Extrapolation from mouse to man.

Despite the above caveat, the impressive new technology described by Gupta et al1 in this issue of Circulation: Cardiovascular Imaging should help to resolve a number of issues relative to the hypothesis that the failing heart is energy starved and that depressed high-energy phosphate flux through the creatine kinase (CK) system is a causative factor.2,3 It will allow longitudinal measurements of CK kinetics during the progression to failure in wild-type and transgenic mice with systematically varied amounts of each component of the CK system. Despite years of research, the importance of the several CK isoforms in myocardial bioenergetics is not clear. CK substrates (total creatine, total adenylates) and enzyme activity typically are depressed in heart failure in both murine and human hearts, contributing to the hypothesis that the failing heart is energy starved. However, knockout of myofibrillar (MM) CK and of both MM and sarcomeric mitochondrial CK isoform has surprisingly little effect: Animals are viable, and cardiac function is relatively normal. Thus, there is no obligatory creatine phosphate (PCr) shuttle where high-energy phosphates generated by mitochondrial oxidative phosphorylation must be transported to the myofibrils by way of PCr. Nevertheless, the evolutionary preservation of the complex myocardial CK system speaks to its importance, and the correlation between derangements in this system and contractile dysfunction is intriguing.