Single-Cell RNA Sequencing and Assay for Transposase-Accessible Chromatin Using Sequencing Reveals Cellular and Molecular Dynamics of Aortic Aging in Mice.

OBJECTIVE: The impact of vascular aging on cardiovascular diseases has been extensively studied; however, little is known regarding the cellular and molecular mechanisms underlying age-related vascular aging in aortic cellular subpopulations. Approach and Results: Transcriptomes and transposase-accessible chromatin profiles from the aortas of 4-, 26-, and 86-week-old C57/BL6J mice were analyzed using single-cell RNA sequencing and assay for transposase-accessible chromatin sequencing. By integrating the heterogeneous transcriptome and chromatin accessibility data, we identified cell-specific TF (transcription factor) regulatory networks and open chromatin states. We also determined that aortic aging affects cell interactions, inflammation, cell type composition, dysregulation of transcriptional control, and chromatin accessibility. Endothelial cells 1 have higher gene set activity related to cellular senescence and aging than do endothelial cells 2. Moreover, construction of senescence trajectories shows that endothelial cell 1 and fibroblast senescence is associated with distinct TF open chromatin states and an mRNA expression model. CONCLUSIONS: Our data provide a system-wide model for transcriptional and epigenetic regulation during aortic aging at single-cell resolution.

HDL and Lipid Metabolism.

Mediating reverse cholesterol transport (RCT) is the most classic function of HDL. HDL and HDL-C participate in the entire process of RCT, including cholesterol removal from cells, cholesterol transport in circulation, and cholesterol excretion. As cholesterol is a component of lipid rafts and lipid droplets in cells, HDL and RCT can influence cell activity. HDL has also been shown to be related to the metabolism of some other biological lipids, such as S1P and ox-PL. Here we will introduce in detail the molecular mechanism of HDL participation in RCT and its significance.

Prevention of Contrast-Induced Nephropathy by Inferior Vena Cava Ultrasonography-Guided Hydration in Chronic Heart Failure Patients.

INTRODUCTION: Contrast-induced nephropathy (CIN) is a common complication resulting from the administration of contrast media. This study was designed to determine whether inferior vena cava (IVC) ultrasonography (IVCU)-guided hydration can reduce the risk of CIN in chronic heart failure patients undergoing coronary angiography or coronary angiography with percutaneous coronary intervention compared with standard hydration. METHODS: This prospective clinical trial enrolled 207 chronic heart failure patients from February 2016 to November 2017, who were randomly assigned to either the IVCU-guided hydration group (n = 104) or the routine hydration group (n = 103). In the IVCU-guided group, the hydration infusion rate was set according to the IVC diameter determined by IVCU, while the control group received intravenous infusion of 0.9% saline at 0.5 mL/(kg·h). Serum Cr was measured before and 48-72 h after the procedure. All patients were followed up for 18 months. The incidence of nephropathy and major adverse cardiovascular or cerebrovascular events (MACCEs) was also compared between the 2 groups. RESULTS: Statistically significant difference between the 2 groups regarding the occurrence of CIN was observed (12.5 vs. 29.1%, p = 0.004). The hydration volume of the IVCU-guided group was significantly higher than that of the routine group (p < 0.001). In addition, patients receiving IVCU-guided hydration had significantly lower risk of developing MACCEs than patients in the control group during the 18-month follow-up (14.4 vs. 27.2%, p = 0.027). CONCLUSION: Our findings support that IVCU-guided hydration is superior to standard hydration in prevention of CIN and may substantially reduce longtime composite major adverse events.

Withdrawal of oral anticoagulants 3 months after successful radiofrequency catheter ablation in patients with atrial fibrillation: A meta-analysis.

