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BACKGROUND: Coronavirus disease 2019 (COVID-19) pneumonitis associated with severe respiratory failure is associated with high mortality. The pathogenesis of COVID-19 is associated with microembolism or microvascular endothelial injuries. Here, we report that syndecan-1 (SDC-1), a component of the endothelial glycocalyx, may be a biomarker of severity classification for COVID-19 related to endothelial injury. METHODS AND ANALYSIS: We analyzed the data of COVID-19 patients for 1 year from February 2020 at Yokohama City University Hospital and Yokohama City University Medical Center Hospital. We selected COVID-19 patients who required admission care, including intensive care, and analyzed the classification of severe and critical COVID-19 retrospectively, using various clinical data and laboratory data with SDC-1 by ELISA. RESULTS: We analyzed clinical and laboratory data with SDC-1 in five severe COVID-19 and ten critical COVID-19 patients. In the two groups, their backgrounds were almost the same. In laboratory data, the LDH, CHE, and CRP levels showed significant differences in each group (P = 0.032, P < 0.0001, and P = 0.007, respectively) with no significant differences in coagulation-related factors (platelet, PT-INR, d-dimer, ISTH score; P = 0.200, 0.277, 0.655, and 0.36, respectively). For the clinical data, the SOFA score was significantly different from admission day to day 14 of admission (p < 0.0001). The SDC-1 levels of critical COVID-19 patients were significantly higher on admission day and all-time course compared with the levels of severe COVID-19 patients (P = 0.009 and P < 0.0001, respectively). CONCLUSIONS: Temporal change of SDC-1 levels closely reflect the severity of COVID-19, therefore, SDC-1 may be a therapeutic target and a biomarker for the severity classification of Covid-19.
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The present study aimed to identify the clinical significance of differences in detection timings of left ventricular reverse remodeling (LVRR) on heart failure (HF) prognosis in patients with idiopathic dilated cardiomyopathy (IDCM). We investigated 207 patients with IDCM who underwent pharmacotherapeutic treatment. LVRR was defined as improvements in both LV ejection fraction ≥10 % and indexed LV end-diastolic dimension (LVEDDi) ≥10 %. Patients were stratified into 3 groups by LVRR timing: patients with LVRR <24 months (Early LVRR), those with LVRR ≥24 months (Delayed LVRR), and those without LVRR during the entire follow-up period (No LVRR). The major endpoint was first detection of composite event including readmission for decompensated HF, major ventricular arrhythmias, or all-cause mortality. LVRR was recognized in 108 patients (52 %): Early LVRR in 83 (40 %), Delayed LVRR in 25 (12 %), and No LVRR in 99 (48 %). The survival rate for the major endpoint was significantly higher for Delayed LVRR than for No LVRR (P = 0.001); there was no significant difference between Early and Delayed LVRR. Among patients without LVRR <24 months (Delayed + No LVRR), receiver operating characteristic curve analysis showed that the area under the curve for improvement in LVEDDi during the first 6 months for predicting subsequent LVRR (Delayed LVRR) [0.822 (95 % confidence interval, 0.740-0.916; P = 0.038)] was greater than that for improvement in LVEF. In conclusion, LVRR was a favorable prognostic indicator in patients with IDCM irrespective of its detection timing. Reduced LVEDDi during the first 6 months was predictive for subsequent LVRR in the later phase.
