The miR-182/Myadm axis regulates hypoxia-induced pulmonary hypertension by balancing the BMP- and TGF-ß-signalling pathways in an SMC/EC-crosstalk-associated manner.

We recently identified oncologic miR-182 as a new regulator of pulmonary artery hypertension (PAH) that targets myeloid-associated differentiation marker (Myadm), which is expressed in bone marrow stem cells and multipotent progenitors. Both miR-182 and Myadm are expressed in the cardiopulmonary system and correlated with the balance between the bone morphogenetic protein (BMP) and the transforming growth factor (TGF)-ß signalling pathways, which are disturbed in PAH. We hypothesize that miR-182/Myadm are involved in BMP-TGF-ß-signalling way in PAH. Hypoxia triggered pathological progression in cardiopulmonary PAH in vivo and in vitro; these changes were accompanied by strongly dowregulated BMP/SMAD1/5/8 expression and enhanced TGF-ß/SMAD2/3 signalling pathway, favouring SMAD4/SMAD2 transcript formation and inhibiting the PAH negative regulator Id1 expression. miR-182 gain-of-function significantly inhibited the pathological progression in hypoxia-induced PAH (HPH) in vivo and in vitro, with a restoration of the balance in BMP-TGF-ß signalling pathway. This recovery was abrogated by overexpression of Myadm. Conversely, loss-of-function of miR-182 increased the pathological progression of HPH followed by severe disturbance of BMP and TGF-ß signal transduction and reduced Id1 expression, which was restored by Myadm knockdown. We also showed that the miR-182/Myadm relate BMP-TGF-ß pathway is associated with NOS3/NO/cGMP via the crosstalk between endothelial cells and smooth muscle cells. Our findings further support the therapeutic significance of miR-182/Myadm in PAH via the balance of BMP- and TGF-ß-associated mechanisms.

Plasma Homocysteine Is a Predictive Factor for Accelerated Renal Function Decline and Chronic Kidney Disease in a Community-Dwelling Population.

BACKGROUND: Whether elevated plasma total homocysteine (tHcy) is a risk factor for the progression of kidney disease in general population has not been well established. The purpose of this study was to investigate the prognostic properties of plasma tHcy for renal function decrement and early chronic kidney disease (CKD) in community-dwelling populations with normal renal function at baseline. METHODS: A total of 1,426 participants were enrolled and followed for a median of 4.8 years (interquartile range, 4.5-5.2), and estimated glomerular filtration rate (eGFR) was evaluated. One main outcome was the rapid eGFR decline defined as a decline in eGFR of >3 mL/min per 1.73 m2 per year; the other was the new incidence of CKD. RESULTS: At the end of follow-up, the incidence of rapid eGFR decline and new-onset CKD was 20.7 and 5.6%, respectively. In multivariate linear regression analysis, age, central pulse pressure, fasting blood glucose, and concentration of tHcy were independent determinants of the change in eGFR. There was a graded association between tHcy quartiles and eGFR decline. Compared with participants with the lowest quartile of tHcy levels, those with the highest quartile had significantly increased risk for rapid eGFR decline (adjusted odds ratio [aOR] = 1.81; 95% confidence interval [CI]: 1.25-2.94) and new onset of CKD (adjusted hazard ratio = 4.29; 95% CI: 1.42-12.99) after adjusting for various confounders. Similarly, significant associations were also found when baseline tHcy was classified as hyperhomocysteinemia (>15 µmol/L) versus normal tHcy level (≤15 µmol/L). However, there was only association between the change in tHcy levels and new occurrence of CKD but not with rapid eGFR decline (aOR = 0.99, p = 0.613). CONCLUSIONS: In this prospective cohort of individuals from community-based population, elevated plasma tHcy emerged as an independent predictor of renal function decline and incident CKD, which might support selection of at-risk individuals.

Functions of Monocytes and Macrophages and the Associated Effective Molecules and Mechanisms at the Early Stage of Atherosclerosis.

