Chronic Thromboembolic Pulmonary Hypertension Patients Research Articles

Exploring the Endothelin-1 pathway in chronic thromboembolic pulmonary hypertension microvasculopathy.

Targeted vasopeptide therapies have significantly advanced the management of pulmonary arterial hypertension (PAH). However, due to insufficient preclinical evidence regarding the involvement of the endothelin-1 (ET-1) pathway in chronic thromboembolic pulmonary hypertension (CTEPH) pathophysiology, the potential of ET-1 receptor antagonism in treating CTEPH remains uncertain. In this study, we investigated the role of the ET-1 pathway in CTEPH microvasculopathy using a multifaceted approach. Plasma ET-1 levels were measured in a cohort of 59 CTEPH patients and 41 healthy controls. Additionally, we evaluated the expression of key ET-1 pathway members in pulmonary explants from CTEPH, idiopathic PAH, and control patients. We used an in vitro system to test the hypothesis that the turbulent flow, observed near the vascular obstructions pathognomonic of CTEPH, enhances ET-1 expression. Our findings were further validated in vivo using a CTEPH piglet model that contains distinct regions representing pre- and post-thrombus lung territories. We found a twofold increase in circulating ET-1 levels in CTEPH patients compared to healthy subjects. Pulmonary explants from CTEPH patients exhibited pronounced overexpression of ET-1, endothelin receptor A (ETA), and phosphorylated myosin light chain (p-MLC) in muscularized pulmonary microvessels, suggesting heightened vascular contraction. In vitro experiments showed that turbulent flow facilitates ET-1 secretion compared to laminar flow regions. Additionally, in the CTEPH piglet model, elevated plasma ET-1 levels were observed compared to controls. Immunofluorescence and confocal microscopy analyses confirmed increased ETA and p-MLC in remodeled arteries from both pulmonary territories. However, ET-1 protein elevation was exclusively observed in the obstructed territory. These findings collectively indicate impaired vascular tone in microvessels of CTEPH patients and the CTEPH piglet model. Furthermore, our data implicates the ET-1 pathway in microvasculopathy, with turbulent flow playing a pathological role. These insights underscore the potential utility of ET-1 receptor antagonists as a promising therapeutic approach for CTEPH treatment.

Abstract 4123631: Significance of collagen triple helix repeat-containing protein 1 as a right ventricular biomarker in pulmonary hypertension

Background: Right ventricular failure is a major prognostic determinant of pulmonary hypertension and progresses with myocardial fibrosis. Extracellular matrix proteins play a major role in myocardial fibrosis. Right ventricular biomarkers for right ventricular function and fibrosis are poorly examined in pulmonary hypertension. This study investigated the significance of collagen triple helix repeat-containing protein 1 (CTHRC1), one of the extracellular matrix proteins, as a right ventricular biomarker. Methods and Results: A monocrotaline-induced pulmonary hypertension rat model was used in this study. CTHRC1 expression in the right ventricle was higher in rats with monocrotaline-induced pulmonary hypertension than in controls. CTHRC1 was associated with fibrosis in the rat's right ventricle. Next, human circulating CTHRC1 levels were evaluated in controls (n = 20), pulmonary arterial hypertension (PAH, n = 46), and chronic thromboembolic pulmonary hypertension (CTEPH) patients (n = 64). Human circulating CTHRC1 levels were higher in PAH (P = 0.006) and CTEPH patients (P = 0.011) than in controls (Figure). Human circulating CTHRC levels were correlated with tricuspid lateral annular peak systolic velocity (R = -0.213, P = 0.029), right ventricular fractional area change (R = -0.225, P = 0.017), and right ventricular global longitudinal strain evaluated by magnetic resonance imaging (R = 0.429, P = 0.009). In addition, human circulating CTHRC1 levels were decreased after balloon pulmonary angioplasty (P < 0.001) in CTEPH patients. Conclusions: CTHRC1 could be a novel biomarker associated with right ventricular failure and fibrosis in pulmonary hypertension patients.

Abstract 4136316: BMP10 as novel marker for right atrial dilatation and pressure in precapillary pulmonary hypertension

