Statins Inhibit Graft Arterial Disease by Cholesterol-Independent Pathways

Robert S. Rosenson, M.D.

Cardiac transplant vasculopathy or graft arterial disease (GAD) is a major limitation to long-term survival in cardiac transplant recipients. In a multicenter analysis that evaluated 2609 cardiac transplant recipients at 5 years, coronary heart disease was present in 42 percent, and death or retransplantation due to coronary disease occurred in 7 percent.[1]

GAD involves an allogenic immune response in which the major histocompatibility complex (MHC) of donor tissue induces clonal expansion of T cells. Activated T cells secrete cytokines that recruit smooth muscle cells that form the intimal hyperplasitic lesion of GAD.

HMG CoA reductase inhibitors (statins) suppress the immune response through reduced MHC class II expression,[2] diminished mixed lymphocyte responses in vitro and inhibition of natural killer cell activity in vivo.[3] In randomized clinical trials, statins (pravastatin, simvastatin) reduce the incidence and severity of GAD, reduce the frequency of cardiac rejection episodes with hemodynamic compromise and improve survival.[4,5]

Shimizu and colleagues investigate whether statins suppress GAD by cholesterol-independent pathways in heterotopic murine cardiac transplants in major histocompatibility complex class II-mismatched combinations.[6] Transplanted normocholesterolemic mice were randomized to control chow, chow containing low-dose cerivastatin (25 mg/kg chow) or high-dose cerivastatin (125 mg/kg chow) for 12 weeks. Cholesterol levels were unchanged in the treatment groups which is consistent with other studies showing that statins do not lower cholesterol levels in mice. Graft-infiltrating cells and GAD lesions were reduced in low-dose (p<0.05) and high-dose cerivastatin (p<0.01). However, there was no effect of cerivastatin on graft survival or rejection scores that comprised monocuclear cell infiltrates and myocyte injury). Since MHC II expression can affect cell recruitment, the investigators examined whether cerivastatin modulated MHC II expression. Levels of MHC II expression by macrophages was not changed with statin therapy; however the number of MHC II-positive cells around vessels of grafts was reduced. Next, the effects of cerivastatin treatment on chemokine expression were investigated. Intragraft mRNA expression of RANTES (regulated on activation and normally T-cell expressed and secreted) and monocyte chemotactic protein-1 were reduced by cerivastatin. This effect on chemokine expression was reversed by L-mevalonate indicating that the cholesterol biosynthetic pathway mediates this effect.

This study provides evidence in mice that cerivastatin inhibits GAD independent of cholesterol-lowering. These beneficial effects of statin therapy were attributed to reduced chemokine release from endothelial cells, fewer inflammatory infiltrates in cardiac allografts and less GAD.

References

1. Costanzo MR, Naftel DC, Pritzker MR, Heilman JK, 3rd, Boehmer JP, Brozena SC, Dec GW, et al. Heart transplant coronary artery disease detected by coronary angiography: a multiinstitutional study of preoperative donor and recipient risk factors. Cardiac Transplant Research Database. J Heart Lung Transplant 1998;17(8):744-53.
2. Kwak B, Mulhaupt F, Myit S, Mach F. Statins as a newly recognized type of immunomodulator. Nat Med 2000;6(12):1399-402.
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4. Kobashigawa JA, Katznelson S, Laks H, Johnson JA, Yeatman L, Wang XM, Chia D, et al. Effect of pravastatin on outcomes after cardiac transplantation. N Engl J Med 1995;333(10):621-7.
5. Wenke K, Meiser B, Thiery J, Nagel D, von Scheidt W, Steinbeck G, Seidel D, et al. Simvastatin reduces graft vessel disease and mortality after heart transplantation: a four-year randomized trial. Circulation 1997;96(5):1398-402.
6. Shimizu K, Aikawa M, Takayama K, Libby P, Mitchell RN. Direct anti-inflammatory mechanisms contribute to attenuation of experimental allograft arteriosclerosis by statins. Circulation 2003;108(17):2113-20.