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2.
Clin Ther ; 2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31447130

RESUMO

PURPOSE: The goal of this study was to assess the long-term safety and efficacy of mepolizumab in patients with the most severe eosinophilic asthma. METHODS: This multicenter, open-label, long-term, Phase IIIb study (COSMEX [COSMOS Extension]; 201312/NCT02135692) enrolled patients from the 52-week, open-label extension study COSMOS (A Study to Determine Long-term Safety of Mepolizumab in Asthmatic Subjects) that previously enrolled patients from the double-blinded, placebo-controlled Phase III studies MENSA (Mepolizumab as Adjunctive Therapy in Patients with Severe Asthma) and SIRIUS (Steroid Reduction with Mepolizumab Study). To enter COSMEX, patients had to have life-threatening/seriously debilitating asthma before entering MENSA or SIRIUS and to have completed these previous studies with demonstrated improvement while receiving mepolizumab. In COSMEX, patients received mepolizumab 100 mg subcutaneously every 4 weeks as add-on therapy for up to 172 weeks. Primary endpoints were adverse event frequency and exacerbation rate per year; also assessed were forced expiratory volume in 1 s, Asthma Control Questionnaire-5 score, and daily oral corticosteroid (OCS) use. FINDINGS: Of the 340 patients enrolled, 339 received mepolizumab; median treatment duration within this extension study was 2.2 years, equating to 718 patient-years of additional exposure. No new safety signals were identified. Patients receiving mepolizumab throughout this study and previous studies had lasting reductions in exacerbation rate and daily OCS use and improvements in forced expiratory volume in 1 s and Asthma Control Questionnaire-5 score. In COSMEX, the on-treatment exacerbation rate (95% CI) was 0.93 (0.81-1.06) event/year for clinically significant exacerbations, 0.13 (0.10-0.18) event/year for exacerbations requiring hospitalization/emergency department visit, and 0.07 (0.05-0.10) event/year for exacerbations requiring hospitalization. In patients requiring systemic/oral corticosteroids with ≥128 weeks of continuous enrollment across SIRIUS, COSMOS, and COSMEX, mepolizumab maintained the median daily OCS dose at 1.3-2.8 mg during COSMEX, with additional patients no longer requiring OCS after extended mepolizumab treatment. IMPLICATIONS: This study indicates that long-term mepolizumab treatment is well tolerated and associated with sustained clinical benefits in patients with severe eosinophilic asthma. ClinicalTrials.gov identifier: NCT02135692.

3.
Eur Respir Rev ; 28(153)2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31366460

RESUMO

Pulmonary arterial hypertension (PAH) is a dreaded complication of systemic sclerosis (SSc) that occurs in ∼10% of patients. Most individuals present with severe symptoms, significant functional impairment and severe haemodynamics at diagnosis, and survival after PAH diagnosis is poor. Therefore, early diagnosis through systematic screening of asymptomatic patients has the potential to identify PAH at an early stage. Current evidence suggests that early diagnosis and treatment of PAH in patients with SSc may lead to better clinical outcomes. Annual screening may include echocardiography, but this can miss some patients due to suboptimal visualisation or insufficient tricuspid regurgitation. Other options for screening include the DETECT algorithm or the use of a combination of pulmonary function testing (forced vital capacity/diffusing capacity of the lung for carbon monoxide ratio) and N-terminal-pro-brain natriuretic peptide levels. Symptomatic patients, those with an elevated tricuspid regurgitation velocity on echocardiogram with or without secondary echocardiographic features of PAH, and those who screen positive on the DETECT or other pulmonary function test algorithms should undergo right heart catheterisation. Exercise echocardiography or cardiopulmonary exercise testing, nailfold capillaroscopy and molecular biomarkers are promising but, as yet, unproven potential options. Future screening studies should employ systematic catheterisation to define the true predictive values for PAH.

