Page 243 - Read Online

Martínez et al. Cardiomyocyte energetic changes in ischemia and arrythmogenesis

heparin or TAG infusions has been reported to result myocardium can prevent or diminish tissue damage
in a 26% increase in oxygen consumption without and dysfunction under conditions of ischemia or
changes in mechanical capacity of the left ventricle [74] , reperfusion, diabetic cardiomyopathy, and AMI. This
which suggests a greater functional capacity for this occurs because the heart shifts towards glucose as
chamber when utilizing glucose [75] . This may be due the main source for ATP synthesis, which reduces
to the higher level of oxidative stress caused by the the oxygen demand by 11%-13% and therefore
oxidation of FA in comparison with carbohydrates, improves cardiac efficiency and protects mitochondrial
due to the increased oxygen consumption rate in the function [43,86] . Nonetheless, the real benefits of this
former [76] . partial inhibition remain uncertain when contemplating
the potential consequences of excessive lipid
The ATP synthesis/oxygen consumption rates accumulation within cardiomyocytes [86] .
for glucose and lactic acid are 3.17 and 3.00,
respectively; whereas they are 2.80 and 2.86 for ARRHYTHMOGENIC METABOLIC
palmitate and oleate, respectively. Although these CHANGES DURING MYOCARDIAL
are theoretical values which may be lower in vivo as
a consequence of the constant proton efflux through ISCHEMIA
the mitochondrial membrane, the differences between
substrates remain substantial [77] . For example, when Cardiac sudden death is responsible for approximately
comparing palmitate with glucose, the complete half of all cardiovascular mortality [87] . The majority of
oxidation of 1 molecule of palmitate yields 105 ATP these are attributed to ventricular tachyarrhythmias
molecules and requires 46 oxygen atoms, while 1 (ventricular tachycardia, ventricular fibrillation), which
molecule of glucose generates 31 ATP molecules are frequently caused by myocardial ischemia [88] .
and uses 12 oxygen atoms. Thus, despite FA The mechanisms through which myocardial ischemia
clearly yielding greater amount of ATP, this occurs leads to local electrophysiological disorders and
at the expense of larger oxygen requirements [39] . arrhythmogenesis have been extensively explored
Furthermore, β-oxidation of FA generates more lipid [Figure 3] [2,89] .
peroxidation due to increased delivery of NADH and
FADH2 to the electron transport chain and production Severe metabolic changes begin a few seconds after
of superoxide anion [78] . coronary occlusion: high-energy phosphates are
hydrolyzed, intracellular pH lowers as a consequence
In addition, elevated free FA are harmful in the of the activation of anaerobic glycolysis, and
ischemic myocardium, augmenting cell damage. In extracellular potassium levels increase [90,91] . The latter
the first hours of an acute myocardial infarction (AMI), lasts for roughly 10 min, during which the resting
free FA can act as detergents on the cell membrane membrane potential decreases, approaching the
of cardiomyocytes [79-81] . Moreover, there is increased firing threshold potential, thus accelerating electrical
generation of free radicals, which can inactivate IRS-1 conduction [92] . The intracellular acidosis also drives
via phosphorylation of serine residues. This directly an increase in cytosolic calcium, facilitating early and
promotes insulin resistance and simultaneously late depolarization, as well as spatial and temporal
stimulates the release of proinflammatory cytokines, fluctuations in the duration of action potentials [93] .
such as TNF-α and IL-6 [82] . Therefore, all conditions Additionally, ischemia leads to dephosphorylation
of metabolic inefficiency in the heart favor insulin- of connexin-43 in gap junctions, which impairs
mediated left ventricular remodeling and diastolic intercellular electrical coupling and anisotropy [94] .
myocardial dysfunction [83] . Lastly, sympathetic stimulation not only promotes
calcium release from the sarcoplasmic reticulum, but
Considering this, various systemic conditions such it also prompts lipolysis, elevating circulating free FA
as obesity cause elevated serum free FA which levels and therefore predisposing to ischemia-induced
can potentiate β-oxidation, and thus increase lipid arrhythmogenesis [95] .
traffic in cardiomyocytes, prompting a phenomenon
termed lipotoxicity [13,84] . This process can lead the cell Other possible mediators of cardiac arrhythmia
towards contractile dysfunction, insulin resistance and include thrombin and endothelin-1. Patients with ST-
ultimately apoptosis in association with accumulation elevation myocardial infarction (STEMI) complicated
of ceramides [85] . with ventricular fibrillation have been found to
have higher levels of thrombin activity markers [96] .
On the other hand, pre-clinical and clinical evidence The production of thrombin at sites of coronary
suggests partial inhibition of free FA oxidation in the occlusion has been suggested to favor accumulation

Vessel Plus ¦ Volume 1 ¦ December 28, 2017 235