COVID-19 vaccination affects short-term anti-coagulation levels in warfarin treatment.

Vaccines against SARS-CoV-2 have been recommended across the world, yet no study has investigated whether COVID-19 vaccination influences short-term warfarin anti-coagulation levels. Patients on stable warfarin treatment who received anti-SARS-CoV-2 vaccination were prospectively enrolled and followed up for three months. INR values less than 10 days before vaccination (baseline), 3-5 days (short-term) and 6-14 days (medium-term) after vaccination were recorded as INR0, INR1, and INR2, respectively. The variations of INR values within individuals were compared, and the linear mixed effect model was used to evaluate the variations of INR values at different time points. Logistic regression analysis was performed to determine covariates related to INR variations after COVID-19 vaccination. Vaccination safety was also monitored. There was a significant difference in INR values between INR0 and INR1 (2.15 vs. 2.26, p = 0.003), yet no marked difference was found between INR0 and INR2. The linear mixed effect model also demonstrated that INR variation was significant in short-term but not in medium-term or long-term period after vaccination. Logistic regression analysis showed that no investigated covariates, including age, vaccine dose, genetic polymorphisms of VKORC1 and CYP2C9 etc., were associated with short-term INR variations. Two patients (2.11%) reported gingival hemorrhage in the short-term due to increased INR values. The overall safety of COVID-19 vaccines for patients on warfarin was satisfying. COVID-19 vaccines may significantly influence warfarin anticoagulation levels 3-5 days after vaccination. We recommend patients on warfarin to perform at least one INR monitoring within the first week after COVID-19 vaccination.

Evaluation of the "safe multidisciplinary app-assisted remote patient-self-testing (SMART) model" for warfarin home management during the COVID-19 pandemic: study protocol of a multi-center randomized controlled trial.

BACKGROUND: Warfarin treatment requires frequent monitoring of INR (international normalized ratio) to adjust dosage in a therapeutic range. In China, patients living in small towns usually go to tertiary hospitals to get warfarin monitoring and dosing, resulting in low frequencies of follow-ups and high incidence of complications. Influenced by the COVID-19 pandemic, patients on warfarin have further reduced their visits to healthcare institutions. While patient self-testing (PST) via using a point-of-care testing device for INR measuring at home has been widely used in developed countries and demonstrated improved clinical outcomes compared to usual care in clinics, it is rarely applied in developing countries, including China. This proposed study will develop and assess the "Safe Multidisciplinary App-assisted Remote patient-self-Testing (SMART) model" for warfarin home management in China during the COVID-19 pandemic. METHODS: This is a multi-center randomized controlled trial. We will carry out the study in three county hospitals, three small tertiary hospitals and three large tertiary hospitals with anticoagulation clinics in Hunan province of China. Eligible patients will be randomly assigned to the SMART model group (n = 360) or the control group (usual care clinic group, n = 360; anticoagulation clinic group, n = 120). Patients in the SMART model group do PST at home once every two to 4 weeks. Controls receive usual care in the clinics. All the patients will be followed up through outpatient clinics, phone call or online interviews at the 3rd, 6th, 9th and 12th month. The percentage of time in therapeutic range (TTR), incidence of warfarin associated major bleeding and thromboembolic events and costs will be compared between the SMART model group and control groups. DISCUSSION: Patients in the SMART model group would show improved TTR, lower incidence of complications and better quality of life compared to the control groups. Our design, implementation and usage of the SMART model will provide experience and evidence in developing a novel model for chronic disease management to solve the problem of healthcare service maldistribution, an issue particularly obvious in developing countries during the COVID-19 pandemic. TRIAL REGISTRATION: ChiCTR, ChiCTR 2000038984 . Registered 11 October, 2020.

Dihydromyricetin increases endothelial nitric oxide production and inhibits atherosclerosis through microRNA-21 in apolipoprotein E-deficient mice.

