Publications by authors named "Jian'an Wang"

106 Publications

Loss of Hepatic Angiotensinogen Attenuates Sepsis-Induced Myocardial Dysfunction.

Circ Res 2021 Jul 9. Epub 2021 Jul 9.

Cardiology, Second Affiliated Hospital, College of Medicine, Zhejiang University, CHINA.

The renin-angiotensin system (RAS) is a complex regulatory network that maintains normal physiological functions. The role of the RAS in sepsis-induced myocardial dysfunction (SIMD) is poorly defined. Angiotensinogen (AGT) is the unique precursor of the RAS and gives rise to all angiotensin peptides. The effects and mechanisms of AGT in development of SIMD have not been defined. To determine a role of AGT in SIMD and investigate the underlying mechanisms. Either intraperitoneal injection of lipopolysaccharide (LPS) or cecal ligation and puncture (CLP) significantly enhanced AGT abundances in liver, heart, and plasma. Deficiency of hepatocyte-derived AGT (hepAGT), rather than cardiomyocyte-derived AGT (carAGT), alleviated septic cardiac dysfunction in mice and prolonged survival time. Further investigations revealed that the effects of hepAGT on SIMD were partially associated with augmented angiotensin II (AngII) production in circulation. In addition, hepAGT was internalized by LDL receptor-related protein 1 (LRP1) in cardiac fibroblasts (CF), and subsequently activated NLRP3 inflammasome via an AngII-independent pathway, ultimately promoting SIMD by suppressing Sarco(endo)plasmic reticulum Ca(2+)-ATPase 2a (SERCA2a) abundances in cardiomyocytes (CM). HepAGT promoted SIMD via both AngII-dependent and AngII-independent pathways. We identified a liver-heart axis by which AGT regulated development of SIMD. Our study may provide a potential novel therapeutic target for SIMD.
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http://dx.doi.org/10.1161/CIRCRESAHA.120.318075DOI Listing
July 2021

Expanding the coronary tree reconstruction to smaller arteries improves the accuracy of FFR.

Eur Radiol 2021 May 25. Epub 2021 May 25.

Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China.

Objectives: We attempted to improve the accuracy of coronary CT angiography (CCTA)-derived fractional flow reserve (FFR) (FFR) by expanding the coronary tree in the computational fluid dynamics (CFD) domain. An observational study was performed to evaluate the effects of extending the coronary tree analysis for FFR from a minimal diameter of 1.2 to 0.8 mm.

Methods: Patients who underwent CCTA and interventional FFR were enrolled retrospectively. Seventy-six patients qualified based on the inclusion criteria. The three-dimensional (3D) coronary artery tree was reconstructed to generate a finite element mesh for each subject with different lower limits of luminal diameter (1.2 mm and 0.8 mm). Outlet boundary conditions were defined according to Murray's law. The Newton-Krylov-Schwarz (NKS) method was applied to solve the governing equations of CFD to derive FFR.

Results: At the individual patient level, extending the minimal diameter of the coronary tree from 1.2 to 0.8 mm improved the sensitivity of FFR by 16.7% (p = 0.022). This led to the conversion of four false-negative cases into true-positive cases. The AUC value of the ROC curve increased from 0.74 to 0.83. Moreover, the NKS method can solve the computational problem of extending the coronary tree to an 0.8-mm luminal diameter in 10.5 min with 2160 processor cores.

Conclusions: Extending the reconstructed coronary tree to a smaller luminal diameter can considerably improve the sensitivity of FFR. The NKS method can achieve favorable computational times for future clinical applications.

Key Points: • Extending the reconstructed coronary tree to a smaller luminal diameter can considerably improve the sensitivity of FFR. • The NKS method applied in our study can effectively reduce the computational time of this process for future clinical applications.
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http://dx.doi.org/10.1007/s00330-021-08012-7DOI Listing
May 2021

Multicenter clinical evaluation of a piezoresistive-MEMS-sensor rapid-exchange pressure microcatheter system for fractional flow reserve measurement.

Catheter Cardiovasc Interv 2021 May 5. Epub 2021 May 5.

Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China.

Objectives: This multicenter, prospective clinical study investigates whether the microelectromechanical-systems-(MEMS)-sensor pressure microcatheter (MEMS-PMC) is comparable to a conventional pressure wire in fractional flow reserve (FFR) measurement.

Background: As a conventional tool for FFR measurement, pressure wires (PWs) still have some limitations such as suboptimal handling characteristics and unable to maintain the wire position during pullback assessment. Recently, a MEMS-PMC compatible with any 0.014″ guidewire is developed. Compared with the existing optical-sensor PMC, this MEMS-PMC has smaller profiles at both the lesion crossing and sensor packaging areas.

Methods: Two hundred and forty-two patients with visually 30-70% coronary stenosis were enrolled at four centers. FFR was measured first with the MEMS-PMC, and then with the PW. The primary endpoint was the Bland-Altman mean bias between the MEMS-PMC and PW FFR.

Results: From the 224-patient per-protocol data, quantitative coronary angiography showed 17.9% and 55.9% vessels had diameter < 2.5 mm and stenosis >50%, respectively. The two systems' mean bias was -0.01 with [-0.08, 0.06] 95% limits-of-agreement. Using PW FFR≤0.80 as cutoff, the MEMS-PMC per-vessel diagnostic accuracy was 93.4% [95% confidence interval: 89.4-96.3%]. The MEMS-PMC's success rate was similar to that of PW (97.5 vs. 96.3%, p = .43) with no serious adverse event, and its clinically-significant (>0.03) drift rate was 43% less (9.5 vs. 16.7%, p = .014).

Conclusions: Our study showed the MEMS-PMC is safe to use and has a minimal bias equal to the resolution of current FFR systems. Given the MEMS-PMC's high measurement accuracy and rapid-exchange nature, it may become an attractive new tool facilitating routine coronary physiology assessment.
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http://dx.doi.org/10.1002/ccd.29678DOI Listing
May 2021

Emerging role of interleukin-13 in cardiovascular diseases: A ray of hope.

J Cell Mol Med 2021 Jun 4;25(12):5351-5357. Epub 2021 May 4.

Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Despite the great progress made in the treatment for cardiovascular diseases (CVDs), the morbidity and mortality of CVDs remains high due to the lack of effective treatment strategy. Inflammation is a central pathophysiological feature of the heart in response to both acute and chronic injury, while the molecular basis and underlying mechanisms remains obscure. Interleukin (IL)-13, a pro-inflammatory cytokine, has been known as a critical mediator in allergy and asthma. Recent studies appraise the role of IL-13 in CVDs, revealing that IL-13 is not only involved in more obvious cardiac inflammatory diseases such as myocarditis but also relevant to acute or chronic CVDs of other origins, such as myocardial infarction and heart failure. The goal of this review is to summarize the advancement in our knowledge of the regulations and functions of IL-13 in CVDs and to discuss the possible mechanisms of IL-13 involved in CVDs. We highlight that IL-13 may be a promising target for immunotherapy in CVDs.
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http://dx.doi.org/10.1111/jcmm.16566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184673PMC
June 2021

Transcatheter mitral valve repair in a high-surgical risk patient with severe degenerative mitral regurgitation using the novel DragonFly™ Transcatheter Repair device-First in man implantation in China.

Catheter Cardiovasc Interv 2021 May 4. Epub 2021 May 4.

Department of Cardiology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Transcatheter repair of mitral regurgitation (MR) by edge-to-edge therapy has become increasingly accepted for patients with severe MR at high or prohibitive surgical risk in primary or degenerative mitral regurgitation (DMR). The technological approach has evolved from the initial transcatheter edge-to-edge device to improve on its acute reduction in MR and durability of results, particularly in complex primary pathology. In this study, we reported the first case of DragonFly™ Transcatheter Valve Repair device in a patient with severe DMR.
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http://dx.doi.org/10.1002/ccd.29687DOI Listing
May 2021

True cost of surgical aortic valve replacement and implications for price setting and diagnosis-related groups: evidence from a tertiary hospital in Eastern China.

J Comp Eff Res 2021 06 15;10(8):697-708. Epub 2021 Apr 15.

The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310002, China.

Surgical aortic valve replacement (SAVR) has long been the standard treatment for patients with severe aortic stenosis in China, but the costs of SAVR from a hospital perspective in China have not been thoroughly researched. Currently, diagnosis-related groups in China are based on historical expenses that are closely related to the unit charges set by the official pricing department and are frequently inaccurate compared with actual resource consumption. Through a retrospective empirical study on the costs and charges of SAVR cases in a tertiary hospital, this study aimed to compare the costs and charges of service items. We collected clinical information from patients undergoing SAVR (isolated or concomitant procedures) and financial information from the hospital in 2015 and 2016. Top-down full cost accounting and step-allocation were the main methods used in this study. This research selected 203 SAVR cases in 2015 and 214 cases in 2016. The median length of hospital stay was 15.92 days (6.07 days pre surgery and 9.57 days post surgery). The average human resource cost of care per day per bed in the cardiovascular surgery department, including doctors and nurses, was US $62.22 in 2015 and $66.17 in 2016, but the corresponding charge was no more than $24. For operation, the cost of isolated SAVR was $665 in 2015 and $1015 in 2016, while the charge was $820. For anesthesiology, the cost of isolated SAVR was $400 in 2015 and $526 in 2016, while the average charge was $192. For examination service items, some costs did not exceed charges. The average total cost of a case was $19,299 ± 8954, while the average total charge was $18,923 ± 9194. SAVR is associated with significant resource utilization and hospital stay duration. The fees for human resources and services associated with SAVR do not reflect the true costs of SAVR in a Chinese hospital setting. This study may assist in future budget planning and price setting for policy makers in China.
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http://dx.doi.org/10.2217/cer-2021-0037DOI Listing
June 2021

Iatrogenic type-A aortic dissection due to transcatheter aortic valve implantation.

Eur Heart J Case Rep 2021 Feb 16;5(2):ytab024. Epub 2021 Feb 16.

Department of Cardiology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, China.

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http://dx.doi.org/10.1093/ehjcr/ytab024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954272PMC
February 2021

Kidney function change after transcatheter aortic valve replacement in patients with diabetes and/or hypertension.

J Zhejiang Univ Sci B 2021 Mar;22(3):241-247

Department of Cardiology, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China.

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http://dx.doi.org/10.1631/jzus.B2000431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982332PMC
March 2021

Small extracellular vesicles containing miR-486-5p promote angiogenesis after myocardial infarction in mice and nonhuman primates.

Sci Transl Med 2021 03;13(584)

Department of Cardiology, Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310009, PR China.

Stem cell-derived small extracellular vesicles (sEVs) promote angiogenesis after myocardial infarction (MI). However, the components of sEVs that contribute to these effects and the safety and efficiency of engineered sEV treatment for MI remain unresolved. Here, we observed improved cardiac function, enhanced vascular density, and smaller infarct size in mice treated with the sEVs from hypoxia-preconditioned (HP) mesenchymal stem cells (MSCs) (HP-sEVs) than in mice treated with normoxia-preconditioned (N) MSCs (N-sEVs). MicroRNA profiling revealed a higher abundance of miR-486-5p in HP-sEVs than in N-sEVs, and miR-486-5p inactivation abolished the benefit of HP-sEV treatment, whereas miR-486-5p up-regulation enhanced the benefit of N-sEV treatment. Matrix metalloproteinase 19 (MMP19) abundance was lower in HP-sEV-treated than N-sEV-treated mouse hearts but was enriched in cardiac fibroblasts (CFs), and was identified as one of the target genes of miR-486-5p. Conditioned medium from CFs that overexpressed miR-486-5p or silenced MMP19 increased the angiogenic activity of endothelial cells; however, medium from CFs that simultaneously overexpressed and miR-486-5p abolished this effect. silencing in CFs reduced the cleavage of extracellular vascular endothelial growth factor (VEGF). Furthermore, miR-486-5p-overexpressing N-sEV treatment promoted angiogenesis and cardiac recovery without increasing arrhythmia complications in a nonhuman primate (NHP) MI model. Collectively, this study highlights the key role of sEV miR-486-5p in promoting cardiac angiogenesis via fibroblastic MMP19-VEGFA cleavage signaling. Delivery of miR-486-5p-engineered sEVs safely enhanced angiogenesis and cardiac function in an NHP MI model and may promote cardiac repair.
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http://dx.doi.org/10.1126/scitranslmed.abb0202DOI Listing
March 2021

LARP7 Protects Against Heart Failure by Enhancing Mitochondrial Biogenesis.

