63 Peripheral endothelial function in patients affected by pulmonary hypertension. Relationship between endothelial function, haemodynamic parameters, and therapy response

Abstract Aims Pulmonary hypertension (PH) is defined as a mean pulmonary arterial pressure (mPAP) of 25 mmHg or greater at rest, confirmed by right heart catheterization (RHC). The World Health Organization has classified PH into five clinical subgroups. Pulmonary arterial hypertension (PAH) (group 1) is characterized by loss and obstructive remodelling of the pulmonary vascular bed. These patients are characterized haemodynamically by the presence of precapillary PH, defined as an mPAP of 25 mm Hg or greater, pulmonary artery wedge pressure (PAWP) of 15 mm Hg or less, and pulmonary vascular resistance (PVR) of three Wood units (WU) or greater. Pulmonary hypertension due to left-sided heart disease (LHD) (PH-LHD) (group 2) occurs in HF. Patients with PH-LHD usually have isolated postcapillary PH (PAWP >15 mm Hg and PVR <3 WU), although some of them have combined postcapillary and precapillary PH (PAWP >15 mm Hg and PVR ≥3 WU). PH due to chronic lung disease (CLD) (PH-CLD) and/or hypoxia (group 3) can occur in many lung diseases. These patients have precapillary PH. Chronic thromboembolic PH (CTEPH) (group 4) is characterized by obstruction of the pulmonary vasculature by organized thromboembolic material and vascular remodelling, resulting from prior pulmonary embolism. Patients with unclear and/or multifactorial mechanisms are listed as group 5. Specific pulmonary vasodilators are approved only in PAH patients. While research was predominantly focused on pulmonary vasculature, little is known about the peripheral endothelial damage in different vascular beds in PH patients. To evaluate the relationship between the peripheral endothelial function and the haemodynamic parameters, in order to provide a non-invasive method for the indirect evaluation of mean pulmonary pressure and vascular resistance, to predict if the PH is a precapillary or postcapillary, to select more accurately the patients who should undergo RHC. Moreover, we investigate if there is a possible correlation between endothelial dysfunction and response to specific PH therapies. Methods and results Patients with suspected PH, based on symptoms, medical history, and clinics will undergo physical examination, ECG, echocardiography, and RHC. In all patients, endothelial function was assessed by FMD. Medical history, heart rate, systolic blood pressure, body mass index, WHO functional class, and medications were recorded. All patients underwent blood analysis, erythrocyte sedimentation rate (ERS), high sensitivity C-reactive protein (CRP), and NT-proBNP levels were assayed. Increased peripheral endothelial dysfunction in patients with precapillary PH, with a linear correlation between endothelium dysfunction and increased PVR at the right catheterization. To differentiate pre and post capillary PH forms by cut-off values of the FMD. The degree of endothelial dysfunction could be a marker of therapy response. Sequential combination therapy in the pre-capillary PH forms could be the one with a worst endothelial response than up-front combination therapy.

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Pentaerythritol Tetranitrate In Vivo Treatment Improves Oxidative Stress and Vascular Dysfunction by Suppression of Endothelin-1 Signaling in Monocrotaline-Induced Pulmonary Hypertension

Oxidative Medicine and Cellular Longevity ◽

10.1155/2017/4353462 ◽

2017 ◽

Vol 2017 ◽

pp. 1-13 ◽

Cited By ~ 9

Author(s):

Sebastian Steven ◽

Matthias Oelze ◽

Moritz Brandt ◽

Elisabeth Ullmann ◽

Swenja Kröller-Schön ◽

...

