Mechanisms of development of chronic obstructive pulmonary disease-associated pulmonary hypertension

Pulmonary hypertension is a prevalent complication of chronic obstructive pulmonary disease (COPD) that is associated with poor prognosis. Although pulmonary hypertension is usually diagnosed in patients with advanced disease, changes in pulmonary vessels are already apparent at early disease stages, and in smokers without airflow obstruction. Changes in pulmonary vessels include intimal hyperplasia, resulting from proliferating mesenchymal cells, and elastic and collagen deposition as well as endothelial dysfunction. Dysregulation of endothelium-derived mediators and growth factors and inflammatory mechanisms underlie the endothelial dysfunction and vessel remodeling. Circumstantial and experimental evidence suggests that cigarette smoke products can initiate pulmonary vascular changes in COPD and that, at advanced disease stages, hypoxia may amplify the effects of cigarette smoke on pulmonary arteries. Bone marrow-derived progenitor cells may contribute to vessel repair and to vessel remodeling, a process that appears to be facilitated by transforming growth factor-β

Impact of Nutrition on Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is characterized by sustained vasoconstriction, vascular remodeling, inflammation, and in situ thrombosis. Although there have been important advances in the knowledge of the pathophysiology of PAH, it remains a debilitating, limiting, and rapidly progressive disease. Vitamin D and iron deficiency are worldwide health problems of pandemic proportions. Notably, these nutritional alterations are largely more prevalent in PAH patients than in the general population and there are several pieces of evidence suggesting that they may trigger or aggravate disease progression. There are also several case reports associating scurvy, due to severe vitamin C deficiency, with PAH. Flavonoids such as quercetin, isoflavonoids such as genistein, and other dietary polyphenols including resveratrol slow the progression of the disease in animal models of PAH. Finally, the role of the gut microbiota and its interplay with the diet, host immune system, and energy metabolism is emerging in multiple cardiovascular diseases. The alteration of the gut microbiota has also been reported in animal models of PAH. It is thus possible that in the near future interventions targeting the nutritional status and the gut dysbiosis will improve the outcome of these patients

Updated Perspectives on Pulmonary Hypertension in COPD

Pulmonary hypertension (PH) is a frequent and important complication of chronic obstructive pulmonary disease (COPD). It is associated with worse clinical courses with more frequent exacerbation episodes, shorter survival, and greater need of health resources. PH is usually of moderate severity and progresses slowly, without altering right ventricular function in the majority of cases. Nevertheless, a reduced subgroup of patients may present disproportionate PH, with pulmonary artery pressure (PAP) largely exceeding the severity of respiratory impairment. These patients may represent a group with an exaggerated vascular impairment (pulmonary vascular phenotype) to factors that induce PH in COPD or be patients in whom idiopathic pulmonary arterial hypertension (PAH) coexist. The present review addresses the current definition and classification of PH in COPD, the distinction among the different phenotypes of pulmonary vascular disease that might present in COPD patients, and the therapeutic approach to PH in COPD based on the available scientific evidence

Lack of systemic oxidative stress during PAF challenge in mild asthma

SummaryTo further establish the role of oxidative stress in the pathogenesis of acute bronchial asthma, we investigated the effects of platelet-activating factor (PAF) challenge on systemic oxidant–antioxidant balance in 12 asthmatic patients (age, 25±3[sem] yr; FEV1, 95±10% predicted), using a double blinded, controlled with Lyso-PAF (L-PAF), cross-over design.Respiratory system resistance (Rrs), arterial blood gases, peripheral blood neutrophils and oxidant–antioxidant balance, including thiobarbituric acid (TBA)-malondialdehyde (MDA) adducts, protein sulphydryls and Trolox equivalent antioxidant capacity (TEAC), were assessed at baseline and 5, 15 and 45min after PAF and L-PAF (18μg each) bronchoprovocation. Urinary leukotriene E4 (uLTE4) elimination was measured 120min after challenge.Compared with baseline, as expected, PAF increased significantly Rrs and AaPO2 and decreased PaO2 and peripheral blood neutrophils along with a rebound neutrophilia and increased uLTE4. By contrast, markers of systemic oxidative stress remained unaltered throughout the study. Unlike PAF, L-PAF-induced changes were negligible.We conclude that there is no systemic oxidant–antioxidant imbalance during acute bronchoconstriction induced by PAF in these patients with mild asthma