Natural products were extracted from traditional Chinese herbal emerging as potential therapeutic drugs for treating cardiovascular diseases. This study examines the role and underlying mechanism of dihydromyricetin (DMY), a natural compound extracted from Ampelopsis grossedentata, in atherosclerosis. DMY treatment significantly inhibits atherosclerotic lesion formation, proinflammatory gene expression and the influx of lesional macrophages and CD4-positive T cells in the vessel wall and hepatic inflammation, whereas increases nitric oxide (NO) production and improves lipid metabolism in apolipoprotein E-deficient (Apoe-/- ) mice. Yet, those protective effects are abrogated by using NOS inhibitor L-NAME in Apoe-/- mice received DMY. Mechanistically, DMY decreases microRNA-21 (miR-21) and increases its target gene dimethylarginine dimethylaminohydrolase-1 (DDAH1) expression, an effect that reduces asymmetric aimethlarginine (ADMA) levels, and increases endothelial NO synthase (eNOS) phosphorylation and NO production in cultured HUVECs, vascular endothelium of atherosclerotic lesions and liver. In contrast, systemic delivery of miR-21 in Apoe-/- mice or miR-21 overexpression in cultured HUVECs abrogates those DMY-mediated protective effects. These data demonstrate that endothelial miR-21-inhibited DDAH1-ADMA-eNOS-NO pathway promotes the pathogenesis of atherosclerosis which can be rescued by DMY. Thus, DMY may represent a potential therapeutic adjuvant in atherosclerosis management.

Mesenchymal stem cell-derived conditioned medium attenuate angiotensin II-induced aortic aneurysm growth by modulating macrophage polarization.

Mesenchymal stem cells (MSCs) exhibit therapeutic benefits on aortic aneurysm (AA); however, the molecular mechanisms are not fully understood. The current study aimed to investigate the therapeutic effects and potential mechanisms of murine bone marrow MSC (BM-MSCs)-derived conditioned medium (MSCs-CM) on angiotensin II (AngII)-induced AA in apolipoprotein E-deficient (apoE-/- ) mice. Murine BM-MSCs, MSCs-CM or control medium were intravenously administrated into AngII-induced AA in apoE-/- mice. Mice were sacrificed at 2 weeks after injection. BM-MSCs and MSCs-CM significantly attenuated matrix metalloproteinase (MMP)-2 and MMP-9 expression, aortic elastin degradation and AA growth at the site of AA. These treatments with BM-MSCs and MSCs-CM also decreased Ly6chigh monocytes in peripheral blood on day 7 and M1 macrophage infiltration in AA tissues on day 14, whereas they increased M2 macrophages. In addition, BM-MSCs and MSCs-CM reduced MCP-1, IL-1Ra and IL-6 expression and increased IL-10 expression in AA tissues. In vitro, peritoneal macrophages were co-cultured with BM-MSCs or fibroblasts as control in a transwell system. The mRNA and protein expression of M2 macrophage markers were evaluated. IL-6 and IL-1ß were reduced, while IL-10 was increased in the BM-MSC systems. The mRNA and protein expression of M2 markers were up-regulated in the BM-MSC systems. Furthermore, high concentration of IGF1, VEGF and TGF-ß1 was detected in MSCs-CM. Our results suggest that MSCs-CM could prevent AA growth potentially through regulating macrophage polarization. These results may provide a new insight into the mechanisms of BM-MSCs in the therapy of AA.

The methylation of Notch1 promoter mediates the osteogenesis differentiation in human aortic valve interstitial cells through Wnt/ß-catenin signaling.

Aortic valve interstitial cells (AVICs) have the potential to undergo calcification, which has been regarded as a critical issue during the pathology of calcific aortic valve disease (CAVD). In the past decade, epigenetics, in particular, DNA methylation dysregulation, has been reported to play a vital role in the occurrence and development of CAVD. In the present study, the expression of Notch1, which can inhibit the osteogenesis differentiation of valve interstitial cells, was downregulated whereas the expression of methyltransferases was upregulated in CAVD tissues, suggesting the potential role of DNA methylation in Notch1 expression and CAVD progression. As revealed by DNA extraction and bisulfite sequencing polymerase chain reaction (PCR), the methylation level in Notch1 promoter was much higher in CAVD tissues and human AVICs on Day 14 of osteogenesis differentiation induction. The silence of Notch1 intercellular domain (NICD) promoted while the treatment of demethylation agent, 5-Aza-dC, inhibited the osteogenesis differentiation. Moreover, NICD overexpression significantly suppressed the transcriptional activity of ß-catenin on TCF4, and the expression of osteogenesis differentiation factors, indicating the involvement of Wnt/ß-catenin signaling in Notch1 modulating the osteogenesis differentiation in human AVICs (hAVICs). Taken together, Notch1 promoter methylation leads to a decreased Notch1 expression and subsequent decreased release of NICD in the nucleus of hAVICs, therefore promoting the activation of Wnt/ß-catenin signaling and the expression of osteogenesis differentiation factors, finally promoting the osteogenesis differentiation in hAVICs. DNA methylation might act as an important bridge to link epigenetic variation and CAVD progression.