BACKGROUND: The best anticoagulation therapy for atrial fibrillation (AF) after radiofrequency catheter ablation (RFCA) remains a challenge. METHODS: A systematic search of PubMed, Ovid, and Cochrane Library was conducted identifying at clinical trials which evaluated the differences between thromboembolism (TE) and hemorrhage in an off-oral anticoagulants (OACs) treatment group (the observation group) and an on-OACs treatment group (the control group), at 3 months after successful RFCA. Meta-analysis was performed using RevMan 5.3 software, and the fixed effect model was used as a relevant statistical model. χ2 test and I2 were used to test for the presence of heterogeneity. Subgroup analysis and sensitivity analysis were also performed. RESULTS: The results showed no significant differences between two groups in TE (relative risk [RR] 0.82, 95% confidence interval [CI], 0.51-1.33, P = 0.42), and only mild heterogeneity (P = 0.22, I2  = 29%). No significant differences in TE between two subgroups were found according to < 3 years and ≥ 3 years follow-up analyses (RR 0.58, 95% CI, 0.26-1.28, P = 0.18; RR 1.00, 95% CI, 0.54-1.85, P = 1.00). Furthermore, there was a lower risk of TE in the observation subgroup (< 60 years) compared to the control group (RR 0.31, 95% CI, 0.12-0.78, P = 0.01). Also, there were no significant differences in TE between two subgroups (≥ 60 years, RR 1.24, 95% CI, 0.67-2.28, P = 0.49). The risk of hemorrhage in the observation group was significantly lower compared to the control group (RR 0.05, 95%CI, 0.02-0.14, P < 0.00001). CONCLUSIONS: The withdrawal of OACs 3 months after successful radiofrequency catheter ablation for patients with AF may be safe and feasible. It needs to be tested by randomized controlled trial.

Upregulation of TRPC1/6 may be involved in arterial remodeling in rat.

BACKGROUND: Hypertension and its complications are associated with arterial remodeling. Transient receptor potential cationic channels (TRPCs) are important nonselective cationic channels that regulate calcium homeostasis in mammalian cell membranes. We aimed to study the expression of various TRPC isoforms in spontaneously hypertensive rat (SHR) carotid arterial remodeling and explore the relationship between SHR carotid arterial remodeling and TRPC expression. MATERIALS AND METHODS: Thirty male SHRs were randomly divided into three groups and sacrificed at ages 4, 8, and 18 wk, respectively, with matching control male Wistar-Kyoto rats (n = 10). Caudal artery systolic blood pressure (SBP) was measured every 2 wk. Carotid artery remodeling parameters including carotid artery wall thickness (MT), lumen diameter (LD), medial area, collagen area rate, and average nuclear area in media cells were determined after histologic staining. Real-time polymerase chain reaction and immunoblot assays were performed to assess TRPC expression. Carotid artery remodeling and TRPC expression were reevaluated after ginsenoside Rb1 treatment from eighth to eighteenth week. RESULTS: Carotid artery remodeling of SHRs was aggravated gradually with age and SBP, as well as MT, LD, MT/LD, medial area, average nuclear area in media cells, and collagen deposition, most obvious at 18 wk. Interestingly, expression of TRPC1, 3, and 6 increased with age and SBP, with TRPC1/6 showing significant differences between the Wistar-Kyoto and 18 wk groups; TRPC4/5 expression was unchanged and TRPC7 was barely detected. Importantly, after ginsenoside Rb1 treatment, TRPC1/6 expressions were significantly inhibited, SBP decreased, and the carotid artery remodeling in SHRs relieved. CONCLUSIONS: Upregulation of TRPC1 and TRPC6 may be involved in carotid arterial remodeling in SHRs.

TRPC1, CaN and NFATC3 signaling pathway in the pathogenesis and progression of left ventricular hypertrophy in spontaneously hypertensive rats.

Spontaneously hypertensive rats (SHR) was used to study left ventricular hypertrophy (LVH) and its dynamic change after the interventions with Telmisartan and Amlodipine. The results showed that the expression of TRPC1, CaN and NFATC3 increased gradually with the pathogenesis and progression of LVH. Telmisartan reduced blood pressure and LVH, and down-regulated the expression of TRPC1, CaN and NFATC3 in left ventricle of SHR. Amlodipine reduced the blood pressure in SHR but had no impact on the hypertrophy and expression of above factors. Our data suggest that the pathogenesis and progression of LVH in SHR are related to upregulation of TRPC1, CaN and NFATC3 signaling pathway.

