Role of hypercholesterolemia in accelerated transplant coronary vasculopathy: results of surgical therapy with partial ileal bypass in rabbits undergoing heterotopic heart transplantation.

BACKGROUND: We tested the hypothesis that plasma cholesterol lowering action of partial ileal bypass (PIB) is beneficial in mitigating accelerated transplantation coronary vasculopathy.
METHODS: Forty-one New Zealand white rabbits were randomized to receive a normal (n = 21) or 1% cholesterol diet (n = 20). They underwent heterotopic heart transplantation with sham-PIB (n = 19) or PIB (n = 22) and immunosuppression with cyclosporine A (CyA).
RESULTS: CyA increased plasma cholesterol of rabbits receiving a normal diet. This effect was mitigated by PIB (101 +/- 50 mg/dl CyA vs baseline 24 +/- 8, p < 0.001; vs 54 +/- 25 mg/dl with PIB, p < 0.05). In cholesterol-fed rabbits, PIB decreased plasma cholesterol levels (520 +/- 236 mg/dl PIB vs baseline 720 +/- 359, p < 0.05; vs 1502 +/- 253 mg/dl with sham PIB, p < 0.00001). Coronary arteries (CA) of 21 5-week survivors were evaluated by light microscopy and digital morphometry. No rejection was noted. Histologic study revealed vasculopathy in 3% of 705 native and 18% of 654 transplant CA (p < 0.05). Graft vasculopathy (GV) was present in 25% of 365 CA of sham-PIB and 10% of 289 CA of PIB rabbits (p = 0.07). In cholesterol-fed rabbits, GV was characterized by fatty proliferative lesions in 75% of 91 pathologic CA of sham and 21% of 28 pathologic CA of PIB rabbits (p < 0.05). Graft intimal hyperplasia was not correlated with cholesterol intake or PIB and was present in 18 of 119 pathologic CA.
CONCLUSIONS: GV was characterized by fatty intimal proliferation, fibrous intimal hyperplasia, and a "mixed type." Fibrous intimal hyperplasia developed in native and transplanted hearts, and CyA seemed to promote this state. Hypercholesterolemia promoted fatty proliferative lesions, worsening GV. PIB significantly decreased total cholesterol and retarded fatty proliferation of CA of native and transplanted hearts but did not prevent intimal hyperplastic vasculopathy. Therapy of hypercholesterolemia is recommended to at least mitigate the fatty intimal proliferation of GV.