Diverse roles of macrophage polarization in aortic aneurysm: destruction and repair.

Aortic aneurysm (AA) is defined as an enlargement of the aorta greater than 1.5 times its normal size. Early diagnosis of AA is challenging and mortality of AA is high. Curative pharmacological treatments for AA are still lacking, highlighting the need for better understanding of the underlying mechanisms of AA progression. Accumulating studies have proven that the polarization state of circulating monocyte-derived macrophages plays a crucial role in regulating the development of AA. Distinct macrophage subtypes display different functions. Several studies targeting macrophage polarization during AA formation and progression showed potential treatment effects. In this review, we focus on the recent advances of research on macrophage polarization in the progression of AA and propose that targeting macrophage polarization could hold great promise for preventing and treating AA.

Severe Pulmonary Embolism was Secondary to Cement Inferior Vena Cava Embolism after Percutaneous Vertebroplasty.

Cement pulmonary embolism (cPE) and inferior vena cava embolism (cIE) are rare but potentially life-threatening complications of percutaneous vertebroplasty (PVP). Most cPE and cIE occurred simultaneously. In this case, a 65-year-old woman complained of dyspnea after PVP for 4 days. Patient's symptom and image tests manifest that the cPE was secondary to cIE. Although cIE was found at the first day after PVP, the local surgeons treat the patient with a regular anticoagulant without another more effective therapeutic measure. Eventually, the long cement inferior vena cava embolus was broken and result in left pulmonary embolism via the systemic circulation. She was admitted to our hospital and performed with embolectomy surgery by cardiopulmonary bypass and discharged after 7 days. We report this case to show that cIE embolism is still underestimated by some spine surgeons in China, and cIE may be developed to severe cPE during conservation management with anticoagulation.

WITHDRAWN: Severe Pulmonary Embolism Secondary to Cement Embolism in the Inferior Vena Cava after Percutaneous Vertebroplasty.

The Publisher regrets that this article is an accidental duplication of an article that has already been published, https://doi.org/10.1016/j.avsg.2018.01.003. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.

Aortic Remodeling Following Sun's Procedure for Acute Type A Aortic Dissection.

BACKGROUND Sun's procedure is a surgical technique widely used in type A aortic dissection. The purpose of this study was to analyze clinical outcomes and morphologic changes in true and false lumen by computed tomography (CT) angiography after Sun's procedure. MATERIAL AND METHODS We retrospectively reviewed 51 patients who underwent Sun's procedure for acute Stanford type A aortic dissection extending down to iliac bifurcation between January 2013 and December 2014. The images of preoperative, one-month, three-month, and six-month follow-up were analyzed by CT angiography to measure the area and diameter of true and false lumen. RESULTS Four patients died before surgical intervention and postoperative deaths occurred in five patients (in-hospital mortality rate 10.6%). Only 42 patients (36 male, 6 female; mean age, 45.9±9.8 years; range, 24-65 years) with acute type A aortic dissection were involved in our study. Thirty-five patients (83.3%) suffered from chest or abdominal pain and only one patient (2.4%) was asymptomatic. Thirty-seven patients (88.1%) had hypertension as the most common comorbidity. In the ascending aorta, false lumen was eliminated and the change of true lumen was not significant (p>0.05). In the descending aorta, complete and partial thrombosis of false lumen were observed in eight patients (19.0%) and 33 patients (78.6%) by one-month follow-up CT scan, respectively. After the six-month follow-up, the rate of complete thrombosis increased to 36.1% and partial thrombosis decreased to 61.9%. The area and maximal diameter of true lumen were increased significantly (p<0.05), whereas significant decreases were found in the area and maximal diameter of false lumen (p<0.05). In the abdominal aorta, thrombosis was found in 52.4% patients at one-month follow-up CT. Furthermore, there were no significant changes in both true and false lumen within three months (p>0.05). Nevertheless, the false luminal area and maximal diameter decreased significantly (p<0.05) after six months, while these changes of true lumen were not significant (p>0.05). CONCLUSIONS After Sun's procedure, aortic remodeling was a continuous process and occurred in a predictable model, and the extent of aortic remodeling varied at different levels. Remodeling in descending thoracic aorta was earlier than it was in abdominal aorta.

