Selection of Animal Model for Cardiovascular Screening | Zoology

In this article we will discuss about the selection of animal model for cardiovascular screening.

Primates:

A wide variety of animal species and strains have been used as models of CVD, with variable degrees of success. As seen in humans, an ideal model – small and economical, yet large enough to permit desired experimental procedures – will precisely mimic CVD. In many respects, nonhuman primates such as chimpanzees and rhesus monkeys are ideal models.

They are phylogenetically close to humans, eat a similar omnivorous diet, have similar metabolism, and develop both metabolic syndrome and CVD as they age. On the negative side, nonhuman primates live for long periods of time (requiring lengthy experiments), are expensive to maintain, and often carry viral zoonoses that are dangerous to humans. The use of primates also raises significant ethical issues, such that it is only indicated in limited circumstances.

Dogs:

The dog can appear to be an attractive species for the study of CVD and has, in the past, been widely used for studies of circulatory physiology. However, while dogs can be of an ideal size and are easy to work with, there are problems associated with the status of dogs in the Western culture and with anthropomorphic attitudes toward them. In addition, as canines, they are carnivores and are in turn, resistant to high-lipid diets and atherosclerosis.

Their cardiovascular system also has important physiological characteristics that differ from those of humans, such as a contractile spleen that compensates for blood loss and hypotension. In addition, dogs have an extensive myocardial collateral circulatory system, much greater than that seen in pigs, primates and rats. This confers a degree of protection against myocardial infarction not seen in other species, except cats.

While most mammalian species respond to chronic ischemia with angiogenesis and/or growth of collateral vessels, these processes are much more efficient in dogs than in pigs or humans. Thus, while the dog is a useful model for the study of processes underlying revascularization, the results can only be extrapolated to the human condition with great care.

Swine:

The domestic pig shares many of the advantages of the nonhuman primate, including susceptibility to atherosclerosis, similar dietary preferences, and similar gastrointestinal system and metabolism. A major drawback is the large size of adult pigs with resultant management difficulties and, for drug assessment, a need for large amounts of experimental agents.

Experimental use of swine, including miniature pigs, to study CVD has generally depended on feeding of high-cholesterol and/or high-sugar diets and/or chemical induction of quasi type 1 diabetes with alloxan or streptozotocin. Spontaneous development of metabolic syndrome and insulin resistance, however, is not common in this species.

Rabbits:

The rabbit has been widely used in studies of atherosclerosis and has the merits of being small and relatively inexpensive, but large enough to permit physiological experiments. An herbivore, the rabbit is not inherently atherosclerosis-prone, and induction of vascular lesions necessitates a high-cholesterol diet. Even mild cholesterol supplementation leads to hypercholesterolemia and aortic lesions in these sensitive animals. Lesions start as fatty streaks, primarily on the aorta, and can develop into advanced lipid-laden intimal lesions.

There are reservations about the nature of the lesions and the mechanisms of induction, given the highly abnormal diet and the major differences in lipid metabolism between rabbits and humans. In addition, there is evidence that even modest dietary manipulation, such as the substitution of casein for soy protein in the diet is atherogenic in the rabbit, in the absence of dietary cholesterol.

On the other hand, familial hypercholesterolemia (FH) has long been recognized as a definitive risk factor for atherosclerotic disease in humans. Kondo and Watanabe isolated a mutation in the rabbit and developed the Watanabe heritable hyperlipidemic strain, which has extreme hypercholesterolemia and associated advanced atherosclerosis. The mutation was shown to cause a defect in the low-density lipoprotein receptor (LDLR), providing an animal model of the previously recognized genetic defect underlying FH in humans.

This facilitated the characterization of the effects of genetic defects on LDL metabolism. These studies, based on a genetic animal model, confirmed the importance of elevated LDL-C levels in CVD in humans and fostered the development of hypocholesterolemic agents, particularly inhibitors of 3- hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase or statins.

