Computer simulation help predict the frame deformation following a Venus-A transcatheter aortic valve implantation in patients with pure aortic regurgitation: a retrospective study.

Background: Patient-specific computer simulation of transcatheter aortic valve implantation (TAVI) predicts the interaction between an implanted device and the surrounding anatomy. In this study, we validated the predictive value of computer simulation for the frame deformation following a Venus-A TAVI implant in patients with pure aortic regurgitation (AR). Furthermore, we used the validated computational model to evaluate the anchoring mechanism within the same cohort. Methods: This was a retrospective study. FEops HEARTguide technology was used to simulate the virtual implantation of a Venus-A valve model in a patient-specific geometry. The predicted frame deformation was quantitatively compared to the postoperative device deformation at multiple levels. The outward forces acting on the frame were extracted for each patient and the total outward force acting around the aortic annular (AA) and sinotubular junction (STJ) planes were recorded. Results: Thirty patients were enrolled in the study with 10 in the migration group and 20 in the non-migration group. The dimensions of the simulated and observed frames had good correlations at Dmax (R2=0.88), Dmin (R2=0.91), perimeter (R2=0.92), and area (R2=0.92). The predicted outward force acting on the frame at the AA level was comparable between the migration and no-migration groups. The predicted outward force acting on the frame at the STJ level was always significantly higher in the migration group than the no migration group at different bandwidths: 3 mm (P=0.002), 5 mm (P=0.005), 10 mm (P=0.002). Conclusions: Patient-specific computer simulation of TAVI accurately predicted frame deformation in Chinese patients with pure AR. The forces at the STJ facilitated stabilization of the device within the aortic root, which might be used as a discriminator to identify patients at risk of device migration prior to intervention.

Integrated multi-omic high-throughput strategies across-species identified potential key diagnostic, prognostic, and therapeutic targets for atherosclerosis under high glucose conditions.

Diabetes is a well-known risk factor for atherosclerosis (AS), but the underlying molecular mechanism remains unknown. The dysregulated immune response is an important reason. High glucose is proven to induce foam cell formation under lipidemia situations in clinical patients. Exploring the potential regulatory programs of accelerated foam cell formation stimulated by high glucose is meaningful. Macrophage-derived foam cells were induced in vitro, and high-throughput sequencing was performed. Coexpression gene modules were constructed using weighted gene co-expression network analysis (WGCNA). Highly related modules were identified. Hub genes were identified by multiple integrative strategies. The potential roles of selected genes were further validated in bulk-RNA and scRNA datasets of human plaques. By transfection of the siRNA, the role of the screened gene during foam cell formation was further explored. Two modules were found to be both positively related to high glucose and ox-LDL. Further enrichment analyses confirmed the association between the brown module and AS. The high correlation between the brown module and macrophages was identified and 4 hub genes (Aldoa, Creg1, Lgmn, and Pkm) were screened. Further validation in external bulk-RNA and scRNA revealed the potential diagnostic and therapeutic value of selected genes. In addition, the survival analysis confirmed the prognostic value of Aldoa while knocking down Aldoa expression alleviated the foam cell formation in vitro. We systematically investigated the synergetic effects of high glucose and ox-LDL during macrophage-derived foam cell formation and identified that ALDOA might be an important diagnostic, prognostic, and therapeutic target in these patients.

Causal effect of lipoprotein(a) level on chronic kidney disease of European ancestry: a two-sample Mendelian randomization study.

