Publications by authors named "Xiao-Dong Zhuang"

34 Publications

Klotho deficiency causes cardiac ageing by impairing autophagic and activating apoptotic activity.

Eur J Pharmacol 2021 Oct 9;911:174559. Epub 2021 Oct 9.

Cardiology Department, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan 2nd Road, Guangzhou, Guangdong, PR China. Electronic address:

Objective: In this study, it was hypothesized that klotho deficiency plays an essential role in cardiac ageing in vivo and demonstrated that supplementation with exogenous klotho protects against cardiomyocyte ageing in vitro.

Methods: We measured the lifespan of wild-type (WT) and klotho-hypomorphic mutant (KL-/-) mice and recorded the cardiac function of the mice through echocardiography. We used immunofluorescence staining to detect the LC3B (microtubule-associated protein light chain 3 B), Beclin 1, Bax and Bcl 2 proteins. In vitro, H9c2 cells were incubated with different levels of D-galactose (D-gal) with or without klotho. SA-β-galactosidase staining and western blotting were performed to detect ageing-associated proteins (P53, P21 and P16), autophagy-associated proteins (LC3 II/LC3 I and Beclin 1) and apoptosis-associated proteins (Bax and Bcl 2). Moreover, one-step TUNEL apoptosis, CCK-8, cell morphology, Hoechst 33258 staining, lactate dehydrogenase (LDH) release, and caspase-3 activity assays were performed, and intracellular reactive oxygen species (ROS) levels were measured.

Results: Genetic klotho deficiency decreased lifespan and cardiac function in mice, impaired autophagic activity and increased apoptotic activity. Exogenous klotho attenuated cardiomyocyte ageing and reversed changes in autophagic and apoptotic activity caused by D-gal. Moreover, klotho supplementation prevented D-gal-induced oxidative stress and cytotoxicity.

Conclusions: Klotho might have a protective effect on cardiac ageing via autophagy activation and apoptosis inhibition.
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http://dx.doi.org/10.1016/j.ejphar.2021.174559DOI Listing
October 2021

NLRP3 inflammasome activation contributes to the pathogenesis of cardiocytes aging.

Aging (Albany NY) 2021 08 25;13(16):20534-20551. Epub 2021 Aug 25.

Cardiology Department, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, P.R. China.

Objective: The NOD-like receptor protein 3 (NOD-like receptor protein 3, NLRP3) inflammasome is associated with many physiological processes related to aging. We investigated whether NLRP3 inflammasome activation contributes to the pathogenesis of cardiocytes aging dissected the underlying mechanism.

Methods: H9c2 cells were treated with different concentrations of D-galactose (D-gal, 0, 2, 10 and 50 g/L) for 24 hours. The cytochemical staining, flow cytometry and fluorescence microscope analysis were employed to detect the β-galactosidase (β-gal) activity. Western blot analysis was used to detect the age-associated proteins (P53, P21) and NLRP3 inflammasome proteins [NLRP3, apoptosis-associated speck-like protein (ASC)]. Confocal fluorescent images were applied to capture the colocalization of NLRP3 and caspase-1. Intracellular reactive oxygen species (ROS) was measured using 2'7'-dichlorodihydrofluorescein diacetate (DCFH-DA) by flow cytometry and visualized using a fluorescence microscope. The IL-1β, IL-18 and lactate dehydrogenase (LDH) release were also detected.

Results: D-gal induced-H9c2 cells caused cardiocytes' aging changes (β-gal staining, CellEvent™ Senescence Green staining, P53, P21) in a concentration-dependent manner. NLRP3 inflammasomes were activated, IL-1β, IL-18 and LDH release and ROS generation were increased in the cardiocytes aging progress. When MCC950 inhibited NLRP3 inflammasomes, it attenuated the cardiocytes aging, yet the ROS generation was similar. Inhibition of ROS by NAC attenuated cardiocytes aging and inhibited the NLRP3 inflammasome activation at the same time. NLRP3 inflammasome activation by nigericin-induced cardiocytes cells aging progress.

Conclusions: NLRP3 inflammasome activation contributes to the pathogenesis of cardiocytes aging, and ROS generation may serve as a potential mechanism by which NLRP3 inflammasome is activated.
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http://dx.doi.org/10.18632/aging.203435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8436929PMC
August 2021

Gut microbiota as prognosis markers for patients with HBV-related acute-on-chronic liver failure.

Gut Microbes 2021 Jan-Dec;13(1):1-15

Department of Infectious Diseases and Guangdong Key Laboratory of Liver Disease Research, Third Affiliated Hospital of Sun Yat-sen University, Key Laboratory of Tropical Disease Control (Sun Yat-Sen University), Ministry of Education, Guangzhou, Guangdong, China.

The gut microbiota in the hepatitis B virus related acute-on-chronic liver failure (HBV-ACLF) is poorly defined. We aim to uncover the characteristics of the gut microbiota in HBV-ACLF and in other HBV associated pathologies. We analyzed the gut microbiome in patients with HBV-ACLF or other HBV associated pathologies and healthy individuals by 16S rRNA sequencing and metagenomic sequencing of fecal samples. 212 patients with HBV-ACLF, 252 with chronic hepatitis B (CHB), 162 with HBV-associated cirrhosis (HBV-LC) and 877 healthy individuals were recruited for the study. CHB and HBV-LC patients are grouped as HBV-Other. We discovered striking differences in the microbiome diversity between the HBV-ACLF, HBV-Other and healthy groups using 16S rRNA sequencing. The ratio of cocci to bacilli was significantly elevated in the HBV-ACLF group compared with healthy group. Further analysis within the HBV-ACLF group identified 52 genera showing distinct richness within the group where was enriched in the progression group whilst was enriched in the regression group. Metagenomic sequencing validated these findings and further uncovered an enrichment of in progression group, while and dominated the regression group. Importantly, our analysis revealed that there was a rapid increase of during the progression of HBV-ACLF. The gut microbiota displayed distinct composition at different phases of HBV-ACLF. High abundance of is associated with progression while that of is associated with regression of HBV-ACLF. Therefore, the microbiota features hold promising potential as prognostic markers for HBV-ACLF.
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http://dx.doi.org/10.1080/19490976.2021.1921925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8143260PMC
May 2021

Hypertension and Atrial Fibrillation: A Study on Epidemiology and Mendelian Randomization Causality.

