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

Abstract

del/ϩ 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/ϩ neonates as early as 1 wk of age. In Tbx5 del/ϩ 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/ϩ 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/ϩ , 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/ϩ 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 HUMAN HOLT-ORAM SYNDROME is an autosomal dominant disease caused by mutations of the TBX5 gene and is characterized by congenital cardiac and forelimb anomalies (1,4,15,16,22). Similar to Holt-Oram syndrome, Tbx5del/ϩ mice demonstrate cardiac anatomic abnormalities including atrial septal defects (ASDs) and/or ventricular septal defects and limb malformations. Secondary changes in cardiac morphology including dilated atria and right ventricle leading to a bulbous shape of the whole heart are observed. Abnormal cardiac electrophysiology, particularly atrioventricular block, has also been found (5, 23).Although the cardiac structural phenotypes of Tbx5 del/ϩ mice have been well identified ex vivo with histology or MRI, the in vivo cardiac functional phenotypes and their comparison with those of corresponding human cardiac disease have not yet been evaluated. As seen in humans with right ventricular volume and/or pressure overload caused by ASD, left ventricular diastolic filling is impaired because of right heart dilatation and abnormal interaction of both ventricles (3,6,19,30). Because ASD and resultant right heart dilatation are the major structural anomalies in Tbx5 del/ϩ mice, it is of interest to explore the consequent functional abnormalities of this model compared with those in humans. Another question is whether Tbx5 mutation that markedly decreases the expression of downstream targeted genes in the developing murine heart (5) affects ventricular myocardial function.Recently, a methodology has been established for comprehensive in vivo cardiac imaging in mice using a high-frequency (ϳ20 -55 MHz) ultrasound imaging, ultrasound biomicroscopy (UBM) (10 -12, 25, 38, 40). This new technology has been successfully applied to measure cardiac dimensions, function, and hemodynamics with various functional modali...

Progressive troponin I loss impairs cardiac relaxation and causes heart failure in mice

“…Isoflurane at the low concentration of ϳ1.5% is thought to have minimal effects on ventricular diastolic function in mice (41). Under this anesthetic condition, the heart rate is about 350 beats/min in these 2-wk-old mice, which is comparable with most reported studies (41,42). Mice were otherwise not adversely affected by the anesthesia procedure and showed no evidence of increased mortality even at 17 days of age.…”

“…The Vevo 770 High-Resolution Imaging System features a RMVTM 707B Scan head designed for high frame rate, real-time small animal imaging applications with a center frequency of 30 MHz and a frequency band 15 to 45 MHz. With this instrument, it was possible to measure cardiac dimensions and function even in neonatal mouse hearts (32,41,42).…”

Emerging Imaging Techniques

“…The images in Figure 1b show the system used for a comprehensive transthoracic cardiac examination in the mouse with anatomical confirmation by MRI. 21,23 The obvious next step in the development of this imaging method is a true phased array transducer that is capable of performing the "raster" by focusing the beam rapidly across the sample as is currently performed in clinical ultrasound systems. Future applications could include dynamic imaging of vessel wall morphology, longitudinal studies of plaque formation, and real-time guidance of microsurgical interventions in small animals.…”

Multimodal imaging of mouse development: Tools for the postgenomic era

“…MRM has evolved as an important phenotyping tool and has been used to identify defects in embryos mutant for developmentally relevant genes such as Gja1/Connexin 43 (Huang et al, 1998;Flenniken et al, 2005), Cited2 (Schneider et al, 2003a,b;2004), phosphatidylserine receptor , and Tbx5 (Zhou et al, 2005). Abnormalities in embryonic and postnatal neural development can be facilitated by highly sensitive methods such as diffusion tensor imaging (DTI), which makes use of water diffusion to highlight ordered structures such as axonal tracts (Mori et al, 2001).…”