The ideal animal model for cardiovascular research would mimic the pathophysiology and the metabolic processes of human subjects to enable physiological studies and to evaluate novel clinically relevant therapies. At the same time, an optimal model should be inexpensive, reproducible, easily manipulated and ethically sound.
Because of the multifactorial nature of cardiovascular diseases, there is not a single specie which is optimal for all studies. The choice of an animal model should be carefully made as it can affect the experimental outcomes and the reasonable translation of study findings to humans.
Large animals are more comparable to humans than small animals in terms of cardiac anatomy, physiology and hemodynamic values. Among the large animal models used in cardiovascular research, pig, dog, sheep and non-human primates stand out due to their cardiac similarities with humans.
However, the considerable expenses involved in housing and maintenance make studies involving large animals financially challenging. When feasible, studies are often constrained by a reduced number of subjects per study group, impacting the statistical significance of findings. Moreover, the rapid weight gain in swine limits their long-term use, as their anatomy and physiology radically change during growth, making it harder to apply findings to clinical settings.
In contrast, small animals present a cost-effective alternative. Their shorter lifespan and their fast reproduction rate enable the analysis of the history of a disease within a limited window of time. Advancements in technology allow for imaging and catheter-based approaches not only on larger animals but on rodents, too. Furthermore, the availability of genetically modified rodents is a significant advantage, enabling the manipulation of specific targets and generating specific models to investigate mechanisms underlying pathogenesis1,2.
Rodents represent the most common cardiovascular disease model because of some physiologic similarities and due to availability as well as reduced costs associated housing and maintenance. Rats, specifically, have significant advantages over mice as they present a 10-fold greater myocardial mass and a larger blood volume. This allows for a higher count of biological and ex-vivo histological analysis, thereby reducing the number of animals used per study, in accordance with the 3Rs principle of animal research.
Likewise, for the same anatomical reasons, rats enable sophisticated surgical procedures as well as repetitive and invasive hemodynamic assessments, which are not feasible in mice. Moreover, while early gene manipulation technologies shifted research focus to mice, the emergence of advanced techniques (i.e. CRISP/Cas-9) now allows for the creation of knock-out rats just like knock-out mice. In practical terms, rat models are ideal for investigating novel pharmacological or molecular agents across various cardiovascular diseases, whereas mouse models are best used in developmental biology and immunology as “proof of principle” to identify important gene or protein targets for the development of new molecular or pharmacological therapies3.
Examples of how rat models are used in cardiovascular research are reported below.
Myocardial infarction (MI) or a “heart attack” is a deadly emergency characterized by a lack of blood flow within the cardiac muscle. In rats MI was originally induced by sequential administration of isoproterenol, causing diffuse myocardial necrosis. Electrocautery technique came after, causing small focal lesion and soon thereafter the coronary ligation method was developed by Pfeffer group4. This MI rat model was essential in ground-breaking clinical trials leading to new therapeutic agents such as angiotensin converting enzyme inhibitors to treat heart failure patients. Nowadays, ligation of left anterior descending (LAD) coronary artery typically results in heart failure after 4 weeks5.
Hypertension, or raised blood pressure, is one of the major causes of mortality and it is a complex multifactorial disease influenced by genetic and environmental factors. Rats are preferred models for hypertension because of the availability of inbred strains such as spontaneous hypertensive rats (SHR), which became the model of choice for the screening of antihypertensive agents. Other forms of murine genetic models became the focus of hypersensitive research such as the Milan Strain, the New Zealand strain and the Dahl salt sensitive rats (DSS)2, based on high-salt diet administration on Sprague-Dawley (SD) rats which gradually results in hypertension. The gradual onset of the pathology makes this model more clinically relevant to heart failure progression in humans5.
Atherosclerosis is a chronic inflammatory disease characterized by a buildup of lipids and inflammatory cells within the artery walls, causing their narrowing and thus possibly leading to stroke and heart attack. Studies showed a significant relationship between serum cholesterol level and atherosclerotic plaque development. Because of a different lipoprotein metabolism compared to humans, mice and rats are typically resistant to atherogenesis. However, it was shown that in adult female SD rats, the combination of heated oil diet fortified with 2% cholesterol together with reduced cardioprotective estrogen levels after ovariectomy (menopause-induced atherosclerosis) leads to low-density-lipoprotein (LDL) increase and arterial thickening2. This model is interesting in terms of cost and complexity compared to genetically manipulated strains, as ApoE-/- and Ldlr-/- rat models showed atherosclerotic lesions formations after a much more extended period and much more intensive high-fat and high-cholesterol (HFHC) diets6.
During the 2023 Safety Pharmacology Society (SPS) Conference in Brussels, Dr. Michael Stonerook (AmplifyBio, OH, USA) highlighted the benefits and limitations of the rat model for cardiovascular screening assays. Key points that were presented during the event are summarized in this article:
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