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1.
Oncogene ; 36(22): 3094-3103, 2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-27941872

RESUMO

The mechanisms of initiation of pancreatic ductal adenocarcinoma (PDAC) are still largely unknown. In the present study, we analysed the role of anterior gradient-2 (AGR2) in the earliest stages of pancreatic neoplasia. Immunohistochemical analysis of chronic pancreatitis (CP) and peritumoral areas in PDAC tissues showed that AGR2 was present in tubular complexes (TC) and early pancreatic intraepithelial neoplasia (PanINs). Moreover, AGR2 was also found in discrete subpopulations of non-transformed cells neighbouring these pre-neoplastic lesions. In primary cells derived from human patient-derived xenograft (PDX) model, flow-cytometry revealed that AGR2 was overexpressed in pancreatic cancer stem cells (CSC) compared with non-stem cancer cells. In LSL-KrasG12D;Pdx1-Cre (KC) mouse model Agr2 induction preceded the formation of pre-neoplastic lesions and their development was largely inhibited by Agr2 deletion in engineered LSL-KrasG12D;Pdx1-Cre; Agr2-/- mice. In vitro, AGR2 expression was stimulated by tunicamycin-induced endoplasmic reticulum (ER) stress in both KRAS wild-type normal pancreas cells, as well as in KRAS mutated pancreatic cancer cells and was essential for ER homoeostasis. The unfolded protein response proteins GRP78, ATF6 and XBP1s were found expressed in CP and PDAC peritumoral tissues, but in contrast to AGR2, their expression was switched off during TC and PanIN formation. Real-time PCR and ELISA analyses showed that ER stress induced a pro-inflammatory phenotype in pancreatic normal, cancer and stellate cells. Moreover, AGR2 expression was inducible by paracrine transfer of ER stress and pro-inflammation between different pancreatic cell types. Our findings demonstrate that AGR2 induced in ER-stressed and inflammatory pre-neoplastic pancreas is a potential marker of cancer progenitor cells with an important functional role in PDAC initiation.


Assuntos
Carcinoma Ductal Pancreático/patologia , Estresse do Retículo Endoplasmático/fisiologia , Mucoproteínas/metabolismo , Neoplasias Pancreáticas/patologia , Animais , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Modelos Animais de Doenças , Chaperona BiP do Retículo Endoplasmático , Humanos , Camundongos , Mucoproteínas/biossíntese , Mucoproteínas/deficiência , Mucoproteínas/genética , Proteínas Oncogênicas , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo
2.
Eur J Histochem ; 59(1): 2512, 2015 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-25820568

RESUMO

Since the first description of cellular autofluorescence over a century ago, we have now come to appreciate that autofluorescence should not be discarded as a biological artifact but embraced as a biological phenomenon with potentially important cellular relevance. Indeed, cellular and tissue autofluorescence has been attributed to a spectrum of unrelated molecules such as porphyrins, vitamins (vitamin A, riboflavin, thiamine), structural proteins, lipofuscin and ceroid pigments. We have recently shown that freshly isolated epithelial cancer stem cells (CSCs) bear autofluorescent vesicles in the cytoplasm. Our studies definitively prove that riboflavin and not lipofuscin is the source of autofluorescence in CSCs as the inhibition of ATP and not autophagy eliminates CSC autofluorescence, that the ATP-dependent transporter ABCG2, for which riboflavin is a substrate, is overexpressed in autofluorescent CSCs and co-localizes with the membrane of intracellular autofluorescent vesicles, the ABCG2-specific inhibitor Fumitremorgin C reversibly eliminates CSC autofluorescence, riboflavin is a substrate for ABCG2, and only the addition of riboflavin to vitamin-deprived CSC cultures is capable of restoring autofluorescence. Thus, the sum of these data unequivocally supports the conclusion that the source of CSC autofluorescence is the vitamin riboflavin.


Assuntos
Células/metabolismo , Lipídeos/química , Lipofuscina/química , Animais , Humanos
3.
Heart ; 97(13): 1061-6, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21558475

RESUMO

OBJECTIVE: To evaluate the predictive value of seven biomarkers, which individually have been shown to be independent predictors, for use in a combined multimarker model for long-term cardiovascular outcome after non-ST-segment elevation acute coronary syndrome (NSTEACS). DESIGN AND SETTING: Levels of high-sensitivity C-reactive protein (hsCRP), myeloperoxidase, pregnancy-associated plasma protein A, placental growth factor (PlGF), soluble CD40 ligand (sCD40L), interleukin 10 (IL-10) and troponin-T (TnT) were determined in patients enrolled in the CAPTURE trial. Cox proportional hazard regression analyses were applied to evaluate the relation between biomarkers and the occurrence of all-cause mortality or non-fatal myocardial infarction (MI). PATIENTS: 1090 patients with NSTEACS. MAIN OUTCOME MEASURE: All-cause mortality and non-fatal MI during a median follow-up of 4 years. RESULTS: The composite endpoint was reached by 15.3% of patients. Admission levels of TnT >0.01 µg/l (adjusted HR 1.8), IL-10 <3.5 ng/l (1.7), myeloperoxidase >350 µg/l (1.5) and PlGF >27 ng/l (1.9) remained significant predictors for the incidence of all-cause mortality or non-fatal MI after multivariable adjustment for other biomarkers and clinical characteristics, whereas hsCRP, pregnancy-associated plasma protein A and sCD40L were only associated with the endpoint in univariate analysis. A multimarker model consisting of TnT, IL-10, myeloperoxidase and PlGF predicted 4-year event rates that varied between 6.0% (all markers normal) and 35.8% (three or more biomarkers abnormal). CONCLUSION: In patients with NSTEACS, biomarkers characterising distinct aspects of the underlying atherosclerotic process and myocardial damage of the initial cardiac event can assist in predicting long-term adverse cardiac outcomes. The use of combinations of selected biomarkers adds incremental predictive value to further risk stratification in an otherwise seemingly homogeneous NSTEACS population.


