Publications by authors named "Zhuang Tian"

119 Publications

The LPS induced pyroptosis exacerbates BMPR2 signaling deficiency to potentiate SLE-PAH.

FASEB J 2021 Dec;35(12):e22044

Institute of Basic Medical Sciences, School of Basic Medicine Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.

Pulmonary arterial hypertension (PAH) is a common and fatal complication of systemic lupus erythematosus (SLE). Whether the BMP receptor deficiency found in the genetic form of PAH is also involved in SLE-PAH patients remains to be identified. In this study, we employed patient-derived samples from SLE-associated PAH (SLE-PAH) and established comparable mouse models to clarify the role of BMP signaling in the pathobiology of SLE-PAH. Firstly, serum levels of LPS and autoantibodies (auto-Abs) directed at BMP receptors were significantly increased in patients with SLE-PAH compared with control subjects, measured by ELISA. Mass cytometry was applied to compare peripheral blood leukocyte phenotype in patients prior to and after treatment with steroids, which demonstrated inflammatory cells alteration in SLE-PAH. Furthermore, BMPR2 signaling and pyroptotic factors were examined in human pulmonary arterial endothelial cells (PAECs) in response to LPS stimulation. Interleukin-8 (IL-8) and E-selectin (SELE) expressions were up-regulated in autologous BMPR2 endothelial cells and siBMPR2-interfered PAECs. A SLE-PH model was established in mice induced with pristane and hypoxia. Moreover, the combination of endothelial specific BMPR2 knockout in SLE mice exacerbated pulmonary hypertension. Pyroptotic factors including gasdermin D (GSDMD) were elevated in the lungs of SLE-PH mice, and the pyroptotic effects of serum samples isolated from SLE-PAH patients on PAECs were analyzed. BMPR2 signaling upregulator (BUR1) showed anti-pyroptotic effects in SLE-PH mice and PAECs. Our results implied that deficiencies of BMPR2 signaling and proinflammatory factors together contribute to the development of PAH in SLE.
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http://dx.doi.org/10.1096/fj.202100851RRDOI Listing
December 2021

Comparative assessment of efficacy and safety of ambrisentan and bosentan in patients with pulmonary arterial hypertension: A meta-analysis.

J Clin Pharm Ther 2021 Jul 28. Epub 2021 Jul 28.

Department of Cardiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

What Is Known And Objective: Two endothelin receptor antagonists, ambrisentan and bosentan, have been demonstrated to be effective individually compared with placebo in the treatment of patients with pulmonary arterial hypertension (PAH). This network meta-analysis compared the efficacy and safety of ambrisentan and bosentan in patients with PAH.

Methods: Clinical trials were identified from the Cochrane Central Register of Controlled Trials (CENTRAL/CCTR), EMBASE and PubMed databases. Weighted mean differences (MD) with 95% confidence intervals (CI) were calculated for continuous outcomes (6-min walk distance [6MWD] and Borg dyspnoea index [BDI]). Hazard ratio (HR) was calculated for binary outcomes, including clinical worsening, discontinuation due to adverse events (AEs) and liver dysfunction. Surface under cumulative ranking curve (SUCRA) was used to rank the treatments in each index.

Results: Five clinical trials from four published studies (total patients: n = 920) were included. Ambrisentan and bosentan showed no significant difference in 6MWD (MD: -1.32; 95% CI: -27.87, 25.31, SUCRA score: ambrisentan 0.73, bosentan 0.77), BDI (MD: -0.16; 95% CI: -0.98, 0.65, SUCRA score: ambrisentan 0.83, bosentan 0.66), clinical worsening (HR: 0.99; 95% CI: 0.33, 2.94, SUCRA score: ambrisentan 0.75, bosentan 0.74) and discontinuation due to AEs (HR: 0.84; 95% CI: 0.11, 5.86, SUCRA score: ambrisentan 0.47, bosentan 0.57). However, ambrisentan was significantly better than bosentan with respect to abnormal liver function (HR: 23.18; 95% CI: 2.24, 377.20, SUCRA score: ambrisentan 0.99, bosentan 0.02).

What Is New And Conclusion: The results of this network meta-analysis suggest that ambrisentan was similar to bosentan in efficacy, while it exhibited better tolerability with respect to abnormal liver function in comparison with bosentan, in patients with PAH.
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http://dx.doi.org/10.1111/jcpt.13481DOI Listing
July 2021

Quality of life in ambulatory pulmonary arterial hypertension in connective tissue diseases and its relationship with risk stratification.

Pulm Circ 2021 Jul-Sep;11(3):20458940211029899. Epub 2021 Jul 11.

Department of Rheumatology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, National Clinical Research Center for Dermatologic and Immunologic Diseases, Ministry of Science & Technology, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, China.

The Pulmonary Arterial Hypertension Symptoms and Impact Questionnaire (PAH-SYMPACT) is a PAH-specific patient-reported outcome scale assessing patients' quality of life from four aspects: cardiopulmonary symptoms, cardiovascular symptoms, physical impacts and cognitive/emotional impacts. This study aimed to validate the Chinese version of PAH-SYMPACT and explore its relationship with risk stratification in patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH). In addition, 75 patients with CTD-PAH confirmed by right heart catheterization were invited to complete questionnaires including PAH-SYMPACT, the 36-item Medical Outcomes Study Short Form Survey (SF-36) and EuroQol five dimensions questionnaire (EQ-5D). The demographic, clinical, laboratory and treatment data were collected. The endpoint was treatment goal achievement status in 6-12 months after completing the questionnaires, defined as an integrated outcome. Participants' mean age was 36.4 ± 11.9 years and the mean pulmonary arterial pressure was 38.9 ± 13.67 mmHg. The reliability of the PAH-SYMPACT domains ranged from 0.83 to 0.88. Results of factor analysis basically conformed the original PAH-SYMPACT. The treatment goal achievement (TGA) status in 6-12 months was significantly associated with physical impacts scores (odds ratio: 0.180, 95% confidence interval: 0.036-0.908, P=0.038). The Chinese version of PAH-SYMPACT is a reliable measurement to evaluate quality of life in CTD-PAH patients and is also a potential predictor of patient's condition change in routine clinical practice.
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http://dx.doi.org/10.1177/20458940211029899DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8278470PMC
July 2021

Interventricular systolic asynchrony predicts prognosis in patients with systemic sclerosis-associated pulmonary arterial hypertension.

Rheumatology (Oxford) 2021 May 31. Epub 2021 May 31.

Department of Rheumatology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, China.

Objective: Pulmonary arterial hypertension (PAH) is a serious complication of systemic sclerosis (SSc) with high mortality. Interventricular systolic asynchrony (IVSA) is observed in PAH patients, but the effect of IVSA and its association with long-term mortality and clinical events in SSc-associated PAH are unclear. This study aimed to investigate the impact of IVSA on the prognosis of SSc-associated PAH.

