Chronic Thromboembolic Pulmonary Hypertension Group Research Articles

Echocardiography in acute pulmonary embolism for the prediction of subsequent CTEPH

Abstract Background Chronic thromboembolic pulmonary hypertension (CTEPH) is a long term complication of acute pulmonary embolism (APE) with poor outcomes if untreated. Identifying already at APE diagnosis patients at risk of subsequent CTEPH can lead to earlier goal-directed management. Since standard echocardiography (TTE) is frequently performed during APE episode for short term risk stratification we aimed to asses prediction vale of echocardiography for subsequent CTEPH. Methods We analyzed retrospectively TTE performed at admission due to APE in consecutive patients, without known CTEPH who were anticoagulated for at least 3 months and were followed up for at least 24 months. After follow-up all patients underwent diagnostic workup for CTEPH according to ESC recommendations. We tried to define a set of echocardiographic parameters recorded during the acute episode predictive for CTEPH. Results The study included consecutive 625 patients with APE diagnosed at computed tomography pulmonary angiogram and managed according to ESC recommendations. During follow up 25 (4%) pts were diagnosed with CTEPH. At APE diagnosis CTEPH(+) group presented more prominent echocardiographic signs of right ventricular (RV) overload than pts without CTEPH (CTEPH(-))(table 1). However, multivariate analysis revealed that only increased TRPG and RV/LV ratio were significant CTEPH predictors with AUC 0.792 (95% CI: 0.683-0.900), p<0.001 and 0.777 (95% CI: 0.675-0.878), p<0.001 respectively (fig 1). Using Youden index in ROC analysis we defined following cut off values useful to identify patients at CTEPH risk and subjects with low probability of CTEPH development. TRPG >44mmHg and RV/LV>1.15 showed PPV for CTPEH 12.9 (95% CI: 9.8-16.7) and 13.8 (95% CI: 10.4-18.1), with high NPV of 98.4 (95% CI: 97.1-99.2) and 98.2 (95% CI: 96.8-99.0) respectively. Importantly, in the group of 61 (9.7%) patients with both signs of RV overload present in the acute phase CTEPH during follow-up was diagnosed in 14 patients (23.0%). Conclusion TRPG above 44 mmHg recorded at APE diagnosis identifies patients at risk of subsequent CTEPH especially in patients with increased RV/LV ratio.

Tissue factor regulates autophagy in pulmonary artery endothelial cells from chronic thromboembolic pulmonary hypertension rats via the p38 MAPK-FoxO1 pathway

AimsTo detect the expression of autophagy components, p38 MAPK (p38) and phosphorylated forkhead box transcription factor O-1 (pFoxO1) in pulmonary vascular endothelial cells of chronic thromboembolic pulmonary hypertension (CTEPH) rats and to investigate the possible mechanism through which tissue factor (TF) regulates autophagy.MethodsPulmonary artery endothelial cells (PAECs) were isolated from CTEPH (CTEPH group) and healthy rats (control group (ctrl group)) which were cocultured with TF at different time points including 12 h, 24 h, 48 h and doses including 0 nM,10 nM, 100 nM, 1µM, 10µM, 100µM and cocultured with TFPI at 48 h including 0 nM, 2.5 nM, 5 nM. The expression of forkhead box transcription factor O-1 (FoxO1), pFoxO1, p38, Beclin-1 and LC3B in PAECs was measured. Coimmunoprecipitation (co-IP) assays were used to detect the interaction between FoxO1 and LC3.ResultsThe protein expression of p-FoxO1/FoxO1 was significantly lower in the CTEPH groups (cocultured with TF from 0 nM to 100 µM) than in the ctrl group at 12 h, 24 h, and 48 h (P < 0.05) and was significantly lower in the CTEPH groups (cocultured with TFPI from 0 nM to 5 nM) than in the ctrl group at 48 h (P < 0.05). The protein expression of p38 in the CTEPH groups treated with 0 nM, 10 nM, 100 nM or 1 µM TF for 48 h significantly increased than ctrl groups (P < 0.05) and was significantly increased in the CTEPH groups (cocultured with TFPI concentration from 0 nM to 5 nM) than in the ctrl group at 48 h (P < 0.05). The protein expression of Beclin1 at the same concentration (cocultured with TF from 0 nM to 100 µM) was significantly lower in the CTEPH groups than ctrl groups after 24 h and 48 h (P < 0.05) and was significantly decreased in the CTEPH groups (cocultured with TFPI concentration from 2.5 nM to 5 nM) than in the ctrl group at 48 h (P < 0.05). The protein expression of LC3-II/LC3-I at the same concentration (cocultured with TF 0 nM, 1 µM, 10 µM, and 100 µM) was significantly lower in the CTEPH than in the ctrl groups after 12 h (P < 0.05) and was significantly lower in the CTEPH groups (cocultured with TFPI concentration from 0 nM to 5 nM) than in the ctrl group at 48 h (P < 0.05). There were close interactions between FoxO1 and LC3 in the control and CTEPH groups at different doses and time points.ConclusionThe autophagic activity of PAECs from CTEPH rats was disrupted. TF, FoxO1 and p38 MAPK play key roles in the autophagic activity of PAECs. TF may regulate autophagic activity through the p38 MAPK-FoxO1 pathway.

