Novel strategies in the treatment of heart failure include mechanical unloading with a left ventricular assist device. Although first considered as a bridge to cardiac transplantation, this surgical treatment may improve cardiac function in patients with heart failure, even after removal of the device. The molecular adaptation of the heart to unloading remains largely unknown. Most of the enzymes involved in the regulation of myocardial energetics (including contractile proteins, ion pumps, and metabolic enzymes)exist in "fetal" and "adult" isoforms. It is known that cardiac hypertrophy due to increased work load in vivo involves a switching from the normally expressed adult isoform to the fetal isoform. Our work has now shown that the same pattern occurs in the unloaded heart. In both conditions, this switching is accompanied by the reexpression of growth factors and proto-oncogenes. The functional improvement of the failing heart after mechanical unloading may in part be the result of a reexpression of fetal genes.