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This Article Full Text Full Text (PDF) All Versions of this Article: 289/3/H992    most recent 00027.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (11) Citing Articles via Google Scholar Google Scholar Articles by Zhou, Y.-Q. Articles by Foster, F. S. Search for Related Content PubMed PubMed Citation Articles by Zhou, Y.-Q. Articles by Foster, F. S.

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

¹Mouse Imaging Centre and ²Cardiovascular Research Program, Hospital for Sick Children, ³Heart and Stroke/Richard Lewer Centre of Excellence, ⁴Sunnybrook and Women's College Health Sciences Centre, ⁵Department of Medical Biophysics, and ⁶Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario, Canada

Submitted 11 January 2005 ; accepted in final form 21 April 2005

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.

Tbx5 mutation; atrial septal defect; left ventricular diastolic function; right ventricular dilatation; Doppler flow sampling

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