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1.
Biomolecules ; 10(4)2020 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-32252487

RESUMO

Surface receptor-mediated adhesion is a fundamental step in the recruitment of leukocytes and platelets, as well as platelet-leukocyte interactions. The surface receptor CD147 is crucially involved in host defense against self-derived and invading targets, as well as in thrombosis. In the current study, we describe the previously unknown interaction of CD147 with integrin αMß2 (Mac-1) in this context. Using binding assays, we were able to show a stable interaction of CD147 with Mac-1 in vitro. Leukocytes from Mac-1-/- and CD147+/- mice showed a markedly reduced static adhesion to CD147- and Mac-1-coated surfaces, respectively, compared to wild-type mice. Similarly, we observed reduced rolling and adhesion of monocytes under flow conditions when cells were pre-treated with antibodies against Mac-1 or CD147. Additionally, as assessed by antibody inhibition experiments, CD147 mediated the dynamic adhesion of platelets to Mac-1-coated surfaces. The interaction of CD147 with Mac-1 is a previously undescribed mechanism facilitating the adhesion of leukocytes and platelets.

2.
Clin Res Cardiol ; 109(5): 539-548, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31401672

RESUMO

AIMS: In the placebo-controlled, double-blind BOne marrOw transfer to enhance ST-elevation infarct regeneration (BOOST) 2 trial, intracoronary autologous bone marrow cell (BMC) transfer did not improve recovery of left ventricular ejection fraction (LVEF) at 6 months in patients with ST-elevation myocardial infarction (STEMI) and moderately reduced LVEF. Regional myocardial perfusion as determined by adenosine stress perfusion cardiac magnetic resonance imaging (S-CMR) may be more sensitive than global LVEF in detecting BMC treatment effects. Here, we sought to evaluate (i) the changes of myocardial perfusion in the infarct area over time (ii) the effects of BMC therapy on infarct perfusion, and (iii) the relation of infarct perfusion to LVEF recovery at 6 months. METHODS AND RESULTS: In 51 patients from BOOST-2 (placebo, n = 10; BMC, n = 41), S-CMR was performed 5.1 ± 2.9 days after PCI (before placebo/BMC treatment) and after 6 months. Infarct perfusion improved from baseline to 6 months in the overall patient cohort as reflected by the semi-quantitative parameters, perfusion defect-infarct size ratio (change from 0.54 ± 0.20 to 0.43 ± 0.22; P = 0.006) and perfusion defect-upslope ratio (0.54 ± 0.23 to 0.68 ± 0.22; P < 0.001), irrespective of randomised treatment. Perfusion defect-upslope ratio at baseline correlated with LVEF recovery (r = 0.62; P < 0.001) after 6 months, with a threshold of 0.54 providing the best sensitivity (79%) and specificity (74%) (area under the curve, 0.79; 95% confidence interval, 0.67-0.92). CONCLUSION: Infarct perfusion improves from baseline to 6 months and predicts LVEF recovery in STEMI patients undergoing early PCI. Intracoronary BMC therapy did not enhance infarct perfusion in the BOOST-2 trial.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31789488

RESUMO

OBJECTIVES: To compare baseline characteristics and outcomes in patients treated with either 1 or 2 MitraClips in the German TRAMI (Transcatheter Mitral Valve Interventions) registry. BACKGROUND: The MitraClip community seems to silently assume that results should intrinsically be better after implantation of more than one clip, although data is still sparse. METHODS: In 2010-2013, 803 patients were enrolled prospectively into TRAMI (461 one-clip and 312 two-clip procedures). Follow-up was performed centrally at 30 days and 1 year. RESULTS: Baseline characteristics of TRAMI-patients with two clips differed significantly from single-clip patients regarding constitutional (more men, taller body height) and heart failure-related factors (larger left ventricular dimensions, reduced left ventricular ejection fraction, more severe heart failure). Also, a significant increase in two-clip procedures over time was present. After propensity score matching for differing baseline characteristics, residual moderate mitral regurgitation (MR) occurred more frequently after implantation of two clips, whereas residual severe MR could more frequently be observed after one-clip procedures. However, no or mild residual MR at discharge was present in 71.6% after single-clip and in 70.1% after two-clips implantation (p = .81). After 1 year, no significant differences regarding mortality or New York Heart Association status could be detected in the propensity matched cohorts. However, TRAMI-patients treated with two clips had a significantly higher incidence of cerebral-vascular events (p = .02). CONCLUSIONS: TRAMI data cannot support the theory that implantation of more than one clip is associated with better clinical outcomes. The finding of more cerebral-vascular events after two-clip procedures might be hypothesis-generating.

