CircNSD1 promotes cardiac fibrosis through targeting the miR-429-3p/SULF1/Wnt/ß-catenin signaling pathway.

Cardiac fibrosis is a detrimental pathological process, which constitutes the key factor for adverse cardiac structural remodeling leading to heart failure and other critical conditions. Circular RNAs (circRNAs) have emerged as important regulators of various cardiovascular diseases. It is known that several circRNAs regulate gene expression and pathological processes by binding miRNAs. In this study we investigated whether a novel circRNA, named circNSD1, and miR-429-3p formed an axis that controls cardiac fibrosis. We established a mouse model of myocardial infarction (MI) for in vivo studies and a cellular model of cardiac fibrogenesis in primary cultured mouse cardiac fibroblasts treated with TGF-ß1. We showed that miR-429-3p was markedly downregulated in the cardiac fibrosis models. Through gain- and loss-of-function studies we confirmed miR-429-3p as a negative regulator of cardiac fibrosis. In searching for the upstream regulator of miR-429-3p, we identified circNSD1 that we subsequently demonstrated as an endogenous sponge of miR-429-3p. In MI mice, knockdown of circNSD1 alleviated cardiac fibrosis. Moreover, silence of human circNSD1 suppressed the proliferation and collagen production in human cardiac fibroblasts in vitro. We revealed that circNSD1 directly bound miR-429-3p, thereby upregulating SULF1 expression and activating the Wnt/ß-catenin pathway. Collectively, circNSD1 may be a novel target for the treatment of cardiac fibrosis and associated cardiac disease.

The impact of visit-to-visit heart rate variability on all-cause mortality in atrial fibrillation.

OBJECTIVE: We aimed to investigate the association between visit-to-visit heart rate variability (VVHRV) and all-cause mortality in patients diagnosed with atrial fibrillation (AF). Previous studies have shown a positive correlation between VVHRV and several adverse outcomes. However, the relationship between VVHRV and the prognosis of AF remains uncertain. METHODS: In our study, we aimed to examine the relationship between VVHRV and mortality rates among 3983 participants with AF, who were part of the AFFIRM study (Atrial Fibrillation Follow-Up Investigation of Rhythm Management). We used the standard deviation of heart rate (HRSD) to measure VVHRV and divided the patients into four groups based on quartiles of HRSD (1st, <5.69; 2nd, 5.69-8.00; 3rd, 8.01-11.01; and 4th, ≥11.02). Our primary endpoint was all-cause death, and we estimated the hazard ratios for mortality using the Cox proportional hazard regressions. RESULTS: Our analysis included 3983 participants from the AFFIRM study and followed for an average of 3.5 years. During this period, 621 participants died from all causes. In multiple-adjustment models, we found that the lowest and highest quartiles of HRSD independently predicted an increased risk of all-cause mortality compared to the other two quartiles, presenting a U-shaped relationship (1st vs 2nd, hazard ratio = 2.28, 95% CI = 1.63-3.20, p < .01; 1st vs. 3rd, hazard ratio = 2.23, 95% CI = 1.60-3.11, p < .01; 4th vs. 2nd, hazard ratio = 1.82, 95% CI = 1.26-2.61, p < .01; and 4th vs. 3rd, hazard ratio = 1.78, 95% CI = 1.25-2.52, p < .01). CONCLUSION: In patients with AF, we found that both lower VVHRV and higher VVHRV increased the risk of all-cause mortality, indicating a U-shaped curve relationship.

Simplified Rapid Hydration Prevents Contrast-Associated Acute Kidney Injury Among CKD Patients Undergoing Coronary Angiography.