Methods: Between March 2010 and July 2018, a total of 60 consecutive patients with SSc-associated PAH were enrolled. The end point was a composite of all-cause mortality and clinical worsening. Asynchrony was assessed by colour-coded tissue Doppler imaging (TDI) echocardiography. The myocardial sustained systole curves (Sm) of the basal portion of the right ventricular (RV) free wall and left ventricular (LV) lateral wall were obtained. IVSA was defined as the time difference from the onset of the QRS complex to the end of Sm between LV and RV.

Results: Patients with greater IVSA time differences presented with advanced pulmonary vascular resistance (PVR). The IVSA time difference was an independent predictive factor (HR = 1.018, 95% CI 1.005-1.031, p = 0.005) for the composite end point and was significantly associated with PVR (r = 0.399, R2=0.092, p = 0.002). Kaplan-Meier survival curves showed that patients with greater IVSA had worse prognoses (log-rank p = 0.001).

Conclusion: In conclusion, IVSA analyzed by colour-coded TDI echocardiography provided added value as a noninvasive, easy-to-use approach for assessing the prognosis of patients with SSc-associated PAH. A significant IVSA time difference identifies the subgroup of patients at high risk of a poor prognosis.
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http://dx.doi.org/10.1093/rheumatology/keab465DOI Listing
May 2021

Porcine fibrin sealant combined with autologous chondrocytes successfully promotes full-thickness cartilage regeneration in a rabbit model.

J Tissue Eng Regen Med 2021 09 4;15(9):776-787. Epub 2021 Jun 4.

Department of Orthopedics Trauma and Hand Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China.

Xenogeneic porcine fibrin sealant (PFS), derived from porcine blood, was used as a scaffold for cartilage tissue engineering. PFS has a porous microstructure, biocompatibility and degradation, and it provides a perfect extracellular matrix environment for the adhesion and proliferation of chondrocytes. Recently, PFS in combination with autologous chondrocytes (ACs) were used to study the microstructure of PFS scaffolds and promotion effect on the proliferation and migration of ACs. In this study, we investigated the effects of PFS in combination with ACs on the healing of cartilage defects in rabbits. A full-thickness cartilage defect was made in the femoral trochlear in rabbits, subsequently, three surgical procedures were used to repair the defect, namely: the defect was treated with microfracture (MF group); the defect was filled with PFS alone (PFS group) or in combination with ACs (PFS + ACs group); the unrepaired cartilage defects served as the control group (CD group). Three and 6 months after the operation, the reparative effect was evaluated using medical imaging, gross scoring, pathological staining, biomechanical testing and biochemical examination. The PFS group showed a limited effect on defect repair, this result was significantly worse than the MF group. The best reparative effect was observed in the PFS + ACs group. These results hinted that PFS in combination with autologous chondrocytes has broad prospects for clinical applications in cartilage tissue engineering.
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http://dx.doi.org/10.1002/term.3224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8453535PMC
September 2021

Right ventricular systolic function is associated with health-related quality of life: a cross-sectional study in community-dwelling populations.

Ann Transl Med 2021 Apr;9(8):640

Department of Cardiology, Peking Union Medical College, Chinese Academy of Medical Sciences, Peking Union Medical College Hospital, Beijing, China.

Background: Considerable evidence has been presented that heart and health-related quality of life are directly linked in patients with various diseases. This exploratory study investigated whether cardiac structure and function were associated with health-related quality of life in the general population.

Methods: This cross-sectional study was performed in five villages of Shunyi, a suburban district of Beijing, from June 2013 to April 2016. All inhabitants aged 35 years or older living in five villages of Shunyi were invited to participate. Exclusion criteria were individuals who declined participation, who had incomplete Health-related quality of life (HRQoL) data, and who had suboptimal echocardiograms. HRQoL was evaluated by the Mandarin version of SF-36. The association between the echocardiography-derived cardiac structure and function and each domain of SF-36 was analyzed by the multivariate linear regression analysis after adjusted for conventional risk factors affecting HRQoL.

Results: The baseline data of 990 individuals were analyzed. The median age of the participants was 57 (50-63) years, and 367 (37.1%) were male, the average physical and mental component summary scores were 89.3 (79.8-94.3) and 90 (83.5-95) respectively. Tricuspid annular plane systolic excursion, an echocardiography-derived right ventricular parameter, was associated with all the subscales and summarized scores of SF-36 (all P<0.05). The independent association between tricuspid annular plane systolic excursion and physical/mental component summary scores remained after adjusting for age, gender, body mass index, education level, annual personal income, smoking and drinking status, and comorbidities (β=0.65, 95% confidence interval 0.30-1.01, P<0.01 and β=0.49, 95% confidence interval 0.23-0.76, P<0.01 for physical and mental component summary scores respectively). Compared with the participants with tricuspid annular plane systolic excursion ≥21 mm, the participants with tricuspid annular plane systolic excursion <21 mm had lower adjusted scores of physical and mental component summary scores (81.8 . 84.5, P=0.015, and 85.5 . 88.1, P<0.01 for physical and mental component summary scores respectively).

Conclusions: In this population-based study, right ventricular systolic function assessed by tricuspid annular plane systolic excursion was independently associated with health-related quality of life assessed by SF-36.
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http://dx.doi.org/10.21037/atm-20-6845DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106091PMC
April 2021

3D-Bioprinted Difunctional Scaffold for In Situ Cartilage Regeneration Based on Aptamer-Directed Cell Recruitment and Growth Factor-Enhanced Cell Chondrogenesis.

ACS Appl Mater Interfaces 2021 May 12;13(20):23369-23383. Epub 2021 May 12.

Beijing Key Lab of Regenerative Medicine in Orthopedics; Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, Institute of Orthopedics, the First Medical Center, Chinese PLA General Hospital, No. 28 Fuxing Road, Haidian District, Beijing 100853, China.

Articular cartilage (AC) lesions are fairly common but remain an obstacle for clinicians and researchers due to their poor self-healing capacity. Recently, a promising therapy based on the recruitment of autologous mesenchymal stem cells (MSCs) has been developed for the regeneration of full-thickness cartilage defects in the knee joint. In this study, a 3D-bioprinted difunctional scaffold was developed based on aptamer HM69-mediated MSC-specific recruitment and growth factor-enhanced cell chondrogenesis. The aptamer, which can specifically recognize and recruit MSCs, was first chemically conjugated to the decellularized cartilage extracellular matrix and then mixed with gelatin methacrylate to form a photocrosslinkable bioink ready for 3D bioprinting. Together with the growth factor that promoted cell chondrogenic differentiation, the biodegradable polymer poly(ε-caprolactone) was further chosen to impart mechanical strength to the 3D bioprinted constructs. The difunctional scaffold specifically recruited MSCs, provided a favorable microenvironment for cell adhesion and proliferation, promoted chondrogenesis, and thus greatly improved cartilage repair in rabbit full-thickness defects. In conclusion, this study demonstrated that 3D bioprinting of difunctional scaffolds could be a promising strategy for in situ AC regeneration based on aptamer-directed cell recruitment and growth-factor-enhanced cell chondrogenesis.
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http://dx.doi.org/10.1021/acsami.1c01844DOI Listing
May 2021

Cell-free decellularized cartilage extracellular matrix scaffolds combined with interleukin 4 promote osteochondral repair through immunomodulatory macrophages: In vitro and in vivo preclinical study.