Association of microRNA polymorphisms with the risk of myocardial infarction in a Chinese population.

MicroRNAs (miRNAs) are involved in the regulation of a variety of biological processes, such as inflammation. Dysregulation of miRNAs have been implicated in many human disease, including cardiovascular diseases. Polymorphisms in miRNA genes may affect the miRNA biogenesis and function, and thus cause changes in the expression of thousands of genes. The aim of this study was to examine whether miRNA polymorphisms (miR-146a rs2910164, miR-149 rs71428439, miR-196a2 rs11614913, miR-218 rs11134527, and miR-499 rs3746444) contribute to the risk for the development of myocardial infarction (MI). Five miRNA polymorphisms were genotyped in a total of 1808 subjects composed of 919 MI patients and 889 control individuals. The GG genotype of rs3746444 was found to be associated with a significantly increased risk of MI (recessive model, adjusted OR = 1.710, 95% CI: 1.058-2.763, P = 0.029). Although the CC genotype of rs2910164 significantly increased the risk of MI under dominant and additive models (P < 0.05), this difference disappeared after adjustment for age, sex, blood pressure, triglycerides, total cholesterol, HDL, LDL and diabetes. In addition, when rs3746444 and rs2910164 were evaluated together by the number of putative high-risk alleles, we found an increased risk of MI for subjects carrying 3-4 risk alleles (3-4 risk alleles vs. 0-1 risk allele, adjusted OR = 1.580, 95% CI: 1.069-2336, P = 0.022; 3-4 risk alleles vs. 0-2 risk allele, adjusted OR = 1.513, 95% CI: 1.031-2.219, P = 0.034). These findings indicate that miR-499 rs3746444 and miR-146a rs2910164 may represent novel markers of MI susceptibility.

Association of pulse pressure and aortic root diameter in elderly Chinese patients with chronic heart failure.

Background: High pulse pressure (PP) and aortic root diameter (AoD) are hallmarks of arterial stiffness or vascular aging and they are considered as risk factors for age-related cardiovascular disease, including heart failure (HF). However, the relationship between PP and AoD in patients with heart failure (HF) is uncertain. This study aimed to evaluate the relationship between PP and AoD in the middle-aged and the elderly with HF. Methods: A total of 1,027 Chinese middle-aged and elderly patients with HF, including HF with reduced ejection fraction (HFrEF), HF with mid-range EF (HFmrEF), and HF with preserved EF (HFpEF) were included in this study. Pearson correlation analysis was used to evaluate the relationship between PP and AoD in the three types of HF. Multiple linear regression analysis was performed to assess the factors that affected AoD. Multivariate logistic regression was performed to determine the association between the PP level quartiles and AoD. The results were validated in an independent dataset included a total of 378 consecutive patients with HFrEF hospitalized at the Pingtan Branch of Fujian Medical University Union Hospital (Fujian, China). Results: There was a positive correlation between PP and AoD in the middle-aged and the elderly with HFrEF. Multiple linear regression analysis revealed that PP, age, and body mass index (BMI) were independently correlated with AoD in HFrEF patients. In multivariate logistic regression analysis, an increased risk of aortic root dilation was observed in the highest quartile of the PP level compared with the lowest quartile. Age significantly interacted with PP (p = 0.047). A significant association between PP levels and AoD was only observed in patients ≥ 65 years old, but not in patients < 65 years old. In the validation dataset, PP was independently related to AoD in patients with HFrEF (ß = 0.205, p = 0.001). Conclusions: PP level was independently and positively associated with AoD, especially in the elderly with HFrEF, but not in patients with HFmrEF and HFpEF. Arterial stiffening or vascular aging may play a certain role in the elderly HFrEF patients.

Influencing and prognostic factors of end-stage hypertrophic cardiomyopathy.

