Biochemistry

of Cardiovascular System

1,2
MarhaenHardjo
1
Head of Biochemistry Department, Medical Faculty of Hasanuddin University
2
Director of Stem Cell Center Hasanuddin University Hospital

DEPARTMENT OF BIOCHEMISTRYY
MEDICAL FACULTI OF
HASANUDDIN UNIVERSITY

Biochemistry of Cardiac Muscle

Specifity of Cardiac
Metabolism

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.

Specifity of Cardiac
Metabolism

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.

Regulation of Metabolic
Pathways in the Heart

Glycolysis + -oxidation acetyl-CoA citric acid cycle NADH, FADH2

electron transport chain ATP
W.C. Stanley et all. Physiol. Rev. 85, 2005

Carbohydrate Metabolism

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).

Carbohydrate Metabolism

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.

Carbohydrate Metabolism

Fosfofructokinase-1 (PFK-1) key

regulatory enzyme in glycolytic
pathway catalyzes the first
irreversible step.

PFK-1 utilized ATP fructose 1,6bisphosphate, 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 PFK2).
W.C. Stanley et all. Physiol. Rev. 85, 2005

Carbohydrate Metabolism

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).

Carbohydrate Metabolism

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.

Fatty Acid Metabolism

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 acylCoA.

W.C. Stanley et all. Physiol. Rev. 85, 2005

Fatty Acid Metabolism

Long chain fatty acyl-CoA can be:

esterified to triglyceride (glycerolphosphate acyltransferase)

converted to long chain fatty acylcarnitine by carnitine palmitoyltransferase-I (CPTI) between inner and outer mitochondria membranes.

or

W.C. Stanley et all. Physiol. Rev. 85, 2005

Fatty Acid Metabolism

Carnitine acyltranslocase (CAT) transports long-chain acylcarnitine

across the inner membrane in exchange for free carnitine.
Carnitine palmitoyltransferase II (CPT-II) regenerates long chain acylCoA .

W.C. Stanley et all. Physiol. Rev. 85, 2005

Fatty Acid Metabolism

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-1is 30-fold more sensitive to malonyl-CoA inhibition.

W.C. Stanley et all. Physiol. Rev. 85, 2005

Fatty Acid Metabolism

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 AMPKacceleration of FA oxidation.

W.C. Stanley et all. Physiol. Rev. 85, 2005

Fatty Acid Metabolism

FA undergo -oxidation generating NADH+H+ and FADH2.

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

citric acid cycle (CAC).
W.C. Stanley et all. Physiol. Rev. 85, 2005

Interregulation of fatty acid

and carbohydrate oxidation

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.

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 matrix.

Keton Body Metabolism

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.

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.

Cardiac Muscle and Ischemia

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)

Cardiac Muscle and Ischemia

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.

Cardiac Markers

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

Cardiac Markers

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.

Cardiac Markers

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.

Cardiac Markers

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 13 hours after process of ischemia.

References
Reviews:
W.C. Stanley, F.A. Recchia, G.D. Lopaschuk:
Myocardial substrate metabolism in the normal and
failing heart. Physiol. Rev. 85:1093-1129, 2005
CH. Depr, M.H. Rider, L. Hue: Mechanism of
control of heart glycolysis. Eur. J. Biochem.
258:277-290, 1998
R. Ventura-Clapier, A. Garnier, V. Veksler: Energy
metabolism in heart failure. J. Physiol. 555:1-13,
2003

Biochemistry of Endothelial
Cells

Doc. Dr. Mine KUCUR

ENDOTHELIUM
Provides

a cellular lining to all blood vessels in the

circulatory system and forms a structural barrier
between the vascular space and the tissue.
In adults, the endothelium weights approximately 1kg,
comprises 1.6x1013 cells and has a surface area
between 1-7 m2.
Each EC comes into contact with numerous smooth
cells.

