Downregulation of the Na+-creatine cotransporter in failing human myocardium and in experimental heart failure

Background-The failing myocardium is characterized by depletion of phosphoc reatine and of total creatine content. We hypothesized that this is due to loss of creatine transporter:protein. Methods and Results-Creatine transporter protein was quantified in nonfaili ng and failing human myocardium (explanted hearts with dilated cardiomyopat hy [DCM; n = 8] and healthy donor,hearts [n = 8]) as well as in experimenta l heart failure (residual intact left ventricular tissue, rats 2 months aft er left anterior descending coronary artery ligation [MI; n = 8] of sham op eration [sham; n = 6]) by Western blotting. Total creatine content was dete rmined by high-performance liquid chromatography. Donor and DCM hearts had total creatine contents of 136.4 +/- 6.1 and 68.7 +/- 4.6 nmol/mg protein, respectively (*P < 0.05); creatine transporter protein was 25.4 +/- 2.2 opt ical density units in donor and 17.7 +/- 2.5 in DCM (*P < 0.05). Total crea tine was 87.5 +/- 4.2 nmol/mg protein in sham and 65.7 +/- 4.2 in MI rats ( *P < 0.05); creatine transporter protein was 139.0 +/- 8.7 optical density units in sham and 821 +/- 4.0 in MI (*P < 0.05). Conclusions-Both in human and in experimental heart failure, creatine trans porter protein content is reduced. This mechanism may contribute to the dep letion of creatine compounds and thus to the reduced energy reserve in fail ing myocardium. This finding may have therapeutic implications, suggesting a search for treatment strategies targeted toward creatine transport.