischemic cardiac event can provide significant cardioprotection via remote ischemic preconditioning (RIPC). Despite understanding its mechanistic basis, its translation to clinical practice has been unsuccessful, likely secondary to the inherent impossibility of predicting (and therefore preconditioning) an ischemic event, as well as the discomfort that is associated with traditional, fully occlusive RIPC stimuli. Our laboratory has previously shown that non-occlusive banding (NOB) via wrapping of a leather band (similar to a traditional Jewish ritual) can elicit an RIPC response in healthy human subjects. This study sought to further the pain-mediated aspect of this observation in a mouse model of NOB with healthy mice that were exposed to treatment with and without lidocaine to inhibit pain sensation prior to ischemia/reperfusion injury. We demonstrated that NOB downregulates key inflammatory markers resulting in a preconditioning response that is partially mediated via pain sensation.
Assuntos
Anestésicos Locais/farmacologia , Membro Anterior/irrigação sanguínea , Precondicionamento Isquêmico/métodos , Lidocaína/farmacologia , Infarto do Miocárdio/prevenção & controle , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Limiar da Dor/efeitos dos fármacos , Artéria Radial/fisiologia , Animais , Citocinas/sangue , Citocinas/genética , Modelos Animais de Doenças , Ecocardiografia , Ligadura , Masculino , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/sangue , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/fisiopatologia , Traumatismo por Reperfusão Miocárdica/sangue , Traumatismo por Reperfusão Miocárdica/diagnóstico por imagem , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miocárdio/metabolismo , Miocárdio/patologia , Artéria Radial/diagnóstico por imagem , Fluxo Sanguíneo Regional , Fatores de TempoRESUMO
Increased histone deacetylase 3 (HDAC3) has been demonstrated to contribute to the pathogenesis of myocardial ischemia-reperfusion injury (MI/RI). Therefore, the goal of this study was to investigate how HDAC3 regulated MI/RI by mediating microRNA (miR)-494-3p/dromodomain-containing protein 4 (BRD4) axis. The MI/RI model was established by ligating the right anterior descending coronary artery. Cardiomyocytes from newborn mice were treated with hypoxia/reoxygenation (H/R). Gain-of-function and loss-of-function approaches were implemented to figure out the roles of miR-494-3p and HDAC3 in MI/RI. miR-494-3p, HDAC3, and BRD4 in myocardial tissues of mice with MI/RI and H/R-treated cardiomyocytes were detected. The relationships between miR-494-3p and HDAC3 and BRD4 were identified. Reduced miR-494-3p and upregulated HDAC3 and BRD4 exhibited in myocardial tissues of mice with MI/RI and H/R-treated cardiomyocytes. Inhibited HDAC3 or elevated miR-494-3p repressed the inflammation and apoptosis, improved cardiac function, and ameliorated myocardial injury in myocardial tissues of mice with MI/RI. Suppression of HDAC3 or elevation of miR-494-3p depressed inflammation and apoptosis and promoted cell viability of primary cardiomyocytes. miR-494-3p targeted BRD4. The study concludes that suppressed HDAC3 plays a protective role in MI/RI by upregulation of miR-494-3p and inhibition of BRD4, which could be helpful for MI/RI therapy.
Assuntos
Histona Desacetilases/metabolismo , Inflamação/metabolismo , MicroRNAs/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Miócitos Cardíacos/metabolismo , Proteínas Nucleares/metabolismo , Fatores de Transcrição/metabolismo , Animais , Apoptose/fisiologia , Modelos Animais de Doenças , Feminino , Inflamação/sangue , Interleucina-1/sangue , Interleucina-6/sangue , Camundongos , Traumatismo por Reperfusão Miocárdica/sangue , Miocárdio/metabolismo , Fator de Necrose Tumoral alfa/sangueRESUMO
We studied the translational cardioprotective potential of P2Y12 inhibitors against acute myocardial ischemia/reperfusion injury (IRI) in an animal model of acute myocardial infarction and in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). P2Y12 inhibitors may have pleiotropic effects to induce cardioprotection against acute myocardial IRI beyond their inhibitory effects on platelet aggregation. We compared the cardioprotective effects of clopidogrel, prasugrel, and ticagrelor on infarct size in an in vivo rat model of acute myocardial IRI, and investigated the effects of the P2Y12 inhibitors on enzymatic infarct size (48-h area-under-the-curve (AUC) troponin T release) and clinical outcomes in a retrospective study of STEMI patients from the CONDI-2/ERIC-PPCI trial using propensity score analyses. Loading with ticagrelor in rats reduced infarct size after acute myocardial IRI compared to controls (37 ± 11% vs 52 ± 8%, p < 0.01), whereas clopidogrel and prasugrel did not (50 ± 11%, p > 0.99 and 49 ± 9%, p > 0.99, respectively). Correspondingly, troponin release was reduced in STEMI patients treated with ticagrelor compared to clopidogrel (adjusted 48-h AUC ratio: 0.67, 95% CI 0.47-0.94). Compared to clopidogrel, the composite endpoint of cardiac death or hospitalization for heart failure within 12 months was reduced in STEMI patients loaded with ticagrelor (HR 0.63; 95% CI 0.42-0.94) but not prasugrel (HR 0.84, 95% CI 0.43-1.63), prior to PPCI. Major adverse cardiovascular events did not differ between clopidogrel, ticagrelor, or prasugrel. The cardioprotective effects of ticagrelor in reducing infarct size may contribute to the clinical benefit observed in STEMI patients undergoing PPCI.
