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.

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.

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.

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.

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 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 effect of hypertension and blood pressure on aortic diseases: evidence from Mendelian randomization.

Hypertension or elevated blood pressure was documented to be an important risk factor for aortic diseases in observational studies, yet the causality remains to be determined. By applying a two-sample Mendelian randomization (MR) approach, we aim to determine whether hypertension or elevated blood pressure (systolic blood pressure [SBP] or diastolic blood pressure [DBP]) is linked causally to aortic aneurysm or aortic dissection. Genetic instruments and summary statistics for hypertension and aortic diseases were obtained from large genome-wide association studies. The traditional inverse variance weighted (IVW) method was used to obtain the causal estimates. Sensitivity analyses including MR-Egger, weighted median and multivariable MR were also performed. Our results suggested that genetic liability to hypertension was associated with aortic dissection (odds ratio [OR]: 1.81; 95% confidence interval [CI]: 1.27-2.58; P = 1.13 × 10-3) and aortic aneurysm (OR: 1.43; 95% CI: 1.22-1.66; P = 7.79 × 10-6). Per standard deviation increase in genetically-determined DBP was significantly associated with increased aortic dissection (OR: 1.14; 95% CI: 1.09-1.19; P = 1.58 × 10-9) and aortic aneurysm (OR: 1.07; 95% CI: 1.05-1.09; P = 8.37 × 10-14). There was a null association between SBP and aortic dissection (OR: 1.01; 95% CI: 0.99-1.94; P = 0.38) or aortic aneurysm (OR: 1.00; 95% CI: 0.99-1.01; P = 0.92). Sensitivity analyses documented similar results. Therefore, hypertension and elevated DBP are causally associated with higher risks of aortic aneurysm and aortic dissection. Preventive interventions for aortic diseases may consider individuals with hypertension, especially those with higher DBP. Meanwhile, further research is required to determine the mechanisms underlying the significantly greater correlation between DBP and aortic diseases than SBP.

Invasive Versus Conservative Management of NSTEMI Patients Aged ≥ 75 Years. / Manejo Invasivo versus Conservador de Pacientes com IAMSSST Com Idade ≥ 75 Anos.

BACKGROUND: The efficiency of invasive management in older patients (≥75 years) with non-ST-segment elevation myocardial infarction (NSTEMI) remains ambiguous. OBJECTIVES: To assess the efficiency of invasive management in older patients with NSTEMI based on meta-analysis and trial sequential analysis (TSA). METHODS: Relevant randomized controlled trials (RCT) and observational studies were included. The primary outcomes were all-cause death, myocardial infarction, stroke, and major bleeding. Pooled odd ratio (OR) and 95% confidence interval (CI) were calculated. P <0.05 was considered statistically significant. RESULTS: Five RCTs and 22 observational studies with 1017374 patients were included. Based on RCT and TSA results, invasive management was associated with lower risks of myocardial infarction (OR: 0.51; 95% CI: 0.40-0.65; I2=0%), major adverse cardiovascular events (MACE; OR: 0.61; 95% CI: 0.49-0.77; I2=27.0%), and revascularization (OR: 0.29; 95% CI: 0.15-0.55; I2=5.3%) compared with conservative management. Pooling results from RCTs and observational studies with multivariable adjustment showed consistently lower risks of all-cause death (OR: 0.57; 95% CI: 0.50-0.64; I2=86.4%), myocardial infarction (OR: 0.63; 95% CI: 0.56-0.71; I2=0%), stroke (OR: 0.59; 95% CI: 0.51-0.69; I2=0%), and MACE (OR: 0.64; 95% CI: 0.54-0.76; I2=43.4%). The better prognosis associated with invasive management was also observed in real-world scenarios. However, for patients aged ≥85 years, invasive management may increase the risk of major bleeding (OR: 2.68; 95% CI: 1.12-6.42; I2=0%). CONCLUSIONS: Invasive management was associated with lower risks of myocardial infarction, MACE, and revascularization in older patients with NSTEMI, yet it may increase the risk of major bleeding in patients aged ≥85 years.