Circulation 2021 May 5;143(20):2007-2022. Epub 2021 Mar 5.

Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Department of Pediatric Cardiology, Xin Hua Hospital, School of Medicine, Xin Hua Hospital, Shanghai Jiao Tong University, China (H.J.Y., F.Z., P.Y.Y., S.S.Z., Y.M.L., Z.L.G., Z.X.L., Y.J.X., Y.N.L., K.S., B.Z.).

Background: Heart failure (HF) is among the leading causes of morbidity and mortality, and its prevalence continues to rise. LARP7 (La ribonucleoprotein domain family member 7) is a master regulator that governs the DNA damage response and RNAPII (RNA polymerase II) pausing pathway, but its role in HF pathogenesis is incompletely understood.

Methods: We assessed LARP7 expression in human HF and in nonhuman primate and mouse HF models. To study the function of LARP7 in heart, we generated global and cardiac-specific knockout mice. We acutely abolished LARP7 in mature cardiomyocytes by Cas9-mediated somatic knockout. We overexpressed LARP7 in cardiomyocytes using adeno-associated virus serotype 9 and ATM (ataxia telangiectasia mutated protein) inhibitor. The therapeutic potential of LARP7-regulated pathways in HF was tested in a mouse myocardial infarction model.

Results: LARP7 was profoundly downregulated in failing human hearts and in nonhuman primate and murine hearts after myocardial infarction. Low LARP7 levels in failing hearts were linked to elevated reactive oxygen species, which activated the ATM-mediated DNA damage response pathway and promoted LARP7 ubiquitination and degradation. Constitutive knockout in mouse resulted in impaired mitochondrial biogenesis, myocardial hypoplasia, and midgestational lethality. Cardiac-specific inactivation resulted in defective mitochondrial biogenesis, impaired oxidative phosphorylation, elevated oxidative stress, and HF by 4 months of age. These abnormalities were accompanied by reduced SIRT1 (silent mating type information regulation 2 homolog 1) stability and deacetylase activity that impaired SIRT1-mediated transcription of genes for oxidative phosphorylation and energy metabolism and dampened cardiac function. Restoring LARP7 expression after myocardial infarction by either adeno-associated virus-mediated LARP7 expression or small molecule ATM inhibitor substantially improved the function of injured heart.

Conclusions: LARP7 is essential for mitochondrial biogenesis, energy production, and cardiac function by modulating SIRT1 homeostasis and activity. Reduction of LARP7 in diseased hearts owing to activation of the ATM pathway contributes to HF pathogenesis and restoring LARP7 in the injured heart confers myocardial protection. These results identify the ATM-LARP7-SIRT1 pathway as a target for therapeutic intervention in HF.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.050812DOI Listing
May 2021

Extraction of Coronary Atherosclerotic Plaques From Computed Tomography Imaging: A Review of Recent Methods.

Front Cardiovasc Med 2021 10;8:597568. Epub 2021 Feb 10.

Research Centre for Intelligent Healthcare, Coventry University, Coventry, United Kingdom.

Atherosclerotic plaques are the major cause of coronary artery disease (CAD). Currently, computed tomography (CT) is the most commonly applied imaging technique in the diagnosis of CAD. However, the accurate extraction of coronary plaque geometry from CT images is still challenging. In this review, we focused on the methods in recent studies on the CT-based coronary plaque extraction. According to the dimension of plaque extraction method, the studies were categorized into two-dimensional (2D) and three-dimensional (3D) ones. In each category, the studies were analyzed in terms of data, methods, and evaluation. We summarized the merits and limitations of current methods, as well as the future directions for efficient and accurate extraction of coronary plaques using CT imaging. The methodological innovations are important for more accurate CT-based assessment of coronary plaques in clinical applications. The large-scale studies, de-blooming algorithms, more standardized datasets, and more detailed classification of non-calcified plaques could improve the accuracy of coronary plaque extraction from CT images. More multidimensional geometric parameters can be derived from the 3D geometry of coronary plaques. Additionally, machine learning and automatic 3D reconstruction could improve the efficiency of coronary plaque extraction in future studies.
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http://dx.doi.org/10.3389/fcvm.2021.597568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903898PMC
February 2021

SRT1720 Pretreatment Promotes Mitochondrial Biogenesis of Aged Human Mesenchymal Stem Cells and Improves Their Engraftment in Postinfarct Nonhuman Primate Hearts.

Stem Cells Dev 2021 04 22;30(7):386-398. Epub 2021 Mar 22.

Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Declined function of aged mesenchymal stem cells (MSCs) diminishes the benefits of cell therapy for myocardial infarction (MI). Our previous study has demonstrated that SRT1720, a specific SIRT1 activator, could protect aged human MSCs (hMSCs) against apoptosis. The purpose of the present study was to investigate the role of mitochondria in the antiapoptotic effects of SRT1720. In addition, we established a nonhuman primate MI model to evaluate cell engraftment of SRT1720-pretreated aged hMSCs (SRT1720-OMSCs). A hydrogen peroxide (HO)-induced apoptosis model was established in vitro to mimic MI microenvironment. Compared with vehicle-treated aged hMSCs (Vehicle-OMSCs), SRT1720-OMSCs showed alleviated apoptosis level, significantly decreased caspase-3 and caspase-9 activation, and reduced release of cytochrome when subjected to HO treatment. Mitochondrial contents were compared between young and aged hMSCs and our data showed that aged hMSCs had lower mitochondrial DNA (mtDNA) copy numbers and protein expression levels of components of the mitochondrial electron transport chain (ETC) than young hMSCs. Also, treatment with SRT1720 resulted in enhanced MitoTracker staining, increased mtDNA levels and expression of mitochondrial ETC components in aged hMSCs. Furthermore, SRT1720-OMSCs exhibited elevated mitochondrial respiratory capacity and higher mitochondrial membrane potential. In vivo study demonstrated that SRT1720-OMSCs had higher engraftment rates than Vehicle-OMSCs at 3 days after transplantation into the infarcted nonhuman primate hearts. Taken together, these results suggest that SRT1720 promotes mitochondrial biogenesis and function of aged hMSCs, which is involved in its protective effects against HO-induced apoptosis. These findings encourage further exploration of the optimization of aged stem cells function via regulating mitochondrial function.
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http://dx.doi.org/10.1089/scd.2020.0149DOI Listing
April 2021

Surface-Anchored Nanogel Coating Endows Stem Cells with Stress Resistance and Reparative Potency via Turning Down the Cytokine-Receptor Binding Pathways.

