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Martínez et al. Cardiomyocyte energetic changes in ischemia and arrythmogenesis

highly ATP-dependent processes, the demand for and transphophorylated by mi-CK to PC and
these metabolites in cardiomyocytes is very high, ADP, with the latter being immediately available
with the heart requiring approximately 20 times its for oxidative phosphorylation, stimulating cellular
weight in ATP per day in order to sustain its energetic respiration [55] . Another isoform of CK is associated
demands [53] . After synthesis, ATP must be transported with myofilaments, acting as a structural protein within
from the mitochondria to the myofilaments and M-bands, which is functionally coupled to the myosin
membrane proton pumps, a process in which the ATPase and can transfer phosphate from PC to ATP,
phosphocreatine-creatine kinase system intervenes providing sufficient energy for maintaining maximum
substantially [54] . contractility [61] .

Creatine kinase (CK) is a key enzyme for phosphate In a healthy heart, approximately two thirds of all
transference in cells with high energetic demand, creatine is phosphorylated by CK to yield PC. In
and works in harmony with other enzymatic heart failure, the level of PC is lower in relation to
machinery in order to facilitate intracellular energetic the concentrations of ATP, with a lower PC/ATP
communication [55] . CK synthesizes phosphocreatine index [62] . Lower values of this index have been
(PC) from creatine and a phosphate group from ATP related to increased mortality [63] . Human and animal
in a reversible reaction, acting as a functional ATP models have demonstrated a progressive reduction
reserve. CK associated with myofilaments catalyzes in the creatine pool of up to 60% in patients with
the transference of the phosphate from PC towards heart failure, with a directly proportional relationship
adenosine diphosphate (ADP), replenishing ATP between the decrease of the index and the severity of
in ATPase active sites, such as myosin heads. In the condition [64] .
cardiomyocytes, CK isoenzymes and the highly
diffusible PC are responsible for sustaining the Fatty acids vs. glucose as energetic
transference of energy from producing centers substrates
(mitochondria and glycolysis) towards ATP-consuming The selection of energetic substrates in cardiomyocytes
sites (myofilaments and ATPase pumps) [15] . is a fundamental step for the constant generation
of ATP which depends on the dynamic metabolic
The PC-CK system represents the first line of milieu in each body at a given time [65] . This flexibility
energetic reserves in cardiomyocytes, providing a is present during fetal development; however, after
quick source of ATP and favoring its transportation birth, FA becomes the preferential substrates, due
to its utilization sites, especially myofilaments [56] . In to the increased availability of oxygen and dietary
animal models, disruptions in the PC-CK system fats [66-68] . Infants with mutations in genes involved in
have been linked to impaired myocardial contractility FA metabolism have been documented to develop
and increased risk for arrhythmias [57,58] . Moreover, cardiomyopathy when under stress, highlighting the
alterations in the functionality of CK have been essential role of FA in this tissue [66] . Likewise, in heart
identified as an independent risk factor for heart failure and left ventricular hypertrophy (when the
failure [59] . oxidative capacity of mitochondria in cardiomyocytes
is diminished), there is a shift towards a predominance
CK is composed of dimers, which consist of subunits for glucose metabolism [69,70] .
M and B, and originate three isoenzymes: CK-
MM, -MB and -BB. A fourth isoenzyme is found in FA are known to be the main source of energy in
mitochondria (mi-CK) and accounts for 20%-40% cardiomyocytes when the heart is at rest and during
of all CK activity in the heart [60] . CK is not evenly fasting periods: most of the acetyl CoA that enters the
distributed within the cell, and is rather a part of a TCA cycle (60%-90%) originates in the β-oxidation of
compartmentalized metabolic pathway, bound to free FA [13] , while the remaining 10%-40% is produced
myofilaments and the sarcoplasmic reticulum to by oxidation of pyruvate, which derives from the
form functional complexes which accelerate ATP oxidation of glucose or lactic acid [71] . Several reports
synthesis [61] . have shown that cardiac efficiency, in terms of oxygen
consumption, is greater when oxidizing glucose and
The mi-CK isoform is coupled to the external surface lactate rather than FA [72] . Studies using ranolazine -
of the internal mitochondrial membrane, near the ATP- an inhibitor of β-oxidation which induces oxidation of
ADP translocases, also termed adenine nucleotide carbohydrates - have found enhanced left ventricular
translocases (ANT). During oxidative phosphorylation, function and improved metabolic efficiency when
the ATP generated in the mitochondrial matrix utilizing glucose as the main energetic substrate [73] .
is exported by ANT to the intermembrane space Similarly, potentiating FA use in the heart with

234 Vessel Plus ¦ Volume 1 ¦ December 28, 2017