Psoriasis may increase the risk of idiopathic pulmonary fibrosis: a two-sample Mendelian randomization study.

BACKGROUND: Although some studies have indicated that Psoriasis could contribute to the risk of idiopathic pulmonary fibrosis (IPF), no study has reported a clear causal association between them. Our aim was to explore the potential relationship between Psoriasis and IPF using Mendelian randomization (MR) design. METHODS: To explore a causal association between Psoriasis and IPF, we used genetic instruments from the largest available genome-wide association study (GWAS) of European ancestry, including psoriasis (5314 cases, 457,619 controls) and IPF (1028 cases, 196,986 controls). Our main analyses were conducted by inverse-variance weighted (IVW) method with random-effects model, with the other complementary four analyses: weighted median method, weighted mode, multivariable MR and MR-Egger approach. RESULTS: The results of IVW methods demonstrated that genetically predicted psoriasis was significantly associated with higher odds of IPF, with an odds ratio (OR) of 1.09 (95%CI, 1.01-1.18; P = 0.02). Weighted median method, weighted mode and multivariable MR also demonstrated directionally similar results (P < 0.05), while the MR-Egger regression did not reveal the impact of psoriasis on IPF (OR = 1.09, 95%CI, 0.98-1.21; P = 0.11). In addition, both funnel plots and MR-Egger intercepts indicated no directional pleiotropic effects between psoriasis and IPF. CONCLUSIONS: Our study provided potential evidence between genetically predicted psoriasis and IPF, which suggests that understanding the mutual risk factors between psoriasis and IPF can facilitate the clinical management of both diseases.

The causality between Type 2 diabetes and breast cancer: a bidirectional two-sample Mendelian randomization study.

Objective: Observational studies showed that Type 2 diabetes increased the risk of breast cancer, and vice versa. However, it is uncertain whether the link is causal or just due to confounding factors. Using bidirectional Mendelian randomization analysis, we assessed the bidirectional causal relationship from a genetic level. Methods: Large genome-wide association studies yielded summary-level data for Type 2 diabetes and breast cancer. Results: Genetically predicted Type 2 diabetes presented no statistically significant association with overall breast cancer or its subtypes. Similarly, genetically predicted overall breast cancer or its subtypes had no causal effect on Type 2 diabetes. Sensitivity analyses yielded similar results. Conclusion: Our bidirectional Mendelian randomization studies revealed no causal links between Type 2 diabetes and breast cancer.

[Box: see text].

Atorvastatin-pretreated mesenchymal stem cell-derived extracellular vesicles promote cardiac repair after myocardial infarction via shifting macrophage polarization by targeting microRNA-139-3p/Stat1 pathway.

BACKGROUND: Extracellular vesicles (EVs) derived from bone marrow mesenchymal stem cells (MSCs) pretreated with atorvastatin (ATV) (MSCATV-EV) have a superior cardiac repair effect on acute myocardial infarction (AMI). The mechanisms, however, have not been fully elucidated. This study aims to explore whether inflammation alleviation of infarct region via macrophage polarization plays a key role in the efficacy of MSCATV-EV. METHODS: MSCATV-EV or MSC-EV were intramyocardially injected 30 min after coronary ligation in AMI rats. Macrophage infiltration and polarization (day 3), cardiac function (days 0, 3, 7, 28), and infarct size (day 28) were measured. EV small RNA sequencing and bioinformatics analysis were conducted for differentially expressed miRNAs between MSCATV-EV and MSC-EV. Macrophages were isolated from rat bone marrow for molecular mechanism analysis. miRNA mimics or inhibitors were transfected into EVs or macrophages to analyze its effects on macrophage polarization and cardiac repair in vitro and in vivo. RESULTS: MSCATV-EV significantly reduced the amount of CD68+ total macrophages and increased CD206+ M2 macrophages of infarct zone on day 3 after AMI compared with MSC-EV group (P < 0.01-0.0001). On day 28, MSCATV-EV much more significantly improved the cardiac function than MSC-EV with the infarct size markedly reduced (P < 0.05-0.0001). In vitro, MSCATV-EV also significantly reduced the protein and mRNA expressions of M1 markers but increased those of M2 markers in lipopolysaccharide-treated macrophages (P < 0.05-0.0001). EV miR-139-3p was identified as a potential cardiac repair factor mediating macrophage polarization. Knockdown of miR-139-3p in MSCATV-EV significantly attenuated while overexpression of it in MSC-EV enhanced the effect on promoting M2 polarization by suppressing downstream signal transducer and activator of transcription 1 (Stat1). Furthermore, MSCATV-EV loaded with miR-139-3p inhibitors decreased while MSC-EV loaded with miR-139-3p mimics increased the expressions of M2 markers and cardioprotective efficacy. CONCLUSIONS: We uncovered a novel mechanism that MSCATV-EV remarkably facilitate cardiac repair in AMI by promoting macrophage polarization via miR-139-3p/Stat1 pathway, which has the great potential for clinical translation.

