Pulmonary arterial remodeling induced by a Th2 immune response

Pulmonary arterial remodeling characterized by increased vascular smooth muscle density is a common lesion seen in pulmonary arterial hypertension (PAH), a deadly condition. Clinical correlation studies have suggested an immune pathogenesis of pulmonary arterial remodeling, but experimental proof has been lacking. We show that immunization and prolonged intermittent challenge via the airways with either of two different soluble antigens induced severe muscularization in small- to medium-sized pulmonary arteries. Depletion of CD4+ T cells, antigen-specific T helper type 2 (Th2) response, or the pathogenic Th2 cytokine interleukin 13 significantly ameliorated pulmonary arterial muscularization. The severity of pulmonary arterial muscularization was associated with increased numbers of epithelial cells and macrophages that expressed a smooth muscle cell mitogen, resistin-like molecule α, but surprisingly, there was no correlation with pulmonary hypertension. Our data are the first to provide experimental proof that the adaptive immune response to a soluble antigen is sufficient to cause severe pulmonary arterial muscularization, and support the clinical observations in pediatric patients and in companion animals that muscularization represents one of several injurious events to the pulmonary artery that may collectively contribute to PAH

Genetics and genomics of pulmonary arterial hypertension

Major discoveries have been obtained within the last decade in the field of hereditary predisposition to pulmonary arterial hypertension (PAH). Among them, the identification of bone morphogenetic protein receptor type 2 (BMPR2) as the major predisposing gene and activin A receptor type II-like kinase-1 (ACVRL1, also known as ALK1) as the major gene when PAH is associated with hereditary hemorrhagic telangiectasia. The mutation detection rate for the known genes is approximately 75 in familial PAH, but the mutation shortfall remains unexplained even after careful molecular investigation of these genes. To identify additional genetic variants predisposing to PAH, investigators harnessed the power of next-generation sequencing to successfully identify additional genes that will be described in this report. Furthermore, common genetic predisposing factors for PAH can be identified by genome-wide association studies and are detailed in this paper. The careful study of families and routine genetic diagnosis facilitated natural history studies based on large registries of PAH patients to be set up in different countries. These longitudinal or cross-sectional studies permitted the clinical characterization of PAH in mutation carriers to be accurately described. The availability of molecular genetic diagnosis has opened up a new field for patient care, including genetic counseling for a severe disease, taking into account that the major predisposing gene has a highly variable penetrance between families. Molecular information can be drawn from the genomic study of affected tissues in PAH, in particular, pulmonary vascular tissues and cells, to gain insight into the mechanisms leading to the development of the disease. High-throughput genomic techniques, on the basis of next-generation sequencing, now allow the accurate quantification and analysis of ribonucleic acid, species, including micro-ribonucleic acids, and allow for a genome-wide investigation of epigenetic or regulatory mechanisms, which include deoxyribonucleic acid methylation, histone methylation, and acetylation, or transcription factor binding. © 2013 by the American College of Cardiology Foundation. Published by Elsevier Inc

The patient tells it! The importance of patient's quality of life perception in pulmonary arterial hypertension risk assessment

Everyone wants quality of life (QoL), regardless whether a person is healthy or diseased. However, QoL means something different for every individual. QoL is not only influenced by the individual's preferences, wishes and expectations towards life, but also by the time of living, geographical, socioeconomic and political environment and, of course, the health state, which all contribute to the individual's resources to live with a high quality in happiness and satisfaction. The World Health Organization defines QoL as the individual's perception of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards and concerns [1]. Due to this complexity and subjectively differently weighted factors, and also the fact that different disciplines define QoL differently, measurement of QoL is challenging in health and disease [2]

