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1.
Eur Heart J ; 2021 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-34624084

RESUMO

Intravascular thrombus formation and embolization are among the most frequent events leading to a number of cardiovascular conditions with high morbidity and mortality. The underlying causes are stasis of the circulating blood, genetic and acquired coagulation disorders, and reduced antithrombotic or prothrombotic properties of the vascular wall (Virchow's triad). In the venous system, intravascular thrombi can cause venous thrombosis and pulmonary and even peripheral embolism including ischaemic stroke [through a patent foramen ovale (PFO)]. Thrombi in the left atrium and its appendage or ventricle form in the context of atrial fibrillation and infarction, respectively. Furthermore, thrombi can form on native or prosthetic aortic valves, within the aorta (in particular at sites of ulcers, aortic dissection, and abdominal aneurysms), and in cerebral and peripheral arteries causing stroke and critical limb ischaemia, respectively. Finally, thrombotic occlusion may occur in arteries supplying vital organs such the heart, brain, kidney, and extremities. Thrombus formation and embolization can be managed with anticoagulants and devices depending on where they form and embolize and on patient characteristics. Vitamin K antagonists are preferred in patients with mechanical valves, while novel oral anticoagulants are first choice in most other cardiovascular conditions, in particular venous thromboembolism and atrial fibrillation. As anticoagulants are associated with a risk of bleeding, devices such as occluders of a PFO or the left atrial appendage are preferred in patients with an increased bleeding risk. Platelet inhibitors such as aspirin and/or P2Y12 antagonists are preferred in the secondary prevention of coronary artery disease, stroke, and peripheral artery disease either alone or in combination depending on the clinical condition. A differential and personalized use of anticoagulants, platelet inhibitors, and devices is recommended and reviewed in this article.

2.
EClinicalMedicine ; 40: 101099, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34490415

RESUMO

Background: Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic, there has been increasing urgency to identify pathophysiological characteristics leading to severe clinical course in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Human leukocyte antigen alleles (HLA) have been suggested as potential genetic host factors that affect individual immune response to SARS-CoV-2. We sought to evaluate this hypothesis by conducting a multicenter study using HLA sequencing. Methods: We analyzed the association between COVID-19 severity and HLAs in 435 individuals from Germany (n = 135), Spain (n = 133), Switzerland (n = 20) and the United States (n = 147), who had been enrolled from March 2020 to August 2020. This study included patients older than 18 years, diagnosed with COVID-19 and representing the full spectrum of the disease. Finally, we tested our results by meta-analysing data from prior genome-wide association studies (GWAS). Findings: We describe a potential association of HLA-C*04:01 with severe clinical course of COVID-19. Carriers of HLA-C*04:01 had twice the risk of intubation when infected with SARS-CoV-2 (risk ratio 1.5 [95% CI 1.1-2.1], odds ratio 3.5 [95% CI 1.9-6.6], adjusted p-value = 0.0074). These findings are based on data from four countries and corroborated by independent results from GWAS. Our findings are biologically plausible, as HLA-C*04:01 has fewer predicted bindings sites for relevant SARS-CoV-2 peptides compared to other HLA alleles. Interpretation: HLA-C*04:01 carrier state is associated with severe clinical course in SARS-CoV-2. Our findings suggest that HLA class I alleles have a relevant role in immune defense against SARS-CoV-2. Funding: Funded by Roche Sequencing Solutions, Inc.

3.
Front Cardiovasc Med ; 8: 622619, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33987209

RESUMO

Background: Omega-3 fatty acids are associated with a lower risk of cardiovascular disease (CVD) and with beneficial effects on CV risk factors. The albumin-creatinine ratio (ACR) is a risk factor for CVD, all-cause mortality and accelerated glomerular filtration rate (GFR) decline in the general population. We aimed to investigate the association between n-3 PUFAS and ACR in heathy individuals with preserved GFR. Design and Methods: The present cross-sectional analysis is part of the GAPP study, a population-based cohort of healthy adults aged 25-41 years. Individuals with known CVD, diabetes, or a BMI >35 kg/m2 were excluded. eGFR was calculated according to the combined Creatinine/Cystatin C CKD-EPI formula. ACR was obtained from a fasting morning urine sample. The Omega-3 Index (relative amount of EPA and DHA of total fatty acids in %) was obtained from whole blood aliquots. Results: Overall, 2001 participants (median age 37 years IQR 31; 40, 53% female) were included in this analysis. Median Omega-3 Index was 4.59 (IQR 4.06; 5.25) and median eGFR 111 ml/min/1.73 m2 (IQR 103; 118). Median ACR was 0.14 mg/mmol (IQR 0; 0.43). We found a significant inverse association of the Omega-3 Index with ACR (ratio 0.84, 95%CI 0.73-0.96; p = 0.011) which remained after comprehensive adjustment (ratio 0.86, 95%CI 0.74-1.00; p = 0.048). No association of the Omega-3 Index with eGFR was found. The adjusted difference in eGFR per 1-unit increase in Omega3-Index was -0.21 (95%CI -0.76; 0.35; p = 0.47). Conclusions: A higher Omega-3 Index was significantly associated with lower ACR in this young and healthy population with preserved eGFR. Omega-3 fatty acids may exhibit cardio- and nephroprotective effects in healthy individuals through modulation of ACR.