Causal relationships of circulating amino acids with cardiovascular disease: a trans-ancestry Mendelian randomization analysis.

BACKGROUND: Epidemiological studies demonstrated that multiple amino acids (AAs) were associated with cardiovascular diseases (CVDs), but whether these associations were causal remains unclear. This study aims to investigate the causal relationships between circulating levels of 20 AAs and 10 CVDs in European and East Asian populations by Mendelian randomization (MR). METHODS: This MR study utilized single-nucleotide polymorphisms that were significantly associated with AAs as instrumental variables. Summary-level data for AAs and CVDs were obtained from public genome-wide association studies. The causal effects were primarily estimated by inverse variance weighting with multiplicative random effect method. Sensitivity analyses, including weighted median, weighted mode, and MR Egger regression, were used to test the robustness of our results. RESULTS: In the European population, alanine and serine were inversely associated with angina pectoris (AP) and chronic heart failure, respectively. With each unit increase of leucine, the risk of ischemic stroke increased by 10%. Moreover, tyrosine was positively associated with AP and deep vein thrombosis. In the East Asian population, each unit increase in glycine was associated with 4.1% and 9.0% decreased risks of coronary artery disease (CAD) and myocardial infarction (MI), respectively. A unit increase in serine was associated with 13.1%, 12.6% and 15.5% decreased risks of AP, CAD and MI, respectively. Sensitivity analyses supported the robustness of our results. CONCLUSIONS: This MR study demonstrated significant causal effects of circulating levels of AAs on CVDs, indicating the potential use of AAs as biomarkers or as therapeutic targets for CVD in clinical scenarios.

Causal Associations Between Cardiovascular Risk Factors and Venous Thromboembolism.

OBJECTIVE: The aim of the study is to assess the causal effects of cardiovascular risk factors on venous thromboembolism (VTE) and its subtypes including deep vein thrombosis (DVT) and pulmonary embolism (PE). METHODS: A summary-level Mendelian randomization (MR) analysis was performed by extracting data from public and large-scale genome-wide association studies for cardiovascular risk factors (hypertension, systolic blood pressure [SBP], diastolic blood pressure [DBP], total cholesterol, triglycerides, high-density lipoprotein [HDL], low-density lipoprotein [LDL], type 2 diabetes, fasting glucose, body mass index [BMI], smoking, alcohol, and physical activity), VTE, DVT, and PE to identify genetic instruments. RESULTS: BMI (per standard deviation [SD] increase; odds ratio [OR]: 1.39; 95% confidence interval [CI]: 1.25-1.54; p = 8.02 × 10-10) could increase the VTE risk, whereas SBP (per SD increase; OR: 0.99; 95% CI: 0.98-0.99; p = 0.0005) could decrease the VTE risk. For DVT, BMI (per SD increase; OR: 1.48; 95% CI: 1.28-1.72; p = 1.53 × 10-7) could increase the risk, whereas physical activity (per SD increase; OR: 0.05; 95% CI: 0.01-0.33; p = 0.0020) could decrease the risk. For PE, BMI (per SD increase; OR: 1.29; 95% CI: 1.12-1.49; p = 0.0005) could increase the risk, whereas SBP (per SD increase; OR: 0.99; 95% CI: 0.98-1.00; p = 0.0032) could decrease the risk. Suggestive evidence between smoking and higher risks of VTE and DVT was also observed. CONCLUSION: Our study supports that BMI is a causal risk factor for VTE, DVT, and PE. SBP is a protective factor for VTE and PE. Physical activity is a protective factor for DVT. However, the effects of other cardiovascular risk factors are not identified.

Individual or familial diabetes in relation to eight cardiovascular diseases: A two-sample Mendelian randomization study.

