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Background. Cytokines soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) and interleukin 6 (IL-6) are involved in immune response, proliferation, apoptosis, and cardiovascular pathologies. We have previously confirmed that changes of their platelet or plasma contents are associated with pulmonary arterial hypertension (PAH). The positron emission tomography/magnetic resonance imaging (PET/MRI) hybrid imaging provides detailed insight into right ventricle (RV) hemodynamic and metabolic function. Objectives. To evaluate the relationship between RV parameters obtained using PET/MRI and concentrations of plasma and platelet sTWEAK and IL-6 in stable PAH patients. Materials and methods. Eighteen stable PAH patients (48.44 ±16.7 years) had simultaneous PET/MRI scans with 18F-fluorodeoxyglucose (18F-FDG) performed. Its uptake was presented as a standardized uptake value (SUV) for RV and left ventricle (LV). Cytokines concentrations were measured in platelet-poor plasma and platelet lysate. Follow-up time of this study was 58 months; the combined endpoint (CEP) was defined as death or clinical deterioration. Results. We observed significant correlations between platelet sTWEAK levels, plasma IL-6 and PET parameter SUVRV/LV (r = -0.57, p = 0.011; r = 0.50, p = 0.032, respectively). In logistic regression, platelet sTWEAK and IL-6 were both prognostic factors for unfavorable ratio of SUVRV/LV higher than 1 (hazard ratio (HR) = 0.44, 95% confidence interval (95% CI): [0.23; 0.84], p = 0.017; and HR = 3.62, 95% CI: [1.21; 10.17], p = 0.011, respectively). Furthermore, their concentrations were related with prognostically important higher late gadolinium enhancement mass index (LGEMI) and RV global longitudinal strain/systolic pulmonary artery pressure (RV GLS/sPAP) values. Patients who had CEP in follow-up (n = 13) had significantly lower platelet sTWEAK content and higher plasma IL-6 at baseline than stable patients. Lower platelet sTWEAK was related to a worse prognosis in log-rank test (p = 0.006). Platelet sTWEAK and plasma IL-6 together with RV GLS/sPAP, RV ejection fraction (RVEF), mean pulmonary arterial pressure (mPAP), and SUVRV/LV were significantly associated with time to CEP in univariate Cox analysis. Conclusions. The sTWEAK and IL-6 concentrations in PAH patients are linked with metabolic and functional changes of RV visualized in PET/MRI, and both sTWEAK and IL-6 predict clinical deterioration. [ABSTRACT FROM AUTHOR]

Background: In pulmonary arterial hypertension (PAH) increased afterload leads to adaptive processes of the right ventricle (RV) that help to maintain arterio-ventricular coupling of RV and preserve cardiac output, but with time the adaptive mechanisms fail. In this study, we propose a multimodal approach which allows to estimate prognostic value of RV coupling parameters in PAH patients. Methods: Twenty-seven stable PAH patients (49.5 ± 15.5 years) and 12 controls underwent cardiovascular magnetic resonance (CMR). CMR feature tracking analysis was performed for RV global longitudinal strain assessment (RV GLS). RV-arterial coupling was evaluated by combination of RV GLS and three proposed surrogates of RV afterload—pulmonary artery systolic pressure (PASP), pulmonary vascular resistance (PVR) and pulmonary artery compliance (PAC). 18-FDG positron emission tomography (PET) analysis was used to assess RV glucose uptake presented as SUVRV/LV. Follow-up time of this study was 25 months and the clinical end-point was defined as death or clinical deterioration. Results: Coupling parameters (RV GLS/PASP, RV GLS/PVR and RV GLS*PAC) significantly correlated with RV function and standardized uptake value (SUVRV/LV). Patients who experienced a clinical end-point (n = 18) had a significantly worse coupling parameters at the baseline visit. RV GLS/PASP had the highest area under curve in predicting a clinical end-point and patients with a value higher than (−)0.29%/mmHg had significantly worse prognosis. It was also a statistically significant predictor of clinical end-point in multivariate analysis (adjusted R2 = 0.68; p < 0.001). Conclusions: Coupling parameters are linked with RV hemodynamics and glucose metabolism in PAH. Combining CMR and hemodynamic measurements offers more comprehensive assessment of RV function required for prognostication of PAH patients. Trial Registration: NCT03688698, 09/26/2018, retrospectively registered; Protocol ID: 2017/25/N/NZ5/02689 [ABSTRACT FROM AUTHOR]