4.
Eur Heart J ; 40(24): 1942-1951, 2019 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-31226213

RESUMO

AIMS: The value of platelet function testing (PFT) in predicting clinical outcomes and guiding P2Y12-inhibitor treatment is uncertain. In a pre-specified sub-study of the TROPICAL-ACS trial, we assessed ischaemic and bleeding risks according to high platelet reactivity (HPR) and low platelet reactivity (LPR) to ADP in patients receiving uniform prasugrel vs. PFT-guided clopidogrel or prasugrel. METHODS AND RESULTS: Acute coronary syndrome patients with PFT done 14 days after hospital discharge were included with prior randomization to uniform prasugrel for 12 months (control group, no treatment modification) vs. early de-escalation from prasugrel to clopidogrel and PFT-guided maintenance treatment (HPR: switch-back to prasugrel, non-HPR: clopidogrel). The composite ischaemic endpoint included cardiovascular death, myocardial infarction, or stroke, while key safety outcome was Bleeding Academic Research Consortium (BARC) 2-5 bleeding, from PFT until 12 months. We identified 2527 patients with PFT results available: 1266 were randomized to the guided and 1261 to the control group. Before treatment adjustment, HPR was more prevalent in the guided group (40% vs. 15%), while LPR was more common in control patients (27% vs. 11%). Compared to control patients without HPR on prasugrel (n = 1073), similar outcomes were observed in guided patients kept on clopidogrel [n = 755, hazard ratio (HR): 1.06 (0.57-1.95), P = 0.86] and also in patients with HPR on clopidogrel switched to prasugrel [n = 511, HR: 0.96 (0.47-1.96), P = 0.91]. In contrast, HPR on prasugrel was associated with a higher risk for ischaemic events in control patients [n = 188, HR: 2.16 (1.01-4.65), P = 0.049]. Low platelet reactivity was an independent predictor of bleeding [HR: 1.74 (1.18-2.56), P = 0.005], without interaction (Pint = 0.76) between study groups. CONCLUSION: Based on this substudy of a randomized trial, selecting prasugrel or clopidogrel based on PFT resulted in similar ischaemic outcomes as uniform prasugrel therapy without HPR. Although infrequent, HPR on prasugrel was associated with increased risk of ischaemic events. Low platelet reactivity was a strong and independent predictor of bleeding both on prasugrel and clopidogrel.

5.
Int J Cardiol ; 277: 35-41, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30153994

RESUMO

BACKGROUND: MitraClip therapy is increasingly used in patients deemed inoperable to treat severe mitral regurgitation (MR), but long-tern data is scarce. AIMS: The multicentre, industry-independent German Transcatheter Mitral Valve Interventions (TRAMI) registry comprises the largest prospectively enrolled cohort of patients treated by MitraClip therapy. The current analysis is focusing on long-term mortality rates, cardiac rehospitalization and reintervention. METHODS AND RESULTS: Long-term follow-up (median time 1037 days) in the TRAMI registry was available for 722 patients treated at 20 German centres. Improvements in New York Heart Association (NYHA) functional class (I/II long-term: 65% vs. 1-year follow-up: 63.3%) and self-rated health-status (EuroQuol visual analogue scale [EQ VAS] long-term: 60 [50-70] vs. 1-year follow-up: 60 [50; 70]) were pertained over time. Estimated mortality rates by Kaplan-Meier method were 19.7% for 1-year, 31.9% for 2-year and 53.1% for 4-year follow-up without differences found for MR aetiology. Multivariable Cox-regression analysis identified previous aortic valve implantation (hazard ratio [HR] = 2.21; p < 0.0001), NYHA class IV (HR = 1.78; p < 0.001), prior cardiac decompensation (HR = 1.63; p < 0.001), creatinine > 1.5 mg/dl (HR = 1.63; p < 0.0001) and left ventricular ejection fraction < 30% (HR = 1.60; p < 0.001) as most predictive for long-term mortality. CONCLUSIONS: Long-term outcome in the TRAMI registry confirmed lasting clinical improvements and low intervention rates. Long-term mortality was strongly influenced by cardiac and non-cardiac co-morbidities and was found comparable for both MR aetiologies.


Assuntos
Insuficiência da Valva Mitral/mortalidade , Insuficiência da Valva Mitral/cirurgia , Sistema de Registros , Instrumentos Cirúrgicos/tendências , Substituição da Valva Aórtica Transcateter/mortalidade , Substituição da Valva Aórtica Transcateter/tendências , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Seguimentos , Alemanha/epidemiologia , Humanos , Masculino , Insuficiência da Valva Mitral/diagnóstico por imagem , Mortalidade/tendências , Valor Preditivo dos Testes , Estudos Prospectivos , Fatores de Tempo , Resultado do Tratamento
6.
Dtsch Med Wochenschr ; 143(17): 1252-1257, 2018 Aug.
Artigo em Alemão | MEDLINE | ID: mdl-30134457

RESUMO

Exercise testing belongs to the most important cardiologic diagnostic prozedures. Even if sensitivity and specifity of ergometry are low, it is used widely for the following: screening for coronary artery disease, as a component of imaging and cardiopulmonary exercise testing, for assessment of arrhythmias, hypertension and congenital heart diseases.


