A reduction in accelerated graft coronary disease and an improvement in cardiac allograft survival using low molecular weight heparin in combination with cyclosporine.
Heparin compounds are a complex mixture of mucopolysaccharides that, in addition to their anticoagulant properties, have immunosuppressive activities and affect the reparative aspects of the response to arterial injury. Heparin inhibits smooth muscle cell migration and proliferation and can alter the accumulation of the components of the extracellular matrix after arterial injury. Heparin also interacts specifically with the endothelium. Our hypothesis was that if heparin compounds do affect the immune system, coagulation, smooth muscle cell proliferation, and the endothelium, then heparin combined with cyclosporine should improve allograft survival, reduce rejection, and prevent accelerated graft coronary disease. Low molecular-weight heparins are derived from the larger molecular-weight unfractionated heparin. We chose to use low molecular-weight heparins because of their longer half-life, better bioavailability, and decreased incidence of induced thrombocytopenia and bleeding. With a rat intraabdominal heterotopic model of heart transplantation (Lewis-Brown Norway to Lewis), low molecular-weight heparin in combination with a low dose of cyclosporine (0.5 mg/kg/day) significantly improved allograft survival compared to controls and either low molecular-weight heparin or cyclosporine alone. Histologically, smooth muscle cells are an important cellular component of the lesions of accelerated graft coronary disease. In comparison to animals treated with cyclosporine alone (2 mg/kg/day), the addition of low molecular-weight heparin to cyclosporine (2 mg/kg/day) reduced the frequency and the severity of accelerated graft coronary disease and the extent of parenchymal rejection.
University of Washington Medical Center, Seattle 98195.
S
S
Aziz
Y
Y
Tada
D
D
Gordon
T O
TO
McDonald
J
J
Fareed
E D
ED
Verrier
D000005:Abdomen; D000818:Animals; D003327:Coronary Disease / Q000473:pathology / Q000517:prevention & control*; D003331:Coronary Vessels / Q000473:pathology; D016572:Cyclosporine / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D006084:Graft Rejection / Q000473:pathology / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects*; D016027:Heart Transplantation / Q000009:adverse effects* / Q000473:pathology; D006495:Heparin, Low-Molecular-Weight / Q000627:therapeutic use*; D008297:Male; D009206:Myocardium / Q000473:pathology; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D016042:Transplantation, Heterotopic
D006495:Heparin, Low-Molecular-Weight; D016572:Cyclosporine