Pulmonary Hypertension In Chronic Obstructive Pulmonary Disease Research Articles

Prediction of clinical risk assessment and survival in chronic obstructive pulmonary disease with pulmonary hypertension.

Patients with pulmonary hypertension (PH) and chronic obstructive pulmonary disease (COPD) have an increased risk of disease exacerbation and decreased survival. We aimed to develop and validate a non-invasive nomogram for predicting COPD associated with severe PH and a prognostic nomogram for patients with COPD and concurrent PH (COPD-PH). This study included 535 patients with COPD-PH from six hospitals. A multivariate logistic regression analysis was used to analyse the risk factors for severe PH in patients with COPD and a multivariate Cox regression was used for the prognostic factors of COPD-PH. Performance was assessed using calibration, the area under the receiver operating characteristic curve and decision analysis curves. Kaplan-Meier curves were used for a survival analysis. The nomograms were developed as online network software. Tricuspid regurgitation velocity, right ventricular diameter, N-terminal pro-brain natriuretic peptide (NT-proBNP), the red blood cell count, New York Heart Association functional class and sex were non-invasive independent variables of severe PH in patients with COPD. These variables were used to construct a risk assessment nomogram with good discrimination. NT-proBNP, mean pulmonary arterial pressure, partial pressure of arterial oxygen, the platelet count and albumin were independent prognostic factors for COPD-PH and were used to create a predictive nomogram of overall survival rates. The proposed nomograms based on a large sample size of patients with COPD-PH could be used as non-invasive clinical tools to enhance the risk assessment of severe PH in patients with COPD and for the prognosis of COPD-PH. Additionally, the online network has the potential to provide artificial intelligence-assisted diagnosis and treatment. A multicentre study with a large sample of chronic obstructive pulmonary disease (COPD) patients diagnosed with PH through right heart catheterisation. A non-invasive online clinical tool for assessing severe pulmonary hypertension (PH) in COPD. The first risk assessment tool was established for Chinese patients with COPD-PH.

The Emerging Therapeutic Role of Prostaglandin E2 Signaling in Pulmonary Hypertension.

Mild-to-moderate pulmonary hypertension (PH) is a common complication of chronic obstructive pulmonary disease (COPD). It is characterized by narrowing and thickening of the pulmonary arteries, resulting in increased pulmonary vascular resistance (PVR) and ultimately leading to right ventricular dysfunction. Pulmonary vascular remodeling in COPD is the main reason for the increase of pulmonary artery pressure (PAP). The pathogenesis of PH in COPD is complex and multifactorial, involving chronic inflammation, hypoxia, and oxidative stress. To date, prostacyclin and its analogues are widely used to prevent PH progression in clinical. These drugs have potent anti-proliferative, anti-inflammatory, and stimulating endothelial regeneration properties, bringing therapeutic benefits to the slowing, stabilization, and even some reversal of vascular remodeling. As another well-known and extensively researched prostaglandins, prostaglandin E2 (PGE2) and its downstream signaling have been found to play an important role in various biological processes. Emerging evidence has revealed that PGE2 and its receptors (i.e., EP1-4) are involved in the regulation of pulmonary vascular homeostasis and remodeling. This review focuses on the research progress of the PGE2 signaling pathway in PH and discusses the possibility of treating PH based on the PGE2 signaling pathway.

Echocardiography and pulmonary hypertension in patients with chronic obstructive pulmonary disease undergoing lung transplantation evaluation

BackgroundThe use of echocardiography in pulmonary hypertension (PH) in advanced chronic obstructive pulmonary disease (COPD) is understudied. We aimed to compare the performance of echocardiography with right heart catheterization (RHC) in the diagnosis of PH in COPD patients undergoing lung transplant evaluation. MethodsWe included 111 patients with severe COPD who underwent RHC in a single center as part of lung transplantation evaluation. COPD-PH and severe COPD-PH were defined based on RHC per the 6th world symposium on pulmonary hypertension. Echocardiographic probability of PH was described according to the European Society of Cardiology guidelines. Summary and univariate analyses were performed. ResultsThe mean age (±SD) was 62 (8) and 47% (n=52) were men. A total of 82 patients (74 %) had COPD-PH. The sensitivity, specificity, positive predictive, and negative predictive values of echocardiography in diagnosing COPD-PH were 43 %, 83 %, 88 %, and 34 % respectively and for severe COPD-PH were 67 %, 75 %, 50 %, and 86 % respectively. Echocardiography was consistent with RHC in ruling in/out PH in 53% (n=59) of patients. After controlling for age, sex. BMI, pack year, echocardiography-RHC time difference, GOLD class, FVC, and CT finding of emphysema, higher TLC decreased consistency (parameter estimate=-0.031; odds ratio: 0.97, 95%CI 0.94-0.99; p=0.037) and higher DLCO increased consistency (parameter estimate=0.070; odds ratio: 1.07, 95%CI 0.94-0.99; p=0.026). ConclusionsEchocardiography has high specificity but low sensitivity for the diagnosis of PH in advanced COPD. Its performance improves when ruling out severe COPD-PH. This performance correlates inversely with lung hyperinflation.