AIMS: End-stage hypertrophic cardiomyopathy (ES-HCM) is a disease with severe complications and a poor prognosis. This study aimed to explore the influencing and prognostic factors of ES-HCM. METHODS AND RESULTS: A total of 1282 patients with HCM who were hospitalized for the first time at Fujian Medical University Union Hospital between 1 January 2013 and 30 September 2021 were recorded. The patients with HCM and left ventricular ejection fraction (LVEF) < 50% were defined as having ES-HCM, and a control group (LVEF ≥ 50%) was generated from the collected medical records of HCM. The patients were matched in a ratio of 4:1 based on age and sex. Logistic regression analysis was used to determine the influencing factors of ES-HCM. Kaplan-Meier survival analysis was performed to analyse the clinical outcomes of ES-HCM patients. A total of 250 inpatients with HCM were enrolled in the study; 50 patients had ES-HCM, and 200 had HCM with LVEF ≥ 50%. The mean age of the patients at enrolment was 62.5 ± 10.3 years, and 215 patients (215/250, 86.0%) were male. The median follow-up time of the patients was 2.8 (1.4-5.4) years. The incidence of all-cause death and cardiovascular death in patients with ES-HCM was higher than those in patients with HCM and LVEF ≥ 50% (22/50 [44.0%] vs. 13/200 [6.5%]; 12/50 [24.0%] vs. 4/200 [2.0%], all P < 0.001). Multivariate logistic regression analysis showed that the influencing factors associated with ES-HCM included age at first symptom onset (odds ratio [OR] = 0.95, 95% CI [0.90, 1.00], P = 0.042), New York Heart Association (NYHA) class (OR = 7.73, 95% CI [2.93, 20.41], P < 0.001), heart rate (OR = 1.07, 95% CI [1.02, 1.12], P = 0.003), QRS duration (OR = 1.03, 95% CI [1.00, 1.05], P = 0.020), left ventricular end-diastolic diameter (LVEDD) (OR = 1.15, 95% CI [1.04, 1.28], P = 0.006), left atrial anteroposterior diameter (LAD) (OR = 1.13, 95% CI [1.03, 1.24], P = 0.012), and maximum left ventricular wall thickness (MLVWT) (OR = 0.80, 95% CI [0.68, 0.93], P = 0.005). Among the 50 patients with ES-HCM, NYHA class (P < 0.001) and heart rate (P = 0.017) were each associated with a higher likelihood and earlier occurrence of heart transplantation or all-cause mortality in univariate analyses. CONCLUSIONS: The influencing factors for ES-HCM included the age at first symptom onset, NYHA class, heart rate, QRS duration, LVEDD, LAD, and MLVWT. Both NYHA class and heart rate were related to the prognosis of ES-HCM.

Loss of Endothelial Annexin A1 Aggravates Inflammation-Induched Vascular Aging.

Chronic inflammation is increasingly considered as the most important component of vascular aging, contributing to the progression of age-related cardiovascular diseases. To delay the process of vascular aging, anti-inflammation may be an effective measure. The anti-inflammatory factor annexin A1 (ANXA1) is shown to participate in several age-related diseases; however, its function during vascular aging remains unclear. Here, an ANXA1 knockout (ANXA1-/-) and an endothelial cell-specific ANXA1 deletion mouse (ANXA1△EC) model are used to investigate the role of ANXA1 in vascular aging. ANXA1 depletion exacerbates vascular remodeling and dysfunction while upregulates age- and inflammation-related protein expression. Conversely, Ac2-26 (a mimetic peptide of ANXA1) supplementation reverses this phenomenon. Furthermore, long-term tumor necrosis factor-alpha (TNF-α) induction of human umbilical vein endothelial cells (HUVECs) increases cell senescence. Finally, the senescence-associated secretory phenotype and senescence-related protein expression, rates of senescence-ß-galactosidase positivity, cell cycle arrest, cell migration, and tube formation ability are observed in both ANXA1-knockdown HUVECs and overexpressed ANXA1-TNF-α induced senescent HUVECs. They also explore the impact of formyl peptide receptor 2 (a receptor of ANXA1) in an ANXA1 overexpression inflammatory model. These data provide compelling evidence that age-related inflammation in arteries contributes to senescent endothelial cells that promote vascular aging.