Front Cardiovasc Med 2021 23;8:644405. Epub 2021 Mar 23.

The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.

Hypertension (HT) and atrial fibrillation (AF) often coexist. However, the causality between these two conditions remains to be determined. We used individual participant data from the Atherosclerosis Risk in Communities (ARIC) prospective cohort with 9,474 participants. HT was ascertained at visit 1 (1987-1989), and incident AF was identified by ECGs conducted during study examinations at each visit, hospital discharge codes, and death certificates. We used the Kaplan-Meier estimate to compute the cumulative incidence of AF by the HT subgroup. Then we used Cox hazard regression model to assess the association between HT and incident AF. The causality between genetically determined HT and AF was analyzed by the two-sample Mendelian randomization (MR) based on publicly summarized genome-wide association studies (GWASs) data. A total of 1,414 cases (14.9%) of AF were identified during the follow-up period (median 24.1 years). After adjusting for all covariates, the hazard ratio between the participants with HT and incident AF was 1.50 [95% confidence interval (CI) 1.29-1.73]. In the HT → AF MR analysis, we detected a causal correlation between HT and AF (OR: 1.90, 95% CI 1.18-3.04, = 0.01) with no evidence of heterogeneity from single-nucleotide polymorphisms. Besides, the genetically determined SBP and DBP (10 mmHg) were consistently associated with a higher risk of AF. In the ARIC study, the incident AF increased by 50% in patients with HT. In the MR analysis, our results supported causal inference between HT and AF.
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http://dx.doi.org/10.3389/fcvm.2021.644405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8021766PMC
March 2021

Causal effect of education on type 2 diabetes: A network Mendelian randomization study.

World J Diabetes 2021 Mar;12(3):261-277

Department of Cardiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, Guangdong Province, China.

Background: The causality between education and type 2 diabetes (T2DM) remains unclear.

Aim: To identify the causality between education and T2DM and the potential metabolic risk factors [coronary heart disease (CHD), total cholesterol, low-density lipoprotein, triglycerides (TG), body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), fasting insulin, fasting glucose, and glycated hemoglobin] from summarized genome-wide association study (GWAS) data used a network Mendelian randomization (MR).

Methods: Two-sample MR and network MR were performed to obtain the causality between education-T2DM, education-mediator, and mediator-T2DM. Summary statistics from the Social Science Genetic Association Consortium (discovery data) and Neale Lab consortium (replication data) were used for education and DIAGRAMplusMetabochip for T2DM.

Results: The odds ratio for T2DM was 0.392 (95%CI: 0.263-0.583) per standard deviation increase (3.6 years) in education by the inverse variance weighted method, without heterogeneity or horizontal pleiotropy. Education was genetically associated with CHD, TG, BMI, WC, and WHR in the discovery phase, yet only the results for CHD, BMI, and WC were replicated in the replication data. Moreover, BMI was genetically associated with T2DM.

Conclusion: Short education was found to be associated with an increased T2DM risk. BMI might serve as a potential mediator between them.
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http://dx.doi.org/10.4239/wjd.v12.i3.261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958473PMC
March 2021

Serum Albumin and Incident Heart Failure: Insights From Epidemiological and Mendelian Randomization Studies.

Circ Genom Precis Med 2020 12 15;13(6):e002989. Epub 2020 Nov 15.

Department of Cardiology, The First Affiliated Hospital of Sun Yat-Sen University (X.-d.Z., S.-z.Z., H.-m.Z., X.-b.Z., X.-t.S., Z.-m.D., X.-x.L.).

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http://dx.doi.org/10.1161/CIRCGEN.120.002989DOI Listing
December 2020

Education and heart failure: New insights from the atherosclerosis risk in communities study and mendelian randomization study.

Int J Cardiol 2021 02 2;324:115-121. Epub 2020 Oct 2.

Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Center, Guangzhou, GuangDong, PR China; Guangdong Engineering Research Center for Light and Health, Guangzhou Higher Education Mega Center, Guangzhou, GuangDong, PR China. Electronic address:

Introduction: We aim to characterize the nature and magnitude of the prospective association between education and incident heart failure (HF) in the Atherosclerosis Risk in Communities (ARIC) Study and investigate any causal relevance to the association between them.

Methods: The final sample size was 12,315 in this study. Baseline characteristics between education levels were compared using 1-way ANOVA test, the Kruskal-Wallis test, or the χ2 test. We used the Kaplan-Meier estimate to compute the cumulative incident of HF by education levels and the difference in estimate was compared using the log-rank test. Cox hazard regression models were used to explore the association between education levels and incident HF. Two-sample Mendelian randomization (MR) based on publicly available summary-level data from genome-wide association studies (GWASs) was used to estimate the causal influence of the education and incident HF.

Results: During a median follow-up of 25.1years, 2453 cases (19.9%) of incident HF occurred. After multiple adjustments in the final model, participants in the intermediate and advanced education levels were still associated with 18% and 21% decreased rate of incident HF separately. In MR analysis, we detected a protective causal association between education and HF (P=0.005).

Conclusions: Participants with higher education levels were associated with a decreased rate of incident HF. There was a causal association between education and HF.
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http://dx.doi.org/10.1016/j.ijcard.2020.09.068DOI Listing
February 2021

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

BMJ Open Diabetes Res Care 2020 09;8(1)

Cardiology, Sun Yat-sen University First Affiliated Hospital, GuangZhou, China

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; p0.023), and 1.032 (95% CI: 1.004 to 1.06; p0.022) 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; p0.002).