Keyword(s):

Oxidative Stress ◽

Pulmonary Hypertension ◽

Endothelial Dysfunction ◽

Endothelial Function ◽

Whole Blood ◽

Pulmonary Arteries ◽

Vascular Wall ◽

Pentaerythritol Tetranitrate ◽

Endothelin 1 ◽

Pulmonary Arterial

Objective. Oxidative stress and endothelial dysfunction contribute to pulmonary arterial hypertension (PAH). The role of the nitrovasodilator pentaerythritol tetranitrate (PETN) on endothelial function and oxidative stress in PAH has not yet been defined.Methods and Results. PAH was induced by monocrotaline (MCT, i.v.) in Wistar rats. Low (30 mg/kg; MCT30), middle (40 mg/kg; MCT40), or high (60 mg/kg; MCT60) dose of MCT for 14, 28, and 42 d was used. MCT induced endothelial dysfunction, pulmonary vascular wall thickening, and fibrosis, as well as protein tyrosine nitration. Pulmonary arterial pressure and heart/body and lung/body weight ratio were increased in MCT40 rats (28 d) and reduced by oral PETN (10 mg/kg, 24 d) therapy. Oxidative stress in the vascular wall, in the heart, and in whole blood as well as vascular endothelin-1 signaling was increased in MCT40-treated rats and normalized by PETN therapy, likely by upregulation of heme oxygenase-1 (HO-1). PETN therapy improved endothelium-dependent relaxation in pulmonary arteries and inhibited endothelin-1-induced oxidative burst in whole blood and the expression of adhesion molecule (ICAM-1) in endothelial cells.Conclusion. MCT-induced PAH impairs endothelial function (aorta and pulmonary arteries) and increases oxidative stress whereas PETN markedly attenuates these adverse effects. Thus, PETN therapy improves pulmonary hypertension beyond its known cardiac preload reducing ability.

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Pulmonary hypertension

European Respiratory Review ◽

10.1183/16000617.0096-2015 ◽

2016 ◽

Vol 25 (139) ◽

pp. 4-11 ◽

Cited By ~ 14

Author(s):

Anton Vonk Noordegraaf ◽

Joanne A. Groeneveldt ◽

Harm Jan Bogaard

Keyword(s):

Pulmonary Hypertension ◽

Pulmonary Arterial Hypertension ◽

Combination Therapy ◽

Review Article ◽

Pulmonary Vasculature ◽

Distant Future ◽

European Guidelines ◽

Enormous Amount ◽

Pulmonary Arterial ◽

The Right

In 2015, more than 800 papers were published in the field of pulmonary hypertension. A Clinical Year in Review article cannot possibly incorporate all this work and needs to be selective. The recently published European guidelines for the diagnosis and treatment of pulmonary hypertension contain an inclusive summary of all published clinical studies conducted until very recently. Here, we provide an overview of papers published after the finalisation of the guideline. In addition, we summarise recent advances in pulmonary vasculature science. The selection we made from the enormous amount of published work undoubtedly reflects our personal views and may not include all papers with a significant impact in the near or more distant future. The focus of this paper is on the diagnosis of pulmonary arterial hypertension, understanding the success of combination therapy on the right ventricle and scientific breakthroughs.

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Pulmonary Vascular Versus Right Ventricular Function Changes During Targeted Therapies of Pulmonary Hypertension – An Argument for Upfront Combination Therapy?

European Cardiology Review ◽

10.15420/ecr.2012.8.3.209 ◽

2012 ◽

Vol 8 (3) ◽

pp. 209

Author(s):

Wouter Jacobs ◽

Anton Vonk-Noordegraaf ◽

◽

Keyword(s):

Combination Therapy ◽

Right Ventricle ◽

Right Ventricular ◽

Pulmonary Vascular Resistance ◽

Vascular Resistance ◽

Meta Analysis ◽

Right Heart Failure ◽

Functional Class ◽

Pulmonary Vasculature ◽

The Right

Pulmonary arterial hypertension is a progressive disease of the pulmonary vasculature, ultimately leading to right heart failure and death. Current treatment is aimed at targeting three different pathways: the prostacyclin, endothelin and nitric oxide pathways. These therapies improve functional class, increase exercise capacity and improve haemodynamics. In addition, data from a meta-analysis provide compelling evidence of improved survival. Despite these treatments, the outcome is still grim and the cause of death is inevitable – right ventricular failure. One explanation for this paradox of haemodynamic benefit and still worse outcome is that the right ventricle does not benefit from a modest reduction in pulmonary vascular resistance. This article describes the physiological concepts that might underlie this paradox. Based on these concepts, we argue that not only a significant reduction in pulmonary vascular resistance, but also a significant reduction in pulmonary artery pressure is required to save the right ventricle. Haemodynamic data from clinical trials hold the promise that these haemodynamic requirements might be met if upfront combination therapy is used.

