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1.
J Am Coll Cardiol ; 81(7): 653-664, 2023 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-36792280

RESUMO

BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by obstruction of major pulmonary arteries with organized thrombi. Clinical risk factors for pulmonary hypertension due to left heart disease including metabolic syndrome, left-sided valvular heart disease, and ischemic heart disease are common in CTEPH patients. OBJECTIVES: The authors sought to investigate prevalence and prognostic implications of elevated left ventricular filling pressures (LVFP) in CTEPH. METHODS: A total of 593 consecutive CTEPH patients undergoing a first diagnostic right and left heart catheterization were included in this study. Mean pulmonary arterial wedge pressure (mPAWP) and left ventricular end-diastolic pressure (LVEDP) were utilized for assessment of LVFP. Two cutoffs were applied to identify patients with elevated LVFP: 1) for the primary analysis mPAWP and/or LVEDP >15 mm Hg, as recommended by the current pulmonary hypertension guidelines; and 2) for the secondary analysis mPAWP and/or LVEDP >11 mm Hg, representing the upper limit of normal. Clinical and echocardiographic features, and long-term mortality were assessed. RESULTS: LVFP was >15 mm Hg in 63 (10.6%) and >11 mm Hg in 222 patients (37.4%). Univariable logistic regression analysis identified age, systemic hypertension, diabetes, atrial fibrillation, calcific aortic valve stenosis, mitral regurgitation, and left atrial volume as significant predictors of elevated LVFP. Atrial fibrillation, calcific aortic valve stenosis, mitral regurgitation, and left atrial volume remained independent determinants of LVFP in adjusted analysis. At follow-up, higher LVFPs were measured in patients who had meanwhile undergone pulmonary endarterectomy (P = 0.002). LVFP >15 mm Hg (P = 0.021) and >11 mm Hg (P = 0.006) were both associated with worse long-term survival. CONCLUSIONS: Elevated LVFP is common, appears to be due to comorbid left heart disease, and predicts prognosis in CTEPH.


Assuntos
Fibrilação Atrial , Hipertensão Pulmonar , Hipertensão , Insuficiência da Valva Mitral , Estenose da Valva Mitral , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/epidemiologia , Hipertensão Pulmonar/etiologia , Função Ventricular Esquerda , Pressão Propulsora Pulmonar , Pressão Ventricular
2.
J Clin Lipidol ; 15(3): 512-521, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33789832

RESUMO

BACKGROUND: Proprotein convertase subtilisin/kexin type-9 (PCSK9) is an enzyme promoting the degradation of low-density lipoprotein receptors (LDL-R) in hepatocytes. Inhibition of PCSK9 has emerged as a novel target for lipid-lowering therapy. Monocytes are crucially involved in the pathogenesis of atherosclerosis and can be divided into three subsets. OBJECTIVE: The aim of this study was to examine whether circulating levels of PCSK9 are associated with monocyte subsets. METHODS: We included 69 patients with stable coronary artery disease. PCSK9 levels were measured and monocyte subsets were assessed by flow cytometry and divided into classical monocytes (CD14++CD16-; CM), intermediate monocytes (CD14++CD16+; IM) and non-classical monocytes (CD14+CD16++; NCM). RESULTS: Mean age was 64 years and 80% of patients were male. Patients on statin treatment (n = 55) showed higher PCSK9-levels (245.4 (206.0-305.5) ng/mL) as opposed to those without statin treatment (186.1 (162.3-275.4) ng/mL; p = 0.05). In patients on statin treatment, CM correlated with circulating PCSK9 levels (R = 0.29; p = 0.04), while NCM showed an inverse correlation with PCSK9 levels (R = -0.33; p = 0.02). Patients with PCSK9 levels above the median showed a significantly higher proportion of CM as compared to patients with PCSK9 below the median (83.5 IQR 79.2-86.7 vs. 80.4, IQR 76.5-85.2%; p = 0.05). Conversely, PCSK9 levels >median were associated with a significantly lower proportion of NCM as compared to those with PCSK9

Assuntos
Doença da Artéria Coronariana/sangue , Monócitos/enzimologia , Pró-Proteína Convertase 9/sangue , Idoso , LDL-Colesterol/sangue , Doença da Artéria Coronariana/tratamento farmacológico , Estudos Transversais , Feminino , Citometria de Fluxo , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Imunidade Inata , Imunofenotipagem , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia
3.
J Leukoc Biol ; 109(6): 1139-1146, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33020969

RESUMO

After successful cardiopulmonary resuscitation (CPR), many patients show signs of an overactive immune activation. Monocytes are a heterogeneous cell population that can be distinguished into 3 subsets by flow cytometry (classical monocytes [CM: CD14++ CD16- ], intermediate monocytes [IM: CD14++ CD16+ CCR2+ ] and non-classical monocytes [NCM: CD14+ CD16++ CCR2- ]). Fifty-three patients admitted to the medical intensive care unit (ICU) after cardiac arrest were included. Blood was taken on admission and after 72 h. The primary endpoint of this study was survival at 6 months and the secondary endpoint was neurological outcome as determined by cerebral performance category (CPC)-score at 6 months. Median age was 64.5 (49.8-74.3) years and 75.5% were male. Six-month mortality was 50.9% and survival with good neurological outcome was 37.7%. Monocyte subset distribution upon admission to the ICU did not differ according to survival. Seventy-two hours after admission, patients who died within 6 months showed a higher percentage of the pro-inflammatory subset of IM (8.3% [3.8-14.6]% vs. 4.1% [1.5-8.2]%; P = 0.025), and a lower percentage of CM (87.5% [79.9-89.0]% vs. 90.8% [85.9-92.7]%; P = 0.036) as compared to survivors. In addition, IM were predictive of outcome independent of time to ROSC and witnessed cardiac arrest, and correlated with CPC-score at 6 months (R = 0.32; P = 0.043). These findings suggest a possible role of the innate immune system in the pathophysiology of post cardiac arrest syndrome.


