Causal impact of gut microbiota and associated metabolites on pulmonary arterial hypertension: a bidirectional Mendelian randomization study.

BACKGROUND: Patients with pulmonary arterial hypertension (PAH) exhibit a distinct gut microbiota profile; however, the causal association between gut microbiota, associated metabolites, and PAH remains elusive. We aimed to investigate this causal association and to explore whether dietary patterns play a role in its regulation. METHODS: Summary statistics of gut microbiota, associated metabolites, diet, and PAH were obtained from genome-wide association studies. The inverse variance weighted method was primarily used to measure the causal effect, with sensitivity analyses using the weighted median, weighted mode, simple mode, MR pleiotropy residual sum and outlier (MR-PRESSO), and MR-Egger methods. A reverse Mendelian randomisation analysis was also performed. RESULTS: Alistipes (odds ratio [OR] = 2.269, 95% confidence interval [CI] 1.100-4.679, P = 0.027) and Victivallis (OR = 1.558, 95% CI 1.019-2.380, P = 0.040) were associated with an increased risk of PAH, while Coprobacter (OR = 0.585, 95% CI 0.358-0.956, P = 0.032), Erysipelotrichaceae (UCG003) (OR = 0.494, 95% CI 0.245-0.996, P = 0.049), Lachnospiraceae (UCG008) (OR = 0.596, 95% CI 0.367-0.968, P = 0.036), and Ruminococcaceae (UCG005) (OR = 0.472, 95% CI 0.231-0.962, P = 0.039) protected against PAH. No associations were observed between PAH and gut microbiota-derived metabolites (trimethylamine N-oxide [TMAO] and its precursors betaine, carnitine, and choline), short-chain fatty acids (SCFAs), or diet. Although inverse variance-weighted analysis demonstrated that elevated choline levels were correlated with an increased risk of PAH, the results were not consistent with the sensitivity analysis. Therefore, the association was considered insignificant. Reverse Mendelian randomisation analysis demonstrated that PAH had no causal impact on gut microbiota-derived metabolites but could contribute to increased the levels of Butyricicoccus and Holdemania, while decreasing the levels of Clostridium innocuum, Defluviitaleaceae UCG011, Eisenbergiella, and Ruminiclostridium 5. CONCLUSIONS: Gut microbiota were discovered suggestive evidence of the impacts of genetically predicted abundancy of certain microbial genera on PAH. Results of our study point that the production of SCFAs or TMAO does not mediate this association, which remains to be explained mechanistically.

Diabetes mellitus, glycemic traits, SGLT2 inhibition, and risk of pulmonary arterial hypertension: A Mendelian randomization study.

This study aimed to investigate the causal role of diabetes mellitus (DM), glycemic traits, and sodium-glucose cotransporter 2 (SGLT2) inhibition in pulmonary arterial hypertension (PAH). Utilizing a two-sample two-step Mendelian randomization (MR) approach, we determined the causal influence of DM and glycemic traits (including insulin resistance, glycated hemoglobin, and fasting insulin and glucose) on the risk of PAH. Moreover, we examined the causal effects of SGLT2 inhibition on the risk of PAH. Genetic proxies for SGLT2 inhibition were identified as variants in the SLC5A2 gene that were associated with both levels of gene expression and hemoglobin A1c. Results showed that genetically inferred DM demonstrated a causal correlation with an increased risk of PAH, exhibiting an odds ratio (OR) of 1.432, with a 95% confidence interval (CI) of 1.040-1.973, and a p-value of 0.028. The multivariate MR analysis revealed comparable outcomes after potential confounders (OR = 1.469, 95%CI = 1.021-2.115, p = 0.038). Moreover, genetically predicted SGLT2 inhibition was causally linked to a reduced risk of PAH (OR = 1.681*10-7, 95%CI = 7.059*10-12-0.004, p = 0.002). Therefore, our study identified the suggestively causal effect of DM on the risk of PAH, and SGLT2 inhibition may be a potential therapeutic target in patients with PAH.

Genetically predicted waist circumference and risk of atrial fibrillation.