4.
Open Heart ; 8(1)2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33883229

RESUMO

OBJECTIVE: The optimal target heart rate in patients with prevalent atrial fibrillation (AF) is not well defined. The aim of this study was to analyse the associations between heart rate and adverse outcomes in a large contemporary cohort of patients with prevalent AF. METHODS: From two prospective cohort studies, we included stable AF outpatients who were in AF on the baseline ECG. The main outcome events assessed during prospective follow-up were heart failure hospitalisation, stroke or systemic embolism and death. The associations between heart rate and adverse outcomes were evaluated using multivariable Cox regression models. RESULTS: The study population consisted of 1679 patients who had prevalent AF at baseline. Mean age was 74 years, and 24.6% were women. The mean heart rate on the baseline ECG was 78 (±19) beats per minute (bpm). The median follow-up was 3.9 years (IQR 2.2-5.0). Heart rate was not significantly associated with heart failure hospitalisation (adjusted HR (aHR) per 10 bpm increase, 1.00, 95% CI 0.94 to 1.07, p=0.95), stroke or systemic embolism (aHR 0.95, 95% CI 0.84 to 1.07, p=0.38) or death (aHR 1.02, 95% CI 0.95 to 1.09, p=0.66). There was no evidence of a threshold effect for heart rates <60 bpm or >100 bpm. CONCLUSIONS: In this large contemporary cohort of outpatients with prevalent AF, we found no association between heart rate and adverse outcome events. These data are in line with recommendations that strict heart rate control is not needed in otherwise stable outpatients with AF.


Assuntos
Fibrilação Atrial/epidemiologia , Insuficiência Cardíaca/etiologia , Medição de Risco/métodos , Acidente Vascular Cerebral/etiologia , Idoso , Fibrilação Atrial/complicações , Feminino , Seguimentos , Insuficiência Cardíaca/epidemiologia , Humanos , Masculino , Prevalência , Estudos Prospectivos , Acidente Vascular Cerebral/epidemiologia
5.
Clin Cardiol ; 44(1): 51-57, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33169859

RESUMO

BACKGROUND: A high burden of cardiovascular comorbidities puts patients with atrial fibrillation (AF) at high risk for hospitalizations, but the role of other factors is less clear. HYPOTHESIS: To determine the relationship between psychosocial factors and the risk of unplanned hospitalizations in AF patients. METHODS: Prospective observational cohort study of 2378 patients aged 65 or older with previously diagnosed AF across 14 centers in Switzerland. Marital status and education level were defined as social factors, depression and health perception were psychological components. The pre-defined outcome was unplanned all-cause hospitalization. RESULTS: During a median follow-up of 2.0 years, a total of 1713 hospitalizations occurred in 37% of patients. Compared to patients who were married, adjusted rate ratios (aRR) for all-cause hospitalizations were 1.28 (95% confidence interval [CI], 0.97-1.69) for singles, 1.31 (95%CI, 1.06-1.62) for divorced patients, and 1.02 (95%CI, 0.82-1.25) for widowed patients. The aRRs for all-cause hospitalizations across increasing quartiles of health perception were 1.0 (highest health perception), 1.15 (95%CI, 0.84-1.59), 1.25 (95%CI, 1.03-1.53), and 1.66 (95%CI, 1.34-2.07). No different hospitalization rates were observed in patients with a secondary or primary or less education as compared to patients with a college degree (aRR, 1.06; 95%CI, 0.91-1.23 and 1.05; 95%CI, 0.83-1.33, respectively). Presence of depression was not associated with higher hospitalization rates (aRR, 0.94; 95%CI, 0.68-1.29). CONCLUSIONS: The findings suggest that psychosocial factors, including marital status and health perception, are strongly associated with the occurrence of hospitalizations in AF patients. Targeted psychosocial support interventions may help to avoid unnecessary hospitalizations. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02105844.


