Table 7.

Examples of animal models of valve disease and animal-free alternatives

Species	Experimental animal model and pathological features	Applications	Animal-free alternatives	Refs
Calcific aortic valve disease
Mouse	Male Notch1+/− mice fed for 10 months with a Western diet Mild phenotype: Notch1+/− mice have increased aortic valve calcification without significant valve stenosis	To study valve sclerosis early during valve disease progression	Notch-signalling can be studied in cultured aortic VICs as a model of cell-autonomous valve calcificationReplacement and reduction	126
	Apolipoprotein E-deficient Mice (ApoE−/−) display ectopic calcification of valves showing bone-marrow-derived cells positive for osteoblast-related proteins, which might represent smooth muscle-like and osteoblast-like cells in degenerative valves; the sclerotic valves displayed frequent apoptotic cell death and chemokine expression	To study the concomitant impact of altered lipid metabolism and ageing for the development of murine aortic sclerosis To develop therapeutic strategies for aortic valve stenosis	Not available	127
Rabbit	New Zealand White rabbits subjected to one-kidney/one-clip model to induce hypertension; mild aortic valve stenosis in hypertensive rabbits, increased valve thickness and inflammation nodules, hypertrophy of valve after 4 months	To investigate the mechanisms underlying the association between hypertension and aortic stenosis and the efficacy of different medical treatments to delay, or even hinder, the disease progression	Not available	128
	High cholesterol diet for 20 and 40 weeks, atherosclerotic lesions present in aortic valves, with increased lipid deposition, inflammatory cell infiltration, osteopontin deposition, changes in collagen and elastin distribution, and mineralization; hypercholesterolemia-induced calcification in the aortic valves depends on Lrp5 receptor pathway	To study the link between atherosclerosis and aortic valve stenosis; results are similar to changes reported in human sclerotic aortic valves, suggesting the suitability of this model of atherosclerosis as a model for CAVD	In vitro cultured aortic valve myofibroblast model of cell proliferation. Replacement and reduction	129,130
	Watanabe heritable hyperlipidaemic (WHHL) rabbits fed with a high-fat/high carbohydrate diet display a spontaneous LDLR mutation; the valve does not show significant haemodynamic stenosis but presents lipid deposition, fibrosis, calcification, and inflammatory cell infiltrations	To study early-stage of CAVD and the impact of dietary cholesterol on valve disease	Not available	130
	White rabbits fed with a standard diet supplemented with 0.5% cholesterol and 50,000 IU/day vitamin D3; non-invasive echocardiographic and invasive measurements confirmed the increase in transvalvular pressure gradient and development of valvular aortic stenosis; histology showed severe calcified and thickened aortic valve	To evaluate the haemodynamic and transvalvular gradient measurements after percutaneous balloon dilation of the valve, for translational research	Not available	131
Pig	Yorkshire swines fed with a high-fat/high-cholesterol diet for 2 or 5 months; valves show the formation of proteoglycan-rich onlays in the fibrosa before significant lipid accumulation, inflammatory cell infiltration, or myofibroblast activation This model shows aortic valve sclerosis without calcification.	This model enables new insights into early pathogenesis, including that of proteoglycan-rich onlays; the model mimics features of early human aortic valve disease; their size makes them ideal for studies that characterize leaflet-mechanical properties and for studies requiring blood analysis	In vitro matrix guided regenerated valves might provide insights into the association between the valve microenvironment and pathological cell responses Replacement and reduction	132
Valve insufficiency or stenosis
Dog, pig	Severing the chorda tendinae, ischaemic injury of the posterior papillary muscle	Mitral valve regurgitation	Not available	133
Sheep	Pacing-induced heart failure with tricuspidal insufficiency	Tricuspidal valve insufficiency	Not available	134
Cat, dog, sheep, pig	Supravalvular aortic stenosis by surgical banding of the aorta	Aortic stenosis	Not available	135