AbstractBackgroundHypertension is a kind of clinical syndrome, characterized by the increase of systemic arterial pressure. There is a lack of identifiable triggers and predictors of hypertensive disease in response to treatment at rest and during exercise. In this study, a mathematical model was used to screen and compare the indicators and related changes at rest and during exercise between normotensive and hypertensive individuals.MethodsBlood pressure and ultrasound-related indicators, blood biochemical indicators and metabolic compounds were collected and logistic regression model and Principal component analysis (PCA) were used to explore the differences of indexes at rest and in different exercise states in healthy and hypertensive patients. An indicator change map for hypertension is established.ResultsThe results reveal that hypertension is not only related to oxidative stress, inflammatory reaction and fatty acid oxidation, but also involves various amino acid metabolism. The defined mathematical models and indicators changes during exercise might be helpful for early screening of hypertension and future studies are needed to explore their value on prevention and control of hypertension.ConclusionThe research shows that the main regulation indicators at different exercise states differ significantly in the normal group and the hypertensive group. The key indicators of the normal group are blood pressure and ultrasound related indicators, while those of the hypertensive group are metabolites related to lactic acid metabolism, glycolysis, aerobic oxidation and lipid metabolism.

心脏类器官可在体外精确模拟机体的病理生理改变,弥补细胞模型与动物实验无法准确模拟机体代谢的不足,在疾病机制探索与药物开发方面有广泛的应用优势与前景.该文主要介绍心脏类器官的构建方法和应用及其优势和面临的挑战,为心脏类器官在生物医学和疾病治疗领域的研究提供新的思路.

ObjectiveTo observe the effect of renal artery denervation (RDN) on cardiac function in patients with acute myocardial infarction after percutaneous coronary intervention (AMI-PCI).MethodsThis is a single-centre, prospective randomized controlled study. A total of 108 AMI-PCI patients were randomly assigned to the RDN group or the control group at 1:1 ratio. All patients received standardized drug therapy after PCI, and patients in the RDN group underwent additional RDN at 4 weeks after the PCI. The follow-up period was 6 months after RDN. Echocardiography-derived parameters, cardiopulmonary exercise testing (CPET) data, Holter electrocardiogram, heart rate variability (HRV) at baseline and at the 6 months-follow up were analyzed.ResultsBaseline indexes were similar between the two groups (all P > 0.05). After 6 months of follow-up, the echocardiography-derived left ventricular ejection fraction was significantly higher in the RDN group than those in the control group. Cardiopulmonary exercise test indicators VO2Max, metabolic equivalents were significantly higher in the RDN group than in the control group. HRV analysis showed that standard deviation of the normal-to-normal R–R intervals, levels of square root of the mean squared difference of successive RR intervals were significantly higher in the RDN group than those in the control group.ConclusionsRDN intervention after PCI in AMI patients is associated with improved cardiac function, improved exercise tolerance in AMI patients post PCI. The underlying mechanism of RDN induced beneficial effects may be related to the inhibition of sympathetic nerve activity and restoration of the sympathetic-vagal balance in these patients.

Objective: The purpose of this study was to explore the effects of renal denervation (RDN) on cardiac function and malignant arrhythmia in patients with reduced left ventricular ejection fraction (HFrEF) and narrow QRS treated with an implantable cardioverter defibrillator (ICD). Methods: A total of 20 eligible HFrEF patients [left ventricular ejection fraction (LVEF) <40%] and narrow QRS complexes (QRS duration <120 ms) were randomized into either the ICD plus RDN group or the ICD only group during 17 April 2014 to 22 November 2016. Clinical data, including clinical characteristics, blood biochemistry, B-type natriuretic peptide, echocardiographic indexes, 6-min walk distance (6MWD), New York Heart Association (NYHA) classification, and count of ICD discharge events before and after the operation were analyzed. Patients were followed up for up to 3 years post ICD or ICD plus RDN. Results: Baseline clinical data were comparable between the two groups. Higher LVEF (%) (mixed model repeated measure, p = 0.0306) (39.50% ± 9.63% vs. 31.20% ± 4.52% at 1 year; 41.57% ± 9.62% vs. 31.40% ± 8.14% at 3 years), systolic blood pressure (p = 0.0356), and longer 6MWD (p < 0.0001) as well as reduction of NYHA classification (p < 0.0001) were evidenced in the ICD plus RDN group compared to ICD only group during follow-up. Patients in the ICD plus RDN group experienced fewer ICD discharge events (2 vs. 40) and decreased diuretic use; rehospitalization rate (30% vs. 100%, p = 0.0031) and cardiogenic mortality rate (0% vs. 50%, p = 0.0325) were also significantly lower in the ICD plus RDN group than in the ICD only group during follow-up. Conclusion: ICD implantation plus RDN could significantly improve cardiac function and cardiac outcome as well as increase exercise capacity compared to ICD only for HFrEF patients with narrow QRS complexes.