The Relationship between Galectin-3 and Different Patterns of Ventricular Geometry Remodelling in Aortic Valve Stenosis.

BACKGROUND: This study was conducted to assess expression of Galectin-3 (Gal-3) in patients with different types of left ventricle (LV) hypertrophy geometry, and the relationship between Gal-3 expression and LV remodelling in patients with aortic valve stenosis (AS). METHODS: Galectin-3 expression was measured in the plasma and myocardia of AS patients who underwent an aortic valve replacement procedure. RESULTS: The study enrolled 77 consecutive patients with severe AS. Fifty-five (71.43%) of the enrolled patients had concentric hypertrophy (CH group), and had the highest degree of fibrosis (27.10±5.25%; p<0.001) and expression of Gal-3 in both plasma (19.11±2.06 ng/mL) and myocardial tissue (3.01±0.79). There was a strong positive correlation between the levels of fibrosis and Gal-3 expression in both plasma (r=0.584, p<0.001) and myocardium (r=0.522, p<0.001). Relative wall thickness (RWT) was strongly correlated with Gal-3 expression in both myocardium (r=0.594, p<0.001) and plasma (r=0.323, p=0.005). Additionally, N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels were positively correlated with both fibrosis (r=0.313, p=0.036) and LV mass index (r=0.559, p<0.001). CONCLUSIONS: Concentric hypertrophy geometry was the most common type of myocardium remodelling, and AS patients with CH geometry showed the highest levels of Gal-3 expression. Galectin-3 levels were positively correlated with fibrosis and RWT, both of which are crucial indicators of geometric remodelling. Galectin-3 and NT-proBNP levels may be valuable prognostic predictors in AS patients with myocardial remodelling.

Apelin attenuates the osteoblastic differentiation of aortic valve interstitial cells via the ERK and PI3-K/Akt pathways.

Aortic valve calcification (AVC), which used to be recognized as a passive and irreversible process, is now widely accepted as an active and regulated process characterized by osteoblastic differentiation of aortic valve interstitial cells (AVICs). Apelin, the endogenous ligand for G-protein-coupled receptor APJ, was found to have protective cardiovascular effects in several studies. However, the effects and mechanisms of apelin on osteoblastic differentiation of AVICs have not been elucidated. Using a pro-calcific medium, we devised a method to produce calcific human AVICs. These cells were used to study the relationship between apelin and the osteoblastic calcification of AVICs and the involved signaling pathways. Alkaline phosphatase (ALP) activity/expression and runt-related transcription factor 2 (Runx2) expression were examined as hallmark proteins in this research. The involved signaling pathways were studied using the extracellular signal-regulated kinase (ERK) inhibitor, PD98059, and the phosphatidylinositol 3-kinase (PI3-K) inhibitor, LY294002. The results indicate that apelin attenuates the expression and activity of ALP, the expression of Runx2, and the formation of mineralized nodules. This protective effect was dependent on the dose of apelin, reaching the maximum at 100 pM, and was connected to activity of ERK and Akt (a downstream effector of PI3-K). The activation of ERK and PI3-K initiated the effects of apelin on ALP activity/expression and Runx2, but PD98059 and LY294002 abolished the effect. These results demonstrate that apelin attenuates the osteoblastic differentiation of AVICs via the ERK and PI3-K/Akt pathway.

[Diagnostic experience in 3 cases of cardiac occupying lesion].

