ENERGY METABOLISM OF THE

HEART

FLORENCE RAJARETNAM M.Sc., M.Phil

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Introduction
The heart has the largest metabolic demands per
gram of any organ in the body.
Adequate amounts of chemical fuel, namely adenosine
triphosphate (ATP), must be generated to support the
hearts contractile demands .
Fatty acids, ketone bodies, and carbohydrates are the
primary substrates of the heart metabolized to generate
ATP.
Optimal cardiac function depends on the efficient
matching of energy generation pathways to energy
expenditure.

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This balance requires the close communication and
regulation of various metabolic pathways.

Under normal conditions, a minimum of 60% of the

ATP is derived from oxidation of free fatty acids (FFA)
and the rest from oxidation of glucose (Figure 1).

Fatty acids are the major source of acetyl coenzyme A

for the Krebs cycle and of the oxidative production of
ATP.

Glycolysis converts glucose to pyruvate and provides

a relatively small amount of ATP to the normal adult
heart.
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 Specifity of cardiac metabolism
Mitochondrial respiration produces more than
90% of energy.

Mitochondria occupy ~30% of cardiomyocyte

space.

>95% of ATP formation comes from oxidative

phosphorylation in mitochondria.

~ 60-70% of ATP hydrolysis is used for muscle

contraction, ~30 - 40% for the sarcoplasmic
reticulum (SR) Ca2+-ATPase and other ion pumps.
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 In the healthy heart the rate of oxidative
phosphorylation is exquisitely linked to the rate of ATP
hydrolysis so that ATP content remains constant even
with large increases in cardiac power.

Under normal conditions there is a complete ATP

turnover of the myocardial pool approximately every
10 seconds .

Under basal aerobic conditions, 60% of energy comes

from FFA and triglycerides, 35% from carbohydrates,
5% from amino acids and ketone bodies.

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SUBSTRATES FOR ATP SYNTHESIS
There are 3 main types of carbon substrates for
myocardial ATP synthesis:
fatty acids, carbohydrates, and ketone bodies .

FATTY ACID- BETA-OXIDATION

Fatty acids are the predominant substrate used in
the heart and generate the most ATP.
The energy outcome of complete oxidation of 1 mol
palmitate is 7 mol FADH, 7 mol NADH, and 8 mol
acetyl-CoA, which ultimately results in approximately
129 mol ATP following Krebs cycle and electron
transport metababolism

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FFA enter the cardiomyocyte by:
passive diffusion
protein-mediated transport across sarcolema
fatty acid translocase (FAT) or plasma membrane
fatty acid binding protein (FABPpm).
Fatty acyl-CoA synthase (FACS) activates
nonesterified FA by esterification to fatty acyl-
CoA.

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Long chain fatty acyl-CoA can be:
esterified to triglyceride (glycerolphosphate
acyltransferase) intracardiac triglyceride pool
(10-30% of FA)
Or
converted to long chain fatty acylcarnitine by
carnitine palmitoyltransferase-I (CPT-I) between
inner and outer mitochondria membranes.

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Carnitine acyltranslocase (CAT) transports long-chain
acylcarnitine across the inner membrane in exchange
for free carnitine.

Carnitine palmitoyltransferase II (CPT-II) regenerates

long chain acyl-CoA to free fatty acyl-CoA
CPT-I can be strongly inhibited by malonyl CoA (on
the cytosolic side of the enzyme).
Two isoforms of CPT-I:
liver CPT-Ia and heart CPT-Ib
CPT-Ib is 30-fold more sensitive to malonyl-CoA
inhibition

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Malonyl-CoA - key physiological regulator of FA
oxidation in heart (in malonyl-CoA FA uptake and
oxidation).
formed from the carboxylation of acetyl-CoA
(acetyl-CoA carboxylase ACC) from
extramitochondrial acetyl-CoA (derived from
citrate via ATP-citrate lyase reaction)
rapid rate of turnover in the heart.
ACC activity is inhibited by phosphorylation of
AMPK (AMP-activated protein kinase)
acceleration of FA oxidation

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FA undergo -oxidation generating NADH and
FADH2.