Conclusions: Higher FBG variability was independently associated with increased prevalence of lower-extremity PAD in people without diabetes.

Trial Registration Number: NCT00005131.
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http://dx.doi.org/10.1136/bmjdrc-2019-000896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526273PMC
September 2020

A systematic review of guidelines for dual antiplatelet therapy in coronary artery bypass graft.

Eur J Clin Invest 2021 Jan 25;51(1):e13405. Epub 2020 Sep 25.

Cardiology Department, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.

Background: In most situations, many patients undergoing coronary artery bypass graft (CABG) are on dual antiplatelet therapy (DAPT), which is also required after CABG. The adjustment of antiplatelet strategy remains controversial. In this study, we systematically review current guidelines, seeking consensus and controversies to facilitate clinical practice.

Methods And Results: Guidelines are searched in PubMed, Embase, ECRI Guidelines Trust and websites of guidelines organizations and professional society. Guidelines with recommendations of DAPT for patients undergo CABG are included. Two reviewers appraised guidelines with the Appraisal of Guidelines for Research and Evaluation II (AGREE II). Relevant recommendations are extracted and summarized. A total of 14 guidelines meeting inclusion criteria are selected, with average AGREE II scores from 44% to 86%. Most guidelines score high in domains other than 'applicability'. Many guidelines are not detailed enough in reporting considerations behind recommendations. Current guidelines are consistent on the management of antiplatelet strategy before elective CABG and using DAPT after surgery for preventing graft vessel occlusion. Evidence is still lacking in urgent CABG and resumption of the previous DAPT after surgery.

Conclusions: Current guidelines on DAPT in CABG are generally satisfying. Suspending P2Y12 inhibitors while aspirin continued before elective CABG is recommended, as well as 12 months of DAPT following CABG. More evidence is needed to guide antiplatelet therapy in urgent CABG and to prove the benefits of resuming previous DAPT.
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http://dx.doi.org/10.1111/eci.13405DOI Listing
January 2021

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

Ther Adv Chronic Dis 2020 27;11:2040622320909040. Epub 2020 May 27.

Cardiology Department, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan 2nd Road, Guangzhou, 510080, PR China.

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 ( = 152,893) for BMI, CARDIoGRAMplusC4D consortium data were used ( = 184,305) for CHD, Global Lipids Genetics Consortium data were used ( = 108,363) for TC, LDL, HDL and TG, and MAGIC consortia data were used ( = 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/m) 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.
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http://dx.doi.org/10.1177/2040622320909040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7257848PMC
May 2020

Causal assessment of sleep on coronary heart disease.

Sleep Med 2020 03 30;67:232-236. Epub 2019 Aug 30.

The First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan 2nd Road, Yue Xiu, GuangZhou, 510080, GuangDong, PR China. Electronic address:

Objective: Sleep is an essential physiological process that protects our physical and mental health. However, the causality of the association between sleep and coronary heart disease (CHD) is unknown. Mendelian randomization (MR), using genetic variants as instrumental variables to test for causality, can infer credible causal associations. We applied a two-sample MR framework to determine the causal association between sleep (sleeplessness, sleep duration, and daytime dozing) and CHD by integrating summary-level genome-wide association study (GWAS) data.

Methods: Data included in this study were the GWAS summary statistics datasets from the C4D Consortium for CHD; Neale Lab UKB-a:13 Consortium for sleeplessness; Neale Lab UKB-a:9 Consortium for sleep duration and Neale Lab UKB-a:15 Consortium for daytime dozing. The conventional MR approach (inverse variance weighted, IVW) method and Egger method were used. Heterogeneity was calculated using each of the different MR methods where possible. Horizontal pleiotropy was evaluated by p-value of the MR-Egger intercept.

Results: The IVW method estimate indicated that the odds ratio (OR) (95% confidence interval, CI) for CHD was 3.924 (1.345-11.447) per standard deviation increase in sleeplessness (p = 0.012). Results were consistent in MR-Egger method (OR, 4.654; 95% CI, 1.191-18.186; p = 0.009). The genetically predicted sleeplessness was positively casually associated with CHD. The causal association between sleep duration (or daytime dozing) and CHD was not established.

Conclusion: Our analysis provided evidence supporting a causal relationship between sleeplessness (not sleep duration or daytime dozing) and CHD.
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http://dx.doi.org/10.1016/j.sleep.2019.08.014DOI Listing
March 2020

Serum albumin and atrial fibrillation: insights from epidemiological and mendelian randomization studies.

Eur J Epidemiol 2020 Feb 18;35(2):113-122. Epub 2019 Nov 18.

Cardiology Department, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan 2nd Road, Yue Xiu, Guangzhou, 510080, Guangdong, People's Republic of China.

Atrial fibrillation (AF) is the most common arrhythmia in clinical practice. Low serum albumin level is linked to the emergence of many cardiovascular diseases, including AF. In this study, we aim to characterize the nature and magnitude of the prospective association between serum albumin and incident AF in the Atherosclerosis Risk in Communities (ARIC) Study and investigate any causal relevance to the association between them. ARIC Study is a population-based, prospective, cohort study of cardiovascular risk factors in four US communities, initially consisting of 15,792 participants, aged 45-64 years, recruited between 1987 and 1989 (visit 1). The final sample size was 12,833 in this study. Baseline (visit 1) characteristics were compared between groups using one-way ANOVA test, Chi square test, or Kruskal-Wallis test as appropriate. We used multivariable Cox' hazard regression models to assess the association between albumin and incident AF. Two-sample Mendelian randomization (MR) based on publicly available summary-level data from genome-wide association studies was used to estimate the causal influence of the serum albumin and incident AF. During a median follow-up of 25.1 years, 2259 (17.6%) participants developed incident AF. After multiple adjustment, serum albumin was inversely associated with incidence of AF [HR = 0.90, 95% CI 0.86-0.94, per SD (0.27 g/dL) increase; HR = 0.80, 95% CI 0.71-0.91, Q4 vs. Q1]. In MR analysis, we detected no evidence for a causal relation between serum albumin level and AF in inverse-variance weighted (IVW) method (odds ratio: 0.996, 95% CI 0.980-1.012, per 1 g/dL increase of albumin; P = 0.620) without evidence of heterogeneity between estimates from individual SNPs (P = 0.981 [MR-Egger] and P = 0.860 [IVW]) nor pleiotropy effect (P = 0.193). The serum albumin level is independently inverse associated with incident AF in a linear pattern. However, MR analyses did not support a causal role of serum albumin in the etiology of AF.
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http://dx.doi.org/10.1007/s10654-019-00583-6DOI Listing
February 2020

Exploring the causal pathway from omega-6 levels to coronary heart disease: A network Mendelian randomization study.

