Large Animal Models of Cardiovascular Disease: From Training to Translation

Cardiovascular diseases (CVDs) represent the main cause of morbidity and mortality worldwide¹. Consequently, research in this field is required. While somewhat controversial, especially if not done right, the use of animals for research and training purposes remains a mandatory step of translational research. Small animal models have contributed considerably to unraveling the cellular and molecular mechanisms of CVDs, but extrapolation to a clinical scenario is hindered by the remarkable cardiovascular dissimilarities with humans^2,3. Hence there is importance in large animal models, as they are closer to humans with respect to size as well as anatomical and physiological features^3,4.

While experimental models cannot fully resemble the clinical condition, this methods collection aims to help researchers choose the large animal model that best represents the disease being investigated to allow researchers the ability to test novel procedures and devices in systems that recreate the human anatomy, while prioritizing animal welfare. These animal models also intend to help medical professionals learn and practice challenging procedures in human-like systems using clinical-grade equipment and surgical techniques⁴.

Cerebrovascular disease involves a series of conditions, including intracranial aneurysms (IA) that present a high mortality rate in case of rupture. The development of new tools or therapeutic strategies for the management of IA must be explored in a preclinical setting before translation to a clinical scenario can be performed. Blanco-Blázquez et al. describe two surgically created aneurysmal swine models that show encouraging results in the research field of nonruptured aneurysms and training in neuroradiology techniques⁵. Although the described models do not completely replicate the physiopathological circumstances involved in the development of aneurysms in terms of hemodynamics, they proved to be equivalent to the condition observed in humans. Accordingly, it was appropriate for medical professionals to practice different endovascular procedures as well as useful for researchers to explore new therapeutic options⁵.

Although current treatments for myocardial infarction (MI) can reduce early mortality, a significant proportion of patients develop progressive heart failure. Martínez-Falguera et al. describe an MI model obtained by permanent coil deployment in swine that may be beneficial in exploring new therapeutic options⁶. The described method is proven to be feasible and highly reproducible. It avoids the need for open-heart procedures and the accompanying inflammatory reaction that takes place after surgery. An important advantage is that this model reproduces the pathogenesis of non-revascularized MI found in humans and it is appropriate for MI models in their acute, sub-acute and even chronic phase, depending on the follow-up duration of a given study⁶.

When studying MI, or other cardiac conditions, post-mortem gross examination of the heart is complex and may be associated with several approach-related or interpretation errors. For that reason, standardized gross examination and sample harvesting protocols are crucial to guarantee the comparability, reproducibility, and success of experimental studies of CVDs carried out in large animal models. Constantin and Tăbăran demonstarte two standard gross examination protocols (inflow-outflow and four-chamber dissection methods), pointing out the gross examination methods and the sampling sites routinely employed for histopathologic analysis that can be adapted to any species⁷. The presented protocol could serve as a guideline for cardiac dissection, which can easily be used in investigations requiring an exhaustive heart evaluation⁷.

Transcatheter pulmonary valve replacement is increasingly common in patients with congenital heart disease, acquired dysfunction of the right ventricular outflow tract, or of a bioprosthetic valve. Although early and late results in the clinical scenario are satisfying, there are numerous clinical challenges that must be taken into account for lifetime employment, especially in young people. The study presented by Hao et al. shows the feasibility and long-term safety of a newly developed pulmonary valve⁸. The authors use the pericardium to engineer an autologous pulmonary valve that is then implanted at the native pulmonary valve location by means of a self-expandable Nitinol stent via catheterization of the jugular vein in a sheep model. While the study has certain limitations, such as the sample size used, it constitutes a considerable advancement for safe and efficient implementation for upcoming preclinical trials as well as translation to the clinical setting.

Atrial fibrillation (AF) is the most extensive cardiac arrhythmia attributable to structural atrial myopathy, defined as structural remodeling of the atria. The discovery of new treatment approaches requires the development of reproducible large animal models of atrial myopathy. Most currently available models rely on atrial tachypacing, which reproduces conduction disorders but in the absence of structural changes that normally precede electrical changes. To meet this requirement, Tubeeckx et al. describe a clinically relevant porcine atrial myopathy model induced by sterile pericarditis, showing inducibility of AF as well as rapid development of inflammation and fibrosis. Presenting previously described features, this large animal model could help explore new strategies for the treatment of atrial myopathy and AF⁹.

In recent years, we have seen impressive advances in the management of CVDs, allowing for mechanistic insights and new therapeutic approaches. While the number of animals employed for research and training purposes must decrease in accordance to current ethical considerations and studies involving animal models must be optimized taking animal welfare into consideration¹⁰, experimental animals cannot entirely be replaced by other systems. Large animal models will remain the best tool for advancing the understanding of mechanisms of human CVDs¹¹, since the use of human-like settings increases the chances of bench findings translating to effective treatments⁴. A platform representative of the complex biological interactions present in clinical diseases is a requirement to further advance the understanding of these highly prevalent conditions. As such, the large animal models described in this methods collection could help bridge the gap from the bench to the bedside, contributing to the knowledge of disease pathogenesis and representing essential tools to develop diagnostic techniques and therapeutic strategies. This comprehensive methods collection ranges from cerebrovascular diseases to structural, rhythmic and ischemic heart disease, up to the all-important sampling techniques necessary to obtain meaningful results. Moreover, these models allow physicians to practice challenging procedures in systems that are close to the human anatomy and enhance clinical approaches to several CVDs.

The authors have nothing to disclose.

We would like to thank all the authors for their excellent contributions to this collection. This research was funded by Agencia Estatal de Investigación (PID2019-107329RA-C22/AEI/10.13039/501100011033), Consejería de Economía, Ciencia y Agencia Digital, Junta de Extremadura (IB20191, GR18199), and Instituto de Salud Carlos III (PI20/00247, CB16/11/00494), cofounded by European Regional Development Fund “A way to make Europe”.