Use of direct oral anticoagulants for chronic thromboembolic pulmonary hypertension

OBJECTIVES: Chronic thromboembolic pulmonary hypertension is one of the most prevalent forms of pulmonary hypertension and is a major complication of acute pulmonary embolism. One mainstay of chronic thromboembolic pulmonary hypertension treatment is lifelong anticoagulation. The recent advent of direct oral anticoagulants for acute pulmonary embolism treatment has provided a viable and effective alternative for treating this condition. However, little is known about the efficacy of this new class of drugs for treating chronic thromboembolic pulmonary hypertension. We aimed to evaluate the safety and efficacy of direct oral anticoagulants in the treatment of chronic thromboembolic pulmonary hypertension. METHODS: A cohort of chronic thromboembolic pulmonary hypertension patients who initiated treatment with direct oral anticoagulants between June 2015 and November 2016 were enrolled in this study. RESULTS: Sixteen patients used rivaroxaban, three used dabigatran and one used apixaban for a mean follow-up of 20.9 months. The mean age was 51 years, and eighteen patients were classified as functional class II/III. Eight patients underwent a pulmonary endarterectomy and exhibited clinical, hemodynamic and functional improvement and currently continue to use direct oral anticoagulants. No episode of venous thromboembolism recurrence was identified during the follow-up period, but there was one episode of major bleeding after a traumatic fall. CONCLUSIONS: Although direct oral anticoagulants appear to be a safe and effective alternative for treating chronic thromboembolic pulmonary hypertension, larger studies are needed to support their routine use

Implementation of 'matrix support' (collaborative care) to reduce asthma and COPD referrals and improve primary care management in Brazil:A pilot observational study

Asthma and chronic obstructive pulmonary disease (COPD) are leading causes of hospitalisation and death in the city of Sao Bernardo do Campo. The municipality had difficulties in sustaining a pulmonology specialist team. Local policy has strengthened the knowledge of the primary care teams to improve the management of these diseases. Our aim is to pilot the implementation of an educational intervention based on collaborative care focused on reducing respiratory-related referrals. We implemented ‘matrix support’: a Brazilian collaborative educational intervention promoting specialist training and support for primary care physicians in three health territories with the highest number of referrals. Clinicians and nurses from primary care attended an 8-h workshop. The backlog of respiratory referrals was prioritised, where Asthma and COPD represented 70% of referral reasons. Initially, pulmonologists held joint consultations with physicians and nurses; as confidence grew, these were replaced by round-table note-based case discussions. The primary outcome was the number of asthma and COPD referrals. Almost all primary healthcare professionals in the three areas (132 of 157–87%) were trained; 360 patients were discussed, including 220 joint consultations. The number of respiratory referrals dropped from 290 (the year before matrix support) to 134 (the year after) (P<0.05). Referrals for asthma/COPD decreased from 13.4 to 5.4 cases per month (P=0.09) and for other lung diseases from 10.8 to 5.3 cases per month (P<0.05). Knowledge scores showed a significant improvement (P<0.001). Matrix-support collaborative care was well-accepted by primary care professionals associated with improved knowledge and reduced respiratory referrals. The initiative attracted specialists to the region overcoming historical recruitment problems

Alterations in proteostasis of endothelial cells in patients with chronic thromboembolic pulmonary hypertension

