scholarly journals Serum and Pulmonary Uric Acid in Pulmonary Arterial Hypertension

2021 ◽  
pp. 2000332
Author(s):  
Laurent Savale ◽  
Satoshi Akagi ◽  
Ly Tu ◽  
Amélie Cumont ◽  
Raphaël Thuillet ◽  
...  
Keyword(s):  
Uric Acid ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Pulmonary Arteries ◽  
High Serum ◽  
Vascular Remodelling ◽  
Vascular Walls ◽  
Pulmonary Arterial ◽  
Pulmonary Vascular Remodelling

RationaleEarlier studies have suggested an association between uric acid (UA) and pulmonary arterial hypertension (PAH) severity, but it remains unknown whether UA contributes to the disease pathogenesis.ObjectivesTo study the prognostic values of circulating UA at era of current management of PAH and investigate the role of UA in the pulmonary vascular remodelling.MethodsSerum UA levels were determined in idiopathic, heritable, or anorexigen PAH at baseline and first re-evaluation in the French PAH registry. We studied protein levels of xanthine oxidase (XO) and the URATv1 transporter in lungs of control and PAH patients and of monocrotaline (MCT) and sugen/hypoxia (SuHx) rats. Functional studies were performed using human pulmonary artery smooth muscle cells (PA-SMCs) and two animal models of pulmonary hypertension (PH).ResultsHigh serum UA levels are associated with a poor prognosis at first follow-up, but not at baseline. Both the generating enzyme XO and URATv1 are upregulated in the wall of remodelled pulmonary arteries in iPAH patients and MCT and SuHx rats. High UA concentrations promote a mild increase in cell growth in iPAH PA-SMCs, but not in control PA-SMCs. Consistent with these observations, we demonstrate that oxonic acid-induced hyperuricemia did not aggravate MCT-induced PH in rats. Finally, we show that chronic treatments of MCT and SuHx rats with benzbromarone mildly attenuate pulmonary vascular remodelling.ConclusionsUA levels in iPAH patients is associated with impaired clinical and hemodynamic profile and might be used as a noninvasive indicator of clinical prognostic during follow-up. Our findings also indicate that metabolism of UA is disturbed in remodelled pulmonary vascular walls in both experimental and human PAH.

scholarly journals A therapeutic antibody targeting osteoprotegerin attenuates severe experimental pulmonary arterial hypertension

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Nadine D. Arnold ◽  
Josephine A. Pickworth ◽  
Laura E. West ◽  
Sarah Dawson ◽  
Joana A. Carvalho ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Standard Of Care ◽  
Therapeutic Antibody ◽  
Human Antibody ◽  
Vascular Remodelling ◽  
Vasodilator Therapy ◽  
Pulmonary Arterial ◽  
Antibody Targeting ◽  
Pulmonary Vascular Remodelling

AbstractPulmonary arterial hypertension (PAH) is a rare but fatal disease. Current treatments increase life expectancy but have limited impact on the progressive pulmonary vascular remodelling that drives PAH. Osteoprotegerin (OPG) is increased within serum and lesions of patients with idiopathic PAH and is a mitogen and migratory stimulus for pulmonary artery smooth muscle cells (PASMCs). Here, we report that the pro-proliferative and migratory phenotype in PASMCs stimulated with OPG is mediated via the Fas receptor and that treatment with a human antibody targeting OPG can attenuate pulmonary vascular remodelling associated with PAH in multiple rodent models of early and late treatment. We also demonstrate that the therapeutic efficacy of the anti-OPG antibody approach in the presence of standard of care vasodilator therapy is mediated by a reduction in pulmonary vascular remodelling. Targeting OPG with a therapeutic antibody is a potential treatment strategy in PAH.

scholarly journals Lung irradiation induces pulmonary vascular remodelling resembling pulmonary arterial hypertension

Thorax ◽  
2011 ◽  
Vol 67 (4) ◽  
pp. 334-341 ◽  
Author(s):  
G Ghobadi ◽  
B Bartelds ◽  
S J van der Veen ◽  
M G Dickinson ◽  
S Brandenburg ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Vascular Remodelling ◽  
Lung Irradiation ◽  
Pulmonary Arterial ◽  
Pulmonary Vascular Remodelling

Abstract 17245: Deficiency of Tet Methylcytosine Dioxygenase 2 (tet2),A Key Enzyme in Cytosine Demethylation,Is an Epigenetic Driver of Inflammation and Disease Progression in Pulmonary Arterial Hypertension

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_1) ◽  
Author(s):  
Francois Potus ◽  
Elina K cook ◽  
Lian Tian ◽  
Charles C Hindmarch ◽  
Patricia Lima ◽  
...  
Keyword(s):  
Gene Expression ◽  
Endothelial Cells ◽  
Pulmonary Arterial Hypertension ◽  
Inflammatory Cytokine ◽  
Pulmonary Arteries ◽  
Vascular Remodelling ◽  
Key Enzyme ◽  
Pulmonary Arterial ◽  
Cytosine Demethylation ◽  
Pulmonary Vascular Remodelling