Nutr Metab Cardiovasc Dis 2020 02 16;30(2):233-240. Epub 2019 Sep 16.

The First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan 2nd Road, Yue Xiu, Guangzhou, 510080, GuangDong, PR China. Electronic address:

Background And Aims: Evidence on the effect of omega-6 fats on coronary heart disease (CHD) risk remains inconclusive. We applied a network MR framework to determine the causal effects between omega-6 levels and CHD and the potential cholesterol metabolic risk factors (Total cholesterol, TC; Low-density lipoprotein cholesterol, LDL-C; High-density lipoprotein cholesterol, HDL-C; Triglycerides, TG) which might act as mediators in the link between omega-6 levels and CHD by integrating summary-level genome wide association study (GWAS) data.

Methods And Results: Network MR analysis-an approach using genetic variants as the instrumental variables for both the exposure and mediator to infer causality was performed to examine the causal effects between omega-6 levels and CHD and cholesterol metabolic risk factors. Summary statistics from the Kettunen et al. 's consortium were used (n = 13506) for omega-6, CARDIoGRAMplusC4D consortium data were used (n = 184305) for CHD, and GLGC consortia data were used (n = 108363) for TC, LDL-C, HDL-C, and TG. The IVW method estimate indicated that the odds ratio (OR) (95% confidence interval [CI]) for CHD was 1.210 (1.118-1.310) per standard deviation increase in omega-6. Results were consistent in MR Egger method (OR, 1.418; 95% CI, 1.087-1.851; P = 0.050) and weighted median methods (OR, 1.239; 95% CI, 1.125-1.364; P = 0.000). Omega-6 was positively causal associated with TC, LDL-C, and TG but was not associated with HDL-C. Moreover, TC, LDL-C, and TG were positively associated with CHD.

Conclusions: Using a network MR framework, we provided evidence supporting a positive causal relationship between omega-6 and CHD, which might be partially mediated by TC, LDL-C, and TG.
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http://dx.doi.org/10.1016/j.numecd.2019.09.013DOI Listing
February 2020

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

Eur J Prev Cardiol 2019 11 18;26(16):1693-1706. Epub 2019 Jun 18.

Department of Cardiology, First Affiliated Hospital of Sun Yat-Sen University, China.

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.
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http://dx.doi.org/10.1177/2047487319856733DOI Listing
November 2019

Evaluation of guidelines on the screening and diagnosis of gestational diabetes mellitus: systematic review.

BMJ Open 2019 05 5;9(5):e023014. Epub 2019 May 5.

Department of Obstetrics and Gynecology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.

Objective: Guidelines for screening and diagnosis of gestational diabetes mellitus (GDM) have been updated in the past several years, and various inconsistencies exist across these guidelines. Moreover, the quality of these updated guidelines has not been clarified. We thus conducted this systematic review to evaluate the relationship between the quality and detailed recommendations of these guidelines.

Data Sources: The Guidelines International Network Library, the National Institute for Health and Clinical Excellence (NICE) database, the Medline database, the Embase and the National Guidelines Clearinghouse were searched for guidelines containing recommendations on screening and diagnosis strategies for GDM between 2009 and November 2018.

Methods: Guidelines included a target group of women with GDM, and contained recommendations for screening and diagnostic strategies for GDM were included in the present systematic review. Reviewers summarised recommendations on screening and diagnosis strategies from each guideline and rated the quality of guidelines by using the Appraisal of Guidelines Research and Evaluation (AGREE) criteria.

Results: A total of 459 citations were collected by the preliminary literature selection, and 16 guidelines that met the inclusion criteria were assessed. The inconsistencies of the guidelines mainly focus on the screening process (one step vs two step) and criteria of oral glucose tolerance test (OGTT) (International Association of Diabetes and Pregnancy Study Groups [IADPSG] vs CarpenterandCoustan). Guidelines with higher AGREE scores usually recommend a one-step OGTT strategy with IADPSG criteria between 24 and 28 gestational weeks, and the majority of these guidelines likely to select evidence by Grading of Recommendations Assessment, Development and Evaluation criteria.

Conclusions: The guidelines of WHO-2013, NICE-2015, American Diabetes Association-2018, Endocrine Society-2013, Society of Obstetricians and Gynaecologists of Canada-2016, International Federation of Gynecology and Obstetrics-2015, American College of Obstetricians and Gynecologists-2018, United States Preventive Services Task Force-2014 and IADPSG-2015 are strongly recommended in the present evaluation, according to the AGREE II criteria. Guidelines with higher quality tend to recommend a one-step 75 g OGTT strategy with IADPSG criteria between 24 and 28 gestational weeks.
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http://dx.doi.org/10.1136/bmjopen-2018-023014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6502228PMC
May 2019

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.

Cardiovasc Diabetol 2019 04 8;18(1):47. Epub 2019 Apr 8.

Department of Cardiology, First Affiliated Hospital of Sun Yat-Sen University, No. 58 Zhong Shan 2nd Road, Guangzhou, 510080, China.

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.
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http://dx.doi.org/10.1186/s12933-019-0853-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454617PMC
April 2019

Comparative cardiovascular outcomes in the era of novel anti-diabetic agents: a comprehensive network meta-analysis of 166,371 participants from 170 randomized controlled trials.