Acta Biomater 2021 06 31;127:131-145. Epub 2021 Mar 31.

Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma and War Injuries PLA, No. 28 Fuxing Road, Haidian District, Beijing 100853, China. Electronic address:

Cartilage regeneration is a complex physiological process. Synovial macrophages play a critical immunomodulatory role in the acute inflammatory response surrounding joint injury. Due to the contrasting differences and heterogeneity of macrophage, the phenotype of macrophages are the key determinants of the healing response after cartilage injury. Biomaterials derived from extracellular matrix have been used for the repair and reconstruction of a variety of tissues by modulating the host macrophage response. However, the immunomodulatory effect of decellularized cartilage extracellular matrix (ECM) on macrophages has not been elucidated. It is necessary to clarify the immunomodulatory properties of decellularized cartilage matrix (DCM) to guide the design of cartilage regeneration materials. Here, we prepared porcine articular cartilage derived DCM and determined the response of mouse bone marrow-derived macrophages (BMDMs) to the pepsin-solubilized DCM (PDCM) in vitro. Macrophages activated by the PDCM could promote bone marrow-derived mesenchymal stem cells (BMSCs) invasion, migration, proliferation, and chondrogenic differentiation. Then, we verified that early optimization of the immunomodulatory effects of the cell-free DCM scaffold using IL-4 in vivo could achieve good cartilage regeneration in a rat knee osteochondral defect model. Therefore, this decellularized cartilage ECM scaffold combined with accurate and active immunomodulatory strategies provides a new approach for the development of cartilage regeneration materials. STATEMENT OF SIGNIFICANCE: This work reports a decellularized cartilage extracellular matrix (DCM) scaffold combined with an accurate and active immunomodulatory strategy to improve cartilage regeneration. Our findings demonstrated that the pepsin-solubilized DCM (PDCM) activated bone marrow-derived macrophages to polarize to a constructive macrophage phenotype. These polarized macrophages promoted bone marrow-derived mesenchymal stem cell invasion, migration, proliferation, and chondrogenic differentiation. DCM scaffolds combined with early-stage intra-articular injection of IL-4 created a wound-healing microenvironment and improved cartilage regeneration in a rat knee osteochondral defect model.
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http://dx.doi.org/10.1016/j.actbio.2021.03.054DOI Listing
June 2021

Validation of the REVEAL Prognostic Models in Systemic Lupus Erythematosus-Associated Pulmonary Arterial Hypertension.

Front Med (Lausanne) 2021 4;8:618486. Epub 2021 Mar 4.

Department of Epidemiology and Bio-Statistics, Institute of Basic Medical Sciences, China Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

No previous studies have investigated the predictive performance of the Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management (REVEAL) prognostic equation and simplified risk score calculator in patients with systemic lupus erythematosus-associated pulmonary arterial hypertension (SLE-PAH). We aimed to validate these prediction tools in an external cohort of patients with SLE-PAH. In this study, the validation cohort consisted of patients with SLE-PAH registered in a prospective, multicenter, nationwide database between November 2006 and May2016. The follow-up of patients was censored at 1 year. Discrimination, calibration, model fit, and risk stratification of the REVEAL prognostic equation and simplified risk score calculator were validated. As a result, a total of 306 patients with SLE-PAH were included. The 1-year overall survival rate was 91.5%. The C-index of the prognostic equation was 0.736, demonstrating reasonably good discrimination, and it was greater than that for the simplified risk score calculator (0.710). The overall calibration slope was 0.83, and the Brier score was 0.079. The risk of renal insufficiency and World Health Organization Functional Class III (WHO FC III) were underestimated, and the risk assigned to a heart rate >92 bpm in the REVEAL prognostic models was not observed in our validation cohort. Both model discrimination and calibration were poor in the very high-risk group. In conclusion, the REVEAL models exhibit good discriminatory ability when predicting 1-year overall survival in patients with SLE-PAH. Findings from both models should be interpreted with caution in cases of renal insufficiency, WHO FC III, and heart rate >92 bpm.
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http://dx.doi.org/10.3389/fmed.2021.618486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969505PMC
March 2021

Enhancement of acellular cartilage matrix scaffold by Wharton's jelly mesenchymal stem cell-derived exosomes to promote osteochondral regeneration.

Bioact Mater 2021 Sep 13;6(9):2711-2728. Epub 2021 Feb 13.

Department of Orthopedics, The First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, China.

Articular cartilage defect repair is a problem that has long plagued clinicians. Although mesenchymal stem cells (MSCs) have the potential to regenerate articular cartilage, they also have many limitations. Recent studies have found that MSC-derived exosomes (MSC-Exos) play an important role in tissue regeneration. The purpose of this study was to verify whether MSC-Exos can enhance the reparative effect of the acellular cartilage extracellular matrix (ACECM) scaffold and to explore the underlying mechanism. The results of in vitro experiments show that human umbilical cord Wharton's jelly MSC-Exos (hWJMSC-Exos) can promote the migration and proliferation of bone marrow-derived MSCs (BMSCs) and the proliferation of chondrocytes. We also found that hWJMSC-Exos can promote the polarization of macrophages toward the M2 phenotype. The results of a rabbit knee osteochondral defect repair model confirmed that hWJMSC-Exos can enhance the effect of the ACECM scaffold and promote osteochondral regeneration. We demonstrated that hWJMSC-Exos can regulate the microenvironment of the articular cavity using a rat knee joint osteochondral defect model. This effect was mainly manifested in promoting the polarization of macrophages toward the M2 phenotype and inhibiting the inflammatory response, which may be a promoting factor for osteochondral regeneration. In addition, microRNA (miRNA) sequencing confirmed that hWJMSC-Exos contain many miRNAs that can promote the regeneration of hyaline cartilage. We further clarified the role of hWJMSC-Exos in osteochondral regeneration through target gene prediction and pathway enrichment analysis. In summary, this study confirms that hWJMSC-Exos can enhance the effect of the ACECM scaffold and promote osteochondral regeneration.
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http://dx.doi.org/10.1016/j.bioactmat.2021.01.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895679PMC
September 2021

Organic acid leaching was an efficient approach for detoxification of metal-containing plant incineration ash.

Environ Sci Pollut Res Int 2021 Feb 25. Epub 2021 Feb 25.

School of Minerals Processing and Bioengineering, Central South University, Changsha, 410083, Hunan, China.