BACKGROUND AND AIMS: Diabetes is associated with increased risk of certain cardiovascular diseases, yet the causality remains to be determined. Meanwhile, given that first-degree relatives share 50% of genes, the effect of familial diabetes is also worthy of attention. Therefore, we sought to investigate the causal relations of individual or familial diabetes with eight cardiovascular diseases, including myocardial infarction, hypertension, atrial fibrillation, heart failure, cardiac death, pulmonary embolism, transient ischemic attack, and ischemic stroke. METHODS AND RESULTS: Applying two-sample Mendelian randomization, we selected instruments for genetic predisposition to individual or familial diabetes based on published genome-wide association studies. The primary analyses were conducted using the random-effects inverse-variance weighted method. We found that genetically predicted individual diabetes was causally associated with higher risks of myocardial infarction (odd ratio [OR] = 1.09; 95% confidence interval [CI]: 1.05-1.13; P < 0.0001), hypertension (OR = 1.08; 95% CI: 1.03-1.13; P = 0.0006), and ischemic stroke (OR = 1.10; 95% CI: 1.05-1.15; P < 0.0001). Genetically predicted paternal diabetes could increase the risk of ischemic stroke (OR = 1.16; 95% CI: 1.04-1.30; P = 0.0061). Genetically predicted maternal diabetes could increase the risk of myocardial infarction (OR = 1.18; 95% CI: 1.09-1.29; P = 0.0001). Genetically predicted siblings' diabetes was causally associated with higher risks of myocardial infarction (OR = 1.17; 95% CI: 1.08-1.27; P = 0.0001) and hypertension (OR = 1.19; 95% CI: 1.06-1.34; P = 0.0036). No significant differences were observed in other outcomes. CONCLUSION: This study supports causal effects of not only individual but also familial diabetes on the development of cardiovascular diseases, which will help realize the potential effect of family history in the prevention of cardiovascular diseases.

Causal relationship between moderate to vigorous physical activity and venous thromboembolism.

Previous studies have shown conflicting results about the impact of moderate to vigorous physical activity on the risk of venous thromboembolism (VTE).  Using Mendelian randomization, we assessed whether moderate to vigorous physical activity causally affects VTE from genetic level. Genetic instruments associated with moderate to vigorous physical activity at the genome-wide significance level (P < 5×10- 8) were selected from the UK Biobank. Summary-level data for VTE were obtained from the FinnGen consortium. Univariable and multivariable Mendelian randomization analyses were conducted. Genetically predicted moderate to vigorous physical activity had no effect on VTE [odds ratio (OR) = 1.08; 95% confidence interval (CI) 0.66-1.78; P = 0.75] under a multiplicative random-effects inverse-variance weighted model. MR-Egger (OR = 0.20; 95% CI 0.01-4.70; P = 0.33), weighted median (OR = 1.08; 95% CI 0.52-2.25; P = 0.84), simple mode (OR = 2.53; 95% CI 0.59-10.92; P = 0.23), weighted mode (OR = 2.21; 95% CI 0.50-9.74; P = 0.31), and multivariable Mendelian randomization (OR = 0.74; 95% CI 0.46-1.19; P = 0.22) also yielded no significant association. The overall estimate was not influenced by individual single nucleotide polymorphism. No evidence of heterogeneity or horizontal pleiotropy was observed. Therefore, moderate to vigorous physical activity had no causal association with VTE in the general population.

De-escalation of Dual Antiplatelet Therapy After Percutaneous Coronary Intervention in Patients With Acute Coronary Syndrome: An Updated Meta-analysis and Trial Sequential Analysis of 21 Studies and 38,741 Patients.

ABSTRACT: Dual antiplatelet therapy (DAPT) is recommended among patients with established acute coronary syndrome. In this meta-analysis, we sought to compare the clinical outcomes between de-escalation versus unchanged DAPT based on both randomized controlled trials (RCTs) and observational studies. The primary outcomes were major adverse cardiovascular events for observational studies and net clinical events for RCTs. Four RCTs and 17 observational studies with a total of 38,741 patients were included. Net clinical events were more common with unchanged DAPT than with de-escalation in RCTs [odd ratio (OR): 1.71; 95% confidence interval (CI), 1.21-2.43; I2 = 69.4%], which was mainly due to higher risks of any bleeding (OR: 1.81; 95% CI, 1.14-2.88; I2 = 75.5%) and major bleeding (OR: 1.58; 95% CI, 1.02-2.46; I2 = 0), without significant differences in ischaemic events. However, trial sequential analysis revealed that sufficient information was obtained just for net clinical events, not for respective ischaemic or bleeding events in RCTs. In the analysis based on real-world observational studies, the risks of myocardial infarction (OR: 0.77; 95% CI, 0.61-0.98; I2 = 0) and stroke (OR: 0.42; 95% CI, 0.22-0.81; I2 = 0) were lower with the unchanged DAPT group. Therefore, de-escalation of DAPT led to a marked reduction in net clinical events compared with unchanged DAPT in RCTs, which was mainly due to reduced bleeding events. However, sufficient information for ischaemic events was not obtained. In the analysis based on real-world observational studies, myocardial infarction and stroke were more common with de-escalation, which should arise our attention.

