Blood circulating proteins display sex specific differences after acute myocardial infarction

Abstract Background Inflammation and its resolution involve a concerted interplay between immune and non-immune cells mediated by numerous cytokines, chemokines and growth factors through paracrine or autocrine mechanisms. Acute myocardial infarction (AMI) remains the leading cause of cardiovascular death in the western world and a strong activation of immune cells is one of the culprits of the disease. Derailed inflammatory regulation results frequently in heart failure or recurrent cardiovascular events and better insight in the regulation of these immune responses will lead to better patient care. Purpose Evaluation of sex-specific differences in circulating protein mediators released during early onset AMI. Methods We collected blood from male and female AMI patients and healthy (H) controls and prepared serum samples (18 AMI: 7 female, 11 male and 22 H: 11 female, 11 male). We preselected 25 candidate proteins of the Olink Flex kit, based on monocyte transcriptome profiles identified in a set of AMI patients. Samples were randomized on a 96-well plate and measurements were performed according to Olink Flex (Panel FKHK-RVDR) standard operating procedures using a Olink Signature Q100. Results All 40 patient samples passed the quality control based on internal controls as did the 25 selected assays, 23 proteins were detected above LOD in 75% of the samples for normalized protein quantification (NPX). We identified 13 circulating proteins that separated H from A. Both Interleukin 6 (IL6), a well-known inflammatory "first responder" acute phase response initiating cytokine, as well as hepatocyte growth factor (HGF), an angiogenic molecule promoting cell proliferation, modifying apoptosis, inducing cell motility and wound healing were significantly increased in sera of both sexes. In male AMI samples we also observed several proteins significantly decreased, such as CD36, CD84, SDF-1, HBEGF, IL4, IFNG, VGEF and CXCL8, whereas CXCL9, a T cell chemoattractant was significantly increased. In female samples the signalling peptide adrenomedullin (ADM), a potential prognostic biomarker for cardiovascular pathophysiology, was significantly increased but no proteins were decreased. When we correlated our findings with clinical parameters of the patient cohort, it was striking that most decreased proteins in male AMI negatively correlated with NT-proBNP and to a lower extent with troponin T. IL6 and HGF also correlated negatively with diastolic blood pressure, but positively with leukocyte and monocyte counts. ADM correlated positively with heart frequency, NT-proBNP and leukocytes and negatively with HDL. Conclusions Whereas IL6 and HGF are significantly increased in both sexes, high ADM levels appear to predominate in female patients and CXCL9 levels can distinguish male patients. Studying identified targets in bigger cohorts can help developing novel therapeutic approaches and biomarkers for assessment of disease severity and potential disease prevention.