Predicting high-risk pre-capillary pulmonary hypertension: an echocardiographic multiparameter scoring index.

BACKGROUND: The risk stratification of pulmonary arterial hypertension proposed by the European Society of Cardiology /European Respiratory Society guidelines in 2015 and 2022 included two to three echocardiographic indicators. However, the specific value of echocardiography in risk stratification of pre-capillary pulmonary hypertension (pcPH) has not been efficiently demonstrated. Given the complex geometry of the right ventricular (RV) and influencing factors of echocardiographic parameter, there is no single echocardiographic parameter that reliably informs about PH status. We hypothesize that a multi-parameter comprehensive index can more accurately evaluate the severity of the pcPH. The purpose of this study was to develop and validate an echocardiographic risk score model to better assist clinical identifying high risk of pcPH during initial diagnosis and follow-up. METHODS: We studied 197 consecutive patients with pcPH. A multivariable echocardiographic model was constructed to predict the high risk of pcPH in the training set. Points were assigned to significant risk factors in the final model based on ß-coefficients. We validated the model internally and externally. RESULTS: The echocardiographic score was constructed by multivariable logistic regression, which showed that pericardial effusion, right atrial (RA) area, RV outflow tract proximal diameter (RVOT-Prox), the velocity time integral of the right ventricular outflow tract (TVIRVOT) and S' were predictors of high risk of pcPH. The area under curve (AUC) of the training set of the scoring model was 0.882 (95%CI: 0.809-0.956, p < 0.0001). External validation was tested in a test dataset of 77 patients. The AUC of the external validation set was 0.852. A 10-point score risk score was generated, with scores ranging from 0 to 10 in the training cohort. The estimate risk of high risk of pcPH ranged from 25.1 to 94.6%. CONCLUSIONS: The echocardiographic risk score using five echocardiographic parameters could be comprehensive and useful to predict the high risk of pcPH for initial assessment and follow-up.

Clinical characteristics and mortality predictors among very old patients with pulmonary thromboembolism: a multicenter study report.

BACKGROUND: Clinical characteristics of patients with pulmonary thromboembolism have been described in previous studies. Although very old patients with pulmonary thromboembolism are a special group based on comorbidities and age, they do not receive special attention. OBJECTIVE: This study aims to explore the clinical characteristics and mortality predictors among very old patients with pulmonary thromboembolism in a relatively large population. DESIGN AND PARTICIPANTS: The study included a total of 7438 patients from a national, multicenter, registry study, the China pUlmonary thromboembolism REgistry Study (CURES). Consecutive patients with acute pulmonary thromboembolism were enrolled and were divided into three groups. Comparisons were performed between these three groups in terms of clinical characteristics, comorbidities and in-hospital prognosis. Mortality predictors were analyzed in very old patients with pulmonary embolism. KEY RESULTS: In 7,438 patients with acute pulmonary thromboembolism, 609 patients aged equal to or greater than 80 years (male 354 (58.1%)). There were 2743 patients aged between 65 and 79 years (male 1313 (48%)) and 4095 patients aged younger than 65 years (male 2272 (55.5%)). Patients with advanced age had significantly more comorbidities and worse condition, however, some predisposing factors were more obvious in younger patients with pulmonary thromboembolism. PaO2 < 60 mmHg, eGFR < 60 mL/min/1.73m2, malignancy, anticoagulation as first therapy were mortality predictors for all-cause death in very old patients with pulmonary thromboembolism. The analysis found that younger patients were more likely to have chest pain, hemoptysis (the difference was statistically significant) and dyspnea triad. CONCLUSION: In very old population diagnosed with pulmonary thromboembolism, worse laboratory results, atypical symptoms and physical signs were common. Mortality was very high and comorbid conditions were their features compared to younger patients. PaO2 < 60 mmHg, eGFR < 60 mL/min/1.73m2 and malignancy were positive mortality predictors for all-cause death in very old patients with pulmonary thromboembolism while anticoagulation as first therapy was negative mortality predictors.

LMWHs dosage and outcomes in acute pulmonary embolism with renal insufficiency, an analysis from a large real-world study.

