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2.
Int J Cardiol ; 301: 183-189, 2020 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-31806280

RESUMO

Pulmonary arterial hypertension is an obstructive pulmonary vasculopathy that leads to increased pulmonary vascular resistance, right ventricular overload and failure, and death. Patients' clinical status and prognosis depend mostly on the capability of the right ventricle to adapt to the increased afterload, maintain function, and preserve cardiac output. As a result, reducing the hemodynamic burden of the right ventricle should be a key target of current treatments, along with improvement in WHO functional class, 6-minute walk distance, and rates of hospitalization. However, physicians still find it challenging to integrate the evaluation of right ventricular function into widely accepted clinical parameters in order to stratify patients more accurately. This limitation is very relevant, since higher-risk patients are more likely to benefit from a more aggressive therapeutic approach. We analyzed the hemodynamic burden in pulmonary arterial hypertension, the importance of echocardiographic evaluation of the right ventricle, the impact of current treatments on hemodynamic parameters, and the identification of patients who are more likely to benefit from a more aggressive therapeutic approach.

4.
Expert Rev Respir Med ; : 1-7, 2019 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-31545126

RESUMO

Introduction: Parenteral treprostinil for patients with pulmonary arterial hypertension has resulted in improvement of exercise capacity, functional class, hemodynamics, and survival. Recently, a first randomized trial performed in patients with chronic thromboembolic pulmonary hypertension confirmed the efficacy of subcutaneous treprostinil in this subset of pulmonary hypertension. Areas covered: Treprostinil sodium is a prostacyclin analog produced synthetically. Drug characteristics include potent systemic and pulmonary vasodilatory effects. Local side-effects of subcutaneous treprostinil have been an obstacle for its use. However, in contrast to other prostacyclins, treprostinil has favorable features. We performed a literature survey by searching PubMed for clinical trials published in any language, investigating medicinal treatments for CTEPH. We used the search terms 'inoperable', and 'chronic thromboembolic pulmonary hypertension' with 'randomized clinical trial', and have put treprostinil for CTEPH in the contest of published literature. Expert opinion: Drugs approved for PAH have recently shown excellent efficacy in patients with non-operable CTEPH. Rather than head-to-head comparisons of drugs, combination treatments are to be expected in the near future. Furthermore, drugs will have to be tested alongside with pulmonary endarterectomy (PEA), and alongside balloon pulmonary angioplasty, a promising percutaneous mechanical treatment for CTEPH that is not suited for PEA.

6.
Int J Cardiol ; 286: 198-207, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-30777407

RESUMO

Thrombotic and bleeding risks, as well as the incidence and presentation of cardiovascular events and related outcomes, appear to differ between genders, partly in relation to variability in age, comorbidities and body size. Women experience frequent fluctuations of pro-thrombotic activity during their lifetime, related to menstrual cycles, the use of oral contraceptives, pregnancy, menopause, and hormone replacement therapy, all with potential impact on the clinical manifestations of atherosclerotic disease. On the other hand, compared with men, women feature an increased risk of bleeding during hospitalization in the setting of acute coronary syndromes or percutaneous coronary interventions. At the same time, benefits of antithrombotic therapy may differ in women compared with men in several clinical settings and according to the type of antithrombotic agent used for primary and secondary cardiovascular prevention, for the prevention of thromboembolism in patients with atrial fibrillation, and for the prevention and treatment of venous thromboembolism. Data from observational and interventional studies do not exclude gender-specific differences in either the thrombotic and hemorrhagic burden, and the effects of antithrombotic drugs on clinical outcomes might also differ between men and women. Pathophysiological mechanisms causing these disparities are not entirely clear. Multiple factors in platelet function and coagulation mechanisms in different vascular beds, partly related to the hormonal status, might contribute to such gender differences.


Assuntos
Hemorragia/epidemiologia , Medição de Risco/métodos , Trombose/epidemiologia , Saúde da Mulher , Fibrilação Atrial/complicações , Fibrilação Atrial/tratamento farmacológico , Feminino , Fibrinolíticos/uso terapêutico , Saúde Global , Hemorragia/etiologia , Humanos , Incidência , Fatores de Risco , Fatores Sexuais , Taxa de Sobrevida/tendências , Trombose/etiologia , Trombose/prevenção & controle
7.
Front Physiol ; 9: 1754, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30574096

