SHAPE Society

1. Editorial Slides
VP Watch, January 16, 2002, Volume 2, Issue 2
Part II - Animal Models of Heart Attack? Plaque
Rupture/Thrombosis

2. Part - I
 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. Part - II
 The process of atherosclerotic plaque disruption has
been difficult to monitor because of the lack of an
animal model of plaque rupture. 23
 More than 30 years ago, Constantinides and
Chakravarti triggered plaque rupture and thrombosis
in aorta of chlolesterol fed rabbits by intraperitoneal
injection of Russell's viper venom (RVV, a potent
procoagulant and endothelial toxin) followed by the
intravenous injection of histamine, a vasopressor. 25
 The aortas of the rabbits were then accordingly
found to have disrupted atherosclerotic plaques with
overlying platelet-rich thrombi. 25

15.  The advantage of Constantinides model is use of
a biological intervention for triggering localized
plaque thrombosis. However the non-physiological
use of a toxic and potent thrombogenic substance
(snake toxin) to induce plaque thrombosis can be
considered a major drawback. 24
 Other disadvantages of the Constantinides model
are the low yield of triggering (only about one third
of the rabbits developed thrombosis) and the long
(8-month) preparatory period. 24

16.  Abela, Muller and colleagues challenged the
limitations of Constantinides model by having the
rabbits undergo aortic balloon injury followed by 8
weeks of 1% cholesterol diet. 24
 In addition, they wanted to determine whether
mechanical injury to the aorta early in the
preparatory phase could enhance the development
of vulnerable plaques, thereby increasing the yield
of disrupted plaques and shortening the preparatory
period. the rate of plaque disruption after
pharmacological triggering increased to 71%. 24
 They found that the rate of plaque disruption after
pharmacological triggering increased up to 71%.24

17.  Johnstone, Manning, and colleagues used the
modified Constantinides model and documented
plaque disruption by MRI that resemble those found
in human coronary arteries. 23
 A major advantage of the use of a rabbit over other
animals is that the rabbit’s aorta is approximately the
same anatomic size as the human coronary artery. 23

18.  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

19.  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

20. 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.

21. 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

22. 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.

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

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