Background: Pulmonary arterial hypertension (PAH) is a lethal vasculopathy characterized by remodelling of distal pulmonary arteries associated with inflammation, endothelial cells (EC) dysfunction and a pro-proliferative/anti-apoptotic phenotype in pulmonary arterial smooth muscle cells (PASMC). Tet methylcytosine dioxygenase 2 (Tet2) is a key enzyme in cytosine demethylation that is crucial for epigenetic control of gene expression. Deficiency of Tet2 expression in myeloid cellsresults in increased inflammatory cytokine levels. Moreover, impaired Tet2 expression in EC has also been associated with decreased autophagy, as well as EC dysfunction. In addition, Tet2 silencing contributes to pro-proliferative phenotype of SMC. Thus, we hypothesized that Tet2 deletion would contribute to PAH by upregulation of inflammation and induction of PASMC proliferation and EC dysfunction. Methods and Results: To assess the ability of Tet2 deficiency to induce PAH we assessed cardiopulmonary hemodynamics in a conditional hematopoietic and endothelial cells Tet2 -/- mouse model. Tet2 -/- mice developed PAH associated with significant increases of right ventricular systolic pressure (RVSP), elevation of total pulmonary resistance (TPR) and increased vascular wall thickness of distal pulmonary arteries. Tet2 -/- lung tissue as well as macrophages and EC sorted from the lung displayed aberrant inflammatory cytokine signalling with robust overexpression of IL1βnoted on a Nanostring immune gene expression panel. In vitro IL1βincreased PASMC proliferation measured using EDU. Downregulation of TET2 in PASMC using siRNA resulted in a similar PAH-like phenotype. Moreover, lung from Tet2 -/- mice exhibited an alteration of vasoactive mediator gene expression (increased endothelin-1 (ET1), Arginase 2 (Arg2) and decreased eNOS). Finally we showed that downregulation of Tet2 (achieved by nebulization of si-Tet2) in rats with monocrotaline-induced PAH exacerbated disease severity (increasing TPR adverse pulmonary vascular remodelling).This phenotype was independent of the sex, was associated with a moderate decrease in RV function but had no significant effect on LV hemodynamic parameters. Conclusions: Tet2 is a protective epigenetic regulator that when conditionally downregulated in hematopoietic and endothelial cells leads toPAH by inducing a state of inflammation that contributes to PASMC proliferation and EC dysfunction which drives adverse pulmonary vascular remodelling.

Spermine promotes pulmonary vascular remodelling and its synthase is a therapeutic target for pulmonary arterial hypertension

2020 ◽  
Vol 56 (5) ◽  
pp. 2000522 ◽  
Author(s):  
Yang-Yang He ◽  
Yi Yan ◽  
Xin Jiang ◽  
Jun-Han Zhao ◽  
Zhe Wang ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Rodent Models ◽  
Vascular Remodelling ◽  
Spermine Synthase ◽  
Pulmonary Arterial ◽  
Pulmonary Vascular Remodelling

Pathological mechanisms of pulmonary arterial hypertension (PAH) remain largely unexplored. Effective treatment of PAH remains a challenge. The aim of this study was to discover the underlying mechanism of PAH through functional metabolomics and to help develop new strategies for prevention and treatment of PAH.Metabolomic profiling of plasma in patients with idiopathic PAH was evaluated through high-performance liquid chromatography mass spectrometry, with spermine identified to be the most significant and validated in another independent cohort. The roles of spermine and spermine synthase were examined in pulmonary arterial smooth muscle cells (PASMCs) and rodent models of pulmonary hypertension.Using targeted metabolomics, plasma spermine levels were found to be higher in patients with idiopathic PAH compared to healthy controls. Spermine administration promoted proliferation and migration of PASMCs and exacerbated vascular remodelling in rodent models of pulmonary hypertension. The spermine-mediated deteriorative effect can be attributed to a corresponding upregulation of its synthase in the pathological process. Inhibition of spermine synthase in vitro suppressed platelet-derived growth factor-BB-mediated proliferation of PASMCs, and in vivo attenuated monocrotaline-mediated pulmonary hypertension in rats.Plasma spermine promotes pulmonary vascular remodelling. Inhibiting spermine synthesis could be a therapeutic strategy for PAH.