Assuntos
Síndrome Coronariana Aguda/diagnóstico , Biomarcadores/sangue , Síndrome Coronariana Aguda/sangue , Síndrome Coronariana Aguda/mortalidade , Síndrome Coronariana Aguda/fisiopatologia , Idoso , Eletrocardiografia , Métodos Epidemiológicos , Europa (Continente)/epidemiologia , Feminino , Humanos , Interleucina-10/sangue , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Peroxidase/sangue , Fator de Crescimento Placentário , Proteínas da Gravidez/sangue , Prognóstico , Troponina T/sangue
4.
Kidney Int ; 71(8): 771-7, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17299523

RESUMO

Lymphatic complications are common side effects of mammalian target of rapamycin (mTOR) inhibitor-based immunosuppression in kidney transplantation. Therefore, we investigated whether the mTOR inhibitor rapamycin, besides its known antihemangiogenic effect, also impedes regenerative lymphangiogenesis. In a murine skin flap model, rapamycin impaired recovery of lymphatic flow across surgical incisions resulting in prolonged wound edema in these animals. Importantly, the antilymphangiogenic effect of rapamycin was not related to a general inhibition of wound healing as demonstrated an in vivo Matrigeltrade mark lymphangiogenesis assay and a model of lymphangioma. Rapamycin concentrations as low as 1 ng/ml potently inhibited vascular endothelial growth factor (VEGF)-C driven proliferation and migration, respectively, of isolated human lymphatic endothelial cells (LECs) in vitro. Mechanistically, mTOR inhibition impairs downstream signaling of VEGF-A as well as VEGF-C via mTOR to the p70S6 kinase in LECs. In conclusion, we provide extensive experimental evidence for an antilymphangiogenic activity of mTOR inhibition suggesting that the early use of mTOR inhibitor following tissue injury should be avoided. Conversely, the antilymphangiogenic properties of rapamycin and its derivates may provide therapeutic value for the prevention and treatment of malignancies, respectively.


Assuntos
Células Endoteliais/efeitos dos fármacos , Endotélio Linfático/efeitos dos fármacos , Imunossupressores/farmacologia , Linfangiogênese/efeitos dos fármacos , Proteínas Quinases/efeitos dos fármacos , Sirolimo/farmacologia , Animais , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Colágeno , Combinação de Medicamentos , Imunossupressores/uso terapêutico , Laminina , Linfangioma/tratamento farmacológico , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias Peritoneais/tratamento farmacológico , Fosforilação/efeitos dos fármacos , Proteoglicanas , Proteínas Quinases S6 Ribossômicas 70-kDa/efeitos dos fármacos , Sirolimo/uso terapêutico , Serina-Treonina Quinases TOR , Fator A de Crescimento do Endotélio Vascular/efeitos dos fármacos , Fator C de Crescimento do Endotélio Vascular/efeitos dos fármacos
5.
Vasc Med ; 10(1): 7-14, 2005 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15920994

RESUMO

Endothelium-derived nitric oxide (NO) plays an important role in transducing the effects of angiogenic factors. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NO synthase (NOS). We used a murine model of hindlimb ischemia to investigate whether genetic or metabolic changes in ADMA levels could impair angiogenic response in vivo. Hindlimb ischemia was surgically induced in C57BL/6J mice, apo E-deficient mice, or transgenic mice overexpressing dimethylarginine dimethylaminohydrolase (DDAH). Some animals were also treated with the NOS antagonist L-nitro-arginine, or the NO precursor L-arginine. Angiogenesis was quantified in the hindlimb skeletal muscle by capillary/myocyte ratio. Plasma or tissue ADMA levels were measured by HPLC. In normal mice, hindlimb ischemia increased tissue ADMA twofold, and reduced DDAH and NOS expression. This was associated with a reduced NOS activity (by over 80%) three days following surgery. On day seven, a threefold increase in DDAH expression and a fall in tissue ADMA levels were associated with a sevenfold increase in NOS activity, whereas NOS expression did not increase above baseline. In DDAH transgenic mice, the elevation of ADMA and decrement in NOS activity was blunted during hindlimb ischemia. Plasma ADMA levels were increased in apo E-mice (1.79 +/- 0.45 versus 1.07 +/- 0.08 pmol/l; p = 0.008). Capillary index was significantly reduced in apo E-mice up to seven weeks after surgery (0.25 +/- 0.05 versus 0.62 +/- 0.08; p < 0.001). The effect of hypercholesterolemia on capillary index was reversed by L-arginine, and (in wild-type mice) mimicked by administration of the NOS antagonist L-nitro-arginine. In conclusion, metabolic or genetic changes in plasma and tissue ADMA levels affect tissue NO production and angiogenic response to ischemia.