4.
Circulation ; 2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31462075

RESUMO

BACKGROUND: Bmpr2 mutations are critical risk factors for hereditary pulmonary arterial hypertension (hPAH) with approximately 20% of carriers developing disease. There is an unmet medical need to understand how environmental factors, such as inflammation, render Bmpr2 mutants susceptible to PAH. Overexpressing 5-lipoxygenase (5-LO) provokes lung inflammation and transient PAH in Bmpr2+/- mice. Accordingly, 5-LO and its metabolite, leukotriene B4 (LTB4), are candidates for the 'second hit'. The purpose of this study was to determine how 5-LO-mediated pulmonary inflammation synergized with phenotypically-silent Bmpr2 defects to elicit significant pulmonary vascular disease in rats. METHODS: Monoallelic Bmpr2 mutant rats were generated and found phenotypically normal for up to one year of observation. To evaluate whether a second hit would elicit disease, animals were exposed to 5-LO-expressing adenovirus (AdAlox5), monocrotaline, SU5416, SU5416 with chronic hypoxia or chronic hypoxia alone. Bmpr2-mutant hPAH patient samples were assessed for neointimal 5-LO expression. Pulmonary artery endothelial cells (PAECs) with impaired BMPR2 signaling were exposed to increased 5-LO-mediated inflammation and were assessed for phenotypic and transcriptomic changes. RESULTS: Lung inflammation, induced by intratracheal delivery of AdAlox5, elicited severe PAH with intimal remodeling in Bmpr2+/- rats but not in their wild-type littermates. Neointimal lesions in the diseased Bmpr2+/- rats gained endogenous 5-LO expression associated with elevated LTB4 biosynthesis. Bmpr2-mutant hPAH patients similarly expressed 5-LO in the neointimal cells. In vitro, BMPR2 deficiency, compounded by 5-LO-mediated inflammation, generated apoptosis-resistant, and proliferative PAECs with mesenchymal characteristics. These transformed cells expressed nuclear envelope-localized 5-LO consistent with induced LTB4 production, as well as a transcriptomic signature similar to clinical disease, including upregulated NF-κB, IL-6, and TGF-ß signaling pathways. The reversal of PAH and vasculopathy in Bmpr2 mutants by TGF-ß antagonism suggests that TGF-ß is critical for neointimal transformation. CONCLUSIONS: In a new 'two-hit' model of disease, lung inflammation induced severe PAH pathology in Bmpr2+/- rats. Endothelial transformation required the activation of canonical and noncanonical TGF-ß signaling pathways and was characterized by 5-LO nuclear envelope translocation with enhanced LTB4 production. This study offers one explanation of how an environmental injury unleashes the destructive potential of an otherwise-silent genetic mutation.

6.
Eur Respir Rev ; 28(152)2019 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-31285291

RESUMO

The European Respiratory Biologics Forum gathered participants from 21 countries in Madrid, Spain, to discuss the management and treatment of severe asthma in the era of biologics. The current insights on the pathophysiology of severe asthma were discussed, as well as the role of respiratory biologics in clinical practice and strategies for eliminating chronic use of oral corticosteroids. The participants also highlighted the key challenges in identifying patients with severe asthma based on phenotypes, biomarkers and treatable traits, and the existing problems in patient referral to specialist care. The monitoring of treatment was debated and the need for a change towards precision medicine and personalised care was emphasised throughout the meeting. This review provides a summary of the discussions and highlights important concerns identified by the participants regarding the current management of severe asthma.