Assuntos
Plaquetas/efeitos dos fármacos , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Intervenção Coronária Percutânea , Inibidores da Agregação Plaquetária/uso terapêutico , Agregação Plaquetária/efeitos dos fármacos , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Receptores Purinérgicos P2Y12/efeitos dos fármacos , Infarto do Miocárdio com Supradesnível do Segmento ST/terapia , Pesquisa Translacional Biomédica , Idoso , Animais , Plaquetas/metabolismo , Clopidogrel/uso terapêutico , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Traumatismo por Reperfusão Miocárdica/sangue , Traumatismo por Reperfusão Miocárdica/etiologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Intervenção Coronária Percutânea/efeitos adversos , Inibidores da Agregação Plaquetária/efeitos adversos , Cloridrato de Prasugrel/uso terapêutico , Antagonistas do Receptor Purinérgico P2Y/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Ratos , Receptores Purinérgicos P2Y12/metabolismo , Estudos Retrospectivos , Infarto do Miocárdio com Supradesnível do Segmento ST/fisiopatologia , Ticagrelor/uso terapêutico , Resultado do TratamentoRESUMO
INTRODUCTION: The morbidity and mortality of acute myocardial infarction patients still remains high after percutaneous coronary intervention (PCI). Myocardial ischemia-reperfusion (MIR) injury is one of the important reasons. Although the phenomenon of MIR injury can paradoxically reduce the beneficial effects of myocardial reperfusion, there currently remains no effective therapeutic agent for preventing MIR. Previous studies have shown that Yiqi Liangxue Shengji prescription (YLS) is effective in improving clinical symptoms and ameliorating the major adverse cardiovascular events of coronary heart disease patients undergoing PCI. This study aims to evaluate the effectiveness and safety of YLS in patients with acute myocardial infarction (AMI) after PCI. METHODS: This study is a randomized, double-blinded, placebo-controlled, single-central clinical trial. A total of 140 participants are randomly allocated to 2 groups: the intervention group and the placebo group. Based on routine medications, the intervention group will be treated with YLS and the placebo group will be treated with YLS placebo. All participants will receive a 8-week treatment and then be followed up for another 12âmonths. The primary outcome measures are N terminal pro B type natriuretic peptide (NT-proBNP) and left ventricular ejection fraction. Secondary outcomes are plasma levels of microRNA-145, plasma cardiac enzyme, and Troponin I levels in blood samples, changes in ST-segment in ECG, Seattle Angina Questionnaire, the efficacy of angina symptoms, and occurrence of major adverse cardiac events. All the data will be recorded in case report forms and analyzed by SPSS V.17.0. DISCUSSION: The trial will investigate whether the postoperative administration of YLS in patients with AMI after PCI will improve cardiac function. And it explores microRNAs (miRNA)-145 as detection of blood-based biomarkers for AMI by evaluating the relation between miRNAs in plasma and cardiac function. TRIAL REGISTRATION: Chinese Clinical Trials Registry identifier ChiCTR2000038816. Registered on October 10, 2020.