OBJECTIVE: This study aimed to explore the functions and possible underlying regulatory molecules and mechanisms of monocytes and macrophages under early atherosclerotic conditions. METHODS: THP-1-derived monocytes or macrophages were induced by 50 µg/ml oxidized low density lipoprotein (ox-LDL) for 24 hours, and the degree of lipid metabolism and inflammation were determined. In addition, we identified differentially expressed genes, noncoding ribonucleic acids (RNAs), pathways and mechanisms by RNA sequencing, and performed further correlation analysis and molecular expression verification. RESULTS: Monocytes could not form foam cells with oil red O staining directly and had low levels of lipids as determined by total cholesterol and triglycerides assays, cholesterol uptake molecules CD36, the class A macrophage scavenger receptor and lectin-like oxidized low-density lipoprotein receptor-1 and cholesterol efflux molecules ATP binding cassette transporter A1, ATP binding cassette transporter G1 and liver X receptor α, and inflammatory factors, which were markedly different from those in macrophages. Additionally, sequencing data showed obviously differentially expressed genes, microRNAs and long noncoding RNAs in the atherosclerotic group. We identified 15 upregulated and downregulated genes, and 10 biological processes and pathways involved in atherosclerosis. Specifically, fatty acid desaturase 2 and apolipoprotein A1 in the peroxisome proliferator-activated receptor signaling pathway were differentially expressed in stimulated macrophages, whereas no changes were observed in the monocyte groups. Furthermore, correlation analysis showed differential expressed lncRNAs targeting miRNAs and mRNAs, and 24 competing endogenous RNA (ceRNA) networks of long noncoding RNA-microRNA-messenger RNA in early oxidative macrophages. CONCLUSIONS: Monocytes did not directly participate in lipid metabolism before differentiation into macrophages at the early stage in vitro. Furthermore, noncoding RNAs and ceRNA networks might play important roles in regulating the lipid metabolism of macrophages at the early stage of atherosclerosis.

Increased risk of aspirin-induced gastric mucosal erosion in elderly Chinese men harboring SLCO1B1*1b/*1b while using aspirin and an ACEI or ARB concomitantly.

BACKGROUND: It is well established that long-term use of aspirin can cause gastric mucosal injury. ACEIs and ARBs are inversely related to gastric ulcer development. This study aimed to evaluate the relationship between SLCO1B1 polymorphisms, which can affect ACEI and ARB transport, and gastric mucosal erosion in elderly male Chinese patients with cardiovascular disease who use aspirin. METHODS: Patients taking aspirin and an ACEI or ARB concomitantly who had undergone endoscopic screening for gastric erosion were analyzed for SLCO1B1 polymorphisms by a TaqMan assay. RESULTS: The frequency of the SLCO1B1*1b/*1b diplotype (42% vs. 24%; p = 0.002) was significantly higher in the gastric mucosal erosion group than in the control group. After adjustment for significant factors, SLCO1B1*1b/*1b (OR, 2.64; 95% CI, 1.59-4.17; p < 0.05) was found to be associated with gastric mucosal erosion in aspirin users. CONCLUSIONS: The presence of the SLCO1B1*1b/*1b diplotype may be a risk factor for aspirin-induced gastric mucosal erosion in elderly Chinese men taking aspirin and an ACEI or ARB concomitantly.

Body mass index is an independent predictive factor for kidney function evaluated by glomerular filtration rate in a community-dwelling population.

BACKGROUND: The effects of overweight and obesity on kidney function have since been identified and become a subject of increased study and concern. But the association between body mass index (BMI) and estimated glomerular filtration rate (eGFR) is not well characterized. The aim of this study was to determine the relationship between BMI and eGFR. METHODS: To better understand the relationship between BMI and kidney function, we investigated the association between BMI and eGFR using both the baseline BMI level and the follow-up eGFR level and investigated the relationship between the change in BMI and the change in eGFR in 1447 patients from a 4.8-year prospective study in Beijing, People's Republic of China. RESULTS: In multiple linear regression analysis, age, antihypertensive treatment, and BMI were negatively associated with the follow-up eGFR levels in all participants (R = -0.622, -0.926, and -0.266, respectively; P < 0.05), or in the elderly (R = -0.883, -1.035, and -0.630, respectively; P < 0.05); sex was found to be associated with the follow-up eGFR levels independently not only in all participants (R = 6.783; P < 0.001), but also in the elderly (R = 3.518; P < 0.05). In addition, the change in eGFR levels was positively related to age, the change in LDL-C, the change in TC, and the change in SBP, but negatively related to the change in BMI and the change in HDL-C (all P < 0.05). CONCLUSIONS: The present study clearly indicated that BMI is an independent predictive factor for kidney function evaluated by the eGFR level during a median 4.8 years of follow-up in Chinese population. LEVEL OF EVIDENCE: Level III, prospective cohort study.

The association between Hepcidin and arterial stiffness in a community-dwelling population.