Assuntos
Biomarcadores , Polaridade Celular/imunologia , Parada Cardíaca/mortalidade , Monócitos/imunologia , Monócitos/metabolismo , Idoso , Citocinas/metabolismo , Feminino , Citometria de Fluxo , Parada Cardíaca/etiologia , Humanos , Imunofenotipagem , Mediadores da Inflamação/metabolismo , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais
4.
PLoS One ; 15(5): e0232483, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32392256

RESUMO

BACKGROUND: Percutaneous coronary intervention represents the most important treatment modality of coronary artery stenosis. In-stent restenosis (ISR) is still a limitation for the long-term outcome despite the introduction of drug eluting stents. It has been shown that adipokines directly influence vessel wall homeostasis by influencing the function of endothelial cells and arterial smooth muscle cells. Visceral adipose tissue-derived serpin vaspin was recently identified as a member of serine protease inhibitor family and serveral studies could demonstrate a relation to metabolic diseases. The aim of this study was to investigate a role of vaspin in the development of in-stent restenosis in vivo and on migration of smooth muscle cells and endothelial cells in vitro. METHODS: We studied 85 patients with stable coronary artery disease who underwent elective and successful PCI with implatation of drug eluting stents. Blood samples were taken directly before PCI. Vaspin plasma levels were measured by specific ELISA. ISR was evaluated eight months later by coronary angiography. Human coronary artery smooth muscle cells (HCASMC) and human umbilical vein endothelial cells (HUVEC) migration was analyzed by an in-vitro migration assay with different concentrations (0.004ng/mL up to 40ng/mL) of vaspin as well as by an scratch assay. For proliferation an impedance measurement with specialiced E-Plates was performed. RESULTS: During the follow up period, 14 patients developed ISR. Patients with ISR had significantly lower vaspin plasma levels compared to patients without ISR (0.213 ng/ml vs 0.382 ng/ml; p = 0.001). In patients with plasma vaspin levels above 1.35 ng/ml we could not observe any restenosis. There was also a significant correlation of plasma vaspin levels and late lumen loss in the stented coronary segments. Further we could demonstrate that vaspin nearly abolishes serum induced migration of HCASMC (100% vs. 9%; p<0.001) in a biphasic manner but not migration of HUVEC. Proliferation of HCASMC and HUVEC was not modulated by vaspin treatment. CONCLUSION: We were able to show that the adipokine vaspin selectively inhibits human coronary SMC migration in vitro and has no effect on HUVEC migration. Vaspin had no effect on proliferation of HUVEC which is an important process of the healing of the stented vessel. In addition, the occurrence of ISR after PCI with implantation of drug eluting stents was significantly associated with low vaspin plasma levels before intervention. Determination of vaspin plasma levels before PCI might be helpful in the identification of patients with high risk for development of ISR after stent implantation. In addition, the selective effects of vaspin on smooth muscle cell migration could potentially be used to reduce ISR without inhibition of re-endothelialization of the stented segment.


Assuntos
Adipocinas/fisiologia , Reestenose Coronária/etiologia , Intervenção Coronária Percutânea/efeitos adversos , Serpinas/fisiologia , Adipocinas/sangue , Adipocinas/farmacologia , Idoso , Movimento Celular/efeitos dos fármacos , Movimento Celular/fisiologia , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Células Cultivadas , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/patologia , Doença da Artéria Coronariana/cirurgia , Reestenose Coronária/patologia , Reestenose Coronária/fisiopatologia , Vasos Coronários/patologia , Vasos Coronários/fisiopatologia , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Técnicas In Vitro , Masculino , Pessoa de Meia-Idade , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/patologia , Miócitos de Músculo Liso/fisiologia , Serpinas/sangue , Serpinas/farmacologia
5.
Shock ; 54(1): 35-43, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-31688663

RESUMO

BACKGROUND: Toll-like receptors (TLRs) play an important role in inflammatory processes in critically ill patients by binding to pathogen-associated molecular patterns and danger-associated molecular patterns (DAMPs). Whether neutrophil or monocyte TLR expression patterns are associated with outcome in critical illness is unknown. OBJECTIVES: To answer this question, we conducted a prospective, observational study including 215 consecutive patients admitted to a medical ICU at a tertiary care center. METHODS: Blood was drawn at admission and expression of TLR-2, TLR-4, and TLR-9 on neutrophils and monocytes were analyzed by flow cytometry. RESULTS: Median Acute Physiology and Chronic Health Evaluation II (APACHE II) score was 19, and 30-day mortality was 26%. TLR-2 expression on neutrophils was associated with APACHE II, Simplified Acute Physiology Score II, and Sepsis-related Organ Failure Assessment score. TLR-2 (P < 0.001) and TLR-9 (P < 0.05) expression on neutrophils was significantly higher in nonsurvivors. In contrast, neutrophil TLR-4 expression and monocyte TLR expression were not associated with survival. Neutrophil TLR-2 (odds ratio 3.8; 95% confidence interval 1.4-10.2; P < 0.05) and TLR-9 (odds ratio 4.0; 95% confidence interval 2.0-8.1; P < 0.001) expression in the third tertile predicted mortality independent from APACHE II, serum lactate, serum creatinine, and procalcitonin, respectively. CONCLUSION: We provide evidence for prognostic properties of neutrophil TLR-2 and TLR-9 expression regarding 30-day mortality in unselected critically ill patients, independent from baseline clinical characteristics, and laboratory values. These findings suggest that specific TLR-dependent activation of the innate immune system via neutrophils possibly caused by cell damage and release of otherwise intracellular components may play a significant role in the pathophysiology of critical illness.