Assuntos
Doença das Coronárias/complicações , Medicamentos de Ervas Chinesas/uso terapêutico , Infarto do Miocárdio/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença das Coronárias/cirurgia , Medicamentos de Ervas Chinesas/farmacologia , Eletrocardiografia , Feminino , Humanos , Masculino , MicroRNAs/sangue , Pessoa de Meia-Idade , Infarto do Miocárdio/sangue , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/etiologia , Traumatismo por Reperfusão Miocárdica/sangue , Traumatismo por Reperfusão Miocárdica/diagnóstico , Traumatismo por Reperfusão Miocárdica/etiologia , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Intervenção Coronária Percutânea , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Troponina I/sangue , Função Ventricular Esquerda/efeitos dos fármacos , Adulto JovemRESUMO
Background Perioperative blood glucose level has shown an association with postoperative outcomes. We compared the incidences of myocardial injury after noncardiac surgery (MINS) and 30-day mortality, according to preoperative blood glucose and hemoglobin A1c (HbA1c) levels. Methods and Results The patients were divided according to blood glucose level within 1 day before surgery. The hyperglycemia group was defined with fasting glucose >140 mg/dL or random glucose >180 mg/dL. In addition, we compared the outcomes according to HbA1c >6.5% among patients with available HbA1c within 3 months before surgery. The primary outcome was MINS, and 30-day mortality was also compared. A total of 12 304 patients were enrolled and divided into 2 groups: 8324 (67.7%) in the normal group and 3980 (32.3%) in the hyperglycemia group. After adjustment with inverse probability of weighting, the hyperglycemia group exhibited significantly higher incidences of MINS and 30-day mortality (18.7% versus 27.6%; odds ratio, 1.29; 95% CI, 1.18-1.42; P<0.001; and 2.0% versus 5.1%; hazard ratio, 2.00; 95% CI, 1.61-2.49; P<0.001, respectively). In contrast to blood glucose, HbA1c was not associated with MINS or 30-day mortality. Conclusions Preoperative hyperglycemia was associated with MINS and 30-day mortality, whereas HbA1c was not. Immediate glucose control may be more crucial than long-term glucose control in patients undergoing noncardiac surgery. Registration URL: https://www.cris.nih.go.kr; Unique identifier: KCT0004244.
Assuntos
Glicemia/metabolismo , Hemoglobinas Glicadas/metabolismo , Traumatismo por Reperfusão Miocárdica/sangue , Complicações Pós-Operatórias/sangue , Procedimentos Cirúrgicos Operatórios/efeitos adversos , Feminino , Seguimentos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Traumatismo por Reperfusão Miocárdica/epidemiologia , Traumatismo por Reperfusão Miocárdica/etiologia , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Período Pós-Operatório , República da Coreia/epidemiologia , Estudos Retrospectivos , Taxa de Sobrevida/tendênciasRESUMO
Oxygen is often administered to patients and occasionally to healthy individuals as well; however, the cellular toxicity of oxygen, especially following prolonged exposure, is widely known. To evaluate the potential effect of oxygen exposure on circulating stem/progenitor cells and cardiac ischemia/reperfusion (I/R) injury, we exposed healthy adult mice to 100% oxygen for 20 or 60 min. We then examined the c-kit-positive stem/progenitor cells and colony-forming cells and measured the cytokine/chemokine levels in peripheral blood. We also induced cardiac I/R injury in mice at 3 h after 60 min of oxygen exposure and examined the recruitment of inflammatory cells and the fibrotic area in the heart. The proportion of c-kit-positive stem/progenitor cells significantly increased in peripheral blood at 3 and 24 h after oxygen exposure for either 20 or 60 min (p < .01 vs. control). However, the abundance of colony-forming cells in peripheral blood conversely decreased at 3 and 24 h after oxygen exposure for only 60 min (p < .05 vs. control). Oxygen exposure for either 20 or 60 min resulted in significantly decreased plasma vascular endothelial growth factor levels at 3 h, whereas oxygen exposure for only 60 min reduced plasma insulin-like growth factor 1 levels at 24 h (p < .05 vs. control). Protein array indicated the increase in the levels of some cytokines/chemokines, such as CXCL6 (GCP-2) at 24 h after 60 min of oxygen exposure. Moreover, oxygen exposure for 60 min enhanced the recruitment of Ly6g- and CD11c-positive inflammatory cells at 3 days (p < .05 vs. control) and increased the fibrotic area at 14 days in the heart after I/R injury (p < .05 vs. control). Prolonged oxygen exposure induced the mobilization and functional impairment of stem/progenitor cells and likely enhanced inflammatory responses to exacerbate cardiac I/R injury in healthy mice.
