Thyroid hormone (TH) is critical for cardiac development and heart function. In 
heart disease, TH metabolism is abnormal, and many biochemical and functional 
alterations mirror hypothyroidism. Although TH therapy has been advocated for 
treating heart disease, a clear benefit of TH has yet to be established, 
possibly because of peripheral actions of TH. To assess the potential efficacy 
of TH in treating heart disease, type 2 deiodinase (D2), which converts the 
prohormone thyroxine to active triiodothyronine (T3), was expressed transiently 
in mouse hearts by using the tetracycline transactivator system. Increased 
cardiac D2 activity led to elevated cardiac T3 levels and to enhanced myocardial 
contractility, accompanied by increased Ca(2+) transients and sarcoplasmic 
reticulum (SR) Ca(2+) uptake. These phenotypic changes were associated with 
up-regulation of sarco(endo)plasmic reticulum calcium ATPase (SERCA) 2a 
expression as well as decreased Na(+)/Ca(2+) exchanger, beta-myosin heavy chain, 
and sarcolipin (SLN) expression. In pressure overload, targeted increases in D2 
activity could not block hypertrophy but could completely prevent impaired 
contractility and SR Ca(2+) cycling as well as altered expression patterns of 
SERCA2a, SLN, and other markers of pathological hypertrophy. Our results 
establish that elevated D2 activity in the heart increases T3 levels and 
enhances cardiac contractile function while preventing deterioration of cardiac 
function and altered gene expression after pressure overload.