Impact of percutaneous coronary intervention on chronic total occlusion in the non-infarct-related artery in patients with STEMI: a systematic review and meta-analysis.

OBJECTIVES: We sought to compare the clinical outcomes between culprit-only percutaneous coronary intervention (PCI) versus multivessel PCI (MV-PCI) in patients with ST-segment elevation myocardial infarction (STEMI) accompanied by chronic total occlusion (CTO) in the non-infarct-related artery(non-IRA). DESIGN: Studies that compared culprit-only PCI versus MV-PCI in patients with STEMI accompanied by CTO in the non-IRA were included. Random odds ratio (OR) and 95% confidence interval (CI) were calculated. RESULTS: Eight studies with 2,259 patients were included. The results suggested that in patients with STEMI accompanied by CTO in the non-IRA, culprit-only PCI was associated with higher risks of all-cause mortality (OR: 2.89; 95% CI: 2.09-4.00; I2 = 0.0%), cardiac death (OR: 3.12; 95% CI: 2.05-4.75; I2 = 16.8%), stroke (OR: 2.80; 95% CI: 1.04-7.53; I2 = 0.0%), major adverse cardiovascular event (MACE; OR: 2.06; 95% CI: 1.39-3.06; I2 = 54.0%), and heart failure (OR: 1.99; 95% CI: 1.22-3.24; I2 = 0.0%) compared with staged MV-PCI, which were mainly derived from retrospective studies. No differences were observed in myocardial infarction or revascularization. Pooled multivariable adjusted results consistently indicated that staged MV-PCI was superior to culprit-only PCI. CONCLUSIONS: For patients with STEMI accompanied by CTO in the non-IRA, staged MV-PCI may be better compared with culprit-only PCI due to potential reduced risks of all-cause mortality, cardiac death, stroke, MACE, and heart failure. Meanwhile, further randomized trials are warranted to confirm or refute our findings.

Sensing of Soil Organic Matter Using Laser-Induced Breakdown Spectroscopy Coupled with Optimized Self-Adaptive Calibration Strategy.

Rapid quantification of soil organic matter (SOM) is a great challenge for the health assessment and fertility management of agricultural soil. Laser-induced breakdown spectroscopy (LIBS) with appropriate modeling algorithms is an alternative tool for this measurement. However, the current calibration strategy limits the prediction performance of the LIBS technique. In this study, 563 soil samples from Hetao Irrigation District in China were collected; the LIBS spectra of the soils were recorded in the wavenumber range of 288-950 nm with a resolution of 0.116 nm; a self-adaptive partial least squares regression model (SAM-PLSR) was employed to explore optimal model parameters for SOM prediction; and calibration parameters including sample selection for the calibration database, sample numbers and sample location sites were optimized. The results showed that the sample capacity around 60-80, rather than all of the samples in the soil library database, was selected for calibration from a spectral similarity re-ordered database regarding unknown samples; the model produced excellent predictions, with R2 = 0.92, RPD = 3.53 and RMSEP = 1.03 g kg-1. Both the soil variances of the target property and the spectra similarity of the soil background were the key factors for the calibration model, and the small sample set led to poor predictions due to the low variances of the target property, while negative effects were observed for the large sample set due to strong interferences from the soil background. Therefore, the specific unknown sample depended strategy, i.e., self-adaptive modelling, could be applied for fast SOM sensing using LIBS for soils in varied scales with improved robustness and accuracy.

Beta-Blocker Use after Discharge in Patients with Acute Myocardial Infarction in the Contemporary Reperfusion Era.

