The FatFed Apolipoprotein E Knockout Mouse

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The Fat-Fed Apolipoprotein E Knockout Mouse
Emerging Animal Models of Vulnerable Plaque

• Chris Jackson
• Bristol Heart Institute, University of Bristol, UK

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Animals

• Closed outbred colony of C57129 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
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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
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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
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Expansive Remodelling
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Lumenal Occlusion
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Cap Thickness
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Previous Healed Ruptures
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Lipid Burden
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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