Unusual cause of muscle weakness, type II respiratory failure and pulmonary hypertension: a case report of ryanodine receptor type 1(RYR1)-related myopathy.

BACKGROUND: Patients with congenital myopathies may experience respiratory involvement, resulting in restrictive ventilatory dysfunction and respiratory failure. Pulmonary hypertension (PH) associated with this condition has never been reported in congenital ryanodine receptor type 1(RYR1)-related myopathy. CASE PRESENTATION: A 47-year-old woman was admitted with progressively exacerbated chest tightness and difficulty in neck flexion. She was born prematurely at week 28. Her bilateral lower extremities were edematous and muscle strength was grade IV-. Arterial blood gas analysis revealed hypoventilation syndrome and type II respiratory failure, while lung function test showed restrictive ventilation dysfunction, which were both worse in the supine position. PH was confirmed by right heart catheterization (RHC), without evidence of left heart disease, congenital heart disease, or pulmonary artery obstruction. Polysomnography indicated nocturnal hypoventilation. The ultrasound revealed reduced mobility of bilateral diaphragm. The level of creatine kinase was mildly elevated. Magnetic resonance imaging showed myositis of bilateral thigh muscle. Muscle biopsy of the left biceps brachii suggested muscle malnutrition and congenital muscle disease. Gene testing revealed a missense mutation in the RYR1 gene (exon33 c.C4816T). Finally, she was diagnosed with RYR1-related myopathy and received long-term non-invasive ventilation (NIV) treatment. Her symptoms and cardiopulmonary function have been greatly improved after 10 months. CONCLUSIONS: We report a case of RYR1-related myopathy exhibiting hypoventilation syndrome, type II respiratory failure and PH associated with restrictive ventilator dysfunction. Pulmonologists should keep congenital myopathies in mind in the differential diagnosis of type II respiratory failure, especially in patients with short stature and muscle weakness.

Evaluating the efficacy of balloon pulmonary angioplasty using quantitative analysis of SPECT pulmonary ventilation/perfusion scintigraphy in patients with chronic thromboembolic pulmonary hypertension.

Background: Single-photon emission computed tomography (SPECT) ventilation perfusion imaging is the main imaging method for the diagnosis of pulmonary embolism, and its application in the diagnosis and efficacy evaluation of chronic thromboembolic pulmonary hypertension (CTEPH) has been paid more and more attention. In recent years, with the development of computer software technology, ventilation/perfusion (V/Q) imaging quantitative analysis technology has become more and more mature. The objective of this study was to investigate the utility of quantitative analysis of pulmonary V/Q scintigraphy in evaluating the efficacy of balloon pulmonary angioplasty (BPA) in patients with CTEPH. Methods: In this retrospective analysis, we collected data of patients diagnosed with CTEPH who underwent BPA at the China-Japan Friendship Hospital from April 2018 to September 2020. The sample consisted of 23 males and 28 females, with an average age of 55.1±12.7 years. All patients underwent V/Q scintigraphy within one week before surgery, and we reviewed the pulmonary angiography within 1-3 months following the last BPA procedure. We repeated V/Q scintigraphy within 1 week before or after the pulmonary angiography, at the time of collecting clinical and hemodynamic parameters of these patients. We divided the patients into two groups based on the presence of residual pulmonary hypertension post-surgery and compared the pre- and post-operative quantitative pulmonary perfusion defect percentage scores (PPDs%) using the t-test. Results: In all, 102 V/Q scintigraphy scans were performed in 51 patients. The quantitative PPDs% were positively correlated with the hemodynamic indexes mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance (PVR), and mean right ventricular pressure (RVP) (r=0.605, 0.391, and 0.464, respectively, all P<0.001) and negatively correlated with the 6-minute walking distance (6MWD) (r=-0.254, P=0.010). The average preoperative quantitative PPDs% were (49.0±15.6)% which significantly decreased to (33.5±13.9)% after surgery (t=11.249, P<0.001). The preoperative quantitative PPDs% were (54.7±15.7)% and (44.0±13.8)% in the residual pulmonary hypertension group and the non-residual pulmonary hypertension group, respectively (t=2.599, P=0.012). The postoperative quantitative PPDs% were (41.5±12.5)% and (26.3±11.0)%, in the residual pulmonary hypertension group and the non-residual pulmonary hypertension group, respectively (t=4.647, P<0.001). Conclusions: In this study, we found that quantitative analysis of SPECT pulmonary V/Q scintigraphy adequately reflected the pulmonary artery pressure and clinical status in patients with CTEPH. Our results demonstrate its definite utility in predicting residual pulmonary hypertension and in evaluating the postoperative efficacy of BPA in patients with CTEPH.