The combination of Salvia miltiorrhiza (Danshen) and rivaroxaban is a promising treatment option in clinical practice in China, but the herb–drug interaction between Danshen and rivaroxaban remains unclear. Therefore, this study aims to reveal the interaction between Danshen and rivaroxaban. We not only investigated the inhibitory properties of Danshen tablet on rivaroxaban metabolism in rat and human liver microsomes but also evaluated the inhibitory effects of Danshen tablet and its eight active components (dihydrotanshinone I, tanshinone I, tanshinone IIA, cryptotanshinone, danshensu, salvianolic acid A, salvianolic acid B, and salvianolic acid C) on cytochrome P450 (CYP) enzymes. The results showed that Danshen tablet potently inhibited the metabolism of rivaroxaban in rat and human liver microsomes. In the CYP inhibition study, we found that dihydrotanshinone I, the active component of Danshen tablet, potently inhibited the activities of rat CYP3A and CYP2J, with IC50 values at 13.85 and 6.39 μM, respectively. In further inhibition kinetic study, we found that Danshen tablet is a mixed inhibitor in rivaroxaban metabolism in rat and human liver microsomes, with the Ki value at 0.72 and 0.25 mg/ml, respectively. In conclusion, there is a potential interaction between Danshen tablet and rivaroxaban. Danshen tablet inhibits the metabolism of rivaroxaban, which may be because its lipid-soluble components such as dihydrotanshinone I strongly inhibit the activities of CYP enzymes, especially CYP3A and CYP2J. Therefore, when Danshen tablet and rivaroxaban are used simultaneously in the clinic, it is necessary to strengthen the drug monitoring of rivaroxaban and adjust the dosage.

Dear Editor, Hypertension affects one billion people in the world.1 Half of the Chinese population aged from 35 to 75 years is also affected with hypertension.2 Genetic factors contribute to hypertension. Different ethnic populations share some common genetic factors; however, populationspecific genetic factors also play important roles in common complex diseases in different ethnic populations. Most genome wide association study (GWAS) for blood pressure have been reported in European ancestry populations; thus, much more GWAS are needed for hypertension in non-European ancestry populations, including the Chinese population. We designed a three-phase GWAS as reported previously3 to identify novel genomic variants conferring risk to hypertension in the Chinese Han population. The overall study design is shown in Figure 1A. Genotyping, imputation, and principal component analyses were conducted in phase 1 GWAS samples with 353 cases with hypertension and 332 controls without hypertension (Figure S1). After quality control, 3,956,088 single nucleotide polymorphisms (SNPs) were analyzed for their association with hypertension with adjustment of age, age2, gender, and the first three principal components (Figure S2). A total of 17,435 SNPs showing p value of <5.0 × 10–3 were selected for the phase 2 in silico replication study using GWAS summary data from the NHAPC cohort (1592 cases and 1302 controls).4 One hundred thirty-six SNPs clustering into 15 independent loci (Table S2) showed nominal association with hypertension (p < 5 × 10–3). Sixteen leading SNPs representing 15 loci were selected for replication in the phase 3 population containing 3274 cases and 2734 controls. Fourteen SNPs at 13 loci were genotyped successfully (two of 16 SNPs failed in genotyping). Two SNPs, including rs10847208 in the last exon of a long noncoding RNA (lncRNA) gene LINC00944 on 12q24.32 and rs2064453 in the promoter of GGT7

The thymic stromal lymphopoietin (TSLP)/TSLP receptor (TSLPR) axis is involved in multiple inflammatory immune diseases, including coronary artery disease (CAD). To explore the causal relationship between this axis and CAD, we performed a three-stage case-control association analysis with 3,628 CAD cases and 3,776 controls using common variants in the genes TSLP, interleukin 7 receptor (IL7R), and TSLPR. Three common variants in the TSLP/TSLPR axis were significantly associated with CAD in a Chinese Han population [rs3806933T in TSLP, Padj = 4.35 × 10-5, odds ratio (OR) = 1.18; rs6897932T in IL7R, Padj = 1.13 × 10-7, OR = 1.31; g.19646A>GA in TSLPR, Padj = 2.04 × 10-6, OR = 1.20]. Reporter gene analysis demonstrated that rs3806933 and rs6897932 could influence TSLP and IL7R expression, respectively. Furthermore, the "T" allele of rs3806933 might increase plasma TSLP levels (R2 = 0.175, P < 0.01). In a stepwise procedure, the risk for CAD increased by nearly fivefold compared with the maximum effect of any single variant (Padj = 6.99 × 10-4, OR = 4.85). In addition, the epistatic interaction between TSLP and IL33 produced a nearly threefold increase in the risk of CAD in the combined model of rs3806933TT-rs7025417TT (Padj = 3.67 × 10-4, OR = 2.98). Our study illustrates that the TSLP/TSLPR axis might be involved in the pathogenesis of CAD through upregulation of mRNA or protein expression of the referenced genes and might have additive effects on the CAD risk when combined with IL-33 signaling.

