Everolimus therapy is associated with reduced lipoprotein-associated phospholipase A2 (Lp-Pla2) activity and oxidative stress in heart transplant recipients

Background: Several studies demonstrated decreased severity and incidence of cardiac allograft vasculopathy (CAV) in heart transplant recipients receiving immunosuppressive therapy with everolimus. However, data regarding the influence of everolimus on risk factors predisposing to CAV are hitherto limited. We here systematically evaluated cardiovascular risk factors in heart transplanted patients, who underwent conversion to everolimus or were maintained on conventional therapy with calcineurin inhibitors (CNI). Methods: 50 Patients receiving everolimus and 91 patients receiving CNI in addition to mycophenolate mofetil and low-dosed steroids were included in the study. CAV risk factors were determined in plasma or urine using standard enzymatic or immunochemical methods. Results: No significant differences were observed between both groups with regard to lipid (total, LDLand HDL-cholesterol), metabolic (glucose, insulin), inflammatory (C-reactive protein, IL-6, myeloperoxidase) and cardiac (troponin I, NT-proBNP) risk factors. However, significantly lower activity of lipoprotein-associated phospholipase A 2 (Lp-PLA2) and a negative correlation between the Lp-PLA2 activity and the everolimus concentration were observed in plasmas from everolimus-treated patients. Conversion to everolimus significantly lowered Lp-PLA2 activity in heart transplant recipients. Studies in vitro revealed reduced Lp-PLA2 expression in hepatocytes and macrophages pre-exposed to everolimus. In addition, reduced plasma markers of oxidative stress including oxidized LDL, 8-iso-prostaglandin F2a and protein carbonyls were noted in heart transplant recipients receiving everolimus therapy. Conclusion: Our results suggest that everolimus specifically lowers plasma activity and cellular production of Lp-PLA2 and thereby dampens oxidative stress. These effects may additionally contribute to the reduced CAV incidence observed in heart transplant recipients receiving everolimus therapy.