A novel mouse model of X-linked cardiac hypertrophy

Abstract

Lo CW. A novel mouse model of X-linked cardiac hypertrophy. Am J Physiol Heart Circ Physiol 294: H2701-H2711, 2008. First published April 18, 2008 doi:10.1152/ajpheart.00160.2007.-We recovered a novel mouse mutant exhibiting neonatal lethality associated with severe fetal cardiac hypertrophy and with some adult mice dying suddenly with left ventricular hypertrophic cardiomyopathy. Using Doppler echocardiography, we screened surviving adult mice in this mutant line for cardiac hypertrophy. Cardiac dimensions were obtained either from two-dimensional images collected using a novel ECG-gated ultra-high-frequency ultrasound system or by traditional M-mode imaging on a clinical ultrasound system. These analyses identified, among the littermates, two populations of mice: those with apparent cardiac hypertrophy with hypercontractile function characterized by ejection fraction of 75-80%, and normal littermates with ejection fraction of 53-55%. Analysis of the ECG-gated two-dimensional cines indicated that the hypertrophy was of the nonobstructive type. Further analysis of heart-to-body weight ratio confirmed the ultrasound diagnosis of left ventricular hypertrophic cardiomyopathy. Histopathology showed increased ventricular wall thickness, enlarged myocyte size, and mild myofiber disarray. Ultrastructural analysis by electron microscopy revealed mitochondria hyperproliferation and dilated sarcoplasmic reticulum. Genome scanning using microsatellite DNA markers mapped the mutation to the X chromosome. DNA sequencing showed no mutations in the coding regions of several candidate genes on the X chromosome, including several known to be associated with left ventricular hypertrophic cardiomyopathy. These findings suggest that this mouse line may harbor a mutation in a novel gene causing X-linked cardiomyopathy.echocardiography; X-linked cardiomyopathy; hypertrophic cardiomyopathy; ultrasound HYPERTROPHIC CARDIOMYOPATHY (HCM) is a major cardiovascular disease in human adults and children (17,22), with a prevalence of 1:500 in the young and likely higher in older individuals due to age-dependent penetrance (23). It has varied presentations, from no symptoms to severe heart failure or sudden cardiac death, that do not correlate directly with the anatomic abnormality. It is a major cause of sudden cardiac death in apparently healthy, young individuals (24). Infants that present with cardiac hypertrophy may present with a murmur, but some also have severe congestive heart failure and a high mortality (38,42). In children and adults, HCM may also be a major cause of morbidity and mortality (25,28,32).HCM is characterized by thickening of the ventricular heart muscle peculiar to the ventricular myocardium and not secondary to another defect, such as aortic valve disease or systemic hypertension. There are clinical subcategories, with 25% of human adults having hypertrophic obstructive cardiomyopathy with asymmetric hypertrophy of the interventricular septum. This is usually associated with obstructive flow from the left ventricula...

The effects of aerobic interval training on the left ventricular morphology and function of VLCAD-deficient mice

“…Based on previous reports and the findings of this study we believe that VLCAD deficiency in mice results in CM starting with histological abnormalities (Exil et al 2003) that progress into structural changes, as observed in this study, and eventually into functional changes (Leatherbury et al 2008;Shen et al 2009;Yang et al 1999). Aerobic interval training was well tolerated by VLCAD-/-deficient mice that survived the training, although it appears to cause little or no adaptations in either heart function or heart structure.…”

“…Similar to this study they reported normal %FS values (&50%) for all three genotypes. In contrast to the aforementioned findings, the %FS was previously shown to be significantly depressed in mice with left ventricular hypertrophic cardiomyopathy (Leatherbury et al 2008;Shen et al 2009) and dilated cardiomyopathy (Lee et al 2004) using cardiac measurements from M-mode images. In contrast to the results reported by Exil et al (2003), this study demonstrated that VLCAD-/-had significantly larger LV wall thicknesses and significantly smaller chamber dimensions (see Fig.…”

Imaging modalities to assess structural birth defects in mutant mouse models

“…Thus with the ultrasound biomicroscope, it is possible to quantitatively assess blood flow velocity and obtain other measurements of cardiovascular function using M-mode echocardiogram, color-flow Doppler imaging and pulsed-wave Doppler for blood flow velocity mapping, tissue Doppler imaging, and speckle tracking measurements (Leatherbury et al, 2003;Shen et al, 2005;Momoi et al, 2008;Yu et al, 2008). With speckle tracking, it is possible to quantitatively assess regional myocardial wall motion and obtain measurements of ventricular mechanics (Hu and Clark, 1989;Keller et al, 1996;Tobita and Keller, 1999;Tobita and Keller, 2000;Ishiwata et al, 2003;Leatherbury et al, 2008;Watanabe et al, 2009;Frank et al, 2010).…”

Cell adhesion molecule mediation of myocardial inflammatory responses associated with ventricular pacing

“…EKV imaging provides a higher temporal resolution than B-mode so cardiac wall abnormalities can be assessed. For EKV imaging, the transducer was attached to a fixed arm, and, over 6 min, synchronized electrocardiogram (ECG) signals and B-mode images were acquired and then processed for reconstruction of two-dimensional cine spanning one cardiac cycle (12,15).…”