146 animal models of vulnerable plaque
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The Fat-Fed Apolipoprotein E Knockout Mouse
Chris JacksonBristol Heart Institute, University of Bristol, UK
Emerging Animal Models of Vulnerable Plaque
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Animals• Closed outbred colony of
C57:129 homozygous apoE knockout mice
• Diet supplemented with 21% lard, 0.15% cholesterol
• Age at start of study was 6 to 8 weeks
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Study Design
• 98 animals (51 male) were put on study
• 34 animals: scheduled termination• Pressure perfusion fixed (10% formalin) at
a constant pressure of 100mmHg
• 64 animals: sudden death• Not pressure perfusion fixed
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Sudden Deaths
605652484440363228242016128400
10
20
30
40
50
60
70
80
90
100
Time (weeks)
Survival (%)
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Brachiocephalic Artery
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Parameters Measured• Presence or absence of rupture• Plaque cross-sectional area• Media cross-sectional area• Plaque/media area ratio• % Lumenal occlusion• Cap thickness• Number of previous ruptures• Lipid burden
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Incidence of Rupture
• 64 sudden deaths• 35 ruptured brachiocephalics
• 34 scheduled terminations• 16 ruptured brachiocephalics
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Time Course of Rupture
6055504540353025201510500
5
10
15
20
25
30
35
Time (Weeks)
Cumulative Ruptures
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Plaque Characterisation
• Acutely ruptured (“ruptured”)• Visible tear or discontinuity in the cap• Blood-derived components within the
lesion
• Healed previous rupture (“intact”)• Buried fibrous cap
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Vessel Dimensions
Intact Ruptured0
25000
50000
75000
100000
125000
150000
175000
200000
225000
Media AreaPlaque Area
Area (sq µm)
NS
p=0.0015
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Expansive Remodelling
363228242016128400
50000
100000
150000
200000
250000
300000
350000
400000
450000
500000
550000
600000MediaPlaqueLumenTotal
Time (Weeks)
Area (sq µm)
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Lumenal Occlusion
Intact Ruptured0
10
20
30
40
50
60Occlusion (%)
p<0.0001
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Cap Thickness
Intact Ruptured0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
5.0
5.5
Cap Thickness (um)
p=0.0004
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Previous Healed Ruptures
Intact Ruptured0.0
0.5
1.0
1.5
2.0
2.5
3.0Buried Caps
p<0.0001
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Lipid Burden
Intact Ruptured0
5
10
15
20
25
30
35
40
45
50
55Lipid Content (%)
p=0.0019
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Summary
• Ruptured plaques:• Are 56% bigger
• Are 52% more occlusive
• Have caps that are 57% thinner
• Have 151% more previous ruptures
• Have a 36% greater lipid burden
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Intervention Study Design
• To detect ∆(rupture, intact) with 80% power:
• Cap thickness: 17 mice
• Lipid content: 22 mice
• Lumenal occlusion: 24 mice
• Rupture frequency: 33 mice
• Plaque area: 53 mice
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Late-Breaking News• Earliest ruptures are seen after 7 weeks
of high-fat diet• 75% of males have ruptures after 8 weeks
• Pravastatin significantly reduces the incidence of sudden death
• PAI-1-/-/apoE-/- double knockouts have significantly more plaque ruptures than apoE-/- single knockouts
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Acknowledgments• Helen Williams, PhD• Jason Johnson, MSc• Kevin Carson, MB ChB• Ray Bush, PhD• Deb Watkins, BSc
• British Heart Foundation• Organon Laboratories• Pfizer• AstraZeneca