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Carbazóis/administração & dosagem , Cardiomiopatia Dilatada/fisiopatologia , Insuficiência Cardíaca/etiologia , Propanolaminas/administração & dosagem , Função Ventricular Esquerda/fisiologia , Remodelação Ventricular/efeitos dos fármacos , Antagonistas Adrenérgicos beta/administração & dosagem , Cardiomiopatia Dilatada/complicações , Cardiomiopatia Dilatada/tratamento farmacológico , Carvedilol , Relação Dose-Resposta a Droga , Ecocardiografia , Feminino , Seguimentos , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/prevenção & controle , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Volume Sistólico/fisiologia , Fatores de TempoRESUMO
BACKGROUND: Viral myocarditis follows a fatal course in ≈30% of patients. Interleukin-1 receptor-associated kinase 4 (IRAK4), a major nodal signal transducer in innate immunity, can play a pivotal role in host inflammatory response. We sought to determine how IRAK4 modulates inflammation and outcome in a mouse model of viral myocarditis. METHODS AND RESULTS: Myocarditis was induced after intraperitoneal inoculation of coxsackievirus B3 into C57Bl/6 IRAK4-deficient mice and their littermate controls. Mortality and viral proliferation were markedly reduced in IRAK4(-/-) mice compared with their IRAK4(+/+) littermates. Disease resistance of IRAK4(-/-) mice paralleled increased amounts of protective heart-infiltrating CCR5(+) monocytes/macrophages and enhanced interferon-α and interferon-γ production 2 days after infection. Competitive bone marrow chimera demonstrated that intact IRAK4 function inhibited heart-specific migration of bone marrow-derived CCR5(+) cells. Mechanistically, lack of IRAK4 resulted in interferon regulatory factor 5 homodimerization via reduced melanoma differentiation-associated protein 5 degradation and enhanced Stat1 and Stat5 phosphorylation. Consequently, antiviral interferon-α and interferon-γ production, as well as CCR5(+) cell recruitment, increased, whereas the overall proinflammatory response was drastically reduced in the absence of IRAK4. CONCLUSIONS: Innate immunity signal transducer IRAK4 exacerbates viral myocarditis through inhibition of interferon production and reduced mobilization of protective CCR5(+) monocytes/macrophages to the heart. The combination of IRAK4 inhibitors and antiviral adjuvants may become an attractive therapeutic approach against viral myocarditis in the future.
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Antígeno CD11b/análise , Infecções por Coxsackievirus/imunologia , Interferons/biossíntese , Quinases Associadas a Receptores de Interleucina-1/fisiologia , Monócitos/fisiologia , Miocardite/imunologia , Receptores CCR5/análise , Transferência Adotiva , Animais , Movimento Celular/fisiologia , Quimiocina CCL5/deficiência , Quimiocina CCL5/fisiologia , Infecções por Coxsackievirus/fisiopatologia , Infecções por Coxsackievirus/virologia , RNA Helicases DEAD-box/metabolismo , Dimerização , Resistência à Doença , Enterovirus Humano B/fisiologia , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/fisiopatologia , Fatores Reguladores de Interferon/química , Fatores Reguladores de Interferon/metabolismo , Helicase IFIH1 Induzida por Interferon , Quinases Associadas a Receptores de Interleucina-1/deficiência , Quinases Associadas a Receptores de Interleucina-1/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miocardite/fisiopatologia , Miocardite/virologia , Doenças da Imunodeficiência Primária , Processamento de Proteína Pós-Traducional , Quimera por Radiação , Receptores CCR5/deficiência , Receptores CCR5/fisiologia , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT5/metabolismo , Replicação ViralRESUMO
c-Cbl-associated protein (CAP), also called Sorbs1 or ponsin, has been described as an essential adapter protein in the insulin-signalling pathway. Here, we describe for the first time a unique protective role for CAP in viral myocarditis. Mortality and heart failure development were increased in CAP(-/-) mice compared to CAP(+/+) littermates after Coxsackievirus (CVB3) infection. Mechanistically, CAP protected from tissue apoptosis because of reduced CD8(+) T and natural killer cell cytotoxicity. Despite reduced cytotoxic elimination of CVB3-infected cells in CAP(+/+) hearts, however, CAP enhanced interferon regulatory factor 3 (IRF3)-dependent antiviral type I interferon production and decreased viral proliferation in vitro by binding to the cytoplasmic RIG-I-like receptor melanoma differentiation-associated protein 5 (MDA5). Taken together, these findings reveal a novel modulatory role for CAP in the heart as a key protein stabilizing antiviral type I interferon production, while protecting from excessive cytotoxic responses. Our study will help to define future strategies to develop treatments to limit detrimental responses during viral heart inflammation.
