Protein expression profiling suggests relevance of noncanonical pathways in isolated pulmonary embolism.

Patients with isolated pulmonary embolism (PE) have a distinct clinical profile from those with deep vein thrombosis (DVT)-associated PE, with more pulmonary conditions and atherosclerosis. These findings suggest a distinct molecular pathophysiology and the potential involvement of alternative pathways in isolated PE. To test this hypothesis, data from 532 individuals from the Genotyping and Molecular Phenotyping of Venous ThromboEmbolism Project, a multicenter prospective cohort study with extensive biobanking, were analyzed. Targeted, high-throughput proteomics, machine learning, and bioinformatic methods were applied to contrast the acute-phase plasma proteomes of isolated PE patients (n = 96) against those of patients with DVT-associated PE (n = 276) or isolated DVT (n = 160). This resulted in the identification of shared molecular processes between PE phenotypes, as well as an isolated PE-specific protein signature. Shared processes included upregulation of inflammation, response to oxidative stress, and the loss of pulmonary surfactant. The isolated PE-specific signature consisted of 5 proteins: interferon-γ, glial cell line-derived neurotrophic growth factor, polypeptide N-acetylgalactosaminyltransferase 3, peptidyl arginine deiminase type-2, and interleukin-15 receptor subunit α. These proteins were orthogonally validated using cis protein quantitative trait loci. External replication in an independent population-based cohort (n = 5778) further validated the proteomic results and showed that they were prognostic for incident primary isolated PE in individuals without history of VTE (median time to event: 2.9 years; interquartile range: 1.6-4.2 years), supporting their possible involvement in the early pathogenesis. This study has identified molecular overlaps and differences between VTE phenotypes. In particular, the results implicate noncanonical pathways more commonly associated with respiratory and atherosclerotic disease in the acute pathophysiology of isolated PE.

Chronic thromboembolic pulmonary hypertension and impairment after pulmonary embolism: the FOCUS study.

AIMS: To systematically assess late outcomes of acute pulmonary embolism (PE) and to investigate the clinical implications of post-PE impairment (PPEI) fulfilling prospectively defined criteria. METHODS AND RESULTS: A prospective multicentre observational cohort study was conducted in 17 large-volume centres across Germany. Adult consecutive patients with confirmed acute symptomatic PE were followed with a standardized assessment plan and pre-defined visits at 3, 12, and 24 months. The co-primary outcomes were (i) diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH), and (ii) PPEI, a combination of persistent or worsening clinical, functional, biochemical, and imaging parameters during follow-up. A total of 1017 patients (45% women, median age 64 years) were included in the primary analysis. They were followed for a median duration of 732 days after PE diagnosis. The CTEPH was diagnosed in 16 (1.6%) patients, after a median of 129 days; the estimated 2-year cumulative incidence was 2.3% (1.2-4.4%). Overall, 880 patients were evaluable for PPEI; the 2-year cumulative incidence was 16.0% (95% confidence interval 12.8-20.8%). The PPEI helped to identify 15 of the 16 patients diagnosed with CTEPH during follow-up (hazard ratio for CTEPH vs. no CTEPH 393; 95% confidence interval 73-2119). Patients with PPEI had a higher risk of re-hospitalization and death as well as worse quality of life compared with those without PPEI. CONCLUSION: In this prospective study, the cumulative 2-year incidence of CTEPH was 2.3%, but PPEI diagnosed by standardized criteria was frequent. Our findings support systematic follow-up of patients after acute PE and may help to optimize guideline recommendations and algorithms for post-PE care.

[Non-invasive Mechanical Ventilation in Acute Respiratory Failure. Clinical Practice Guidelines - on behalf of the German Society of Pneumology and Ventilatory Medicine]. / S2k-Leitlinie Nichtinvasive Beatmung als Therapie der akuten respiratorischen Insuffizienz.