Serum proteome profiling reveals heparanase as a candidate biomarker for chronic thromboembolic pulmonary hypertension.

Determining novel biomarkers for early identification of chronic thromboembolic pulmonary hypertension (CTEPH) could improve patient outcomes. We used the isobaric tag for relative and absolute quantitation approach to compare the serum protein profiles between CTEPH patients and the controls. Bioinformatics analyses and ELISA were also performed. We identified three proteins including heparanase (HPSE), gelsolin (GSN), and secreted protein acidic and rich in cysteine (SPARC) had significant changes in CTEPH. The receiver operating characteristic curve analysis showed that the areas under the curve of HPSE in CTEPH diagnosis were 0.988. Furthermore, HPSE was correlated with multiple parameters of right ventricular function. HPSE concentrations were significantly higher in patients with a low TAPSE/sPAP ratio (≤0.31 mm/mmHg) (65.4 [60.5,68.0] vs. 59.9 [35.9,63.2] ng/mL, p < 0.05). The CTEPH patients treated by balloon pulmonary angioplasty had significantly lower HPSE levels. The study demonstrates that HPSE may be a promising biomarker for noninvasive detection of CTEPH.

Comparison of pulmonary artery sarcoma and pulmonary thromboembolism according to clinical and computed tomography pulmonary angiography and magnetic resonance imaging characteristics: a single-center retrospective study.

Background: Pulmonary artery sarcoma (PAS) is a very rare malignancy with a poor prognosis; however, its clinical manifestations and imaging findings are often indistinguishable from pulmonary thromboembolism (PTE). We thus aimed to accurately diagnose PAS by comparing the clinical and computed tomography pulmonary angiography (CTPA) and magnetic resonance imaging (MRI) imaging characteristics of PAS and PTE. Methods: This case-control study retrospectively enrolled 20 patients with PAS (from March 2017 to September 2022), 40 patients with central acute PTE, and 40 patients with central chronic PTE (from January 2021 to December 2022) in the China-Japan Friendship Hospital. The following clinical and imaging findings were compared between the three groups: initial symptoms; D-dimer, C-reactive protein, and N-terminal pro B-type natriuretic peptide levels; wall-eclipsing sign (WES); scope of lesion involvement; and morphological characteristics. Signal intensity was also observed on different MRI sequences. Results: The D-dimer level in PAS was significantly lower than that in central acute PTE (P<0.001). The WES was present in 17 cases of PAS (85.0%), which was a greater proportion than that of the central acute PTE and chronic PTE groups (all P values <0.001). The involvement of the pulmonary valve or right ventricular outflow tract was observed in five PAS cases but none of the central acute PTE or chronic PTE cases (all P values =0.001). In 19 PAS cases (95.0%), the lesions grew expansively in the central pulmonary artery. The proximal margin of 18 patients with PAS (90.0%) was bulging or lobulated. Nine cases of PAS (45.0%) showed aneurysm-like dilatation (grape-like sign) of the distal pulmonary artery, representing significantly greater proportion than that of the central acute PTE and chronic PTE groups (all P values <0.001). In 37 patients with central acute PTE (92.5%), the clots were observed to be floating in the pulmonary artery lumen with saddle, tubular or polypoid shape. Eccentric filling defects attached to the pulmonary artery wall were observed in 32 cases of central chronic PTE (80.0%). On MRI, PAS lesions were hyperintense on fat-suppressed T2-weighted imaging and diffusion-weighted imaging, demonstrating heterogeneous enhancement. Conclusions: Comprehensive analysis of the clinical data and imaging features on CTPA and MRI can aid in the accurate differential diagnosis of PAS and PTE.

Clot ratio, new clot burden score with deep learning, correlates with the risk stratification of patients with acute pulmonary embolism.