Assuntos
Estado Terminal/mortalidade , Neutrófilos/metabolismo , Receptor 2 Toll-Like/metabolismo , Receptor Toll-Like 9/metabolismo , APACHE , Idoso , Feminino , Citometria de Fluxo , Humanos , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , Estudos Prospectivos , Receptor 2 Toll-Like/sangue , Receptor 4 Toll-Like/sangue , Receptor 4 Toll-Like/metabolismo , Receptor Toll-Like 9/sangue
6.
Resuscitation ; 143: 22-28, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31394153

RESUMO

BACKGROUND: Early prognostication in post-cardiac arrest (CA) patients remains challenging and biomarkers have evolved as helpful tools in risk assessment. The stress-response cytokine growth differentiation factor-15 (GDF-15) is dramatically up-regulated during various kinds of tissue injury and predicts outcome in many pathological conditions. We aimed to assess the predictive value of circulating GDF-15 in post-CA patients. METHODS: This prospective observational study included 128 consecutive patients (median age 60.3 years, 75.8% male) with return of spontaneous circulation after in- or out-of-hospital CA who were treated at a tertiary university hospital. GDF-15 serum levels were determined at admission. RESULTS: A total of 52 patients (40.6%) died during the 6-month follow-up. Median GDF-15 levels were significantly lower in survivors (1601 ng/L (interquartile range: 1114-2983 ng/L) than in non-survivors (3172 ng/L (1927-8340 ng/L); p < 0.001). GDF-15 levels were also significantly lower in patients with favourable neurological 6-month outcome (cerebral performance category (CPC) 1-2) than in those with poor neurological outcome (CPC 3-5; p < 0.001). GDF-15 significantly predicted 6-month mortality in univariate Cox regression analysis (hazard ratio (HR) per 1-standard deviation increase 1.76 [95% confidence interval (CI) 1.35-2.31; p < 0.001] and remained significant after multivariable adjustment (HR 1.57 [95% CI 1.19-2.07; p = 0.001]). Subgroup analysis revealed that the association between GDF-15 and 6-month outcome was present both in patients with in- and out-of-hospital CA. CONCLUSIONS: GDF-15 predicts poor survival and neurological outcome in post-CA patients. GDF-15 may reflect the extent of hypoxic injury to the brain and other organs and might help to improve early risk stratification after CA.


Assuntos
Fator 15 de Diferenciação de Crescimento/sangue , Parada Cardíaca/sangue , Ressuscitação/métodos , Áustria/epidemiologia , Biomarcadores/sangue , Feminino , Seguimentos , Parada Cardíaca/mortalidade , Parada Cardíaca/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Taxa de Sobrevida/tendências
7.
Shock ; 51(4): 410-415, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-29847500

RESUMO

BACKGROUND: Acute heart failure and cardiogenic shock are associated with an impaired intestinal perfusion, which may lead to a release of cytoplasmatic proteins by hypoxic epithelial injury. Intestinal fatty acid binding protein (iFABP), highly specific for the small bowel enterocyte, may pose a useful novel and very sensitive biomarker for predicting outcome of these patients.The aim of this study was to investigate whether circulating levels of iFABP are associated with mortality in patients with acute heart failure or cardiogenic shock requiring intensive care unit (ICU) admission. METHODS: We included 90 consecutive patients with cardiogenic shock (74.4%) or severe acute heart failure (25.6%) admitted to a cardiac ICU. Blood samples were taken at day 0 and day 3. Median age was 64.7 (49.4-74.3), 76.7% of patients were male and median NT-proBNP levels were 4,986 (1,525-23,842) pg/mL. 30-day survival was 64.4%. RESULTS: Patients with serum levels of iFABP at day 0 in the highest quartile (iFABP ≥ 588.4 pg/mL) had a 2.5-fold risk (P = 0.02) of dying independent of demographics, NT-proBNP levels, and vasopressor use. Extensively elevated admission levels of iFABP above the 90th percentile (iFABP ≥ 10208.4 pg/mL) were associated with an excessive mortality rate of 88.9%. In contrast, iFABP levels at day 3 were not associated with outcome. CONCLUSION: Circulating levels of iFABP at admission predict mortality. This suggests that early inadequate perfusion of the small intestine may be associated with a dramatically decreased survival in patients with cardiogenic shock or severe acute heart failure.


Assuntos
Biomarcadores/sangue , Proteínas de Ligação a Ácido Graxo/sangue , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/mortalidade , Choque Cardiogênico/sangue , Choque Cardiogênico/mortalidade , Doença Aguda , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Inflamação/sangue , Inflamação/mortalidade , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
8.
Vascul Pharmacol ; 90: 44-50, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28192257