BACKGROUND: An association of hepcidin with cardiovascular (CV) disease and atherosclerosis has been reported in different patient groups. However, it has not been well described clinically the association between hepcidin and arterial stiffness. In this study,We analysed the possible mechanism of Hepcidin and arterial stiffness. METHODS: This article related measurements of plasma hepcidin and arterial stiffness (carotid-femoral pulse wave velocity [PWV]) in a community-based sample. RESULTS: After a median follow-up interval of 4.8 years, multiple linear regression analysis revealed that hepcidin was independently associated with carotid-femoral PWV (ß = 1.498, P < 0.001). In a multivariable linear regression analysis, HDL3-C levels were negatively and independently associated with hepcidin at baseline (ß = - 0.857, P = 0.024). HDL2-C was not associated with hepcidin at baseline (ß = - 1.121, P = 0.133). CONCLUSIONS: We found an association between baseline hepcidin and follow-up arterial stiffness that was independent of age, gender and other vascular risk factors. We also identified an association between hepcidin and HDL3-C at baseline, which indicates that the HDL3-C level may reflect the change in cholesterol efflux from peripheral arteries and partly explain the relationship between hepcidin and the change of arterial stiffness.

Oncological miR-182-3p, a Novel Smooth Muscle Cell Phenotype Modulator, Evidences From Model Rats and Patients.

OBJECTIVE: Vascular smooth muscle cell (VSMC) phenotype change is a hallmark of vascular remodeling, which contributes to atherosclerotic diseases and can be regulated via microRNA-dependent mechanisms. We recently identified that asymmetrical dimethylarginine positively correlates to vascular remodeling-based diseases. We hypothesized that asymmetrical dimethylarginine induces smooth muscle cell (SMC) phenotypic change via a microRNA-dependent mechanism. APPROACH AND RESULTS: Microarray analysis enabled the identification of downregulation of miR-182-3p in asymmetrical dimethylarginine-treated human aortic artery SMCs. The myeloid-associated differentiation marker (MYADM) was identified as the downstream target of miR-182-3p and implicated to contribute to miR-182-3p knockdown-mediated SMC phenotype change, which was evidenced by the increased proliferation and migration and reduced expression levels of phenotype-related genes in human aortic artery SMCs through the ERK/MAP (extracellular signal-regulated kinase/mitogen-activated protein) kinase-dependent mechanism. When inhibiting MYADM in the presence of miR-182-3p inhibitor or overexpressing MYADM in the presence of pre-miR-182-3p, human aortic artery SMCs were reversed to the differentiation phenotype. In vivo, adeno-miR-182-3p markedly suppressed carotid neointimal formation by using balloon-injured rat carotid artery model, specifically via decreased MYADM expression, whereas adeno-miR-182-3p inhibitor significantly promoted neointimal formation. Atherosclerotic lesions from patients with high asymmetrical dimethylarginine plasma levels exhibited decreased miR-182-3p expression levels and elevated MYADM expression levels. CONCLUSIONS: miR-182-3p is a novel SMC phenotypic modulator by targeting MYADM.

Triglycerides are a predictive factor for arterial stiffness: a community-based 4.8-year prospective study.

BACKGROUND: Epidemiological studies have disclosed an independent effect of triglycerides on coronary heart disease despite achievement of low-density lipoprotein cholesterol goals with statin therapy. Arterial stiffness has been increasingly recognized as a strong predictor of cardiovascular disease and atherosclerotic disease. The association between triglycerides and arterial stiffness is not well characterized. We aimed to determine the relationship between triglycerides and arterial stiffness in a community-based longitudinal sample from Beijing, China. METHODS: We related levels of plasma TGs to measures of arterial stiffness (carotid-femoral pulse wave velocity [PWV] and carotid-radial PWV) in 1447 subjects (mean age, 61.3 years) from a community-based population in Beijing, China. RESULTS: After a median follow-up interval of 4.8 years, multiple linear regression analysis revealed that TGs were independently associated with carotid-femoral PWV (ß = 0.747, P < 0.001) and carotid-radial PWV (ß = 0.367, P = 0.001). In the group older than 65 years, the association between baseline TG levels and follow-up carotid-femoral PWV (ß = 1.094, P = 0.001) and carotid-radial PWV (ß = 0.524, P = 0.002) were strengthened. In forward stepwise multivariate logistic regression analysis, every SD increase in TGδ was associated with a 1.296-increased likelihood of the presence of carotid-femoral PWVδII (OR [per SD increase in TGδ]: 1.296; 95% CI: 1.064 ~ 1.580; P = 0.010) in Model 2, whereas the relationship between TGδ and carotid-radial PWVδII disappeared. In addition, the relationship was strengthened between TGδ and the presence of carotid-femoral PWVδII (OR 1.526, 95% CI: 1.088-2.141, P = 0.014) in the group older than 65 years but not carotid-radial PWVδII. No association was noted in subjects younger than 65 years. CONCLUSIONS: Lower triglyceride levels were significantly associated with decreases in carotid-femoral PWV, indicating that achieving low TG levels may be an additional therapeutic consideration in subjects with atherosclerotic disease.