Background: Risk stratification for patients with acute pulmonary embolism (APE) is significantly important for treatment and prognosis evaluation. We aimed to develop a novel clot burden score on computed tomography pulmonary angiography (CTPA) based on deep learning (DL) algorithm for risk stratification of APE. Methods: The study retrospectively enrolled patients newly diagnosed with APE in China-Japan Friendship Hospital consecutively. We collected baseline data and CTPA parameters, and calculated four different clot burden scores, including Qanadli score, Mastora score, clot volume and clot ratio. The former two were calculated by two radiologists separately, while clot volume and clot ratio were based on the DL algorithm. The area under the curve (AUC) of four clot burden scores were analyzed. Results: Seventy patients were enrolled, including 17 in high-/intermediate-high risk and 53 in low-/intermediate-low risk. Clot burden was related to the risk stratification of APE. Among four clot burden scores, clot ratio had the highest AUC (0.719, 95% CI: 0.569-0.868) to predict patients with higher risk. In the patients with hemodynamically stable APE, only clot ratio presented statistical difference (P=0.046). Conclusions: Clot ratio is a new imaging marker of clot burden which correlates with the risk stratification of patients with APE. Higher clot ratio may indicate higher risk and acute right ventricular dysfunction in patients with hemodynamically stable status.

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.

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.

Development and validation of a lung graph-based machine learning model to predict acute pulmonary thromboembolism on chest noncontrast computed tomography.

Background: Computed tomography pulmonary angiography (CTPA) is a first-line noninvasive method to diagnose acute pulmonary thromboembolism (APE); however, whether chest noncontrast CT (NC-CT) could aid in the diagnosis of APE remains unknown. The aim of this study was to build and evaluate a holistic lung graph-based machine learning (HLG-ML) using NC-CT for the diagnosis of APE and to compare its performance with that of radiologists and the YEARS algorithm. Methods: This study enrolled 178 cases (77 males; age 63.9±16.7 years) who underwent NC-CT and CTPA in the same day from January 2019 to December 2020. Of these patients, 133 (75% of cases; 58 males; age 65.4±15.6 years) were placed into a training group and 45 (25% of cases; 19 males; age 59.6±19.2 years) into a testing group. The other 43 cases (18 males; age 62.8±20.0 years) were used to externally validate the model between January 2021 and March 2022. A HLG was developed with a pulmonary radiomics descriptor derived from NC-CT images. The approach extracted local radiomics features and encoded these local features into a radiomics descriptor as a characterization of global radiomics feature distribution. Subsequently, 8 ML models were trained and compared based on the radiomics descriptor. In the validation group, area under the curves (AUCs) of the HLG-ML model in the diagnosis of APE were compared with those of the 3 radiologists and the YEARS algorithm. Results: Among the 8 ML models, gradient boosting decision tree demonstrated the best classification performance (AUC =0.772) on the training set. In the testing set, the AUC of gradient boosting decision trees was 0.857 [95% confidence intervals (CIs): 0.699-0.951]. In the validation set, the performance of gradient boosting decision tree (AUC =0.810; 95% CI: 0.669-0.952; Youden index =0.621) outperformed 3 radiologists (AUC =0.508, 95% CI: 0.335-0.681, Youden index =0.016; AUC =0.504, 95% CI: 0.354-0.654, Youden index =0.008; AUC =0.527, 95% CI: 0.363-0.691, Youden index =0.050) and the YEARS algorithm (AUC =0.618; 95% CI: 0.469-0.767; Youden index =0.237). Conclusions: Compared to all 3 radiologists and the YEARS algorithm, the proposed HLG-based gradient boosting decision tree model achieved a superior performance in the diagnosis of APE on the NC-CT and may thus serve as a valuable tool for physicians in the diagnosis of APE.

Severe adverse reaction induced by albendazole and praziquantel for cystic echinococcosis.

