D.

Hythem Saeed Abdalla Saeed

 Myocardial function depends on a fine
equilibrium between the work the heart has
to perform to meet the requirements of the
body & energy that it is able to synthesize
and transfer in the form of energy-rich
phosphate bonds to sustain excitation-
contraction coupling.

 To support high rates of cardiac power,

metabolism is design to generate large
amount of ATP.
 Heart muscle is highly oxidative tissue.
 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.
Glycolysis + -oxidation  acetyl-CoA  citric acid cycle  NADH, FADH2 
electron transport chain  ATP
• Glycolytic substrate is derived from exogenous
glucose and glycogen stores.

• Glycogen pool in the heart is relatively small (~30

mol/g wet wt compared with ~150 mol/g wet wt in
skeletal muscles).

• 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).
 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+H+, generate 2 ATP for each
glucose molecule.

 Pyruvate and NADH+H+ are shuttled to the

mitochondrial matrix to generate CO2 and NAD+ -
complete aerobic oxidative glycolysis.
 Fosfofructokinase-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).
 Glyceraldehyde-3-phosphate dehydrogenase (GAPDH)
converts glyceraldehyde-3-phosphate to 1,3-
diphosphoglycerate → production of NADH.

 GAPDH is major regulatory step → accumulation of NADH

within cytoplasm inhibits, and NAD+ activates the GAPDH
activity

 Severe ischemia in heart → lactate and NADPH accumulation

→ cessation of oxidative metabolism and lactate production.

 Under anaerobic condition pyruvate is converted to lactic acid

– no-noxidative glycolysis.

 Lactate is released in the blood stream through specific

monocarboxylate transporter (MCT).

 Critical role of transporter in maintaining the intracellular pH

(removes also the protons produced by glycolysis).
 In the mitochondria pytuvate is:
 dexarboxylated and oxidized into acetyl CoA by
pyruvate dehydrogenase (PDH)
 or carboxylated into oxalacetate by pyruvate
carboxylase.

 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.
FFA enter the cardiomyocyte by:
passive diffusion
protein-mediated transport across sarcolema – fatty acid translocase (FAT) or plasma
membrane fatty acid binding protein (FABPpm).
Acyl-CoA synthase (FACS) activates nonesterified FA by esterification to fatty acyl-
CoA.
Long chain fatty acyl-CoA can be:
esterified to triglyceride (glycerolphosphate acyltransferase).
converted to long chain fatty acylcarnitine by carnitine palmitoyltransferase-I
(CPT-I) between inner and outer mitochondria membranes.
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 .
 CPT-1 can be strongly inhibited by malonyl CoA (on the cytosolic
side of the enzyme).
 Two isoforms of CPT-1:
 liver CPT-1 and heart CPT-1
 CPT-1is 30-fold more sensitive to malonyl-CoA inhibition.
 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-citratelyase reaction)
 rapid rate of turnover in the heart.
 ACC activity is inhibited by fosforylation of AMPKacceleration of FA oxidation.
 FA undergo -oxidation generating NADH+H+ and FADH2.

 Acetyl-CoA formed in -oxidation generate more NADH+H+ in

citric acid cycle (CAC).
 The primary physiological
regulator of flux through PDH
and the rate of glucose
oxidation in the heart is fatty
acid oxidation.

 PDH activity is inhibited by

high rate of FA oxidation via
an increase in mitochondrial
acetyl-CoA/free CoA and
NADH/NAD+ which activates
PDH kinase.
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 matrix.
 During starvation or poorly controlled
diabetes the heart extracts and oxidized
ketone bodies (-hydroxybutyrate and
acetoacetat).
 Low insuline 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.
 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.
 Coronary artery occlusion → ischemia → significant
change in cell structure, chemistry and function
 loss of contractile function
 arrhythmias
 cell death

 The decrease of the ATP / ADP, the accumulation of

AMP, inorganic phosphate, metabolic products are
removed (lactate).

 The rapid decline in creatine phosphate - creatine

kinase + ADP → ​phosphorylation of ADP → ATP (only
short-term mechanism to compensate for reduced
ATP production in mitochondria)
 Even mild ischemia reduces the concentration of ATP
and creatinephosphate, increases the level of
inorganic phosphate → activation of glycolysis
(glucose needed from the bloodstream into the heart
cells) → increase in the concentration of pyruvate →
conversion by LDH to lactate.

 Prolonged ischemia - the accumulation of substrates

(lactate, NADH+ and H+) → inhibition of glycolysis at
the level of phosphofructokinase and glyceraldehyde-
3-dehydrogenase.
 Troponin (T or I) - the
most sensitive and
specific test for
myocardial damage
 released during MI from
the cytosolic pool of the
myocytes.
 Approximate peak
release in 12 hours in MI
 Creatin kinase (CK) is relatively specific
when skeletal muscle damage is not present.
 CK has two subunits – CK-M (muscle), CK-B
(brain) and mitochondrial CKmi

 CK-MM (CK-1) - skeletal muscle 95%, heart

42%, smooth muscle 2 – 3%
 CK-MB (CK2) – skeletal muscle 3%, heart 28%,
smooth muscle 1 – 5%
 CK-BB (CK-3) – skeletal muscle 1%, heart 1%,
smooth muscle 87%
 Approximate peak release in 10 to 24 hours.
 Lactate dehydrogenase (10 – 24 hours) is not as specific
as troponin.
 LDH is tetramer with 2 subunits – H – heart, M - muscle

 Isoenzymes
 LDH1 (4 H) – heart and red blood cells,
 LDH2 (3HM) – heart and reticuloendothelial system,
 LDH3 (2H2M) - lungs,
 LDH4 (H3M) – kidneys, placenta, pancreas,
 LDH5 (4M) – liver and striated muscles
 In normoxia – LDH2 is higher than LDH1
 A high LDH1 level to LDH2 suggest MI

 Myoglobin (2 hours) has low specificity for MI – it is high

when muscle tissue is damaged but it lacks specificity.
 Aspartate transaminase (AST)
 was the first used
 it is also one of the liver function test

 Glycogen phosphorylase isoenzyme BB

(GPBB)
 One of 3 isoforms of glycogen phosphorylase exists in
heart and brain tissue
 Because of the blood-brain barrier GP-BB can be seen as
heart muscle specific.
 One of the "new cardiac markers" which are discussed to
improve early diagnosis in acute coronary syndrome.
 Elevated 1–3 hours after process of ischemia.