Abstract
BACKGROUND: The growing obesity epidemic highlights the need to understand how various obesity phenotypes affect myocardial structure and increase non-ischaemic cardiomyopathy (NICM) incidence. The aim of this study was to investigate the causal effect of eight obesity-related traits on NICM and 16 cardiac MRI parameters. Potential mediators between obesity and NICM were also investigated. METHODS: Two-sample Mendelian randomisation was used to explore the causal relationship between eight obesity-related traits and NICM and assess their impact on cardiac MRI indicators. The study also used validation dataset analysis and multivariable Mendelian randomisation to ensure robustness, and mediation Mendelian randomisation analysis to identify metabolic markers as potential mediators. RESULTS: All eight obesity-related traits demonstrated a causal relationship with NICM, with the relationship between BMI and NICM persisting after adjustment for LDL cholesterol, urate level and hypertension (HTN). These traits also influenced arterial and cardiac structure and function, especially with regard to left ventricular mass. HTN was identified as a significant mediator, with a mediation effect ratio of 31%. CONCLUSION: There is a robust causal association between obesity and NICM, and with abnormalities in myocardial structure and function. HTN emerges as a pivotal mediator in the obesity-NICM pathway, underscoring the critical role of managing obesity and HTN in preventing NICM progression.