Identification of features and differences in PD-1 inhibitor-associated myocarditis and acute myocardial infarction using proteomic analysis: a clinical and preclinical study

Immune checkpoint inhibitors (ICIs)-related myocarditis, a severe complication characterized by elevated cardiac troponin I, poses significant clinical challenges in distinguishing it from acute myocardial infarction (AMI). Our study aimed to identify plasma protein biomarkers that differentiate ICIs-myocarditis from AMI. Plasma samples from 5 ICIs-myocarditis patients (with paired baseline and diagnosis samples) and 5 angiography-confirmed AMI patients, matched for age, gender, smoking history, and pre-existing heart disease, were analyzed using label-free liquid chromatography-mass spectrometry proteomics. A total of 1521 plasma proteins were identified, with 1325 quantifiable. Proteomic profiling revealed differentially expressed proteins (DEPs) in ICIs-myocarditis associated with myocardial contraction, proteasome activity, NF-κB signaling, immunoregulation, and amino acid metabolism. Through validation in animal models of ICIs-myocarditis and AMI, two plasma proteins-MYOM3 (myomesin 3) and galectin-1 (LGALS1)-were identified as potential biomarkers linked to the onset of ICIs-related myocarditis. Further validation using expanded clinical cohorts confirmed their differential expression. These findings highlight MYOM3 and galectin-1 as promising biomarkers for distinguishing ICIs-related myocarditis from AMI, providing insights for clinical diagnosis and mechanistic research into immune-related cardiotoxicity.