Fig. 1. Study design.

This study comprised the following three steps: (1) HF-related biological processes and proteins were identified using serum proteomics in a cross-sectional set of patients with AMI who developed HF during hospitalization (n = 10), patients with AMI without HF (n = 10), and HCs (n = 10). (2) The association between candidate proteins and HF was prospectively evaluated in the discovery (HF: n = 296, no-HF: n = 766) and validation (HF: n = 192, no-HF: n = 851) cohorts. (3) The causal relationship between HF-associated proteins and HF was confirmed using MR analysis. For individual-level one-sample MR analysis, the causal association of genetic instruments with post-AMI HF events was assessed in the validation cohort (HF: n = 192, no-HF: n = 851). For the two-sample MR analysis, estimates of the association between the genetic instruments and S100A8/A9 levels from the validation cohort (n = 1043) and the association between the genetic instruments and post-AMI HF from the UKB cohort (n = 1144) were used to examine the causal effect of S100A8/A9 levels on post-AMI HF. Moreover, a statistical summary of the association between genetic instruments and S100A9 levels from the validation cohort and a statistical summary of the GWAS from the finn-b-I9_HEARTFAIL study (n = 208178) were used to evaluate the causal association between genetic instruments and general HF. AMI acute myocardial infarction, HC healthy control, HF heart failure, MR Mendelian randomization, UKB UK Biobank.