An integrative study of risk assessment, mediation analysis, and causal inference for the relationship between metabolic syndrome and dilated cardiomyopathy

Aims: Although metabolic dysregulation is implicated in DCM, the involvement of metabolic syndrome (MetS) remains unclear. This study aims to systematically examine MetS in DCM pathogenesis. Materials and methods: By leveraging 378,837 UK Biobank participants, instead of the conventional binary MetS, we calculated a continuous metabolic risk score (MRS) and evaluated its influence on DCM risk within a multi-model evidence framework. Bidirectional weighted quantile sum regression identified key MRS components, a nested case-control study assessed 14-year pre-diagnosis MRS trajectories, mediation analyses evaluated MRS mediating lifestyle-DCM links and inflammation mediating MRS-DCM relationships, and Mendelian randomization (MR) evaluated causality for genetically predicted MetS and components on DCM. Results: During a median follow-up period of 13.4 years (interquartile range 12.7~14.1 years), 820 (0.2%) participants developed DCM. Higher MRS (HR=1.26 [1.18~1.34]) was associated with increased DCM risk, and such an association persisted across all robustness assessments even among non-MetS individuals. Waist circumference (WC, HR=1.36 [1.28~1.45], weight=0.58) and glycated hemoglobin (HR=1.23 [1.16~1.30], weight=0.22) dominated MRS' risk contribution. The trajectories of MRS diverged in cases approximately 10 years pre-diagnosis. MRS mediated 5.1~26.2% of lifestyle-related DCM risk, while inflammation mediated 16.4% of the MRS-DCM association. MR analysis further confirmed causal effects of MetS (OR=1.65 [1.45~1.88]), WC (OR=1.79 [1.58~2.03]) on DCM risk. Conclusions: Metabolic dysfunction, which was dominated by central adiposity and hyperglycemia, plays a key role in the occurrence of DCM. Early intervention targeting metabolic factors may prevent DCM onset.