Endothelial cells in chronic thromboembolic pulmonary hypertension exhibit cytoskeletal alteration

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): Health Research Fund (Fondo de Investigación Sanitaria [FIS]) from the Instituto de Salud Carlos III Introduction Endothelial dysfunction (ED) is pivotal in Chronic Thromboembolic Pulmonary Hypertension (CTEPH) due to structural and functional alterations in endothelial. Previous studies have shown the critical function of cytoskeletal elements, particularly actin microfilaments and microtubules, along with associated cell adhesion complexes, in the endothelial integrity. Nevertheless, precise alterations in the cytoskeletal elements of endothelial cells (ECs) in CTEPH patients remain unclear. Purpose This study aims to investigate the cytoskeleton changes in CTEPH-ECs compared to healthy ECs, characterizing morphological and structural differences. Objectives involve assessing microtubules and microfilaments expression, and their influence on ECs migratory capacity. Finally, our study aims to gain novel insights into the spatial organization of cytoskeleton components in CTEPH patients. Methods CTEPH-ECs were isolated from freshly resected pulmonary endarterectomy specimens of CTEPH patients, while human pulmonary artery ECs (HPAE) were used as healthy controls. Fluorescence immunocytochemistry assessed phenotypic and compositional characteristics of the cytoskeleton. Morphometric analysis described morphology and filament organization of cytoskeletal proteins using a custom-built pipeline. X-ray microscopy examined the phenotype and cytoskeletal components distribution. The migration assay evaluated how these structural differences affected ECs migratory capacity and the cytoskeletal elements expression. Results CTEPH-ECs exhibited larger surface area (1352 vs 662µm2, p&amp;lt;0.01) and a more stellate morphology (0.365 vs 0.289, p&amp;lt;0.01) than HPAE-ECs. Immunostaining indicated altered cytoskeletal composition in CTEPH-ECs with significantly higher tubulin expression, expressed in microtubules, (3327 vs 2238AU, p&amp;lt;0.01) and F-actin microfilaments (2068 vs 1300AU, p&amp;lt;0.01) compared to HPAE. Similarly, CTEPH-ECs showed reduced G-actin expression (3002 vs 7461AU, p&amp;lt;0.01). Morphometric analysis demonstrated that microfilaments were thinner (0.623 vs 0.831AU, p&amp;lt;0.01), more straight (0.135 vs. 0.172, p&amp;lt;0.01) and more aligned (0.132 vs. 0.156, p&amp;lt;0.01) in CTEPH-ECs. Microtubule thickness decreased compared to HPAE-ECs (0.341 vs 1.371AU, p&amp;lt;0.01). CTEPH-ECs showed impaired wound healing (60 vs 89% closure, p&amp;lt;0.05). CTEPH group showed an increase in microtubules and microfilaments expression during wound healing, but with irregular patterns, unlike the constant levels in HPAE. TXM-technology revealed spatial organization differences, especially expansive microtubules distribution in CTEPH-ECs (4.2*10^7 vs. 8.7*10^6 nm³, p&amp;lt;0.05). Conclusion These preliminary findings highlight significant structural and compositional differences in CTEPH-ECs, along with altered wound healing capacity, suggesting dynamic cytoskeletal and cellular changes in CTEPH. Understanding these alterations is crucial for advancing CTEPH knowledge and identifying potential therapeutic targets.

Continuous heart monitoring to evaluate treatment effects in pulmonary hypertension

BackgroundThe treatment of pulmonary hypertension (PH) has improved rapidly in recent decades. There is increasing evidence to support the role of early intervention and treatment in affecting clinical outcomes in...

Patients with CTEPH and mild hemodynamic severity of disease improve to a similar level of exercise capacity after pulmonary endarterectomy compared to patients with severe hemodynamic disease.

The correlation between hemodynamics and degree of pulmonary vascular obstruction (PVO) is known to be poor in chronic thromboembolic pulmonary hypertension(CTEPH), which makes the selection of patients eligible for pulmonary endarterectomy (PEA) challenging. It can be postulated that patients with similar PVO but different hemodynamic severity have different postoperative hemodynamics and exercise capacity. Therefore, we aimed to assess the effects of PEA on hemodynamics and exercise physiology in mild and severe CTEPH patients. We retrospectively studied 18 CTEPH patients with a mild hemodynamic profile (mean pulmonary arterial pressure[mPAP] between 25 and 30 mmHg at rest) and CTEPH patients with a more severe hemodynamic profile (mPAP > 30 mmHg), matched by age, gender, and PVO. Cardiopulmonary exercise testing parameters were evaluated at baseline and 18 months following PEA. At baseline, exercise capacity, defined as oxygen uptake, was less severely impaired in the mild CTEPH group compared to the severe CTEPH group. After PEA, in the mild CTEPH group, ventilatory efficiency and oxygen pulse improved significantly (p < 0.05), however, the change in ventilatory efficiency and oxygen pulse was smaller compared to the severe CTEPH group. Only in the severe CTEPH group exercise capacity improved significantly (p < 0.001). Hence, in the present study, postoperative hemodynamic outcome and the CPET-determined recovery of exercise capacity in mild CTEPH patients did not differ from a matched group of severe CTEPH patients.