RESUMO

AIMS: Levosimendan is an inodilator for the treatment of acute decompensated heart failure (HF). Data from clinical studies suggest that levosimendan is particularly effective in HF due to myocardial infarction. After acute revascularization, no reflow-phenomenon is a common complication that may lead to pump failure and cardiogenic shock. Our aim was to examine whether levosimendan interferes with the pro-thrombotic phenotype of activated endothelial cells in vitro. METHODS: Human heart microvascular endothelial cells (HHMEC) and human umbilical vein endothelial cells (HUVEC) were treated with interleukin-1ß (IL-1ß) (200U/mL) or thrombin (5U/mL) and co-treated with or without levosimendan (0.1-10µM) for 2-24h. In addition, flow experiments were performed. Effects on plasminogen activator inhibitor-1 (PAI-1) and tissue factor (TF) expression and activity were measured by rt-PCR, specific ELISA and flow cytometry. RESULTS: Treatment with IL-1ß or thrombin significantly increased the expression of PAI-1 and TF in endothelial cells. Co-treatment with levosimendan strongly attenuated the effects of IL-1ß and thrombin on PAI-1 and TF mRNA by up to 50% and 45%, in a dose- and time-dependent manner. Similar results were obtained under flow conditions. Furthermore, co-treatment with levosimendan dampened the antigen production of PAI-1 and the surface expression of TF by 35% and 45%, respectively. Additionally, levosimendan diminished both TF and PAI-1 activity. CONCLUSION: Levosimendan down-regulates the expression of the pro-thrombotic and anti-fibrinolytic biomolecules TF and PAI-1 in activated human endothelial cells. Our findings may, at least in part, explain some of the beneficial effects of levosimendan after myocardial reperfusion.


Assuntos
Fibrinólise/efeitos dos fármacos , Fibrinolíticos/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Hidrazonas/farmacologia , Piridazinas/farmacologia , Células Cultivadas , Relação Dose-Resposta a Droga , Regulação para Baixo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Interleucina-1beta/farmacologia , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Simendana , Trombina/farmacologia , Tromboplastina/metabolismo , Fatores de Tempo
9.
BMC Pregnancy Childbirth ; 16(1): 128, 2016 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-27251149

RESUMO

BACKGROUND: Pregnancy associated cardiovascular pathologies have a significant impact on outcome for mother and child. Bioimpedance cardiography may provide additional outcome-relevant information early in pregnancy and may also be used as a predictive instrument for pregnancy-associated diseases. METHODS: We performed a prospective longitudinal cohort trial in an outpatient setting and included 242 pregnant women. Cardiac output and concomitant hemodynamic data were recorded from 11(th)-13(th) week of gestation every 5(th) week as well as at two occasions post partum employing bioimpedance cardiography. RESULTS: Cardiac output increased during pregnancy and peaked early in the third trimester. A higher heart rate and a decreased systemic vascular resistance were accountable for the observed changes. Women who had a pregnancy-associated disease during a previous pregnancy or developed hypertension or preeclampsia had a significantly increased cardiac output early in pregnancy. Furthermore, an effect of cardiac output on birthweight was found in healthy pregnancies and could be confirmed with multiple linear regression analysis. CONCLUSIONS: Cardiovascular adaptation during pregnancy is characterized by distinct pattern described herein. These may be altered in women at risk for preeclampsia or reduced birthweigth. The assessment of cardiac parameters by bioimpedance cardiography could be performed at low costs without additional risks.


Assuntos
Adaptação Fisiológica , Peso ao Nascer , Complicações Cardiovasculares na Gravidez/fisiopatologia , Trimestres da Gravidez/fisiologia , Gravidez/fisiologia , Adulto , Pressão Sanguínea , Cardiografia de Impedância , Feminino , Idade Gestacional , Síndrome HELLP/fisiopatologia , Voluntários Saudáveis , Frequência Cardíaca , Humanos , Recém-Nascido , Estudos Longitudinais , Período Pós-Parto/fisiologia , Pré-Eclâmpsia/fisiopatologia , Complicações Cardiovasculares na Gravidez/diagnóstico , Estudos Prospectivos , Volume Sistólico , Resistência Vascular
10.
PLoS One ; 10(11): e0142532, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26555480

RESUMO

Granulocyte-colony-stimulating-factor (G-CSF) induces mobilization of progenitor cells but may also exert pro-inflammatory and pro-thrombotic effects. Treatment with recombinant G-CSF after acute myocardial infarction is currently under examination and has been associated with in-stent restenosis. However, it is not known whether plasma levels of endogenous G-CSF are also associated with an increased cardiovascular risk. Therefore we included 280 patients with angiographically proven stable coronary artery disease. G-CSF was measured by specific ELISA and patients were followed for a median of 30 months for the occurrence of major adverse cardiovascular events (MACE: death, myocardial infarction, re-hospitalization). Those with cardiac events during follow-up showed significant higher G-CSF levels (32.3 pg/mL IQR 21.4-40.5 pg/mL vs. 24.6 pg/mL IQR 16.4-34.9 pg/mL; p<0.05) at baseline. Patients with G-CSF plasma levels above the median had a 2-fold increased risk for MACE (p<0.05). This was independent from established cardiovascular risk factors. In addition, G-CSF above the median was a predictor of clinical in-stent restenosis after implantation of bare-metal stents (6.6% vs. 19.4%; p<0.05) but not of drug-eluting stents (7.7% vs. 7.6%; p = 0.98). This data suggests that endogenous plasma levels of G-CSF predict cardiovascular events independently from established cardiac risk factors and are associated with increased in-stent restenosis rates after implantation of bare metal stents.


