Journal reading

Presented by
Dimas Ariadie
Supervisor
dr Erika Maharani, SpJP (K)
British Heart Foundation Centre of Excellence, Cardiovascular Division, Kings
College London, London, UK

 Type 2 diabetes mellitus (T2DM) is a

global pandemic that is associated
with a more than 2-fold greater risk
of developing heart failure and a
60%80% greater probability of
death in those with established
HF.
Evidence suggests that T2DM itself
can
drive
adverse
cardiac
remodelling and give rise to a
diabetic cardiomyopathy (DiCM).
DiCM is reportedly evident in up to
60% of patients with T2DM and
is characterised by unexplained
myocardial
hypertrophy
and
fibrosis, with left ventricular (LV)
diastolic (systolic) impairment
At the cardiomyocyte level, defects
in excitationcontraction coupling,
calcium mishandling and increased
oxidative
stress
are
presentPromising
therapeutic

Background
T2DM

Normal Myocardial
Metabolism

The heart is an astonishing organbeats 23

billion times circulates 200 million litres of
bloodconsume up to 30 kg of ATP/daily 75
100 times its own weight.
Uninterrupted ATP generation is dependent on
the continuous supply of oxygen & fuel
substrates of oxidative phosphorylation.
While the heart can switch its substrate [fatty
acids (FAs), glucose, ketones, Lactate, amino
acids] preference depending on workload,
oxygen supply and hormones.

FA FAs
uptake
and fuel
utilisation
are the preferred
substrates and

account for 70%90% of myocardial ATP

generation.
Circulate in plasma as triglyceride (TG)-rich
lipoproteins
Endothelial lipoprotein lipases cleave lipoproteins
to release free FAs which then enter cardiomyocytes
via specific transporters.
Free FAs are esterified to fatty acyl-CoA which is
either stored in the intracellular TG pool (10%30%)
or transported into the mitochondrion for oxidation (70%90%).
Carnitine palmitoyltransferase (CPT)-I is the ratelimiting enzyme of FA Metabolism
FA metabolism is principally regulated by the
transcription factor peroxisome proliferatoractivated receptor- (PPAR-) which, upon activation
by high myocardial FA levels, upregulates FA uptake

FA uptake and utilisation

In turn, increased glucose oxidation can reduce FA
utilisation. This reciprocal inhibition is termed the
Randle cycle
FAs generate more ATP than glucose for each
molecule metabolised, the ATP production to oxygen
consumption ratio is lower for FAs increased FA
oxidation reduces cardiac efficiency (cardiac
work/myocardial oxygen consumption).

Glucose uptake and utilisation

Myocardium
Glucose oxidation accounts for
10%30% of cardiac ATP
production

Glucose entry into

cardiomyocytes via glucose
transporter (GLUT)-1 mediates
basal insulin-independent
glucose and while GLUT-4 is
insulin responsive.
The vast majority of imported
glucose is converted to glucose6-phosphate by glucokinase.
Glucose-6-phosphate
channelled
into
glycolysis
(~85%), glycogenesis (<5%),
the pentose phosphate pathway
(PPP; <5%) for nucleic acid and
NADPH synthesis.

has the

highest
mitochondrial
density (35% of
cardiomyocyte
volume versus 3%
8% in skeletal and
smooth muscle
cells) of any organ,
and its mitochondria
exhibit the greatest
Irrespective
of
OxPhos
substrate
preference, the final
end product of fuel
oxidation is acetylCoA which enters
the Krebs cycle to
generate OxPhos
which produces
>95% of myocardial

Myocardial metabolism in
Abnormal cardiac FA uptake and utilisation in
T2DM
T2DM

The heart preference for FAs as energetic

substrates is exaggerated in T2DM. This is
due to the increase in plasma FA levels as a
result of increased lipolysis from insufficient
insulin action, increased hepatic TG
production and inefficient adipocyte TG
storage.
In T2DM, a twofold increase in cardiac FA
oxidation has been described, aberrant FA
metabolism has been correlated to
adverse cardiac changes .
Excessive FA storage is thought to be

Myocardial metabolism in
Abnormal cardiac FA uptake and utilisation in
T2DM
T2DM

FA accumulation within the heart is postulated to

increase mitochondrial ROS by augmenting -oxidation and
ETC activity implicated in myocardial hypertrophy, defective
excitationcontraction coupling and cardiac inefficiency via
mitochondrial uncoupling.