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Sex Dimorphism in Pulmonary Hypertension: The Role of the Sex Chromosomes

Antioxidants ◽

10.3390/antiox10050779 ◽

2021 ◽

Vol 10 (5) ◽

pp. 779

Author(s):

Daria S. Kostyunina ◽

Paul McLoughlin

Keyword(s):

Pulmonary Hypertension ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Pulmonary Vascular Resistance ◽

Vascular Resistance ◽

Sex Chromosomes ◽

Bone Morphogenetic Protein 2 ◽

Sex Dimorphism ◽

Pulmonary Arterial ◽

The Impact

Pulmonary hypertension (PH) is a condition characterised by an abnormal elevation of pulmonary artery pressure caused by an increased pulmonary vascular resistance, frequently leading to right ventricular failure and reduced survival. Marked sexual dimorphism is observed in patients with pulmonary arterial hypertension, a form of pulmonary hypertension with a particularly severe clinical course. The incidence in females is 2–4 times greater than in males, although the disease is less severe in females. We review the contribution of the sex chromosomes to this sex dimorphism highlighting the impact of proteins, microRNAs and long non-coding RNAs encoded on the X and Y chromosomes. These genes are centrally involved in the cellular pathways that cause increased pulmonary vascular resistance including the production of reactive oxygen species, altered metabolism, apoptosis, inflammation, vasoconstriction and vascular remodelling. The interaction with genetic mutations on autosomal genes that cause heritable pulmonary arterial hypertension such as bone morphogenetic protein 2 (BMPR2) are examined. The mechanisms that can lead to differences in the expression of genes located on the X chromosomes between females and males are also reviewed. A better understanding of the mechanisms of sex dimorphism in this disease will contribute to the development of more effective therapies for both women and men.

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Haemodynamic assessment of right ventricular overload in pulmonary hypertension: old parameters still fit better than new ones

European Heart Journal ◽

10.1093/ehjci/ehaa946.2302 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

A Pereira ◽

J.G Santos ◽

M.J Loureiro ◽

F Ferreira ◽

A.R Almeida ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Logistic Regression ◽