Assuntos
Doença da Artéria Coronariana/complicações , Fator Estimulador de Colônias de Granulócitos/fisiologia , Infarto do Miocárdio/complicações , Idoso , Doença da Artéria Coronariana/fisiopatologia , Feminino , Fator Estimulador de Colônias de Granulócitos/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/fisiopatologia
11.
J Clin Lipidol ; 9(4): 533-41, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26228671

RESUMO

BACKGROUND: Lipoprotein(a) (Lp(a)) is a proatherogenic plasma lipoprotein currently established as an independent risk factor for the development of atherosclerotic disease and as a predictor for acute thrombotic complications. In addition, Lp(a) is the major carrier of proinflammatory oxidized phospholipids (OxPL). Today, atherosclerosis is considered to be an inflammatory disease of the vessel wall in which monocytes and monocyte-derived macrophages are crucially involved. Circulating monocytes can be divided according to their surface expression pattern of CD14 and CD16 into at least 3 subsets with distinct inflammatory and atherogenic potential. OBJECTIVE: The aim of this study was to examine whether elevated levels of Lp(a) and OxPL on apolipoprotein B-100-containing lipoproteins (OxPL/apoB) are associated with changes in monocyte subset distribution. METHODS: We included 90 patients with stable coronary artery disease. Lp(a) and OxPL/apoB were measured, and monocyte subsets were identified as classical monocytes (CMs; CD14++CD16-), intermediate monocytes (IMs; CD14++CD16+), and nonclassical monocytes (NCMs; CD14+CD16++) by flow cytometry. RESULTS: In patients with elevated levels of Lp(a) (>50 mg/dL), monocyte subset distribution was skewed toward an increase in the proportion of IM (7.0 ± 3.8% vs 5.2 ± 3.0%; P = .026), whereas CM (82.6 ± 6.5% vs 82.0 ± 6.8%; P = .73) and NCM (10.5 ± 5.3 vs 12.8 ± 6.0; P = .10) were not significantly different. This association was independent of clinical risk factors, choice of statin treatment regime, and inflammatory markers. In addition, OxPL/apoB was higher in patients with elevated Lp(a) and correlated with IM but not CM and NCM. CONCLUSIONS: In conclusion, we provide a potential link between elevated levels of Lp(a) and a proatherogenic distribution of monocyte subtypes in patients with stable atherosclerotic disease.


Assuntos
Aterosclerose/sangue , Doença da Artéria Coronariana/sangue , Monócitos/metabolismo , Oxirredução , Idoso , Apolipoproteína B-100/sangue , Aterosclerose/patologia , Linhagem da Célula , Doença da Artéria Coronariana/patologia , Feminino , Proteínas Ligadas por GPI/sangue , Humanos , Receptores de Lipopolissacarídeos/sangue , Lipoproteína(a)/sangue , Masculino , Pessoa de Meia-Idade , Monócitos/patologia , Fosfolipídeos/sangue , Receptores de IgG/sangue , Fatores de Risco
12.
PLoS One ; 10(4): e0123367, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25849089

RESUMO

OBJECTIVE: Atherosclerosis is considered to be an inflammatory disease in which monocytes and monocyte-derived macrophages play a key role. Circulating monocytes can be divided into three distinct subtypes, namely in classical monocytes (CM; CD14++CD16-), intermediate monocytes (IM; CD14++CD16+) and non-classical monocytes (NCM; CD14+CD16++). Low density lipoprotein particles are heterogeneous in size and density, with small, dense LDL (sdLDL) crucially implicated in atherogenesis. The aim of this study was to examine whether monocyte subsets are associated with sdLDL serum levels. METHODS: We included 90 patients with angiographically documented stable coronary artery disease and determined monocyte subtypes by flow cytometry. sdLDL was measured by an electrophoresis method on polyacrylamide gel. RESULTS: Patients with sdLDL levels in the highest tertile (sdLDL≥4mg/dL;T3) showed the highest levels of pro-inflammatory NCM (15.2±7% vs. 11.4±6% and 10.9±4%, respectively; p<0.01) when compared with patients in the middle (sdLDL=2-3mg/dL;T2) and lowest tertile (sdLDL=0-1mg/dL;T1). Furthermore, patients in the highest sdLDL tertile showed lower CM levels than patients in the middle and lowest tertile (79.2±8% vs. 83.9±7% and 82.7±5%; p<0.01 for T3 vs. T2+T1). Levels of IM were not related to sdLDL levels (5.6±4% vs. 4.6±3% vs. 6.4±3% for T3, T2 and T1, respectively). In contrast to monocyte subset distribution, levels of circulating pro- and anti-inflammatory markers were not associated with sdLDL levels. CONCLUSION: The atherogenic lipoprotein fraction sdLDL is associated with an increase of NCM and a decrease of CM. This could be a new link between lipid metabolism dysregulation, innate immunity and atherosclerosis.


Assuntos
Biomarcadores/análise , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/patologia , Lipoproteínas LDL/sangue , Monócitos/patologia , Idoso , Angiografia Coronária , Estudos Transversais , Feminino , Citometria de Fluxo , Humanos , Masculino , Pessoa de Meia-Idade
13.
Thromb Haemost ; 113(2): 350-62, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25273157

RESUMO

Levosimendan is a positive inotropic drug for the treatment of acute decompensated heart failure (HF). Clinical trials showed that levosimendan was particularly effective in HF due to myocardial infarction. Myocardial necrosis induces a strong inflammatory response, involving chemoattractants guiding polymorphonuclear neutrophils (PMN) into the infarcted myocardial tissue. Our aim was to examine whether levosimendan exhibits anti-inflammatory effects on human adult cardiac myocytes (HACM) and human heart microvascular endothelial cells (HHMEC). Cardiac myocytes and endothelial cells were stimulated with interleukin-1ß (IL)-1ß (200 U/ml) and treated with levosimendan (0.1-10 µM) for 2-48 hours. IL-1ß strongly induced expression of IL-6 and IL-8 in HACM and E-selectin and intercellular adhesion molecule-1 (ICAM-1) in HHMEC and human umbilical vein endothelial cells (HUVEC). Treatment with levosimendan strongly attenuated IL-1ß-induced expression of IL-6 and IL-8 in HACM as well as E-selectin and ICAM-1 in ECs. Levosimendan treatment further reduced adhesion of PMN to activated endothelial cells under both static and flow conditions by approximately 50 %. Incubation with 5-hydroxydecanoic acid, a selective blocker of mitochondrial ATP-dependent potassium channels, partly abolished the above seen anti-inflammatory effects. Additionally, levosimendan strongly diminished IL-1ß-induced reactive oxygen species and nuclear factor-κB (NF-κB) activity through inhibition of S536 phosphorylation. In conclusion, levosimendan exhibits anti-inflammatory effects on cardiac myocytes and endothelial cells in vitro. These findings could explain, at least in part, the beneficial effects of levosimendan after myocardial infarction.