Introdução: A hipertensão pulmonar tromboembólica crônica (HPTEC) está incluída no grupo 4 da Classificação Internacional de Hipertensão Pulmonar (HP). É caracterizada pela persistência de obstrução por trombos sanguíneos na circulação pulmonar, associada à presença de HP, após três meses de anticoagulação efetiva. O tratamento de escolha é a cirurgia de tromboendarterectomia pulmonar (TEAP), mas alguns dos mecanismos fisiopatológicos envolvidos nesta forma de hipertensão ainda permanecem incertos. O redirecionamento dos fluxos sanguíneos pulmonares e a hipóxia exercem papel importante na HPTEC, como também em casos de hipertensão pulmonar residual, após a cirurgia de TEAP. Entretanto, existem poucos dados sobre as respostas das células endoteliais pulmonares a essas mudanças de fluxo e de oxigenação, surgindo a necessidade do estudo da proteostase celular nesta doença. Objetivo: (A) Caracterização morfológica das células em culturas provenientes de artéria pulmonar de pacientes com HPTEC submetidos à TEAP. (B) Avaliação da resposta das células endoteliais, a partir da análise de proteínas envolvidas na proteostase celular, quando submetidas a diferentes níveis de stress mecânico e à hipóxia. Método: Trombos extraídos por TEAP foram processados, as células retiradas foram cultivadas, marcadas com CD31 e submetidas a stress mecânico por vinte e quatro horas, constituindo o grupo HPTEC. A proteostase celular foi avaliada pela medida de proteínas expressas por essas células, tanto em culturas quanto pela análise imuno-histoquímica do tecido vascular pulmonar. Como grupo controle foram utilizadas células endoteliais pulmonares humanas de linhagem (CE) e tecido de artérias pulmonares de doadores de transplante de pulmão. As culturas de ambos os grupos também foram colocadas em hipóxia e analisada a expressão indireta de óxido nítrico (NO) por meio da medida de nitrato. Resultado: as células do grupo HPTEC com morfologia endotelial foram marcadas positivamente com CD31 e apresentaram características semelhantes às do grupo CE. Em relação ao stress mecânico, na condição estática as células HPTEC expressaram menor quantidade de óxido nítrico sintase endotelial (eNOS). Quando submetidas a stress de alta intensidade (shear stress >= 15 dynes/cm2), as reduções ficaram ainda mais evidentes, sinalizando uma disfunção endotelial. Na análise de outras proteínas, como GRP94, GRP78, HSP70, as respostas também foram menores no alto fluxo. Na avaliação imunohistoquímica da camada íntima do vaso pulmonar, a HSP70 apresentava-se diminuída, corroborando os achados das culturas. Os valores de NO foram inferiores no grupo HPTEC quando se comparam hipóxia e normóxia. Conclusão: (A) A avaliação morfológica mostrou que as culturas de células HPTEC eram endoteliais. (B) A análise funcional revelou que estas células apresentaram redução de resposta, o que caracteriza alteração da proteostase, que se tornou mais evidente quando foram submetidas a shear stress de alta magnitude. A hipóxia reduziu a produção de NO, entretanto sem diferenciar os grupos celulares estudadosIntroduction: Chronic Thromboembolic Pulmonary Hypertension (CTEPH) is included in group 4 of the International Classification of Pulmonary Hypertension (PH). It is characterized by persistent obstruction by blood clots in the pulmonary circulation, associated with the presence of PH, after 3 months of effective anticoagulation. The treatment of choice is pulmonary endarterectomy (PEA). However, some of the pathophysiological mechanisms involved in this form of hypertension still remain uncertain. The redirection of pulmonary blood flow and hypoxia play an important role in CTEPH, and also, in cases of residual pulmonary hypertension after PEA surgery. Nevertheless, there is insufficient data from the pulmonary endothelial cell responses to this flow and oxygenation changes, reflecting the need to further study of cellular proteostasis in this disease. Objective: (A) Morphological characterization of cells in cultures from the pulmonary artery of CTEPH patients submitted to PEA. (B) Evaluation of the response of endothelial cells, through the analysis of proteins involved in cellular proteostasis, when submitted to different levels of mechanical stress and hypoxia. Method: Thrombus extracted by PEA were processed and the cells removed were cultured, marked with CD31 and submitted to mechanical stress for 24 hours and constituted the group CTEPH. Cellular proteostasis was measured by the quantification of the proteins expressed in cultures and in pulmonary vascular tissue by immunohistochemistry analysis. As a control group, the human pulmonary endothelial cells (EC) and pulmonary artery tissue from lung transplant donors were used. Cultures of both groups were also placed in hypoxia and the indirect expression of nitric oxide (NO) was analyzed by nitrate measurement. Results: The cells with endothelial morphology from the CTEPH group were positively marked with CD31 and presented similar characteristics as the EC group. Regarding mechanical stress, in the static condition, the CTEPH cells expressed a lesser amount of endothelial nitric oxide synthase (eNOS). When submitted to high flow (shear stress > 15 dynes / cm2) the reductions became even more evident, signaling an endothelial dysfunction. In the analysis of other proteins, such as GRP94, GRP78, HSP70, responses were also lower in high shear stress. In the immunohistochemistry analysis of the intimal layer of the pulmonary vessel HSP70 was diminished, corroborating with the findings of the cultures. The NO values were lower in the CTEPH group when compared hypoxia and normoxia. Conclusion: (A) Morphological evaluation showed that cultures of CTEPH cells were endothelial. (B) Functional analysis revealed that these cells had reduced response, which characterizes proteostasis alterations, which became more evident when they underwent shear stress of high magnitude. Hypoxia reduced NO production, however without differentiating the cell groups studie