Assuntos
Fibrilação Atrial/terapia , Hospitalização/estatística & dados numéricos , Sistema de Registros , Estresse Psicológico/epidemiologia , Idoso , Fibrilação Atrial/psicologia , Feminino , Humanos , Incidência , Masculino , Estudos Prospectivos , Fatores de Risco , Estresse Psicológico/psicologia , Suíça/epidemiologia
6.
PLoS One ; 15(10): e0240167, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33035257

RESUMO

BACKGROUND: Atrial fibrillation (AF), the most common sustained cardiac arrhythmia, is considered as risk factor for the development of mild cognitive impairment (MCI) and dementia. However, dynamics of cognitive functions are subtle, and neurocognitive assessments largely differ in detecting these changes. We aimed to develop and evaluate a score which represents the common aspects of the cognitive functions measured by validated tests (i.e., "general cognitive construct"), while reducing overlap between tests and be more sensitive to identify changes in overall cognitive functioning. METHODS: We developed the CoCo (cognitive construct) score to reflect the cognitive performance obtained by all items of four neurocognitive assessments (Montreal Cognitive Assessment (MoCA); Trail Making Test; Semantic Fluency, animals; Digital Symbol Substitution Test). The sample comprised 2,415 AF patients from the Swiss Atrial Fibrillation Cohort Study (Swiss-AF), 87% aged at least 65 years. Psychometric statistics were calculated for two cognitive measures based on (i) the full set of items from the neurocognitive test battery administered in the Swiss-AF study (i.e., CoCo item set) and (ii) the items from the widely used MoCA test. For the CoCo item set, a factor score was derived based on a principal component analysis, and its measurement properties were analyzed. RESULTS: Both the MoCA item set and the full neurocognitive test battery revealed good psychometric properties, especially the full battery. A one-factor model with good model fit and performance across time and groups was identified and used to generate the CoCo score, reflecting for each patient the common cognitive skill performance measured across the full neurocognitive test battery. The CoCo score showed larger effect sizes compared to the MoCA score in relation to relevant clinical variables. CONCLUSION: The derived factor score allows summarizing AF patients' cognitive performance as a single score. Using this score in the Swiss-AF project increases measurement sensitivity and decreases the number of statistical tests needed, which will be helpful in future studies addressing how AF affects the risk of developing cognitive impairment.


Assuntos
Fibrilação Atrial/complicações , Disfunção Cognitiva/diagnóstico , Testes Neuropsicológicos/normas , Idoso , Idoso de 80 Anos ou mais , Fibrilação Atrial/epidemiologia , Cognição , Disfunção Cognitiva/epidemiologia , Feminino , Humanos , Masculino , Psicometria/métodos , Psicometria/normas
7.
Swiss Med Wkly ; 150: w20287, 2020 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-32725609

RESUMO

AIMS: Exercise stress testing is frequently used for the assessment of coronary artery disease. As the validity of the test result is highly dependent on the patient’s cooperation and motivation, we hypothesised that virtual group motivation would result in a higher exercise capacity and may increase the test’s validity. METHODS: 108 patients at a Swiss teaching hospital with an indication for exercise testing were included in a controlled, open-label trial and randomised 1:1 to treadmill exercise testing whilst either watching a video of a walking group (video group, n = 43), or watching a static image of flowers (image group, n = 43). The video showed a group of five amateur runners, giving the patients the impression of running within the group. As primary outcomes, the performance achieved and the perceived level of comfort during the test were analysed. RESULTS: The video group achieved significantly higher percentages of their age-predicted METs (149 ± 32% vs 135 ± 29%, p = 0.041) and longer exercise durations (11:12 ± 2:54 min vs 08:54 ± 02:39 min, p <0.001). Levels of comfort (8.4 ± 1.4 vs 7.5 ± 1.7 analogue scale, p = 0.011) and closeness to their physical limits (8.9 ± 0.8 vs 8.1 ± 1.5, p = 0.005) were rated significantly higher by patients in the video group. CONCLUSIONS: Patients watching a video of a running group achieved significantly higher maximum exercise levels and longer test durations. This may have implications for the test’s validity. Furthermore, the virtual setting enhanced patient comfort. (This trial was formally registered at clinicaltrials.gov: trial ID NCT03704493.).


Assuntos
Doença da Artéria Coronariana , Corrida , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/reabilitação , Exercício Físico , Teste de Esforço , Humanos , Motivação
8.
Sci Rep ; 10(1): 2495, 2020 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-32051462

RESUMO

The association of glycated hemoglobin (HbA1c) with venous thromboembolism (VTE) and death in the elderly is unknown. In the SWEETCO 65+ study we analyzed prospectively a Swiss Cohort of Elderly Patients with Venous Thromboembolism (SWITCO 65+). 888 patients were enrolled for the SWEETCO 65+ analysis. HbA1c was determined at baseline and divided into three categories (HbA1c < 5.7%, normal range; 5.7-6.49%, pre-diabetic range; and >6.5%, diabetic range). Median follow-up was 2.5 years. The primary endpoint was recurrent VTE. Secondary endpoints included all-cause mortality and major bleeds. The total prevalence of diabetes was 22.1%. The risk of recurrent VTE was similar in patients with HbA1c with pre-diabetes (adjusted subhazard ratio (aSHR) 1.07 [0.70 to 1.63]) and diabetes (aSHR 0.73 [0.39 to 1.37]) as compared to those with a HbA1c in the normal range. However, a HbA1c ≥ 6.5% (median IQ range 7.0 [6.70;7.60]) was significantly associated with a higher risk of all-cause mortality (adjusted hazard ratio [aHR] 1.83 [1.21 to 2.75]). In summary we found no association between HbA1c and major bleeding. Elevated HbA1c levels are not associated with recurrent VTE but with increased all-cause mortality in an elderly population with acute VTE.


