Different tryptophan-kynurenine metabolism profiles in human pulmonary arterial hypertension and animal models of pulmonary hypertension

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
Z Cai ◽  
T Klein ◽  
L Tu ◽  
L.W Geenen ◽  
S Tian ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Arterial Hypertension ◽  
Animal Models ◽  
Arterial Hypertension ◽  
Quinolinic Acid ◽  
Funding Source ◽  
Healthy Controls ◽  
Cardiovascular Research ◽  
Pulmonary Arterial ◽  
Hydroxyanthranilic Acid

Abstract Background De novo NAD+ synthesis through the tryptophan-kynurenine (TK) metabolism was recognized as an important pathway in improving mitochondrial function and survival of injury or apoptotic cells, which are key processes involved in the pathogenesis of pulmonary arterial hypertension (PAH). Although abnormal TK metabolism has been reported in human PAH, the difference between human and animal models of pulmonary hypertension (PH) are currently unknown. Objective Determine and compare TK metabolism profiles in plasma from human PAH and 3 animal models of PH. Methods Human plasma was collected from treatment naïve patients with PAH (n=43) and healthy controls (n=111). Animal plasma was collected from 3 animal models of PH and corresponding controls, including monocrotaline (MCT) induced PH in rat (n=7, control n=6), Sugen + hypoxia (SuHx) induced PH in rat (n=5, control n=6), and pulmonary vein banding (PVB) induced PH in swine (n=7, control n=6). TK metabolites were determined using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Results TK metabolism was altered in the plasma from of PAH compared to healthy controls (Figure 1A). Lower tryptophan (0.8 fold vs Control, p<0.0001), maintained 3-hydroxyanthranilic acid, and higher kynurenine, 3-hydroxykynurenine, anthranilic acid, and quinolinic acid (1.5, 2.6, 2.0, 2.6 fold vs Control, respectively, p all<0.0001) were seen in the plasma from human PAH. In the rat SuHx-PH model, kynurenine (0.7 fold, p<0.01) and quinolinic acid (0.5 fold, p<0.001) were lower, while 3-hydroxyanthranilic acid (4.3 fold, p<0.001) was higher in PH compared to control (Figure 1B). However, the TK metabolism was unaltered in MCT-PH model in rat (Figure 1C), and PVB-PH model in swine (Figure 1D). Conclusions TK metabolism was altered in the plasma from human PAH. The TK metabolism profiles were different among 3 animal models of PH, but did not mimic the profile in human PAH. Further research is required to determine the mechanism(s) behind the abnormal TK metabolism in human PAH as well as whether these mechanisms relate to disease onset or progression. Figure 1 Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): This work was supported by the China Scholarship Council (201606230252) as well as the Netherlands CardioVascular Research Initiative: an initiative with support of the Dutch Heart Foundation (CVON2014-11, RECONNECT), and German Center for Cardiovascular Research (DZHK81Z0600207). Instrumentation support was received from AB Sciex, ltd. for LC-MS/MS analyses performed in this study.

scholarly journals Lower plasma melatonin levels predict worse long-term survival in pulmonary arterial hypertension

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
Z Cai ◽  
T Klein ◽  
L.W Geenen ◽  
L Tu ◽  
S Tian ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Funding Source ◽  
Cardiovascular Research ◽  
Term Survival ◽  
Long Term Survival ◽  
Treatment Naïve ◽  
Pulmonary Arterial ◽  
Endogenous Melatonin