RESUMO

Intermittent hypoxia is a major factor in clinical conditions like the obstructive sleep apnea syndrome or the cyclic recruitment and derecruitment of atelectasis in acute respiratory distress syndrome and positive pressure mechanical ventilation. In vivo investigations of the direct impact of intermittent hypoxia are frequently hampered by multiple co-morbidities of patients. Therefore, cell culture experiments are important model systems to elucidate molecular mechanisms that are involved in the cellular response to alternating oxygen conditions and could represent future targets for tailored therapies. In this study, we focused on mouse lung endothelial cells as a first frontier to encounter altered oxygen due to disturbances in airway or lung function, that play an important role in the development of secondary diseases like vascular disease and pulmonary hypertension. We analyzed key markers for endothelial function including cell adhesion molecules, molecules involved in regulation of fibrinolysis, hemostasis, redox balance, and regulators of gene expression like miRNAs. Results show that short-time exposure to intermittent hypoxia has little impact on vitality and health of cells. At early timepoints and up to 24 h, many endothelial markers are unchanged in their expression and some indicators of injury are even downregulated. However, in the long-term, multiple signaling pathways are activated, that ultimately result in cellular inflammation, oxidative stress, and apoptosis.

8.
Thromb Haemost ; 118(11): 1875-1884, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30296815

RESUMO

Patients with cancer are at risk of developing venous and arterial thromboembolism (VTE and ATE). Elevated platelet-to-lymphocyte (PLR) and neutrophil-to-lymphocyte ratios (NLR) have been suggested as potential biomarkers for cancer-associated chronic inflammation, VTE and mortality. We investigated the association between PLR and NLR with VTE, ATE and mortality in patients with cancer. Within a prospective cohort study, we followed-up patients with newly diagnosed or progressing cancer for objectively confirmed, symptomatic VTE, ATE and death. Fine and Gray competing-risk regression was used to model the risk of VTE and ATE. Overall survival was analysed with Kaplan-Meier estimators. From 2003 to 2013, 1,469 patients with solid cancer (median age: 61 years; 47.3% female) were recruited and followed for 2 years. Overall, 128 (8.7%) patients developed VTE, 41 (2.8%) ATE and 643 (43.8%) patients died. The sub-distribution hazard ratios (SHRs) for VTE per doubling of PLR and NLR were 1.0 (95% confidence interval [CI]: 0.8-1.3, p = 0.899) and 1.2 (1.0-1.4, p = 0.059), respectively. For ATE, the SHR per doubling of PLR and NLR were 1.0 (0.7-1.5, p = 0.940) and 1.2 (0.9-1.6, p = 0.191), respectively. A higher PLR (hazard ratio [HR] per doubling = 1.5, 1.4-1.7, p < 0.001) and a higher NLR (HR per doubling = 1.5, 1.4-1.7, p < 0.001) were associated with an increased risk of mortality after adjusting for age, sex and cancer stage. There was no statistically significant association between NLR and VTE occurrence in patients with cancer. Neither PLR nor NLR were associated with the risk of ATE. Both elevated PLR and NLR were independently associated with a twofold increased risk of mortality.


Assuntos
Plaquetas/patologia , Linfócitos/patologia , Neoplasias/patologia , Neutrófilos/patologia , Tromboembolia/patologia , Biomarcadores/metabolismo , Contagem de Células , Estudos de Coortes , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/epidemiologia , Neoplasias/mortalidade , Prognóstico , Estudos Prospectivos , Risco , Análise de Sobrevida , Tromboembolia/epidemiologia , Tromboembolia/mortalidade
10.
J Heart Lung Transplant ; 37(9): 1067-1074, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29802084

RESUMO

BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) results from persistent pulmonary vascular obstructions, presumably due to inflammatory thrombosis. Because estimates of thrombus volume at diagnosis have no predictive value, we investigated the role of the thrombosis marker, D-dimer, and the inflammation marker, C-reactive protein (CRP), for predicting outcomes in CTEPH. METHODS: A total 289 consecutive patients with CTEPH were followed for 57 (median 45 to 69) months. One hundred fifty-seven of these patients underwent surgical pulmonary endarterectomy (PEA). D-dimer and CRP were collected at the time of CTEPH diagnosis and their impact on outcome was analyzed using Cox and logistic regression models. Their association with thrombus composition was analyzed utilizing HistoQuest. RESULTS: D-dimer and CRP levels were separately and independently predictive of death or need for lung transplantation (p = 0.012 and p = 0.025, respectively). For example, 5-year survival was 90% (confidence limits 84% to 96%) in patients with D-dimer levels <0.5 µg/ml and CRP <1 mg/dl at diagnosis, as compared with 50% (36% to 64%) for patients with D-dimer ≥0.5 µg/ml and CRP ≥1 mg/dl (p < 0.001). D-dimer and CRP both decreased significantly after PEA (p < 0.01). The amount of fresh red thrombus in thrombendarterectomy specimens correlated positively with D-dimer levels at diagnosis (r = 0.37, p = 0.003). CONCLUSIONS: D-dimer and CRP at the time of diagnosis are independent and significant predictors of outcome in CTEPH, available at the time of diagnosis. This observation suggests an important role for fibrin turnover and inflammation in the pathogenesis of CTEPH and the associated complications.

