Heterozygous mice bearing an Arg403Gln missense mutation in the alpha cardiac 
myosin heavy chain gene (alpha-MHC403/+) exhibit the histopathologic features of 
human familial hypertrophic cardiomyopathy. Surprisingly, homozygous 
alpha-MHC403/403 mice die by postnatal day 8. Here we report that neonatal 
lethality is caused by a fulminant dilated cardiomyopathy characterized by 
myocyte dysfunction and loss. Heart tissues from neonatal wild-type and 
alpha-MHC403/403 mice demonstrate equivalent switching of MHC isoforms; alpha 
isoforms in each increase from 30% at birth to 70% by day 6. Cardiac dimensions 
and function, studied for the first time in neonatal mice by high frequency (45 
MHz) echocardiography, were normal at birth. Between days 4 and 6, 
alpha-MHC403/403 mice developed a rapidly progressive cardiomyopathy with left 
ventricular dilation, wall thinning, and reduced systolic contraction. 
Histopathology revealed myocardial necrosis with dystrophic calcification. 
Electron microscopy showed normal architecture intermixed with focal 
myofibrillar disarray. We conclude that 45-MHz echocardiography is an excellent 
tool for assessing cardiac physiology in neonatal mice and that the 
concentration of Gln403 alpha cardiac MHC in myocytes influences both cell 
function and cell viability. We speculate that variable incorporation of mutant 
and normal MHC into sarcomeres of heterozygotes may account for focal myocyte 
death in familial hypertrophic cardiomyopathy.