INCREASED LEVELS OF PROINFLAMMATORY CYTOKINES IN BLOOD PLASMA IN PATIENTS WITH CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION

HighlightsIL-8 and MCP-1 have a significant role in the CTEPH pathogenesis, which indicates the importance of nonspecific immunity in the formation and progression of CTEPH. The coupling between cytokines and hemodynamic parameters, cardiac structural changes and plasma biochemical parameters were determined. AbstractBackground. Chronic thromboembolic pulmonary hypertension (CTEPH) pathogenesis is complex and not fully understood. Particular attention to the microvascular damage genesis in CTEPH is given to aseptic inflammation, which in turn could be mediated through various molecular mechanisms. According to the conflicting and incomplete data on changes in the profile of factors controlling inflammation in CTEPH, research in this field would identify new therapeutic targets for the prevention and treatment of CTEPH.Aim. To study the profile of plasma proinflammatory cytokines in patients with chronic thromboembolic pulmonary hypertension (CTEPH) and evaluate the coupling of these cytokines with the main morphofunctional and laboratory values of the disease severity.Methods. 34 patients with CTEPH were included in this study. To characterize the group, the following methods were used: echocardiographic examination, catheterization of the right cardiac chambers. Biomarkers of heart failure, systemic inflammation, as well as erythropoiesis and iron metabolism were assessed in all patients. The control group included 10 donors. To study the proinflammatory cytokine profile in plasma, interleukins (IL) 6, 8, 18, monocyte chemoattractant protein-1 (MCP-1) and matrix metalloproteinase 9 were determined using standard enzyme-linked immunosorbent assay (ELISA) kits.Results. Hemodynamic and morphofunctional changes in the pulmonary circulation specific to pulmonary hypertension were determined with catheterization of the right cardiac chambers and echocardiography. During plasma proinflammatory cytokines analysis, a significant increase in the level of IL-8 (p = 0.030) and MCP-1 (p = 0.031) in CTEPH group compared to the control group was observed. No significant differences for other analyzed markers were found. In the elaboration of the correlation analysis, moderate inverse coupling between proinflammatory markers and hemodynamic parameters characterizing the CTEPH severity were revealed, as well as positive correlations with parameters of remodeling of the right cardiac chambers and iron metabolism.Conclusion. The increased levels of IL-8 and MCP-1 in patients with CTEPH identified in the present study indicate a significant role of nonspecific immunity in the formation and progression of CTEPH. The coupling between cytokines and hemodynamic parameters, structural cardiac changes and plasma biochemical parameters were determined. Based on the obtained data, it is possible to develop new medicinal substances, targeting towards proinflammatory cytokines, their receptors and signaling pathways.

Comparison of cardiovascular metrics on computed tomography pulmonary angiography of the updated and old diagnostic criteria for pulmonary hypertension in patients with chronic thromboembolic pulmonary hypertension.

In the 2022 European Society of Cardiology (ESC) and the European Respiratory Society (ERS) guidelines, the diagnostic criteria for pulmonary hypertension (PH) included a reduced mean pulmonary artery pressure (mPAP) of 20 mmHg (mPAP >20 mmHg). This study aimed to reassess cardiovascular metrics on computed tomography pulmonary angiography (CTPA) for chronic thromboembolic pulmonary hypertension (CTEPH) to optimize the timely diagnosis of patients with suspected PH. Patients with suspected CTEPH who underwent CTPA and right heart catheterization (RHC) between January 2019 and December 2022 in China-Japan Friendship Hospital were retrospectively included. They were grouped into CTEPH and non-PH groups according to the new and old criteria (2022 and 2015 ESC/ERS guidelines) for the diagnosis of PH. Cardiovascular metrics including the main pulmonary artery diameter (MPAd), Cobb angle, and right ventricular free wall thickness (RVWT), among others, were measured. The correlation of these metrics with hemodynamic data was analyzed with Spearman rank correlation analysis, while the differences in cardiovascular metrics between the updated (mPAP >20 mmHg) and old PH criteria (mPAP ≥25 mmHg) were compared with independent samples t-test or the Mann-Whitney test. Receiver operator characteristic (ROC) curve analysis was performed for the prediction model. The study enrolled 180 patients (males n=86; age 55.5±12.0 years old). According to the old guidelines, 119 patients were placed into the PH group (mPAP ≥25 mmHg) , while according to the new guidelines, 130 patients were placed into the PH group (mPAP >20 mmHg). Cardiovascular metrics on CTPA between the updated and old guidelines were comparable (P>0.05). Compared to other metrics, an MPAd of 30.4 mm exhibited the highest area under the curve (AUC: 0.934±0.021), with a sensitivity of 0.88 and specificity of 0.90. MPAd [odds ratio (OR) =1.271], transverse diameter of the right ventricle (RVtd; OR =1.176), Cobb angle (OR =1.108), and RVWT (OR =3.655) were independent factors for diagnosing CTEPH (P<0.05). Cobb angle, right and left ventricular transverse diameter ratio, and right and left ventricular area ratio moderately correlated with mPAP (r=0.586, r=0.583, r=0.629) and pulmonary vascular resistance (PVR) (r=0.613, r=0.593, r=0.642). Cardiovascular metrics on CTPA were comparable between the new and old guidelines for CTEPH diagnosis. Cardiovascular metrics on CTPA can noninvasively assess the hemodynamics of patients with CTEPH.