Alterations in proteostasis of endothelial cells in patients with chronic thromboembolic pulmonary hypertension

Introdução: A hipertensão pulmonar tromboembólica crônica (HPTEC) está incluída no grupo 4 da Classificação Internacional de Hipertensão Pulmonar (HP). É caracterizada pela persistência de obstrução por trombos sanguíneos na circulação pulmonar, associada à presença de HP, após três meses de anticoagulação efetiva. O tratamento de escolha é a cirurgia de tromboendarterectomia pulmonar (TEAP), mas alguns dos mecanismos fisiopatológicos envolvidos nesta forma de hipertensão ainda permanecem incertos. O redirecionamento dos fluxos sanguíneos pulmonares e a hipóxia exercem papel importante na HPTEC, como também em casos de hipertensão pulmonar residual, após a cirurgia de TEAP. Entretanto, existem poucos dados sobre as respostas das células endoteliais pulmonares a essas mudanças de fluxo e de oxigenação, surgindo a necessidade do estudo da proteostase celular nesta doença. Objetivo: (A) Caracterização morfológica das células em culturas provenientes de artéria pulmonar de pacientes com HPTEC submetidos à TEAP. (B) Avaliação da resposta das células endoteliais, a partir da análise de proteínas envolvidas na proteostase celular, quando submetidas a diferentes níveis de stress mecânico e à hipóxia. Método: Trombos extraídos por TEAP foram processados, as células retiradas foram cultivadas, marcadas com CD31 e submetidas a stress mecânico por vinte e quatro horas, constituindo o grupo HPTEC. A proteostase celular foi avaliada pela medida de proteínas expressas por essas células, tanto em culturas quanto pela análise imuno-histoquímica do tecido vascular pulmonar. Como grupo controle foram utilizadas células endoteliais pulmonares humanas de linhagem (CE) e tecido de artérias pulmonares de doadores de transplante de pulmão. As culturas de ambos os grupos também foram colocadas em hipóxia e analisada a expressão indireta de óxido nítrico (NO) por meio da medida de nitrato. Resultado: as células do grupo HPTEC com morfologia endotelial foram marcadas positivamente com CD31 e apresentaram características semelhantes às do grupo CE. Em relação ao stress mecânico, na condição estática as células HPTEC expressaram menor quantidade de óxido nítrico sintase endotelial (eNOS). Quando submetidas a stress de alta intensidade (shear stress >= 15 dynes/cm2), as reduções ficaram ainda mais evidentes, sinalizando uma disfunção endotelial. Na análise de outras proteínas, como GRP94, GRP78, HSP70, as respostas também foram menores no alto fluxo. Na avaliação imunohistoquímica da camada íntima do vaso pulmonar, a HSP70 apresentava-se diminuída, corroborando os achados das culturas. Os valores de NO foram inferiores no grupo HPTEC quando se comparam hipóxia e normóxia. Conclusão: (A) A avaliação morfológica mostrou que as culturas de células HPTEC eram endoteliais. (B) A análise funcional revelou que estas células apresentaram redução de resposta, o que caracteriza alteração da proteostase, que se tornou mais evidente quando foram submetidas a shear stress de alta magnitude. A hipóxia reduziu a produção de NO, entretanto sem diferenciar os grupos celulares estudadosIntroduction: Chronic Thromboembolic Pulmonary Hypertension (CTEPH) is included in group 4 of the International Classification of Pulmonary Hypertension (PH). It is characterized by persistent obstruction by blood clots in the pulmonary circulation, associated with the presence of PH, after 3 months of effective anticoagulation. The treatment of choice is pulmonary endarterectomy (PEA). However, some of the pathophysiological mechanisms involved in this form of hypertension still remain uncertain. The redirection of pulmonary blood flow and hypoxia play an important role in CTEPH, and also, in cases of residual pulmonary hypertension after PEA surgery. Nevertheless, there is insufficient data from the pulmonary endothelial cell responses to this flow and oxygenation changes, reflecting the need to further study of cellular proteostasis in this disease. Objective: (A) Morphological characterization of cells in cultures from the pulmonary artery of CTEPH patients submitted to PEA. (B) Evaluation of the response of endothelial cells, through the analysis of proteins involved in cellular proteostasis, when submitted to different levels of mechanical stress and hypoxia. Method: Thrombus extracted by PEA were processed and the cells removed were cultured, marked with CD31 and submitted to mechanical stress for 24 hours and constituted the group CTEPH. Cellular proteostasis was measured by the quantification of the proteins expressed in cultures and in pulmonary vascular tissue by immunohistochemistry analysis. As a control group, the human pulmonary endothelial cells (EC) and pulmonary artery tissue from lung transplant donors were used. Cultures of both groups were also placed in hypoxia and the indirect expression of nitric oxide (NO) was analyzed by nitrate measurement. Results: The cells with endothelial morphology from the CTEPH group were positively marked with CD31 and presented similar characteristics as the EC group. Regarding mechanical stress, in the static condition, the CTEPH cells expressed a lesser amount of endothelial nitric oxide synthase (eNOS). When submitted to high flow (shear stress > 15 dynes / cm2) the reductions became even more evident, signaling an endothelial dysfunction. In the analysis of other proteins, such as GRP94, GRP78, HSP70, responses were also lower in high shear stress. In the immunohistochemistry analysis of the intimal layer of the pulmonary vessel HSP70 was diminished, corroborating with the findings of the cultures. The NO values were lower in the CTEPH group when compared hypoxia and normoxia. Conclusion: (A) Morphological evaluation showed that cultures of CTEPH cells were endothelial. (B) Functional analysis revealed that these cells had reduced response, which characterizes proteostasis alterations, which became more evident when they underwent shear stress of high magnitude. Hypoxia reduced NO production, however without differentiating the cell groups studie

