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INNOSC Theranostics and
Pharmacological Sciences Cardiac metabolism in health and disease

(ATP) in healthy adult human hearts. Typically, around disorders and heart diseases. In addition, it examines
1,2
70% of the heart’s total ATP is derived from FA β-oxidation influential factors affecting cardiac metabolisms, such as
(FAO) under normal physiological conditions. Studies oxygen demand, myocardial substrate metabolism, cardiac
3,4
have indicated that heart diseases trigger changes in cellular mitochondrial performance, and energetics in health,
mechanisms and metabolic regulations, leading to alterations metabolic disorders, and heart diseases.
in cellular morphology and damage to cellular structures.
Considering the heart’s high-energy demanding function, 2. Cardiac metabolism in health
especially during contractions, metabolic control within the The heart, with its high energy demands but limited energy
heart is of utmost importance for sustaining its high energy reserves, heavily relies on specific substrates for myocardial
requirements. However, under pathological conditions, energy metabolism. In a normal, healthy human heart,
3,4
the primary energy source in the cardiac metabolic pathway approximately 70% of ATP is derived from FAs, with
can undergo alterations, resulting in varied major energy glucose contributing about 25% and the remaining 5%
sources among different types of heart diseases. originating from alternate substrates such as ketone bodies

Currently, several concepts attempt to elucidate and pyruvate. 3,4,8,16-19 Transport mechanisms for FAs into
these metabolic changes in heart diseases. First, there the heart vary; short-chain and medium-chain FAs utilize
is the observed shift from utilizing mitochondrial FAO passive diffusion, while long-chain FAs rely on plasma
to glycolysis and/or ketone bodies, documented in membrane-bound FA binding proteins (FABP) and FA
5-7
cardiac hypertrophy and heart failure. Second, there transport proteins. 8,20-22 Subsequently, the acyl-coenzyme
is an elevated utilization of mitochondrial FAO, beyond A (CoA) group is added to FAs before their entry into
normal physiological levels, noted in conditions such mitochondria through specific transporters. Carnitine
as obesity, diabetes, diabetic cardiomyopathy (DCM), palmitoyltransferase-1 (CPT-1), a crucial enzyme located
and cardiac ischemia/reperfusion injury. 8-12 Various on the outer mitochondrial membrane (OMM), acts as a
conditions, such as obesity, diabetes, and heart diseases, rate-limiting step in this process, converting long-chain
disrupt this equilibrium, leading to alterations in energy fatty acyl CoA to carnitine forms for mitochondrial entry,
utilization, substrate preferences, and cellular metabolism where they are reconverted back to fatty acyl CoA for
8,20
within cardiac tissues. These disruptions often manifest FAO. Key regulators of FA transporters include factors
3,4
as changes in the utilization of primary energy sources, such as acetyl CoA carboxylase, malonyl CoA, malonyl
such as FA, glucose, and ketone bodies. In healthy states, CoA decarboxylase, and other enzymes, exerting direct
the heart predominantly relies on FAO to meet its energy and indirect effects on CPT-1 activity. 23-25
demands. However, under pathological conditions, such as In contrast, glucose, which contributes approximately
heart failure or DCM, this preference may shift, leading to 25% of total ATP in the basal state, cannot pass through the
an increased reliance on glucose or alternative substrates. 8-12 cell membrane by simple diffusion due to its hydrophilic
Moreover, hormonal imbalances, mitochondrial nature. The human heart employs two classes of glucose
dysfunction, and alterations in enzyme activity further transporters, namely glucose transporters (GLUTs) and
26
compound these pathological changes, impacting the sodium-glucose co-transporters (SGLTs). GLUT1,
heart’s ability to generate sufficient energy for its functions. GLUT2, and GLUT4 are three identified isoforms, with
This dysregulation not only affects energy production but GLUT4 taking precedence in adult hearts, responsible
also influences cardiac contractility, efficiency, and overall for approximately 70% of glucose transport after birth. 27,28
performance. 13-15 GLUT1 serves as a basal cardiac glucose transporter
primarily responsible for embryonic cardiac glucose
Understanding these intricate regulatory pathways transport. However, after birth, there is a rapid transition
and the factors influencing cardiac metabolism in health to utilizing GLUT4 for transporting glucose, which
and disease is pivotal for developing targeted therapies. contributes to approximately 70% of glucose transport in
By elucidating the underlying molecular mechanisms, the adult heart. Insulin mediates GLUT4 translocation in
29
identifying genetic predispositions, and uncovering the cardiomyocytes, while SGLT1, abundantly expressed in the
complex network of metabolic alterations, researchers heart, is regulated by insulin and leptin, though its exact
strive to refine therapeutic strategies. Ultimately, the goal role remains unclear. A previous study demonstrated that
19
is to mitigate the impact of metabolic disorders on heart SGLT1 is an abundantly expressed isoform in the human
health and improve the efficacy of treatments for various heart, with expression levels approximately 10-fold higher
cardiac conditions. than those in the kidney. Surprisingly, another study
30
This review focuses on elucidating metabolic regulation demonstrated that cardiac SGLT1 expression and activity
in healthy hearts and adaptive mechanisms in metabolic are regulated by insulin and leptin. However, the crucial
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Volume 7 Issue 2 (2024) 2 doi: 10.36922/itps.2302