Adv Sci (Weinh) 2021 Feb 6;8(3):2003348. Epub 2021 Jan 6.

Department of Cardiology, The Second Affiliated Hospital Zhejiang University School of Medicine Hangzhou 310009 China.

Stem cell-based therapy has great potential in regenerative medicine. However, the survival and engraftment rates of transplanted stem cells in disease regions are poor and limit the effectiveness of cell therapy due to the fragility of stem cells. Here, an approach involving a single-cell coating of surface-anchored nanogel to regulate stem cell fate with anti-apoptosis capacity in the hypoxic and ischemic environment of infarcted hearts is developed for the first time. A polysialic acid-based system is used to anchor microbial transglutaminase to the external surface of the cell membrane, where it catalyzes the crosslinking of gelatin. The single-cell coating with surface-anchored nanogel endows mesenchymal stem cells (MSCs) with stress resistance by blocking the activity of apoptotic cytokines including the binding of tumor necrosis factor α (TNFα) to tumor necrosis factor receptor, which in turn maintains mitochondrial integrity, function and protects MSCs from TNF-induces apoptosis. The administration of surface engineered MSCs to hearts results in significant improvements in engraftment, cardiac function, infarct size, and vascularity compared with using uncoated MSCs in treating myocardial infarction. The surface-anchored, biocompatible cell surface engineering with nanogel armor provides a new way to produce robust therapeutic stem cells and may explore immense potentials in cell-based therapy.
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http://dx.doi.org/10.1002/advs.202003348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856906PMC
February 2021

Automatic segmentation of coronary lumen and external elastic membrane in intravascular ultrasound images using 8-layer U-Net.

Biomed Eng Online 2021 Feb 6;20(1):16. Epub 2021 Feb 6.

ArteryFlow Technology Co., Ltd., Hangzhou, China.

Background: Intravascular ultrasound (IVUS) is the golden standard in accessing the coronary lesions, stenosis, and atherosclerosis plaques. In this paper, a fully automatic approach by an 8-layer U-Net is developed to segment the coronary artery lumen and the area bounded by external elastic membrane (EEM), i.e., cross-sectional area (EEM-CSA). The database comprises single-vendor and single-frequency IVUS data. Particularly, the proposed data augmentation of MeshGrid combined with flip and rotation operations is implemented, improving the model performance without pre- or post-processing of the raw IVUS images.

Results: The mean intersection of union (MIoU) of 0.937 and 0.804 for the lumen and EEM-CSA, respectively, were achieved, which exceeded the manual labeling accuracy of the clinician.

Conclusion: The accuracy shown by the proposed method is sufficient for subsequent reconstruction of 3D-IVUS images, which is essential for doctors' diagnosis in the tissue characterization of coronary artery walls and plaque compositions, qualitatively and quantitatively.
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http://dx.doi.org/10.1186/s12938-021-00852-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7866471PMC
February 2021

Long noncoding RNA regulates cardiac fibrosis.

Mol Ther Nucleic Acids 2021 Mar 26;23:377-392. Epub 2020 Nov 26.

Department of Cardiology, Provincial Key Lab of Cardiovascular Research, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China.

Cardiac fibrosis occurs in most cardiac diseases, which reduces cardiac muscle compliance, impairs both systolic and diastolic heart function and, ultimately, leads to heart failure. Long noncoding RNAs (lncRNAs) have recently emerged as important regulators of a variety of biological processes; however, little is known about the expression and function of lncRNAs in cardiac fibrosis. Using unbiased transcriptome profiling in a mouse model of myocardial infarction (MI), we identified a cardiac fibroblast-enriched lncRNA (AK048087) named cardiac fibroblast-associated transcript (), which is significantly elevated after MI. Silencing expression by small interfering RNAs (siRNAs) or lentiviral short hairpin RNAs (shRNAs) resulted in suppression of fibrosis-related gene expression and transdifferentiation of myofibroblasts into cardiac fibroblasts. Depletion of by lentiviral shRNAs in mouse hearts significantly attenuated cardiac fibrosis induced by MI or isoproterenol-infusion. Importantly, inhibition of ameliorated cardiac function following cardiac injury. RNA pull-down followed by mass spectrometry analyses identified COTL1 (coactosin-like 1) as one of the interacting proteins. Mechanistically, competitively inhibits the COTL1 interaction with TRAP1 (transforming growth factor-β receptor-associated protein 1), which enhances TGF-β signaling by augmenting SMAD2/SMAD4 complex formation. Therefore, our study identifies as a novel cardiac fibroblast-enriched lncRNA that regulates cardiac fibroblast activation in response to pathophysiological stress. could serve as a potential therapeutic target for the prevention of cardiac fibrosis and cardiac diseases.
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http://dx.doi.org/10.1016/j.omtn.2020.11.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787992PMC
March 2021

Sex differences in patients undergoing transcatheter aortic valve replacement in Asia.

Open Heart 2021 01;8(1)

Department of Cardiology, Sichuan University West China Hospital, Chengdu, China.

Objectives: Transcatheter aortic valve replacement (TAVR) is increasingly performed. Physically small Asians have smaller aortic root and peripheral vessel anatomy. The influence of gender of Asian patients undergoing TAVR is unknown and may affect outcomes. The aim of this study was to assess sex differences in Asian patients undergoing TAVR.

Methods: Patients undergoing TAVR from eight countries were enrolled. In this retrospective analysis, we examined differences in characteristics, 30-day clinical outcomes and 1-year survival between female and male Asian patients.

Results: Eight hundred and seventy-three patients (54.4% women) were included. Women were older, smaller and had less coronary artery and lung disease but tended to have higher logistic EuroSCOREs. Smaller prostheses were used more often in women. Major vascular complications occurred more frequently in women (5.5% vs 1.8%, p<0.01); however, 30-day stroke and mortality (women vs men: 1.5% vs 1.6%, p=0.95% and 4.3% vs 3.4%, p=0.48) were similar. Functional status improvement was significant and comparable between the sexes. Conduction disturbance and permanent pacemaker requirements (11.2% vs 9.0%, p=0.52) were also similar as was 1-year survival (women vs men: 85.6% vs 88.2%, p=0.25). The only predictors of 30-day mortality were major vascular injury in women and age in men.