Albendazole and praziquantel have been used to treat various parasitic infections for many years. Studies have confirmed the efficacy in the treatment of cystic echinococcosis (CE). We reported the case of a 45-year-old Chinese patient with pulmonary CE. He experienced diarrhea, stomachache, increase bilirubin, hair loss and acute fatal pancytopenia 10 days after albendazole and praziquantel treatment. We performed a literature review of severe adverse reaction caused by albendazole and praziquantel. It showed that severe adverse reactions such as bone marrow suppression caused by albendazole or praziquantel are rare, but patients with a course of treatment exceeding 10 days or with liver diseases are more likely to experience. Clinicians should pay attention to monitoring the patient's gastrointestinal tract reaction and peripheral blood cells (PBCs). If the patient showed a progressive disease, the medication should be immediately stopped. Supportive treatments should be considered, such as the administration of granulocyte colony-stimulating factor (G-CSF) against neutropenia or antibiotics to prevent infection.

Current status of diagnosis and treatment of pulmonary hypertension in Chinese tertiary hospitals: A nationwide survey.

We intended to evaluate the diagnosis and treatment status of pulmonary hypertension (PH) in China and provide the basis for the design of the Chinese PH centers system. A questionnaire survey was conducted by sampling from Chinese Class A tertiary hospitals that have carried out the clinical work of PH, including the composition of PH clinical team, the current application of examinations related to PH diagnosis, the availability of PAH-specific medicine and the implementation of PH-related intervention and surgery. A total of 44 valid questionnaires from 20 provinces were collected in this survey. In the vast majority of centers (83.33%, n = 35), pulmonary artery catheterization was routinely performed under X-ray guidance. In 19.05% (n = 8) of centers, pressure measurements were determined at the right time (the end of normal expiration). Only 73.81% (n = 31) centers have carried out acute vasoreactivity testing. Prostacyclin analogues and prostaglandin receptor agonists were just prescribed in 45.45% (n = 20) of the centers. 19 centers (43.18%) were capable of performing balloon pulmonary angioplasty (BPA) and pulmonary endarterectomy (PEA), while 25% (n = 11) were able to perform BPA, PEA, and lung transplantation. There was no significant difference in the diagnosis and treatment of PH between economic regions. The majority of Chinese tertiary hospitals were well equipped with the corresponding personnel, examinations and medicines related to PH, but the standardization and specialization of the management of PH need to be strengthened.

Clinical features and metabolic reprogramming of atherosclerotic lesions in patients with chronic thromboembolic pulmonary hypertension.

Background: Chronic thromboembolic pulmonary hypertension (CTEPH) patients may present with atherosclerotic lesions in their pulmonary arteries, but their clinical characteristics remain unclear. The metabolic pathways associated with the atherosclerotic lesions may explain their occurrence and have implications for interventions, but they have not been investigated. Methods: We collected pulmonary endarterectomy (PEA) samples of CTEPH patients from December 2016 to August 2021. Following a detailed pathological examination of the PEA specimen, the patients were divided into those with and without lesions, and age- and sex matching were performed subsequently using propensity score matching (n = 25 each). Metabolomic profiling was used to investigate the metabolites of the proximal lesions in the PEA specimens. Results: In our study population, 27.2% of all PEA specimens were found to contain atherosclerotic lesions. CTEPH patients with atherosclerotic lesions were more likely to have a history of symptomatic embolism and had a longer timespan between embolism and surgery, whereas the classic risk factors of systemic and coronary circulation could not distinguish CTEPH patients with or without atherosclerotic lesions. Metabolomic profiling revealed that the formation of atherosclerotic lesions in CTEPH was closely related to altered glycine, serine, and threonine metabolic axes, possibly involved in cellular senescence, energy metabolism, and a proinflammatory microenvironment. Conclusion: The occurrence of atherosclerotic lesions in the pulmonary arteries of CTEPH was associated with symptomatic thromboembolic history and prolonged disease duration. The results revealed a new link between atherosclerotic lesions and aberrant amino acid metabolism in the context of CTEPH for the first time. This study has characterized the clinical and metabolic profiles of this distinct group of CTEPH patients, providing new insights into disease pathogenesis and potential interventions.

Clinicopathological Correlation of Chronic Thromboembolic Pulmonary Hypertension: A Retrospective Study.