Use of medical therapies before pulmonary endarterectomy in chronic thromboembolic pulmonary hypertension patients with severe hemodynamic impairment.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare complication of acute pulmonary embolism, characterized by non-resolving fibro-thrombotic obstructions of large pulmonary arteries. Pulmonary endarterectomy (PEA) is the treatment of choice for the disease, significantly improving survival. Patients with worse hemodynamic profile have worse prognosis after surgery, raising the question of whether the use of medical therapy prior to surgery to optimize hemodynamics could improve outcomes. The aim of this study was to evaluate the role of medical therapy pre-PEA, according to the hemodynamic profile at the diagnosis. We retrospectively analyzed all patients submitted to PEA, from January 2013 to December 2017. Functional, clinical and hemodynamic data were collected to evaluate the main prognostic determinants. Patients were stratified according to the hemodynamic severity and use of targeted therapies prior to surgery. A total of 108 patients were included. Thirty-five patients (32,4%) used targeted therapy pre-PEA. The use of medical therapy delayed the surgical procedure by about 7 months. There was no difference in overall survival between patients that received targeted therapy and those treated only with supportive therapy (87.8% vs 80.3%, respectively, p = 0.426). Nevertheless, when analyzing the group of patients with severe hemodynamic impairment, defined by low cardiac output(<3.7L/min) at baseline, patients treated with targeted therapies presented a significantly better one-year survival. In higher-risk CTEPH patients, characterized by the presence of low cardiac output, the use of targeted therapies prior to PEA was associated with better outcome, suggesting a potential role for pre-operative use of medical treatment in this particular subgroup