Tunica
intima

LUMEN

Tunica
adventitia

Tunica
media

Note the individual Endothelial Cells

Vasoconstriction and dilatation

Normal

Vasoconstriction

Vasodilatation

Vasoconstriction and dilatation

Resistance to flow

Vasodilatation

Resistance to flow

Vasoconstriction

Endothelial Apoptosis

Normal

Apoptosed

The Endothelium
As an Endocrine
Organ

The Vascular Endothelium

The

inner lining of our bloods vessels is the Endothelium

It

plays a central role in regulating the vasomotor tone

(vasoregulation)

Local

homeostasis & control of the coagulation process

(provision of anti-thrombotic surface and selective
permeability to haematopoietic cells and nutrients)

Endothelial

cells have Sensors and release Mediators

Mediators are

the functional molecules on the cell surface

Vascular Endothelial Mediators

Include the following
Nitric

oxide (NO)

Cycloxygenase

(CxO)

Endothelin-1

(ET-1)

Endothelium

Depolarisation Factor (EDF)

And
It

many others - thus

is the largest endocrine gland

Nitric Oxide (NO)

NO

is generated in ECs by the oxidation of L-arginine to

L-citrulline by a family of enzumes, NO synthases
(NOS)

Half-life

of NO, is affected by its chemical reaction and

inactivation by superoxide anion

NO

is the most abundant free-radical in the body

It

is the only biological molecule in high concentrations

to out-compete superoxide dismutase for superoxide

NO

has an anti-thrombogenic & anti-atherogenic role

Protective actions of NO
Endothelial NO has the following actions
Smooth muscle relaxation and vasodilatationmaintenance of basal vasomotor tone
Essential for regulation of blood pressure
Reduces proliferation of vascular smooth muscle
Protects blood vessel intima from injurious
consequences of platelet aggregation-inhibition of
thrombosis by inhibiting platelet adhesion,
activation and agonist-induced secretion.

(L-NMMA) = N(G)-mono-methyl-L-arginine

ED and NO
NO deficiency in the vessel wall promotes

Inflammation

Oxidation of lipoproteins

Smooth muscle proliferation

Accumulation of lipid rich material

Platelet activation and thrombus formation

Finally results in atherosclerosis.

Endothelins
A family

of 21 amino acid peptides.

Three members: ET-1,ET-2 and ET-3.
Regulate vasomotor tone, cellular proliferation and
hormone production.
ECs produce only ET-1, also syntesized by vascular
smooth cells.
Production is induced by hypoxia, ischemia.
ET-1 binds to specific receptors on smooth cells:
vasoconstriction.

Endothelins Disease
Elevated

plasma concentrations of ETs are found in

congestive cardiac failure.
Plasma ET-1 levels are normal in essential
hypertension.
Endothelins have been implicated in vascular diseases
of the kidney and cyclosporin induced nephrotoxicity.
Plasma ET levels are elevated after ischaemic cerebral
infarction.

Prostacyclin(PGI2)
Eicosanoid.
Synthesis

is induced by disturbances in
endothelial function or vascular haemodynamics.

Released

from ECs and acts in a paracrine

manner.
Binds

to a specific receptor on platelets and

vascular smooth muscle cells to limit
vasoconstriction and influence platelet deposition.

Platelet Activating Factor (PAF)

Phospholipid,
Most

remains bound to the EC surface.

important effect is recruiting leucocytes to

the EC surface, and its effects on vascular tone
are indirect and exerted through the generation of
other eicosanoids and leukotrienes.

ENDOTHELIUM IN INFLAMMATION
Leucocyte

transmigration to extravascular sites of

inflammation.

Initial

step is the arrest of leucocytes and random

contact with the ECs.

Mediated

by the selectins.

Increasing

adhesion occurs with activation of the

leucocyte integrins.

Leucocytes

flatten and
endothelium: diapedesis.

migrate

along

the

ENDOTHELIUM IN INFLAMMATION
Activated
Is

endothelium bind leucocytes.

activated in response to cytokines including IL-1,

TNF- and lipopolysaccharide which expresses
adhesion molecules and bind leucocytes.

Selectins
Three

members: E-Selectin, L-Selectin and PSelectin.

Characterized

by a C-terminal lectin like domain

that binds complex carbohydrates.

Involved

in leucocyte recruitment to sites of

inflammation.

Integrins
relevant to leucocyte recruitment are 1
integrins and the 2 integrins.

Integrins

1 integrins mediate binding to the ECM

(fibronectin and laminin). Binds cell surface VCAM1.

2 integrins are present only on leucocytes and

their activity depends on conformational changes
that occuron leucocyte activation.

Integrin-immunglobulin

superfamily interaction is
essential for extravasation to occur.