Evaluation the value of H2FPEF score and HFA-PEFF step E score in the diagnosis of heart failure with preserved ejection fraction.

BACKGROUND: Clinical diagnosis of heart failure with preserved ejection fraction (HFpEF) remains challenging. The aim of the study is to evaluate the value of the H2FPEF score and HFA-PEFF step E score in the diagnosis of HFpEF. METHODS: 319 hospitalised patients with 'shortness of breath' or 'dyspnoea' were retrospectively collected and scored with the above two scores, respectively. They were divided into HFpEF group and non-HFpEF group in the study. RESULTS: Both the negative and positive predictive value of H2FPEF score and HFA-PEFF Step E score were 95.52%, 96.83% and 98.28%, 93.63%, respectively. However, there were 189 (59.25%) and 104 (32.60%) cases could not be diagnosed or excluded in the H2FPEF score and the HFA-PEFF step E score, respectively. CONCLUSIONS: Both scores of the H2FPEF and the HFA-PEFF step E may be used to effectively rule out or confirm HFpEF according to the score point. However, there are three fifths and one third patients in the H2FPEF score and the HFA-PEFF step E score, respectively, in the intermediate scores who are needed further invasive catheterisation or exercise stress tests.

Vitamin D/vitamin D receptor pathway in non-alcoholic fatty liver disease.

INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide, but underlying mechanisms are not fully understood. In recent years, a growing body of evidence has emphasized the therapeutic role of vitamin D in NAFLD, but the specific mechanism remains to be investigated. AREAS COVERED: This review summarized the roles of vitamin D/VDR (vitamin D receptor) pathway in different types of liver cells (such as hepatocytes, hepatic stellate cells, liver macrophages, T lymphocytes, and other hepatic immune cells) in case of NAFLD. Meanwhile, the effects of pathways in the gut-liver axis, adipose tissue-liver axis, and skeletal muscle-liver axis on the development of NAFLD were further reviewed. Relevant literature was searched on PubMed for the writing of this review. EXPERT OPINION: The precise regulation of regional vitamin D/VDR signaling pathway based on cell-specific or tissue-specific function will help clarify the potential mechanism of vitamin D in NAFLD, which may provide new therapeutic targets to improve the safety and efficacy of vitamin D based drugs.

Elevated serum chemerin levels are associated with the presence of coronary artery disease in patients with type 2 diabetes.

BACKGROUND: Coronary artery disease (CAD) is a major vascular complication of type 2 diabetes mellitus (T2DM) and reveals high mortality. Serum levels of chemerin have been suggested to be involved in glucose and lipid metabolism and associated with several cardiovascular factors. The aim of this study is to investigate the association of serum chemerin levels with the presence of CAD in patients with T2DM. METHODS: Serum levels of chemerin were determined in 286 patients with T2DM who underwent coronary angiography for the evaluation of CAD and 128 healthy subjects. The T2DM patients group included 150 patients with CAD and 136 patients without CAD. RESULTS: Serum chemerin levels were significantly higher in T2DM patients with CAD compared with those without CAD and healthy controls. However, there was no significant difference in the levels of serum chemerin between T2DM patients without CAD and healthy controls. Multivariable logistic regression analysis revealed that serum chemerin levels were an independent determinant of the presence of CAD in patients with T2DM (OR 1.057, 95% CI 1.040 to 1.075; p < 0.001). In addition, linear regression analysis showed that serum chemerin levels were positively correlated with body mass index, systolic blood pressure, homeostasis model assessment of insulin resistance, and serum triglycerides. CONCLUSIONS: There is an independent association between serum levels of chemerin and the presence of CAD in patients with T2DM.

The positive correlation between brachial-ankle pulse wave velocity and aortic diameter in Chinese patients with diabetes.

