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

Abstract

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

Sodium‐Glucose Co‐Transporter 2 (SGLT2) Inhibitor Dapagliflozin Stabilizes Diabetes‐Induced Atherosclerotic Plaque Instability

“…We have previously validated a unique mouse model of plaque instability/rupture by introducing a tandem stenosis (TS) to the carotid artery. 2 , 3 This TS model closely reflects plaque instability/rupture as seen in patients 4 and has recently been successfully used to define the plaque‐stabilizing effects of a myeloperoxidase inhibitor 5 and anti‐CD47 antibodies. 6 We now systematically use this model to investigate whether diabetes promotes plaque instability and, most importantly, whether SGLT2i exhibit plaque‐stabilizing effects.…”

Pharmacological Inhibition of Factor XIIa Attenuates Abdominal Aortic Aneurysm, Reduces Atherosclerosis, and Stabilizes Atherosclerotic Plaques

“…The TS mouse model representing unstable plaques as seen in patients is a unique preclinical tool both to develop diagnostic approaches for the detection of unstable plaques and for the development and testing of drugs for plaque-stabilizing effects. 42 For the latter, the promising effects of FXIIa inhibition hold great promise for clinical translation, particularly as first clinical applications, utilizing the anti-inflammatory and antithrombotic effects of FXIIa inhibition are currently trialed. However, our data also indicate that FXIIa targeting can be used for diagnostic approaches.…”

“…The tandem stenosis mouse model representing unstable plaques as seen in patients is a unique preclinical tool both to develop diagnostic approaches for the detection of unstable plaques as well as for the development and testing of drugs for plaque stabilizing effects 42 .…”

How good are our models of cardiovascular disease?

“…However, it has been extremely challenging to study unstable plaque pathology so as to effectively prevent plaque rupture, and most atherosclerosis research has utilised preclinical animal models exhibiting stable atherosclerosis. Here, Noonan et al (2021) describe their novel Tandem Stenosis mouse model that reflects plaque instability and rupture as seen in patients, exhibiting key characteristics of human unstable plaques. This model appears to represent an ideal preclinical tool for improving our understanding of human plaque instability/rupture, developing imaging technologies to identify unstable plaques and testing plaque‐stabilising therapeutics.…”