Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.418
Filtrar
1.
Yonsei Med J ; 62(2): 129-136, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33527792

RESUMO

PURPOSE: Acute decompensated heart failure (ADHF) caused by ischemic heart disease is associated with higher mortality and requires immediate diagnosis. Recently, novel methods to diagnose non-ST elevation myocardial infarction (NSTEMI) using high-sensitivity cardiac troponin have been applied. We compared the clinical utility of high-sensitivity troponin I (hS-TnI), delta troponin I, and other traditional methods to diagnose NSTEMI in patients with ADHF. MATERIALS AND METHODS: This retrospective cross-sectional study was conducted to analyze patients with ADHF who underwent hS-TnI evaluation of 0-2-h protocol in our emergency department. Patients were grouped according to a diagnosis of NSTEMI. RESULTS: A total of 524 ADHF [ADHF with NSTEMI, n=109 (20.8%)] patients were enrolled in this analysis. The mean values of hS-TnI (ng/mL) in the ADHF with and without NSTEMI groups were 2.44±5.60 and 0.25±0.91, respectively. Multivariable analysis revealed that regional wall-motion abnormality, T-wave inversion/hyperacute T wave, and initial and delta hS-TnI were predictive factors for NSTEMI. Laboratory values related to cardiac biomarkers, including hS-TnI [odds ratio (OR) (95% confidence interval, CI): 2.18], and the delta hS-TnI [OR (95% CI): 1.55] were significant predictors of NSTEMI. Moreover, receiver operating characteristic analysis showed that the areas under receiver operating characteristic curves for electrocardiographic abnormalities, initial hS-TnI, and delta hS-TnI were 0.794, 0.802, and 0.773, respectively. CONCLUSION: For diagnosis of suspected NSTEMI in patients with ADHF, initial hS-TnI assay has similar predictive value as ischemic changes on electrocardiogram and superior predictive value than delta hS-TnI calculated by the 0-2-h protocol.


Assuntos
Bioensaio , Insuficiência Cardíaca/complicações , Infarto do Miocárdio/complicações , Infarto do Miocárdio/diagnóstico , Troponina I/metabolismo , Idoso , Biomarcadores , Estudos Transversais , Diagnóstico Diferencial , Eletrocardiografia , Serviço Hospitalar de Emergência , Feminino , Insuficiência Cardíaca/diagnóstico por imagem , Humanos , Modelos Logísticos , Masculino , Análise Multivariada , Infarto do Miocárdio/diagnóstico por imagem , Peptídeo Natriurético Encefálico/metabolismo , Curva ROC , Estudos Retrospectivos
2.
Int Heart J ; 62(1): 148-152, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33518653

RESUMO

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is erupting and spreading globally. Cardiovascular complications secondary to the infection have caught notice. This study aims to delineate the relationship of cardiac biomarkers and outcomes in severe cases of corona virus disease 2019 (COVID-19). One hundred forty-eight critically ill adult patients with COVID-19 were enrolled. From these patients, the demographic data, symptoms, cardiac biomarkers, treatments, and clinical outcomes were collected. Data were compared between survivors and non-survivors. Four patients in the non-survivor group were selected, and their cardiac biomarkers were collected and analyzed. Among the 148 patients, the incidence of cardiovascular complications was 19 (12.8%). Five of them were survivors (5.2%), and 14 of them were non-survivors (26.9%). Compared with the survivors, the non-survivors had higher levels of high-sensitivity cardiac troponin I, creatine kinase isoenzyme-MB, myoglobin, and N-terminal pro-brain natriuretic peptide (P < 0.05). The occurrence of cardiovascular events began at 11-15 days after the onset of the disease and reached a peak at 14-20 days. COVID-19 not only is a respiratory disease but also causes damage to the cardiovascular system. Cardiac biomarkers have the potential for early warning and prognostic evaluation in patients with COVID-19. It is recommended that cardiac biomarker monitoring in patients with COVID-19 should be initiated at least from the 11th day of the disease course.


Assuntos
Biomarcadores/metabolismo , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/metabolismo , Adulto , Idoso , Fator Natriurético Atrial/metabolismo , /epidemiologia , Doenças Cardiovasculares/epidemiologia , Estudos de Casos e Controles , China/epidemiologia , Creatina Quinase Forma MB/metabolismo , Estado Terminal/mortalidade , Estado Terminal/enfermagem , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Prognóstico , Precursores de Proteínas/metabolismo , Taxa de Sobrevida , Sobreviventes/estatística & dados numéricos , Troponina I/metabolismo
3.
Metabolism ; 114: 154400, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33058853

RESUMO

OBJECTIVE: Dyslipidaemia is a major risk factor for myocardial infarction that is known to correlate with atherosclerosis in the coronary arteries. We sought to clarify whether metabolic alterations induced by dyslipidaemia in cardiomyocytes collectively constitute an alternative pathway that escalates myocardial injury. METHODS: Dyslipidaemic apolipoprotein E and low-density lipoprotein receptor (ApoE/LDLR) double knockout (ApoE-/-/LDLR-/-) and wild-type C57BL/6 (WT) mice aged six months old were studied. Cardiac injury under reduced oxygen supply was evaluated by 5 min exposure to 5% oxygen in the breathing air under electrocardiogram (ECG) recording and with the assessment of troponin I release. To address the mechanisms LC/MS was used to analyse the cardiac proteome pattern or in vivo metabolism of stable isotope-labelled substrates and HPLC was applied to measure concentrations of cardiac high-energy phosphates. Furthermore, the effect of blocking fatty acid use with ranolazine on the substrate preference and cardiac hypoxic damage was studied in ApoE-/-/LDLR-/- mice. RESULTS: Hypoxia induced profound changes in ECG ST-segment and troponin I leakage in ApoE-/-/LDLR-/- mice but not in WT mice. The evaluation of the cardiac proteomic pattern revealed that ApoE-/-/LDLR-/- as compared with WT mice were characterised by coordinated increased expression of mitochondrial proteins, including enzymes of fatty acids' and branched-chain amino acids' oxidation, accompanied by decreased expression levels of glycolytic enzymes. These findings correlated with in vivo analysis, revealing a reduction in the entry of glucose and enhanced entry of leucine into the cardiac Krebs cycle, with the cardiac high-energy phosphates pool maintained. These changes were accompanied by the activation of molecular targets controlling mitochondrial metabolism. Ranolazine reversed the oxidative metabolic shift in ApoE-/-/LDLR-/- mice and reduced cardiac damage induced by hypoxia. CONCLUSIONS: We suggest a novel mechanism for myocardial injury in dyslipidaemia that is consequent to an increased reliance on oxidative metabolism in the heart. The alterations in the metabolic pattern that we identified constitute an adaptive mechanism that facilitates maintenance of metabolic equilibrium and cardiac function under normoxia. However, this adaptation could account for myocardial injury even in a mild reduction of oxygen supply.