Rehabilitation in patients with pulmonary arterial hypertension

Exertional dyspnoea is a leading symptom in patients with pulmonary arterial hypertension (PAH). Patients suffering from PAH report poor quality of life, have skeletal muscle dysfunction and in the absence of advanced medical therapy deteriorate progressively due to right heart failure which can lead to death. For decades, patients with PAH were advised to avoid exercise in fear of exacerbated right heart failure. Recently, it has been shown that a highly supervised rehabilitation programme in expert centres leads to significant improvements in symptoms, quality of life, exercise capacity and may even enhance haemodynamics in selected stable patients treated with advanced regimens of PAH-targeted drugs. As a consequence of these promising results, pulmonary rehabilitation performed in an expert centre has been included in recent guidelines. The underlying mechanisms are not completely understood, but positive effects can be measured in different organ systems such as skeletal muscles, the cardiopulmonary system and immune system (inflammation), and also on the psychological level. Thus, improvements in 6-minute walking distance (6MWD), peak oxygen uptake (VO2 peak), muscle strength and muscle endurance, as well as physical and mental quality of life scores (SF-36 questionnaire) have been shown. Different training protocols have been used. Essential are qualified patient selection in expert centres, a low workload endurance and dumbbell (weight lifting) training avoiding strenuous exercise and exhaustion, thorough patient education and close supervision by experts especially during the first weeks. Adverse events may occur (e.g., pre-/syncope, arrhythmia, respiratory infections). PAH patients tend to overestimate their physical capacity, not perceiving their own limits properly, which makes education and expert advice even more important as exercise training can also worsen the right heart failure. Therefore, a core issue of the multidisciplinary rehabilitation is the close cooperation between the experienced rehabilitation clinic offering a specialised programme for PAH patients and the PAH expert centre, which takes care of the patient and is thoroughly involved in the training programme. Further multicentre international randomised trials are needed to evaluate whether this specialised programme is feasible within different healthcare systems and to assess long term effects and survival

Circulating MicroRNA Markers for Pulmonary Hypertension in Supervised Exercise Intervention and Nightly Oxygen Intervention

Rationale: Therapeutic exercise training has been shown to significantly improve pulmonary hypertension (PH), including 6-min walking distance and right heart function. Supplemental nightly oxygen also has therapeutic effects. A biomarker tool that could query critical gene networks would aid in understanding the molecular effects of the interventions.Methods: Paired bio-banked serum (n = 31) or plasma (n = 21) samples from the exercise or oxygen intervention studies, respectively, and bio-banked plasma samples (n = 20) from high altitude induced PH in cattle were tested. MicroRNAs (miRNAs) markers were chosen for study because they regulate gene expression, control the function of specific gene networks, and are conserved across species.Results: miRNAs that control muscle (miR-22-3p, miR-21-5p) or erythrocyte function (miR-451a) were chosen based on pilot experiments. Plasma samples from cattle that developed PH in high altitude had significantly higher miR-22-3p/(relative to) miR-451a values when compared to control cattle tolerant to high altitude. Measurements of miR-22-3p/miR-451a values in serum from patients receiving exercise training showed that the values were significantly decreased in 74.2% of the samples following intervention and significantly increased in the remainder (25.8%). In samples obtained after exercise intervention, a higher composite miRNA value, made of miR-22-3p and miR-21-5p/miR-451a and spike RNA, was significantly decreased in 65% of the samples and significantly increased in 35% of the samples. In the study of nightly oxygen intervention, when comparing placebo and oxygen, half of the samples showed a significant down-ward change and the other half a significant up-ward change measuring either of the miRNA markers. Samples that had a downward change in the miRNA marker following either intervention originated from patients who had a significantly higher 6-min-walking-distance at baseline (mean difference of 90 m or 80 m following exercise or oxygen intervention, respectively) when compared to samples that had an upward change in the miRNA marker.Conclusion: These natural animal model and human sample studies further highlight the utility of miRNAs as future biomarkers. The different directional changes of the miRNA markers following supervised exercise training or nightly oxygen intervention could indicate different PAH molecular pathomechanisms (endotypes). Further studies are needed to test this idea

Image_1_Circulating MicroRNA Markers for Pulmonary Hypertension in Supervised Exercise Intervention and Nightly Oxygen Intervention.JPEG

