Platelet inhibition reduces cyclic flow variations and neointimal proliferation in normal and hypercholesterolemic-atherosclerotic canine coronary arteries

Background-Platelet-derived growth factors help stimulate the neointimal pr oliferation of restenosis after coronary interventions. Reducing platelet a ccumulation at treated sites may attenuate restenosis. We tested this hypot hesis by inducing repetitive platelet aggregation at coronary angioplasty s ites in dogs and measuring subsequent neointima formation. Methods and Results-Cholesterol-sensitive dogs (n=74) received either 4% ch olesterol-enriched diets for >8 months (n=29), creating visible atheromas, or normal canine diets (n=45). A coronary balloon angioplasty cyclic flow v ariation (CFV) model was used. One group of control dogs (group 1, n =8)had angioplasty with no arterial constriction applied and no drug treatment. T hree other groups had arterial constrictors applied to provoke CFVs: group 2 (n=28) received no drug therapy, group 3 (n=18) received oral aspirin alo ne, and group 4 (n=20) received 3 oral antiplatelet agents: ridogrel, ketan serin, and clopidogrel (R+K+C) to simultaneously inhibit the thromboxane A( 2), serotonin, and ADP treated group pathways of platelet aggregation respe ctively. Bleeding times were moderately prolonged in the aspirin (124 +/-9 seconds after 3 weeks versus 76 +/-6 seconds at baseline, P <0.01) and grea tly prolonged on R+K+C (> 600 versus 104 +/-5 seconds, P <0.001). The frequ ency and severity of CFVs were inversely related to the degree of platelet inhibition and prolongation of bleeding times, as was sudden death due to a cute thrombotic coronary occlusion. Quantitative histology at 8 weeks revea led increased intima-to-media ratio with CFVs: 0.89 +/-0.14 in the untreate d group 2 versus 0.11 +/-0.04 in the control group (P <0.001). Intima-to-me dia ratio was significantly reduced with antiplatelet treatment (0.27 +/-0. 05 with aspirin treatment and 0.20 +/-0.05 with R+K+C treatment, respective ly, P <0.001). Cholesterol feeding did not appear to influence results. Conclusions-Repetitive platelet accumulation at coronary angioplasty sites caused enhanced neointimal proliferation by 8 weeks. Oral inhibitors of pla telet aggregation attenuated platelet function, prolonged bleeding times, r educed or prevented cyclic flows and abrupt thrombotic occlusions, and ther eby inhibited neointimal proliferation. Platelet inhibition should continue to receive attention in efforts to reduce restenosis after coronary interv entions.