Assuntos
Aterosclerose/metabolismo , Dislipidemias/metabolismo , Metabolismo Energético/fisiologia , Infarto do Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Animais , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Doença da Artéria Coronariana/metabolismo , Eletrocardiografia , Camundongos , Camundongos Knockout , Receptores de LDL/genética , Receptores de LDL/metabolismo , Troponina I/metabolismo
4.
Cardiol Rev ; 29(1): 39-42, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33136582

RESUMO

Patients older than 65 years hospitalized with COVID-19 have higher rates of intensive care unit admission and death when compared with younger patients. Cardiovascular conditions associated with COVID-19 include myocardial injury, acute myocarditis, cardiac arrhythmias, cardiomyopathies, cardiogenic shock, thromboembolic disease, and cardiac arrest. Few studies have described the clinical course of those at the upper extreme of age. We characterize the clinical course and outcomes of 73 patients with 80 years of age or older hospitalized at an academic center between March 15 and May 13, 2020. These patients had multiple comorbidities and often presented with atypical clinical findings such as altered sensorium, generalized weakness and falls. Cardiovascular manifestations observed at the time of presentation included new arrhythmia in 7/73 (10%), stroke/intracranial hemorrhage in 5/73 (7%), and elevated troponin in 27/58 (47%). During hospitalization, 38% of all patients required intensive care, 13% developed a need for renal replacement therapy, and 32% required vasopressor support. All-cause mortality was 47% and was highest in patients who were ever in intensive care (71%), required mechanical ventilation (83%), or vasopressors (91%), or developed a need for renal replacement therapy (100%). Patients older than 80 years old with COVID-19 have multiple unique risk factors which can be associated with increased cardiovascular involvement and death.


Assuntos
Lesão Renal Aguda/terapia , Mortalidade Hospitalar , Terapia de Substituição Renal/estatística & dados numéricos , Respiração Artificial/estatística & dados numéricos , Vasoconstritores/uso terapêutico , Centros Médicos Acadêmicos , Acidentes por Quedas , Lesão Renal Aguda/etiologia , Idoso de 80 Anos ou mais , Arritmias Cardíacas/etiologia , Arritmias Cardíacas/fisiopatologia , Aspartato Aminotransferases/metabolismo , Proteína C-Reativa/metabolismo , /metabolismo , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/fisiopatologia , Causas de Morte , Transtornos da Consciência/fisiopatologia , Dispneia/fisiopatologia , Feminino , Ferritinas/metabolismo , Febre/fisiopatologia , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Hospitalização , Humanos , Hipóxia/fisiopatologia , Hipóxia/terapia , Vida Independente , Unidades de Terapia Intensiva/estatística & dados numéricos , Hemorragias Intracranianas/etiologia , Hemorragias Intracranianas/fisiopatologia , Contagem de Leucócitos , Hepatopatias/etiologia , Hepatopatias/metabolismo , Contagem de Linfócitos , Masculino , Debilidade Muscular/fisiopatologia , Peptídeo Natriurético Encefálico/metabolismo , Casas de Saúde , Oxigenoterapia , Pró-Calcitonina/metabolismo , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/fisiopatologia , Troponina I/metabolismo
5.
J Korean Med Sci ; 35(39): e349, 2020 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-33045772

RESUMO

BACKGROUNDS: The severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) has spread worldwide. Cardiac injury after SARS-CoV-2 infection is a major concern. The present study investigated impact of the biomarkers indicating cardiac injury in coronavirus disease 2019 (COVID-19) on patients' outcomes. METHODS: This study enrolled patients who were confirmed to have COVID-19 and admitted at a tertiary university referral hospital between February 19, 2020 and March 15, 2020. Cardiac injury was defined as an abnormality in one of the following result markers: 1) myocardial damage marker (creatine kinase-MB or troponin-I), 2) heart failure marker (N-terminal-pro B-type natriuretic peptide), and 3) electrical abnormality marker (electrocardiography). The relationship between each cardiac injury marker and mortality was evaluated. Survival analysis of mortality according to the scoring by numbers of cardiac injury markers was also performed. RESULTS: A total of 38 patients with COVID-19 were enrolled. Twenty-two patients (57.9%) had at least one of cardiac injury markers. The patients with cardiac injuries were older (69.6 ± 14.9 vs. 58.6 ± 13.9 years old, P = 0.026), and were more male (59.1% vs. 18.8%, P = 0.013). They showed lower initial oxygen saturation (92.8 vs. 97.1%, P = 0.002) and a trend toward higher mortality (27.3 vs. 6.3%, P = 0.099). The increased number of cardiac injury markers was significantly related to a higher incidence of in-hospital mortality which was also evidenced by Kaplan-Meier survival analysis (P = 0.008). CONCLUSION: The increased number of cardiac injury markers is related to in-hospital mortality in patients with COVID-19.