Assuntos
Arginina/análogos & derivados , Arginina/fisiologia , Neovascularização Fisiológica/fisiologia , Óxido Nítrico Sintase/antagonistas & inibidores , Animais , Arginina/análise , Western Blotting , Modelos Animais de Doenças , Feminino , Hipercolesterolemia/fisiopatologia , Isquemia/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos
6.
Circulation ; 110(3): 349-55, 2004 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-15238461

RESUMO

BACKGROUND: Several studies have suggested that stem cells are present in the stroma-vascular fraction (SVF) of adipose tissue (AT). METHODS AND RESULTS: To characterize the cell populations that compose the SVF of human AT originating from subcutaneous and visceral depots, fluorescence-activated cell sorter analysis was performed by use of fluorescent antibodies directed against the endothelial and stem cell markers CD31, CD34, CD133, and ABCG2. The freshly harvested SVF contained large numbers of CD34+ cells as well as cells expressing CD133 and ABCG2. Further analysis of the CD34+ cells revealed 2 CD34+ cell populations with differential expression of the endothelial cell marker CD31. Selection of the CD34+/CD31- cells by use of magnetic microbeads, followed by cell culture, demonstrated that this cell population could differentiate under appropriate conditions into endothelial cells. Moreover, in mouse ischemic hindlimb, intravenous injection of CD34(+)/CD31(-) cells was associated with an increase in the blood flow and the capillary density and an incorporation of the cells in the leg vasculature. CONCLUSIONS: Our data indicate the presence of a cell population within the SVF of human AT characterized as CD34+/CD31- exhibiting characteristics of endothelial progenitor cells. Therefore, human AT might represent a source of stem/progenitor cells useful for cell therapy to improve vasculogenesis in adults.


Assuntos
Tecido Adiposo/citologia , Endotélio Vascular/citologia , Isquemia/terapia , Células-Tronco/citologia , Tecido Adiposo/irrigação sanguínea , Animais , Antígenos CD34/análise , Biomarcadores/análise , Diferenciação Celular , Proliferação de Células , Membro Posterior/irrigação sanguínea , Humanos , Camundongos , Camundongos Nus , Molécula-1 de Adesão Celular Endotelial a Plaquetas/análise , Fluxo Sanguíneo Regional , Células-Tronco/classificação , Células-Tronco/metabolismo , Células Estromais/metabolismo
7.
Z Kardiol ; 93(2): 103-8, 2004 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-14963675

RESUMO

OBJECTIVE: HMG CoA reductase inhibitors (statins) may exert a wide array of cholesterol independent effects including antihypertrophic effects on the heart. Their role in the treatment of heart failure has not been studied. METHODS AND RESULTS: 15 patients with heart failure NYHA II-III based on non-ischemic dilated cardiomyopathy were randomized in a double-blind study to 0.4 mg cerivastatin or placebo for an average treatment period of 20 weeks. Quality of life and exercise capacity increased significantly in the statin treatment but not in the placebo group (Minnesota Living with Heart Failure Questionnaire, 6 min walking test). Concomitantly, there was a trend towards increased left ventricular ejection fraction (radionuclear ventriculography) and improved endothelial function (forearm blood flow). Statins decreased plasma concentrations of troponine T, high sensitive C-reactive protein (hsCRP), plasminogen activator inhibitor-1 (PAI-1) and tumor necrosis factor alpha (TNFalpha). CONCLUSIONS: Statins induce beneficial effects in patients with non-ischemic cardiomyopathy leading to improvement of quality of life and exercise capacity disclosing a promising novel treatment strategy for patients with heart failure.


Assuntos
Anticolesterolemiantes/uso terapêutico , Cardiomiopatia Dilatada/tratamento farmacológico , Insuficiência Cardíaca/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Piridinas/uso terapêutico , Anticolesterolemiantes/efeitos adversos , Cardiomiopatia Dilatada/complicações , Cardiomiopatia Dilatada/diagnóstico , Método Duplo-Cego , Teste de Esforço/efeitos dos fármacos , Feminino , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/etiologia , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Mediadores da Inflamação/sangue , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Piridinas/efeitos adversos , Qualidade de Vida , Volume Sistólico/efeitos dos fármacos , Resultado do Tratamento
8.
Eur Heart J ; 24(1): 77-85, 2003 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-12559939

