[Diagnostics of Interstitial Lung Diseases - Practical Instructions with a Focus on Rheumatologic Systemic Diseases]. / Diagnostik interstitieller Lungenerkrankungen ­ Handlungsempfehlung mit Fokus auf rheumatologische Systemerkrankungen.

Interstitial lung diseases (ILD) are etiologically heterogeneous with unknown and known causes like rheumatologic systemic diseases differing in their therapeutic and prognostic consequences. In consensus between pulmonologists, rheumatologists, radiologists, and pathologists, we developed practical instructions for ILD diagnosis in rheumatologic systemic diseases, in particular because ILD can present in early stages of rheumatic systemic diseases. ILD diagnosis is based on clinical assessment results including a detailed medical history, physical examination, focused laboratory tests, radiology with a high-resolution computed tomography, lung function, and histopathology also to differentiate it from cardiac and infection associated lung diseases. The ILD diagnosis is made in a multidisciplinary discussion leading to therapeutic and prognostic consequences. The occurrence of acute exacerbations is especially critical. They are often the causes for ILD progression and are associated with considerable mortality.

Bronchoscopic Probe-Based Confocal Laser Endomicroscopy to Diagnose Diffuse Parenchymal Lung Diseases.

Background: Diagnosis of diffuse parenchymal lung disease (DPLD) is based on clinical evaluation, radiological imaging and histology. However, additional techniques are warranted to improve diagnosis. Aims and objective: Probe based confocal laser endomicroscopy (pCLE) allows real time in vivo visualisation of the alveolar compartment during bronchoscopy based on autofluorescence of elastic fibres. We used pCLE (Cellvizio®, Mauna Kea Technology. Inc, Paris, France) to characterise alveolar patterns in patients with different types of DPLD. Methods: In this pilot study we included 42 therapy naive patients (13 female, age 72.6 +/- 2.3 years), who underwent bronchoscopy for workup of DPLD. pCLE images were obtained during rigid bronchoscopy in affected lung segments according to HR-CT scan, followed by cryobiopsies in the identical area. Diagnoses were made by a multidisciplinary panel. The description of pCLE patterns was based on the degree of distortion of the hexagonal alveolar pattern, the density of alveolar structures, the presence of consolidations or loaded alveolar macrophages (AM). The assessment was performed by 2 investigators blinded for the final diagnosis. Results: The normal lung showed a typical alveolar loop pattern. In amiodarone lung disease loaded AM were predominant. COP showed characteristic focal consolidations. IPF was characterized by significant distortion and destruction, NSIP showed significant increase in density, and chronic HP presented with consolidations, mild distortion and density. Conclusion: pCLE shows potential as an adjunctive bronchoscopic imaging technique in the differential diagnosis of DPLD. Structured and quantitative analysis of the images is required.

Integrative analysis of cell state changes in lung fibrosis with peripheral protein biomarkers.

The correspondence of cell state changes in diseased organs to peripheral protein signatures is currently unknown. Here, we generated and integrated single-cell transcriptomic and proteomic data from multiple large pulmonary fibrosis patient cohorts. Integration of 233,638 single-cell transcriptomes (n = 61) across three independent cohorts enabled us to derive shifts in cell type proportions and a robust core set of genes altered in lung fibrosis for 45 cell types. Mass spectrometry analysis of lung lavage fluid (n = 124) and plasma (n = 141) proteomes identified distinct protein signatures correlated with diagnosis, lung function, and injury status. A novel SSTR2+ pericyte state correlated with disease severity and was reflected in lavage fluid by increased levels of the complement regulatory factor CFHR1. We further discovered CRTAC1 as a biomarker of alveolar type-2 epithelial cell health status in lavage fluid and plasma. Using cross-modal analysis and machine learning, we identified the cellular source of biomarkers and demonstrated that information transfer between modalities correctly predicts disease status, suggesting feasibility of clinical cell state monitoring through longitudinal sampling of body fluid proteomes.

Automated evaluation of probe-based confocal laser endomicroscopy in the lung.