BACKGROUND: Renal function is associated with prognoses for acute pulmonary embolism (PE). OBJECTIVE: To investigate the application of anticoagulants and dosage of LMWH among patients with renal insufficiency (RI), and the association between LWMH dosage and the patients' in-hospital outcomes. METHODS: Adult patients diagnosed with non-high risk acute PE from 2009 to 2015, with available data of creatinine clearance (CCr) were enrolled from a multicenter registry in China. Renal insufficiency (RI) was defined as CCr < 60 ml/min. LMWH dosage was converted into IU/kg daily dose and presented as adjusted dose (≤ 100 IU/kg/day) and conventional dose (> 100 IU/kg/day). All-cause death, PE-related death and bleeding events during hospitalization were analyzed as endpoints. RESULTS: Among the enrolled 5870 patients, RI occurred in 1311 (22.3%). 30 ≤ CCr < 60 ml/min was associated with higher rate of bleeding events and CCr < 30 ml/min was associated with all-cause death, PE-related death and major bleeding. Adjusted-dose LMWH was applied in 26.1% of patients with 30 ≤ CCr < 60 ml/min and in 26.2% of CCr < 30 ml/min patients. Among patients with RI, in-hospital bleeding occurred more frequently in those who were administered conventional dose of LMWH, compared with adjusted dose (9.2% vs 5.0%, p = 0.047). Adjusted dose of LMWH presented as protective factor for in-hospital bleeding (OR 0.62, 95%CI 0.27-1.00, p = 0.0496) and the risk of bleeding increased as length of hospital stay prolonged (OR 1.03, 95%CI 1.01-1.06, p = 0.0014). CONCLUSIONS: The proportion of adjusted usage of LMWH was low. The application of adjusted-dose LMWH was associated with lower risk of in-hospital bleeding for RI patients, in real-world setting of PE treatment. Anticoagulation strategy for RI patients should be paid more attention and requires evidence of high quality. TRIAL REGISTRATION: The CURES was registered in ClinicalTrias.gov, identifier number: NCT02943343 .

Plasminogen activator Inhibitor-2 inhibits pulmonary arterial smooth muscle cell proliferation in pulmonary arterial hypertension via PI3K/Akt and ERK signaling.

BACKGROUND: The proliferation of pulmonary arterial smooth muscle cells (PASMCs) and subsequent pulmonary vascular remodeling leads to pulmonary arterial hypertension (PAH). Understanding the underlying mechanisms and identifying molecules that can suppress PASMCs proliferation is critical for developing effective pharmacological treatment. We previously showed that plasminogen activator inhibitor-2 (PAI-2) inhibited human PASMC (hPASMCs) proliferation in vitro. However, its inhibitory effect on PAH remains to be determined, and the mechanism remains to be illustrated. METHODS: We compared serum PAI-2 levels between PAH patients and healthy controls, and examined the correlation between PAI-2 level and disease severity. In monocrotaline-induced PAH rats, we examined the effects of exogenous PAI-2 administration on pulmonary vascular remodeling and PAH development. The effect of PAI-2 and potential mechanisms was further examined in cultured hPASMCs. RESULTS: The serum PAI-2 was decreased in PAH patients compared with controls. PAI-2 level was negatively correlated with mean pulmonary arterial pressure and estimated systolic pulmonary arterial pressure in ultrasonic cardiogram, while positively correlated with 6-min walking distance. In rats, administration of exogenous PAI-2 significantly reversed monocrotaline-induced PAH, as indicated by the decrease in right ventricle systolic pressure, right ventricular hypertrophy index and percent media thickness of pulmonary arterioles. Further mechanistic investigation in hPASMCs showed that PAI-2 inhibited cell proliferation by preventing the activation of PI3K/Akt and ERK pathways. CONCLUSION: PAI-2 is downregulated in PAH patients. PAI-2 attenuates PAH development by suppressing hPASMCs proliferation via the inhibition of PI3K/Akt and ERK pathways. PAI-2 may serve as a potential biomarker and therapeutic target for PAH.

The accuracy and influencing factors of Doppler echocardiography in estimating pulmonary artery systolic pressure: comparison with right heart catheterization: a retrospective cross-sectional study.

