Atherosclerotic Plaque Instability and Rupture: Recommended Mouse Models to Empower Clinically Relevant Discoveries, Diagnostics, and Therapeutics.

Clinical problem: Atherosclerotic plaque instability/rupture is the major driver of myocardial infarction and stroke, the leading causes of cardiovascular morbidity/mortality. However, the mechanisms leading to plaque rupture are poorly understood. This limits our ability to establish sensitive and diagnostic tools to identify plaques that are prone to rupture and to develop much-needed plaque-stabilizing therapies.

Recommendations: The diagnostic identification and therapeutic stabilization of unstable plaques are considered the holy grail of cardiovascular medicine, holding the potential to significantly reduce cardiovascular morbidity/mortality. To achieve this, it is vital that preclinical models reflect plaque instability/rupture as observed in patients. This will allow mechanistic discoveries, the development of diagnostic tools, and treatment options to identify and stabilize rupture-prone, unstable atherosclerotic plaques. This can be achieved using appropriate, research question-dependent, but currently underutilized mouse models with direct translational relevance.

Summary of strengths and weaknesses of mouse models for atherosclerosis: Conventional mouse models of atherosclerosis, LDLR^-/- (low-density lipoprotein receptor) and ApoE^-/- (apolipoprotein E) mice fed a high-fat diet, do not develop unstable atherosclerosis and plaque rupture as observed in patients with myocardial infarction. Modification of these mice with additional gene mutations (eg, in SRB1 [scavenger receptor class B type 1] and Fbn1 [fibrillin-1]^C1039G+/-) induces the development of unstable plaques and plaque rupture. However, some genetic approaches pose challenges as they can generate additional phenotypes and comorbidities and may not be commercially available or simple to breed. In contrast, surgically induced models of plaque instability/rupture (eg, carotid tandem stenosis or transverse aortic constriction) can easily be used in any athero-susceptible mouse in which a single gene mutation increases atherogenic lipids or can be combined with newer atherosclerosis-inducing approaches (eg, AAV-PCSK9 [proprotein convertase subtilisin/kexin type 9]) to cause unstable atherosclerotic disease. Such increasingly used surgical approaches are suitable for detailed mechanistic studies as they reflect most characteristics of human plaque instability/rupture and can be adapted to many different experimental conditions and research questions.