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Apoptose , Infecções por Coxsackievirus/prevenção & controle , Enterovirus Humano B/imunologia , Interferon Tipo I/metabolismo , Proteínas dos Microfilamentos/metabolismo , Miocardite/prevenção & controle , Miocárdio/metabolismo , Animais , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/virologia , Células Cultivadas , Infecções por Coxsackievirus/genética , Infecções por Coxsackievirus/imunologia , Infecções por Coxsackievirus/metabolismo , Infecções por Coxsackievirus/patologia , Infecções por Coxsackievirus/virologia , RNA Helicases DEAD-box/metabolismo , Modelos Animais de Doenças , Enterovirus Humano B/genética , Enterovirus Humano B/crescimento & desenvolvimento , Enterovirus Humano B/patogenicidade , Fator Regulador 3 de Interferon/metabolismo , Helicase IFIH1 Induzida por Interferon , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Células Matadoras Naturais/virologia , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas dos Microfilamentos/deficiência , Proteínas dos Microfilamentos/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Miocardite/genética , Miocardite/imunologia , Miocardite/metabolismo , Miocardite/patologia , Miocardite/virologia , Miocárdio/imunologia , Miocárdio/patologia , Fatores de Tempo , Replicação ViralRESUMO
Although an increased heart rate (HR) is a strong predictor of poor prognosis in cases of chronic heart failure (HF), the clinical value of HR as a predictor in acute decompensated HF (ADHF) is unclear. Seventy-eight patients with nonischemic dilated cardiomyopathy (NIDCM) with sinus rhythm who were first hospitalized for ADHF from 2002 to 2010 were retrospectively investigated after exclusion of patients with tachycardia-induced cardiomyopathy. The patients were divided into two groups stratified by HR on admission with a median value of 113 beats/min (Group H with HR ≥ 113 beats/min; Group L with HR < 113 beats/min). Despite similar backgrounds, including pharmacotherapy for HF, HR changes responding to titration of ß-blocker (BB) therapy and myocardial interstitial fibrosis, left ventricular (LV) ejection fractions improved more significantly 1 year later in Group H than in Group L (57 % ± 11 % vs. 46 % ± 12 %, P < 0.001). Cardiac event-free survival rates were also significantly improved in Group H (P = 0.038). Multiple regression analysis revealed that only the peak HR on admission was an independent predictor of LV reverse remodeling (LVRR) 1 year later (ß = 0.396, P = 0.005). High HR on first admission for ADHF is a strong predictor of LVRR, with a better prognosis in the event of NIDCM in response to optimal pharmacotherapy, independent of pre-existing myocardial damage and subsequent HR reduction by BB therapy.
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Cardiomiopatia Dilatada/tratamento farmacológico , Fármacos Cardiovasculares/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Frequência Cardíaca/efeitos dos fármacos , Isquemia Miocárdica/complicações , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Adulto , Idoso , Cardiomiopatia Dilatada/diagnóstico , Cardiomiopatia Dilatada/etiologia , Cardiomiopatia Dilatada/fisiopatologia , Intervalo Livre de Doença , Feminino , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Isquemia Miocárdica/diagnóstico , Admissão do Paciente , Estudos Retrospectivos , Fatores de Risco , Volume Sistólico/efeitos dos fármacos , Fatores de Tempo , Resultado do TratamentoRESUMO
Endomyocardial biopsy (EMB) and late gadolinium enhancement cardiovascular magnetic resonance (LGE-CMR) imaging performed at baseline are both used to evaluate the extent of myocardial fibrosis. However, no study has directly compared the effectiveness of these diagnostic tools in the prediction of left ventricular reverse remodeling (LVRR) and prognosis in response to therapy in patients with idiopathic dilated cardiomyopathy (IDCM). Seventy-five patients with newly diagnosed IDCM who were undergoing optimal therapy were assessed at baseline using LGE-CMR imaging and EMB; the former measured LGE area and the latter measured collagen volume fraction (CVF) as possible predictive indices of LVRR and cardiac event-free survival. Among all the baseline primary candidate factors with P < 0.2 as per univariate analysis, multivariate analysis indicated that only LGE area was an independent predictor of subsequent LVRR (ß = 0.44; 95 % confidence interval (CI) 0.87-2.53; P < 0.001), as indicated by decreasing left ventricular end-systolic volume index over the 1-year follow-up. Kaplan-Meier curves indicated significantly lower cardiac event-free survival rates in patients with LGE at baseline than in patients without (P < 0.01). By contrast, there was no significant difference in prognosis between patients with CVF values above (severe fibrosis) and below (mild fibrosis) the median of 4.9 %. Cox proportional hazard analysis showed that LGE area was an independent predictor of subsequent cardiac events (hazard ratio 1.06; 95 % CI 1.02-1.10; P ≤ 0.01). The degree of myocardial fibrosis estimated by baseline LGE-CMR imaging, but not that estimated by baseline EMB, can predict LVRR and cardiac event-free survival in response to therapy in patients with newly diagnosed IDCM.