Assuntos
Hemoglobina A Glicada/metabolismo , Mortalidade/tendências , Tromboembolia Venosa/sangue , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Feminino , Humanos , Masculino , Tromboembolia Venosa/epidemiologia
9.
Eur J Clin Invest ; 49(9): e13154, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31246275

RESUMO

BACKGROUND: Combining high-sensitivity cardiac Troponin T (hs-cTnT), NT-pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity C-reactive protein (hs-CRP) may improve risk stratification of patients with pulmonary embolism (PE) beyond the PESI risk score. METHODS: In the prospective multicentre SWITCO65+ study, we analysed 214 patients ≥ 65 years with a new submassive PE. Biomarkers and clinical information for the PESI risk score were ascertained within 1 day after diagnosis. Associations of hs-TnT, NT-proBNP, hs-CRP and the PESI risk score with the primary endpoint defined as 6-month mortality were assessed. The discriminative power of the PESI risk score and its combination with hs-cTnT, NT-proBNP and hs-CRP for 6-month mortality was compared using integrated discrimination improvement (IDI) index and net reclassification improvement (NRI). RESULTS: Compared with the lowest quartile, patients in the highest quartile had a higher risk of death during the first 6 months for hs-cTnT (adjusted HR 10.22; 95% CI 1.79-58.34; P = 0.009) and a trend for NT-proBNP (adjusted HR 4.3; 95% CI 0.9-20.41; P = 0.067) unlike hs-CRP (adjusted HR 1.97; 95% CI 0.48-8.05; P = 0.344). The PESI risk score (c-statistic 0.77 (95% CI 0.69-0.84) had the highest prognostic accuracy for 6-month mortality, outperforming hs-cTnT, NT-proBNP and hs-CRP (c-statistics of 0.72, 0.72, and 0.54), respectively. Combining all three biomarkers had no clinically relevant impact on risk stratification when added to the PESI risk score (IDI = 0.067; 95% CI 0.012-0.123; P = 0.018; NRI = 0.101 95% CI -0.099-0.302; P = 0.321). CONCLUSIONS: In elderly patients with PE, 6-month mortality can adequately be predicted by the PESI risk score alone.


Assuntos
Proteína C-Reativa/metabolismo , Mortalidade , Peptídeo Natriurético Encefálico/metabolismo , Fragmentos de Peptídeos/metabolismo , Embolia Pulmonar/metabolismo , Troponina T/metabolismo , Doença Aguda , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Masculino , Valor Preditivo dos Testes , Prognóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Medição de Risco
10.
J Am Coll Cardiol ; 73(9): 989-999, 2019 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-30846109

RESUMO

BACKGROUND: Patients with atrial fibrillation (AF) have an increased risk of cognitive decline, potentially resulting from clinically unrecognized vascular brain lesions. OBJECTIVES: This study sought to assess the relationships between cognitive function and vascular brain lesions in patients with AF. METHODS: Patients with known AF were enrolled in a multicenter study in Switzerland. Brain magnetic resonance imaging (MRI) and cognitive testing using the Montreal Cognitive Assessment (MoCA) were performed in all participants. Large noncortical or cortical infarcts (LNCCIs), small noncortical infarcts (SNCIs), microbleeds, and white matter lesions were quantified by a central core laboratory. Clinically silent infarcts were defined as infarcts on brain MRI in patients without a clinical history of stroke or transient ischemic attack. RESULTS: The study included 1,737 patients with a mean age of 73 ± 8 years (28% women, 90% taking oral anticoagulant agents). On MRI, LNCCIs were found in 387 patients (22%), SNCIs in 368 (21%), microbleeds in 372 (22%), and white matter lesions in 1715 (99%). Clinically silent infarcts among the 1,390 patients without a history of stroke or transient ischemic attack were found in 201 patients with LNCCIs (15%) and 245 patients with SNCIs (18%). The MoCA score was 24.7 ± 3.3 in patients with and 25.8 ± 2.9 in those without LNCCIs on brain MRI (p < 0.001). The difference in MoCA score remained similar when only clinically silent LNCCIs were considered (24.9 ± 3.1 vs. 25.8 ± 2.9; p < 0.001). In a multivariable regression model including all vascular brain lesion parameters, LNCCI volume was the strongest predictor of a reduced MoCA (ß = -0.26; 95% confidence interval: -0.40 to -0.13; p < 0.001). CONCLUSIONS: Patients with AF have a high burden of LNCCIs and other brain lesions on systematic brain MRI screening, and most of these lesions are clinically silent. LNCCIs were associated with worse cognitive function, even among patients with clinically silent infarcts. Our findings raise the question of MRI screening in patients with AF.


