SHAPE Society

1. Editorial Slides
VP Watch, January 9, 2002, Volume 2, Issue 1
Animal Models of Heart Attack?

2.  Cell culture is a convenient way to ask
mechanistic questions, but it lacks complexity of a
real disease thus limiting the scope of testable
hypotheses. Human observations provide rich soil
for making hypotheses, but for obvious ethical
reasons our ability to test these hypotheses in
men is very limited. Animal models are essential
for testing mechanistic hypotheses in a controlled
manner.1
 Ideal animal model is situated in the middle of this
range. 1

3. 1- Japanese
quail
2- Pigeon
3- Chicken
Reported Animal Models for
Atherosclerosis
4- Dog
5- Monkey
6- Pig
7- Rat
8- Rabbit
9- Mouse

4.  Quail:
- Studies on Japanese quail have shown that the
RES birds were resistant to the disease and
developed little atherosclerosis on a diet
containing 1% cholesterol. The SUS birds were
sensitive and developed severe atherosclerosis in
8-9 wks on a diet containing only 0.5%
cholesterol. 14,15,16

5.  Pigeon:
- Tesar and Kottke showed that two distinct types of
fatty streaks can be identified in white Carneau
pigeon and their biologic features can be defined
and related to their propensity for atherogenesis.6

6.  Chicken:
- Wong discussed that chicken is a good animal
model for the study of atherosclerosis research
because it is able to develop spontaneous
atherosclerosis and capable of producing
atherosclerosis after cholesterol feeding with
elevated hypercholesterolemia. There is no
essential difference between vascular lesions
seen in chickens as a result of cholesterol diet and
that of atherosclerosis observed in man.2,3

7.  Dog:
- Reducing platelet accumulation at sites of balloon
angioplasty may attenuate restenosis. Willerson,
et al. tested this hypothesis by inducing repetitive
platelet aggregation at coronary angioplasty sites
in cholesterol sensitive dogs and measured
subsequent neointima formation. 4,5

8.  Monkey:
- Blaton and Peeters discussed that the
chimpanzee lipoproteins are useful models for
understanding the relationship between function
and structure of the plasma lipoproteins in health
and disease. Baboon and rhesus monkeys show
similar results, but more differences to the human
lipoproteins in health and disease were
observed.8,9

9.  Swine:
- Massmann, and others showed relations between
spontaneous and induced arterial lesions in swine
and arteriosclerosis in humans. 7,21

10.  Rat:
- Bennani-Kabchi et al. showed the potential of the
sand rat to develop atherosclerotic lesions at
different stages which opens the field to
therapeutic tests of new anti-atherogenic agents.
- More recently Herrera et al. demonstrated that
cholesteryl ester transfer protein can be
proatherogenic. The interaction of polygenic
hypertension and hyperlipidemia in the
pathogenesis of atherosclerosis in Tg [hCETP] DS
rats substantiates epidemiological observations in
humans.10,11

11.  Rabbit:
- Hereditary Watanabe rabbit - Clubb et
al. evaluated temporal distribution of leukocytes,
macrophages, foam cells, vascular smooth
muscle cells, and subendothelial lipid in Watanabe
heritable hyperlipedimic (WHHL) rabbit aortas.19
- Cholesterol fed New Zealand rabbit -
Atherosclerotic plaques were produced in New
Zealand White rabbits by intermittent cholesterol
feeding.20

12.  Rekhter, et al. have developed a rabbit
model in which an atherosclerotic
plaque can be ruptured at will after an
inflatable balloon becomes embedded
into the plaque. This model as well can
be used for induction of thrombi
associated with plaque rupture. 17

13.  Mouse:
- The apoE-deficient mouse contains the entire
spectrum of lesions observed during
atherogenesis and is the first mouse model to
develop lesions similar to those in humans. 12,13

14.  As highlighted in this week of VP Watch,
Braun, Krieger, et al. showed that mice with
homozygous null mutations in the genes for
both the LDL and apoE receptors (SR-BI/apoE
double knockout mice) exhibit morphological
and functional defects with similarities to those
seen in human coronary heart disease.22
 The SR-BI/apoE dKO mice are distinct
because they have extensive coronary artery
lesions with fibrin deposition and
spontaneously develop extensive MIs on a
standard chow diet at a very young age (5
weeks).22

15.  The authors indicated that severe occlusive,
fibrin-containing coronary arterial lesions,
probable ischemia, multiple MIs, enlarged
hearts, and cardiac dysfunction in very young
('5 weeks old), low-fat/ low-cholesterol fed
SR-BI/apoE dKO mice provide a novel model
of CHD.22
 Fibrin deposits were found in the core
regions
of 8 of 10 lesions in 3 of 3 dKO mice.22
 However, clear evidence for plaque rupture
was not found in these animals neither was
thin fibrous cap.22

16. Conclusion:
I. Comparing to the previous animal models of
atherosclerosis, double knockout LDL/apoE mice
seem to offer an improvement in studying the clinical
complications of atherosclerosis closer to human
ischemic heart disease.
II. However, it is unclear as to what degree the new
model simulates the pathophysiology and pathology
characteristic of human vulnerable atherosclerotic
plaques.

