**2. Advantages of large animal models for cardiovascular research**

#### **2.1 Clinical relevance by virtue of the proximity in size to humans**

To develop therapeutic materials and procedures in cardiovascular medicine, preclinical validation of therapeutic efficacy and safety of medical materials using large animal models is an important step considering the comparable body and heart size with those in humans, which provides clinically relevant experimental procedures (**Figure 1**).

Since Gibbon first described cardiac surgery using cardiopulmonary bypass more than a half century ago [12], it is no overstatement to say that the history of cardiac surgery is the history of cardiopulmonary bypass development. Large animal models such as sheep and baboons have been used for the development of cardiopulmonary bypass and perioperative management, including anesthesia management models [13–17]. In the recent development of left ventricular assist devices (LVADs) for severe heart failure, large animal models such as bovine, dog, goat, pig, and sheep have been used. The device itself and cannula design, the surgical technique, performance, and the integration within the cardiovascular system must translate from these large animals to human patients [18]. Bovines, such as calves, are considered the most useful large animal model for this study [19].

On the other hand, Stephenson et al. reported the feasibility of the usage of Holstein calves in developing a robotically assisted microsurgical system to perform coronary artery anastomoses [20]. In another review, studies on the pathophysiology

#### **Figure 1.** *Advantages of the usage of large animal models.*

#### *Large Animal Models in Cardiovascular Research DOI: http://dx.doi.org/10.5772/intechopen.105754*

of chronic thromboembolic pulmonary hypertension using large animal models such as dogs and pigs using either indwelling or Swan Ganz catheters are summarized [21]. An important translational feature of pig models is the possibility of percutaneous coronary intervention using human clinical equipment, and the procedures using metallic stents or angioplasty balloons [22, 23]. These previous reports indicate the importance of using large animal models with similar cardiovascular system sizes to that of humans, enabling human-like experiments.

Additionally, in primary screening tests of drug discovery and toxicology studies, rodents such as mice and rats are mainly used [5]. However, the risk of under- or overestimation of the therapeutic efficacy or side effects remains in studies using animal models where the size of the body and the organs differ so much from humans. Recently, large animals are increasingly taking place as an alternative to rodents [9, 10]. Especially, mini-pigs have been largely utilized as they are easier to handle and suitable for drug discovery and toxicology researches. In addition to their anatomical and physiological similarities to humans, mini-pigs can be used for all routes of drug administration, such as the dietary, continuous intravenous infusion, dermal, or inhalation routes. Furthermore, compared to other laboratory animals, mini-pigs have a much closer metabolism of chemicals to humans [24–26].

Large animal models have been recently introduced not only in pharmaceutical toxicology evaluations but also in cardiovascular regenerative medicine using cell-free materials such as exosomes, microRNAs, proteins such as growth factors, and extracellular matrix components [27]. Therefore, it would be possible that the validation of therapeutical dosage in cardiovascular regenerative medicine would also be tested in preclinical efficacy and safety tests using large animal models [28].

### **2.2 Advantage of pigs as a large animal model**

Pigs are considered a suitable model for cardiovascular research because of the similarities in anatomy, physiology, metabolism, genomics, and proteomics to those in humans (**Figure 2**). Compared with other animal models, pigs acquire early sexual maturity, sizeable litter size, and have a quick reproduction time. They also breed year-round, which makes them highly suitable for biomedical research programs [29]. On the other hand, like other animals, there is moderate genetic variation between breeds (such as the human population) and within breeds that makes variations in the occurrence of abiogenetic diseases [30].

There are several advantages of pigs as a model animal for research in cardiovascular medicine as listed below:


**Figure 2.** *Significance of the pig model.*

Furthermore, the porcine cardiovascular system shares many similarities with those of humans, not only in the anatomical structure but also in the lipid profiles and lipoprotein metabolism, and is known to develop spontaneous lesions in the vasculature and cardiac valves [33]. Likewise, pigs show greater similarity to humans as neutrophils are also the predominant circulating blood cell population [34].

Based on these advantages, pig models are widely used in preclinical models in toxicology evaluations or developing medical materials, taking advantage of their anatomical characteristics. Their natural characteristics have also been widely used in the research of aortic valve stenosis, vascular calcification, and atherosclerosis [35–37]. In transplantation medicine, pigs have also been proposed as xenotransplantation donors. Due to the donor shortage, these procedures might enable the future xenotransplantation of porcine organs into humans as the main approach for transplantation medicine [38, 39].

Large animal models are also advantageous allowing much more precise disease model preparations compared to those in small animal models, which enables to create predictable injury sizes at a preferred region of the myocardium [40]. In this context, pig modes are largely used to create myocardial infarction models for stemcell-based regenerative medicine research [6, 41]. Munz et al. reported a surgical myocardial infarction through permanent coronary ligation that provided a reproducible and standardized pig myocardial infarction model. They showed that the optimal occlusion site in terms of morbidity, mortality, and lesion extent was the midpoint of the left anterior descending artery [31]. On the other hand, ameroid constrictors have been used to create a gradual coronary artery occlusion that might avoid lethal arrhythmia during surgical ischemia induction [42, 43]. Catheter-based coronary occlusion models are reported as well [44, 45].