11.
Heart ; 104(14): 1195-1199, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29436381

RESUMO

OBJECTIVE: To assess the efficacy and safety of subcutaneous treprostinil in adult patients with congenital heart disease (CHD)-associated pulmonary arterial hypertension (PAH) after 12 months of treatment. METHODS: Consecutive adult patients with CHD-PAH received subcutaneous treprostinil to maximum tolerated doses in an observational study. RESULTS: Advanced CHD-PAH patients with WHO class III or IV disease (n=32, age 40±10 years, 20 females) received treprostinil for suboptimal response to bosentan (n=12), WHO functional class IV disease (FC, n=7) or prior to bosentan approval (n=13). In the multivariate mixed model, mean increase in 6 min walk distance (6-MWD) from baseline to 12 months was 114 m (76; 152) (P<0.001). WHO FC improved significantly (P=0.001) and B-type brain natriuretic peptide decreased from 1259 (375; 2368) pg/mL to 380 (144; 1468) pg/mL (P=0.02). In those 14 patients who had haemodynamic data before and after initiation of treprostinil, pulmonary vascular resistance decreased significantly (from 18.4±11.1 to 12.6±7.9 Wood units, P=0.003). The most common adverse events were infusion-site erythema and pain. One patient stopped treatment because of intolerable infusion-site pain after 8 months of treatment. No other major treatment-related complications were observed. Five patients died during early follow-up, having experienced a decrease in their 6-MWD prior. CONCLUSIONS: Subcutaneous treprostinil therapy is generally safe and effective for at least 12 months and may be used in CHD-related PAH class III and IV.


Assuntos
Anti-Hipertensivos/uso terapêutico , Epoprostenol/análogos & derivados , Cardiopatias Congênitas/complicações , Hipertensão Pulmonar/tratamento farmacológico , Bombas de Infusão , Adulto , Estudos de Coortes , Epoprostenol/uso terapêutico , Feminino , Humanos , Hipertensão Pulmonar/classificação , Hipertensão Pulmonar/etiologia , Infusões Subcutâneas , Masculino , Peptídeo Natriurético Encefálico/sangue , Oxigênio/sangue , Resistência Vascular , Teste de Caminhada
13.
Clin Res Cardiol ; 105(4): 349-55, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26493304

RESUMO

BACKGROUND: Morphine decreases the concentrations and effects of clopidogrel, which could lead to treatment failure in myocardial infarction. OBJECTIVES: To clarify whether more potent P2Y12-inhibitors may provide an effective alternative, we examined drug-drug interactions between morphine and prasugrel. METHODS: Twelve healthy volunteers received 60 mg prasugrel with placebo or 5 mg morphine intravenously in a randomized, double-blind, placebo-controlled, cross-over trial. Pharmacokinetics were determined by liquid chromatography tandem mass spectrometry, and prasugrel effects were measured by platelet function tests. RESULTS: Morphine neither diminished total drug exposure (AUC), which was the primary endpoint, nor significantly delayed drug absorption of prasugrel. However, morphine reduced maximal plasma concentrations (C max) of prasugrel active metabolite by 31 % (p = 0.019). Morphine slightly, but not significantly, delayed the onset of maximal inhibition of platelet plug formation under high shear rates (30 vs. 20 min). Whole blood aggregation was not influenced. CONCLUSIONS: Although morphine significantly decreases the maximal plasma concentrations of prasugrel active metabolite, it does not diminish its effects on platelets to a clinically relevant degree in healthy volunteers. However, it should be considered that the observed decrease in C max of prasugrel active metabolite caused by morphine co-administration may gain relevance in STEMI patients. CLINICAL TRIAL REGISTRATION: NCT01369186, EUDRA-CT#: 2010-023761-22.


Assuntos
Analgésicos Opioides/administração & dosagem , Morfina/administração & dosagem , Inibidores da Agregação de Plaquetas/farmacocinética , Agregação Plaquetária/efeitos dos fármacos , Cloridrato de Prasugrel/farmacocinética , Antagonistas do Receptor Purinérgico P2Y/farmacocinética , Adulto , Analgésicos Opioides/efeitos adversos , Áustria , Biotransformação , Cromatografia Líquida , Estudos Cross-Over , Método Duplo-Cego , Interações Medicamentosas , Monitoramento de Medicamentos/métodos , Feminino , Voluntários Saudáveis , Humanos , Masculino , Morfina/efeitos adversos , Inibidores da Agregação de Plaquetas/administração & dosagem , Inibidores da Agregação de Plaquetas/efeitos adversos , Inibidores da Agregação de Plaquetas/sangue , Testes de Função Plaquetária , Cloridrato de Prasugrel/administração & dosagem , Cloridrato de Prasugrel/efeitos adversos , Cloridrato de Prasugrel/sangue , Antagonistas do Receptor Purinérgico P2Y/administração & dosagem , Antagonistas do Receptor Purinérgico P2Y/efeitos adversos , Antagonistas do Receptor Purinérgico P2Y/sangue , Medição de Risco , Espectrometria de Massas em Tandem , Adulto Jovem
15.
Expert Opin Pharmacother ; 15(3): 429-36, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24392948