Adverse Events ◽

Predictive Value ◽

Roc Curves ◽

Multivariate Logistic Regression ◽

Discrimination Power ◽

Haemodynamic Parameters ◽

All Cause Mortality ◽

Pulmonary Arterial

Abstract Introduction Right ventricular (RV) adaptation to the increased pulmonary load is a key determinant of outcomes in pulmonary hypertension (PH). Pulmonary vascular resistance (PVR) is widely recognized as haemodynamic measure of RV overload. Cardiac filling pressure (CFP), RV stroke work (RVSW), pulmonary artery (PA) compliance and PA pulsatility index (PAPi) are emerging as new haemodynamic parameters to assess RV function. Aims To assess the predictive value of CFP, RVSW, PA compliance and PAPi in PH and to compare it with standard haemodynamic parameters. Methods Retrospective study including all consecutive right heart catheterizations performed from April/2009 to October/2019 in a PH referral centre. Procedures presenting PH were selected [mean pulmonary arterial pressure (mPAP) >20 mmHg, according to the new definition of the 6st World Symposium on PH]. CFP was calculated as [right atrial pressure (RAP) − pulmonary capillary wedge pressure], value >0.63 associated with RV failure; RVSW as CO / [(heart rate × (mPAP-RAP) × 0.0136], value <15; PA compliance [SV / pulmonary arterial systolic pressure (PASP) − pulmonary arterial diastolic pressure (PADP)], value <2.5]; PAPi [(PSAP − PDAP) / RAP, value <1.85]. Multivariate logistic regression was used to identify predictors of all-cause mortality. Receiver operating characteristic (ROC) curves and area under curve (AUC) were used to assess discrimination power. Results From a total of 569 procedures, 470 fulfilled PH criteria: mean age 57.9±16.0 years, 67.7% female, 35.5% performed under pulmonary vasodilator therapy. Pre-capillary PH was diagnosed in 71.9% of cases. Chronic thromboembolic PH was the most common subtype (34.4%). Concerning standard haemodynamic parameters: mPAP was 39.0±12.0 mmHg, mean RAP 8.0±5.0 mmHg, mean RVP 7.5±5.0 uWood and CI 2.5±0.8 L/min/m2. Median value of CFP was 0.6 (IQR 0.4–0.8), RVSW 15.2 (IQR 9.7–25.0), PA compliance 2.1 (IQR 0.9–2.9) and PAPi 5.3 (IQR 3.2–8.5). All-cause mortality rate was 22.8%. Patients experiencing adverse events had lower values of cardiac index (2.3±0.6 vs 2.6±0.8 L/min/m2, p<0.01), RVSW (11.2 vs 16.7, p<0.01) and PA compliance (2.2 vs 2.9, p<0.01) and higher values of PVR (10.0±5.5 versus 6.8±4.6 uWood, p<0.01) and mean RAP (9.9±6.1 versus 7.4±4.5, p<0.01). Multivariate logistic regression identified 2 independent predictors of adverse events: mean RAP (OR 1.08, 95% CI 1.02–1.13, p<0.01) and PVR (OR 1.11, 95% CI 1.06–1.17, p<0.01). According to the ROC curves, new haemodynamic parameters did not have acceptable discrimination power to adverse events occurrence (figure). Conclusions In this study, new haemodynamic parameters to assess RV overload in PH were not independent predictors of adverse events as opposite to standard haemodynamic parameters. Further studies are needed to clarify their predictive value, as it has major implications for understanding the arterial load in diseases of the pulmonary circulation. Funding Acknowledgement Type of funding source: None

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Temporal trends in pulmonary arterial hypertension: Results from the COMPERA registry

European Respiratory Journal ◽

10.1183/13993003.02024-2021 ◽

2021 ◽

pp. 2102024

Author(s):

Marius M. Hoeper ◽

Christine Pausch ◽

Ekkehard Grünig ◽

Gerd Staehler ◽

Doerte Huscher ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Pulmonary Arterial Hypertension ◽

Combination Therapy ◽

Arterial Hypertension ◽

Temporal Trends ◽

Survival Rates ◽

Term Survival ◽

Pulmonary Arterial ◽

Early Combination Therapy

BackgroundSince 2015, the European pulmonary hypertension guidelines recommend the use of combination therapy in most patients with pulmonary arterial hypertension (PAH). However, it is unclear to what extend this treatment strategy is adopted in clinical practice and if it is associated with improved long-term survival.MethodsWe analysed data from COMPERA, a large European pulmonary hypertension registry, to assess temporal trends in the use of combination therapy and survival of patients with newly diagnosed PAH between 2010 and 2019. For survival analyses, we look at annualized data and at cumulated data comparing the periods 2010–2014 and 2015–2019.ResultsA total of 2,531 patients were included. The use of early combination therapy (within 3 months after diagnosis) increased from 10.0% in patients diagnosed with PAH in 2010 to 25.0% in patients diagnosed with PAH in 2019. The proportion of patients receiving combination therapy 1 year after diagnosis increased from 27.7% to 46.3%. When comparing the 2010–2014 and 2015–2019 periods, 1-year survival estimates were similar (89.0% [95% CI, 87.2%, 90.9%] and 90.8% [95% CI, 89.3%, 92.4%]), respectively, whereas there was a slight but non-significant improvement in 3-year survival estimates (67.8% [95% CI, 65.0%, 70.8%] and 70.5% [95% CI, 67.8%, 73.4%]), respectively.ConclusionsThe use of combination therapy increased from 2010 to 2019, but most patients still received monotherapy. Survival rates at 1 year after diagnosis did not change over time. Future studies need to determine if the observed trend suggesting improved 3-year survival rates can be confirmed.