7.
Circ Res ; 2019 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-31347976

RESUMO

RATIONALE: Pulmonary arterial hypertension (PAH) is a severe lethal cardio-pulmonary disease. Loss of function mutations in KCNK3 gene, which encodes an outward rectifier K+ channel, have been identified in PAH patients. OBJECTIVE: We have demonstrated that KCNK3 dysfunction is common to heritable and non-heritable PAH and to experimental pulmonary hypertension (PH). Finally, KCNK3 is not functional in mouse pulmonary vasculature. METHODS AND RESULTS: Using CRISPR/Cas9 technology, we generated a 94 bp out of frame deletion in exon 1 of Kcnk3 gene and characterized these rats at the electrophysiological, echocardiographic, hemodynamic, morphological, cellular and molecular levels, to decipher the cellular mechanisms associated with loss of KCNK3. Using patch-clamp technique we validated our transgenic strategy by demonstrating the absence of KCNK3 current in freshly isolated pulmonary arterial smooth muscle cells from Kcnk3-mutated rats. At 4 months of age, echocardiographic parameters revealed shortening of the pulmonary artery acceleration time associated with elevation of right ventricular systolic pressure. Kcnk3-mutated rats developed more severe PH than wild-type rats after monocrotaline-exposure or chronic hypoxia-exposure. Kcnk3-mutation induced a lung distal neomuscularization and perivascular extracellular matrix activation. Lungs of Kcnk3-mutated rats were characterized by overactivation of ERK1/2, AKT, Src, and overexpression of HIF1-α, survivin and Von Willebrand factor. Linked with plasma membrane depolarization, reduced eNOS expression and desensitization of endothelial-derived hyperpolarizing factor, Kcnk3-mutated rats presented predisposition to vasoconstriction of pulmonary arteries and a severe loss of sildenafil-induced pulmonary arteries relaxation. Moreover, we showed strong alteration of right ventricular cardiomyocyte excitability. Finally, Kcnk3-mutated rats developed age-dependent PH associated with low serum-albumin concentration. CONCLUSIONS: We established the first Kcnk3-mutated rat model of PH. Our results confirm that KCNK3 loss of function is a key event in PAH pathogenesis. This model presents new opportunities for understanding the initiating mechanisms of PH and testing biologically relevant therapeutic molecules in the context of PH.

8.
Int J Mol Sci ; 20(14)2019 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-31336611

RESUMO

Idiopathic pulmonary arterial hypertension (IPAH) is a complex disease associated with vascular remodeling and a proliferative disorder in pulmonary artery smooth muscle cells (PASMCs) that has been variably described as having neoplastic features. To decode the phenotype of PASMCs in IPAH, PASMCs from explanted lungs of patients with IPAH (IPAH-PASMCs) and from controls (C-PASMCs) were cultured. The IPAH-PASMCs grew faster than the controls; however, both growth curves plateaued, suggesting contact inhibition in IPAH cells. No proliferation was seen without stimulation with exogenous growth factors, suggesting that IPAH cells are incapable of self-sufficient growth. IPAH-PASMCs were more resistant to apoptosis than C-PASMCs, consistent with the increase in the Bcl2/Bax ratio. As cell replication is governed by telomere length, these parameters were assessed jointly. Compared to C-PASMCs, IPAH-PASMCs had longer telomeres, but a limited replicative capacity. Additionally, it was noted that IPAH-PASMCs had a shift in energy production from mitochondrial oxidative phosphorylation to aerobic glycolysis. As DNA damage and genomic instability are strongly implicated in IPAH development a comparative genomic hybridization was performed on genomic DNA from PASMCs which showed multiple break-points unaffected by IPAH severity. Activation of DNA damage/repair factors (γH2AX, p53, and GADD45) in response to cisplatin was measured. All proteins showed lower phosphorylation in IPAH samples than in controls, suggesting that the cells were resistant to DNA damage. Despite the cancer-like processes that are associated with end-stage IPAH-PASMCs, we identified no evidence of self-sufficient proliferation in these cells-the defining feature of neoplasia.