The role of vitamin D in chronic obstructive pulmonary disease with pulmonary hypertension.

Hypoxia pulmonary hypertension (PH) belongs to the third major category in PH classification. Chronic obstructive pulmonary disease (COPD) is a common cause of hypoxia PH. Low serum vitamin D concentration is considered to be a possible risk factor for chronic lung disease; epidemiological studies have found that vitamin D deficiency increases pulmonary artery pressure. Therefore, this study aimed to explore the role of vitamin D levels in COPD and chronic hypoxic PH. This retrospective study selected three groups of people as research subjects, including: Group N: normal control group (people without any chronic lung disease or PH); Group C: patients with COPD, but without PH; Group C + PH: patients with COPD and PH. Vitamin D levels and pulmonary artery pressure were observed in the three groups. Vitamin D levels of the three groups showed statistical differences in every pairwise comparison; the vitamin D level of Group C (20.27 ng/mL) was lower than Group N (23.48 ng/mL), Group C + PH was the lowest (14.92 ng/mL). The levels of vitamin D in the three groups in this study were generally low. Vitamin D is negatively correlated with pulmonary artery systolic blood pressure. Low vitamin D levels may have a certain relationship with the occurrence and development of COPD. Further reductions in vitamin D levels may influence the development of PH in COPD.

Mitochondrial Rieske iron-sulfur protein is a crucial molecule in COPD-associated pulmonary hypertension

Pulmonary hypertension (PH) often occurs in chronic obstructive pulmonary disease (COPD) and is the major cause of death in COPD patients. Molecular mechanisms for PH in COPD remain poorly understood, and clinical treatments are neither specific nor effective. Cigarette and e-cigarette smoking (CS) account for up to 90% of COPD cases, in which nicotine is the major active component and causes COPD-like cellular responses; moreover, hypoxia is a known key factor in the development of PH. In this study, we aim to develop a PH in COPD animal model and determine the underlying molecular mechanisms. Our findings revealed that co-exposure of nicotine (or CS) and hypoxia synergistically elevated PH (i.e., right ventricular pressure and weight) compared to nicotine, CS, or hypoxia alone. We also found that mitochondrial reactive oxygen species ([ROS] m ), assessed using mitochondrial-specific ROS indicator MitoSOX, was significantly increased in pulmonary artery smooth muscle cells (PASMCs) from CS patients with COPD compared to normal PASMCs from non-CS patients. The increased [ROS] m was blocked by lentiviral short hairpin RNA (shRNA)-mediated knockdown of Rieske iron-sulfur protein (RISP) in mitochondrial complex III. More importantly, SMC-specific RISP gene knockout blocked nicotine/hypoxia exposure-induced PA remodeling and hypertension, whereas SMC-specific RISP overexpression exacerbated PH in mice. We further discovered that RISP regulated DNA damage following nicotine/hypoxia co-exposure via ataxia telangiectasia-mutated (ATM) signaling. RISP also mediated nuclear factor (NF)-κB inflammatory signaling. Together, our studies for the first time demonstrate that nicotine/hypoxia co-exposure leads to RISP-dependent [ROS] m , ATM-mediated DNA damage-dependent NF-κB-associated inflammation, PA vasoremodeling and PH in COPD in a sex-dependent manner. Moreover, RISP, ATM, and NF-κB may serve as novel and effective molecular targets in treating COPD and its associated PH. NIH R01 HL122865, NIH R03AG070784, and NIH R01 HL108232 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

COUNTERPOINT: Pulmonary Vascular Resistance 2.0— Shedding Light or Casting Shadows?

