Causal Association of Golgi Protein 73 With Coronary Artery Disease: Evidence from Proteomics and Mendelian Randomization.

Background: Identification of the unknown pathogenic factor driving atherosclerosis not only enhances the development of disease biomarkers but also facilitates the discovery of new therapeutic targets, thus contributing to the improved management of coronary artery disease (CAD). We aimed to identify causative protein biomarkers in CAD etiology based on proteomics and 2-sample Mendelian randomization (MR) design. Methods: Serum samples from 33 first-onset CAD patients and 31 non-CAD controls were collected and detected using protein array. Differentially expressed analyses were used to identify candidate proteins for causal inference. We used 2-sample MR to detect the causal associations between the candidate proteins and CAD. Network MR was performed to explore whether metabolic risk factors for CAD mediated the risk of identified protein. Vascular expression of candidate protein in situ was also detected. Results: Among the differentially expressed proteins identified utilizing proteomics, we found that circulating Golgi protein 73 (GP73) was causally associated with incident CAD and other atherosclerotic events sharing similar etiology. Network MR approach showed low-density lipoprotein cholesterol and glycated hemoglobin serve as mediators in the causal pathway, transmitting 42.1% and 8.7% effects from GP73 to CAD, respectively. Apart from the circulating form of GP73, both mouse model and human specimens imply that vascular GP73 expression was also upregulated in atherosclerotic lesions and concomitant with markers of macrophage and phenotypic switching of vascular smooth muscle cells (VSMCs). Conclusions: Our study supported GP73 as a biomarker and causative for CAD. GP73 may involve in CAD pathogenesis mainly via dyslipidemia and hyperglycemia, which may enrich the etiological information and suggest future research direction on CAD.

Enhanced Cardiomyocyte NLRP3 Inflammasome-Mediated Pyroptosis Promotes d-Galactose-Induced Cardiac Aging.

BACKGROUND: Cardiac aging represents an independent risk factor for aging-associated cardiovascular diseases. Although evidence suggests an association between NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome formation and numerous cardiovascular diseases, its role in cardiac aging remains largely unclear. METHODS AND RESULTS: The longevity of mice with wild-type and NLRP3 knockout (NLRP3-/-) genotypes was assessed, with or without d-galactose treatment. Cardiac function was evaluated using echocardiography, and cardiac histopathology was examined through hematoxylin and eosin and Masson's trichrome staining. Senescence-associated ß-galactosidase (SA-ß-gal) staining was employed to detect cardiac aging. Western blotting was used to assess aging-related proteins (p53, p21) and pyroptosis-related proteins. Additionally, dihydroethidium staining, lactate dehydrogenase release, and interleukin-1ß ELISA assays were performed, along with measurements of total superoxide dismutase and malondialdehyde levels. In vitro, H9c2 cells were exposed to d-galactose for 24 hours in the absence or presence of N-acetyl-l-cysteine (reactive oxygen species inhibitor), BAY-117082 (nuclear factor κ-light-chain enhancer of activated B cells inhibitor), MCC950 (NLRP3 inhibitor), and VX-765 (Caspase-1 inhibitor). Immunofluorescence staining was employed to detect p53, gasdermin D, and apoptosis-associated speck-like protein proteins. Intracellular reactive oxygen species levels were assessed using fluorescence microscopy and flow cytometry. Senescence-associated ß-galactosidase staining and Western blotting were also employed in vitro for the same purpose. The results showed that NLRP3 upregulation was implicated in aging and cardiovascular diseases. Inhibition of NLRP3 extended life span, mitigated the aging phenotype, improved cardiac function and blood pressure, ameliorated lipid metabolism abnormalities, inhibited pyroptosis in cardiomyocytes, and ultimately alleviated cardiac aging. In vitro, the inhibition of reactive oxygen species, nuclear factor κ-light-chain enhancer of activated B cells, NLRP3, or caspase-1 attenuated NLRP3 inflammasome-mediated pyroptosis. CONCLUSIONS: The reactive oxygen species/nuclear factor κ-light-chain enhancer of activated B cells/NLRP3 signaling pathway loop contributes to d-galactose-treated cardiomyocyte senescence and cardiac aging.

Long-term insulin resistance is associated with frailty, frailty progression, and cardiovascular disease.