The guideline update outlines the advantages as well as the limitations of NIV in the treatment of acute respiratory failure in daily clinical practice and in different indications.Non-invasive ventilation (NIV) has a high value in therapy of hypercapnic acute respiratory failure, as it significantly reduces the length of ICU stay and hospitalization as well as mortality.Patients with cardiopulmonary edema and acute respiratory failure should be treated with continuous positive airway pressure (CPAP) and oxygen in addition to necessary cardiological interventions. This should be done already prehospital and in the emergency department.In case of other forms of acute hypoxaemic respiratory failure with only mild or moderately disturbed gas exchange (PaO2/FiO2 > 150 mmHg) there is no significant advantage or disadvantage compared to high flow nasal oxygen (HFNO). In severe forms of ARDS NIV is associated with high rates of treatment failure and mortality, especially in cases with NIV-failure and delayed intubation.NIV should be used for preoxygenation before intubation. In patients at risk, NIV is recommended to reduce extubation failure. In the weaning process from invasive ventilation NIV essentially reduces the risk of reintubation in hypercapnic patients. NIV is regarded useful within palliative care for reduction of dyspnea and improving quality of life, but here in concurrence to HFNO, which is regarded as more comfortable. Meanwhile NIV is also recommended in prehospital setting, especially in hypercapnic respiratory failure and pulmonary edema.With appropriate monitoring in an intensive care unit NIV can also be successfully applied in pediatric patients with acute respiratory insufficiency.

Late outcomes after acute pulmonary embolism: rationale and design of FOCUS, a prospective observational multicenter cohort study.

Acute pulmonary embolism (PE) is a frequent cause of death and serious disability. The risk of PE-associated mortality and morbidity extends far beyond the acute phase of the disease. In earlier follow-up studies, as many as 30 % of the patients died during a follow-up period of up to 3 years, and up to 50 % of patients continued to complain of dyspnea and/or poor physical performance 6 months to 3 years after the index event. The most feared 'late sequela' of PE is chronic thromboembolic pulmonary hypertension (CTEPH), the true incidence of which remains obscure due to the large margin of error in the rates reported by mostly small, single-center studies. Moreover, the functional and hemodynamic changes corresponding to early, possibly reversible stages of CTEPH, have not been systematically investigated. The ongoing Follow-Up after acute pulmonary embolism (FOCUS) study will prospectively enroll and systematically follow, over a 2-year period and with a standardized comprehensive program of clinical, echocardiographic, functional and laboratory testing, a large multicenter prospective cohort of 1000 unselected patients (all-comers) with acute symptomatic PE. FOCUS will possess adequate power to provide answers to relevant remaining questions regarding the patients' long-term morbidity and mortality, and the temporal pattern of post-PE abnormalities. It will hopefully provide evidence for future guideline recommendations regarding the selection of patients for long-term follow-up after PE, the modalities which this follow-up should include, and the findings that should be interpreted as indicating progressive functional and hemodynamic post-PE impairment, or the development of CTEPH.

Management of patients with idiopathic pulmonary fibrosis in clinical practice: the INSIGHTS-IPF registry.

After introduction of the new international guidelines on idiopathic pulmonary fibrosis (IPF) in 2011, we investigated clinical management practices for patients with IPF according to physicians' diagnoses. A prospective, multicenter, noninterventional study with comprehensive quality measures including on-site source data verification was performed in Germany. 502 consecutive patients (171 newly diagnosed, 331 prevalent; mean±SD age 68.7±9.4 years, 77.9% males) with a mean disease duration of 2.3±3.5 years were enrolled. IPF diagnosis was based on clinical assessments and high-resolution computed tomography (HRCT) in 90.2%, and on surgical lung biopsy combined with histology in 34.1% (lavage in 61.8%). The median 6-min walk distance was 320 m (mean 268±200 m). The mean forced vital capacity was 72±20% pred and diffusing capacity of the lung for carbon monoxide was 35±15% pred. No drugs were administered in 17.9%, oral steroids in 23.7%, N-acetylcysteine in 33.7%, pirfenidone in 44.2% and other drugs in 4.6% of patients. Only 2.8% of the cohort was listed for lung transplantation. IPF patients were diagnosed in line with the new guidelines. They had more severe disease than those enrolled in recent randomised controlled trials. In addition to HRCT, the frequency of lung biopsies was surprisingly high. Treatment patterns varied substantially.

Post-Pulmonary Embolism Syndrome: An Update Based on the Revised AWMF-S2k Guideline.