BACKGROUND: Patients with chronic kidney disease (CKD) undergoing coronary angiography (CAG) are at high risk of contrast-associated acute kidney injury (CA-AKI) and mortality. Therefore, there is a clinical need to explore safe, convenient, and effective strategies for preventing CA-AKI. OBJECTIVES: This study sought to assess whether simplified rapid hydration is noninferior to standard hydration for CA-AKI prevention in patients with CKD. METHODS: This multicenter, open-label, randomized controlled study was conducted across 21 teaching hospitals and included 1,002 patients with CKD. Patients were randomized to either simplified hydration (SH) (SH group, with normal saline from 1 hour before to 4 hours after CAG at a rate of 3 mL/kg/h) or standard hydration (control group, with normal saline 12 hours before and 12 hours after CAG at a rate of 1 mL/kg/h). The primary endpoint of CA-AKI was a ≥25% or 0.5-mg/dL rise in serum creatinine from baseline within 48 to 72 hours. RESULTS: CA-AKI occurred in 29 of 466 (6.2%) patients in the SH group and in 38 of 455 (8.4%) patients in the control group (relative risk: 0.8; 95% CI: 0.5-1.2; P = 0.216). In addition, the risk of acute heart failure and 1-year major adverse cardiovascular events did not differ significantly between the groups. However, the median hydration duration was significantly shorter in the SH group than in the control group (6 vs 25 hours; P < 0.001). CONCLUSIONS: In CKD patients undergoing CAG, SH is noninferior to standard hydration in preventing CA-AKI with a shorter hydration duration.

7,8-Dihydroxyflavone alleviates cardiac fibrosis by restoring circadian signals via downregulating Bmal1/Akt pathway.

Brain-derived neurotrophic factor (BDNF)/tyrosine kinase receptor B (TrkB) pathway is a therapeutic target in cardiac diseases. A BDNF mimetic, 7,8-dihydroxyflavone (7,8-DHF), is emerging as a protective agent in cardiomyocytes; however, its potential role in cardiac fibroblasts (CFs) and fibrosis remains unknown. Thus, we aimed to explore the effects of 7,8-DHF on cardiac fibrosis and the possible mechanisms. Myocardial ischemia (MI) and transforming growth factor-ß1 (TGF-ß1) were used to establish models of cardiac fibrosis. Hematoxylin & eosin and Masson's trichrome stains were used for histological analysis and determination of collagen content in mouse myocardium. Cell viability kit, EdU (5-ethynyl-2'-deoxyuridine) assay and immunofluorescent stain were employed to examine the effects of 7,8-DHF on the proliferation and collagen production of CFs. The levels of collagen I, α-smooth muscle actin (α-SMA), TGF-ß1, Smad2/3, and Akt as well as circadian rhythm-related signals including brain and muscle Arnt-like protein 1 (Bmal1), period 2 (Per2), and cryptochrome 2 (Cry2) were analyzed. Treatment with 7,8-DHF markedly alleviated cardiac fibrosis in MI mice. It inhibited the activity of CFs accompanied by decreasing number of EdU-positive cells and downregulation of collagen I, α-SMA, TGF-ß1, and phosphorylation of Smad2/3. 7,8-DHF significantly restored the dysregulation of Bmal1, Per2, and Cry2, but inhibited the overactive Akt. Further, inhibition of Bmal1 by SR9009 effectively attenuated CFs proliferation and collagen production of CFs. In summary, these findings indicate that 7,8-DHF attenuates cardiac fibrosis and regulates circadian rhythmic signals, at least partly, by inhibiting Bmal1/Akt pathway, which may provide new insights into therapeutic cardiac remodeling.

Small-molecule 7,8-dihydroxyflavone counteracts compensated and decompensated cardiac hypertrophy via AMPK activation.