Aortic dilation is associated with an increased risk of cardiovascular diseases. Increased brachial-ankle pulse wave velocity (baPWV) is a hallmark of vascular aging and arterial stiffness, as well as an important risk factor for vascular disease. This study aimed to retrospectively analyze the correlation between baPWV and aortic diameter (AoD) of inpatients with diabetes. A total of 1294 diabetic patients with the detailed medical records were investigated. Arterial stiffness was assessed using baPWV and AoD using echocardiography. The results showed that baPWV and AoD increase with age (p <0.05). Based on multiple linear regression analysis, age, systolic and diastolic blood pressure, left atrial diameter, right ventricle diameter, pulmonary artery diameter, peak velocity of early transmitral blood flow/peak velocity of late transmitral blood flow, and baPWV independently correlated with AoD in patients with diabetes. Additionally, an increased risk of aortic dilation occurred in the highest baPWV quartile compared with the lowest quartile (p <0.001). In conclusion, baPWV is independently and positively associated with AoD. Hence, prospective cohorts or randomized clinical trials will be the next step to further determine whether interventions designed to improve arterial stiffness in patients with diabetes will reduce the risk of aortic dilation.

Clinical outcomes of severe sepsis and septic shock patients with left ventricular dysfunction undergoing continuous renal replacement therapy.

Baseline left ventricular (LV) dysfunction is associated with subsequent risks of acute kidney injury (AKI) and mortality in patients with sepsis. This study investigated the therapeutic effects of continuous renal replacement therapy (CRRT) in hemodynamically unstable patients with severe sepsis and septic shock combined with LV dysfunction. In this multicenter retrospective study, severe sepsis and septic shock patients with LV dysfunction were classified into one of two groups according to the timing of CRRT: the early group (before AKI was detected) or the control group (patients with AKI). Patients from the control group received an accelerated strategy or a standard strategy of CRRT. The primary outcome was all-cause intensive care unit (ICU) mortality. Patients were weighted by stabilized inverse probability of treatment weights (sIPTW) to overcome differences in baseline characteristics. After sIPTW analysis, the ICU mortality was significantly lower in the early group than the control group (27.7% vs. 63.5%, p < 0.001). Weighted multivariable analysis showed that early CRRT initiation was a protective factor for the risk of ICU mortality (OR 0.149; 95% CI 0.051-0.434; p < 0.001). The ICU mortality was not different between the accelerated- and standard-strategy group (52.5% vs. 52.9%, p = 0.970). Early CRRT in the absence of AKI is suggested for hemodynamically unstable patients with severe sepsis and septic shock combined with LV dysfunction since it benefits survival outcomes.

[The value of aggressive diuretic therapy in acute decompensated stage of chronic heart failure].

OBJECTIVE: To evaluate both the efficacy, safety, length of stay in hospital and expenses of aggressive diuretic therapy in patients with acute decompensation of chronic heart failure (CHF). METHODS: The retrospective analysis was conducted in the patients with acute decompensation CHF New York Heart Association (NYHA) class III or IV in department of cardiology of Fujian Medical University Union Hospital from January 1st 2006 to September 1st 2007. The 24-hour urine volume on the 2nd day was equivalent or over 2 400 ml was defined as aggressive diuretic therapy group, and those with less than 2 400 ml of urine as non-aggressive diuretic therapy group. The biochemical parameters and vital signs were compared before and after aggressive diuretic therapy, and the mortality, the length of stay and expenses were also compared between the two groups. RESULTS: One hundred and ninety-five patients were enrolled in the study, there were 73 and 122 patients in aggressive diuretic therapy group and in non-aggressive diuretic therapy group respectively. The mortality in aggressive diuretic therapy group was lower than that in non-aggressive diuretic therapy group (1.4% vs. 9.8%, P<0.05). The length of stay, total expenses and average cost in aggressive diuretic therapy group were lower than those in non-aggressive diuretic therapy group respectively [the length of stay: 11 days vs. 16 days; total expenses: 8 483 yuan vs. 12 182 yuan; average expenseI: 721.1 yuan/d vs. 854.4 yuan/d; average expenseII (except for examination expenses): 580.0 yuan/d vs. 698.2 yuan/d, P<0.05 or P<0.01]. There were no significant changes in biochemical parameters and heart rate before and after aggressive diuretic therapy. The systolic pressure (SBP) and diastolic pressure (DBP) were reduced significantly after aggressive diuretic therapy [SBP: (118.2±16.9) mm Hg vs. (127.0±24.9) mm Hg; DBP: (67.2±4.5) mm Hg vs. (75.2±4.9) mm Hg, 1 mm Hg=0.133 kPa, P<0.05 and P<0.01]. No hypotension symptoms such as dizziness and chest distress were found in all patients. CONCLUSION: Aggressive diuretic therapy in patients with acute decompensation CHF is a safe, effective mode of therapy. It can reduce the length of stay in hospital, expenses and the mortality during hospitalization.

