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1.
BMC Cardiovasc Disord ; 19(1): 207, 2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31477020

RESUMO

BACKGROUND: Colchicine has been used as anti-inflammatory agent in pericardial effusion (PE). We sought to perform a meta-analysis of randomized trials assessing the efficacy and safety of colchicine in patients with pericarditis or postpericardiotomy syndrome (PPS). METHODS: In the systematic literature search following the PRISMA statement, 10 prospective randomized controlled studies with 1981 patients with an average follow-up duration of 13.6 months were identified. RESULTS: Colchicine reduced the recurrence rate of pericarditis in patients with acute and recurrent pericarditis and reduced the incidence of PPS (RR: 0.57, 95% CI: 0.44-0.74). Additionally, the rate of rehospitalizations as well as the symptom duration after 72 h was significantly decreased in pericarditis (RR 0.33; 95% CI 0.18-0.60; and RR 0.43; 95% CI 0.34-0.54; respectively), but not in PPS. Treatment with colchicine was associated with significantly higher adverse event (AE) rates (RR 1.42; 95% CI 1.05-1.92), with gastrointestinal intolerance being the leading AE. The reported number needed to treat (NNT) for the prevention of recurrent pericarditis ranged between 3 and 5. The reported NNT for PPS prevention was 10, and the number needed to harm (NNH) was 12, respectively. Late colchicine administration > 7 days after heart surgery did not reduce postoperative PE. CONCLUSIONS: Our meta-analysis confirms that colchicine is efficacious and safe for prevention of recurrent pericarditis and PPS, while it reduces rehospitalizations and symptom duration in pericarditis. The clinical use of colchicine for the setting of PPS and postoperative PE after heart surgery should be investigated in further multicenter RCT.

2.
Heart Fail Rev ; 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31372789

RESUMO

Takotsubo syndrome (TTS) is an acute and mostly reversible cardiomyopathy that mimics an acute coronary syndrome with left ventricular (LV) systolic dysfunction without relevant obstructive coronary artery disease. Its prevalence is probably underestimated and reaches 1.2-2% in patients with acute coronary syndrome undergoing coronary catheterization. Although supraphysiological epinephrine levels have been associated with TTS, the detailed pathophysiology is incompletely understood. Chest pain is the most common clinical presentation; however, cardiac decompensation, cardiogenic shock, and sudden cardiac death due to ventricular fibrillation may also be the first clinical manifestations. Patients are mostly postmenopausal women, in whom the condition is commonly associated with emotional triggers; however, men have a higher prevalence of TTS being associated with physical triggers, which has a worse prognosis compared with TTS associated with emotional triggers. As a diagnosis of exclusion, TTS has no single definitive diagnostic test. According to the distribution of LV wall motion abnormalities, various morphological subtypes have been identified. The final diagnosis depends on cardiac imaging with left ventricular angiography during acute heart catheterization, as well as on echocardiography and cardiac magnetic resonance. Most patients recover completely, albeit several factors have been associated with worse prognosis. Management is based on observational data, while randomized multicenter studies are still lacking. This review provides a general overview of TTS and focuses on the hypothesized pathophysiology, and especially on current practices in diagnosis, prognosis, and treatment.

3.
Heart Fail Rev ; 2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31396762

RESUMO

Meta-analysis on immunohistological (IHC) concepts for the detection of inflammatory cardiomyopathy (InfCM) in endomyocardial biopsies (EMB). We included 61 publications, with 10,491 patients (mean age 47.1 years; men 66%) who underwent EMB and IHC evaluation. The 460 control patients were devoid of IHC proof of InfCM. The mean IHC detection rate of InfCM was 50.8% (95% CI 47.7-53.8%; range 18.4-91.7%). A publication bias was excluded (Funnel Plot p = 0.4264). This IHC detection rate was significantly (p < 0.0001) higher compared to the histological detection of myocarditis according to the Dallas criteria (mean 8.04%; 95% CI 5.08-12.5%; subset of 3274 patients in 30 publications). However, 13 different diagnostic IHC criteria were described in the publications, with various thresholds of diverse phenotypes of quantified infiltrates, and endothelial expression of diverse cell adhesion molecules (CAM), quantified either visually or by digital image analysis (DIA). The comparison of IHC with cardiac magnetic resonance (CMR) data available in a subset of 13 publications with 1185 patients revealed a sensitivity for CMR of 69% (95% CI 58-79%), a specificity of 73% (95% CI 59-84%), and a ROC-AUC of 0.77 (95% CI 0.73-0.81). This meta-analysis encompassing 10,491 patients confirms a mean detection rate of InfCM in 50.8% of EMB, being significantly more sensitive compared to the histological Dallas criteria. IHC cannot be fully substituted by CMR. However, standardization of the diverse IHC markers and protocols seems pertinent, especially considering the published adverse prognostic impact of IHC-confirmed InfCM and its published suitability for the selection of candidates responding favorably to immunosuppression.

