Creatine deficiency and heart failure

Abstract

Impaired cardiac energy metabolism has been proposed as a mechanism common to different heart failure aetiologies. The energy-depletion hypothesis was pursued by several researchers, and is still a topic of considerable interest. Unlike most organs, in the heart, the creatine kinase system represents a major component of the metabolic machinery, as it functions as an energy shuttle between mitochondria and cytosol. In heart failure, the decrease in creatine level anticipates the reduction in adenosine triphosphate, and the degree of myocardial phosphocreatine/adenosine triphosphate ratio reduction correlates with disease severity, contractile dysfunction, and myocardial structural remodelling. However, it remains to be elucidated whether an impairment of phosphocreatine buffer activity contributes to the pathophysiology of heart failure and whether correcting this energy deficit might prove beneficial. The effects of creatine deficiency and the potential utility of creatine supplementation have been investigated in experimental and clinical models, showing controversial findings. The goal of this article is to provide a comprehensive overview on the role of creatine in cardiac energy metabolism, the assessment and clinical value of creatine deficiency in heart failure, and the possible options for the specific metabolic therapy.

Keywords: Cardiac energy metabolism; Creatine; Creatine deficiency; Heart failure.

Fig. 1

Role of creatine in the cardiomyocyte. A specific carrier (CrT) mediates creatine (Cr) uptake from bloodstream into cardiomyocytes. Cr links adenosine triphosphate (ATP) production site to energy utilization sites, like myofibrils and ion pumps. Phosphocreatine (PCr) acts as a highly mobile and short-term energy store. After releasing the phosphate group to generate ATP thanks to the cytosolic creatine kinases (CK) closely coupled to ATPases, free Cr diffuses back to request further ATP production. β-FAO beta fatty acid oxidation, FATP1 fatty acid transport protein 1, FFA free fatty acid, GLUT4 glucose transporter type 4, PiC mitochondrial phosphate carrier, TCA tricarboxylic acid

Fig. 2

Creatine biosynthesis. Creatine 2-step biosynthesis: the transfer of an amidino group from arginine to glycine, catalysed by L-arginine:glycine amidinotransferase (AGAT), yields the guanidinoacetate (GA); GA is converted into Cr via the enzyme S-adenosyl-L-methionine:guanidinoacetate N-methyltransferase (GAMT). The first step occurs in the kidney, the second in the liver. Cr and phosphocreatine (PCr), together with creatine kinase (CK), constitute an energy shuttle system. Cr degrades into creatinine, excreted by the kidney

Fig. 3

31P magnetic resonance spectroscopy (MRS) cardiac evaluation. Characteristic cardiac 31P MRS spectra in A a healthy and B failing heart. In the pathological condition, PCr concentration and CK flux are reduced