BACKGROUND: Insulin resistance and diabetes are associated with an increased risk of frailty, and frailty is associated with cardiovascular disease and premature mortality. We aim to investigate the impact of long-term insulin resistance trajectories on future frailty and cardiovascular risk among young adults. METHODS: In total, 3168 participants with a 30-year follow-up period. The baseline period covered the first 15 years as the exposure period. Insulin resistance was determined using the homeostasis model assessment for insulin resistance (HOMA-IR), and three trajectories (low, moderate, and high) were constructed. The subsequent 15 years constituted the event accrual period. Frailty was assessed using a deficit accumulation mode, and cardiovascular outcomes were obtained from the 15-year event accrual period. RESULTS: The mean age of all 3168 participants was 41.0 (37.0-43.0) years, with 1750 (55.2%) being women. Participants in the high level of insulin resistance trajectory had an increased prevalence of frailty (OR: 1.55, 95% CI: 1.05-2.30, P = 0.028). Although no statistically significant associations were observed after full adjustment, single-factor analysis indicated association between the moderate and high trajectories and frailty progression. Additionally, participants with high level of insulin resistance trajectory were associated with an increased risk of cardiovascular disease, coronary heart disease, and stroke. A notable correlation between HOMA-IR trajectory and cardiovascular diseases was still discernible within the subgroup where the frailty index ≥0.12 (HR: 2.12, 95% CI: 1.17-3.83, P = 0.013) (P for interaction >0.05). CONCLUSIONS: Long-term high level of insulin resistance is associated with high prevalence of frailty, and an increased risk of cardiovascular events. Emphasizing the importance of early prevention and intervention for abnormal glucose metabolism in young adults to prevent frailty and cardiovascular disease.

Protocol for a randomized controlled trial exploring the brain mechanism and therapeutic effect of electroacupuncture on cognitive function and sleep quality in chronic insomnia.

BACKGROUND: Insomnia is a prevalent sleep disorder that affects up to 15% of the population worldwide and is the second most common mental health issue. There is increasing interest in the effects of long-term insomnia on cognitive function. Electroacupuncture can effectively improve cognitive function and sleep quality, yet the underlying brain network mechanisms remain unclear. This study aims to explore the network regulatory mechanisms associated with enhanced cognitive function and sleep quality, providing theoretical support for the use of electroacupuncture in the clinical treatment of chronic insomnia. METHODS: This study is divided into two parts. Sixteen individuals with chronic insomnia and 16 healthy controls of similar age and gender will be recruited in Study 1 to examine the brain network topology of individuals with chronic insomnia. Study 2 will be a randomized controlled trial with 120 chronic insomnia patients divided into three groups: Group A (electroacupuncture plus placebo drug), Group B (drug plus placebo electroacupuncture), and Group C (placebo electroacupuncture plus placebo drug). Participants will be exposed to 24 treatments over an 8-week period (3 times per week) and monitored for 12 additional weeks. The primary outcome measure will be changes in brainwave data from before to after the treatment. In addition, the Wisconsin Card Sorting Test and the Pittsburgh Sleep Quality Index will be utilized as secondary outcomes to measure from before to after treatment and during the follow-up. A correlation analysis will be conducted to explore links among modifications in brainwave patterns, Wisconsin Card Sorting Test scores, and Pittsburgh Sleep Quality Index scores. Additionally, any adverse events will be strictly monitored. DISCUSSION: Electroacupuncture may represent an alternative treatment for chronic insomnia, and this trial is expected to reveal the brain mechanism by which electroacupuncture improves cognitive function and sleep quality in chronic insomnia patients. TRIAL REGISTRATION: ChiCTR2200060150 (Chinese Clinical Trial Registry, http://www.chictr.org.cn , registered on 20 May 2022).

GP73 enhances the ox-LDL-induced inflammatory response in THP-1 derived macrophages via affecting NLRP3 inflammasome signaling.