4.
Tissue Eng Part A ; 25(13-14): 936-948, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30648499

RESUMO

IMPACT STATEMENT: We here showed that even under optimized conditions for biochemical differentiation of adipose-derived stem cells (with respect to a pronounced marker protein expression for a reasonable period of time) it was not possible to obtain functional smooth muscle cells from all donors. Moreover, an underestimated role may play the effect of the scaffold material on smooth muscle cell functionality. Both aspects are crucial for the successful tissue engineering of the vascular medial layer combining autologous cells with a suitable scaffold material and thus should be thoroughly addressed in each individualized therapeutic approach.

5.
JACC Cardiovasc Interv ; 11(18): 1811-1820, 2018 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-30236353

RESUMO

OBJECTIVES: This study sought to analyze the impact of mandatory therapeutic hypothermia and cardiac catheterization in the absence of overt noncardiac cause of arrest as part of the Hannover Cardiac Resuscitation Algorithm before intensive care admission. BACKGROUND: Despite advanced therapies, out-of-hospital cardiac arrest (OHCA) is still associated with high mortality rates. Recently, the TTM (Target Temperature Management 33°C Versus 36°C After Out-of-Hospital Cardiac Arrest)-trial caused severe uncertainty about the efficacy of and need for therapeutic hypothermia. Furthermore, the role of early coronary angiography in OHCA survivors without ST-segment elevation remains undetermined. METHODS: In the HACORE (HAnnover Cooling REgistry) we investigated 233 consecutive patients (median age 64 [interquartile range: 53 to 74] years) with OHCA admitted to our institution between January 2011 and December 2015 who were treated according to the algorithm. RESULTS: A total of 73% had ventricular fibrillation as primary rhythm. Return of spontaneous circulation was achieved after 20 (interquartile range: 10 to 30) min. Immediate percutaneous coronary angiography was performed in 96% and coronary angioplasty in 59% of all cases. ST-segment elevation was present in 47%. Critical coronary stenosis requiring percutaneous coronary intervention was present in 67% of patients with and 52% of patients without ST-segment elevation. Overall 30-day intrahospital mortality in this real-world registry was 37%. Patients in our local registry who matched the inclusion/exclusion criteria of the TTM-trial (n = 145) had a markedly lower 30-day mortality (27%) compared with the published trial (44%). CONCLUSIONS: Standardized treatment of patients with OHCA following a strict protocol incorporating computed tomography, cardiac catheterization and revascularization, liberal use of active hemodynamic support in presence of shock, and mandatory therapeutic hypothermia results in mortality rates lower than previously reported.

6.
Eur J Nucl Med Mol Imaging ; 45(11): 1934-1944, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29967943

RESUMO

PURPOSE: The chemokine receptor CXCR4 is a promising target for molecular imaging of CXCR4+ cell types, e.g. inflammatory cells, in cardiovascular diseases. We speculated that a specific CXCR4 ligand, [68Ga]pentixafor, along with novel techniques for motion correction, would facilitate the in vivo characterization of CXCR4 expression in small culprit and nonculprit coronary atherosclerotic lesions after acute myocardial infarction by motion-corrected targeted PET/CT. METHODS: CXCR4 expression was analysed ex vivo in separately obtained arterial wall specimens. [68Ga]Pentixafor PET/CT was performed in 37 patients after stent-based reperfusion for a first acute ST-segment elevation myocardial infarction. List-mode PET data were reconstructed to five different datasets using cardiac and/or respiratory gating. Guided by CT for localization, the PET signals of culprit and various groups of nonculprit coronary lesions were analysed and compared. RESULTS: Ex vivo, CXCR4 was upregulated in atherosclerotic lesions, and mainly colocalized with CD68+ inflammatory cells. In vivo, elevated CXCR4 expression was detected in culprit and nonculprit lesions, and the strongest CXCR4 PET signal (median SUVmax 1.96; interquartile range, IQR, 1.55-2.31) was observed in culprit coronary artery lesions. Stented nonculprit lesions (median SUVmax 1.45, IQR 1.23-1.88; P = 0.048) and hot spots in naive remote coronary segments (median SUVmax 1.34, IQR 1.23-1.74; P = 0.0005) showed significantly lower levels of CXCR4 expression. Dual cardiac/respiratory gating provided the strongest CXCR4 PET signal and the highest lesion detectability. CONCLUSION: We demonstrated the basic feasibility of motion-corrected targeted PET/CT imaging of CXCR4 expression in coronary artery lesions, which was triggered by vessel wall inflammation but also by stent-induced injury. This novel methodology may serve as a platform for future diagnostic and therapeutic clinical studies targeting the biology of coronary atherosclerotic plaque.