RESUMO

INTRODUCTION: Selexipag is a first-in-class orally available selective non-prostanoid IP receptor agonist. This review was based on a PubMed search and focuses on the potential role of selexipag in the treatment of pulmonary arterial hypertension (PAH). AREAS COVERED: Selexipag is rapidly hydrolyzed to an active metabolite, ACT-333679. Both selexipag and its metabolite are highly selective for the IP receptor compared with other prostanoid receptors. This selectivity for the IP receptor offers the potential for improved tolerability with selexipag, as side effects (e.g., nausea and vomiting) that might result from activation of the other prostanoid receptors may be minimized. In addition, the selexipag metabolite has a half-life of 7.9 h, thus permitting oral dosing twice daily. Selexipag showed effects on pharmacodynamic end points obtained with right heart catheterization in a Phase II trial in patients with PAH, and is being evaluated in the ongoing Phase III trial (GRIPHON trial, Clinicaltrials.gov NCT01106014). EXPERT OPINION: The signal of a beneficial effect of selexipag on disease progression may become more robust for long term under prolonged exposure. Pending the GRIPHON trial results, selexipag could provide a convenient first-line prostacyclin treatment option for patients with PAH.


Assuntos
Acetamidas/uso terapêutico , Hipertensão Pulmonar/tratamento farmacológico , Pirazinas/uso terapêutico , Receptores de Prostaglandina/agonistas , Acetamidas/farmacocinética , Acetatos/metabolismo , Administração Oral , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Hipertensão Pulmonar Primária Familiar , Humanos , Hipertensão Pulmonar/metabolismo , Prostaglandinas I/metabolismo , Pirazinas/metabolismo , Pirazinas/farmacocinética , Transdução de Sinais
16.
Thorax ; 69(2): 116-22, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24052543

RESUMO

BACKGROUND: Chronic thromboembolic pulmonary hypertension is surgically curable by pulmonary endarterectomy (PEA). It is unclear whether PEA impacts primarily steady state right ventricular afterload (ie, pulmonary vascular resistance (PVR)) or pulsatile right ventricular afterload (ie, pulmonary arterial compliance (C(PA))). Our objectives were to (1) quantify PEA specimens and measure the impact of PEA on PVR and C(PA) in a structure/function study and (2) analyse the effects of haemodynamic changes on long-term survival/freedom of lung transplantation in an outcome study. METHODS: Thrombi were laid out, weighed, photographed and measured. PVR, C(PA) and resistance times compliance (RC-time) were assessed at baseline, within 4 days after PEA ('immediately postoperative') and 1 year after PEA, in 110 consecutive patients who were followed for 34.5 (11.9; 78.3) months. RESULTS: Lengths and numbers of PEA specimen tails were inversely correlated with immediate postoperative PVR (p<0.0001, r=-0.566; p<0.0001, r=-0.580). PVR and C(PA) normalised immediately postoperatively while RC-time remained unchanged. Immediate postoperative PVR was the only predictor of long-term survival/freedom of lung transplantation (p<0.0001). Patients with immediate postoperative PVR<590 dynes.s.cm(-5) had better long-term outcomes than patients with PVR≥590 dynes.s.cm(-5) (p<0.0001, respectively). CONCLUSIONS: PEA immediately decreased PVR and increased C(PA) under a constant RC-time. However, immediate postoperative PVR was the only predictor of long-term survival/freedom of lung transplantation. Our study confirms the importance of a complete, bilateral surgical endarterectomy. Low PVR measured immediately postoperative predicts excellent long-term outcome.


Assuntos
Endarterectomia , Hipertensão Pulmonar/cirurgia , Embolia Pulmonar/cirurgia , Adulto , Idoso , Doença Crônica , Feminino , Seguimentos , Hemodinâmica/fisiologia , Humanos , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/fisiopatologia , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , Artéria Pulmonar/fisiopatologia , Embolia Pulmonar/complicações , Embolia Pulmonar/patologia , Embolia Pulmonar/fisiopatologia , Recidiva , Volume Sistólico/fisiologia , Resultado do Tratamento , Resistência Vascular/fisiologia
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