<p>Rationale: Therapeutic exercise training has been shown to significantly improve pulmonary hypertension (PH), including 6-min walking distance and right heart function. Supplemental nightly oxygen also has therapeutic effects. A biomarker tool that could query critical gene networks would aid in understanding the molecular effects of the interventions.</p><p>Methods: Paired bio-banked serum (n = 31) or plasma (n = 21) samples from the exercise or oxygen intervention studies, respectively, and bio-banked plasma samples (n = 20) from high altitude induced PH in cattle were tested. MicroRNAs (miRNAs) markers were chosen for study because they regulate gene expression, control the function of specific gene networks, and are conserved across species.</p><p>Results: miRNAs that control muscle (miR-22-3p, miR-21-5p) or erythrocyte function (miR-451a) were chosen based on pilot experiments. Plasma samples from cattle that developed PH in high altitude had significantly higher miR-22-3p/(relative to) miR-451a values when compared to control cattle tolerant to high altitude. Measurements of miR-22-3p/miR-451a values in serum from patients receiving exercise training showed that the values were significantly decreased in 74.2% of the samples following intervention and significantly increased in the remainder (25.8%). In samples obtained after exercise intervention, a higher composite miRNA value, made of miR-22-3p and miR-21-5p/miR-451a and spike RNA, was significantly decreased in 65% of the samples and significantly increased in 35% of the samples. In the study of nightly oxygen intervention, when comparing placebo and oxygen, half of the samples showed a significant down-ward change and the other half a significant up-ward change measuring either of the miRNA markers. Samples that had a downward change in the miRNA marker following either intervention originated from patients who had a significantly higher 6-min-walking-distance at baseline (mean difference of 90 m or 80 m following exercise or oxygen intervention, respectively) when compared to samples that had an upward change in the miRNA marker.</p><p>Conclusion: These natural animal model and human sample studies further highlight the utility of miRNAs as future biomarkers. The different directional changes of the miRNA markers following supervised exercise training or nightly oxygen intervention could indicate different PAH molecular pathomechanisms (endotypes). Further studies are needed to test this idea.</p

Die neue Definition und Klassifikation der pulmonalen Hypertonie

In der Neufassung der ESC/ERS-Leitlinien 2022 zur pulmonalen Hypertonie (PH) kam es zu wesentlichen Änderungen in der hämodynamischen Definition sowie zu einer weiteren Verfeinerung in der Klassifikation des Lungenhochdrucks.Als bedeutende Neuerung gilt die Einführung eines neuen Grenzwerts des mittleren pulmonalarteriellen Druckes (mPAP) für die Definition der PH. Eine PH wird nun durch eine Erhöhung des mPAP > 20 mmHg, ermittelt durch Rechtsherzkatheter, definiert. Des Weiteren wurde der Grenzwert des pulmonalen Gefäßwiderstands (PVR) zur Definition einer präkapillären PH verringert. Eine präkapilläre PH liegt nun bereits ab einem PVR > 2 WU und einem pulmonalarteriellen Verschlussdruck (PAWP) ≤ 15 mmHg vor. Die zunehmende Evidenz für die klinische Relevanz der pulmonalen Belastungshämodynamik führte schließlich auch zur Wiederaufnahme des Belastungs-PH-Terminus in die Leitlinien. Die Belastungs-PH wird als Verhältnis zum Herzzeitvolumen (CO) über einen pathologischen mPAP/CO-Slope > 3 mmHg/L/min definiert. In der Klassifikation werden weiterhin fünf Gruppen unterschieden: die pulmonalarterielle Hypertonie (Gruppe 1), PH assoziiert mit Linksherzerkrankungen (Gruppe 2), PH assoziiert mit Lungenerkrankungen und/oder Hypoxie (Gruppe 3), PH assoziiert mit pulmonalarterieller Obstruktion (Gruppe 4) und PH mit unklaren und/oder multifaktoriellen Mechanismen (Gruppe 5).In der folgenden Leitlinienübersetzung soll auf die Neuerungen eingegangen, deren Hintergründe näher beleuchtet und mögliche Schwierigkeiten in ihrer klinischen Anwendung diskutiert werden