INTRODUCTION: Observational studies have revealed an association between waist circumference (WC) and atrial fibrillation (AF). However, it is difficult to infer a causal relationship from observational studies because the observed associations could be confounded by unknown risk factors. Therefore, the causal role of WC in AF is unclear. This study was designed to investigate the causal association between WC and AF using a two-sample Mendelian randomization (MR) analysis. METHODS: In our two-sample MR analysis, the genetic variation used as an instrumental variable for MR was acquired from a genome-wide association study (GWAS) of WC (42 single nucleotide polymorphisms with a genetic significance of P <5 × 10 -8 ). The data of WC (from the Genetic Investigation of ANthropometric Traits consortium, containing 232,101 participants) and the data of AF (from the European Bioinformatics Institute database, containing 55,114 AF cases and 482,295 controls) were used to assess the causal role of WC on AF. Three different approaches (inverse variance weighted [IVW], MR-Egger, and weighted median regression) were used to ensure that our results more reliable. RESULTS: All three MR analyses provided evidence of a positive causal association between high WC and AF. High WC was suggested to increase the risk of AF based on the IVW method (odds ratio [OR] = 1.43, 95% confidence interval [CI], 1.30-1.58, P = 2.51 × 10 -13 ). The results of MR-Egger and weighted median regression exhibited similar trends (MR-Egger OR = 1.40 [95% CI, 1.08-1.81], P = 1.61 × 10 -2 ; weighted median OR = 1.39 [95% CI, 1.21-1.61], P = 1.62 × 10 -6 ). MR-Egger intercepts and funnel plots showed no directional pleiotropic effects between high WC and AF. CONCLUSIONS: Our findings suggest that greater WC is associated with an increased risk of AF. Taking measures to reduce WC may help prevent the occurrence of AF.

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.

Exploring the association between COVID-19 and male genital cancer risk in European population: evidence from mendelian randomization analysis.

BACKGROUND: Recently accumulated evidence indicates a potential association between COVID-19 and elevated susceptibility to cancer, including male genital cancer. However, the causal nature of this relationship remains unclear. METHODS: In this Mendelian randomization (MR) study, we investigated the potential causal relationship between COVID-19 and male genital cancer using genetic variants as instrumental variables. We utilized summary statistics from two large-scale genome-wide association studies of COVID-19 hospitalized Vs. controls, as well as data from a population-based male genital cancer database based on European ancestry. We applied stringent quality control measures to select instrumental variables, including checking for linkage disequilibrium, removing low-quality variants, and assessing the strength of the instruments using the F-statistic. We conducted the MR  analysis using the inverse-variance weighted method and several sensitivity analyses (including MR Egger and Weighted Median MR analysis) to test the robustness of our results. RESULTS: Our MR analysis revealed no causal associations between COVID-19 hospitalization and the incidence of male genital cancer. In the inverse-variance weighted analysis, no causal associations were observed between patients with COVID-19 hospitalization and the incidence of male genital cancer (odds ratio = 1.000 and 95% confidence interval = 0.998-1.001, p = 0.668). The estimated causal effect was consistent across all sensitivity analyses (including the Weighted Median, the MR Egger analysis, and the MR PROSSO analysis). The leave-one-out analysis showed that there was no any sing Single-nucleotide polymorphism significantly influencing our results. CONCLUSIONS: Our study provides evidence that there is no causal association between COVID-19 hospitalization and male genital cancer.

Asociación del nivel de ácido úrico en suero con los beneficios del control intensivo de la presión arterial / Association of serum uric acid with benefits of intensive blood pressure control