COAGULATION
ECs maintain anticogulant activity:
Prevent

activation of thrombin- if activated,

stimulates coagulation by causing platelet
activation and the activation of several coagulation
factors.

Express

heparan suphate- stimulates antithrombin

III.
Express

tissue factor pathway inhibitor (TFPI)prevents thrombin formation.

COAGULATION
Express

thrombomodulin.

Thrombomodulin-thrombin

interaction
protein C- strong anticoagulant activity.

Synthesize

activates

protein S, a cofactor for activated

protein C.
THE BALANCE IS TOWARDS ANTICOAGULANT
FACTORS IN HEALTHY ENDOTHELIUM !!!

The Endothelium in
Health and Disease

The Universal
Damage
The Essential
Components

Genes
Coronary
Risk Factors

Endothelial
Dysfunction
NO
Inflammation
Thrombosis

Coronary
Heart
Disease

 endothelial

NOS (eNOS) is induced by receptor

dependent agonists such as thrombin, bradykinin and
substance P.
NO causes vascular smooth muscle relaxation by
binding to guanyl cyclase.
plays a critical role in the inhibition of thrombosis by
inhibiting platelet adhesion, activation and agonistinduced secretion.
NO promotes platelet desegregation.

Regulatory Functions of the Endothelium

Normal

Dysfunction
Vasodilation
NO, PGI2, EDHF,
BK, C-NP
Thrombolysis

Vasoconstriction
ROS, ET-1, TxA2,
A-II, PGH2

tPA, Protein C, TF-I, vWF

Thrombosis
PAI-1, TF-, Tx-A2

Platelet Disaggregation

Adhesion Molecules

NO, PGI2

CAMs, P,E Selectins

Antiproliferation

Growth Factors

NO, PGI2, TGF-, Hep

ET-1, A-II, PDGF, ILGF, ILs

Lipolysis
LPL

Inflammation
ROS, NF-B

Vogel R

Clinical Sequelae

Oxidative stress and

Endothelial dysfunction
Oxidative

Stress leads to ED

Endothelial

dysfunction is mainly due to reduced

bioavailability and bioactivity of Nitric Oxide (NO)

It

is also a physiological process

Takes

place gradually by age and menopause.

The Effects of ED
Oxidant stress and Endothelial dysfunction are major
factors for atherosclerosis the common pathway
for most of the cardiovascular risk factors including
Hypertension, DM, Dyslipidemia and Smoking.
Both endothelial dysfunction and oxidant stress result
in clinical conditions - Heart failure, IHD and MI

CONCLUSIONS
Advances

in the understanding of endothelial

function have been the basis for many therapeutic
strategies.

Expanding

the understanding of endothelial

function will lead to targeted therapies to a myriad
of diseases such as cancer, cardiovascular
disease and inflammatory conditions.

Clinical Biochemistry aspects of

Cardiovascular Disease

Basic Learning Objectives

To understand the risk factors for developing atherosclerosis

To know how to clinically classify hypertension
To understand the basic concepts underpinning lipoprotein metabolism
To know what the components of a measured lipid profile are
To understand the classification and aetiology of Dyslipidaemia
To understand the aetiology, clinical manifestation and diagnosis of
Familial Hypercholesterolaemia
To understand the clinical biochemistry changes associated with acute
coronary syndrome
To understand how biochemical tests may be used to facilitate diagnosis of
Heart failure

Recommended Reading
Lecture Notes in Clinical Biochmesitry 7th Edition
G Beckett, S Walker, P Rae, P Ashby (Blackwell publishing)
Clinical Chemistry 5th Edition
W J Marshall, S K Bangert (Pubslished by Mosby)
An illustrated Colour text - Clinical Biochmeistry 3rd edition
Alan Gaw et al (Churchill Livingston)
Handbook of Clinical biochmeistry 1st Edition
R Swaminathan (Oxford University Press)
Clinical Chemistry in diagnosis and treatment
Philip Mayne (Edward Arnold)
A Guide to Diagnostic Clinical Chemistry 3rd Edition
Walmsely & White (Blackwell)

Atherosclerotic plaque is the key pathological

lesion Underlying the morbidity and mortality
associated with atherosclerosis

What are the risk factors for the development

of atherosclerotic disease?
Modifiable
Smoking
*Dyslipidaemia
*Hypertension
*Obesity/T2DM
Lack of
exercise

Nonmodifiable
Age
Gender
Family history
Ethnicity
Premature
menopause

Other risk factors for atherosclerosis

Stress/Personality
Homocysteine
Lipoprotein (a)
Fibrinogen
Socioeconomic
Geographic
? Depressive illness

How isobese defined?