BACKGROUND: Noninvasive assessment of pulmonary artery systolic pressure by Doppler echocardiography (sPAPECHO) has been widely adopted to screen for pulmonary hypertension (PH), but there is still a high proportion of overestimation or underestimation of sPAPECHO. We therefore aimed to explore the accuracy and influencing factors of sPAPECHO with right heart catheterization (RHC) as a reference. METHODS: A total of 218 highly suspected PH patients who underwent RHC and echocardiography within 7 days were included. The correlation and consistency between tricuspid regurgitation (TR)-related methods and RHC results were tested by Pearson and Bland-Altman methods. TR-related methods included peak velocity of TR (TR Vmax), TR pressure gradient (TR-PG), TR mean pressure gradient (TR-mPG), estimated mean pulmonary artery pressure (mPAPECHO), and sPAPECHO. With mPAP ≥ 25 mm Hg measured by RHC as the standard diagnostic criterion of PH, the ROC curve was used to compare the diagnostic efficacy of sPAPECHO with other TR-derived parameters. The ratio (sPAPECHO-sPAPRHC)/sPAPRHC was calculated and divided into three groups as follows: patients with an estimation error between - 10% and + 10% were defined as the accurate group; patients with an estimated difference greater than + 10% were classified as the overestimated group; and patients with an estimation error greater than - 10% were classified as the underestimated group. The influencing factors of sPAPECHO were analyzed by ordinal regression analysis. RESULTS: sPAPECHO had the highest correlation coefficient (r = 0.781, P < 0.001), best diagnostic efficiency (AUC = 0.98), and lowest bias (mean bias = 0.07 mm Hg; 95% limits of agreement, - 32.08 to + 32.22 mm Hg) compared with other TR-related methods. Ordinal regression analysis showed that TR signal quality, sPAPRHC level, and pulmonary artery wedge pressure (PAWP) affected the accuracy of sPAPECHO (P < 0.05). Relative to the good signal quality, the OR values of medium and poor signal quality were 0.26 (95% CI: 0.14, 0.48) and 0.23 (95% CI: 0.07, 0.73), respectively. Compared with high sPAPRHC level, the OR values of low and medium sPAPRHC levels were 21.56 (95% CI: 9.57, 48.55) and 5.13 (95% CI: 2.55, 10.32), respectively. The OR value of PAWP was 0.94 (95% CI: 0.89, 0.99). TR severity and right ventricular systolic function had no significant effect on the accuracy of sPAPECHO. CONCLUSIONS: In this study, we found that all TR-related methods, including sPAPECHO, had comparable and good efficiency in PH screening. To make the assessment of sPAPECHO more accurate, attention should be paid to TR signal quality, sPAPRHC level, and PAWP.

Prevalence and risk prediction value of tricuspid regurgitation by echocardiography in precapillary pulmonary hypertension.

BACKGROUND: In precapillary pulmonary hypertension (PH), the incidence of different tricuspid regurgitation (TR) degree is poorly defined. The impact of TR severity on pulmonary artery pressure (PAP) assessment and clinical risk stratification in precapillary PH remains unclear. METHODS: A total of 207 patients diagnosed precapillary PH who underwent right heart catheterization (RHC) and echocardiography within 3 days were included. The severity of TR was graded as trace, mild, moderate and severe. Pearson correlation analysis was performed to evaluate the correlation between systolic PAP by echocardiography (sPAPECHO) and mean PAP by RHC (mPAPRHC) in different TR degree groups. The impact factors on risk stratification of precapillary PH were analyzed by logistic regression analysis. RESULTS: The proportion of None, Trace, Mild, Moderate and Severe TR group was 2.4%, 23.7%, 39.1%, 28.5% and 6.3% respectively. Right atrium (RA) area increased gradually with TR aggravation (p < 0.001). Moderate and Severe TR group had higher N-terminal pro-B-type natriuretic peptide (p < 0.001), right atrial pressure (RAP) (p = 0.018), right ventricular basal diameter (RVD)/left ventricular basal diameter (LVD) ratio (p < 0.001), larger right ventricle (RV) (p < 0.001) and lower tricuspid annular plane systolic excursion (p = 0.006) compared with Trace and Mild group. TR-sPAPECHO in Moderate TR group had the greatest correlation coefficient with mPAPRHC (0.742, p < 0.001) followed by Mild (0.635, p < 0.001) and severe group (0.592, p = 0.033), while there was no correlation in Trace TR group (0.308, p = 0.076). Multivariate logistic regression showed three significant independent echocardiography predictors of high-risk precapillary PH: RVD/LVD ratio (OR = 5.734; 95%CI1.502-21.889, p = 0.011), RA area (OR 1.054; 95% CI 1.004-1.107, p = 0.035) and systolic annular tissue velocity of the lateral tricuspid annulus (S') (OR 0.735, 95% CI 0.569-0.949, p = 0.018). CONCLUSIONS: Precapillary PH was not necessarily accompanied by significant TR. None or Trace TRaccounted for 26% in our population and TR-sPAPECHO was not applicable to estimate PAP in these patients. RVD/LVD ratio, RA area and S' can independently predict the high-risk patients with precapillary PH. TR may play an indirect role in risk stratification by affecting these indicators.

Trends in risk stratification, in-hospital management and mortality of patients with acute pulmonary embolism: an analysis from the China pUlmonary thromboembolism REgistry Study (CURES).

