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
Specifity of Cardiac
Metabolism
Specifity of Cardiac
Metabolism
Regulation of Metabolic
Pathways in the Heart
Carbohydrate Metabolism
Carbohydrate Metabolism
Carbohydrate Metabolism
Carbohydrate Metabolism
Carbohydrate Metabolism
passive diffusion
protein-mediated transport across sarcolema fatty acid translocase (FAT) or plasma
membrane fatty acid binding protein (FABPpm).
converted to long chain fatty acylcarnitine by carnitine palmitoyltransferase-I (CPTI) between inner and outer mitochondria membranes.
or
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.
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
Cardiac Markers
Cardiac Markers
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
ENDOTHELIUM
Provides
Tunica
intima
LUMEN
Tunica
adventitia
Tunica
media
Normal
Vasoconstriction
Vasodilatation
Vasodilatation
Resistance to flow
Vasoconstriction
Endothelial Apoptosis
Normal
Apoptosed
The Endothelium
As an Endocrine
Organ
It
Local
Endothelial
Mediators are
oxide (NO)
Cycloxygenase
(CxO)
Endothelin-1
(ET-1)
Endothelium
And
It
Half-life
NO
It
NO
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
Endothelins
A family
Endothelins Disease
Elevated
Prostacyclin(PGI2)
Eicosanoid.
Synthesis
is induced by disturbances in
endothelial function or vascular haemodynamics.
Released
manner.
Binds
ENDOTHELIUM IN INFLAMMATION
Leucocyte
Initial
Mediated
by the selectins.
Increasing
Leucocytes
flatten and
endothelium: diapedesis.
migrate
along
the
ENDOTHELIUM IN INFLAMMATION
Activated
Is
Selectins
Three
Characterized
Involved
Integrins
relevant to leucocyte recruitment are 1
integrins and the 2 integrins.
Integrins
Integrin-immunglobulin
superfamily interaction is
essential for extravasation to occur.
COAGULATION
ECs maintain anticogulant activity:
Prevent
Express
III.
Express
COAGULATION
Express
thrombomodulin.
Thrombomodulin-thrombin
interaction
protein C- strong anticoagulant activity.
Synthesize
activates
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
Dysfunction
Vasodilation
NO, PGI2, EDHF,
BK, C-NP
Thrombolysis
Vasoconstriction
ROS, ET-1, TxA2,
A-II, PGH2
Thrombosis
PAI-1, TF-, Tx-A2
Platelet Disaggregation
Adhesion Molecules
NO, PGI2
Antiproliferation
Growth Factors
Lipolysis
LPL
Inflammation
ROS, NF-B
Vogel R
Clinical Sequelae
Stress leads to ED
Endothelial
It
Takes
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
Expanding
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)
Nonmodifiable
Age
Gender
Family history
Ethnicity
Premature
menopause
BMI 30
Health
Health
Hazard
Hazard
overweight
overweight
BMI 25
Healthy
Healthy
weight
weight
Insufficient
Insufficient
weight
weight
BMI 20
USA
Germany
20
UK
15
10
Netherlands
5
0
1980
1985
1990
1995
1998
Year
WHO MONICA 1997
data , 1997
Defining value
Abdominal obesity
WC >88cm in females
>102cm in males
> 1.65mmol/L
Elevated BP
SBP 130mmHg OR
SBP 85mmHg
6.0mmol/L
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
Female
Male
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
Diagnosis of FH
History family hx
Examination
Lipid profile
Mutation detection
MB
MB
Reduced perfusion