Cardiovasc Diabetol 2018 06 5;17(1):79. Epub 2018 Jun 5.

Department of Cardiology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China.

Background: Cardiovascular (CV) safety of one anti-diabetic medication over another remains partially delineated. We sought to assess the comparative effect on CV outcomes among novel anti-diabetic agents.

Methods: This study was registered with the International Prospective Register of Systematic Reviews (CRD 42016042063). MEDLINE, EMBASE, and Cochrane Library Central Register of Controlled Trials were searched between Jan 1, 1980, and June 30, 2016. Randomized controlled trials comparing anti-diabetic drugs with other comparators in adults with type 2 diabetes were included. We used network meta-analysis to obtain estimates for the outcomes of interests. In addition, post hoc correlation analysis of severe hypoglycemia and primary outcome as per ranking order was conducted. Outcomes were major adverse cardiovascular events (MACE) and all-cause mortality.

Results: A total of 170 trials (166,371 participants) were included. By class and by individual, sulfonylureas (SU) ranked last. Therefore, with SU as reference, categorically sodium-glucose co-transporter 2 inhibitor (SGLT2i), insulin (INS), glucagon-like peptide-1 receptor agonist, and dipeptidyl peptidase 4 inhibitor were significantly superior in term of MACE; as were SGLT2i and INS in term of all-cause mortality. Moreover, ranking orders of MACE and all-cause mortality were both positively correlated with that of severe hypoglycemia risk (by individual: R = 0.3178, P = 0.018; by class: R = 0.2574, P = 0.038).

Conclusions: Novel anti-diabetic agents possess favorable CV safety profile, despite small but robust differences between individuals. In addition, increase in CV risk was again shown to be partly attributable to a concomitant increase in the risk of severe hypoglycemia, for which SU performed the worst.
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http://dx.doi.org/10.1186/s12933-018-0722-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5989345PMC
June 2018

Serum Klotho, vitamin D, and homocysteine in combination predict the outcomes of Chinese patients with multiple system atrophy.

CNS Neurosci Ther 2017 Aug 19;23(8):657-666. Epub 2017 Jun 19.

Department of Cardiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.

Aims: Neuroinflammation contributed to the pathogenesis of multiple system atrophy (MSA). We aimed to detect the correlation between inflammatory mediators, such as Klotho (Klt), vitamin D (25(OH)D) and homocysteine (Hcy), and disease severity among MSA patients.

Methods: A total of 53 MSA patients, 65 PD patients, and 62 normal subjects were recruited in our cross-sectional study. Serum Klotho (Klt), vitamin D (25(OH)D), and homocysteine (Hcy) levels were measured. Several scales were undertaken to assess the motor/nonmotor function and cognitive impairment of MSA.

Results: Decreased Serum Klt and 25(OH)D levels and increased Hcy levels were found in patients with MSA, compared with healthy controls. These results were more pronounced in male patients. The three biomarkers also displayed differences between MSA and PD subgroups based on genders. Interestingly, Klt, 25(OH)D and Hcy levels associated with cognition impairment, motor dysfunction, mood/cardiovascular disorder among MSA patients. In addition, the combination of Klt, 25(OH)D and Hcy had a better diagnostic ability for distinguishing MSA patients from healthy subjects, as well as distinguishing male MSA patients from male PD patients.

Conclusion: This study suggested that Klt, 25(OH)D and Hcy levels could be a potential predictor for MSA severity evaluation.
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http://dx.doi.org/10.1111/cns.12711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6492708PMC
August 2017

The relationship between job satisfaction, work stress, work-family conflict, and turnover intention among physicians in Guangdong, China: a cross-sectional study.

BMJ Open 2017 05 12;7(5):e014894. Epub 2017 May 12.

Sun Yat-sen University, Guangdong Key Laboratory of Health Informatics, Health Information Research Center, Department of Medical Statistics and Epidemiology, School of Public Health, Guangzhou, Guangdong, China.

Objective: To investigate the relationship between job satisfaction, work stress, work-family conflict and turnover intention, and explore factors associated with turnover intention, among physicians in Guangdong Province, China.

Methods: From August to October 2013, physicians completed questionnaires and scales with regard to their job satisfaction, work stress, work-family conflict, and turnover intention. Binary logistic regression and structural equation modelling (SEM) were used in data analysis.

Results: A total of 3963 physicians were approached, with 3563 completing the questionnaire. The mean score of the overall perception of turnover intention of physicians who worked in Guangdong was 2.71 on a scale ranging from 1 to 6. Hours worked per week, working in an urban/rural area, type of institution, and age significantly impacted on turnover intention. Turnover intention was directly and negatively related to job satisfaction, and it was directly, indirectly and positively related to work stress and work-family conflict.

Conclusion: Job satisfaction, work stress, work-family conflict, hours worked per week, working in an urban/rural area, types of institution and age are influencing factors of turnover intention. Reducing working hours, raising salary, providing more opportunities for career development and training, supporting and encouraging physicians by senior managers could potentially contribute to the reduction in turnover intention.
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http://dx.doi.org/10.1136/bmjopen-2016-014894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5566636PMC
May 2017

A Nomogram to Predict Contrast Induced Nephropathy in Patients Undergoing Percutaneous Coronary Intervention.

Int Heart J 2017 Apr 21;58(2):191-196. Epub 2017 Mar 21.

Department of Cardiology, The First Affiliated Hospital, Sun Yat-sen University.