Similar trends of management and in-hospital mortality of acute pulmonary embolism (PE) have been reported in European and American populations. However, these tendencies are not clear in Asian countries. We retrospectively analysed the trends of risk stratification, management and in-hospital mortality for patients with acute PE through a multicentre registry in China (CURES).Adult patients with acute symptomatic PE were included between 2009 and 2015. Trends in disease diagnosis, treatment and death in hospital were fully analysed. Risk stratification was retrospectively classified by haemodynamic status and the simplified Pulmonary Embolism Severity Index (sPESI) score according to the 2014 European Society of Cardiology/European Respiratory Society guidelines.Among 7438 patients, the proportions with high (haemodynamic instability), intermediate (sPESI≥1) and low (sPESI=0) risk were 4.2%, 67.1% and 28.7%, respectively. Computed tomographic pulmonary angiography was the most widely used diagnostic approach (87.6%) and anticoagulation was the most frequently adopted initial therapy (83.7%). Between 2009 and 2015, a significant decline was observed for all-cause mortality (from 3.1% to 1.3%, adjusted pfor trend=0.0003), with a concomitant reduction in the use of initial systemic thrombolysis (from 14.8% to 5.0%, pfor trend<0.0001). The common predictors for all-cause mortality shared by haemodynamically stable and unstable patients were co-existing cancer, older age and impaired renal function.The considerable reduction of mortality over the years was accompanied by changes in initial treatment. These findings highlight the importance of risk stratification-guided management throughout the nation.

Gremlin-1 is a key regulator of endothelial-to-mesenchymal transition in human pulmonary artery endothelial cells.

BACKGROUND: Endothelial-to-mesenchymal transition (EndMT) has been implicated in initiation and progression of pulmonary arterial hypertension (PAH). Gremlin-1 promotes vascular remodeling of PAH and mediates epithelial-mesenchymal transition, which is similar to EndMT. In the present study we investigated the potential role of gremlin-1 plays in EndMT of pulmonary artery endothelial cells (PAECs). METHODS: Immunofluorescence staining was performed to detect the expression of alpha smooth muscle actin (α-SMA) and von Willebrand factor (VWF). Migration and angiogenic responses of PAECs were determined by transwell assay and tube formation assay, respectively. Protein expression levels were determined by western blotting. RESULTS: Gremlin-1 induced EndMT of PAECs in a phospho-smad2/3-dependent manner. This was characterized by the loss of platelet endothelial cell adhesion molecule 1 and an increase in protein levels of a-SMA, nerve-cadherin, and matrix metalloproteinase 2. It was also determined that gremlin-1 facilitated the migration and angiogenic responses of PAECs in a dose-dependent manner. Bone morphogenetic protein 7 (BMP-7) was found to attenuate gremlin-1-mediated EndMT, migration and angiogenesis of PAECs by inducing phosphorylation of Smad1/5/8 and suppressing phosphorylation of Smad2/3. CONCLUSION: Gremlin-1 mediates EndMT in PAECs, and BMP-7 reverses gremlin-1-induced EndMT by an induction of p-Smad1/5/8 and suppression of p-Smad2/3.

Evaluation of acute pulmonary embolism and clot burden on CTPA with deep learning.

OBJECTIVES: To take advantage of the deep learning algorithms to detect and calculate clot burden of acute pulmonary embolism (APE) on computed tomographic pulmonary angiography (CTPA). MATERIALS AND METHODS: The training set in this retrospective study consisted of 590 patients (460 with APE and 130 without APE) who underwent CTPA. A fully deep learning convolutional neural network (DL-CNN), called U-Net, was trained for the segmentation of clot. Additionally, an in-house validation set consisted of 288 patients (186 with APE and 102 without APE). In this study, we set different probability thresholds to test the performance of U-Net for the clot detection and selected sensitivity, specificity, and area under the curve (AUC) as the metrics of performance evaluation. Furthermore, we investigated the relationship between the clot burden assessed by the Qanadli score, Mastora score, and other imaging parameters on CTPA and the clot burden calculated by the DL-CNN model. RESULTS: There was no statistically significant difference in AUCs with the different probability thresholds. When the probability threshold for segmentation was 0.1, the sensitivity and specificity of U-Net in detecting clot respectively were 94.6% and 76.5% while the AUC was 0.926 (95% CI 0.884-0.968). Moreover, this study displayed that the clot burden measured with U-Net was significantly correlated with the Qanadli score (r = 0.819, p < 0.001), Mastora score (r = 0.874, p < 0.001), and right ventricular functional parameters on CTPA. CONCLUSIONS: DL-CNN achieved a high AUC for the detection of pulmonary emboli and can be applied to quantitatively calculate the clot burden of APE patients, which may contribute to reducing the workloads of clinicians. KEY POINTS: • Deep learning can detect APE with a good performance and efficiently calculate the clot burden to reduce the physicians' workload. • Clot burden measured with deep learning highly correlates with Qanadli and Mastora scores of CTPA. • Clot burden measured with deep learning correlates with parameters of right ventricular function on CTPA.