Assuntos
Complexos de Coordenação , Regulação Neoplásica da Expressão Gênica , Movimento , Peptídeos Cíclicos , Placa Aterosclerótica/diagnóstico por imagem , Placa Aterosclerótica/metabolismo , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Receptores CXCR4/metabolismo , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/complicações , Placa Aterosclerótica/complicações , Placa Aterosclerótica/fisiopatologia , Respiração , Estudos Retrospectivos
7.
Front Immunol ; 9: 706, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29719532

RESUMO

Plaque microvascularization and increased endothelial permeability are key players in the development of atherosclerosis, from the initial stages of plaque formation to the occurrence of acute cardiovascular events. First, endothelial dysfunction and increased permeability facilitate the entry of diverse inflammation-triggering molecules and particles such as low-density lipoproteins into the artery wall from the arterial lumen and vasa vasorum (VV). Recognition of entering particles by resident phagocytes in the vessel wall triggers a maladaptive inflammatory response that initiates the process of local plaque formation. The recruitment and accumulation of inflammatory cells and the subsequent release of several cytokines, especially from resident macrophages, stimulate the expansion of existing VV and the formation of new highly permeable microvessels. This, in turn, exacerbates the deposition of pro-inflammatory particles and results in the recruitment of even more inflammatory cells. The progressive accumulation of leukocytes in the intima, which trigger proliferation of smooth muscle cells in the media, results in vessel wall thickening and hypoxia, which further stimulates neoangiogenesis of VV. Ultimately, this highly inflammatory environment damages the fragile plaque microvasculature leading to intraplaque hemorrhage, plaque instability, and eventually, acute cardiovascular events. This review will focus on the pivotal roles of endothelial permeability, neoangiogenesis, and plaque microvascularization by VV during plaque initiation, progression, and rupture. Special emphasis will be given to the underlying molecular mechanisms and potential therapeutic strategies to selectively target these processes.

9.
Vascul Pharmacol ; 2017 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-29274772

RESUMO

Mineralocorticoid receptor antagonists (MRAs), such as spironolactone and eplerenone have an established role in the treatment of heart failure. However, many experimental and clinical studies have shown that aldosterone also plays a pivotal role in a variety of other pathophysiological conditions within the cardiovascular system. Aldosterone has been suggested to promote inflammation, endothelial dysfunction and smooth muscle cell hyperplasia during the development of atherosclerosis, thereby promoting the development of coronary artery disease (CAD). Since CAD and subsequent ischemic cardiomyopathy are the major causes of heart failure, it is of major interest, whether pharmacological therapy with MRAs among heart failure patients will also affect the common underlying conditions, namely, atherosclerosis and subsequent coronary vessel narrowing/rarefication. Therefore, in this article, we reviewed and discussed the preclinical and clinical evidence of MRAs for the treatment of acute or chronic vascular remodeling processes, such as atherosclerosis and post-angioplasty restenosis, which determine the progression of CAD and subsequent ischemic cardiomyopathy.

