Association of amino acids and parameters of bone metabolism with endothelial dysfunction and vasculopathic changes in limited systemic sclerosis

ObjectivesPathways contributing to endothelial dysfunction in patients with limited cutaneous systemic sclerosis (lcSSc) are largely unknown. The aim of this study was to investigate potential associations of amino acids and parameters of bone metabolism with endothelial dysfunction and vasculopathy-related changes in patients with lcSSc and early-stage vasculopathy.MethodsAmino acids, calciotropic parameters, including 25-hydroxyvitamin D and parathyroid hormone (PTH), and bone turnover parameters, including osteocalcin and N-terminal peptide of procollagen-3 (P3NP), were measured in 38 lcSSc patients and 38 controls. Endothelial dysfunction was assessed by biochemical parameters, pulse-wave analysis, flow-mediated and nitroglycerine-mediated dilation. Additionally, vasculopathy-related and SSc-specific clinical changes including capillaroscopic, skin, renal, pulmonary, gastrointestinal and periodontal parameters were recorded.ResultsNo significant differences in amino acids, calciotropic and bone turnover parameters were observed between lcSSc patients and controls. In patients with lcSSc, several significant correlations were found between selected amino acids, parameters of endothelial dysfunction, vasculopathy-related and SSc-specific clinical changes (all with p < 0.05). In addition, significant correlations were observed between PTH and 25-hydroxyvitamin D with homoarginine, and between osteocalcin, PTH and P3NP with modified Rodnan skin score and selected periodontal parameters (all with p < 0.05). Vitamin D deficiency defined as 25-hydroxyvitamin D < 20 ng/ml was associated with the presence of puffy finger (p = 0.046) and early pattern (p = 0.040).ConclusionSelected amino acids may affect endothelial function and may be associated to vasculopathy-related and clinical changes in lcSSc patients, while the association with parameters of bone metabolism seems to be minor

Endotyping COPD: hypoxia-inducible factor-2 as a molecular "switch" between the vascular and airway phenotypes?

COPD is a heterogeneous disease with multiple clinical phenotypes. COPD endotypes can be determined by different expressions of hypoxia-inducible factors (HIFs), which, in combination with individual susceptibility and environmental factors, may cause predominant airway or vascular changes in the lung. The pulmonary vascular phenotype is relatively rare among COPD patients and characterised by out-of-proportion pulmonary hypertension (PH) and low diffusing capacity of the lung for carbon monoxide, but only mild-to-moderate airway obstruction. Its histologic feature, severe remodelling of the small pulmonary arteries, can be mediated by HIF-2 overexpression in experimental PH models. HIF-2 is not only involved in the vascular remodelling but also in the parenchyma destruction. Endothelial cells from human emphysema lungs express reduced HIF-2α levels, and the deletion of pulmonary endothelial Hif-2α leads to emphysema in mice. This means that both upregulation and downregulation of HIF-2 have adverse effects and that HIF-2 may represent a molecular "switch" between the development of the vascular and airway phenotypes in COPD. The mechanisms of HIF-2 dysregulation in the lung are only partly understood. HIF-2 levels may be controlled by NAD(P)H oxidases via iron- and redox-dependent mechanisms. A better understanding of these mechanisms may lead to the development of new therapeutic targets

ERS International Congress, Madrid, 2019: highlights from the Pulmonary Vascular Diseases Assembly.

The 2019 European Respiratory Society (ERS) International Congress, held in Madrid, Spain, had exciting sessions regarding the field of pulmonary vascular disease. The symposia related to the new ERS/European Society of Cardiology (ESC) Guidelines for the diagnosis and management of acute pulmonary embolism were well received, as were sessions on pulmonary hypertension related to lung disease, demonstrating the concept of pulmonary hypertension not being the rarity that it was previously thought to be. The use of risk stratification in relation to pulmonary arterial hypertension (PAH) was heavily featured and the scientific sessions informing the respiratory community of potential biomarkers and targets for future therapies were thought-provoking. This article discusses highlights of the 2019 pulmonary vascular disease sessions as a summary of current knowledge and practice. We have summarised the key points from the sessions pertaining to the new ERS/ESC Guidelines for the management of acute pulmonary embolism. We have also focused on prognostic factors and potential therapies in pulmonary hypertension related to interstitial lung disease. Relating to PAH, we have reviewed the symposia on risk stratification, along with the use of noninvasive measures and the sessions relating to biomarkers in PAH.status: Published onlin

DataSheet1_Apelin-17 to diagnose idiopathic pulmonary arterial hypertension: A biomarker study.pdf

Background: NT-proBNP and GDF-15 are established blood-derived biomarkers for risk assessment in pulmonary hypertension (PH), despite limited sensitivity and specificity. Apelin has a crucial function in endothelial homeostasis, thus it might represent a new biomarker for PH. However, there are numerous circulating apelin isoforms, and their potential role in this setting is unknown. This study evaluated different apelin isoforms in PH patients and prospectively evaluated the role of apelin-17 in comparison with NT-proBNP and GDF-15 as diagnostic marker in idiopathic pulmonary arterial hypertension (IPAH).Methods: Based on our pilot study, we performed a power calculation for apelin-13, apelin-17, apelin-36, as predictor of IPAH vs healthy controls. Apelin-17 provided the best discriminatory power, and accordingly, we enrolled n = 31 patients with IPAH and n = 31 matched healthy controls in a prospective study. NT-proBNP and GDF-15 was determined in all patients. ROC curve analysis was performed to assess the diagnostic value of the markers and their combinations.Results: Apelin-17, NT-proBNP, and GDF-15 were significantly elevated in IPAH patients as compared to controls (p 1,480 pg/ml (AUC 0.86, 95%CI:0.76–0.95) as compared to GDF-15 (sensitivity 86%; specificity 72%, AUC 0.81 (95%CI:0.7–0.92)) and NT-proBNP (sensitivity 86%; specificity 72% (AUC 0.85, 95%CI:0.75–0.95)). Combinations of these markers could be used to increase either specificity or sensitivity.Conclusion: Apelin-17 appears to be suitable blood derived diagnostic marker for idiopathic pulmonary arterial hypertension.</p