Introduction: Precapillary pulmonary hypertension (precPH) leads to increased right atrial (RA) stretch and pressure. The right atrium is the major source of bone morphogenetic protein 10 (BMP10) in adults. Aim: This study aims to investigate BMP10 in relation to RA dilatation and pressure overload. Methods: We studied BMP10 mRNA in fresh RA tissue of N=5 Chronic Thromboembolic Pulmonary Hypertension (CTEPH) patients and N=9 controls and protein expression in paraffin-embedded RA tissue of N=4 Pulmonary Arterial Hypertension (PAH) patients and N=6 controls. We prospectively included 48 precPH patients (N=22 idiopathic PAH, N=14 hereditary PAH and N=12 CTEPH, and N=16 controls. To study BMP10-induced transcriptional activity, we assayed serum samples in human microvascular endothelial cells (HMEC) with a BMP-responsive transcriptional luciferase assay. BMP10 activity was calculated by subtracting BMP activity after incubation with antibodies for Alk1Fc and bone morphogenetic protein 9 (BMP9). We assessed correlations between BMP10 activity and RA dilatation (RA max volume>79 ml/m 2 for male or >69 ml/m 2 for female) and right ventricular (RV) dilatation (RV end-diastolic volume>108 ml/m 2 for male and >96 ml/m 2 for female). In a cohort of CTEPH patients that underwent pulmonary endarterectomy (PEA) we assessed the effect of pressure unloading on BMP10 activity. Normality of data was checked and statistical differences between groups were tested using an independent sample t-test or Wilcoxon rank-sum test. Results: BMP10 mRNA, protein and downstream activity were higher in the precPH RA tissue (Figure 1A-F). High systemic BMP10 activity was associated with RA dilatation and high RA pressure, but not RV dilatation in precPH (Figure 2A-C). Finally, pressure unloading after PEA in CTEPH patients results in a reduction in BMP10 activity (figure 2D). Conclusions: Local RA BMP10 expression and activity is increased in precPH. Increased systemic BMP10 activity was related to RA dilatation and pressure. Pressure unloading of the right heart leads to a reduction of systemic BMP10 activity. Future studies are needed to determine whether increased BMP10 release is an adaptative mechanism or can be used as therapeutic target.

Abstract 4115531: Relationship between Ventricular Workload and Functional Response to Balloon Pulmonary Angioplasty (BPA) Therapy for Chronic Thromboembolic Pulmonary Hypertension (CTEPH)

Background: WHO functional classification (FC) is used to evaluate clinical response to BPA therapy and is associated with hemodynamic improvements in CTEPH patients. The relationships between FC and specific metrics of left and right ventricular workload during BPA remain unclear. Methods: CTEPH patients who underwent at least six BPA sessions and were included in the UCSD BPA registry were included for analysis. Left ventricular (LV) and right ventricular (RV) cardiac power output (CPO) and stroke work index (SWI) using thermodilution cardiac output were measured, along with FC, during each BPA session. BPA “responders” showed improved FC from III/IV at baseline to I/II after BPA therapy. BPA “non-responders” had unchanged FC III/IV symptoms before and after BPA therapy. ANOVA and Student T tests were used and P-value <0.05 was significant. Results: A total of 66 subjects (55.5% female, BMI 28.3±6.10kg/m 2 ,16.7% prior pulmonary thromboendarterectomy surgery) were enrolled. Greater subject functionality by FC was significantly associated with higher LVCPO (class IV to I: 0.88±0.15, 0.94±0.28, 1.08±0.31, 0.95±0.27 watt; p<0.001), higher LVSWI (29.4±6.6, 35.6±9.4, 40.8±8.8, 43.4±11.1 g*m/beat/m 2 ; p<0.001), and lower RVCPO (0.37±0.10, 0.34±0.12, 0.34±0.14, 0.24±0.09 watt; p=0.003). RVSWI was not significantly associated with FC (14.8±3.7, 15.4±5.1, 15.1±5.0, 12.5±3.3 g*m/beat/m 2 ; p=0.075). Likewise, higher mean LVCPO (1.1±0.30 vs 0.93±0.27 watt; p<0.001) and LVSWI (41.1±9.1 vs 35.2±9.4 g*m/beat/m 2 ; p<0.001), but not RVCPO or RVSWI, were observed in subjects with FC I/II versus FC III/IV symptoms. BPA responders versus non-responders had higher overall LVCPO (1.01±0.27 vs 0.89±0.27 watt; p<0.001) and LVSWI (39.0±8.9 vs 33.2±8.4 g*m/beat/m 2 ; p<0.001), but not RVCPO (0.33±0.13 vs 0.34±0.13 watt; p=0.465) or RVSWI (15.2±4.8 vs 14.9±5.1 g*m/beat/m 2 ; p=0.694). Responders also had higher baseline LVSWI (p=0.029) and post-BPA LVSWI (p=0.028) compared to non-responders. Conclusions: CTEPH patient functionality and symptoms during BPA therapy are associated with metrics of left and right ventricular workload. Patients with more severe FC III/IV symptoms produce lower LV workload. Treatment responders with improved FC after BPA therapy achieve higher overall, pre-BPA, and post-BPA LV workload. Specific metrics of ventricular workload may be helpful determinants of CTEPH patient symptoms and BPA treatment response.