Change of myocardial fluorodeoxyglucose uptake distribution after specific therapy of pulmonary arterial hypertension patients

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
R Kazimierczyk ◽  
P Szumowski ◽  
L.M Malek ◽  
P Blaszczak ◽  
D Jurgilewicz ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Glucose Uptake ◽  
Funding Source ◽  
Hemodynamic Parameters ◽  
Fdg Uptake ◽  
Baseline Visit ◽  
Pulmonary Arterial ◽  
Rv Function

Abstract Background Right ventricular (RV) function is a major determinant of survival in patients with pulmonary arterial hypertension (PAH). In our previous study, we confirmed that increased RV fluorodeoxyglucose (FDG) uptake in positron emission tomography (PET) (presented as higher ratio of FDG uptake of RV to LV) was associated with progressive RV dysfunction and preceded hemodynamic and clinical deterioration in PAH patients. Now, we obtained second PET/MRI assessments of the study group after 2-years of PAH-targeted treatment. Aim The aim of the study was to obtain change of cardiac FDG uptake in PAH patients after follow-up period and to indicate factors mainly affecting this change. Methods Twenty-eight PAH patients (51.32±15.91 years) had simultaneous PET/MRI scans performed during baseline visit. FDG was used and its uptake was quantified as mean standardized uptake value (SUV) for both left (LV) and RV. Second PET/MRI assessments were done after 2 years in the group of twenty patients (four deaths, four patients did not agree to perform additional scans). Results After follow-up period, we observed significant change of MRI-derived RV ejection fraction (45±10% to 51.2±12.7%, p=0.03), and improvement in hemodynamic parameters obtained from right heart catheterization (RHC) e.g. mean pulmonary artery pressure, mPAP (48.5±17.2 to 41.8±17.1 mmHg, p=0.01) and pulmonary vascular resistance, PVR (8.7±5.3 to 7.0±4.2 WU, p=0.04). Follow-up SUVRV/SUVLV ratio significantly correlated with follow-up RV hemodynamic parameters confirming relationship between RV function and cardiac metabolic alterations (Table 1). Interestingly, patients who had improvement in SUVRV/SUVLV (lower follow-up value than baseline, n=11) had significantly higher mPAP at baseline visit (58.9±18.7 vs 40.3±11.8 mmHg, p=0.02), suggesting that RV FDG accumulation in advanced PAH may decrease after the PAH-specific treatment in accordance with the degree of reduction in the pulmonary vascular resistance. Conclusion Impaired RV function is associated with increased glucose uptake of RV myocytes estimated by FDG PET in PAH patients. Targeted treatment may improve RV function and thus affect previously altered cardiac glucose uptake. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Polish National Science Centre

The Role of Uric Acid in Pediatric Idiopathic Pulmonary Arterial Hypertension: Analysis From a 10-Year Registry

CHEST Journal ◽  
2010 ◽  
Vol 138 (4) ◽  
pp. 805A
Author(s):  
Jose G. Gomez-Arroyo ◽  
Juan P. Sandoval-Jones ◽  
Paulina Ramirez-Neria ◽  
Armando Rodriguez ◽  
Carla Murillo ◽  
...  
Keyword(s):  
Uric Acid ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Idiopathic Pulmonary Arterial Hypertension ◽  
Pulmonary Arterial

scholarly journals Use of Sildenafil in Pulmonary Arterial Hypertension: Findings from a U.S. Healthcare Claims Database

10.36469/9871 ◽  
2014 ◽  
Vol 1 (3) ◽  
pp. 254-265 ◽  
Author(s):  
Ariel Berger ◽  
John Edelsberg ◽  
Simon Teal ◽  
Marko A. Mychaskiw ◽  
Gerry Oster
Keyword(s):  
United States ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Medication Possession Ratio ◽  
The United States ◽  
The European Union ◽  
Claims Database ◽  
Pharmacy Claims ◽  
Pulmonary Arterial

Background: Pulmonary arterial hypertension (PAH) is a disease characterized by dyspnea, fatigue, chest pain and syncope. As there is no known cure for PAH, the goal of treatment is to control symptoms and slow disease progression. Sildenafil, a phosphodiesterase-5 inhibitor, has been indicated to improve exercise capacity in PAH in both the United States and the European Union since 2005; since 2009, it also has been indicated in the United States to delay clinical worsening. Patterns of sildenafil use in PAH patients have not been reported. Objectives: To describe patterns of treatment with sildenafil among commercially insured patients in the United States with PAH. Methods: Using a large U.S. healthcare claims database, we identified all patients with evidence of PAH (International Classification of Disease, 9th Revision, Clinical Modification [ICD-9-CM] diagnosis codes 416.0, 416.8) and receipt of sildenafil between January 1, 2005 and September 30, 2008. The date of each patient’s earliest pharmacy claim for sildenafil was designated as his or her “index date”; patients with <6 months of data prior to this date were excluded. Post-index use of sildenafil was then examined in terms of the numbers of pharmacy claims and therapy-days, the medication possession ratio (MPR), and the incidence of therapy switching. Results: We identified a total of 855 PAH patients who began sildenafil therapy and met all other entry criteria. Mean (standard deviation [SD]) follow-up was 423.4 (313.0) days. Over this period, these patients averaged 7.1 (6.8) (median, 5) pharmacy dispensings for sildenafil, representing 273.4 (254.8) therapy-days (median, 180). Mean MPR was 71% (median, 83%). Fourteen percent of sildenafil patients switched to another agent during follow-up. Conclusions: In “real-world” clinical practice, many PAH patients beginning treatment with sildenafil remain on therapy for extended periods and are relatively compliant with treatment.

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