RATIONALE: Probe-based confocal endomicroscopy provides real time videos of autoflourescent elastin structures within the alveoli. With it, multiple changes in the elastin structure due to different diffuse parenchymal lung diseases have previously been described. However, these evaluations have mainly relied on qualitative evaluation by the examiner and manually selected parts post-examination. OBJECTIVES: To develop a fully automatic method for quantifying structural properties of the imaged alveoli elastin and to perform a preliminary assessment of their diagnostic potential. METHODS: 46 patients underwent probe-based confocal endomicroscopy, of which 38 were divided into 4 groups categorizing different diffuse parenchymal lung diseases. 8 patients were imaged in representative healthy lung areas and used as control group. Alveolar elastin structures were automatically segmented with a trained machine learning algorithm and subsequently evaluated with two methods developed for quantifying the local thickness and structural connectivity. MEASUREMENTS AND MAIN RESULTS: The automatic segmentation algorithm performed generally well and all 4 patient groups showed statistically significant differences with median elastin thickness, standard deviation of thickness and connectivity compared to the control group. CONCLUSION: Alveoli elastin structures can be quantified based on their structural connectivity and thickness statistics with a fully-automated algorithm and initial results highlight its potential for distinguishing parenchymal lung diseases from normal alveoli.

Screening for Bronchoscopic Lung Volume Reduction: Reasons for Not Receiving Interventional Treatment.

BACKGROUND: Evidence for bronchoscopic lung volume reduction (BLVR) is based on phase 2 studies and small randomized controlled trials with in- and exclusion criteria defining a therapeutic window and contraindications. Little is known about the applicability in routine clinical practice. AIM: Which percentage of patients with severe emphysema referred to a specialized treatment center for BLVR is ultimately suitable for interventional bronchoscopic treatment? What is the relevance of the different contraindications? METHODS: Retrospective evaluation of emphysema patients referred to Asklepios Fachkliniken Munich-Gauting for BLVR between January 2014 and June 2015. RESULTS: 138 patients were referred for evaluation of BLVR. 38 patients (27.5%) underwent BLVR procedures (valves n = 18; coils n = 18; thermal vapor ablation n = 2). 100 patients (72.5%) were deemed not eligible for BLVR based on the following contraindications: 34% emphysema morphology and emphysema-related findings (severe homogeneous emphysema, extensive pleuropulmonary adhesions, postinflammatory scaring with natural volume reduction, giant bullae), 16% active smoking; 9% pulmonary function not within indication range; 8% unexpected CT findings (nodules, cancer, interstitial disease); 8% chronic ventilatory failure; 8% patient refused BLVR; 5% relevant comorbidity; 5% frequent exacerbations, 3% preserved quality of life, 4% other. CONCLUSION: BLVR is a therapeutic option for highly selected patients. In our cohort, one in four could be treated. These data highlight the limitations of BLVR under real-life conditions.

Pulmonary hypertension due to lung diseases: Updated recommendations from the Cologne Consensus Conference 2018.

The 2015 European Guidelines on Pulmonary Hypertension did not only cover pulmonary arterial hypertension (PAH) but also some aspects of pulmonary hypertension (PH) associated with chronic lung disease. The European Guidelines point out that the drugs currently used to treat patients with PAH (prostanoids, endothelin receptor antagonists, phosphodiesterase­5 inhibitors, sGC stimulators) have not been sufficiently investigated in other forms of PH. Therefore, the European Guidelines do not recommend the use of these drugs in patients with chronic lung disease and PH. This recommendation, however, is not always in agreement with medical ethics as physicians sometimes feel inclined to treat other forms of PH which may affect quality of life and survival of these patients in a similar manner. To this end, it is crucial to consider the severity of both PH and the underlying lung disease. In June 2016, a Consensus Conference organized by the PH working groups of the German Society of Cardiology (DGK), the German Society of Respiratory Medicine (DGP) and the German Society of Paediatric Cardiology (DGPK) was held in Cologne, Germany, to discuss open and controversial issues surrounding the practical implementation of the European Guidelines. Several working groups were created, one of which was dedicated to the diagnosis and treatment of PH in patients with chronic lung disease. The 2018 updated recommendations of this working group are summarized in the present paper.