Comparison of pulmonary vascular tortuosity and fractal dimension in patients with chronic thromboembolic pulmonary disease and chronic thromboembolic pulmonary hypertension

Objective: To compare the differences in pulmonary vascular morphological parameters between patients with chronic thromboembolic pulmonary disease (CTEPD) and chronic thromboembolic pulmonary hypertension(CTEPH), and to explore the value of pulmonary artery morphology in the differential diagnosis of CTEPD and CTEPH. Methods: Thirty-nine patients with CTEPH [14 males, 25 females, mean age: (54.1±12.4) years] and 29 patients with CTEPD [10 males, 19 females, mean age: (51.4±18.0) years] from January 2018 to December 2020 were retrospectively included. The pulmonary artery and vein tree was segmented from the computed tomography pulmonary angiography (CTPA) images, and the morphological parameters of pulmonary vessels including the number of pulmonary arteries, pulmonary arterial tortuosity(distance metric, DM) and fractal dimension (FD), were calculated. The differences in pulmonary vascular morphological parameters between the two groups were compared, and the correlation between morphological parameters and hemodynamics was analyzed. Results: There was no significant difference in gender and age between CTEPH and CTEPD groups (χ2=0.015,P=0.904 & t=-0.729, P=0.469). The number of pulmonary arteries in CTEPH group (n=249.43±76.27) was significantly lower than that in CTEPF group (n=298.79±78.11, t=2.612, P=0.011). The pulmonary arterial tortuosity in CTEPH group (DM=1.26±0.17) was significantly higher than that in CTEPD group (DM=1.17±0.10, t=3.516, P=0.002). There was no significant difference in FD between CTEPH and CTEPD (FD=3.01±0.21 & 3.08±0.22, t=1.359, P=0.179). The number of pulmonary arteries was negatively correlated with pulmonary vascular resistance (r=-0.325, P=0.026). Pulmonary arterial tortuosity was positively correlated with mean pulmonary artery pressure (r=0.387,P=0.017), and was positively correlated with pulmonary vascular resistance (r=0.647, P<0.001). Conclusion: Pulmonary artery curvature is an important morphological parameter in differentiating CTEPH from CTEPD, and is related to mean pulmonary artery pressure and pulmonary vascular resistance.

Chronic thromboembolic pulmonary hypertension is associated with a loss of total lung volume on computed tomography.

Although lung volumes are usually normal in individuals with chronic thromboembolic pulmonary hypertension (CTEPH), approximately 20%-29% of patients exhibit a restrictive pattern on pulmonary function testing. To quantify longitudinal changes in lung volume and cardiac cross-sectional area (CSA) in patients with CTEPH. In a retrospective cohort study of patients seen in our hospital between January 2012 and December 2019, we evaluated 15 patients with CTEPH who had chest computed tomography (CT) performed at baseline and after at least 6 mo of therapy. We matched the CTEPH cohort with 45 control patients by age, sex, and observation period. CT-based lung volumes and maximum cardiac CSAs were measured and compared using the Wilcoxon signed-rank test and the Mann-Whitney u test. Total, right lung, and right lower lobe volumes were significantly reduced in the CTEPH cohort at follow-up vs baseline (total, P = 0.004; right lung, P = 0.003; right lower lobe; P = 0.01). In the CTEPH group, the reduction in lung volume and cardiac CSA was significantly greater than the corresponding changes in the control group (total, P = 0.01; right lung, P = 0.007; right lower lobe, P = 0.01; CSA, P = 0.0002). There was a negative correlation between lung volume change and cardiac CSA change in the control group but not in the CTEPH cohort. After at least 6 mo of treatment, CT showed an unexpected loss of total lung volume in patients with CTEPH that may reflect continued parenchymal remodeling.

Automated quantification of the pulmonary vasculature in pulmonary embolism and chronic thromboembolic pulmonary hypertension.

The shape and distribution of vascular lesions in pulmonary embolism (PE) and chronic thromboembolic pulmonary hypertension (CTEPH) are different. We investigated whether automated quantification of pulmonary vascular morphology and densitometry in arteries and veins imaged by computed tomographic pulmonary angiography (CTPA) could distinguish PE from CTEPH. We analyzed CTPA images from a cohort of 16 PE patients, 6 CTEPH patients, and 15 controls. Pulmonary vessels were extracted with a graph-cut method, and separated into arteries and veins using deep-learning classification. Vascular morphology was quantified by the slope (α) and intercept (β) of the vessel radii distribution. To quantify lung perfusion defects, the median pulmonary vascular density was calculated. By combining these measurements with densities measured in parenchymal areas, pulmonary trunk, and descending aorta, a static perfusion curve was constructed. All separate quantifications were compared between the three groups. No vascular morphology differences were detected in contrast to vascular density values. The median vascular density (interquartile range) was -567 (113), -452 (95), and -470 (323) HU, for the control, PE, and CTEPH group. The static perfusion curves showed different patterns between groups, with a statistically significant difference in aorta-pulmonary trunk gradient between the PE and CTEPH groups (p = 0.008). In this proof of concept study, not vasculature morphology but densities differentiated between patients of three groups. Further technical improvements are needed to allow for accurate differentiation between PE and CTEPH, which in this study was only possible statistically by measuring the density gradient between aorta and pulmonary trunk.