Assuntos
Infecções por Coronavirus/diagnóstico , Miocárdio/metabolismo , Pneumonia Viral/diagnóstico , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/virologia , Creatina Quinase Forma MB/metabolismo , Eletrocardiografia , Feminino , Traumatismos Cardíacos/metabolismo , Traumatismos Cardíacos/patologia , Mortalidade Hospitalar , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Miocárdio/patologia , Peptídeo Natriurético Encefálico/metabolismo , Pandemias , Fragmentos de Peptídeos/metabolismo , Pneumonia Viral/mortalidade , Pneumonia Viral/virologia , Fatores Sexuais , Centros de Atenção Terciária , Troponina I/metabolismo
6.
Eur Rev Med Pharmacol Sci ; 24(14): 7816-7825, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32744709

RESUMO

Currently, the outbreak and spread of coronavirus disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), are increasing worldwide. Furthermore, it has been considered as a major challenge, which threatens human beings and affects all aspects of their life. Understanding the cellular and molecular pathophysiology of the disease is currently under the focus of investigations. Accordingly, this turns the human scientific community attention to find a solution for addressing the challenge. The development of vaccines and efficient therapeutic modality is critical. So, both primary and clinical scientists are not only trying to decipher the structure of SARS-CoV-2, but also attempting to understand the underlying molecular mechanisms that cause tissues and cell injuries. SARS-CoV and SARS-CoV2 are highly homologous and share a highly similar function and behavior patterns. Therefore, this might guide us toward decoding the molecular mechanisms that are behind the SARS-CoV2 pathologic effects. It is noteworthy to mention that, the undesired host immune reactions play important roles in the pathophysiology of the disease, and it also seems that, renin-angiotensin signaling (RAS) is a key contributor in this regard. In this review, we provided a vision, highlight as well as discussing on potential therapeutic targets that might be considered to address the COVID-19 challenge.


Assuntos
Betacoronavirus/fisiologia , Vírus da SARS/fisiologia , Síndrome Respiratória Aguda Grave/patologia , Basigina/metabolismo , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Humanos , Integrinas/metabolismo , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Sistema Renina-Angiotensina , Vírus da SARS/isolamento & purificação , Síndrome Respiratória Aguda Grave/virologia , Troponina I/metabolismo
7.
Vascul Pharmacol ; 133-134: 106781, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32827678

RESUMO

INTRODUCTION: Stem cell-derived cardiac myocytes are potential sources for testing cardiocytoprotective molecules against ischemia/reperfusion injury in vitro. MATERIALS AND METHODS: Here we performed a systematic analysis of two different induced pluripotent stem cell lines (iPSC 3.4 and 4.1) and an embryonic stem cell (ESC) line-derived cardiac myocytes at two different developmental stages. Cell viability in simulated ischemia/reperfusion (SI/R)-induced injury and a known cardiocytoprotective NO-donor, S-nitroso-n-acetylpenicillamine (SNAP) was tested. RESULTS: After analysis of full embryoid bodies (EBs) and cardiac marker (VCAM and cardiac troponin I) positive cells of three lines at 6 conditions (32 different conditions altogether), we found significant SI/R injury-induced cell death in both full EBs and VCAM+ cardiac cells at later stage of their differentiation. Moreover, full EBs of the iPS 4.1 cell line after oxidative stress induction by SNAP was protected at day-8 samples. CONCLUSION: We have shown that 4.1 iPS-derived cardiomyocyte line could serve as a testing platform for cardiocytoprotection.


Assuntos
Diferenciação Celular , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miócitos Cardíacos/efeitos dos fármacos , Doadores de Óxido Nítrico/farmacologia , Células-Tronco Pluripotentes/efeitos dos fármacos , S-Nitroso-N-Acetilpenicilamina/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Humanos , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Estresse Oxidativo/efeitos dos fármacos , Fenótipo , Células-Tronco Pluripotentes/metabolismo , Células-Tronco Pluripotentes/patologia , Troponina I/metabolismo , Molécula 1 de Adesão de Célula Vascular/metabolismo
8.
Stroke ; 51(9): 2770-2777, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32811388

RESUMO

BACKGROUND AND PURPOSE: Stroke is a common cause of death and a leading cause of disability and morbidity. Stroke risk assessment remains a challenge, but circulating biomarkers may improve risk prediction. Controversial evidence is available on the predictive ability of troponin concentrations and the risk of stroke in the community. Furthermore, reports on the predictive value of troponin concentrations for different stroke subtypes are scarce. METHODS: High-sensitivity cardiac troponin I (hsTnI) concentrations were assessed in 82 881 individuals (median age, 50.7 years; 49.7% men) free of stroke or myocardial infarction at baseline from 9 prospective European community cohorts. We used Cox proportional hazards regression to determine relative risks, followed by measures of discrimination and reclassification using 10-fold cross-validation to control for overoptimism. Follow-up was based upon linkage with national hospitalization registries and causes of death registries. RESULTS: Over a median follow-up of 12.7 years, 3033 individuals were diagnosed with incident nonfatal or fatal stroke (n=1654 ischemic strokes, n=612 hemorrhagic strokes, and n=767 indeterminate strokes). In multivariable regression models, hsTnI concentrations were associated with overall stroke (hazard ratio per 1-SD increase, 1.15 [95% CI, 1.10-1.21]), ischemic stroke (hazard ratio, 1.14 [95% CI, 1.09-1.21]), and hemorrhagic stroke (hazard ratio, 1.10 [95% CI, 1.01-1.20]). Adding hsTnI concentrations to classical cardiovascular risk factors (C indices, 0.809, 0.840, and 0.736 for overall, ischemic, and hemorrhagic stroke, respectively) increased the C index significantly but modestly. In individuals with an intermediate 10-year risk (5%-20%), the net reclassification improvement for overall stroke was 0.038 (P=0.021). CONCLUSIONS: Elevated hsTnI concentrations are associated with an increased risk of incident stroke in the community, irrespective of stroke subtype. Adding hsTnI concentrations to classical risk factors only modestly improved estimation of 10-year risk of stroke in the overall cohort but might be of some value in individuals at an intermediate risk.