Abstract 4138793: Impact of diabetes mellitus on the severity and long-term outcomes of chronic thromboembolic pulmonary hypertension: a retrospective cohort study

Background: Previous studies have indicated that diabetes mellitus (DM) is linked to the severity and mortality of both pulmonary thromboembolism and pulmonary arterial hypertension. But the relationships between diabetes and chronic thromboembolic pulmonary hypertension (CTEPH) have not been discussed. This study aims to investigate the relationships of DM with disease severity and clinical worsening events in patients with CTEPH. Methods: We analysed data of patients with CTEPH from the National Center for Cardiovascular Diseases in China between January 1, 2013 and August 31, 2023. A 2-group propensity score matching was conducted to adjust for differences between CTEPH patients with and without DM, employing a 1:1 pairing algorithm. The association between DM and long-term adverse outcomes was appraised utilizing multivariable Cox regression models. Subgroup analyses, predicated on age, sex, World Health Organization functional class (WHO-FC) and body mass index, were carried out to evaluated interaction effects. Results: In total, 489 consecutive CTEPH patients were included in the study, with 25.97% diagnosed with DM. Subsequent matched analysis comprised 127 patients with DM and 127 without DM. CTEPH patients with DM exhibited inferior WHO-FC as well as cardiac index, elevated N-terminal pro–brain natriuretic peptide levels, pericardial effusion, tricuspid annular plane systolic excursion / systolic pulmonary arterial pressure ratio and pulmonary vascular resistance. After adjusting for confounding factors, DM remained independently associated with adverse outcomes in patients with CTEPH. In addition, further subgroup analyses disclosed a more robust association in patients without overweight or obesity. Conclusions: DM correlates with heightened severity of CTEPH and serves as an autonomous predictor of long-term prognosis in CTEPH. Moreover, this correlation is more pronounced in individuals devoid of overweight or obesity.

Abstract 4113405: The Role of Cardiac Power Output and Stroke Work Index in Balloon Pulmonary Angioplasty Therapy for Chronic Thromboembolic Pulmonary Hypertension

Background: Right ventricular (RV) and left ventricular (LV) measures of cardiac power output (CPO) and stroke work index (SWI) are existing markers of cardiac function and clinical outcomes. These metrics have not been used to evaluate the effects of balloon pulmonary angioplasty (BPA) therapy in patients with chronic thromboembolic pulmonary hypertension (CTEPH). Methods: CTEPH patients who underwent at least six BPA sessions and were included in the UC San Diego BPA registry were included for analysis. Left and right ventricular CPO and SWI during each session were recorded. Cardiac output was measured using the thermodilution technique. Differences in continuous variable measurements before versus after BPA therapy were evaluated using the Student T-test. P-value <0.05 was significant. Results: A total of 66 subjects underwent six consecutive BPA sessions (55.5% female, BMI 28.3±6.10kg/m 2 ,16.7% prior pulmonary thromboendarterectomy surgery) and were included for analysis. Measurements of RV function, including RVCPO (Pre-BPA 0.38±0.14 vs Post-BPA 0.30±0.13 W, p=0.001)(Figure 1) and RVSWI (Pre-BPA 16.52±5.09 vs Post-BPA 14.14±4.00 g*m/beat/m 2 , p=0.004) significantly decreased after BPA therapy. Measurements of LV function, including LVCPO (Pre-BPA 1.00±0.32 vs Post-BPA 1.04±0.31 W, p=0.523) (Figure 2) and LVSWI (Pre-BPA 37.13±10.14 vs Post-BPA 39.73±9.37 g*m/beat/m 2 , p=0.152) did not change significantly after BPA therapy. The ratio of LVCPO/RVCPO increased in stepwise fashion from baseline to the last BPA session (2.82± 0.95 vs. 3.54±1.31 W, p<0.001)(Figure 3). Conclusions: Hemodynamic work expended by the RV decreased after BPA therapy, while work expended by the LV remained unchanged during BPA therapy. The ratio of LV-to-RV work increased in a stepwise manner during consecutive BPA sessions. These measurements may be useful parameters to monitor clinical response to BPA therapy.