COUNTERPOINT: Pulmonary Vascular Resistance 2.0— Shedding Light or Casting Shadows?

Imbalanced prostanoid release mediates cigarette smoke-induced human pulmonary artery cell proliferation

BackgroundPulmonary hypertension is a common and serious complication of chronic obstructive pulmonary disease (COPD). Studies suggest that cigarette smoke can initiate pulmonary vascular remodelling by stimulating cell proliferation; however, the underlying cause, particularly the role of vasoactive prostanoids, is unclear. We hypothesize that cigarette smoke extract (CSE) can induce imbalanced vasoactive prostanoid release by differentially modulating the expression of respective synthase genes in human pulmonary artery smooth muscle cells (PASMCs) and endothelial cells (PAECs), thereby contributing to cell proliferation.MethodsAqueous CSE was prepared from 3R4F research-grade cigarettes. Human PASMCs and PAECs were treated with or without CSE. Quantitative real-time RT-PCR and Western blotting were used to analyse the mRNA and protein expression of vasoactive prostanoid syhthases. Prostanoid concentration in the medium was measured using ELISA kits. Cell proliferation was assessed using the cell proliferation reagent WST-1.ResultsWe demonstrated that CSE induced the expression of cyclooxygenase-2 (COX-2), the rate-limiting enzyme in prostanoid synthesis, in both cell types. In PASMCs, CSE reduced the downstream prostaglandin (PG) I synthase (PGIS) mRNA and protein expression and PGI2 production, whereas in PAECs, CSE downregulated PGIS mRNA expression, but PGIS protein was undetectable and CSE had no effect on PGI2 production. CSE increased thromboxane (TX) A synthase (TXAS) mRNA expression and TXA2 production, despite undetectable TXAS protein in both cell types. CSE also reduced microsomal PGE synthase-1 (mPGES-1) protein expression and PGE2 production in PASMCs, but increased PGE2 production despite unchanged mPGES-1 protein expression in PAECs. Furthermore, CSE stimulated proliferation of both cell types, which was significantly inhibited by the selective COX-2 inhibitor celecoxib, the PGI2 analogue beraprost and the TXA2 receptor antagonist daltroban.ConclusionsThese findings provide the first evidence that cigarette smoke can induce imbalanced prostanoid mediator release characterized by the reduced PGI2/TXA2 ratio and contribute to pulmonary vascular remodelling and suggest that TXA2 may represent a novel therapeutic target for pulmonary hypertension in COPD.

The Potential Important Role of Mitochondrial Rieske Iron-Sulfur Protein as a Novel Therapeutic Target for Pulmonary Hypertension in Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide, which is often due to pulmonary hypertension (PH). The underlying molecular mechanisms are poorly understood, and current medications are neither specific nor always effective. In this review, we highlight the recent findings on the roles of altered mitochondrial bioenergetics in PH in COPD. We also discuss the central role of mitochondrial reactive oxygen species (ROS) generation mediated by Rieske iron–sulfur protein (RISP) and review the contributions of RISP-dependent DNA damage and NF-κB-associated inflammatory signaling. Finally, the potential importance of mitochondrial RISP and its associated molecules as novel therapeutic targets for PH in COPD are meticulously discussed.

TIMP-1: A Circulating Biomarker for Pulmonary Hypertension Diagnosis Among Chronic Obstructive Pulmonary Disease Patients.

Pulmonary hypertension (PH) is a common complication of chronic obstructive pulmonary disease (COPD) and induces increased mortality among COPD patients. However, there are no blood biomarkers to identify PH in COPD. Here, we investigated whether circulating angiogenic factors and cytokines could serve as (a) biomarker (s) for COPD-PH patients. Using Angiogenesis and Cytokine proteome profile array assay, we measured the level of 36 cytokines and 55 angiogenesis-associated proteins in plasma from four COPD patients with PH (COPD-PH) and four COPD patients without PH (COPD), respectively, tissue inhibitor of metalloproteinase 1 (TIMP-1) and thrombospondin 1(TSP-1) were significantly different between the two groups. Enzyme-linked immunosorbent assay (ELISA) was applied to measured TIMP-1 and TSP-1 in a validation cohort (COPD-PH, n = 28; COPD, n = 18), and TIMP-1 was the only factor that was significantly different between COPD-PH and COPD patients (P < 0.01). Logistic regression analysis demonstrated that elevated TIMP-1 was an independent risk factor for COPD-PH [odds ratio (OR) = 1.258, 95% CI: 1.005–1.574, P < 0.05). Next, we explored the expression level and function of TIMP-1 in human pulmonary arterial smooth muscle cells (hPASMCs) exposed to cigarette smoking extract (CSE, a major etiological factor of COPD). In cultured hPASMCs, CSE treatment increased both TIMP-1 protein level and cell proliferation, and exogenous TIMP-1 (25 ng/mL) treatment inhibited CSE-induced hPASMCs proliferation. Overall, our results indicated that TIMP-1 elevation could serve as a circulating biomarker to diagnose PH among COPD patients, and TIMP-1 elevation in COPD-PH could be adaptive.