BACKGROUND: Pathological cardiac hypertrophy is a compensated response to various stimuli and is considered a key risk factor for heart failure. 7,8-Dihydroxyflavone (7,8-DHF) is a flavonoid derivative that acts as a small-molecule brain-derived neurotrophic factor mimetic. The present study aimed to explore the potential role of 7,8-DHF in cardiac hypertrophy. METHODS: Kunming mice and H9c2 cells were exposed to transverse aortic constriction or isoproterenol (ISO) with or without 7,8-DHF, respectively. F-actin staining was performed to calculate the cell area. Transcriptional levels of hypertrophic markers, including ANP, BNP, and ß-MHC, were detected. Echocardiography, hematoxylin-eosin staining, and transmission electron microscopy were used to examine the cardiac function, histology, and ultrastructure of ventricles. Protein levels of mitochondria-related factors, such as adenosine monophosphate-activated protein kinase (AMPK), and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), were detected. RESULTS: 7,8-DHF inhibited compensated and decompensated cardiac hypertrophy, diminished the cross-sectional area, and alleviated the mitochondrial disorders of cardiomyocytes. Meanwhile, 7,8-DHF reduced the cell size and repressed the mRNA levels of the hypertrophic markers of ISO-treated cardiomyocytes. In addition, 7,8-DHF activated AMPK and PGC-1α signals without affecting the protein levels of mitochondrial dynamics-related molecules. The effects of 7,8-DHF were eliminanted by Compound C, an AMPK inhibitor. CONCLUSIONS: These findings suggest that 7,8-DHF inhibited cardiac hypertrophy and mitochondrial dysfunction by activating AMPK signaling, providing a potential agent for the treatment of pathological cardiac hypertrophy.

Deep Phenotyping and Prediction of Long-term Cardiovascular Disease: Optimized by Machine Learning.

BACKGROUND: Prediction of cardiovascular disease (CVD) is important in clinical practice. Machine learning (ML) may offer an improved alternative to current CVD risk stratification in individual patients. We aim to identify important predictors and compare ML models with traditional models according to their prediction performance in a large long-term follow-up cohort. METHODS: The Atherosclerosis Risk in Communities (ARIC) study was designed to study the progression of subclinical disease to cardiovascular events over a 25-year follow-up period. All phenotypic variables at visit 1 were obtained. All-cause death, CVD, and coronary heart disease were the outcomes for analysis. The ML framework involved variable selection using the random survival forest (RSF) method, model building, and 5-fold cross-validation. Model performance was evaluated by discrimination using the Harrell concordance index (C-index), accuracy using the Brier score (BS), and interpretability using the number of variables in the model. RESULTS: Of the 14,842 participants in ARIC, the average age was 54.2 years, with 45.2% male and 26.2% Black participants. Thirty-eight unique variables were selected in the RSF top 20 importance ranking of all 6 outcomes. Aging, hypertension, glucose metabolism, renal function, coagulation, adiposity, and sodium retention dominated the predictions of all outcomes. The ML models outperformed the regression models and established risk scores with a higher C-index, lower BS, and varied interpretability. CONCLUSIONS: The ML framework is useful for identifying important predictors of CVD and for developing models with robust performance compared with existing risk models.

MicroRNA-98 ameliorates doxorubicin-induced cardiotoxicity via regulating caspase-8 dependent Fas/RIP3 pathway.

Cardiotoxicity is one of the primary limitations in the clinical use of the anticancer drug doxorubicin (DOX). However, the role of microRNAs (miRNAs) in DOX-induced cardiomyocyte death has not yet been covered. To investigate this, we observed a significant increase in miR-98 expression in neonatal rat ventricular myocytes after DOX treatment, and MTT, LIVE/Dead and Viability/Cytotoxicity staining showed that miR-98 mimic inhibited DOX-induced cell death. This was also confirmed by Flow cytometry and Annexin V-FITC/PI staining. Interestingly, the protein expression of caspase-8 was upregulated by miR-98 mimics during this process, whereas Fas and RIP3 were downregulated. In addition, the effect of miR-98 against the expression of Fas and RIP3 were restored by the specific caspase-8 inhibitor Z-IETD-FMK. Thus, we demonstrate that miR-98 protects cardiomyocytes from DOX-induced injury by regulating the caspase-8-dependent Fas/RIP3 pathway. Our findings enhance understanding of the therapeutic role of miRNAs in the treatment of DOX-induced cardiotoxicity.

The Emerging Role of BDNF/TrkB Signaling in Cardiovascular Diseases.