Peri-procedural complications in patients with chronic thromboembolic pulmonary hypertension who underwent balloon pulmonary angioplasty

Abstract Background Complication rate in patients with chronic thrombo-embolic pulmonary hypertension (CTEPH) who undergo balloon pulmonary angioplasty (BPA) is high, especially in patients with compromised pulmonary hemodynamics. Purpose Here we describe complications based on the new definition in a cohort of CTEPH patients who underwent BPA. Methods All patients with CTEPH who completed BPA treatments before September 15th 2023 were selected from the CTEPH database. Peri-procedural complications were collected and classified according to the 2023 consensus paper on BPA in CTEPH patients. Complications were analyzed in subgroups of patients with pulmonary vascular resistance (PVR) or >6.6 WU and mean pulmonary artery pressure (mPAP) or >45 mmHg at first BPA. Results In total, 87 patients (63.2% women; mean age 61.1±14.0 years; 62.1% on dual PH targeted medical therapy) underwent 426 (mean 4.9±1.6 per patient) BPAs. Non-severe complications occurred in 59 (13.8%) of the interventions; in 47.1% of the patients; 64.4% were thoracic, and 35.6% were non-thoracic complications. The thoracic complications were mostly mild (71.1%) or moderate (28.9%), and none were severe. Patients with a PVR >6.6 WU (n=8) underwent more BPA-procedures (6.6±1.5 versus 4.6±1.5, p=0.002), had more overall complications (87.5% versus 40.6% of patients, p=0.020), and more thoracic complications (17.0% vs 6.8% of BPAs, p=0.013) than patients with PVR 6.6 WU. Patients with mPAP >45 mmHg (n=13) also had more BPA-procedures (6.5±1.7 versus 4.6±1.4, p<0.001), more overall complications (76.9% versus 43.5% of patients, p=0.027) and more thoracic complications (14.1% versus 7.9% of BPAs, p=0.039) than patients with mPAP 45 mmHg. Conclusions Complications occurred in 13.8% of BPA procedures and were mostly mild. Patients with increased pulmonary hemodynamics at baseline suffered more (thoracic) complications.Overview complications

Targeted medical treatment of patients with chronic thromboembolic pulmonary hypertension who undergo balloon pulmonary angioplasty

Abstract Introduction In patients with chronic thromboembolic pulmonary hypertension (CTEPH) who undergo balloon pulmonary angioplasty (BPA), pre-treatment with PH-targeted medical therapy may be beneficial in improving clinical parameters and pulmonary hemodynamics. Purpose This study aims to describe the clinical results of PH-specific therapy prior to BPA. Methods Patients with CTEPH who underwent BPA treatment were selected from the St. Antonius CTEPH database. Medical treatment strategy, clinical parameters, and pulmonary hemodynamics at time of diagnosis and at the first BPA were collected from medical records. Results In total 93 BPA patients (62.4% women; age 60.4±14.1 years; NYHA FC III/IV 60.9%) were included; the majority of patients received dual PH targeted medical therapy (64.1%). Between diagnosis and the first BPA significant improvements were observed for both clinical parameters (6MWD: 26.8m [5.2 - 48.4], Log NTproBNP: -0.5 pg/ml [-0.8 to -0.2]) and pulmonary hemodynamic (mRAP: -2.2 mmHg [-3.7 to -0.8], mPAP: -6.4mmHg [-8.3 to -4.5], CO: 0.5L/min [0.2 - 0.9] and PVR: -2.6WU [-3.3 to -2]). Dual PH targeted medical therapy resulted in significantly greater improvements in PVR (p = 0.03) in comparison to patients without and mono PH targeted medical therapy (CO and mPAP both p-value: 0.01). Conclusion Between diagnosis and the initial BPA, substantial improvements were observed for 6MWD, NTproBNP and most pulmonary hemodynamics in CTEPH patients who underwent BPA. Patients who received dual PH targeted medical therapy had significantly greater improvements compared to patients without (PVR) and on mono PH targeted medical therapy (CO and mPAP).Clinical parameters: Baseline-1st BPAPH medication: ANOVA Post hoc analyses

Monitoring anti-factor Xa activity in patients with chronic thromboembolic pulmonary hypertension treated with factor Xa inhibitors

Direct oral anticoagulants (DOACs) have been used clinically in patients with chronic thromboembolic pulmonary hypertension (CTEPH) for secondary prevention after acute venous thromboembolism, although the data are limited. We evaluated the effects of DOACs—especially factor Xa (FXa) inhibitors—by measuring anti-factor Xa activity (AXA). Fifty consecutive CTEPH patients treated with rivaroxaban, apixaban, or edoxaban were enrolled. Heparin-calibrated AXA was measured at peak and trough. The median peak heparin-calibrated AXA across all 50 patients was 1.90 IU/mL and was comparable among the three FXa inhibitors. At trough, heparin-calibrated AXA was significantly higher in apixaban-treated patients (median 0.70 IU/mL) than in those given rivaroxaban (median 0.11 IU/mL) or edoxaban (median 0.11 IU/mL, p < 0.001). Peak heparin-calibrated AXA was significantly lower with reduced-dosage FXa inhibitor (edoxaban 30 mg/day) than with the reference dosage (edoxaban 60 mg/day, apixaban 10 mg/day, or rivaroxaban 15 mg/day, p = 0.01). The heparin-calibrated AXA of both rivaroxaban and apixaban was strongly significantly correlated with the plasma concentration of each drug. The cumulative rate of major and clinically relevant non-major bleeding was significantly higher in patients with peak heparin-calibrated AXA ≥ 2.09 IU/mL. Heparin-calibrated AXA could provide useful information for treating CTEPH patients with FXa inhibitors.

