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Martínez et al. Cardiomyocyte energetic changes in ischemia and arrythmogenesis

arrhythmia remain unclear, yet various alternatives drugs for rapid inhibition of lipolysis would yield better
have been proposed [111] . During an infarction, results, yet research efforts in this line remain scarce
numerous events develop in parallel, with some and poor.
of the earliest being precordial pain and increased
sympathetic activity [112] . Although a moderate increase Quick myocardial FA availability has been closely
in catecholamines may aid in maintaining cardiac related with epicardial adipose tissue (EAT) or
contractility in the face of oxygen depletion, excessive the epicardial fat pad which is found between the
signaling can augment the energetic demands of the myocardium and the visceral pericardium. This isin
myocardium, impairing functionality [113] . close proximity with the coronary arteries and so
facilitates the activity of anti-inflammatory and pro-
It has been proposed that for the ischemic cardiomyocyte, inflammatory adipokines and FA in the myocardium
glucose metabolism is more beneficial, and FA and arterial walls [124,125] . The Framingham Heart
metabolism is deleterious [114] . However, FA availability Study [126] has identified the EAT volume as a predictor
is much greater: catecholamines induce lipolysis in of atrial fibrillation - the most frequent arrhythmia in
adipose tissue, abruptly rising circulating FA levels [115] , clinical practice - independent of other methods for
and inhibit insulin signaling, reducing glucose entry the measurement of adiposity such as the body mass
into the myocardium [116] . Likewise, FA can inhibit index. Other studies have reported the EAT volume
glucose oxidation and potentiate oxygen consumption to be associated with the prevalence and severity of
in ischemic myocardial areas, leading to a preferential atrial fibrillation [127] .
utilization of FA over glucose during ischemia [117] .
The EAT has also been found to release pro-
The mechanisms underlying FA-related toxicity inflammatory messengers such as activin A, which
appear to be fundamentally linked with adrenergic induces the expression of the transforming growth
stimulation [118] . However, FA also exhibit direct factor β1 (TGF-β1) and several metalloproteinases.
arrhythmogenic activity. Even without ischemia, a These are key regulators in the homeostasis of
sufficiently high free FA/albumin molar rate can inhibit the extracellular matrix - in particular by modifying
β-oxidation, leading to accumulation of acyl-carnitine collagen fibers - and mediate the profibrotic effect
and acyl-CoA in the cytosol. In turn, acyl-carnitine of EAT in the atrial myocardium [128] . Many other
++
inhibits Ca pumps in the sarcoplasmic reticulum, inflammatory mediators secreted by EAT also
+
+
++
as well as the Na /Ca exchanger and the Na /K intervene in the pathogenesis of atrial fibrillation,
+
++
ATPase pump, finalizing in an overload of Ca in the including TNF-α, IL-8, and the monocyte chemotactic
[129]
cytosol [119] . protein 1 (MCP-1) .
Furthermore, other metabolic processes activated Finally, increased EAT has been associated with fatty
upon elevation of free FA levels, such as membrane infiltration in the myocardium, which contributes to
lipid peroxidation, inhibition of β-oxidation, uncoupling tissue disorganization and promotes an arrhythmia-
[130]
of proteins in the mitochondrial respiratory chain, prone environment . At the same time, these
+
accumulation of CoA derivates and extracellular K deposits favor the proliferation of myofibroblasts and
[130]
with shortening of action potentials, are all harmful increase the amount of dystrophic cardiomyocytes .
for the ischemic cardiomyocyte [120] . On this basis, In this context, the EAT has been proposed as
strong arguments propose the reduction of circulating a novel therapeutic target in the management of
[125]
free FA as a therapeutic measure in AMI, although cardiovascular disease .
further evidence is required to encourage this
practice. Regarding instrumentation, the glucose- CONCLUSION
insulin-potassium (GIK) infusion is a well-known
and viable alternative, as it promotes glucose entry The cardiomyocyte is the protagonist cell in the heart
into the myocardium and inhibits lipolysis, with the which allows it to function as a pump. This capacity
metabolic benefits this implies in cardiomyocytes [121] . requires strict electrophysiological and mechanical
Despite early clinical trials failing to demonstrate control and large amounts of ATP. These energetic
the utility of GIK at decreasing sudden death during demands are covered by a dynamic selection
the first 3 days following an AMI [122] , more recent of substrates, shifting between carbohydrates
reports, such as the IMMEDIATE study have shown and FA depending on various intracellular and
better outcomes at a 1-year follow-up: in patients systemic circumstances. Myocardial metabolism
with STEMI, 1-year mortality and hospitalizations for has been historically described as the “lost child of
heart failure decreased significantly [123] . Theoretically, cardiology” [131] , as clinicians have rather focused on

Vessel Plus ¦ Volume 1 ¦ December 28, 2017 237