Soluble ST2 for predicting heart failure, atrial fibrillation and death in patients with coronary heart disease with or without renal insufficiency.

Background: This study aimed to investigate the relationship between baseline soluble suppression of tumorigenesis-2 (sST2) concentration and the outcomes of heart failure (HF), atrial fibrillation (AF) or death in patients with coronary heart disease (CHD) with or without renal insufficiency (RI). Methods: Between March 2011 and December 2015, 3454 patients with CHD from the Chinese PLA General Hospital were enrolled in this cohort study. The patients were followed up until October 2021. AF, HF, and death events were recorded. Associations between baseline sST2 concentrations and clinical outcomes were assessed using Kaplan-Meier (K-M) curves, and Cox regression and generalised additive models. Subgroup analysis were carried out between RI and non-RI groups. Results: Among the patients with CHD (61.5 ± 11.8 years; 78.6 % men), 415 (12.02 %) had RI. During a median follow-up of 8.37 years, HF and AF were reported in 216 (6.25 %) and 174 (5.04 %) patients, respectively, and 297 (8.60 %) died. The K-M curves indicated that patients in the higher quartiles of sST2 concentrations were correlated with a poor survival rate of HF, AF, or death (all Ps < 0.001). Generalised additive model (GAM) demonstrated a nonlinear positive association between sST2 concentration and the risk of HF, AF, and death in CHD patients. The cut-off value of sST2 for predicting HF, AF and death were 32.1, 25.4 and 28.6 ng/mL, respectively. CHD patients with sST2 higher than the cut-off value had higher risks of HF (HR: 3.02, 95%CI: 2.24-4.05), AF (HR: 2.86; 95%CI: 2.10-3.90), and death (HR:2.11, 95%CI: 1.67-2.67). Furthermore, in patients with RI (12.02 %, n = 415), the prognostic value of sST2 over the cut-off value for HF and death remained unchanged (HR: 3.21 and 2.35; P < 0.05). In patients with CHD with or without RI, sST2 improved the area under the curve (AUC) of traditional risk models for predicting clinical endpoint events. Conclusions: The biomarker sST2 may be useful for predicting HF, AF, and death in patients with CHD. The predicted value was not affected by renal function.

Antiviral effectiveness and survival correlation of azvudine and nirmatrelvir/ritonavir in elderly severe patients with COVID-19: a retrospective real-world study.

Background: Azvudine and nirmatrelvir/ritonavir are approved to treat mild-to-moderate coronavirus disease 2019 (COVID-19) in adults with a high risk for progression to severe infection. We sought to compare the antiviral effectiveness and clinical outcomes of elderly severe patients with COVID-19 receiving these two antiviral agents. Methods: In this observational study, we identified 249 elderly patients with severe COVID-19 infection who were admitted to the Second Medical Center of the People's Liberation Army General Hospital from December 2022 to January 2023, including 128 azvudine recipients, 66 nirmatrelvir/ritonavir recipients and 55 patients not received antiviral treatments. We compared the cycle threshold (Ct) value dynamic change of all three groups. The primary outcome was a composite outcome of disease progression, including all-cause death, intensive care unit admission, and initiation of invasive mechanical ventilation. The outcomes of all enrolled patients were followed up from the electronic medical record system. Kaplan-Meier and Cox risk proportional regression analyses were used to compare the clinical outcomes of all three groups. To more directly compare the effectiveness of the two antiviral drugs, we performed propensity-score matching between the two antiviral groups and compared antiviral efficacy and clinical outcomes in the matched population. Findings: Among 249 patients (mean age, 91.41 years), 77 patients died during the follow-up period. When compared to patients who did not receive any antivirals, neither nirmatrelvir/ritonavir nor azvudine demonstrated a survival benefit. The Cox analysis of the all-cause death of the three groups showed that the risk of death was 0.730 (0.423-1.262) in the azvudine group 0.802 (0.435-1.480) and in the nirmatrelvir/ritonavir group compared with the non-antiviral group. After propensity score matching, we included 58 azvudine recipients and 58 nirmatrelvir/ritonavir recipients. The fitted curve of the Ct value after matching illustrated that the rate of viral decline in the early stage of nirmatrelvir/ritonavir treatment seems to surpass that of azvudine, but there was no statistical significance. Azvudine was seemly associated with a lower risk of composite outcomes (HR:1.676, 95% CI:0.805-3.488) and short-term all-cause death (HR: 1.291, 95%CI: 0.546-3.051). Interpretation: Patients who received azvudine have a similar antiviral effectiveness and survival curve trend compared to nirmatrelvir/ritonavir. In this limited series, antiviral treatment was not associated with a significant clinical benefit. This lack of clinical benefit might be attributed to potential bias. Funding: This study was supported by the "National Key R&D Program of China" (Funding No. 2020YFC2008900) and the National Defense Science and Technology Innovation Special Zone Project (223-CXCY-N101-07-18-01).