Mapping the amplitude and phase of dissolved 129Xe red blood cell signal oscillations with keyhole spectroscopic lung imaging.

To assess the regional amplitude and phase of dissolved 129Xe red blood cell (RBC) signal oscillations in the lung vasculature with keyhole spectroscopic imaging and to compare with previous methodology, which does not account for oscillation phase. 129Xe gas transfer was measured with a four-echo 3D radial spectroscopic imaging sequence. Keyhole reconstruction-based RBC signal oscillation amplitude mapping was applied retrospectively to data acquired from 28 healthy volunteers, 4 chronic thromboembolic pulmonary hypertension (CTEPH) patients, and 5 patients who were hospitalized due to COVID-19 pneumonia and had residual lung abnormalities. Using a sliding window keyhole reconstruction, maps of RBC oscillation amplitude were corrected for regional phase difference. Repeatability of the phase-adjusted oscillation amplitude was assessed in 8 healthy volunteers across three scans. With sliding window keyhole reconstruction, regional phase differences were observed in the RBC signal oscillations: mean phase = (0.27 ± 0.19) rad in healthy volunteers, (0.24 ± 0.13) rad in CTEPH patients, and (0.33 ± 0.19) rad in patients with post-COVID-19 residual lung abnormality. The oscillation amplitude and phase maps were more heterogeneous (i.e., they showed increased coefficient of variation) for the CTEPH patients. The RBC oscillation amplitude was repeatable, and the mean three-scan coefficient of variation was smaller when the phase adjustment was made (0.07 ± 0.04 compared with 0.16 ± 0.05). Sliding window keyhole reconstruction of radial dissolved 129Xe imaging reveals regional phase differences in the RBC oscillations, which are not captured when performing two phase keyhole reconstruction. This regional phase information may reflect the hemodynamic effect of the cardiac pulse wave in the pulmonary microvasculature.

Cost-effectiveness of follow-up algorithms for chronic thromboembolic pulmonary hypertension in pulmonary embolism survivors

IntroductionAchieving an early diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH) in pulmonary embolism (PE) survivors results in better quality of life and survival. Importantly, dedicated follow-up strategies to achieve an earlier CTEPH diagnosis involve costs that were not explicitly incorporated in the models assessing their cost-effectiveness. We performed an economic evaluation of 11 distinct PE follow-up algorithms to determine which should be preferred.Materials and methods11 different PE follow-up algorithms and 1 hypothetical scenario without a dedicated CTEPH follow-up algorithm were included in a Markov model. Diagnostic accuracy of consecutive tests was estimated from patient-level data of the InShape II study (n=424). The life-long costs per CTEPH patient were compared and related to Quality-Adjusted Life-Years (QALYs) for each scenario.ResultsCompared to not performing dedicated follow-up, the integrated follow-up algorithms are associated with an estimated increase of 0.89–1.2 QALY against an incremental cost-effectiveness ratio (ICER) of 25 700–46 300 € per QALY per CTEPH patient. When comparing different algorithms with each other, the maximum differences were 0.27 QALY and €27 600. The most cost-effective algorithm was the InShape IV algorithm, with an ICER of €26 700 per QALY compared to the next best algorithm.ConclusionSubjecting all PE survivors to any of the currently established dedicated follow-up algorithm to detect CTEPH is cost-effective and preferred above not performing a dedicated follow-up, evaluated against the Dutch acceptability threshold of €50 000 per QALY. The model can be used to identify the locally preferred algorithm from an economical point-of-view within local logistical possibilities.

Quantitative pulmonary perfusion in acute pulmonary embolism and chronic thromboembolic pulmonary hypertension.

Current methods for quantifying perfusion from computed tomography pulmonary angiography (CTPA) often rely on semi-quantitative scoring systems and requires an experienced evaluator. Few studies report on absolute quantitative variables derived from the images, and the methods are varied with mixed results. Dual-energy CTPA (DE-CTPA) enables automatic quantification of lung and lobar perfusion with minimal user interaction by utilizing machine learning based software. We aimed to evaluate differences in DE-CTPA derived quantitative perfusion variables between patients with acute pulmonary embolism (PE) and chronic thromboembolic pulmonary hypertension (CTEPH). This retrospective, single-center, observational study included 162 adult patients diagnosed with PE (n = 81) or CTEPH (n = 81) and scanned using dual-energy CT between 2020 and 2023. Mann-Whitney U tests and permutational analysis of variance (PERMANOVA) were used for comparative analyses. We found whole lung perfusion blood volume to be lower (p < 0.001) in PE patients (median 3399 mL [2554, 4284]) than in CTEPH patients (median 4094 mL [3397, 4818]). The same was observed at single lung and lobar level. PERMANOVA encompassing all perfusion variables showed a difference between the two groups (F-statistic = 13.3, p = 0.002). Utilizing logistic regression, right and left lower lobe perfusion blood volume showed some ability to differentiate between PE and CTEPH with area under the receiver operation characteristics curve values of 0.71 (95% CI: 0.56; 0.84) and 0.72 (95% CI: 0.56; 0.86). Pulmonary perfusion is lower in patients with PE than patients with CTEPH, highlighted by differences in DECT-derived perfusion blood volume. Quantitative perfusion variables might be useful to differentiate between the two diseases.