Introducción y objetivos: El control intensivo de la presión arterial sistólica (PAS) mejora los resultados de la estrategia de control de la presión arterial en el ensayo STEP con pacientes ancianos hipertensos. Sin embargo, se desconoce si los niveles de ácido úrico pueden afectar los beneficios del control intensivo de la PAS. Métodos: El ensayo STEP fue un estudio controlado y aleatorizado que comparó el efecto del control intensivo (PAS objetivo de 110 o <130mm Hg) frente al tratamiento estándar (PAS objetivo de 130 o <150mm Hg) de la PAS en pacientes chinos hipertensos de entre 60 y 80 años. El objetivo primario incluyó un conjunto de eventos asociados a la enfermedad cardiovascular. Se utilizaron los modelos de curvas spline cúbicas restringidas y análisis de subgrupos para estudiar si los efectos del control intensivo de la PAS difieren en función las concentraciones basales de ácido úrico. Ambos modelos se basaron en la subdistribución de riesgos de Fine-Gray para el análisis del objetivo primario y los objetivos secundarios. El modelo de regresión de Cox se utilizó para el análisis de muerte por cualquier causa. También se analizaron las concentraciones de ácido úrico durante el seguimiento. Resultados: El riesgo del objetivo primario se incrementó con el incremento de la concentración de ácido úrico tanto en el grupo de tratamiento intensivo como en el de tratamiento estándar. Los pacientes bajo tratamiento intensivo mostraron menor subdistribución (ajustada de forma multivariable) del cociente de riesgo para el objetivo primario, aunque con un amplio solapamiento del IC 95%. La estratificación de pacientes por terciles de concentración de ácido úrico mostró un CR de 0,55 (IC95%, 0,36-0,86; p=0,008) para el tercil 1 (ácido úrico <303,0μmol/l), de 0,80 (IC95%, 0.56-1.14; p=0,22) para el tercil 2 (AcU 303,0 a <375,8μmol/l) y de 0,86 (IC95%, 0,60–1,21; p=0,39) para el tercil 3 (AcU ≥ 375,8μmol/l); p=0,29 para la interacción...(AU)

Introduction and objectives: Intensive systolic blood pressure (SBP) control improved outcomes in the Strategy of Blood Pressure Intervention in the Elderly Hypertensive Patients (STEP) trial. Whether the serum uric acid concentration at baseline alters the benefits of intensive SBP control is unknown. Methods: The STEP trial was a randomized controlled trial that compared the effects of intensive (SBP target of 110 to<130mmHg) and standard (SBP target of 130 to <150mmHg) SBP control in Chinese patients aged 60 to 80 years with hypertension. The primary outcome was a composite of cardiovascular disease events. This post hoc analysis was performed to examine whether the effects of intensive SBP intervention differed by the baseline uric acid concentration using 2 models: restricted cubic spline curves and subgroup analyses, both based on the Fine-Gray subdistribution hazard model in the analysis of the primary outcome and secondary outcomes (excluding all-cause death). In the analysis of all-cause death, the Cox regression model was used. We also examined the change in the follow-up uric acid concentrations. Results: Overall, the risk of the primary outcome rose as the cumulative uric acid concentration increased in both the intensive and standard treatment groups. Patients with intensive treatment had a lower multivariable-adjusted subdistribution hazard ratio for the primary outcome, but with a wide overlap of 95%CI. Next, we stratified patients according to their baseline uric acid concentration (tertile 1 [T1], <303.0μmol/L; tertile 2 [T2], 303.0 to <375.8μmol/L; and tertile 3 [T3], ≥375.8μmol/L). Subgroup analyses using tertiles provided HRs and 95%CI in T1 (HR, 0.55; 95%CI, 0.36–0.86; P=.008), T2 (HR, 0.80; 95%CI, 0.56–1.14; P=.22) and T3 (HR, 0.86; 95%CI, 0.60–1.21; P=.39), with an interaction P value of .29. The results for most of the secondary outcomes followed the same trends...(AU)

Untargeted metabolomics reveal the metabolic profile of normal pulmonary circulation.

BACKGROUND: As an important place of material exchange, the homeostasis of the pulmonary circulation environment and function lays an essential foundation for the normal execution of various physiological functions of the body. Small metabolic molecules in the circulation can reflect the corresponding state of the pulmonary circulation. METHODS: We enrolled patients with Patent Foramen Ovale and obtained blood from the pulmonary arteries and veins through heart catheterization. UPLC-MS based untargeted metabolomics was used to compare the changes and metabolic differences of plasma between pulmonary vein and pulmonary artery. RESULTS: The plasma metabolomics revealed that pulmonary artery had a different metabolomic profile compared to venous. 1060 metabolites were identified, and 61 metabolites were differential metabolites. Purine, Amino acids, Nicotinamide, Tetradecanedioic acid and Bile acid were the most markedly. CONCLUSION: The differential metabolites are mostly related to immune inflammation and damage repaired. It is suggested that the pulmonary circulation is always in a steady state of injury and repair while pathological changes may be triggered when the homeostasis is broken. These changes play an important role in revealing the development process and etiology of lung homeostasis and related diseases. Relevant metabolites can be used as potential targets for further study of pulmonary circulation homeostasis.