Assuntos
Doenças Cardiovasculares , Ergometria , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/fisiopatologia , Ergometria/métodos , Ergometria/normas , Teste de Esforço , Humanos , Programas de Rastreamento
7.
Int J Cardiol ; 263: 104-110, 2018 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-29678512

RESUMO

BACKGROUND: Plasma Galectin-3 is a marker of myocardial inflammation and fibrosis, was associated with left ventricular (LV) reverse remodeling after conventional surgical mitral valve repair (MVR) and predicted clinical events in patients undergoing transcatheter aortic valve replacement (TAVR). We aimed to evaluate the association between pre-interventional Galectin-3 levels and (1) reverse LV remodeling and (2) major adverse cardiovascular events (MACE) in patients undergoing percutaneous MVR. METHODS: Forty-four consecutive patients (median age 79 years, LV ejection fraction 39.5 ±â€¯11.4%, 91% in NYHA functional class ≥III) with symptomatic moderate to severe mitral regurgitation undergoing percutaneous MVR were prospectively included. Plasma Galectin-3 levels were measured before the procedure. Echocardiographic and clinical assessment was performed at baseline and after 3 months. LV reverse remodeling was prospectively defined as a ≥10% increase in global longitudinal strain. MACE included death, myocardial infarction, heart failure related rehospitalization and stroke and was assessed after a mean follow-up time of 2 years. RESULTS: 72.7% of the patients showed LV reverse remodeling. Pre-interventional Galectin-3 < 10 ng/ml was an independent predictor of LV reverse remodeling (OR 10.3, 95% CI 1.2-83.9, p = 0.036). 25 patients (56.8%) experienced a MACE. Patients with Galectin-3 levels ≥ 10 ng/ml had significantly more MACE than patients with Galectin-3 levels < 10 ng/ml (100% vs. 45.5%, p = 0.003). Diabetes independently predicted MACE (HR 3.1, 95% CI 1.0-9.4, p = 0.049); Galectin-3 ≥ 10 ng/ml was of borderline significance (HR 2.2, 95% CI 0.9-5.4, p = 0.088). CONCLUSIONS: Pre-interventional plasma Galectin-3 levels are associated with LV reverse remodeling and with clinical outcome after percutaneous MVR.


Assuntos
Galectina 3/sangue , Insuficiência da Valva Mitral/sangue , Insuficiência da Valva Mitral/cirurgia , Substituição da Valva Aórtica Transcateter/tendências , Remodelação Ventricular/fisiologia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Feminino , Seguimentos , Humanos , Masculino , Insuficiência da Valva Mitral/diagnóstico por imagem , Estudos Prospectivos , Resultado do Tratamento
8.
Eur Heart J ; 38(39): 2936-2943, 2017 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-28431003

RESUMO

Aims: Intracoronary infusion of autologous nucleated bone marrow cells (BMCs) enhanced the recovery of left ventricular ejection fraction (LVEF) after ST-segment elevation myocardial infarction (STEMI) in the randomised-controlled, open-label BOOST trial. We reassessed the therapeutic potential of nucleated BMCs in the randomised placebo-controlled, double-blind BOOST-2 trial conducted in 10 centres in Germany and Norway. Methods and results: Using a multiple arm design, we investigated the dose-response relationship and explored whether γ-irradiation which eliminates the clonogenic potential of stem and progenitor cells has an impact on BMC efficacy. Between 9 March 2006 and 16 July 2013, 153 patients with large STEMI were randomly assigned to receive a single intracoronary infusion of placebo (control group), high-dose (hi)BMCs, low-dose (lo)BMCs, irradiated hiBMCs, or irradiated loBMCs 8.1 ± 2.6 days after percutaneous coronary intervention (PCI) in addition to guideline-recommended medical treatment. Change in LVEF from baseline (before cell infusion) to 6 months as determined by MRI was the primary endpoint. The trial is registered at Current Controlled Trials (ISRCTN17457407). Baseline LVEF was 45.0 ± 8.5% in the overall population. At 6 months, LVEF had increased by 3.3 percentage points in the control group and 4.3 percentage points in the hiBMC group. The estimated treatment effect was 1.0 percentage points (95% confidence interval, -2.6 to 4.7; P = 0.57). The treatment effect of loBMCs was 0.5 percentage points (-3.0 to 4.1; P = 0.76). Likewise, irradiated BMCs did not have significant treatment effects. BMC transfer was safe and not associated with adverse clinical events. Conclusion: The BOOST-2 trial does not support the use of nucleated BMCs in patients with STEMI and moderately reduced LVEF treated according to current standards of early PCI and drug therapy.


Assuntos
Transplante de Medula Óssea/métodos , Infarto do Miocárdio com Supradesnível do Segmento ST/terapia , Células da Medula Óssea/efeitos da radiação , Método Duplo-Cego , Feminino , Raios gama , Humanos , Infusões Intralesionais , Angiografia por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Intervenção Coronária Percutânea , Transplante de Células-Tronco/métodos , Células-Tronco/efeitos da radiação , Transplante Autólogo , Resultado do Tratamento , Função Ventricular Esquerda/fisiologia
10.
EuroIntervention ; 12(4): 508-14, 2016 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-26348678