Abstract Background Exogenous melatonin has been reported to be beneficial in the treatment of pulmonary hypertension (PH) in animal models. Multiple mechanisms may be involved, with melatonin exerting anti-oxidant and anti-inflammatory effects, as well as inducing vasodilation and cardio-protection. However, endogenous levels of melatonin in treatment-naïve pulmonary arterial hypertension (PAH) patients and their clinical significance are still unknown. Methods and results Plasma levels of endogenous melatonin were measured by liquid chromatography-tandem mass spectrometry in treatment-naïve PAH patients (n=43) and healthy controls (n=111). Melatonin levels were higher in PAH patients when compared with controls (Median 118.9 [IQR 109.3–147.7] versus 108.0 [102.3–115.2] pM, P<0.001) (Figure 1A). The overall mortality was 26% (11/43) during a median long-term follow-up of 42 [IQR: 32–58] months. When PAH patients were stratified into 4 groups according to the quartiles of melatonin levels, the mortality from below 1st quartile to above 4th quartile was 55% (6/11), 10% (1/10), 0% (0/12), and 40% (4/10), respectively (Figure 1B). Kaplan-Meier analysis further showed that patients with melatonin levels below the 1st quartile (<109.3 pM) had a worse long-term survival than patients with melatonin levels above the 1st quartile (Mean survival times were 46 [95% CI: 30–65] versus 68 [58–77] months, Log-rank, p=0.026) (Figure 1C). Conclusion Endogenous melatonin levels were increased in treatment-naïve PAH patients, and lower levels of melatonin were associated with worse long-term survival in patient with PAH, however, whether exogenous melatonin supplements may be effective as a therapeutic strategy in human PAH remains to be established. Figure 1 Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): This work was supported by the China Scholarship Council (201606230252) as well as the Netherlands CardioVascular Research Initiative: an initiative with support of the Dutch Heart Foundation (CVON2014-11, RECONNECT), and German Center for Cardiovascular Research (DZHK81Z0600207). Instrumentation support was received from AB Sciex, ltd. for LC-MS/MS analyses performed in this study.

scholarly journals Sex Differences in Pulmonary Hypertension

2021 ◽  
Vol 2 ◽  
Author(s):  
Juan José Rodriguez-Arias ◽  
Ana García-Álvarez
Keyword(s):  
Pulmonary Hypertension ◽  
Sex Differences ◽  
Pulmonary Arterial Hypertension ◽  
Animal Models ◽  
Pulmonary Artery ◽  
Arterial Hypertension ◽  
Gender Bias ◽  
Response To Treatment ◽  
Experimental Animal Models ◽  
Pulmonary Arterial

Pulmonary hypertension (PH) includes multiple diseases that share as common characteristic an elevated pulmonary artery pressure and right ventricular involvement. Sex differences are observed in practically all causes of PH. The most studied type is pulmonary arterial hypertension (PAH) which presents a gender bias regarding its prevalence, prognosis, and response to treatment. Although this disease is more frequent in women, once affected they present a better prognosis compared to men. Even if estrogens seem to be the key to understand these differences, animal models have shown contradictory results leading to the birth of the estrogen paradox. In this review we will summarize the evidence regarding sex differences in experimental animal models and, very specially, in patients suffering from PAH or PH from other etiologies.

scholarly journals Plasma adrenomedullin peptides and precursor levels in pulmonary arterial hypertension disease severity and risk stratification

2020 ◽  
Vol 10 (3) ◽  
pp. 204589402093131
Author(s):  
Habib Bouzina ◽  
Göran Rådegran
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Early Treatment ◽  
Chronic Thromboembolic Pulmonary Hypertension ◽  
Risk Scores ◽  
Healthy Controls ◽  
Thromboembolic Pulmonary Hypertension ◽  
Pulmonary Arterial