10.
Cardiovasc Res ; 2019 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-31173066

RESUMO

AIMS: The progressive accumulation of cells in pulmonary vascular walls is a key pathological feature of pulmonary arterial hypertension (PAH) that results in narrowing of the vessel lumen, but treatments targeting this mechanism are lacking. The C-X-C motif chemokine 12 (CXCL12) appears to be crucial in these processes. We investigated the activity of two CXCL12 neutraligands on experimental PH, using two complementary animal models. METHODS AND RESULTS: Male Wistar rats were injected with monocrotaline or were subjected to SU5416 followed by 3-week Hypoxia to induce severe PH. After PH establishment, assessed by pulsed-wave Doppler echocardiography, MCT-injected or SuHx rats were randomized to receive CXCL12 neutraligands chalcone 4 or LIT-927 (100 mg/kg/day), the CXCR4 antagonist AMD3100 (5 mg/kg/day), or vehicle, for 2 or 3 weeks respectively. At the end of these treatment periods, echocardiographic and hemodynamic measurements were performed and tissue samples were collected for protein expression and histological analysis. Daily treatment of MCT-injected or SuHx rats with established PH with chalcone 4 or LIT-927 partially reversed established PH, reducing total pulmonary vascular resistance, and remodelling of pulmonary arterioles. Consistent with these observations, we found that neutralization of CXCL12 attenuates right ventricular hypertrophy, pulmonary vascular remodelling, and decreases PA-SMC proliferation in lungs of MCT-injected rats and SuHx rats. Importantly, CXCL12 neutralization with either chalcone 4 or LIT-927 inhibited the migration of PA-SMCs and pericytes in vitro with a better efficacy than AMD3100. Finally, we found that CXCL12 neutralization decreases vascular pericyte coverage and macrophage infiltration in lungs of both MCT-injected and SuHx rats. CONCLUSION: We report here a greater beneficial effect of CXCL12 neutralization versus the conventional CXCR4 blockade with AMD3100 in the MCT and SuHx rat models of severe PH, supporting a role for CXCL12 in the progression of vascular complications in PH and opening to new therapeutic options.

11.
Respir Med ; 154: 69-75, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31220806

RESUMO

BACKGROUND: Patients with severe asthma can present with overlapping eosinophilic and allergic phenotypes, which makes it challenging when deciding which biologic therapy is most appropriate to reduce exacerbations and help achieve asthma control. OBJECTIVE: This post hoc meta-analysis evaluated the efficacy of the licensed dose of mepolizumab (100 mg administered subcutaneously [SC]) versus placebo in patients with severe eosinophilic asthma (SEA), according to omalizumab eligibility and associated allergic characteristics. METHODS: Data from two Phase 3 studies (MENSA [MEA115588/NCT01691521]; MUSCA [200862/NCT02281318]) were analyzed. Patients ≥12 years of age with SEA who experienced ≥2 exacerbations in the previous year received placebo, mepolizumab 100 mg SC or 75 mg intravenously, plus standard of care (high-dose inhaled corticosteroids and other controllers), every 4 weeks. Data from patients who received ≥1 dose placebo or mepolizumab 100 mg SC were used for this analysis. The primary endpoint was the rate of clinically significant exacerbations; other outcomes included forced expiratory volume in 1 s (FEV1), Asthma Control Questionnaire (ACQ-5) score and quality of life measured using St George's Respiratory Questionnaire (SGRQ). RESULTS: Rate reductions in clinically significant exacerbations with mepolizumab versus placebo were similar in omalizumab eligible and ineligible patients (57% vs 55%). FEV1, ACQ-5 and SGRQ scores improved with mepolizumab versus placebo regardless of omalizumab eligibility, Immunoglobulin E levels, or atopic status. CONCLUSION: This analysis indicated that mepolizumab 100 mg SC has clinical benefit in patients with blood eosinophil counts ≥150 cells/µL (or history of ≥300 cells/µL), regardless of allergic characteristics or omalizumab eligibility.

