A Network Analysis to Identify Pathophysiological Pathways Associated with Systolic Function Recovery After Myocardial Infarction

Introduction: Identification of factors involved in early stages of left ventricular systolic function recovery after acute myocardial infarction (AMI) can provide a basis for novel therapies. We aimed to characterize proteomic biomarkers and underlying mechanistic pathways associated with improvement of left ventricular systolic function. Hypothesis: Proteomic biomarkers and protein-protein interaction pathways differ between patients with and without systolic function recovery after AMI. Methods: Patients with ejection fraction (EF) <40% at hospital discharge were selected from a prospective registry of AMI patients (n=819). We used matched case-control design. Cases were patients with EF<40% at hospital discharge, but EF>50% at the follow-up visit 3-6 months after discharge (EF recovery group). Controls were patients with EF<40% both at hospital discharge and follow-up visit. Controls were matched for age, gender, and discharge EF. Blood samples were drawn within 24h since hospital admission. We used proximity extension assays (Olink, Uppsala) to measure plasma biomarkers and protein-protein interaction network to identify pathophysiological pathways distinguishing cases and controls. Results: In total, 41 cases and 41 controls (mean age 59±10 years, 73% males) were included. At baseline, study groups did not differ in the main clinical variables. Of the 362 biomarkers tested, and after adjustment for age, gender and baseline EF, 44 proteins were differentially expressed, of which 2 (interleukin 6 and stem cell factor) showed association with EF recovery after false discovery rate correction. In the Reactome pathway analysis, Interleukin-6 family signaling was the most significant pathway associated with systolic function recovery. Conclusions: We identified the Interleukin-6 family signaling pathway with IL-6 and leukemia inhibitory factor (LIF) as potential early factors supporting recovery of systolic function after AMI.