scholarly journals Reduced plasma levels of small HDL particles transporting fibrinolytic proteins in pulmonary arterial hypertension

Thorax ◽  
2018 ◽  
Vol 74 (4) ◽  
pp. 380-389 ◽  
Author(s):  
Lars Harbaum ◽  
Pavandeep Ghataorhe ◽  
John Wharton ◽  
Beatriz Jiménez ◽  
Luke S G Howard ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Plasma Levels ◽  
Density Lipoprotein ◽  
Coagulation Factor ◽  
Resonance Spectroscopy ◽  
Lipoprotein Subclasses ◽  
Physical Presence ◽  
Pulmonary Arterial ◽  
Fibrinolytic Proteins

BackgroundAberrant lipoprotein metabolism has been implicated in experimental pulmonary hypertension, but the relevance to patients with pulmonary arterial hypertension (PAH) is inconclusive.ObjectiveTo investigate the relationship between circulating lipoprotein subclasses and survival in patients with PAH.MethodsUsing nuclear magnetic resonance spectroscopy, 105 discrete lipoproteins were measured in plasma samples from two cohorts of patients with idiopathic or heritable PAH. Data from 1124 plasma proteins were used to identify proteins linked to lipoprotein subclasses. The physical presence of proteins was confirmed in plasma lipoprotein subfractions separated by ultracentrifugation.ResultsPlasma levels of three lipoproteins from the small high-density lipoprotein (HDL) subclass, termed HDL-4, were inversely related to survival in both the discovery (n=127) and validation (n=77) cohorts, independent of exercise capacity, comorbidities, treatment, N-terminal probrain natriuretic peptide, C reactive protein and the principal lipoprotein classes. The small HDL subclass rich in apolipoprotein A-2 content (HDL-4-Apo A-2) exhibited the most significant association with survival. None of the other lipoprotein classes, including principal lipoprotein classes HDL and low-density lipoprotein cholesterol, were prognostic. Three out of nine proteins identified to associate with HDL-4-Apo A-2 are involved in the regulation of fibrinolysis, namely, the plasmin regulator, alpha-2-antiplasmin, and two major components of the kallikrein–kinin pathway (coagulation factor XI and prekallikrein), and their physical presence in the HDL-4 subfraction was confirmed.ConclusionReduced plasma levels of small HDL particles transporting fibrinolytic proteins are associated with poor outcomes in patients with idiopathic and heritable PAH.

scholarly journals Lack of elevation in plasma levels of pro-inflammatory cytokines in common rodent models of pulmonary arterial hypertension: questions of construct validity for human patients

2017 ◽  
Vol 7 (2) ◽  
pp. 476-485 ◽  
Author(s):  
Kenny Schlosser ◽  
Mohamad Taha ◽  
Yupu Deng ◽  
Baohua Jiang ◽  
Lauralyn A McIntyre ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Animal Models ◽  
Arterial Hypertension ◽  
Inflammatory Cytokines ◽  
Plasma Levels ◽  
Rodent Models ◽  
Plasma Cytokine ◽  
Cytokine Levels ◽  
Pulmonary Arterial ◽  
Pro Inflammatory Cytokines

Translational research depends on the relevance of animal models and how well they replicate human disease. Here, we investigated plasma levels of three important pro-inflammatory cytokines (TNFα, IL-6, and MCP-1), known to be elevated in human pulmonary arterial hypertension (PAH), and systematically assessed their levels in PAH patients compared to five different rodent models of pulmonary hypertension (PH). A consistent immunoassay platform (Luminex xMAP) and source (Millipore) was used to measure all specimens. PAH patients (n = 29) exhibited significant elevations in all three cytokines (median [IQR] pg/mL; TNFα, 7.0 [4.8–11.7]; IL-6, 9.2 [3.8–17.2]; MCP-1, 109 [65–142]) versus healthy participants (n = 20) (median [IQR] pg/mL; TNFα, 3.0 [2.0–3.6]; IL-6, 1.7 [0.5–7.2]; MCP-1, 79 [49–93]. In contrast, mice with PH established after three weeks of hypoxia (n = 18) or SU5416 plus hypoxia (n = 20) showed no significant change in their plasma cytokine levels versus controls (n = 16), based on three to four independent experiments per group. Similarly, plasma cytokine levels were not elevated in rats with PH established three weeks after monocrotaline (n = 23), eight weeks after SU5416 alone (n = 10) or six to eight weeks after SU5416 plus hypoxia (n = 21) versus controls (n = 36 rats), based on three to eight independent experiments per group. Positive biologic control specimens from sepsis patients (n = 9), cecal-ligation and puncture (CLP)-induced septic mice (n = 6), and lipopolysaccharide-induced septic rats (n = 4) showed robust elevations in all three cytokines. This study suggests that animal models commonly used for the development of novel diagnostic and therapeutic approaches for PAH may have limited construct validity with respect to markers of systemic immune activation seen in human patients.

