Aged Zebrafish as a Spontaneous Model of Cardiac Valvular Disease

Valvular heart disease (VHD) is a highly prevalent age-associated cardiovascular pathology. VHD can be characterised by stenosis, an increase in valve stiffening commonly due to leaflet calcification, or regurgitation, where backflow of blood can occur as a result of valve remodelling. At present, there is a paucity of spontaneous animal models of valve disease which would aid mechanistic investigations and allow therapeutic screening. Here, we report a spontaneously occurring zebrafish valve disease model, which is associated with natural ageing. Using 2D and 3D morphometric approaches, we identify that aged zebrafish (> 2.5 years old) show greater valve volume and leaflet width/area when compared to young fish (< 1.5 years old). Size and shape changes occur in both the atrioventricular (AV) and bulboventricular valves (BV). Immunofluorescence and histological analyses reveal cellular changes, increased immune cell infiltration and altered distribution of elastin and collagen in aged leaflets, similar to that observed in mammalian clinical samples. Finally, we show that aged zebrafish exhibit cardiac dysfunction associated with valve degeneration. We have demonstrated that this novel zebrafish model of spontaneously occurring age-related valve degeneration may have utility as a human disease model and could be used to determine mechanistic insights in the future.