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Pulmonary hypertension: From an orphan disease to a global epidemic

Global Cardiology Science and Practice ◽

10.21542/gcsp.2020.5 ◽

2020 ◽

Vol 2020 (1) ◽

Author(s):

Ghazwan Butrous

Keyword(s):

Pulmonary Hypertension ◽

Vascular Resistance ◽

Progressive Disease ◽

Right Ventricular Failure ◽

Medical Community ◽

Pulmonary Vasculature ◽

Current Interest ◽

Ventricular Failure ◽

Global Epidemic ◽

Chronic Progressive Disease

[No abstract. Showing first paragraph of article]Pulmonary hypertension is a progressive disease characterized by an elevation of pulmonary artery pressure and pulmonary vascular resistance, leading to right ventricular failure and death. It remains a challenging chronic progressive disease, but the current interest and advent of medical therapy in the last 20 years has significantly changed the perception of medical community in this disease. Pulmonary hypertension is not a specific disease; the majority of cases present with other diseases and various pathological processes that affect the pulmonary vasculature, and consequently increase pulmonary pressure and vascular resistance.

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Hypoxia- or PDGF-BB-dependent paxillin tyrosine phosphorylation in pulmonary hypertension is reversed by HIF-1α depletion or imatinib treatment

Thrombosis and Haemostasis ◽

10.1160/th13-12-1031 ◽

2014 ◽

Vol 112 (12) ◽

pp. 1288-1303 ◽

Cited By ~ 11

Author(s):

Christine Veith ◽

Dariusz Zakrzewicz ◽

Bhola Kumar Dahal ◽

Zoltán Bálint ◽

Kirsten Murmann ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Tyrosine Phosphorylation ◽

Molecular Mechanisms ◽

Hypoxia Inducible Factor ◽

Pulmonary Vasculature ◽

Hypoxic Exposure ◽

Imatinib Treatment ◽

Pulmonary Arterial ◽

Arterial Smooth Muscle Cells ◽

Pulmonary Arterial Smooth Muscle

SummaryChronic exposure to hypoxia induces a pronounced remodelling of the pulmonary vasculature leading to pulmonary hypertension (PH). The remodelling process also entails increased proliferation and decreased apoptosis of pulmonary arterial smooth muscle cells (PASMC), processes regulated by the cytoskeletal protein paxillin. In this study, we aimed to examine the molecular mechanisms leading to deregulation of paxillin in PH. We detected a time-dependent increase in paxillin tyrosine 31 (Y31) and 118 (Y118) phosphorylation following hypoxic exposure (1 % O2) or platelet-derived growth factor (PDGF)-BB stimulation of primary human PASMC. In addition, both, hypoxia- and PDGF-BB increased the nuclear localisation of phospho-paxillin Y31 as indicated by immunofluorescence staining in human PASMC. Elevated paxillin tyrosine phosphorylation in human PASMC was attenuated by hypoxia-inducible factor (HIF)-1α depletion or by treatment with the PDGF-BB receptor antagonist, imatinib. Moreover, we observed elevated paxillin Y31 and Y118 phosphorylation in the pulmonary vasculature of chronic hypoxic mice (21 days, 10 % O2) which was reversible by imatinib-treatment. PDGF-BB-dependent PASMC proliferation was regulated via the paxillin-Erk1/2-cyclin D1 pathway. In conclusion, we suggest paxillin up-regulation and phosphorylation as an important mechanism of vascular remodelling underlying pulmonary hypertension.Note: Parts of the doctoral thesis of Christine Veith are integrated into this report.

