陈慧
西安交通大学第一附属医院 心血管内科
Background:Genetic risk factors substantially contributed to the development of coronary atherosclerosis. Genome-wide association study (GWAS) has identified many risk loci for coronary atherosclerosis, but the translation of these loci into therapeutic targets is limited for their location in non-coding regions. Here, we aimed to screen the potential coronary atherosclerosis pathogenic genes expressed though TWAS (transcriptome wide association study) and explore the underlying mechanism association.Methods:Four TWAS approaches (PrediXcan, JTI, UTMOST, and FUSION) were used to screen genes associated with coronary atherosclerosis. Enrichment analysis of TWAS-identified genes was applied through the Metascape website. The summary-data-based Mendelian randomization (SMR) analysis was conducted to provide the evidence of causal relationship between the candidate genes and coronary atherosclerosis. At last, the cell type-specific expression of the intersection genes was examined by using human coronary artery single-cell RNA-seq, interrogating the immune microenvironment of human coronary atherosclerotic plaque at different stages of maturity.Results:We identified 19 genes by at least three approaches and 1 gene (NBEAL1) by four approaches. Enrichment analysis enriching the genes identified at least by two TWAS approaches, suggesting that these genes were markedly enriched in asthma and leukocyte mediated immunity reaction. Further, the summary-data-based Mendelian randomization (SMR) analysis provided the evidence of causal relationship between NBEAL1 gene and coronary atherosclerosis, confirming the protecting effects of NBEAL1 gene and coronary atherosclerosis. At last, the single cell cluster analysis demonstrated that NBEAL1 gene has differential expressions in macrophages, plasma cells and endothelial cells.Conclusion:Our study identified the novel genes associated with coronary atherosclerosis and suggested the potential biological function for these genes, providing insightful guidance for further biological investigation and therapeutic approaches development in atherosclerosis-related diseases.
Frontiers in cardiovascular medicine 2023
Background The epicardial adipose tissue (EAT) of metabolic syndrome (MetS) is abnormally accumulated with dysfunctional secretion of adipokines, closely relating to cardiac dysfunction. The current study was designed to identify the effects of EAT-derived leptin on the myocardium of MetS rats and explore the potential molecular mechanisms. Methods and Results A MetS rat model was established in 8-week-old Wistar rats by a 12-week high-fat diet. MetS rats exhibited increased leptin secretion from EAT, cardiac hypertrophy, and diastolic dysfunction with preserved systolic function. The myocardium of MetS rats had abnormal structure, increased oxidative stress injury, and higher inflammatory factor levels, especially the subepicardial myocardium, which was correlated with the EAT-derived leptin level but not the serum leptin. The EAT was separated from each group of rats to prepare EAT-conditioned medium. H9C2 rat cardiomyoblasts were treated with EAT-conditioned medium or leptin, plus various inhibitors. EAT-derived leptin from MetS rats promoted mitochondrial oxidative stress and dysfunction, induced mitochondrial pathway apoptosis, and inhibited cell viability in H9C2 cardiomyoblasts via the protein kinase C/reduced nicotinamide adenine dinucleotide phosphate oxidase/reactive oxygen species (PKC/NADPH oxidase/ROS) pathway. EAT-derived leptin from MetS rats stimulated inflammation in H9C2 cardiomyocytes by promoting activator protein 1 nuclear translocation via the PKC/NADPH oxidase/ROS pathway. Leptin promoted the interaction between p-p47phox and gp91phox in H9C2 cardiomyocytes via protein kinase C, activating nicotinamide adenine dinucleotide phosphate oxidase, increasing reactive oxygen species generation, and inhibiting cell viability. Conclusions EAT-derived leptin induces MetS-related myocardial injury through the following 2 cooperative ways via PKC/NADPH oxidase/ROS pathway: (1) inducing mitochondrial pathway apoptosis by promoting mitochondrial oxidative stress and dysfunction; and (2) stimulating inflammation by promoting activator protein 1 nuclear translocation.