Adrenomedullin is a potent vasodilatory peptide, linked to pulmonary arterial hypertension pathology. Proximity extension assays were utilized to study plasma biomarkers related to vasoregulation, with focus on adrenomedullin peptides and precursor levels, collectively referred to as ADM. ADM was measured in 48 treatment-naïve pulmonary arterial hypertension patients at diagnosis, and in 31 of them at an early treatment follow-up. Plasma ADM was additionally assessed in patients with chronic thromboembolic pulmonary hypertension ( n = 20) and pulmonary hypertension due to heart failure with preserved (HFpEF(PH)) ( n = 33) or reduced (HFrEF(PH)) ( n = 36) ejection fraction, as well as healthy controls ( n = 16). ADM was studied in relation to pulmonary arterial hypertension hemodynamics, risk assessment, prognosis, treatment response, and differentiation. Plasma ADM levels in pulmonary arterial hypertension patients at diagnosis were higher than in healthy controls ( p < 0.001), similar as in chronic thromboembolic pulmonary hypertension patients ( p = ns), but lower compared to HFpEF(PH) ( p < 0.03) and HFrEF(PH) ( p < 0.001). In pulmonary arterial hypertension, specifically, plasma ADM at diagnosis correlated mainly to mean right atrial pressure ( r = 0.73, p < 0.001), N-terminal prohormone of brain natriuretic peptide ( r = 0.75, p < 0.001), six-minute walking distance ( r = –0.57, p < 0.001), and venous oxygen saturation ( r = –0.57, p < 0.001). ADM also correlated to the ECS/ERS- ( r = 0.74, p < 0.001) and REVEAL risk scores ( r = 0.54, p < 0.001) at pulmonary arterial hypertension diagnosis. Plasma ADM in pulmonary arterial hypertension patients was unaltered at early treatment follow-up compared to baseline ( p = ns). Pulmonary arterial hypertension patients with supra-median ADM at diagnosis showed worse overall survival than those with infra-median levels (median survival 34 versus 66 months, p = 0.0077). In conclusion, the present results suggest that baseline plasma ADM levels mirror disease severity, correlating to both ECS/ERS- and the REVEAL risk scores.

scholarly journals Plasma receptor tyrosine kinase RET in pulmonary arterial hypertension diagnosis and differentiation

2019 ◽  
Vol 5 (4) ◽  
pp. 00037-2019 ◽  
Author(s):  
Joanna Säleby ◽  
Habib Bouzina ◽  
Salaheldin Ahmed ◽  
Jakob Lundgren ◽  
Göran Rådegran
Keyword(s):  
Heart Failure ◽  
Pulmonary Hypertension ◽  
Growth Factor ◽  
Pulmonary Arterial Hypertension ◽  
Protein Kinase ◽  
Arterial Hypertension ◽  
Vegf Receptor ◽  
Healthy Controls ◽  
Tyrosine Protein Kinase ◽  
Pulmonary Arterial

BackgroundPulmonary arterial hypertension (PAH) is a serious disease exhibiting unspecific symptoms, as a result of which diagnosis is often delayed and prognosis is poor. The underlying pathophysiology includes vasoconstriction and remodelling of small pulmonary arteries. As receptor tyrosine kinases (RTKs) and their ligands have been shown to promote PAH remodelling, our aim was to evaluate if their plasma levels may be utilised to differentiate between various causes of pulmonary hypertension.Methods28 biomarkers involved in RTK signalling were measured using proximity extension assays in venous plasma from patients with PAH (n=48), chronic thromboembolic pulmonary hypertension (CTEPH) (n=20), pulmonary hypertension due to diastolic (n=33) or systolic (n=36) heart failure and heart failure patients without pulmonary hypertension (n=15), as well as healthy controls (n=20).ResultsPlasma proto-oncogene tyrosine-protein kinase receptor Ret (RET) was decreased (p<0.04) in PAH compared with all disease groups and controls. RET generated a sensitivity of 64.6% and a specificity of 81.6% for detecting PAH from other disease groups. PAH and the other pulmonary hypertension groups showed elevated plasma tyrosine-protein kinase MER (p<0.01), vascular endothelial growth factor (VEGF)-A (p<0.02), VEGF-D (p<0.01), placental growth factor (p<0.01), amphiregulin (p<0.02), hepatocyte growth factor (p<0.01) and transforming growth factor-α (p<0.05) and decreased VEGF receptor-2 (p<0.04) and epidermal growth factor receptor (p<0.01) levels compared with controls.ConclusionPlasma RET differentiates patients with PAH from those with CTEPH, systolic or diastolic heart failure with or without pulmonary hypertension as well as healthy controls. Future studies would be of value to determine the clinical usefulness of RET as a biomarker and its link to PAH pathophysiology.

scholarly journals EXPRESS: Plasma ADAMTS-13 and von Willebrand factor in diagnosis and prediction of prognosis in pulmonary arterial hypertension

