Hyperhomocyst(e)inemia Induces Accelerated Transplant Vascular Sclerosis in Syngeneic and Allogeneic Rat Cardiac Transplants

Abstract

Chronic rejection (CR) and transplant vascular sclerosis (TVS) cause the majority of graft failures in cardiac transplantation. Hyperhomocyst(e)inemia [hH(e)] is associated with human TVS without a proven causal relationship. This study investigated the effect of hH(e) on graft survival and TVS in allogeneic and syngeneic rat cardiac transplants. Lewis recipients of heterotopic F344 heart allografts, received normal or hH(e)-inducing (↓folate, ↑methionine) diets {controls: syngeneic transplanted [± hH(e), + CsA] and nontransplanted rats [± hH(e), ± CsA]}. Serial plasma homocyst(e)ine [H(e)] levels were measured. TVS was assessed in clinically rejected grafts and a subset of pre-rejection normal diet allografts (day 64) (neointimal index, NI). The hH(e) diet elevated plasma H(e) levels. When compared with normal diet controls (n = 9), hH(e) diet allografts (n = 9) had decreased time to onset of CR (40 ± 9 vs. 72 ± 10 d, p = 0.02), and graft failure (64 ± 10 vs. 107 ± 12 d, p = 0.009). hH(e) diet allografts at rejection (n = 9, 64 d) had more severe TVS (NI = 68 ± 2) than both time-matched normal diet allografts (NI = 49 ± 6, n = 8, 64 d, p < 0.001) and normal diet allografts at rejection (NI = 58 ± 5, n = 9, 107 d, p = 0.007). hH(e) induced TVS in syngeneic grafts (NI = 50 ± 3, n = 10 vs. NI = 5 ± 3, n = 10, 130 d, p < 0.001). hH(e) accelerated rejection and increased the severity of TVS in allogeneic cardiac transplants, and induced TVS in syngeneic cardiac transplants.