Body mass index (BMI)=
weight/height2 (kg/m2)

BMI 30

Health
Health
Hazard
Hazard

overweight
overweight

BMI 25

Healthy
Healthy
weight
weight

Insufficient
Insufficient
weight
weight

BMI 20

Classification of Obesity & Overweight

Time trends in the prevalence of obesity (BMI > 30kg/m2)

25

USA
Germany

20

UK

15
10

Netherlands

5
0
1980

1985

1990

1995

1998

Year
WHO MONICA 1997
data , 1997

Central (Visceral) adiposity is associated with a greater

risk of developing metabolic syndrome

Criteria for clinical identification of

Metabolic syndrome
Component

Defining value

Abdominal obesity

WC >88cm in females
>102cm in males

Elevated fasting Triglyceride

> 1.65mmol/L

Reduced HDL cholesterol

< 1/3mmol/L in females

<1.0mmol/L in males

Elevated BP

SBP 130mmHg OR
SBP 85mmHg

Elevated fasting glucose

6.0mmol/L

Waist circumference is a clinically useful measure

of adiposity

Hypertension
Defined as BP 140/90
Associated with stroke, CHD, Cardiac Failure, renal failure
Aetiology
- Essential (primary HT) polygenic disorder
- Secondary HT (consider in younger hypertensive)
Prevalence
- 33% White males
- 38% Black males

Secondary Hypertension
Chronic Renal disease
Renovascular disease (Renal artery stenosis)
-Atheroma in older subjects
-Fibromuscular dysplasia in younger subjects
Coarctation of Aorta
Endocrine causes
-Primary hyperaldosteronism (Conns syndrome)
-Cushings Syndrome
-Phaeochromocytoma
Renal tubular genetic defects
-Liddles syndrome
Drugs
-Steroids
-OCP

Dyslipidaemia is a major risk factor for

atherosclerosis
Dyslipidaemia refers to any perturbation in lipoprotein metabolism
-Hyperlipidaemia e.g. hypercholesterolaemia
-Hypolipidaemia e.g. hypoalphalipoproteinaemia (low HDL)

The major lipoprotein particles circulating in the fasted state

Very low density lipoprotein (VLDL)
VLDL remnant
Low density lipoprotein (LDL)
High density lipoprotein (HDL)

Outline of normal lipoprotein metabolism

LDL accumulates in the atherosclerotic plaque

What is the relationship of plasma lipids and CHD?

The plasma lipid profile consists of
Total Cholesterol (TC)
HDL Cholesterol (HDLC)
LDL Cholesterol (LDLC)
Triglycerides (TG)
TC:HDLC
Raised TC and LDLC levels are positively associated with CHD
HDLC levels are inversely associated with CHD
-High level implies lower risk
-Low level implies higher risk (M < 1.0mmol/L, F <1.3mmol/L)
Raised Triglyceride levels are independently associated with CHD

LDL cholesterol is calculated using the Friedewald formula

Treatment targets for Plasma lipids

TC <5.0mmol/L
LDLC <3.2mmol/L (primary prevention)
<2.5mmol/L (secondary prevention)
HDL >1.0mmol/L in males
>1.3mmol/L in females

Elevated Plasma Cholesterol levels are associated

with increased CHD mortality

Plasma Total Cholesterol levels vary with age and gender

Female
Male

CHD-related mortality is in decline over the last 30 years

Related to recognition and treatment of dyslipidaemia

Classification of Hyperlipidaemia

Primary

Secondary

Primary Hyperlipidaemia
Hypercholesterolamia (high LDL)
-Polygenic
-Familial Hypercholesterolaemia (FH) (Type IIa)
-Sometimes Familial Combined Hyperlipidaemia (FCH)
Mixed Hyperlipidaemia
- FCH (high LDL +VLDL) (Type IIb)
- Type III (dysbetalipoproteinameia or remnant hypelipidameia)
(abnormal ApoE genotype)
Hypertriglyceridaemia
- Lipoprotein lipase (LPL) deficiency high Chylomicrons
- Familial Hypetriglyceridaemia (Type IV) high VLDL
- Familial Hypertriglyceridaemia (Type V) high VLDL + Chylos