BACKGROUND: Atherosclerosis is a chronic inflammatory disease with its molecular basis incompletely understood. Here, we determined whether the Golgi phosphoprotein 73 (GP73), a novel protein highly related to inflammation and disrupted lipid metabolism, was involved in the development of atherosclerosis. METHODS: Public microarray databases of human vascular samples were analyzed for expression patterns. Apolipoprotein-E-gene-deficient (ApoE-/-) mice (8-week-old) were randomly assigned to either a chow diet group or a high-fat diet group. The levels of serum GP73, lipid profiles and key inflammatory cytokines were determined by ELISA. The aortic root plaque was isolated and used for by Oil Red O staining. PMA-differentiated THP-1 macrophages were transfected with GP73 small interfering RNA (siRNA) or infected with adenovirus expressing GP73, and then stimulated with oxidized low density lipoprotein (ox-LDL). The expressions of pro-inflammatory cytokines and signal pathway key targets were determined by ELISA kit and Western blot respectively. In addition, ichloro-dihydro-fluorescein diacetate (DCFH-DA) was used to measure the intracellular ROS levels. RESULTS: The expressions of GP73 and NLRP3 were substantially upregulated in human atherosclerotic lesions. There were significant linear correlations between GP73 and inflammatory cytokines expressions. High-fat diet-induced atherosclerosis and increased levels of plasma inflammatory mediators (IL-1ß, IL-18, and TNF-α) were observed in ApoE-/- mice. Besides, the expressions of GP73 in the aorta and serum were significantly upregulated and positively correlated with the NLRP3 expression. In the THP-1 derived macrophages, ox-LDL treatment upregulated the expressions of GP73 and NLRP3 proteins and activated the inflammatory responses in a concentration-dependent and time-dependent manner. Silencing of GP73 attenuated the inflammatory response and rescued the decreased migration induced by ox-LDL, inhibiting the NLRP3 inflammasome signaling and the ROS and p-NF-κB activation. CONCLUSIONS: We demonstrated that GP73 promoted the ox-LDL-induced inflammation in macrophages by affecting the NF-κB/NLRP3 inflammasome signaling, and may play a role in atherosclerosis.

D-galactose-induced cardiac ageing: A review of model establishment and potential interventions.

Cardiovascular disease (CVD) is highly prevalent in an ageing society. The increased incidence and mortality rates of CVD are global issues endangering human health. There is an urgent requirement for understanding the aetiology and pathogenesis of CVD and developing possible interventions for preventing CVD in ageing hearts. It is necessary to select appropriate models and treatment methods. The D-galactose-induced cardiac ageing model possesses the advantages of low mortality, short time and low cost and has been increasingly used in the study of cardiovascular diseases in recent years. Therefore, understanding the latest progress in D-galactose-induced cardiac ageing is valuable. This review highlights the recent progress and potential therapeutic interventions used in D-galactose-induced cardiac ageing in recent years by providing a comprehensive summary of D-galactose-induced cardiac ageing in vivo and in vitro. This review may serve as reference literature for future research on age-related heart diseases.

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

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

NLRP3 inflammasome activation contributes to the pathogenesis of cardiocytes aging.

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 ß-galactosidase (ß-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-1ß, IL-18 and lactate dehydrogenase (LDH) release were also detected. RESULTS: D-gal induced-H9c2 cells caused cardiocytes' aging changes (ß-gal staining, CellEvent™ Senescence Green staining, P53, P21) in a concentration-dependent manner. NLRP3 inflammasomes were activated, IL-1ß, 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.

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

Introduction: Hypertension (HT) and atrial fibrillation (AF) often coexist. However, the causality between these two conditions remains to be determined. Methods: 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. Results: 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, P = 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. Conclusions: 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.

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

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.

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

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.

Association between calf girth and peripheral artery disease in the Atherosclerosis Risk in Communities Study.

BACKGROUND: The pathogenesis of peripheral artery disease (PAD) is associated with impaired calf muscle. We sought to investigate the association between gender-specific calf girth and the prevalence of PAD among participants from a community-based cohort study. METHODS: A total 13,808 participants in the Atherosclerosis Risk in Communities (ARIC) study without prior PAD were included in the final analysis. Calf girth was measured at baseline (1985-1987). A hospital diagnosis with an ICD-9 code defined incident PAD during follow up. Cox regression analysis adjusted for demographic variables and other covariates was used to estimate hazard ratios (HR) and 95% confidence interval (CI) for the association between calf girth and PAD. RESULTS: After a medium follow-up of 25.2 years, the overall prevalence of PAD in our study was 5.2% (721/13,808), 335 patients were women and 386 were men. The adjusted HR for PAD with calf girth as continuous variables was 0.99 (95% CI 0.95-1.04) in females and 0.93 (95% CI 0.88-0.99) in males, respectively. Moreover, interaction for gender was statistically significant between calf girth and PAD in overall population (p=0.001). CONCLUSIONS: Our findings revealed a linear association of calf girth with the prevalence of PAD among male participants in ARIC.

Causal assessment of sleep on coronary heart disease.

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.

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

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 (Pheterogeneity = 0.981 [MR-Egger] and Pheterogeneity = 0.860 [IVW]) nor pleiotropy effect (Ppleiotropy = 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.

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

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.

Effectiveness of blood pressure-lowering treatment by the levels of baseline Framingham risk score: A post hoc analysis of the Systolic Blood Pressure Intervention Trial (SPRINT).

