Aterosklerozes Biochemija

Atherosclerosis and
Metabolic Risk Factors
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Section 1
Epidemiology and Risk Factors
Factors Contributing to Death
Worldwide
 10 global risk factors account for more than one
third of deaths worldwide ( childhood and maternal :
underweight; unsafe sex; high blood pressure; tobacco;

alcohol; unsafe water, sanitation and hygiene; high
cholesterol; indoor smoke from solid fuels; iron deficiency
and overweight/obesity )
 Small number of risk factors cause high number of
premature deaths and large share of global burden
of disease
 Risk factors causing premature deaths include:
 high cholesterol - 4.4 million deaths (7.9% of total)
- 40.4 million DALYs* (2.8% of total)
 tobacco - about 4.9 million deaths
 elevated blood pressure - 7.1 million deaths
*DALY; disability-adjusted life years
The World Health Report 2002.
Global Burden of Cardiovascular Disease
In 2002:
 CVD contributed to approximately a third of all
global deaths (17 million)
 80% of burden is in low and middle-income
countries
By 2020:
 CHD and stroke will become the leading cause of
death and disability worldwide
 Mortality from CVD will increase to 20 million
Clinical care of CVD is costly and prolonged

5.International Cardiovascular Disease Statistics 2005; AHA
Mortality from CVD and CHD in Selected
Countries
Mortality rate per 100,000 population
1000
(men aged 35 - 74 years)
CVD deaths
CHD deaths
500
6.International Cardiovascular Disease Statistics 2003: AHA
Risk Factors
1. Major Risk Factors

2. Minor Risk Factors
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Major Risk Factors
 Famillial Hypercholesterolemia:
Refers to an autosomal–dominat disorder,
characterized by markedly elevated Total
Cholesterol Levels and Low Density
Lipoprotein (LDL) due to mutations in the
LDLR Genes encoding for LDL-Receptor Protein
or Apoprotein B. Incidence of Heterozygous FH
is 1:500, while Homozygous FH is 1: 100 000
and associated with early Coronary Heart
disease.
 Tobacco Smoking:
Nicotine promotes vasoconstriction and causes
injury to the vascular endothelium
Major Risk Factors
 Diabetes Mellitus:
Persistent Hyperglycemia promotes vascular
endothelium damage and is characterized by
arterial hypertension.
 Chronic Arterial Hypertension:

Includes as well damage to the vascular
endothelium.
 Age/Gender:
Women =>65 years; men =< 60 years
Minor Risk Factors
 Central Obesity:
Is characterized by a waist circumference of
Womens > 80cm, men >94cm.
 Diminished Physical Activity:

Due to lifestyle or Occupation.
 Elevated C-Reactive Protein:

Chronic inflamatory Disease are assumed to
cause endothelial damage increasing the risk
for Atherogenesis.
Minor Risk Factors
 Elevated Fibrinogen Levels ( >300mg/dl):

Are related to an increase in Thrombocyte
aggregation and decrease in Blood’s viscosity.
 Elevated Lipoprotein α Levels (>30mg/dl):

Lipoprotein α is selectively retained in the intima
and engulfed by macrophages in unmodified
form. Human Apo(a) is very similar to
plasminogen, which suggests that
lipoprotein(α) represents a link between
atherosclerosis and thrombosis.
Minor Risk Factors
 Hyperhomocysteinemia:
Deficiencies in Vitamin B6, B9 and B 12 are
linked to Atherosclerosis.
 Infections:
Caused by Chlamydia pneumonia have been
linked to Atherogenesis, but till now is no
certain consensus made.
Cholesterol: A Modifiable Risk Factor
 Plasma cholesterol at levels >200 mg/dL

(5.2mmol/L) cause 4.4 million deaths a year1
 Incidence of plasma cholesterol >200 mg/dL in:
 51% (107 million) adults in the USA2
 58% of patients with established CHD in
EUROASPIRE II3
 10% reduction in plasma cholesterol results in:

 15% reduction in CHD mortality (p<0.001)
 11% reduction in total mortality (p<0.001)4
 LDL-C is a major target to prevent CHD
1. International CVD Statistics 2005 AHA;

2. 2. Heart and Stroke Statistical Update 2004 AHA;
3. EUROASPIRE II Study Group. Eur Heart J 2001;22:554-572;
4. Gould AL et al. Circulation 1998;97:946–952.
The Metabolic Syndrome and
Associated CVD Risk Factors
Hypertension
Abdominal obesity
Atherosclerosis
Hyperinsulinaemia
Insulin Diabetes
Resistance
Hypercoagulability
Endothelial
Dyslipidaemia Dysfunction
• high TGs
• small dense LDL
• low HDL-C
Deedwania PC. Am J Med 1998;105(1A);1S-3S..
The Progression from CV Risk Factors to
Endothelial Injury and Clinical Events
LDL-C BP Risk factors Diabetes Smoking Heart failure
Oxidative stress
Endothelial dysfunction
NO Local mediators Tissue ACE-Ang II
Endothelium Growth factors Proteolysis

PAI-1 VCAM
matrix
ICAM cytokines
Vascular lesion
Thrombosis Inflammation Vasoconstriction Plaque rupture
and remodelling
Clinical endpoints
NO Nitric oxide
Gibbons GH, Dzau VJ. N Engl J Med 1994;330;1431-1438. 12.
AVD – Clinical Manifestations
Organ Condition Impairment Clinical Presentation

Heart Coronary Heart Ischemia Angina Pectoris
Disease (CHD) Infarction Myocardial Infarction
Brain Cerebro vascular Ischemia Transient Ischemia attack