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Pulmonary Hypertension Due to Left Heart Disease

Hypertension ◽

10.1161/hypertensionaha.119.14330 ◽

2020 ◽

Vol 75 (6) ◽

pp. 1397-1408 ◽

Cited By ~ 4

Author(s):

Mohammed S. Al-Omary ◽

Stuart Sugito ◽

Andrew J. Boyle ◽

Aaron L. Sverdlov ◽

Nicholas J. Collins

Keyword(s):

Pulmonary Hypertension ◽

Heart Disease ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Pulmonary Vascular Resistance ◽

Vascular Resistance ◽

Left Atrial ◽

Left Atrial Pressure ◽

Left Heart ◽

Pulmonary Arterial

Pulmonary hypertension (PH) due to left heart disease (LHD) is the most common type of PH and is defined as mean pulmonary artery systolic pressure of >20 mm Hg and pulmonary capillary wedge pressure >15 mm Hg during right heart catheterization. LHD may lead to elevated left atrial pressure alone, which in the absence of intrinsic pulmonary vascular disease will result in PH without changes in pulmonary vascular resistance. Persistent elevation in left atrial pressure may, however, also be associated with subsequent pulmonary vascular remodeling, vasoconstriction, and an increase in pulmonary vascular resistance. Hence, there are 2 subgroups of PH due to LHD, isolated postcapillary PH and combined post- and precapillary PH, with these groups have differing clinical implications. Differentiation of pulmonary arterial hypertension and PH due to LHD is critical to guide management planning; however, this may be challenging. Older patients, patients with metabolic syndrome, and patients with imaging and clinical features consistent with left ventricular dysfunction are suggestive of LHD etiology rather than pulmonary arterial hypertension. Hemodynamic measures such as diastolic pressure gradient, transpulmonary gradient, and pulmonary vascular resistance may assist to differentiate pre- from postcapillary PH and offer prognostic insights. However, these are influenced by fluid status and heart failure treatment. Pulmonary arterial hypertension therapies have been trialed in the treatment with concerning results reflecting disease heterogeneity, variation in inclusion criteria, and mixed end point criteria. The aim of this review is to provide an updated definition, discuss possible pathophysiology, clinical aspects, and the available treatment options for PH due to LHD.

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Pulmonary vessel casting in a rat model of monocrotaline-mediated pulmonary hypertension

Pulmonary Circulation ◽

10.1177/2045894020922129 ◽

2020 ◽

Vol 10 (3) ◽

pp. 204589402092212

Author(s):

Zhongkai Zhu ◽

Yifan Wang ◽

Amy Long ◽

Tianyu Feng ◽

Maria Ocampo ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Rat Model ◽

Vascular System ◽

Pulmonary Arteries ◽

Pulmonary Vasculature ◽

Control Group ◽

Wall Thickening ◽

Arterial Remodeling ◽

Pulmonary Vessel ◽

Pulmonary Arterial

Pulmonary hypertension is a chronic vascular disease characterized by pulmonary vasoconstriction and pulmonary arterial remodeling. Pulmonary arterial remodeling is mainly due to small pulmonary arterial wall thickening and lumen occlusion. Previous studies have described intravascular changes in lung sections using histopathology, but few were able to obtain a fine detailed image of the pulmonary vascular system. In this study, we used Microfil compounds to cast the pulmonary arteries in a rat model of monocrotaline-induced pulmonary hypertension. High-quality images that enabled quantification of distal pulmonary arterial branching based on the number of vessel bifurcations/junctions were demonstrated in this model. The branch and junction counts of distal pulmonary arteries significantly decreased in the monocrotaline group compared to the control group, and this effect was inversely proportional to the mean pulmonary artery pressure observed in each group. The patterns of pulmonary vasculature and the methods for pulmonary vessel casting are presented to provide a basis for future studies of pulmonary arterial remodeling due to pulmonary hypertension and other lung diseases that involve the remodeling of vasculature.

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