Increased lipid intermediary metabolites Derange signalling

and can trigger cardiomyocyte
apoptosis
directly
Lipotoxicity Genesis of DiCM
FA Metabolism higher oxygen cost (~86% greater myocardial
oxygen consumption compared to glucose), increased FA
metabolism further diminishes cardiac mechanoenergetic
efficiency

Mitochondrial oxidative phosphorylation in type 2 diabetic

Myocardial metabolism in
Abnormal cardiac glucose uptake and utilisation in
T2DM
T2DM
Despite systemic hyperglycaemia cardiac glucose
oxidation is reduced by 30%40% in patients with
T2DM FA excess in the myocardium.
Hyperglycaemia elevates cardiomyocyte glucose
levels
which
can
non-enzymatically
glycate
proteins to form advanced glycation end-products
(AGEs)
AGEs enhance ROS production and can cross-link and
damage macromolecules such as collagen (leading to
myocardial fibrosis and stiffness), SERCA (leading to
diastolic impairment) and the ryanodine receptor
(leading to contractile imparment)

Myocardial metabolism in
Cardiac mitochondrial OxPhos defects in T2DM
T2DM
Mitochondrial
dysfunction

abnormal
myocardial structure and function in T2DM.
Reductions in OxPhos decreases in
myocardial ATP.
Mitochondrial dysfunction deleterious
solely limiting ATP supply to myofibrils
(leading
to
systolic impairment)
and
SERCA (leading to diastolic impairment), it
also augments ROS production cardiac
remodelling.

Therapeutic targeting of cardiac

metabolism
T2DM
Diabetic and HF in
medications
Good diabetic control seems intuitively important
for preventing DiCM.
Animal studies Early Achieving euglycaemia
arrests the development of DiCM.
Certain diabetic drugs can have specific antiremodelling effects :
Glucose insulin
infusions
improved glucose
oxidation and contractile efficiency.
Incretin based therapies steatosis, oxidative
stress.
Metformin natiuretic peptide levels and lower
cardiovascular morbidity and mortality

Therapeutic targeting of cardiac

metabolism
T2DM
Diabetic and HF in
medications

increased hospitalisations for HF were

documented
with
thiazolidinediones
(e.g.
rosiglitazone),
incretin-based
therapies
(e.g.
saxagliptin)
and
sulfonyureas (e.g. glicazide) Glycaemic
control alone might not be sufficient for
preventing or managing DiCM.
-blockers directly suppress oxidative
stress and FA metabolism Decelerate
DiCM

Therapeutic targeting of cardiac

metabolism
in
T2DM
Strategies to modulate cardiac substrate utilisation
Increased FA utilisation is a key feature of deranged
metabolism in T2DM
Besides statins to reduce cholesterol levels, excessive FA
metabolism, reduce plasma-free FA can also be targeted.
In patients with T2DM and HF, trimetazidine reduced
natiuretic peptides and improved exercise capacity and
LV function despite no change in cardiac perfusion.
In a large clinical trial, ranolazine relieved angina more in
diabetic than in non-diabetic patients.
Besides inhibiting FA utilisation, directly stimulating
glucose oxidation with dichloroacetate, a PDH activator,
could also rebalance cardiac substrate use in T2DM

Therapeutic targeting of cardiac

metabolism
in T2DM
Strategies
to improve
mitochondrial OxPhos
Mitochondrial oxidative stress is implicated in the
reduction in ETC activity, and mitochondrialtargeted antioxidants ROS Production.
MitoQ reduced oxidative stress, increased OxPhos
and promoted survival cell.
Coenzyme Q 10 (ubiquinone) carries electrons
from their sites of donation
420 patients with chronic HF, coenzyme Q 10
was
shown to improve New York Heart Association (NYHA)
class and survival )

coenzyme Q 10 attenuated LV remodelling and

diastolic dysfunction in a mice model of T2DM.

Summary
Type 2 diabetic heart is characterised by
excessive FA utilisation and storage,
suppressed
glucose
oxidation
and
impaired OxPhos.
Myocardial FA excess is posited to play a
pivotal role. By inducing steatosis and an
abundance
of
ROS
and
toxic
intermediary metabolites
FAs adverse cardiac remodelling.
FAs can
shunt
glucose
more
pathological pathways

TERIMA
KASIH
THANK YOU