The pathophysiology of chronic thromboembolic pulmonary hypertension (CTEPH) is largely unknown. Although pulmonary endarterectomy (PEA) is potentially curative, inoperable patients and persistent pulmonary hypertension (PH) following surgery remain a significant problem. In this study, we aim to describe the histopathological characteristics of CTEPH and explore the potential relationship between pulmonary arterial lesions, radiological parameters, and clinical manifestations. Endarterectomized tissues from 81 consecutive patients of CTEPH were carefully collected, sectioned, and examined by experienced pathologists. Pertinent clinical and radiological data were obtained from medical records and operative reports. Neointima, fresh/organized thrombi, recanalized regions, and atherosclerotic lesions were microscopically examined as previously described. Thrombi and atherosclerosis were dominant in UCSD classification level I PEA materials, while recanalized neo-vessels were more frequently observed in UCSD classification level III cases. Degenerative changes of the extracellular matrix were also noticed in the vascular bed. Atherosclerotic lesions were more frequently observed in cases with higher ratio of the pulmonary artery diameter to ascending aorta diameter (PA/AA) reflected by computed tomographic pulmonary arterial scanning. Furthermore, the removal of pulmonary artery complex lesions (with the combination of three to four types of lesions) by PEA was associated with lower postoperative mean pulmonary arterial pressure (mPAP) and decreased incidences of persistent PH. Our study demonstrates that the histopathological features of CTEPH are strongly linked with clinical manifestations and the postoperative outcome after PEA. These data may provide possible evidence for further studies in searching for appropriate causal factors underlying this disease.

Assessment of the Effect on Thromboprophylaxis with Multifaceted Quality Improvement Intervention based on Clinical Decision Support System in Hospitalized Patients: A Pilot Study.

Background: To explore the feasibility and effectiveness of multifaceted quality improvement intervention based on the clinical decision support system (CDSS) in VTE prophylaxis in hospitalized patients. Methods: A randomized, department-based clinical trial was conducted in the department of respiratory and critical care medicine, orthopedic, and general surgery wards. Patients aged ≥18 years, without VTE in admission, were allocated to the intervention group and received regular care combined with multifaceted quality improvement intervention based on CDSS during hospitalization. VTE prophylaxis rate and the occurrence of hospital-associated VTE events were analyzed as primary and secondary outcomes. Results: A total of 3644 eligible residents were enrolled in this trial. With the implementation of the multifaceted quality improvement intervention based on the CDSS, the VTE prophylaxis rate of the intervention group increased from 22.93% to 34.56% (p < 0.001), and the incidence of HA-VTE events increased from 0.49% to 1.00% (p = 0.366). In the nonintervention group, the VTE prophylaxis rate increased from 24.49% to 27.90% (p = 0.091), and the incidence of HA-VTE events increased from 0.47% to 2.02% (p = 0.001). Conclusions: Multifaceted quality improvement intervention based on the CDSS strategy is feasible and expected to facilitate implementation of the recommended VTE prophylaxis strategies and reduce the incidence of HA-VTE in hospital. However, it is necessary to conduct more multicenter clinical trials in the future to provide more reliable real-world evidence.

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 .

Clinical Phenotypes With Prognostic Implications in Pulmonary Embolism Patients With Syncope.

OBJECTIVES: There are conflicting data concerning the prognostic significance of syncope in acute pulmonary embolism (PE). This study aimed to investigate the impact of syncope on clinical outcomes of acute PE, and determine the clinical phenotypes of PE patients with syncope and their correlation with prognosis. METHODS: In the ongoing, national, multicenter, registry study, the China pUlmonary thromboembolism REgistry Study (CURES) enrolling consecutive patients with acute PE, patients with and without syncope were investigated. Principal component analysis (PCA) was performed using nine variables relevant to syncope and PE, including age, sex, body mass index, history of cardiovascular disease, recent surgery or trauma, malignancy, pulse, systolic blood pressure, and respiratory rate. Patient classification was performed using cluster analysis based on the PCA-transformed data. The clinical presentation, disease severity and outcomes were compared among the phenotypes. RESULTS: In 7,438 patients with acute PE, 777 (10.4%) had syncope, with younger age, more females and higher body mass index. Patients with syncope had higher frequency of precordial pain, palpitation, and elevated cardiac biomarkers, as well as higher D-Dimer level. In the syncope group, more patients had right ventricular/left ventricular ratio > 0.9 in ultrasonic cardiogram and these patients had higher estimated pulmonary arterial systolic pressure compared with patients without syncope. As the initial antithrombotic treatment, more patients with syncope received systemic thrombolysis. Despite a higher prevalence of hemodynamic instability (OR 7.626, 95% CI 2.960-19.644, P < 0.001), syncope did not increase in-hospital death. Principal component analysis revealed that four independent components accounted for 60.3% of variance. PE patients with syncope were classified into four phenotypes, in which patients with high pulse and respiratory rate had markedly higher all-cause mortality during admission. CONCLUSION: Syncope was associated with hemodynamic instability and more application of thrombolysis, without increasing in-hospital deaths. Different clinical phenotypes existed in PE patients with syncope, which might be caused by various mechanisms and thus correlated with clinical outcomes.