Background and objectives: The effect of beta-blocker use after discharge on patients with acute myocardial infarction (AMI) in the contemporary reperfusion era remains ambiguous. By applying meta-analysis, we sought to assess the role of beta-blockers in the contemporary reperfusion era. Materials and Methods: Randomized controlled trials (RCT) and observational studies using propensity score matching, comparing use of beta-blockers with non-use of beta-blockers, in patients with AMI after discharge. The primary outcome was all-cause mortality. Odds ratios (OR) and associated 95% confidence intervals (CI) were calculated. Results: One RCT and eight observational studies, containing 47,339 patients with AMI, were included. Compared with non-use of beta-blockers, beta-blocker use after discharge may have reduced the risk of all-cause mortality (OR: 0.70, 95% CI: 0.61 to 0.80, I2 = 14.4%), cardiac death (OR: 0.63, 95% CI: 0.44 to 0.91, I2 = 22.8%), myocardial infarction (OR: 0.73, 95% CI: 0.62 to 0.86, I2 = 0), and revascularization (OR: 0.92, 95% CI: 0.85 to 0.99, I2 = 0). No significant differences were found in major adverse cardiovascular events (MACE, OR: 0.88, 95% CI: 0.66 to 1.17, I2 = 78.4%), heart failure (OR: 0.56, 95% CI: 0.29 to 1.08, I2 = 0) or stroke (OR: 1.13, 95% CI: 0.92 to 1.39, I2 = 0). For patients with preserved left ventricular function, beta-blocker use after discharge may have also reduced the risk of all-cause mortality (OR: 0.61, 95% CI: 0.44 to 0.84, I2 = 0). Conclusions: Use of beta-blockers after discharge may still be beneficial for AMI patients in the contemporary reperfusion era, with or without preserved left ventricular function.

Facile one-pot synthesis, antiproliferative evaluation and structure-activity relationships of 3-amino-1H-indoles and 3-amino-1H-7-azaindoles.

A highly efficient method has been developed for the one-pot synthesis of substituted 3-amino-1H-indole and 3-amino-1H-7-azaindole derivatives starting from ethyl 2-cyanophenylcarbamate/ethyl 3-cyanopyridin-2-ylcarbamate, and α-bromoketones in good to excellent yields. All newly synthesized analogues were screened for their antiproliferative activities against four cancer cell lines. The most promising compound 8v demonstrated 13-, 5-, and 1.4-fold improvement compared to fluorouracil in inhibiting HeLa, HepG2, and MCF-7 cell proliferation with IC50 values of 3.7, 8.0, and 19.9 µM, respectively. Furthermore, 8v induced significant cell cycle arrest at the G2/M phase in HeLa cell lines via a concentration-dependent manner. These encouraging findings indicate that the common 3-amino-1H-7-azaindole is a very favorable scaffold for the design of novel anticancer small-molecule drugs.

Design, synthesis and biological evaluation of novel 3-alkylsulfanyl-4-amino-1,2,4-triazole derivatives.

Based on our previous work, a series of novel 3-alkylsulfanyl-4-amino-1,2,4-triazole derivatives were designed, synthesized and evaluated for their antiproliferative activities. The results indicated that some compounds possessed significant antiproliferative activities against four cancer cell lines, HepG2, HCT116, PC-3, and Hela. Particularly, the most promising compound 8d displayed 184-, 18-, and 17-fold improvement compared to fluorouracil in inhibiting HCT116, Hela and PC-3 cell proliferation with IC50 values of 0.37, 2.94, and 31.31µM, respectively. Most interestingly, the compound did not affect the normal human embryonic kidney cells, HEK-293. Moreover, mechanistic investigation showed that the representative compound 8d induced apoptosis and blocked cell cycle in G2/M phase in Hela cells in a dose-dependent manner. These findings suggest that compound 8d may have potential to be developed as a promising lead for the design of novel anticancer small-molecule drugs.

Causal Associations of Education Level With Cardiovascular Diseases, Cardiovascular Biomarkers, and Socioeconomic Factors.

