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1.
Clin Res Cardiol ; 2019 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-31451915

RESUMO

AIMS: To examine the clinical experience and practical use of the PASCAL transcatheter valve repair system (Edwards Lifesciences, Irvine, CA, USA) and to report some of the first clinical results. METHODS AND RESULTS: A total of 18 consecutive patients with severe, symptomatic mitral regurgitation (MR) were included in this German multicentre registry. All patients underwent clinical, echocardiographic, and laboratory assessment prior to the PASCAL procedure and before hospital discharge. MR was classified as functional in 6 patients, degenerative in 2, and combined in 10. All except one received a single PASCAL implant. The preprocedural severe MR present in all patients was reduced: grade 0 in 4 (22.2%), grade I in 11 (61.1%), grade II in 3 (16.7%). The v-wave was significantly reduced from 31.7 ± 9.5 to 18 ± 7.7 mmHg (p < 0.001). Independent leaflet capture, performed in 4 (22.2%) of the patients, wide clasps, and the 10-mm central spacer are features of the PASCAL device to optimize mitral leaflet repair. There were no periprocedural complications. CONCLUSION: PASCAL is a safe and effective mitral valve repair device for the treatment of severe MR. Device-specific features allow valve repair tailored to the individual anatomy of the underlying mitral pathology in each patient.

2.
Eur Heart J ; 2019 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-31004144

RESUMO

AIMS: Heart failure with preserved ejection fraction (HFpEF) and pathological cardiac aging share a complex pathophysiology, including extracellular matrix remodelling (EMR). Protease-activated receptor 2 (PAR2) deficiency is associated with EMR. The roles of PAR1 and PAR2 have not been studied in HFpEF, age-dependent cardiac fibrosis, or diastolic dysfunction (DD). METHODS AND RESULTS: Evaluation of endomyocardial biopsies from patients with HFpEF (n = 14) revealed that a reduced cardiac PAR2 expression was associated with aggravated DD and increased myocardial fibrosis (r = -0.7336, P = 0.0028). In line, 1-year-old PAR2-knockout (PAR2ko) mice suffered from DD with preserved systolic function, associated with an increased age-dependent α-smooth muscle actin expression, collagen deposition (1.7-fold increase, P = 0.0003), lysyl oxidase activity, collagen cross-linking (2.2-fold increase, P = 0.0008), endothelial activation, and inflammation. In the absence of PAR2, the receptor-regulating protein caveolin-1 was down-regulated, contributing to an augmented profibrotic PAR1 and transforming growth factor beta (TGF-ß)-dependent signalling. This enhanced TGF-ß/PAR1 signalling caused N-proteinase (ADAMTS3) and C-proteinase (BMP1)-related increased collagen I production from cardiac fibroblasts (CFs). PAR2 overexpression in PAR2ko CFs reversed these effects. The treatment with the PAR1 antagonist, vorapaxar, reduced cardiac fibrosis by 44% (P = 0.03) and reduced inflammation in a metabolic disease model (apolipoprotein E-ko mice). Patients with HFpEF with upstream PAR inhibition via FXa inhibitors (n = 40) also exhibited reduced circulating markers of fibrosis and DD compared with patients treated with vitamin K antagonists (n = 20). CONCLUSIONS: Protease-activated receptor 2 is an important regulator of profibrotic PAR1 and TGF-ß signalling in the heart. Modulation of the FXa/FIIa-PAR1/PAR2/TGF-ß-axis might be a promising therapeutic approach to reduce HFpEF.