The clinic symptoms of cardiac occupying lesions are complex and difficult to diagnose currently. In this study, three cases of atrial angiosarcoma, left ventricular aneurysm and left ventricular diverticulum were selected, respectively. The clinical characteristics, imaging features (echocardiogram, cardiac CT and MRI) and the postoperative and pathological results for patients were studied. We compared the differences in clinical symptoms, morphology, histology and haemodynamics among the three patients. The diagnosis were confirmed by intraoperative and postoperative pathological examination. We conclude that proper imaging approaches would be beneficial to diagnose the cardiac occupying lesions. Accurate preoperative diagnosis is beneficial to preoperative preparation as well as the decrease in operative risks.

AXL and SHC1 confer crizotinib resistance in patient-derived xenograft model of ALK-driven lung cancer.

Anaplastic lymphoma kinase (ALK) inhibitor crizotinib has dramatic effect in non-small cell lung cancer patients with ALK rearrangement. However, most patients eventually develop resistance. To discover therapeutic targets to overcome crizotinib resistance (CR), we generated patient-derived xenograft CR mice and subjected them to phosphorylation profiling, together with CR mice treated with ASP3026 or alectinib. We identified 100 proteins with different phosphorylation status in CR mice. Among them, AXL phosphorylation was increased in CR mice, which could not be reversed by ASP3026 or alectinib. Importantly, the combined treatment of crizotinib and AXL inhibitor in CR mice significantly inhibited tumor growth, compared to crizotinib alone. We also found that SHC1 phosphorylation was increased in CR mice and SHC1 knockdown sensitized ALK-driven cells to crizotinib. Our study provides a new view of signaling pathways leading to CR, suggesting AXL and SHC1 as potential targets for combination therapy to overcome CR.

Colchicine Blocks Abdominal Aortic Aneurysm Development by Maintaining Vascular Smooth Muscle Cell Homeostasis.

Development of non-surgical treatment of human abdominal aortic aneurysm (AAA) has clinical significance. Colchicine emerges as an effective therapeutic regimen in cardiovascular diseases. Yet, whether colchicine slows AAA growth remain controversy. Here, we demonstrated that daily intragastric administration of low-dose colchicine blocked AAA formation, prevented vascular smooth muscle cell (SMC) phenotype switching and apoptosis, and vascular inflammation in both peri-aortic CaPO4 injury and subcutaneous angiotensin-II infusion induced experimental AAA mice models. Mechanistically, colchicine increased global mRNA stability by inhibiting the METTL14/YTHDC1-mediated m6A modification, resulting in increased sclerostin (SOST) expression and consequent inactivation of the WNT/ß-catenin signaling pathway in vascular SMCs from mouse AAA lesions and in cultured human aortic SMCs. Moreover, human and mouse AAA lesions all showed increased m6A methylation, decreased SOST expression, and skewed synthetic SMC de-differentiation phenotype, compared to those without AAA. This study uncovers a novel mechanism of colchicine in slowing AAA development by using the METTL14/SOST/WNT/ß-catenin axis to control vascular SMC homeostasis in mouse aortic vessels and in human aortic SMCs. Therefore, use of colchicine may benefit AAA patients in clinical practice.

Liraglutide Attenuates Aortic Valve Calcification in a High-Cholesterol-Diet-Induced Experimental Calcific Aortic Valve Disease Model in Apolipoprotein E-Deficient Mice.

BACKGROUND: Calcific aortic valve disease (CAVD) is a significant cause of morbidity and mortality among elderly people. However, no effective medications have been approved to slow or prevent the progression of CAVD. Here, we examined the effect of liraglutide on aortic valve stenosis. METHODS: Male Apoe-/- mice were fed with a high-cholesterol diet for 24 weeks to generate an experimental CAVD model and randomly assigned to a liraglutide treatment group or control group. Echocardiography and immunohistological analyses were performed to examine the aortic valve function and morphology, fibrosis, and calcium deposition. Plasma Glucagon-like peptide-1 (GLP-1) levels and inflammatory contents were measured via ELISA, FACS, and immunofluorescence. RNA sequencing (RNA-seq) was used to identify liraglutide-affected pathways and processes. RESULTS: Plasma GLP-1 levels were reduced in the CAVD model, and liraglutide treatment significantly improved aortic valve calcification and functions and attenuated inflammation. RNA-seq showed that liraglutide affects multiple myofibroblastic and osteogenic differentiations or inflammation-associated biological states or processes in the aortic valve. Those liraglutide-mediated beneficial effects were associated with increased GLP-1 receptor (GLP-1R) expression. CONCLUSIONS: Liraglutide blocks aortic valve calcification and may serve as a potential therapeutic drug for CAVD treatment.