RESUMO

AIMS: Treatment with the glycoprotein IIb/IIIa receptor antagonist abciximab before and during coronary intervention in refractory unstable angina improves early outcome. We collected 4-year follow-up data to assess whether this benefit is sustained. Additionally, we investigated the predictive value of baseline troponin T and CRP for long-term cardiovascular events. METHODS AND RESULTS: Of 1265 patients enrolled in the CAPTURE trial follow-up was available in 94% of the patients alive after 6 months (median 48 months). Survival was similar in both groups. Both elevated troponin T and CRP were associated with impaired outcome, independently of other established risk factors, but with a different time course. Elevated troponin was associated with increased procedure related risk, and elevated CRP with increased risk for subsequent events. Lower rates of the composite end-point of death or myocardial infarction with abciximab vs. placebo were sustained during long-term follow up: 15.7% vs 17.2% at 4 years (P=ns), particularly in patients with elevated troponin T: 16.9% with abciximab vs 28.4% with placebo: P=0.015. Elevated CRP was not associated with specific benefit of abciximab. CONCLUSION: Troponin T as a marker of thrombosis and CRP as a marker of inflammation are independent predictors of impaired outcome at 4 years follow-up. The initial benefit from abciximab with regard to death and myocardial infarction was preserved at 4 years. No specific benefit with abciximab was observed for patients with elevated CRP, suggesting that a chronic inflammatory process is not affected by abciximab. In contrast the benefit of treatment in patients with elevated troponin T implies that the acute thrombotic process in refractory unstable angina is treated effectively.


Assuntos
Angina Instável/terapia , Angioplastia Coronária com Balão/métodos , Anticorpos Monoclonais/uso terapêutico , Proteína C-Reativa/metabolismo , Fragmentos Fab das Imunoglobulinas/uso terapêutico , Inibidores da Agregação Plaquetária/uso terapêutico , Troponina T/metabolismo , Abciximab , Angina Instável/sangue , Angina Instável/tratamento farmacológico , Doença Crônica , Terapia Combinada/métodos , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores , Valor Preditivo dos Testes , Análise de Sobrevida , Resultado do Tratamento
9.
Eur Heart J ; 23(18): 1441-8, 2002 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12208224

RESUMO

AIMS: To assess the efficacy of platelet glycoprotein IIb/IIIa inhibitors in patients with acute coronary syndromes primarily medically managed. METHODS AND RESULTS: We performed a meta-analysis of the randomized clinical trials of platelet glycoprotein IIb/IIIa inhibitor therapy in the medical management of non-ST-elevation acute coronary syndromes. Among 29570 patients, IIb/IIIa integrin blockade was associated with a reduction in death or non-fatal myocardial infarction at 30 days, from 11.5% to 10.7% (odds ratio 0.91,P =0.02). Patients undergoing percutaneous coronary intervention during index hospitalization sustained a greater reduction in ischaemic events (odds ratio 0.82, P=0.01) than patients medically managed (odds ratio 0.95, P=0.27). Among patients undergoing intervention, the benefit was more pronounced if the procedure was performed during glycoprotein IIb/IIIa inhibitor infusion (odds ratio 0.74; P=0.02), than if revascularization was performed after drug discontinuation (odds ratio 0.87,P =0.17). CONCLUSION: This analysis, including the entire large-scale trial experience of intravenous glycoprotein IIb/IIIa inhibitors in patients with acute coronary syndromes primarily medically managed, demonstrates an overall significant, albeit moderate, reduction in 30-day death or myocardial infarction associated with therapy. Although not based on a prospectively defined hypothesis, the findings suggest a gradient of benefit conferred by these agents depending on the revascularization strategy used.


Assuntos
Angina Instável/tratamento farmacológico , Anticoagulantes/uso terapêutico , Infarto do Miocárdio/mortalidade , Infarto do Miocárdio/terapia , Inibidores da Agregação Plaquetária/uso terapêutico , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores , Doença Aguda , Angioplastia Coronária com Balão , Ponte de Artéria Coronária , Avaliação de Medicamentos , Determinação de Ponto Final , Heparina/uso terapêutico , Humanos , Razão de Chances , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco , Análise de Sobrevida , Resultado do Tratamento
10.
Circulation ; 104(23): 2767-71, 2001 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-11733392

RESUMO

BACKGROUND: Diabetes mellitus is a major risk factor for adverse outcomes after acute coronary syndromes (ACS). Because this disease may be associated with increased platelet aggregation, we investigated whether diabetic patients with ACS derive particular benefit from platelet glycoprotein (GP) IIb/IIIa receptor inhibition. METHODS AND RESULTS: We performed a meta-analysis of the diabetic populations enrolled in the 6 large-scale platelet GP IIb/IIIa inhibitor ACS trials: PRISM, PRISM-PLUS, PARAGON A, PARAGON B, PURSUIT, and GUSTO IV. Among 6458 diabetic patients, platelet GP IIb/IIIa inhibition was associated with a significant mortality reduction at 30 days, from 6.2% to 4.6% (OR 0.74; 95% CI 0.59 to 0.92; P=0.007). Conversely, 23 072 nondiabetic patients had no survival benefit (3.0% versus 3.0%). The interaction between platelet GP IIb/IIIa inhibition and diabetic status was statistically significant (P=0.036). Among 1279 diabetic patients undergoing percutaneous coronary intervention (PCI) during index hospitalization, the use of these agents was associated with a mortality reduction at 30 days from 4.0% to 1.2% (OR 0.30; 95% CI 0.14 to 0.69; P=0.002). CONCLUSIONS: This meta-analysis, including the entire large-scale trial experience of intravenous platelet GP IIb/IIIa inhibitors for the medical management of non-ST-segment-elevation ACS, shows that these agents may significantly reduce mortality at 30 days in diabetic patients. Although not based on a randomized assessment, the survival benefit appears to be of greater magnitude in patients undergoing PCI. Therefore, the use of platelet GP IIb/IIIa inhibitors should be strongly considered in diabetic patients with ACS.