In survivors of acute pulmonary embolism (PE), the post-PE syndrome (PPES) may occur. In PPES, patients typically present with persisting or progressive dyspnea on exertion despite 3 months of therapeutic anticoagulation. Therefore, a structured follow-up is warranted to identify patients with chronic thromboembolic pulmonary disease (CTEPD) with normal pulmonary pressure or chronic thromboembolic pulmonary hypertension (CTEPH). Both are currently understood as a dual vasculopathy, that is, secondary arterio- and arteriolopathy, affecting the large and medium-sized pulmonary arteries as well as the peripheral vessels (diameter < 50 µm). The follow-up algorithm after acute PE commences with identification of clinical symptoms and risk factors for CTEPH. If indicated, a stepwise performance of echocardiography, ventilation-perfusion scan (or alternative imaging), N-terminal prohormone of brain natriuretic peptide (NT-proBNP) level, cardiopulmonary exercise testing, and pulmonary artery catheterization with angiography should follow. CTEPH patients should be treated in a multidisciplinary center with adequate experience in the complex therapeutic options, comprising pulmonary endarterectomy, balloon pulmonary angioplasty, and pharmacological interventions.

Pulmonary Embolism: An Update Based on the Revised AWMF-S2k Guideline.

Pulmonary embolism (PE) is the third most common acute cardiovascular disease. The risk of PE increases with age and mortality is high. Patients are stratified into hemodynamically stable versus unstable patients, as this has important implications for diagnosis and therapy. Since clinical signs and symptoms of acute PE are nonspecific, the clinical likelihood of PE is estimated to guide diagnostic pathways. D-dimer testing is performed in hemodynamically stable patients with low or intermediate probability of PE and the visualization of thromboembolism and its sequelae is commonly achieved with computed tomography pulmonary angiography (CTPA), supplemented by ultrasound techniques. With confirmed PE, another risk stratification estimates disease severity and defines intensity and setting of the ensuing treatment. The therapeutic spectrum ranges from outpatient treatment with initial oral anticoagulation to thrombolytic or interventional treatment in the intensive care unit or catheterization laboratory. In single cases, even acute surgical thrombectomy is attempted.

Using Machine Learning-Based Algorithms to Identify and Quantify Exercise Limitations in Clinical Practice: Are We There Yet?

INTRODUCTION: Well-trained staff is needed to interpret cardiopulmonary exercise tests (CPET). We aimed to examine the accuracy of machine learning-based algorithms to classify exercise limitations and their severity in clinical practice compared with expert consensus using patients presenting at a pulmonary clinic. METHODS: This study included 200 historical CPET data sets (48.5% female) of patients older than 40 yr referred for CPET because of unexplained dyspnea, preoperative examination, and evaluation of therapy progress. Data sets were independently rated by experts according to the severity of pulmonary-vascular, mechanical-ventilatory, cardiocirculatory, and muscular limitations using a visual analog scale. Decision trees and random forests analyses were calculated. RESULTS: Mean deviations between experts in the respective limitation categories ranged from 1.0 to 1.1 points (SD, 1.2) before consensus. Random forests identified parameters of particular importance for detecting specific constraints. Central parameters were nadir ventilatory efficiency for CO 2 , ventilatory efficiency slope for CO 2 (pulmonary-vascular limitations); breathing reserve, forced expiratory volume in 1 s, and forced vital capacity (mechanical-ventilatory limitations); and peak oxygen uptake, O 2 uptake/work rate slope, and % change of the latter (cardiocirculatory limitations). Thresholds differentiating between different limitation severities were reported. The accuracy of the most accurate decision tree of each category was comparable to expert ratings. Finally, a combined decision tree was created quantifying combined system limitations within one patient. CONCLUSIONS: Machine learning-based algorithms may be a viable option to facilitate the interpretation of CPET and identify exercise limitations. Our findings may further support clinical decision making and aid the development of standardized rating instruments.

Exercise capacity affects quality of life in patients with pulmonary hypertension.

BACKGROUND: The objective of this prospective study was to evaluate the impact of exercise capacity, mental disorders, and hemodynamics on quality-of-life (QoL) parameters in patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). METHODS: Sixty-three patients with invasively diagnosed PAH (n = 48) or CTEPH (n = 15) underwent a broad panel of assessments, including cardiopulmonary exercise testing (CPET), 6-minute walking distance (6-MWD), World Health Organization functional class (WHO-FC), and assessment of hemodynamics. QoL was evaluated by the 36-item Medical Outcome Study Short Form Health Survey Questionnaire (SF-36). Exercise capacity, hemodynamics, age, gender, and mental disorders (anxiety and depression) were assessed for association with QoL subscores by uni- and multivariate regression analyses. RESULTS: Exercise capacity, WHO-FC, oxygen therapy, symptoms of right heart failure, right atrial pressure, and mental disorders were significantly associated with QoL (p < 0.05). In the stepwise backward selection multivariate analysis, depression remained an independent parameter in seven of eight subscales of the SF-36. Furthermore, peak oxygen uptake (peakVO2) during CPET, 6-MWD, anxiety, long-term oxygen therapy, right heart failure, and age remained independent factors for QoL. Hemodynamic parameters at rest did not independently correlate with any domain of the SF-36 QoL subscores. CONCLUSIONS: Mental disorders, exercise capacity, long-term oxygen therapy, right heart failure, and age play important role in the quality of life in patients with PAH and CTEPH.