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Cardiomiopatia Dilatada , Endocárdio/patologia , Gadolínio DTPA , Miocárdio/patologia , Remodelação Ventricular , Adulto , Biópsia , Cardiomiopatia Dilatada/complicações , Cardiomiopatia Dilatada/terapia , Pesquisa Comparativa da Efetividade , Meios de Contraste , Intervalo Livre de Doença , Feminino , Fibrose/diagnóstico , Fibrose/etiologia , Humanos , Imagem Cinética por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Disfunção Ventricular Esquerda/diagnóstico , Disfunção Ventricular Esquerda/etiologiaRESUMO
The appropriate indication for, management of and limitations to extracorporeal life support (ECLS) and the timing of a switch to a ventricular assist device (VAD) remain controversial issues in patients with acute myocardial infarction (AMI) complicated with cardiogenic shock or cardiopulmonary arrest. To evaluate and discuss these issues, we studied patients with AMI treated with ECLS and compared deceased and discharged patients. Thirty-eight patients with AMI who needed ECLS [35 men (92.1 %), aged 59.9 ± 13.5 years] were enrolled in this study. Of these 38 patients, 34 subsequently underwent percutaneous coronary intervention (PCI), and four subsequently received coronary artery bypass grafting (CABG). Fourteen patients (36.8 %) were discharged from the hospital. The outcome was not favorable for those patients with deteriorating low output syndrome (LOS) and the development of leg ischemia, hemolysis and multiple organ failure during ECLS. Levels of creatine kinase, creatine kinase-MB (CK-MB), lactate dehydrogenase, serum creatinine (Cr) and amylase after the patient had been put on ECLS and fluctuation of the cardiac index, blood pressure, arterial blood gas analysis and CK-MB and Cr levels during ECLS were indicators to switch from the ECLS to VAD. In the case of patients with no complication associated with ECLS, 4.6-5.6 days after initiation of ECLS was assumed to be the threshold to decide whether to switch from ECLS to VAD. Patients with AMI who suddenly developed refractory pulseless ventricular tachycardia or ventricular fibrillation without deteriorating LOS and who underwent successful PCI or CABG, and who prevented the complications associated with ECLS, showed a high probability of recovering with ECLS.
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Suporte Vital Cardíaco Avançado , Circulação Extracorpórea , Parada Cardíaca/terapia , Coração Auxiliar , Infarto do Miocárdio/terapia , Idoso , Biomarcadores , Feminino , Parada Cardíaca/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/mortalidade , Estudos RetrospectivosRESUMO
Optimal timing for intubating patients with coronavirus disease 2019 (COVID-19) has been debated throughout the pandemic. Early use of high-flow nasal cannula (HFNC) can help reduce the need for intubation, but delay can result in poorer outcomes. This study examines trends in laboratory parameters and serum severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA levels of patients with COVID-19 in relation to HFNC failure. Patients requiring HFNC within three days of hospitalization between July 1 and September 30, 2021 were enrolled. The primary outcome was HFNC failure (early failure ≤Day 3; late failure ≥Day 4), defined as transfer to intensive care just before/after intubation or in-hospital death. We examined changes in laboratory markers and SARS-CoV2-RNAemia on Days 1, 4, and 7, together with demographic data, oxygenation status, and therapeutic agents. We conducted a univariate logistic regression with the explanatory variables defined as 10% change rate in each laboratory marker from Day 1 to 4. We utilized the log-rank test to assess the differences in HFNC failure rates, stratified based on the presence of SARS-CoV2 RNAemia. Among 122 patients, 17 (13.9%) experienced HFNC failure (early: n = 6, late: n = 11). Seventy-five patients (61.5%) showed an initial SpO2/FiO2 ratio ≤243, equivalent to PaO2/FiO2 ratio ≤200, and the initial SpO2/FiO2 ratio was significantly lower in the failure group (184 vs. 218, p = 0.018). Among the laboratory markers, a 10% increase from Day 1 to 4 of lactate dehydrogenase (LDH) and interleukin (IL)-6 was associated with late failure (Odds ratio [OR]: 1.42, 95% confidence interval [CI]: 1.09-1.89 and OR: 1.04, 95%CI: 1.00-1.19, respectively). Furthermore, in patients with persistent RNAemia on Day 4 or 7, the risk of late HFNC failure was significantly higher (Log-rank test, p<0.01). In conclusion, upward trends in LDH and IL-6 levels and the persistent RNAemia even after treatment were associated with HFNC failure.
