Comparison of Large Animal Models for Acute Ischemic Stroke: Which Model to Use?

Abstract

Translation of acute ischemic stroke research to the clinical setting remains limited over the last few decades with only one drug, recombinant tissue-type plasminogen activator, successfully completing the path from experimental study to clinical practice. To improve the selection of experimental treatments before testing in clinical studies, the use of large gyrencephalic animal models of acute ischemic stroke has been recommended. Currently, these models include, among others, dogs, swine, sheep, and nonhuman primates that closely emulate aspects of the human setting of brain ischemia and reperfusion. Species-specific characteristics, such as the cerebrovascular architecture or pathophysiology of thrombotic/ischemic processes, significantly influence the suitability of a model to address specific research questions. In this article, we review key characteristics of the main large animal models used in translational studies of acute ischemic stroke, regarding (1) anatomy and physiology of the cerebral vasculature, including brain morphology, coagulation characteristics, and immune function; (2) ischemic stroke modeling, including vessel occlusion approaches, reproducibility of infarct size, procedural complications, and functional outcome assessment; and (3) implementation aspects, including ethics, logistics, and costs. This review specifically aims to facilitate the selection of the appropriate large animal model for studies on acute ischemic stroke, based on specific research questions and large animal model characteristics.

Keywords: brain ischemia; dogs; models, animal; sheep; stroke; swine.

Figure 1.

Antero-posterior (panel A) and lateral (panel B) view of 3-D angiography showing rete mirabile epidurale rostrale (RM), middle cerebral arteries (MCA) and ascending pharyngeal arteries (APA) in swine.

Figure 2.

Comparative overview of circle of Willis (CoW) in humans, dogs, swine, sheep and NHP. In men, the CoW is composed of the left and right anterior cerebral artery (ACA), the anterior communicating artery (ACoA), left and right internal carotid arteries (ICA), left and right posterior cerebral arteries (PCA), as well as left and right posterior communicating arteries (PCoA). The CoW in dogs and NHP is relatively similar to humans with the exception of an absent ACoA. Instead, both ACAs merge into a single median ACA, which then divides into right and left branches. This anatomical variation also exists in human anatomy and is known as ‘azygos ACA’. As a variation, swine and sheep can have a fine plexiform network of vessels between the two ACAs, instead of one complete ACoA. The PCA branches off the PCoA in swine and sheep whereas it branches off the basilar artery in humans. The anterior cerebellar artery in dogs and sheep is a branch of the PCA, whereas a similar artery arises from the basilar artery in primates and humans, namely the anterior inferior cerebellar artery. Anatomical variations in the CoW exist in both humans and animals and an incomplete circle is associated with a reduction of the compensatory ability and a higher risk of stroke.

Figure 3.

Flowchart describing the most relevant aspects to take into account when choosing a large animal model of AIS. For perfusion studies requiring direct visualization of the tissue, we advise craniectomy and consequently an external/surgical approach rather than an endovascular approach. However, in general, the choice between external/surgical or endovascular should be based on the specific expertise of the research center. Moreover, when infrastructure, funding and ethical approval are available for NHP models, we recommend their use due to the anatomical and physiological similarities to humans. However, for proof-of-concept, descriptive, or non-stroke EVT studies, we recommend using sheep and swine models due to wider availability, less demanding housing requirements, and lower associated costs compared to dog and NHP models. When studying EVT in a thromboembolic stroke model, dogs and NHP are the only options due to the rete mirabile in swine and sheep. CV indicates cerebrovascular; EVT, endovascular treatment; and NHP, non-human primate.