Additional Value of Early Repolarization Pattern in Prediction of Obstructive Coronary Artery Disease as Assessed by Coronary Angiography.

Recent reports show that an early repolarization pattern (ERP) is associated with a higher incidence of sudden cardiac death in patients with obstructive coronary artery disease (CAD). Sporadic case studies have pointed out that ERP might be related to obstructive CAD.In consecutive patients who had undergone coronary angiography, we investigated the relationship between ERP and obstructive CAD by evaluating its association with coronary artery stenosis.The study population consisted of 3785 patients (59.9% men; mean age 63.1 years) with or without obstructive CAD. Adjusting for major cardiovascular risk factors, ERP was significantly associated with obstructive CAD (adjusted odds ratio (OR): 2.24 [95% CI 1.70-2.95]) with an incremental predictive value (ROC AUC 0.76 versus 0.71, P = 0.02; NRI 55.3%, P < 0.001; IDI = 0.05, P = 0.008), specifically in subjects with low risk and intermediate risk. ERP also significantly improved the predictive value for multi-vessel disease (AUC: 0.77 versus 0.72, P = 0.02 for two-vessel disease; 0.79 versus 0.73, P = 0.04 for three-vessel disease). ERP was consistently associated with stenoses of 3 main coronary arteries.ERP is associated with significant increased risk for obstructive CAD.Further studies are warranted to confirm our results and to elucidate the specific pathogenic mechanisms.

Ginsenoside Rg1 promotes nonamyloidgenic cleavage of APP via estrogen receptor signaling to MAPK/ERK and PI3K/Akt.

BACKGROUND: The pathogenic accumulation of amyloid ß peptide (Aß), a natural occurring peptide processed from beta-amyloid precursor protein (APP), is considered to play a key role in the development of Alzheimer's disease (AD). Ginsenoside Rg1, an active component in ginseng, has been identified as a phytoestrogen and also found to be neuroprotective. However, it is unknown whether Rg1-induced estrogenic activity intervenes in APP processing, and improves memory performance. METHODS: Using HT22 cells and SH-SY5Y cells stably expressing the Swedish mutant APP (APPsw), this study investigated whether Rg1 intervened in APP metabolism through estrogenic activity. Using the ovariectomized (OVX) rats to mimic age-related changes in postmenopausal females, this study also tested the long-term effect of Rg1 on APP metabolism. RESULTS: The in vitro study demonstrated that Rg1 increased extracellular secretion of soluble amyloid precursor protein α (sAPPα), enhanced α-secretase activity and decreased extracellular release of Aß. These effects of Rg1 could be prevented by inhibitors of protein kinase C (PKC), Extracellular-Signal Regulated Kinase/Mitogen-Activated Protein Kinase (ERK/MAPK) and Phosphoinositide-3 kinase (PI3K)/Akt pathways. Inhibition of endogenous estrogen receptor (ER) activity abrogated Rg1-triggered release of sAPPα, increase of α-secretase activity, and activation of ERK and Akt signaling. In addition, Rg1 promoted phosphorylation of ERα at Ser118 residue. The in vivo study demonstrated that 8-week Rg1 treatment of OVX rats increased sAPPα levels and decreased Aß content in the hippocampi, and improved the spatial learning and memory. GENERAL SIGNIFICANCE: Rg1 might be used to slow or prevent AD, in particular in postmenopausal females.

Current and former smoking and risk for venous thromboembolism: a systematic review and meta-analysis.