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Biomarcadores , COVID-19 , Oxigenoterapia , RNA Viral , SARS-CoV-2 , Humanos , COVID-19/terapia , COVID-19/sangue , COVID-19/virologia , Masculino , Feminino , Biomarcadores/sangue , Pessoa de Meia-Idade , RNA Viral/sangue , Oxigenoterapia/métodos , Idoso , L-Lactato Desidrogenase/sangue , Falha de Tratamento , Resultado do Tratamento , CânulaRESUMO
INTRODUCTION: Cardiac remodeling is defined as cellular interstitial changes that lead dysfunction of the heart after injury. Placental growth factor (PlGF), a member of the VEGF family, has been reported to regulate cardiac hypertrophy in hemodynamic state. We therefore analyze the function of PlGF during cardiac remodeling using cardiac cells and fibroblasts, under Angiotensin II (AngII) stimulation. METHODS: PlGF overexpressed mouse embryonic fibroblasts derived from C57BL/6 mice, were made by deficient retrovirus vector, designated as C57/PlGF. Only retrovirus vector introduced C57 cells (C57/EV) were used as control. After AngII stimulation, wound scratching assay and MTT proliferation assay with or without p38 MAPK inhibitor, SB205580 were performed in retrovirally-introduced C57 cells. Reactive oxygen species (ROS) production, NF-kB activation, IL-6 and TNF-α production were also measured. Then we assessed AngII-induced cell proliferation of mouse cardiac fibroblasts (CFs) and rat primary cardiomyocytes incubating with C57/PlGF conditioned-medium. RESULTS: The PlGF production in C57/PlGF were confirmed by ELISA (1093.48 ± 3.5 pg/ml, ±SE). AngII-induced cell migration, proliferation and H2O2 production were increased in C57/PlGF compared with C57/EV. SB205580 inhibited the AngII-induced cell proliferation in C57/PlGF. In C57/PlGF cells, NF-kB activation was higher, followed by up-regulation of IL-6 and TNF-α production. CFs and cardiomyocytes proliferation increased when stimulated with C57/PlGF conditioned-medium. DISCUSSION: The activation of fibroblast is stimulated by PlGF signaling via p38 MAPK/NF-kB pathway accompanied by elevation of ROS and inflammatory response. Furthermore, these signals stimulate the activation of CFs and cardiomyocytes, indicating that high circulating level of PlGF have a potential to regulate cardiac remodeling.
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Acute respiratory distress syndrome (ARDS) with COVID-19 is aggravated by hyperinflammatory responses even after the peak of the viral load has passed; however, its underlying mechanisms remain unclear. In the present study, analysis of the alveolar tissue injury markers and epithelial cell death markers in patients with COVID-19 revealed that COVID-19-induced ARDS was characterized by alveolar epithelial necrosis at an early disease stage. Serum levels of HMGB-1, one of the DAMPs released from necrotic cells, were also significantly elevated in these patients. Further analysis using a mouse model mimicking COVID-19-induced ARDS showed that the alveolar epithelial cell necrosis involved two forms of programmed necrosis, namely necroptosis, and pyroptosis. Finally, the neutralization of HMGB-1 attenuated alveolar tissue injury in the mouse model. Collectively, necrosis, including necroptosis and pyroptosis, is the predominant form of alveolar epithelial cell death at an early disease stage and subsequent release of DAMPs is a potential driver of COVID-19-induced ARDS.
