Micro and Macrovascular Cardiac Allograft Vasculopathy in Relation to 92 Cardiovascular Biomarkers Evaluated by a Novel Proximity Extension Assay in Heart Transplant Recipients

Abstract

Cardiac allograft vasculopathy (CAV) remains a leading cause of morbidity and mortality following heart transplantation (HTx). The pathogenesis is multifactorial and involves inflammation, thrombosis, endothelial dysfunction and immunological factors. Non-invasive biomarkers for the diagnosis of CAV have not yet been identified. We aimed to investigate the relation between micro and macrovascular CAV and a wide range of cardiovascular protein biomarkers. Using a novel proximity extension assay (Olink® CARDIOVASCULAR III), blood samples from 48 HTx patients (median 9.1 years after HTx) were analyzed for 92 biomarkers reflecting inflammation, immune response, cell adhesion, hemostasis, fibrinolysis, tissue remodeling, and proteolysis. Patients were dichotomized according to micro and macrovascular CAV burden determined by coronary angiography, optical coherence tomography, and coronary flow reserve by (15)O-H2O positron emission tomographic imaging. Twenty-seven patients had angiographic CAV. A total of 13 biomarkers differed significantly between groups (Table 1). In particular, N-terminal prohormone brain natriuretic peptide (NT-proBNP), proprotein convertase subtilisin/kexin type 9 (PCSK9), and paraoxonase 3 (PON3) differed consistently between groups. However, after correcting for multiple testing with Bonferroni correction (p<0.0005), the differences did not remain significant. Using a novel proximity extension assay, we found several potential biomarkers of CAV. Especially, signals in the heart failure biomarker NT-proBNP as well as two proteins involved in catabolic processes, PCSK9 and PON3, were seen. However, the risk of mass significance should be considered. Further studies are warranted to confirm the findings of our exploratory study.