Metal-containing plant incineration ash (MPIA), which was the by-product for metal extraction from soil by phytoextraction process, contains various kinds of heavy metal that have post potential risk to the environment. This study investigated the leaching efficiency and metal redistribution of MPIA using organic acid as leaching agents. The MPIA before and after leaching was characterized using the toxicity characteristic leaching procedure (TCPL) test, X-ray diffraction, scanning electronic microscopy, and Fourier transform infrared spectroscopy. The results showed that all tested organic acids resulted in the dissolution of metals, especially 1 mol L citric acid leaching achieved for the dissolution efficiency of 84% Mn, 87.01% Cd, 66.97% Zn, and 55.83% Pb. During leaching progress, the synergetic of chelation and acid soluble action accelerated the metal release and redistribution, and the dissolution of Mn, Zn, Pb, and Cd fit best to the shrinking core model of chemical control. Meanwhile, the leaching residue reached the regulatory standard. Thus, organic acid leaching may be a feasible strategy for detoxification of MPIA.
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http://dx.doi.org/10.1007/s11356-021-13027-0DOI Listing
February 2021

Research Progress on Stem Cell Therapies for Articular Cartilage Regeneration.

Stem Cells Int 2021 12;2021:8882505. Epub 2021 Feb 12.

Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma and War Injuries PLA, No. 28 Fuxing Road, Haidian District, Beijing 100853, China.

Injury of articular cartilage can cause osteoarthritis and seriously affect the physical and mental health of patients. Unfortunately, current surgical treatment techniques that are commonly used in the clinic cannot regenerate articular cartilage. Regenerative medicine involving stem cells has entered a new stage and is considered the most promising way to regenerate articular cartilage. In terms of theories on the mechanism, it was thought that stem cell-mediated articular cartilage regeneration was achieved through the directional differentiation of stem cells into chondrocytes. However, recent evidence has shown that the stem cell secretome plays an important role in biological processes such as the immune response, inflammation regulation, and drug delivery. At the same time, the stem cell secretome can effectively mediate the process of tissue regeneration. This new theory has attributed the therapeutic effect of stem cells to their paracrine effects. The application of stem cells is not limited to exogenous stem cell transplantation. Endogenous stem cell homing and in situ regeneration strategies have received extensive attention. The application of stem cell derivatives, such as conditioned media, extracellular vesicles, and extracellular matrix, is an extension of stem cell paracrine theory. On the other hand, stem cell pretreatment strategies have also shown promising therapeutic effects. This article will systematically review the latest developments in these areas, summarize challenges in articular cartilage regeneration strategies involving stem cells, and describe prospects for future development.
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http://dx.doi.org/10.1155/2021/8882505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895563PMC
February 2021

Prognostic Value of Circulating sST2 for the Prediction of Mortality in Patients With Cardiac Light-Chain Amyloidosis.

Front Cardiovasc Med 2020 20;7:597472. Epub 2021 Jan 20.

Department of Cardiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Systemic light-chain (AL) amyloidosis is a multisystemic disorder leading to multiple organ dysfunction and mortality that is often caused by cardiac involvement. Soluble suppression of tumorigenicity 2 (sST2) is a novel biomarker identified for risk stratification of heart disease. The aim of this study was to investigate the value of circulating sST2 levels in prognosis and mortality risk assessments for the AL amyloidosis population. A total of 56 patients diagnosed with AL amyloidosis were enrolled in Peking Union Medical College Hospital (PUMCH) from January 2015 to May 2018. The relationships between the clinical parameters and overall survival (OS) and risk factors for disease progression were assessed. Additionally, receiver operating characteristic (ROC) curves, Kaplan-Meier analysis, and Cox hazard models were performed to explore the predictive value of sST2 in mortality rates. We found that the median OS of all patients was 7.3 [interquartile range (IQR) 4.4, 15.9] months. The median baseline sST2 level was 12.2 (IQR 5.1, 31.1) ng/ml, and the sST2 high group had more severe patients with a higher Mayo stage. In the ROC analysis, the area under the curve (AUC) was 0.728 [95% confidence interval (CI) 0.603-0.853] for sST2 to predict the outcomes of AL amyloidosis patients, and the optimal cutoff value was 12.34 ng/ml (sensitivity 80.2%, specificity 61.1%). Moreover, in multivariate Cox proportional hazards regression analysis, sST2 acted as an independent predictor of poor functional outcome in patients with AL amyloidosis. In AL amyloidosis patients, sST2 was a strong and independent prognostic biomarker for all-cause mortality, providing complementary prognostic information of a novel scoring system for risk stratification.
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http://dx.doi.org/10.3389/fcvm.2020.597472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855859PMC
January 2021

Wild type transthyretin amyloidosis, a reason not to be forgotten for heart failure of preserved ejection fraction in the elderly.

J Geriatr Cardiol 2020 Dec;17(12):793-796

Department of Cardiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

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http://dx.doi.org/10.11909/j.issn.1671-5411.2020.12.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762698PMC
December 2020

Assessment of cardiac amyloidosis with Tc-pyrophosphate (PYP) quantitative SPECT.

EJNMMI Phys 2021 Jan 7;8(1). Epub 2021 Jan 7.

Department of Nuclear Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in Nuclear Medicine, Shuaifuyuan, Dongcheng District, Beijing, 100730, People's Republic of China.

Background: Tc-PYP scintigraphy provides differential diagnosis of ATTR cardiomyopathy (ATTR-CM) from light chain cardiac amyloidosis and other myocardial disorders without biopsy. This study was aimed to assess the diagnostic feasibility and the operator reproducibility of Tc-PYP quantitative SPECT.

Method: Thirty-seven consecutive patients who underwent a Tc-PYP thorax planar scan followed by SPECT and CT scans to diagnose suspected ATTR-CM were enrolled. For the quantitative SPECT, phantom studies were initially performed to determine the image conversion factor (ICF) and partial volume correction (PVC) factor to recover Tc-PYP activity concentration in the myocardium for calculating the standardized uptake value (SUV) (unit: g/ml). SUV was compared among groups of ATTR-CM, AL cardiac amyloidosis, and other pathogens (others) and among categories of Perugini visual scores (grades 0-3). The intra- and inter-operator reproducibility of quantitative SPECT was verified, and the corresponded repeatability coefficient (RPC) was calculated.

Results: The ICF was 79,327 Bq/ml to convert count rate in pixel to Tc activity concentration. PVC factor as a function of the measured activity concentration ratio in the myocardium and blood-pool was [y = 1.424 × (1 - exp(- 0.759 × x)) + 0.104]. SUV of ATTR-CM (7.50 ± 2.68) was significantly higher than those of AL (1.96 ± 0.35) and others (2.00 ± 0.74) (all p < 0.05). SUV of grade 3 (8.95 ± 1.89) and grade 2 (4.71 ± 0.23) were also significantly higher than those of grade 1 (1.92 ± 0.31) and grade 0 (1.59 ± 0.39) (all p < 0.05). Correlation coefficient (R) of SUV reached 0.966 to 0.978 with only small systematic difference (intra = - 0.14; inter = - 0.23) between two repeated measurements. Intra- and inter-operator RPCs were 0.688 and 0.877.

