Page 52 - ITPS-7-2

INNOSC Theranostics and
Pharmacological Sciences Cardiac metabolism in health and disease

mechanisms through which this regulation occurs, as well obesity, diabetes, DCM, and cardiac ischemia/reperfusion,
as the role of SGLT1 in the heart, are still unknown and exceeding the normal physiological levels. 8-12 In these
were not examined in this study. 31 conditions, cardiomyocyte metabolism shifts to derive over
Regarding ketone bodies, primarily generated within 70% of cardiac energy from mitochondrial FAs, which,
hepatocyte mitochondria during ketogenesis, they serve as despite being a less efficient energy source (having a higher
an alternative fuel source, particularly in states such as fasting, oxygen consumption-to-ATP production ratio compared
8,16-18,20
exercise, pregnancy, and when following low-carbohydrate to glucose and ketone bodies), leads to compromised
38,39
diets. 32,33 Acetoacetate and beta-hydroxybutyrate serve as cardiac function. Conversely, in other cardiac
energy sources, particularly beneficial for the brain and pathological states such as cardiac hypertrophy and heart
heart. While efficient, their contribution to total cardiac failure, the metabolic profile of cardiomyocytes reverses to
energy production under normal physiological conditions predominantly derive ATP from glucose rather than FAs,
is relatively minimal, typically <5%. Despite their offering a more efficient energy source (with a lower oxygen
efficiency, their role in cardiac energy provision remains consumption-to-ATP production ratio compared to
8,16-18,20
5
modest within the broader context of the heart’s energy FA), potentially leading to improved cardiac function.
metabolism. 16,34 However, during specific physiological These observations underscore the difference between
states such as fasting, post-exercise recovery, and pregnancy, mitochondrial FAO and glycolysis in their respective
ketone bodies play a more significant role in cardiac energy oxygen consumption per ATP produced (differences in
8,16-18,20
metabolism. They augment ATP synthesis by maintaining oxygen demands). For instance, complete glucose
oxidized ubiquinone and widening the redox span in the oxidation consumes six oxygen molecules to yield 31 ATP
electron transport chain (ETC). 16,34,35 molecules (Glucose oxidation: O :ATP = 1:5.167), while
2
one palmitate molecule, in full mitochondrial FAO, requires
3. Cardiometabolic alteration in heart 23 oxygen molecules to generate 105 ATP molecules
8,20
diseases (Palmitate: O :ATP = 1:4.565). The comparatively lower
2
ATP production per oxygen molecule consumed in the
The shift in cardiac substrate utilization for ATP production mitochondrial FAO system elucidates why heightened
to sustain cardiac contractile function signifies a notable mitochondrial FAO diminishes cardiac efficiency. 8,20
change in the heart’s biological activity, often linked to
various heart diseases. 8,19-21 Recent evidence supports 4. The reciprocal alteration of metabolism
two distinct concepts indicating that metabolic changes under the “Randle cycle” concept
occurring in heart diseases result from alterations in the
primary substrates utilized for ATP generation within Randle et al. demonstrated that elevated mitochondrial
diseased cardiomyocytes. FAO disrupts mitochondrial glucose oxidation,
establishing a reciprocal relationship between the two
The first concept involves a shift from mitochondrial metabolic pathways. This reciprocal interaction is
11
FA utilization (via FAO) to alternative energy sources such articulated in the widely recognized “Randle cycle” or
as glucose and potentially other substrates such as ketone “glucose-FA cycle”. According to the “Randle cycle,”
11
bodies, notably observed in cardiac hypertrophy and heart heightened mitochondrial FAO can impede both glycolysis
failure. This transition also includes an observed increase and mitochondrial glucose oxidation through several
5-7
in ketone body utilization. While ketone bodies enhance mechanisms: (i) increased mitochondrial FAO enhances
36
cardiac metabolism by facilitating ATP synthesis through nicotinamide adenine dinucleotide and acetyl CoA
the maintenance of oxidized ubiquinone and extending the production, thereby inhibiting pyruvate dehydrogenase
redox span in the ETC, 16,34,35 their oxidation concurrently (PDH) activity; 38,39 (ii) elevated citrate levels resulting
elevates reactive oxygen species production, contributing to from increased FAO can inhibit phosphofructokinase 1
oxidative stress. Despite increased hepatic ketogenesis in (PFK1) activity; and (iii) elevated glucose-6-phosphate
35
pathological heart conditions or metabolic disorders such as levels can inhibit hexokinase enzymes in glycolysis
hormone resistance and diabetes mellitus (DM), 32,33 ketone oxidation. 10,20 These mechanisms collectively contribute
body metabolism remains a contributor to heightened ATP to the suppression of glycolysis and glucose oxidation.
23
production. 16,34,35 However, this process is also associated Conversely, reducing mitochondrial FAO levels can lead to
with acidosis and increased oxidative stress, potentially an upsurge in glycolysis and glucose oxidation. 23
resulting in a redox imbalance, 35,37 subsequently elevating
the morbidity and mortality risk among patients. 37 5. Cardiac metabolism in obesity and diabetes
The second concept revolves around the heightened In obesity and DM, elevated levels of circulating FAs
utilization of mitochondrial FAs in pathological states such as and/or glucose, alongside hormonal resistance, including

Volume 7 Issue 2 (2024) 3 doi: 10.36922/itps.2302