Validity of the Modified Dyspnea Index for the French-Canadian Population.

BACKGROUND AND PURPOSE: Multidimensional tools could evaluate the dyspnea of patients with chronic lung disease. The aim was to validate the use of the French-Canadian version of the modified dyspnea index (MDI) among patients with pulmonary arterial hypertension (PAH) and interstitial lung disease (ILD). METHODS: The Spearman test analyzed the convergent validation of the MDI with pulmonary function tests (PFTs), New York Heart Association (NYHA) functional classification, the Modified Borg Scale, the Veterans Specific Activity Questionnaire (VSAQ), physical capacity, physical activity (Godin-Shephard Leisure-Time Physical Activity Questionnaire [GSLTPAQ]), and quality of life (SF-12). RESULTS: The MDI had a low correlation with PFT and physical activity; a moderate with physical capacity; a high with the physical dimension (SF-12). CONCLUSION: The results support the convergent validation of the MDI French-Canadian version with PAH or ILD.

Current and future treatments of pulmonary arterial hypertension.

Therapeutic options for pulmonary arterial hypertension (PAH) have increased over the last decades. The advent of pharmacological therapies targeting the prostacyclin, endothelin, and NO pathways has significantly improved outcomes. However, for the vast majority of patients, PAH remains a life-limiting illness with no prospect of cure. PAH is characterised by pulmonary vascular remodelling. Current research focusses on targeting the underlying pathways of aberrant proliferation, migration, and apoptosis. Despite success in preclinical models, using a plethora of novel approaches targeting cellular GPCRs, ion channels, metabolism, epigenetics, growth factor receptors, transcription factors, and inflammation, successful transfer to human disease with positive outcomes in clinical trials is limited. This review provides an overview of novel targets addressed by clinical trials and gives an outlook on novel preclinical perspectives in PAH. 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.

Effect of p53 activation on experimental right ventricular hypertrophy.

The leading cause of death in Pulmonary Arterial Hypertension (PAH) is right ventricular (RV) failure. The tumor suppressor p53 has been associated with left ventricular hypertrophy (LVH) and remodeling but its role in RV hypertrophy (RVH) is unclear. The purpose of this study was to determine whether pharmacological activation of p53 by Quinacrine affects RV remodeling and function in the pulmonary artery banding (PAB) model of compensated RVH in mice. The effects of p53 activation on cellular functions were studied in isolated cardiomyocytes, cardiac fibroblasts and endothelial cells (ECs). The expression of p53 was examined both on human RV tissues from patients with compensated and decompensated RVH and in mouse RV tissues early and late after the PAB. As compared to control human RVs, there was no change in p53 expression in compensated RVH, while a marked upregulation was found in decompensated RVH. Similarly, in comparison to SHAM-operated mice, unaltered RV p53 expression 7 days after PAB, was markedly induced 21 days after the PAB. Quinacrine induced p53 accumulation did not further deteriorate RV function at day 7 after PAB. Quinacrine administration did not increase EC death, neither diminished EC number and capillary density in RV tissues. No major impact on the expression of markers of sarcomere organization, fatty acid and mitochondrial metabolism and respiration was noted in Quinacrine-treated PAB mice. p53 accumulation modulated the expression of Heme Oxygenase 1 (HO-1) and Glucose Transporter (Glut1) in mouse RVs and in adult cardiomyocytes. We conclude that early p53 activation in PAB-induced RVH does not cause substantial detrimental effects on right ventricular remodeling and function.

Molecular imaging of the human pulmonary vascular endothelium in pulmonary hypertension: a phase II safety and proof of principle trial.

