Inhibition of coronary restenosis by antithrombin III in atherosclerotic swine.
BACKGROUND
Thrombin-mediated vascular smooth muscle cell proliferation has been implicated in coronary restenosis. Attempts to inhibit this mitogenic activity have recently focused on non-physiologic direct thrombin inhibitors, whereas endogenous thrombin inhibitors such as antithrombin III (ATIII) have received little attention. ATIII is the main physiologic inhibitor of thrombin and may thus be a potential therapeutic agent for prevention of restenosis.


METHODS
Human ATIII (125 U/kg) and heparin (200 U/kg) were administered to 12 atherosclerotic swine 30 min prior to inducing restenosis by oversized stent (left anterior descending and right coronary arteries; stent-to-artery ratio approximately 1.2) and balloon injury (circumflex; balloon artery ratio approximately 1.2). Eleven control swine received only heparin every 6 h for 24 h and were subjected to similar stent and balloon injury. Quantitative coronary angiography [change in minimal lumen diameter (delta MLD)] and morphometric analysis [percentage area stenosis (PAS)] were performed 4 weeks later.


RESULTS
ATIII activity (mean +/- SD) of treated swine increased from a baseline of 103 +/- 10% to a peak of 266 +/- 48%, whereas trough levels were maintained at 259 +/- 55% for 72 h by drug infusions every 6 h. The delta MLD, the primary angiographic endpoint in the balloon injured vessel was -0.57 +/- 0.33 mm in heparin group versus -0.26 +/- 0.27 mm in the ATIII group (P < or = 0.03). For stented vessels the delta MLD was -0.61 +/- 0.33 mm in the heparin group versus -0.41 +/- 0.37 mm in the ATIII group (P < or = 0.06). The PAS for the balloon injured vessels was 30 +/- 12% in the heparin group versus 19 +/- 14 in the ATIII group (P < or = 0.06). In stented vessels the PAS was 45 +/- 16% in the heparin group versus 38 +/- 16% in the ATIII group (P < or = 0.1).


CONCLUSIONS
Supraphysiologic ATIII levels in combination with heparin inhibits the reduction in MLD in coronary arteries subjected to oversized balloon injury and demonstrates a beneficial trend in arteries subjected to oversized stent injury. These data provide cautious optimism for further investigation with ATIII to prevent coronary restenosis.
Ali
M N
MN
Department of Medicine, Baylor College of Medicine, Houston, Texas, USA.
Mazur
W
W
Kleiman
N S
NS
Rodgers
G P
GP
Abukhalil
J M
JM
French
B A
BA
Raizner
A E
AE
D000800:Angioplasty, Balloon / Q000009:adverse effects; D000818:Animals; D000990:Antithrombin III / Q000008:administration & dosage* / Q000009:adverse effects; D001161:Arteriosclerosis / Q000097:blood / Q000150:complications / Q000473:pathology; D002455:Cell Division; D002784:Cholesterol / Q000097:blood; D017023:Coronary Angiography; D003327:Coronary Disease / Q000175:diagnosis / Q000188:drug therapy* / Q000209:etiology; D003331:Coronary Vessels / Q000293:injuries / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000009:adverse effects; D005500:Follow-Up Studies; D006493:Heparin / Q000008:administration & dosage / Q000009:adverse effects; D007262:Infusions, Intravenous; D012008:Recurrence; D012449:Safety; D015842:Serine Proteinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D013552:Swine; D013556:Swine, Miniature; D017539:Tunica Intima / Q000293:injuries / Q000473:pathology*
D005343:Fibrinolytic Agents; D015842:Serine Proteinase Inhibitors; D000990:Antithrombin III; D006493:Heparin; D002784:Cholesterol