Brain-derived neurotrophic factor (BDNF) is one of the most abundantneurotrophins in the central nervous system. Numerous studies suggestthat BDNF has extensive roles by binding to its specific receptor, tropomyosin-related kinase receptor B (TrkB), and thereby triggering downstream signaling pathways. Recently, growing evidence highlightsthat the BDNF/TrkB pathway is expressed in the cardiovascular system andclosely associated with the development and outcome of cardiovascular diseases (CVD), including coronary artery disease, heart failure, cardiomyopathy, hypertension, and metabolic diseases. Furthermore, circulating BDNF has also been revealed as a new potential biomarker for both diagnosis and prognosis of CVD. In this review, we discuss the current evidence of the emerging role of BDNF/TrkBsignalingand address the challenges that remain in translating these discoveries to novel therapeutic strategies for CVD.

Comparison of intravascular ultrasound-guided with angiography-guided double kissing crush stenting for patients with complex coronary bifurcation lesions: Rationale and design of a prospective, randomized, and multicenter DKCRUSH VIII trial.

BACKGROUND: Double kissing (DK) crush approach for patients with coronary bifurcation lesions, particularly localized at distal left main or lesions with increased complexity, is associated with significant reduction in clinical events when compared with provisional stenting. Recently, randomized clinical trial has demonstrated the net clinical benefits by intravascular ultrasound (IVUS)-guided implantation of drug-eluting stent in all-comers. However, the improvement in clinical outcome after DK crush treatment guided by IVUS over angiography guidance for patients with complex bifurcation lesions have never been studied in a randomized fashion. TRIAL DESIGN: DKCRUSH VIII study is a prospective, multicenter, randomized controlled trial designed to assess superiority of IVUS-guided vs angiography-guided DK crush stenting in patients with complex bifurcation lesions according to DEFINITION criteria. A total of 556 patients with complex bifurcation lesions will be randomly (1:1 of ratio) assigned to IVUS-guided or angiography-guided DK crush stenting group. The primary end point is the rate of 12-month target vessel failure, including cardiac death, target vessel myocardial infarction, or clinically driven target vessel revascularization. The secondary end points consist of the individual component of primary end point, all-cause death, myocardial infarction, and in-stent restenosis. The safety end point is the incidence of definite or probable stent thrombosis. An angiographic follow-up will be performed for all patients at 13 months and clinical follow-up will be continued annually until 3 years after the index procedure. CONCLUSIONS: DKCRUSH VIII trial is the first study designed to evaluate the differences in efficacy and safety between IVUS-guided and angiography-guided DK crush stenting in patients with complex true bifurcation lesions. This study will also provide IVUS-derived criteria to define optimal DK crush stenting for bifurcation lesions at higher complexity.

Meta-Analysis of Atrial Fibrillation and Outcomes in Patients With Heart Failure and Preserved Ejection Fraction.

BACKGROUND: Atrial fibrillation (AF) is common in heart failure with preserved ejection fraction (HFpEF); However, the prognostic impact of AF on HFpEF patients has not been fully elucidated. METHODS: A literature search of the PubMed and EMBASE databases on literature published through April 2019 was undertaken. Combined hazard ratio (HR) estimates and 95% confidence intervals (CIs) were calculated using fixed-effects or random-effects models, depending on the heterogeneity. Subgroup analyses, sensitivity analysis and meta-regression analyses were also performed. RESULTS: Fourteen (14) eligible studies with 1,948,923 patients with HFpEF were included in the analysis. Atrial fibrillation was associated with an 11% increased risk of all-cause mortality in patients with HFpEF (HR 1.11, 95% CI 1.09-1.12). Sensitivity analysis confirmed the stability of the results. The stratification of studies by controlled or uncontrolled confounding factors affected the final estimate (confounder-controlled HR 1.21, 95% CI 1.12-1.30; confounder-uncontrolled HR 1.13, 95% CI 0.96-1.31). In addition, AF was an independent predictor of hospitalisation for heart failure (HR 1.32, 95% CI 1.15-1.52), cardiovascular death (HR 1.38, 95% CI 1.01-1.89) and stroke (HR 1.87, 95% CI 1.54-2.27). CONCLUSIONS: Atrial fibrillation was associated with worse clinical outcomes in patients with HFpEF. Further investigation is required to see whether AF is the primary offender in these patients or merely a bystander to worse diastolic function.