Dysfunction of the right ventricle (RV) is an important determinant of survival in patients with pulmonary arterial hypertension (PAH). The presence of late gadolinium enhancement (LGE) in cardiac magnetic resonance (CMR) at RV insertion points (RVIPs) has been found in majority of PAH patients and was associated with parameters of RV dysfunction. We hypothesize, that more detailed quantification of LGE may provide additional prognostic information. Twenty-eight stable PAH patients (mean age 49.9 ​± ​15.9 years) and 12 healthy subjects (control group, 44.8 ​± ​13.5 years) were enrolled into the study. Septal LGE mass was quantified at the RVIPs and subsequently indexed by subject's body surface area. Mean follow-up time of this study was 16.6 ​± ​7.5 months and the clinical end-point (CEP) was defined as death or clinical deterioration. Median LGE mass index (LGEMI) at the RVIPs was 2.75 ​g/m2 [1.41–4.85]. We observed statistically significant correlations between LGEMI and hemodynamic parameters obtained from right heart catheterization – mPAP (r ​= ​0.61, p ​= ​0.001); PVR (r ​= ​0.52, p ​= ​0.007) and from CMR – RVEF (r ​= ​−0.54, p ​= ​0.005); RV global longitudinal strain (r ​= ​0.42, p ​= ​0.03). Patients who had CEP (n ​= ​16) had a significantly higher LGEMI (4.49 [2.75–6.17] vs 1.67 [0.74–2.7], p ​= ​0.01); univariate Cox analysis confirmed prognostic value of LGEMI. Furthermore, PAH patients with LGEMI higher than median had worse prognosis in Kaplan-Meier analysis (log-rank test, p ​= ​0.0006). The body surface indexed mass of LGE at RV septal insertion points are suggestive of RV hemodynamic dysfunction and could be a useful non-invasive marker of PAH prognosis. [ABSTRACT FROM AUTHOR]

Inflammatory processes and platelet activity play an important role in the pathophysiology of pulmonary arterial hypertension (PAH). Enhanced IL-6 signaling and higher concentration of stromal-derived factor alpha (SDF-1) have been previously shown to be linked with prognosis in PAH. We hypothesized that platelets of PAH patients have higher content of IL-6 and SDF-1 and thus are involved in disease progression. We enrolled into study 22 PAH patients and 18 healthy controls. Patients with PAH presented significantly higher plasma concentrations and platelet contents of IL-6, sIL-6R, and SDF-1 than healthy subjects (platelet content normalized to protein concentration: IL-6 (0.85*10–10 [0.29 – 1.37] vs. 0.45*10–10 [0.19–0.65], sIL-6R 1.54*10–7 [1.32–2.21] vs. 1.14*10–7 [1.01–1.28] and SDF-1 (2.72*10–7 [1.85–3.23] vs. 1.70*10–7 [1.43–2.60], all p < 0.05). Patients with disease progression (death, WHO class worsening, or therapy escalation, n = 10) had a significantly higher platelet SDF-1/total platelet protein ratio (3.68*10–7 [2.45–4.62] vs. 1.69*10–7 [1.04–2.28], p = 0.001), with no significant differences between plasma levels. Kaplan–Meier analysis revealed that patients with higher platelet SDF-1/total platelet protein ratio had more frequently deterioration of PAH in the follow-up (15.24 ± 4.26 months, log-rank test, p = 0.01). Concentrations of IL-6, sIL-6 receptor and SDF-1 in plasma and platelets are elevated in PAH patients. Higher content of SDF-1 in platelets is associated with poorer prognosis. Our study, despite of limitation due to small number of enrolled patients, suggests that activated platelets may be an important source of cytokines at the site of endothelial injury, but their exact role in the pathogenesis of PAH requires further investigation. [ABSTRACT FROM AUTHOR]