Daily Chronic Intermittent Hypobaric Hypoxia Does Not Induce Chronic Increase in Pulmonary Arterial Pressure Assessed by Echocardiography.

Chronic hypoxia causes pulmonary vascular remodeling resulting in persistently increased pulmonary arterial pressures (PAP) even after return to normoxia. Recently, interest in chronic intermittent hypobaric hypoxia (CIHH) was raised because it occurs in subjects working at high altitude (HA) but living in lowland. However, effects of daily CIHH on PAP are unknown. In this pilot study, we included 8 healthy subjects working at (2650 m) each workday for 8-9 h while living and sleeping at LA and 8 matched control subjects living and working at LA. Cardiorespiratory measurements including echocardiography at rest and during exercise were performed at LA (Munich, 530 m) and HA (Zugspitze, 2650 m). Hemoglobin was higher in CIHH subjects. LA echocardiography showed normal right and left cardiac dimensions and function in all subjects. Systolic PAP (sPAP) and tricuspid annular plane systolic excursion (TAPSE) at rest were similar in both groups. Resting blood gas analysis (BGA) at HA revealed decreased pCO2 in CIHH compared to controls (HA: 28.4 versus 31.7 mmHg, p=0.01). During exercise, sPAP was lower in CIHH subjects compared to controls (LA: 28.7 versus 35.3 mmHg, p=0.02; HA: 26.3 versus 33.6 mmHg, p=0.04) and peripheral oxygen saturation (SpO2) was higher. In sum, subjects exposed to CIHH showed no signs of pulmonary vascular remodeling.

Pulmonary CCR2+CD4+ T cells are immune regulatory and attenuate lung fibrosis development.

BACKGROUND: Animal models have suggested that CCR2-dependent signalling contributes to the pathogenesis of pulmonary fibrosis, but global blockade of CCL2 failed to improve the clinical course of patients with lung fibrosis. However, as levels of CCR2+CD4+ T cells in paediatric lung fibrosis had previously been found to be increased, correlating with clinical symptoms, we hypothesised that distinct CCR2+ cell populations might either increase or decrease disease pathogenesis depending on their subtype. OBJECTIVE: To investigate the role of CCR2+CD4+ T cells in experimental lung fibrosis and in patients with idiopathic pulmonary fibrosis and other fibrosis. METHODS: Pulmonary CCR2+CD4+ T cells were analysed using flow cytometry and mRNA profiling, followed by in silico pathway analysis, in vitro assays and adoptive transfer experiments. RESULTS: Frequencies of CCR2+CD4+ T cells were increased in experimental fibrosis-specifically the CD62L-CD44+ effector memory T cell phenotype, displaying a distinct chemokine receptor profile. mRNA profiling of isolated CCR2+CD4+ T cells from fibrotic lungs suggested immune regulatory functions, a finding that was confirmed in vitro using suppressor assays. Importantly, adoptive transfer of CCR2+CD4+ T cells attenuated fibrosis development. The results were partly corroborated in patients with lung fibrosis, by showing higher percentages of Foxp3+ CD25+ cells within bronchoalveolar lavage fluid CCR2+CD4+ T cells as compared with CCR2-CD4+ T cells. CONCLUSION: Pulmonary CCR2+CD4+ T cells are immunosuppressive, and could attenuate lung inflammation and fibrosis. Therapeutic strategies completely abrogating CCR2-dependent signalling will therefore also eliminate cell populations with protective roles in fibrotic lung disease. This emphasises the need for a detailed understanding of the functions of immune cell subsets in fibrotic lung disease.

Inspiratory capacity is not altered in operable chronic thromboembolic pulmonary hypertension.

Pathological alterations of inspiratory capacity (IC) have been observed in pulmonary hypertension. However, the clinical significance of IC in operable chronic thromboembolic pulmonary hypertension (CTEPH) without other pulmonary diseases remains unknown. CTEPH patients scheduled for pulmonary endarterectomy were prospectively screened. Despite being associated with functional capacity, pathological alterations of IC were not observed.