RESUMO

AIMS: Factors predicting outcomes after MitraClip implantation are not well defined. We aimed to report the influence of baseline renal function on short-term outcomes of patients enrolled in the investigator-initiated German transcatheter mitral valve interventions (TRAMI) registry. METHODS AND RESULTS: Twenty participating German centres prospectively included 778 patients (mean age 76.0 years [71-81], 38.8% female gender) at high surgical risk (mean logistic EuroSCORE 20% [12-32%]) undergoing TMVR with the MitraClip for the treatment of symptomatic functional (70%) or degenerative (30%) mitral valve regurgitation (FMR, DMR). The patients were stratified according to renal function before clip implantation. The prevalence of moderate to severe renal impairment (glomerular filtration rate [GFR] <60 ml/min) was 62.7% (37.3%, normal renal function [GFR >60 ml/min]; 49.6%, moderate renal impairment [GFR 30-60 ml/min]; 13.1%, severe renal impairment [GFR <30 ml/min]). TMVR was successfully completed in 98.2% of cases; acute procedural failure, in-hospital and 30-day mortality rates were 1.8%, 2.3% and 4.4%, respectively. Acute procedural failure and mortality rates (in-hospital, 30-day) were significantly higher in patients with severe renal impairment (5.9%, 7.8%, 14.1%), as compared to patients with moderately (1%, 1.3%, 3.0%) or mildly impaired to normal (1.4%, 1.7%, 2.9%) renal function (p<0.0001). Following Cox regression analysis, the prevalence of severe renal impairment at the time of TMVR was the only predictor for increased 30-day mortality rates (hazard ratio 3.42, 95% confidence interval 1.88-6.2; p<0.0001). CONCLUSIONS: Renal function at the time of interventional mitral valve repair with the MitraClip system is a strong predictor for procedural outcomes. Patients with severe renal impairment have a more than threefold increased risk for acute procedural failure, in-hospital death and 30-day mortality.


Assuntos
Implante de Prótese de Valva Cardíaca/efeitos adversos , Próteses Valvulares Cardíacas/efeitos adversos , Insuficiência da Valva Mitral/cirurgia , Valva Mitral/cirurgia , Insuficiência Renal/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Cateterismo Cardíaco/efeitos adversos , Feminino , Alemanha , Implante de Prótese de Valva Cardíaca/métodos , Humanos , Masculino , Estudos Prospectivos , Sistema de Registros , Insuficiência Renal/diagnóstico , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
11.
Platelets ; 27(2): 155-8, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26084004

RESUMO

OBJECTIVE: Recently, we reported that extracellular cyclophilin A (CyPA) is an important agonist for platelets. Whereas soluble CyPA-levels have been associated with cardiovascular risk factors, cell-bound CyPA has not been investigated yet. In this study, we analyzed for the first time platelet-bound CyPA in patients with symptomatic coronary artery disease (CAD). METHODS AND RESULTS: blood was obtained from 388 consecutive patients: 204 with stable CAD and 184 with acute coronary syndrome (76 with unstable angina, 78 with non ST-elevation myocardial infarction (NSTEMI), and 30 with STEMI). In vitro stimulation of platelets with classical agonists revealed an enhanced expression of CyPA on the platelet surface. In patients with stable CAD, platelet-bound CyPA correlated excellently with platelet activity measured by P-selectin exposure in flow cytometry. The analysis of classical risk factors for atherosclerosis revealed that patients with hypertension and hypercholesterolemia had significantly enhanced platelet-bound CyPA, whereas diabetes and smoking were not associated with enhanced CyPA-binding to the platelet surface. In multivariate analysis, hypercholesterolemia was the only significant predictor of enhanced platelet-bound CyPA. Interestingly, in patients with acute myocardial infarction (AMI) platelet-bound CyPA was significantly decreased compared with patients with stable CAD. CONCLUSIONS: Enhanced platelet-bound CyPA is associated with hypertension and hypercholesterolemia in stable CAD patients. In patients with AMI platelet-bound CyPA is significantly decreased.


Assuntos
Angina Instável/sangue , Plaquetas/metabolismo , Doença da Artéria Coronariana/sangue , Ciclofilina A/sangue , Hipercolesterolemia/sangue , Hipertensão/sangue , Idoso , Idoso de 80 Anos ou mais , Angina Instável/complicações , Angina Instável/patologia , Plaquetas/patologia , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/patologia , Ciclofilina A/genética , Diabetes Mellitus/fisiopatologia , Feminino , Expressão Gênica , Humanos , Hipercolesterolemia/complicações , Hipercolesterolemia/patologia , Hipertensão/complicações , Hipertensão/patologia , Masculino , Pessoa de Meia-Idade , Selectina-P/sangue , Selectina-P/genética , Ativação Plaquetária , Ligação Proteica , Fatores de Risco , Fumar/fisiopatologia
12.
Clin Res Cardiol ; 104(12): 1044-53, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26022739

