BACKGROUND: The cardiac sodium-calcium exchanger (NCX1) is a key sarcolemmal 
protein for the maintenance of calcium homeostasis in the heart. Because heart 
failure is associated with increased expression of NCX1, heterozygous (HET) and 
homozygous (HOM) transgenic mice overexpressing NCX1 were developed and 
evaluated.
METHODS AND RESULTS: The NCX1 transgenic mice display 2.3-fold (HET) and 
3.1-fold (HOM) increases in exchanger activity from wild-type (WT) mice. 
Functional information was obtained by echocardiography and catheterizations 
before and after hemodynamic stress from pregnancy, treadmill exercise or 
transaortic constriction (TAC). HET and HOM mice exhibited hypertrophy and 
blunted responses with beta-adrenergic stimulation. Postpartum mice from all 
groups were hypertrophied, but only the HOM mice exhibited premature death from 
heart failure. HOM mice became exercise intolerant after 6 weeks of daily 
treadmill running. After 21 days TAC, HET, and HOM mice exhibited significant 
contractile dysfunction and 15% to 40% mortality with clinical evidence of heart 
failure.
CONCLUSIONS: Hemodynamic stress results in a compensated hypertrophy in WT mice, 
but NCX1 transgenic mice exhibit decreased contractile function and heart 
failure in proportion to their level of NCX1 expression. Thus exchanger 
overexpression in mice leads to abnormal calcium handling and a decompensatory 
transition to heart failure with stress.