12.
Cochrane Database Syst Rev ; 5: CD012785, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31042010

RESUMO

BACKGROUND: Pulmonary arterial hypertension (PAH) is characterised by pulmonary vascular changes, leads to elevated pulmonary artery pressures, dyspnoea, a reduction in exercise tolerance, right heart failure, and ultimately death.Prostacyclin analogue drugs mimic endogenous prostacyclin which leads to vasodilation, inhibition of platelet aggregation, and reversal of vascular remodelling. Prostacyclin's short half-life theoretically enhances selectivity for the pulmonary vascular bed by direct (via central venous catheter) administration. Initial continuous infusion prostacyclins were efficacious, but use of intravenous access increases the risk of adverse events. Newer and safer subcutaneous, oral and inhaled preparations are now available, though possibly less potent.Selexipag is an oral selective prostacyclin receptor (IP receptor) agonist that works similarly to prostacyclin, potentially more stable, with less complex administration and titration. OBJECTIVES: To determine the efficacy and safety of prostacyclin, prostacyclin analogues or prostacyclin receptor agonists for PAH in adults and children. SEARCH METHODS: We performed searches on CENTRAL, MEDLINE, and Embase up to 16 September 2018. We handsearched review articles, clinical trial registries, and reference lists of retrieved articles. SELECTION CRITERIA: We included any randomised controlled trials (RCTs) which compared prostacyclin, prostacyclin analogues or prostacyclin receptor agonists to control (placebo, any other treatment or usual care) for at least six weeks. DATA COLLECTION AND ANALYSIS: We used standard methods specified by Cochrane. Primary outcomes included change in World Health Organization (WHO) functional class, six-minute walk distance (6MWD), and mortality. MAIN RESULTS: Seventeen trials with 3765 mostly adult participants were included; median trial duration was 12 weeks. Fifteen trials used prostacyclin analogues: intravenous (N = 4); subcutaneous (N = 1); oral (N = 5); inhaled (N = 5); two used oral prostacyclin receptor agonists. Three intravenous and two inhaled trials were open-label.Participants using prostacyclin had 2.39 times greater odds of improving by at least one WHO functional class (95% confidence interval (CI) 1.72 to 3.32; 24 per 100 (95% CI 18.5 to 30.4) with prostacyclin compared to 12 per 100 with control; 8 trials, 1066 participants; moderate-certainty evidence). Improvement occurred with intravenous (odds ratio (OR) 14.96, 95% CI 4.76 to 47.04), and inhaled (OR 2.94, 95% CI 1.53 to 5.66), but not with oral preparations. Participants using prostacyclin increased their 6MWD by 19.50 metres (95% CI 14.82 to 24.19; 13 trials, 2283 participants; low-certainty evidence), which was clinically significant with intravenous (mean difference (MD) 91.76 metres; 95% CI 58.97 to 124.55), but not with non-intravenous preparations (subcutaneous: MD 16.00 metres, 95% CI 7.38 to 24.62; oral: MD 14.76 metres, 95% CI 7.81 to 21.70; inhaled: MD 26.97 metres, 95% CI 17.21 to 36.73). Mortality was reduced in the intravenous (OR 0.29, 95% CI 0.12 to 0.69; risk of death 6 per 100 (95% CI 2.38 to 12.31) with prostacyclin compared to 17 per 100 with control; 4 trials, 255 participants), but not in the non-intravenous studies (OR 0.82, 95% CI 0.48 to 1.40; risk of death 21 per 1000 (95% CI 12.00 to 34.20) with prostacyclin compared to 25 per 1000 with control; moderate-certainty evidence; 12 trials, 2299 participants). We reduced the certainty of evidence due to few studies per subgroup and use of open-label trials.Prostacyclins improved cardiopulmonary haemodynamics (reduction in mean pulmonary artery pressure by 3.60 mmHg (95% CI -4.73 to -2.48); pulmonary vascular resistance by 2.81 WU (95% CI -3.80 to -1.82); right atrial pressure by 1.90 mmHg (95% CI -2.58 to -1.22), and increase in cardiac index by 0.31 L/min/m2 (95% CI 0.23 to 0.38); low-certainty evidence), improved dyspnoea (low-certainty evidence, and improved quality of life (moderate-certainty evidence), when compared to control. When only subcutaneous/inhaled trials were included the effect was still significant, but the magnitude was smaller. There was no difference across oral trials.Adverse events were increased in all prostacyclin preparations, including vasodilation (OR 5.03, 95% CI 3.84 to 6.58), headache (OR 3.16, 95% CI 2.62 to 3.80), jaw pain (OR 5.25, 95% CI 3.96 to 6.98), diarrhoea (OR 2.81, 95% CI 2.29 to 3.46), nausea/vomiting (OR 2.39, 95% CI 1.98 to 2.88), myalgias (OR 2.75, 95% CI 1.65 to 4.58), upper respiratory tract events (OR 1.61, 95% CI 1.22 to 2.13), extremity pain (OR 3.36, 95% CI 2.32 to 4.85), and infusion site reactions (OR 14.41, 95% CI 9.16 to 22.66). In the intravenous trials, there was a 12%-25% risk of serious non-fatal events including sepsis, haemorrhage, pneumothorax and pulmonary embolism.Two trials (1199 participants) compared oral selexipag to placebo; no trials compared selexipag with prostacyclin. There was a small 12.62 metre improvement in 6MWD (95% CI 1.90 to 23.34; high-certainty evidence), and weak evidence for haemodynamics. The effect was uncertain for WHO functional class. The risk of death with selexipag was five per 100 compared to three per 100 with placebo, though the CI crossed zero so the true effect is uncertain (risk difference (RD) 0.02 (95% CI -0.00 to 0.04). There was less clinical worsening with selexipag (OR 0.47, 95% CI 0.37 to 0.60), though more side effects, including vasodilation (OR 2.67, 95% CI 1.72 to 4.17), headache (OR 3.91, 95% CI 3.07 to 4.98), jaw pain (OR 5.33, 95% CI 3.64 to 7.81), diarrhoea (OR 3.11, 95% CI 2.39 to 4.05), nausea/vomiting (OR 2.92, 95% CI 2.29 to 3.73), pain in the extremities (OR 2.44, 95% CI 1.69 to 3.52), and myalgias (OR 3.05, 95% CI 2.02 to 4.58). AUTHORS' CONCLUSIONS: This review demonstrates clinical and statistical benefit for intravenous prostacyclin (compared to control) with improved functional class, 6MWD, mortality, symptoms scores, and cardiopulmonary haemodynamics, but at a cost of adverse events. This may be due to a true effect, or may be overestimated due to the inclusion of small, short or open-label studies. There was a statistical and small clinical benefit in function and haemodynamics for inhaled prostacyclin, but the effect is uncertain for mortality. The effect of oral prostacyclins are less certain. Selexipag demonstrated less clinical worsening without discernable impact on survival, increased adverse events; and the effect on other outcomes is less certain. Real-world registry data may provide further information about clinical effect.