Disease (CVD) Infarction Stroke
Kidney Reno vascular Ischemia Renal HT, Renal impairment
Disease (RVD) Infarction Renal Failure
Leg Peripheral Vascular Ischemia Intermittent Claudication
Muscles Disease (PVD) Infarction Gangrene
For every thing the common denominator is ED
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Section 2
Pathogenesis of Atherosclerosis
Biochemistry of atherosclerosis
Acute phase proteins
Atherosclerosis – is a systemic pathological
process characterized by accumulation of lipids in the
arteries (aorta and its branches, coronary and cerebral
arteries) and focal proliferation of the connective
tissue that leads to atherosclerotic plaques, which
narrow the lumen to total occlusion.
Complications:
1) Coronary heart disease
2) Lesions of the cerebral arteries
3) Aortic aneurysm
Normal Arterial Wall
Intima:
Endothelium
Internal elastic membrane
Media:
Smooth muscle cell
Lumen
Matrix proteins
External elastic membrane
Endothelial functions:
 Barrier: control of LP, monocyte, etc., transit to the

subendothelium;
 Formation of a non-thrombogenic surface;
 Local inflammation and immune system regulation;
 Production of:
 Growth factor,
 Coagulation factors: t-PA, PAI;
 Vasoactive substances: PI2, NO.
Smooth muscle functions:
 Contractile;
 Extracellular matrix production:
 Collagen;
 Elastin;
 Proteoglycans.
 Participates in the regenerative processes: reacts to
cytokines, growth factors.
Groups of risk factors that are significant for
development and progression of atherosclerosis:
 Serum lipid alterations,
 Factors that impair endothelial function,
 Factors that influence proliferation of the smooth muscle

cells in the vascular wall.
Endothelial dysfunction factors:
 Smoking
 Nicotine induces vasoconstriction due to decreased
production of endothelium derived vascular relaxation
factor.
 Nicotine releases norepinephrine from the endings of the
adrenergic nerves -  BP and  adrenal secretion of
catecholamines;
 Nicotine promotes platelet aggregation – balance of the
coagulation system is impaired;
 Smoke carbon monoxide binds to hemoglobin by forming
carboxyhemoglobin, thus blood O2 severely decreases and
vascular permeability increases.
  BP (Mechanical endothelial damage- hemodynamic factors):
 Pulse wave;
 Blood flow velocity;
 Specific features of vascular anatomy (branches, curves);
 Lipid peroxidation.
Factors that influence vascular wall smooth
muscle proliferation:
 Hyperhomocysteinemia
 Hyperglycaemia
 Excess of growth hormone
Mechanisms of hyperhomocysteinemia
induced vascular damage:
 Endothelial damage (first, transforms normal endothelial

antithrombotic activity, resulting in XII and V clotting
factors activity change; second, inhibits expression of
thrombomodulin and heparin sulphate, inducing
thrombin synthesis; third, increases plasma ADMA,
which inhibits NO synthase, thus larger amounts of
peroxynitrite are produced, BH4 is oxidated and eNOS
dimers detach),
 LDL oxidation is activated due to inhibition of
superoxiddismutase,
 Lipoprotein and fibrin binding is increased.
 Smooth muscle proliferation is activated, collagen
2/3 stored.
of hyperhomocysteinemia cases are due to B vitamin deficiency
 Cholesterol production in the liver is stimulated.
Recently acknowledged tests for
evaluation of cardiovascular risk factors:
 Lipid and lipoprotein metabolism measures (total

cholesterol, TG, HDLch, LDLch, lipoprotein phenotype,
Lp(a), apoB,apoA1, apoE),
 Homocysteine,
 Fibrinogen,
 Magnesium,
 Microalbuminuria (it is unclear if it indicates an early
glomerular nephropathy or is caused by increased renal
perfusion pressure, or a measure of impaired
endothelial function),
 Uric acid,
  glutamyltransferase (prooxidator in formation of an
atherosclerotic plaque).
Historical Model of Atherogenesis
Threshold
Decades Years-Months Months-Days

healthy subclinical symptomatic
Intima
Lumen
Media
Plaque
• Stable angina
• Stable plaques with narrowing
• Simple diagnostic (ECG, angiography)
• Rare MI
• Easy to treat
Antischkow N. Beitr Path Anat Allg Path 1913;56:379-404. 17
New Paradigm
Threshold
Decades Years-Months Months-Days

healthy subclinical symptomatic
Thrombus
Intima
Lumen
Media
Plaque
• Unstable angina
• Unstable plaque no narrowing
• Difficult to diagnose (IVUS, MRI)
• Frequent MI with sudden death
• Easy to prevent
Pathogenesis of Atherosclerotic Plaques
Endothelial damage
Protective response results in production of

cellular adhesion molecules
Monocytes and T lymphocytes attach to

‘sticky’ surface of endothelial cells
Migrate through arterial wall to subendothelial space
Macrophages take up oxidised LDL-C
Lipid-rich foam cells
Fatty streak and plaque
Progression of Atherosclerosis
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The ‘Activated’ Endothelium
‘activated’
endothelium
cytokines (eg. IL-1, TNF-)

CELLULAR
chemokines (eg.MCP-1, IL-8) ADHESION
MOLECULES
growth factors (eg. PDGF, FGF)
attracts monocytes and T induces cell

lymphocytes proliferation and
which adhere to a prothrombic
endothelial cells state
Koenig W. Eur Heart J Suppl 1999;1(Suppl T);T19-26.
Endothelial Dysfunction in Atherosclerosis
Upregulation of endothelial
adhesion molecules
Migration of leucocytes into

the artery wall
Lipoprotein infiltration
Increased endothelial
permeability
Leucocyte adhesion
Fatty Streak Formation in
Atherosclerosis
Adherence and aggregation

of platelets
Migration of smooth
muscle cells
Formation of foam cells
Activation of T cells
Adherence and entry of

leucocytes
Formation of the Complicated
Atherosclerotic Plaque
Formation of
necrotic core
Accumulation of
macrophages
Formation of
the fibrous cap
The Unstable Atherosclerotic Plaque
Thinning of the
fibrous cap
Rupture of the fibrous

cap
Haemorrhage from
plaque microvessels
Atherosclerotic Plaque Rupture and
Thrombus Formation
Intraluminal thrombus
Lipid pool
Intraplaque thrombus
The Synthesis and Breakdown of
Atheromatous Plaques
Libby P. Circulation 1995;91:2844-2850.
The Vulnerable Atherosclerotic Plaque
SMC – smooth muscle cell