3.
Cardiovasc Res ; 2018 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-30101304

RESUMO

Background: The immune system is considered a key driver of atherosclerosis, and beyond proteins and microRNAs (miRs), long noncoding RNAs (lncRNAs) are implicated in immune control. We previously described that lncRNA MALAT1 is involved in cardiac innate immunity in a myocarditis model. Here, we investigated the impact of MALAT1 deficiency upon atherosclerosis development. Methods and Results: Heterozygous MALAT1-deficient ApoE-/- mice displayed massive immune system dysregulation and atherosclerosis within two months even when kept on normal diet. Aortic plaque area (p < 0.05) and aortic root plaque size (p < 0.001) were increased in MALAT1-deficient vs. MALAT1-wildtype ApoE-/- mice. Serum levels of interferon-γ (IFN-γ), tumor necrosis factor (TNF), and interleukin 6 (IL6) were elevated (p < 0.001) in MALAT1-deficient animals. MALAT1-deficient bone marrow derived macrophages showed enhanced expression of TNF (p = 0.001) and inducible NO synthase (NOS2) (p = 0.002), suppressed MMP9 (p < 0.001), and impaired phagocytic activity (p < 0.001) upon LPS stimulation. RNA-sequencing revealed grossly altered transcriptomes of MALAT1-deficient splenocytes already at baseline, with massive induction of IFN-γ, TNF, NOS2, and granzyme B; CC and CXC chemokines and CCR8; and innate immunity genes IFIT1/3, IFITM1/3, ISG15. Multiple miRs were up to 45-fold upregulated. Further, selective ablation of the cytosolic part of the MALAT1 system only, the enzymatically MALAT1-derived mascRNA, resulted in massive induction of TNF (p = 0.004) and IL6 (p = 0.028) in macrophages. Northern analysis of post-MI patient vs. control PBMCs showed reduced (p = 0.005) mascRNA in the patients. CHART-enriched RNA-sequencing reads at the genomic loci of MALAT1 and neighbouring NEAT1 documented direct interaction between these lncRNA transcripts. Conclusion: The data suggest a molecular circuit involving the MALAT1-mascRNA system, interactions between MALAT1 and NEAT1, and key immune effector molecules, cumulatively impacting upon the development of atherosclerosis. It appears reasonable to look for therapeutic targets in this circuit and to screen for anomalies in the NEAT1-MALAT1 region in humans, too, as possible novel disease risk factors.

4.
Cardiovasc Diabetol ; 17(1): 34, 2018 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-29477147

RESUMO

BACKGROUND: Diabetes mellitus is characterized by chronic vascular disorder and presents a main risk factor for cardiovascular mortality. In particular, hyperglycaemia and inflammatory cytokines induce vascular circulating tissue factor (TF) that promotes pro-thrombotic conditions in diabetes. It has recently become evident that alterations of the post-transcriptional regulation of TF via specific microRNA(miR)s, such as miR-126, contribute to the pathogenesis of diabetes and its complications. The endothelial miR-19a is involved in vascular homeostasis and atheroprotection. However, its role in diabetes-related thrombogenicity is unknown. Understanding miR-networks regulating procoagulability in diabetes may help to develop new treatment options preventing vascular complications. METHODS AND RESULTS: Plasma of 44 patients with known diabetes was assessed for the expression of miR-19a, TF protein, TF activity, and markers for vascular inflammation. High miR-19a expression was associated with reduced TF protein, TF-mediated procoagulability, and vascular inflammation based on expression of vascular adhesion molecule-1 and leukocyte count. We found plasma expression of miR-19a to strongly correlate with miR-126. miR-19a reduced the TF expression on mRNA and protein level in human microvascular endothelial cells (HMEC) as well as TF activity in human monocytes (THP-1), while anti-miR-19a increased the TF expression. Interestingly, miR-19a induced VCAM expression in HMEC. However, miR-19a and miR-126 co-transfection reduced total endothelial VCAM expression and exhibited additive inhibition of a luciferase reporter construct containing the F3 3'UTR. CONCLUSIONS: While both miRs have differential functions on endothelial VCAM expression, miR-19a and miR-126 cooperate to exhibit anti-thrombotic properties via regulating vascular TF expression. Modulating the post-transcriptional control of TF in diabetes may provide a future anti-thrombotic and anti-inflammatory therapy.