Regional right ventricular longitudinal systolic strain for detection of severely impaired right ventricular performance in pulmonary hypertension.

OBJECTIVES: Right ventricular (RV) function is identified as a key determinant of the outcome in patients with pulmonary hypertension (PH). Several studies have assessed the role of peak global longitudinal RV strain in PH patients; however, less emphasis was given to the RV regional longitudinal strain. The aim of this study was to evaluate the regional RV systolic strain in PH patients and investigate the relationship of these parameters with the severity of PH. METHODS: RV regional longitudinal peak systolic strain (LPSS) and strain rate (LPSSR) were measured using speckle tracking echocardiography on 100 patients with PH who underwent right heart catheterization, and 29 control subjects. Severe PH was identified by a decreased cardiac index (CI) (<2.0 L/min/m2 ). RESULTS: LPSS and LPSSR of the RV free wall were significantly lower in PH patients than control subjects, especially when comparing the basal and mid regions (P < .001). When comparing severe PH and nonsevere PH, basal and mid LPSS and LPSSR were significantly lower (P < .001). RV free wall mid LPSSR correlated with CI (r = -.703, P < .001). In the multiple logistic regression analysis, mid LPSSR was identified as an independent predictor of severe PH (odds ratio 1.82; 95% confidential interval 1.39-2.40; P < .001). In the receiver operating characteristics curve analysis, a cutoff value of mid LPSSR of -0.92 s-1 predicted severe PH, with a sensitivity and specificity of 75.0% and 93.7%, respectively (AUC = 0.889, P < .001). CONCLUSIONS: RV free wall mid longitudinal peak systolic strain rate may be useful for the detection of severely impaired RV performance in PH.

Safety and efficacy of balloon pulmonary angioplasty for technically operable chronic thromboembolic pulmonary hypertension.

Balloon pulmonary angioplasty (BPA) has been proven effective for addressing technically inoperable chronic thromboembolic pulmonary hypertension (CTEPH). However, the effectiveness of BPA in technically operable CTEPH patients who, for various reasons, did not undergo the procedure remains an area requiring exploration. This study sought to assess the safety and efficacy of BPA in such cases. We collected and reviewed data from CTEPH patients who underwent BPA in a consecutive manner. Following multidisciplinary team (MDT) decisions, patients were classified into two groups: technically inoperable (group A) and operable (group B). Group B comprised patients deemed technically suitable for pulmonary endarterectomy (PEA) but who did not undergo the procedure for various reasons. All patients underwent a comprehensive diagnostic work-up, including right heart categorization at baseline and the last intervention. This study compared changes in hemodynamic parameters, functional capacity, and quality of life between the two groups. In total, 161 patients underwent 414 procedures at our center, with Group A comprising 112 patients who underwent 282 BPA sessions and group B comprising 49 patients who underwent 132 BPA sessions. Significantly, both groups exhibited improvements in hemodynamics, functional capacity, and quality of life. The occurrence rate of complications, including hemoptysis and lung injury, was similar [12 (63.2%) vs. 7 (36.8%), p = 0.68]. BPA demonstrated favorable outcomes in patients with proximal CTEPH who did not undergo pulmonary endarterectomy. However, the clinical impact of BPA in technically operable CTEPH was found to be less significant than in inoperable cases.

Inhibition of heterogeneous nuclear ribonucleoproteins A1 and oxidative stress reduces glycolysis via pyruvate kinase M2 in chronic thromboembolic pulmonary hypertension.

Background and Objective: Chronic thromboembolic pulmonary hypertension (CTEPH) is a lethal complication of pulmonary embolism involving pulmonary artery occlusion and microvascular disease. The glucose metabolism and reactive oxygen species (ROS) production may be perturbed in CTEPH, but the precise mechanisms are unclear. This study investigated glucose metabolism in CTEPH employing pulmonary endarterectomy (PEA)-derived pulmonary artery smooth muscle cells (PASMCs) and characterized the roles of pyruvate kinase M2 (PKM2) and its regulation by heterogeneous nuclear ribonucleoproteins A1 (hnRNPA1) and ROS in CTEPH. Methods: PEA tissues and blood samples of CTEPH patients were collected to study the levels of PKM2. Primary PASMCs were isolated from PEA tissues. We used small interfering RNAs to knock down PKM2 and hnRNPAI, and applied antioxidant N-acetylcysteine (NAC) and mito-TEMPO to reduce ROS production. The expression of glucometabolic genes, ROS production, glycolysis rate and proliferative and migratory activities were analyzed in PEA-derived PASMCs. Results: PKM2 levels in serum and PEA tissues of CTEPH patients were higher than that of the healthy controls. Compared to the control PASMCs, PEA-derived PASMCs showed increased PKM2 expression and ROS production. The rates of glycolysis, proliferation and migration were increased in PEA-PASMCs and could be mitigated by PKM2 downregulation through hnRNPA1 or ROS inhibition. Conclusions: Increased glycolysis and PKM2 expression were found in PEA-PASMCs. Inhibition of hnRNPA1 or ROS corrected the aberrant glycolysis, cell proliferation and migration by downregulating PKM2. Regulation of the hnRNPA1/PKM2 axis represents a potential therapeutic target for the treatment of CTEPH.