Conclusions: Tc-PYP quantitative SPECT integrated with adjustable PVC factors is feasible to quantitatively and objectively assess the burden of cardiac amyloidosis for diagnosis of ATTR-CM.
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http://dx.doi.org/10.1186/s40658-020-00342-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790978PMC
January 2021

Vaccine of RANKL mutant conjugated with KLH effectively stabilizing bone metabolism and preventing trabecular microstructural degeneration in osteoporotic rats.

J Orthop Res 2021 Nov 13;39(11):2465-2473. Epub 2021 Jan 13.

Department of Orthopedics, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.

Receptor activator of nuclear factor kappa-B ligand (RANKL) is one of the key factors regulating the maturation of osteoclasts and an important target for osteoporosis treatment. A monoclonal antibody against RANKL showed effective therapeutic activity against osteoporosis by inhibiting bone resorption by osteoclasts. However, being an exogenous protein, its efficacy decreases after long-term use, and its discontinuation increases the risk of vertebral fractures. Here, we aimed to design an active immunotherapeutic agent to induce a T-cell dependent primary response. The agent, a mutant RANKL vaccine (mRv), was produced by cross-linking mutant RANKL, lacking the ability to stimulate osteoclast maturation, with the carrier protein keyhole limpet hemocyanin, a neo-antigen with a large molecular mass. Subcutaneous injection of mRv stimulated rats with ovariectomy-induced osteoporosis to produce high titers of anti-RANKL antibodies. The mutant RANKL vaccine decreased serum CTX-1 and BALP levels and inhibited the microstructural degeneration of trabecular bone in osteoporotic rats. mRv overcame immune system tolerance, stimulated rats to produce therapeutic antibodies, stabilized bone metabolism, and inhibited trabecular microstructural degeneration. These findings confirm the potential of the mutant RANKL vaccine to be developed into an effective preventive and therapeutic agent for osteoporosis.
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http://dx.doi.org/10.1002/jor.24980DOI Listing
November 2021

3D bioprinting of a biomimetic meniscal scaffold for application in tissue engineering.

Bioact Mater 2021 Jun 30;6(6):1711-1726. Epub 2020 Nov 30.

Medical School of Chinese PLA, Beijing, 100853, China.

Appropriate biomimetic scaffolds created via 3D bioprinting are promising methods for treating damaged menisci. However, given the unique anatomical structure and complex stress environment of the meniscus, many studies have adopted various techniques to take full advantage of different materials, such as the printing combined with infusion, or electrospining, to chase the biomimetic meniscus, which makes the process complicated to some extent. Some researchers have tried to tackle the challenges only by 3D biopringting, while its alternative materials and models have been constrained. In this study, based on a multilayer biomimetic strategy, we optimized the preparation of meniscus-derived bioink, gelatin methacrylate (GelMA)/meniscal extracellular matrix (MECM), to take printability and cytocompatibility into account together. Subsequently, a customized 3D bioprinting system featuring a dual nozzle + multitemperature printing was used to integrate the advantages of polycaprolactone (PCL) and meniscal fibrocartilage chondrocytes (MFCs)-laden GelMA/MECM bioink to complete the biomimetic meniscal scaffold, which had the best biomimetic features in terms of morphology and components. Furthermore, cell viability, mechanics, biodegradation and tissue formation in vivo were performed to ensure that the scaffold had sufficient feasibility and functionality, thereby providing a reliable basis for its application in tissue engineering.
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http://dx.doi.org/10.1016/j.bioactmat.2020.11.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7711190PMC
June 2021

Pathological Mechanisms and Potential Therapeutic Targets of Pulmonary Arterial Hypertension: A Review.

Aging Dis 2020 Dec 1;11(6):1623-1639. Epub 2020 Dec 1.

1Department of Cardiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Pulmonary arterial hypertension (PAH) is a progressive cardiovascular disease characterized by pulmonary vasculature reconstruction and right ventricular dysfunction. The mortality rate of PAH remains high, although multiple therapeutic strategies have been implemented in clinical practice. These drugs mainly target the endothelin-1, prostacyclin and nitric oxide pathways. Management for PAH treatment includes improving symptoms, enhancing quality of life, and extending survival rate. Existing drugs developed to treat the disease have resulted in enormous economic and healthcare liabilities. The estimated cost for advanced PAH has exceeded $200,000 per year. The pathogenesis of PAH is associated with numerous molecular processes. It mainly includes germline mutation, inflammation, dysfunction of pulmonary arterial endothelial cells, epigenetic modifications, DNA damage, metabolic dysfunction, sex hormone imbalance, and oxidative stress, among others. Findings based on the pathobiology of PAH may have promising therapeutic outcomes. Hence, faced with the challenges of increasing healthcare demands, in this review, we attempted to explore the pathological mechanisms and alternative therapeutic targets, including other auxiliary devices or interventional therapies, in PAH. The article will discuss the potential therapies of PAH in detail, which may require further investigation before implementation.
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http://dx.doi.org/10.14336/AD.2020.0111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673851PMC
December 2020

Establishment of an induced pluripotent stem cell line PUMCHi004-A from a hereditary transthyretin amyloid cardiomyopathy patient with transthyretin (TTR) p.Asp38Asn mutation.

Stem Cell Res 2020 12 2;49:102022. Epub 2020 Oct 2.

Department of Cardiology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100005, China. Electronic address:

Hereditary transthyretin amyloid cardiomyopathy is cardiac involvement in systemic transthyretin amyloidosis. For the first time, we generated induced pluripotent stem cell (iPSC) line of hATTR-CM carrying the TTR mutation p.Asp38Asn. We isolated peripheral blood mononuclear cells from the patient's peripheral blood. The reprogramming of PBMCs achieved a pluripotent state by the transfection of non-integrated episomal vectors. We demonstrated pluripotency with the presence of cell surface markers, the expression of pluripotency-related genes and the ability to form teratoma composed of three germ layers in vivo. This iPSC line is a useful model for studying the pathogenic mechanism of TTR p.Asp38Asn mutation.
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http://dx.doi.org/10.1016/j.scr.2020.102022DOI Listing
December 2020

How should a physician approach the pharmacological management of chronic thromboembolic pulmonary hypertension?

Expert Opin Pharmacother 2021 Apr 5;22(5):557-563. Epub 2020 Oct 5.

Head of Cardiology Department, Key Laboratory of Pulmonary Vascular Medicine, Peking Union Medical College Hospital, Chinese Academy Medical Sciences, Beijing, China.