Prevalence, clinical predictors, and prognostic impact of chronic renal insufficiency in very old Chinese patients with coronary artery disease.

BACKGROUND AND AIMS: An aging population leads to the increased prevalence of coronary artery disease (CAD) and chronic renal insufficiency (CRI). Nevertheless, the prevalence, clinical predictors, and prognostic impact of CRI in very old Chinese patients with CAD are unclear. METHODS: Baseline characteristics were obtained from 1,050 old patients with CAD. The endpoint was all-cause mortality during the mean follow-up period of 417 days. RESULTS: The median age of the subjects was 86 years (range 60-104 years). CRI was present in 372 patients (35.4%). Age [hazard ratio (HR) 1.032, 95% confidence interval (95% CI) 1.010-1.054], chronic heart failure (CHF) (HR 2.361, 95% CI 1.747-3.191), hypertension (HR 1.878, 95% CI 1.291-2.731), hemoglobin (HR 0.973, 95% CI 0.965-0.981), serum albumin (HR 0.954, 95% CI 0.912-0.995), HDL-C (HR 0.371, 95% CI 0.238-0.580), and LDL-C levels (HR 0.795, 95% CI 0.656-0.965) were independent predictors of CRI (all P < 0.05). In addition, CRI was independently associated with mortality in patients with CAD (HR 1.366, 95% CI 1.024-1.822, P = 0.034). Age (HR 1.036, 95% CI 1.015-1.059), acute myocardial infarction (AMI; HR 1.795, 95% CI 1.239-2.602), CHF New York Heart Association class IV (HR 1.691, 95% CI 1.187-2.410), heart rate (HR 1.019, 95% CI 1.011-1.026), hemoglobin (HR 0.982, 95% CI 0.975-0.990), and serum albumin levels (HR 0.905, 95% CI 0.874-0.938) were also independently related to mortality in CAD patients (all P < 0.05). CONCLUSIONS: A high prevalence of CRI with a high associated mortality rate existed in very old Chinese patients with CAD. CRI was an independent risk factor of adverse prognosis for these patients, and multiple predictors could be used to identify CAD patients at increased risk for CRI or poor survival.

Artificial Intelligence-Assisted Left Ventricular Diastolic Function Assessment and Grading: Multiview Versus Single View.

BACKGROUND: Clinical assessment and grading of left ventricular diastolic function (LVDF) requires quantification of multiple echocardiographic parameters interpreted according to established guidelines, which depends on experienced clinicians and is time consuming. The aim of this study was to develop an artificial intelligence (AI)-assisted system to facilitate the clinical assessment of LVDF. METHODS: In total, 1,304 studies (33,404 images) were used to develop a view classification model to select six specific views required for LVDF assessment. A total of 2,238 studies (16,794 two-dimensional [2D] images and 2,198 Doppler images) to develop 2D and Doppler segmentation models, respectively, to quantify key metrics of diastolic function. We used 2,150 studies with definite LVDF labels determined by two experts to train single-view classification models by AI interpretation of strain metrics or video. The accuracy and efficiency of these models were tested in an external data set of 388 prospective studies. RESULTS: The view classification model identified views required for LVDF assessment with good sensitivity (>0.9), and view segmentation models successfully outlined key regions of these views with intersection over union > 0.8 in the internal validation data set. In the external test data set of 388 cases, AI quantification of 2D and Doppler images showed narrow limits of agreement compared with the two experts (e.g., left ventricular ejection fraction, -12.02% to 9.17%; E/e' ratio, -3.04 to 2.67). These metrics were used to detect LV diastolic dysfunction (DD) and grade DD with accuracy of 0.9 and 0.92, respectively. Concerning the single-view method, the overall accuracy of DD detection was 0.83 and 0.75 by strain-based and video-based models, and the accuracy of DD grading was 0.85 and 0.8, respectively. These models could achieve diagnosis and grading of LVDD in a few seconds, greatly saving time and labor. CONCLUSION: AI models successfully achieved LVDF assessment and grading that compared favorably with human experts reading according to guideline-based algorithms. Moreover, when Doppler variables were missing, AI models could provide assessment by interpreting 2D strain metrics or videos from a single view. These models have the potential to save labor and cost and to facilitate work flow of clinical LVDF assessment.

Joint association of hyperuricemia and chronic kidney disease with mortality in patients with chronic heart failure.

