The profound effects of thyroid hormone (TH) on heart development and function 
are mediated by the thyroid hormone receptors (TR) alpha(1) and beta(1). While 
numerous patients with TRbeta(1) mutations have been identified, patients with 
similar mutations in TRalpha(1) are yet to be discovered. Recently generated 
heterozygous mice with a dominant negative mutation in TRalpha(1) (TRalpha(1)+/m 
mice) have normal TH levels, which may have hampered the discovery of patients 
with such mutations. We now measure intracellular Ca(2+) and contraction in 
cardiomyocytes isolated from TRalpha(1)+/m mice and wildtype littermates (WT). 
TRalpha(1)+/m cardiomyocytes showed a phenotype similar to that in 
hypothyroidism with significant slowing of voltage-activated Ca(2+) transients 
and contractions. Increased stimulation frequency (from 0.5 to 3 Hz) or 
beta-adrenergic stimulation reduced the differences between TRalpha(1)+/m and WT 
cardiomyocytes. However, in TRalpha(1)+/m cells stimulation at 3 Hz gave a 
marked increase in diastolic Ca(2+) and beta-adrenergic stimulation triggered 
spontaneous Ca(2+) release events during relaxation. Both TRalpha(1)+/m and WT 
cardiomyocytes responded to TH treatment by displaying a "hyperthyroid" 
phenotype with faster and larger Ca(2+) transients and contractions. Excised 
TRalpha(1)+/m hearts showed an increased expression of phospholamban (PLB). In 
conclusion, isolated TRalpha(1)+/m cardiomyocytes display major dysfunctions 
with marked slowing of the Ca(2+) transients and contractions.