13.
Blood Rev ; 37: 100579, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31113643

RESUMO

Pulmonary hypertension (PH) comprises a cluster of severe conditions characterized by elevated mean pulmonary arterial pressure. While targeted therapies have been approved over the last twenty years for pulmonary arterial hypertension (PAH) and chronic-thrombo-embolic PH (CTEPH), the possible role of anticoagulant therapy as a supportive treatment PAH is still debated. In PAH, anticoagulant use remains frequent, although evidence appear to be poor (recommendation class IIb-C in international guidelines). In CTEPH treatment, anticoagulants are highly recommended, because it often involves thrombosis (recommendation class I-C in international guidelines). Historically, PH patients have been treated with vitamin K antagonists (VKA), which are the only available oral anticoagulants. In this context, risk/benefit ratio of VKA is affected by the risk of major bleeding events. This drawback could be mitigated with direct oral anticoagulants (DOACs): in addition to being less constraining for patients, DOACs have shown a lower risk of major bleeding events in their already approved indications (venous thromboembolism, atrial fibrillation). However, DOACs have never been specifically assessed in PAH and CTEPH patients. Bioaccumulation risk should be considered if DOACs are prescribed in PAH and CTEPH patients, especially the risk of drug-drug interaction mediated by P-glycoprotein and cytochrome 3A4 with targeted therapies.