10.
Cardiovasc Res ; 113(13): 1653-1663, 2017 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-29088375

RESUMO

Aims: Adventitial cells have been suggested to contribute to neointima formation, but the functional relevance and the responsible signalling pathways are largely unknown. Sonic hedgehog (Shh) is a regulator of vasculogenesis and promotes angiogenesis in the adult. Methods and results: Here we show that proliferation of vascular smooth muscle cells (SMC) after wire-induced injury in C57BL/6 mice is preceded by proliferation of adventitial fibroblasts. Simultaneously, the expression of Shh and its downstream signalling protein smoothened (SMO) were robustly increased within injured arteries. In vitro, combined stimulation with Shh and platelet-derived growth factor (PDGF)-BB strongly induced proliferation and migration of human adventitial fibroblasts. The supernatant of these activated fibroblasts contained high levels of interleukin-6 and -8 and strongly induced proliferation and migration of SMC. Inhibition of SMO selectively prevented fibroblast proliferation, cytokine release, and paracrine SMC activation. Mechanistically, we found that PDGF-BB activates protein kinase A in fibroblasts and thereby induces trafficking of SMO to the plasma membrane, where it can be activated by Shh. In vivo, SMO-inhibition significantly prevented the proliferation of adventitial fibroblasts and neointima formation following wire-induced injury. Conclusions: The initial activation of adventitial fibroblasts is essential for the subsequent proliferation of SMC and neointima formation. We identified SMO-dependent Shh signalling as a specific process for the activation of adventitial fibroblasts.


Assuntos
Túnica Adventícia/metabolismo , Lesões das Artérias Carótidas/metabolismo , Fibroblastos/metabolismo , Proteínas Hedgehog/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Neointima , Receptor Smoothened/metabolismo , Lesões do Sistema Vascular/metabolismo , Túnica Adventícia/efeitos dos fármacos , Túnica Adventícia/patologia , Anilidas/farmacologia , Animais , Becaplermina , Artérias Carótidas/metabolismo , Artérias Carótidas/patologia , Lesões das Artérias Carótidas/patologia , Movimento Celular , Proliferação de Células , Células Cultivadas , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Artéria Femoral/metabolismo , Artéria Femoral/patologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/patologia , Masculino , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/lesões , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/patologia , Comunicação Parácrina , Proteínas Proto-Oncogênicas c-sis/farmacologia , Piridinas/farmacologia , Transdução de Sinais , Receptor Smoothened/antagonistas & inibidores , Fatores de Tempo , Lesões do Sistema Vascular/patologia
11.
PLoS One ; 12(9): e0184888, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28926607

RESUMO

BACKGROUND: The novel nonsteroidal mineralocorticoid receptor (MR) antagonist finerenone holds promise to be safe and efficient in the treatment of patients with heart failure and/or chronic kidney disease. However, its effects on vascular function remain elusive. PURPOSE: The aim of this study was to determine the functional effect of selective MR antagonism by finerenone in vascular cells in vitro and the effect on vascular remodeling following acute vascular injury in vivo. METHODS AND RESULTS: In vitro, finerenone dose-dependently reduced aldosterone-induced smooth muscle cell (SMC) proliferation, as quantified by BrdU incorporation, and prevented aldosterone-induced endothelial cell (EC) apoptosis, as measured with a flow cytometry based caspase 3/7 activity assay. In vivo, oral application of finerenone resulted in an accelerated re-endothelialization 3 days following electric injury of the murine carotid artery. Furthermore, finerenone treatment inhibited intimal and medial cell proliferation following wire-induced injury of the murine femoral artery 10 days following injury and attenuated neointimal lesion formation 21 days following injury. CONCLUSION: Finerenone significantly reduces apoptosis of ECs and simultaneously attenuates SMC proliferation, resulting in accelerated endothelial healing and reduced neointima formation of the injured vessels. Thus, finerenone appears to provide favorable vascular effects through restoring vascular integrity and preventing adverse vascular remodeling.


Assuntos
Lesões das Artérias Carótidas/tratamento farmacológico , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Naftiridinas/uso terapêutico , Aldosterona/toxicidade , Animais , Apoptose/efeitos dos fármacos , Artérias Carótidas/patologia , Lesões das Artérias Carótidas/etiologia , Lesões das Artérias Carótidas/patologia , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Células Endoteliais da Veia Umbilical Humana , Humanos , Leucócitos/citologia , Leucócitos/imunologia , Leucócitos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Músculo Liso Vascular/citologia , Músculo Liso Vascular/metabolismo , Naftiridinas/farmacologia , Neointima/patologia , Neointima/prevenção & controle , Neovascularização Fisiológica/efeitos dos fármacos
12.
Vascul Pharmacol ; 96-98: 5-10, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28830735

RESUMO

Vasa vasorum are blood microvessels which penetrate the adventitia and outer layers of the media of large blood vessels, supplying them with nutrients and oxygen. A growing body of evidence suggests that vasa vasorum play a central role in the pathogenesis of atherosclerosis. In this review, we will make a case for the role of microvascular dysfunction in the initiation of disease. When seen through this lens, new therapeutic opportunities for prevention can be envisioned. In particular, we discuss how targeting the cellular metabolism and epigenetic machinery of vasa vasorum neovessels could be harnessed to render vasa vasorum endothelial cells less sensitive to atherogenic stimuli.