Conclusions: Asian women had significantly smaller stature and anatomy with some differences in clinical profiles. Despite more frequent major vascular complications, women had similar 30-day stroke or mortality rates. Functional status improvement was significant and comparable between the sexes. Conduction disturbance and permanent pacemaker requirements were similar as was 1-year survival.
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http://dx.doi.org/10.1136/openhrt-2020-001541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7798412PMC
January 2021

Polysaccharides of Hemsl.: Extraction, Antioxidant, and Anti-Inflammatory Evaluation.

Evid Based Complement Alternat Med 2020 15;2020:8899762. Epub 2020 Dec 15.

School of Pharmacy, Jining Medical University, Rizhao, Shandong 276826, China.

The roots of Hemsl. are a famous traditional Chinese medicinal herb and are also used as health food. However, information about polysaccharides from (SNPS) is very limited. We applied the ultrasonic-assisted extraction (UAE) process to extract SNPS. The UAE conditions were optimized using single-factor experiments and response surface analysis. Under the optimized conditions of ultrasonic power of 550 W, extraction time of 26 min, and extraction temperature at 50°C, the highest yield of 13.47% ± 1.63% was obtained, which was in accordance with the predicted value of 13.71%. In comparison with traditional hot water extraction, the optimized UAE method significantly increased the extraction yield with lower extraction temperature and shorter extraction time. Furthermore, the antioxidant evaluation showed that EC values of SNPS were 2.43 ± 0.21, 4.40 ± 0.35, and 0.56 ± 0.062 mg/mL for 2,2-diphenyl-1-picrylhydrazyl radical (DPPH) radical, hydroxyl free radical, and 2,2'-azinobis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical scavenging assay, respectively. The anti-inflammatory potential of SNPS was detected in lipopolysaccharide (LPS) induced ICR mice. Real-time reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay showed that SNPS significantly improved LPS-stimulated inflammatory response by decreasing mRNA and protein expression of interleukin (IL)-6 and tumour necrosis factor (TNF)- in a dose-dependent manner. In conclusion, the extraction process of SNPS established in this study is reliable, and SNPS possesses potential antioxidant and anti-inflammatory activities, which will provide a theoretical basis for guiding the clinical application of .
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http://dx.doi.org/10.1155/2020/8899762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755497PMC
December 2020

Loss of Phosphatase and Tensin Homolog Promotes Cardiomyocyte Proliferation and Cardiac Repair After Myocardial Infarction.

Circulation 2020 Dec 30;142(22):2196-2199. Epub 2020 Nov 30.

Department of Cardiology, Provincial Key Lab of Cardiovascular Research, Second Affiliated Hospital (T.L., F.G., J.J., F.Z., N.L., X.F., X.D., X.H., J.W., J.C.), Hangzhou, China.

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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.046372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7853321PMC
December 2020

Brain Injury After Transcatheter Replacement of Bicuspid Versus Tricuspid Aortic Valves.

J Am Coll Cardiol 2020 12;76(22):2579-2590

Columbia University Medical Center, New York, New York; Cardiovascular Research Foundation, New York, New York.

Background: An increasing number of bicuspid aortic valve (BAV) patients are undergoing transcatheter aortic valve replacement (TAVR), but the risk of brain injury in diffusion-weighted magnetic resonance imaging (DW-MRI) is currently unknown.

Objectives: This study sought to evaluate the risk of brain injury in BAV patients following TAVR.

Methods: A total of 204 consecutive severe aortic stenosis patients who underwent TAVR were enrolled. A total of 83 (40.7%) patients were BAV patients, and the other 121 patients were tricuspid aortic valve (TAV) patients. All patients received DW-MRI at baseline, and after TAVR.

Results: Median ages (76 years [interquartile range (IQR): 71 to 81 years] vs. 79 years [IQR: 74 to 83 years]; p = 0.004) and Society of Thoracic Surgeons scores (4.87 [IQR: 3.72 to 8.54] vs. 6.38 [IQR: 3.96 to 9.50]; p = 0.044) of the BAV and TAV patients were significantly different, while the overt stroke rates (2.4% vs. 1.7%; p = 0.704) were comparable between the 2 groups. BAV patients were associated with higher number of new lesions (4.0 [IQR: 1.0 to 8.0] vs. 2.0 [IQR: 1.0 to 5.0]; p = 0.008), total lesion volume (290 mm [IQR: 70 to 930 mm] vs. 140 mm [IQR: 35 to 480 mm]; p = 0.008), and the volume per lesion (70.0 mm [IQR: 45.0 to 115.0 mm] vs. 57.5 mm [IQR: 24.5 to 93.0 mm]; p = 0.037) in DW-MRI. Moreover, the proportion of patients with lesions larger than 1 cm (28.6% vs. 10.9%; p = 0.005) was higher in BAV patients than in TAV patients.

Conclusions: BAV patients may encounter more severe brain injuries not only due to greater number of lesions, but also due to larger lesion size in the early phase after TAVR. (Transcatheter Aortic Valve Replacement Single Center Registry in Chinese Population [TORCH]; NCT02803294).
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http://dx.doi.org/10.1016/j.jacc.2020.09.605DOI Listing
December 2020

TPP1 Enhances the Therapeutic Effects of Transplanted Aged Mesenchymal Stem Cells in Infarcted Hearts via the MRE11/AKT Pathway.

Front Cell Dev Biol 2020 29;8:588023. Epub 2020 Oct 29.

Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Background: Poor cell survival after transplantation restricts the therapeutic potential of mesenchymal stem cell (MSC) transplantation into infarcted hearts, particularly in older individuals. TPP1, a component of the shelterin complex that is involved in telomere protection, is highly expressed in young MSCs but declines in aged ones. Here, we explore whether TPP1 overexpression in aged mouse MSCs improves cell viability and .