Assuntos
Traumatismo por Reperfusão Miocárdica/patologia , Oxigênio/efeitos adversos , Células-Tronco/patologia , Animais , Quimiocina CXCL12/sangue , Ensaio de Unidades Formadoras de Colônias , Mediadores da Inflamação/sangue , Masculino , Camundongos Endogâmicos C57BL , Traumatismo por Reperfusão Miocárdica/sangue , Miocárdio/metabolismo , Miocárdio/patologia , Proteínas Proto-Oncogênicas c-kit/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fator A de Crescimento do Endotélio Vascular/sangueAssuntos
Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Inibidores da Agregação Plaquetária/uso terapêutico , Sevoflurano/uso terapêutico , Sirtuína 1/metabolismo , Alanina Transaminase/sangue , Animais , Catalase/metabolismo , Creatina Quinase Forma MB/sangue , Creatinina/sangue , Humanos , Malondialdeído/metabolismo , Infarto do Miocárdio/patologia , Infarto do Miocárdio/terapia , Reperfusão Miocárdica , Traumatismo por Reperfusão Miocárdica/sangue , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Ratos , Superóxido Dismutase/metabolismoRESUMO
OBJECTIVE: This study examined the correlation between serum miR-98-5p levels and indices of microvascular reperfusion in patients undergoing primary percutaneous coronary intervention (pPCI) after ST-segment elevation myocardial infarction (STEMI). Additionally, we evaluated the mechanisms by which miR-98-5p promoted ischemia/reperfusion (I/R)-induced injury in both cultured cell lines and an animal model. METHODS: Circulating miR-98-5p levels were measured and compared from 171 STEMI patients undergoing pPCI, who were divided into two groups: no-reflow and reflow. The levels of miR-98-5p, nerve growth factor (NGF), and transient receptor potential vanilloid 1 (TRPV1) were analyzed in cultured human coronary endothelial cells (HCECs) exposed to hypoxia/reoxygenation (H/R). The effects of antagomir-98-5p on myocardial I/R-induced microvascular dysfunction in vivo were evaluated. Target gene expression and activity were assessed. RESULTS: Higher miR-98-5p levels were associated with compromised indices of microvascular reperfusion. In vitro experiments on HCECs showed that exposure to H/R significantly increased miR-98-5p levels. We identified NGF as a novel target of miR-98-5p. Further, antagomir-98-5p relieved microvascular dysfunction and enhanced the expression of NGF and TRPV1 in the rat myocardial I/R model. CONCLUSIONS: MiR-98-5p promotes microvascular dysfunction by targeting the NGF-TRPV1 axis. Serum miR-98-5p serves as a potential biomarker for microvascular reperfusion.
Assuntos
Vasos Coronários/metabolismo , MicroRNAs/sangue , Microvasos/metabolismo , Traumatismo por Reperfusão Miocárdica/sangue , Fator de Crescimento Neural/sangue , Idoso , Biomarcadores/sangue , Células Cultivadas , Vasos Coronários/patologia , Células Endoteliais/metabolismo , Células Endoteliais/fisiologia , Feminino , Seguimentos , Regulação da Expressão Gênica , Humanos , Masculino , Microvasos/patologia , Pessoa de Meia-Idade , Traumatismo por Reperfusão Miocárdica/patologiaRESUMO
Ischaemia/reperfusion (I/R) injury can lead to severe arrhythmia and aggravate myocardial damage. Exosomes are small-membrane vesicles that play a protective role in myocardial I/R injury. This study aimed to explore the protective effects of ischaemic preconditioning (IPC)-induced serum exosomes (IPC-Exo) on myocardial I/R injury in rats and its underlying mechanism. Serum exosomes were extracted from IPC rats and quantified using a bicinchoninic acid assay kit. IPC-Exo (50 µg) was injected into the infarcted myocardium immediately after ligation. Rats were randomly divided into Sham, I/R, IPC-Exo + I/R, I/R + LY294002, and I/R + IPC-Exo + LY294002 groups. Haemodynamic parameters were measured by physiological recording. Transthoracic echocardiography was used to detect cardiac function. The serum levels of creatine kinase isomer-MB, lactate dehydrogenase, aspartate transaminase, tumour necrosis factor-alpha, interleukin (IL)-1ß, and IL-10 were detected by enzyme-linked immunosorbent assay. Triphenyl tetrazolium chloride staining was used to measure the myocardial infarct size. Apoptosis in myocardial tissues was detected by TUNEL staining. Western blotting was used to detect the levels of PI3K/AKT and apoptosis-related proteins. Our results showed that treatment with IPC-Exo ameliorated cardiac function and reduced inflammatory factor production, cardiomyocyte apoptosis, and myocardial infarct size. Moreover, IPC-Exo treatment promoted the protein expression of Bcl-2, p-PI3K, and p-AKT but inhibited that of caspase-3 and Bax. However, treatment with LY294002 significantly reversed that IPC-Exo-induced increase in p-PI3K and p-AKT levels, improvement of haemodynamics, and decrease of inflammatory factor production and apoptosis in the I/R + IPC-Exo group. Taken together, our results suggest that IPC-Exo may alleviate I/R injury via activating the PI3K/AKT signalling pathway.
