OBJECTIVE We examined whether unloading of the left ventricle with a ventricular assist device (LVAD) can result in normalization of the creatine kinase (CK) abnormalities in the failing human heart. BACKGROUND Left ventricular failure is associated with a decrease of myocardial total CK activity and a fetal shift in CK isoform expression that results in an increase in the cytosolic brain type homodimeric-creatine kinase (CK-B) subunit and decreases of the cytosolic muscle-creatine kinase (CK-M) and CK-mitochondrial (CK-Mt) isoforms. The mechanisms of this abnormality are not known. METHODS Total CK activity and CK protein isoform expression (Western blotting) were examined in 11 patients with end-stage cardiomyopathy. In 7 patients, myocardial tissue was also obtained after 4.1 +/- 1.1 months of left ventricular assist device (LVAD) support. RESULTS Left ventricular unloading produced by LVAD implantation resulted in a 270% +/- 114% increase in total CK activity (p < 0.01) that was associated with a 69% +/- 18% increase in CK-M protein expression (p < 0.01) and a 121% +/- 69% increase in CK-Mt protein expression (p < 0.01), but no significant change in CK-B expression. CONCLUSIONS Systolic and diastolic unloading provided by the LVAD resulted in increases of total CK activity as well as CK-Mt and CK-M protein expression. The failure of CK-B expression to decrease suggests that abnormalities other than increased loading are responsible for the increase in CK-B expression in the failing heart.