INTRODUCTION: Chronic kidney disease is a growing health issue, and the options of prevention and therapy remain limited. Although a number of observational studies have linked higher Lp(a) [lipoprotein(a)] levels to the kidney impairment, the causal relationship remains to be determined. The purpose of this study was to assess the causal association between Lp(a) levels and CKD. METHODS: We selected eight single-nucleotide polymorphisms (SNPs) significantly associated with Lp(a) levels as instrumental variables. Genome-wide association study (GWAS) from CKDGen consortium yielded the summary data information for CKD. We designed the bidirectional two-sample Mendelian randomization (MR) analyses. The estimates were computed using inverse-variance weighted (IVW), simple median, weighted median, and maximum likelihood. MR-Egger regression was used to detect pleiotropy. RESULTS: Fixed-effect IVW analysis indicated that genetically predicted Lp(a) levels were associated with CKD significantly (odds ratio, 1.039; 95% CI, 1.009-1.069; p = 0.010). The SNPs showed no pleiotropy according to result of MR-Egger test. Results from sensitivity analyses were consistent. In the inverse MR analysis, random-effect IVW method showed CKD had no causal effect on the elevated Lp(a) (odds ratio, 1.154; 95% CI, 0.845-1.576; p = 0.367). CONCLUSION: In this bidirectional two-sample MR analysis, the causal deteriorating effects of genetically predicted plasma Lp(a) levels on the risk of CKD were identified. On the contrary, there is no evidence to support a causal effect of CKD on Lp(a) levels.

Immune patterns of cuproptosis in ischemic heart failure: A transcriptome analysis.

Cuproptosis is a recently discovered programmed cell death pattern that affects the tricarboxylic acid (TCA) cycle by disrupting the lipoylation of pyruvate dehydrogenase (PDH) complex components. However, the role of cuproptosis in the progression of ischemic heart failure (IHF) has not been investigated. In this study, we investigated the expression of 10 cuproptosis-related genes in samples from both healthy individuals and those with IHF. Utilizing these differential gene expressions, we developed a risk prediction model that effectively distinguished healthy and IHF samples. Furthermore, we conducted a comprehensive evaluation of the association between cuproptosis and the immune microenvironment in IHF, encompassing infiltrated immunocytes, immune reaction gene-sets and human leukocyte antigen (HLA) genes. Moreover, we identified two different cuproptosis-mediated expression patterns in IHF and explored the immune characteristics associated with each pattern. In conclusion, this study elucidates the significant influence of cuproptosis on the immune microenvironment in ischemic heart failure (IHF), providing valuable insights for future mechanistic research exploring the association between cuproptosis and IHF.

Smoking and coronary artery disease risk in patients with diabetes: A Mendelian randomization study.

Background: Previous observational studies have shown an association between smoking and coronary artery disease (CAD) in patients with diabetes. Whether this association reflects causality remains unestablished. This study aimed to explore the causal effect of smoking on CAD in patients with diabetes. Methods: Genetic signatures for smoking were extracted from a large genome-wide association study (GWAS), consisted of up to 1.2 million participants. Four smoking phenotypes were included: smoking initiation, cigarettes per day, age at initiation of regular smoking, and smoking cessation. Genetic associations with CAD in patients with diabetes were extracted from another GWAS, which included 15,666 participants (3,968 CAD cases and 11,696 controls). The analyses were performed using the univariable and multivariable Mendelian randomization (MR) method. Results: MR analysis revealed that smoking initiation was positively related to CAD risk in patients with diabetes (OR = 1.322, 95% CI = 1.114 - 1.568, P = 0.001), but this association was attenuated when adjusted for cardiovascular risk factors (OR = 1.212, 95% CI = 1.008 - 1.457, P = 0.041). Age at initiation of regular smoking was negatively related to CAD in patients with diabetes (OR = 0.214, 95% CI = 0.070 - 0.656, P = 0.007), but this association became insignificant when adjusted for cardiovascular risk factors. Conclusions: This study supported the effect of smoking initiation on the risk of CAD in patients with diabetes.

The impact of personality on the risk and survival of breast cancer: a Mendelian randomization analysis.

BACKGROUND: It has long been hypothesized that personality plays a causative role in incidence and outcome of breast cancer (BC), but epidemiological evidence of association between personality and BC is inconsistent. METHOD: We used two-sample Mendelian randomization analysis to estimate the impact of personality on the risk and survival of BC. In total, 109 single nucleotide polymorphisms (SNPs) were utilized as instruments of neuroticism from a large-scale Genome-Wide Association Studies (GWAS), and five SNPs were utilized as instruments of extraversion from Genetic of Personality Consortium and 23andMe. Genetic association with the risk and survival of overall and individual subtype BC were obtained from the Breast Cancer Association Consortium. RESULT: Neuroticism is significantly associated with the risk of overall BC [odds ratio (OR) 1.06; 95% confidence interval (CI) 1.01-1.11; p = 0.015] and the risk of luminal A BC (OR 1.09; 95% CI 1.03-1.16; p = 0.004). Extraversion is not associated with the risk of BC. None of neuroticism or extraversion is associated with the survival of BC. CONCLUSION: Neuroticism was associated with a modest increased risk of BC and particularly luminal A BC.