Exploring the causal pathway from body mass index to coronary heart disease: a network Mendelian randomization study.

BACKGROUND: We applied a network Mendelian randomization (MR) framework to determine the causal association between body mass index (BMI) and coronary heart disease (CHD) and explored whether glycated hemoglobin (HbA1c) and lipid parameters (total cholesterol, TC; low-density lipoprotein cholesterol, LDL; high-density lipoprotein cholesterol, HDL; triglycerides, TG) serve as causal mediators from BMI to CHD by integrating summary-level genome-wide association study data. METHODS: Network MR analysis, an approach using genetic variants as the instrumental variables for both the exposure and mediator to infer causality was performed. Summary statistics from the GIANT consortium were used (n = 152,893) for BMI, CARDIoGRAMplusC4D consortium data were used (n = 184,305) for CHD, Global Lipids Genetics Consortium data were used (n = 108,363) for TC, LDL, HDL and TG, and MAGIC consortia data were used (n = 108,363) for HbA1c. RESULTS: The inverse-variance-weighted-method estimate indicated that the odds ratio (95% confidence interval) for CHD was 1.562 (1.391-1.753) per 1 standard deviation (kg/m2) increase in BMI. Results were consistent in MR Egger method and weighted-median methods. MR estimate indicated that BMI was positively associated with HbA1c and TG, and negatively associated with HDL, but was not associated with TC or LDL. Moreover, HbA1c, TC, LDL, and TG were positively associated with CHD, yet there was no causal association between HDL and CHD. HbA1c was positively associated with TC, LDL, and HDL, but was not associated with TG. CONCLUSIONS: Higher BMI conferred an increased risk of CHD, which was partially mediated by HbA1c and lipid parameters. HbA1c and TG might be the main mediators in the link from BMI to CHD.

Aloe-emodin exerts cholesterol-lowering effects by inhibiting proprotein convertase subtilisin/kexin type 9 in hyperlipidemic rats.

Hyperlipidemia (HPL) characterized by metabolic disorder of lipids and cholesterol is one of the important risk factors for cardiovascular diseases. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a potent circulating regulator of LDL through its ability to induce degradation of the low-density lipoprotein cholesterol receptor (LDLR) in the lysosome of hepatocytes. Aloe-emodin (AE) is one of potentially bioactive components of Chinese traditional medicine Daming capsule. In this study we evaluated the HPL-lowering efficacy of AE in both in vivo and in vitro HPL models. High-fat diet-induced rats were treated with AE (100 mg/kg per day, ig) for 6 weeks. We found that AE administration significantly decreased the levels of total cholesterol (TC) and LDL in the serum and liver tissues. Moreover, AE administration ameliorated HPL-induced hepatic lipid aggregation. But AE administration did not significantly inhibit HMG-CoA reductase activity in the liver of HPL rats. A cellular model of HPL was established in human hepatoma (HepG2) cells treated with cholesterol (20 µg/mL) and 25-hydroxycholesterol (2 µg/mL), which exhibited markedly elevated cholesterol levels. The increased cholesterol levels could be reversed by subsequent treatment with AE (30 µM). In both the in vivo and in vitro HPL models, we revealed that AE selectively suppressed the sterol-regulatory element-binding protein-2 (SREBP-2) and hepatocyte nuclear factor (HNF)1α-mediated PCSK9 signaling, which in turn upregulated LDL receptor (LDLR) and promoted LDL uptake. This study demonstrates that AE reduces cholesterol content in HPL rats by inhibiting the hepatic PCSK9/LDLR pathway.

Meta-Analysis of the Impact of Pre-Procedural Serum Albumin on Mortality in Patients Undergoing Transcatheter Aortic Valve Replacement.