CT MEASURES OF INTRAPARENCHYMAL VASCULAR VOLUME IN COPD PATIENTS WITH AND WITHOUT PULMONARY HYPERTENSION

TOPIC: Pulmonary Vascular Disease TYPE: Original Investigations PURPOSE: Pulmonary hypertension (PH) is a significant contributing factor of overall morbidity and mortality in patients with COPD. Pruning in the form of loss of small vessel fractional volume has been shown to be associated with right heart disease and poor outcomes in COPD. In this investigation we sought to explore the relationship between this marker and the presence of precapillary pulmonary hypertension by hemodynamic measures. METHODS: We conducted a retrospective chart review study using the Research Patient Data Registry (RPDR) across patients in at Brigham and Women’s Hospital for patients with a diagnosis of Chronic Obstructive Pulmonary Disease (COPD) and measured FEV1/FVC of less than 70%. Patients with other forms of lung disease and risk factors for group 1 PH were excluded. Those patients with CT angiography within one year of right heart catheterization were further reviewed and we excluded those with poor image quality, pneumonia, significant fibrosis or lung collapse. All data collection was approved by the IRB at Mass General Brigham (IRB #2018P000419).We generated 3D models of the pulmonary vasculature using the Chest Imaging Platform (www.chestimagingplatform.org) and measured the total vascular volume (TBV), the volume of vessels with a cross sectional area <= 5 mm2 (BV5) and > 20mm2( BVg20); The small vessel fraction (aBV5/TBV) a marker of pruning, and the lung volume normalized arterial BVg20 (aBVg20/LV), a marker of proximal arterial enlargement were used for analysis. All data was analyzed using R version 4.0.1. Wilcoxon Rank-sum test and Spearman correlation were used for analysis and medians with IQR are reported. RESULTS: Of the Total Cohort (N=44), 17 had precapillary PH, 12 had PH associated with elevated wedge pressures and the remaining 15 did not meet diagnostic criteria for PH (mPAP > 20mmHg; PVR > 3 for precapillary, PAOP > 15mmHg for postcapillary). In the full cohort (N = 44), decrease in aBV5/TBV was associated with increase in mean PA pressure (R = -0.40, p = 0.007). We then restricted the analysis to those with less than 5% emphysema (N = 31). Here the aBV5/TBV was again negatively correlated with mean PA pressure (-0.6, p = 0.0004), but additionally aBVg20/LV was proportional to mean PA pressure (R = 0.46, p = 0.01).Within the group with less than 5% emphysema, those with precapillary PH had a lower aBV5/TBV (0.33[0.28-0.43] vs 0.46[0.46-0.55] p = 0.006, N = 13 and 7) than those without PH. There was no difference between age (66[62-80] vs 64[55-70], p = 0.34) and percent predicted FEV1 (53[48-69] vs 63[38-69] p>0.5). In those with > 5% emphysema (N = 13) there were no statistically significant correlations between aBV5/TBV and aBVg20/LV and mean PA pressure. CONCLUSIONS: In this retrospective study of COPD patients with CT angiography and hemodynamic assessment, decreased small arterial vascular fraction and proximal arterial volume increase was associated with increasing mPAP and was different between patients with precapillary PH versus those with no PH. The effect appears to be modulated by the presence of significant emphysema which independently may lead to loss of small vessel volume and additionally represents a specific sub-phenotype of COPD. CLINICAL IMPLICATIONS: Combining parenchymal and vascular phenotypic markers derived from CT imaging may help improve detection and phenotyping of PH in COPD. DISCLOSURES: No relevant relationships by Imama Ahmad, source=Web Response No relevant relationships by Sneha Lakshman, source=Web Response No relevant relationships by Pietro Nardelli, source=Web Response No relevant relationships by Farbod Rahaghi, source=Web Response Consultant relationship with Quantitative Imaging solutions Please note: 2016-2021 Added 05/03/2021 by Ruben San Jose Estepar, source=Web Response, value=Consulting fee Owner/Founder relationship with Quantitative Imaging Solutions Please note: 2015 Added 04/30/2021 by Raúl San José Estépar, source=Web Response, value=Ownership interest My spouse/partner as a Employee relationship with biogen Please note: >$100000 by George Washko, source=Web Response, value=Salary Owner/Founder relationship with Quantitative Imaging Solutions Please note: >$100000 by George Washko, source=Web Response, value=Ownership interest Advisory Committee Member relationship with Boehringer Ingelheim Please note: $1001 - $5000 by George Washko, source=Web Response, value=Consulting fee Consultant relationship with Vertex Please note: $5001 - $20000 by George Washko, source=Web Response, value=Consulting fee Advisory Committee Member relationship with PulmonX Please note: $1001 - $5000 by George Washko, source=Web Response, value=Consulting fee Advisory Committee Member relationship with CSL Behring Please note: $1001 - $5000 by George Washko, source=Web Response, value=Consulting fee Consultant relationship with Johnson and Johnson Please note: $5001 - $20000 by George Washko, source=Web Response, value=Consulting fee