Combined effects of physical activity and sedentary behavior on all-cause mortality in heart failure patients: A cohort study of national health and nutrition examination survey analysis.

Background: Physical activity and sedentary behavior are independently related to the risk of cardiovascular disease. Physical activity is recognized as having a protective effect, while being sedentary seems to be adverse. Nonetheless, the interactions between physical activity and sedentary behavior and the combined effect on the prognosis of heart failure patients remain unclear. Methods and results: This cohort study included 886 heart failure patients from the National Health and Nutrition Examination Survey (NHANES) 2007-2018. Physical activity and sedentary behavior were assessed by the NHANES questionnaires. The all-caused deaths of enrolled subjects were identified from National Death Index (NDI) database. During a median follow-up of 51 months, 321 (36.2%) deaths from any causes occurred. Multivariable Cox proportional hazards models were used to estimate the hazard ratios (HRs) and 95% confidence interval (CI) for the all-cause mortality in heart failure patients associated with physical activity and sedentary behavior. Physical activity was independently associated with lower mortality [HR = 0.51, 95% CI (0.38-0.68), p < 0.001] and sedentary behavior was associated with adverse prognosis [HR = 1.79, 95% CI (1.41-2.28), p < 0.001]. Kaplan-Meier survival curve showed that physical activity appeared to attenuate the negative consequences of SB, while sedentary behavior increased the all-cause mortality, particularly those without physical activity. Conclusion: Physical activity has a protective effect on HF patients' prognosis, particularly those with sedentary behavior. Sedentary behavior independently exhibited a negative association in populations without physical activity, while it does not increase mortality in those with moderate physical activity.

Genetic liability to sedentary behavior in relation to myocardial infarction and heart failure: A mendelian randomization study.

BACKGROUND AND AIMS: Observational studies have indicated that sedentary behavior is associated with myocardial infarction (MI), heart failure (HF), and atrial fibrillation (AF). Nevertheless, whether these associations are causal remain controversial, due to confounding factors (e.g., physical activity) and reverse causality. METHODS AND RESULTS: Instrumental variables were obtained from the largest genome-wide association studies of sedentary behavior (408,815 individuals) to date. We obtained summary statistics of MI from the CARDIoGRAMplusC4D consortium (171,875 individuals), HF from the HERMES Consortium (977,323 individuals), and AF from the Atrial Fibrillation Consortium (588,190 individuals). The inverse-variance weighted method was applied to obtain Mendelian randomization (MR) estimates, and other statistical methods were conducted in the sensitivity analyses. The main analyses were repeated using data from the FinnGen study. Multivariable MR analysis and mediation analysis were performed to evaluate the role of physical activity and other confounders. Genetically determined television watching was associated with MI (odds ratio [OR], 1.38; 95% CI, 1.19-1.59; p = 1.9 × 10-5) and HF (OR, 1.23; 95%CI, 1.09-1.38; p = 7.0 × 10-4) but not AF. The main results kept robust in most sensitivity analyses. The effect of sedentary behavior on MI and HF was partly mediated by body mass index (BMI). No consistent evidence was found for the causal effect of computer use and driving on MI, HF, or AF. CONCLUSIONS: Genetic liability to prolonged television watching is associated with higher risks of MI and HF. Interventions for reducing television watching time, such as public education and awareness campaigns, should be further investigated.

Association between electronic cigarettes use and whole blood cell among adults in the USA-a cross-sectional study of National Health and Nutrition Examination Survey analysis.