Roles of obesity in mediating the causal effect of attention-deficit/hyperactivity disorder on diabetes.

AIMS: Previous observational studies have reported potential associations among attention-deficit/hyperactivity disorder (ADHD), obesity, and diabetes (including type 1 and type 2 diabetes mellitus [T1DM/T2DM]). However, whether the association between ADHD and diabetes is mediated by obesity is unknown. METHODS: With two-sample Mendelian randomization, we analysed the causal effect of ADHD on T1DM and T2DM and six obesity-related traits [including body mass index, waist circumference (WC), hip circumference, waist-to-hip ratio (WHR), body fat percentage and basal metabolic rate] and the causal effect of these obesity-related traits on T1DM/T2DM. Finally, with multivariable Mendelian randomization, we explored and quantified the possible mediation effects of obesity-related traits on the causal effect of ADHD on T1DM/T2DM. RESULTS: Our results showed that ADHD increased the risk of T2DM by 14% [odds ratio (OR) = 1.140, 95% confidence interval (CI) = 1.005-1.293] but with no evidence of an effect on T1DM (OR = 0.916, 95% CI = 0.735-1.141, P = 0.433.). In addition, ADHD had a 6.1% increased causal effect on high WC (OR = 1.061, 95% CI = 1.024-1.099, P = 0.001) and an 8.2% increased causal effect on high WHR (OR = 1.082, 95% CI = 1.035-1.131, P = 0.001). In addition, a causal effect of genetically predicted high WC (OR = 1.870, 95% CI = 1.594-2.192, P < 0.001) on a higher risk of T2DM was found. In further analysis, WC mediated approximately 26.75% (95% CI = 24.20%-29.30%) of the causal association between ADHD and T2DM. CONCLUSIONS: WC mediates a substantial proportion of the causal effect of ADHD on the risk of T2DM, which indicated that the risk of T2DM induced by ADHD could be indirectly reduced by controlling WC as a main risk factor.

An inverse causal association between genetically predicted vitamin D and chronic obstructive pulmonary disease risk.

Aim: Observational studies have reported that levels of vitamin D were associated with the incidence of chronic obstructive pulmonary disease (COPD), but the relationship between them may have been confounded in previous studies. In this study, we aimed to determine the relationship between the levels of 25-hydroxyvitamin D (25OHD) and the risk of COPD by two-sample Mendelian randomization (MR) analysis. Methods: Summary statistics for 25OHD and COPD in this study were obtained from the EBI (n = 496,946) consortium and Finn (n = 187,754) consortium. MR was adopted to explore the effect of the genetically predicted levels of 25OHD on the risk of COPD. Based on three assumptions of MR analysis, inverse variance weighting was used as the main analysis. To make our results more robust and reliable, MR Egger's intercept test, Cochran's Q test, funnel plot, and "leave-one-out" sensitivity analysis were used to assess the potential pleiotropy and heterogeneity in this study. Then, colocalization analysis and MR Steiger approaches were used to estimate the possible directions of estimates between them. Finally, we analyzed the causal associations between the four core genes (DHCR7, GC, CYP2R1, and CYP24A1) of vitamin D and the levels of 25OHD or the risk of COPD. Results: Our results showed that each 1 standard deviation (SD) increase in the genetically predicted 25OHD level was associated with a 57.2% lower relative risk of COPD [odds ratio (OR): 0.428, 95% Cl: 0.279-0.657, p = 1.041 × 10-4], and the above association was also verified by maximum likelihood (OR: 0.427, 95% Cl: 0.277-0.657, p = 1.084 × 10-4), MR-Egger (OR: 0.271, 95% CI: 0.176-0.416, p = 2.466 × 10-4), MR-PRESSO (OR: 0.428, 95% Cl: 0.281-0.652, p = 1.421 × 10-4) and MR-RAPS (OR: 0.457, 95% Cl: 0.293-0.712, p = 5.450 × 10-4). Furthermore, colocalization analyses (rs3829251, PP.H4 = 0.99) and MR Steiger ("TRUE") also showed a reverse association between them. Besides, the core genes of vitamin D also showed similar results except for CYP24A1. Conclusion: Our findings provide evidence for a reverse association between genetically predicted 25OHD levels and COPD risk. Taking measures to supplement 25OHD may help reduce the incidence of COPD.

