The tandem stenosis mouse model: Towards understanding, imaging, and preventing atherosclerotic plaque instability and rupture

The rupture of unstable atherosclerotic plaques is the major cause of cardiovascular mortality and morbidity. Despite significant limitations in our understanding and ability to identify unstable plaque pathology and prevent plaque rupture, most atherosclerosis research utilises preclinical animal models exhibiting stable atherosclerosis. Here, we introduce the tandem stenosis (TS) mouse model that reflects plaque instability and rupture, as seen in patients. The TS model involves dual ligation of the right carotid artery, leading to locally predefined unstable atherosclerosis in hypercholesterolaemic mice. It exhibits key characteristics of human unstable plaques, including plaque rupture, luminal thrombosis, intraplaque haemorrhage, large necrotic cores, thin or ruptured fibrous caps and extensive immune cell accumulation. Altogether, the TS model represents an ideal preclinical tool for improving our understanding of human plaque instability and rupture, for the development of imaging technologies to identify unstable plaques, and for the development and testing of plaque‐stabilising treatments for the prevention of atherosclerotic plaque rupture. LINKED ARTICLES This article is part of a themed issue on Preclinical Models for Cardiovascular disease research (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.5/issuetoc The present lack of mechanistic data pertaining to plaque instability, erosion, and rupture represents a fundamental gap in knowledge that must be addressed if we are to facilitate a more informed approach to drug and diagnostic development to prevent myocardial infraction and stroke. The TS model represents an ideal preclinical tool for improving our understanding of human plaque instability/rupture, for the development of imaging technologies towards the identification of unstable plaques, and for the development and testing of plaque‐stabilising therapeutics for the prevention of atherosclerotic plaque rupture.