Contrast-induced nephropathy (CIN) is the third leading cause of hospital-acquired acute kidney injury (AKI). Emerging evidence has revealed that soluble klotho (sklotho) could be a novel biomarker for early AKI diagnosis. The aims of this study were to assess the predictive role of sklotho for CIN and to develop a prediction nomogram in patients undergoing percutaneous coronary intervention (PCI). This study is registered on Clinicaltrials.gov (NCT 02650336).Patients aged 18 years or older undergoing planned PCI were prospectively recruited between May 2014 and July 2015. CIN was defined as an increase in serum creatinine of 0.5 mg/dL within 48-72 hours after the procedure. Plasma sklotho was measured by enzyme linked immunosorbent assay (ELISA). Stratified analysis, interaction test, covariate screening, and curve fitting were performed to explore the association between sklotho and CIN. A nomogram was then developed and validated using the bootstrapped technique.A total of 192 patients aged 54.75 ± 12.19 years were selected, 32 (16.7%) of whom were diagnosed with CIN. A logistic regression model indicated significant associations between CIN and sklotho, age > 75 years, diabetes, and the Mehran risk score. Saturation effects analysis detected a two-stage change between sklotho and CIN, with the inflection point was 477.4 pg/mL. The area under the ROC curve was 0.758 and the sensitivity and specificity of this point were 90.6% and 53.9%, respectively. A nomogram was developed for the prediction of CIN and showed a bootstrapped-corrected area under the curve value of 0.913. In addition, sklotho significantly increased the predictive value of the nomogram.A strong association between sklotho and CIN was identified in patients undergoing elective PCI. A lower level of sklotho would be well correlated with CIN. The nomogram with sklotho is a useful tool to predict CIN in patients who will undergo PCI.
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http://dx.doi.org/10.1536/ihj.16-213DOI Listing
April 2017

Job satisfaction and associated factors among healthcare staff: a cross-sectional study in Guangdong Province, China.

BMJ Open 2016 07 19;6(7):e011388. Epub 2016 Jul 19.

Department of Medical Statistics and Epidemiology, Guangdong Key Laboratory of Health Informatics, Health Information Research Center, School of Public Health, Sun Yat-Sen University, Guangzhou, Guangdong, China.

Objectives: This cross-sectional study aimed to explore job satisfaction among healthcare staff in Guangdong following the health system reforms in 2009, and to investigate the association between job satisfaction and work stress, work-family conflict and doctor-patient relationship.

Design: Cross-sectional survey.

Setting: The Fifth National Health Service Survey was carried out in Guangdong, China.

Participants: All participants in this study were healthcare staff including physicians, nurses and public health staff from hospitals, health service centres and health clinics. A total of 6583 questionnaires were distributed and collected. After excluding the incomplete questionnaires, 5845 questionnaires were included for the analysis.

Outcome Measures: Sociodemographic information and scores for evaluating job satisfaction, work stress, work-family conflict and doctor-patient relationship were obtained using the questionnaire developed by the National Health and Family Planning Commission of the People's Republic of China. To assess the significantly associated factors on job satisfaction of the healthcare staff in Guangdong, a binary logistic regression model was used.

Results: Based on the 5845 valid responses of the healthcare staff who worked in Guangdong, the mean score of overall perception of job satisfaction was 3.99 on a scale of 1-6. Among the sociodemographic variables, occupation, educational background, professional status, years of service, annual income and night shift frequency significantly influenced the level of job satisfaction. Work stress, work-family conflict and doctor-patient relationship also had significant effect on job satisfaction.

Conclusions: The overall job satisfaction exceeded slightly dissatisfied (score 3) and approached slightly satisfied (score 4). Measures to enhance job satisfaction include the reduction of workload, increase of welfare, maintaining moderate stress and balancing work-family conflict. Moreover, relevant laws should be issued to protect the healthcare staff from violent acts.
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http://dx.doi.org/10.1136/bmjopen-2016-011388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4964254PMC
July 2016

Renin-angiotensin system inhibitors in patients with coronary artery disease who have undergone percutaneous coronary intervention.

Ther Adv Cardiovasc Dis 2016 Jun 15;10(3):172-7. Epub 2016 May 15.

Department of Cardiology, the First Affiliated Hospital of Sun Yat-sen University, No. 58, ZhongShan Er Road, Guangzhou 510080, P. R. China

The percutaneous coronary intervention (PCI) procedure has become one of the pivotal options in the treatment of coronary artery disease (CAD). Although the PCI procedure has rapidly developed in China, some concerns including in-stent restenosis and dissatisfactory long-term prognosis remain unsolved. Large-scale randomized controlled clinical trials indicate that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) can reduce all-cause mortality and recurrent cardiac events in patients with CAD. ACEIs/ARBs are recommended as a fundamental treatment in the secondary prevention of CAD and reduce in-stent restenosis after PCI. This review focuses on the role of ACEIs/ARBs in improving long-term prognosis and reducing in-stent restenosis.
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http://dx.doi.org/10.1177/1753944716648851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5933676PMC
June 2016

Design, synthesis, and antihypertensive activity of curcumin-inspired compounds via ACE inhibition and vasodilation, along with a bioavailability study for possible benefit in cardiovascular diseases.

Drug Des Devel Ther 2016 5;10:129-39. Epub 2016 Jan 5.

Department of Cardiology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China.

This study describes the synthesis of a novel series of curcumin-inspired compounds via a facile synthetic route. The structures of these derivatives were ascertained using various spectroscopic and analytic techniques. The pharmacological effects of the target analogs were assessed by assaying their inhibition of angiotensin-converting enzyme (ACE). All of the synthesized derivatives exhibited considerable inhibition of ACE, with half-maximal inhibitory concentrations ranging from 1.23 to 120.32 μM. In a docking analysis with testicular ACE (tACE), the most promising inhibitor (4j) was efficiently accommodated in the deep cleft of the protein cavity, making close interatomic contacts with Glu162, His353, and Ala356, comparable with lisinopril. Compounds 4i, 4j, 4k, and 4l were further selected for determination of their vasodilator activity (cardiac output and stroke volume) on isolated rat hearts using the Langendorff technique. The bioavailability of compound 4j was determined in experimental mice.
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http://dx.doi.org/10.2147/DDDT.S96315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4708961PMC
October 2016

Calcitriol prevents peripheral RSC96 Schwann neural cells from high glucose & methylglyoxal-induced injury through restoration of CBS/H2S expression.