Assuntos
Complicações do Diabetes , Infarto do Miocárdio/tratamento farmacológico , Inibidores da Agregação Plaquetária/uso terapêutico , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores , Diabetes Mellitus/mortalidade , Humanos , Infarto do Miocárdio/complicações , Infarto do Miocárdio/mortalidade , Ensaios Clínicos Controlados Aleatórios como Assunto , Análise de Sobrevida , Taxa de Sobrevida , Síndrome , Resultado do Tratamento
11.
Nat Med ; 7(7): 833-9, 2001 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-11433349

RESUMO

We provide anatomic and functional evidence that nicotine induces angiogenesis. We also show that nicotine accelerates the growth of tumor and atheroma in association with increased neovascularization. Nicotine increased endothelial-cell growth and tube formation in vitro, and accelerated fibrovascular growth in vivo. In a mouse model of hind-limb ischemia, nicotine increased capillary and collateral growth, and enhanced tissue perfusion. In mouse models of lung cancer and atherosclerosis, we found that nicotine enhanced lesion growth in association with an increase in lesion vascularity. These effects of nicotine were mediated through nicotinic acetylcholine receptors at nicotine concentrations that are pathophysiologically relevant. The endothelial production of nitric oxide, prostacyclin and vascular endothelial growth factor might have a role in these effects.


Assuntos
Arteriosclerose/complicações , Carcinoma Pulmonar de Lewis/irrigação sanguínea , Carcinoma Pulmonar de Lewis/patologia , Neoplasias Pulmonares/irrigação sanguínea , Neoplasias Pulmonares/patologia , Neovascularização Patológica/etiologia , Nicotina/farmacologia , Animais , Arteriosclerose/patologia , Camundongos , Camundongos Endogâmicos C57BL
12.
Clin Biochem ; 33(5): 359-68, 2000 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-11018687

RESUMO

BACKGROUND: The controversy whether there is a clinically significant difference between troponin T (cTnT) and troponin I (cTnI) in regard to predictive value and cardiac specificity is still ongoing. METHODS: We evaluated enzyme-linked immunosorbent assay systems for cTnI and cTnT in patients with acute coronary syndromes and multiple control groups to define threshold values for risk stratification and compare their predictive value. RESULTS: In 312 patients with noncardiac chest pain, cTnI levels were below the detection limit of 0.2 microg/L and cTnT levels were 0.011 [0.010-0. 013] microg/L. In patients with end-stage renal failure (n = 26) and acute (n = 38) or chronic (n = 16) skeletal muscle damage, median concentrations were 0.20 [0.20-0.35], below the detection limit, and 0.20 [0.20-0.25] for cTnI, and 0.04 [0.01-0.10], 0.011 [0.005-0.025], and 0.032 [0.009-0.054] microg/L for cTnT. In patients with acute coronary syndromes (n = 1130), maximized prognostic value for 30-day outcome (death, infarction) was observed at a threshold level of 1.0 microg/L for cTnI (29.0% positive) and at 0.06 microg/L for cTnT (35. 0% positive). Significant differences in the area-under-the-curve values were observed between cTnI and cTnT (0.685 vs. 0.802; p = 0. 005). For both markers, the area-under-the-curve values did not increase with the second (within 24 h after enrollment) or third (48 h) blood draw. CTnI showed a less strong association with 30-day outcome than cTnT. When cTnI was put in a logistic multiple-regression model first, cTnT did add significant information. CONCLUSION: By using the defined threshold values and the employed test systems, single testing for cTnI and cTnT within 12 h after symptom onset was appropriate for risk stratification. Despite the lower cardiac specificity for cTnT, it appears to have a stronger association with the patients' outcome, whereas, as previously shown, the ability to identify patients who benefit from treatment with a GP IIb/IIIa receptor antagonist is similar.


Assuntos
Doença das Coronárias/sangue , Kit de Reagentes para Diagnóstico/normas , Troponina/sangue , Doença Aguda , Adulto , Idoso , Biomarcadores/sangue , Dor no Peito/sangue , Doença das Coronárias/diagnóstico , Método Duplo-Cego , Ensaio de Imunoadsorção Enzimática , Feminino , Seguimentos , Heparina/farmacologia , Humanos , Recém-Nascido , Infarto/sangue , Infarto/diagnóstico , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Análise Multivariada , Músculo Esquelético/lesões , Transtornos Musculares Atróficos/sangue , Isquemia Miocárdica/sangue , Isquemia Miocárdica/diagnóstico , Valor Preditivo dos Testes , Prognóstico , Recidiva , Insuficiência Renal/sangue , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Troponina I/sangue , Troponina T/sangue
13.
Int J Clin Lab Res ; 30(1): 13-5, 2000.
Artigo em Inglês | MEDLINE | ID: mdl-10984126