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.

Association of serum uric acid with benefits of intensive blood pressure control.

INTRODUCTION AND OBJECTIVES: Intensive systolic blood pressure (SBP) control improved outcomes in the Strategy of Blood Pressure Intervention in the Elderly Hypertensive Patients (STEP) trial. Whether the serum uric acid concentration at baseline alters the benefits of intensive SBP control is unknown. METHODS: The STEP trial was a randomized controlled trial that compared the effects of intensive (SBP target of 110 to<130mmHg) and standard (SBP target of 130 to <150mmHg) SBP control in Chinese patients aged 60 to 80 years with hypertension. The primary outcome was a composite of cardiovascular disease events. This post hoc analysis was performed to examine whether the effects of intensive SBP intervention differed by the baseline uric acid concentration using 2 models: restricted cubic spline curves and subgroup analyses, both based on the Fine-Gray subdistribution hazard model in the analysis of the primary outcome and secondary outcomes (excluding all-cause death). In the analysis of all-cause death, the Cox regression model was used. We also examined the change in the follow-up uric acid concentrations. RESULTS: Overall, the risk of the primary outcome rose as the cumulative uric acid concentration increased in both the intensive and standard treatment groups. Patients with intensive treatment had a lower multivariable-adjusted subdistribution hazard ratio for the primary outcome, but with a wide overlap of 95%CI. Next, we stratified patients according to their baseline uric acid concentration (tertile 1 [T1], <303.0µmol/L; tertile 2 [T2], 303.0 to <375.8µmol/L; and tertile 3 [T3], ≥375.8µmol/L). Subgroup analyses using tertiles provided HRs and 95%CI in T1 (HR, 0.55; 95%CI, 0.36-0.86; P=.008), T2 (HR, 0.80; 95%CI, 0.56-1.14; P=.22) and T3 (HR, 0.86; 95%CI, 0.60-1.21; P=.39), with an interaction P value of .29. The results for most of the secondary outcomes followed the same trends. CONCLUSIONS: There was no evidence that the benefit of the intensive SBP control differed by baseline uric acid concentrations. This trial was registered at ClinicalTrial.gov (Identifier: NCT03015311).

Corrigendum: Genetic predisposition between COVID-19 and four mental illnesses: A bidirectional, two-sample Mendelian randomization study.

[This corrects the article DOI: 10.3389/fpsyt.2021.746276.].

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.

Causal associations between disorders of lipoprotein metabolism and ten cardiovascular diseases.

Disorders of lipoprotein metabolism have been linked with an increased risk of cardiovascular diseases (CVDs) but the causal association is unclear. In this study, we investigated the causal association between disorders of lipoprotein metabolism and CVDs using two-sample Mendelian randomization (MR). The exposure was obtained from Finn genome-wide association studies (14,010 cases, 197,259 controls), and the corresponding CVDs were extracted from the largest published genome-wide association studies. A random-effects inverse-variance weighted method was used for the main analyses with a complementary analysis using the weighted median and MR-Egger approaches. Multiple sensitivity analyses were performed to assess horizontal pleiotropy. The MR analysis indicated positive associations of disorders of lipoprotein metabolism with coronary artery disease (odds ratio [OR] 1.670, 95% confidence interval [CI] 1.373-2.031; p < 0.001), aortic aneurysm (OR 1.394, 95% CI 1.199-1.619; p < 0.001), heart failure (OR 1.20, 95% CI 1.115-1.294; p < 0.001), hypertension (OR 1.011, 95% CI 1.006-1.091; p < 0.001), old myocardial infarction (OR 1.004, 95% CI 1.002-1.007; p = 0.001), and stroke (OR 1.002, 95% CI 1.001-1.003; p = 0.002). There is a suggestive causal relationship between disorders of lipoprotein metabolism and atrial fibrillation (OR 1.047, 95% CI 1.006-1.091; p = 0.026) and acute myocardial infarction (OR 1.003, 95% CI 1.001-1.005; p = 0.012). There was limited evidence of a causal association between disorders of lipoprotein metabolism and peripheral vascular disease and venous thromboembolism. Our findings indicate a significant causal association between disorders of lipoprotein metabolism and many CVDs, including coronary artery disease, aortic aneurysm, heart failure, hypertension, old myocardial infarction, and stroke. These associations may be useful for development of treatment strategies that regulate lipoprotein metabolism in patients with CVD.