Assuntos
Fibrilação Atrial/complicações , Encéfalo/patologia , Infarto Cerebral/diagnóstico , Cognição/fisiologia , Disfunção Cognitiva/diagnóstico , Imageamento por Ressonância Magnética/métodos , Idoso , Infarto Cerebral/complicações , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/fisiopatologia , Feminino , Seguimentos , Humanos , Masculino , Testes Neuropsicológicos , Estudos Prospectivos , Fatores de Risco
11.
J Hypertens ; 36(7): 1548-1554, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29570511

RESUMO

BACKGROUND: Omega-3 fatty acids (n - 3 FA) may have blood pressure (BP)-lowering effects in untreated hypertensive and elderly patients. The effect of n - 3 FA on BP in young, healthy adults remains unknown. The Omega-3 Index reliably reflects an individuals' omega-3 status. We hypothesized that the Omega-3 Index is inversely associated with BP levels in young healthy adults. METHODS: The current study (n = 2036) is a cross-sectional study investigating the baseline characteristics of a cohort, which includes healthy adults, age 25-41 years. Individuals with cardiovascular disease, known diabetes or a BMI higher than 35 kg/m were excluded. The Omega-3 Index was determined in whole blood using gas chromatography. Association with office and 24-h BP was assessed using multivariable linear regression models adjusted for potential confounders. RESULTS: Median Omega-3 Index was 4.58% (interquartile range 4.08; 5.25). Compared with individuals in the lowest Omega-3 Index quartile, individuals in the highest had a SBP and DBP that was 4 and 2 mmHg lower, respectively (P < 0.01). A significant linear inverse relationship of the Omega-3 Index with 24-h and office BP was observed. Per 1-U increase in log-transformed Omega-3 Index the lowering in BP (given as multivariable adjusted ß coefficients; 95% confidence interval) was -2.67 mmHg (-4.83; -0.51; P = 0.02) and -2.30 mmHg (-3.92; -0.68; P = 0.005) for 24-h SBP and DBP, respectively. CONCLUSION: A higher Omega-3 Index is associated with statistically significant, clinically relevant lower SBP and DBP levels in normotensive young and healthy individuals. Diets rich in n - 3 FA may be a strategy for primary prevention of hypertension.


Assuntos
Pressão Sanguínea , Ácidos Graxos Ômega-3/sangue , Adulto , Estudos de Coortes , Estudos Transversais , Feminino , Voluntários Saudáveis , Humanos , Masculino
14.
Cardiovasc Res ; 113(1): 61-69, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-28028070

RESUMO

AIMS: The P2Y12 antagonist ticagrelor reduces mortality in patients with acute coronary syndrome (ACS), compared with clopidogrel, and the mechanisms underlying this effect are not clearly understood. Arterial thrombosis is the key event in ACS; however, direct vascular effects of either ticagrelor or clopidogrel with focus on arterial thrombosis and its key trigger tissue factor have not been previously investigated. METHODS AND RESULTS: Human aortic endothelial cells were treated with ticagrelor or clopidogrel active metabolite (CAM) and stimulated with tumour necrosis factor-alpha (TNF-α); effects on procoagulant tissue factor (TF) expression and activity, its counter-player TF pathway inhibitor (TFPI) and the underlying mechanisms were determined. Further, arterial thrombosis by photochemical injury of the common carotid artery, and TF expression in the murine endothelium were examined in C57BL/6 mice treated with ticagrelor or clopidogrel. Ticagrelor, but not CAM, reduced TNF-α-induced TF expression via proteasomal degradation and TF activity, independently of the P2Y12 receptor and the equilibrative nucleoside transporter 1 (ENT1), an additional target of ticagrelor. In C57BL/6 mice, ticagrelor prolonged time to arterial occlusion, compared with clopidogrel, despite comparable antiplatelet effects. In line with our in vitro results, ticagrelor, but not clopidogrel, reduced TF expression in the endothelium of murine arteries. CONCLUSION: Ticagrelor, unlike clopidogrel, exhibits endothelial-specific antithrombotic properties and blunts arterial thrombus formation. The additional antithrombotic properties displayed by ticagrelor may explain its greater efficacy in reducing thrombotic events in clinical trials. These findings may provide the basis for new indications for ticagrelor.