RESUMO

The detection of cardiac troponins in peripheral blood as protein markers of myocardial infarction is a new diagnostic tool in the diagnosis of cardiac disease. In order to increase the sensitivity and specificity of this diagnostic approach, a reverse transcription polymerase chain reaction assay has been developed to detect the mRNA encoding cardiac troponin I from myocardial cells hypothetically released from damaged cardiac tissue. The detection is specific for cardiac troponin I mRNA, with no amplification of homologous sequences of other troponin I isoforms, i.e., troponin I from skeletal muscle cells. However, a strong amplification signal for cardiac troponin I mRNA was detected in samples of peripheral blood from healthy human volunteers. In patients with acute myocardial infarction or angina pectoris, the cardiac troponin I mRNA levels were not increased over background levels. In conclusion, a reverse transcription polymerase chain reaction approach based on the amplification of cardiac troponin I mRNA is not feasible in the diagnosis of cardiac diseases.


Assuntos
Angina Pectoris/sangue , Infarto do Miocárdio/sangue , Miocárdio/metabolismo , Isoformas de Proteínas/genética , RNA Mensageiro/sangue , Troponina I/genética , Angina Pectoris/diagnóstico , Angina Instável/sangue , Angina Instável/diagnóstico , Sequência de Bases , Biomarcadores , Estudos de Viabilidade , Humanos , Dados de Sequência Molecular , Infarto do Miocárdio/diagnóstico , Reação em Cadeia da Polimerase , Valor Preditivo dos Testes , Alinhamento de Sequência , Homologia de Sequência do Ácido Nucleico
14.
Eur Heart J ; 21(14): 1159-66, 2000 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-10924299

RESUMO

AIMS: Elevation of troponin T in patients with unstable angina is predictive of adverse outcomes. Since no advanced therapeutic concept for such high-risk patients has been established, we investigated cardiac risk prior to, during, and after coronary revascularization in patients with unstable angina stratified according to the troponin T status. METHODS AND RESULTS: Out of 351 patients with unstable angina, troponin was elevated for 36% of the patients as determined by qualitative bedside tests. The patients were followed during hospitalization and 30 days after discharge for incidence of death and myocardial infarction. In troponin-positive patients, clinical symptoms were more refractory to medical treatment than in troponin-negative patients (78% vs 44%;P=0.002). Although these patients were catheterized earlier (1.6 vs 3.4 days;P=0.005) and more frequently (95% vs 69%;P<0.001), troponin-positive patients suffered a higher incidence of cardiac events prior to scheduled revascularization (death, myocardial infarction; 6.4% vs 0.4%;P<0.001). The angiogram for troponin-positive patients confirmed a more severe coronary artery disease requiring revascularization (69% vs 50%;P=0.001). Also the following coronary intervention was more complicated (death, myocardial infarction; 15.3% vs 4.8%;P=0.02). During the 30-day follow-up period, cardiac risk remained elevated for troponin-positive patients. CONCLUSIONS: Troponin T rapid testing reliably identified high-risk patients with unstable angina. A higher event rate was observed prior to and particularly in association with the coronary intervention. Coronary revascularization did not abrogate the increased risk of troponin-positive patients during the 30-day follow-up.


Assuntos
Angina Instável/sangue , Revascularização Miocárdica , Medição de Risco , Troponina T/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Angina Instável/diagnóstico por imagem , Angina Instável/cirurgia , Biomarcadores/sangue , Angiografia Coronária , Tomada de Decisões , Eletrocardiografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Revascularização Miocárdica/métodos , Índice de Gravidade de Doença
15.
J Am Coll Cardiol ; 35(6): 1535-42, 2000 May.
Artigo em Inglês | MEDLINE | ID: mdl-10807457

RESUMO

OBJECTIVES: We evaluated C-reactive protein (CRP) and troponin T (TnT) for predicting six-month cardiac risk in patients with unstable angina. BACKGROUND: Troponin T is predictive of cardiac risk in patients with unstable angina. The clinical implications of elevated CRP in such patients remains controversial. METHODS: Baseline TnT and CRP values were determined in 447 patients with unstable angina enrolled in the placebo group of the Chimeric c7E3 AntiPlatelet Therapy in Unstable angina REfractory to standard treatment trial (CAPTURE) trial. All patients underwent a coronary intervention and were followed for a six month period in which 13 deaths and 47 myocardial infarctions were documented (MIs). RESULTS: Troponin T was >0.1 microg/liter in 30% and CRP was >10 mg/L in 41% of the patients. For the initial 72-h period (including coronary intervention), TnT (17.4% vs. 4.2%; p < 0.001) but not CRP (10.3% vs. 8%; p = 0.41) was predictive of mortality and MI. The TnT-positive patients displayed more frequent recurrent instability before the planned intervention (44.8% vs. 16.9%; p < 0.001), but in the CRP-positive patients, no such increase was observed (25.9% vs. 24.8%; p = 0.92). In contrast, for the six month follow-up period, CRP was predictive of cardiac risk (mortality, MI) (18.9% vs. 9.5%; p = 0.003). Using multivariate analysis, both CRP and TnT emerged as independent predictors of mortality and MI at six-month follow-up. Furthermore, the incidence of coronary restenosis during six-month follow-up was not related to TnT status (3% vs. 4.5%; p = 0.49); however, it was significantly related to CRP status (7% vs. 2.3%; p = 0.03). CONCLUSIONS: Troponin T, but not CRP, was predictive of cardiac risk during the initial 72-h period, whereas CRP was an independent predictor of both cardiac risk and repeated coronary revascularization (coronary artery bypass graft surgery and percutaneous transluminal coronary angioplasty) during six month follow-up.