RESUMO

AIMS: To investigate the influence of non-cardiac comorbidities on outcomes of patients enrolled in the German transcatheter mitral valve interventions (TRAMI) registry. METHODS AND RESULTS: Intrahospital and 30-day MACCE rates (death of all causes, stroke and myocardial infarction) of 828 patients from the TRAMI registry were stratified by the number of non-cardiac comorbidities. The following non-cardiac comorbidities were prospectively recorded in the registry: diabetes, renal insufficiency, extracardiac arteriopathy, chronic lung disease, neurological disease or malignancy on palliative care. The 375 (45.3 %) patients with multiple (≥2) non-cardiac comorbidities presented with higher NYHA classes, higher logistic Euroscores, higher levels of NT-proBNP and a shorter 6-min walk distance. Rates of intraprocedural death (0.3 vs. 0.0 %, p = 0.41) and intrahospital MACCE (3.6 vs. 1.9 %, p = 0.16) were not significantly higher in patients with multiple non-cardiac comorbidities, but 30-day MACCE rate was significantly enhanced (6.4 vs. 3.6 %, p = 0.049). However, both patient groups showed a similar clinical improvement after 30 days. Renal insufficiency was the only non-cardiac comorbidity which was independently associated with the 30-day MACCE rate. CONCLUSIONS: MitraClip device placement is feasible and safe in patients with multiple non-cardiac comorbidities resulting in a significant clinical improvement and acceptable intrahospital and 30-day event rates. Renal failure is an independent predictor of outcome.


Assuntos
Cateterismo Cardíaco/métodos , Insuficiência da Valva Mitral/terapia , Valva Mitral/patologia , Insuficiência Renal/complicações , Idoso , Idoso de 80 Anos ou mais , Feminino , Alemanha/epidemiologia , Mortalidade Hospitalar , Humanos , Masculino , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/mortalidade , Estudos Prospectivos , Sistema de Registros , Insuficiência Renal/epidemiologia , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/mortalidade , Fatores de Tempo , Resultado do Tratamento
13.
Thromb Res ; 135(6): 1160-4, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25824988

RESUMO

INTRODUCTION: The role of individual monocyte subsets in inflammatory cardiovascular diseases is insufficiently understood. Although the Extracellular Matrix Metalloproteinase Inducer (EMMPRIN) regulates important processes for inflammation such as MMP-release, its expression and regulation on monocyte subsets has not been characterized. MATERIALS AND METHODS: In this clinical study, blood was obtained from 80 patients with stable coronary artery disease (CAD), 49 with acute myocardial infarction (AMI) and 34 healthy controls. Monocytes were divided into 3 subsets: CD14(++)CD16(-) (low), CD14(++)CD16(+) (intermediate), CD14(+)CD16(++) (high) according to phenotypic markers analyzed by flow cytometry. Surface expression of EMMPRIN was evaluated and compared with CD36 and CD47 expression. RESULTS: In all patients, EMMPRIN expression was significantly different among monocyte subsets with the highest expression on "classical" CD14(++)CD16(-) monocytes. EMMPRIN was upregulated on all monocyte subsets in patients with AMI as compared to patients with stable CAD. Notably, neither CD47 nor CD36 revealed a significant difference in patients with AMI compared to patients with stable CAD. CONCLUSION: EMMPRIN could serve as a marker for classical monocytes, which is upregulated in patients with acute myocardial infarction.


Assuntos
Basigina/biossíntese , Doença da Artéria Coronariana/sangue , Regulação da Expressão Gênica , Monócitos/metabolismo , Infarto do Miocárdio/sangue , Síndrome Coronariana Aguda/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD36/biossíntese , Separação Celular , Feminino , Citometria de Fluxo , Proteínas Ligadas por GPI/biossíntese , Voluntários Saudáveis , Humanos , Inflamação , Receptores de Lipopolissacarídeos/biossíntese , Masculino , Pessoa de Meia-Idade , Fenótipo , Receptores de IgG/biossíntese
14.
PLoS One ; 10(4): e0124606, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25894208

RESUMO

Cyclophilins are a group of highly conserved cytosolic enzymes that have a peptidylprolyl cis/trans isomerase activity. Cyclophilin A (CyPA) can be secreted in the extracellular space by inflammatory cells and upon cell death. The presence of CyPA in patients with non-ischemic cardiomyopathy is associated with poor clinical prognosis. Here, we investigated the inhibition of extracellular CyPA in a mouse model of troponin I-induced autoimmune myocarditis using the strictly extracellular CyPA-inhibitor MM284. Since A/J mice develop severe inflammation and fibrosis after immunization with murine cardiac troponin I (mcTn I), we used this model to analyze the effects of an extracellular CyPA inhibition. As extracellular CyPA-inhibitor we used the recently described CsA-derivate MM284. In vitro studies confirmed that MM284 inhibits CyPA-induced monocytic migration and adhesion. A/J mice immunized with mcTnI were treated with MM284 or vehicle every second day. After 28 days, we found a considerable reduction of myocardial injury and fibrosis. Further analysis revealed a reduced myocardial presence of T-cells and macrophages compared to control treated animals. Whereas MMP-9 expression was reduced significantly by MM284, we observed no significant reduction of inflammatory cytokines such as IL-6 or TNFα. Extracellular CyPA plays an important role in autoimmune myocarditis for myocardial damage and fibrosis. Our data suggest a new pharmacological approach for the treatment of myocardial inflammation and reduction of cardiac fibrosis by inhibition of extracellular CyPA.