2021 ◽  
pp. 204589402110415
Author(s):  
Abdulla Ahmed ◽  
Salaheldin Ahmed ◽  
Göran Rådegran
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Arterial Hypertension ◽  
Ejection Fraction ◽  
Arterial Hypertension ◽  
Von Willebrand Factor ◽  
Chronic Thromboembolic Pulmonary Hypertension ◽  
Healthy Controls ◽  
Pulmonary Arterial ◽  
Von Willebrand ◽  
Willebrand Factor

To improve outcome in pulmonary arterial hypertension (PAH), earlier diagnosis and better prognostic assessments are required. We aimed to investigate the diagnostic and prognostic potential of plasma proteins related to pathways recognized in PAH including coagulation, inflammation, and metabolism. Forty-two proteins were analysed with proximity extension assay from plasma of 20 healthy controls and 150 patients, including (PAH, n=48, whereof 33 also during early treatment follow-ups); chronic thromboembolic pulmonary hypertension (CTEPH, n=20); pulmonary hypertension (PH) due to heart failure (HF) with preserved ejection fraction (HFpEF-PH, n=31); PH due to HF with reduced ejection fraction (HFrEF-PH, n=36); and HF without PH (Dyspnoea/HF-non-PH, n=15). Patients’ haemodynamics were assessed by right heart catheterization. Plasma ADAMTS-13 in incident PAH was lower compared to the healthy controls (p=0.055), as well as CTEPH (p<0.0001), HFrEF-PH (p<0.0001), HFrEF-PH (p<0.0001), and Dyspnoea/HF-non-PH (p<0.0001). Adjusted for age and sex, ADAMTS-13 discriminated PAH from the other disease groups with an AUC of 0.91 (sensitivity=87.5%, and specificity=78.4%). Higher plasma von Willebrand factor (vWF) was associated with worse survival (log-rank p=0.0029), and a higher mortality rate (adjusted hazard ratio 1.002, 95% confidence interval 1-1.004: p=0.041). Adjusted for age, sex, and combined with the ESC/ERS risk score, vWF predicted mortality (median follow-up 3.6 years) in PAH with an AUC of 0.94 (sensitivity=81.3%, and specificity=93.8%). ADAMTS-13 may be a promising biomarker for early detection of PAH, and vWF as a candidate prognostic biomarker. The putative additional value of vWF to the European multiparametric risk assessment strategy remains to be elucidated.

scholarly journals Plasma metabolomic profile in chronic thromboembolic pulmonary hypertension

2020 ◽  
Vol 10 (1) ◽  
pp. 204589401989055 ◽  
Author(s):  
Gustavo A. Heresi ◽  
Jacob T. Mey ◽  
John R. Bartholomew ◽  
Ihab S. Haddadin ◽  
Adriano R. Tonelli ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Chronic Thromboembolic Pulmonary Hypertension ◽  
Idiopathic Pulmonary Arterial Hypertension ◽  
Healthy Controls ◽  
Metabolomic Profile ◽  
Plasma Metabolome ◽  
Thromboembolic Pulmonary Hypertension ◽  
Pulmonary Arterial

We aimed to characterize the plasma metabolome of chronic thromboembolic pulmonary hypertension patients using a high-throughput unbiased omics approach. We collected fasting plasma from a peripheral vein in 33 operable chronic thromboembolic pulmonary hypertension patients, 31 healthy controls, and 21 idiopathic pulmonary arterial hypertension patients matched for age, gender, and body mass index. Metabolomic analysis was performed using an untargeted approach (Metabolon Inc. Durham, NC). Of the total of 862 metabolites identified, 362 were different in chronic thromboembolic pulmonary hypertension compared to controls: 178 were higher and 184 were lower. Compared to idiopathic pulmonary arterial hypertension, 147 metabolites were different in chronic thromboembolic pulmonary hypertension: 45 were higher and 102 were lower. The plasma metabolome allowed us to distinguish subjects with chronic thromboembolic pulmonary hypertension and healthy controls with a predictive accuracy of 89%, and chronic thromboembolic pulmonary hypertension versus idiopathic pulmonary arterial hypertension with 80% accuracy. Compared to idiopathic pulmonary arterial hypertension and healthy controls, chronic thromboembolic pulmonary hypertension patients had higher fatty acids and glycerol; while acyl cholines and lysophospholipids were lower. Compared to healthy controls, both idiopathic pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension patients had increased acyl carnitines, beta-hydroxybutyrate, amino sugars and modified amino acids and nucleosides. The plasma global metabolomic profile of chronic thromboembolic pulmonary hypertension suggests aberrant lipid metabolism characterized by increased lipolysis, fatty acid oxidation, and ketogenesis, concomitant with reduced acyl choline and phospholipid moieties. Future research should investigate the pathogenetic and therapeutic potential of modulating lipid metabolism in chronic thromboembolic pulmonary hypertension.