Electronic cigarettes (E-cigarettes) use is an emerging public health problem. Trying to assess the independent associations between E-cigarettes use and whole blood cell in a nationally representative sample of the US adults is very important for the smoking population. Using E-cigarettes data from NHANES (National Health and Nutrition Examination Survey) 2013-2018, 17,180 adults were included in this cross-sectional analysis. All participants were stratified into four different groups (non-smoke group N=10087, E-cigarettes group N=52, dual-smoke group N=249, cigarettes group N=6792) based on questions SMQ020 (smoked at least 100 cigarettes in life) and SMQ690H (used last 5 days E-cigarettes). Whole blood cell tests included white blood cell (WBC) with differentials, red blood cell (RBC) with characteristics, and platelet variables. With adjusted by age, gender, and race ethnicity, multivariate logistic regression analyses were used to assess independent associations between E-cigarettes group and other groups for different whole blood cell variables. A total of 17,180 participants were included in the study; 47.9% were males, with a mean age of 46.99 (±0.29). In WBC-related variables, non-smoke group had the lowest value in WBC counts (7.15±0.05), lymphocyte (2.15±0.02), and monocyte (0.57±0.01), among the four different groups. In RBC-related variables, non-smoke group had the lowest value in mean cell volume (MCV, 88.46±0.14, p<0.05) and mean cell hemoglobin (MCH, 29.73±0.06, p<0.05), among the four different groups. In adjusted analysis, WBC (OR = 0.97, 95% CI: 0.96-0.98, p<0.001), especially lymphocyte (OR = 0.97, 95% CI: 0.96-0.98, p<0.001) and monocyte (OR = 0.11, 95% CI: 0.02-0.66, p<0.001) of non-smoke group, showed negative significant effect for E-cigarettes group. Meanwhile, lower odds of MCV (OR = 0.91, 95% CI: 0.81-1.04, p<0.05) and MCH (OR = 0.81, 95% CI: 0.65-1.00, p<0.05) in non-smoke group were observed compared to E-cigarettes group. Conversely, for dual-smoke group and cigarette group, there was no significant results in all whole blood cell variables compared to E-cigarettes group. E-cigarettes use might be associated with a systemic response that could lead to an increase in WBC, especially lymphocytes and monocytes, in the US adults. Meanwhile, the properties of RBC might also be influenced simultaneously; MCV and MCH in E-cigarettes population were bigger than the non-smoke population.

Gensini score values for predicting periprocedural myocardial infarction: An observational study analysis.

The Gensini score (GS) is a convenient, powerful tool for assessing the severity and complexity of coronary artery diseases. Our research investigated the relationship between the GS and periprocedural myocardial infarction (PMI). We recruited 4949 patients (3366 men, 1583 women; mean age 66.45 ± 10.09 years) with a single coronary artery revascularization. Based on the tertile of the GS 20 and 36, the population was divided into 3 groups: Low Group (0 < GS ≤ 20, N = 1809); Intermediate Group (20 < GS ≤ 36, N = 1579); High Group (GS > 36, N = 1561). PMI3 represented the endpoint for cTnI > 3-fold upper reference limit, while PMI5 represented the endpoint for cTnI > 5-fold upper reference limit. The incidence of PMI of High Group was statistically higher than that of Intermediate Group (P < .05), while that of Intermediate Group was statistically higher than Low Group (P < .05). With the adjustment of some general variables, GS was an independent significantly predictor for PMI3 (ß = 0.006, P < .05) and PMI5 (ß = 0.007, P < .05). Following receiver operating characteristic curve analysis, the optimal cut-off value to predict PMI are 22.5 for PMI3 and 27 for PMI5. The GS was an independent predictor of PMI in the single-coronary revascularization population. Additionally, the 22.5 of GS was the optimal cut-off value for determining the presence of PMI3, while the 27 of GS for PMI5.

Admission electrolyte and osmotic pressure levels are associated with the incidence of contrast-associated acute kidney injury.