Assuntos
Adenosina/análogos & derivados , Coagulação Sanguínea/efeitos dos fármacos , Lesões das Artérias Carótidas/tratamento farmacológico , Células Endoteliais/efeitos dos fármacos , Fibrinolíticos/farmacologia , Tromboplastina/metabolismo , Trombose/prevenção & controle , Ticlopidina/análogos & derivados , Adenosina/farmacologia , Animais , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Lesões das Artérias Carótidas/sangue , Lesões das Artérias Carótidas/genética , Células Cultivadas , Clopidogrel , Modelos Animais de Doenças , Regulação para Baixo , Células Endoteliais/metabolismo , Transportador Equilibrativo 1 de Nucleosídeo/efeitos dos fármacos , Transportador Equilibrativo 1 de Nucleosídeo/metabolismo , Humanos , Masculino , Camundongos Endogâmicos C57BL , Inibidores da Agregação Plaquetária/farmacologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteólise , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Receptores Purinérgicos P2Y12/efeitos dos fármacos , Receptores Purinérgicos P2Y12/metabolismo , Tromboplastina/genética , Trombose/sangue , Trombose/genética , Ticagrelor , Ticlopidina/farmacologia , Fatores de Tempo , Fator de Necrose Tumoral alfa/farmacologia
15.
Blood ; 122(6): 1026-33, 2013 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-23801636

RESUMO

Previously we reported that dietary intake of alpha-linolenic acid (ALA) reduces atherogenesis and inhibits arterial thrombosis. Here, we analyze the substantial increase in platelet count induced by ALA and the mechanisms of reduced platelet clearance. Eight-week-old male apolipoprotein E knockout (ApoE(-/-)) mice were fed a 0.21g% cholesterol diet complemented by either a high- (7.3g%) or low-ALA (0.03g%) content. Platelet counts doubled after 16 weeks of ALA feeding, whereas the bleeding time remained similar. Plasma glycocalicin and glycocalicin index were reduced, while reticulated platelets, thrombopoietin, and bone marrow megakaryocyte colony-forming units remained unchanged. Platelet contents of liver and spleen were substantially reduced, without affecting macrophage function and number. Glycoprotein Ib (GPIb) shedding, exposure of P-selectin, and activated integrin αIIbß3 upon activation with thrombin were reduced. Dietary ALA increased the platelet count by reducing platelet clearance in the reticulo-endothelial system. The latter appears to be mediated by reduced cleavage of GPIb by tumor necrosis factor-α-converting enzyme and reduced platelet activation/expression of procoagulant signaling. Ex vivo, there was less adhesion of human platelets to von Willebrand factor under high shear conditions after ALA treatment. Thus, ALA may be a promising tool in transfusion medicine and in high turnover/high activation platelet disorders.


Assuntos
Apolipoproteínas E/genética , Aterosclerose/genética , Plaquetas/efeitos dos fármacos , Ácido alfa-Linoleico/uso terapêutico , Proteínas ADAM/metabolismo , Proteína ADAM17 , Ração Animal , Animais , Aterosclerose/metabolismo , Plaquetas/metabolismo , Humanos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Selectina-P/metabolismo , Ativação Plaquetária , Adesividade Plaquetária , Contagem de Plaquetas , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Complexo Glicoproteico GPIb-IX de Plaquetas/metabolismo , Complexo Glicoproteico GPIb-IX de Plaquetas/fisiologia , Transdução de Sinais , Baço/metabolismo
16.
Toxicol In Vitro ; 26(6): 930-8, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22542759

RESUMO

OBJECTIVE: Air pollution with fine particulates (PM(10) and PM(2.5)) is associated with an increased incidence of cardiovascular events. The proposed mechanisms include indirect proinflammatory and procoagulant reactions involving activation of pulmonary macrophages, endothelial cells and the TNF/TF pathway, or direct procoagulant effects. Our laboratory has observed a reduction of the platelet responsiveness to collagen after exposure to diesel exhaust particles (DEP). HYPOTHESIS: DEP directly interfere with platelet-collagen interactions by selectively inducing the shedding of platelet signaling receptors via metalloproteinases, which would represent a novel mechanism for DEP action on platelets. METHODS: Citrated blood from healthy volunteers was exposed to highly standardized DEP at concentrations of 0.1, 2.5 and 5.0µg/ml or ultrafine carbon black (ufCB, 0.1µg/ml) and the plasmatic and platelet response was analysed. The closure times with the PFA-100 device and the platelet aggregation in response to a variety of agonists were monitored. Interleukins (IL)-1ß and IL-8 levels were determined by ELISA and soluble P-selectin by the Luminex bead assay. Thrombin activity was measured as the endogenous thrombin potential (ETP) by fluorescence spectrometry. Soluble GPVI and GPIbα (glycocalicin) ectodomain fragments were measured by ELISA. ADAMTS13 activity was determined by a FRETS based assay and plasmin activity with Spectrozyme PL. RESULTS: Aggregation assays where platelets were treated with low dose DEP or ultrafine carbon black (ufCB) revealed a significantly increased response to low doses of collagen (p<0.05, n=5). At higher doses, however, collagen induced aggregation was suppressed by DEP treatment: at 2.5µg/ml, the inhibition was 34±12% (p<0.01, n=10). Aggregations with cross-linked collagen related peptide (CRPxl), convulxin and with the monoclonal antibody 9O12.2 (all known to specifically bind to and activate GPVI) were also diminished. Ristocetin, arachidonic acid and ADP responses were normal at all DEP concentrations. No cleavage of GPVI ectodomain was detected (soluble GPVI 27.8±3 vs. 28±4µg/ml mean±SEM, n=10); however increased plasma glycocalicin (GPIbα ectodomain) was detected upon diesel exposure (2.58±0.11 vs. 2.28±0.03µg/ml p<0.01, n=10). ADAMTS13 and plasmin activity remained unaffected by DEP under the conditions tested. Platelets were not activated by either DEP or ufCB as soluble P-selectin was insensitive to these. CONCLUSIONS: DEP specifically and directly interferes with platelet-collagen interactions. The functional consequences are biphasic and include enhance platelet aggregation at lower DEP concentrations and inhibition at a higher dose. Our data indicate that this interaction does not involve P-selectin or GPVI shedding. It is however associated with an increase in GPIb cleavage.