7.
Science ; 354(6310): 358-362, 2016 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-27846573

RESUMO

Intestinal inflammation can impair mucosal healing, thereby establishing a vicious cycle leading to chronic inflammatory bowel disease (IBD). However, the signaling networks driving chronic inflammation remain unclear. Here we report that CD4+ T cells isolated from patients with IBD produce high levels of interleukin-22 binding protein (IL-22BP), the endogenous inhibitor of the tissue-protective cytokine IL-22. Using mouse models, we demonstrate that IBD development requires T cell-derived IL-22BP. Lastly, intestinal CD4+ T cells isolated from IBD patients responsive to treatment with antibodies against tumor necrosis factor-α (anti-TNF-α), the most effective known IBD therapy, exhibited reduced amounts of IL-22BP expression but still expressed IL-22. Our findings suggest that anti-TNF-α therapy may act at least in part by suppressing IL-22BP and point toward a more specific potential therapy for IBD.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Doenças Inflamatórias Intestinais/imunologia , Mucosa Intestinal/imunologia , Receptores de Interleucina/imunologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Animais , Anticorpos/uso terapêutico , Modelos Animais de Doenças , Humanos , Imunidade nas Mucosas , Imunoterapia , Doenças Inflamatórias Intestinais/terapia , Camundongos , Receptores de Interleucina/antagonistas & inibidores , Fator de Necrose Tumoral alfa/imunologia
9.
Crit Care Med ; 44(10): e1014-5, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27635513
10.
Cardiovasc Revasc Med ; 17(3): 169-75, 2016 Apr-May.
Artigo em Inglês | MEDLINE | ID: mdl-27157293

RESUMO

BACKGROUND: The reactivity of platelets is increased in patients with peripheral artery disease (PAD). RANTES and sCD40L are chemokines which are stored in the alpha-granules of platelets. Clopidogrel inhibits and thus reduces platelet reactivity. Whether a treatment with clopidogrel is associated with an inhibition of systemic inflammation in patients with PAD has not been thoroughly explored. This study examined the effect of clopidogrel on platelet reactivation and the release of inflammatory chemokines in patients with PAD. METHODS: 40 patients with PAD were randomized into two groups. In the first group A the patients were treated with 100mg acetylsalicylic acid (ASA) and additional placebo for 4weeks. The patients in group B received 75mg/d clopidogrel in addition to ASA 100mg for 4weeks. After obtaining blood at days 0, 7 and 28 the platelet activation was determined by measuring the surface protein expression of CD63, CD62p and thrombospondin (TSP) after stimulation with TRAP and ADP. The release of the chemokines RANTES and sCD40L from platelets was analyzed by ELISA. RESULTS: Platelet activation markers (CD62p and CD63) and chemokine RANTES were significantly reduced in patients with PAD after 7 and 28days after treatment with clopidogrel. No alterations were found in TSP expression and sCD40L during the treatment. CONCLUSION: The treatment with clopidogrel leads to a reduction of platelet reactivity and release of RANTES from the platelets of patients with PAD.


Assuntos
Anti-Inflamatórios/uso terapêutico , Plaquetas/efeitos dos fármacos , Inflamação/tratamento farmacológico , Doença Arterial Periférica/tratamento farmacológico , Inibidores da Agregação de Plaquetas/uso terapêutico , Ticlopidina/análogos & derivados , Anti-Inflamatórios/efeitos adversos , Aspirina/uso terapêutico , Biomarcadores/sangue , Plaquetas/metabolismo , Ligante de CD40/sangue , Quimiocina CCL5/sangue , Clopidogrel , Quimioterapia Combinada , Ensaio de Imunoadsorção Enzimática , Alemanha , Humanos , Inflamação/sangue , Inflamação/diagnóstico , Mediadores da Inflamação/sangue , Selectina-P/sangue , Doença Arterial Periférica/sangue , Doença Arterial Periférica/diagnóstico , Ativação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/efeitos adversos , Testes de Função Plaquetária , Tetraspanina 30/sangue , Trombospondinas/sangue , Ticlopidina/efeitos adversos , Ticlopidina/uso terapêutico , Fatores de Tempo , Resultado do Tratamento
11.
J Mol Med (Berl) ; 94(6): 645-53, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27080394

