Long-term tracking of fasting blood glucose variability and peripheral artery disease in people without diabetes.

INTRODUCTION: Long-term changes of fasting blood glucose (FBG) in relation to lower-extremity peripheral artery disease (lower-extremity PAD) in people without diabetes has barely been reported. Our study aimed to investigate the association between FBG variability and the incidence of lower-extremity PAD in people without diabetes. RESEARCH DESIGN AND METHODS: We included 7699 participants without prior lower-extremity PAD and diabetes from the Atherosclerosis Risk in Communities study in the final analysis. At least two measurements of FBG were required during follow-up. Variability of FBG was identified using SD, coefficient of variation (CV), variability independent of the mean (VIM) and average real variability. Lower-extremity PAD was defined as an ankle brachial index <0.9, or hospitalization with a lower-extremity PAD diagnosis. Cox regression model was used to calculate HR for incidence of lower-extremity PAD and FBG variability. RESULTS: During a median follow-up of 19.5 years, 504 (6.5 %) lower-extremity PAD events were observed, 54.4% (n=274) were male, and 17.5% (n=88) were African-American. FBG variability was positively associated with incident lower-extremity PAD, with a linear relationship. HRs for CV and VIM were 1.015 (95% CI: 1.001 to 1.03; p=0.023), and 1.032 (95% CI: 1.004 to 1.06; p=0.022) for lower-extremity PAD, respectively. Participants in the lowest quartile of CV were at lower lower-extremity PAD risk compared with the highest ones (HR: 1.499, 95% CI: 1.16 to 1.938; p=0.002). CONCLUSIONS: Higher FBG variability was independently associated with increased prevalence of lower-extremity PAD in people without diabetes. TRIAL REGISTRATION NUMBER: NCT00005131.

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.

[Corrigendum] Protective effect of angiotensin­(1­7) against hyperglycaemia­induced injury in H9c2 cardiomyoblast cells via the PI3K̸Akt signaling pathway.

Subsequently to the publication of this article, the authors have realized that an address affiliation associated with certain of the authors had been omitted. The authors' affiliation information should have appeared as follows (the omitted address affiliation is featured in bold): Yi­Ying Yang1,2*, Xiu­Ting Sun1,2*, Zheng­Xun Li1,2, Wei­Yan Chen3, Xiang Wang4, Mei­Ling Liang5, Hui Shi1,2, Zhi­Sheng Yang1,2 and Wu­Tao Zeng1,2 1Department of Cardiology, The First Affiliated Hospital, Sun Yat­Sen University; 2Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou, Guangdong 510080; 3Intensive Care Unit, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510260; 4Department of Cardiology, Laiwu City People's Hospital, Laiwu, Shandong 27110; 5Department of Cardiology, Sun Yat­Sen Cardiovascular Hospital, Shenzhen, Guangdong 518020, P.R. China *Contributed equally. The authors regret this error in the affiliations, and apologize for any inconvenience caused. [the original article was published in the International Journal of Molecular Medicine 41: 1283­1292, 2018; DOI: 10.3892/ijmm.2017.3322].

Protective effect of angiotensin-(1-7) against hyperglycaemia-induced injury in H9c2 cardiomyoblast cells via the PI3K̸Akt signaling pathway.

Angiotensin-(1-7) [Ang-(1-7)], a heptapeptide mainly generated from cleavage of AngⅠ and AngⅡ, possesses physiological and pharmacological properties, including anti­inflammatory and antidiabetic properties. Activation of the phosphoinositide 3-kinase and protein kinase B (PI3K̸Akt) signaling pathway has been confirmed to participate in cardioprotection against hyperglycaemia-induced injury. The aim of the present study was to test the hypothesis that Ang-(1-7) protects H9c2 cardiomyoblast cells against high glucose (HG)-induced injury by activating the PI3K̸Akt pathway. To examine this hypothesis, H9c2 cells were treated with 35 mmol/l (mM) glucose (HG) for 24 h to establish a HG-induced cardiomyocyte injury model. The cells were co-treated with 1 µmol/l (µM) Ang-(1-7) and 35 mM glucose. The findings of the present study demonstrated that exposure of H9c2 cells to HG for 24 h markedly induced injury, as evidenced by an increase in the percentage of apoptotic cells, generation of reactive oxygen species and level of inflammatory cytokines, as well as a decline in cell viability and mitochondrial luminosity. These injuries were significantly attenuated by co-treatment of the cells with Ang-(1-7) and HG. In addition, PI3K̸Akt phosphorylation was suppressed by HG treatment, but this effect was abolished when the H9c2 cells were co-treated with Ang-(1-7) and HG. Furthermore, the cardioprotection of Ang-(1-7) against HG-induced injury in H9c2 cardiomyoblasts was highly attenuated in the presence of either D-Ala7-Ang-(1-7) (A-779, an antagonist of the Mas receptor) or LY294002 (an inhibitor of PI3K̸Akt). In conclusion, the present study provided new evidence that Ang-(1-7) protects H9c2 cardiomyoblasts against HG-induced injury by activating the PI3K̸Akt signaling pathway.

Influence of genetic polymorphisms in cytochrome P450 oxidoreductase on the variability in stable warfarin maintenance dose in Han Chinese.