Prostacyclin pathway vasodilators in patients with chronic thromboembolic pulmonary hypertension (CTEPH): A systemic review and meta-analysis of randomized controlled trials.

Although surgical and interventional therapy has emerged as the primary treatment for patients with chronic thromboembolic pulmonary hypertension (CTEPH), there remains a subset of patients who need medication therapy. This study aimed to evaluate the efficacy and safety outcomes of prostacyclin pathway vasodilators, providing further insight for clinical decision-making. A literature search was conducted in PubMed, Embase, and CENTRAL databases from inception to December 2023. Literature screening and quality assessment were carried out with the Cochrane Risk of Bias Tool. Data analysis was conducted using RevMan 5.4 software. We included 6 randomized controlled trials with 387 patients. Prostacyclin pathway vasodilators demonstrated a significant improvement in PVR (-125.26 dynes·sec·cm-5, 95%CI: -219.29 to -31.23, Z = 2.61, and p < 0.009), RAP (-0.78 mmHg, 95%CI: -1.52 to -0.04, Z = 2.06, and p = 0.04), cardiac index (0.62, 95%CI: 0.54 to 0.69, Z = 16.13, and p < 0.00001), and the number of patients showing improvement in WHO functional class (3.86, 95%CI: 1,92 to 7.77, Z = 3.79, and p = 0.0002) compared to controls, moreover, a trend towards improvement was observed in mPAP, 6MWD, and NT-proBNP. Regarding the safety endpoints, no significant difference was found in both groups in terms of serious adverse events and all-cause deaths. The prostacyclin pathway vasodilators present therapeutic potential for CTEPH patients with inoperable or persistent/recurrent PH after PEA/BPA primarily characterized by distal small-vessel and microvasculopathy. However, the current clinical evidence remains insufficient and controversial, necessitating further validation.

Tricuspid annular plane systolic excursion to pulmonary artery systolic pressure ratio in chronic thromboembolic pulmonary hypertension improves with balloon pulmonary angioplasty.

Right ventricle (RV)-to-pulmonary artery (PA) coupling measured by the ratio of echocardiography-derived tricuspid annular plane systolic excursion (TAPSE) and pulmonary artery systolic pressure (PASP) is a meaningful prognostic marker in pulmonary hypertension (PH). It's unclear if balloon pulmonary angioplasty (BPA) treatment of chronic thromboembolic pulmonary hypertension (CTEPH) alters RV-PA coupling measured by TAPSE/PASP. We reviewed CTEPH patients treated with BPA at our institution who had a transthoracic echocardiogram (TTE) before BPA and a follow-up TTE at any point during BPA. TAPSE was obtained from the initial and lattermost TTE; hemodynamics were obtained before each BPA session. Between March 2015 to October 2023, there were 228 patients treated with BPA. After excluding post-PTE patients and those without PH, 67 were included. Initial TAPSE/PASP was 0.39 ± 0.21 mm/mmHg. Using previously defined TAPSE/PASP tertiles in PH (<0.19, 0.19-0.32, >0.32 mm/mmHg), there were 6 patients (9%) in low, 30 (45%) in middle, and 31 (46%) in the high tertiles at baseline. The lower TAPSE/PASP tertiles had more severe baseline hemodynamics (p < 0.001) compared to the high TAPSE/PASP cohort. At follow-up, TAPSE/PASP improved to 0.47 ± 0.20 mm/mmHg (p = 0.023), with 2 (3%), 13 (19%), and 52 (78%) patients in the low, middle, high TAPSE/PASP tertiles, respectively. As patients progress through BPA sessions, the TAPSE/PASP ratio increases, possibly reflecting improved RV mechanics and RV-PA coupling. TAPSE/PASP ratio as a marker of RV-PA coupling can improve with BPA treatment and may be an important measure to follow during treatment of CTEPH.