PURPOSE: The adrenomedullin receptor is densely expressed in the pulmonary vascular endothelium. PulmoBind, an adrenomedullin receptor ligand, was developed for molecular diagnosis of pulmonary vascular disease. We evaluated the safety of PulmoBind SPECT imaging and its capacity to detect pulmonary vascular disease associated with pulmonary hypertension (PH) in a human phase II study. METHODS: Thirty patients with pulmonary arterial hypertension (PAH, n = 23) or chronic thromboembolic PH (CTEPH, n = 7) in WHO functional class II (n = 26) or III (n = 4) were compared to 15 healthy controls. Lung SPECT was performed after injection of 15 mCi 99mTc-PulmoBind in supine position. Qualitative and semi-quantitative analyses of lung uptake were performed. Reproducibility of repeated testing was evaluated in controls after 1 month. RESULTS: PulmoBind injection was well tolerated without any serious adverse event. Imaging was markedly abnormal in PH with ∼50% of subjects showing moderate to severe heterogeneity of moderate to severe extent. The abnormalities were unevenly distributed between the right and left lungs as well as within each lung. Segmental defects compatible with pulmonary embolism were present in 7/7 subjects with CTEPH and in 2/23 subjects with PAH. There were no segmental defects in controls. The PulmoBind activity distribution index, a parameter indicative of heterogeneity, was elevated in PH (65% ± 28%) vs. controls (41% ± 13%, p = 0.0003). In the only subject with vasodilator-responsive idiopathic PAH, PulmoBind lung SPECT was completely normal. Repeated testing 1 month later in healthy controls was well tolerated and showed no significant variability of PulmoBind distribution. CONCLUSIONS: In this phase II study, molecular SPECT imaging of the pulmonary vascular endothelium using 99mTc-PulmoBind was safe. PulmoBind showed potential to detect both pulmonary embolism and abnormalities indicative of pulmonary vascular disease in PAH. Phase III studies with this novel tracer and direct comparisons to lung perfusion agents such as labeled macro-aggregates of albumin are needed. CLINICAL TRIAL: ClinicalTrials.gov, NCT02216279.

High Oxygen Delivery to Preserve Exercise Capacity in Patients with Idiopathic Pulmonary Fibrosis Treated with Nintedanib. Methodology of the HOPE-IPF Study.

RATIONALE: Pulmonary rehabilitation improves dyspnea and exercise capacity in idiopathic pulmonary fibrosis (IPF); however, it is unknown whether breathing high amounts of oxygen during exercise training leads to further benefits. OBJECTIVES: Herein, we describe the design of the High Oxygen Delivery to Preserve Exercise Capacity in IPF Patients Treated with Nintedanib study (the HOPE-IPF study). The primary objective of this study is to determine the physiological and perceptual impact of breathing high levels of oxygen during exercise training in patients with IPF who are receiving antifibrotic therapy. METHODS: HOPE-IPF is a two-arm double-blind multicenter randomized placebo-controlled trial of 88 patients with IPF treated with nintedanib. Patients will undergo 8 weeks of three times weekly aerobic cycle exercise training, breathing a hyperoxic gas mixture with a constant fraction of 60% inhaled oxygen, or breathing up to 40% oxygen as required to maintain an oxygen saturation level of at least 88%. MEASUREMENTS AND MAIN RESULTS: End points will be assessed at baseline, postintervention (Week 8), and follow-up (Week 26). The primary analysis will compare the between-group baseline with post-training change in endurance time during constant work rate cycle exercise tests. Additional analyses will evaluate the impact of training with high oxygen delivery on 6-minute walk distance, dyspnea, physical activity, and quality of life. CONCLUSIONS: The HOPE-IPF study will lead to a comprehensive understanding of IPF exercise physiology, with the potential to change clinical practice by indicating the need for increased delivery of supplemental oxygen during pulmonary rehabilitation in patients with IPF. Clinical trial registered with www.clinicaltrials.gov (NCT02551068).

[Right heart adaptation to pulmonary arterial hypertension: physiology and pathobiology]. / Pulmoner arter hipertansiyonuna sag kalp adaptasyonu: Fizyoloji ve patobiyoloji.

Survival in patients with pulmonary arterial hypertension (PAH) is closely related to right ventricular (RV) function. Although pulmonary load is an important determinant of RV systolic function in PAH, there remains a significant variability in RV adaptation to pulmonary hypertension. In this report, the authors discuss the emerging concepts of right heart pathobiology in PAH. More specifically, the discussion focuses on the following questions. 1) How is right heart failure syndrome best defined? 2) What are the uderlying molecular mechanisms of the failing right ventricle in PAH? 3) How are RV contractility and function and their prognostic implications best assessed? 4) What is the role of targeted RV therapy? Throughout the report, the authors highlight differences between right and left heart failure and outline key areas of future investigation. (J Am Coll Cardiol 2013;62:D22-33) a 2013 by the American College of Cardiology Foundation).