Abstract 15033: Chronic Thromboembolic Pulmonary Hypertension Patients Have Reduced Bi-Ventricular Myocardial Perfusion Reserve, Which Improves Following Pulmonary Thromboendarterectomy

Introduction: This study seeks to determine whether bi-ventricular myocardial perfusion reserve (MPR) is reduced in patients with chronic thromboembolic pulmonary hypertension (CTEPH) compared to a control group using quantitative myocardial perfusion MRI. Methods: We prospectively enrolled 4 CTEPH patients (55±14 years, 4 males) and performed stress-rest (10 min apart) protocol using our 5-fold accelerated radial perfusion sequence. In one patient, we repeated stress-rest perfusion acquisition following pulmonary thromboendarterectomy (PTE). As a control group, we retrospectively identified 8 subjects (49±12 years, 5 males) with no evidence of vascular late gadolinium enhancement or perfusion defects who underwent a similar stress-rest protocol. The pixel-wise stress-rest myocardial blood flow (MBF) maps and MPR were quantified for both the left ventricular (LV) and right ventricular (RV) free walls. Two sample t-test was used to compare between the CTEPH and control groups. Results: Figure 1a shows representative stress and rest MBF maps and the corresponding MPR values comparing a CTEPH patient and a control subject. Summarizing the results of all patients (Figure 1b), compared to the control group, the CTEPH group had significantly (p &lt; 0.05) lower stress LV MBF (1.56 ± 0.34 vs. 2.66 ± 0.50 ml/g/min), RV MBF (1.48 ± 0.19 vs. 2.56 ± 0.53 ml/g/min), LV MPR (1.65 ± 0.43 vs. 2.32 ± 0.50), and RV MPR (1.59±0.46 vs. 2.50 ± 0.53), but non-significant difference (p &gt; 0.05) in resting LV MBF (0.96 ± 0.12 vs. 1.21 ± 0.43 ml/g/min) and RV MBF (0.96 ± 0.14 vs. 1.07 ± 0.36 ml/g/min). In one patient, PTE improved RV MPR from 1.43 to 2.49 as well as LV MPR from 1.24 to 2.36. Conclusions: This study suggests that both RV and LV MPR are reduced in CTEPH patients compared with controls and that PTE may improve RV as well as LV MPR in CTEPH patients. Future studies include additional enrollment of CTEPH patients, determining the diagnostic and prognostic role of RV and LV MPR in the context of PTE.

Analysis of the dynamics of the daily variability of the sinus rhythm according to Holter monitoring to assess the effectiveness of treatment of patients with pulmonary hypertension

Purpose: search for criteria for assessing the relationship between the dynamics of the patient’s condition with pulmonary hypertension according to clinical and instrumental examination with the dynamics of the daily variability of his sinus rhythm. Material and methods. The study included 25 patients with idiopathic pulmonary hypertension (IPH) and 25 patients with chronic thromboembolic pulmonary hypertension (CTPH), who were examined twice at two different hospitalizations: before treatment and after 6–18 months to assess the effectiveness of treatment (50 pairs of examinations). In all examinations, the daily HRV was evaluated according to the Holter ECG data. The functional state was determined comprehensively taking into account the FCLH and the distance covered in the 6-minute walk test. In all patients, the right atrium area (RAA) was determined according to EchoCG data. In 15 out of 50 patients, catheterization of the right parts of the heart (CRPH) was performed during two examinations with determination of pressure in the right atrium (PRA), in the right ventricle, in the pulmonary artery and jamming pressure in the pulmonary artery, as well as oximetry with determination of oxygen saturation of mixed venous blood (SvO2) and cardiac index (CI).The parameters of the daily HRV were determined using a modifi cation of the VSRA-SSR method, taking into account the presence of double fractures (DFR) on the rhythmogram. The dynamics of the parameters of the daily HRV were compared with the dynamics of the functional state, ARA, and also (in 15 cases) — with the dynamics of the average PRA (aPRA), SI and SvO2. Results 1. The connection between the dynamics of the results of a comprehensive assessment of the functional state of patients with PH and the dynamics of the parameters of their daily HRV is traced. A reflection of this is both a large percentage of cases with unidirectional dynamics of the functional state and HRV, and a small number of cases with multidirectional dynamics. These trends are especially evident in the treatment of patients with IPH. There is a high percentage of coincidences of HRV dynamics and right atrium area (RAA) according to EchoCG data, and this percentage is the highest (with a small number of cases with multidirectional dynamics) in the CTPH group. In most cases, CRPH revealed the correspondence of HRV dynamics to the dynamics of oxygen saturation of SvO2 and SI. Conclusion. HRV analysis over long periods of time in patients with hypertension can be used not only to assess the functional state of the patient, but also to assess the dynamics of the functional state of the patient, reflecting the effectiveness of the treatment.