14.
J Heart Lung Transplant ; 38(8): 833-842, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31103383

RESUMO

BACKGROUND: Treatment options for inoperable chronic thromboembolic pulmonary hypertension (CTEPH) have recently evolved with the availability of balloon pulmonary angioplasty (BPA) and pulmonary vasodilators. Our aim was to analyze the prognostic variables associated with long-term outcome in a cohort of patients with not-operated CTEPH. METHODS: From January 2006 to December 2016, 343 newly diagnosed consecutive patients with not-operated CTEPH were diagnosed and followed up in the French Reference Center for Pulmonary Hypertension. Overall long-term survival and prognostic factors according to the diagnosis period (early period, 2006-2012, vs recent period, since 2013, i.e., one year before availability of BPA) were analyzed. RESULTS: In the overall population, baseline New York Heart Association functional class, right atrial pressure, 6-minute walk distance (6MWD), and diagnosis period were independent predictors of survival. The 1- and 3-year survival rates of patients diagnosed in the recent period (n = 170) were 91.6% and 85.0%, compared with 89.0% and 74.3% in patients diagnosed in the early period (n = 173), respectively (p = 0.030). Multivariate analysis from patients diagnosed in the recent period found that baseline 6MWD (per 20 m increase in distance) (hazard ratio [HR], 0.879; 95% confidence interval [CI], 0.832-0.928, p < 0.001) and BPA (HR, 0.307; 95% CI, 0.099-0.957; p = 0.042) were independently associated with survival. CONCLUSIONS: Survival of not-operated patients with CTEPH has significantly improved in the recent management era. New treatment options, including BPA, might have the potential to improve the prognosis of patients with inoperable CTEPH.

16.
Eur Respir J ; 53(5)2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31023842

RESUMO

AIMS: To evaluate safety and efficacy of balloon pulmonary angioplasty (BPA) in a large cohort of patients with chronic thromboembolic pulmonary hypertension (CTEPH). METHODS: From 2014 to 2017, 184 inoperable CTEPH patients underwent 1006 BPA sessions. Safety and efficacy during the first 21 months (initial period) were compared with those of the last 21 months (recent period). A total of 154 patients had a full evaluation after a median duration of 6.1 months. RESULTS: Overall, there was a significant improvement in New York Heart Association functional class, 6-min walk distance (mean change +45 m), and a significant decrease in mean pulmonary artery pressure (PAP) and in pulmonary vascular resistance (PVR) by 26% and 43%, respectively. The percentage decreases of mean PAP and PVR were 22% and 37% in the initial period versus 30% and 49% in the recent period, respectively (p<0.05). The main complications included lung injury, which occurred in 9.1% of 1006 sessions (13.3% in the initial period versus 5.9% in the recent period; p<0.001). Per-patient multivariate analysis revealed that baseline mean PAP and the period during which BPA procedure was performed (recent versus initial period) were the strongest factors related to the occurrence of lung injury. 3-year survival was 95.1%. CONCLUSION: This study confirms that a refined BPA strategy improves short-term symptoms, exercise capacity and haemodynamics in inoperable CTEPH patients with an acceptable risk-benefit ratio. Safety and efficacy improve over time, underscoring the unavoidable learning curve for this procedure.