Assuntos
Miocárdio/metabolismo , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/metabolismo , Troponina I/metabolismo , Biomarcadores , Estudos de Coortes , Europa (Continente)/epidemiologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Sistema de Registros , Fatores de Risco
9.
Proc Natl Acad Sci U S A ; 117(37): 23113-23124, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32859761

RESUMO

Currently there is an unmet need for treatments that can prevent hypertrophic cardiomyopathy (HCM). Using a murine model we previously identified that HCM causing cardiac troponin I mutation Gly203Ser (cTnI-G203S) is associated with increased mitochondrial metabolic activity, consistent with the human condition. These alterations precede development of the cardiomyopathy. Here we examine the efficacy of in vivo treatment of cTnI-G203S mice with a peptide derived against the α-interaction domain of the cardiac L-type calcium channel (AID-TAT) on restoring mitochondrial metabolic activity, and preventing HCM. cTnI-G203S or age-matched wt mice were treated with active or inactive AID-TAT. Following treatment, targeted metabolomics was utilized to evaluate myocardial substrate metabolism. Cardiac myocyte mitochondrial metabolic activity was assessed as alterations in mitochondrial membrane potential and flavoprotein oxidation. Cardiac morphology and function were examined using echocardiography. Cardiac uptake was assessed using an in vivo multispectral imaging system. We identified alterations in six biochemical intermediates in cTnI-G203S hearts consistent with increased anaplerosis. We also reveal that AID-TAT treatment of precardiomyopathic cTnI-G203S mice, but not mice with established cardiomyopathy, restored cardiac myocyte mitochondrial membrane potential and flavoprotein oxidation, and prevented myocardial hypertrophy. Importantly, AID-TAT was rapidly targeted to the heart, and not retained by the liver or kidneys. Overall, we identify biomarkers of HCM resulting from the cTnI mutation Gly203Ser, and present a safe, preventative therapy for associated cardiomyopathy. Utilizing AID-TAT to modulate cardiac metabolic activity may be beneficial in preventing HCM in "at risk" patients with identified Gly203Ser gene mutations.


Assuntos
Cardiomiopatia Hipertrófica/tratamento farmacológico , Cardiomiopatia Hipertrófica/metabolismo , Animais , Cálcio/metabolismo , Canais de Cálcio Tipo L/metabolismo , Modelos Animais de Doenças , Humanos , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Mutação/genética , Miocárdio/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Peptídeos/farmacologia , Troponina I/metabolismo
10.
Am J Physiol Heart Circ Physiol ; 319(2): H306-H319, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32618513

RESUMO

Dilated cardiomyopathy (DCM) is clinically characterized by dilated ventricular cavities and reduced ejection fraction, leading to heart failure and increased thromboembolic risk. Mutations in thin-filament regulatory proteins can cause DCM and have been shown in vitro to reduce contractility and myofilament Ca2+-affinity. In this work we have studied the functional consequences of mutations in cardiac troponin T (R131W), cardiac troponin I (K36Q) and α-tropomyosin (E40K) using adenovirally transduced isolated guinea pig left ventricular cardiomyocytes. We find significantly reduced fractional shortening with reduced systolic Ca2+. Contraction and Ca2+ reuptake times were slowed, which contrast with some findings in murine models of myofilament Ca2+ desensitization. We also observe increased sarcoplasmic reticulum (SR) Ca2+ load and smaller fractional SR Ca2+ release. This corresponds to a reduction in SR Ca2+-ATPase activity and increase in sodium-calcium exchanger activity. We also observe dephosphorylation and nuclear translocation of the nuclear factor of activated T cells (NFAT), with concordant RAC-α-serine/threonine protein kinase (Akt) phosphorylation but no change to extracellular signal-regulated kinase activation in chronically paced cardiomyocytes expressing DCM mutations. These changes in Ca2+ handling and signaling are common to all three mutations, indicating an analogous pathway of disease pathogenesis in thin-filament sarcomeric DCM. Previous work has shown that changes to myofilament Ca2+ sensitivity caused by DCM mutations are qualitatively opposite from hypertrophic cardiomyopathy (HCM) mutations in the same genes. However, we find several common pathways such as increased relaxation times and NFAT activation that are also hallmarks of HCM. This suggests more complex intracellular signaling underpinning DCM, driven by the primary mutation.NEW & NOTEWORTHY Dilated cardiomyopathy (DCM) is a frequently occurring cardiac disorder with a degree of genetic inheritance. We have found that DCM mutations in proteins that regulate the contractile machinery cause alterations to contraction, calcium-handling, and some new signaling pathways that provide stimuli for disease development. We have used guinea pig cells that recapitulate human calcium-handling and introduced the mutations using adenovirus gene transduction to look at the initial triggers of disease before remodeling.