HDL-DR – transplantation antigen indicating ‘activation’ of SMCs Libby P. Circulation 1995;91:2844-2850.
Plaque Rupture with Thrombus
Imaging Techniques Used to Assess
Atherosclerosis
 Invasive techniques
 Intravascular ultrasound (IVUS)
 Coronary angiography
 Non-invasive techniques
 Magnetic resonance imaging (MRI)
 Computed tomography (CT)
 Ultrasound (B-mode)
NEW
The Intravascular Ultrasound (IVUS)

coronary imaging technique
Rotating transducer Normal coronary anatomy
Images courtesy of Cleveland Clinic Intravascular Ultrasound Core Laboratory
Intravascular Ultrasound (IVUS)
Showing Atheromatous Plaque
Angiogram IVUS
normal
vessel
atheroma
Reproduced from Circulation 2001;103:604–616, with permission from Lippincott Williams & Wilkins. 29.
Coronary Angiography
of Stenotic Coronary Artery
Arrow indicates atherosclerosis (stenosis) of the coronary artery
Magnetic Resonance Image (MRI) of
a Stenotic Carotid Artery Bifurcation
left carotid artery relatively

bifurcation with an normal artery
atherosclerotic
plaque with a
necrotic core
Chu B et al. Stroke 2004;8:2444–2448. 31.
Computed Tomography (CT)
Showing Atherosclerotic Artery
B-mode Ultrasound
Reproduced with permission from Kastelein, JJP et al. Am Heart J 2005;149:234–239.
Clinical Manifestations of
Atherosclerosis
 Coronary heart disease

 Angina pectoris, myocardial infarction, sudden
cardiac death, congestive heart failure (CHF),
and arrhythmias
 Cerebrovascular disease
 Transient ischaemic attack, stroke
 Peripheral vascular disease

 Intermittent claudication, gangrene, cold feet,
painful feet, impotence
Response to acute damage
 Local:  Systemic:
 Alterations in  Phagocyte activation (circulating
granulocyte level is increased),
vascular
permeability,  Metabolic activity change in the
liver and other tissues (synthesis
 Release of active of acute phase proteins),
cell components
 Production of eicosanoids
(lysosome
(prostaglandins, prostacyclins,
enzymes, thromboxan, leukotriens, release
vasoactive of peptide hormons from the
peptides, cell,
eicosanoids).
 Cytokine release from the cell.
The acute reaction response is induced by monocytes after they contact the
pathogen. They release IL-1 – endogenous pyrogen. It increases temperature,
promotes liver production of IL-6 and acute phase proteins. At the same time the
amount of other proteins in hepatocytes is reduced.
Production: albumins, transportins, lipoproteins.
Acute phase proteins (inhibitors of the
enzymes that are released after cell death
and can induce secondary damage):
 Ceruloplasmin,
 C reactive protein,
 Fibrinogen,
 Complement components C3, C4 and activated complex C56.
The extent of damage is limited due to fibrin precipitation.
Structure and functions of ceruloplasmin
 This protein contains  Synthesized by

93% of blood copper; hepatocytes and acts as
 0,34 % of molecular a feroxidase: oxidizes
mass is comprised of various aromatic
copper. phenols, polyamins, iron.
Ceruloplasmin is increased in the acute phase of

inflammation and reduced in patients diagnosed with a
rare Wilson’s disease (increase of copper in the brain and
liver causing neurological and liver damage symptoms).
CRP functions:
 Stimulates activity of Also,

phagocyte cells,  Prognosis of progression
 Participates in and tearing of an
complement activation, atheromic plaque can be
made according to the
 Neutralizes exogenous
increased level of CRP.
and endogenous
substances (CRP  CRP is an important
attaches to negatively marker of rheumatic,
charged molecules, e. g. infectious, connective
phosphatidylcholine, also tissue diseases and MI.
components of bacteria,
fungi and parasite
membrane
phospholipids) and
 Stimulates phagocytes in
eliminating them from
blood and tissues.
Importance of CRP in MI diagnosis and
follow-up
 CRP level starts increasing 4-6 hours after the onset of

MI, reaches its maximum on the third or fourth day,
and returns to normal range after 7-10 days. If
symptoms are unclear, it is a sensitive marker of
damage and is found in 50% patients with acute MI and
100 % in Q wave MI.
 If elevated levels of CRP persist more than 10 days,
complications should be sought after; it is a marker of a
poor prognosis.
 Increased levels of CRP in patients with stable and
unstable AP indicate impending coronary complications.
Structure and functions of fibrinogen
 A dimer composed of three  Coagulation;
different pairs A, B and 
 Inflammation (promotes
chains. granulocyte migration to a
 Thrombin cleaves A and B damaged site);
peptides (fibrinopeptides)  Being an adhesion molecule
from  and  chains, interacts with platelets,
respectively. After the endotheliocytes,
cleavage cross-linked macrophages, fibroblasts;
covalent bonds are created  Glycoprotein synthesized by
between fibrin threads – hepatocytes and converted
fibrin fibers are formed, by thrombin and calcium to
followed by a clot. fibrin
Fibrinogen levels start rising 24-48 hours after the damage onset: during infectious,
malignant process, after trauma, surgery. If disseminated intravascular coagulation
syndrome develops, fibrinogen levels decrease below normal due to intense
catabolism.
Fibrinogen is an independent risk factor for MI and stroke.
Complement components and their
diagnostic value
 More than 20 proteins of  Levels of C3, C4 and

the complement system activated complex C56
are known; increase during
 They are proenzymes of inflammation, trauma.
esterases and proteases;
 Once activated, the
system functions as a
cascade;
 Participates in the lysis of
the cells containing
foreign complement.
 Stimulates activity of
phagocyte cells;
chemotaxis
Antioxidative system
 Free radicles have the potency to cause severe

damage to tissues and for this reason those
require strict metabolic control, which is
provided by antioxidative system.
Antioxidative system
 Prevention and control of Free Radicle

Reactive O2 species generation
(ceruloplasmin)
 Neutralization of reactive O2 species
(glutathion)
 Elemination of previously formed free radicles
and reactive O2 species
 Repair of previously damaged tissues
(vitaminc/Q10)
Antioxidative system:
 Proteins:
 Non enzymes: Fe and Cu binding proteins
• Albumin,
• Transferin,
• Ceruloplasmin, etc.;
 Enzymes (intracellular derivatives):
• superoxiddismutase,
• catalase,
• peroxidases;
 Low molecular mass derivatives:
 Water soluble:
• Uric acid,
• vitamin C,
• glutathione;
 Lipid soluble:
• vitamin E, Q10,
• provitamin A (-carotene),
• licopen.
Antioxidative system:
 An antioxidant is a molecule that is capable to

inhibit oxidation of other molecules.
 Oxidation reactions are essential for life, but
may result in the formation of ROS, causing
damage to cells and even cell death.
 Antioxidants are widely used ingredients of
foods and are linked to various disease
prevention including Neurodegenerative, CHD.
Antioxidant Compound Foods containing Antioxidant Compound
Vitamin C Fresh Foods, Vegetables and Fruits
Vitamin E Vegetable Oils and Nuts
Polyphenolic Antioxidant Coffe, tea, Red Wine, Chocolate and Olive Oil
Carotenes Vegetables and Eggs
Section 3
Lipoproteins, Lipid Metabolism
LIPIDS
The main clases of lipids in plasma :