Background: The joint association of hyperuricemia and chronic kidney disease (CKD) with mortality in patients with chronic heart failure (CHF) is not conclusive. Methods: This retrospective cohort study was conducted in Chinese People's Liberation Army General Hospital, Beijing, China. We included 9,367 patients with CHF, who were hospitalized between January 2011 and June 2019. The definitions of hyperuricemia and CKD were based on laboratory test, medication use, and medical record. We categorized patients with CHF into 4 groups according to the absence (-) or presence (+) of hyperuricemia and CKD. The primary outcomes included in-hospital mortality and long-term mortality. We used multivariate logistic regression and Cox proportional hazards regression to estimate the mortality risk according to the hyperuricemia/CKD groups. Results: We identified 275 cases of in-hospital mortality and 2,883 cases of long-term mortality in a mean follow-up of 4.81 years. After adjusting for potential confounders, we found that compared with the hyperuricemia-/CKD- group, the risks of in-hospital mortality were higher in the hyperuricemia+/CKD- group (odds ratio [OR], 95% confidence interval [CI]: 1.58 [1.01-2.46]), hyperuricemia-/CKD+ group (OR, 95% CI: 1.67 [1.10-2.55]), and hyperuricemia+/CKD+ group (OR, 95% CI: 2.12 [1.46-3.08]). Similar results were also found in long-term mortality analysis. Compared with the hyperuricemia-/CKD- group, the adjusted hazard ratios and 95% CI for long-term mortality were 1.25 (1.11-1.41) for hyperuricemia+/CKD- group, 1.37 (1.22-1.53) for hyperuricemia-/CKD+ group, and 1.59 (1.43-1.76) for hyperuricemia+/CKD+ group. The results remained robust in the sensitivity analysis. Conclusions: Hyperuricemia and CKD, both individually and cumulatively, are associated with increased mortality risk in patients with CHF. These results highlighted the importance of the combined control of hyperuricemia and CKD in the management of heart failure.

A functional variant in the 3'-UTR of angiopoietin-1 might reduce stroke risk by interfering with the binding efficiency of microRNA 211.

Angiopoietin-1 is a vascular strengthening factor during vascular development and a protective factor for pathological vascular inflammation and leakage. Brain vascular leaking and inflammation are two important pathological processes of stroke; therefore, we hypothesized that variants of the microRNA-binding site in angiopoietin-1 would affect its expression and confer a risk of stroke. To test our hypothesis, a predicted microRNA-binding site was found in the 3'-UTR of angiopoietin-1 using bioinformatics; variant rs2507800 was identified to be located in the miR-211-binding site of angiopoietin-1. Secondly, the effects of the identified variant on angiopoietin-1 translation were assessed using a luciferase reporter assay and ELISA. We found that the A allele of rs2507800 suppressed angiopoietin-1 translation by facilitating miR-211 binding, but not the T allele. Subjects carrying the TT genotype had higher plasma angiopoietin-1 levels than those with the A allele. Finally, the association of the variant with stroke was tested in 438 stroke patients and 890 controls, and replicated in an independent population of 1791 stroke patients and 1843 controls. The TT genotype resulted in a significant reduction in overall stroke risk {OR, 0.51 [95% confidence interval (CI), 0.36-0.74], P = 0.0003}, ischemic stroke [OR, 0.56 (95% CI, 0.36-0.85), P = 0.007] and hemorrhagic stroke [OR, 0.46 (95% CI, 0.26-0.80), P = 0.007]. These results were confirmed in an independent study. Our results provide evidence that the TT genotype (rs2507800) in the 3'-UTR of angiopoietin-1 might reduce the risk of stroke by interfering with miR-211 binding.

A functional variant in promoter region of platelet-derived growth factor-D is probably associated with intracerebral hemorrhage.

BACKGROUND: Platelet-derived growth factor D (PDGF-D) plays an important role in angiogenesis, vessel remodeling, inflammation and repair in response to injury. We hypothesized that genetic variation in PDGFD gene might alter the susceptibility to stroke. FINDINGS: We determined the genotypes of a single nucleotide polymorphism (SNP) (-858A/C, rs3809021) in 1484 patients with stroke (654 cerebral thrombosis, 419 lacunar infarction, 411 intracerebral hemorrhage [ICH]) and 1528 control subjects from an unrelated Chinese Han population and followed the stroke patients up for a median of 4.5 years.The -858AA genotype showed significantly increased risk of ICH (dominant model: odds ratio [OR] 1.29, 95% confidence interval [CI] 1.00-1.68, P = 0.05; additive model: OR 1.24, 95% CI 1.01-1.52, P = 0.04) than wild-type genotype. Further analyses showed that -858AA genotype conferred about 2-fold increase in risk of non-hypertensive ICH (dominant model: OR 2.1, 95%CI 1.34-3.29, P = 0.001; additive model: OR 1.75, 95% CI 1.24-2.46, P = 0.001). After a median follow-up of 4.5 years, -858AA genotype was associated with a reduced risk of ICH recurrence (dominant model: adjusted hazard ratio [HR] 0.09, 95%CI 0.01-0.74, P = 0.025; additive model: HR 0.21, 95% CI 0.04-1.16, P = 0.073) in non-hypertensive patients. CONCLUSIONS: The -858AA genotype is probably associated with risk for non-hypertensive ICH. Further studies should be conducted to reveal the role of PDGF-D at various stages of ICH development--beneficial, or deleterious.