Journal of the American Heart Association 2023
Background: The causal direction and magnitude of the associations between blood cell count and coronary heart disease (CHD) remain uncertain due to susceptibility of reverse causation and confounding. This study aimed to investigate the associations between blood cell count and CHD using Mendelian randomization (MR). Methods: In this two-sample MR study, we identified independent blood cell count associated genetic variants from a genome-wide association studies (GWAS) among European ancestry individuals. Summary level data of CHD was obtained from a GWAS consisting of 547261 subjects. Methods of inverse variance weighted (IVW), Mendelian Randomization-Egger (MR-Egger), weighted median, and outlier test (MR-PRESSO) were conducted to investigate the associations between blood cell and CHD. Results: Among all cardiovascular outcomes of interest, blood cell counts were only associated with CHD. Our findings indicated that white blood cell count and neutrophil cell count were significantly associated with increased risk of CHD [odds ratio (OR) = 1.07, 95% confidence interval (CI), 1.01-1.14; OR = 1.09, 1.02-1.16). However, there was no significant association between monocyte cell count, basophil cell count, lymphocyte cell count, eosinophil cell count, and CHD (p > 0.05). The results after excluding outliers were consistent with main results and the sensitivity analyses showed no evidence of pleiotropy (MR-Egger intercept, p > 0.05). Conclusion: Our MR study suggested that greater white blood cell count and neutrophil cell count were associated with a higher risk of CHD. Future studies are still warranted to validate the results and investigate the mechanisms underlying these associations.
Frontiers in genetics 2023
As the boom of data storage and processing, brain-inspired computing provides an effective approach to solve the current problem. Various emerging materials and devices have been reported to promote the development of neuromorphic computing. Thereinto, the neuromorphic device represented by memristor has attracted extensive research due to its outstanding property to emulate the brain's functions from synaptic plasticity, sensory-memory neurons to some intelligent behaviors of living creatures. Herein, we mainly review the progress of these brain functions mimicked by neuromorphic devices, concentrating on synapse (i.e. various synaptic plasticity trigger by electricity and/or light), neurons (including the various sensory nervous system) and intelligent behaviors (such as conditioned reflex represented by Pavlov's dog experiment). Finally, some challenges and prospects related to neuromorphic devices are presented.
Science and technology of advanced materials 2023
OBJECTIVE:To compare the risk of stroke and coronary heart disease (CHD) among various blood pressure (BP) levels in diabetic and people without diabetes Chinese patients.METHODS:This cross-sectional study was part of Prospective Urban Rural Epidemiology China study. Patients aged 35 to70 years were recruited from 12 provinces of China between 2005 and 2009. The participants were classified into three groups: hypertension (HTN), high normal BP, and normal BP, and also into SBP and DBP quintiles.RESULTS:A total of 42 959 patients were analyzed with 38 975 (90.7% of total population) people without diabetes and 3984 (9.3% of total population) diabetic patients. Among diabetic patients, the HTN group was associated with an increased risk of stroke (odds ratio, 3.03; 95% confidence interval, 1.47-6.25) and CHD (odds ratio, 2.21; 95% confidence interval, 1.45-3.38), when compared with normal BP group. Similar results were drawn in nondiabetic patients. However, no significant difference in risk of stroke or CHD was found between high normal BP and normal BP groups in either diabetic or nondiabetic patients. Risk of CHD and stroke increased significantly when SBP was above 125 mmHg or DBP above 72 mmHg in people without diabetes, whereas this trend was attenuated in diabetic patients.CONCLUSION:HTN was associated with a two-fold increased risk of CHD and a three-fold increased risk of stroke compared with normotension irrespective of diabetes status. For diabetic patients with HTN, a more comprehensive method is essential for assessing cardiovascular risk.
Journal of hypertension 2018
BACKGROUND AND OBJECTIVE:The association between hypertension and obesity has been confirmed, while no agreement has been reached about which anthropometric adiposity index is the best. This meta-analysis aimed to perform a systematic review and meta-analysis on the associations of hypertension risk with body mass index (BMI), waist circumstance (WC), waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR), and a prospective urban and rural epidemiology study from China (PURE-China) was added into this meta-analysis as an individual study.METHODS:Systematic literature searching was conducted to identify relevant articles published up to September 2018 in CNKI, WANFANG Data, Web of Science, SinoMed, PubMed, MEDLINE, EMBASE, Cochrane Library and cross-referencing. Literature reporting the association of hypertension risk with BMI, WC, WHR, and WHtR were defined as eligible. PURE-China data were analyzed and included as 1 eligible study into meta-analyses. Summary odds ratio (OR) and area under receiver operating characteristic curve (AUC) were pooled using meta-analysis methods. Heterogeneity and publication bias were evaluated. Subgroups based on gender, country and study design were conducted as well.RESULTS:Thirty-eight original articles including PURE-China were included into meta-analyses, involving 309,585 subjects. WHtR had the strongest association with hypertension risk (OR, 1.68; 95% confidence interval, [CI]:1.29-2.19) and prediction ability (AUC, 70.9%; 95% CI: 67.8%-74.2%), which were also confirmed in subgroup analyses based on gender and country. However, BMI was found to have the highest prediction ability in adjusted models of PURE-China and followed WC, both of which were superior to WHtR (73.7% and 73.4% vs 73.2%).CONCLUSIONS:Our overall meta-analysis further confirmed WHtR as a good indicator at discriminating those individuals at increased risk of hypertension, and in some cases, it is better than BMI, WC, and WHR.