scholarly journals Matrix metalloproteinase 7 in diagnosis and differentiation of pulmonary arterial hypertension

2019 ◽  
Vol 9 (4) ◽  
pp. 204589401989541 ◽  
Author(s):  
Mattias Arvidsson ◽  
Abdulla Ahmed ◽  
Habib Bouzina ◽  
Göran Rådegran
Keyword(s):  
Heart Failure ◽  
Pulmonary Hypertension ◽  
Pulmonary Arterial Hypertension ◽  
Matrix Metalloproteinases ◽  
Ejection Fraction ◽  
Matrix Metalloproteinase ◽  
Arterial Hypertension ◽  
Healthy Controls ◽  
Matrix Metalloproteinase 7 ◽  
Pulmonary Arterial

Pulmonary arterial hypertension is a severe disease for which diagnosis often is delayed. Matrix metalloproteinases have been suggested to play a role in vascular remodeling and pulmonary hypertension development. Our aim was therefore to investigate the potential role of matrix metalloproteinases as biomarkers in diagnosis and differentiation of pulmonary arterial hypertension in relation to various causes of dyspnea and pulmonary hypertension. Using proximity extension assays, 10 matrix metalloproteinases and associated proteins were analyzed in venous plasma from healthy controls (n = 20), as well as patients diagnosed with pulmonary arterial hypertension (n = 48), chronic thromboembolic pulmonary hypertension (n = 20), pulmonary hypertension due to heart failure with preserved (n = 33) or reduced (n = 36) ejection fraction, and heart failure with reduced ejection fraction and heart failure with preserved ejection fraction without pulmonary hypertension (n = 15). Plasma levels of matrix metalloproteinase-2, -7, -9, -12 and TIMP-4 were elevated (p < 0.01) in pulmonary arterial hypertension compared to controls. Plasma levels of matrix metalloproteinase-7 were furthermore lower (p < 0.0081) in pulmonary arterial hypertension than in all the other disease groups, but higher compared to controls (p < 0.0001). Receiver operating characteristic analysis of matrix metalloproteinase-7 resulted in sensitivity of 58.7% and a specificity of 83.3% for detecting pulmonary arterial hypertension among the other disease groups. Plasma matrix metalloproteinase-7 may provide a potential new diagnostic tool to differentiate pulmonary arterial hypertension from other causes of dyspnea, including heart failure with or without pulmonary hypertension and healthy controls. Matrix metalloproteinase-7 may furthermore be involved in the development of pulmonary hypertension and pulmonary arterial hypertension. Future studies investigating the clinical usefulness of matrix metalloproteinase-7 in the differentiation and earlier diagnosis of pulmonary arterial hypertension, as well as its relationship to pulmonary arterial hypertension pathogenesis, are encouraged.

Pulmonary Arterial Hypertension: Epidemiology and Registries

2014 ◽  
Vol 13 (1) ◽  
pp. 21-26 ◽  
Author(s):  
Michael D. McGoon ◽  
Marc Humbert
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Task Force ◽  
The World ◽  
Important Means ◽  
Pulmonary Arterial

Registries of pulmonary arterial hypertension (PAH) are important means by which to characterize the presentation and outcome of patients and to provide a basis for predicting the course of the disease. This article summarizes the published conclusions of the World Symposium of Pulmonary Hypertension task force that addressed registries and epidemiology of PAH.

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