Methods: Aged mouse MSCs overexpressing TPP1 were injected into the peri-infarct area of the mouse heart after left anterior descending coronary artery ligation. In parallel, to evaluate cellular-level effects, HO was applied to MSCs to mimic the microenvironment of myocardial injury.

Results: , the transplantation of aged MSCs overexpressing TPP1 resulted in improved cell survival, enhanced cardiac function, and reduced fibrosis compared to unmodified aged MSCs. , TPP1 overexpression protected aged MSCs from HO-induced apoptosis and enhanced DNA double-strand break (DSB) repair. In addition, the phosphorylation of AKT and the key DSB repair protein MRE11 were both significantly upregulated in aged MSCs that overexpressed TPP1.

Conclusions: Our results reveal that TPP1 can enhance DNA repair through the AKT/MRE11 pathway, thereby improving the therapeutic effects of aged MSC transplantation and offering significant potential for the clinical application of autologous transplantation in aged patients.
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http://dx.doi.org/10.3389/fcell.2020.588023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658181PMC
October 2020

Inflammatory Cytokines Alter Mesenchymal Stem Cell Mechanosensing and Adhesion on Stiffened Infarct Heart Tissue After Myocardial Infarction.

Front Cell Dev Biol 2020 23;8:583700. Epub 2020 Oct 23.

Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Mesenchymal stem cell (MSC) transplantation has demonstrated its potential in repairing infarct heart tissue and recovering heart function after myocardial infarction (MI). However, its therapeutic effect is still limited due to poor MSC engraftment at the injury site whose tissue stiffness and local inflammation both dynamically and rapidly change after MI. Whether and how inflammatory cytokines could couple with stiffness change to affect MSC engraftment in the infarct zone still remain unclear. In this study, we characterized dynamic stiffness changes of and inflammatory cytokine expression in the infarct region of rat heart within a month after MI. We found that the tissue stiffness of the heart tissue gradually increased and peaked 21 days after MI along with the rapid upregulation of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) in the first 3 days, followed by a sharp decline. We further demonstrated that immobilized inflammatory cytokine IL-6 performed better than the soluble form in enhancing MSC adhesion to stiffened substrate through IL-6/src homology 2 (SH2) domain-containing tyrosine phosphatase-2 (SHP2)/integrin signaling axis. We also confirmed such mechano-immune coupling of tissue stiffness and inflammatory cytokines in modulating MSC engraftment in the rat heart after MI . Our study provides new mechanistic insights of mechanical-inflammation coupling to improve MSC mechanosensing and adhesion, potentially benefiting MSC engraftment and its clinical therapy for MI.
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http://dx.doi.org/10.3389/fcell.2020.583700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645114PMC
October 2020

Knockdown of estrogen-related receptor α inhibits valve interstitial cell calcification in vitro by regulating heme oxygenase 1.

FASEB J 2021 02 13;35(2):e21183. Epub 2020 Nov 13.

Department of Cardiology of the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.

Calcific aortic valve disease (CAVD) is the most common valvular heart disease in adults. The cellular mechanisms of CAVD are still unknown, but accumulating evidence has revealed that osteogenic differentiation of human valve interstitial cells (hVICs) plays an important role in CAVD. Thus, we aimed to investigate the function of estrogen-related receptor α (ERRα) in the osteogenic differentiation of hVICs. We found that the level of ERRα was significantly increased in CAVD samples compared to normal controls. In addition, ERRα was significantly upregulated during hVIC osteogenic differentiation in vitro. Gain- and loss-of-function experiments were performed to identify the function of ERRα in hVIC calcification in vitro. Inhibition of endogenous ERRα attenuated hVIC calcification, whereas overexpression of ERRα in hVICs promoted this process. RNA sequencing results suggested that heme oxygenase-1 (Hmox1) was a downstream target of ERRα, which was further confirmed by western blotting. Additionally, we also found that downregulation of Hmox1 by shHmox1 efficiently reversed the inhibition of calcification induced by ERRα shRNA in hVICs. ChIP-qPCR and luciferase assays indicated that Hmox1 was negatively regulated by ERRα. We found that overexpression of Hmox1 or its substrates significantly inhibited hVIC calcification in vitro. In conclusion, we found that knockdown of ERRα can inhibit hVIC calcification through upregulating Hmox1 and that ERRα and Hmox1 are potential targets for the treatment of CAVD.
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http://dx.doi.org/10.1096/fj.202001588RRDOI Listing
February 2021

Aldo-keto reductase family 1 member B induces aortic valve calcification by activating hippo signaling in valvular interstitial cells.

J Mol Cell Cardiol 2021 01 9;150:54-64. Epub 2020 Oct 9.

Department of Cardiology of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, PR China; Cardiovascular Key Laboratory of Zhejiang Province, Hangzhou, PR China. Electronic address:

Aims: Calcific aortic valve disease (CAVD) is a primary cause of cardiovascular mortality; however, its mechanisms are unknown. Currently, no effective pharmacotherapy is available for CAVD. Aldo-keto reductase family 1 member B (Akr1B1) has been identified as a potential therapeutic target for valve interstitial cell calcification. Herein, we hypothesized that inhibition of Akr1B1 can attenuate aortic valve calcification.

Methods And Results: Normal and degenerative tricuspid calcific valves from human samples were analyzed by immunoblotting and immunohistochemistry. The results showed significant upregulation of Akr1B1 in CAVD leaflets. Akr1B1 inhibition attenuated calcification of aortic valve interstitial cells in osteogenic medium. In contrast, overexpression of Akr1B1 aggravated calcification in osteogenic medium. Mechanistically, using RNA sequencing (RNAseq), we revealed that Hippo-YAP signaling functions downstream of Akr1B1. Furthermore, we established that the protein level of the Hippo-YAP signaling effector active-YAP had a positive correlation with Akr1B1. Suppression of YAP reversed Akr1B1 overexpression-induced Runx2 upregulation. Moreover, YAP activated the Runx2 promoter through TEAD1 in a manner mediated by ChIP and luciferase reporter systems. Animal experiments showed that the Akr1B1 inhibitor epalrestat attenuated aortic valve calcification induced by a Western diet in LDLR mice.

