Abnormal cardiac inflow patterns during postnatal development in a mouse model of Holt-Oram syndrome

Tbx5(del/+) mice provide a model of human Holt-Oram syndrome. In this study, the cardiac functional phenotypes of this mouse model were investigated with 30-MHz ultrasound by comparing 12 Tbx5(del/+) mice with 12 wild-type littermates at 1, 2, 4, and 8 wk of age. Cardiac dimensions were measured with two-dimensional and M-mode imaging. The flow patterns in the left and right ventricular inflow channels were evaluated with Doppler flow sampling. Compared with wild-type littermates, Tbx5(del/+) mice showed significant changes in the mitral flow pattern, including decreased peak velocity of the left ventricular (LV) early filling wave ( E wave), increased peak velocity of the late filling wave ( A wave), and decreased or even reversed peak E-to-A ratio. The prolongation of LV isovolumic relaxation time was detected in Tbx5(del/+) neonates as early as 1 wk of age. In Tbx5(del/+) mice, LV wall thickness appeared normal but LV chamber dimension was significantly reduced. LV systolic function did not differ from that in wild-type littermates. In contrast, the Doppler flow spectrum in the enlarged tricuspid orifice of Tbx5(del/+) mice demonstrated increased peak velocities of both E and A waves and increased total time-velocity integral but unchanged peak E/A. In another 13 mice ( 7 Tbx5(del/+), 6 wild-type) at 2 wk of age, significant correlation was found between Tbx5 gene expression level in ventricular myocardium and LV filling parameters. In conclusion, the LV diastolic function of Tbx5(del/+) mice is significantly deteriorated, whereas the systolic function remains normal.