The prognostic relevance of oxygen uptake in inoperable chronic thromboembolic pulmonary hypertension.

BACKGROUND: Patients with chronic thromboembolic pulmonary hypertension (CTEPH) present with a decreased oxygen uptake, however, the prognostic relevance of oxygen uptake (VO2 ) in inoperable CTEPH is unknown. METHODS: Patients with inoperable CTEPH were retrospectively analyzed. All patients were assessed by means of right heart catheterisation and cardio pulmonary exercise testing in semisupine position with a 30 Watt increment step-protocol. RESULTS: One-hundred and fifty-one patients (82 female (54.3%), mean age 61 ± 12.4 years) presented with a mean pulmonary arterial pressure of 40.2 ± 14.2 mmHg and pulmonary vascular resistance (PVR) of 641.9 ± 374.8 dyne∗s/cm5 . The peak VO2 (mean 13.1 ± 4.5 mL∗kg-1 ∗min-1 ) was measured at initial referral. Over a follow-up of up to 10 years (mean 4.41 ± 2.57 years), 31 patients had died. Patients with a baseline peak VO2 ≥ 10.7 mL∗kg-1 ∗min-1 [area under the receiver-operating characteristic curve (AUC) = 0.728, P = 0.001] had better survival than those with a peak VO2 ≤ 10.7 mL∗kg-1 ∗min-1 using Kaplan-Meier analysis (88.8% vs 60.1%; log rank P = 0.001). Adjusting for age, gender and PVR, multivariate analysis identified peak VO2 as a predictor of mortality [hazard ratio (HR): 2.78, 95% CI 1.01-7.63, P = 0.047]. In addition, peak VO2 failed as an independent prognostic factor in a stepwise multivariate model including all variables significant in the univariate analysis. CONCLUSIONS: In patients with inoperable CTEPH the peak VO2 is a significant predictor of survival, when adjusting for age, gender and PVR. However, peak VO2 failed as an independent prognostic factor when correcting for all significant baseline variables, which is limiting the clinical usability.

Collapse phenomenon during Chartis collateral ventilation assessment.

Chartis is increasingly used for bronchoscopic assessment of collateral ventilation before endobronchial valve (EBV) treatment for severe emphysema. Its prognostic value is, however, limited by the airway collapse phenomenon. The frequency and clinical significance of the collapse phenomenon remain largely unknown.We performed a retrospective analysis of 92 patients undergoing Chartis evaluation under spontaneous breathing (n=55) or jet ventilation (n=37) from May 2010 to November 2013. Collateral ventilation status (positive/negative/collapse phenomenon/unclear) was reassessed and correlated with high-resolution computed tomography (HRCT) fissure analysis and clinical response.In the absence of the collapse phenomenon, the predictive value of Chartis measurements and HRCT fissural analysis was comparable. The collapse phenomenon was observed in 31.5% of all assessments, and was more frequent in lower lobes (44.9% versus 16.9% in upper lobes) and under jet ventilation (41.4% versus 22.1% under spontaneous breathing). 69.8% of lobes with the collapse phenomenon had complete fissures. Most patients with the collapse phenomenon in the target lobe and complete fissures treated with EBVs were responders (n=11/15). All valve-treated collapse phenomenon patients with fissure defects were nonresponders (n=3).In the absence of the collapse phenomenon Chartis measurement is reliable to predict response to valve treatment. In patients with the collapse phenomenon, treatment decisions should be based on HRCT detection of fissure integrity. Chartis assessment should be performed under spontaneous breathing.

The H2S-generating enzymes cystathionine ß-synthase and cystathionine γ-lyase play a role in vascular development during normal lung alveolarization.