BACKGROUND: Smoking is a well-established risk factor for atherosclerotic disease, but its role as an independent risk factor for venous thromboembolism (VTE) remains controversial. We conducted a meta-analysis to summarize all published prospective studies and case-control studies to update the risk for VTE in smokers and determine whether a dose-response relationship exists. METHODS AND FINDINGS: We performed a literature search using MEDLINE (source PubMed, January 1, 1966 to June 15, 2013) and EMBASE (January 1, 1980 to June 15, 2013) with no restrictions. Pooled effect estimates were obtained by using random-effects meta-analysis. Thirty-two observational studies involving 3,966,184 participants and 35,151 VTE events were identified. Compared with never smokers, the overall combined relative risks (RRs) for developing VTE were 1.17 (95% CI 1.09-1.25) for ever smokers, 1.23 (95% CI 1.14-1.33) for current smokers, and 1.10 (95% CI 1.03-1.17) for former smokers, respectively. The risk increased by 10.2% (95% CI 8.6%-11.8%) for every additional ten cigarettes per day smoked or by 6.1% (95% CI 3.8%-8.5%) for every additional ten pack-years. Analysis of 13 studies adjusted for body mass index (BMI) yielded a relatively higher RR (1.30; 95% CI 1.24-1.37) for current smokers. The population attributable fractions of VTE were 8.7% (95% CI 4.8%-12.3%) for ever smoking, 5.8% (95% CI 3.6%-8.2%) for current smoking, and 2.7% (95% CI 0.8%-4.5%) for former smoking. Smoking was associated with an absolute risk increase of 24.3 (95% CI 15.4-26.7) cases per 100,000 person-years. CONCLUSIONS: Cigarette smoking is associated with a slightly increased risk for VTE. BMI appears to be a confounding factor in the risk estimates. The relationship between VTE and smoking has clinical relevance with respect to individual screening, risk factor modification, and the primary and secondary prevention of VTE. Please see later in the article for the Editors' Summary.

The phosphatidyl inositol 3 kinase-glycogen synthase kinase 3ß pathway mediates bilobalide-induced reduction in amyloid ß-peptide.

Bilobalide (BB), a sesquiterpenoid extract of Ginkgo biloba leaves, has been demonstrated to have neuroprotective effects. The neuroprotective mechanisms were suggested to be associated with modulation of intracellular signaling cascades such as the phosphatidyl inositol 3-kinase (PI3K) pathway. Since some members of intracellular signalling pathways such as PI3K have been demonstrated to be involved in amyloid precursor protein (APP) processing, the present study investigated whether BB has an influence on the ß-secretase-mediated APP cleavage via PI3K-dependent pathway. Using HT22 cells and SAMP8 mice (a senescence-accelerated strain of mice), this study showed that BB treatment reduced generation of two ß-secretase cleavage products of APP, the amyloid ß-peptide (Aß) and soluble APPß (sAPPß), via PI3K-dependent pathway. Additionally, glycogen synthase kinase 3ß (GSK3ß) signaling might be involved in BB-induced Aß reduction as a downstream target of the activated PI3K pathway. BB showed no significant effects on ß-site APP cleaving enzyme 1 (BACE-1) or γ-secretase but inhibited the ß-secretase activity of another protease cathepsin B, suggesting that BB-induced Aß reduction was probably mediated through modulation of cathepsin B rather than BACE-1. Similarly, inhibition of GSK3ß did not affect BACE-1 activity but decreased cathepsin B activity, suggesting that the PI3K-GSK3ß pathway was probably involved in BB-induced Aß reduction. Increasing evidence suggests that decreasing Aß production in the brain via modulation of APP metabolism should be beneficial for the prevention and treatment of Alzheimer's disease (AD). BB may offer such an approach to combat AD.

Inhibition of ROS-activated ERK1/2 pathway contributes to the protection of H2S against chemical hypoxia-induced injury in H9c2 cells.

Hydrogen sulfide (H(2)S) has been shown to exert cardioprotective effects. However, the roles of extracellular signal-regulated protein kinases 1/2 (ERK1/2) in H(2)S-induced cardioprotection have not been completely elucidated. In this study, cobalt chloride (CoCl(2)), a chemical hypoxia mimetic agent, was applied to treat H9c2 cells to establish a chemical hypoxia-induced cardiomyocyte injury model. The results showed that pretreatment with NaHS (a donor of H(2)S) before exposure to CoCl(2) attenuated the decreased cell viability, the increased apoptosis rate, the loss of mitochondrial membrane potential (ΔΨm), and the intracellular accumulation of reactive oxygen species (ROS) in H9c2 cells. Exposure of H9c2 cells to CoCl(2) or hydrogen peroxide (H(2)O(2)) upregulated expression of phosphorylated (p) ERK1/2, which was reduced by pretreatment with NaHS or N-acetyl-L-cysteine, a ROS scavenger. More importantly, U0126, a selective inhibitor of ERK1/2, mimicked the above cytoprotection of H(2)S against CoCl(2)-induced injury in H9c2 cells. In conclusion, these results indicate that H(2)S protects H9c2 cells against chemical hypoxia-induced injury partially by inhibiting ROS-mediated activation of ERK1/2.