Case Report: 3D Printing Guided Cardiac Autotransplantation for Treatment of a Giant Complex Primary Left Atrial Tumor.

Primary cardiac tumors are rare and complete surgical resection is the optimal treatment. However, it is a great challenge to resect some malignant or complex benign left-sided cardiac tumors situated on the posterior aspect of the heart using conventional surgical resection techniques. Previous studies reported that cardiac autotransplantation is a feasible and safe technique for resection of such cardiac tumors. We report a successful case of cardiac autotransplantation with 3-dimensional (3D) printing technique for complete resection of a giant complex primary left atrial tumor.

Management Strategies for Patients After CABG Surgery in the Outbreak of the COVID-19 Pandemic.

BACKGROUND: The novel coronavirus 2019 pandemic (COVID-19) has quickly spread over the world and affected over 100 countries so far. Patients with pre-existing cardiovascular disease may have a higher risk of infection of COVID-19 and worse outcomes than others. To improve the outcome during the pandemic, management strategies for the patients recovering from coronary artery bypass graft (CABG) surgery need to be reconsidered. METHODS: Some precaution advices including self-protection, blood glucose and blood pressure controlling are recommended for the patients recovering from CABG during the pandemic. They are encouraged to communicate with doctors by telephone or Internet when COVID-19 related symptoms such as cough, fever and dyspnea occur. As a follow-up strategy for patients after CABG surgery, cardiac biomarkers and CTA could also be helpful to the diagnosis of COVID-19. Some medications being investigated for COVID-19 therapy may have side effects relevant to cardiovascular disease. Appropriate personal protection equipment (PPE) is necessary for cardiovascular health-care workers operating in clinical settings. RESULTS: There was zero out of over 300 follow-up patients after CABG surgery confirmed to be infected with COVID-19 from January to June 2020. No cardiovascular health-care workers were reported to be infected neither in the Second Xiangya Hospital during the pandemic. CONCLUSION: The management strategy here we proposed could improve the outcome of patients after CABG during the pandemic and benefit both cardiovascular patients and health-care workers.

Dihydromyricetin inhibits cell proliferation, migration, invasion and promotes apoptosis via regulating miR-21 in Human Cholangiocarcinoma Cells.

Dihydromyricetin, the most abundant natural flavonoid isolated from Ampelopsis grossedentata, exhibits broad anti-tumor effects. However, the effects of dihydromyricetin on cholangiocarcinoma remain unclear. This study examined the anti-tumor effects of dihydromyricetin in two human cholangiocarcinoma cell lines HCCC9810 and TFK-1, and the underlying mechanism was also investigated. Our study was the first to show that dihydromyricetin significantly inhibited cell proliferation, migration, invasion and promoted apoptosis in cholangiocarcinoma cells. By analyzing the TCGA dataset, we found that expression of miR-21, an oncogene and a potential target of anticancer drugs for cholangiocarcinoma, was upregulated in cholangiocarcinoma tissues compared to paired control tissues. Moreover, dihydromyricetin significantly reduced the expression of miR-21 in a dose-dependent manner. Overexpression of miR-21 remarkably abolished the inhibitory effects of dihydromyricetin on cell proliferation, migration, invasion and abrogated its effect of promoting cell apoptosis in both HCCC9810 and TFK-1 cells. Dihydromyricetin remarkably increased the expression of PTEN and decreased the expression of phosphorylated Akt, while overexpression of miR-21 abrogated the modulation of PTEN/ Akt pathway by dihydromyricetin. Taken together, our study demonstrates that dihydromyricetin inhibits cell proliferation, migration, invasion and promotes apoptosis in cholangiocarcinoma cells via regulating miR-21.