 Cholesterol esters
 Triglycerides
 Phospholipids
These are all esters of long-chain fatty acids,

which also present in plasma in free form, and
are transported in plasma as complexes with
proteins. Fatty acids are transported bound to
albumin.
Main lipids of the blood plasma and their
function
 Lipoproteins are macromolecular aggregates

of lipids and apolipoproteins. Lipids can be
divided into two main groups, simple and
complex.
 The two most important simple lipids are
cholesterol and fatty acids. Lipids become
complex lipids when fatty acids undergo
esterification to produce esters.
function
The main clases of lipids in plasma :
 Simple lipids (no esterification of fatty acids)

 Complex lipids (esterification of fatty acids)
Two Types of Lipids
LIPIDS IN BLOOD
TOTAL CHOLESTEROL TRIGLYCERIDES
GOOD CHOLESTEROL BAD CHOLESTEROL

HDL 1 and HDL 2 LDL, ( IDL, VLDL, Lp(a))
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function
 Simple lipids.
Cholesterol is a soft waxy substance present in
all cells of the body. Most tissues can produce
cholesterol, but it is synthesised primarily
in the liver and small intestine.
Approximately 50% of the cholesterol
requirement is synthesised, whilst the rest is
obtained from animal produce in the diet.
Function: Cholesterol is important in the repair
of cell membranes and in the synthesis of
steroid hormones, vitamin D and bile acids.
function
 Fatty acids are the simplest form of lipids

found in the plasma where those are bounded
to albumin and stored as triglycerides in
adipose tissue and are an important energy
source.
They exist as saturated, monounsaturated and
polyunsaturated forms, distinguished by the
number of bonds between the hydrocarbon
chain and carbon atoms. The most common
fatty acids in the body are stearic and palmitic
(saturated), and oleic (monounsaturated).
function
 Complex Lipids:
 Triglycerides are mainly stored in adipose
tissue and are the main lipid currency of the
body.
 Phospholipids are glycerol esters containing
two fatty acids. They have a water-soluble and
a lipid-soluble surface and are an important
component of the cell membrane.
 Cholesterol esters, oleate and linoleate, are
the storage molecules of cholesterol in cells.
Triglycerides
 May be associated with increased risk of CHD
events
 Link with increased CHD risk is complex
 may be direct effect of smaller TG-rich
lipoproteins and/or
 may be related to:
• low HDL levels
• highly atherogenic forms of LDL-C
• hyperinsulinaemia/insulin resistance
• procoagulation state
• hypertension
• abdominal obesity
Structure of Lipoproteins
Phospholipid
Free cholesterol
Triglyceride
Apolipoprotein Cholesteryl ester
Types of Lipoprotein Particles
 Triglyceride-rich lipoproteins
 Chylomicrons
 Very low-density lipoprotein (VLDL)
 Intermediate density lipoprotein (IDL)
 Cholesterol-rich lipoproteins
 Low-density lipoprotein (LDL)
 High-density lipoprotein (HDL)
Lipoproteins
 Chylomicrons are the largest in size, lowest

in density and are not associated with
atherosclerosis. They are synthesised in the
intestinal mucosal cells after a fatty meal.
Function: They transport dietary triglyceride
from the intestine to the sites of use and
storage, and are cleared rapidly from the
bloodstream.
 Each chylomicron also contains many
different apolipoproteins including one
molecule of ApoB45 and other such as ApoE
and ApoC-II.
Lipoproteins
 VLDL particles are similar in structure to

chylomicrons but are smaller.
 Function: They are produced in the liver and
are the main carriers of endogenous
(synthesised in the liver rather then dietary)
triglycerides and cholesterol to sites for use or
storage.
 As the triglycerides are removed, the VLDL
remnants continue to circulate as LDL
particles. Thus, VLDL are implicated in
atherosclerosis development.
Lipoproteins
 Intermediate density lipoproteins (IDL)

are particles formed by the removal of
triglycerides from VLDL, during transition from
VLDL to LDL.
Lipoproteins
 LDL particles are the principal lipoproteins

involved in atherosclerosis. Oxidised LDL is the
most atherogenic form of LDL.
 Function: They are the main carriers of cholesterol
– as cholesteryl ester or free cholesterol -
accounting for 60–70% of plasma cholesterol. Thus, the
concentration of LDL-C provides a good estimate
of the total concentration of serum cholesterol.
 LDL particles are remnants of VLDL particles,formed
from IDL by the removal of more triglyceride and
apolipoprotein,but they contain only a single
apolipoprotein, ApoB100
Lipoproteins
 HDL particles are the smallest, but most

abundant of the lipoproteins, and contain
almost one quarter of serum cholesterol.
 They do not cause atherosclerosis, but
actually protect against its development.
This is because they return about 20-30% of
cholesterol in the blood to the liver from
peripheral tissue for excretion (reverse
cholesterol transport). They also inhibit the
oxidation of LDL and they decrease the
attraction of macrophages to the artery wall.
 HDL particles also contain apolipoproteins,
including ApoA-I.
Lipoproteins
 The sixth type of lipoprotein particle, Lp(a), is

synthesized in the liver and has about the same lipid
composition as LDL but is probably not derived from
VLDL.
 Lp(a) to compete with plasminogen for tissue
plasminogen receptors. Contain unique
glycoprotein apo(a). Apo(a) bears remarkable
structural homology to plasminogen, and LP(a), in
turn, competes for plasminogen binding sites, inhibits
endothelial cell surface fibrinolysis, may inhibit the
activation of plasminogen by fibrinolytic agents,
accumulating in cultured macrophages – stimulates
thrombogenesis and inhibits fibrinolysis.
Lipoproteins
 Epidemiological data show a strong and

independent association of increasing plasma
Lp(a) concentration in cerebral, peripheral,
saphenous vein graft and native coronary
atherosclerosis.
Apolipoproteins
 Protein content of lipoproteins
 ApoB levels used to estimate LDL particle number
and increased CVD risk
 ApoA-I – major apolipoprotein in HDL and is
linked to reduced CVD risk
 Functions of apolipoproteins include:
 facilitation of lipid transport through aqueous
environment
 activation of three enzymes in lipid metabolism
• lecithin cholesterol acyltransferase (LCAT)
• lipoprotein lipase (LPL)
• hepatic triglyceride lipase (HTGL)
 binding to cell surface receptors
Key points
Chylomicrons and Very Low-density
Lipoproteins
 Chylomicrons are much larger than VLDL