Assuntos
Plaquetas/efeitos dos fármacos , Glicoproteínas de Membrana/sangue , Emissões de Veículos/toxicidade , Coagulação Sanguínea/efeitos dos fármacos , Plaquetas/fisiologia , Colágeno/metabolismo , Humanos , Agregação Plaquetária/efeitos dos fármacos , Complexo Glicoproteico GPIb-IX de Plaquetas/metabolismo , Glicoproteínas da Membrana de Plaquetas/metabolismo , Fuligem/toxicidade , Trombina/metabolismo
17.
J Thromb Thrombolysis ; 32(2): 215-22, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21505785

RESUMO

The role of platelet receptor gain-of-function single nucleotide polymorphisms (SNP) in cardiovascular disease is controversial. We hypothesised that certain SNPs may accelerate the development of carotid artery stenosis. The intronic PAR-1 receptor intervening sequence-14 A/T (IVSn-14 A/T) polymorphism and three additional platelet receptor polymorphisms, i.e. GPIa (807C/T), GPIbα (5T/C) and HPA-1a/HPA-1b (Pl (A1/A2)) of GPIIIa were studied. The interaction of SNPs with conventional risk factors including male gender, hypertension, high cholesterol, diabetes, advanced age and smoking were investigated. The hypothesis was tested in 114 well-characterised patients with symptomatic carotid or vertebral stenosis from the British CAVATAS population and compared the results with 97 unrelated controls. The allele frequency of the platelet gain-of-function SNP was not significantly different in the CAVATAS population as compared to controls (PAR-1A/T (P = 0.13), GPIa C/T (P = 0.25), GPIIIa HPA-1a/HPA-1b (PlA1/A2) (P = 0.66) and GPIb T/C (P = 0.20)). In the subgroup of smokers, however, the prothrombotic GPIbα C mutated allele was found in a significantly higher frequency in the patient as compared to the control group (P = 0.04). Contrary to the primary hypothesis, the PAR-1A/T SNP as well as the other SNPs tested were not over- or underrepresented in the CAVATAS population. However, a significantly increased prevalence of GPIb-α (5C/T) was found in the subgroup of smokers and may represent an important cofactor in this patient group of our hypothesis-generating study.


Assuntos
Estenose das Carótidas/genética , Epistasia Genética , Glicoproteínas da Membrana de Plaquetas/genética , Polimorfismo de Nucleotídeo Único , Insuficiência Vertebrobasilar/genética , Fatores Etários , Idoso , Estenose das Carótidas/terapia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Fatores Sexuais , Reino Unido , Insuficiência Vertebrobasilar/terapia
18.
Blood ; 117(21): 5723-32, 2011 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-21389318

RESUMO

This study investigated the immature platelet fraction (IPF) in assessing treatment effects in immune thrombocytopenia (ITP). IPF was measured on the Sysmex XE2100 autoanalyzer. The mean absolute-IPF (A-IPF) was lower for ITP patients than for healthy controls (3.2 vs 7.8 × 109/L, P < .01), whereas IPF percentage was greater (29.2% vs 3.2%, P < .01). All 5 patients with a platelet response to Eltrombopag, a thrombopoietic agent, but none responding to an anti-FcγRIII antibody, had corresponding A-IPF responses. Seven of 7 patients responding to RhoD immuneglobulin (anti-D) and 6 of 8 responding to intravenous immunoglobulin (IVIG) did not have corresponding increases in A-IPF, but 2 with IVIG and 1 with IVIG anti-D did. This supports inhibition of platelet destruction as the primary mechanism of intravenous anti-D and IVIG, although IVIG may also enhance thrombopoiesis. Plasma glycocalicin, released during platelet destruction, normalized as glycocalicin index, was higher in ITP patients than controls (31.36 vs 1.75, P = .001). There was an inverse correlation between glycocalicin index and A-IPF in ITP patients (r² = -0.578, P = .015), demonstrating the relationship between platelet production and destruction. Nonresponders to thrombopoietic agents had increased megakaryocytes but not increased A-IPF, suggesting that antibodies blocked platelet release. In conclusion, A-IPF measures real-time thrombopoiesis, providing insight into mechanisms of treatment effect.


