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

H. Vernon Anderson, Janice McNatt, Fred J. Clubb, Michael Herman, Jean Pierre Maffrand, Fred DeClerck, Chul Ahn, L. Maximilian Buja, James T. Willerson

Research output: Contribution to journalArticle

41 Citations (Scopus)

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 A2, 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.

Original languageEnglish (US)
Pages (from-to)2331-2337
Number of pages7
JournalCirculation
Volume104
Issue number19
StatePublished - Nov 6 2001

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Canidae
Coronary Vessels
Blood Platelets
Bleeding Time
Angioplasty
Coronary Restenosis
Aspirin
clopidogrel
Platelet Aggregation Inhibitors
Cholesterol
Dogs
ridogrel
Platelet Aggregation
Diet
Neointima
Ketanserin
Control Groups
Thromboxane A2
Coronary Balloon Angioplasty
Coronary Occlusion

Keywords

  • Arteries
  • Atherosclerosis
  • Blood flow
  • Hypercholesterolemia
  • Platelets

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Anderson, H. V., McNatt, J., Clubb, F. J., Herman, M., Maffrand, J. P., DeClerck, F., ... Willerson, J. T. (2001). Platelet inhibition reduces cyclic flow variations and neointimal proliferation in normal and hypercholesterolemic-atherosclerotic canine coronary arteries. Circulation, 104(19), 2331-2337.

Platelet inhibition reduces cyclic flow variations and neointimal proliferation in normal and hypercholesterolemic-atherosclerotic canine coronary arteries. / Anderson, H. Vernon; McNatt, Janice; Clubb, Fred J.; Herman, Michael; Maffrand, Jean Pierre; DeClerck, Fred; Ahn, Chul; Buja, L. Maximilian; Willerson, James T.

In: Circulation, Vol. 104, No. 19, 06.11.2001, p. 2331-2337.

Research output: Contribution to journalArticle

Anderson, HV, McNatt, J, Clubb, FJ, Herman, M, Maffrand, JP, DeClerck, F, Ahn, C, Buja, LM & Willerson, JT 2001, 'Platelet inhibition reduces cyclic flow variations and neointimal proliferation in normal and hypercholesterolemic-atherosclerotic canine coronary arteries', Circulation, vol. 104, no. 19, pp. 2331-2337.
Anderson, H. Vernon ; McNatt, Janice ; Clubb, Fred J. ; Herman, Michael ; Maffrand, Jean Pierre ; DeClerck, Fred ; Ahn, Chul ; Buja, L. Maximilian ; Willerson, James T. / Platelet inhibition reduces cyclic flow variations and neointimal proliferation in normal and hypercholesterolemic-atherosclerotic canine coronary arteries. In: Circulation. 2001 ; Vol. 104, No. 19. pp. 2331-2337.
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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 A2, 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.",
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T1 - Platelet inhibition reduces cyclic flow variations and neointimal proliferation in normal and hypercholesterolemic-atherosclerotic canine coronary arteries

AU - Anderson, H. Vernon

AU - McNatt, Janice

AU - Clubb, Fred J.

AU - Herman, Michael

AU - Maffrand, Jean Pierre

AU - DeClerck, Fred

AU - Ahn, Chul

AU - Buja, L. Maximilian

AU - Willerson, James T.

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N2 - 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 A2, 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.

AB - 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 A2, 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.

KW - Arteries

KW - Atherosclerosis

KW - Blood flow

KW - Hypercholesterolemia

KW - Platelets

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