High-sensitive Troponin T increase after exercise in patients with pulmonary arterial hypertension.

BACKGROUND: The current study aimed to investigate the release of myocardial high-sensitive Troponin T (hsTnT) in patients with pulmonary arterial hypertension (PAH) in response to maximal physical exercise. METHODS: In 24 patients with PAH, symptom-limited cardiopulmonary exercise testing was performed. hsTnT was measured by the novel hsTnT assay with a lower limit of detection of 2 ng/L and a total imprecision of less than 10% at the 99th percentile value. hsTnT was related to NT-proBNP, WHO functional class and right ventricular (RV) function. Serial measurement was performed before and 30 min, 180 min, and 300 min after exercise. Healthy volunteers served as a control group. RESULTS: In 21 PAH patients, hsTnT levels were detectable before exercise with a close correlation between hsTnT and NT-proBNP. hsTnT was detectable in all PAH patients after exercise and significantly increased from 7.5 ng/L at baseline to 14.62 ng/L after 300 min, whereas levels of NT-proBNP remained constant with time. CONCLUSIONS: Using the novel hsTnT assay, the current study provides first evidence that hsTnT levels increase in PAH patients after maximal physical exercise, while levels of other biomarkers remain constant after exercise testing. This might provide new insights into pathophysiology and individual risk assessment in patients with PAH.

The correlation between endothelin-1 levels and spirometry in dialysis patients compared to healthy subjects.

BACKGROUND AND AIM: Several studies demonstrated a six-fold increase in plasma concentration of endothelin-1 (ET-1) in diaysis patients (hemodialysis and peritoneal dialysis) compared to healthy control subjects. However, the effects of ET-1 on respiratory function in these patients are less known. The aim of this study was to determine the potential differences in spirometric values in relation to ET-1 levels. METHODS: The study included 28 patients (15 male, 13 female, mean age 55.9 +/- 16. 2 years) with end stage renal diseases (ESRD) receiving regular hemodialysis (HD), 23 patients (10 males, 13 females, mean age 55.8 +/- 15.8 years) with ESRD treated with continuous ambulatory peritoneal dialysis (CAPD) without any cardiovascular or respiratory diseases, and 30 healthy volunteers (14 male, 16 female, mean age 51.8 +/- 15.6 years) in control group. In each of the three groups the participants were divided into two additional sub-groups according to the serum levels of ET-1. The spirometry values were recorded before the onset of hemodialysis and prior to emptying the peritoneal cavity in CAPD patients. The results were analyzed using standard statistical methods (Student's t-test). RESULTS: Patients who were treated with HD or CAPD were found to have significant difference in values of most pulmonary function parameters between subjects with ET-1 levels lower than 6.6 pg/ml and subjects with ET-1 levels higher than 6.6 pg/ml. In the control group there was no difference in pulmonary function parameters in correlation with ET-1 levels. ET-1 values in patients of both dialysis groups were significantly higher compared to healthy subjects. CONCLUSIONS: Higher levels of ET-1 in dialysis patients over healthy subjects is associated with lower parameters of lung function tests. A possible pathophysiological mechanism for deterioration of pulmonary function might be explained by progression of inflammation, pulmonary oedema also known as "uraemic lung" or/and the progression of pulmonary hypertension.

Osteopontin predicts adverse right ventricular remodelling and dysfunction in pulmonary hypertension.