Assuntos
Ciclofilina A/antagonistas & inibidores , Ciclosporinas/uso terapêutico , Espaço Extracelular/química , Inflamação/patologia , Miocardite/tratamento farmacológico , Miocárdio/patologia , Remodelação Ventricular/efeitos dos fármacos , Animais , Doenças Autoimunes/complicações , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/patologia , Doenças Autoimunes/fisiopatologia , Adesão Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Ciclofilina A/metabolismo , Ciclosporinas/farmacologia , Modelos Animais de Doenças , Fibrose , Humanos , Inflamação/complicações , Interleucina-6/metabolismo , Macrófagos/efeitos dos fármacos , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Monócitos/efeitos dos fármacos , Monócitos/patologia , Miocardite/complicações , Miocardite/patologia , Miocardite/fisiopatologia , Linfócitos T/efeitos dos fármacos , Troponina I , Fator de Necrose Tumoral alfa/metabolismo
15.
Dtsch Arztebl Int ; 112(12): 202-8, 2015 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-25838022

RESUMO

BACKGROUND: There are 60,000 to 100,000 new cases of borreliosis in Germany each year. This infectious disease most commonly affects the skin, joints, and nervous system. Lyme carditis is a rare manifestation with potentially lethal complications. METHODS: This review is based on selected publications on the clinical manifestations, diagnosis, and treatment of Lyme carditis, and on the authors' scientific and clinical experience. RESULTS: Lyme carditis is seen in 4% to 10% of all patients with Lyme borreliosis. Whenever the clinical suspicion of Lyme carditis arises, an ECG is mandatory for the detection or exclusion of an atrioventricular conduction block. Patients with a PQ interval longer than 300 ms need continuous ECG monitoring. 90% of patients with Lyme carditis develop cardiac conduction abnormalities, and 60% develop signs of perimyocarditis. Borrelia serology (ELISA) may still be negative in the early phase of the condition, but is always positive in later phases. Cardiac MRI can be used to confirm the diagnosis and to monitor the patient's subsequent course. The treatment of choice is with antibiotics, preferably ceftriaxone. The cardiac conduction disturbances are usually reversible, and the implantation of a permanent pacemaker is only exceptionally necessary. There is no clear evidence at present for an association between borreliosis and the later development of a dilated cardiomyopathy. When Lyme carditis is treated according to the current guidelines, its prognosis is highly favorable. CONCLUSION: Lyme carditis is among the rarer manifestations of Lyme borreliosis but must nevertheless be considered prominently in differential diagnosis because of the potentially severe cardiac arrhythmias that it can cause.


Assuntos
Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/terapia , Doença de Lyme/diagnóstico , Doença de Lyme/terapia , Miocardite/diagnóstico , Miocardite/terapia , Diagnóstico Diferencial , Eletrocardiografia/métodos , Humanos , Doença de Lyme/complicações , Miocardite/etiologia , Prognóstico
16.
Catheter Cardiovasc Interv ; 86(4): 728-35, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25601532

RESUMO

AIMS: To analyze risk and outcomes of complications during and after MitraClip implantation using multicenter data from the prospective German Transcatheter Mitral Valve Interventions (TRAMI) registry. METHODS AND RESULTS: Data of 828 patients (mean age: 76.0 [71-81] years, 327 (40%) females) undergoing MitraClip implantation in Germany between 2010 and 2013 were analyzed. Most patients (85%) underwent elective procedures with on average implantation of 1.4 ± 0.6 clips. Emergent cardiac surgery was not required; a single patient died intraoperatively. During the in-hospital period, complications occurred in 215 (25.9%) patients, of which 106 (12.8%) were considered major. Major bleeding complications were among the most frequent major complications (7.4%), while rates of pericardial tamponade (1.9%) and clip-specific complications (embolization: 0%, partial clip detachment: 1.9%) were low. In-hospital death, stroke or myocardial infarction (MACCE) occurred in 2.2, 0.9, and 0% patients, respectively. Patients with complications appeared to be older and more critically ill pre-interventionally; in-hospital mortality was significantly higher as compared to those without procedural complications. CONCLUSIONS: MitraClip implantation appears to be a safe treatment option with low rates of MACCE and clip-specific complications. Nevertheless, MitraClip therapy is not without complications. Careful patient selection and improvements in preventing peri-procedural bleeding have the potential of reducing post-procedural complications and improving outcomes.


Assuntos
Cateterismo Cardíaco/métodos , Procedimentos Cirúrgicos Eletivos/métodos , Implante de Prótese de Valva Cardíaca/métodos , Insuficiência da Valva Mitral/terapia , Falha de Prótese , Idoso , Idoso de 80 Anos ou mais , Cateterismo Cardíaco/efeitos adversos , Distribuição de Qui-Quadrado , Estudos de Coortes , Procedimentos Cirúrgicos Eletivos/efeitos adversos , Feminino , Seguimentos , Alemanha , Próteses Valvulares Cardíacas , Implante de Prótese de Valva Cardíaca/efeitos adversos , Mortalidade Hospitalar/tendências , Humanos , Masculino , Insuficiência da Valva Mitral/diagnóstico por imagem , Insuficiência da Valva Mitral/mortalidade , Segurança do Paciente , Desenho de Prótese , Sistema de Registros , Estudos Retrospectivos , Medição de Risco , Estatísticas não Paramétricas , Taxa de Sobrevida , Resultado do Tratamento , Ultrassonografia
17.
Arterioscler Thromb Vasc Biol ; 35(3): 655-63, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25550208

