DIABETES AND DYSLIPIDEMIA - A NEW MODEL FOR TRANSPLANT CORONARY-ARTERY DISEASE

Background-Clinical observations suggest that transplant coronary arte ry disease (TxCAD) is immunologically mediated but may be accelerated by metabolic derangements. We developed a rat model of heterotopic hea rt transplantation in the presence of diabetes and dyslipidemia to fur ther study their role in TxCAD development. Methods and Results-Major histocompatibility complex-mismatched strains of inbred rats underwent heterotopic heart transplantation (ACI-to-Lewis allografts), Diabetes (DM) was induced by streptozotocin injection (80 mg/kg) after transpl antation; dyslipidemia was worsened by feeding of a 60% high-fructose diet (SF), Allograft transplants were divided into four groups: (1) +D M/+F; (2) +DM/-F; (3) -DM/+F; and (4) -DM/-F, Isograft transplants (Le wis to Lewis, + DM/+/-F) were controls. All animals received daily cyc losporine (5 mg/kg). Grafts surviving >30 days were evaluated for TxCA D on histological sections and graded 0 to 5 for intimal thickness. Al l streptozotocin-treated animals were diabetic within 2 weeks, with fo urfold increases in plasma glucose concentrations versus nondiabetics. Severe TxCAD was observed in diabetic allografts only. The mean grade of TxCAD in diabetic allografts was 3.2+/-0.5 versus 1.1+/-0.4 in dia betic isografts (P<0.03) and zero TxCAD in nondiabetic allografts (P l ess than or equal to 0.0001). Fructose feeding resulted in a 1.5-fold higher triglyceride and a 1.3-fold higher cholesterol level versus the regular diet (-F) but showed no independent contribution to the devel opment of TxCAD. Conclusions These findings suggest that metabolic der angements associated with diabetes play an important role in TxCAD dev elopment in heterotopic ACI-to-Lewis rat heart transplantation. In thi s model of TxCAD in major histocompatibility complex-mismatched, diabe tic, and dyslipidemic rats, immunologic and metabolic mechanisms that contribute to TxCAD can be further delineated and approaches to its pr evention assessed.