Conclusion: This study demonstrates that inhibition of Akr1B1 can attenuate the degree of calcification both in vitro and in vivo. The Akr1B1 inhibitor epalrestat may be a potential treatment option for CAVD.
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http://dx.doi.org/10.1016/j.yjmcc.2020.10.002DOI Listing
January 2021

Next-generation sequencing identified novel Desmoplakin frame-shift variant in patients with Arrhythmogenic cardiomyopathy.

BMC Cardiovasc Disord 2020 02 11;20(1):74. Epub 2020 Feb 11.

Department of Cardiology, the Second Affiliated Hospital, Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, 310009, Zhejiang, China.

Background: Arrhythmogenic cardiomyopathy (AC) is one of the leading causes for sudden cardiac death (SCD). Recent studies have identified mutations in cardiac desmosomes as key players in the pathogenesis of AC. However, the specific etiology in individual families remains largely unknown.

Methods: A 4-generation family presenting with syncope, lethal ventricular arrhythmia and SCD was recruited. Targeted next generation sequencing (NGS) was performed and validated by Sanger sequencing. Plasmids containing the mutation and wild type (WT) were constructed. Real-time PCR, western-blot and immunofluorescence were performed to detect the functional change due to the mutation.

Results: The proband, a 56-year-old female, presented with recurrent palpitations and syncope. An ICD was implanted due to her family history of SCD/ aborted SCD. NGS revealed a novel heterozygous frame-shift variant (c.832delG) in Desmoplakin (DSP) among 5 family members. The variant led to frame-shift and premature termination, producing a truncated protein. Cardiac magnetic resonance (CMR) of the family members carrying the same variant shown myocardium thinning and fatty infiltration in the right ventricular, positive bi-ventricular late gadolinium enhancement and severe RV dysfunction, fulfilling the diagnostic criteria of AC. HEK293T cells transfected with mutant plasmids expressed truncated DSP mRNA and protein, upregulation of nuclear junction plakoglobin (JUP) and downregulation of β-catenin, when compared with WT.

Conclusion: We infer that the novel c.832delG variant in DSP was associated with AC in this family, likely through Wnt/β-catenin signaling pathway.
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http://dx.doi.org/10.1186/s12872-020-01369-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7011609PMC
February 2020

Isolation and identification of alkaloids from by UHPLC-Q-TOF-MS and their cytotoxic activity in vitro, antiangiogenic activity in vivo.

BMC Chem 2020 Dec 22;14(1). Epub 2020 Jan 22.

1College of Pharmacy, Jining Medical University, Rizhao, 276826 Shandong China.

Background: Extensive bioactivities of alkaloids from the genus ( (Willd.) R. Br. and (Maxim.) Fedde) have been widely reported, as well as more and more concerned from the scientific communities. However, systematic research on the phytochemical information of is incomplete. The aim of this study was to rapidly and conveniently qualitative analyze alkaloids from by ultra-performance liquid chromatography/quadrupole-time-of-fight mass spectrometry (UHPLC-Q-TOF-MS) using accurate mass weight and characteristic fragment ions, furthermore separate and identify the main alkaloids, test antitumor activity in vitro and antiangiogenic activity in vivo.

Results: A total of 14 alkaloids from fruits of were identified by UHPLC-Q-TOF-MS, including 5 protopines, 2 benzophenanthridines, 1 dimer, 1 dihydrobenzophenanthridines and 5 unknown structure compounds. Two major alkaloids were isolated by various column chromatographic methods. Their structures were determined by NMR data and related literatures. The two major alkaloids were evaluated for intro cytotoxic activities against HL-60, MCF-7, A-549, and in vivo antiangiogenic activity using transgenic zebrafish.

Conclusions: Current qualitative method based on UHPLC-Q-TOF-MS technique provided a scientific basis for isolation, structural identification, and in vitro or in vivo pharmacological further study of alkaloids from in the future.
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http://dx.doi.org/10.1186/s13065-020-0660-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6977315PMC
December 2020

Incidence and Predictors of Permanent Pacemaker Implantation in Patients Who Underwent Transcatheter Aortic Valve Replacement: Observation of a Chinese Population.

Cardiology 2020 13;145(1):27-34. Epub 2019 Nov 13.

Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China,

Aims: Permanent pacemaker (PPM) implantation is one of the most common complications after transcatheter aortic valve replacement (TAVR). We studied the incidence of PPM implantation and identified the predictors in patients who underwent TAVR in a Chinese population.

Methods And Results: A total of 256 patients who underwent TAVR with self-expandable valves were included. The incidence of PPM implantation in our study population was 14.8%. In patients who received PPM implantation, the proportion of bicuspid aortic valve (BAV) patients was much lower compared to tricuspid aortic valve (TAV) patients (18.4 vs. 81.6%, p < 0.05). Patients with BAV were associated with a significantly lower PPM implantation rate and shallower implantation depth compared to patients with TAV (6.4 vs. 21.7% and 4.2 ± 4.4 vs. 6.2 ± 5.0 mm, respectively, p < 0.05 for both). In the multivariable logistic regression analysis, prior right bundle branch block (RBBB; OR 8.3, 95% CI 2.2-32.1, p < 0.05), implantation depth (OR 1.3, 95% CI 1.1-1.5, p = 0.01), and TAV (OR 4.7, 95% CI 1.5-14.4, p < 0.05) were independent predictors of PPM implantation after TAVR. There was no difference in 30-day and 1-year all-cause mortality between the 2 groups.

Conclusions: The incidence of PPM implantation in patients with self-expandable valves after TAVR was 14.8% in our cohort study. Independent predictors of PPM implantation included prior RBBB, TAV, and implantation depth at the noncoronary sinus side. TAVR in BAV with a supra-annular structure-based sizing strategy might decrease the risk of PPM implantation.
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http://dx.doi.org/10.1159/000502792DOI Listing
September 2020

Incorporation of small extracellular vesicles in sodium alginate hydrogel as a novel therapeutic strategy for myocardial infarction.

Theranostics 2019 11;9(24):7403-7416. Epub 2019 Oct 11.

Department of Cardiology of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, PR China.