RESUMO

UNLABELLED: Ischemia impairs the adenine nucleotide translocase (ANT), which transports ADP and ATP across the inner mitochondrial membrane. We investigated whether ANT1 overexpression has protective effects on ischemic hearts. Myocardial infarction was induced in wild-type (WT) and heart-specific ANT1-transgenic (ANT1-TG) rats, and hypoxia was set in isolated cardiomyocytes. ANT1 overexpression reduced the myocardial infarct area and increased the survival rate of infarcted rats. Reduced ANT1 expression and increased 4-hydroxynonenal modification of ANT paralleled to impaired ANT function in infarcted WT hearts. ANT1 overexpression improved ANT expression and function. This was accompanied by reduced mitochondrial cytochrome C release and caspase-3 activation. ANT1-TG hearts suffered less from oxidative stress, as shown by lower protein carbonylation and 4-hydroxynonenal modification of ANT. ANT1 overexpression also increased cell survival of hypoxic cardiomyocytes and attenuated reactive oxygen species (ROS) production. This was linked to higher stability of mitochondrial membrane potential and lower activity of ROS detoxifying catalase. ANT1-TG cardiomyocytes also showed higher resistance against H2O2 treatment, which was independent of catalase activity. In conclusion, ANT1 overexpression compensates impaired ANT activity under oxygen-restricted conditions. It reduces ROS production and oxidative stress, stabilizes mitochondrial integrity, and increases survival, making ANT1 a component in ROS management and heart protection during ischemia. KEY MESSAGES: ANT1 overexpression reduces infarct size and increases survival after infarction. ANT1 overexpression compensates restricted ANT expression and function in infarcted hearts. Increased ANT1 expression enhances mitochondrial integrity. ANT1-overexpressing hearts reduce oxidative stress by decreasing ROS generation. ANT1 is a component in ROS management and heart protection.


Assuntos
Translocador 1 do Nucleotídeo Adenina/genética , Mitocôndrias Cardíacas/genética , Infarto do Miocárdio/genética , Miócitos Cardíacos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Translocador 1 do Nucleotídeo Adenina/metabolismo , Aldeídos/metabolismo , Animais , Caspase 3/genética , Caspase 3/metabolismo , Catalase/genética , Catalase/metabolismo , Hipóxia Celular , Sobrevivência Celular , Citocromos c/metabolismo , Regulação da Expressão Gênica , Peróxido de Hidrogênio/farmacologia , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Potencial da Membrana Mitocondrial/genética , Mitocôndrias Cardíacas/efeitos dos fármacos , Infarto do Miocárdio/mortalidade , Infarto do Miocárdio/patologia , Infarto do Miocárdio/prevenção & controle , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Estresse Oxidativo , Cultura Primária de Células , Carbonilação Proteica/efeitos dos fármacos , Ratos , Ratos Transgênicos , Transdução de Sinais , Análise de Sobrevida
12.
Trends Cardiovasc Med ; 26(4): 297-303, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26877187

RESUMO

Due to its receptor activity for factor VII, tissue factor (TF) is primary initiator of the blood coagulation cascade and ensures rapid hemostasis in case of organ damage. Inflammatory cytokines, such as tumor necrosis factor-α or interleukins, strongly induce expression of both full-length TF as well as the alternatively spliced TF in endothelial and blood cells. Beyond its role in hemostasis, TF also has signaling activity and promotes pleiotropic inflammatory responses via protease-activated receptors in concert with other coagulation factors. Alteration of TF expression and TF alternative splicing provides an effective means to change the endothelial phenotype and modulate inflammatory responses of the vessel.