17. Questions:
1. Which one the following animal models more closely
resembles human coronary artery disease?
- Watanabe rabbits
- New Zealand cholesterol fed rabbits
- CETP/DS transgenic rat
- Apo-E deficient mice
- LDL deficient mice
- Double KO LDL/apoE mice

18. Questions:
2. Since clinical atherosclerosis is predominantly an
athero-thrombotic disease, besides the plaque
characteristics in these animals, the question is how
closely their blood factors and coagulation system
resembles of those in human?
3. Since transgenic animal models of atherosclerosis do
not live long, knowing the major role of age in the
natural history of human atherosclerosis and its
complications such as plaque rupture, can we find a
representative model of repeated plaque rupture in
these animals.

19. Suggestion:
VP.org Editorial Suggestion:
- Please email your thoughts to:
Discussion-Group@VP.org or DG@VP.org

20. 1. Rekhter MD, Hicks GW, Brammer DW, Work CW, Kim JS, Gordon D, Keiser JA, Ryan MJ.
Animal model that mimics atherosclerotic plaque rupture. Circ Res. 1998 Oct 5;83(7):705-13.
2. Wong HY; The cockerel as an animal model for atherosclerosis research.
Adv Exp Med Biol. 1975;63:381-91.
3. Lucas A, Yue W, Jiang XY, Liu L, Yan W, Bauer J, Schneider W, Tulip J, Chagpar A,
Dai E, Perk M,
Montague P, Garbutt M, Radosavljevic M. Development of an avian model for restenosis.
Atherosclerosis. 1996 Jan 5;119(1):17-41.
4. Folts JD, Crowell EB, Rowe GG. Platelet aggregation in partially obstructed vessels and
its
elimination with aspirin. Circulation. 1976; 54: 365–370.
5. Anderson HV, McNatt J, Clubb FJ, Herman M, Maffrand JP, DeClerck F, Ahn C, Buja LM,
Willerson
JT.; Platelet inhibition reduces cyclic flow variations and neointimal proliferation in normal and
hypercholesterolemic-atherosclerotic canine coronary arteries.; Circulation. 2001 Nov
6;104(19):2331-7.
6. Tesar GE, Kottke BA.; Location and sequence of atherosclerotic plaque formation in
white Carneau
and show racer pigeons: reevaluation and redefinition.Arch Pathol Lab Med. 1978
Nov;102(11):581
7. Massmann J, Muller H, Weidenbach H, Wagner J, Krug H.; Relations between
spontaneous and
induced arterial lesions in swine and arteriosclerosis in humans. Exp Pathol (Jena). 1977 Jul-
Aug;14(1-2):89-99
8. Blaton V, Peeters H.; The nonhuman primates as models for studying human
atherosclerosis: studies
References

21. 10. Herrera VL, Makrides SC, Xie HX, Adari H, Krauss RM, Ryan US, Ruiz-Opazo N.;
Spontaneous
combined hyperlipidemia, coronary heart disease and decreased survival in Dahl salt-sensitive
hypertensive rats transgenic for human cholesteryl ester transfer protein.; Nat Med. 1999
Dec;5(12):1383-9.
11. Bennani-Kabchi N, Kehel L, el Bouayadi F, Fdhil H, Amarti A, Saidi A, Marquie G.; New
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12. Nakashima Y, Plump AS, Raines EW, Breslow JL, Ross R. ApoE-deficient mice develop
lesions of all
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14. Velleman SG, McCormick RJ, Ely D, Jarrold BB, Patterson RA, Scott CB, Daneshvar H,
Bacon WL.
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15. Wu TC, Donaldson WE. Effect of cholesterol feeding on serum lipoproteins and
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atherosclerosis-susceptible and atherosclerosis-resistant Japanese quail. Poult Sci. 1982
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References

22. 17. Rekhter MD, Hicks GW, Brammer DW, Work CW, Kim J-S, Gordon D, Keiser JA, Ryan MJ: Animal
model that mimics atherosclerotic plaque rupture. Circ.Res. 1998;83:705-713
18. Plump AS, Smith JD, Hayek T, Aalto-Setala K, Walsh A, Verstuyft JG, Rubin EM, Breslow JL.
Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by
homologous recombination in ES cells. Cell. 1992 Oct 16;71(2):343-53.
19. Clubb FJ, Cerny JL, Deferrari DA, Butler-Aucoin MM, Willerson JT, Buja LM.
Development of atherosclerotic plaque with endothelial disruption in Watanabe heritable
hyperlipidemic rabbit aortas.Cardiovasc Pathol. 2001 Jan-Feb;10(1):.
20. Johnstone MT, Botnar RM, Perez AS, Stewart R, Quist WC, Hamilton JA, Manning WJ.
In vivo magnetic resonance imaging of experimental thrombosis in a rabbit model.
Arterioscler Thromb Vasc Biol. 2001 Sep;21(9):1556-60.
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22. Anne Braun, Bernardo L. Trigatti, Mark J. Post, Kaori Sato, Michael Simons, Jay M. Edelberg,
Robert
D. Rosenberg, Mark Schrenzel, and Monty Krieger Loss of SR-BI Expression Leads to the Early
Onset of Occlusive Atherosclerotic Coronary Artery Disease, Spontaneous Myocardial Infarctions,
Severe Cardiac Dysfunction, and Premature Death in Apolipoprotein E--Deficient Mice
Circulation Research published January 3, 2002, 10.1161/hh0302.104462
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