 Chlylomicrons contain more triglyceride per particle
than VLDL
 They contain apolipoproteins on their surface such
as:
 B apolipoproteins (B100 – VLDL; B48 – chylomicrons)
 C apolipoproteins (CII and CIII)
 A apolipoproteins (A-I and A-II)
 ApoE
LDL cholesterol
 Strongly associated with atherosclerosis and CVD
events
 10% increase results in an approximate 20% increase
in CHD risk
 Most of the cholesterol in plasma is found in LDL
particles
 Smaller denser LDL are more atherogenic than larger,
less dense particles
 Risk associated with LDL-C is increased by other risk
factors:
 low HDL-C
 smoking
 hypertension
 diabetes and the metabolic syndrome
HDL cholesterol
 HDL-C has a protective effect for risk of

atherosclerosis and CHD
 Epidemiological studies show the lower the HDL-C

level, the higher the risk for atherosclerosis and
CHD
 low level (<40 mg/dL, 1 mmol/L) increases risk
 HDL-C tends to be low when triglycerides are high
 HDL-C is lowered by smoking, obesity and

physical inactivity
 ApoA-I is the major apolipoprotein in HDL and an

elevated ApoA-I is linked to reduced CVD risk
Apolipoproteins
 Protein content of lipoproteins
 ApoB levels used to estimate LDL particle number
and increased CVD risk
 ApoA-I – major apolipoprotein in HDL and is
linked to reduced CVD risk
 Functions of apolipoproteins include:
 facilitation of lipid transport through aqueous
environment
 activation of three enzymes in lipid metabolism
• lecithin cholesterol acyltransferase (LCAT)
• lipoprotein lipase (LPL)
• hepatic triglyceride lipase (HTGL)
 binding to cell surface receptors
Lipid Transport
TG EC
Apoprotein boat
Apo A I and A II for HDL Apo B100 for LDL, Lp(a)

Apo B100+C+E – VLDL, IDL Apo B48+C+A+E - Chylomicrons
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Lipoproteins
HDL LDL
C C
T TG
G
A I, A II B 100
VLDL CM
TG TG
C
B 100 + E +C B 48+E+C
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Particle size & Density
Chylomicrons VLDL IDL

<< 1.006 < 1.006 < 1.019
LDL Small LDL HDL
< 1.063 < 1.085 < 1.210
Atherogenicity increases as density increases

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The main pathways of lipid transport to the tissues:
1. Exogenous. Lipids processed in the enterocytes are packaged to
chylomicrons, which access lymph and later enter blood circulation.
Lipoproteinlipase (LPL) that is found on the surface of endothelial
cells enables cholesterol transfer from chylomicrons to the tissue
cells.
2. Endogenous. Cholesterol and triglycerides (TG) are produced in
the liver, included in the VLDL and excreted to the blood. Here the
aformentioned LPL frees cholesterol and it enters the cells. Thus
VLDL transforms to LDL, which includes cholesterol used in:
- Peripheral tissues;
- Synthesis of bile acids in the liver;
- Can be affected by free radicals.
Endogenous Pathway of Lipid
Metabolism
LPL Lipoprotein lipase

HL Hepatic lipase
LPL
LDL
IDL
HL LPL
LDL
receptor
HL Small
VLDL LPL
Liver
HL Large
VLDL
Reverse Cholesterol Transport
 As cholesterol cannot be broken down within the

body, it is eliminated intact.
 It is transported via HDL from the peripheral
tissues to be excreted by the liver. HDL begins as a
lipid-deficient precursor which transforms into lipid-rich
lipoprotein. In this form it transfers cholesterol either
directly to the liver or to other circulating lipoproteins to
be transported to the liver for elimination.
 The observation that HDL acts as a vehicle for the
transport of cholesterol for elimination has led to the
identification of HDL as a protective factor against the
development of atherosclerosis.
Reverse Cholesterol Transport
Cell SRB1 Liver

membrane
LDL
CE CE receptor
FC
ABCA1 VLDL, IDL, LDL
LCAT CETP
HDL HDL3
TG
Peripheral
tissues
FC Free cholesterol
TG Triglycerides
CE Cholesteryl esters
LCAT Lecithin cholesterol acyltransferase
CETP Cholesteryl ester transfer protein
SRB1 Scavenger receptor class B, member 1
ABCA1 ATP-binding cassette, sub-family A, member 1
Diagnostic tests for impaired lipid metabolism
Main program Cholesterol, triglycerides, LDL cholesterol, HDL

cholesterol
Extensive program: Lipoprotein phenotypes (lipoprotein electrophoresis),
Lp(a), ApoA1, ApoB, ApoE;
Special tests: receptor test; measurement of lipolytic enzymes,