Acetyl-CoA formed in -oxidation generate more

NADH in citric acid cycle (CAC).

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 Carbohydrate metabolism

Glycolytic substrate is derived from exogenous

glucose and glycogen stores.

Glycogen pool in the heart is relatively small

Glucose transport into cardiomyocyte is regulated

by transmembrane glucose gradient and the
content of glucose transporter in the sarcolema
GLUT-4 (lesser extent GLUT-1).

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Insulin stimulation, increased work demand, or
ischemia increase glucose transport and rate of glucose
uptake.
Glycolytic pathway converts glucose 6-phosphate
and NAD+ to pyruvate and NADH, generate 2 ATP
for each glucose molecule.
Pyruvate and NADH are shuttled to the
mitochondrial matrix to generate CO2 and NAD+ -
complete aerobic oxidative glycolysis generate 36 ATP
for each glucose molecule.

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Phosphofructokinase-1 (PFK-1) key regulatory
enzyme in glycolytic pathway catalyzes the first
irreversible step.

PFK-1 utilized ATP fructose 1,6-bisphosphate, is

activated by ADP, AMP and Pi and inhibited by ATP
and fall in pH.

PFK-1 can be also stimulated by fructose 2,6-

bisphosphate (formed from fructose 6-phosphate by
PFK-2).

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 In the mitochondria pyruvate is:
dexarboxylated and oxidized into acetyl CoA by
pyruvate dehydrogenase (PDH)
or carboxylated into oxalacetate by pyruvate
carboxylase.
or reducted to lactate.
The control of PDH activity is an essential part of
overall control of glucose metabolism.
PDH mitochondrial multicomplex, activity is
controlled by work, substrate and hormones.

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 Under anaerobic condition (ischemia) pyruvate is
converted to lactic acid nonoxidative glycolysis.

Lactate is released in the blood stream through

specific transporter.

Critical role of transporter in maintaining the

intracellular pH (removes also the protons
produced by glycolysis).

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 Lactate metabolism
During starvation, lactate can be recycled to
pyruvate.

NAD+ is reduced to NADH (3 ATP - lactate

oxidation to pyruvate)

Pyruvate is then burned aerobically in the CAC,

liberating 15 ATP per cycle.

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Interregulation of fatty acid and carbohydrate
oxidation
Inhibition of FA oxidation increases glucose and
lactate uptake and oxidation by:
1. decreasing citrate levels and inhibition of PFK
2. lowering acetyl CoA and/or NADH levels in the
mitochondria

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 Ketone body metabolism

During starvation or poorly controlled diabetes

the heart extracts and oxidized ketone bodies (-
hydroxybutyrate and acetoacetat).
Low insulin and high fatty acids ketone bodies.
Ketone bodies become a major substrate for
myocardium.
Ketone bodies inhibit PDH (inhibition of glucose
oxidation) and fatty acid -oxidation.

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 Some aspects of myocardial biochemistry of
heart failure
Heart failure reduces the capacity to
transduce the energy from foodstuff into
ATP.
In the advanced stage of HF
down regulation in FA oxidation,
increased glycolysis and glucose oxidation
reduced respiratory chain activity

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Creatine phosphate (PCr) is the other major high-
energy phosphate in the heart. PCr is twice as abun-
dant as ATP and serves as a source of ATP through the
rapid and readily reversible creatine kinase reaction:

creatine phosphate + ADP + H+ creatine + ATP

During ischemia, PCr levels fall rapidly to preserve

ATP levels.
The creatine kinase reaction serves as a
temporal buffer to maintain high ATP and low adeno-
sine diphosphate (ADP).

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In the healthy heart myocardial energy substrate
preference varies in a dynamic manner as depicted
on the left panel. Mitochondrial fatty acid oxidation
is the chief source of energy but the relative
contribution of glucose utilization is significant. The
substrate plasticity is necessary for constant cellular
energy production in diverse physiological and
dietary conditions.

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