Although aberrant reactivation of embryonic gene programs is intricately linked 
to pathological heart disease, the transcription factors driving these gene 
programs remain ill-defined. Here we report that increased calcineurin/Nfat 
signalling and decreased miR-25 expression integrate to re-express the basic 
helix-loop-helix (bHLH) transcription factor dHAND (also known as Hand2) in the 
diseased human and mouse myocardium. In line, mutant mice overexpressing Hand2 
in otherwise healthy heart muscle cells developed a phenotype of pathological 
hypertrophy. Conversely, conditional gene-targeted Hand2 mice demonstrated a 
marked resistance to pressure-overload-induced hypertrophy, fibrosis, 
ventricular dysfunction and induction of a fetal gene program. Furthermore, in 
vivo inhibition of miR-25 by a specific antagomir evoked spontaneous cardiac 
dysfunction and sensitized the murine myocardium to heart failure in a 
Hand2-dependent manner. Our results reveal that signalling cascades integrate 
with microRNAs to induce the expression of the bHLH transcription factor Hand2 
in the postnatal mammalian myocardium with impact on embryonic gene programs in 
heart failure.