Introduction: Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by the presence of organized thromboembolic material and proliferative fibrous intima occluding varying degrees of the pulmonary arteries, and is also accompanied by small vessel vasculopathy in occluded and non-occluded pulmonary vasculature. The similarity in hemodynamics and pathophysiology between CTEPH and group 1 pulmonary arterial hypertension provides the rationale for clinical use of pulmonary arterial hypertension (PAH)-specific therapy.

Areas Covered: The authors present the current knowledge concerning the updated therapeutic strategies in CTEPH, and try to illustrate the established and uncertain role of PAH-specific therapy and anticoagulation therapy. The real-world observational registries and landmark randomized controlled trials of PAH-specific drugs in CTEPH are emphasized in the manuscript.

Expert Opinion: Despite surgical and interventional therapies, which could provide effective and potential curable treatments, medical therapies are still the substantial and irreplaceable option for patients with CTEPH. More and more PAH-specific drugs have demonstrated favorable efficacy and safety profiles in patients with CTEPH. Additionally, anticoagulation therapy is also a substantial medical treatment in all CTEPH patients without contradiction. However, the benefit-to-risk balance in life-long anticoagulation and whether more individualized anticoagulation strategies are needed warrants further investigation.
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http://dx.doi.org/10.1080/14656566.2020.1828349DOI Listing
April 2021

Predictive Value of Pulmonary Arterial Compliance in Systemic Lupus Erythematosus Patients With Pulmonary Arterial Hypertension.

Hypertension 2020 10 10;76(4):1161-1168. Epub 2020 Aug 10.

Department of Rheumatology (J.Z., M.L., X.Z.), Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.

Pulmonary arterial hypertension is a serious complication of systemic lupus erythematosus. It is characterized by increased right ventricular afterload which mainly comprises pulmonary arterial compliance (PAC) and pulmonary vascular resistance. The role of PAC in predicting the outcome of systemic lupus erythematosus-associated pulmonary arterial hypertension has not been investigated yet. Between February 2012 to December 2016, 120 consecutive patients diagnosed with systemic lupus erythematosus-associated pulmonary arterial hypertension based on right heart catheterization were enrolled, prospectively. Baseline clinical characteristics and hemodynamic assessment were analyzed. Baseline right ventricular afterload was stratified according to the PAC and pulmonary vascular resistance. The end point was a composite of all-cause mortality and clinical worsening. Among them, end points occurred in 49 (41%) patients after 15 months (interquartile range, 8.5-24.0). Patients with a PAC <1.39 mL/mm Hg had a 3.09-fold higher risk (95% CI, 1.54-6.20, =0.001) of the end point events than the patients with a PAC ≥1.39 mL/mm Hg. Multivariable Cox regression analysis showed that stratified right ventricular afterload was the only independent predictor for the end point (hazard ratio, 2.009 [95% CI, 1.390-2.904], <0.001). A 3-group prediction risk was created. The patients with the highest right ventricular afterload (PAC <1.39 mL/mm Hg and pulmonary vascular resistance ≥10.3Wood Unit) had the highest risk (χ, 6.10; <0.014) of experiencing the end point. Our results suggest that PAC is a good predictor of mortality and clinical worsening in systemic lupus erythematosus-associated pulmonary arterial hypertension. PAC, in addition to pulmonary vascular resistance, may be an attractive tool for screening high-risk populations in these patients.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.15682DOI Listing
October 2020

Left and right ventricular myocardial deformation and late gadolinium enhancement: incremental prognostic value in amyloid light-chain amyloidosis.

Cardiovasc Diagn Ther 2020 Jun;10(3):470-480

Department of Radiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.

Background: Previous cardiac magnetic resonance (CMR) studies have shown that both late gadolinium enhancement (LGE) and left ventricular (LV) strain have prognostic value in amyloid light-chain (AL) amyloidosis, but the right ventricular (RV) strain has not yet been studied. We aim to determine the incremental prognostic value of LV and RV LGE and strain in AL amyloidosis.

Methods: This prospective study recruited 87 patients (age, 56.9±9.1 years; M/F, 56/31) and 20 healthy subjects (age, 52.7±8.1 years; M/F, 11/9) who underwent CMR. The LV LGE was classified into no, patchy and global groups. The RV LGE was classified into negative and positive groups. Myocardial deformation was measured using a dedicated software. Follow-up was performed for all-cause mortality using Cox proportional hazards regression and Kaplan-Meier curves.

Results: During a median follow-up of 21 months, 34 deaths occurred. Presence of LV LGE [HR 2.44, 95% confidence interval (CI), 1.10-5.45, P=0.029] and global longitudinal strain (GLS) (HR 1.13 per 1% absolute decrease, 95% CI, 1.02-1.25, P=0.025) were independent LV predictors. RV LGE (HR 4.07, 95% CI, 1.09-15.24, P=0.037) and GLS (HR 1.10 per 1% absolute decrease, 95% CI, 1.00-1.21, P=0.047) were independent RV predictors. Complementary to LV LGE, LV GLS impairment or RV LGE further reduced survival (both log rank P<0.001).

Conclusions: This study confirms the incremental prognostic value of LV GLS and RV LGE in AL amyloidosis, which refines the conventional risk evaluation based on LV LGE. GLS based on non-contrast-enhanced CMR are promising new predictors.
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http://dx.doi.org/10.21037/cdt-20-181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7369280PMC
June 2020

Pulmonary arterial hypertension associated with primary Sjögren's syndrome: a multicentre cohort study from China.

Eur Respir J 2020 11 19;56(5). Epub 2020 Nov 19.

Dept of Rheumatology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, China

Objectives: Primary Sjögren's syndrome (pSS) is an important cause of pulmonary arterial hypertension (PAH), which remains insufficiently studied and needs attention. This study aimed to investigate the clinical characteristics, risk factors, prognosis and risk assessment of pSS-PAH.

Methods: We established a multicentre cohort of pSS-PAH diagnosed by right heart catheterisation. The case-control study was conducted with pSS-non-PAH patients as a control group to identify the risk factors for PAH. In the cohort study, survival was calculated, and risk assessment was performed at both baseline and follow-up visits.

Results: In total, 103 patients with pSS-PAH were enrolled, with 526 pSS-non-PAH patients as controls. The presence of anti-SSB (p<0.001, OR 4.095) and anti-U1RNP antibodies (p<0.001, OR 29.518), the age of pSS onset (p<0.001, OR 0.651) and the positivity of corneal staining (p=0.003, OR 0.409) were identified as independent risk factors for PAH. The 1-, 3- and 5-year survival rates were 94.0%, 88.8% and 79.0%, respectively. Cardiac index (p=0.010, hazard ratio (HR) 0.161), pulmonary vascular resistance (p=0.016, HR 1.105) and Sjögren's syndrome disease damage index (p=0.006, HR 1.570) were identified as potential predictors of death in pSS-PAH. Long-term outcomes were improved in patients in the low-risk category at baseline (p=0.002) and follow-up (p<0.0001).