This retrospective study aimed to explore the relationships between electrolytes and osmotic pressure homeostasis with contrast-associated acute kidney injury (CA-AKI) risk in patients with percutaneous coronary intervention or coronary angiography. We totally enrolled 4386 hospitalized patients, who were categorized into five groups based on the predetermined cutoff values of electrolytes and osmotic pressure. CA-AKI was defined as an increase in serum creatine by 0.5 mg/dL (44.2 mol/L) or a 25% increase of the highest level post-operation compared to baseline. Multivariable logistic analysis was used to examine the association of CA-AKI incidence with electrolytes and osmotic pressure levels. Piecewise linear regression models and restricted cubic spline analysis were further utilized to determine the nonlinear relationship. The results showed U-shaped relationships between sodium, chloride, magnesium, and osmotic pressure levels and CA-AKI incidence. The lowest incidence was observed in the categories of 139-141.9 mmol/L, 107.0-109.9 mmol/L, 0.91-1.07 mmol/L, and 290.0-299.9 mOsm/kg, respectively. J-shaped associations were observed for potassium and phosphate levels and CA-AKI incidence, with the lowest incidence in the categories of 3.50-4.09 mmol/L and 0.96-1.28 mmol/L, respectively. A negative correlation was observed between calcium level and CA-AKI incidence, with the lowest CA-AKI risk in the category of ≥ 2.58 mmol/L. In conclusion, abnormally higher or lower sodium, chloride, magnesium, phosphate, and osmotic pressure levels on admission were associated with increased risks of CA-AKI. While for potassium and calcium, the status of hyperkalemia and hypocalcemia on admission showed more susceptibility for CA-AKI.

Low Intelligence Predicts Higher Risks of Coronary Artery Disease and Myocardial Infarction: Evidence From Mendelian Randomization Study.

Background: Low intelligence has been shown to be associated with a high risk of cardiovascular disease in observational studies. It remains unclear whether the association is causal. This study aimed to explore the causal association of intelligence with coronary artery disease (CAD) and myocardial infarction (MI). Methods: A two-sample Mendelian randomization study was designed to infer the causality. A total of 121 single nucleotide polymorphisms were selected as a genetic instrumental variable for intelligence. Summary data on CAD (n = 184,305) and MI (n = 171,875) were obtained from the Coronary ARtery DIsease Genome-wide Replication and Meta-analysis (CARDIoGRAM) plus The Coronary Artery Disease (C4D) Genetics (CARDIoGRAMplusC4D) consortium and the FinnGen study. Inverse variance weighting method was used to calculate the effect estimates. Sensitivity analyses including other statistical models and leave-one-out analysis were conducted to verify the robustness of results. MR-Egger test was performed to assess the pleiotropy. Results: Genetically predicted higher intelligence was significantly associated with lower risk of CAD (OR, .76; 95%CI, .69-.85; p = 1.5 × 10-7) and MI (OR, .78; 95%CI, .70-.87; p = 7.9 × 10-6). The results remained consistent in the majority of the sensitivity analyses and were repeated in the FinnGen datasets. MR-Egger test suggested no evidence of directional pleiotropy for the association with coronary artery disease (intercept = -.01, p = .19) and myocardial infarction (intercept = -.01, p = .06). Conclusion: This Mendelian randomization analysis provided genetic evidence for the causal association between low intelligence and increased risks of CAD and MI.

Sex-specific effect of serum urate levels on coronary heart disease and myocardial infarction prevention: A Mendelian randomization study.