Assuntos
Coagulação Sanguínea , Mediadores da Inflamação/sangue , Inflamação/sangue , Tromboplastina/metabolismo , Processamento Alternativo , Animais , Regulação da Expressão Gênica , Humanos , Inflamação/genética , Conformação Proteica , Transdução de Sinais , Tromboplastina/química , Tromboplastina/genética
13.
Thromb Res ; 139: 90-7, 2016 03.
Artigo em Inglês | MEDLINE | ID: mdl-26916302

RESUMO

Thrombosis is a leading cause of morbidity and mortality. Detection of a prothrombotic state using biomarkers would be of great benefit to identify patients at risk of thrombosis that would benefit from thromboprophylaxis. Tissue factor (TF) is a highly procoagulant protein that under normal conditions is not present in the blood. However, increased levels of TF in the blood in the form of microparticles (MPs) (also called extracellular vesicles) are observed under various pathological conditions. In this review, we will discuss studies that have measured MP-TF activity in a variety of diseases using two similar FXa generation assay. One of the most robust signals for MP-TF activity (16-26 fold higher than healthy controls) is observed in pancreatic cancer patients with venous thromboembolism. In this case, the TF+ MPs appear to be derived from the cancer cells. Surprisingly, cirrhosis and acute liver injury are associated with 17-fold and 38-fold increases in MP-TF activity, respectively. Based on mouse models, we speculate that the TF+ MPs are derived from hepatocytes. More modest increases are observed in patients with urinary tract infections (6-fold) and in a human endotoxemia model (9-fold) where monocytes are the likely source of the TF+ MPs. Finally, there is no increase in MP-TF activity in the majority of cardiovascular disease patients. These studies indicate that MP-TF activity may be a useful biomarker to identify patients with particular diseases that have an increased risk of thrombosis.


Assuntos
Micropartículas Derivadas de Células/patologia , Tromboplastina/metabolismo , Trombose/diagnóstico , Animais , Biomarcadores/análise , Biomarcadores/sangue , Biomarcadores/metabolismo , Testes de Coagulação Sanguínea/métodos , Micropartículas Derivadas de Células/metabolismo , Fator Xa/metabolismo , Humanos , Neoplasias/sangue , Neoplasias/complicações , Neoplasias/metabolismo , Neoplasias/patologia , Tromboplastina/análise , Trombose/sangue , Trombose/complicações , Trombose/metabolismo
14.
Curr Pharm Des ; 22(4): 472-84, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26696253

RESUMO

Protease-activated receptors (PARs) are a unique group of four G-protein coupled receptors. They are widely expressed within the cardiovascular system and the heart. PARs are activated via cleavage by serine proteases. In vitro and in vivo studies showed that the activation of PAR1 and PAR2 plays a crucial role in virus induced inflammatory diseases. The receptors enable cells to recognize pathogen-derived changes in the extracellular environment. An infection with Coxsackie-virus B3 (CVB3) can cause myocarditis. Recent studies have been shown that PAR1 signaling enhanced the antiviral innate immune response via interferon ß (IFNß) and thus limited the virus replication and cardiac damage. In contrast, PAR2 signaling decreased the antiviral innate immune response via IFNß und thus increased the virus replication, which caused severe myocarditis. Along with CVB3 other viruses such as influenza A virus (IAV) and herpes simplex virus (HSV) can induce myocarditis. The role of PAR signaling in IAV infections is contrarily discussed. During HSV infections PARs facilitate the virus infection of the host cell. These studies show that PARs might be interesting drug targets for the treatment of virus infections and inflammatory heart diseases. First studies with PAR agonists, antagonists, and serine protease inhibitors have been conducted in mice. The inhibition of thrombin the main PAR1 activating protease decreased the IFNß response and increased the virus replication in CVB3-induced myocarditis. This indicates that further studies with direct PAR agonists and antagonists are needed to determine whether PARs are useful drug targets for the therapy of virus-induced heart diseases.