FUNDAMENTO: A eficiência do manejo invasivo em pacientes mais velhos (≥75 anos) com infarto do miocárdio sem supradesnivelamento do segmento ST (IAMSSST) permanece ambígua. OBJETIVOS: Avaliar a eficiência do tratamento invasivo em pacientes idosos com IAMSSST com base em metanálise e análise sequencial de estudo (TSA). MÉTODOS: Ensaios clínicos randomizados relevantes (ECR) e estudos observacionais foram incluídos. Os resultados primários foram morte por todas as causas, infarto do miocárdio, acidente vascular cerebral e hemorragia grave. O odd ratio agrupado (OR) e o intervalo de confiança de 95% (IC) foram calculados. P<0,05 foi considerado estatisticamente significativo. RESULTADOS: Cinco ECRs e 22 estudos observacionais com 1.017.374 pacientes foram incluídos.Com base nos resultados de ECR e TSA, o manejo invasivo foi associado a menores riscos de infarto do miocárdio (OR: 0,51; 95% IC: 0,40-0,65; I2=0%), eventos cardiovasculares adversos maiores (MACE; OR: 0,61; 95% IC: 0,49-0,77; I2=27,0%) e revascularização (OR: 0,29; 95% IC: 0,15-0,55; I2=5,3%) em comparação com o tratamento conservador. A combinação de resultados de ECRs e estudos observacionais com ajuste multivariável mostrou riscos consistentemente menores de morte por todas as causas (OR: 0,57; IC 95%: 0,50-0,64; I2 = 86,4%), infarto do miocárdio (OR: 0,63; IC 95%: 0,56 -0,71; I2=0%), acidente vascular cerebral (OR: 0,59; 95% IC: 0,51-0,69; I2=0%) e MACE (OR: 0,64; 95% IC: 0,54-0,76; I2=43,4%). O melhor prognóstico associado ao manejo invasivo também foi observado em cenários do mundo real. No entanto, para pacientes com idade ≥85 anos, o manejo invasivo pode aumentar o risco de sangramento maior (OR: 2,68; IC 95%: 1,12-6,42; I2=0%). CONCLUSÕES: O manejo invasivo foi associado a menores riscos de infarto do miocárdio, MACE e revascularização em pacientes idosos com IAMSSST,no entanto, pode aumentar o risco de sangramento maior em pacientes com idade ≥85 anos.

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.

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.

The Causality between Diabetes and Venous Thromboembolism: A Bidirectional Two-Sample Mendelian Randomization Study.

BACKGROUND: Diabetes was considered as a risk factor for venous thromboembolism (VTE), but conflicting findings have been reported from observational studies. This study aimed at investigating the causal associations of type 1 and type 2 diabetes with VTE, including deep vein thrombosis (DVT) and pulmonary embolism (PE). METHODS: We designed a bidirectional two-sample Mendelian randomization (MR) analysis by using summary-level data from large genome-wide association studies performed in European individuals. Inverse variance weighting with multiplicative random effect method was used to obtain the primary causal estimates, and weighted median, weighted mode, and MR egger regression were replenished as sensitivity analyses to test the robustness of the results. RESULTS: We found no significant causal effects of type 1 diabetes on VTE (odds ratio [OR]: 0.98, 95% confidence interval [CI]: 0.96-1.00, p = 0.043), DVT (OR: 0.98, 95% CI: 0.95-1.00, p = 0.102), and PE (OR: 0.98, 95% CI: 0.96-1.01, p = 0.160). Similarly, no significant associations of type 2 diabetes with VTE (OR: 0.97, 95% CI: 0.91-1.03, p = 0.291), DVT (OR: 0.96, 95% CI: 0.89-1.03, p = 0.255), and PE (OR: 0.97, 95% CI: 0.90-1.04, p = 0.358) were also observed. Results from multivariable MR analysis were consistent with the findings in univariable analysis. In the other direction, the results showed no significant causal effects of VTE on type 1 and type 2 diabetes. CONCLUSION: This MR analysis demonstrated no significant causal associations of type 1 and type 2 diabetes with VTE in both directions, in conflict with previous observational studies reporting positive association, which provided clues for understanding the underlying pathogenesis of diabetes and VTE.

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.

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.

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.

Use of Mendelian randomization to evaluate the effect of atrial fibrillation on cardiovascular diseases and cardiac death.