Hydrogen sulfide protects H9c2 cells against doxorubicin-induced cardiotoxicity through inhibition of endoplasmic reticulum stress.

The roles of hydrogen sulfide (H(2)S) and endoplasmic reticulum (ER) stress in doxorubicin (DOX)-induced cardiotoxicity are still unclear. This study aimed to dissect the hypothesis that H(2)S could protect H9c2 cells against DOX-induced cardiotoxicity by inhibiting ER stress. Our results showed that exposure of H9c2 cells to DOX significantly inhibited the expression and activity of cystathionine-γ-lyase (CSE), a synthetase of H(2)S, accompanied by the decreased cell viability and the increased reactive oxygen species (ROS) accumulation. In addition, exposure of cells to H(2)O(2) (an exogenous ROS) mimicked the inhibitory effect of DOX on the expression and activity of CSE. Pretreatment with N-acetyl-L: -cysteine (NAC) (a ROS scavenger) attenuated intracellular ROS accumulation, cytotoxicity, and the inhibition of expression and activity of CSE induced by DOX. Notably, the ER stress-related proteins, including glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP) were obviously upregulated in DOX-treated H9c2 cells. Pretreatment with sodium hydrosulfide (NaHS, a H(2)S donor) before DOX exposure markedly suppressed DOX-induced overexpressions of GRP78 and CHOP, cytotoxicity and oxidative stress. In conclusion, we have demonstrated that ROS-mediated inhibition of CSE is involved in DOX-induced cytotoxicity in H9c2 cells, and that exogenous H(2)S can confer protection against DOX-induced cardiotoxicity partly through inhibition of ER stress.

Efficacy and safety of xuezhikang once per day versus two times per day in patients with mild to moderate hypercholesterolaemia (APEX study): a protocol for a multicentre, prospective randomised controlled, open-label, non-inferiority study.

INTRODUCTION: Reduction in low-density lipoprotein cholesterol (LDL-C) improves clinical outcomes in patients with coronary artery disease. However, rates of lipid-lowering medication adherence are far from ideal. Reducing dosage frequency from multiple dosing to once-daily dosing may improve patients' medication adherence. Xuezhikang (XZK), an extract of Chinese red yeast rice, contains a family of naturally occurring statins and is traditionally prescribed as 600 mg two times per day. A comParative Efficacy study of XZK (APEX study) is designed to test the hypothesis that XZK prescribed 1200 mg once per day (OD group) is non-inferior to 600 mg two times per day (TD group) in patients with hypercholesterolaemia. METHODS AND ANALYSIS: The APEX study is a multicentre, prospective randomised controlled, open-label, non-inferiority study. We plan to recruit 316 patients aged ≥18 years with a diagnosis of mild to moderate hypercholesterolaemia for primary prevention. Patients will be randomised (1:1) to OD group and TD group. The OD group take XZK 1200 mg once per day after dinner while TD group take a traditional dose of 600 mg, two times per day after meals. Participants will have an 8-week medication period and be followed up at weeks 0, 4 and 8. The primary end point is the mean percentage change from baseline to week 8 in serum LDL-C. Secondary end points are safety and lipid-lowering effect on other lipoproteins and compliance. Data analyses will be on the intention-to-treat principle using non-inferiority analysis. ETHICS AND DISSEMINATION: The research had been approved by the Clinical Research and Laboratory Animal Ethics Committee of the First Affiliated Hospital, Sun Yat-sen University ((2017)286). The results will be reported through peer-reviewed journals, seminars and conference presentations. TRIAL REGISTRATION NUMBER: ChiCTR-IIR-17013660.

Long-term prognosis associated with early repolarisation pattern in Chinese population with atherosclerotic risk factors.