Stability of Citrus tristeza virus protective isolates in field conditions Estabilidade de isolados protetores contra Citrus tristeza virus em condições de campo

The objective of this work was to monitor the maintenance of Citrus tristeza virus (CTV) protective isolates stability in selected clones of 'Pêra' sweet orange (Citrus sinensis), preimmunized or naturally infected by the virus, after successive clonal propagations. The work was carried out in field conditions in the north of Paraná State, Brazil. Coat protein gene (CPG) analysis of 33 isolates collected from 16 clones of 'Pêra' sweet orange was performed using single strand conformational polymorphism (SSCP). Initially, the isolates were characterized by symptoms of stem pitting observed in clones. Then viral genome was extracted and used as template for the amplification of CPG by reverse transcription polimerase chain reaction (RTPCR). RTPCR products electrophoretic profiles were analyzed using the Jaccard coefficient and the UPGMA method. The majority of the clones had weak to moderate stem pitting symptoms and its CTV isolates showed alterations in the SSCP profiles. However, the stability of the protective complex has been maintained, except for isolates from two analised clones. Low genetic variability was observed within the isolates during the studied years.<br>O objetivo deste trabalho foi monitorar a manutenção da estabilidade de isolados protetores contra Citrus tristeza virus (CTV) em clones selecionados de laranja 'Pêra' (Citrus sinensis) pré-imunizados ou infectados naturalmente pelo vírus, após sucessivas propagações clonais. O trabalho foi realizado em condições de campo, no norte do Estado do Paraná. A análise do gene da capa protéica (GPC) de 33 isolados, coletados de 16 clones de laranjeira 'Pêra', foi realizada com o uso da técnica polimorfismo conformacional da fita simples (SSCP). Inicialmente, os isolados foram caracterizados por meio de sintomas de caneluras observados nos clones. Em seguida, o genoma viral foi extraído e utilizado como molde para a amplificação do GCP com uso da transcrição reversa da reação em cadeia da polimerase (RTPCR). Os perfis eletroforéticos dos produtos da RTPCR foram analisados com emprego do coeficiente de Jaccard e do método UPGMA. A maioria dos clones apresentou sintomas fracos a moderados de caneluras, bem como alterações nos perfis dos isolados de CTV. Contudo, a estabilidade dos complexos protetores foi mantida, com exceção dos isolados presentes em dois dos clones analisados. Foi observada baixa variabilidade genética nos isolados durante os anos avaliados

A workshop on asthma management programs and centers in Brazil: reviewing and explaining concepts

Objective: To report the results of a workshop regarding asthma management programs and centers (AMPCs) in Brazil, so that they can be used as a tool for the improvement and advancement of current and future AMPCs. Methods: The workshop consisted of five presentations and the corresponding group discussions. The working groups discussed the following themes: implementation of asthma management strategies; human resources needed for AMPCs; financial resources needed for AMPCs; and operational maintenance of AMPCs. Results: The workshop involved 39 participants, from all regions of the country, representing associations of asthma patients (n = 3), universities (n = 7), and AMPCs (n = 29). We found a direct relationship between a lack of planning and the failure of AMPCs. Based on the experiences reported during the workshop, the common assumptions about AMPCs in Brazil were the importance of raising awareness of managers; greater community participation; interdependence between primary care and specialized care; awareness of regionalization; and use of medications available in the public health system. Conclusions: Brazil already has a core of experience in the area of asthma management programs. The implementation of strategies for the management of chronic respiratory disease and their incorporation into health care system protocols would seem to be a natural progression. However, there is minimal experience in this area. Joint efforts by individuals with expertise in AMPCs could promote the implementation of asthma management strategies, thus speeding the creation of treatment networks, which might have a multiplier effect, precluding the need for isolated centers to start from zero