Evaluation of the profile of circulating extracellular vesicles of different cell origin and their activity in patients with postthromboembolic syndrome

Background. Chronic thromboembolic pulmonary hypertension (CTEPH) and chronic thromboembolic disease (CTEP) are manifestations of post-thromboembolic syndrome in patients with pulmonary embolism. Extracellular vesicles (EVs) are involved in the pathogenesis of these diseases due to the activation of the hemostasis system.Objective. Evaluation of the relative amount of EVs and their coagulation activity using the thrombin generation test in CTEP and CTEPH patients. Design and methods. The study included 21 patients: the CTEP group (n = 7) and the CTEPH group (n = 14); and 11 healthy donors. EVs were isolated with the Exo-FACS kit and analyzed by flow cytometry using fluorescently labeled antibodies. The activity of the microparticles was assessed in a thrombin generation test using a trigger reagent without the addition of TF using a plate fluorimeter.Results. The relative content of EVs of platelet and endothelial origin was increased in CTEPH and CTEP groups. The level of platelet EVs correlates with the levels of CRP and D-dimer. LT and ttPeak were significantly increased in patients with CTEPH.Conclusion. An increase in the level of platelet and endothelial EVs in patients with CTEPH and CTEP indicates the contribution of microvesiculation to the formation of post-thromboembolic syndrome. The activity of thrombin generation decrease under the action of TF-EVs could be a result of TF consumption in endothelial dysfunction, or prolonged activation of procoagulant pathways.

Metformin Improves Pulmonary Artery Remodeling in Chronic Thromboembolic Pulmonary Hypertension Rats

Abstract Background To investigate the effect of metformin on pulmonary artery remodeling and indexes of endothelial–mesenchymal transition in rats with chronic thromboembolic pulmonary hypertension (CTEPH). Methods Sixty Sprague Dawley rats were randomly divided into normal control, metformin control, CTEPH, metformin low-dose (50 mg/kg d) CTEPH, and metformin high-dose group (100 mg/kg d) CTEPH groups. The autologous blood clots were repeatedly injected through the jugular vein to establish the CTEPH model. After 6 weeks treatment with or without metformin, the mean pulmonary artery pressure (mPAP), pulmonary artery wall area to total tube area ratio (WA%), and protein levels of vimentin, α-smooth muscle actin (α-SMA), CD31, E-cadherin, β-catenin, and p-adenosine 5′-monophosphate activated protein kinase (p-AMPK) in the pulmonary artery were measured. Results The mPAP and WA% were significantly higher in CTEPH compared with normal control rats (P &amp;lt; 0.05). Metformin treatment dose dependently decreased mPAP and WA% in CTEPH rats (P &amp;lt; 0.01). Compared with normal controls, protein levels of vimentin, α-SMA, and β-catenin were significantly increased while CD31 and E-cadherin levels were decreased in CTEPH rats (all P &amp;lt; 0.05). There was no significant difference in p-AMPK levels between normal control and CTEPH groups. Metformin treatment increased p-AMPK (P &amp;lt; 0.05) but had no significant effect on vimentin, α-SMA, CD31, E-cadherin, or β-catenin levels in control rats. Metformin treatment dose dependently decreased vimentin, α-SMA, and β-catenin levels, and increased CD31, E-cadherin, and p-AMPK levels in CTEPH rats (P &amp;lt; 0.05). Conclusions Metformin reduces mPAP and improves pulmonary vascular remodeling possibly through attenuating endothelial–mesenchymal transition of the pulmonary artery in CTEPH rats.

Diagnosis of Chronic Thromboembolic Pulmonary Hypertension Using Quantitative Lung Perfusion Parameters Extracted From Dual-energy Computed Tomography Images.

To evaluate quantified iodine mapping parameters in dual-energy computed tomography in normal patients versus those with chronic thromboembolic pulmonary hypertension (CTEPH) with and without pulmonary thromboembolism. Using automatically quantified iodine mapping in dual-energy computed tomography, we evaluated lung relative average enhancement, standard deviation (SD), and the SD/lung relative average enhancement ratio. We compared the values for these parameters in normal patients versus those with CTEPH. We also performed a receiver operating characteristic curve analysis to determine the diagnostic cutoffs for the parameters. Patients constituted 41 patients (10 male [24.4%] and 31 female [75.6%]; mean age [SD]: 70.0 y [13.3]) with CTEPH and 237 (92 male [38.8%] and 145 female [61.2%]; mean age [SD]: 65.9 y [15.9]) normal patients. We found significant differences in lung relative average enhancement (34.9±6.3 vs. 26.9±6.3; P <0.0001), SD (11.6±1.9 vs. 14.7±3.3; P <0.001), and the SD/lung relative average enhancement ratio (33.7±5.0 vs. 55.7±10.4; P <0.001) between the normal and CTEPH groups, respectively. The ROC analyses demonstrated high discriminatory power (area under the curve=0.99) for using the SD/lung relative average enhancement ratio to differentiate between patients in the normal group and CTEPH group. At a threshold for the area under the curve of 44.2, diagnostic sensitivity, specificity, positive predictive value, and negative predictive value for the ratio were 92.7%, 97.5%, 86.5%, and 98.7%, respectively. Patients with CTEPH were well-discriminated from normal patients using the SD/lung relative average enhancement ratio.

Identification of a Novel Gene Correlated With Vascular Smooth Muscle Cells Proliferation and Migration in Chronic Thromboembolic Pulmonary Hypertension.