AIMS: Several observational studies indicated that atrial fibrillation might aggravate other cardiovascular diseases apart from ischaemic stroke. However, it remains to be determined whether these associations reveal independent causation. Using Mendelian randomization (MR), we systematically investigated how genetically predicted atrial fibrillation affected other cardiovascular diseases and cardiac death. METHODS AND RESULTS: Summary-level data for atrial fibrillation and other cardiovascular diseases were obtained from public genome-wide association study data. The random inverse-variance weighted method was treated as the primary analysis. Sensitivity analyses (including weighted median, MR-Egger, and multivariable MR methods) were also performed. Atrial fibrillation was significantly associated with higher risks of heart failure [odds ratio (OR): 1.24; 95% confidence interval (CI): 1.19-1.28; P < 0.001], ischaemic stroke (OR: 1.21; 95% CI: 1.17-1.25; P < 0.001), transient ischaemic attack (OR: 1.10; 95% CI: 1.05-1.15; P < 0.001), peripheral artery diseases (OR: 1.09; 95% CI: 1.03-1.15; P = 0.002), cardiac death (OR: 1.08; 95% CI: 1.02-1.15; P = 0.008), and hypertension (OR: 1.06; 95% CI: 1.01-1.11; P = 0.010), without effects on coronary heart disease or pulmonary embolism. Associations for heart failure and ischaemic stroke remained robust to the sensitivity analyses. MR-Egger method (P > 0.05) and funnel plot yielded no indication of directional pleiotropy. The leave-one-out analysis suggested that the causal associations were not driven by individual single nucleotide polymorphism. CONCLUSIONS: This comprehensive MR analysis verified the causal associations between atrial fibrillation and high risks of heart failure, ischaemic stroke, transient ischaemic attack, peripheral artery diseases, cardiac death, and hypertension. Interventions to reduce cardiovascular diseases beyond ischaemic stroke are warranted in patients with atrial fibrillation.

Coronary Intervention in ST-Segment Elevation Myocardial Infarction Patients With Symptom Onset >12 Hours: Data from China Acute Myocardial Infarction Registry.

To determine whether late percutaneous coronary intervention (PCI) of an infarct-related artery >12 h after ST-segment elevation myocardial infarction onset is beneficial, patients were included from the prospective, nationwide, multicenter China Acute Myocardial Infarction registry. The number of patients who underwent PCI or received drug therapy alone was 4791 and 1149, respectively. Hazard ratio (HR) and associated 95% confidence interval (CI) were calculated. Compared with drug therapy, PCI was associated with lower incidences of 2-year major adverse cardiac and cerebrovascular events (MACCE; 6.43 vs 20.19%; HR, .27; 95% CI, .23-.32; P < .001), all-cause death (4.13 vs 15.74%; HR, .24; 95% CI, .20-.30; P < .001), myocardial infarction (1.73 vs 3.31%; HR, .49; 95% CI, .33-.72; P = .0003), stroke (1.02 vs 2.00%; HR, .47; 95% CI, .28-.77; P = .0026), and revascularization (10.96 vs 27.56%; HR, .32; 95% CI, .26-.39; P < .001). Subgroup analysis consistently indicated that PCI was superior to drug therapy. Moreover, the left ventricular ejection fraction in the PCI group was increased after 2-year follow-up, whereas there was no significant increase in the drug therapy group. In conclusion, late PCI is common in Chinese clinical practice, and it is associated with significant improvements in cardiac function and survival compared with drug therapy alone.

Manejo Invasivo versus Conservador de Pacientes com IAMSSST Com Idade ≥ 75 Anos / Invasive Versus Conservative Management of NSTEMI Patients Aged ≥ 75 Years

Resumo Fundamento A eficiência do manejo invasivo em pacientes mais velhos (≥75 anos) com infarto do miocárdio sem supradesnivelamento do segmento ST (IAMSSST) permanece ambígua. Objetivos Avaliar a eficiência do tratamento invasivo em pacientes idosos com IAMSSST com base em metanálise e análise sequencial de estudo (TSA). Métodos Ensaios clínicos randomizados relevantes (ECR) e estudos observacionais foram incluídos. Os resultados primários foram morte por todas as causas, infarto do miocárdio, acidente vascular cerebral e hemorragia grave. O odd ratio agrupado (OR) e o intervalo de confiança de 95% (IC) foram calculados. P<0,05 foi considerado estatisticamente significativo. Resultados Cinco ECRs e 22 estudos observacionais com 1.017.374 pacientes foram incluídos.Com base nos resultados de ECR e TSA, o manejo invasivo foi associado a menores riscos de infarto do miocárdio (OR: 0,51; 95% IC: 0,40-0,65; I2=0%), eventos cardiovasculares adversos maiores (MACE; OR: 0,61; 95% IC: 0,49-0,77; I2=27,0%) e revascularização (OR: 0,29; 95% IC: 0,15-0,55; I2=5,3%) em comparação com o tratamento conservador. A combinação de resultados de ECRs e estudos observacionais com ajuste multivariável mostrou riscos consistentemente menores de morte por todas as causas (OR: 0,57; IC 95%: 0,50-0,64; I2 = 86,4%), infarto do miocárdio (OR: 0,63; IC 95%: 0,56 -0,71; I2=0%), acidente vascular cerebral (OR: 0,59; 95% IC: 0,51-0,69; I2=0%) e MACE (OR: 0,64; 95% IC: 0,54-0,76; I2=43,4%). O melhor prognóstico associado ao manejo invasivo também foi observado em cenários do mundo real. No entanto, para pacientes com idade ≥85 anos, o manejo invasivo pode aumentar o risco de sangramento maior (OR: 2,68; IC 95%: 1,12-6,42; I2=0%). Conclusões O manejo invasivo foi associado a menores riscos de infarto do miocárdio, MACE e revascularização em pacientes idosos com IAMSSST,no entanto, pode aumentar o risco de sangramento maior em pacientes com idade ≥85 anos.