The gasotransmitter hydrogen sulfide (H2S) is emerging as a mediator of lung physiology and disease. Recent studies revealed that H2S administration limited perturbations to lung structure in experimental animal models of bronchopulmonary dysplasia (BPD), partially restoring alveolarization, limiting pulmonary hypertension, limiting inflammation, and promoting epithelial repair. No studies have addressed roles for endogenous H2S in lung development. H2S is endogenously generated by cystathionine ß-synthase (Cbs) and cystathionine γ-lyase (Cth). We demonstrate here that the expression of Cbs and Cth in mouse lungs is dynamically regulated during lung alveolarization and that alveolarization is blunted in Cbs(-/-) and Cth(-/-) mouse pups, where a 50% reduction in the total number of alveoli was observed, without any impact on septal thickness. Laser-capture microdissection and immunofluorescence staining indicated that Cbs and Cth were expressed in the airway epithelium and lung vessels. Loss of Cbs and Cth led to a 100-500% increase in the muscularization of small- and medium-sized lung vessels, which was accompanied by increased vessel wall thickness, and an apparent decrease in lung vascular supply. Ablation of Cbs expression using small interfering RNA or pharmacological inhibition of Cth using propargylglycine in lung endothelial cells limited angiogenic capacity, causing a 30-40% decrease in tube length and a 50% decrease in number of tubes formed. In contrast, exogenous administration of H2S with GYY4137 promoted endothelial tube formation. These data confirm a key role for the H2S-generating enzymes Cbs and Cth in pulmonary vascular development and homeostasis and in lung alveolarization.

Carcinoid tumours of the lung and the 'PEPPS' approach: evaluation of preoperative bronchoscopic tumour debulking as preparation for subsequent parenchyma-sparing surgery.

BACKGROUND: Preoperative bronchoscopic tumour ablation has been suggested as a beneficial treatment for bronchopulmonary carcinoid tumours, although data regarding its effects and long-term outcome are lacking. METHODS: In our case-matched cohort study with 208 patients with bronchopulmonary carcinoid tumours we investigated the role of preoperative bronchoscopic interventions before subsequent surgery and analysed the safety of this Procedure of Endobronchial Preparation for Parenchyma-sparing Surgery (PEPPS) based on metastasis and recurrence rates as well as survival data from 1991 to 2010. The subsequent surgery was classified into parenchyma-sparing procedures and classical lobectomies, bilobectomies and pneumonectomies. Data were obtained from the tumour registry and medical reports. Outcomes were the frequency of parenchyma-sparing surgery after bronchoscopic treatment as well as rates of metastasis, recurrence and survival. RESULTS: 132 of 208 carcinoids were located centrally. Among them, 77 patients could be recanalised preoperatively. After bronchoscopic preparation, the rate of subsequent parenchyma-sparing surgery methods was higher (p=0.021). The effect was measured by the number of segments removed. The 10-year survival rate was 89% (typical carcinoids) and 68% (atypical carcinoids), respectively. After applying PEPPS, long-term survival was slightly higher (p=0.23). Metastasis and recurrence rates showed no relevant differences between the bronchoscopically treated or non-treated groups, or between the two types of surgery classes or between the PEPPS and non-PEPPS groups. CONCLUSIONS: After preoperative bronchoscopic treatment, parenchyma-sparing surgery techniques can be applied more frequently. Furthermore, we detected no negative effects after PEPPS based on metastasis, recurrence and survival rates.

Sildenafil versus nitric oxide for acute vasodilator testing in pulmonary arterial hypertension.

Vasoreactivity testing with inhaled NO is recommended for pulmonary arterial hypertension (PAH) because of its therapeutic and prognostic value. Sildenafil has acute pulmonary vasodilating properties, but its diagnostic and prognostic impact in PAH is unknown. Our objective was to compare acute vasodilating responses to sildenafil and those to NO during right heart catheterization and also their prognostic values in patients with PAH. Ninety-nine patients with idiopathic PAH and 99 with associated PAH underwent vasoreactivity testing with NO and sildenafil. Only mild adverse effects of sildenafil, in the form of hypotension, were observed, at a rate of 4.5%. The acute responder rate was 8.1% for NO and 11.6% for sildenafil. The NO-induced response in mean pulmonary arterial pressure and cardiac output correlated with the response to sildenafil. Thirteen patients were long-term responders to calcium channel blockers (CCBs), and 3 of them were correctly identified by acute vasoreactivity test with both drugs. The specificity of the vasoreactivity test for identifying long-term CCB responders was 88.9% for NO and 85.1% for sildenafil testing. A trend toward better survival was found in sildenafil and NO responders, compared with nonresponders. Use of sildenafil for vasoreactivity testing is safe. Sildenafil may be useful as alternative vasoreactivity-testing agent, identifying the same number of long-term CCB responders as NO. However, NO seems to be a more ideal testing drug because of its pharmacologic properties. Moreover, sildenafil vasoreactivity testing might contribute to an improved estimate of prognosis among patients with PAH.