Assuntos
Angina Instável/diagnóstico , Proteína C-Reativa/metabolismo , Infarto do Miocárdio/diagnóstico , Troponina T/sangue , Abciximab , Idoso , Angina Instável/sangue , Angina Instável/tratamento farmacológico , Angina Instável/mortalidade , Anticorpos Monoclonais/uso terapêutico , Feminino , Humanos , Fragmentos Fab das Imunoglobulinas/uso terapêutico , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/sangue , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/mortalidade , Inibidores da Agregação Plaquetária/uso terapêutico , Valor Preditivo dos Testes , Recidiva , Taxa de Sobrevida
17.
Lancet ; 354(9192): 1757-62, 1999 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-10577636

RESUMO

BACKGROUND: A major challenge for physicians is to identify patients with acute coronary syndromes who may benefit from treatment with glycoprotein-IIb/IIIa-receptor antagonists. We investigated whether troponin concentrations can be used to stratify patients for benefit from treatment with tirofiban. METHODS: We enrolled 2222 patients of the Platelet Receptor Inhibition in Ischemic Syndrome Management study with coronary artery disease and who had had chest pain in the previous 24 h. All patients received aspirin and were randomly assigned treatment with tirofiban or heparin. We took baseline measurements of troponin I and troponin T. We recorded death, myocardial infarction, or recurrent ischaemia after 48 h infusion treatment and at 7 days and 30 days. FINDINGS: 629 (28.3%) patients had troponin I concentrations higher than the diagnostic threshold of 1.0 microg/L and 644 (29.0%) troponin T concentrations higher than 0.1 microg/L. 30-day event rates (death, myocardial infarction) were 13.0% for troponin-I-positive patients compared with 4.9% for troponin-I-negative patients (p<0.0001), and 13.7% compared wth 3.5% for troponin T (p<0.001). At 30 days, in troponin-I-positive patients, tirofiban had lowered the risk of death (adjusted hazard ratio 0.25 [95% CI 0.09-0.68], p=0.004) and myocardial infarction (0.37 [0.16-0.84], p=0.01). This benefit was seen in medically managed patients (0.30 [0.10-0.84], p=0.004) and those undergoing revascularisation (0.37 [0.15-0.93] p=0.02) after 48 h infusion treatment. By contrast, no treatment effect was seen for troponin-I-negative patients. Similar benefits were seen for troponin-T-positive patients. INTERPRETATION: Troponin I and troponin T reliably identified high-risk patients with acute coronary syndromes, managed medically and by revascularisation, who would benefit from tirofiban.


Assuntos
Doença das Coronárias/tratamento farmacológico , Fibrinolíticos/uso terapêutico , Heparina/uso terapêutico , Inibidores da Agregação Plaquetária/uso terapêutico , Troponina I/sangue , Troponina T/sangue , Tirosina/análogos & derivados , Idoso , Biomarcadores/sangue , Doença das Coronárias/sangue , Creatina Quinase/sangue , Creatina Quinase/efeitos dos fármacos , Feminino , Humanos , Infusões Intravenosas , Isoenzimas , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/mortalidade , Fatores de Risco , Tirofibana , Tirosina/uso terapêutico
18.
Circulation ; 100(14): 1509-14, 1999 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-10510053

RESUMO

BACKGROUND: The CAPTURE (C7E3 fab AntiPlatelet Therapy in Unstable REfactory angina) trial enrolled patients with refractory unstable angina and documented a therapeutic benefit for abciximab, a platelet glycoprotein IIb/IIIa receptor antagonist, that was particularly evident in patients with elevated troponin T (TnT) levels. In the current study, we related the angiographic data to the TnT status of the CAPTURE patients. METHODS AND RESULTS: In 853 patients, angiographic data at baseline and 18 to 24 hours after treatment were available and assessed by an Angiographic Committee with respect to TIMI flow, lesion severity, and visibility of thrombus. TnT levels >0.1 microg/L were found in 30.9% of the patients. Before randomization, thrombus was visible in 14.6% of TnT-positive patients (TnT levels >0.1 microg/L) and 4.2% of TnT-negative patients (P=0.004). Complex lesion characteristics B2+/C (72.0% versus 53.9%; P<0.001) and TIMI flow <2 (15.6% versus 5. 1%; P<0.001) were more frequent in TnT-positive patients. Abciximab was effective with respect to reduction of visible thrombus, increase of TIMI flow, and reduction of cardiac events in TnT-positive patients only. Multivariate analysis identified TnT status, but not angiographic findings, as an independent predictor for both outcome and efficacy of treatment with abciximab. CONCLUSIONS: Complex lesion characteristics and visible thrombus formation at baseline were significantly linked to TnT elevation. However, TnT status was a more powerful predictor of increased cardiac risk and efficacy of treatment with abciximab than either. Relative to the angiogram, TnT can thus be considered a more sensitive marker for the underlying pathology, identifying patients with unstable angina who will particularly benefit from antiplatelet treatment.