Assuntos
Aterosclerose/prevenção & controle , Fármacos Cardiovasculares/uso terapêutico , Vasa Vasorum/efeitos dos fármacos , Animais , Aterosclerose/metabolismo , Aterosclerose/patologia , Aterosclerose/fisiopatologia , Permeabilidade Capilar , Epigênese Genética/efeitos dos fármacos , Humanos , Mediadores da Inflamação/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Microcirculação/efeitos dos fármacos , Neovascularização Patológica , Transdução de Sinais/efeitos dos fármacos , Vasa Vasorum/metabolismo , Vasa Vasorum/patologia , Vasa Vasorum/fisiopatologia
13.
J Am Heart Assoc ; 6(6)2017 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-28637776

RESUMO

BACKGROUND: Following myocardial infarction (MI), peri-infarct myocardial edema formation further impairs cardiac function. Extracellular RNA (eRNA) released from injured cells strongly increases vascular permeability. This study aimed to assess the role of eRNA in MI-induced cardiac edema formation, infarct size, cardiac function, and survival after acute MI and to evaluate the therapeutic potential of ribonuclease 1 (RNase-1) treatment as an eRNA-degrading intervention. METHODS AND RESULTS: C57BL/6J mice were subjected to MI by permanent ligation of the left anterior descending coronary artery. Plasma eRNA levels were significantly increased compared with those in controls starting from 30 minutes after ligation. Systemic application of RNase-1, but not DNase, significantly reduced myocardial edema formation 24 hours after ligation compared with controls. Consequently, eRNA degradation by RNase-1 significantly improved the perfusion of collateral arteries in the border zone of the infarcted myocardium 24 hours after ligation of the left anterior descending coronary artery, as detected by micro-computed tomography imaging. Although there was no significant difference in the area at risk, the area of vital myocardium was markedly larger in mice treated with RNase-1 compared with controls, as detected by Evans blue and 2,3,5-triphenyltetrazolium chloride staining. The increase in viable myocardium was associated with significantly preserved left ventricular function, as assessed by echocardiography. Moreover, RNase-1 significantly improved 8-week survival following MI. CONCLUSIONS: eRNA is an unrecognized permeability factor in vivo, associated with myocardial edema formation after acute MI. RNase-1 counteracts eRNA-induced edema formation and preserves perfusion of the infarction border zone, reducing infarct size and protecting cardiac function after MI.


Assuntos
Fármacos Cardiovasculares/farmacologia , Infarto do Miocárdio/tratamento farmacológico , Miocárdio/metabolismo , Estabilidade de RNA , RNA/metabolismo , Ribonuclease Pancreático/farmacologia , Animais , Apoptose/efeitos dos fármacos , Circulação Coronária/efeitos dos fármacos , Modelos Animais de Doenças , Edema Cardíaco/genética , Edema Cardíaco/metabolismo , Edema Cardíaco/patologia , Edema Cardíaco/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Miocárdio/patologia , RNA/genética , Fatores de Tempo , Sobrevivência de Tecidos/efeitos dos fármacos , Função Ventricular Esquerda/efeitos dos fármacos
14.
Int J Cardiol ; 238: 79-91, 2017 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-28433555

RESUMO

BACKGROUND: Systemic treatment with sirolimus, as used for immunosuppression in transplant patients, results in markedly low rates of in-stent restenosis. Since the underlying mechanisms remain obscure, we aimed to determine the molecular and cellular effects of systemic sirolimus treatment on vascular remodeling processes. METHODS AND RESULTS: Systemic sirolimus treatment significantly reduced smooth muscle cell (SMC) proliferation 14days after wire-induced injury and neointima formation 28days after injury in C57BL/6 mice, while simultaneously impairing re-endothelialization. Interestingly, in vitro, sirolimus had no direct effect on the proliferation of SMC or endothelial cells (EC) at serum concentrations observed after systemic application. In contrast, sirolimus reduced the adhesion of leukocytes (CD45+) and bone marrow-derived progenitor cells (CD34+) to activated EC by down-regulating the adhesion molecules ICAM-1 and VCAM-1. In addition, sirolimus treatment also significantly reduced the upregulation of ICAM-1 and VCAM-1 and the recruitment of monocytic cells (MOMA-2+) in neointimal lesions in vivo. CONCLUSION: Our findings show that systemic sirolimus treatment effectively prevents SMC and EC proliferation in vivo without directly affecting these cells. Instead, sirolimus prevents neointima formation and re-endothelialization by attenuating the inflammatory response after injury with secondary effects on SMC and EC proliferation. Thus, despite a similar net effect, the mechanisms of systemic sirolimus treatment are largely different from the local effects achieved after application of sirolimus-eluting stents.


Assuntos
Anti-Inflamatórios/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Neointima/prevenção & controle , Sirolimo/uso terapêutico , Animais , Anti-Inflamatórios/farmacologia , Proliferação de Células/fisiologia , Células Cultivadas , Relação Dose-Resposta a Droga , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neointima/patologia , Distribuição Aleatória , Sirolimo/farmacologia , Resultado do Tratamento
15.
Int J Mol Sci ; 18(2)2017 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-28146050

RESUMO

Platelet P2Y12 is an important adenosine diphosphate (ADP) receptor that is involved in agonist-induced platelet aggregation and is a valuable target for the development of anti-platelet drugs. Here we characterise the effects of thio analogues of uridine triphosphate (UTP) on ADP-induced platelet aggregation. Using human platelet-rich plasma, we demonstrate that UTP inhibits P2Y12 but not P2Y1 receptors and antagonises 10 µM ADP-induced platelet aggregation in a concentration-dependent manner with an IC50 value of ~250 °µM. An eight-fold higher platelet inhibitory activity was observed with a 2-thio analogue of UTP (2S-UTP), with an IC50 of 30 µM. The 4-thio analogue (4S-UTP) with an IC50 of 7.5 µM was 33-fold more effective. A three-fold decrease in inhibitory activity, however, was observed by introducing an isobutyl group at the 4S- position. A complete loss of inhibition was observed with thio-modification of the γ phosphate of the sugar moiety, which yields an enzymatically stable analogue. The interaction of UTP analogues with P2Y12 receptor was verified by P2Y12 receptor binding and cyclic AMP (cAMP) assays. These novel data demonstrate for the first time that 2- and 4-thio analogues of UTP are potent P2Y12 receptor antagonists that may be useful for therapeutic intervention.


Assuntos
Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Inibidores da Agregação de Plaquetas/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Receptores Purinérgicos P2Y12/metabolismo , Uridina Trifosfato/farmacologia , Trifosfato de Adenosina/metabolismo , Trifosfato de Adenosina/farmacologia , Adulto , Moléculas de Adesão Celular/metabolismo , AMP Cíclico/metabolismo , Feminino , Voluntários Saudáveis , Humanos , Masculino , Proteínas dos Microfilamentos/metabolismo , Pessoa de Meia-Idade , Estrutura Molecular , Fosfoproteínas/metabolismo , Fosforilação , Plasma Rico em Plaquetas , Uridina Trifosfato/análogos & derivados , Adulto Jovem
16.
Cardiovasc Pathol ; 27: 68-70, 2017 Mar - Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28171828

RESUMO

Immunological vascular phenomena can be the initial manifestation of bacterial infection and endocarditis. Here, we report a rare case of leukocytoclastic vasculitis without immune complexes or cryoglobulinemia in a patient with infective endocarditis, congenital heart disease, and a prior mechanical valve replacement. The patient completely recovered following antibiotic therapy, and skin lesions disappeared without immune suppression, which suggested infection-mediated vasculitis. While the treatment of leukocytoclastic vasculitis typically involves immunosuppressive therapy, the treatment for infection-mediated vasculitis is eradication of the infection.


Assuntos
Endocardite Bacteriana/complicações , Transposição dos Grandes Vasos/complicações , Vasculite Leucocitoclástica Cutânea/etiologia , Adulto , Feminino , Próteses Valvulares Cardíacas , Humanos , Complicações Pós-Operatórias , Infecções Estafilocócicas/complicações
18.
Basic Res Cardiol ; 111(6): 69, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27743118

RESUMO

In this meeting report, particularly addressing the topic of protection of the cardiovascular system from ischemia/reperfusion injury, highlights are presented that relate to conditioning strategies of the heart with respect to molecular mechanisms and outcome in patients' cohorts, the influence of co-morbidities and medications, as well as the contribution of innate immune reactions in cardioprotection. Moreover, developmental or systems biology approaches bear great potential in systematically uncovering unexpected components involved in ischemia-reperfusion injury or heart regeneration. Based on the characterization of particular platelet integrins, mitochondrial redox-linked proteins, or lipid-diol compounds in cardiovascular diseases, their targeting by newly developed theranostics and technologies opens new avenues for diagnosis and therapy of myocardial infarction to improve the patients' outcome.