BACKGROUND: Osteopontin (OPN) was found upregulated in several heart failure models and appears to play an important role in myocardial remodelling. As we have previously demonstrated that OPN predicts mortality in patients with pulmonary hypertension (PH), we now evaluated whether OPN also predicts adverse right ventricular (RV) remodelling and dysfunction in PH. METHODS: We prospectively included 71 patients with PH of different etiology in this study. OPN plasma level were determined by ELISA and assessed for correlation with RV dilatation and dysfunction determined by echocardiography. RESULTS: OPN plasma values significantly correlated with RV end-diastolic diameter, Tricuspid Annular Plane Systolic Excursion (TAPSE) and Tricuspid Annular Systolic Velocity (TASV) (r = 0·43, P = 0·0002; r = -0·46, P = 0·0006; r = -0·31, P = 0·02). Furthermore, stratification of our study population according to RV end-diastolic diameter and RV dysfunction revealed that patients with enlarged and functionally impaired RV's display higher OPN levels (956 ng/mL vs. 628 ng/mL, P = 0·0005; 1108 ng/mL vs. 792 ng/mL; P = 0·02). Next, we determined OPN cut-off values for the detection of RV remodelling and dysfunction by receiver operating curve analyses and further stratified these parameters in a multivariate analysis. Here, OPN emerged as an independent predictor of RV dilatation and dysfunction. Finally, we demonstrate synergism of OPN and NT-proBNP in the prediction of RV dilatation and dysfunction by calculation of the Rothman Synergy Index. CONCLUSION: In summary, OPN predicts adverse RV remodelling and dysfunction in PH. Together with our previously published data regarding OPN's value for the prognostication of death in PH, we believe that OPN can improve risk stratification in patients with PH beyond current assessment standards.

Effect of exercise and respiratory training on clinical progression and survival in patients with severe chronic pulmonary hypertension.

BACKGROUND: Even though specific agents for the treatment of patients with pulmonary hypertension (PH) are available, in PH patients, physical capacity and quality of life (QoL) are often restricted and survival is reduced. OBJECTIVES: This study prospectively investigated the long-term effects of respiratory and exercise training in patients with severe chronic PH regarding safety, time to clinical worsening and survival. METHODS: Fifty-eight consecutive patients with severe PH on stable disease-targeted medication received exercise and respiratory training in hospital for 3 weeks and continued at home. They were prospectively followed for 24 ± 12 months. Primary endpoints were time to clinical worsening and survival. Adverse events and changes in the 6-min walking test, QoL, WHO functional class and gas exchange were secondary endpoints and were evaluated at baseline and at weeks 3 and 15. RESULTS: All patients tolerated the exercise training well without severe adverse events. In week 15, 6-min walking test results were significantly improved compared to baseline (by 84 ± 49 m, p < 0.001), as well as QoL scores, WHO functional class (from 2.9 ± 0.5 to 2.6 ± 0.6, p < 0.01), peak oxygen consumption (from 12.5 ± 3.0 to 14.6 ± 3.9 ml/min/kg, p < 0.001), heart rate at rest (from 75 ± 12 to 61 ± 18 beats/min, p < 0.001) and maximal workload (from 65 ± 21 to 80 ± 25 W, p < 0.001). Survival at 1 and 2 years was 100 and 95%, respectively. Fifteen events occurred during the follow-up. CONCLUSION: This study indicates that exercise and respiratory training as add-on to medical treatment may improve exercise capacity and QoL, and that they have a good long-term safety in the described setting.

Quality of Life 3 and 12 Months Following Acute Pulmonary Embolism: Analysis From a Prospective Multicenter Cohort Study.

BACKGROUND: Few data are available on the long-term course and predictors of quality of life (QoL) following acute pulmonary embolism (PE). RESEARCH QUESTION: What are the kinetics and determinants of disease-specific and generic health-related QoL 3 and 12 months following an acute PE? STUDY DESIGN AND METHODS: The Follow-up after Acute Pulmonary Embolism (FOCUS) study prospectively followed up consecutive adult patients with objectively diagnosed PE. Patients were considered for study who completed the Pulmonary Embolism Quality of Life (PEmb-QoL) questionnaire at predefined visits 3 and 12 months following PE. The course of disease-specific QoL as assessed using the PEmb-QoL and the impact of baseline characteristics using multivariable mixed effects linear regression were studied; also assessed was the course of generic QoL as evaluated by using the EuroQoL Group 5-Dimension 5-Level utility index and the EuroQoL Visual Analog Scale. RESULTS: In 620 patients (44% women; median age, 62 years), overall disease-specific QoL improved from 3 to 12 months, with a decrease in the median PEmb-QoL score from 19.4% to 13.0% and a mean individual change of -4.3% (95% CI, -3.2 to -5.5). Female sex, cardiopulmonary disease, and higher BMI were associated with worse QoL at both 3 and 12 months. Over time, the association with BMI became weaker, whereas older age and previous VTE were associated with worsening QoL. Generic QoL also improved: the mean ± SD EuroQoL Group 5-Dimension 5-Level utility index increased from 0.85 ± 0.22 to 0.87 ± 0.20 and the visual analog scale from 72.9 ± 18.8 to 74.4 ± 19.1. INTERPRETATION: In a large cohort of survivors of acute PE, the change of QoL was quantified between months 3 and 12 following diagnosis, and factors independently associated with lower QoL and slower recovery of QoL were identified. This information may facilitate the planning and interpretation of clinical trials assessing QoL and help guide patient management. CLINICAL TRIAL REGISTRATION: German Clinical Trials Registry (Deutsches Register Klinischer Studien: www.drks.de); No.: DRKS00005939.

