Animal Models of Calcific Aortic Valve Disease

Abstract

Calcific aortic valve disease (CAVD), once thought to be a degenerative disease, is now recognized to be an active pathobiological process, with chronic inflammation emerging as a predominant, and possibly driving, factor. However, many details of the pathobiological mechanisms of CAVD remain to be described, and new approaches to treat CAVD need to be identified. Animal models are emerging as vital tools to this end, facilitated by the advent of new models and improved understanding of the utility of existing models. In this paper, we summarize and critically appraise current small and large animal models of CAVD, discuss the utility of animal models for priority CAVD research areas, and provide recommendations for future animal model studies of CAVD.

Development of Aortic Valve Disease in Familial Hypercholesterolemic Swine: Implications for Elucidating Disease Etiology

“…Hyperlipidemia is frequently accompanied by inflammation in both human and animal diseased valves,50, 55, 56 and this was also the case in RFH swine, where macrophages infiltrated thickened areas of adult leaflets. Our results indicate that leaflet thickening and lipid oxidation preceded the emergence of inflammation.…”

“…The search for an animal model of CAVD that accurately mimics human anatomy and physiology and recapitulates key CAVD hallmarks is an ongoing effort motivated by the need to better understand the etiology and progression of CAVD in FH and non‐FH individuals alike. Though mice and rabbits are commonly used for this purpose, these animals exhibit numerous dissimilarities from humans with respect to valve properties and lipid metabolism, as reviewed elsewhere 56. Despite their numerous cardiovascular and genetic similarities with humans, swine have been underexplored as CAVD models, perhaps because the large size of standard swine can make such de novo development of an animal model an unwieldy and risky endeavor.…”

Miniature Swine for Preclinical Modeling of Complexities of Human Disease for Translational Scientific Discovery and Accelerated Development of Therapies and Medical Devices

“…The platform has led to the development of noninvasive clinical methods, including ones for evaluating electrophysiology (Smith et al 1997), platelet physiology (Llanes et al 2001), thrombus formation (Martini et al 2008), and blood flow (Lee et al 2011). These methods have further enhanced studies in which swine have been used to model a host of cardiovascular diseases, including atherosclerosis (Granada et al 2009), arrhythmias (Park et al 2015;Janse, Opthof, and Kleber 1998), acute (Feng et al 1998) and chronic (White, Roth, and Bloor 1986) myocardial infarction Ye et al 2014), venous occlusion (Shi et al 2015), hypertrophic cardiomyopathy (Lin et al 2002), endocarditis (Christiansen et al 2013), and valvular disease (Sider, Blaser, and Simmons 2011;Porras et al 2016). The availability of these relevant models has facilitated the advancement of novel therapies for clinical evaluation.…”

Animal Models as Tools for Translational Research: Focus on Atherosclerosis, Metabolic Syndrome and Type-II Diabetes Mellitus

“…Unlike humans, rabbits are hepatic lipase-deficient and do not have an analogue of human apo A-II. Rabbits do not form spontaneous atherosclerotic lesions and therefore require very high cholesterol levels to induce more advanced disease (see review [110]). Rabbits also have significant differences in their lipid metabolism from humans, which can result in their development of "cholesterol storage syndrome" while on high-cholesterol diets (0.5-3%), with cholesterol deposited in their liver, adrenal cortex, and reticuloendothelial and genitourinary systems [108].…”