BACKGROUND AND AIMS: Observational studies have examined serum urate levels in relation to coronary heart disease (CHD) and myocardial infarction (MI). Whether these associations are causal remains controversial, due to confounding factors and reverse causality. We aim to investigate the causality of these associations using Mendelian randomization method. METHODS AND RESULTS: Instrumental variables were obtained from the largest genome-wide association studies of serum urate (457,690 individuals) to date. Summary statistics were from CARDIoGRAMplusC4D consortium (60,801 CHD cases; 43,676 MI cases), FinnGen (21,012 CHD cases; 12,801 MI cases), UK Biobank (10,157 CHD cases; 7018 MI cases), and Biobank Japan (29,319 CHD cases). Inverse-variance weighted method was applied as the main results. Other statistical methods and reverse MR analysis were conducted in the supplementary analyses. Elevated genetically determined serum urate levels were associated with increased risks of CHD and MI. The association pattern remained for the datasets in FinnGen, the combined results of three independent data sources (CHD: odds ratio (OR), 1.10; 95%CI, 1.06-1.15; p = 4.2 × 10-6; MI: OR, 1.12; 95%CI, 1.07-1.18; p = 2.7 × 10-6), and East Asian population. Interestingly, sex-specific subgroup analyses revealed that these associations kept in men only, but not among women in individuals of European ancestry. No consistent evidence was found for the causal effect of CHD or MI on serum urate levels. CONCLUSION: We provide consistent evidence for the causal effect of genetically predicted serum urate levels on CHD and MI, but not the reverse effect. Urate-lowering therapy may be of cardiovascular benefit in the prevention of CHD and MI, especially for men.

Genetic Liability to Sedentary Behavior in Relation to Stroke, Its Subtypes and Neurodegenerative Diseases: A Mendelian Randomization Study.

Objective: To investigate the causal association of domain-specific sedentary behaviors with cerebrovascular diseases and neurodegenerative diseases, and the potential mediators among these associations. Methods: Genetic instruments were identified for television watching, computer use and driving behavior from a genome-wide association study including 408,815 subjects. Mendelian randomization (MR) analysis was used to estimate the causal effect of sedentary behaviors on the cerebrovascular diseases and neurodegenerative diseases. Multivariable MR analysis was applied to adjust potential confounding factors, and mediation analysis was conducted to explore potential mediators. Results: Genetically predisposition to 1.5 h/day increase in leisure time watching television was associated with increased risk of all-cause stroke [odds ratio (OR) = 1.32, 95% confidence interval (CI) = 1.15-1.52, p-value for MR-Egger method (P Egger) = 0.11, I 2 = 37%, Cochrane's Q = 212, p-value for Cochran Q test (P Q) < 0.001], and ischemic stroke (OR = 1.28, 95%CI = 1.10-1.49, P Egger = 0.04, I 2 = 35%, Cochrane's Q = 206, P Q = 0.002). Interestingly, television watching may decrease the risk of Parkinson's disease (OR = 0.65, 95%CI = 0.50-0.84, P Egger = 0.47, I 2 = 19%, Cochrane's Q = 157, P Q = 0.04). Television watching was a detrimental factor of cognitive performance (estimate = -0.46, 95%CI = -0.55 - -0.37, P Egger = 0.001, I 2 = 85%, Cochrane's Q = 862, P Q < 0.001). Sensitivity analyses using leave out method and MR-PRESSO method suggested weak evidence of pleiotropy. Conclusion: We provided genetic evidence for the causal association of television watching with increased risk of all-cause stroke and ischemic stroke, decreased risk of Parkinson's disease, and worse cognitive performance. The results should be interpreted with caution considering the pleiotropy.

The impact of serum 25-hydroxyvitamin D, calcium, and parathyroid hormone levels on the risk of coronary artery disease in patients with diabetes: a Mendelian randomization study.

BACKGROUND: To investigate the causal association between serum 25-hydroxyvitamin D (25OHD), calcium (Ca), and parathyroid hormone (PTH) levels and the risk of coronary artery disease (CAD) in patients with diabetes using a Mendelian randomization approach. METHODS: Genetic signatures associated with serum 25OHD, Ca, and PTH levels were extracted from recently published genome-wide association study (GWAS), including 79,366, 39,400, 29,155 individuals, respectively. Genetic association estimates for CAD in patients with diabetes were obtained from a GWAS of 15,666 individuals with diabetes (3,968 CAD cases, 11,696 controls). The inverse-variance-weighted method was employed for the primary analysis, and other robust methods were applied for sensitivity analyses. RESULTS: Six, seven and five single nucleotide polymorphisms were identified as instrumental variables for serum 25OHD, Ca and PTH levels, respectively. There was no significant association between genetically predicted serum 25OHD levels and the risk of CAD in patients with diabetes (odds ratio (OR) = 1.04, 95% confidence interval (CI): 0.58 - 1.87, P = 0.888). Similarly, genetically predicted serum Ca (OR = 1.83, 95% CI: 0.62 - 5.35, P = 0.273) and PTH levels (OR = 1.27, 95% CI: 0.67 - 2.44, P = 0.464) were not significantly associated with the risk of CAD in patients with diabetes. These findings were robust in sensitivity analyses. CONCLUSIONS/INTERPRETATION: Serum 25OHD, Ca and PTH levels may not be causally associated with the risk of CAD in patients with diabetes.

Genetic Determinants of Increased Body Mass Index Partially Mediate the Effect of Elevated Birth Weight on the Increased Risk of Atrial Fibrillation.

Background: Although several observational studies have shown an association between birth weight (BW) and atrial fibrillation (AF), controversy remains. In this study, we aimed to explore the role of elevated BW on the etiology of AF. Methods: A two-sample Mendelian randomization (MR) study was designed to infer the causality. The genetic data on the associations of single-nucleotide polymorphisms (SNPs) with BW and AF were separately obtained from two large-scale genome-wide association studies with up to 321,223 and 1,030,836 individuals, respectively. SNPs were identified at a genome-wide significant level (p <5 × 10-8). The inverse variance-weighted (IVW) method was employed to obtain causal estimates as our primary analysis. Sensitivity analyses with various statistical methods were applied to evaluate the robustness of the results, and multivariable MR analysis was conducted to determine whether this association was mediated by the body mass index (BMI). Results: In total, 144 SNPs were identified as the genetic instrumental variables. MR analysis revealed a causal effect of elevated BW on AF (OR = 1.27, 95% CI = 1.14-1.40, p = 5.70 × 10-6). All the results in sensitivity analyses were consistent with the primary result. The effect of BW on AF was attenuated when adjusted for BMI (OR = 1.16, 95% CI = 1.01-1.33, p = 0.04). Conclusions: This study indicated that elevated BW was significantly associated with increased lifelong risk of AF, which may be partially mediated by BMI.

Appraising the Causal Association of Plasma Homocysteine Levels With Atrial Fibrillation Risk: A Two-Sample Mendelian Randomization Study.

BACKGROUND: Although several observational studies have suggested an association of elevated plasma homocysteine (Hcy) levels with increased risk of atrial fibrillation (AF), it remains unclear whether this association reflects causality. In this study, we aimed to investigate the causal association of plasma Hcy levels with AF risk. METHODS: A two-sample Mendelian randomization (MR) study was designed to investigate the causal association of Hcy with AF. Summary data on association of single nucleotide polymorphisms (SNPs) with Hcy were extracted from the hitherto largest genome-wide association study (GWAS) with up to 44,147 individuals, and statistics data on association of SNPs with AF were obtained from another recently published GWAS with up to 1,030,836 individuals. SNPs were selected at a genome-wide significance threshold (p < 5 × 10-8). Fixed-effect inverse variance weighting (IVW) method was used to calculate the causal estimate. Other statistical methods and leave-one-out analysis were applied in the follow-up sensitivity analyses. MR-Egger intercept test was conducted to detect the potential directional pleiotropy. RESULTS: In total, nine SNPs were identified as valid instrumental variables in our two-sample MR analysis. Fixed-effect IVW analysis indicated no evidence of causal association of genetically predicted Hcy with AF. The odds ratio (OR) and 95% confidence interval (CI) of AF per standard deviation (SD) increase in Hcy were 1.077 (0.993, 1.168), p = 0.075. Similar results were observed in the sensitivity analyses. MR-Egger intercept test suggested no evidence of potential horizonal pleiotropy. CONCLUSIONS: This two-sample MR analysis found no evidence to support causal association of Hcy with AF.

Genetically predicted serum uric acid levels and the risk of coronary artery disease in patients with diabetes: A Mendelian randomization study.