Pre-procedural serum albumin's impact on prognosis after transcatheter aortic valve replacement (TAVR) has been studied. Literature on the prognostic role of serum albumin in the survival of patients undergoing TAVR shows conflicting results. This meta-analysis was conducted to evaluate the impact of pre-procedural serum albumin on outcomes after TAVR. A comprehensive literature search of EMBASE, MEDLINE, and the Cochrane Library was undertaken through July 2019. The primary end points were 30-day and one-year all-cause mortality after TAVR. Risk ratios (HRs) and 95% confidence intervals (CIs) were calculated using the random-effect model. Ten eligible studies with 8,236 patients were analyzed. Of the 8,236 patients undergoing TAVR, with a mean age of 83 years, 48.8% were men and were categorized into two groups according to low and normal serum albumin (cut-off value: 3.5 or 4 g/dL). Overall, low albumin was significantly associated with an approximately two-fold increase in 30-day all-cause mortality (HR, 2.09; 95% CI, 1.53-2.86) and a 61% increase risk for one-year mortality (HR, 1.61; 95% CI, 1.31-1.98) in patients after TAVR. Sensitivity analyses showed the results to be robust. The association of low albumin level with an increase in one-year mortality risk was not modified by study design, albumin cut-off value, Society of Thoracic Surgeons Predicted Risk of Mortality (STS-PROM), and study quality. In conclusion, low albumin levels were associated with poor prognosis in patients after TAVR. Pre-procedural albumin can be used as a simple tool related to prognosis after TAVR.

The long non-coding RNA TUG1-miR-9a-5p axis contributes to ischemic injuries by promoting cardiomyocyte apoptosis via targeting KLF5.

Non-coding RNAs participate in many cardiac pathophysiological processes, including myocardial infarction (MI). Here we showed the interplay between long non-coding RNA taurine-upregulated gene 1 (lncR-TUG1), miR-9a-5p (miR-9) and Krüppel-like factor 5 (KLF5). LncR-TUG1 was upregulated in ischemic heart and in cultured cardiomyocytes exposed to H2O2. Knockdown of lncR-TUG1 markedly ameliorated impaired cardiac function of MI mice. Further study showed that lncR-TUG1 acted as a competitive endogenous RNA of miR-9, and silencing of lncR-TUG1 inhibited cardiomyocyte apoptosis by upregulating miR-9 expression. Furthermore, the miR-9 overexpression obviously prevented ischemia injury and significantly inhibited H2O2-induced cardiomyocyte apoptosis via inhibition of mitochondrial apoptotic pathway. KLF5, as a target gene of miR-9 by dual-luciferase reporter assay, was involved in the process of miR-9 in regulating cardiomyocyte apoptosis. Our data identified the KLF5 was downregulated by miR-9 overexpression and knockdown of KLF5 inhibited cardiomyocyte apoptosis induced by H2O2. MiR-9 exerts anti-cardiomyocyte apoptotic affects by targeting KLF5. Collectively, our data identify a novel function of lncR-TUG1/miR-9/KLF5 axis in regulating cardiomyocyte apoptosis that affects myocardial infarction progression.

Brain-derived neurotrophic factor mimetic, 7,8-dihydroxyflavone, protects against myocardial ischemia by rebalancing optic atrophy 1 processing.

Brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase B (TrkB) pathway is associated with ischemic heart diseases (IHD). 7,8-dihydroxyflavone (7,8-DHF), BDNF mimetic, is a potent agonist of TrkB. We aimed to investigate the effects and the underlying mechanisms of 7,8-DHF on cardiac ischemia. Myocardial ischemic mouse model was induced by ligation of left anterior descending coronary artery. 7,8-DHF (5 mg/kg) was administered intraperitoneally two days after ischemia for four weeks. Echocardiography, HE staining and transmission electron microscope were used to examine the function, histology and ultrastructure of the heart. H9c2 cells were treated with hydrogen peroxide (H2O2), 7,8-DHF or TrkB inhibitor ANA-12. The effects of 7,8-DHF on cell viability, mitochondrial membrane potential (MMP) and mitochondrial superoxide generation were examined. Furthermore, mitochondrial fission and protein expression of mitochondrial dynamics (Mfn2 [mitofusin 2], OPA1 [optic atrophy 1], Drp1 [dynamin-related protein 1] and Fis-1 [fission 1]) was detected by mitotracker green staining and western blot, respectively. 7,8-DHF attenuated cardiac dysfunction and cardiomyocyte abnormality of myocardial ischemic mice. Moreover, 7,8-DHF increased cell viability and reduced cell death accompanied by improving MMP, inhibiting mitochondrial superoxide and preventing excessive mitochondrial fission of H2O2-treated H9c2 cells. The cytoprotective effects of 7,8-DHF were antagonized by ANA-12. Mechanistically, 7,8-DHF repressed OMA1-dependent conversion of L-OPA1 into S-OPA1, which was abolished by Akt inhibitor. In conclusion, 7,8-DHF protects against cardiac ischemic injury by inhibiting the proteolytic cleavage of OPA1. These findings provide a novel pharmacological effect of 7,8-DHF on mitochondrial dynamics and a new potential target for IHD.

