Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 877
Filtrar
1.
Eur Heart J ; 2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31603194

RESUMO

AIMS: Aging is an established risk factor for stroke; genes regulating longevity are implicated in the pathogenesis of ischaemic stroke where to date, therapeutic options remain limited. The blood-brain barrier (BBB) is crucially involved in ischaemia/reperfusion (I/R) brain injury thus representing an attractive target for developing novel therapeutic agents. Given the role of endothelial cells in the BBB, we hypothesized that the endothelial-specific expression of the recently described longevity gene SIRT6 may exhibit protective properties in stroke. METHODS AND RESULTS: SIRT6 endothelial expression was reduced following stroke. Endothelial-specific Sirt6 knockout (eSirt6-/-) mice, as well as animals in which Sirt6 overexpression was post-ischaemically induced, underwent transient middle cerebral artery occlusion (tMCAO). eSirt6-/- animals displayed increased infarct volumes, mortality, and neurological deficit after tMCAO, as compared to control littermates. Conversely, post-ischaemic Sirt6 overexpression decreased infarct size and neurological deficit. Analysis of ischaemic brain sections revealed increased BBB damage and endothelial expression of cleaved caspase-3 in eSIRT6-/- mice as compared to controls. In primary human brain microvascular endothelial cells (HBMVECs), hypoxia/reoxygenation (H/R) reduced SIRT6 expression and SIRT6 silencing impaired the barrier function (transendothelial resistance) similar to what was observed in mice exposed to I/R. Further, SIRT6-silenced HBMVECs exposed to H/R showed reduced viability, increased cleaved caspase-3 expression and reduced activation of the survival pathway Akt. In ischaemic stroke patients, SIRT6 expression was higher in those with short-term neurological improvement as assessed by NIHSS scale and correlated with stroke outcome. CONCLUSION: Endothelial SIRT6 exerts a protective role in ischaemic stroke by blunting I/R-mediated BBB damage and thus, it may represent an interesting novel therapeutic target to be explored in future clinical investigation.

2.
Eur Heart J ; 40(37): 3067-3070, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31573036
3.
Eur Heart J ; 2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31593239
5.
Eur Heart J ; 2019 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-31513235
6.
Eur Heart J ; 2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31529020

RESUMO

AIMS: Nuclear receptors and their cofactors regulate key pathophysiological processes in atherosclerosis development. The transcriptional activity of these nuclear receptors is controlled by the nuclear receptor corepressors (NCOR), scaffolding proteins that form the basis of large corepressor complexes. Studies with primary macrophages demonstrated that the deletion of Ncor1 increases the expression of atherosclerotic molecules. However, the role of nuclear receptor corepressors in atherogenesis is unknown. METHODS AND RESULTS: We generated myeloid cell-specific Ncor1 knockout mice and crossbred them with low-density lipoprotein receptor (Ldlr) knockouts to study the role of macrophage NCOR1 in atherosclerosis. We demonstrate that myeloid cell-specific deletion of nuclear receptor corepressor 1 (NCOR1) aggravates atherosclerosis development in mice. Macrophage Ncor1-deficiency leads to increased foam cell formation, enhanced expression of pro-inflammatory cytokines, and atherosclerotic lesions characterized by larger necrotic cores and thinner fibrous caps. The immunometabolic effects of NCOR1 are mediated via suppression of peroxisome proliferator-activated receptor gamma (PPARγ) target genes in mouse and human macrophages, which lead to an enhanced expression of the CD36 scavenger receptor and subsequent increase in oxidized low-density lipoprotein uptake in the absence of NCOR1. Interestingly, in human atherosclerotic plaques, the expression of NCOR1 is reduced whereas the PPARγ signature is increased, and this signature is more pronounced in ruptured compared with non-ruptured carotid plaques. CONCLUSIONS: Our findings show that macrophage NCOR1 blocks the pro-atherogenic functions of PPARγ in atherosclerosis and suggest that stabilizing the NCOR1-PPARγ binding could be a promising strategy to block the pro-atherogenic functions of plaque macrophages and lesion progression in atherosclerotic patients.