Assuntos
Miocardite/tratamento farmacológico , Miocardite/metabolismo , Receptores Ativados por Proteinase/antagonistas & inibidores , Receptores Ativados por Proteinase/metabolismo , Animais , Anticoagulantes/farmacologia , Anticoagulantes/uso terapêutico , Humanos , Imunidade Inata/efeitos dos fármacos , Imunidade Inata/fisiologia , Miocardite/imunologia , Receptores Ativados por Proteinase/imunologia , Receptores Toll-Like/antagonistas & inibidores , Receptores Toll-Like/imunologia , Receptores Toll-Like/metabolismo
15.
Crit Care Med ; 44(4): e227-30, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26571183

RESUMO

OBJECTIVE: To report a case of intra-arterial amiodarone injection in a hemodynamically unstable patient leading to acute vessel occlusion and a subsequent compartment syndrome. DESIGN: Case report. SETTING: Prehospital setting, emergency department and ICU of a university hospital. PATIENT: A 58-year-old woman presenting with a ventricular tachycardia of 190 beats/min was administered amiodarone through an accidently placed arterial access in the left cubital fossa. Quickly, the woman developed clinical signs of an acute arterial occlusion. INTERVENTIONS: Immediate left brachial artery angiography with subsequent thrombectomy was performed. MEASUREMENTS AND MAIN RESULTS: A thrombotic occlusion at the injection side was found, which was immediately recanalized by thrombus aspiration. In addition to anticoagulation and an adenosine diphosphate-antagonist an adjunct therapy with vasodilators and gpIIb/IIIa inhibitors was given and repetitive duplex sonography confirmed arterial flow. However, despite restoration of blood flow the patient developed a severe compartment syndrome of the arm and had to receive multistep surgical interventions. CONCLUSIONS: This is the first report of an acute thrombotic vessel occlusion leading to a compartment syndrome upon accidental intra-arterial injection of amiodarone in an emergency setting. In the hemodynamically unstable patient healthcare providers should be aware of arterial miscanulation and its consequences. Upon intra-arterial injection, a direct antithrombotic and vasodilative therapy should be administered via the initially misplaced arterial access, which may include a gpIIb/IIIa inhibitor.


Assuntos
Amiodarona/administração & dosagem , Antiarrítmicos/administração & dosagem , Síndromes Compartimentais/etiologia , Infusões Intra-Arteriais/efeitos adversos , Trombose/etiologia , Artéria Braquial/diagnóstico por imagem , Feminino , Humanos , Pessoa de Meia-Idade , Taquicardia Ventricular/complicações , Taquicardia Ventricular/tratamento farmacológico , Tomografia Computadorizada por Raios X
16.
Cell Signal ; 28(1): 152-9, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26548633

RESUMO

The influence of mitochondrial function on intracellular signalling is currently under intense investigation. In this regard, we analysed the effect of adenine nucleotide translocase 1 (ANT1), which facilitates the exchange of ADP and ATP across the mitochondrial membrane, on cell-protective survival signalling under hypoxia. ANT1 overexpression enhanced the survival rate in hypoxic cardiomyocytes. The effect was related to stabilization of the mitochondrial membrane potential, suppression of caspase 3 activity, and a reduction in DNA fragmentation. Activation of the cell-protective signalling proteins extracellular signal-regulated kinases 1 and 2 (ERK1/2) and protein kinase B (AKT) was substantially higher in hypoxic ANT1-transgenic (ANT1-TG) cardiomyocytes than in wild-type cardiomyocytes. Kinase activation was associated with significantly higher expression of hypoxia-inducible factor 1α, which induces glycolytic pathway to stabilize ATP production. Accordingly, ANT1-TG cardiomyocytes exhibited earlier and stronger activation of lactate dehydrogenase and a higher ATP content. Treatment with PD980559 and triciribine, inhibitors of ERK1/2 and AKT activation, respectively, abolished cell protection in hypoxic ANT1-TG cardiomyocytes. Inhibition of ANT by carboxyatractyloside prevented the increase in ERK1/2 and AKT phosphorylation and eliminated the cell protective program in hypoxic ANT1-TG cardiomyocytes. In conclusion, the cytoprotective effect observed in hypoxic ANT1-overexpressing cardiomyocytes involves an interdependence between ANT1, activation of ERK1/ERK2 and AKT, and induction of the survival processes regulated by these kinases.