Medicine 2018
We aim to evaluate the association of systolic and diastolic blood pressure (SBP and DBP) with estimated urinary sodium (Na) and potassium(K) excretions, and their gram-to-gram Na/K ratio across various salt-diet regions during 2005-2009 in China. A prospective cohort study was conducted to recruit 46,285 participants in China. A single fasting morning urine specimen was collected to estimate 24-hour urinary Na and K excretion using Kawasaki formula. Means of estimated Na and K were 5.7 ± 1.7 and 2.1 ± 0.5 grams/day, respectively, and mean estimated Na/K ratio was 2.8 ± 0.8. Adjusted analyses showed 1.70 mmHg SBP and 0.49 mmHg DBP increase per 1-g increment of estimated Na, while 1.10 mmHg SBP and 0.91 mmHg DBP decrease for one-gram increase of K. A significant increase in SBP (4.33 mmHg) and DBP (1.54 mmHg) per 1 unit increase in Na/K ratio was observed. More changes of SBP (4.39 mmHg) and DBP (1.67 mmHg) per one-unit increase of Na/K ratio were observed in low-salt regions, though significant changes were also found in moderate- and heavy-salt regions (P for heterogeneity < 0.01). Conclusively, decreasing sodium combined with increasing potassium is likely to have a more beneficial effect than decreasing sodium alone, even if those were living in low-salt regions.
Scientific reports 2018
BACKGROUND:The relation between dietary nutrients and cardiovascular disease risk markers in many regions worldwide is unknown. In this study, we investigated the effect of dietary nutrients on blood lipids and blood pressure, two of the most important risk factors for cardiovascular disease, in low-income, middle-income, and high-income countries.METHODS:We studied 125 287 participants from 18 countries in North America, South America, Europe, Africa, and Asia in the Prospective Urban Rural Epidemiology (PURE) study. Habitual food intake was measured with validated food frequency questionnaires. We assessed the associations between nutrients (total fats, saturated fatty acids, monounsaturated fatty acids, polyunsaturated fatty acids, carbohydrates, protein, and dietary cholesterol) and cardiovascular disease risk markers using multilevel modelling. The effect of isocaloric replacement of saturated fatty acids with other fats and carbohydrates was determined overall and by levels of intakes by use of nutrient density models. We did simulation modelling in which we assumed that the effects of saturated fatty acids on cardiovascular disease events was solely related to their association through an individual risk marker, and then compared these simulated risk marker-based estimates with directly observed associations of saturated fatty acids with cardiovascular disease events.FINDINGS:Participants were enrolled into the study from Jan 1, 2003, to March 31, 2013. Intake of total fat and each type of fat was associated with higher concentrations of total cholesterol and LDL cholesterol, but also with higher HDL cholesterol and apolipoprotein A1 (ApoA1), and lower triglycerides, ratio of total cholesterol to HDL cholesterol, ratio of triglycerides to HDL cholesterol, and ratio of apolipoprotein B (ApoB) to ApoA1 (all ptrend<0·0001). Higher carbohydrate intake was associated with lower total cholesterol, LDL cholesterol, and ApoB, but also with lower HDL cholesterol and ApoA1, and higher triglycerides, ratio of total cholesterol to HDL cholesterol, ratio of triglycerides to HDL cholesterol, and ApoB-to-ApoA1 ratio (all ptrend<0·0001, apart from ApoB [ptrend=0·0014]). Higher intakes of total fat, saturated fatty acids, and carbohydrates were associated with higher blood pressure, whereas higher protein intake was associated with lower blood pressure. Replacement of saturated fatty acids with carbohydrates was associated with the most adverse effects on lipids, whereas replacement of saturated fatty acids with unsaturated fats improved some risk markers (LDL cholesterol and blood pressure), but seemed to worsen others (HDL cholesterol and triglycerides). The observed associations between saturated fatty acids and cardiovascular disease events were approximated by the simulated associations mediated through the effects on the ApoB-to-ApoA1 ratio, but not with other lipid markers including LDL cholesterol.INTERPRETATION:Our data are at odds with current recommendations to reduce total fat and saturated fats. Reducing saturated fatty acid intake and replacing it with carbohydrate has an adverse effect on blood lipids. Substituting saturated fatty acids with unsaturated fats might improve some risk markers, but might worsen others. Simulations suggest that ApoB-to-ApoA1 ratio probably provides the best overall indication of the effect of saturated fatty acids on cardiovascular disease risk among the markers tested. Focusing on a single lipid marker such as LDL cholesterol alone does not capture the net clinical effects of nutrients on cardiovascular risk.FUNDING:Full funding sources listed at the end of the paper (see Acknowledgments).
