Cardiac involvement in creatine-transporter deficiency: a metabolic, functional and structural study

It is common belief that being able to increase creatine levels in heart diseases could provide beneficial effects; however, dietary creatine supplementation failed to achieve this result, probably due to the downregulation of the specific creatine transporter. Thus, to clarify the behaviour of this phenomena, it is essential to fully understand the role of creatine in cardiac metabolism. In this regard, the present thesis focuses on the effects related to the absence of creatine. Creatine deficiency syndromes consist of rare inborn errors that primarily affect the nervous system, resulting either from the alteration of creatine transporter or the dysfunction of creatine biosynthesis. Subjects with creatine deficiency syndrome usually show evident symptoms reflecting the derangement of the higher-order neurological functions. On the other hand, cardiac involvement is described only in few cases of creatine transporter deficiency, too few to shed light to the potential cardiac injury derived from the absence of creatine. In this thesis, a comprehensive clinical evaluation was performed in subjects with this syndrome, and in a transgenic murine model with creatine transporter deficiency. The results reveal that deficiency of creatine transporter is associated with cardiac electrical modifications, whereas deficiency of one of the two enzyme involved in creatine biosynthesis is associated with an activation of the neurohormonal profile and early structural alterations. Murine model experiments demonstrate similar findings and allow to partially disclose the molecular mechanisms underlying the cardiac phenotype associated with deficiency of creatine transporter.