"Guidezilla" extension catheter combined with balloon technique for treating pulmonary artery stenosis caused by Takayasu arteritis.

Takayasu arteritis (TA) is a rare systemic vasculitis of the aorta and its primary branches, which usually occurs in young women. Due to its insidious onset and lack of specific symptoms, this disease can be easily misdiagnosed or missed. Approximately 50 â€‹% of the patients having TA with pulmonary artery involvement develop pulmonary hypertension (PH). The 3-year survival rate among patients with TA-related PH is lower than that among patients with TA alone. Early balloon pulmonary angioplasty (BPA) can improve the clinical symptoms and survival of patients with stable TA. To the best of our knowledge, this is the first case reported in the English literature in which a "Guidezilla" catheter was used during BPA to treat stenosis and occlusion of the pulmonary artery caused by Takayasu arteritis (TA).

Qualification of Ventricular Flow in Patients With Precapillary Pulmonary Hypertension With 4-dimensional Flow Magnetic Resonance Imaging.

PURPOSE: Our goal was to study both right and left ventricular blood flow in patients with precapillary pulmonary hypertension (pre-PH) with 4-dimensional (4D) flow magnetic resonance imaging (MRI) and to analyze their correlation with cardiac functional metrics on cardiovascular magnetic resonance (CMR) and hemodynamics from right heart catheterization (RHC). MATERIALS AND METHODS: 129 patients (64 females, mean age 47 ± 13 y) including 105 patients with pre-PH (54 females, mean age 49 ± 13 y) and 24 patients without PH (10 females, mean age 40 ± 12 y) were retrospectively included. All patients underwent CMR and RHC within 48 hours. 4D flow MRI was acquired using a 3-dimensional retrospectively electrocardiograph-triggered, navigator-gated phase contrast sequence. Right and left ventricular flow components including the percentages of direct flow (PDF), retained inflow (PRI), delayed ejection flow (PDE), and residual volume (PRVo) were respectively quantified. The ventricular flow components between patients with pre-PH and non-PH were compared and correlations of flow components with CMR functional metrics and hemodynamics measured with RHC were analyzed. Biventricular flow components were compared between survivors and deceased patients during the perioperative period. RESULTS: Right ventricular (RV) PDF and PDE significantly correlated with RVEDV and RV ejection fraction. RV PDF negatively correlated with pulmonary arterial pressure (PAP) and pulmonary vascular resistance. When the RV PDF was <11%, the sensitivity and specificity of RV PDF for predicting mean PAP ≥25 mm Hg were 88.6% and 98.7%, respectively, with an area under the curve value of 0.95 ± 0.02. When RV PRVo was more than 42%, the sensitivity and specificity of RV PRVo for predicting mean PAP ≥25 mm Hg were 85.7% and 98.5%, respectively, with an area under the curve value of 0.95 ± 0.01. Nine patients died during the perioperative period. Biventricular PDF, RV PDE, and PRI of survivors were higher than nonsurvivors whereas RV PRVo increased in deceased patients. CONCLUSIONS: Biventricular flow analysis with 4D flow MRI provides comprehensive information about the severity and cardiac remodeling of PH and may be a predictor of perioperative death of patients with pre-PH.

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.

Background: 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. Methods: 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. Results: 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). Conclusions: 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.

Different response of the oxygen pathway in patients with chronic thromboembolic pulmonary hypertension treated with pulmonary endarterectomy versus balloon pulmonary angioplasty.