Concomitant pulmonary thromboendarterectomy and supracoronary ascending aorta replacement: a case report

Pulmonary thromboendarterectomy (PTE) is the treatment of choice for patients with operable chronic thromboembolic pulmonary hypertension (CTEPH). PTE with additional cardiac procedures has been reported to be safely applicable. However, there are not enough publications in the literature regarding the treatment strategy of CTEPH patients with ascending aortic aneurysms. In this case report, we present a successful case of concomitant PTE and supracoronary ascending aorta replacement.

Role of Optical Coherence Tomography in Vasculitis-Associated Pulmonary Hypertension and Chronic Thromboembolic Pulmonary Hypertension.

Identifying and understanding the microstructural changes within the wall of the pulmonary artery (PA) is crucial for elucidating disease mechanisms and guiding treatment strategies. We assessed the utility of optical coherence tomography (OCT) in identifying such changes within segmental/subsegmental PAs and compared the morphological variations in WHO group 4 pulmonary hypertension associated with Behcet Disease (BD), Takayasu arteritis (TA) and chronic thromboembolic pulmonary hypertension (CTEPH). Idiopathic pulmonary arterial hypertension (IPAH) patients served as controls.Methods and Results: A total of 197 cross-sectional images were analyzed from 20 consecutive patients. BD patients exhibited lower %wall area and mean wall thickness (MWT) compared with CTEPH, TA and, IPAH patients. TA patients showed a notably higher %wall area, which was significant in IPAH and BD patients. Variations in %wall area measurements were observed across distinct cross-sectional segments of the PA within individual patients (22% in CTEPH, 19% in BD, 16% in TA, 23% in IPAH patients). Intravascular webs, bands, and thrombi were observed in BD and CTEPH patients. OCT provided clear delineation of vascular wall calcifications and adventitial vasa vasorum. No procedure-related complications were observed. PA involvement differs among the various etiologies of PH, with the PA being heterogeneously affected. OCT offers promise in elucidating microstructural vascular wall changes and providing insights into disease mechanisms and treatment effects.

An exploration into CTEPH medications: Combining natural language processing, embedding learning, in vitro models, and real-world evidence for drug repurposing.

In the modern era, the growth of scientific literature presents a daunting challenge for researchers to keep informed of advancements across multiple disciplines. We apply natural language processing (NLP) and embedding learning concepts to design PubDigest, a tool that combs PubMed literature, aiming to pinpoint potential drugs that could be repurposed. Using NLP, especially term associations through word embeddings, we explored unrecognized relationships between drugs and diseases. To illustrate the utility of PubDigest, we focused on chronic thromboembolic pulmonary hypertension (CTEPH), a rare disease with an overall limited number of scientific publications. Our literature analysis identified key clinical features linked to CTEPH by applying term frequency-inverse document frequency (TF-IDF) scoring, a technique measuring a term's significance in a text corpus. This allowed us to map related diseases. One standout was venous thrombosis (VT), which showed strong semantic links with CTEPH. Looking deeper, we discovered potential repurposing candidates for CTEPH through large-scale neural network-based contextualization of literature and predictive modeling on both the CTEPH and the VT literature corpora to find novel, yet unrecognized associations between the two diseases. Alongside the anti-thrombotic agent caplacizumab, benzofuran derivatives were an intriguing find. In particular, the benzofuran derivative amiodarone displayed potential anti-thrombotic properties in the literature. Our in vitro tests confirmed amiodarone's ability to reduce platelet aggregation significantly by 68% (p = 0.02). However, real-world clinical data indicated that CTEPH patients receiving amiodarone treatment faced a significant 15.9% higher mortality risk (p<0.001). While NLP offers an innovative approach to interpreting scientific literature, especially for drug repurposing, it is crucial to combine it with complementary methods like in vitro testing and real-world evidence. Our exploration with benzofuran derivatives and CTEPH underscores this point. Thus, blending NLP with hands-on experiments and real-world clinical data can pave the way for faster and safer drug repurposing approaches, especially for rare diseases like CTEPH.

Novel Computed Tomography Angiography Parameter Is Associated with Low Cardiac Index in Patients with Chronic Thromboembolic Pulmonary Hypertension: A Retrospective Analysis.