An inverse association of education level with cardiovascular diseases has been documented in observational studies, yet the causality and potential mechanisms remain to be determined. To systematically investigate the causal associations of education level with cardiovascular diseases, cardiovascular biomarkers, and socioeconomic factors, a 2-sample Mendelian randomization was performed. The results revealed that higher genetically determined education level was associated with lower risks of type 2 diabetes mellitus (odds ratio [OR] 0.54, 95% confidence interval [CI] 0.47 to 0.61, p = 3.04 × 10-23), peripheral artery disease (OR 0.62, 95% CI 0.51 to 0.76, p = 2.14 × 10-06), hypertension (OR 0.62, 95% CI 0.56 to 0.70, p = 4.22 × 10-16), coronary heart disease (OR 0.62, 95% CI 0.56 to 0.69, p = 3.50 × 10-19), myocardial infarction (OR 0.62, 95% CI 0.55 to 0.69, p = 2.58 × 10-16), ischemic stroke (OR 0.67, 95% CI 0.62 to 0.74, p = 6.00 × 10-19), deep vein thrombosis (OR 0.69, 95% CI 0.55 to 0.87, p = 0.0017), atrial fibrillation (OR 0.70, 95% CI 0.57 to 0.86, p = 0.0007), cardiac death (OR 0.71, 95% CI 0.60 to 0.86, p = 0.0003), heart failure (OR 0.72, 95% CI 0.65 to 0.79, p = 6.37 × 10-12), transient ischemic attack (OR 0.76, 95% CI 0.64 to 0.90, p = 0.0010), and venous thromboembolism (OR 0.79, 95% CI 0.67 to 0.92, p = 0.0028). Systolic blood pressure, diastolic blood pressure, C-reactive protein, body mass index, waist circumference, and triglycerides were decreased, whereas telomere length was increased. Subjects with higher education were less likely to smoke, intake salt, or be exposed to air pollution and depression state. They were more likely to take physical activity and possess more household income. In conclusion, higher education may causally decrease cardiovascular diseases through socioeconomic factors and cardiovascular biomarkers. Reducing education inequality is important in the management of cardiovascular diseases.

Causal associations between atrial fibrillation and breast cancer: A bidirectional Mendelian randomization analysis.

BACKGROUND: Previous observational studies indicated that atrial fibrillation may increase the risk of breast cancer. Following a breast cancer diagnosis, the chance of developing atrial fibrillation may increase as well. However, it is uncertain whether the link is causal or just due to confounding factors. OBJECTIVE: Using bidirectional Mendelian randomization (MR) analysis, we sought to assess the bidirectional causal relationship between atrial fibrillation and breast cancer from a genetic level. METHODS: Large genome-wide association studies yielded summary-level data for atrial fibrillation and breast cancer. The preliminary estimate was inverse variance weighted (IVW) under a random model. MR-Egger, weighted median, simple mode, weighted mode, and multivariable MR (adjusting body mass index, smoking, and alcohol drinking) were performed as sensitivity analyses. RESULTS: Genetically predicted atrial fibrillation presented no statistically significant association with overall breast cancer (odds ratio [OR] = 1.00; 95% confidence interval [CI]: 0.97-1.04; p = 0.79), estrogen receptor (ER) + (OR = 1.00; 95% CI: 0.96-1.03; p = 0.89) or ER- subtypes (OR = 1.00; 95% CI: 0.97-1.04; p = 0.89). Similarly, genetically predicted overall breast cancer (OR = 1.01; 95% CI: 0.98-1.04; p = 0.37), ER+ (OR = 1.02; 95% CI: 0.99-1.05; p = 0.16) or ER- (OR = 0.98; 95% CI: 0.93-1.02; p = 0.32) subtypes had no causal effect on atrial fibrillation. Sensitivity analyses yielded similar results. Individual single nucleotide polymorphism had little effect on the total estimate. We did not observe any evidence of horizontal pleiotropy. CONCLUSIONS: Our bidirectional MR studies revealed that there may be no causal links between atrial fibrillation and breast cancer.

Effect of Household Income on Cardiovascular Diseases, Cardiovascular Biomarkers, and Socioeconomic Factors.

PURPOSE: To examine whether household income is causally related to cardiovascular diseases and investigate the potential reasons. METHODS: Using 2-sample Mendelian randomization analyses, we obtained summary statistics from genome-wide association studies of household income and a range of cardiovascular diseases, biomarkers, and socioeconomic factors. FINDINGS: Higher household income was causally associated with lower risks of coronary heart disease (odd ratio [OR] = 0.63; 95% CI: 0.49-0.79; P = 0.0001), myocardial infarction (OR = 0.64; 95% CI: 0.50-0.82; P = 0.0003), and hypertension (OR = 0.71; 95% CI: 0.58-0.88; P = 0.0015). With increasing household income, the cardiovascular biomarkers including triglycerides, C-reactive protein, body mass index, fasting glucose were decreased whereas telomere length and high-density lipoprotein cholesterol were increased. Besides, individuals with higher household income were less likely to smoke (ß = -0.34; 95% CI: -0.47 to -0.21; P = 1.91×10-07), intake salt (ß = -0.14; 95% CI: -0.21 to -0.07; P = 0.0001), or be exposed to air pollution (ß = -0.10; 95% CI: -0.15 to -0.06; P = 8.81×10-06) or depression state (ß = -0.03; 95% CI: -0.04 to -0.02; P = 5.16×10-07). They were more likely to take physical activity (ß = 0.06; 95% CI: 0.02 to 010; P = 0.0016) and have long years of schooling (ß = 0.70; 95% CI: 0.62 to 0.78; P = 5.32×10-67). IMPLICATIONS: Higher household income is causally associated with better socioeconomic factors and improved cardiovascular biomarkers, which translates into a reduced prevalence of cardiovascular diseases. Policies to improve income equality may result in a reduced burden of cardiovascular diseases.