Assuntos
Anti-Inflamatórios/química , Hidrazonas/química , Inflamação/fisiopatologia , Miócitos Cardíacos/citologia , Piridazinas/química , Adesão Celular , Células Cultivadas , Ácidos Decanoicos/química , Selectina E/metabolismo , Ensaio de Imunoadsorção Enzimática , Insuficiência Cardíaca/fisiopatologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Hidroxiácidos/química , Molécula 1 de Adesão Intercelular/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Microcirculação , Microscopia de Fluorescência , Células Musculares/patologia , Infarto do Miocárdio/fisiopatologia , Miócitos Cardíacos/efeitos dos fármacos , NF-kappa B/metabolismo , Necrose , Neutrófilos/citologia , Fosforilação , Espécies Reativas de Oxigênio/metabolismo , Simendana , Vasodilatadores/química
14.
Atherosclerosis ; 237(2): 589-96, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25463093

RESUMO

OBJECTIVE: High-density lipoprotein (HDL) particles are heterogeneous in structure and function and the role of HDL subfractions in atherogenesis is not well understood. It has been suggested that small HDL may be dysfunctional in patients with coronary artery disease (CAD). Monocytes are considered to play a key role in atherosclerotic diseases. Circulating monocytes can be divided into three subtypes according to their surface expression of CD14 and CD16. Our aim was to examine whether monocyte subsets are associated with HDL subfractions in patients with atherosclerosis. METHODS: We included 90 patients with angiographically stable CAD. Monocyte subsets were defined as classical monocytes (CD14++CD16-; CM), intermediate monocytes (CD14++CD16+; IM) and non-classical monocytes (CD14+CD16++; NCM). HDL subfractions were measured by electrophoresis on polyacrylamide gel. RESULTS: Serum levels of small HDL correlated with circulating pro-inflammatory NCM and showed an inverse relationship to circulating CM independently from other lipid parameters, risk factors, inflammatory parameters or statin treatment regime, respectively. IM were not associated with small HDL. In particular, patients with small HDL levels in the highest tertile showed dramatically increased levels of NCM (14.7 ± 7% vs. 10.7 ± 5% and 10.8 ± 5%; p = 0.006) and a decreased proportion of CM (79.3 ± 7% vs. 83.7 ± 6% and 83.9 ± 6%; p = 0.004) compared to patients in the two lower tertiles. In contrast, intermediate HDL, large HDL and total HDL were not associated with monocyte subset distribution. CONCLUSION: Small HDL levels are associated with pro-inflammatory NCM and inversely correlated with CM. This may suggest that small HDL could have dysfunctional anti-inflammatory properties in patients with established CAD.


Assuntos
Doença da Artéria Coronariana/sangue , Lipoproteínas HDL/sangue , Monócitos/citologia , Idoso , Aterosclerose , Atorvastatina , Pressão Sanguínea , Angiografia Coronária , Estudos Transversais , Feminino , Fluorbenzenos/uso terapêutico , Fator Estimulador de Colônias de Granulócitos/metabolismo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Ácidos Heptanoicos/uso terapêutico , Humanos , Inflamação , Interleucina-10/metabolismo , Lipídeos/química , Fator Estimulador de Colônias de Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Fatores de Risco , Rosuvastatina Cálcica , Sulfonamidas/uso terapêutico
15.
EuroIntervention ; 10(2): 224-30, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24168783

RESUMO

AIMS: Drug-eluting stents (DES) reduce late lumen loss compared to bare metal stents but were not able to eradicate in-stent restenosis (ISR) fully. Vascular endothelial growth factor (VEGF) may inhibit late lumen loss through accelerated reendothelialisation, but may also promote neointima formation by proinflammatory effects. The aim of this study was to evaluate whether endogenous plasma levels of VEGF are associated with development of ISR after implantation of DES. METHODS AND RESULTS: We studied 85 patients who were treated with 159 DES. VEGF plasma levels were determined before and 24 hours after PCI. During the eight-month follow-up period, two patients (2.4%) died of cardiovascular causes and 12 patients (14.5% of patients, 7.6% of stents) developed angiographic ISR. Basal VEGF plasma levels were not different in patients with and without ISR at follow-up. In contrast to patients without ISR, VEGF increased significantly upon PCI in patients with ISR (p<0.005). Patients with a decrease of VEGF after PCI had a restenosis rate of 2.4% compared to a restenosis rate of 26.2% in patients with an increase of VEGF after the procedure (p<0.05). This was independent from clinical and angiographic risk factors. CONCLUSIONS: Basal plasma levels of VEGF are not associated with the development of ISR. However, an increase of VEGF after PCI is associated with a dramatically increased ISR rate after implantation of DES.


