Cardiac development and physiology are modulated by FGF 2 in an isoform‐ and sex‐specific manner

Abstract The low‐molecular‐weight isoform (Lo) of fibroblast growth factor 2 ( FGF 2) has distinct functions from the high‐molecular‐weight isoforms (Hi) of FGF 2 in the adult stressed heart. However, the specific roles of these isoforms in the unstressed heart were not examined. We investigated whether the FGF 2 isoforms modulate cardiac development and physiology in isoform‐ and sex‐specific manners. Young adult male and female mice that were deficient in either Hi FGF 2 (Hi KO ) or Lo FGF 2 (Lo KO ) underwent echocardiographic analysis and were compared to their wild‐type ( WT ) counterparts. By comparison to WT cohorts, female Lo KO hearts display a 33% larger left ventricular ( LV ) volume and smaller LV mass and wall thickness. Mitral valve flow measurements from these hearts reveal that the early wave to atrial wave ratio (E/A) is higher, the deceleration time is 30% shorter and the mitral valve E‐A velocity–time integral is reduced by 20% which is consistent with a restrictive filling pattern. The female Hi KO hearts do not demonstrate any significant abnormality. In male Hi KO mice the cardiac output from the LV is 33% greater and the fractional shortening is 29% greater, indicating enhanced systolic function, while in male Lo KO hearts we observe a smaller E/A ratio and a prolonged isovolumic relaxation time, consistent with an impaired relaxation filling pattern. We conclude that the developmental and physiological functions of FGF 2 isoforms in the unstressed heart are isoform specific and nonredundant and that these roles are modulated by sex.