7.
Haematologica ; 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31488556

RESUMO

Tissue factor is highly expressed in sub-endothelial tissue. The extracellular allosteric disulfide bond Cys186-Cys209 of human tissue factor shows high evolutionary conservation and in vitro evidence suggests that it significantly contributes to tissue factor procoagulant activity. To investigate the role of this allosteric disulfide bond in vivo, we generated a C213G mutant tissue factor mouse by replacing Cys213 of the corresponding disulfide Cys190-Cys213 in murine tissue factor. A bleeding phenotype was prominent in homozygous C213G tissue factor mice. Pre-natal lethality of 1/3rd of homozygous offspring was observed between E9.5 and E14.5 associated with placental hemorrhages. After birth, homozygous mice suffered from bleedings in different organs and reduced survival. Homozygous C213G tissue factor male mice showed higher incidence of lung bleedings and lower survival rates than females. In both sexes, C213G mutation evoked a reduced protein expression (about 10-fold) and severely reduced pro-coagulant activity (about 1000-fold). Protein glycosylation was impaired and cell membrane exposure decreased in macrophages in vivo. Single housing of homozygous C213G tissue factor males reduced the occurrence of severe bleeding and significantly improved survival, suggesting that inter-male aggressiveness might significantly account for the sex differences. These experiments show that the tissue factor allosteric disulfide bond is of crucial importance for normal in vivo expression, post-translational processing and activity of murine tissue factor. Although C213G tissue factor mice do not display the severe embryonic lethality of tissue factor knock-out mice, their postnatal bleeding phenotype emphasizes the importance of fully functional tissue factor for hemostasis.

9.
Eur Heart J ; 40(27): 2177-2179, 2019 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-31505612
10.
Eur Heart J ; 40(34): 2833-2836, 2019 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-31539907
11.
Eur Heart J ; 40(36): 2999-3002, 2019 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-31541553
12.
Cardiovasc Res ; 115(12): e125-e126, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31544943
13.
Artigo em Inglês | MEDLINE | ID: mdl-31464553

RESUMO

Objectives: Understanding sex differences in myocarditis is crucial to improve clinical care. We sought to investigate sex differences focusing on clinical presentation and laboratory parameters. Methods: From 2011 to 2018, 77 patients were diagnosed with myocarditis according to European Society of Cardiology (ESC) criteria with available clinical, laboratory, and cardiac magnetic resonance imaging data. First, we investigated sex differences of clinical and laboratory parameters in the entire cohort of 77 patients. Second, we focused on patients with acute myocarditis (n = 51) defined as recent symptom onset (≤10 days). Results: Myocarditis was present in 63 men (82%) and 14 women (18%). While men most frequently presented with chest pain (78%), a considerable amount of women presented with dyspnea as the only symptom (40%). Within the entire cohort, only creatinine kinase (CK) was higher in men versus women (364 ± 286 vs. 147 ± 148 U/L, p = 0.007), while in patients with acute myocarditis both CK and myoglobin (Mb) were higher in men versus women (CK: 327 ± 223 vs. 112 ± 65 U/L, p = 0.004 and Mb: 111 ± 126 vs. 25 ± 29 µg/L, p = 0.04). No sex differences were found for high-sensitivity troponin T, C-reactive protein, and NT-probrain natriuretic peptide. Conclusions: This is the first study reporting sex differences in clinical presentation and routine laboratory parameters in myocarditis. While clinical presentation appeared to be subtle in women with dyspnea being the only presenting symptom of myocarditis in a considerable part, men typically complained of chest pain. Similarly to observations in myocardial infarction, atypical symptoms and underdiagnosis may be a cause for under-representation of women in cohorts of myocarditis.