Assuntos
Sinalização do Cálcio , Cardiomiopatia Dilatada/genética , Proteínas dos Microfilamentos/genética , Mutação , Contração Miocárdica , Miócitos Cardíacos/enzimologia , Fatores de Transcrição NFATC/metabolismo , Proteína Oncogênica v-akt/metabolismo , Função Ventricular Esquerda , Animais , Cardiomiopatia Dilatada/metabolismo , Cardiomiopatia Dilatada/fisiopatologia , Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/metabolismo , Cardiomiopatia Hipertrófica/fisiopatologia , Células Cultivadas , Predisposição Genética para Doença , Cobaias , Masculino , Proteínas dos Microfilamentos/metabolismo , Fenótipo , Retículo Sarcoplasmático/metabolismo , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Trocador de Sódio e Cálcio/metabolismo , Tropomiosina/genética , Tropomiosina/metabolismo , Troponina I/genética , Troponina I/metabolismo , Troponina T/genética , Troponina T/metabolismo
11.
Metabolism ; 107: 154231, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32298723

RESUMO

BACKGROUND: The mechanism of pyruvate kinase M2 (PKM2)-mediated inflammatory signalling in macrophages when plaques rupture and the impact of hyperglycaemia on the signalling are unclear. The present study aimed to explore the impact of hyperglycaemia on PKM2-mediated NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome/stress granule signalling in macrophages and its correlation with plaque vulnerability in vivo and in vitro. METHODS: From July to December 2019, 80 patients with coronary heart disease (CHD) were divided into acute ST-segment elevation myocardial infarction (STEMI) (n = 57) (DM-STEMI, n = 21; non-DM-STEMI, n = 36) and stable CHD (SCHD) groups (n = 23). Circulating mononuclear cells were isolated. The value of peak troponin I (TnI), the Global Registry of Acute Coronary Events (GRACE) risk score, and the expression levels of the related markers were quantified and compared. In vitro studies on the THP-1 cells were also performed. RESULTS: The DM-STEMI group had a higher value of peak TnI and a higher GRACE risk score than the non-DM-STEMI group (p < 0.05). The highest expression levels of PKM2, NLRP3, interleukin (IL)-1ß, and IL-18 and the lowest expression level of GTPase activating protein (SH3 domain)-binding protein 1 (G3BP1) (a stress granule marker protein) were observed in the DM-STEMI group, and they were followed by the non-DM-STEMI group and the SCHD group (p < 0.05). In vitro studies showed similar results and that TEPP-46 (a PKM2 activator) and 2-deoxy-d-glucose (a toxic glucose analogue) reversed the hyperglycaemia-induced increase in the NLRP3 inflammasome and decrease in G3BP1 expression. CONCLUSION: Hyperglycaemia might increase the activation of PKM2-mediated NLRP3 inflammasome/stress granule signalling and increase plaque vulnerability, associating it with worse prognosis. PKM2 may be a novel prognostic indicator and a new target for the treatment of patients with CHD and DM.


Assuntos
Proteínas de Transporte/metabolismo , Grânulos Citoplasmáticos , Hiperglicemia/fisiopatologia , Inflamassomos , Macrófagos/metabolismo , Proteínas de Membrana/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Placa Aterosclerótica/metabolismo , Hormônios Tireóideos/metabolismo , Idoso , Linhagem Celular , Doença das Coronárias/metabolismo , DNA Helicases/sangue , Feminino , Humanos , Hiperglicemia/induzido quimicamente , Interleucinas/sangue , Masculino , Pessoa de Meia-Idade , Proteínas de Ligação a Poli-ADP-Ribose/sangue , RNA Helicases/sangue , Proteínas com Motivo de Reconhecimento de RNA/sangue , Infarto do Miocárdio com Supradesnível do Segmento ST/metabolismo , Troponina I/metabolismo
12.
Am J Physiol Regul Integr Comp Physiol ; 318(5): R894-R900, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32209023

RESUMO

The goal of this investigation was to compare the effects of chronic (4 wk) transverse aortic constriction (TAC) in Sprague-Dawley rats and C57BL/6J mice. TAC, after 1 day, induced similar left ventricular (LV) pressure gradients in both rats (n = 7) and mice (n = 7) (113 ± 5.4 vs. 103 ± 11.5 mmHg), and after 4 wk, the percent increase in LV hypertrophy, as reflected by LV/tibial length (51% vs 49%), was similar in rats (n = 12) and mice (n = 12). After 4 wk of TAC, LV systolic and diastolic function were preserved in TAC rats. In contrast, in TAC mice, LV ejection fraction decreased by 31% compared with sham, along with increases in LV end-diastolic pressure (153%) and LV systolic wall stress (86%). Angiogenesis, as reflected by Ki67 staining of capillaries, increased more in rats (n = 6) than in mice (n = 6; 10 ± 2 vs. 6 ± 1 Ki67-positive cells/field). Myocardial blood flow fell by 55% and coronary reserve by 28% in mice with TAC (n = 4), but they were preserved in rats (n = 4). Myogenesis, as reflected by c-kit-positive myocytes staining positively for troponin I, is another mechanism that can confer protection after TAC. However, the c-kit-positive cells in rats with TAC were all negative for troponin I, indicating the absence of myogenesis. Thus, rats showed relative tolerance to severe pressure overload compared with mice, with mechanisms involving angiogenesis but not myogenesis.