Assuntos
Doença da Artéria Coronariana/terapia , Reestenose Coronária/sangue , Reestenose Coronária/etiologia , Stents Farmacológicos , Intervenção Coronária Percutânea/instrumentação , Fator A de Crescimento do Endotélio Vascular/sangue , Idoso , Angiografia Coronária , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/diagnóstico por imagem , Reestenose Coronária/diagnóstico por imagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Intervenção Coronária Percutânea/efeitos adversos , Estudos Prospectivos , Fatores de Risco , Fatores de Tempo , Regulação para Cima
16.
Atherosclerosis ; 222(1): 251-6, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22391424

RESUMO

OBJECTIVE: Besides its effects on glucose and lipid metabolism, the Wnt pathway has been increasingly implicated in the regulation of proliferation, migration and survival of vascular cells. In addition, defective Wnt signaling has been identified in a family with autosomal dominant early coronary artery disease. The aim of this study was to investigate whether premature coronary artery disease is associated with features of decreased Wnt signaling. METHODS AND RESULTS: We prospectively enrolled 100 consecutive young survivors of myocardial infarction (MI≤40 years of age) from two high-volume cardiac catheterization centers and 100 sex and age matched hospital controls. We determined serum levels of Wnt-1 and its antagonist Dkk-1 by ELISA. MI patients showed significantly lower Wnt-1 levels as compared to controls (151 ng/mL, IQR 38-473 ng/mL vs. 233 ng/mL, IQR 62-1756; p<0.005) whereas Dkk-1 was not different at baseline. Wnt-1 levels remained stable over time, whereas Dkk-1 significantly increased at one-year follow-up from 3557, IQR 2306-5810 pg/mL to 4973, IQR 3293-7093 pg/mL (p<0.001). In the stable phase of the disease, Wnt-1 levels were lower (p<0.005) and Dkk-1 levels were significantly higher (p<0.001) as compared to controls. Wnt-1 at follow-up was associated with glucose, HbA1c, non-HDL-, HDL-cholesterol and triglyceride levels but no other features of the metabolic syndrome. CONCLUSION: This study establishes an association between low Wnt-1 and high Dkk-1 serum levels and premature myocardial infarction. Wnt-1 is associated with markers of glucose and lipid metabolism. Further research elucidating the role of Wnt pathways in premature coronary artery disease and metabolic syndrome is warranted.


Assuntos
Peptídeos e Proteínas de Sinalização Intercelular/sangue , Infarto do Miocárdio/sangue , Proteína Wnt1/sangue , Adulto , Feminino , Seguimentos , Humanos , Masculino , Via de Sinalização Wnt
17.
Arterioscler Thromb Vasc Biol ; 31(9): 2080-9, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21737781

RESUMO

OBJECTIVE: Interleukin (IL)-33 is the most recently described member of the IL-1 family of cytokines and it is a ligand of the ST2 receptor. While the effects of IL-33 on the immune system have been extensively studied, the properties of this cytokine in the cardiovascular system are much less investigated. Methods/Results- We show here that IL-33 promoted the adhesion of human leukocytes to monolayers of human endothelial cells and robustly increased vascular cell adhesion molecule-1, intercellular adhesion molecule-1, endothelial selectin, and monocyte chemoattractant protein-1 protein production and mRNA expression in human coronary artery and human umbilical vein endothelial cells in vitro as well as in human explanted atherosclerotic plaques ex vivo. ST2-fusion protein, but not IL-1 receptor antagonist, abolished these effects. IL-33 induced translocation of nuclear factor-κB p50 and p65 subunits to the nucleus in human coronary artery endothelial cells and human umbilical vein endothelial cells and overexpression of dominant negative form of IκB kinase 2 or IκBα in human umbilical vein endothelial cells abolished IL-33-induced adhesion molecules and monocyte chemoattractant protein-1 mRNA expression. We detected IL-33 and ST2 on both protein and mRNA level in human carotid atherosclerotic plaques. CONCLUSIONS: We hypothesize that IL-33 may contribute to early events in endothelial activation characteristic for the development of atherosclerotic lesions in the vessel wall, by promoting adhesion molecules and proinflammatory cytokine expression in the endothelium.


Assuntos
Moléculas de Adesão Celular/biossíntese , Células Endoteliais/fisiologia , Inflamação/etiologia , Interleucinas/fisiologia , Placa Aterosclerótica/etiologia , Adesão Celular , Células Cultivadas , Humanos , Proteína 1 Semelhante a Receptor de Interleucina-1 , Interleucina-33 , Leucócitos/fisiologia , NF-kappa B/fisiologia , Fosfatidilinositol 3-Quinases/fisiologia , Receptores de Superfície Celular/fisiologia
18.
FASEB J ; 25(1): 35-44, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20813982

RESUMO

The complement component C5a is formed during activation of the complement cascade and exerts chemotactic and proinflammatory effects. Macrophages, which are localized in the rupture-prone shoulder regions of coronary plaques, are thought to play a major role in plaque destabilization and rupture through the production of matrix metalloproteinases (MMPs). When human monocyte-derived macrophages were stimulated in vitro with C5a, MMP-1 and MMP-9 mRNA levels were significantly increased. Furthermore, C5a up-regulated MMP-1 and MMP-9 antigens and activity, as determined by ELISA and specific activity assays. These effects were blocked by antibodies against the receptor C5aR/CD88. In addition, blocking experiments revealed that MMP-1 expression was mediated by activation of the transcription factor AP-1, and MMP-9 expression was induced by activation of NF-κB and AP-1. Immunohistochemical analysis of human coronary plaques demonstrated the colocalization of C5a, MMP-1, and MMP-9 in vivo. Together, these observations indicate that activation of the complement cascade and formation of C5a may play a role in the onset of acute coronary events by induction of MMPs in atherosclerotic lesions.