14.
Am J Cardiol ; 124(7): 1049-1055, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31395295

RESUMO

The prognosis associated with prolonged intraventricular conduction on electrocardiogram (ECG) remains uncertain. We aimed to compare clinical outcomes of narrow versus prolonged intraventricular conduction on ECG stratified by QRS morphology and cardiovascular disease (CVD) status. A post-hoc analysis was performed of the randomized-control PRECISION trial. Patients with centrally adjudicated, nonpaced baseline ECGs were included. QRS duration was classified narrow (≤100 ms) versus prolonged (>100 ms) with additional categorization into left (LBBB) or right (RBBB) bundle branch block or nonspecific intraventricular conduction delay (IVCD). IVCD was subclassified if left ventricular conduction delay (LVCD) was present (L-IVCD) or absent (O-IVCD). The primary outcome was adjudicated all-cause and cardiovascular (CV) mortality. Of 24,081 patients randomized, 22,067 (92%) were included with follow-up 34 ± 13 months. Study patients were 63 ± 9 years, 64% female, 75% Caucasian, 23% with established CVD. The prevalence of QRS prolongation was 5.6% (1,240): 760 right bundle branch block (3.4%), 313 LBBB (1.4%), and 161 IVCD (0.7%), 95 subclassified L-IVCD (0.4%). After adjustment, LBBB and L-IVCD were similarly associated with increased all-cause (LBBB: 2.3 [1.4 to 3.8], p = 0.001; L-IVCD: 4.0 [2.1 to 7.9], p <0.001) and CV (LBBB: 3.6 [2.0 to 6.5], p <0.001; L-IVCD 3.6 [1.3 to 9.7], p = 0.001) mortality. The presence of LVCD (LBBB or L-IVCD) was associated with all-cause (2.8 [1.8 to 4.2], p <0.001) and CV (3.6 [2.2 to 6.1], p <0.001) mortality exceeding the observed risks of coronary artery disease, left ventricular hypertrophy, or diabetes. The LVCD hazard persisted across QRS durations (100 to 120 vs >120 ms) and CVD status. In conclusion, LVCD, whether LBBB or L-IVCD, was strongly associated with increased mortality in patients with and at-risk for CVD.

16.
17.
Haematologica ; 2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31439672

RESUMO

Platelet adhesion to the sub-endothelial matrix and damaged endothelium occurs through a multi-step process mediated in the initial phase by glycoprotein Ib binding to von Willebrand factor, which leads to the subsequent formation of a platelet plug. The plant-derived omega-3 fatty acid alpha-linolenic acid is an abundant alternative to fish-derived n-3 FA and has anti-inflammatory and anti-thrombotic properties. In this study, we investigated the impact of alpha-linolenic acid on human platelet binding to vWF under high-shear flow conditions (mimicking blood flow in stenosed arteries). Pre-incubation of fresh human blood from healthy donors with alpha-linolenic acid at dietary relevant concentrations reduced platelet binding and rolling on vWF-coated microchannels at a shear rate of 100 dyn/cm2. Depletion of membrane cholesterol by incubation of platelet-rich-plasma with methyl-beta cyclodextrin abrogated platelet rolling on vWF. Analysis of glycoprotein Ib by applying cryo-electron tomography to intact platelets revealed local clusters of glycoprotein Ib complexes, upon shear-force exposure, whose formation could be prevented by alpha-linolenic acid treatment. This study provides novel findings on the rapid local rearrangement of the glycoprotein Ib complexes in response to high-shear flow and highlights the mechanism of in vitro inhibition of platelet binding to and rolling on vWF by alpha-linolenic acid.

18.
Swiss Med Wkly ; 149: w20098, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31269222

RESUMO

BACKGROUND: Systematic work-up of patients with myocardial infarction and non-obstructive coronary artery disease (MINOCA) using cardiac magnetic resonance imaging (CMR) led to a more than six-fold increase in the detection rate of myocarditis. In this study, we expanded on our prior two-year analysis by including preceding and subsequent years. METHODS: We performed a retrospective chart review of patients with angina-like symptoms and elevated high-sensitivity troponin T (TnT-hs ≥14 ng/l) but without significant coronary artery disease, from 2011 to 2017. Patients underwent CMR to test for myocarditis. From 2011 to 2015, only patients with elevated TnT-hs, no significant coronary artery disease and moderate to high clinical likelihood of suffering from myocarditis, underwent CMR. In 2016 and 2017, CMR images were obtained from all patients with MINOCA, independent of the clinical likelihood that patients were suffering from myocarditis. RESULTS: A total of 556 patients who underwent CMR (70.5% male, 57 ± 17 years, with an average left ventricular ejection fraction of 51 ± 15%) qualified for inclusion in this study’s analysis. From 2011 to 2015, 240 CMR examinations were performed, with the number increasing to 316 between 2016 and 2017. In total, myocarditis was diagnosed in 76 out of the 556 patients (13.7%). Between 2011 and 2015, the detection rate of myocarditis was 12.7 per 100,000 hospitalisations and increased 4.9-fold (p <0.0001), to 62.5 per 100,000 hospitalisations, between 2016 and 2017. CONCLUSION: A novel diagnostic algorithm led to an average 4.9-fold increase in the rate of myocarditis detection in our hospital over the two subsequent years. This highlights that myocarditis continues to be underdiagnosed when CMR is not systematically used in patients with MINOCA.  .

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA