Mediators between body mass index and atrial fibrillation: a Mendelian randomization study.

Background: Although obesity is a recognized risk factor of atrial fibrillation (AF), the mechanisms are not fully understood. Objective: We aimed to identify the potential mediators between body mass index (BMI) and AF. Methods: We conducted a two-sample Mendelian randomization (MR) analysis using publicly available summary-level data from genome-wide association studies. Univariable MR analyses were applied to identify potential mediators, and then the multivariable MR analyses were conducted to explore the mediated roles of circulating biomarkers, metabolic markers and comorbidities in the association between BMI and AF. Results: This MR study found a significant causal association between BMI and AF (OR = 1.41, 95% CI = 1.33-1.50; p < 0.001), which was attenuated to 1.21 (95% CI = 1.03-1.43) after being adjusted for leptin, in which 48.78% excess risk was mediated. After further adjustment for leptin and some cormorbidies, the association was attenuated to null (adjusted for leptin and sleep apnoea: OR=1.05, 95% CI = 0.85-1.30; adjusted for leptin and coronary heart disease: OR = 1.08, 95% CI = 0.90-1.30; adjusted for leptin and systolic blood pressure: OR = 1.11, 95% CI = 0.88-1.41), resulting in 87.80%, 80.49% and 73.17% excess risk being mediated, respectively. Conclusion: These results identified an important mediated role of leptin, particularly for individuals with sleep apnoea, coronary heart disease or hypertension, providing some clues for the underlying mechanisms behind the impact of obesity on AF risk.

Differential age-specific associations of LDL cholesterol and body mass index with coronary heart disease.

BACKGROUND AND AIMS: Low-density lipoprotein cholesterol (LDLc) and body mass index (BMI) are not always correlated and their relationship is probably dependent on age, indicating differential age-specific associations of these factors with health outcomes. We aim to discriminate the roles of LDLc and BMI in coronary heart disease (CHD) across different age groups. METHODS: This is a prospective cohort study of 368,274 participants aged 38-73 years and free of CHD at baseline. LDLc and BMI were measured at baseline, and incident CHD was the main outcome. Cox proportional hazards model and restricted cubic spline (RCS) regression were used to estimate hazard ratio (HR) and 95% confidence interval (CI) of exposure on CHD. RESULTS: After a mean of 12 years of follow-up, similar relationships of LDLc and BMI with CHD risk were observed in the overall population but in differential age-specific patterns. Across the age groups of <50, 50-54, 55-59, 60-64 and ≥ 65 years, the LDLc-CHD association diminished with the adjusted HRs decreasing from 1.35, 1.26, 1.19, 1.11 to 1.08; while no declining trend was found in BMI-CHD relationship with the adjusted HRs of 1.15, 1.11, 1.12, 1.13 and 1.15, respectively. The interaction and mediation between LDLc and BMI on CHD risk were more pronounced at young-age groups. LDLc-CHD but not BMI-CHD association was dependent on sex, metabolic syndrome and lipid-lowering drugs use. CONCLUSIONS: There were differential age-specific associations of LDLc and BMI with the risk of developing CHD, calling for future efforts to discriminate the age-different benefits from lipids management or weight control on the primary prevention for CHD.

Bi-directional association of body size and composition with heart failure: A Mendelian randomization study.

PURPOSE: The effect of obesity on the development of heart failure (HF) has received attention, and this study intends to further explore the bidirectional association between body size or composition and HF by using Mendelian Randomization (MR) approach. DESIGN: We performed a two-sample bidirectional MR study to investigate the association between body size or composition and the risk of HF using aggregated data from genome-wide association studies. Univariable MR analysis was used to investigate the causal relationship, and multivariable MR analysis was used to explore the mediating role of general and central obesity in the relationship between body size or composition and HF. RESULTS: This forward MR study found that body mass index (BMI), waist circumference (WC), waist-hip ratio (WHR), fat mass (FM) and fat-free mass (FFM) were risk factors for the development of HF with the strength of causal association BMI > FM > WC > FFM > WHR. After adjusting for BMI, the observed associations between the remaining indicators and heart failure attenuated to null. After adjusting for WC, only BMI (OR = 1.59, 95%CI: 1.32-1.92, P = 9.53E-07) and FM (OR = 1.39, 95%CI: 1.20-1.62, P = 1.35E-0.5) kept significantly related to the risk of HF. Reverse MR analysis showed no association of changes in body size or composition with the onset of HF. CONCLUSION: The two-sample bidirectional MR study found that general obesity, measured by BMI, was an independent indicator of the development of HF, while other related indicators were associated with HF incidence dependent on BMI, besides, no association was observed between HF diagnosis and the body size or composites.

From the Cover: An Animal-Free In Vitro Three-Dimensional Testicular Cell Coculture Model for Evaluating Male Reproductive Toxicants.

Primary testicular cell coculture model has been used to evaluate testicular abnormalities during development, and was able to identify the testicular toxicity of phthalates. However, the primary testicular cell coculture model has disadvantages in employing animals for the isolation of testicular cells, and the complicated isolation procedure leads to inconsistent results. We developed an invitro testicular coculture model from rodent testicular cell lines, including spermatogonial cells, Sertoli cells, and Leydig cells with specified cell density and extracellular matrix (ECM) composition. Using comparative high-content analysis of F-actin cytoskeletal structure between the coculture and single cell culture models, we demonstrated a 3D structure of the coculture, which created an invivo-like niche, and maintained and supported germ cells within a 3D environment. We validated this model by discriminating between reproductive toxicants and nontoxicants among 32 compounds in comparison to the single cell culture models. Furthermore, we conducted a comparison between the invitro (IC50) and invivo reproductive toxicity testing (lowest observed adverse effect level on reproductive system). We found the invitro coculture model could classify the tested compounds into 4 clusters, and identify the most toxic reproductive substances, with high concordance, sensitivity, and specificity of 84%, 86.21%, and 100%, respectively. We observed a strong correlation of IC50 between the invitro coculture model and the invivo testing results. Our results suggest that this novel invitro coculture model may be useful for screening testicular toxicants and prioritize chemicals for further assessment in the future.