Assuntos
Hipóxia/metabolismo , Potencial da Membrana Mitocondrial/fisiologia , Mitocôndrias/metabolismo , Translocases Mitocondriais de ADP e ATP/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Animais , Animais Geneticamente Modificados , Sobrevivência Celular/efeitos dos fármacos , Potencial da Membrana Mitocondrial/genética , Mitocôndrias/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Substâncias Protetoras/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Sprague-Dawley
18.
Cardiovasc Diabetol ; 14: 15, 2015 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-25645908

RESUMO

BACKGROUND: Although antiplatelet therapy involving clopidogrel is a standard treatment for preventing cardiovascular events after coronary stent implantation, patients can display differential responses. Here, we assessed the effectiveness of clopidogrel on platelet function inhibition in subjects with and without type-2 diabetes and stable coronary artery disease. In addition, we investigated the correlation between platelet function and routine clinical parameters. METHODS: A total of 64 patients with stable coronary heart disease were enrolled in the study. Among these, 32 had known type-2 diabetes, whereas the remaining 32 subjects were non-diabetics (control group). A loading dose of 300 mg clopidogrel was given to clopidogrel-naïve patients (13 patients in the diabetes group and 14 control patients). All patients were given a daily maintenance dose of 75 mg clopidogrel. In addition, all patients received 100 mg ASA per day. Agonist-induced platelet aggregation measurements were performed on hirudin-anticoagulated blood using an impedance aggregometer (Multiple Platelet Function Analyzer, Dynabyte, Munich, Germany). Blood samples were drawn from the antecubital vein 24 h after coronary angiography with percutaneous coronary intervention. The platelets were then stimulated with ADP alone or ADP and prostaglandin-E (ADP and ADP-PGE tests, respectively) in order to evaluate clopidogrel-mediated inhibition of platelet function. The effectiveness of ASA was measured by stimulation with arachidonic acid (ASPI test). In addition, maximal platelet aggregation was assessed via stimulation with thrombin receptor-activating peptide (TRAP test). RESULTS: Patients with diabetes exhibited significantly less inhibition of platelet function than patients without diabetes (ADP-PGE test p = 0.003; ASPI test p = 0.022). Administering a clopidogrel loading dose of 300 mg did not result in a lower level of ADP-PGE-induced platelet reactivity in comparison to the use of a 75 mg maintenance dose. Moreover, we observed that ADP-PGE-induced platelet inhibition was positively correlated with fasting blood glucose and HbA1c (p < 0.01). CONCLUSIONS: Patients with type-2 diabetes exhibited increased platelet reactivity compared to patients without diabetes despite combined treatment with clopidogrel and ASA. Using a loading dose of clopidogrel rather than small daily doses was not sufficient for adequately overcoming increased platelet reactivity in patients with type-2 diabetes, highlighting the need for more effective anti-platelet drugs for such patients.


Assuntos
Plaquetas/efeitos dos fármacos , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Ativação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/uso terapêutico , Ticlopidina/análogos & derivados , Idoso , Plaquetas/metabolismo , Clopidogrel , Diabetes Mellitus Tipo 2/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ativação Plaquetária/fisiologia , Inibidores da Agregação de Plaquetas/farmacologia , Ticlopidina/farmacologia , Ticlopidina/uso terapêutico , Resultado do Tratamento
19.
J Card Fail ; 21(4): 330-8, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25498756