Assuntos
Hipertrofia Ventricular Esquerda/fisiopatologia , Disfunção Ventricular Esquerda/fisiopatologia , Função Ventricular Esquerda , Pressão Ventricular , Remodelação Ventricular , Animais , Aorta/fisiopatologia , Aorta/cirurgia , Capilares/metabolismo , Capilares/fisiopatologia , Circulação Coronária , Modelos Animais de Doenças , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/metabolismo , Antígeno Ki-67/metabolismo , Ligadura , Camundongos Endogâmicos C57BL , Desenvolvimento Muscular , Miócitos Cardíacos/metabolismo , Neovascularização Fisiológica , Proteínas Proto-Oncogênicas c-kit/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais , Especificidade da Espécie , Fatores de Tempo , Troponina I/metabolismo , Disfunção Ventricular Esquerda/etiologia , Disfunção Ventricular Esquerda/metabolismo
13.
Clin Chem ; 66(2): 333-341, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-32040581

RESUMO

BACKGROUND: Although cardiac troponin I (cTnI) and troponin T (cTnT) form a complex in the human myocardium and bind to thin filaments in the sarcomere, cTnI often reaches higher concentrations and returns to normal concentrations faster than cTnT in patients with acute myocardial infarction (MI). METHODS: We compared the overall clearance of cTnT and cTnI in rats and in patients with heart failure and examined the release of cTnT and cTnI from damaged human cardiac tissue in vitro. RESULTS: Ground rat heart tissue was injected into the quadriceps muscle in rats to simulate myocardial damage with a defined onset. cTnT and cTnI peaked at the same time after injection. cTnI returned to baseline concentrations after 54 h, compared with 168 h for cTnT. There was no difference in the rate of clearance of solubilized cTnT or cTnI after intravenous or intramuscular injection. Renal clearance of cTnT and cTnI was similar in 7 heart failure patients. cTnI was degraded and released faster and reached higher concentrations than cTnT when human cardiac tissue was incubated in 37°C plasma. CONCLUSION: Once cTnI and cTnT are released to the circulation, there seems to be no difference in clearance. However, cTnI is degraded and released faster than cTnT from necrotic cardiac tissue. Faster degradation and release may be the main reason why cTnI reaches higher peak concentrations and returns to normal concentrations faster in patients with MI.


Assuntos
Infarto do Miocárdio/metabolismo , Troponina I/metabolismo , Troponina T/metabolismo , Animais , Biomarcadores/sangue , Insuficiência Cardíaca/sangue , Humanos , Cinética , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/fisiopatologia , Miocárdio/metabolismo , Ratos , Ratos Endogâmicos WKY , Sarcômeros/metabolismo , Troponina I/sangue , Troponina T/sangue
14.
Sci Rep ; 10(1): 1555, 2020 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-32005888

RESUMO

Capture myopathy (CM), is a syndrome that occurs as the result of the stress during and after capture, handling, restraint, and transport of wild animals. Although CM has been described for many species of cetaceans, characterization of the acute cardiac injury - an important component of this syndrome - are still scarce. In this study, we firstly estimated a normal range for cardiac troponin I (cTnI) on cetaceans. Here, through biochemical analysis (especially of cTnI) and histopathological, histochemical, and immunohistochemical correlations with decreased troponin immunolabelling, we studied the cardiac injury in live-stranded cetaceans. Nine cetaceans which stranded alive on the Canary Islands (January 2016 - June 2019) were included in this study. Sampled individuals presented elevated values of plasma cTnI, which were correlated to histopathological lesions comprised of vascular changes and acute degenerative lesions. Immunohistochemically, injured cardiomyocytes showed a decreased intrafibrillar troponin immunoreaction. This is the first attempt to establish a normal baseline range for cTnI in cetaceans, and the first study comparing plasma biomarkers values with histopathological and immunohistochemical findings. This approach allowed us to demonstrate the degree of cardiac damage as a result of injury, consistent with ischemia-reperfusion lesions. The knowledge gained here could improve decision-making procedures during stressful situations, mainly in live-strandings, handling, and rehabilitation, thereby reducing the mortality of cetaceans.


Assuntos
Proteínas Sanguíneas/metabolismo , Cetáceos , Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Traumatismo por Reperfusão/metabolismo , Rabdomiólise/metabolismo , Troponina I/metabolismo , Doença Aguda , Animais , Miócitos Cardíacos/patologia , Restrição Física , Estresse Fisiológico , Regulação para Cima
15.
Am J Physiol Heart Circ Physiol ; 318(3): H715-H722, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-32083971

RESUMO

Thin filament hypertrophic cardiomyopathy (HCM) mutations increase myofilament Ca2+ sensitivity and alter Ca2+ handling and buffering. The myosin inhibitor mavacamten reverses the increased contractility caused by HCM thick filament mutations, and we here test its effect on HCM thin filament mutations where the mode of action is not known. Mavacamten (250 nM) partially reversed the increased Ca2+ sensitivity caused by HCM mutations Cardiac troponin T (cTnT) R92Q, and cardiac troponin I (cTnI) R145G in in vitro ATPase assays. The effect of mavacamten was also analyzed in cardiomyocyte models of cTnT R92Q and cTnI R145G containing cytoplasmic and myofilament specific Ca2+ sensors. While mavacamten rescued the hypercontracted basal sarcomere length, the reduced fractional shortening did not improve with mavacamten. Both mutations caused an increase in peak systolic Ca2+ detected at the myofilament, and this was completely rescued by 250 nM mavacamten. Systolic Ca2+ detected by the cytoplasmic sensor was also reduced by mavacamten treatment, although only R145G increased cytoplasmic Ca2+. There was also a reversal of Ca2+ decay time prolongation caused by both mutations at the myofilament but not in the cytoplasm. We thus show that mavacamten reverses some of the Ca2+-sensitive molecular and cellular changes caused by the HCM mutations, particularly altered Ca2+ flux at the myofilament. The reduction of peak systolic Ca2+ as a consequence of mavacamten treatment represents a novel mechanism by which the compound is able to reduce contractility, working synergistically with its direct effect on the myosin motor.NEW & NOTEWORTHY Mavacamten, a myosin inhibitor, is currently in phase-3 clinical trials as a pharmacotherapy for hypertrophic cardiomyopathy (HCM). Its efficacy in HCM caused by mutations in thin filament proteins is not known. We show in reductionist and cellular models that mavacamten can rescue the effects of thin filament mutations on calcium sensitivity and calcium handling although it only partially rescues the contractile cellular phenotype and, in some cases, exacerbates the effect of the mutation.


