A structural cardiac pathway mediates the risk of ischemic heart disease from TyG-related indices: A prospective cohort study

The triglyceride-glucose (TyG) index and its derivatives are surrogate markers of insulin resistance and are closely associated with cardiovascular risk. However, whether and to what extent they are associated with IHD risk through subclinical cardiac remodeling remains unclear. This prospective cohort study included 31,828 IHD-free UK Biobank participants who underwent cardiac magnetic resonance (CMR). We calculated the TyG index and its obesity-composite derivatives (TyG-BMI, TyG-WC, TyG-WHtR). Multivariable Cox models and restricted cubic splines were used to assess their associations with incident IHD. Counterfactual mediation analysis quantified the mediating effects of CMR-derived cardiac parameters. During follow-up, 1,768 incident IHD cases occurred. All TyG-related indices were positively associated with IHD risk, with TyG-WHtR showing the strongest association (HR = 1.221), followed by TyG (HR = 1.210), TyG-WC (HR = 1.200), and TyG-BMI (HR = 1.163) (all P < 0.001). Regarding cardiac structure and function, left ventricular parameters were significantly associated with IHD risk. Cardiac structural remodeling partially mediated the TyG-IHD association: left ventricular parameters (LVEDV, LVESV, and LVEF) mediated 7.57%, 7.60%, and 3.49% of the effect, respectively, while left atrial volume showed the highest mediation proportion (LAVmax 21.09%), and right ventricular and atrial volumes also contributed (RVEDV 18.67%; RAVmax 14.83%). Elevated TyG-related indices, particularly TyG-WHtR, are independently associated with an increased risk of incident IHD. This association is partially mediated by subclinical structural remodeling across all four cardiac chambers, suggesting a multi‑chamber sensitivity of the heart to early metabolic injury. TyG-WHtR may be the preferred metabolic risk surrogate among the TyG-related indices evaluated in this study.