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The fat fed apoe ko mouse- chris jackson- u of bristol

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The fat fed apoe ko mouse- chris jackson- u of bristol

  1. 1. The Fat-Fed Apolipoprotein E Knockout Mouse Chris Jackson Bristol Heart Institute, University of Bristol, UK Emerging Animal Models of Vulnerable Plaque
  2. 2. 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
  3. 3. 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
  4. 4. Sudden Deaths 60565248444036322824201612840 0 10 20 30 40 50 60 70 80 90 100 Time (weeks) Survival (%)
  5. 5. Brachiocephalic Artery
  6. 6. 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
  7. 7. Incidence of Rupture • 64 sudden deaths • 35 ruptured brachiocephalics • 34 scheduled terminations • 16 ruptured brachiocephalics
  8. 8. Time Course of Rupture 605550454035302520151050 0 5 10 15 20 25 30 35 Time (Weeks) Cumulative Ruptures
  9. 9. 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
  10. 10. Vessel Dimensions Intact Ruptured 0 25000 50000 75000 100000 125000 150000 175000 200000 225000 Media Area Plaque Area Area (sq µm) NS p=0.0015
  11. 11. Expansive Remodelling 36322824201612840 0 50000 100000 150000 200000 250000 300000 350000 400000 450000 500000 550000 600000 Media Plaque Lumen Total Time (Weeks) Area (sq µm)
  12. 12. Lumenal Occlusion Intact Ruptured 0 10 20 30 40 50 60 Occlusion (%) p<0.0001
  13. 13. Cap Thickness Intact Ruptured 0.0 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
  14. 14. Previous Healed Ruptures Intact Ruptured 0.0 0.5 1.0 1.5 2.0 2.5 3.0 Buried Caps p<0.0001
  15. 15. Lipid Burden Intact Ruptured 0 5 10 15 20 25 30 35 40 45 50 55 Lipid Content (%) p=0.0019
  16. 16. 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
  17. 17. 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
  18. 18. 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
  19. 19. Acknowledgments • Helen Williams, PhD • Jason Johnson, MSc • Kevin Carson, MB ChB • Ray Bush, PhD • Deb Watkins, BSc • British Heart Foundation • Organon Laboratories • Pfizer • AstraZeneca

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