Neurochem Int 2016 Jan 17;92:49-57. Epub 2015 Dec 17.

Department of Physiology, Guangzhou Medical University, Guangzhou 511436, China. Electronic address:

A meta-analysis has suggested that vitamin D deficiency is involved in diabetic peripheral neuropathy (DPN) and the levels of hydrogen sulfide (H2S) are also decreased in type 2 diabetes. The injection of vitamin D induces cystathionine-β-synthase (CBS) expression and H2S generation. However, it remains unclear whether the supplementation of vitamin D prevents DPN through improvement of CBS/H2S expression. In the present study, RSC96 cells, a rat Schwann cell line, were exposed to high glucose and methylglyoxal (HG&MG) to simulate diabetic peripheral nerve injury in vivo. Before the exposure to HG&MG, the cells were preconditioned with calcitriol (CCT), an active form of vitamin D, and then CCT-mediated neuroprotection was investigated in respect of cellular viability, superoxide anion (O2(-)) generation, inducible nitric oxide (NO) synthase (iNOS)/NO expression, mitochondrial membrane potential (MMP), as well as CBS expression and activity. It was found that both high glucose and MGO decreased cell viability and co-treatment with the two induced a more serious injury in RSC96 cells. Therefore, the exposure to HG&MG was used in the present study. The exposure to HG&MG markedly induced iNOS expression, NO and O2(-) generation, as well as MMP loss. In addition, the exposure to HG&MG depressed CBS expression and activity in RSC96 cells. However, the preconditioning with CCT significantly antagonized HG&MG-induced cell injury including the decreased viability, iNOS overexpression, NO and O2(-) accumulation, as well as MMP loss. CCT also partially restored the decreased CBS expression and activity triggered by HG&MG, while the inhibition of CBS with hydroxylamine attenuated CCT-mediated neuroprotection. Moreover, the exogenous donation of H2S produced similar cellular protective effects to CCT. The data indicate that the supplementation of vitamin D prevents HG&MG-induced peripheral nerve injury involving the restoration of endogenous H2S system, which may provide a basal support for the treatment of DPN with vitamin D clinically.
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http://dx.doi.org/10.1016/j.neuint.2015.12.005DOI Listing
January 2016

Critical appraisal of international guidelines on chronic heart failure: Can China AGREE?

Int J Cardiol 2016 Jan 20;203:111-4. Epub 2015 Oct 20.

Department of Cardiology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China. Electronic address:

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http://dx.doi.org/10.1016/j.ijcard.2015.10.105DOI Listing
January 2016

Rationale and design of RETAIN study: Rosuvastatin Effect on Telomere-telomerase system in Acute coronary syndrome patients undergoing percutaneous coronary Intervention.

Int J Cardiol 2015 Apr 24;184:388-390. Epub 2015 Feb 24.

Department of cardiology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, PR China. Electronic address:

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http://dx.doi.org/10.1016/j.ijcard.2015.02.032DOI Listing
April 2015

Efficacy and safety of low-dose clopidogrel after 12-month dual antiplatelet therapy for patients having drug-eluting stent implantation.

J Thorac Dis 2014 May;6(5):459-65

1 Division of Cardiology, 2 Department of Ultrasound, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.

Background: To prevent stent thrombosis (ST) after implantation of drug-eluting stents (DESs) in patients with coronary heart disease, 12-month dual antiplatelet therapy (DAPT) is recommended. However, the optimal long-term antiplatelet regimen is not clear for the patients who have completed the 12-month DAPT.

Methods: We reviewed the data of 755 consecutive patients who had undergone percutaneous coronary intervention (PCI) three years ago and completed 12-month DAPT. They were divided into three groups according to the antiplatelet medication they had used for two years after 12-month DAPT [low-dose clopidogrel (Talcom(®), 25mg/d), clopidogrel (Plavix(®), 75mg/d) and aspirin (100 mg/d)]. The efficacy (a composite incidence of cardiac death, myocardial infarction and target vessel revascularization) and safety (incidences of bleeding, gastrointestinal trouble and drug discontinuation) were compared among the three groups.

Results: The rates of multi-vessel lesions, prior MI, hemoglobin A1C (HbA1c) and low-density lipoprotein cholesterol were significantly higher in the clopidogrel (75 mg/day) group than in the other two groups (P>0.05 for both comparisons). There was no significant difference in the overall composite incidence of cardiac death, myocardial infarction and target vessel revascularization in the three groups at three years after PCI. The rates of bleeding (especially minor bleeding), gastrointestinal trouble, drug discontinuation and any blood transfusion were markedly lower in the low-dose clopidogrel (25 mg/d) group than in the other two treatment groups (P<0.05).

Conclusions: The 25-mg maintenance dose of clopidogrel after 12-month DAPT may be more preferable to Chinese patients who have undergone DES implantation, because of its lower cost but no less efficacy and safety.
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http://dx.doi.org/10.3978/j.issn.2072-1439.2014.02.23DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4015003PMC
May 2014

Exogenous hydrogen sulfide alleviates high glucose-induced cardiotoxicity via inhibition of leptin signaling in H9c2 cells.

Mol Cell Biochem 2014 Jun 1;391(1-2):147-55. Epub 2014 Apr 1.

Department of Cardiovasology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, People's Republic of China.