Objective: Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by thrombofibrotic obstruction of the proximal pulmonary arteries, which result in vascular remodeling of the distal pulmonary artery. While the cellular and molecular mechanisms underlying CTEPH pathogenesis remain incompletely understood, recent evidence implicates vascular remodeling. Here, we identify the molecular mechanisms that contribute to vascular remodeling in CTEPH.Methods: Microarray data (GSE130391) for patients with CTEPH and healthy controls were downloaded from the Gene Expression Omnibus (GEO) and screened for differentially expressed genes (DEGs). DEGs were functionally annotated using Gene Ontology (GO) functional analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. A protein–protein interaction (PPI) network was constructed to identify hub genes. Finally, pulmonary artery samples were harvested from patients with CTEPH (n = 10) and from controls (n = 10) and primary vascular smooth muscle cells (VSMCs) were cultured. Effects of the proto-oncogene FOS on VSMC proliferation and migration were assessed using expression and knockdown studies.Results: We detected a total of 292 DEGs, including 151 upregulated and 141 downregulated genes. GO analysis revealed enrichment of DEGs in biological processes of signal transduction, response to lipopolysaccharide, signal transduction, and myeloid dendritic cell differentiation. Molecular function analysis revealed enrichment in tumor necrosis factor (TNF)-activated receptor activity, transcriptional activator activity, and protein homodimerization activity. The expression of TNF-α and its receptor (sTNFR1 and sTNFR2) were significantly higher in CTEPH group, compared with control group. KEGG pathway analysis revealed enrichment in salmonella infection, pathways in cancer, osteoclast differentiation, and cytokine-cytokine receptor interaction. Hub genes in the PPI included FOS, suggesting an important role for this gene in vascular remodeling in CTEPH. Primary VSMCs derived from patients with CTEPH showed increased FOS expression and high proliferation and migration, which was attenuated by FOS inhibition. In control VSMCs, TNF-α treatment increased proliferation and migration, which FOS inhibition likewise attenuated.Conclusion: TNF-α drives CTEPH pathogenesis by promoting VSMC proliferation and migration via increased FOS expression. These results advance our understanding of the molecular mechanisms of vascular remodeling in CTEPH, and may inform the development of new therapeutic targets.

Diagnostic value of right heart and pulmonary artery catheterization in patients with suspected pulmonary hypertension. Part 2. Invasive study of parameters of hemodynamics and oxygen transport

The aim – evaluate the parameters of pulmonary and systemic hemodynamics obtained in patients with various forms of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) in Ukraine.Materials and methods. The study included 195 patients: IPAH was in 68 patients; PAH associated with connective tissue diseases (CTD) – in 21 patients; PAH associated with HIV infection – in 4 patients; PAH associated with portal hypertension (PH) – in 4 patients; PAH associated with congenital heart disease – in 25 patients; CTEPH – in 51 patients, pulmonary hypertension (PH) associated with left heart disease (LHC) – in 5 patients and 17 patients who were excluded from the diagnosis of PH. From 2014 to 2019, these patients underwent 220 procedures of right heart catheterization (RHC) in accordance with current European Guidelines. Also, all patients underwent echocardiographic examination and determined the gas composition of blood and indicators of acid-base balance using the ABL 735 analyzer, calculated the parameters of the affinity of hemoglobin to oxygen (p50).Results and discussion. The lowest level of arterial blood oxygen saturation was in the group of patients with PH due to LHD – 88.9 % (p&lt;0.05); in other groups it averaged 94–97 %. The oxygen content in arterial blood was the lowest in the group of patients with PH due to LHD – 15.7 ml/L (p&lt;0.05); in other groups this indicator was equal to 17.4–18.7 ml/L. The lowest oxygen saturation of mixed venous blood (SvO2) was in the PAH group associated with HIV – 58 % (p&lt;0.05), and close to critical (&lt; 65 %) SvO2 level was observed in the IPAH group – 66.3 %. CTEPH – 66.0 %. The highest level of this indicator was in the PAH group associated with portal hypertension – 81.1 %. The arterio-venous difference was highest in the PAH associated with HIV group – 5.6 ml/L, and the smallest in the PAH associated with PH group – 2 ml/L. On the other hand, the oxyhemoglobin dissociation curve was almost normal in all groups, except for the group of patients with PAH associated with portal hypertension.Conclusions. The most severe disorders of hemodynamics and oxygen transport were observed in the group of PAH patients associated with HIV compared with other forms of PAH and CTEPH. The IPAH and CTEPH groups were similar in terms of hemodynamics, despite a different pathophysiological mechanism. In the group of patients with PAH associated with CTD, the results of the RHC were slightly better than in the group of patients with IPAH, reflecting that the hemodynamic component is not the leading one for prognosis in these patients. Also, the performance of the right ventricle was significantly higher in patients with PAH compared with the group without PH.