Association of cardiac and renal function with extreme N-terminal fragment pro-B-type natriuretic peptide levels in elderly patients.

BACKGROUND: The data are inconsistent regarding whether extreme N-terminal fragment pro-B-type natriuretic peptide (NT pro-BNP) levels are associated with impaired renal function. Furthermore, the relationship between extreme NT pro-BNP levels and cardiac and renal function in elderly patients has not been reported. The aim of the present study was to examine a hypothesis that extreme NT pro-BNP levels may be associated with impaired cardiac and renal function in elderly patients. METHODS: We retrospectively analyzed the data of demographic, clinical, and echocardiographic features on 152 consecutive elderly patients aged more than 80 years old (average age, 83.65 ± 3.58 years) with NT pro-BNP levels ≥ 3000 pg/ml. The participants were divided into two categories according to their NT pro-BNP levels: (1) 3000-10000 pg/mL and (2) >10000 pg /mL. RESULTS: The number of patients with impaired renal function (P = 0.019) and the mortality (P < 0.001) in the period of inpatient was higher in the group with NT pro-BNP > 10000 pg /mL. The levels of serum creatinine and creatine kinase MB (CK-MB) in the group of NT pro-BNP > 10000 pg / mL were higher than those in the group of NT pro-BNP = 3000-10000 pg/mL (P = 0.001 and P = 0.023, respectively). Furthermore, no significant difference in the distribution by NYHA class in different NT pro-BNP levels was observed. Multiple linear regression analyses demonstrated that with NT pro-BNP levels as the dependent variable, NT pro-BNP levels were positively correlated with CK-MB (ß = 0.182, P = 0.024) and creatinine levels (ß = 0.281, P = 0.001). The area under the receiver-operating characteristic (ROC) curve of NT pro-BNP levels and clinical diagnosis of impaired renal function was 0.596 and reached significant difference (95%CI:0.503-0.688, P = 0.044). CONCLUSION: These data suggest that the extreme elevation of NT pro-BNP levels (≥3000 pg/ml) is mainly determined by impaired renal function in elderly patients above 80 years. Extreme NT pro-BNP levels may be useful for assessing the severity of impaired renal function.

Efficacy and safety of a modified dosage regimen of nesiritide in patients older than 75 years with acute heart failure.

BACKGROUND AND AIMS: To explore efficacy and safety of a modified dosage regimen of nesiritide in patients (≥75 years) with acute heart failure (AHF). METHODS: Total 140 patients (≥75 years) with AHF were enrolled in this study. They were randomly and evenly divided into two group--control and nesiritide group. The control group received only conventional treatment for AHF, while the nesiritide group received conventional treatment plus a continual intravenous infusion of nesiritide at a rate of 0.0075-0.015 µg·kg(-1)·min(-1) for 10-15 hours (total 0.5- 1.0 mg) once daily for 13 days. RESULTS: Medical research council scales in nesiritide group were significantly lower than those in control group on day 4, 8 and 14. Scores of edema had no significant difference, but were lower in nesiritide group on day 8 and 14. The nesiritide group had markedly more net body fluid losses. NT-proBNP, serum creatinine, blood pressure, cTnI, 30-day and 60-day mortality had no significant difference between two groups. CONCLUSIONS: Nesiritide resulted in improvements in dyspnea and edema, and similar adverse effects compared with conventional treatment. In spite of no reduction on short-term mortality and a reversible influence on renal function, nesiritide was still an important choice for the elderly (≥75 years) with AHF.

MicroRNA miR-27a-3p accelerates cardiac hypertrophy by targeting neuro-oncological ventral antigen 1.