BACKGROUND: Recent evidence has linked early repolarisation pattern (ERP) to sudden cardiac death (SCD) in patients without structural heart disease. However, no studies have clarified the prognostic value of ERP in people at high risk for atherosclerotic heart disease. METHODS: We prospectively assessed the prognostic significance of ERP on ECGs in a community-based population of 18 231 subjects with atherosclerotic risk factors (49.3% men, mean age 64.0 years). Mean follow-up was 7.6 years. Cox models were used to estimate the hazard ratios (HRs) adjusted for possible confounding factors. RESULTS: Compared with those without ERP, subjects with ERP had a significantly increased risk of developing SCD (HR 1.91, 95% CI 1.30 to 2.82), death from coronary heart disease (CHD) (HR 1.80, 95% CI 1.45 to 2.22) and death from any cause (HR 1.35, 95% CI 1.22 to 1.50). ERP was not associated with an increased risk of non-sudden CHD death and non-CHD death. ERP with J wave pattern in inferior leads, high amplitude of J wave pattern, notching configuration and horizontal or descending ST segment indicated a higher risk for SCD. ERP was associated with an absolute risk increase of 52.3 additional SCDs per 100 000 person-years in the population at high risk for atherosclerotic heart disease. CONCLUSIONS: ERP is associated with a significantly increased risk for SCD, CHD death and death from any cause in people with atherosclerotic risk factors. The observed association between ERP and all-cause mortality appears to be driven by an association with CHD death, in particular SCD.

More favorable response to cardiac resynchronization therapy in women than in men.

BACKGROUND: Data on sex difference in response to cardiac resynchronization therapy (CRT) remain controversial. We conducted a meta-analysis to summarize all published studies to determine whether sex-based differences in response to CRT exist. METHODS AND RESULTS: We performed a literature search using MEDLINE (source PubMed; January 1966 to March 2014) and EMBASE (January 1980 to March 2014) with no restrictions. Pooled effect estimates were obtained by using random-effects meta-analysis. Seventy-two studies involving 33 434 patients were identified. Overall, female patients had better outcomes from CRT compared with male patients, with a significant 33% reduction in the risk of death from any cause (hazard ratio, 0.67; 95% confidence interval, 0.61-0.74; P<0.001), 20% reduction in death or hospitalization for heart failure (hazard ratio, 0.80; 95% confidence interval, 0.71-0.90; P<0.001), 41% reduction in cardiac death (hazard ratio, 0.59; 95% confidence interval, 0.42-0.84; P<0.001), and 41% reduction in ventricular arrhythmias or sudden cardiac death (hazard ratio, 0.59; 95% confidence interval, 0.49-0.70; P<0.001). These more favorable responses to CRT in women were consistently associated with greater echocardiographic evidence of reverse cardiac remodeling in women than in men. CONCLUSIONS: Women obtained greater reductions in the risk of death from any cause, cardiac cause, death or hospitalization for heart failure, and ventricular arrhythmias or sudden cardiac death with CRT therapy compared with men, with consistently greater echocardiographic evidence of reverse cardiac remodeling in women than in men. Further studies are needed to investigate the exact reasons for these results and determine whether indications for CRT in women should be different from men.

Activation of the p38 MAPK/NF-κB pathway contributes to doxorubicin-induced inflammation and cytotoxicity in H9c2 cardiac cells.

A number of studies have demonstrated that inflammation plays a role in doxorubicin (DOX)-induced cardiotoxicity. However, the molecular mechanism by which DOX induces cardiac inflammation has yet to be fully elucidated. The present study aimed to investigate the role of the p38 mitogen-activated protein kinase (MAPK)/nuclear factor-κB (NF-κB) pathway in DOX-induced inflammation and cytotoxicity. The results of our study demonstrated that the exposure of H9c2 cardiac cells to DOX reduced cell viability and stimulated an inflammatory response, as demonstrated by an increase in the levels of interleukin-1ß (IL-1ß) and IL-6, as well as tumor necrosis factor-α (TNF-α) production. Notably, DOX exposure induced the overexpression of phosphorylated p38 MAPK and phosphorylation of the NF-κB p65 subunit, which was markedly inhibited by SB203580, a specific inhibitor of p38 MAPK. The inhibition of NF-κB by pyrrolidine dithiocarbamate (PDTC), a selective inhibitor of NF-κB, significantly ameliorated DOX-induced inflammation, leading to a decrease in the levels of IL-1ß and IL-6, as well as TNF-α production in H9c2 cells. The pretreatment of H9c2 cells with either SB203580 or PDTC before exposure to DOX significantly attenuated DOX-induced cytotoxicity. In conclusion, our study provides novel data demonstrating that the p38 MAPK/NF-κB pathway is important in the induction of DOX-induced inflammation and cytotoxicity in H9c2 cardiac myocytes.