A purging procedure for pantoprazole and 4-lumen catheters to prevent IV drug incompatibilities.

OBJECTIVE OF THE STUDY: The purpose of this prospective intervention study was to assess the number of patients with Y-site incompatibilities before and after implementation of quality improvement measures to prevent incompatibilities consisting of a focused instruction for pantoprazole as a drug frequently involved in incompatible drug pairs and of a recommendation to use 4-lumen instead of 3-lumen catheters to increase the number of available central infusion lines. SETTING: Cardiovascular intensive care unit where several standard operating procedures (SOPs) dealing with compatibility were already in place. METHOD: In a prospective intervention study, patients' IV medication was assessed for potential incompatibilities using a database containing compatibility information on approximately 60,000 drug pairs. In a first period, routine administration was monitored in 53 consecutive patients (control group). Then, quality improvement measures were implemented recommending a purging procedure before and after bolus administration of pantoprazole as a drug frequently causing incompatibilities in this setting. Additionally, the use of 4-lumen instead of 3-lumen catheters was suggested whenever considered useful by the responsible physicians. The monitoring was repeated during a second period in another 58 patients consecutively admitted to the same unit (intervention group). MAIN OUTCOME MEASURE: Overall number of patients with at least one incompatible drug pair and number of patients receiving incompatible pantoprazole combinations. RESULTS: The number of patients receiving incompatible pantoprazole combinations decreased from 15 of the 15 patients receiving pantoprazole (100.0%) in controls to 9/16 (56.2%) in the intervention group (P < 0.01). The overall number of patients with incompatibilities was not influenced by the intervention with 36/58 (62.1%) compared to controls with 38/53 (71.7%, P = 0.28). The fraction of central lines contributed by four lumen central catheters was larger due to the intervention (80/168 lines, 47.6%) compared to controls (16/184, 8.7%, P < 0.001). Only sporadically there were incompatible combinations of drugs governed by the already existing SOPs. CONCLUSION: In an intensive care setting with good SOP adherence, purging before and after administration decreased the respective incompatibility rate whereas the use of 4-lumen instead of 3- lumen catheters had not the expected benefit on separating drug pairs.

Endothelin receptor antagonist and airway dysfunction in pulmonary arterial hypertension.

BACKGROUND: In idiopathic pulmonary arterial hypertension (IPAH), peripheral airway obstruction is frequent. This is partially attributed to the mediator dysbalance, particularly an excess of endothelin-1 (ET-1), to increased pulmonary vascular and airway tonus and to local inflammation. Bosentan (ET-1 receptor antagonist) improves pulmonary hemodynamics, exercise limitation, and disease severity in IPAH. We hypothesized that bosentan might affect airway obstruction. METHODS: In 32 IPAH-patients (19 female, WHO functional class II (n = 10), III (n = 22); (data presented as mean +/- standard deviation) pulmonary vascular resistance (11 +/- 5 Wood units), lung function, 6 minute walk test (6-MWT; 364 +/- 363.7 (range 179.0-627.0) m), systolic pulmonary artery pressure, sPAP, 79 +/- 19 mmHg), and NT-proBNP serum levels (1427 +/- 2162.7 (range 59.3-10342.0) ng/L) were measured at baseline, after 3 and 12 months of oral bosentan (125 mg twice per day). RESULTS AND DISCUSSION: At baseline, maximal expiratory flow at 50 and 25% vital capacity were reduced to 65 +/- 25 and 45 +/- 24% predicted. Total lung capacity was 95.6 +/- 12.5% predicted and residual volume was 109 +/- 21.4% predicted. During 3 and 12 months of treatment, 6-MWT increased by 32 +/- 19 and 53 +/- 69 m, respectively; p < 0.01; whereas sPAP decreased by 7 +/- 14 and 10 +/- 19 mmHg, respectively; p < 0.05. NT-proBNP serum levels tended to be reduced by 123 +/- 327 and by 529 +/- 1942 ng/L; p = 0.11). There was no difference in expiratory flows or lung volumes during 3 and 12 months. CONCLUSION: This study gives first evidence in IPAH, that during long-term bosentan, improvement of hemodynamics, functional parameters or serum biomarker occur independently from persisting peripheral airway obstruction.