RESUMO

OBJECTIVE: Cyclophilin A (CyPA) is secreted under inflammatory conditions by various cell types. Whereas the important role of intracellular CyPA for platelet function has been reported, the effect of extracellular CyPA on platelet function has not been investigated yet. APPROACH AND RESULTS: Inhibition of extracellular CyPA through a novel specific inhibitor MM284 reduced thrombus after ferric chloride-induced injury in vivo. In vitro extracellular CyPA enhanced thrombus formation even in CyPA(-/-) platelets. Treatment of isolated platelets with recombinant CyPA resulted in platelet degranulation in a time- and dose-dependent manner. Inhibition of the platelet surface receptor extracellular matrix metalloproteinase inducer (cluster of differentiation 147) by an anticluster of differentiation 147 monoclonal antibody significantly reduced CyPA-dependent platelet degranulation. Pretreatment of platelets with CyPA enhanced their recruitment to mouse carotid arteries after arterial injury, which could be inhibited by an anticluster of differentiation 147 monoclonal antibody (intravital microscopy). The role of extracellular CyPA in adhesion could be confirmed by infusing CyPA(-/-) platelets in CyPA(+/+) mice and by infusing CyPA(+/+) platelets in CyPA(-/-) mice. Stimulation of platelets with CyPA induced phosphorylation of Akt, which could in turn be inhibited in the presence of phosphoinositid-3-kinase inhibitors. Akt-1(-/-) platelets revealed a markedly decreased degranulation on CyPA stimulation. Finally, ADP-induced platelet aggregation was attenuated by MM284, as well as by inhibiting paracrine-secreted CyPA without directly affecting Ca(2+)-signaling. CONCLUSIONS: Extracellular CyPA activates platelets via cluster of differentiation 147-mediated phosphoinositid-3-kinase/Akt-signaling, leading to enhanced adhesion and thrombus formation independently of intracellular CyPA. Targeting extracellular CyPA via a specific inhibitor may be a promising strategy for platelet inhibition without affecting critical functions of intracellular CyPA.


Assuntos
Basigina/sangue , Plaquetas/enzimologia , Ciclofilina A/sangue , Fosfatidilinositol 3-Quinases/sangue , Adesividade Plaquetária , Proteínas Proto-Oncogênicas c-akt/sangue , Transdução de Sinais , Trombose/enzimologia , Animais , Plaquetas/efeitos dos fármacos , Lesões das Artérias Carótidas/sangue , Lesões das Artérias Carótidas/enzimologia , Lesões das Artérias Carótidas/genética , Degranulação Celular/efeitos dos fármacos , Cloretos , Ciclofilina A/antagonistas & inibidores , Ciclofilina A/genética , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Compostos Férricos , Fibrinolíticos/farmacologia , Humanos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Adesividade Plaquetária/efeitos dos fármacos , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/farmacologia , Proteínas Proto-Oncogênicas c-akt/deficiência , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais/efeitos dos fármacos , Trombose/sangue , Trombose/induzido quimicamente , Trombose/genética , Trombose/prevenção & controle , Fatores de Tempo
18.
FASEB J ; 28(7): 2864-78, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24668750

RESUMO

Platelet-derived SDF-1α (CXCL12) mediates inflammatory and regenerative mechanisms. The present study characterizes the effect of SDF-1α ligation in platelets. SDF-1α (0-100 µM) dose and time dependently caused internalization of its receptor CXCR4 (28.9 ± 1.6 vs. 16.1 ± 1.9 in SDF-1α-treated platelets), coupled to the surface externalization of CXCR7 (65.5 ± 8 vs. 162.8 ± 27.6 following SDF-1α treatment), both in vitro and in vivo. This was inhibited in the presence of AMD3100 (100 µM), CXCR4 blocking and vesicular transport inhibitors (brefeldin A, 10 µM; rapamycin, 100 nM). SDF-1α/CXCR-4-mediated CXCR7 translocation was significantly reduced by inhibitors of ERK1/2-(U0126-10 µM) and cyclophilinA (CyPA)-(NIM811-10 µM) by 28 and 46%, respectively. Further, SDF-1α-induced downstream phosphorylation of Erk1/2 led to CyPA-dependent ubiquitination of CXCR7, which is essential for its surface translocation. CyPA-PPIase-activity inhibitor NIM-811, Erk1/2, and E1-ligase inhibitor-(PYR-41-25 µM) significantly abolished SDF-1α-driven CXCR7 ubiquitination and subsequent surface translocation. SDF-1α induced CXCR7 ubiquitination, and its surface exposure was observed in wild-type murine platelets, but not in CyPA-deficient platelets. SDF-1α/CXCR4-CyPA-dependent CXCR7 translocation and its subsequent ligation attenuated activation-induced apoptosis both in vitro and when administered in vivo. This antiapoptotic effect of SDF-1α was abrogated by blocking CXCR7, also significantly affected in Cypa(-/-) platelets. Thus, we decipher a novel mechanism, whereby SDF-1α regulates relative receptor availability in circulating platelets and exerts its prosurvival benefits.-Chatterjee, M., Seizer, P., Borst, O., Schönberger, T., Mack, A., Geisler, T., Langer, H. F., May, A. E., Vogel, S., Lang, F., Gawaz, M. SDF-1α induces differential trafficking of CXCR4-CXCR7 involving cyclophilin A, CXCR7 ubiquitination and promotes platelet survival.