BACKGROUND AND AIMS: Serum uric acid (SUA) levels have been reported to be associated with an increased risk of coronary artery disease (CAD) among patients with diabetes in observational study. Whether this relationship is causal remains unclear. The current study aimed to explore the causal association between SUA and the risk of CAD in patients with diabetes. METHODS AND RESULTS: A two-sample Mendelian randomization (MR) approach was employed to evaluate the causal effect of SUA on the risk of CAD in patients with diabetes. A total of 28 single nucleotide polymorphisms (SNPs) related to SUA were identified as instruments. Genetic association with CAD were obtained from a recently published genome-wide association study (GWAS) of 15,666 patients with diabetes (3968 CAD cases and 11,696 controls). The fixed-effects inverse variance-weighted method was employed to estimate the causal effect for the primary analysis, and other robust methods were employed for sensitivity analyses. In addition, the whole analyses were repeated using 9 non-pleiotropic SNPs. Genetic determined SUA levels were not significantly associated with the risk of CAD in patients with diabetes in the primary analysis (odds ratio = 1.13, 95% confidence interval: 0.98-1.16, P = 0.09). Consistent results were observed in the sensitivity analyses using various robust methods. In addition, this finding was confirmed by the repeated analyses using 9 non-pleiotropic SNPs. CONCLUSIONS: This two-sample MR study does not support a causal effect of genetically predicted SUA levels on the risk of CAD in patients with diabetes.

Serum Uric Acid Levels and Risk of Eight Site-Specific Cancers: A Mendelian Randomization Study.

The relationship between serum uric acid (UA) levels and cancer risk remains controversial. Here, a two-sample Mendelian randomization analysis was performed to identify a causal effect of serum UA levels on cancer risk. Twenty-six single nucleotide polymorphisms strongly associated with serum UA levels were screened as genetic variants from large-scale meta-analysis data of a genome-wide association study of 110,347 European individuals. Genetic associations with eight common site-specific cancers were subsequently explored. A total of six Mendelian randomization methods were used to estimate the potential effect of serum UA levels on cancer risk, including random effects inverse variance weighting, fix effects inverse variance weighting, MR-Egger, median weighting, mode weighting, and simple mode analysis. Our primary random effects inverse variance weighted analysis revealed that no significant associations with cancers was found (all p > 0.05). Sensitivity analyses and additional analyses also showed similar pooled results. In conclusion, no significant causality between serum UA levels and cancer risk was evidenced.

New perspective on the risk markers for left atrial thrombosis in patients with atrial fibrillation.

BACKGROUND: Anticoagulant therapy is one of the important aspects of atrial fibrillation (AF) management, which can effectively reduce the formation of left atrial thrombosis (LAT) and the occurrence of embolic events. The CHA2DS2-VASc score is a commonly used risk assessment tool for embolic events, and it has guiding significance for anticoagulant therapy. However, a large number of recent studies have clearly shown that some of the markers that are not included in the score affect the formation of LAT. OBJECTIVE: This single-center study probed for risk markers for LAT by analyzing the clinical features of patients who experienced AF. METHODS: We reviewed patients with AF who had undergone a transesophageal echocardiography exam over the past 6 years and used binary logistic regression analysis to identify risk markers other than CHA2DS2-VASc score. For the risk markers found, the propensity score matching (PSM) was used to further evaluate whether it was an independent risk marker for LAT. The newly discovered markers were added to the score, and receiver operating characteristic analysis was used to evaluate whether the ability of the model to predict LAT was improved. RESULTS: A total of 2246 patients were included in the study. In total, 838 of them were anticoagulated (314 with rivaroxaban, 57 with dabigatran, and 467 with warfarin) and 30 patients (1.33%) had LAT. Regression analysis revealed abnormal uric acid metabolism (abUA) and obesity were risk markers for LAT. Further PSM analysis found that abUA was an independent risk marker for LAT. After including abUA, the CHA2DS2-VASc score was more accurate for LAT prediction (area under the curve difference is 0.0651, 95% confidence interval: 0.0247, 0.1050, Z = 3.158, P = 0.0016). CONCLUSIONS: AbUA is an independent risk marker for LAT. After considering abUA, the CHA2DS2-VASc score for LAT is more accurate.