Microvascular Thrombosis and Cardiac Allograft Vasculopathy in Rat Heart Transplantation

Abstract

We studied association between microvascular thrombosis (MT) and cardiac allograft vasculopathy (CAV) in rat heart transplants (Tx). Male PVG (RT1c) rats were transplanted into ACI (RT1av1) (n=29). ACI into ACI (n=31) and sham-operated rats (n=33) served as controls. Recipient rats received cyclosporine (10 mg/kg/day) on days 0–9 post-Tx. Grafts and native hearts were harvested 10 days, 1, 2 and 3 mo. post-Tx. Hearts were processed for immunofluorescence and light microscopy. MT was defined as presence of fibrin and capillary antithrombin binding (CATB). CAV was assessed by computer-assisted image analysis. PVG-ACI donor hearts had the highest deposition of fibrin (Median: 14.0–16.1%, 10 days-3 mo. post-Tx) and CATB (Median: 12.8–18.4%, 10 days-3 mo. post-Tx). PVG-ACI native hearts also had high levels of fibrin (Median: 8.0–18.3%, 10 days-3 mo. post-Tx) and CATB (Median: 5.8–19.0%, 10 days-3 mo. post-Tx). ACI-ACI donor and native hearts had significantly lower (p<0.01) deposition of fibrin (Median: 1.0–5.6%, 10 days-3 mo. post-Tx) and CATB (Median: 2.0–7.9%, 1–3 mo. post-Tx) than donor and native hearts from PVG-ACI rats. Rats with a sham operation had negligible amounts of fibrin (Median: 0.4–1.0%, 10 days-3 mo. post-Tx) and CATB (Median: 0.8–1.8%, 10 days-3 mo. post-Tx). A strong association was found between presence of fibrin and CATB and development of CAV. These data show that MT in rat cardiac grafts is associated with CAV as found in humans. This model could be used to study pathogenesis of CAV and evaluate new therapies.