Phenome-Wide Investigation of the Causal Associations Between Pre-Pregnancy Obesity Traits and Gestational Diabetes: A Two-Sample Mendelian Randomization Analyses.

Pre-pregnancy obesity was associated with gestational diabetes in observational studies, but whether this relationship is causal remains to be determined. To evaluate whether pre-pregnancy obesity traits causally affect gestational diabetes risk, a two-sample Mendelian randomization (MR) analysis was performed utilizing summary-level statistics from published genome-wide association studies (GWAS). Obesity-related traits included body mass index (BMI), overweight, obesity, obesity class 1, obesity class 2, obesity class 3, childhood obesity, waist circumference (WC), hip circumference (HC), waist-to-hip ratio (WHR), percent liver fat, visceral adipose tissue volume, abdominal subcutaneous adipose tissue volume. Effect estimates were evaluated using the inverse-variance weighting method. Weighted median, MR-Egger, simple mode, and weighted mode were performed as sensitivity analyses. Genetically predicted pre-pregnancy BMI [odds ratio (OR) = 1.68; 95% confidence interval (CI): 1.45-1.95; P = 9.13 × 10-12], overweight (OR = 1.49; 95% CI: 1.21-1.85; P = 2.06 × 10-4), obesity (OR = 1.25; 95% CI: 1.18-1.33; P = 8.01 × 10-13), obesity class 1 (OR = 1.31; 95% CI: 1.17-1.46; P = 1.49 × 10-6), obesity class 2 (OR = 1.26; 95% CI: 1.16-1.37; P = 5.23 × 10-8), childhood obesity (OR = 1.33; 95% CI: 1.23-1.44; P = 4.06 × 10-12), and WHR (OR = 2.35; 95% CI: 1.44-3.83; P = 5.89 × 10-4) were associated with increased risk of gestational diabetes. No significant association was observed with obesity class 3, WC, HC, percent liver fat, visceral adipose tissue volume, or abdominal subcutaneous adipose tissue volume. Similar results were observed in sensitivity analyses. Therefore, genetically predicted pre-pregnancy obesity traits may increase the risk of gestational diabetes. Weight control before pregnancy may be beneficial to prevent gestational diabetes.

The prevalence and outcomes in STEMI patients aged ≥75 undergoing primary percutaneous coronary intervention in China.

Objective: To investigate the prevalence and outcomes of primary percutaneous coronary intervention (PCI) in Chinese patients with ST-segment elevation myocardial infarction (STEMI) aged ≥75 years. Methods: We identified STEMI patients aged ≥75 years between 2013 and 2014 from a multicenter registry. The primary outcome was all-cause mortality. The secondary outcome was major adverse cardiac and cerebrovascular event (MACCE) including a composite of all-cause mortality, cardiac death, recurrent MI, stroke, revascularization, and major bleeding. Hazard ratios (HR) and associated 95% confidence interval (CI) were calculated. Results: Approximately 32.9% (n = 999) patients received primary PCI. Primary PCI was associated with lower risks of two-year all-cause mortality (18.0% vs. 36.4%; adjusted HR: 0.54, 95% CI: 0.45 to 0.65, P < 0.0001), MACCE (28.7% vs. 43.5%; adjusted HR: 0.68, 95% CI: 0.59 to 0.80, P < 0.0001), and cardiac death (10.0% vs. 23.6%; adjusted HR: 0.49, 95% CI: 0.38 to 0.62, P < 0.0001) relative to no reperfusion (n = 2041) in patients aged ≥75 years. The better outcomes in two-year all-cause mortality, MACCE, and cardiac death were consistently observed in STEMI patients aged ≥85 years. No differences were observed in recurrent MI, stroke, revascularization, and major bleeding between the two groups. Additionally, in patients with relatively high-risk profiles such as cardiogenic shock or delaying hospital admission, primary PCI was also superior to no reperfusion. Conclusion: Primary PCI may decrease two-year all-cause mortality, MACCE, and cardiac death in STEMI patients aged ≥75 years, even in these with age ≥85 years, cardiogenic shock, or delaying hospital admission. However, primary PCI was underutilized in Chinese clinical practice.