Phenomapping of subgroups in hypertensive patients using unsupervised data-driven cluster analysis: An exploratory study of the SPRINT trial.

BACKGROUND: Hypertensive patients are highly heterogeneous in cardiovascular prognosis and treatment responses. A better classification system with phenomapping of clinical features would be of greater value to identify patients at higher risk of developing cardiovascular outcomes and direct individual decision-making for antihypertensive treatment. METHODS: An unsupervised, data-driven cluster analysis was performed for all baseline variables related to cardiovascular outcomes and treatment responses in subjects from the Systolic Blood Pressure Intervention Trial (SPRINT), in order to identify distinct subgroups with maximal within-group similarities and between-group differences. Cox regression was used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs) for cardiovascular outcomes and compare the effect of intensive antihypertensive treatment in different clusters. RESULTS: Four replicable clusters of patients were identified: cluster 1 (index hypertensives); cluster 2 (chronic kidney disease hypertensives); cluster 3 (obese hypertensives) and cluster 4 (extra risky hypertensives). In terms of prognosis, individuals in cluster 4 had the highest risk of developing primary outcomes. In terms of treatment responses, intensive antihypertensive treatment was shown to be beneficial only in cluster 4 (HR 0.73, 95% CI 0.55-0.98) and cluster 1 (HR 0.54, 95% CI 0.37-0.79) and was associated with an increased risk of severe adverse effects in cluster 2 (HR 1.18, 95% CI 1.05-1.32). CONCLUSION: Using a data-driven approach, SPRINT subjects can be stratified into four phenotypically distinct subgroups with different profiles on cardiovascular prognoses and responses to intensive antihypertensive treatment. Of note, these results should be taken as hypothesis generating that warrant further validation in future prospective studies.

MicroRNA-155 Promotes Myocardial Infarction-Induced Apoptosis by Targeting RNA-Binding Protein QKI.

Acute myocardial infarction (AMI) is the leading cause of sudden death worldwide. MicroRNA-155 (miR-155) has been reported to target antiapoptotic genes in various diseases models, but the functional role of miR-155 in response to MI injury needs further investigations. This study investigated the role of miR-155 in myocardial ischemia injury. TUNEL and flow cytometry were performed to measure cell apoptosis. Western blot analysis was employed to detect protein expressions of Bcl-2, XIAP, Bax, and caspase-3. qRT-PCR was used to quantify miRNA levels. We showed that miR-155 was dynamically elevated in murine hearts subjected to MI and in neonatal rat ventricular cardiomyocyte (NRVM) injury induced by hydrogen peroxide (H2O2). In response to H2O2, the silencing of miR-155 using AMO-155 (antisense inhibitor oligodeoxyribonucleotides) significantly increased cell viability and reduced cell apoptosis. Moreover, AMO-155 reversed the H2O2-induced downregulation of Bcl-2 and XIAP and upregulation of Bax and cleaved-caspase-3. Further study revealed that AMO-155 resulted in a decrease of H2O2-induced JC-1-labelled monomeric cell number. In addition, AMO-155 markedly decreased infarct size, ameliorated impaired cardiac function, and significantly reduced apoptotic cell percentages in MI mice heart. The RNA-binding protein Quaking (QKI) was predicted as a target gene of miR-155 through bioinformatic analysis, and AMO-155 attenuated the downregulation of QKI in H2O2-treated cardiomyocytes and MI mice heart. Knockdown of QKI by siRNA abolished the antiapoptotic effects of AMO-155. Taken together, miR-155 is upregulated in the MI heart and NRVMs in response to H2O2 stress, and downregulating of miR-155 protects cardiomyocytes against apoptosis. Mechanistically, it is probably due to the repression of QKI signaling pathway.

