Experimental models of murine atherosclerosis: does perception match reality?

Background: Murine models of atherosclerosis have been invaluable to gain mechanistic understanding of this chronic disease. Induction of atherosclerosis with relative ease in ApoE-/- and Ldlr-/- mice fed a Western-type diet to cause hyperlipidaemia has provided researchers with popular tools to manipulate and characterise the action of genes that affect atherogenesis. Seminal studies and reviews have discussed key phenotypic differences between different models and "target levels of hyperlipidaemia" have also been published. However, despite widespread use of these models and firm beliefs about differences in severity between them, there has been no meta-analysis and critical appraisal of published literature reporting phenotypes of murine atherosclerosis, focusing on the degree of hyperlipidaemia and aortic atheroma burden. Methods and Results: A systematic search in PubMed and Web of Knowledge with the key words: "atherosclerosis", "western diet" and "mice" identified 483 studies between 2006-2018. These reports used ApoE-/-, Ldlr-/- or proprotein convertase subtilisin/kexin type 9 overexpressing- adeno-associated virus (PCSK9-AAV8) models of experimental atherosclerosis (including bone marrow transplants, BMT), induced by western-diet (WD) feeding. We chose to assess standard WD (0.2% cholesterol) as it is the most widely used diet in atherosclerosis studies 1. These publications were filtered based on the content of their abstracts; those that described experiments of experimental atherosclerosis (204 papers) were considered for further assessment. Of these, articles that reported at least two of the following measures were included in the main analysis to allow for correlative comparisons; lesion area in the aortic root (numerical values and not %), % en face Oil-Red O staining in the whole aorta, total plasma cholesterol and triglyceride (mg/dL) levels. These criteria yielded 144 research articles (22 used BMT of either model, 75 used ApoE-/-, 27 used Ldlr-/-, 10 used both BMT and single ApoE-/- or Ldlr-/-, 2 used PCSK9, the remaining 8 studies used mixed models BMT) where the mice were fed a diet for 4-28 weeks.