Body Mass Index and Right Ventricular Structure: Insights From Observational and Mendelian Randomization Analyses

Overweight and obesity have emerged as modifiable risk factors for right ventricular (RV) phenotypic changes, but their genetic relationship remains unclear. This study examined RV phenotypes using cardiac magnetic resonance imaging in European participants from the UK Biobank without overt heart disease. Observational and Mendelian randomization approaches, based on individual- and summary-level genetic data, were integrated to assess the effects of BMI on RV imaging phenotypes. Among 33,801 individuals with a mean age of 64 years, 52% were women, 41% were overweight, and 18% were obese. Overweight and obese participants exhibited larger RV volumes and lower RV ejection fractions compared to normal-weight participants, even after adjusting for left heart parameters, cardiometabolic risk factors, and diseases. One-sample Mendelian randomization revealed that higher lifetime BMI was related to larger RV end-diastolic volume (3.4 mL per standard deviation BMI increase, 95% CI 2.8-4.0 mL), RV end-systolic volume (1.6 mL, 95% CI 1.3-1.9 mL), and stroke volume (1.8 mL, 95% CI 1.4-2.2 mL). Adjustment for left ventricular measures reduced these effect sizes by 51%-67%, but relationships remained statistically significant. Two-sample Mendelian randomization confirmed these findings using robust methods and correction for pleiotropic outliers. While the observational associations were more pronounced in women than in men, the genetic effects were similar across sexes. In conclusion, the relationships between BMI and RV volumes were generally consistent across observational and genetic analyses. Genetic predisposition to higher lifetime BMI influenced RV volumes in a population with a low prevalence of cardiopulmonary diseases, an effect not fully explained by left ventricular measures. These findings suggest that managing overweight and obesity may help prevent structural RV remodeling.