Bone marrow mesenchymal stem cell (MSC)-derived small extracellular vesicles (sEVs) have been widely used for treating myocardial infarction (MI). However, low retention and short-lived therapeutic effects are still significant challenges. This study aimed to determine whether incorporation of MSC-derived sEVs in alginate hydrogel increases their retention in the heart thereby improving therapeutic effects. The optimal sodium alginate hydrogel incorporating sEVs system was determined by its release ability of sEVs and rheology of hydrogel. fluorescence imaging was utilized to evaluate the retention of sEVs in the heart. Immunoregulation and effects of sEVs on angiogenesis were analyzed by immunofluorescence staining. Echocardiography and Masson's trichrome staining were used to estimate cardiac function and infarct size. The delivery of sEVs incorporated in alginate hydrogel (sEVs-Gel) enhanced their retention in the heart. Compared with sEVs only treatment (sEVs), sEVs-Gel treatment significantly decreased cardiac cell apoptosis and promoted the polarization of macrophages at day 3 after MI. sEVs-Gel treatment also increased scar thickness and angiogenesis at four weeks post-infarction. Measurement of cardiac function and infarct size were significantly better in the sEVs-Gel group than in the group treated with sEVs only. Delivery of sEVs incorporated in alginate hydrogel provides a novel approach of cell-free therapy and optimizes the therapeutic effect of sEVs for MI.
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http://dx.doi.org/10.7150/thno.32637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6831299PMC
September 2020

Left ventricular remodeling and dysfunction in obstructive sleep apnea : Systematic review and meta-analysis.

Herz 2020 Dec 25;45(8):726-738. Epub 2019 Sep 25.

Department of Cardiology, Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, China.

Background: Obstructive sleep apnea syndrome (OSAS) is associated with cardiovascular mortality and morbidity. Several studies have reported that it affects the left ventricle; however, large randomized controlled trials are lacking. The current study aimed to summarize the association between OSAS and left ventricular (LV) structure and function.

Methods: Electronic databases (PubMed, Embase, and Cochrane) and references were searched for articles published until March 2018. A systematic review and meta-analysis were performed to assess LV structure and function in OSAS patients based on echocardiography.

Results: In total, 17 studies with 747 OSAS patients and 426 control participants were included. Patients with OSAS showed an increase in LV diastolic diameter (weighted mean difference [WMD], 95% CI: 1.24 [0.68, 1.80]; p < 0.001), LV systolic diameter (WMD, 95% CI: 1.14 [0.47, 1.81]; p = 0.001), and LV mass (WMD, 95% CI: 35.34 [20.67, 50.00]; p < 0.001). In addition, left ventricular ejection fraction (LVEF) significantly decreased in the OSAS group compared with the controls (WMD, 95% CIs: -1.82 [-2.76, -0.87]; p < 0.001), and the reduction in LVEF was consistent with the severity of OSAS. The OSAS group also showed an increase in left atrial diameter (WMD, 95% CI: 2.13 [1.48, 2.77]; p < 0.001) and left atrial diameter volume index (WMD, 95% CIs: 3.96 [3.32, 4.61]; p < 0.001).

Conclusion: Obstructive sleep apnea syndrome leads to atrial dilatation, left ventricular hypertrophy, enlargement, mass increase and reduction of systolic function. Treatments for OSAS might be beneficial for the preservation of left cardiac structure and function.
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http://dx.doi.org/10.1007/s00059-019-04850-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695673PMC
December 2020

Therapeutic role of miR-19a/19b in cardiac regeneration and protection from myocardial infarction.

Nat Commun 2019 04 17;10(1):1802. Epub 2019 Apr 17.

Department of Cardiology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA, 02115, USA.

The primary cause of heart failure is the loss of cardiomyocytes in the diseased adult heart. Previously, we reported that the miR-17-92 cluster plays a key role in cardiomyocyte proliferation. Here, we report that expression of miR-19a/19b, members of the miR-17-92 cluster, is induced in heart failure patients. We show that intra-cardiac injection of miR-19a/19b mimics enhances cardiomyocyte proliferation and stimulates cardiac regeneration in response to myocardial infarction (MI) injury. miR-19a/19b protected the adult heart in two distinctive phases: an early phase immediately after MI and long-term protection. Genome-wide transcriptome analysis demonstrates that genes related to the immune response are repressed by miR-19a/19b. Using an adeno-associated virus approach, we validate that miR-19a/19b reduces MI-induced cardiac damage and protects cardiac function. Finally, we confirm the therapeutic potential of miR-19a/19b in protecting cardiac function by systemically delivering miR-19a/19b into mice post-MI. Our study establishes miR-19a/19b as potential therapeutic targets to treat heart failure.
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http://dx.doi.org/10.1038/s41467-019-09530-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6470165PMC
April 2019

One amino acid change of Angiotensin II diminishes its effects on abdominal aortic aneurysm.

Biosci Rep 2019 05 3;39(5). Epub 2019 May 3.

Department of Cardiology, The Second Affiliated Hospital, Cardiovascular Key Laboratory of Zhejiang Province, College of Medicine, Zhejiang University Hangzhou, Zhejiang, China

Angiotensin (Ang) A is formed by the decarboxylation of the N terminal residue of AngII. The present study determined whether this one amino acid change impacted effects of AngII on abdominal aortic aneurysm (AAA) formation in mice. Computational analyses implicated that AngA had comparable binding affinity to both AngII type 1 and 2 receptors as AngII. To compare effects of these two octapeptides , male low-density lipoprotein receptor () or apolipoprotein E () deficient mice were infused with either AngII or AngA (1 μg/kg/min) for 4 weeks. While AngII infusion induced AAA consistently in both mouse strains, the equivalent infusion rate of AngA did not lead to AAA formation. We also determined whether co-infusion of AngA would influence AngII-induced aortic aneurysm formation in male mice. Co-infusion of the same infusion rate of AngII and AngA did not change AngII-induced AAA formation. Since it was reported that a 10-fold higher concentration of AngA elicited comparable vasoconstrictive responses as AngII, we compared a 10-fold higher rate (10 μg/kg/min) of AngA infusion into male mice with AngII (1 μg/kg/min). This rate of AngA led to abdominal aortic dilation in three of ten mice, but no aortic rupture, whereas the 10-fold lower rate of AngII infusion led to abdominal aortic dilation or rupture in eight of ten mice. In conclusion, AngA, despite only being one amino acid different from AngII, has diminished effects on aortic aneurysmal formation, implicating that the first amino acid of AngII has important pathophysiological functions.
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http://dx.doi.org/10.1042/BSR20182055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6500891PMC
May 2019