Role of Selexipag in Chronic Obstructive Pulmonary Disease (COPD) Patients With Out-of-Proportion Pulmonary Hypertension.

Pulmonary hypertension (PH) in patients with chronic obstructive pulmonary disease (COPD) is associated with an increase in the risk of COPD exacerbation, increased hospitalization, and worse survival in this patient population. No specific treatment is available for PH in COPD. However, reported out-of-proportion PH may benefit from a certain type of treatment. This study shows that the use of selexipag in the treatment of out-of-proportion PH in COPD patients was associated with an improvement in functional status evaluated by a six-minute walk test (6MWT) and a mean pulmonary artery pressure at 6 +/- 2 months of treatment.

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.

Pulmonary hypertension in chronic obstructive pulmonary disease.

Even mild pulmonary hypertension (PH) is associated with increased mortality and morbidity in patients with chronic obstructive pulmonary disease (COPD). However, the underlying mechanisms remain elusive; therefore, specific and efficient treatment options are not available. Therapeutic approaches tested in the clinical setting, including long-term oxygen administration and systemic vasodilators, gave disappointing results and might be only beneficial for specific subgroups of patients. Preclinical studies identified several therapeutic approaches for the treatment of PH in COPD. Further research should provide deeper insight into the complex pathophysiological mechanisms driving vascular alterations in COPD, especially as such vascular (molecular) alterations have been previously suggested to affect COPD development. This review summarizes the current understanding of the pathophysiology of PH in COPD and gives an overview of the available treatment options and recent advances in preclinical studies. LINKED ARTICLES: This article is part of a themed issue on Risk factors, comorbidities, and comedications in cardioprotection. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.1/issuetoc.

Assessing pulmonary hypertension in COPD. Is there a role for computed tomography?

Pulmonary hypertension (PH) is a common complication of chronic obstructive pulmonary disease (COPD) and is associated with increased morbidity and mortality. Reference standard method to diagnose PH is right heart catheterization. Several non-invasive imaging techniques have been employed in the detection of PH. Among them, computed tomography (CT) is the most commonly used for phenotyping and detecting complications of COPD. Several CT findings have also been described in patients with severe PH. Nevertheless, CT analysis is currently based on visual findings which can lead to reproducibility failure. Therefore, there is a need for quantification in order to assess objective criteria. In this review, progresses in automated analyses of CT parameters and their values in predicting PH and COPD outcomes are presented.

Pulmonary Hypertension in COPD: A Case Study and Review of the Literature.

Pulmonary hypertension (PH) is a frequently encountered complication of chronic obstructive pulmonary disease (COPD) and is associated with worsened clinical symptoms and prognosis. The prevalence of PH-COPD is not concretely established as classification criteria vary historically, but the presence of severe disease out of proportion to underlying COPD is relatively rare. Right heart catheterization, the gold standard in diagnosis of PH, is infrequently performed in COPD, and the overlap in the clinical symptoms of PH and COPD presents diagnostic challenges. Proven treatments are limited. Trials exploring the use of vasodilator therapy in this patient group generally demonstrate improvements in hemodynamics accompanied by worsening gas exchange without clearly demonstrated improvements in clinically meaningful outcomes. In-depth workup of underlying pulmonary hypertension and use of pulmonary vasodilator medications may be appropriate on an individual basis. We present a case study and a review and discussion of the pertinent literature on this topic.

