title: Inhibition of graft coronary arteriosclerosis after heart transplantation.
abstract: Graft coronary arteriosclerosis (GCA) is the leading cause of long-term mortality after heart transplantation (HTx). The goal of this study was to demonstrate that inhibition of immunemediated injury by cyclosporine (CsA) protects the allograft from GCA. ACI-to-Lewis rat allografts were disparate in major and nonmajor histocompatibility loci. Isografts (Lewis-Lewis) were controls. Treatment groups received either olive oil or CsA at 2.5, 5, 10, or 20 mg/kg/day for 3 months. Histology (elastin) and immunohistochemistry using monoclonal antibodies to CD4, CD8, CD45R, RT1B, CD11b/c, CD25, and alpha-actin was performed to examine the epicardial and intramyocardial coronary arteries. Computerized image morphometry was utilized to measure intimal and medial thickness and area. Rats receiving olive oil or CsA at 2.5 mg/kg/day had severe rejection and no graft survival. CsA at 5 mg/kg/day resulted in less severe rejection with significant intimal and medial proliferation (P < 0.001). CsA at 10-20 mg/kg/day paralleled Lewis-Lewis isograft outcomes and inhibited arteriosclerotic vascular changes in the allograft (P < 0.001). Perivascular T-helper cells and macrophages were a characteristic finding with low-dose CsA but rare with higher CsA doses. In this new model of accelerated GCA in rats, immune-mediated antigen-dependent vasculopathy as a result of inadequate immunosuppresion is fundamental in the development of GCA, which appeared equally in epicardial arteries and intramyocardial arterioles. CsA prevents GCA in a dose-dependent fashion in the rat allograft.
authors.affiliation: Division of Cardiothoracic Surgery, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.
authors.forename: Harmik J
authors.initials: HJ
authors.lastname: Soukiasian
authors.forename: Lawrence S C
authors.initials: LS
authors.lastname: Czer
authors.forename: Hai-Mei
authors.initials: HM
authors.lastname: Wang
authors.forename: Daniel
authors.initials: D
authors.lastname: Luthringer
authors.forename: Charles
authors.initials: C
authors.lastname: Wang
authors.forename: Andreas
authors.initials: A
authors.lastname: Kamlot
authors.forename: Adrian
authors.initials: A
authors.lastname: Quartel
authors.forename: Alfredo
authors.initials: A
authors.lastname: Trento
mesh_terms: D000818:Animals; D003324:Coronary Artery Disease / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D003331:Coronary Vessels / Q000276:immunology / Q000473:pathology; D016572:Cyclosporine / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D006083:Graft Occlusion, Vascular / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D006084:Graft Rejection / Q000503:physiopathology; D016027:Heart Transplantation / Q000009:adverse effects* / Q000276:immunology; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D023421:Models, Animal; D051381:Rats; D011912:Rats, Inbred ACI; D011917:Rats, Inbred Lew; D017539:Tunica Intima / Q000276:immunology / Q000473:pathology; D017540:Tunica Media / Q000276:immunology / Q000473:pathology
chemical_list: D007166:Immunosuppressive Agents; D016572:Cyclosporine