Assuntos
Exossomos/metabolismo , Precondicionamento Isquêmico , Traumatismo por Reperfusão Miocárdica/patologia , Transdução de Sinais , Animais , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Cromonas/farmacologia , Creatina Quinase Forma MB/metabolismo , Hemodinâmica/efeitos dos fármacos , Masculino , Morfolinas/farmacologia , Traumatismo por Reperfusão Miocárdica/sangue , Traumatismo por Reperfusão Miocárdica/metabolismo , Miocárdio/citologia , Miocárdio/metabolismo , Miocárdio/patologia , Fosfatidilinositol 3-Quinases/química , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Tetraspanina 30/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Função Ventricular Esquerda/fisiologiaRESUMO
Ferroptosis is an iron-dependent regulated necrosis. This study aims to evaluate the contribution of ferroptosis to ischemia or reperfusion injury, and lay a basis for precise therapy of myocardial infarction. The Sprague-Dawley (SD) rat hearts were subjected to ischemia for different duration or the hearts were treated with 1 h-ischemia plus different duration of reperfusion. The myocardial injury was assessed by biochemical assays and hematoxylin & eosin (HE) staining. The ferroptosis was evaluated with the levels of acyl-CoA synthetase long-chain family member 4 (ACSL4), glutathione peroxidase 4 (GPX4), iron, and malondialdehyde. Iron chelator (deferoxamine) was applied to verify the contribution of ferroptosis to ischemia and reperfusion injury. The results showed that ischemic injury (infarction and CK release) was getting worse with the extension of ischemia, but no significant changes in ferroptosis indexes (ACSL4, GPX4, iron, and malondialdehyde) in cardiac tissues were observed. Differently, the levels of ACSL4, iron, and malondialdehyde were gradually elevated with the extension of reperfusion concomitant with a decrease of GPX4 level. In the ischemia-treated rat hearts, no significant changes in myocardial injury were observed in the presence of deferoxamine, while in the ischemia/reperfusion-treated rat hearts, myocardial injury was markedly attenuated in the presence of deferoxamine concomitant with a reduction of ferroptosis. Based on these observations, we conclude that ferroptosis occurs mainly in the phase of myocardial reperfusion but not ischemia. Thus, intervention of ferroptosis exerts beneficial effects on reperfusion injury but not ischemic injury, laying a basis for precise therapy for patients with myocardial infarction.
Assuntos
Ferroptose , Isquemia , Traumatismo por Reperfusão Miocárdica , Animais , Biomarcadores/sangue , Biomarcadores/metabolismo , Coenzima A Ligases/metabolismo , Creatina Quinase/sangue , Desferroxamina/farmacologia , Ferro/metabolismo , Isquemia/metabolismo , Masculino , Malondialdeído/metabolismo , Traumatismo por Reperfusão Miocárdica/sangue , Traumatismo por Reperfusão Miocárdica/metabolismo , Miocárdio/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Ratos Sprague-Dawley , Sideróforos/farmacologiaRESUMO
Blood coagulation is central to myocardial ischemia and reperfusion (IR) injury. Studies on the light elicited circadian rhythm protein Period 2 (PER2) using whole body Per2-/- mice found deficient platelet function and reduced clotting which would be expected to protect from myocardial IR-injury. In contrast, intense light induction of PER2 protected from myocardial IR-injury while Per2 deficiency was detrimental. Based on these conflicting data, we sought to evaluate the role of platelet specific PER2 in coagulation and myocardial ischemia and reperfusion injury. We demonstrated that platelets from mice with tissue-specific deletion of Per2 in the megakaryocyte lineage (Per2loxP/loxP-PF4-CRE) significantly clot faster than platelets from control mice. We further found increases in infarct sizes or plasma troponin levels in Per2loxP/loxP-PF4-CRE mice when compared to controls. As intense light increases PER2 protein in human tissues, we also performed translational studies and tested the effects of intense light therapy on coagulation in healthy human subjects. Our human studies revealed that intense light therapy repressed procoagulant pathways in human plasma samples and significantly reduced the clot rate. Based on these results we conclude that intense light elicited PER2 has an inhibitory function on platelet aggregation in mice. Further, we suggest intense light as a novel therapy to prevent or treat clotting in a clinical setting.