Reactive Oxygen Species-Dependent Calpain Activation Contributes to Airway and Pulmonary Vascular Remodeling in Chronic Obstructive Pulmonary Disease.

Aims: Airway and pulmonary vascular remodeling is an important pathological feature in the pathogenesis of chronic obstructive pulmonary disease (COPD). Tobacco smoke (TS) induces the production of large amounts of reactive oxygen species (ROS) in COPD lungs. We investigated how ROS lead to airway and pulmonary vascular remodeling in COPD. Results: We used in vitro bronchial and pulmonary artery smooth muscle cells (BSMCs and PASMCs), in vivo TS-induced COPD rodent models, and lung tissues of COPD patients. We found that H2O2 and TS extract (TSE) induced calpain activation in BSMCs and PASMCs. Calpain activation was elevated in smooth muscle of bronchi and pulmonary arterioles in COPD patients and TS-induced COPD rodent models. Calpain inhibition attenuated H2O2- and TSE-induced collagen synthesis and proliferation of BSMCs and PASMCs. Exposure to TS causes increases in airway resistance, right ventricular systolic pressure (RVSP), and thickening of bronchi and pulmonary arteries. Calpain inhibition by smooth muscle-specific knockout of calpain and the calpain inhibitor MDL28170 attenuated increases in airway resistance, RVSP, and thickening of bronchi and pulmonary arteries. Moreover, smooth muscle-specific knockout of calpain did not reduce TS-induced emphysema in the mouse model, but MDL28170 did reduce TS-induced emphysema in the rat model. Innovation: This study provides the first evidence that ROS-induced calpain activation contributes to airway and pulmonary vascular remodeling in TS-induced COPD. Calpain might be a novel therapeutic target for the treatment of COPD. Conclusion: These results indicate that ROS-induced calpain activation contributes to airway and pulmonary vascular remodeling and pulmonary hypertension in COPD.

Riociguat for treatment of pulmonary hypertension in COPD: a translational study.

Chronic obstructive pulmonary disease (COPD), which comprises the phenotypes of chronic bronchitis and emphysema, is often associated with pulmonary hypertension (PH). However, currently, no approved therapy exists for PH-COPD. Signalling of the nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) axis plays an important role in PH and COPD.We investigated the treatment effect of riociguat, which promotes the NO-cGMP pathway, in the mouse model of smoke-induced PH and emphysema in a curative approach, and retrospectively analysed the effect of riociguat treatment on PH in single patients with PH-COPD.In mice with established PH and emphysema (after 8 months of cigarette smoke exposure), riociguat treatment for another 3 months fully reversed PH. Moreover, histological hallmarks of emphysema were decreased. Microarray analysis revealed involvement of different signalling pathways, e.g. related to matrix metalloproteinases (MMPs). MMP activity was decreased in vivo by riociguat. In PH-COPD patients treated with riociguat (n=7), the pulmonary vascular resistance, airway resistance and circulating MMP levels decreased, while oxygenation at rest was not significantly changed.Riociguat may be beneficial for treatment of PH-COPD. Further long-term prospective studies are necessary to investigate the tolerability, efficacy on functional parameters and effect specifically on pulmonary emphysema in COPD patients.

Survival in pulmonary hypertension due to chronic lung disease: Influence of low diffusion capacity of the lungs for carbon monoxide.