Acute hemodynamic effects of nebulized iloprost via the I-neb Adaptive Aerosol Delivery system in pulmonary hypertension.

Inhaled iloprost has proven to be an effective therapy in patients with pulmonary hypertension (PH). However, the acute hemodynamic effect of nebulized iloprost delivered via the I-neb Adaptive Aerosol Delivery (AAD) system remains unclear and needs to be assessed. In this study, 126 patients with PH were classified according to current guidelines (59, 34, 29, and 4 patients in groups 1/1', 3, 4, and 5, respectively; 20 patients had idiopathic pulmonary arterial hypertension [iPAH]), were randomly assigned to inhale iloprost 2.5 [Formula: see text]g (n = 67) or 5.0 [Formula: see text]g (n = 59) via the I-neb AAD system, and were assessed by right heart catheterization. In seven patients with iPAH, iloprost plasma levels were measured. The two iloprost doses caused decreases from baseline in pulmonary vascular resistance (PVR; 2.5 [Formula: see text]g: -14.7%; 5.0 [Formula: see text]g: -15.6%) and mean pulmonary arterial pressure (mPAP; 2.5 [Formula: see text]g: -11.0%; 5.0 [Formula: see text]g: -10.1%) while cardiac index (CI) increased (2.5 [Formula: see text]g: +6.5%; 5.0 [Formula: see text]g: +6.4%). The subset with iPAH also showed decreases from baseline in PVR and mPAP and an increase in CI. Peak iloprost plasma levels showed no significant difference after inhalation of 2.5 [Formula: see text]g or 5.0 [Formula: see text]g iloprost (95.5 pg/mL vs. 73.0 pg/mL; P = 0.06). In summary, nebulized iloprost delivered via the I-neb AAD system reduced mPAP and PVR and increased CI from baseline in a heterogeneous group of patients with PH and in the subset with iPAH. In patients with iPAH, inhalation of 2.5 [Formula: see text]g or 5.0 [Formula: see text]g iloprost resulted in broadly similar peak iloprost plasma levels.

Poor sleep quality is associated with exercise limitation in precapillary pulmonary hypertension.

BACKGROUND: Patients with precapillary pulmonary hypertension (PH) have been reported to suffer from poor sleep quality, however, if this is related to physical exercise performance has not yet been thoroughly investigated. METHODS: Clinically stable out-patients with idiopathic pulmonary arterial hypertension (IPAH, n = 52) and chronic thromboembolic PH (CTEPH, n = 64) in NYHA classes II and III were prospectively enrolled. 54 healthy volunteers matched for anthropometric variables served as a control group. The Pittsburgh Sleep Quality Index (PSQI) was used to rate subjective sleep quality. In the PH patients, six-minute walk tests (6MWT) were performed to assess exercise capacity. RESULTS: Poor sleep quality (i.e. a PSQI score > 5) occurred more frequently in PH (IPAH: n = 25 [48.1%], CTEPH: n = 39 [60.9%], controls: n = 10 [18.5%]; p < 0.01 when compared to controls). In addition, poor vs. good sleepers had significantly higher average NYHA class (IPAH: 2.6 ± 0.1 vs. 2.3 ± 0.1, CTEPH: 2.8 ± 0.1 vs. 2.3 ± 0.2; p < 0.01) and shorter 6MWT distances (IPAH: 338 ± 23 vs. 441 ± 29 m, CTEPH: 355 ± 15 vs. 413 ± 26 m; p < 0.05). CONCLUSIONS: Self-reported poor sleep quality is more common in PH than in healthy controls. Furthermore, it is related to reduced physical exercise capacity.