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The increasing requirement of mechanical ventilation (MV) due to the novel coronavirus disease (COVID-19) is still a global threat. The aim of this study is to identify markers that can easily stratify the impending use of MV in the emergency room (ER). A total of 106 patients with COVID-19 requiring oxygen support were enrolled. Fifty-nine patients were provided MV 0.5 h (interquartile range: 0.3 to 1.4) post-admission. Clinical and laboratory data before intubation were collected. Using a multivariate logistic regression model, we identified four markers associated with the impending use of MV, including the ratio of peripheral blood oxygen saturation to fraction of inspired oxygen (SpO2/FiO2 ratio), alanine aminotransferase, blood glucose (BG), and lymphocyte counts. Among these markers, SpO2/FiO2 ratio and BG, which can be measured easily and immediately, showed higher accuracy (AUC: 0.88) than SpO2/FiO2 ratio alone (AUC: 0.84), despite no significant difference (DeLong test: P = 0.591). Moreover, even in patients without severe respiratory failure (SpO2/FiO2 ratio > 300), BG (> 138 mg/dL) was predictive of MV use. Measuring BG and SpO2/FiO2 ratio may be a simple and versatile new strategy to accurately identify ER patients with COVID-19 at high risk for the imminent need of MV.
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Glicemia , COVID-19 , Humanos , Oximetria , Oxigênio , Serviço Hospitalar de EmergênciaRESUMO
Cardioprotective effect of prostaglandin-E2 receptor-4 (EP4) stimulation on the ischemic heart has been demonstrated. Its effect on the heart affected by myocarditis, however, remains uncertain. In this study, we investigated therapeutic effect of EP4 stimulant using a mouse model of autoimmune myocarditis (EAM) that progresses to dilated cardiomyopathy (DCM). EP4 was present in the hearts of EAM mice. Treatment with EP4 agonist (ONO-0260164: 20 mg/kg/day) improved an impaired left ventricular (LV) contractility and reduction of blood pressure on day 21, a peak myocardial inflammation. Alternatively, DCM phenotype, characterized by LV dilation, LV systolic dysfunction, and collagen deposition, was observed on day 56, along with activation of matrix metalloproteinase (MMP)-2 critical for myocardial extracellular matrix disruption, indicating an important molecular mechanism underlying adverse ventricular remodeling after myocarditis. Continued treatment with ONO-0260164 alleviated the DCM phenotype, but this effect was counteracted by its combination with a EP4 antagonist. Moreover, ONO-0260164 inhibited in vivo proteolytic activity of MMP-2 in association with up-regulation of tissue inhibitor of metalloproteinase (TIMP)-3. EP4 stimulant may be a promising and novel therapeutic agent that rescues cardiac malfunction during myocarditis and prevents adverse ventricular remodeling after myocarditis by promoting the TIMP-3/MMP-2 axis.