A role for coagulation factor Xa in experimental pulmonary arterial hypertension

2011 ◽  
Vol 92 (1) ◽  
pp. 159-168 ◽  
Author(s):  
Martina Delbeck ◽  
Katrin F. Nickel ◽  
Elisabeth Perzborn ◽  
Peter Ellinghaus ◽  
Julia Strassburger ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Factor Xa ◽  
Coagulation Factor ◽  
Pulmonary Arterial

Circulating Plasma Levels of Bone Morphogenic Protein Antagonist Gremlin-1 Are Increased in Patients with Pulmonary Arterial Hypertension

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 5189-5189
Author(s):  
Jasmin Wellbrock ◽  
Jan K. Hennigs ◽  
Björn Schulz ◽  
Gabi Vohwinkel ◽  
Hans Jörg Baumann ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Pulmonary Artery ◽  
Arterial Hypertension ◽  
Plasma Levels ◽  
Research Funding ◽  
Bmp Signaling ◽  
Pulmonary Arterial ◽  
Bmp Antagonist ◽  
Minute Walk Distance ◽  
Gremlin 1

Abstract Abstract 5189 Background: Pulmonary arterial hypertension (PAH) is a severe and life-threatening disease. It is characterized by excessive growth of pulmonary artery endothelial and smooth muscle cells leading to a profound pulmonary artery remodeling and consequently increased pulmonary artery pressure and vascular resistance. Most patients with the heritable form of PAH harbor a mutation in the bone morphogenic protein (BMP) receptor 2 (BMPR2) resulting in dysregulated BMP signaling. In addition, aberrant BMP signaling was also observed in the idiopathic form of PAH although the underlying molecular mechanisms have not been elucidated. Recently, it was shown that BMP antagonist Gremlin-1 was elevated in pulmonary vessels of mice during development of hypoxic pulmonary hypertension (Cahill et al, Circulation. 2012;125(7):920–30). Methods and Results: The aim of this prospective study was to investigate the plasma levels of Gremlin-1 in PAH patients (Dana point classification group I) and to correlate Gremlin-1 levels to clinical and hemodynamic parameters. Thirty subjects were included in the study (19 patients with PAH treated at the PH clinics of the University Medical Center Hamburg-Eppendorf, Germany and 11 healthy volunteers) after giving informed consent. The mean Gremlin-1 plasma level was 2. 6-fold increased with 333 ± 160 ng/ml, in patients with pulmonary arterial hypertension compared to those of healthy control subjects with a mean Gremlin-1 plasma level of 118 ± 115 ng/ml (p=0. 001 in t-test). Gremlin-1 plasma levels of PAH patients were correlated to demographic, clinical and hemodynamic parameters including age, sex, 6-minute walk distance, systemic and pulmonary blood pressure & vascular resistance, lung function testing, NT-proBNP (N terminal pro-brain natriuretic peptide) and NYHA/WHO functional classification. A positive correlation between Gremlin-1 plasma levels and NT-proBNP plasma levels was observed (Spearman Rho 0. 809 with p<0. 001). Furthermore, a negative correlation was observed between the Gremlin-1 levels and the 6-minute walk distance (Spearman Rho −0. 522 with p=0. 032). Conclusion: The plasma levels of BMP antagonist Gremlin-1 are significantly elevated in patients with pulmonary arterial hypertension and may serve as new serological marker. Gremlin-1 might mirror the state of BMP dysregulation and represent a potential follow up marker under a future targeted therapy. Furthermore, since Gremlin-1 was shown to induce proliferative effects on both endothelial as well as smooth muscle cells, it might also contribute directly to the aberrant vessel growth observed in PAH. Gremlin-1 plasma levels of patients with pulmonary hypertension (n=19) were analyzed in an enzyme-linked immunosorbent assay. Compared to healthy subjects (n=11), mean plasma levels of Gremlin-1 were 2. 6-fold increased in PH patients (t-test p=0. 001). Box plots show the median (center horizontal line), the 25th to the 75th percentile (box) and the range (whiskers).** indicates p<0. 01. Disclosures: Hennigs: Bayer: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Actelion: Research Funding; GlaxoSmithKline: Honoraria; Novartis: Honoraria. Fiedler:Pfizer Inc. : Consultancy, Research Funding; Novartis: Consultancy, Research Funding.

BASELINE VENOUS ENDOTHELIN-1 (ET1) PLASMA LEVELS DOES NOT PREDICT CLINICAL RESPONSE TO BOSENTAN IN PULMONARY ARTERIAL HYPERTENSION

CHEST Journal ◽  
2005 ◽  
Vol 128 (4) ◽  
pp. 202S
Author(s):  
Carmine D. Vizza ◽  
Claudio Letizia ◽  
Roberto Badagliacca ◽  
Susanna Sciomer ◽  
Roberto Poscia ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Clinical Response ◽  
Plasma Levels ◽  
Endothelin 1 ◽  
Pulmonary Arterial
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