The prognostic significance of inspiratory capacity in pulmonary arterial hypertension.

BACKGROUND: Patients with pulmonary arterial hypertension (PAH) present with an altered inspiratory capacity (IC) reflecting dynamic hyperinflation (DH) that leads to mechanical constraints and excessive ventilatory demand, particularly during exercise, resulting in exertional dyspnea. OBJECTIVES: Assessment of the long-term consequences of altered IC and DH in PAH. METHODS: 50 patients with newly diagnosed PAH were prospectively recruited. All patients were assessed by means of right heart catheterization, 6-min walking distance (6MWD) test, lung function and cardiopulmonary exercise testing, including the assessment of IC. RESULTS: 37 patients with idiopathic PAH and 13 patients with conditions associated with PAH (29 female; mean age 51.6 ± 15.1 years; World Health Organization, WHO class, 2.7 ± 0.6) presented with a mean pulmonary arterial pressure of 42.8 ± 15.9 mm Hg and pulmonary vascular resistance (PVR) of 737.2 ± 592.8 dyn*s/cm(5). The mean IC at rest was 87.2 ± 17.3% pred. Kaplan-Meier analysis revealed that patients with an IC at rest >89% pred. had a significantly better 5-year survival than those with lower values (94.1 vs. 75.1%; log-rank p = 0.036). Univariate analysis identified IC at rest (% pred.) as a predictor of survival with a hazard ratio (HR) of 5.05 (95% confidence interval, CI, 0.97-26.24, p = 0.054). In multivariate analysis including PVR, WHO class, 6MWD and peak oxygen uptake as covariates, IC at rest remained an independent predictor of survival (HR: 8.06, 95% CI 0.92-70.34; p = 0.059). DH expressed as ΔIC or static hyperinflation expressed as IC/total lung capacity at rest revealed no prognostic significance. CONCLUSION: In patients with PAH, IC at rest is of prognostic significance at the time of diagnosis.

Lysyl oxidases play a causal role in vascular remodeling in clinical and experimental pulmonary arterial hypertension.

OBJECTIVE: Pulmonary vascular remodeling, the pathological hallmark of pulmonary arterial hypertension, is attributed to proliferation, apoptosis resistance, and migration of vascular cells. A role of dysregulated matrix cross-linking and stability as a pathogenic mechanism has received little attention. We aimed to assess whether matrix cross-linking enzymes played a causal role in experimental pulmonary hypertension (PH). APPROACH AND RESULTS: All 5 lysyl oxidases were detected in concentric and plexiform vascular lesions of patients with idiopathic pulmonary arterial hypertension. Lox, LoxL1, LoxL2, and LoxL4 expression was elevated in lungs of patients with idiopathic pulmonary arterial hypertension, whereas LoxL2 and LoxL3 expression was elevated in laser-capture microdissected vascular lesions. Lox expression was hypoxia-responsive in pulmonary artery smooth muscle cells and adventitial fibroblasts, whereas LoxL1 and LoxL2 expression was hypoxia-responsive in adventitial fibroblasts. Lox expression was increased in lungs from hypoxia-exposed mice and in lungs and pulmonary artery smooth muscle cells of monocrotaline-treated rats, which developed PH. Pulmonary hypertensive mice exhibited increased muscularization and perturbed matrix structures in vessel walls of small pulmonary arteries. Hypoxia exposure led to increased collagen cross-linking, by dihydroxylysinonorleucine and hydroxylysinonorleucine cross-links. Administration of the lysyl oxidase inhibitor ß-aminopropionitrile attenuated the effect of hypoxia, limiting perturbations to right ventricular systolic pressure, right ventricular hypertrophy, and vessel muscularization and normalizing collagen cross-linking and vessel matrix architecture. CONCLUSIONS: Lysyl oxidases are dysregulated in clinical and experimental PH. Lysyl oxidases play a causal role in experimental PH and represent a candidate therapeutic target. Our proof-of-principle study demonstrated that modulation of lung matrix cross-linking can affect pulmonary vascular remodeling associated with PH.