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Miocardite/tratamento farmacológico , Receptores de Prostaglandina E Subtipo EP4/agonistas , Remodelação Ventricular/efeitos dos fármacos , Animais , Cardiomiopatia Dilatada/tratamento farmacológico , Modelos Animais de Doenças , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Camundongos Endogâmicos BALB C , Miocardite/imunologia , Receptores de Prostaglandina E Subtipo EP4/antagonistas & inibidores , Inibidor Tecidual de Metaloproteinase-3/metabolismoRESUMO
BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic rapidly increases the use of mechanical ventilation (MV). Such cases further require extracorporeal membrane oxygenation (ECMO) and have a high mortality. OBJECTIVE: We aimed to identify prognostic biomarkers pathophysiologically reflecting future deterioration of COVID-19. METHODS: Clinical, laboratory, and outcome data were collected from 102 patients with moderate to severe COVID-19. Interleukin (IL)-6 level and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA copy number in plasma were assessed with ELISA kit and quantitative PCR. RESULTS: Twelve patients died or required ECMO owing to acute respiratory distress syndrome despite the use of MV. Among various variables, a ratio of oxygen saturation to fraction of inspired oxygen (SpO2/FiO2), IL-6, and SARS-CoV-2 RNA on admission before intubation were strongly predictive of fatal outcomes after the MV use. Moreover, among these variables, combining SpO2/FiO2, IL-6, and SARS-CoV-2 RNA showed the highest accuracy (area under the curve: 0.934). In patients with low SpO2/FiO2 (< 261), fatal event-rate after the MV use at the 30-day was significantly higher in patients with high IL-6 (> 49 pg/mL) and SARS-CoV-2 RNAaemia (> 1.5 copies/µL) compared to those with high IL-6 or RNAaemia or without high IL-6 and RNAaemia (88% vs. 22% or 8%, log-rank test P = 0.0097 or P < 0.0001, respectively). CONCLUSIONS: Combining SpO2/FiO2 with high IL-6 and SARS-CoV-2 RNAaemia which reflect hyperinflammation and viral overload allows accurately and before intubation identifying COVID-19 patients at high risk for ECMO use or in-hospital death despite the use of MV.
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COVID-19/mortalidade , Interleucina-6/sangue , RNA Viral/metabolismo , SARS-CoV-2/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , COVID-19/patologia , COVID-19/virologia , Feminino , Mortalidade Hospitalar , Humanos , Masculino , Pessoa de Meia-Idade , Consumo de Oxigênio , Prognóstico , Estudos Prospectivos , Curva ROC , Respiração Artificial , SARS-CoV-2/isolamento & purificação , Carga ViralRESUMO
The COVID-19 pandemic is an unprecedented threat to humanity that has provoked global health concerns. Since the etiopathogenesis of this illness is not fully characterized, the prognostic factors enabling treatment decisions have not been well documented. Accurately predicting the progression of the disease would aid in appropriate patient categorization and thus help determine the best treatment option. Here, we have introduced a proteomic approach utilizing data-independent acquisition mass spectrometry (DIA-MS) to identify the serum proteins that are closely associated with COVID-19 prognosis. Twenty-seven proteins were differentially expressed between severely ill COVID-19 patients with an adverse or favorable prognosis. Ingenuity Pathway Analysis revealed that 15 of the 27 proteins might be regulated by cytokine signaling relevant to interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF), and their differential expression was implicated in the systemic inflammatory response and in cardiovascular disorders. We further evaluated practical predictors of the clinical prognosis of severe COVID-19 patients. Subsequent ELISA assays revealed that CHI3L1 and IGFALS may serve as highly sensitive prognostic markers. Our findings can help formulate a diagnostic approach for accurately identifying COVID-19 patients with severe disease and for providing appropriate treatment based on their predicted prognosis.
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Biomarcadores/sangue , Teste Sorológico para COVID-19/métodos , COVID-19/sangue , Perfilação da Expressão Gênica , Proteômica/métodos , Proteína 1 Semelhante à Quitinase-3/metabolismo , Ensaio de Imunoadsorção Enzimática , Cromatografia Gasosa-Espectrometria de Massas , Regulação da Expressão Gênica , Humanos , Inflamação , Interleucina-1beta/biossíntese , Interleucina-6/biossíntese , Prognóstico , SARS-CoV-2 , Fator de Necrose Tumoral alfa/biossíntese , VirosesRESUMO
BACKGROUND: The therapeutic potential of beta2-adrenergic receptor (AR) agonists in the treatment of autoimmune diseases has been reported. However, the role of these drugs in the myocardial structure-induced autoimmune process, which is thought to play a crucial role in the progression of myocarditis to subsequent complications, has not been elucidated. METHODS AND RESULTS: Experimental autoimmune myocarditis (EAM) was induced in rats by immunization with cardiac myosin. On daily administration from day 0 after immunization, the beta2-selective AR agonists formoterol or salbutamol ameliorated EAM on day 21 and increased myocardial interleukin-10/interferon-gamma mRNA levels. Propranolol, a nonselective beta-AR antagonist, aggravated EAM on day 21 and decreased mRNA levels, whereas metoprolol, a beta1-selective AR antagonist, showed no effect. These results were reflected in vivo by the proliferation of cardiac myosin-primed lymph node cells from drug-treated rats. In vitro addition of beta2-selective AR agonists inhibited the activation of cardiac myosin fragment-specific myocarditogenic T lymphocytes, and this effect was reversed by ICI118,551, a beta2-selective AR antagonist. Furthermore, treatment with 2 different beta2-selective AR agonists starting on day 14 also ameliorated EAM on day 21. CONCLUSIONS: beta2-AR stimulation suppressed the development of EAM by inhibiting cardiac myosin-specific T-lymphocyte activation in lymphoid organs and by shifting the imbalance in Th1/Th2 cytokine toward Th2 cytokine. Furthermore, it also ameliorated established myocardial inflammation. beta2-AR-stimulating agents may represent important immunomodulators of the cardiac myosin-induced autoimmune process and have potential as a new therapy for myocarditis.