Chronic Thromboembolic Pulmonary Hypertension in Females: Clinical Features and Survival.

Sparse data are available on the female-specific features of chronic thromboembolic pulmonary hypertension (CTEPH). We prospectively enrolled 160 consecutive female patients who were firstly diagnosed with CTEPH between 2013 and 2019 to explore their clinical phenotypes, treatment patterns, and long-term survival. The patients' mean age was 54.7 ± 13.8 years, 70.6% provided a confirmed history of venous thromboembolism, 46 (28.8%) patients underwent pulmonary endarterectomy (PEA), 65 (40.6%) received balloon pulmonary angioplasty (BPA), and 49 (30.6%) were treated with medical therapy alone. The patients were followed for a median of 51 (34-70) months; three patients were lost to follow-up, and twenty-two patients died. The estimated survival rates at 1, 3, 5, and 7 years were 98.1% (95% CI 96.0-100), 96.9% (95% CI 94.2-99.6), 85.1% (95% CI 78.1-92.2), and 76.2% (95% CI 65.2-87.2), respectively. After adjusting for the confounders, the results of the multivariate Cox analysis showed that the presence of anemia (5.56, 95% CI 1.6-19.22) was associated with an increased risk of all-cause death, and compared with medical treatment, receiving PEA and BPA decreased the risk of death by 74% (0.26, 95% CI 0.07-0.97) and 86% (0.14, 95% CI 0.04-0.57), respectively. In conclusion, in the modern era of CTEPH treatment, invasive revascularization combined with targeted therapy display good clinical outcomes for females; anemia should be actively modified, which may lead to clinical improvements. (ClinicalTrials.gov Identifier: NCT05360992).

Safety of chronic high-dose calcium channel blockers exposure in children with pulmonary arterial hypertension.

Background: Chronic calcium channel blockers (CCBs) are indicated in children with idiopathic/heritable pulmonary arterial hypertension (IPAH/HPAH) and positive response to acute vasodilator challenge. However, minimal safety data are available on the long-term high-dose exposure to CCBs in this population. Methods: Patients aged 3 months to 18 years who were diagnosed with IPAH/HPAH and treated with CCB in the past 15 years were retrospectively reviewed. The maximum tolerated dose and the long-term safety of high-dose CCBs on the cardiovascular and noncardiovascular systems were assessed. Results: Thirty-two eligible children were enrolled in the study, with a median age of 9 (6-11) years old. Thirty-one patients were treated with diltiazem after diagnosis. The median maximum tolerated dose was 12.9 (9.8-16.8) mg/kg/day. Children younger than 7 years used higher doses than children in the older age group, 16.4 (10.5-28.5) mg/kg/day vs. 12.7 (6.6-14.4) mg/kg/day, P < 0.05. Patients were followed up for a median period of 6.2 (2.6-10.8) years. One patient died from a traffic accident, and others showed a stable or improved WHO functional class status. Thirteen (40.6%) and 10 (31.3%) patients developed arrhythmias and hypotension. Nine (28.1%) patients had sinus bradycardia, five (21.9%) had first-degree or second-degree type II atrial-ventricular blocks, and two (6.3%) had second-degree type II atrial-ventricular blocks. Most of these arrhythmias were transient and relieved after CCB dose adjustment. The most reported noncardiovascular adverse effect was gingival hyperplasia (13, 40.6%), accompanied by different degrees of dental dysplasia. No liver or kidney dysfunction was reported. Conclusion: Diltiazem was used in a very high dose for eligible children with IPAH/HPAH. The toxicity of long-term CCB use on the cardiovascular system is mild and controllable. Clinicians should also monitor the noncardiovascular adverse effects associated with drug therapy.