Abstract Background The efficiency of invasive management in older patients (≥75 years) with non-ST-segment elevation myocardial infarction (NSTEMI) remains ambiguous. Objectives To assess the efficiency of invasive management in older patients with NSTEMI based on meta-analysis and trial sequential analysis (TSA). Methods Relevant randomized controlled trials (RCT) and observational studies were included. The primary outcomes were all-cause death, myocardial infarction, stroke, and major bleeding. Pooled odd ratio (OR) and 95% confidence interval (CI) were calculated. P <0.05 was considered statistically significant. Results Five RCTs and 22 observational studies with 1017374 patients were included. Based on RCT and TSA results, invasive management was associated with lower risks of myocardial infarction (OR: 0.51; 95% CI: 0.40-0.65; I2=0%), major adverse cardiovascular events (MACE; OR: 0.61; 95% CI: 0.49-0.77; I2=27.0%), and revascularization (OR: 0.29; 95% CI: 0.15-0.55; I2=5.3%) compared with conservative management. Pooling results from RCTs and observational studies with multivariable adjustment showed consistently lower risks of all-cause death (OR: 0.57; 95% CI: 0.50-0.64; I2=86.4%), myocardial infarction (OR: 0.63; 95% CI: 0.56-0.71; I2=0%), stroke (OR: 0.59; 95% CI: 0.51-0.69; I2=0%), and MACE (OR: 0.64; 95% CI: 0.54-0.76; I2=43.4%). The better prognosis associated with invasive management was also observed in real-world scenarios. However, for patients aged ≥85 years, invasive management may increase the risk of major bleeding (OR: 2.68; 95% CI: 1.12-6.42; I2=0%). Conclusions Invasive management was associated with lower risks of myocardial infarction, MACE, and revascularization in older patients with NSTEMI, yet it may increase the risk of major bleeding in patients aged ≥85 years.

Association of beta-blocker therapy at discharge with clinical outcomes in patients without heart failure or left ventricular systolic dysfunction after acute coronary syndrome: An updated systematic review and meta-analysis.

BACKGROUND: Beta-blockers are the standard treatment for acute coronary syndrome (ACS) based on evidence from the prethrombolytic era. We sought to examine the effect of beta-blocker treatment on patients without heart failure or left ventricular systolic dysfunction after ACS in the contemporary percutaneous coronary intervention (PCI) era. METHODS: We systematically searched PubMed, Web of Science, Cochrane Library, ClinicalTrials.gov and Google Scholar for studies comparing beta-blockers versus no beta-blockers in ACS patients in the contemporary PCI era. The primary outcome was all-cause death. Pooling unadjusted and multivariable adjusted results were calculated under random-effects models. RESULTS: Data from 15 studies (n=205,672), including 1 randomized trial, were analysed. Compared with no beta-blockers, beta-blocker therapy at discharge may reduce the risk of all-cause death (odds ratio [OR] 0.66, 95% confidence interval [CI]: 0.50-0.86; I2=81.9%). Subgroup analysis according to single or multicentre studies indicated similar results. Prospective studies suggested that all-cause death was less common in the beta-blocker group. After multivariable adjustment, a lower risk of all-cause death was still observed with beta-blockers (OR: 0.74, 95% CI: 0.59-0.94; I2=40.1%). No differences existed in major adverse cardiovascular events (MACE), cardiac death, myocardial infarction, heart failure, revascularization or stroke, before and after multivariable adjustment. CONCLUSIONS: In patients without heart failure or left ventricular systolic dysfunction after ACS in the contemporary PCI era, beta-blocker therapy may still be beneficial due to a potential reduced risk of all-cause death.