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by proliferative changes in pulmonary arteries. There is growing evidence suggesting that soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) and P-selectin could be involved in PAH development and progression. Here we investigate whether circulating platelets may be a source of sTWEAK and contribute to diminished availability of sTWEAK and P-selectin in PAH patients. We have prospectively enrolled two independent study groups of stable patients with confirmed PAH and age matched controls: derivation (10 PAH; 15 controls) and validation (20 PAH; 12 controls). P-selectin and sTWEAK concentrations were measured in platelet-poor plasma and platelet lysate. To avoid procedural bias, in each group we employed different protocols for platelet isolation. Consistently, both in derivation and validation groups PAH patients presented significantly lower sTWEAK content in platelets than control group with no significant differences in plasma levels. Similarly, patients presented comparable to controls plasma P-selectin concentrations and lower concentration in platelet lysate. Kaplan-Meier analysis revealed that patients with low platelet sTWEAK/total protein concentration ratio had more frequently detoriation of PAH in the follow-up (16.51 ± 3.32 months), log-rank test, p = .03. Patients diagnosed with pulmonary arterial hypertension present diminished sTWEAK and P-selectin storage capacity in platelets. Thrombocytes appear to be a major source of sTWEAK that could be released upon local injury and its decreased availability could have an impact on pathophysiology and prognosis in PAH. [ABSTRACT FROM AUTHOR]

Objective: We evaluated blood concentrations of kynurenine pathway metabolites, natural and induced regulatory T cells (nTreg, iTreg), and Th17 cells in order to examine the activity of the kynurenine pathway and its relation to immune status in patients with pulmonary arterial hypertension (PAH).Methods: Plasma concentrations of tryptophan, kynurenine, kynurenic acid, anthranilic acid, and 3-hydroxykynurenine were quantified in 26 patients with PAH (vs 30 healthy controls) at baseline and after 6 months, and assessed them in relation to clinical parameters, frequencies of lymphocyte subsets, and outcome.Results: The PAH group presented higher concentrations of tryptophan (52.9 (IQR 46.3-57.5) vs 40.3 (35.2-46.3) µmol/L, p=0.00003), kynurenine 2.8 (2.4-3.4) vs 1.9 (1.5-2.3) µmol/L, p=0.000007), kynurenine/tryptophan ratio (0.051 (0.044-0.064) vs 0.043 (0.039-0.055), p=0.03), iTreg frequencies (10.5 (8.8-13.9)% vs 6.8 (5.2-9.5)%, p=0.002) and iTreg/Th17 (1.73 (1.2-2.8) vs 0.93 (0.61-1.27), p=0.003) together with lower ratios of kynurenic acid/kynurenine, 3-hydroxykynurenine/kynurenine, and anthranilic acid/kynurenine. Kynurenine concentrations and kynurenine/tryptophan ratio correlated positively with iTreg/Th17, and inversely with Th17 subsets, whereas kynurenic acid/kynurenine and anthranilic acid/kynurenine ratios correlated positively with Th17. Adverse outcomes occurred in 9 of 26 patients and they showed higher baseline concentrations of kynurenine (3.6 (2.8-4.3) vs 2.7 (2.1-3.2) µmol/L, p=0.033). Median kynurenine values ≥3.4 µmol/L (67% sensitivity, 94% specificity) identified patients with a worse clinical course.Conclusions: PAH is characterised by upregulated tryptophan metabolism and enhanced biosynthesis of kynurenine. Elevated kynurenine concentration is associated with an adverse clinical course. Dysregulated immunity, delineated by Treg-Th17 imbalance, is directly related to diverse activation of the kynurenine pathway, indicating the potential interplay between kynurenines and the immune system in PAH. [ABSTRACT FROM AUTHOR]