Association Between the Use of Pre- and Post-thrombolysis Anticoagulation With All-Cause Mortality and Major Bleeding in Patients With Pulmonary Embolism.

Objective: To explore the comparative clinical efficacy and safety outcomes of anticoagulation before (pre-) or following (post-) thrombolytic therapy in systemic thrombolytic therapy for pulmonary embolism (PE). Methods: PubMed, the Cochrane Library, EMBASE, EBSCO, Web of Science, and CINAHL databases were searched from inception through 1 May 2021. All randomized clinical trials comparing systemic thrombolytic therapy vs. anticoagulation alone in patients with PE and those that were written in English were eligible. The primary efficacy and safety outcomes were all-cause mortality and major bleeding, respectively. Odds ratios (OR) estimates and associated 95% confidence intervals (CIs) were calculated. A Bayesian network analysis was performed using R studio software, and then the efficacy and safety rankings were derived. Results: This network meta-analysis enrolled 15 trials randomizing 2,076 patients. According to the plot rankings, the anticoagulant therapy was the best in terms of major bleeding, and the post-thrombolysis anticoagulation was the best in terms of all-cause mortality. Taking major bleeding and all-cause mortality into consideration, the most safe-effective treatment was the post-thrombolysis anticoagulation in patients who needed thrombolytic therapy. The net clinical benefit analysis comparing associated ICH benefits vs. mortality risks of post-thrombolysis anticoagulation demonstrated a net clinical benefit of 1.74%. Conclusion: The systemic thrombolysis followed by anticoagulation had a better advantage in all-cause mortality and major bleeding than the systemic thrombolysis before anticoagulation. The adjuvant anticoagulation treatment of systemic thrombolytic therapy should be optimized.

Genetic Predisposition of Anti-Cytomegalovirus Immunoglobulin G Levels and the Risk of 9 Cardiovascular Diseases.

Background: Accumulating evidence has indicated that persistent human cytomegalovirus (HCMV) infection is associated with several cardiovascular diseases including atherosclerosis and coronary artery disease. However, whether there is a causal association between the level of anti-HCMV immune response and the risk of cardiovascular diseases remains unknown. Methods: Single-nucleotide polymorphisms associated with anti-cytomegalovirus immunoglobulin (Ig) G levels were used as instrumental variables to estimate the causal effect of anti-cytomegalovirus IgG levels on 9 cardiovascular diseases (including atrial fibrillation, coronary artery disease, hypertension, heart failure, peripheral artery disease, pulmonary embolism, deep vein thrombosis of the lower extremities, rheumatic valve diseases, and non-rheumatic valve diseases). For each cardiovascular disease, Mendelian randomization (MR) analyses were performed. Inverse variance-weighted meta-analysis (IVW) with a random-effects model was used as a principal analysis. In addition to this, the weighted median approach and MR-Egger method were used for further sensitivity analysis. Results: In the IVW analysis, genetically predicted anti-cytomegalovirus IgG levels were suggestively associated with coronary artery disease with an odds ratio (OR) of 1.076 [95% CI, 1.009-1.147; p = 0.025], peripheral artery disease (OR 1.709; 95% CI, 1.039-2.812; p = 0.035), and deep vein thrombosis (OR 1.002; 95% CI, 1.000-1.004; p = 0.025). In the further analysis, similar causal associations were obtained from weighted median analysis and MR-Egger analysis with lower precision. No notable heterogeneities and horizontal pleiotropies were observed (p > 0.05). Conclusions/Interpretation: Our findings first provide direct evidence that genetic predisposition of anti-cytomegalovirus IgG levels increases the risk of coronary artery disease, peripheral artery disease, and deep vein thrombosis.