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.

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.

Radiological, histopathological findings, and clinical outcome of pulmonary artery sarcoma.

Pulmonary artery sarcoma is a rare malignancy with poor prognosis. Lack of specific clinical manifestations, some patients are even confirmed postoperatively or at autopsy, that leads to the delay in treatment. Early diagnosis and radical surgical resection provide the possibility of prolonged survival. We retrospectively enrolled 13 patients diagnosed with pulmonary artery sarcoma at our hospital between 2015 and 2019. Their clinical, laboratory, radiological, and histopathological data were collected and analyzed. Published case series were also reviewed. Results show that, the median age of the patients was 53 years, with 6 (46.2%) males. The most common symptom is exertional dyspnea. Erythrocyte sedimentation rate and C-reactive protein were increased in 76.9% and 69.2% of these patients, while D-Dimer remained normal or elevated slightly. Metastasis was present at diagnosis in eight (61.5%) patients. Ten patients were diagnosed histologically: three were diagnosed after pulmonary endarterectomy, four by endobronchial ultrasound-guided transbronchial needle aspiration, two by percutaneous lung biopsy, and one by endovascular aspiration biopsy. Four patients underwent surgery and one is waiting for surgery. Nine patients received chemotherapy; and three of them received targeted therapy with anlotinib after chemotherapy. Two patients received anti-PD-1 monoclonal antibody. One patient died during endobronchial ultrasound-guided transbronchial needle aspiration. Two patients died 9 and 13 months after diagnosis, respectively; one refused invasive diagnostic procedures and died three months after clinical diagnosis. In conclusion, the most appropriate approach to get tissue specimen needs to be tailored to every pulmonary artery sarcoma patient. Pulmonary endarterectomy combined with chemotherapy and targeted therapy has prolonged their survival time.

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.

AKT2 regulates endothelial-mediated coagulation homeostasis and promotes intrathrombotic recanalization and thrombus resolution in a mouse model of venous thrombosis.

Venous thromboembolism (VTE) carries a high risk of morbidity and mortality. Understanding the mechanisms of venous thrombus formation and resolution is critical for improving VTE management. AKT2 kinase is essential for platelet activation and arterial thrombosis. In this study, we examined the role of AKT2 in venous thrombosis in a mouse model of venous thrombosis induced by inferior vena cava (IVC) ligation. We observed an induction of AKT2 expression in the ligated IVC of wild-type (WT) mice. Interestingly, although the initial thrombus size of the ligated IVC was similar between Akt2-/- mice and WT mice, thrombus resolution was delayed in the ligated IVC of Akt2-/- mice. Compared with the ligated IVC of WT mice, the ligated IVC of Akt2-/- mice displayed decreased levels of thrombomodulin (TM) and increased levels of tissue factor (TF), apoptosis, and necroptosis. In addition, intrathrombotic endothelial cells in the ligated IVC of Akt2-/- mice failed to form small vessels, resulting in impaired recanalization and thrombus resolution. TGF-ß signaling activation and fibrotic remodeling were increased in the thrombus and vein wall of the ligated IVC of Akt2-/- mice. We further investigated the AKT2-mediated regulation of coagulation factors in endothelial cells and found that forkhead box protein O1 (FOXO1), a target of AKT, enhanced TF and inhibited TM expression. By inhibiting FOXO1, AKT2 suppressed TF expression while increasing TM expression. Our findings indicate that AKT2 may protect endothelial cells against cell death, regulate endothelial-mediated coagulation homeostasis, and promote intrathrombotic recanalization and thrombus resolution in venous thrombosis. These observations suggest dynamic roles of AKT2 in venous thrombus formation and resolution.