This was a post hoc analysis of Systolic Blood Pressure Intervention Trial (SPRINT), aimed to investigate whether intensive blood pressure treatment has differential therapeutic outcomes on patients with different baseline Framingham risk score (FRS). The 9298 SPRINT participants were categorized into low-risk (baseline FRS < 10%), intermediate-risk (FRS = 10%-20%), or high-risk (FRS > 20%) arms. The primary outcome was a composite of myocardial infarction, acute coronary syndrome not resulting in myocardial infarction, stroke, acute decompensated heart failure, or death from cardiovascular causes. Serious adverse events were defined as hypotension, syncope, and bradycardia. Multiple Cox regression was used to calculate hazard ratios for study outcomes with intensive compared with standard SBP treatment between these three groups. After a median follow-up time of 3.26 years, the primary outcome hazard ratio (HR) for intensive versus standard treatment was 0.73 (95% CI: 0.61-0.88, P = .0044) in the high-risk arm. And, for all-cause mortality, the hazard ratio with intensive SBP treatment was 1.58 (95% CI: 0.55-1.06), 0.9 (95% CI: 0.26-9.50), and 0.53 (95% CI: 0.34-0.82) in three arms (all P values for interaction > 0.05). Effects of intensive versus standard SBP control on serious adverse events were similar among patients with different FRS. Our results suggested that regardless of the FRS level, the intensive blood pressure control was beneficial.

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

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

Immunosuppressive Effect of Ticagrelor on Dendritic Cell Function: A New Therapeutic Target of Antiplatelet Agents in Cardiovascular Disease.

Atherosclerosis is being thought of as an autoimmune disease. As the most potent antigen-presenting cells, dendritic cells (DCs) have been regarded as a major target for the control of this harmful immune response. In this study, we investigated the effect of ticagrelor, a new antiplatelet drug antagonizing the P2Y12 receptor, on the function of mouse bone marrow-derived DCs. RT-PCR revealed relatively high P2Y12 mRNA levels in DCs, and expression of the P2Y12 protein was documented by western blot analysis. Moreover, antigen (Ag) uptake by DCs was markedly increased following activation of the P2Y12 receptor by adenosine-5'-O-(2-thiodiphosphate) (ADPßS). Ticagrelor reduced the ADPßS-stimulated uptake of fluorescein-labeled dextran by DCs while exerting no significant effect on spontaneous endocytosis. In addition, ticagrelor suppressed the capacity of ADPßS-stimulated DCs to induce activation of T lymphocytes. Ticagrelor blocked the activation of phosphatidylinositol 3-kinase (PI3K) and extracellular signal-regulated kinase 1/2 (ERK1/2) in ADPßS-treated DCs. Preventing the activation of PI3K reduced significantly ADPßS-induced endocytosis by DCs. Thus, ticagrelor decreases Ag uptake by DCs via the inhibition of P2Y12 receptor-mediated PI3K activity, attenuating the stimulation of Ag-specific T cells. Our findings indicate that ticagrelor may directly target DCs and inhibit their function, suggesting a possible explanation for the immunoregulatory activity of this drug.

Toward a panoramic perspective of the association between environmental factors and cardiovascular disease: An environment-wide association study from National Health and Nutrition Examination Survey 1999-2014.

OBJECTIVES: An environment-wide association study (EWAS) may be useful to comprehensively test and validate associations between environmental factors and cardiovascular disease (CVD) in an unbiased manner. APPROACH AND RESULTS: Data from National Health and Nutrition Examination Survey (1999-2014) were randomly 50:50 spilt into training set and testing set. CVD was ascertained by a self-reported diagnosis of myocardial infarction, coronary heart disease or stroke. We performed multiple linear regression analyses associating 203 environmental factors and 132 clinical phenotypes with CVD in training set (false discovery rate < 5%) and significant factors were validated in the testing set (P < 0.05). Random forest (RF) model was used for multicollinearity elimination and variable importance ranking. Discriminative power of factors for CVD was calculated by area under the receiver operating characteristic (AUROC). Overall, 43,568 participants with 4084 (9.4%) CVD were included. After adjusting for age, sex, race, body mass index, blood pressure and socio-economic level, we identified 5 environmental variables and 19 clinical phenotypes associated with CVD in training and testing dataset. Top five factors in RF importance ranking were: waist, glucose, uric acid, and red cell distribution width and glycated hemoglobin. AUROC of the RF model was 0.816 (top 5 factors) and 0.819 (full model). Sensitivity analyses reveal no specific moderators of the associations. CONCLUSION: Our systematic evaluation provides new knowledge on the complex array of environmental correlates of CVD. These identified correlates may serve as a complementary approach to CVD risk assessment. Our findings need to be probed in further observational and interventional studies.