Nicorandil-Pretreated Mesenchymal Stem Cell-Derived Exosomes Facilitate Cardiac Repair After Myocardial Infarction via Promoting Macrophage M2 Polarization by Targeting miR-125a-5p/TRAF6/IRF5 Signaling Pathway.

Background: Exosomes derived from bone marrow mesenchymal stem cells (MSC-exo) have been considered as a promising cell-free therapeutic strategy for ischemic heart disease. Cardioprotective drug pretreatment could be an effective approach to improve the efficacy of MSC-exo. Nicorandil has long been used in clinical practice for cardioprotection. This study aimed to investigate whether the effects of exosomes derived from nicorandil pretreated MSC (MSCNIC-exo) could be enhanced in facilitating cardiac repair after acute myocardial infarction (AMI). Methods: MSCNIC-exo and MSC-exo were collected and injected into the border zone of infarcted hearts 30 minutes after coronary ligation in rats. Macrophage polarization was detected 3 days post-infarction, cardiac function as well as histological pathology were measured on the 28th day after AMI. Macrophages were separated from the bone marrow of rats for in vitro model. Exosomal miRNA sequencing was conducted to identify differentially expressed miRNAs between MSCNIC-exo and MSC-exo. MiRNA mimics and inhibitors were transfected to MSCs or macrophages to explore the specific mechanism. Results: Compared to MSC-exo, MSCNIC-exo showed superior therapeutic effects on cardiac functional and structural recovery after AMI and markedly elevated the ratio of CD68+ CD206+/ CD68+cells in infarcted hearts 3 days post-infarction. The notable ability of MSCNIC-exo to promote macrophage M2 polarization was also confirmed in vitro. Exosomal miRNA sequencing and both in vivo and in vitro experiments identified and verified that miR-125a-5p was an effector of the roles of MSCNIC-exo in vivo and in vitro. Furthermore, we found miR-125a-5p promoted macrophage M2 polarization by inhibiting TRAF6/IRF5 signaling pathway. Conclusion: This study suggested that MSCNIC-exo could markedly facilitate cardiac repair post-infarction by promoting macrophage M2 polarization by upregulating miR-125a-5p targeting TRAF6/IRF5 signaling pathway, which has great potential for clinical translation.

Mendelian Randomization Study Does Not Support a Bidirectional Link between Atherosclerosis and Venous Thromboembolism.

AIM: Some observational studies suggested that atherosclerosis increased the risk of venous thromboembolism (VTE), and vice versa. However, the results were conflicting, and the causal relationship is yet to be established. Therefore, we applied Mendelian randomization (MR) analyses to assess the bidirectional causality between coronary heart disease (CHD) and VTE, deep venous thrombosis (DVT), and pulmonary embolism (PE). METHODS: A total of 184,305 individuals with CHD were included from the CARDIoGRAMplusC4D Consortium. Information on VTE, DVT, and PE were obtained from the FinnGen biobank. Genetic instruments for CHD and VTE were constructed using 37 and 12 single-nucleotide polymorphisms, respectively. Inverse-variance weighted meta-analysis under a random-effect model was used as the preliminary estimate. Five complementary MR methods were also used, including weighted median, MR-Egger, multivariable MR (adjusted for the body mass index), simple mode, and weighted mode methods. RESULTS: The genetically instrumented VTE (odds ratio [OR]: 1.05; 95% confidence interval [CI]: 1.00-1.11; P=0.06), DVT (OR: 1.03; 95% CI: 0.99-1.08; P=0.19), or PE (OR: 1.07; 95% CI: 0.98-1.16; P=0.11) showed no causal relationships with CHD. There was also no clear evidence showing the causal effects of CHD on VTE (OR: 1.00; 95% CI: 0.82-1.22; P=0.98), DVT (OR: 1.00; 95% CI: 0.79-1.27; P=0.97), or PE (OR: 0.98; 95% CI: 0.82-1.18; P=0.87). No pleiotropic bias was found in the MR analyses. As heterogeneity was significant, a random model was used to minimize the effect of heterogeneity. CONCLUSIONS: No causal associations existed between CHD and VTE. Arterial and venous thromboses may represent separate entities.