Transdifferentiation of endothelial cells to smooth muscle cells play an important role in vascular remodelling

Pulmonary artery remodelling it is a major feature of pulmonary hypertension (PH). It is characterised by cellular and structural changes of the pulmonary arteries causing higher pulmonar vascular resistance and right ventricular failure. Abnormal deposition of smooth muscle-like (SM-like) cells in normally non-muscular, small diameter vessels and a deregulated control of endothelial cells are considered pathological features of PH. The origin of the SM-like cells and the mechanisms underlying the development and progression of this remodelling process are not understood. Endothelial cells within the intima may migrate from their organised layer of cells and transition to mesenchymal or SM-like phenotype in a process called endothelial-mesenchymal transition (EnMT). Traditionally, Waddington's epigenetic landscape illustrates that fates of somatic cells are progressively determined to compulsorily follow a downhill differentiation pathway. EnMT induces the transformation of cells with stem cell traits, therefore contrasting Waddington's theory and confirming that cell fate seems to be far more flexible than previously thought. The prospect of therapeutic inhibition of EnMT to delay or prevent PH may represent a promising new treatment modality

Use of automatic 6-minute walking test recording system in patients with chronic respiratory diseases

To the editor: Physical capacity tests are used for the diagnosis, prognosis and monitoring of chronic respiratory diseases (CRD), such as Chronic Obstructive Pulmonary Disease (COPD) or Pulmonary Hypertension (PH).1 Among these tests, the most widely used is the 6-minute walking test (6MWT).2 Additionally, the guidelines highlight the need to continuously record biological signals, particularly oxygen saturation (SpO2), which has been shown to be a prognostic marker in CRD.2 [...]The study was supported by grants from Societat Catalana de Pneumologia (SOCAP) (ESTEVE TEIJIN/2021), PI17/1515 and PI21/0555 from the Instituto de Salud Carlos III (ISCiii), co-funded by the European Union (ERDF/ESF, ”A way to make Europe” “Investing in your future”) and Premi d’Innovació de l’Hospital Clínic de Barcelona (2021). For UPC authors this work has been supported by the Spanish Ministry of Science and Innovation under contract PID2021-124463OB-I00, the Catalan Government under contract 2021 SGR 00326 and the Catalan Department of Research and Universities.Peer ReviewedPostprint (published version

Pulmonary hemodynamic profile in chronic obstructive pulmonary disease

Introduction: Few data are available in regards to the prevalence of pulmonary hypertension (PH) in the broad spectrum of COPD. This study was aimed at assessing the prevalence of PH in a cohort of COPD patients across the severity of airflow limitation, and reporting the hemodynamic characteristics at rest and during exercise. Methods: We performed a retrospective analysis on COPD patients who underwent right-heart catheterization in our center with measurements obtained at rest (n=139) and during exercise (n=85). PH was defined as mean pulmonary artery pressure (mPAP) >/25 mmHg and pulmonary capillary wedge pressure 3. Results: PH was present in 25 patients (18%). According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification, PH prevalence in GOLD 2 was 7% (3 patients); 25% (14 patients) in GOLD 3; and 22% (8 patients) in GOLD 4. Severe PH (mPAP >/35 mmHg) was identified in four patients (2.8%). Arterial partial oxygen pressure was the outcome most strongly associated with PH (r=-0.29, P<0.001). EIPH was observed in 60 patients (71%)and had a similar prevalence in both GOLD 2 and 3, and was present in all GOLD 4 patients. Patients with PH had lower cardiac index during exercise than patients without PH (5.0±1.2 versus 6.7±1.4 L/min/m2 ,respectively; P=0.001). Conclusion: PH has a similar prevalence in COPD patients with severe and very-severe airflow limitation, being associated with the presence of arterial hypoxemia. In contrast, EIPH is highly prevalent, even in moderate COPD, and might contribute to limiting exercise tolerance

Impact of the new definition for pulmonary hypertension in patients with lung disease: an analysis of the United Network for Organ Sharing database