We completed a retrospective analysis of CTEPH patients in which individuals with low CI (<2.2-L/min/m2) were identified. Both absolute and fractional HU-Δ were derived from pulmonary CTA by subtracting the HU value of the left atrium (LA) and left ventricle (LV) from the main pulmonary artery (MPA) (absolute) and expressing them as a percentage of MPA-HU (fractional) on static axial images. These were compared between low and normal CI. Of the 237 patients, 50.2% were female, 53.2% were White, 36.7% were Black. Hemodynamics were mean pulmonary artery (PA) pressure = 45.4 ± 11.2-mmHg, pulmonary vascular resistance = 9.2 ± 4.4-WU, CI = 2.05 ± 0.48-L/min/m2. There was a higher mean MPA-HU = 391.1 ± 113.6 than LA-HU = 251.6 ± 81. In patients with low CI, the HU-Δ was higher, HU-ΔMPA-LA was 148.9 ± 78.4 vs. 124.5 ± 77.2 (p = 0.02), and HU-ΔMPA-LV was 170.7 ± 87 vs. 140 ± 82 (p = 0.009). A HU-ΔMPA-LA = 118 had a sensitivity of 75.6% and specificity of 77% to detect low CI, AUC 0.61, p = 0.003. A HU-ΔPA-LV = 156 had a sensitivity of 77% and specificity of 53% to detect low CI, AUC = 0.62, p = 0.001. A fractional reduction HU-ΔMPA-LA of 35% had a sensitivity and specificity of 79% and 53%, respectively, to detect low CI (AUC 0.65, p < 0.001). A fractional reduction of the HU-ΔMPA-LV of 40% had a sensitivity and specificity of 80% and 55%, respectively, to detect low CI (AUC 0.65, p < 0.001). HU Δ were highly reproducible (Kappa = 0.9, p < 0.001, 95% CI 0.86-0.95). High HU Δ between MPA-LA and MPA-LV were associated with low CI in patients with CTEPH.

Incidence and clinical course of chronic thromboembolic pulmonary hypertension with or without a history of venous thromboembolism in Denmark

BackgroundA considerable number of patients with chronic thromboembolic pulmonary hypertension (CTEPH) lack a history of venous thromboembolism (VTE). ObjectivesWe aimed to examine the annual incidence and prevalence of CTEPH in Denmark and to compare the rates of VTE, bleeding, and mortality between CTEPH patients with and without a history of VTE. MethodsThe Danish National Patient Registry covering all Danish hospitals was used to identify all CTEPH cases between 2009 and 2018, based on combinations of discharge diagnoses using International Classification of Diseases, 10th Revision codes for CTEPH and relevant diagnostic and/or therapeutic interventions. Incidence rates of CTEPH per 100 000 person-years, rates of VTE and bleeding, and 5-year survival estimates were calculated. ResultsIn total, 509 CTEPH patients were identified, of whom 82% had a history of VTE. The yearly incidence rate of CTEPH was 0.5 to 0.8 per 100 000 person-years during the study period. Patients with a history of VTE experienced a 2.5-fold rate of VTE compared with those without prior VTE (2571 vs 980 per 100 000 person-years), while the rate of bleeding events was lower (5008 vs 7139 per 100 000 person-years). The 5-year survival of CTEPH patients with a VTE history was 65% (95% CI, 58%-71%) compared with 45% (95% CI, 31%-58%) in patients without a history of VTE. ConclusionThe Danish incidence rate of CTEPH was comparable with that of other European countries. We identified notable differences in the prognosis of patients with CTEPH with or without a history of VTE. These findings may support generation of hypotheses regarding the pathophysiology of CTEPH and inform current patient care.

Epidemiology of supplemental oxygen in patients with pulmonary hypertension.

Patients with pulmonary hypertension (PH) may present with hypoxaemia at rest or during daily activities. There is no epidemiological data on the prescription of long-term oxygen therapy (LTOT) in patients with PH. The study sought to analyse the prevalence and incidence of LTOT prescription among patients with pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH) in Spain and to determine predictors for this prescription. A retrospective analysis was performed from the Spanish Registry of Pulmonary Arterial Hypertension (REHAP). Collected data included demographics and anthropometric measurements, functional class (FC), arterial blood gases, pulmonary function tests, haemodynamic measurements, six-minute walking distance (6MWD) and LTOT prescription. In addition, we assessed the prevalence and incidence of LTOT prescription by PH group and subtype and potential predictors for LTOT initiation in the first 5 years after diagnosis. We analysed 4533 patients (69.9% PAH and 30.1% CTEPH), mostly female (64.5%), with a mean age of 53.0 ± 18.3 years. The prevalence of LTOT was 19.3% for all patients. The incidence of LTOT prescriptions decreased from 5.6% to 1.6% between 2010 and 2019, respectively. Predictors for LTOT prescription, excluding those that represent the indication for oxygen therapy were: FC (HR: 1.813), 6MWD (HR: 1.002), mean pulmonary arterial pressure (mPAP) (HR: 1.014), cardiac index (CI) (HR: 1.253), pulmonary vascular resistance (PVR) (HR: 1.023) and diffusing capacity of carbon monoxide (DLCO) (HR: 1.294). The prevalence of LTOT in PAH and CTEPH patients is close to 20%. FC, 6MWD, mPAP, CI, PVR and DLCO were predictors for LTOT prescription.