Secondary Hyperlipidaemia
Diabetes mellitus
Obesity
Alochol abuse
Hypothyroidism*
Nephrotic syndrome*
Chronic Renal failure*
Cholestasis*
PCOS
Drugs
-Retinoic acid
-Diurestics
-Steroids
-OCP
-HAART
-Cyclosporin
* Predominant Hypercholesterolamia

Familial Hypercholesterolaemia
1 in 500 Heterozygote
1 in 1,000,000 Homozygote
Autosomal Dominant
Heterozygotes Plasma Cholesterol 6-12mmol/L
Homozygotes Plasma Cholesterol 10-20mmol/L
Mutations in
-LDL receptor
-ApoB
-PCSK9

Clinical aspects of FH
Family Hx of hyperlipidaemia
Family Hx of premature CHD
- <55yr in Male
- <65yr in Female

Specific Clinical manifestations

Xanthomata e.g. on extensor tendons of hands, achilles tendon
Xanthelasma
Corneal arcus (particularly if age under 45yr)

Diagnosis of FH
History family hx
Examination
Lipid profile
Mutation detection

Simon Broome Register Criteria for FH Diagnosis

Definite FH
-Total Cholesterol >7.5mmol/L (LDL > 4.9mmol/L)
Plus one of the following
-Tendon xanthomata in patient or first degree relative
-Molecular genetic diagnosis of LDL-receptor mutation
Possible FH
-Total Cholesterol >7.5mmol/L (LDL > 4.9mmol/L)
Plus one of the following
-Family hx of MI<50 yr in first degree relative (<60yr in 2 o relative)
-Family hx of raised Cholesterol (>7.5mmol/L)

Lipaemia retinalis occurs in association with severe hypertriglyceridaemia

Palmar xamthomata are a feature of Type III HPLA

CHD clinical aspects

Spectrum of clinical presentation
Angina
Acute Coronary Syndrome (ACS)
Unstable angina
MI
Symptoms of ACS
-Severe crushing central chest pain
-Dyspnoea
-Cold sweat
-Pallor
-Nausea

Diagnosis of Acute Coronary Syndrome (ACS)

Clinical history
ECG
-STEMI or NSTEMI
-Q waves appear later
Clinical Biochemistry

Older Cardiac Biomarkers for ACS Diagnosis

Creatine Kinase (CK)
muscle enzyme
Nonspecific in that it may originate from skeletal or cardiac muscle
start to increase at 3-8h
Peak level 18-24h
Returns to normal 3-4 days
Aspartate transaminase (AST)
Found in Liver and muscle (an dother tissues)
Nonsepcific
Incraese 6-10h
Paek level 24h
Return to normal 3-5 days
Lactate dehydrogenase (LDH)
Nonspecific (LDH 1 isoform is more cardiospecific)
Peak at 72hrs
Return to normal 8-14 days

MB

New Cardiac Biomarkers for ACS Diagnosis

CK-MB
Myocardium has higher concentration of CK-MB, more specific for heart
In ACS similar kinetics to total CK
CK-MB >6%of total CK indicates myocardial origin (Fractionated)
CK-MB mass > 5 ( interpret with caution if total CK elevated)
Troponins
Regulatory complex in muscle consisting of 3 protein T, C, I
Increases in Troponin T or I are very specific for cardiac muscle damage
In ACS increase at 3-6 hr
Peak 18-24 hr
Can remain elevated for 7-10 days
A Troponin T or I taken at 12 hrs post onset of chest pain is very sensitive

MB

Biochemical changes in Cardiac Failure

Biochemical abnormality Pathophysiology

Hyponatraemia
Diuretics, increased AVP
Hypokalaemia
Diuretics, 2o hyperaldosteronism
Renal Failure

Reduced perfusion

Biomarkers in Diagnosis of Cardiac Failure

Natriuretic peptides
Atrial Natriuretic peptide
B-type Natriuretic peptide (BNP)
-Both are normally produced in atrium
-Induce natriuresis (Na loss in urine)
BNP - produced in ventricle in cardiac failure

Measurement of BNP or its precleavage product NT-proBNP

-Can facilitate the diagnosis of LVF in acute dyspnoeic patient
-Also can assist in identifying patinets with early LVF for echocardiograhy