Creatine is a principle component of the creatine kinase (CK) phosphagen system common
to all vertebrates. It is found in excitable cells, such as cardiomyocytes, where it plays an important
role in the buffering and transport of chemical energy to ensure that supply meets the dynamic
demands of the heart. Multiple components of the CK system, including intracellular creatine levels,
are reduced in heart failure, while ischaemia and hypoxia represent acute crises of energy provision.
Elevation of myocardial creatine levels has therefore been suggested as potentially beneficial, however, achieving this
goal is not trivial. This mini-review outlines the evidence in support of creatine elevation and critically examines the
pharmacological approaches that are currently available. In particular, dietary creatine-supplementation does not
sufficiently elevate creatine levels in the heart due to subsequent down-regulation of the plasma membrane creatine
transporter (CrT). Attempts to increase passive diffusion and bypass the CrT, e.g. via creatine esters, have yet to be tested
in the heart. However, studies in mice with genetic overexpression of the CrT demonstrate proof-of-principle that elevated
creatine protects the heart from ischaemia-reperfusion injury. This suggests activation of the CrT as a major unmet
pharmacological target. However, translation of this finding to the clinic will require a greater understanding of CrT
regulation in health and disease and the development of small molecule activators.