Assuntos
Plaquetas/metabolismo , Quimiocina CXCL12/metabolismo , Ciclofilina A/metabolismo , Transporte Proteico/fisiologia , Receptores CXCR4/metabolismo , Receptores CXCR/metabolismo , Ubiquitinação/fisiologia , Animais , Apoptose/fisiologia , Plaquetas/fisiologia , Humanos , Sistema de Sinalização das MAP Quinases/fisiologia , Camundongos , Fosforilação/fisiologia , Transdução de Sinais/fisiologia
19.
Catheter Cardiovasc Interv ; 84(4): 591-8, 2014 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-24664460

RESUMO

OBJECTIVE: To evaluate in-hospital and short-term outcomes of percutaneous mitral valve repair according to patients' logistic EuroSCORE (logEuroSCORE) in a multicenter registry BACKGROUND: The logEuroSCORE is an established tool to predict the risk of mortality during cardiac surgery. In high-risk patients percutaneous mitral valve repair with the MitraClip system represents a less-invasive alternative METHODS: Data from 1002 patients, who underwent percutaneous mitral valve repair with the MitraClip system, were analyzed in the German Transcatheter Mitral Valve Interventions (TRAMI) Registry. A logEuroSCORE (mortality risk in %) ≥ 20 was considered high risk RESULTS: Of all patients, 557 (55.6%) had a logEuroSCORE ≥ 20. Implantation of the MitraClip was successful in 95.5 % (942/986) patients. Moderate residual mitral valve regurgitation was more often detected in patients with a logEuroSCORE ≥ 20 (23.8% vs. 17.1%, respectively, P < 0.05). In patients with a logEuroSCORE ≥ 20 the procedural complication rate was 8.9% (vs. 6.4, n.s.) and the in-hospital MACCE rate 4.9% (vs. 1.4% P < 0.01). The in-hospital mortality rate in patients with a logEuroSCORE ≥ 20 and logEuroSCORE < 20 was 4.3 and 1.1%, respectively (P ≤ 0.01) CONCLUSION: Percutaneous mitral valve repair with the MitraClip system is feasible in patients with a logEuroSCORE ≥ 20 with similar procedural results compared to patients with lower predicted risk. Although mortality was four times higher than in patients with logEuroSCORE < 20, mortality in high risk patients was lower than predicted. In those with a logEuroSCORE ≥ 20, moderate residual mitral valve regurgitation was more frequent.


Assuntos
Cateterismo Cardíaco/instrumentação , Implante de Prótese de Valva Cardíaca/instrumentação , Próteses Valvulares Cardíacas , Insuficiência da Valva Mitral/terapia , Valva Mitral , Idoso , Idoso de 80 Anos ou mais , Cateterismo Cardíaco/efeitos adversos , Cateterismo Cardíaco/mortalidade , Distribuição de Qui-Quadrado , Estudos de Viabilidade , Feminino , Alemanha , Implante de Prótese de Valva Cardíaca/efeitos adversos , Implante de Prótese de Valva Cardíaca/mortalidade , Mortalidade Hospitalar , Humanos , Modelos Logísticos , Masculino , Valva Mitral/fisiopatologia , Insuficiência da Valva Mitral/diagnóstico , Insuficiência da Valva Mitral/mortalidade , Insuficiência da Valva Mitral/fisiopatologia , Seleção de Pacientes , Estudos Prospectivos , Desenho de Prótese , Sistema de Registros , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
20.
Cardiovasc Res ; 102(1): 17-23, 2014 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-24518139

RESUMO

Cyclophilin A (CyPA) is an abundantly expressed intracellular protein. It exerts a variety of functions due to its peptidyl-prolyl cis-trans isomerase (PPIase) activity. When released into the extracellular space, CyPA binds to its extracellular receptor CD147 (EMMPRIN) and thereby initiates a cascade of inflammatory processes. Recent data indicate that both extra- and intracellular CyPA significantly contribute to cardiovascular inflammation, myocardial ischaemia and reperfusion injury, and myocardial remodelling processes. Thus, CyPA appears to represent a novel target to treat vascular and myocardial inflammation.


Assuntos
Basigina/metabolismo , Doenças Cardiovasculares/metabolismo , Ciclofilina A/metabolismo , Animais , Basigina/imunologia , Plaquetas/metabolismo , Doenças Cardiovasculares/imunologia , Ciclofilina A/imunologia , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Miocárdio/metabolismo
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