Development and Validation of a Prediction Model for Elevated Arterial Stiffness in Chinese Patients With Diabetes Using Machine Learning.

BACKGROUND: Arterial stiffness assessed by pulse wave velocity is a major risk factor for cardiovascular diseases. The incidence of cardiovascular events remains high in diabetics. However, a clinical prediction model for elevated arterial stiffness using machine learning to identify subjects consequently at higher risk remains to be developed. METHODS: Least absolute shrinkage and selection operator and support vector machine-recursive feature elimination were used for feature selection. Four machine learning algorithms were used to construct a prediction model, and their performance was compared based on the area under the receiver operating characteristic curve metric in a discovery dataset (n = 760). The model with the best performance was selected and validated in an independent dataset (n = 912) from the Dryad Digital Repository (https://doi.org/10.5061/dryad.m484p). To apply our model to clinical practice, we built a free and user-friendly web online tool. RESULTS: The predictive model includes the predictors: age, systolic blood pressure, diastolic blood pressure, and body mass index. In the discovery cohort, the gradient boosting-based model outperformed other methods in the elevated arterial stiffness prediction. In the validation cohort, the gradient boosting model showed a good discrimination capacity. A cutoff value of 0.46 for the elevated arterial stiffness risk score in the gradient boosting model resulted in a good specificity (0.813 in the discovery data and 0.761 in the validation data) and sensitivity (0.875 and 0.738, respectively) trade-off points. CONCLUSION: The gradient boosting-based prediction system presents a good classification in elevated arterial stiffness prediction. The web online tool makes our gradient boosting-based model easily accessible for further clinical studies and utilization.

Adropin-based dual treatment enhances the therapeutic potential of mesenchymal stem cells in rat myocardial infarction.

Both weak survival ability of stem cells and hostile microenvironment are dual dilemma for cell therapy. Adropin, a bioactive substance, has been demonstrated to be cytoprotective. We therefore hypothesized that adropin may produce dual protective effects on the therapeutic potential of stem cells in myocardial infarction by employing an adropin-based dual treatment of promoting stem cell survival in vitro and modifying microenvironment in vivo. In the current study, adropin (25 ng/ml) in vitro reduced hydrogen peroxide-induced apoptosis in rat bone marrow mesenchymal stem cells (MSCs) and improved MSCs survival with increased phosphorylation of Akt and extracellular regulated protein kinases (ERK) l/2. Adropin-induced cytoprotection was blocked by the inhibitors of Akt and ERK1/2. The left main coronary artery of rats was ligated for 3 or 28 days to induce myocardial infarction. Bromodeoxyuridine (BrdU)-labeled MSCs, which were in vitro pretreated with adropin, were in vivo intramyocardially injected after ischemia, following an intravenous injection of 0.2 mg/kg adropin (dual treatment). Compared with MSCs transplantation alone, the dual treatment with adropin reported a higher level of interleukin-10, a lower level of tumor necrosis factor-α and interleukin-1ß in plasma at day 3, and higher left ventricular ejection fraction and expression of paracrine factors at day 28, with less myocardial fibrosis and higher capillary density, and produced more surviving BrdU-positive cells at day 3 and 28. In conclusion, our data evidence that adropin-based dual treatment may enhance the therapeutic potential of MSCs to repair myocardium through paracrine mechanism via the pro-survival pathways.