Conclusion: The routine screening of PAH is suggested in pSS patients with early onset and positivity for anti-SSB or anti-U1RNP antibodies. Patient prognosis might be improved by improving reserved cardiopulmonary function, by achieving a damage-free state and especially by achieving low-risk category, which supports the treat-to-target strategy for pSS-PAH.
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http://dx.doi.org/10.1183/13993003.02157-2019DOI Listing
November 2020

Eltrombopag is a potential target for drug intervention in SARS-CoV-2 spike protein.

Infect Genet Evol 2020 11 12;85:104419. Epub 2020 Jun 12.

Department of Cardiology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China; School of Medicine, Tsinghua University, Haidian District, Beijing, China; Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China. Electronic address:

The COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is a current global threat for which there is an urgent need to search for an effective therapy. The transmembrane spike (S) glycoprotein of SARS-CoV-2 directly binds to the host angiotensin-converting enzyme 2 (ACE2) and mediates viral entrance, which is therefore considered as a promising drug target. Considering that new drug development is a time-consuming process, drug repositioning may facilitate rapid drug discovery dealing with sudden infectious diseases. Here, we compared the differences between the virtual structural proteins of SARS-CoV-2 and SARS-CoV, and selected a pocket mainly localizing in the fusion cores of S2 domain for drug screening. A virtual drug design algorithm screened the Food and Drug Administration-approved drug library of 1234 compounds, and 13 top scored compounds were obtained through manual screening. Through in vitro molecular interaction experiments, eltrombopag was further verified to possess a high binding affinity to S protein plus human ACE2 and could potentially affect the stability of the ACE2-S protein complex. Hence, it is worth further exploring eltrombopag as a potential drug for the treatment of SARS-CoV-2 infection.
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http://dx.doi.org/10.1016/j.meegid.2020.104419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290210PMC
November 2020

Preclinical safety evaluation of body protective compound-157, a potential drug for treating various wounds.

Regul Toxicol Pharmacol 2020 Jul 22;114:104665. Epub 2020 Apr 22.

State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China. Electronic address:

BPC157 displays protective activity in various organs and tissues. This report presents preclinical toxicity studies with BPC157 in mice, rats, rabbits and dogs. The single-dose toxicity study did not show any test-related effects that could be attributed to the test article. In repeated-dose toxicity evaluations, BPC157 was well tolerated in dogs, with no abnormal changes between the BPC157-treated groups and the solvent control group, with the exception of a decrease in creatinine level at a dose of 2 mg/kg but not at lower doses. The animals recovered spontaneously after 2 weeks of withdrawal. This may be due to the pharmacological activity of BPC157. A local tolerance test showed that the irritation caused by BPC157 was mild. BPC157 also showed no genetic or embryo-fetal toxicity. In summary, BPC157 was well tolerated and did not cause any serious toxicity in mice, rats, rabbits and dogs. These preclinical safety data contribute to the initiation of an ongoing clinical study. Based on the stability and protective effect of BPC157, which has been widely reported, BPC157 may have a better application prospect than the widely used cytokine drugs in wound therapy.
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http://dx.doi.org/10.1016/j.yrtph.2020.104665DOI Listing
July 2020

Predictive value of non-invasive right ventricle to pulmonary circulation coupling in systemic lupus erythematosus patients with pulmonary arterial hypertension.

Eur Heart J Cardiovasc Imaging 2021 01;22(1):111-118

Department of Rheumatology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, No 1. Shuaifuyuan, Dongcheng District, Beijing 100730, China.

Aims: Pulmonary arterial hypertension (PAH) is a serious and devastating complication of systemic lupus erythematosus (SLE), especially when the right ventricle (RV) fails. Whether the ratio between tricuspid annular plane systolic excursion (TAPSE) and pulmonary artery systolic pressure (PASP) measured by echocardiography as a simple surrogate of RV to pulmonary circulation (PC) coupling predicts the outcome of SLE-associated PAH has not been investigated.

Methods And Results: Between February 2010 and August 2015, 112 consecutive patients with a diagnosis of SLE-associated PAH confirmed by right heart catheterization were enrolled prospectively. The endpoint was a composite of all-cause mortality and clinical worsening. Baseline clinical characteristics and echocardiographic assessment were analysed. Among all the patients, 47 (42%) patients experienced the endpoint (mean follow-up period 18.1 ± 12.0 months), including 20 patients who died during a median follow-up period of 48.5 months. Multivariable Cox regression analysis showed that TAPSE/PASP ratio [hazard ratio (HR) 0.004, P = 0.017] and 6-min walk distance (6MWD) (HR 0.997, P = 0.036) were the independent predictors for the endpoint. A three-group prediction risk was created based on combined assessment of the TAPSE/PASP ratio and 6MWD relative to their cut-off values. The patients with the worse RV-PC coupling (TAPSE/PASP <0.184 mm/mmHg) and the lower 6MWD (<395 m) had the highest risk (HR 4.62, confidence interval 2.27-9.41, P < 0.001) of experiencing the endpoint.

Conclusion: The TAPSE/PASP ratio, combined with 6MWD, provides clinical and prognostic insights into patients with SLE-associated PAH. A low TAPSE/PASP and low 6MWD identifies the subgroup of patients with high risk of poor prognosis.
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http://dx.doi.org/10.1093/ehjci/jez311DOI Listing
January 2021

Clinical characteristics and prognosis of Chinese patients with hereditary transthyretin amyloid cardiomyopathy.

Orphanet J Rare Dis 2019 11 12;14(1):251. Epub 2019 Nov 12.

Department of Cardiology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100005, China.

Background: Hereditary transthyretin amyloid cardiomyopathy (ATTR-CM) is an increasingly recognized progressive cardiomyopathy with heterogenous clinical manifestations that lead to its misdiagnosis and poor prognosis. This study was performed to describe the clinical characteristics and natural history of Chinese patients to improve clinical awareness of this condition.

Methods: In this study, we retrospectively investigated 23 patients with a confirmed diagnosis of hereditary ATTR-CM in Peking Union Medical College hospital from From January 1, 2000 to December 31, 2018.

Results: In all, 16 patients (69.6%) were males, the median age at disease onset was 45 (33,55) years old. The median duration from symptom onset to diagnosis was 30 (18,46) months. Phenotypes were classified as exclusively cardiac (n = 1, 4.3%) and mixed type (n = 22, 95.6%). The common mutations were Gly47Arg (7 patients [30.4%]) and Val30Ala (3 patients [13%]). Ventricular hypertrophy was observed in 23 (100%) patients, the mean thickness of the ventricular septum was 16.1 ± 3.9 mm, the mean thickness of the left ventricular posterior wall was 15.1 ± 2.8 mm. The mean left ventricle ejection fraction (LVEF) was 57.3 ± 11.9% and only 5 patients (21.7%) had LVEF < 50%. 18 (78.3%) patients had abnormal electrocardiography and the most common feature was pseudoinfarct pattern (56.5%). Overall survival at 12, 24, 36, 48, and 60 months after diagnosis was 77.8, 55.6, 38.9, 27.8, and 11.1%, respectively. Survival was better in patients with EF ≥50% than in those with EF < 50% [log Rank (Mantel-Cox), χ2 = 4.03, P = 0.045].