Right heart adaptation to pulmonary arterial hypertension: physiology and pathobiology.

Survival in patients with pulmonary arterial hypertension (PAH) is closely related to right ventricular (RV) function. Although pulmonary load is an important determinant of RV systolic function in PAH, there remains a significant variability in RV adaptation to pulmonary hypertension. In this report, the authors discuss the emerging concepts of right heart pathobiology in PAH. More specifically, the discussion focuses on the following questions. 1) How is right heart failure syndrome best defined? 2) What are the underlying molecular mechanisms of the failing right ventricle in PAH? 3) How are RV contractility and function and their prognostic implications best assessed? 4) What is the role of targeted RV therapy? Throughout the report, the authors highlight differences between right and left heart failure and outline key areas of future investigation.

Adjustments in cardiorespiratory function after pneumonectomy: results of the pneumonectomy project.

OBJECTIVE: To assess lung function, gas exchange, exercise capacity, and right-sided heart hemodynamics, including pulmonary artery pressure, in patients long term after pneumonectomy. METHODS: Among 523 consecutive patients who underwent pneumonectomy for lung cancer between January 1992 and September 2001, 117 were alive in 2006 and 100 were included in the study. During a 1-day period, each patient had complete medical history, chest radiographs, pulmonary function studies, resting arterial blood gas analysis, 6-minute walk test, and Doppler echocardiography. RESULTS: Most patients (N = 73) had no or only minimal dyspnea. On the basis of predicted values, functional losses in forced expiratory volume in 1 second and forced vital capacity were 38% ± 18% and 31% ± 24%, respectively, and carbon monoxide diffusing capacity decreased by 31% ± 18%. There was a significant correlation between preoperative and postoperative forced expiratory volume in 1 second (P < .01), and more hyperinflation was associated with better lung function (P < .01 for forced expiratory volume in 1 second). Gas exchange was normal at rest (Pao(2) = 88 ± 10 mm Hg; Paco(2) = 42 ± 3 mm Hg), and exercise tolerance (6-minute walk) was also normal (83% ± 17% of predicted values). Thirty-two patients had some degree of pulmonary hypertension, but in most of those cases, it was mild to moderate (mean systolic pressure of 36 ± 9 mm Hg) and not associated with significant differences in lung function (P = .57 for forced expiratory volume in 1 second), gas exchange (P = .08), and exercise capacity (P = .66). CONCLUSIONS: These findings indicate that despite worsening of lung function by approximately 30% after pneumonectomy, most patients can adjust to living with only 1 lung. Pulmonary hypertension is uncommon and in most cases only mild to moderate.

Ipsilateral diaphragmatic motion and lung function in long-term pneumonectomy patients.

BACKGROUND: The physiologic advantages of preserving phrenic nerve integrity and normal diaphragmatic motion (DM) during the course of pnemonectomy are incompletely understood. This study was conducted to investigate potential benefits of this strategy on postoperative lung function. METHODS: Among 523 consecutive patients who underwent pneumonectomy for lung cancer between January 1992 and September 2001, 117 were alive at the time of study (March to December 2006) and thus had 5 years' minimum follow-up. Of those, 17 were excluded and 12 could not have magnetic resonance imaging (MRI), leaving 88 patients available for study. Diaphragmatic motion was assessed by MRI during deep breathing, and patients were classified as having normal and synchronous diaphragmatic motion (n = 44) or abnormal diaphragmatic motion (immobile or paradoxical, n = 44). These findings were correlated with expiratory volume measurements, gas exchange (arterial blood gases), and exercise tolerance (6-minute walk test). RESULTS: The mean follow-up time was 9.3 years. Patients with abnormal DM were younger than patients with normal DM and were more likely to have had a right or an extended pneumonectomy (p < 0.01). Despite comparable preoperative lung function, patients with abnormal DM had significantly worse postoperative lung volumes (forced expiratory voume in 1 second, forced vital capacity, lung diffusion capacity for carbon monoxide; p < 0.01) and exercise capacity (6-minute walk test, percent predicted, p < 0.05) than patients with normal DM. CONCLUSIONS: Because the long-term effects of a paralyzed hemidiaphragm in pneumonectomy patients are characterized by significant alterations in lung function, all surgeons doing this type of work should take every precaution to avoid technical errors that could lead to phrenic nerve injury or interruption.