The biventricular dysfunction evaluation in the different types of pulmonary hypertension

Abstract Background Right ventricular (RV) function is well-known prognostic factor in patients with pulmonary hypertension (PH). However, situation becomes critical when underfilling of left ventricle (LV) leads to systemic hypoperfusion and scenario worsening. Objective To evaluate the relationship of RV and LV dysfunction in patients with the different forms of PH. Methods We evaluated parameters of RV and LV function and their relationship during right heart catheterization (RHC) in 125 patients with different forms of pulmonary arterial hypertension (PAH) and 51 patients with chronic thromboembolic PH (CTEPH), 7 patients with PH associated with left heart disease (LHD) and 17 patients in whom PH was excluded after procedure. In all patients recommended echocardiography protocol (Echo) and NT-proBNP level evaluation were performed. Results In the group without PH the RV stroke work index (RVSWI) level and its ratio to the LV stroke work index (LVSWI) were lowest and in the normal range: 7,0±0,7 ml·mmHg/m2 and 0,13±0,02 respectively. In all patients with PH, we noted the significant elevation of RVSWI &amp;gt;20 ml·mmHg/m2. Patients with PAH and CTEPH had a smaller left atrium, LV volumes on Echo and decreased stroke volume and pulmonary artery wedge pressure. The underfilling of LV in IPAH and CTEPH groups accompanied by severe lowering of LWSWI to 35–45 ml·mmHg/m2 (p&amp;lt;0,05 compared with LHD group and patients without PH). In spite of the levels of cardiac index were similar in patients with LHD and without PH, the RVSWI (23,1±2,7 ml·mmHg/m2) and its RVSWI/LVSWI ratio (0,53±0,09) were significantly higher in LHD group and confirmed severe RV overload. Only in HIV infection group observed severe depression of the pumping function of both heart's sides and levels of RWSWI and LVSWI were lowest, but the ratio was elevated (0,53) and indicated RV overload. Similar data were observed when we compare pumping coefficients of RV and LV in different groups. We did not find any association between NT-proBNP level and the LV volume and function. Conclusion The simultaneous evaluation of parameters of RV and LV function and their ratio during RHC in patients with different types of PH allowed not just to estimate the degree of RV overload and dysfunction, but also LV underfilling and dysfunction. Funding Acknowledgement Type of funding sources: None.

Different characteristics of mitochondrial dynamics-related miRNAs on the hemodynamics of pulmonary artery hypertension and chronic thromboembolic pulmonary hypertension

BackgroundMitochondria are dynamic organelles that undergo fission or fusion. These mitochondrial dynamics are reported to be associated with pulmonary hypertension (PH). PH is divided into 5 groups, including pulmonary artery hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH), based on its pathogenesis. However, it is still unknown whether and how miRNAs related to mitochondrial dynamics (MD) affect PAH and CTEPH. MethodsWe investigated patients who underwent right heart catheterization between October 2016 and January 2019. Out of 34 PH patients, 12 were diagnosed with PAH, and 22 were diagnosed with CTEPH. In addition, there were 30 patients diagnosed with left heart disease. We enrolled the 34 PH patients as the PH group and 30 left heart disease patients as the control group. ResultsAmong MD-related miRNAs, the circulating levels of miR-140-3p were higher, and those of miR-485-5p were lower in the PH group than in the control group (p < 0.01), suggesting that miRNAs inducing mitochondrial fission are related to PH. The miR-140-3p levels in the PAH and CTEPH groups were higher than those in the control group (p < 0.01). The levels of miR-140-3p and miR-485-5p in the PAH group correlated with pulmonary vascular resistance (r = 0.582, p = 0.046) and cardiac index (r = −0.36, p = 0.04), respectively. The miR-485-5p levels in the CTEPH group correlated with right atrium pressure (r = −0.456, p = 0.049). ConclusionMD-related miRNAs levels change to induce fission and are closely related to the hemodynamics of PAH and CTEPH.

Endostatin and Vascular Endothelial Growth Factor-A165b May Contribute to Classification of Pulmonary Hypertension.

Background: Pulmonary hypertension (PH) is characterized by dysregulation of small pulmonary arteries. In addition to endostatin (ES), placenta growth factor (PlGF), vascular endothelial growth factor-A (VEGF-A), and the anti-angiogenesis isoform of VEGF-A (VEGF-A165b) are associated with PH. However, the usefulness of these biomarkers in PH in unknown. We investigated whether these 4 biomarkers are related to PH classification.Methods and Results: Between July 2015 and August 2017, 33 control patients and 107 PH patients were enrolled in the study. Among the PH patients, 48 had pulmonary arterial hypertension (PAH), 5 had left heart disease-associated PH (LHD-PH), 4 had lung disease-associated PH (LD-PH), and 50 had chronic thromboembolic PH (CTEPH). Among the PAH patients, 16 had idiopathic PAH (IPAH) and 17 had connective tissue disease-associated PAH (CTD-PAH). PlGF, total VEGF-A, and VEGF-A165b levels were measured in the control and PH groups. ES was only measured in the PH group. VEGF-A165b levels were significantly higher in the LD-PH group than in the PAH, LHD-PH, and CTEPH groups (all P<0.001). PlGF levels were significantly higher in the CTD-PAH group than in the IPAH and control groups. ES levels were significantly correlated with the 6-min walk distance (P<0.001), B-type natriuretic peptide (P<0.001), and pulmonary vascular resistance (P=0.008).Conclusions: ES could detect CTD-PAH in PAH and may be an indicator of PH severity. VEGF-A165b was useful in detecting LD-PH.