Assuntos
Benzilaminas/farmacologia , Cálcio/metabolismo , Cardiomiopatia Hipertrófica/metabolismo , Coração/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Sarcômeros/efeitos dos fármacos , Uracila/análogos & derivados , Animais , Cardiomiopatia Hipertrófica/genética , Camundongos , Mutação , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Sarcômeros/metabolismo , Troponina I/genética , Troponina I/metabolismo , Troponina T/genética , Troponina T/metabolismo , Uracila/farmacologia
16.
Int J Mol Sci ; 21(4)2020 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-32075078

RESUMO

The consumption of water-pipe smoking (WPS) has been promoted by the use of flavoured tobacco. However, little is known about the impact of flavouring on the cardiovascular toxicity induced by WPS inhalation. Here, we compared the cardiovascular effects and underlying mechanism of actions of plain (P) (unflavoured) versus apple-flavoured (AF) WPS (30 minutes/day, 5 days/week for 1 month) in mice. Control mice were exposed to air. Both P- and AF-WPS inhalation induced an increase in systolic blood pressure, thrombogenicity and plasma concentration of fibrinogen and von Willebrand factor. In heart homogenates, AF-WPS inhalation caused an increase of 8-isoprostane and a decrease in the levels of reduced glutathione (GSH) and superoxide dismutase (SOD). Nevertheless, P-WPS decreased only the activity of SOD. The concentrations of tumour necrosis factor α and interleukin 1ß were increased only in heart homogenates of mice exposed to AF-WPS. Although both P- and AF-WPS increased the concentration of troponin I in heart homogenates and induced DNA damage, the concentration of cleaved caspase 3 was only increased in mice exposed to AF-WPS. Immunohistochemical analysis of the hearts showed that both P- and AF- WPS inhalation decreased the expression of SOD. Moreover, the expression of nuclear factor erythroid-derived 2-like 2 at nuclear level in the heart was higher in both AF-WPS and P-WPS compared with control group, and the effect observed in AF-WPS group was more significant than that seen in P-WPS group. Likewise, the concentration of heme oxygenase-1 was significantly increased in both P-WPS and AF-WPS groups compared with control group, and the effect seen in AF-group was higher than that observed in P-WPS group. In conclusion, our findings showed that both P- and AF-WPS induce thrombogenicity and cardiac injury, and that this toxicity is potentiated by the presence of flavouring.


Assuntos
Aromatizantes/farmacologia , Miocárdio/patologia , Estresse Oxidativo/efeitos dos fármacos , Fumar , Tabaco para Cachimbos de Água/toxicidade , Animais , Pressão Sanguínea/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Fibrinogênio/análise , Aromatizantes/química , Glutationa/metabolismo , Heme Oxigenase-1/metabolismo , Interleucina-1beta/metabolismo , Camundongos , Miocárdio/metabolismo , Agregação Plaquetária/efeitos dos fármacos , Tempo de Protrombina , Superóxido Dismutase/metabolismo , Troponina I/metabolismo , Regulação para Cima/efeitos dos fármacos
17.
Clin Chim Acta ; 505: 15-25, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32061575

RESUMO

The early concentration kinetic profiles of cardiac troponin in patients with non-ST-elevated myocardial infarction (NSTEMI) measured by high-sensitivity cardiac troponin I (hs-cTnI) and T (hs-cTnT) assays have not been described. In intermediate-to-high-risk of NSTEMI patients we measured serial cTn concentrations on ED arrival, at 1, 2, 3, 6-12, 24 and 48-hours with hs-cTnI and hs-cTnT assays. Log-normal curves were fitted to concentrations from time from symptom onset, and the time to rule-out decision thresholds estimated (hs-cTnI: 2 ng/L and 5 ng/L; hs-cTnT: 5 ng/L). Among 164 patients there were 58 NSTEMI. The hs-cTnI to hs-cTnT ratio increased linearly over the first 6-12 h following symptom onset. The estimated times from symptom onset to the 2 ng/L and 5 ng/L thresholds for hs-cTnI were 1.8 (0.1-3.1) and 1.9 (1.1-3.5) hours, and to the 5 ng/L threshold for hs-cTnT 1.9 (1.1-3.8) hours. The estimated time to exceed 5 ng/L was ≥3 hours in 32.6% (95%CI: 20.0% to 48.1%) cases for hs-cTnI and 33.3% (19.6% to 50.0%) for hs-cTnT. cTnI concentrations increased at a much more rapid rate than cTnT concentrations in patients with NSTEMI. Concentrations of a high proportion of patients took longer than 3 hours from symptom onset to exceed the 5 ng/L rule-out decision threshold.


Assuntos
Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/metabolismo , Troponina I/análise , Troponina I/metabolismo , Troponina T/análise , Troponina T/metabolismo , Idoso , Biomarcadores , Tomada de Decisão Clínica , Feminino , Humanos , Cinética , Limite de Detecção , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio sem Supradesnível do Segmento ST/metabolismo , Estudos Prospectivos , Medição de Risco , Resultado do Tratamento
18.
J Physiol Sci ; 70(1): 10, 2020 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-32066368

RESUMO

Exercise has been reported to induce autophagy. We hypothesized that exercise preconditioning (EP)-related autophagy in cardiomyocytes could be attributed to intermittent ischemia-hypoxia, allowing the heart to be protected for subsequent high-intensity exercise (HE). We applied approaches, chromotrope-2R brilliant green (C-2R BG) staining and plasma cTnI levels measuring, to characterize two periods of cardioprotection after EP: early EP (EEP) and late EP (LEP). Further addressing the relationship between ischemia-hypoxia and autophagy, key proteins, Beclin1, LC3, Cathepsin D, and p62, were determined by immunohistochemical staining, western blotting, and by their adjacent slices with C-2R BG. Results indicated that exercise-induced ischemia-hypoxia is a key factor in Beclin1-dependent autophagy. High-intensity exercise was associated with the impairment of autophagy due to high levels of LC3II and unchanged levels of p62, intermittent ischemia-hypoxia by EP itself plays a key role in autophagy, which resulted in more favorable cellular effects during EEP-cardioprotection compared to LEP.