Hypertension accelerates age-related intrarenal small artery (IRSA) remodelling and stiffness in rats with possible involvement of AGEs and RAGE.

OBJECTIVES: To study changes in morphology, advanced glycation end products (AGEs) and the AGEs receptor, RAGE, that occur with ageing in intrarenal small arteries (IRSAs) of spontaneously hypertensive rats (SHRs) and to investigate the possible roles of hypertension, AGEs and RAGE in the progression of IRSA remodelling and stiffness with ageing in rats. METHODS: Ageing SHRs and ageing normotensive Wistar Kyoto (WKY) rats were studied. The minimal renal vascular resistance (minRVR) was measured. Renal arcuate arteries (RAAs) and interlobular arteries (RILAs), the expression of α-smooth muscle actin, proliferating cell nuclear antigen, AGEs, RAGE and the plasma concentrations of AGEs were also examined. RESULTS: The IRSA minRVR, wall thickening, cell proliferation and collagen deposition in RILAs and RAAs gradually increased with age in SHRs and were much higher in 24-week-old SHRs than in age-matched WKY rats (p<0.05); these indexes in WKY rats were only elevated in the 72-week group (p<0.05). The expression of RAGE in the RAA and RILA tunica media in SHRs was upregulated by 24 weeks and 12 weeks (p<0.05), respectively, while AGEs levels in the plasma and in the IRSA tunica media were increased by 48 weeks (p<0.05) and increased gradually with age. The levels of both RAGE and AGEs in WKY rats were increased only at 72 weeks (p<0.05). CONCLUSION: Hypertension accelerates the development of age-related IRSA remodelling and stiffness in rats, which may be related to upregulation of RAGE in the IRSA tunica media and increased expression of AGEs at the late stage.

Recombinant Extracellular Domain (p75ECD) of the Neurotrophin Receptor p75 Attenuates Myocardial Ischemia-Reperfusion Injury by Inhibiting the p-JNK/Caspase-3 Signaling Pathway in Rat Microvascular Pericytes.

Background Pro-NTs (precursor of neurotrophins) and their receptor p75 are potential targets for preventing microvascular dysfunction induced by myocardial ischemia-reperfusion injury (IRI). p75ECD (ectodomain of neurotrophin receptor p75) may physiologically produce neurocytoprotective effects by scavenging pro-NTs. We therefore hypothesized that p75ECD may have a cardioprotective effect on IRI through microvascular mechanisms. Methods and Results Myocardial IRI was induced in Sprague-Dawley rats by occluding the left main coronary arteries for 45 minutes before a subsequent relaxation. Compared with the ischemia-reperfusion group, an intravenous injection of p75ECD (3 mg/kg) 5 minutes before reperfusion reduced the myocardial infarct area at 24 hours after reperfusion (by triphenyltetrazolium chloride, 44.9±3.9% versus 34.6±5.7%, P<0.05); improved the left ventricular ejection fraction (by echocardiography), with less myocardial fibrosis (by Masson's staining), and prevented microvascular dysfunction (by immunofluorescence) at 28 days after reperfusion; and reduced myocardial pro-NTs expression at 24 hours and 28 days after reperfusion (by Western blotting). A simulative IRI model using rat microvascular pericytes was established in vitro by hypoxia-reoxygenation (2/6 hours) combined with pro-NTs treatment (3 nmol/L) at R. p75ECD (3 µg/mL) given at R improved pericyte survival (by methyl thiazolyl tetrazolium assay) and attenuated apoptosis (by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling). In the reperfused hearts and hypoxia-reoxygenation +pro-NTs-injured pericytes, p75ECD inhibited the expression of p-JNK (phospho of c-Jun N-terminal kinase)/caspase-3 (by Western blotting). SP600125, an inhibitor of JNK, did not enhance the p75ECD-induced infarct-sparing effects and pericyte protection. Conclusions p75ECD may attenuate myocardial IRI via pro-NTs reduction-induced inhibition of p-JNK/caspase-3 pathway of microvascular pericytes in rats.