Background: Oxygen pathway limitation exists in chronic thromboembolic pulmonary hypertension (CTEPH). Pulmonary endarterectomy (PEA) and balloon pulmonary angioplasty (BPA) are two effective interventions for CTEPH, but their effects and comparison of these two interventions on the oxygen pathway are not well demonstrated. Methods: CTEPH patients with available pulmonary function test, hemodynamics, and blood gas analysis before and after the interventions were included for comparison of oxygen pathway in terms of lung ventilation, lung gas exchange, oxygen delivery, and oxygen extraction between these two interventions. Results: The change in the percentage of the predicted forced expiratory volume in the 1 s (-3.4 ± 12.7 vs. 3.8 ± 8.7%, P = 0.006) and forced vital capacity (-5.5 ± 13.0 vs. 4.2 ± 9.9%, P = 0.001) among the PEA group (n = 24) and BPA group (n = 46) were significantly different. Patients in the PEA group had a significant increase in their arterial oxygen saturation (from 92.5 ± 3.6 to 94.6 ± 2.4%, P = 0.022), while those in the BPA group had no change, which could be explained by a significant improvement in ventilation/perfusion (-0.48 ± 0.53 vs. -0.17 ± 0.41, P = 0.016). Compared with patients post-BPA, patients post-PEA were characterized by higher oxygen delivery (756.3 ± 229.1 vs. 628.8 ± 188.5 ml/min, P = 0.016) and higher oxygen extraction (203.3 ± 64.8 vs. 151.2 ± 31.9 ml/min, P = 0.001). Conclusion: Partial amelioration of the oxygen pathway limitations could be achieved in CTEPH patients treated with PEA and BPA. CTEPH patients post-PEA had better performance in lung gas exchange, oxygen delivery, and extraction, while those post-BPA had better lung ventilation. Cardiopulmonary rehabilitation may assist in improving the impairment of the oxygen pathway.

Right ventricular end-systolic remodeling index on cardiac magnetic resonance imaging: comparison with other functional markers in patients with chronic thromboembolic pulmonary hypertension.

BACKGROUND: Cardiac magnetic resonance imaging (CMR) can provide important metrics of pulmonary hypertension. In the current study, we investigated whether the CMR-derived right ventricular end-systolic remodeling index (RVESRI) could be a metric in assessing the function and hemodynamics of chronic thromboembolic pulmonary hypertension (CTEPH). METHODS: A total of 64 patients (45±14 years, 37 males), including 46 patients with CTEPH and 18 patients with chronic pulmonary thromboembolism (CTE), were retrospectively enrolled. All patients underwent right heart catheterization and CMR within 7 days. RVESRI, right ventricular eccentricity index, right ventricular end-diastolic and end-systolic volume index, right ventricular ejection fraction, right ventricular cardiac output, and strain were analyzed on cine images of CMR. Hemodynamic parameters including mean pulmonary arterial pressure, pulmonary vascular resistance, and cardiac output were obtained from right heart catheterization. RESULTS: RVESRI of all patients was 1.50 (IQR, 1.26-1.90). Compared with CTE patients, RVESRI in patients with CTEPH was significantly increased (U=27.5, P<0.001). The interclass correlation coefficients of intra-observer reproducibility and inter-observer reproducibility for RVESRI measurement were 0.96 (95% CI, 0.93-0.97) and 0.99 (95% CI, 0.98-0.99), respectively. RVESRI positively correlated with right ventricular end-diastolic and end-systolic volume index and right ventricular global longitudinal strain (r=0.79, 0.83, 0.62, P<0.001), while it was negatively correlated with right ventricular ejection fraction (r=-0.64, P<0.001), right ventricular cardiac output (r=-0.50, P<0.001), and right ventricular eccentricity index (r=-0.81, P<0.001). RVESRI had a positive correlation with mean pulmonary arterial pressure (r=0.65, P<0.001) and pulmonary vascular resistance (r=0.69, P<0.001), while it was negatively correlated with cardiac output (r=-0.64, P<0.001). The receiver operating characteristic curve indicated that RVESRI >1.35 had a sensitivity of 97.8% and specificity of 83.3% in predicting mean pulmonary arterial pressure ≥25 mmHg, and its area under the curve (AUC) was 0.96±0.02. Meanwhile, the AUC of RVESRI was similar to RVEI (Z=1.635, P=0.102) and was more than the diameter of the main pulmonary artery (MPA) (Z=2.26, P=0.02) and the ratio of the MPA and ascending aorta diameter (MPA/AAo) (Z=3.826, P<0.001) in predicting mean pulmonary arterial pressure ≥25 mmHg. CONCLUSIONS: RVESRI measured on CMR is a simple and reproducible metric in assessing right ventricular function and hemodynamics in CTEPH patients.

Characteristics of Right Ventricular Blood Flow in Patients With Chronic Thromboembolic Pulmonary Hypertension: An Analysis With 4-Dimensional Flow Cardiovascular Magnetic Resonance Imaging.