Patients with pulmonary hypertension (PH) due to chronic lung disease (Group 3 PH) have poor long-term outcomes. However, predictors of survival in Group 3 PH are not well described. We performed a cohort study of Group 3 PH patients (n = 143; mean age 65 ± 12 years, 52% female) evaluated at the University of Minnesota. The Kaplan-Meier method and Cox regression analysis were used to assess survival and predictors of mortality, respectively. The clinical characteristics and survival were compared in patients categorized by PH severity based on the World Health Organization (WHO) classification and lung disease etiology. After a median follow-up of 1.4 years, there were 69 (48%) deaths. The 1-, 3-, and 5-year survival rates were 79%, 48%, and 31%. Age, coronary artery disease, atrial fibrillation, Charlson comorbidity index, serum N-terminal pro‒brain natriuretic peptide (NT-proBNP), creatinine, diffusion capacity of carbon monoxide (DLCO), total lung capacity, left ventricular ejection fraction, right atrial and right ventricular enlargement on echocardiography, cardiac index, and pulmonary vascular resistance (PVR) were univariate predictors of survival. On multivariable analysis, DLCO was the only predictor of mortality (adjusted hazard ratio [HR] for every 10% decrease in predicted value: 1.31 [95% confidence interval 1.12 to 1.47]; p = 0.003). The 1-/5-year survival by tertiles of DLCO was 84%/56%, 82%/44%, and 63%/14% (p = 0.01), respectively. On receiver-operating characteristic curve analysis, DLCO <32% of predicted had the highest sensitivity and specificity for predicting survival. The 1- and 5-year survival in patients with a DLCO ≥32% predicted was 84% and 60% vs 68% and 13% in patients with a DLCO <32% predicted (adjusted HR: 2.5 [95% confidence interval 1.3 to 5.0]; p = 0.007). Lung volumes and DLCO were not related, but higher PVR was strongly associated with reduced DLCO. There was increased mortality in interstitial lung disease‒PH as compared with chronic obstructive pulmonary disease‒PH, but PH severity based on the WHO classification did not alter survival. Low DLCO is a predictor of mortality and should be used to risk-stratify Group 3 PH patients.

NOX4 expression and distal arteriolar remodeling correlate with pulmonary hypertension in COPD

BackgroundPulmonary hypertension (PH) in chronic obstructive pulmonary disease (COPD) is suggested as the consequence of emphysematous destruction of vascular bed and hypoxia of pulmonary microenvironment, mechanisms underpinning its pathogenesis however remain elusive. The dysregulated expression of nicotinamide adenine dinucleotide phosphate (NADPH)-oxidases and superoxide generation by pulmonary vasculatures have significant implications in the hypoxia-induced PH.MethodsIn this study, the involvement of NADPH oxidase subunit 4 (NOX4) in pulmonary arteriolar remodeling of PH in COPD was investigated by ascertaining the morphological alteration of pulmonary arteries and pulmonary blood flow using cardiac magnetic resonance imaging (cMRI), and the expression and correlation of NOX4 with pulmonary vascular remodeling and pulmonary functions in COPD lungs.ResultsResults demonstrated that an augmented expression of NOX4 was correlated with the increased volume of pulmonary vascular wall in COPD lung. While the volume of distal pulmonary arteries was inversely correlated with pulmonary functions, despite it was positively associated with the main pulmonary artery distensibility, right ventricular myocardial mass end-systolic and right ventricular myocardial mass end-diastolic in COPD. In addition, an increased malondialdehyde and a decreased superoxide dismutase were observed in sera of COPD patients. Mechanistically, the abundance of NOX4 and production of reactive oxygen species (ROS) in pulmonary artery smooth muscle cells could be dynamically induced by transforming growth factor-beta (TGF-β), which in turn led pulmonary arteriolar remodeling in COPD lungs.ConclusionThese results suggest that the NOX4-derived ROS production may play a key role in the development of PH in COPD by promoting distal pulmonary vascular remodeling.

Prophylactic function of excellent compliance with LTOT in the development of pulmonary hypertension due to COPD with hypoxemia.

The long-term oxygen therapy (LTOT) for patients with chronic obstructive pulmonary disease (COPD) has been shown to increase survival in patients with severe resting hypoxemia. The adherence to LTOT may also simultaneously affect the development of concomitant pulmonary hypertension (PH) due to COPD with hypoxemia. We retrospectively reviewed 276 cases of COPD with or without PH assessed by right heart catheterization (RHC) to investigate whether adherence to continuous LTOT had a prophylactic effect on the development of PH in a time interval of two years. In contrast to the patients in the non-compliance group (PH prevalence 64.2%), patients with excellent compliance of adhering to continuous LTOT > 15 h per day in the compliance group (PH prevalence 37.6%) are more liable to postpone the development of PH due to hypoxic COPD for at least two years. Adherence to LTOT ≥ 15 h/day is strongly recommended in order to lower the risk and delay the development of consequent PH in COPD with hypoxemia.