Platelet Inhibition Reduces Cyclic Flow Variations and Neointimal Proliferation in Normal and Hypercholesterolemic-Atherosclerotic Canine Coronary Arteries

Abstract

Background Platelet-derived growth factors help stimulate the neointimal proliferation of restenosis after coronary interventions. Reducing platelet accumulation at treated sites may attenuate restenosis. We tested this hypothesis by inducing repetitive platelet aggregation at coronary angioplasty sites in dogs and measuring subsequent neointima formation. Methods and Results Cholesterol-sensitive dogs (n=74) received either 4% cholesterol-enriched diets for >8 months (n=29), creating visible atheromas, or normal canine diets (n=45). A coronary balloon angioplasty cyclic flow variation (CFV) model was used. One group of control dogs (group 1, n=8) had angioplasty with no arterial constriction applied and no drug treatment. Three other groups had arterial constrictors applied to provoke CFVs: group 2 (n=28) received no drug therapy, group 3 (n=18) received oral aspirin alone, and group 4 (n=20) received 3 oral antiplatelet agents: ridogrel, ketanserin, and clopidogrel (R+K+C) to simultaneously inhibit the thromboxane A 2 , serotonin, and ADP pathways of platelet aggregation, respectively. Bleeding times were moderately prolonged in the aspirin-treated group (124±9 seconds after 3 weeks versus 76±6 seconds at baseline, P <0.01) and greatly prolonged on R+K+C (>600 versus 104±5 seconds, P <0.001). The frequency and severity of CFVs were inversely related to the degree of platelet inhibition and prolongation of bleeding times, as was sudden death due to acute thrombotic coronary occlusion. Quantitative histology at 8 weeks revealed increased intima-to-media ratio with CFVs: 0.89±0.14 in the untreated group 2 versus 0.11±0.04 in the control group ( P <0.001). Intima-to-media ratio was significantly reduced with antiplatelet treatment (0.27±0.05 with aspirin treatment and 0.20±0.05 with R+K+C treatment, respectively, 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 platelet aggregation attenuated platelet function, prolonged bleeding times, reduced or prevented cyclic flows and abrupt thrombotic occlusions, and thereby inhibited neointimal proliferation. Platelet inhibition should continue to receive attention in efforts to reduce restenosis after coronary interventions.