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

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• 作者：Katharina Rosing ; Manfred Fobker ; Frank Kannenberg ; Stefan Gunia ; Angelo Maria Dell'Aquila ; Robert Kwiecien ; J?rg Stypmann ; Jerzy-Roch Nofer
• 关键词：Lipoprotein-associated phospholipase A2 (Lp-PLA2) ; Everolimus oxidative stress ; Cardiovascular risk ; Heart transplantation ; Atherosclerosis
• 刊名：Atherosclerosis
• 出版年：2013
• 出版时间：September, 2013
• 年：2013
• 卷：230
• 期：1
• 页码：164-170
• 全文大小：441 K

文摘

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, LDL- and 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 A₂ (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 F_2¦Á 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.