The lancet. Diabetes & endocrinology 2017
24-h urinary sodium excretion is the gold standard for evaluating dietary sodium intake, but it is often not feasible in large epidemiological studies due to high participant burden and cost. Three methods--Kawasaki, INTERSALT, and Tanaka--have been proposed to estimate 24-h urinary sodium excretion from a spot urine sample, but these methods have not been validated in the general Chinese population. This aim of this study was to assess the validity of three methods for estimating 24-h urinary sodium excretion using spot urine samples against measured 24-h urinary sodium excretion in a Chinese sample population. Data are from a substudy of the Prospective Urban Rural Epidemiology (PURE) study that enrolled 120 participants aged 35 to 70 years and collected their morning fasting urine and 24-h urine specimens. Bias calculations (estimated values minus measured values) and Bland-Altman plots were used to assess the validity of the three estimation methods. 116 participants were included in the final analysis. Mean bias for the Kawasaki method was -740 mg/day (95% CI: -1219, 262 mg/day), and was the lowest among the three methods. Mean bias for the Tanaka method was -2305 mg/day (95% CI: -2735, 1875 mg/day). Mean bias for the INTERSALT method was -2797 mg/day (95% CI: -3245, 2349 mg/day), and was the highest of the three methods. Bland-Altman plots indicated that all three methods underestimated 24-h urinary sodium excretion. The Kawasaki, INTERSALT and Tanaka methods for estimation of 24-h urinary sodium excretion using spot urines all underestimated true 24-h urinary sodium excretion in this sample of Chinese adults. Among the three methods, the Kawasaki method was least biased, but was still relatively inaccurate. A more accurate method is needed to estimate the 24-h urinary sodium excretion from spot urine for assessment of dietary sodium intake in China.
PloS one 2016
To explore a scientific boundary of WHtR to evaluate central obesity and CVD risk factors in a Chinese adult population. The data are from the Prospective Urban Rural Epidemiology (PURE) China study that was conducted from 2005-2007. The final study sample consisted of 43 841 participants (18 019 men and 25 822 women) aged 35-70 years. According to the group of CVD risk factors proposed by Joint National Committee 7 version and the clustering of risk factors, some diagnosis parameters, such as sensitivity, specificity and receiver operating characteristic (ROC) curve least distance were calculated for hypertension, diabetes, high serum triglyceride (TG), high serum low density lipoprotein cholesterol (LDL-C), low serum high density lipoprotein cholesterol (HDL-C) and clustering of risk factors (number≥2) to evaluate the efficacy at each value of the WHtR cut-off point. The upper boundary value for severity was fixed on the point where the specificity was above 90%. The lower boundary value, which indicated above underweight, was determined by the percentile distribution of WHtR, specifically the 5th percentile (P5) for both males and females population. Then, based on convenience and practical use, the optimal boundary values of WHtR for underweight and obvious central obesity were determined. For the whole study population, the optimal WHtR cut-off point for the CVD risk factor cluster was 0.50. The cut-off points for severe central obesity were 0.57 in the whole population. The upper boundary values of WHtR to detect the risk factor cluster with specificity above 90% were 0.55 and 0.58 for men and women, respectively. Additionally, the cut-off points of WHtR for each of four cardiovascular risk factors with specificity above 90% in males ranged from 0.55 to 0.56, whereas in females, it ranged from 0.57 to 0.58. The P5 of WHtR, which represents the lower boundary values of WHtR that indicates above underweight, was 0.40 in the whole population. WHtR 0.50 was an optimal cut-off point for evaluating CVD risks in Chinese adults of both genders. The optimal boundaries of WHtR were 0.40 and 0.57, indicating low body weight and severe risk for CVD, respectively, in Chinese adults.
PloS one 2015