Assuntos
Plaquetas/fisiologia , Imunoglobulinas Intravenosas/uso terapêutico , Isoanticorpos/uso terapêutico , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Trombopoese/efeitos dos fármacos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzoatos/uso terapêutico , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Humanos , Hidrazinas/uso terapêutico , Lactente , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas , Prognóstico , Púrpura Trombocitopênica Idiopática/imunologia , Pirazóis/uso terapêutico , Receptores de IgG/imunologia , Estudos Retrospectivos , Sistema do Grupo Sanguíneo Rh-Hr , Imunoglobulina rho(D) , Trombocitose , Adulto Jovem
19.
Ther Umsch ; 67(12): 635-6, 2010 Dec.
Artigo em Alemão | MEDLINE | ID: mdl-21108190

RESUMO

UNLABELLED: The association of periodontal disease and cardiovascular events is discussed. Low grade inflammation, with elevated CRP and elevated fibrinogen might contribute. A recent study from Scotland in which the dental brushing was evaluated found a relative risk for a cardiovascular event of 1.69 associated with rare tooth brushing. However, there was a bias with elderly patients, male gender and low socioeconomic status. CONCLUSION: The common risk factor is smoking; active "dentogenic" inflammation should be checked before surgery, particularly before surgery with implants.


Assuntos
Infarto do Miocárdio/prevenção & controle , Periodontite/complicações , Escovação Dentária , Proteína C-Reativa/metabolismo , Fibrinogênio/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Periodontite/prevenção & controle , Fatores de Risco , Escócia , Fatores Socioeconômicos
20.
Blood Coagul Fibrinolysis ; 19(8): 801-6, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19002047

RESUMO

Our aim was to investigate the role of filamin cleavage and protein tyrosine phosphorylation in shear-stress-induced platelet microparticle formation and of its suppression by the monoclonal antibody (mAb) Ib-23 directed against GPIbalpha. PPACK-anticoagulated or EDTA-anticoagulated platelet-rich plasma or washed platelets were exposed to high shear stress (5000 s-1 for 5 min) in the presence of antagonists of GP Ibalpha (mAb Ib-23), of GP IIb/IIIa (abciximab) and their combination. We assessed the generation of microparticle by flow cytometry, the filamin cleavage and the protein tyrosine phosphorylation by western blotting. Microparticle formation decreased by more than 50% with mAb Ib-23 alone (P < 0.01, n = 23) but filamin cleavage was not inhibited. In contrast, abciximab did not change microparticle numbers nor filamin cleavage under the same conditions. However, when combined, the inhibitors against GP Ibalpha and GP IIb/IIIa decreased microparticle by 70% and the filamin cleavage by 20% (P < 0.05). Focal adhesion kinase and p72Syk phosphorylation was enhanced by mAb Ib-23, whereas treatment with abciximab reduced it. mAb Ib-23 inhibits platelet microparticle induced by high shear stress. The mechanism seems not to depend on filamin cleavage: abciximab allowed for full microparticle formation at similar levels of cleaved filamin, whereas the combined inhibitors reduced it. The effect of mAb Ib-23 on protein tyrosine phosphorylation supports previous data, which correlates microparticle formation with the extent of protein tyrosine dephosphorylation and mirrors the dephosphorylation by protein tyrosine phosphatase (PTP-1B) in platelets of calpain-/- knockout mice.


Assuntos
Plaquetas/metabolismo , Plaquetas/ultraestrutura , Micropartículas Derivadas de Células/efeitos dos fármacos , Proteínas Contráteis/metabolismo , Proteínas dos Microfilamentos/metabolismo , Complexo Glicoproteico GPIb-IX de Plaquetas/imunologia , Proteínas/metabolismo , Abciximab , Anticorpos Monoclonais/farmacologia , Proteínas Contráteis/fisiologia , Filaminas , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Humanos , Fragmentos Fab das Imunoglobulinas/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas dos Microfilamentos/fisiologia , Fosforilação/efeitos dos fármacos , Fosforilação/fisiologia , Proteínas Tirosina Quinases/metabolismo , Estresse Mecânico , Quinase Syk , Tirosina/metabolismo
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