Triggering of plaque disruption and arterial thrombosis in an atherosclerotic rabbit model.
BACKGROUND
It is now recognized that plaque disruption and thrombosis, a process often triggered by activities of the patient, is generally the cause of the onset of acute coronary syndromes. Understanding of disease onset could be greatly enhanced by the availability of a suitable animal model of plaque disruption and thrombosis. The aim of this study was to replicate and further characterize an atherosclerotic rabbit model of triggering of arterial thrombosis that was introduced by Constantinides and Chakravarti more than 30 years ago but not subsequently used. Aortic plaques were induced by a high-cholesterol diet, by mechanical balloon injury of the artery, or by a combination of the two. Triggering was attempted by injection of Russell's viper venom (RVV), which is a proteolytic procoagulant, and histamine.


RESULTS
A total of 53 New Zealand White rabbits were exposed to one of four preparatory regimens: rabbits in group I (n = 9) were fed a regular diet for 8 months; rabbits in group II (n = 13) were fed a diet of 1% cholesterol for 2 months alternated with 2 months of a regular diet for a total of 8 months; rabbits in group III (n = 5) underwent balloon-induced arterial wall injury, then were given a regular diet for 8 months; and rabbits in group IV (n = 14) underwent balloon-induced arterial wall injury, then were given a diet of 1% cholesterol for 2 months followed by a regular diet for 2 months for a total of 4 months. After completion of the preparatory regimen, triggering of plaque disruption and thrombosis was attempted by injection of RVV (0.15 mg/kg IP) and histamine (0.02 mg/kg IV). In group I, normal control rabbits without atherosclerosis, only one small thrombus was noted in 1 of 9 rabbits. In group II, cholesterol-fed rabbits, thrombosis occurred in 3 of 13 rabbits. Thrombus occurred in all rabbits in group III (5 of 5) and in 10 of 14 rabbits in group IV. Although the frequency of thrombosis was not significantly different between groups I and II, possibly due to a small sample size, it was significantly different among all four groups (P < .001). Also, the frequency and amount of thrombus formation were significantly different among all four groups (P < .001; P < .0001) but not between groups I and II. Rabbits with atherosclerosis (those in groups II and IV) demonstrated plaque disruption and overlying platelet-rich thrombus formation similar to that observed in patients with acute coronary syndromes. The surface area covered by thrombus was 2 mm2 in group I, 15.3 +/- 19.2 mm2 in group II, 223 +/- 119 mm2 in group III, and 263 +/- 222 mm2 in group IV. Rabbits in groups III and IV had the greatest amount of thrombus, and this amount was significantly greater than in rabbits in groups I and II (P < .001 and P < .03, respectively).


CONCLUSIONS
A suitable animal model is available for the study of plaque disruption and arterial thrombosis. Hypercholesterolemia and mechanical arterial wall injury seemed to produce plaques vulnerable to triggering of disruption and thrombosis, whereas normal arteries were relatively resistant to triggering. This model provides a method to evaluate agents that might decrease the occurrence of vulnerable plaques or the amount of thrombus formed after triggering. Most important, the model can be used to identify the features of vulnerable plaques and the pharmacological stressors that trigger plaque disruption and thrombus formation.
Abela
G S
GS
Institute for Prevention of Cardiovascular Disease, Deaconess Hospital, Harvard Medical School, Boston, Mass. 02115.
Picon
P D
PD
Friedl
S E
SE
Gebara
O C
OC
Miyamoto
A
A
Federman
M
M
Tofler
G H
GH
Muller
J E
JE
D000818:Animals; D001161:Arteriosclerosis / Q000150:complications* / Q000473:pathology; D002784:Cholesterol / Q000097:blood; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D003328:Coronary Thrombosis / Q000209:etiology; D004195:Disease Models, Animal; D005340:Fibrinogen / Q000032:analysis; D006632:Histamine / Q000494:pharmacology; D011817:Rabbits; D013927:Thrombosis / Q000209:etiology*; D014757:Viper Venoms / Q000494:pharmacology
D002791:Cholesterol, Dietary; D014757:Viper Venoms; D006632:Histamine; D005340:Fibrinogen; D002784:Cholesterol