Background: Blood flow is closely related to function, but currently, the relationship of right ventricular (RV) blood flow components with RV function and hemodynamics in patients with chronic thromboembolic pulmonary hypertension (CTEPH) remains unclear. Our objective is to qualify RV function with 4-dimensional flow cardiovascular magnetic resonance (4D-Flow CMR) imaging and to investigate the correlation between RV flow and hemodynamics in patients with CTEPH. Methods: Retrospective enrollment included 67 patients with CTEPH (mean age 47.8±14.2 years, 47 men) who underwent CMR and right heart catheterization (RHC) within 2 days. RHC was used to evaluate hemodynamics. RV flow components including the percentages of direct flow (PDF), retained inflow (PRI), delayed ejection flow (PDEF), and residual volume (PRVo) were quantified on 4D-Flow sequence. RV functional metrics were determined with the CINE balanced steady-state free precession sequence. The sum of PDF and PDEF was compared with RV eject fraction (RVEF). The correlation among RV flow components, RV functional metrics and hemodynamics was analyzed with spearman correlation analysis. Results: The median (interquartile range) of RVEF, PDF, PDEF, PRI, and PRVo, respectively was 35.5% (18.2, 45.6%), 18% (8.4, 21.4%), 15.1% (13.5, 19.0%), 15.9% (13.8, 20.8%), and 50.6% (35.6, 60.4%). The sum of PDF and PDEF is 35.1% (24.8, 46.6%), which was similar to RVEF (z = 0.58, p = 0.561). PDF negatively correlated with right ventricular end-systolic volume index (RVESVI), right ventricular myocardial mass index (RVMI) and right ventricular global longitudinal strain (r = -0.61, -0.65, -0.64, p < 0.001). PRVo positively correlated with RVESVI and RVMI (r = 0.50, 0.58, p < 0.001). PDF negatively correlated with pulmonary vascular resistance (PVR) (r = -0.72, p < 0.001) while it positively correlated with cardiac output (CO) and cardiac index (CI) (r = 0.64 & 0.52, p < 0.001). PRVo positively correlated with mean pulmonary pressure and PVR (r = 0.57&0.54, p < 0.001). Total five patients died in the perioperative period. RVEF in the deceased patients was similar to survivors (z = -1.163, p = 0.092). In comparison with the survivors, RVPDF in the deceased patients significantly reduced (z = -2.158, p = 0.029) while RVPDEF, RVPRI, and RVPRVo in deceased patients were similar to survivors. Conclusion: 4D-Flow CMR can provide simultaneous quantification of RV function and hemodynamics in the assessment of CTEPH without breath-holding. The reduced PDF and increased PRVo were the main characteristics of RV flow in CTEPH.

The alterations in molecular markers and signaling pathways in chronic thromboembolic pulmonary hypertension, a study with transcriptome sequencing and bioinformatic analysis.

Background: At present, the alterations in molecular markers and signaling pathways in chronic thromboembolic pulmonary hypertension (CTEPH) remain unclear. We aimed to compare the difference of molecular markers and signaling pathways in patients with CTEPH and healthy people with transcriptome sequencing and bioinformatic analysis. Methods: We prospectively included 26 patients with CTEPH and 35 sex- and age-matched healthy volunteers as control. We extracted RNA from whole blood samples to construct the library. Then, qualified libraries were sequenced using PE100 strategy on BGIseq platform. Subsequently, the DESeq2 package in R was used to screen differentially expressed mRNAs (DEmRNAs) and differentially expressed long non-coding RNAs (DElncRNAs) of 7 patients with CTEPH and 5 healthy volunteers. Afterwards, we performed functional enrichment and protein-protein interaction analysis of DEmRNAs. We also performed lncRNA-mRNA co-expression analysis and lncRNA-miRNA-mRNA network construction. In addition, we performed diagnostic analysis on the GSE130391 dataset. Finally, we performed reverse transcription polymerase chain reaction (RT-PCR) of genes in 19 patients with CTEPH and 30 healthy volunteers. Results: Gender and age between patients with CTEPH and healthy controls, between sequencing group and in vitro validation group, were comparable. A total of 437 DEmRNAs and 192 DElncRNAs were obtained. Subsequently, 205 pairs of interacting DEmRNAs and 232 pairs of lncRNA-mRNA relationship were obtained. DEmRNAs were significantly enriched in chemokine signaling pathway, metabolic pathways, arachidonic acid metabolism, and MAPK signaling pathway. Only one regulation pathway of SOBP-hsa-miR-320b-LINC00472 was found through ceRNA network construction. In diagnostic analysis, the area under curve (AUC) values of LINC00472, PIK3R6, SCN3A, and TCL6, respectively, were 0.964, 0.893, 0.750, and 0.732. Conclusion: The identification of alterations in molecules and pathways may provide further research directions on pathogenesis of CTEPH. Additionally, LINC00472, PIK3R6, SCN3A, and TCL6 may act as the potential gene markers in CTEPH.