LDL oxidation and antioxidant status.
Apolipoprotein measurements are more stable, less influenced by various factors or laboratory
artefacts.
Importance of apolipoprotein test: a) more specific and sensitive than HDL and LDL diagnosing
atherosclerosis b) better reflection of congenital abnormalities compared to HDL and LDL c)
fasting is not necessary d) small chronologic variability of values.
ApoA1 reflects HDL, apoB - LDL. No risk of atherosclerosis is determined as ApoA1/apoB ratio
>1,2. The bigger is the ratio, the smaller is the risk for CAD.
ApoE participates in eliminating plasma chylomicrons and VLDL. It plays a role in the diagnosis
of type III lipoproteinemia (ApoE ), also its treatment and follow-up; and in the diagnosis of
familial form of Alzheimer’s disease.
Section 4
Dyslipoproteinemias and the

molecular basis of their treatment
STEPWISE APPROACH TO THE EVALUATION AND TREATMENT OF
DYSLIPIDEMIA IN ADULTS
STEPWISE APPROACH TO THE EVALUATION AND TREATMENT OF
DYSLIPIDEMIA IN ADULTS
FULL CLINICAL EVALUATION
STEP-BY-STEP APPROACH TO OBTAINING FAMILY HISTORY
STEP-BY-STEP APPROACH TO OBTAINING FAMILY HISTORY
Types of hyperlipoproteinemia:
 Primary (due to genetic  Secondary (due to

defects in lipid various causes, e.g.
metabolism) nephrotic syndrome,
alcoholism,
hypothyroidism,
diabetes, DM,
hepatobiliary disease)
Hyperlipidemias
Primary 5%
Familial & genetic
Secondary 95%
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SELECTED CAUSES OF SECONDARY DYSLIPIDEMIA
SELECTED CAUSES OF SECONDARY DYSLIPIDEMIA
Classification of Dyslipidaemias:
Fredrickson (WHO) Classification
 The Fredrickson classification was the first

classification of dyslipidaemias. It was based
on the analysis of plasma for various
lipoprotein fractions, but took no account of
the underlying aetiology of any of the
dyslipidaemias. In addition, high-density
lipoprotein (HDL) cholesterol levels are not
considered in this classification.
 Today it is more common to identify the
dyslipidaemias by the particular lipoprotein or
apolipoprotein that is abnormal.
Classification of Dyslipidaemias:
Fredrickson (WHO) Classification
Phenotype Lipoprotein Serum Serum Atherogenicity Prevalence
elevated cholesterol TG
I Chylomicrons mean to None seen Rare
IIa LDL mean +++ Common
IIb LDL and VLDL +++ Common
III IDL +++ Intermediate
IV VLDL mean to + Common
V VLDL and mean to + Rare

chylomicrons
LDL – low-density lipoprotein; IDL – intermediate-density lipoprotein; VLDL – very low-density

lipoprotein. (High-density lipoprotein (HDL) cholesterol levels are not considered
in the Fredrickson classification.)
Yeshurun D, Gotto AM. Southern Med J 1995;88(4):379–391 14.
Lipoprotein electrophoresis
Type I Type II Type III
Type III
(Wide beta fraction) Type IV Type V
Blue indicates normal
Familial Hypercholesterolaemia
(WHO types IIa, IIb)
 Most common genetic disorder in Europe and the
US
 Caused by a mutation of the LDL receptor
 Increases risk of CVD
 Two types of FH:
 Heterozygous FH
• one LDL-receptor gene affected
• affects about 1 in 500 people
• TC 9.0-14.0 mmol/L (360-560 mg/dL) in
adulthood
 Homozygous FH
• both LDL-receptor genes affected
• rare – affects about 1 in 1,000,000 people
• TC 15.0-30.0 mmol/L (600-1200 mg/dL) in
adulthood
Clinical Photoes
Tuberous xanthoma.
Flat-topped, yellow, firm tumor
Xanthelasma. Multiple, longitudinal, creamy-

orange, slightly elevated papules on eyelids .
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Clinical Photoes
Tendinous xanthomas. Large sub-

cutaneous tumors adherent to the
Achilles tendons.
Papular eruptive xanthomas. Multiple,
discrete, red-to-yellow confluent papules
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Familial hypertriglyceridaemia
(WHO types IV,V)
 Associated with defects either in the

production or in catabolism of VLDL.
  TG, VLDL, TC;  HDL ,LDL
  risk of ischaemic heart disease

 In patient with type V phenotype, 
chylomicronaemia, VLDL ( by alcohol axcess
and in diabetics).
 Noninsulin-dependet DM is most common
cause of secondary hypertriglyceridemia
(overproduction of VLDL).
Lipoproteinlipase deficiency (WHO type I)
 Autosomal recessive disorder.

 Hypertriglyceridaemia and chylomicronaemia
  risk of ischaemic heart diseae and acute
pancreatitis.
 Eruptive xanthomas.
 The primary defect is deficiency of either
lipoprotein lipase or its activator, apoC –II.
Home
Phenotype Elevated Lipid Possible Defect Frequency ATS

Particles Abnormality
I Chylomicron TG LP lipase Very rare Not
seen
IIa LDL LDL-C LDL-R defect Common ***
IIb LDL and LDL-C, TG HMG-CoA Common ***
VLDL reductase
III IDL TC, TG Apo-E Rare ***
deficiency
IV VLDL TG VLDL Common *
overproduction
V Chylomicron TG Apo-CII Uncommon *
and VLDL deficiency
Arcus cornealis
IIa
IIa
IIa
I
I
IIa
IIa
IIa or hepatic
Treatment Options
 Diet – Two step approach

 Drug therapy
1. HMG¢ co A Reductase Inhibitors
2. Fibric Acid derivatives
3. Nicotinic Acid
4. Ezetimibe
5. Bile Acid binding Resins (BAR)
6. Probucol
¢ HMG is Hydroxy Methyl Glutaryl
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Therapeutic Lifestyle Changes - TLC
Nutrient Recommended Intake

 Saturated fat < 7% of calories
 PUFA fat Up to 10% of calories
 MUFA fat Up to 20% of calories
 Total fat 25–35% of calories
 Carbohydrate 50–60% of calories
 Fiber 20–30 grams per day
 Protein Approx. 15% of calories
 Cholesterol Less than 200 mg/day
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Our dietary fats
 SFA (saturated) – meet and diary products, coconut oil, Kernel,

Ghee, Butter, Palm oil,
 Trans fatty acids in vanaspati, chocolates confectionaries, baked,
deep fat fried food
 MUFA (N1) – Olive oil, Gingili oil
 PUFA (N6) – Soya, Sun Flower oil, GN oil
 PUFA (N3) – Fish oils – Twice a wk ↓ 76% CAD
 Legumes, fruits, olive oil – ↓ all cause mortality
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Mechanism of Action of Statins:
Cholesterol Synthesis Pathway
acetyl CoA
HMG-CoA synthase
HMG-CoA
HMG-CoA reductase X Statins
mevalonic acid
mevalonate pyrophosphate
isopentenyl pyrophosphate
geranyl pyrophosphate
ubiquinones farnesyl pyrophosphate dolichols

