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1 Mouse Imaging Centre, The Hospital for Sick Children, Toronto, Ontario, Canada
2 Cardiovascular Research Program, The Hospital for Sick Children, Toronto, Ontario, Canada; Heart and Stroke and Richard Lewer Centre of Excellence, Toronto, Ontario, Canada
3 Mouse Imaging Centre, The Hospital for Sick Children, Toronto, Ontario, Canada; Sunnybrook and Womens College Health Sciences Centre, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
4 Cardiovascular Research Program, The Hospital for Sick Children, Toronto, Ontario, Canada; Heart and Stroke and Richard Lewer Centre of Excellence, Toronto, Ontario, Canada; Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario, Canada
* To whom correspondence should be addressed. E-mail: yqzhou{at}sickkids.ca.
Tbx5del/+ mice provide a model of human Holt-Oram syndrome, which includes cardiac structural malformations such as atrial septal defect. In this study, the in vivo cardiac functional phenotypes of this mouse model are investigated. In 12 Tbx5del/+ mice and 12 wild-type littermates, the hearts were observed using 30 MHz ultrasound imaging at 1, 2, 4 and 8 weeks of age. Cardiac dimensions were measured using two-dimensional and M-mode imaging. The flow patterns in the left and right ventricular inflow channels were evaluated using Doppler. Compared to the wild-type littermates, Tbx5del/+ mice showed significant changes in the mitral flow pattern, including decreased peak velocity of the early ventricular filling wave (E wave), increased peak velocity of the late filling wave (A wave) and consequently decreased or even reversed peak E/A ratio. The prolongation of left ventricular isovolumic relaxation time was detected in Tbx5del/+ neonates as early as 1 week of age. In Tbx5del/+ mice, the left ventricular wall thickness appeared normal but the ventricular chamber dimension was significantly reduced. Left ventricular systolic function did not differ from that in the wild-type littermates. In contrast, Doppler flow spectrum in the enlarged tricuspid orifice of Tbx5del/+ mice demonstrated increased peak velocities of both E and A waves and increased total time-velocity integral but unchanged peak E/A ratios. In another 13 mice (7 Tbx5del/+, 6 wild-type) at 2 weeks of age, significant correlation was found between the Tbx5 gene expression level in ventricular myocardium and the left ventricular filling parameters as well as the dimension of the right heart. In conclusion, the left ventricular diastolic function of Tbx5del/+ mice is significantly deteriorated while the systolic function remains normal. The right heart dilates due to volume overload but its diastolic function is unchanged.
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