Microvascular thrombosis and cardiac allograft vasculopathy in rat heart transplantation.
BACKGROUND
The role of a hypercoagulable microvasculature in the development of cardiac allograft vasculopathy (CAV) after heart transplantation in humans is not well understood. The aim of this study was to identify an animal model by which to further evaluate the role of coagulation in the pathogenesis of CAV.


METHODS
Adult male PVG (RT-1(c)) rats were transplanted into ACI (RT-1(av1)) recipients (n = 29). ACI donors into ACI recipients (n = 31) and rats with a sham operation (n = 33) served as controls. All rats received cyclosporine (10 mg/kg/day) on Days 0 to 9 after surgery. Grafts and native hearts were harvested at 10 days to 3 months after surgery. Hearts were processed for immunohistochemistry and light microscopy. A hypercoagulable microvasculature was defined as presence of microvascular fibrin and capillary antithrombin. CAV was defined as the presence of concentric intimal proliferation and chronic inflammatory infiltrate in the arterial intima, and assessed by computer-assisted image analysis.


RESULTS
Donor and recipient hearts from PVG-ACI rats showed high levels of fibrin (donors 7.5% to 21.9%, recipients 5.1% to 20.2%) and antithrombin (donors 5.2% to 27.9%, recipients 3.3% to 20.8%) at 10 days to 3 months post-transplant. ACI-ACI donor and recipient hearts had lower deposition of fibrin (donors 0.9% to 9.9%, recipients 0% to 4.0%) and antithrombin (donors 1.4% to 15.2%, recipients 0.8% to 4.5%). Hearts from sham-operated rats had negligible amounts of fibrin (0% to 1.5%) and antithrombin (0% to 2.8%). There was a strong association (p < 0.001) between presence of fibrin and capillary antithrombin and development of CAV.


CONCLUSIONS
A hypercoagulable microvasculature in a rat model of heart transplantation was associated with development of CAV, as found in humans.
Labarrere
Carlos A
CA
Division of Experimental Pathology, Methodist Research Institute, Clarian Health Partners, Indianapolis, Indiana 46202, USA. clabarrere@clarian.org
Ortiz
Miguel A
MA
Ruzmetov
Nargiz
N
Sosa
Marcelo J
MJ
Campana
Gonzalo
G
Terry
Colin
C
Baldridge
Lee Ann
LA
Antonopoulos
Roula
R
DiCarlo
Hector L
HL
D000818:Animals; D000991:Antithrombins / Q000378:metabolism; D002196:Capillaries / Q000378:metabolism; D003327:Coronary Disease / Q000209:etiology* / Q000473:pathology; D003328:Coronary Thrombosis / Q000209:etiology*; D003331:Coronary Vessels / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005337:Fibrin / Q000378:metabolism; D016027:Heart Transplantation / Q000009:adverse effects*; D007150:Immunohistochemistry; D008297:Male; D008833:Microcirculation; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D051381:Rats; D011919:Rats, Inbred Strains; D016042:Transplantation, Heterotopic; D014184:Transplantation, Homologous
D000991:Antithrombins; D005337:Fibrin