Comparative outcomes of heart failure among existent classes of anti-diabetic agents: a network meta-analysis of 171,253 participants from 91 randomized controlled trials.

BACKGROUND: The cardiovascular (CV) safety in terms of heart failure among different classes of treatment remains largely unknown. We sought to assess the comparative effect of these agents on heart failure outcomes. METHODS: This study was registered in the International Prospective Register of Systematic Reviews (CRD 42016042063). MEDLINE, EMBASE, and the Cochrane Library Central Register of Controlled Trials were searched. For the primary outcomes reported previously, studies between Jan 1, 1980 and June 30, 2016 were screened, and subsequently updated till Jan 24, 2019. We performed network meta-analysis to obtain estimates for the outcomes of heart failure, in particular by rankograms for ranking of heart failure risk as well as by pairwise comparisons among all classes of anti-diabetic medications. RESULTS: A total of 91 trials were included, among which were 171,253 participants and 4163 reported cases of heart failure events. As for rankograms, the surface under the cumulative ranking curves (SUCRA) of sodium-glucose co-transporters 2 and thiazolidinediones were 93.4% and 4.3%, respectively, signifying the lowest and highest risk of heart failure, respectively. As for pairwise comparisons in the network, sodium-glucose co-transporters 2 were significantly superior to insulin (OR: 0.75, 95% CI 0.62-0.91), dipeptidyl peptidase 4 inhibitors (OR: 0.68, 95% CI 0.59-0.78), glucagon-like peptide-1 receptor agonists (OR: 0.65, 95% CI 0.54-0.78), and thiazolidinediones (OR: 0.46, 95% CI 0.27-0.77) in terms of heart failure risk. Furthermore, in an exploratory analysis among subjects with underlying heart failure or at risk of heart failure, the superiority of sodium-glucose co-transporters 2 was still significant. CONCLUSIONS: In terms of heart failure risk, sodium-glucose co-transporters 2 were the most favorable option among all classes of anti-diabetic medications.

Ablation of interleukin-17 alleviated cardiac interstitial fibrosis and improved cardiac function via inhibiting long non-coding RNA-AK081284 in diabetic mice.

Interleukin 17 (IL-17) plays an important role in the pathogenesis of cardiac interstitial fibrosis. In this study, we explored the role of interleukin-17 in the development of diabetic cardiomyopathy and the underlying mechanisms. The level of IL-17 increased in both the serum and cardiac tissue of diabetic mice. Knockout of IL-17 improved cardiac function of diabetic mice induced by streptozotocin (STZ), and significantly alleviated interstitial fibrosis as manifested by reduced collagen mRNA expression and collagen deposition evaluated by Masson's staining. High glucose treatment induced collagen production were abolished in cultured IL-17 knockout cardiac fibroblasts (CFs). The levels of long noncoding RNA-AK081284 were increased in the CFs treated with high glucose or IL-17. Knockout of IL-17 abrogated high glucose induced upregulation of AK081284. Overexpression of AK081284 in cultured CFs promoted the production of collagen and TGFß1. Both high glucose and IL-17 induced collagen and TGFß1 production were mitigated by the application of the siRNA for AK081284. In summary, deletion of IL-17 is able to mitigate myocardial fibrosis and improve cardiac function of diabetic mice. The IL-17/AK081284/TGFß1 signaling pathway mediates high glucose induced collagen production. This study indicates the therapeutic potential of IL-17 inhibition on diabetic cardiomyopathy disease associated with fibrosis.