RESUMO

BACKGROUND: Nicotinamide phosphoribosyltransferase (Nampt) is an enzyme involved in nicotinamide adenine dinucleotide biosynthesis. Nampt functions as gatekeeper of energy status and survival in cardiac myocytes in animal models of ischemia-reperfusion and might regulate inflammatory processes. Therefore, we performed for the 1st time a clinical study to determine the effects of Nampt on cardiac function in patients with nonischemic dilated (DCM) and inflammatory (DCMi) cardiomyopathy. METHODS AND RESULTS: A total of 113 patients were enrolled in the study and classified into control (n = 25), DCM (n = 38), and DCMi (n = 50) groups. Cardiac functional and inflammatory parameters as well as plasma Nampt and cardiac mRNA and protein Nampt expression were determined at baseline and follow-up after 6 months. Patients with DCM (1.04 ± 0.8 ng/mL; P < .001) and DCMi (1.07 ± 0.7 ng/mL; P < .001) showed significantly increased Nampt plasma concentrations at baseline compared with the control group (0.57 ± 0.5 ng/mL). Patients with higher Nampt concentrations in both heart failure groups showed significant better improvement of cardiac functional parameters (correlation between Nampt plasma levels and the change of left ventricular ejection fraction after 6 months: DCM: r = 0.698, P < .001; DCMi: r = 0.503, P < .001). Moreover, cardiac inflammation did not influence Nampt expression, and Nampt concentrations did not modulate cardiac inflammation in DCMi. A multivariate linear regression model revealed high plasma Nampt expression to contribute to better improvement of cardiac function in patients of both heart failure groups. Moreover, heart failure patients with high plasma Nampt levels showed suppressed cardiac TNF-α and IL-6 mRNA expression after 6 months' follow-up as well as lower B-type natriuretic peptide levels compared with heart failure patients with low Nampt plasma concentrations. CONCLUSIONS: High Nampt expression in patients with nonischemic DCM and DCMi is associated with a favorable outcome and improvement in functional status.


Assuntos
Cardiomiopatia Dilatada/sangue , Citocinas/genética , Regulação da Expressão Gênica , Miocárdio/metabolismo , Nicotinamida Fosforribosiltransferase/genética , Células Precursoras de Linfócitos B/metabolismo , RNA Mensageiro/genética , Função Ventricular Esquerda/fisiologia , Idoso , Cardiomiopatia Dilatada/genética , Cardiomiopatia Dilatada/fisiopatologia , Citocinas/biossíntese , Progressão da Doença , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Nicotinamida Fosforribosiltransferase/biossíntese , Reação em Cadeia da Polimerase em Tempo Real
20.
Nanoscale ; 6(16): 9646-54, 2014 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-24991655

RESUMO

Monodisperse small iron oxide nanoparticles functionalized with dendritic polyglycerol (dPG) or dendritic polyglycerol sulfate (dPGS) are prepared. They are highly stable in aqueous solutions as well as physiological media. In particular, oleic acid capped iron oxide particles (core diameter = 11 ± 1 nm) were modified by a ligand exchange process in a one pot synthesis with dPG and dPGS bearing phosphonate as anchor groups. Dynamic light scattering measurements performed in water and different biological media demonstrate that the hydrodynamic diameter of the particles is only slightly increased by the ligand exchange process resulting in a final diameter of less than 30 nm and that the particles are stable in these media. It is also revealed by magnetic resonance studies that their magnetic relaxivity is reduced by the surface modification but it is still sufficient for high contrast magnetic resonance imaging (MRI). Additionally, incubation of dPGS functionalized iron oxide nanoparticles with human umbilical vein endothelial cells showed a 50% survival at 85 nM (concentration of nanoparticles). Surface plasmon resonance (SPR) studies demonstrate that the dPGS functionalized iron oxide nanoparticles inhibit L-selectin ligand binding whereas the particles containing only dPG do not show this effect. Experiments in a flow chamber with human myelogenous leukemia cells confirmed L-selectin inhibition of the dPGS functionalized iron oxide nanoparticles and with that the L-selectin mediated leukocyte adhesion. These results indicate that dPGS functionalized iron oxide nanoparticles are a promising contrast agent for inflamed tissue probed by MRI.


Assuntos
Meios de Contraste/química , Glicerol/química , Imagem por Ressonância Magnética/métodos , Nanopartículas de Magnetita/química , Polímeros/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Meios de Contraste/toxicidade , Glicerol/toxicidade , Células Endoteliais da Veia Umbilical Humana , Humanos , Nanopartículas de Magnetita/toxicidade , Tamanho da Partícula , Polímeros/toxicidade
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