Abstract 16819: Type 1 Diabetes Mellitus-induced Cardiac Dysfunction is Further Impaired After Transplantation - Involvement of the Pi3k/akt Pathway
Introduction: Cardiac transplantation is the only sufficient therapy in end-stage heart failure, however it is severely limited by the marked shortage of appropriate donor organs. The discovery of pathways associated with graft dysfunction in marginal donor heart transplantation, such as donors with diabetes mellitus (DM), could offer an opportunity for finding new therapies and expanding the donor pool.
Hypothesis: We evaluated the influence of type 1 DM on the cardiac function in a rat model of a potential heart donor, and explored how the disease’s effect in donors might influence recipients’ myocardial function after transplantation. Additionally, in the diabetic donor hearts after transplantation, we tested 84 genes involved in the PI3K/Akt signaling, as the components of this pathway have been found to be defective in DM.
Methods: In the donor rats DM was induced with a single dose of streptozotocin (60 mg/kg, ip). Nondiabetic rats received only a buffer. Eight weeks after confirming DM, cardiac function was measured. Then, the hearts were heterotopically transplanted into nondiabetic recipients. We evaluated in vivo graft function 1.5h after transplantation.
Results: In diabetic donor rats, elevated levels of plasma glucose (18.8±2.9 vs. 9.5±0.9 mM, p<0.05) and haemoglobin A1c (13.6±1.5 vs. 7.6±0.1%, p<0.05) were observed when compared to nondiabetics. DM was associated with significantly decreased LV contractility and impaired relaxation in donors. After transplantation, in the DM group, significantly lower LV systolic pressure, dP/dtmax, dP/dtmin and prolonged Tau were observed compared with the control group, indicating decreased myocardial contractility and relaxation. In the transplanted diabetic heart, the expression of 11 genes involved in PI3K/Akt signaling (Akt2, Prkcz, Jun, Adar, Ccnd1, Tlr4, Pak1, Pdgfra, Irs1, Ywhah and Ldha) were downregulated and phosphorylated Akt/Akt protein expression ratio, evidenced by Western blot, was significantly decreased.
Conclusions: Untreated type 1 DM induced cardiac dysfunction is further impaired after transplantation. Altered expression of genes involved in PI3K/Akt signaling may be one of the responsible mechanisms in the transplanted diabetic heart.
Author Disclosures: S. Korkmaz-Icöz: Research Grant; Significant; B. Braun Stiftung. S. Li: None. S. Loganathan: None. T. Radovits: None. M. Ruppert: None. P. Brlecic: None. T. Fleming: None. B. Maik: None. P. Most: None. M. Karck: None. G. Szabó: Research Grant; Significant; B. Braun Stiftung.
- © 2016 by American Heart Association, Inc.