Squalene synthase
squalene
cholesterol
Statins – Mechanism of Action
Cholesterol VLDL
synthesis
LDL receptor VLDL Apo B LDL receptor–mediated
R
HMGCoA Apo E hepatic uptake of LDL
(B–E receptor)
and VLDL remnants
Intracellular synthesis Apo B Serum LDL-C
Cholesterol LDL Serum VLDL remnants
Serum IDL
Hepatocyte Systemic Circulation

1. Reduce hepatic cholesterol synthesis (HMG CoA),
2. lowering intracellular cholesterol,
3. Upregulation of LDL receptor and
4.
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↑ the uptake of non-HDL from circulation.
HMG-CoA REDUCTASE INHIBITORS (STATINS) (CONT’D)
Time course of Statin effects
Vulnerable
LDL-C Inflammation plaques
lowered* reduced stabilized
Endothelial Ischemic Cardiac events

function episodes reduced*
restored reduced
Days Years
* Time course established
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Main Effects of Statins
 Effects on lipids:
 Reduce LDL-C, TC and TG
 Increase HDL-C
 Pleiotropic effects:
 Improve or restore endothelial function
 Enhance the stability of atherosclerotic plaques
 Decrease oxidative stress
 Decrease vascular inflammation
 Anti-thrombotic effects
Takemoto M, Liao JK. Arterioscler Thromb Vasc Biol 2001;21:1712-1719.
Effects of Statins on Lipids
LDL-C HDL-C TG
Statin
% change % change % change
rosuvastatin (10 mg) -52 +14 -10

atorvastatin (10 mg) -39 +6 -19
simvastatin (20 mg) -33 +8 -19
pravastatin (20 mg) -32 +2 -11
fluvastatin (20 mg) -22 +3 -12
US Product Data Sheets.
Pharmacokinetics of Statins
Statin Metabolised Protein Lipophilic Half-

by CYP450 binding life (h)
(%)
rosuvastatin minimal ~90% No ~19

atorvastatin Yes >98% Yes ~15
simvastatin Yes 95–8% Yes ~3
pravastatin No ~50% No ~2
fluvastatin Yes >98% intermediate* ~3
* intermediate between hydrophilic and lipophilic
Horsmans Y. Eur Heart J Supplements 1999;1(Suppl T):T7–12, Vaughan CJ et al. J Am

Coll Cardiol 2000;35:1–10. Rosuvastatin data from Core Data Sheet.
BILE – ACID SEQUESTRANTS (RESINS)
BILE – ACID SEQUESTRANTS (RESINS)
FIBRIC – ACID DERIVATIVES (FIBRATES)
Fenofibrate
Mode of Action
 Enhances the activity of lipoprotein lipase
 Reduces hepatic fatty acid synthesis
 Inhibits HMG co-enzyme A reductase

activity
 Reduces the CETP activity
 Increases the LCAT activity
 Increases the production of Apo AI and Apo

A II
FIBRIC – ACID DERIVATIVES (FIBRATES)
Fibric Acid Derivatives
 Major actions
 Lower TG 20–50%,↓VLDL synthesis
 Raise HDL-C 10–20%
 ↓ LDL (TG is N), ↑ LDL (TG is ↑)
 Increase the SDL particle size (less athero)
 Side effects
Dyspepsia, gallstones, myopathy, Abn. LFT
 Contraindications
Severe renal or hepatic / biliary disease
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NICOTINIC ACID (NIACIN)
Nicotinic Acid
 Products available
 Immediate-release, 2–4 g/d, Sustained Release 3 g /d
 Extended-release (Niaspan®) 1–2 g/d

 Best agent to raise HDL-C
 Reduces coronary events
 Adverse effects
 Flushing, itching, headache (immediate-release, Niaspan®)
 Hepatotoxicity, GI (sustained-release)
 Activation of peptic ulcer
 Hyperglycemia and reduced insulin sensitivity
 Contraindications
 Active liver disease or unexplained LFT elevations
 Peptic ulcer disease

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CHOLESTEROL ABSORPTION INHIBITOR
CHOLESTEROL ABSORPTION INHIBITOR
Probucol
1. Probucol (Lorelco) 500mg b.i.d with food

2. Third line drug – erratic effect on LDL & HDL
3. Lowers Cholesterol and the only drug which
regresses xanthomas
4. It is an antioxidant of LDL
5. Diarrohea, flatulence, nausea, increases QTc
6. Can be combined with BAR
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Statin + Fibrate – Precautions
 Use statin alone for non-HDL-C goals

 Use fish oils or niacin rather than fibrates
 Keep the doses of the statin and fibrate low
 Dose the fibrate in the AM and the statin in the PM
 Avoid (or cautiously use) combo in renal impairment
 Teach the patient to recognize muscle symptoms
 Discontinue therapy if muscle symptoms are present
and CK is >10 times the upper limit of normal
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Effect of Lipid-modifying Therapies
on Lipids
Therapy TC LDL HDL TG Patient
tolerability
Bile acid Down Down Up Neutral or up Poor
sequestrants 20% 15–30% 3–5%
Nicotinic acid Down Down Up Down Poor to
25% 25% 15–30% 20–50% reasonable
Fibrates Down Down Up Down Good
15% 5–15% 20% 20–50%
Probucol Down Down Down Neutral Reasonable
25% 10–15% 20–30%
Statins* Down Down Up Down Good
19–37% 25–50% 4–12% 14-29%
Ezetimibe - Down Up Down Good
18% 1% 8%
TC–total cholesterol, LDL–low density lipoprotein, HDL–high density lipoprotein, TG–triglyceride.