Assuntos
Complemento C5a/metabolismo , Vasos Coronários/metabolismo , Macrófagos/metabolismo , Placa Aterosclerótica/metabolismo , Células Cultivadas , Complemento C5a/genética , Complemento C5a/farmacologia , Vasos Coronários/patologia , Imunofluorescência , Expressão Gênica/efeitos dos fármacos , Humanos , Imuno-Histoquímica , Macrófagos/efeitos dos fármacos , Masoprocol/farmacologia , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 1 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Placa Aterosclerótica/patologia , Quinazolinas/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptor da Anafilatoxina C5a/metabolismo , Proteínas Recombinantes/farmacologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Transcrição AP-1/antagonistas & inibidores , Fator de Transcrição AP-1/metabolismo
19.
Basic Res Cardiol ; 106(2): 217-31, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21174212

RESUMO

The pleiotropic cytokine oncostatin M (OSM), a member of the glycoprotein (gp)130 ligand family, plays a key role in inflammation and cardiovascular disease. As inflammation precedes and accompanies pathological angiogenesis, we investigated the effect of OSM and other gp130 ligands on vascular endothelial growth factor (VEGF) production in human vascular smooth muscle cells (SMC). Human coronary artery SMC (HCASMC) and human aortic SMC (HASMC) were treated with different gp130 ligands. VEGF protein was determined by ELISA. Specific mRNA was detected by RT-PCR. Western blotting was performed for signal transducers and activators of transcription1 (STAT1), STAT3, Akt and p38 mitogen-activated protein kinase (p38 MAPK). OSM mRNA and VEGF mRNA expression was analyzed in human carotid endaterectomy specimens from 15 patients. OSM increased VEGF production in both HCASMC and HASMC derived from different donors. OSM upregulated VEGF and OSM receptor-specific mRNA in these cells. STAT3 inhibitor WP1066, p38 MAPK inhibitors SB-202190 and BIRB 0796, extracellular signal-regulated kinase1/2 (Erk1/2) inhibitor U0126, and phosphatidylinositol 3-kinase (PI3K) inhibitors LY-294002 and PI-103 reduced OSM-induced VEGF synthesis. We found OSM expression in human atherosclerotic lesions where OSM mRNA correlated with VEGF mRNA expression. Interferon-γ (IFN-γ), but not IL-4 or IL-10, reduced OSM-induced VEGF production in vascular SMC. Our findings that OSM, which is present in human atherosclerotic lesions and correlates with VEGF expression, stimulates production of VEGF by human coronary artery and aortic SMC indicate that OSM could contribute to plaque angiogenesis and destabilization. IFN-γ reduced OSM-induced VEGF production by vascular SMC.


Assuntos
Interferon gama/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Oncostatina M/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Adulto , Idoso , Aterosclerose/metabolismo , Células Cultivadas , Vasos Coronários/metabolismo , Feminino , Humanos , Interleucina-10/metabolismo , Interleucina-4/metabolismo , Sistema de Sinalização das MAP Quinases , Masculino , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , RNA Mensageiro/metabolismo , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT3/metabolismo , Regulação para Cima , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
20.
JACC Cardiovasc Interv ; 3(1): 90-7, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20129576

RESUMO

OBJECTIVES: Our aim was to test whether serum levels of matrix metalloproteinase (MMP)-2 and -9 are associated with the development of in-stent restenosis (ISR) after implantation of drug-eluting stents (DES). BACKGROUND: With the introduction of DES coronary ISR could be reduced dramatically. However, it still plays a significant role, particularly after treatment of multiple, complex lesions. METHODS: We studied 85 patients who were treated with 159 DES. Blood samples for measurement of MMP-2 and -9 antigen and activity were taken directly before and 24 h after percutaneous coronary intervention (PCI). Restenosis was evaluated at 6 to 8 months by coronary angiography. RESULTS: During the follow-up period, 2 patients (2.4%) died of cardiovascular causes, and 12 patients developed angiographic ISR. Patients with ISR showed significantly higher serum activity of MMP-9 at baseline (p = 0.017) and of MMP-2 (p < 0.0001) and MMP-9 (p < 0.0001) after the procedure. The PCI increased serum activity of MMP-2 (p = 0.005) and MMP-9 (p = 0.008) only in patients with ISR. The restenosis rates of patients in the highest quartile of MMP-2 after and MMP-9 before and after PCI were 40.0%, 38.9%, and 42.9% compared with 6.3%, 7.7%, and 4.0% in the lower quartiles, respectively. This was independent of clinical and procedural characteristics. CONCLUSIONS: Elevated serum activities of MMP-2 and -9 are associated with dramatically increased restenosis rates after PCI with implantation of DES. Determination of MMP levels might be useful for identification of patients who are at high risk for ISR despite implantation of DES.


Assuntos
Angioplastia Coronária com Balão/efeitos adversos , Angioplastia Coronária com Balão/instrumentação , Doença da Artéria Coronariana/terapia , Reestenose Coronária/etiologia , Stents Farmacológicos , Metaloproteinase 2 da Matriz/sangue , Metaloproteinase 9 da Matriz/sangue , Fármacos Cardiovasculares/administração & dosagem , Angiografia Coronária , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/enzimologia , Reestenose Coronária/diagnóstico por imagem , Reestenose Coronária/enzimologia , Humanos , Modelos Logísticos , Razão de Chances , Paclitaxel/administração & dosagem , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Sirolimo/administração & dosagem , Fatores de Tempo , Resultado do Tratamento , Regulação para Cima
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