The implications of the recent change in the definition of pulmonary hypertension on epidemiology and outcomes are not known. We sought to determine the percentage of patients with the two most common lung diseases that would be reclassified regarding the presence/absence of pulmonary hypertension with the revised definition. A query of the United Network for Organ Sharing database was performed. The percentage of patients meeting the current and previous definition of pulmonary hypertension was described. Outcomes of patients stratified by the current and previous definitions were compared. There were 15,563 patients with right heart catheterization data analyzed. Pulmonary hypertension was more prevalent in both chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis under the new definition at 52.4% versus 82.4%, and 47.6% versus 73.6%, respectively. 'Pre-capillary' pulmonary hypertension by the new definition was lower at 28.1% for chronic obstructive pulmonary disease and 36.8% for idiopathic pulmonary fibrosis. Of the patients with pulmonary hypertension by the old definition, 23.9% of chronic obstructive pulmonary disease patients and 18.7% of idiopathic pulmonary fibrosis patients were not classified as pulmonary hypertension by the new definition. Conversely, 15.9% of chronic obstructive pulmonary disease patients and 15.1% of idiopathic pulmonary fibrosis patients who did not meet diagnostic criteria for pulmonary hypertension by the old definition did have pulmonary hypertension by the new definition. Patients in both disease categories had shorter transplant-free waitlist survival in the presence of pulmonary hypertension by both the new and old definitions. There was a trend toward the new definition of pre-capillary pulmonary hypertension better discerning outcomes compared to the old definition of pulmonary hypertension in idiopathic pulmonary fibrosis patients. Most patients with advanced lung disease who are listed for lung transplantation have pulmonary hypertension, but fewer have pre-capillary pulmonary hypertension than pulmonary hypertension by the old definition. Both the old and new definition of precapillary pulmonary hypertension appear to discern outcomes among the two groups of lung disease analyzed, with some evidence to suggest that the new definition performs slightly better in the idiopathic pulmonary fibrosis population

Un método nuevo y más sensible para integrar la relación entre distancia y desaturación durante la prueba de la marcha de seis minutos en las enfermedades respiratorias crónicas: correlaciones fisiológicas

Case Report

Changes in REVEAL risk score in patients with pulmonary arterial hypertension treated with macitentan in clinical practice: results from the PRACMA study

Background: Macitentan is a dual endothelin receptor antagonist indicated for the long-term treatment of pulmonary arterial hypertension (PAH). We evaluated the change over time in REVEAL risk score in incident and prevalent patients receiving macitentan for the first time. Methods: Retrospective, observational study including adult patients with idiopathic/heritable PAH or PAH associated with connective tissue disorders or congenital heart disease treated with macitentan for ≥6-month follow-up in Spain. The REVEAL risk score and risk strata were computed at the start of macitentan and after ≥6-month in patients with ≥7 out of 12 valid REVEAL components. Results: Overall, 81 patients (57 for the REVEAL score) were analysed, 77.8% women. The mean age was 57.2 years and 50.6% of patients had idiopathic/heritable PAH. Prevalent patients were 59.3 and 40.7% were incident. Main therapies for PAH included macitentan monotherapy (42.0%) and macitentan in combination with phosphodiesterase type 5 inhibitor (44.4%). With a median time of macitentan treatment of 10.5 months, the mean REVEAL score was 8.7 points at baseline and was 7.2 points after ≥6-month follow-up. The mean change (95% CI) in REVEAL risk score was - 1.4 (- 2.0, - 0.9) points (p < 0.0001), being - 1.8 (- 3.0, - 0.7) points (p = 0.0040) and - 1.2 (- 1.8, - 0.5) points (p = 0.0010), in incident and prevalent patients, respectively. The reduction was also significant by risk stratum (36.8% of patients in the high-very high risk strata at baseline versus 14.0% after ≥6-month, p < 0.05) and therapy group. The REVEAL components that significantly improved were WHO functional class (FC) (63.9% FC III at macitentan initiation and 23.6% after ≥6-month, p < 0.0001), 6-min walk test (mean change: 41.8 m, p < 0.01), brain natriuretic peptide (BNP) or N-terminal proBNP (NT-proBNP) (mean change of - 157.6 pg/mL and - 530.0 pg/mL, respectively, p < 0.05 both), and pulmonary vascular resistance (PVR) (mean change: - 3.4 WU, p < 0.01). Conclusions: In this study, treatment with macitentan improved the REVEAL risk strata and score in both incident and prevalent PAH patients, and in all patients regardless of the therapy strategy. Macitentan significantly improved some of REVEAL components including WHO FC, BNP/NT-proBNP, PVR, and 6-min walk test after at least 6-month follow-up