Hypertrophic cardiomyopathy 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

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 2D 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 amongst 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 2D cines indicated the hypertrophy was of the nonobstructive type. Further analysis of heart and body weight ratio confirmed the ultrasound diagnosis of left ventricular hypertrophic (LVH) 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 LVH cardiomyopathy. These findings suggest this mouse line may harbor mutation in a novel gene causing X-linked cardiomyopathy. Page 2 of 48 Copyright Information A novel mouse model of X-linked cardiomyopathy 3