Effect of Donor Simvastatin Treatment on Gene Expression Profiles in Human Cardiac Allografts during Reperfusion

Abstract

Purpose Statin therapy initiated early after heart transplantation has beneficial effects on the development of cardiac allograft vasculopathy. Recently, we showed in a randomized clinical trial that simvastatin treatment of brain-dead donors conditions the heart transplant to endure ischemia-reperfusion injury and to reduce the need for rejection-related treatments early after transplantation (Nykanen et al, 2019). In this study, we analyzed the effect of simvastatin treatment on myocardial gene expression profiles of cardiac allografts before and after reperfusion. Methods In a prospective, randomized, controlled double-blinded trial, 42 of 84 heart transplant donors received 80 mg of simvastatin via nasogastric tube, whereas the other 42 donors received no treatment. Transmural Tru-Cut biopsies were taken from the apex of the donor heart's left ventricle immediately before reperfusion and 1 hour after reperfusion. After quality control, the RNA of 40 heart biopsies from donors with simvastatin treatment and of 37 heart biopsies from donors without treatment was analyzed with RNA sequencing. Results The analysis of RNA sequencing data from myocardial biopsies of 40 + 37 patients revealed altogether 314 significantly differentially expressed genes due to simvastatin effects. Gene ontology analysis showed these genes to be related to biological functions such as leukocyte migration, regulation of complement cascade, platelet activation, chemokine receptor binding, and epithelial cell proliferation. Conclusion We have shown in previous studies that donor simvastatin treatment has protective effects against IRI in heart transplant recipients. In this study, we were able to detect significantly differentially expressed genes related to effects of simvastatin treatment. In order to single out genes that show beneficial effects of simvastatin treatment, further analysis will be conducted by exploring gene expression changes in specific biological functional categories. The complete analysis will be presented at the ISHLT 2021 congress.