Conclusions: The clinical characteristics of ATTR are heterogeneous: men are more likely to be affected and onset symptoms are not obvious in the heart and mainly include peripheral neuropathy and autonomic neuropathy; however, LV hypertrophy, especially a thick ventricular septum and posterior wall with preserved LVEF, are often detected on echocardiography. Abnormal ECG manifestations are common. The prognosis is poor, and patients with EF > 50% have better survival. Clinicians should be more aware of the complex clinical profile of ATTR amyloidosis to avoid misdiagnosis in practice.
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http://dx.doi.org/10.1186/s13023-019-1235-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6852775PMC
November 2019

Evaluating heart function in patients with POEMS syndrome.

Echocardiography 2019 11 6;36(11):1997-2003. Epub 2019 Nov 6.

Department of Cardiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Aims: Our aim is to investigate the characterized echocardiographic cardiac measurements of POEMS syndrome and determine its relationship with clinical manifestations.

Methods And Results: The cross-sectional study included 27 treatment-naïve patients with newly diagnosed POEMS syndrome and 26 age- and sex-matched healthy volunteers. Information of clinical manifestations, serological tests, pulmonary function tests, and both conventional echocardiograph and tissue Doppler imaging (TDI) were collected and analyzed. Pearson's correlation coefficient was used for determining the related clinical and echocardiographic parameters. Compared to healthy people, left ventricular (LV) mass index (LVMI) was elevated in patients with POEMS syndrome (41.3 ± 11.0 g/m , P < .05). LV systolic dysfunction was found by decreased mitral S' (9.0 ± 2.2 m/sec, P < .01), and diastolic dysfunction by mitral E'/A' (1.10 ± 0.42, P < .05), E/E' (8.69 ± 4.06, P < .001) on lateral, and E/E' (7.90 ± 3.28, P = .133) on septal mitral annulus. The presence of decreased tricuspid annular plane systolic excursion (TAPSE) (22.2 ± 3.5 mm, P < .01) and lateral tricuspid S' (11.1 ± 1.8 m/sec, P < .05) suggested deterioration of right ventricular (RV) systolic function. Parameters obtained from standard echocardiograph (tricuspid E/A ratio and DT) and TDI ((lateral tricuspid annulus E'/A' and E/E') indicated reduced RV diastolic function. Pulmonary hypertension (PH) was presented in six patients. Correlation analysis suggested that PH was related to total lung capacity (TLC) and diffusion capacity of carbon monoxide (DLCO).

Conclusion: Echocardiographic measurements found that there was elevation of LVMI, pulmonary artery hypertension, and subclinical impairment of systolic and diastolic functions of both the right and left heart in patients with POEMS syndrome.
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http://dx.doi.org/10.1111/echo.14516DOI Listing
November 2019

A rare simultaneous coexistence of epithelioid gastrointestinal stromal tumors and schwannoma in the stomach: a case report.

Diagn Pathol 2019 Oct 23;14(1):116. Epub 2019 Oct 23.

Department of Pathology, the First Hospital of Jilin University, Changchun, China.

Background: Gastrointestinal stromal tumors (GISTs), a type of mesenchymal tumor in the gastrointestinal tract, are believed to be closely associated with PDGFRA and C-KIT mutations. Schwannoma in the stomach, which is an unusual location, is a rare disorder. The simultaneous occurrence of the two diseases is rarer than metachronous occurrences, and its pathological characteristics have not been reported to date. We present a case report on a patient with simultaneous coexistence of gastric schwannoma and GISTs.

Case Presentation: A 39-year-old female visited our hospital complaining of intermittent abdominal pain for the previous 3 months. CT revealed a 3.4 cm slight homogeneous enhancement in the lesser curvature of the stomach; the mass was nodular soft tissue, which was removed by radical surgery. Two solid tumors with different volumes were located in the stomach. Histologically and immunohistochemically different, the larger tumor consisted of spindle cells surrounded by a peripheral lymphoid cuff, and was positive for S-100. The larger tumor was therefore classified as a gastric schwannoma. The smaller tumor was composed of medium-sized round, oval cells with amphiphilic granular cytoplasm; vacuolization was also observed. The tumor cells were positive for DOG1 and sporadically positive for CD34 and CD117. Hence, the smaller tumor was diagnosed as epithelioid GISTs. Sanger sequencing revealed that the GIST tumor cells contained a deletion mutation (c.2527_2538 del12,843-846del4), which was located in exon 18 of PDGFRA.

Conclusion: GISTs combined with gastric schwannoma are a considerably rare subgroup of gastric tumors. Related clinical research is comparatively weak, and the mechanism remains unknown. We reviewed related articles to provide knowledge to improve the correct identification, diagnosis and management of patients with gastric cancer. All pathologists involved in the diagnosis and clinicians involved in the treatment should be aware of this new kind of disease pattern to improve their understanding of the disease.
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http://dx.doi.org/10.1186/s13000-019-0898-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6813059PMC
October 2019

Genomic profiling in amyloid light-chain amyloidosis reveals mutation profiles associated with overall survival.

Amyloid 2020 Mar 22;27(1):36-44. Epub 2019 Oct 22.

Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Amyloid light chain (AL) amyloidosis is characterized by tissue deposition of amyloid fibres derived from immunoglobulin that can lead to irreversible organ damage. Information about genomic profiles of AL amyloidosis is lacking. In this study, we adopted a two-step strategy to investigate the mutational profile of AL amyloidosis bone marrow plasma cells (PCs) and their clinical implications. In step one, whole-exome sequencing was performed in bone marrow PCs and paired with normal tissue from 10 AL amyloidosis patients, by which we identified 10 significantly mutated genes (SMGs). In step two, we constituted a targeted gene sequencing (TGS) panel covering the frequently mutated genes identified in step one, genes reported in prior AL amyloidosis studies, and known cancer driver mutations. Then, we analysed an expanded cohort of AL amyloidosis patients ( = 48) with this panel comprising 98 genes. Four recurrent mutations were identified by TGS and verified by Sanger sequencing: (c. 844 C > T), (c. 1595 A > G), (c. 311 C > T) and (c. 35 G > A), among which the first three mutations were associated with inferior overall survival (OS). Additionally, we found that the number of mutations identified by the TGS panel of 98 genes could be a prognostic predictor for OS. In summary, we revealed genomic profiling in AL amyloidosis and found mutation profiles associated with OS.
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http://dx.doi.org/10.1080/13506129.2019.1678464DOI Listing
March 2020
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