Assuntos
Coagulação Sanguínea/fisiologia , Plaquetas/metabolismo , Isquemia Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Proteínas Circadianas Period/metabolismo , Fototerapia , Animais , Humanos , Luz , Masculino , Camundongos , Isquemia Miocárdica/sangue , Traumatismo por Reperfusão Miocárdica/sangue , Proteínas Circadianas Period/genética , Agregação Plaquetária/fisiologia , ProteômicaRESUMO
AIMS: The purpose of this study was to investigate the protective effects of puerarin and elucidate the underlying mechanisms of puerarin in myocardial ischemia/reperfusion (MI/R) injury. MAIN METHODS: C57BL/6 mice were exposed to puerarin (100 mg/kg) with or without the SIRT1 inhibitor nicotinamide (500 mg/kg) and then subjected to MI/R operation. Myocardial infarct size, serum creatine kinase-MB (CK-MB) activity, apoptotic cell death, and cardiac structure and function were examined to evaluate MI/R injury. RT-PCR and western blotting were used to determine the inflammatory response and inflammasome activation, as well as activation of SIRT1/NF-κB pathway. RESULTS: Puerarin significantly reduced myocardial infarct size, serum CK-MB activity, and apoptotic cell death, and improved cardiac structural damage and dysfunction. Moreover, puerarin notably decreased the mRNA and protein levels of TNF-α, IL-6, and IL-1ß, indicating that puerarin attenuated MI/R-induced inflammation. Furthermore, puerarin markedly decreased the protein levels of Ac-NF-κB, NLRP3, cleaved caspase-1, cleaved IL-1ß, and cleaved IL-18 and increased the protein level of SIRT1. More importantly, the SIRT1 inhibitor nicotinamide prevented these puerarin-induced cardioprotective effects and regulation of the SIRT1/NF-κB pathway, as well as the NLRP3 inflammasome activation. CONCLUSION: Puerarin protected against MI/R injury by inhibiting inflammatory responses probably via the SIRT1/NF-κB pathway, and inhibition of the NLRP3 inflammasome was also involved in puerarin-induced cardioprotective effects. These results suggest that puerarin may be a novel candidate for the treatment of ischemic heart disease.
Assuntos
Cardiotônicos/farmacologia , Inflamação/metabolismo , Isoflavonas/farmacologia , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Animais , Cardiotônicos/administração & dosagem , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacologia , Coração/efeitos dos fármacos , Inflamassomos/antagonistas & inibidores , Inflamassomos/efeitos dos fármacos , Inflamação/etiologia , Masculino , Camundongos Endogâmicos C57BL , Traumatismo por Reperfusão Miocárdica/sangue , Traumatismo por Reperfusão Miocárdica/complicações , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Subunidade p50 de NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Niacinamida/administração & dosagem , Niacinamida/farmacologia , Sirtuína 1/metabolismoRESUMO
INTRODUCTION: Achieving reperfusion immediately after acute myocardial infarction improves outcomes; despite this, patients remain at a high risk for mortality and morbidity at least for the first year after the event. Ischemia-reperfusion injury (IRI) has a complex pathophysiology and plays an important role in myocardial tissue injury, repair, and remodeling. AREAS COVERED: In this review, the authors discuss the various mechanisms and their pharmacological agents currently available for reducing myocardial ischemia-reperfusion injury (IRI). They review important original investigations and trials in various clinical databases for treatments targeting IRI. EXPERT OPINION: Encouraging results observed in many preclinical studies failed to show similar success in attenuating myocardial IRI in large-scale clinical trials. Identification of critical risk factors for IRI and targeting them individually rather than one size fits all approach should be the major focus of future research. Various newer therapies like tocilizumab, anakinra, colchicine, revacept, and therapies targeting the reperfusion injury salvage kinase pathway, survivor activating factor enhancement, mitochondrial pathways, and angiopoietin-like peptide 4 hold promise for the future.