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.
Zhou
Yu-Qing
YQ
Mouse Imaging Centre, Hospital for Sick Children, 555 University Ave., Toronto, ON, Canada M5G 1X8. yqzhou@sickkids.ca
Zhu
Yonghong
Y
Bishop
Jonathan
J
Davidson
Lorinda
L
Henkelman
R Mark
RM
Bruneau
Benoit G
BG
Foster
F Stuart
FS
D000818:Animals; D003971:Diastole; D004195:Disease Models, Animal; D004452:Echocardiography; D005260:Female; D006321:Heart / Q000254:growth & development / Q000503:physiopathology; D006330:Heart Defects, Congenital / Q000000981:diagnostic imaging / Q000235:genetics / Q000503:physiopathology*; D006344:Heart Septal Defects, Atrial / Q000000981:diagnostic imaging / Q000235:genetics / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D010641:Phenotype; D013599:Systole; D020825:T-Box Domain Proteins / Q000235:genetics*; D018487:Ventricular Dysfunction, Left / Q000000981:diagnostic imaging / Q000235:genetics / Q000503:physiopathology; D018497:Ventricular Dysfunction, Right / Q000000981:diagnostic imaging / Q000235:genetics / Q000503:physiopathology
D020825:T-Box Domain Proteins; C103172:T-box transcription factor 5