Assuntos
Cardiologia/tendências , Doenças Cardiovasculares , Nanomedicina Teranóstica/tendências , Animais , Cardiologia/métodos , Humanos
19.
Vasc Cell ; 8: 4, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27790365

RESUMO

Angiogenesis is a fundamental process during development and disease, and many details of the underlying molecular and cellular mechanisms are incompletely understood. Mitogen-activated protein kinase (MAPK)-activated protein kinase 2 (MK2), a major downstream target of p38 MAPK, has recently been identified as a regulator of Interleukin 1ß dependent angiogenesis in vivo, and in vitro data suggest a role of MK2 for VEGF-dependent angiogenic processes in endothelial cells. We thus hypothesized that MK2 plays a role during physiological vascular development in vivo. Vascular development was investigated in the retina of MK2-deficient mice. Retinal angiogenesis such as sprouting, branching and pruning was unchanged in MK2-/- mice compared to wildtype littermates. Early arterial development was also comparable between genotypes. However, with further expansion of vascular smooth muscle cells (SMC) during maturation of the arterial network at later time points, the number of arterial branch points was significantly lower in MK2-/- mice, resulting in a reduced total arterial area in adult mice. Isolated aortic smooth muscle cells from MK2-/- mice showed a more dedifferentiated phenotype in vitro and downregulation of central SMC marker genes, consistent with the known impaired migration of MK2-/- SMC. In conclusion, MK2 is not required for physiological retinal angiogenesis. However, its loss is associated with an altered genetic profile of SMC and an impaired arterial network in adult mice, indicating a distinct and probably cell-specific role of MK2 in arteries.

20.
Urologe A ; 55(2): 218-25, 2016 Feb.
Artigo em Alemão | MEDLINE | ID: mdl-26637324

RESUMO

BACKGROUND: Androgen deprivation therapy (ADT) with gonadotropin-releasing hormone (GnRH) agonists or GnRH antagonists is the mainstay of treatment for metastatic prostate cancer (mCaP). However, ADT is associated with serious cardiovascular events. Only a few studies that directly compare the cardiovascular risk of LHRH agonists versus GnRH antagonists have been published. OBJECTIVES: This review aims to compare the cardiovascular risk of LHRH agonists versus GnRH antagonists based on the literature. METHODS: A literature search that considered full publications and abstracts published before December 10, 2014 was performed. Due to their high evidence quality, only meta-analyses and pooled studies were included in this review. RESULTS: Four studies were included. These investigated the cardiovascular risk of patients receiving an ADT with LHRH agonists and/or GnRH antagonists. However, only one of these directly compared the cardiovascular risk of ADT with LHRH agonists versus GnRH antagonists. This meta-analysis showed a significant reduction in cardiovascular risk for patients receiving a GnRH antagonist compared to those patients receiving a LHRH agonist (HR: 0.597; 95 % CI: 0.380-0.938; P = 0.0253). Subgroup analyses showed that, in particular, patients with pre-existing cardiovascular diseases who were treated with a GnRH antagonist have a significantly lower risk of experiencing a cardiovascular event when compared with patients receiving a GnRH agonist (HR: 0.44; 95 % CI: 0.26-0.74; P = 0.002). CONCLUSION: In conclusion, GnRH antagonists are associated with a lower risk of cardiovascular events, compared with LHRH agonists, when administered as ADT in CaP patients, and particularly in patients with a history of cardiovascular disease. Thus, patients with a history of cardiovascular disease may benefit from ADT with a GnRH antagonist.


Assuntos
Doenças Cardiovasculares/induzido quimicamente , Hormônio Liberador de Gonadotropina/análogos & derivados , Hormônio Liberador de Gonadotropina/administração & dosagem , Hormônio Liberador de Gonadotropina/antagonistas & inibidores , Neoplasias da Próstata/tratamento farmacológico , Androgênios , Medicina Baseada em Evidências , Humanos , Masculino , Fatores de Risco , Resultado do Tratamento
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