Hamster:

The Syrian hamster is a small rodent of Middle Eastern origin that is also sensitive to high-fat, cholesterol-supplemented diets. The hamster carries a significant portion of its plasma cholesterol in the LDL lipoprotein fraction, and is thus, closer to humans than to rodents and this has led to numerous studies of lipid metabolism in the hamster, largely involving high-fat, cholesterol-supplemented diets. Cholesterol-fed hamsters develop mild atherosclerosis that is exacerbated by the inhibition of NO synthesis.

The aortic lesions seen are confined to fatty streaks, and the cardiovascular effects reported do not include advanced intimal lesions or myocardial infarcts. Hamsters fed a very high (60%) fructose diet become insulin-resistant and have been used to study the effects on insulin signaling and lipoprotein metabolism, but evidence of CVD has not been reported in this model.

Ablation of pancreatic h cells with streptozotocin, to create quasi type 1 diabetes, results in significant atherosclerosis and glomerular sclerosis in cholesterol-fed hamsters that can develop into advanced aortic lesions. Some of the reservations regarding mouse models, as detailed above, also apply to the hamster as a model of human CVD, especially because the creation of CVD requires highly abnormal diets and/or treatment with a cytotoxic chemical agent, such as streptozotocin.

Rat:

Rats are generally considered to be resistant to atherogenesis, although lesions have been produced by heroic measures. Naturally-occurring lesions in rats are not very similar to that seen in man. Although lipid-containing lesions can be produced in rats, they are generally considered to be residual lesions following acute arteritis.

The development of genetically-engineered mice with disorders of lipid metabolism, such as apolipoprotein E (apoE) and LDL receptor knockout mice, was therefore a major step forward in animal models of atherosclerosis. These mice develop atherosclerosis spontaneously. The plaques that develop are widespread and reproducible and have some architectural features reminiscent of human lesions.

These mice have formed the basis for a plethora of studies identifying specific molecules critical to atherosclerosis, in particular, those regulating monocyte adherence/chemotaxis and macrophage differentiation/foam cell development. The major dissent has been that lesions occur at sites very different from human lesions – the aortic root and thoracic aorta, for instance.

Lesions in the aortic root are also foam cell-rich, rather than smooth muscle cell-rich, and may not have a single definable fibrous cap, and represent xanthomata rather than clinically important advanced lesions. Most important of all, these mice are models of atherogenesis, not advanced atherosclerosis, and they do not exhibit the single most important event in human atherosclerosis, that of plaque rupture leading to vessel occlusion.

Guinea Pig:

The most striking similarity between guinea pigs and humans is that the majority of circulating cholesterol is transported in LDL19 .Guinea pigs carry the majority of cholesterol in LDL and possess cholesterol ester transfer protein and lipoprotein lipase activities, which results in reverse cholesterol transport and delipidation cascades equivalent to the human situation. Guinea pigs develop atherosclerosis, and gender and hormonal status affect the extent of the atherosclerotic plaques. The Guinea pig is a model to study the inflammatory component of diet-induced atherosclerosis.

Advantages and Disadvantages of Animal Models:

Due to their short life span they react and age faster. They can be sacrificed after the entire disease process is studied and sufficient numbers are available, sp we can study the interactions of various factors, as the physiology and anatomy of the animals may be already known.

The disadvantages of animal models are that we may not be able to reproduce the same history of pathogenesis in animals as in man. To reproduce some models may not be feasible. Some may be difficult to reproduce or not possible to reproduce uniformly. Greater variability can occur in the experimental results and there is difficulty in reducing the number of animals used (one experimental result is obtained per animal).

Types of Animal Models:

1. Experimental Model:

This type is surgically induced, should mimic the disease being studied, and be easily manipulated and readily reproducible. If this model does not reproduce the disease exactly, the correlation between animal and man must be significant, verifiable and predictable.

2. Negative Model:

This type of model does not develop the disease and is usually avoided. It can be helpful in determining why some species are resistant.

3. Orphan Model:

This type of model includes diseases of animals, which do not have human counterparts, or diseases similar to those in man with dissimilar etiologies or pathogenesis.

4. Spontaneous Model:

These are naturally-occurring diseases of animals, which mimic those occurring in man.