Hydrogen sulfide (H₂S) protects cardiomyoblasts against high glucose (HG)-induced injury by inhibiting the activation of p38 mitogen-activated protein kinase (MAPK). This study aims to determine whether the leptin-p38 MAPK pathway is involved in HG-induced injury and whether exogenous H2S prevents the HG-induced insult through inhibition of the leptin-p38 MAPK pathway in H9c2 cells. H9c2 cells were treated with 35 mM glucose (HG) for 24 h to establish a HG-induced cardiomyocyte injury model. Cell viability; mitochondrial membrane potential (ΔΨ m); apoptosis; reactive oxygen species (ROS) level; and leptin, leptin receptor, and p38 MAPK expression level were measured by the methods indicated. The results showed pretreatment of H9c2 cells with NaHS before exposure to HG led to an increase in cell viability, decrease in apoptotic cells, ROS generation, and a loss of ΔΨ m. Exposure of H9c2 cells to 35 mM glucose for 24 h significantly upregulated the expression levels of leptin and leptin receptors. The increased expression levels of leptin and leptin receptors were markedly attenuated by pretreatment with 400 μM NaHS. In addition, the HG-induced increase in phosphorylated (p) p38 MAPK expression was ameliorated by pretreatment with 50 ng/ml leptin antagonist. In conclusion, the present study has demonstrated for the first time that the leptin-p38 MAPK pathway contributes to the HG-induced injury in H9c2 cells and that exogenous H₂S protects H9c2 cells against HG-induced injury at least in part by inhibiting the activation of leptin-p38 MAPK pathway.
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http://dx.doi.org/10.1007/s11010-014-1997-3DOI Listing
June 2014

PDE5 inhibitor sildenafil in the treatment of heart failure: a meta-analysis of randomized controlled trials.

Int J Cardiol 2014 Apr 24;172(3):581-7. Epub 2014 Jan 24.

Department of Cardiology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510000, PR China. Electronic address:

Background: Clinical trials have evaluated the use of phosphodiesterase (PDE) 5 inhibitors sildenafil as a potential adjunct in the treatment of heart failure (HF) with mixed results. Thus, we undertook a meta-analysis to evaluate the clinical viability of sildenafil in HF.

Methods: Relevant studies were searched and identified in the MEDLINE and EMBASE databases. Randomized clinical trials (RCT) comparing sildenafil to placebo, in heart failure patients, reporting at least one outcome of interest were included. Data were extracted regarding the characteristics and clinical outcomes.

Results: We identified 9 RCTs enrolling 612 HF patients. There were no significant differences in adverse events between sildenafil group and placebo group (RR=1.10, 95% CI=0.74 to 1.65, P=0.41), whereas sildenafil therapy was associated with a marked improvement in hemodynamic parameter peak VO2 (MD=3.25, 95% CI=2.07 to 4.42, P<0.00001) in HF with reduced ejection fraction (HFrEF) patients but not in HF with preserved ejection fraction (HFpEF) patients. Also, sildenafil therapy improved VO2 at anaerobic threshold (AT) (MD=3.47, 95% CI=1.68 to 5.27, P=0.0002), VE/VCO2 slope (MD=-7.06, 95% CI=-8.93 to -5.19, P<0.00001) and LV ejection fraction (MD=5.43, 95% CI=3.66 to 7.20, P<0.00001) compared to placebo in HF patients, which had no impact on blood pressure and heart rate. For quality of life (emotional function, fatigue and breathlessness), there was no significant difference between the two groups.

Conclusions: Sildenafil improved hemodynamic parameters particularly in HFrEF patients when compared to placebo, with no increase in adverse events. Sildenafil treatment was well tolerated and had no impact on quality of life.
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http://dx.doi.org/10.1016/j.ijcard.2014.01.102DOI Listing
April 2014

[The effects of chloride channel inhibitor on bFGF-induced proliferation of lens epithelial cells].

Zhonghua Yan Ke Za Zhi 2013 Nov;49(11):1014-9

Department of Ophthalmology,Union Hospital of Fujian Medical University, Fuzhou 350001, China. Email:

Objective: To study the effect of chloride channel on proliferation induced by basic-fibroblast growth factor (bFGF) in human lens epithelial cells HLE B-3 (LEC).

Methods: HLE B-3 cells at Logarithmic growth phase were incubated in the 6 or 96 well plate overnight and the proliferation was induced by 10 µg/L bFGF. The cells were divided into bFGF group treated with bFGF and the blank control group with the regular cells culture. LEC were treated with different concentrations of chloride channel inhibitors: 5-nitro-2-[3-phenylpropylamino] benzoic acid (NPPB) at 50, 100, 150 µmol/L and 4 , 4'-2 diisothiocyanostilbene-2, 2' -disulfonic acid (DIDS) at 10, 50, 100 µmol/L with bFGF or without bFGF in 10% serum for 24, 48, 72 hours. The cell viability and the drug toxicity were detected by CCK-8 colorimetric assay. The expression of proliferating cell nuclear antigen (Ki-67) of LEC treated with NPPB or DIDS were observed by immunocytochemistry staining assay. The phase change of cell cycle was examined by flow cytometry. Each experiment group and control group were compared using two-way ANOVA, further pairwise comparisons using LSD-t test or by the Independent-Samples t test.

Results: 10 µg/L bFGF induced LEC proliferation and the values of A stage were gradually declined with the increase of chloride channel inhibitors' concentrations and time at 24 hours, 48 hours and 72 hours (bFGF+NPPB group: Ftime = 305.28, Fconcentrations = 18.76, P = 0.000;bFGF+ DIDS group:Ftime = 94.44, Fconcentrations = 24.42, P = 0.000). Different concentrations of chloride channel inhibitor reduced the values of a stage with 10 µg/L bFGF in a dose- and time-dependent manner. The expression of Ki-67 was significantly lowered compared with the bFGF group (bFGF+NPPB group: 18.32% ± 1.23%, F = 580.3, P = 0.000;bFGF+DIDS group: 11.21% ± 1.02%, F = 507.4, P = 0.000), when 150 µmol/L NPPB and 100 µmol/L DIDS with 10 µg/L bFGF were added at 48 hours. After 150 µmol/L NPPB and 100 µmol/L DIDS treatment at the 48th hour, the rate of G1 stage was significantly increased (F = 390.754, P = 0.000), where as that of S stage decreased significantly (F = 166.240, P = 0.000).

Conclusions: These results indicate that chloride channel inhibitors play an important role in modulating the proliferation cycle of LEC treated with bFGF by limiting the cell at cycle S/G1 stage from dividing into S stage.
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November 2013
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