*Daily dose of 40 mg of atorvastatin, simvastatin, pravastatin and fluvastatin.
Yeshurun D, Gotto AM. Southern Med J 1995;88(4):379–391. Knopp RH. N Engl J Med 1999;341:498–
511. Product Prescribing Information. Gupta EK, Ito MK. Heart Dis 2002;4:399-409.
The Three Canons
DYSLIPIDEMIA
↑ LDL - STATIN
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Summary of Drug choice
Lipid abnormality type First choice Additional Remarks
↑ LDL Statin Ezetimibe Myopathy ↑
↑ TG Fibrate Niacin ↓ CHO intake
↓ HDL Niacin Fibrate Exercise
↑ LDL + ↑ TG Statin + Fibrate Niacin Myo risk ↑ ↑
↑ LDL + ↓ HDL Statin + Niacin Fibrate Exercise
↑ TG + ↓ HDL Fibrate + Niacin Statin Exercise
↑ LDL + ↑ TG + ↓ HDL Statin + Fibrate E, N, BA, FO Myo risk ↑ ↑ ↑
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Metabolic Syndrome -
Characteristics
 Hypertriglyceridemia  Insulin resistance

 Low HDL-cholesterol  Hyperinsulinemia
 Elevated apolipoprotein B  Glucose intolerance
 Small, dense LDL particles  Impaired fibrinolysis
 Inflammatory profile  Endothelial dysfunction
These features can lead to

type 2 diabetes,
hypertension and
cardiovascular disease
The interaction between our current genotype and our
present day life style and eating habits places us at very
high risk of having this phenotype B that makes us highly
susceptible to Atherosclerosis.
Journal of Internal Medicine 2003:254(2):114-25
ATP-III Criteria for Metabolic Syndrome
 Abdominal obesity (waist circumference): men

>90 cm (40 in); women >85 cm (35 in)
 Triglycerides > 150 mg/dl
 HDL cholesterol: men < 40 mg/dl; women < 50

mg/dl
 Blood pressure > 130/ 85 mmHg.
 Fasting glucose > 110 mg/dl

Diagnosis of metabolic syndrome is made when 3 or
more of the risk determinants shown above are present.
Atherosclerosis and IR and DM
Hypertension
Obesity
Hyperinsulinemia
Insulin Diabetes
Atherosclerosis
Resistance Hypertriglyceridemia
Small, dense LDL
Low HDL
Hypercoagulability
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Dyslipidemia in IR and DM
 Elevated TG
 Elevated VLDL
 Reduced HDL-C
 Increase in SD-LDL
 Decrease in Apo A I
 Increase in Apo B
 Ratio of Apo A I / Apo B < 1
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All Diabetics must be given
STATIN
Where are we heading ? ?
20000 B.C. 2012
Paleolithic sup. age Neolithic age 19th century 21st century
Processed
Hunting-gathering foods
subsistence
Animal fats
and glucides
¯ Dietary fibre
High level of
physical activity Sedentary
life
Thrifty genotype Susceptibility genotype
Technology has changed a lot in the way
we live
But, we have not altered our life style
We have to pay the very heavy price !!
What could be prevented, we treat or leave
Lifestyle Modifiable Non-modifiable
biochemical or factors
physiological
factors
Poor diet LDLch Age

(excessive intake
of saturated FA,
excessive calorie
Relation of lifestyle
load) BP Gender
and individual
characteristics to
Smoking Impaired Heredity atherosclerosis risk
carbohydrate
Excessive metabolism,
alcohol intake HDLch
Low physical TG

activity Hyperglycaemia/
diabetes
Obesity
(especially
abdominal)
Summary
• Atherosclerosis is associated with CVD, which is a
major cause of death in developed countries
• Dyslipidaemia, in particular elevated LDL-C and low
HDL-C, is associated with increased risk for CVD
• Large statin trials have shown that the lower the level
of LDL-C achieved the greater the reduction in CV
events
• Diabetes is a risk factor for CVD, which is the leading
cause of death amongst people with diabetes
• Dyslipidaemia is associated with diabetes and the
metabolic syndrome
• Guidelines recommend lipid levels to reduce the
morbidity and mortality caused by dyslipidaemia, and
proposed recommendations suggest even more
stringent levels for the future

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Atherosclerosis and

Metabolic Risk Factors

Epidemiology and Risk Factors

underweight; unsafe sex; high blood pressure; tobacco;

Clinical care of CVD is costly and prolonged

6.International Cardiovascular Disease Statistics 2003: AHA

1. Major Risk Factors

 Chronic Arterial Hypertension:

 Diminished Physical Activity:

 Elevated C-Reactive Protein:

 Elevated Fibrinogen Levels ( >300mg/dl):

 Elevated Lipoprotein α Levels (>30mg/dl):

 Plasma cholesterol at levels >200 mg/dL

 10% reduction in plasma cholesterol results in:

 LDL-C is a major target to prevent CHD

1. International CVD Statistics 2005 AHA;

Deedwania PC. Am J Med 1998;105(1A);1S-3S..

LDL-C BP Risk factors Diabetes Smoking Heart failure

NO Local mediators Tissue ACE-Ang II

Endothelium Growth factors Proteolysis

Organ Condition Impairment Clinical Presentation

Brain Cerebro vascular Ischemia Transient Ischemia attack

For every thing the common denominator is ED

External elastic membrane

 Barrier: control of LP, monocyte, etc., transit to the

 Serum lipid alterations,

 Factors that impair endothelial function,

 Factors that influence proliferation of the smooth muscle

 Endothelial damage (first, transforms normal endothelial

 Lipid and lipoprotein metabolism measures (total

Decades Years-Months Months-Days

Antischkow N. Beitr Path Anat Allg Path 1913;56:379-404. 17

Decades Years-Months Months-Days

Protective response results in production of

Monocytes and T lymphocytes attach to

Migrate through arterial wall to subendothelial space

Macrophages take up oxidised LDL-C

Lipid-rich foam cells

Fatty streak and plaque

cytokines (eg. IL-1, TNF-)

attracts monocytes and T induces cell

Koenig W. Eur Heart J Suppl 1999;1(Suppl T);T19-26.

Migration of leucocytes into

Adherence and aggregation

Formation of foam cells

Adherence and entry of

Rupture of the fibrous

Libby P. Circulation 1995;91:2844-2850.

SMC – smooth muscle cell

The Intravascular Ultrasound (IVUS)

Images courtesy of Cleveland Clinic Intravascular Ultrasound Core Laboratory

Arrow indicates atherosclerosis (stenosis) of the coronary artery

left carotid artery relatively

Chu B et al. Stroke 2004;8:2444–2448. 31.

Reproduced with permission from Kastelein, JJP et al. Am Heart J 2005;149:234–239.

 Coronary heart disease

 Peripheral vascular disease

The extent of damage is limited due to fibrin precipitation.

 This protein contains  Synthesized by

Ceruloplasmin is increased in the acute phase of

 Stimulates activity of Also,

 CRP level starts increasing 4-6 hours after the onset of

 More than 20 proteins of  Levels of C3, C4 and