Validity, prognostic value and optimal cutoff of respiratory muscle strength in patients with chronic heart failure changes with beta-blocker treatment.

BACKGROUND: Training studies frequently use maximum inspiratory mouth occlusion pressure (PImax) as a therapeutic target and surrogate marker. For patients on beta-blocker (BBL), prognostic data allowing this extrapolation do not exist. Furthermore, the effects of BBL, mainstay of modern chronic heart failure therapy, on respiratory muscle function remain controversial. Finally, no proper separate cutoff according to treatment exists. DESIGN: Prospective, observational inclusion of patients with stable systolic chronic heart failure and recording of 1 year and all-time mortality for endpoint analysis. METHODS: In 686 patients, 81% men, 494 patients on BBL, PImax was measured along with clinical evaluation. The median follow-up was 50 months (interquartile range: 26-75 months). RESULTS: Patients with or without BBL did not differ significantly for PImax, percentage of predicted PImax or other marker of disease severity. PImax was a significant (hazard ratio: 0.925; 95% confidence interval: 0.879-0.975; chi(2): 8.62) marker of adverse outcome, independent of BBL-status or aetiology. Percentage of predicted PImax was not independent of PImax. The cutoff identified through receiver-operated characteristics for 1-year mortality was 4.14 kPa for patients on BBL and 7.29 kPa for patients not on BBL. When separated accordingly, 1-year mortality was 8.5 versus 21.4%, P=0.02, for patients not on BBL and 4.3 versus 16.2%, P<0.001, for patients on BBL. CONCLUSION: This study fills the gap between trials targeting respiratory muscle on a functional basis and the resultant prognostic information with regard to BBL. BBL lowered the optimal PImax cutoff values for risk stratification without changing the measured values of PImax. This should be considered at inclusion and evaluation of trials and interpretation of exercise parameters.

Exercise and respiratory training improve exercise capacity and quality of life in patients with severe chronic pulmonary hypertension.

BACKGROUND: Pulmonary hypertension (PH) is associated with restricted physical capacity, limited quality of life, and a poor prognosis because of right heart failure. The present study is the first prospective randomized study to evaluate the effects of exercise and respiratory training in patients with severe symptomatic PH. METHODS AND RESULTS: Thirty patients with PH (21 women; mean age, 50+/-13 years; mean pulmonary artery pressure, 50+/-15 mm Hg; mean World Health Organization [WHO] class, 2.9+/-0.5; pulmonary arterial hypertension, n=23; chronic thromboembolic PH, n=7) on stable disease-targeted medication were randomly assigned to a control (n=15) and a primary training (n=15) group. Medication remained unchanged during the study period. Primary end points were the changes from baseline to week 15 in the distance walked in 6 minutes and in scores of the Short Form Health Survey quality-of-life questionnaire. Changes in WHO functional class, Borg scale, and parameters of echocardiography and gas exchange also were assessed. At week 15, patients in the primary and secondary training groups had an improved 6-minute walking distance; the mean difference between the control and the primary training group was 111 m (95% confidence interval, 65 to 139 m; P<0.001). Exercise training was well tolerated and improved scores of quality of life, WHO functional class, peak oxygen consumption, oxygen consumption at the anaerobic threshold, and achieved workload. Systolic pulmonary artery pressure values at rest did not change significantly after 15 weeks of exercise and respiratory training (from 61+/-18 to 54+/-18 mm Hg) within the training group. CONCLUSIONS: This study indicates that respiratory and physical training could be a promising adjunct to medical treatment in severe PH. The effects add to the beneficial results of modern medical treatment.