Assuntos
Angina Instável/diagnóstico por imagem , Angiografia Coronária , Troponina T/sangue , Abciximab , Adulto , Idoso , Angina Instável/sangue , Angina Instável/tratamento farmacológico , Angioplastia Coronária com Balão , Anticorpos Monoclonais/uso terapêutico , Circulação Coronária/efeitos dos fármacos , Trombose Coronária/diagnóstico por imagem , Feminino , Humanos , Fragmentos Fab das Imunoglobulinas/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
19.
Clin Chem ; 45(10): 1789-96, 1999 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-10508126

RESUMO

BACKGROUND: Troponin I (cTnI) provides important prognostic information in patients with chest pain. We wished to evaluate a rapid, whole-blood analyzer for quantitative point-of-care testing. METHODS: A quantitative point-of-care test system (Stratus CS((R)); Dade-Behring) for cTnI with an incorporated centrifuge was evaluated in 412 patients with chest pain less than 12 h. RESULTS: Results were available within 15 min. CVs were 4.5% at 0.1 microgram/L, 4.2% at 0.25 microgram/L, and 6.5% at 0.82 microgram/L. The detection limit was 0. 01 microgram/L. The 97.5% percentile in a healthy population was 0.08 microgram/L. Based on ROC curve analysis, a threshold of 0.15 microgram/L was calculated for the detection of acute myocardial infarction (AMI). With it, sensitivity for the detection of patients with AMI (n = 62) was 63% at arrival and 98% after 4 h (Stratus II((R)), 48% and 85%, respectively; P <0.01). In 42% of patients with unstable angina (n = 121), cTnI was >/=0.08 microgram/L (Stratus II, 28%; P <0. 01). During 30 days, death or AMI occurred in 25.5% of these cTnI-positive vs 2.9% of cTnI-negative patients (Stratus II, 29.4% vs 5.8%). CONCLUSION: The Stratus CS provided better analytical performance and comparable or better prognostic information than the Stratus II.


Assuntos
Angina Instável/diagnóstico , Dor no Peito/diagnóstico , Infarto do Miocárdio/diagnóstico , Sistemas Automatizados de Assistência Junto ao Leito , Troponina I/sangue , Doença Aguda , Biomarcadores/sangue , Ensaio de Imunoadsorção Enzimática , Feminino , Fluorimunoensaio , Humanos , Masculino , Pessoa de Meia-Idade , Curva ROC
20.
N Engl J Med ; 340(21): 1623-9, 1999 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-10341274

RESUMO

BACKGROUND: In patients with refractory unstable angina, the platelet glycoprotein IIb/IIIa-receptor antibody abciximab reduces the incidence of cardiac events before and during coronary angioplasty. We investigated whether serum troponin T levels identify patients most likely to benefit from therapy with this drug. METHODS: Among 1265 patients with unstable angina who were enrolled in the c7E3 Fab Antiplatelet Therapy in Unstable Refractory Angina (CAPTURE) trial, serum samples drawn at the time of randomization to abciximab or placebo were available from 890 patients; we used these samples for the determination of troponin T and creatine kinase MB levels. Patients with postinfarction angina were not included. RESULTS: Serum troponin T levels at the time of study entry were elevated (above 0.1 ng per milliliter) in 275 patients (30.9 percent). Among patients receiving placebo, the risk of death or nonfatal myocardial infarction was related to troponin T levels. The six-month cumulative event rate was 23.9 percent among patients with elevated troponin T levels, as compared with 7.5 percent among patients without elevated troponin T levels (P<0.001). Among patients treated with abciximab, the respective six-month event rates were 9.5 percent for patients with elevated troponin T levels and 9.4 percent for those without elevated levels. As compared with placebo, the relative risk of death or nonfatal myocardial infarction associated with treatment with abciximab in patients with elevated troponin T levels was 0.32 (95 percent confidence interval, 0.14 to 0.62; P=0.002). The lower event rates in patients receiving abciximab were attributable to a reduction in the rate of myocardial infarction (odds ratio, 0.23; 95 percent confidence interval, 0.12 to 0.49; P<0.001). In patients without elevated troponin T levels, there was no benefit of treatment with respect to the relative risk of death or myocardial infarction at six months (odds ratio, 1.26; 95 percent confidence interval, 0.74 to 2.31; P=0.47). CONCLUSIONS: The serum troponin T level, which is considered to be a surrogate marker for thrombus formation, identifies a high-risk subgroup of patients with refractory unstable angina suitable for coronary angioplasty who will particularly benefit from antiplatelet treatment with abciximab.


Assuntos
Angina Instável/tratamento farmacológico , Anticorpos Monoclonais/uso terapêutico , Fragmentos Fab das Imunoglobulinas/uso terapêutico , Inibidores da Agregação Plaquetária/uso terapêutico , Troponina T/sangue , Abciximab , Angina Instável/sangue , Angina Instável/mortalidade , Biomarcadores/sangue , Creatina Quinase/sangue , Feminino , Humanos , Isoenzimas , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores , Valor Preditivo dos Testes , Fatores de Risco , Resultado do Tratamento
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