Animal models for plaque rupture: a biomechanical assessment

Abstract

SummaryRupture of atherosclerotic plaques is the main cause of acute cardiovascular events. Animal models of plaque rupture are rare but essential for testing new imaging modalities to enable diagnosis of the patient at risk. Moreover, they enable the design of new treatment strategies to prevent plaque rupture. Several animal models for the study of atherosclerosis are available. Plaque rupture in these models only occurs following severe surgical or pharmaceutical intervention. In the process of plaque rupture, composition, biology and mechanics each play a role, but the latter has been disregarded in many animal studies. The biomechanical environment for atherosclerotic plaques is comprised of two parts, the pressure-induced stress distribution, mainly -but not exclusively -influenced by plaque composition, and the strength distribution throughout the plaque, largely determined by the inflammatory state. This environment differs considerably between humans and most animals, resulting in suboptimal conditions for plaque rupture. In this review we describe the role of the biomechanical environment in plaque rupture and assess this environment in animal models that present with plaque rupture.

Temporal and spatial changes in wall shear stress during atherosclerotic plaque progression in mice

“…At 13 weeks of age, normal chow diet was replaced with an atherogenic Western diet and provided ad libitum (Arie Blok, The Netherlands). Cast surgery was performed two weeks later on the animals under isoflurane-induced anaesthesia as described previously [ 33 , 41 , 42 ]. The average weight of the mice was 21.9 g. A tapering cast was placed around the right common carotid artery (RCCA), leading to changes in local WSS environment and subsequent plaque development.…”

“…In addition, we focused on computing WSS and did not compute wall stress which is expected to play a role, especially close to the cast [ 42 ], which is why we did not include the sections close to the cast in our histological analysis. A limitation of our model is that mice do not present with vulnerable plaques in accordance with the definition of a human vulnerable plaque; that is, mouse plaques are not rupture-prone [ 42 ]. The differences between mice—and animal models in general—and humans were reviewed by us and others [ 42 , 57 , 58 ].…”

“…A limitation of our model is that mice do not present with vulnerable plaques in accordance with the definition of a human vulnerable plaque; that is, mouse plaques are not rupture-prone [ 42 ]. The differences between mice—and animal models in general—and humans were reviewed by us and others [ 42 , 57 , 58 ]. The implication of these differences is that translation of the findings based on these animal data to patient studies should, therefore, be done cautiously.…”

Perspectives on Small Animal Radionuclide Imaging; Considerations and Advances in Atherosclerosis

“…Moreover, thin caps or intraplaque hemorrhage are rare in traditional mouse models, whereas they are characteristic of human vulnerable atherosclerosis (21), and plaque rupture is rarely seen in commonly used mouse models (22). To create a mouse model with plaque rupture, double knock outs (23, 24) or invasive experimental interventions are required, which arguably do not mimic human plaque rupture mechanisms (25).…”

Molecular Imaging of Vulnerable Atherosclerotic Plaques in Animal Models

“…This PCSK9 DY mutation in ApoE −/− mice mimics a genetic condition of hypercholesterolemia in patients, and it showed a synergistic effect in combination with ApoE deficiency, resulting in a strong increase in serum low-density lipoprotein, accelerated plaque growth and doubling of lesion size compared to wild-type ApoE −/− mice. Therefore, intravenous administration of an adenoviral vector for stable transfection of the PCSK9 DY mutated gene in ApoE −/− mice has been described as a promising approach to study the development of advanced atherosclerotic plaques related to the interaction of different genetic mutations, without time-consuming backcrosses, and further long-term studies to well characterize this model are expected to be published [ 146 ].…”