Assuntos
Autofagia , Traumatismos Cardíacos/metabolismo , Precondicionamento Isquêmico Miocárdico/métodos , Condicionamento Físico Animal/efeitos adversos , Traumatismo por Reperfusão , Troponina I/sangue , Animais , Regulação da Expressão Gênica/fisiologia , Humanos , Isquemia Miocárdica/metabolismo , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Ratos , Ratos Sprague-Dawley , Troponina I/genética , Troponina I/metabolismo
19.
Medicine (Baltimore) ; 99(8): e18973, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32080075

RESUMO

This study investigated the relationship between angiographic complexities of coronary artery disease (CAD) assessed by SYNTAX Score synergy between percutaneous coronary intervention with taxus and cardiac surgery score (SYNTAX Score) and cardiac biomarker elevation after revascularization procedures.This is a post-hoc analysis of the medicine, angioplasty or surgery study V study of patients with stable CAD. High-sensitivity troponin 1 (hs-TnI) and creatinine kinase-muscle/brain (CK-MB) were assessed before and after cardiovascular procedures. Baselines SYNTAX Scores (SXScores) were calculated by blinded investigators to patient characteristics.Of the 202 patients studied, the mean SXScore was 21.25 ±â€Š9.24; 40.10 ±â€Š7.09 in the high SXScore group and 19.06 ±â€Š6.61 in low/mid SXscore group (P < .0001). Positive correlations existed between SXScore and median peaks after procedural hs-TnI (r = 0.18, P = .009) and CK-MB (r = 0.24, P = .001) levels. In patients with high SXScores (≥33), the median peaks of post-procedural hs-TnI (P = .034)and CK-MB (P = .004) levels were higher than in low/mid SXScore group (<33).The release of hs-TnI at 6 (P = .002), 12 (P = .008), and 24 hours (P = .039) was higher in high SXScore group than in low/mid SXscore group (<33) as was the release of CK-MB at 6 (P < .0001), 12 (P < .0001), 24 (P = .001), 36 (P = .007), 48 (P = .008), and 72 hours (P = .023). After multivariable analysis, high SXScore was a significant independent predictor of release of CK-MB and hs-TnI peaks higher than the median.The increase in release of cardiac biomarkers was significantly associated with the extent of atherosclerosis identified by the SYNTAX Score.


Assuntos
Biomarcadores/metabolismo , Angiografia Coronária/métodos , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/cirurgia , Idoso , Angioplastia/métodos , Aterosclerose/metabolismo , Aterosclerose/patologia , Procedimentos Cirúrgicos Cardíacos/métodos , Angiografia Coronária/tendências , Ponte de Artéria Coronária/métodos , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/terapia , Intervenção Coronária Percutânea/métodos , Estudos Prospectivos , Troponina I/metabolismo
20.
PLoS One ; 15(1): e0226892, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31923216

RESUMO

BACKGROUND: Serial conventional cardiac troponin (cTn) measurements 6-9 hours apart are recommended for non-ST-elevation MI (NSTEMI) diagnosis. We sought to develop a pathway with 3-hour changes for major adverse cardiac event (MACE) identification and assess the added value of the HEART [History, Electrocardiogram (ECG), Age, Risk factors, Troponin] score to the pathway. METHODS: We prospectively enrolled adults with NSTEMI symptoms at two-large emergency departments (EDs) over 32-months. Patients with STEMI, unstable angina and one cTn were excluded. We collected baseline characteristics, Siemens Vista conventional cTnI at 0, 3 or 6-hours after ED presentation; HEART score predictors; disposition and ED length of stay (LOS). Adjudicated primary outcome was 15-day MACE (acute MI, revascularization, or death due to cardiac ischemia/unknown cause). We analyzed multiples of 99th percentile cut-off cTnI values (45, 100 and 250ng/L). RESULTS: 1,683 patients (mean age 64.7 years; 55.3% female; median LOS 7-hours; 88 patients with 15-day MACE) were included. 1,346 (80.0%) patients with both cTnI≤45 ng/L; and 155 (9.2%) of the 213 patients with one value≥100ng/L but both<250ng/L or ≤20% change did not suffer MACE. Among 124 patients (7.4%) with one of the two values>45ng/L but<100ng/L based on 3 or 6-hour cTnI, one patient with absolute change<10ng/L and 6 of the 19 patients with≥20ng/L were diagnosed with NSTEMI (patients with Δ10-19ng/L between first and second cTnI had third one at 6-hours). Based on the results, we developed the Ottawa Troponin Pathway (OTP) with a 98.9% sensitivity (95% CI 93.8-100%) and 94.6% specificity (95% CI 93.3-95.6%). Addition of the HEART score improved the sensitivity to 100% (95% CI 95.9-100%) and decreased the specificity to 26.5% (95% CI 24.3-28.7%). CONCLUSION: The OTP with conventional cTnI 3-hours apart, should lead to better NSTEMI identification particularly those with values >99th percentile, standardize management and reduce the ED LOS.


Assuntos
Miocárdio/metabolismo , Infarto do Miocárdio sem Supradesnível do Segmento ST/diagnóstico , Infarto do Miocárdio sem Supradesnível do Segmento ST/metabolismo , Troponina I/metabolismo , Idoso , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA