Systemic inflammatory regulators and heart failure: A bidirectional 2-sample Mendelian randomization study

The causal relationship between systemic inflammation and heart failure (HF) remains controversial, with unresolved questions about whether inflammatory dysregulation is a driver or consequence of HF pathogenesis. To evaluate bidirectional causal associations between systemic inflammatory regulators and HF using Mendelian randomization (MR). The genetic association with HF came from the largest and most recent genome-wide association study (cases and proxy cases: 47,309; Control: 9,30,014), as well as inflammatory regulators from the nearest cytokine genome-wide association study. Estimates were obtained by inverse variance weighting using the sensitivity analysis of MR-Egger, weighted median and MR-PRESSO. Three of the 41 systemic inflammatory regulators were associated with the risk of HF, macrophage inflammatory protein-1β and regulated on activation, normal T cell expressed and secreted were positively associated with HF, and Macrophage migration inhibitory factor was negatively associated with HF. In contrast, HF was not associated with 41 systemic inflammatory regulators, and the results of the validation analysis were consistent. This MR study identifies macrophage inflammatory protein-1β and regulated on activation, normal T cell expressed and secreted as causal risk factors and migration inhibitory factor as a protective factor for HF, implicating these regulators as upstream therapeutic targets. Reverse analyses found no evidence of HF-induced inflammatory changes, supporting the unidirectional causality model.