MiRNAs are a class of small non-coding RNAs (ncRNAs) responsible for post-transcriptional regulation of target genes. Accumulating evidence indicates that miRNAs are implicated in the progression of cardiac hypertrophy. Therefore, understanding the molecular mechanisms how these miRNAs regulate cardiac hypertrophy is useful for diagnosis and monitoring of disease progression. In this study, to investigate the effect of miR-27a-3p, we established an in vitro cardiac hypertrophy model by treating H9c2 cardiomyocytes with angiotensin II (Ang II) and an in vivo model through the chronic infusion of Ang II into mice. As revealed by our experimental results, miR-27a-3p expression was significantly increased in clinical samples, animal and cell models of cardiac hypertrophy. Inhibiting miR-27a-3p mitigated cardiac hypertrophy phenotype induced by Ang II. Additionally, our work identified NOVA1 (neuro-oncological ventral antigen 1) as a downstream target of miR-27a-3p. miR-27a-3p overexpression reduced NOVA1 protein level and mRNA expression. Consistently, NOVA1 silencing promoted cardiac hypertrophy phenotype induced by Ang II. In summary, these results suggest that the upregulation of miR-27a-3p may serve as a diagnostic factor for cardiac hypertrophy, and miR-27a-3p upregulation promotes cardiac hypertrophy by targeting NOVA1.

Revealing the Critical Regulators of Modulated Smooth Muscle Cells in Atherosclerosis in Mice.

Background: There are still residual risks for atherosclerosis (AS)-associated cardiovascular diseases to be resolved. Considering the vital role of phenotypic switching of smooth muscle cells (SMCs) in AS, especially in calcification, targeting SMC phenotypic modulation holds great promise for clinical implications. Methods: To perform an unbiased and systematic analysis of the molecular regulatory mechanism of phenotypic switching of SMCs during AS in mice, we searched and included several publicly available single-cell datasets from the GEO database, resulting in an inclusion of more than 80,000 cells. Algorithms implemented in the Seurat package were used for cell clustering and cell atlas depiction. The pySCENIC and SCENIC packages were used to identify master regulators of interested cell groups. Monocle2 was used to perform pseudotime analysis. clusterProfiler was used for Gene Ontology enrichment analysis. Results: After dimensionality reduction and clustering, reliable annotation was performed. Comparative analysis between cells from normal artery and AS lesions revealed that three clusters emerged as AS progression, designated as mSMC1, mSMC2, and mSMC3. Transcriptional and functional enrichment analysis established a continuous transitional mode of SMCs' transdifferentiation to mSMCs, which is further supported by pseudotime analysis. A total of 237 regulons were identified with varying activity scores across cell types. A potential core regulatory network was constructed for SMC and mSMC subtypes. In addition, module analysis revealed a coordinate regulatory mode of regulons for a specific cell type. Intriguingly, consistent with gain of ossification-related transcriptional and functional characteristics, a corresponding small set of regulators contributing to osteochondral reprogramming was identified in mSMC3, including Dlx5, Sox9, and Runx2. Conclusion: Gene regulatory network inference indicates a hierarchical organization of regulatory modules that work together in fine-tuning cellular states. The analysis here provides a valuable resource that can provide guidance for subsequent biological experiments.

Establishment of a diagnostic model of coronary heart disease in elderly patients with diabetes mellitus based on machine learning algorithms.

OBJECTIVE: To establish a prediction model of coronary heart disease (CHD) in elderly patients with diabetes mellitus (DM) based on machine learning (ML) algorithms. METHODS: Based on the Medical Big Data Research Centre of Chinese PLA General Hospital in Beijing, China, we identified a cohort of elderly inpatients (≥ 60 years), including 10,533 patients with DM complicated with CHD and 12,634 patients with DM without CHD, from January 2008 to December 2017. We collected demographic characteristics and clinical data. After selecting the important features, we established five ML models, including extreme gradient boosting (XGBoost), random forest (RF), decision tree (DT), adaptive boosting (Adaboost) and logistic regression (LR). We compared the receiver operating characteristic curves, area under the curve (AUC) and other relevant parameters of different models and determined the optimal classification model. The model was then applied to 7447 elderly patients with DM admitted from January 2018 to December 2019 to further validate the performance of the model. RESULTS: Fifteen features were selected and included in the ML model. The classification precision in the test set of the XGBoost, RF, DT, Adaboost and LR models was 0.778, 0.789, 0.753, 0.750 and 0.689, respectively; and the AUCs of the subjects were 0.851, 0.845, 0.823, 0.833 and 0.731, respectively. Applying the XGBoost model with optimal performance to a newly recruited dataset for validation, the diagnostic sensitivity, specificity, precision, and AUC were 0.792, 0.808, 0.748 and 0.880, respectively. CONCLUSIONS: The XGBoost model established in the present study had certain predictive value for elderly patients with DM complicated with CHD.