Previous genetic studies suggested that variants in NINJ2 (encode ninjurin2) confer risk to ischemic stroke or large artery atherosclerotic stroke. However, the underlying mechanisms of NINJ2 in ischemic stroke or atherosclerosis are still unknown. In this study, we hypothesized that NINJ2 may play a role in endothelial inflammation and activation, and regulate the process of atherosclerosis. Here, we demonstrated that NINJ2 can regulate the expression of a panel of genes that are associated with inflammation and atherosclerosis (e.g. IL-1β, TNF-α, IL-8, IL-6, ICAM-1 and E-selectin) in human vascular endothelial cells (HUVECs). Moreover, we found the expression of ninjurin2 is upregulated in LPS stimulated HUVECs and mouse aorta, and it can regulate LPS-induced endothelial activation and the adhesion of monocytes to endothelial cells. We also found that NINJ2 can regulate NF-κB and c-jun through interacting with TLR4. In conclusion, our study suggests that ninjurin2 is a novel regulator of endothelia inflammation and activation through TLR4 signaling pathways, and these data provided new insights into the mechanisms between NINJ2 and atherosclerosis.

The interleukin 1 family plays an important role in the immune and inflammatory responses. Coronary artery disease (CAD) is a chronic inflammatory disease. However, the genetic association between IL-37, the seventh member of the IL-1 family, and CAD is unknown. Here we show that a single nucleotide polymorphism in the IL-37 gene (rs3811047) confers a significant risk of CAD. We have performed an association analysis between rs3811047 and CAD in two independent populations with 2,501 patients and 3,116 controls from China. Quantitative RT-PCR analysis has been performed to determine if the IL-37 expression level is influenced by rs3811047. We show that the minor allele A of rs3811047 is significantly associated with CAD in two independent populations under a recessive model (Padj = 5.51 × 10−3/OR = 1.56 in the GeneID Northernern population and Padj = 1.23 × 10−3/OR = 1.45 in the GeneID Central population). The association became more significant in the combined population (Padj = 9.70 × 10−6/OR = 1.47). Moreover, the association remains significant in a CAD case control population matched for age and sex. Allele A of rs3811047 shows significant association with a decreased mRNA expression level of IL-37 (n = 168, P = 3.78 × 10−4). These data suggest that IL37 is a new susceptibility gene for CAD, which provides a potential target for the prevention and treatment of CAD.

The tissue factor pathway inhibitor ( TFPI ) gene encodes a protease inhibitor with a critical role in regulation of blood coagulation. Some genomic variants in TFPI were previously associated with plasma TFPI levels, however, it remains to be further determined whether TFPI variants are associated with other coagulation factors. In this study, we carried out a large population-based study with 2313 study subjects for blood coagulation data, including fibrinogen levels, prothrombin time (PT), activated partial thromboplastin time (APTT), and thrombin time (TT). We identified significant association of TFPI variant rs10931292 (a functional promoter variant with reduced transactivation) with increased plasma fibrinogen levels ( P = 0.017 under a recessive model), but not with PT, APTT or TT ( P > 0.05). Using a large case–control association study population with 4479 CAD patients and 3628 controls, we identified significant association between rs10931292 and CAD under a recessive model (OR 1.23, P = 0.005). For the first time, we show that a TFPI variant is significantly associated with fibrinogen levels and risk of CAD. Our finding contributes significantly to the elucidation of the genetic basis and biological pathways responsible for fibrinogen levels and development of CAD.

BACKGROUND:The CAV1 gene encodes caveolin-1 expressed in cell types relevant to atherosclerosis. Cav-1-null mice showed a protective effect on atherosclerosis under the ApoE(-/-) background. However, it is unknown whether CAV1 is linked to CAD and MI in humans. In this study we analyzed a tagSNP for CAV1 in intron 2, rs3807989, for potential association with CAD. METHODS AND RESULTS:We performed case-control association studies in three independent Chinese Han populations from GeneID, including 1249 CAD cases and 841 controls in Population I, 1260 cases and 833 controls in Population II and 790 cases and 1212 controls in Population III (a total of 3299 cases and 2886 controls). We identified significant association between rs3807989 and CAD in three independent populations and in the combined population (Padj = 2.18 × 10(-5), OR = 1.19 for minor allele A). We also detected significant association between rs3807989 and MI (Padj = 5.43 × 10(-5), OR = 1.23 for allele A). Allele A of SNP rs3807989 was also associated with a decreased level of LDL cholesterol. Although rs3807989 is a tagSNP for both CAV1 and nearby CAV2, allele A of SNP rs3807989 was associated with an increased expression level of CAV1 (both mRNA and protein), but not CAV2. CONCLUSIONS:The data in this study demonstrated that rs3807989 at the CAV1/CAV2 locus was associated with significant risk of CAD and MI by increasing expression of CAV1 (but not CAV2). Thus, CAV1 becomes a strong candidate susceptibility gene for CAD/MI in humans.