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Agonistas Adrenérgicos beta/uso terapêutico , Doenças Autoimunes/prevenção & controle , Etanolaminas/uso terapêutico , Miocardite/imunologia , Miocardite/prevenção & controle , Propranolol/uso terapêutico , Animais , Primers do DNA , Modelos Animais de Doenças , Feminino , Fumarato de Formoterol , Regulação da Expressão Gênica/efeitos dos fármacos , Interferon gama/genética , Interleucina-10/genética , Ratos , Ratos Endogâmicos Lew , Reação em Cadeia da Polimerase Via Transcriptase ReversaAssuntos
Doenças Cardiovasculares/induzido quimicamente , Inibidores da Angiogênese/efeitos adversos , Antraciclinas/efeitos adversos , Antineoplásicos/efeitos adversos , Doenças Cardiovasculares/prevenção & controle , Humanos , Hipertensão/induzido quimicamente , Inibidores de Proteínas Quinases/efeitos adversos , Psicotrópicos/efeitos adversos , Receptor ErbB-2/antagonistas & inibidores , Trombose/induzido quimicamente , Torsades de Pointes/induzido quimicamenteAssuntos
COVID-19 , Biomarcadores , Colinesterases , Humanos , Fígado , SARS-CoV-2 , Índice de Gravidade de DoençaRESUMO
OBJECTIVES: We assessed the significance of serum cytokine levels in patients with fulminant myocarditis. BACKGROUND: Although many investigations have demonstrated the crucial role of cytokines in the development of myocarditis, it remains uncertain whether serum levels of cytokines enable one to predict the prognosis of human myocarditis, especially concerning cardiogenic shock (CS) requiring a mechanical cardiopulmonary support system (MCSS). METHODS: We studied 22 consecutive patients with fulminant myocarditis and compared them with 15 patients with acute myocardial infarction (AMI) requiring MCSS. The patients with myocarditis were classified into three groups: eight patients with CS requiring MCSS on admission (group 1); six patients who unexpectedly lapsed into CS requiring MCSS more than two days after catecholamine had been initiated (group 2); and eight patients without MCSS (group 3). Furthermore, 14 patients with myocarditis requiring MCSS were divided into a fatal group (n = 5) and a survival group (n = 9). Biochemical markers, including serum cytokine levels and hemodynamic variables on admission, were analyzed. RESULTS: Serum levels of interleukin (IL)-10 and tumor necrosis factor-alpha, but not other cytokines, were significantly higher in myocarditis than in AMI. Only serum levels of IL-10 were significantly higher in group 1 and 2 than in group 3 (49.1 +/- 37.5/20.7 +/- 17.6 pg/ml vs. 2.4 +/- 1.1 pg/ml; p = 0.0008/0.0012). Serum IL-10 levels were also significantly higher in the fatal group than in the survival group with myocarditis (74.0 +/- 27.0 pg/ml vs. 16.4 +/- 8.8 pg/ml; p = 0.003). CONCLUSIONS: Serum IL-10 levels on admission enabled one to predict subsequent CS requiring MCSS and mortality of fulminant myocarditis patients.