17.
Int J Mol Sci ; 20(7)2019 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-30934680

RESUMO

The bromodomain and extra-terminal domain family inhibitors (BETi) are a promising new class of anticancer agents. Since numerous anticancer drugs have been correlated to cardiomyopathy, and since BETi can affect non-cancerous tissues, we aimed to investigate in healthy animals any ultrastructural BETi-induced alterations of the heart as compared to skeletal muscle. Male Wistar rats were either treated during 3 weeks with I-BET-151 (2 or 10 mg/kg/day) (W3) or treated for 3 weeks then allowed to recover for another 3 weeks (W6) (3-weeks drug washout). Male C57Bl/6J mice were only treated during 5 days (50 mg/kg/day). We demonstrated the occurrence of ultrastructural alterations and progressive destruction of cardiomyocyte mitochondria after I-BET-151 exposure. Those mitochondrial alterations were cardiac muscle-specific, since the skeletal muscles of exposed animals were similar in ultrastructure presentation to the non-exposed animals. I-BET-151 decreased the respiration rate of heart mitochondria in a dose-dependent manner. At the higher dose, it also decreased mitochondrial mass, as evidenced by reduced right ventricular citrate synthase content. I-BET-151 reduced the right and left ventricular fractional shortening. The concomitant decrease in the velocity-time-integral in both the aorta and the pulmonary artery is also suggestive of an impaired heart function. The possible context-dependent cardiac side effects of these drugs have to be appreciated. Future studies should focus on the basic mechanisms of potential cardiovascular toxicities induced by BETi and strategies to minimize these unexpected complications.


Assuntos
Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/ultraestrutura , Animais , Eletrocardiografia , Coração/efeitos dos fármacos , Coração/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Mitocôndrias Cardíacas/efeitos dos fármacos , Especificidade de Órgãos , Ratos Wistar
18.
J Allergy Clin Immunol Pract ; 7(5): 1418-1429, 2019 May - Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30928481

RESUMO

Allergic asthma often coexists with different pathological conditions, called multimorbidities, that are mostly of allergic nature and share a common underlying inflammatory pathophysiological mechanism. Multimorbidities of allergic asthma may influence asthma control, its severity, and patients' response to treatment, and contribute to the overall socioeconomic burden of the disease. Immunoglobulin E (IgE) is known to play a central role in the pathogenesis of various allergic diseases, including asthma. Thus, IgE-mediated immunologic pathways present an attractive target for intervention in asthma and multimorbidities. In this review, we discuss the most frequently reported IgE-mediated multimorbidities in allergic asthma, including allergic rhinitis, rhinoconjunctivitis, atopic dermatitis, vernal keratoconjunctivitis, chronic rhinosinusitis with nasal polyps, food allergies, and allergic bronchopulmonary aspergillosis. Omalizumab is a recombinant humanized monoclonal antibody against IgE and has been in use to treat allergic asthma for more than a decade. We comprehensively review the clinical evidence for omalizumab in the treatment of the aforementioned multimorbidities in allergic asthma.

20.
Eur Respir J ; 53(6)2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30923187

RESUMO

BACKGROUND: Current pulmonary hypertension treatment guidelines recommend use of a risk stratification model encompassing a range of parameters, allowing patients to be categorised as low, intermediate or high risk. Three abbreviated versions of this risk stratification model were previously evaluated in patients with pulmonary arterial hypertension (PAH) in the French, Swedish and COMPERA registries. Our objective was to investigate the three abbreviated risk stratification methods for patients with mostly prevalent PAH and chronic thromboembolic pulmonary hypertension (CTEPH), in patients from the PATENT-1/2 and CHEST-1/2 studies of riociguat. METHODS: Risk was assessed at baseline and at follow-up in PATENT-1 and CHEST-1. Survival and clinical worsening-free survival were assessed in patients in each risk group/strata. RESULTS: With all three methods, riociguat improved risk group/strata in patients with PAH after 12 weeks. The French non-invasive and Swedish/COMPERA methods discriminated prognosis for survival and clinical worsening-free survival at both baseline and follow-up. Furthermore, patients achieving one or more low-risk criteria or a low-risk stratum at follow-up had a significantly reduced risk of death and clinical worsening compared with patients achieving no low-risk criteria or an intermediate-risk stratum. Similar results were obtained in patients with inoperable or persistent/recurrent CTEPH. CONCLUSIONS: This analysis confirms and extends the results of the registry analyses, supporting the value of goal-oriented treatment in PAH. Further assessment of these methods in patients with CTEPH is warranted.

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