Pulmonale Hypertonie assoziiert mit Lungenerkrankungen

Nicht selten sind Lungenerkrankungen und Hypoventilationssyndrome mit einer pulmonalen Hypertonie (PH) assoziiert. In den meisten Fällen liegt eine nicht schwere PH vor. Diese ist hämodynamisch definiert durch einen pulmonalarteriellen Mitteldruck (PAPm) > 20 mmHg, einen pulmonalarteriellen Verschlussdruck (PAWP) ≤ 15 mmHg und einen pulmonal-vaskulären Widerstand von ≤ 5 Wood-Einheiten (WU). Sowohl die nicht schwere (PVR ≤ 5 WU) als auch deutlich ausgeprägter die schwere PH (PVR > 5 WU) sind prognostisch ungünstig. Bei Verdacht auf eine PH wird empfohlen, primär zu prüfen, ob Risikofaktoren für eine pulmonalarterielle Hypertonie (PAH, Gruppe 1 PH) oder eine chronisch thromboembolische pulmonale Hypertonie (CTEPH, Gruppe 4 PH) vorliegen. Falls Risikofaktoren vorliegen oder bei Lungenkranken der Verdacht auf eine schwere PH besteht, wird eine zeitnahe Vorstellung der Patient*innen in einer PH-Ambulanz empfohlen. Bei Patient*innen mit einer schweren PH assoziiert mit Lungenerkrankungen wird eine personalisierte, individuelle Therapie – möglichst im Rahmen von Therapiestudien – empfohlen. Aktuell sollte bei COPD-Patient*innen nur ein Therapieversuch erwogen werden, wenn die assoziierte PH schwergradig und ein „pulmonalvaskulärer“ Phänotyp (schwere präkapilläre PH, aber typischerweise nur milde bis moderate Atemwegsobstruktion, keine oder milde Hyperkapnie und DLCO < 45 % vom Soll) vorliegt. Bei schwerer PH assoziiert mit einer interstitiellen Lungenerkrankung können entsprechend individueller Abwägung Phosphodiesterase-5-Inhibitoren erwogen werden. Inhaliertes Treprostinil kommt bei diesen Patient*innen auch bei nicht schwerer PH in Betracht. Lung diseases and hypoventilation syndromes are often associated with pulmonary hypertension (PH). In most cases, PH is not severe. This is defined hemodynamically by a mean pulmonary arterial pressure (PAPm) > 20 mmHg, a pulmonary arterial wedge pressure (PAWP) ≤ 15 mmHg and a pulmonary vascular resistance of ≤ 5 Wood units (WU). Both the non-severe (PVR ≤ 5 WU) and much more the severe PH (PVR > 5 WU) have an unfavorable prognosis. If PH is suspected, it is recommended to primarily check whether risk factors for pulmonary arterial hypertension (PAH, group 1 PH) or chronic thromboembolic pulmonary hypertension (CTEPH, group 4 PH) are present. If risk factors are present or there is a suspicion of severe PH in lung patients, it is recommended that the patient should be presented to a PH outpatient clinic promptly. For patients with severe PH associated with lung diseases, personalized, individual therapy is recommended – if possible within the framework of therapy studies. Currently, a therapy attempt with PH specific drugs should only be considered in COPD patients if the associated PH is severe and a “pulmonary vascular” phenotype (severe precapillary PH, but typically only mild to moderate airway obstruction, no or mild hypercapnia and DLCO < 45 % of predicted value) is present. In patients with severe PH associated with interstitial lung disease phosphodiesterase-5-inhibitors may be considered in individual cases. Inhaled treprostinil may be considered also in non-severe PH in this patient population

Use of ECG and Other Simple Non-Invasive Tools to Assess Pulmonary Hypertension - Fig 4

<p><b>A-D.</b> Associations between the simple non-invasive parameters and mean pulmonary arterial pressure–data based on the analysis of the prospective cohort. The red dot represents the patient with pulmonary hypertension who was missed by the algorithm. (mPAP: mean pulmonary arterial pressure, NTproBNP: N-terminal pro brain natriuretic peptide, art SO2: arterial oxygen saturation).</p

Algorithm to identify and to exclude pulmonary hypertension by simple non-invasive tools–data based on the analysis of the prospective cohort.

<p>(RAD: right axis deviation, PAP: mean pulmonary arterial pressure, WHO: WHO functional class, NTproBNP: N-terminal pro brain natriuretic peptide, art SO2: arterial oxygen saturation).</p

Risk for PH according to multivariate regression analysis.

<p>Risk for PH according to multivariate regression analysis.</p

Association between changes in the electrical axis and changes in mean pulmonary arterial pressure in patients where two right heart catheterizations were performed at different time points.

<p>(mPAP: mean pulmonary arterial pressure).</p