PURPOSE: The aim of this study was to investigate whether any of the single-nucleotide polymorphisms (SNPs) in the POR gene were significantly associated with CYP activity and expression, and could contribute to the total variability in stable warfarin maintenance doses in Han Chinese. METHODS: A total of 408 patients treated at the First Affiliated Hospital of Sun Yat-Sen University were eligible for the study and had attained a stable warfarin maintenance dose at the start of the investigation. Demographics, warfarin maintenance doses, and concomitant medications were documented. Genomic DNA was extracted from peripheral blood samples and genotyped for ten SNPs (CYP 2C9*2 and *3, CYP4F2 rs2108622, VKORC1 -1639C>T, and potential POR genes of rs10239977, rs3815455, rs41301394, rs56256515, rs1057868, and rs2286823) using the Sequenom MassARRAY genotyping system. RESULTS: A predictive model of warfarin maintenance dose was established and indicated that age, gender, body surface area, aspirin use, CYP2C9*3, CYP4F2 rs2108622, VKORC1 -1639C>T, and POR*37 831-35C>T accounted for 42.4 % of dose variance in patients undergoing anticoagulant treatment. The contribution of POR*37 831-35C>T to warfarin dose variation was only 3.9 %. CONCLUSIONS: For the first time, the SNP POR*37 831-35C>T was confirmed as a minor but statistically significant factor associated with interindividual variation in warfarin maintenance dose in Han Chinese. The POR*37 gene polymorphism should be considered in future algorithms for faster and more reliable achievement of stable warfarin maintenance doses.

Risk of thromboembolic events in atrial fibrillation with chronic kidney disease.

BACKGROUND AND PURPOSE: Chronic kidney disease may increase the risk for ischemic stroke or systemic embolism in patients with nonvalular atrial fibrillation (AF). We conducted a meta-analysis to summarize all published studies to investigate the link between chronic kidney disease and risk of thromboembolic events in AF. METHODS: We performed a literature search using MEDLINE (source PubMed, 1966 to July, 2014) and EMBASE (1980 to July 2014) with no restrictions. Pooled effect estimates were obtained by using random-effects meta-analysis. RESULTS: Eighteen studies involving 538 479 patients and 41 719 incident thromboembolic events were identified. From the pooled analysis, AF patients with estimated glomerular filtration rate <60 mL/min compared with those with estimated glomerular filtration rate ≥60 mL/min experienced a significantly increased risk for developing thromboembolic events (relative risk, 1.62 [95% confidence interval, 1.40-1.87; P<0.001]). The annual rate of thromboembolic events increased by 0.41% (95% confidence interval, 0.17%-0.65%) for a 10 mL/min decrease in renal function. Addition of renal impairment to CHADS2 slightly improved the stroke risk stratification. CONCLUSIONS: Impaired renal function is an independent predictor of stroke or systemic embolism in patients with nonvalvular AF. Consideration of renal function may improve stroke risk stratification in patients with AF.

Impairment of cardiac function and remodeling induced by myocardial infarction in rats are attenuated by the nonpeptide angiotensin-(1-7) analog AVE 0991.

AIMS: We evaluated effects of the nonpeptide angiotensin (ANG)-(1-7) analog AVE 0991 (AVE) on cardiac function and remodeling as well as transforming growth factor-beta1 (TGF-ß1)/tumor necrosis factor-alpha (TNF-α) expression in myocardial infarction rat models. METHODS AND RESULTS: Sprague-Dawley rats underwent either sham surgery or coronary ligation. They were divided into four groups: sham, control, AVE, and AVE+A-779 [[D-Ala(7) ]-ANG-(1-7), a selective antagonist for the ANG-(1-7)] group. After 4 weeks of treatment, the AVE group displayed a significant elevation in left ventricular fractional shorting (LVFS) (25.5 ± 7.3% vs. 18.4 ± 3.3%, P < 0.05) and left ventricular ejection fraction (LVEF) (44.8 ± 7.6% vs. 32.7 ± 6.5%, P < 0.05) when compared to the control group, but no effects on the left ventricular end-diastolic and end-systolic diameters (LVDd and LVDs, respectively) were observed. In addition, we found that the myocyte diameter (18 ± 2 µm vs. 22 ± 4 µm, P < 0.05), infarct size (42.6 ± 3.6% vs. 50.9 ± 4.4%, P < 0.001) and collagen volume fraction (CVF) (16.4 ± 2.2% vs. 25.3 ± 3.2%, P < 0.001) were significantly reduced in the AVE group when compared to the control group. There were no differences in LVFS, LVEF, myocyte diameter, and infarct size between the control and AVE+A-779 groups. AVE also markedly attenuated the increased mRNA expression of collagen I (P < 0.001) and collagen III (P < 0.001) and inhibited the overexpression of TGF-ß1 (P < 0.05) and TNF-α (P < 0.05) compared to the control group. CONCLUSION: AVE could improve cardiac function and attenuate ventricular remodeling in MI rat models. It may involve the inhibition of inflammatory factors TGF-ß1/TNF-α overexpression and the action on the specific receptor Mas of ANG-(1-7).