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Atherogenesis, atherogenic risk factors

and control of atherogenic dyslipidemias

Assoc Prof Serban Balanescu, MD


The normal
structure of
arterial wall

Intima (endothelium)
Media
Adventitia
The main endothelium functions
Vasodilation: Anti-thrombotic:
Pro:
Pro: Plasminogen (t-PA)
Prostacyclin
NO (EDRF)
Thrombomodulin, heparan-
Prostacycline sulphate
Against:
Bradykinin PAI 1
Acetylcholine Tissue factor (prothrombin)
von Willebrand factor
Against:
Angiotensin II - ACE Anti-inflammatory anti-proliferative:
Pro:
Endothelin
NO
Cathecolamines Against:
Thromboxane The lack of NO
AT-II, aldosterone
Na++ in excess
IL-6, VCAM, ICAM
MCP, MCSF, PDGF, FGF
Atherosclerosis: definition
Athre: porridge, gruel; skleros: rigid

chronic inflammatory disease of arterial wall

determined by endothelial dysfunction due to

various causes defined by:

Sub-intimal load with ox-LDL cholesterol

Cellular inflammation by focal subintimal

accumulation of circulating monocytes and T

lymphocytes

Healing process with fibrosis by proliferation of

smooth muscle cells


The theory of response to injury:
causes

Hypercholesterolemia Infectious factors:

oxLDL, apoB, Lp(a) Viruses

Bacteria
Chronic mechanical stress:
Chlamydia
hypertension
Immunologic disease
Smoking
Genetic factors
Toxic factors: i.e. homocysteine,

uric acid, a.s.o


1. Initiation of AS
(early phase)

4. Subintimal load with LDL


1. The presence of risk factors
5. LDL oxidation (potent pro-
2. Expression of adhesion molecules
inflammatory molecule)
3. Subintimal migration of monocytes 6. Macrophages loaded with ox-LDL
Subintimal loading with atherogenic lipoproteins

Extracellular
VLDL
matrix

LDL

Collagen
fibers

Frank JF, Fogelman AM. J Lipid Res 1989;30(7):967-978.


Endothelial injury:
Total cholesterol > 180
mg/dl
BP > 160/90 mmHg
high blood glucose - AGE
homocystein
hypoxemia + CO

Monocyte and T-lymphcyste adhere to


endothelium mediated by adhesion molecules:
selectins (E, L, P)

VCAM-1 and ICAM-1

Macrophage proliferation (MCP, MCSF-1)


and load with ox-LDL (foam-cells)
2. The fatty streak

Pure inflammatory lesion:


macrophages derived from circulating monocytes:

foam cells

T-cells

smooth muscle cells migrated CMN migrate din medie

does not induce symptoms, does not reduce blood flow


Coronary fatty streak

Foam cells

Macroscopic view

Microscopic view (HE)


Atherosclerosis starts in early life
Diagnosis by intravascular ultrasound on cardiac grafts before heart
transplantation
100%

80% 70%
Atherosclerosis
prevalence (%)

60% 47%

40%
22%

20%

0%
< 25 years 25-35 years >35 years old

Nissen
Nissen S.
S. Am
Am JJ Cardiol
Cardiol 2001:87(suppl):15A-20A.
2001:87(suppl):15A-20A.
3. Fibrous plaque
cholesterol loaded macrophages:

foam cells

CD8 and CD4 T-lymphocytes


LIPID CORE
Smooth muscle cells - transformed

in fibroblasts
Lumen
Variable calcium load (osteopontin)

FIBROUS CAP Capison


fibros
Miez lipidic
DYSFUNCTIONAL ENDOTHELIUM
Glagov phenomenon or
positive vessel remodelling

Glagov et al. NEJM 1987;316:1371-5.


4. Thin cap fibro-
atheroma and the Lumen containing
thrombus
ulcerated plaque
Focal disruption of fibrous cap
Ulcerated
fibrous cap

Excesive cellular inflammation + Lipid core

Low collagen and SMCs

Large necrotic lipid core

+/- intraluminal thrombus

Intraplaque haemorrhage

Excessive vasa vasorum in adventitia

Determines ACS: unstable angina,


NSTEMI or STEMI
Ulcerated aortic
plaques
(penetrating
ulcerated plaque)
AHA classification of AS lesions
Type I: monocytes migrated subintimally

Type II: fatty streak (celule spumoase)

Type III: extracellular ox-LDL deposits

Type IV: intimal migration of SMCs, formation of lipid necrotic core

Type V: formation of the fibrous cap


Va: lipid core + fibrous cap

Vb: calcification

Vc: collagen + smooth muscle cells, small lipid core

Type VI: ulcerated, complicated plaque with intra-luminal thrombus

Stary HC et al. Circulation 1995;92:1355-74.


1. Dyslipidemia

Cholesterol is a basic component


of:
cell membranes
bile salts and acids
Steroid hormones
Circulates in plasma as esters binded to
lipoproteins

National
National Cholesterol Education
Education Program.
Program. Adult
Adult Treatment
Treatment Panel
Panel III.
III. JAMA
JAMA 2001;285:2486-97.
2001;285:2486-97.
Serum lipoprotein structure
Differences between serum LP are due to different types of apo and % of lipid loads

Apo-lipoproteins: Phosfolipids
formation and secretion of LP

(apo B100 si B48)

structurala integrity of LP

(apo B, apo E, apo AI and AII)

enzyme coactivators or inhibitors


Triglycerides
(apo AI, apo CI - CIII)

binding to cell receptors to


Free cholesterol

incorporate the complex particle

or selective uptake of a

component (apo AI, B100, E)

Cholesterol
esters
Serum lipoproteins
Lipoprotein Density Major lipid Major apo- Electrophoretic
(g/ml) constituent lipoprotein migration
Chilomicrons <0.95 Food triglycerides B48 Origin

VLDL <1.006 Endogenous B100 Pre-


triglycerides

IDL 1.006 - 1.019 Cholesterol esters, B100, E Slow pre-


TG

1.019- Cholesterol B100


LDL 1.063 esters
1.063- Cholesterol A I, A II
HDL 1.210 esters,

phospholipids
Lp(a) 1.055 - 1.085 Cholesterol esters B100, (a) Slow pre-
Relative dimensions of serum LP
- explains electrophoretic migration -
Endogenous lipoprotein metabolism
LPL LPL

LPL

HL
HL

Oxidation
CETP
CD36
SR-A

Recycled Macrophage
(foam cell)

LCAT ABCA1
LCAT Nascent
HDL Arterial wall
Brewer HB et al. Am J Cardiol 2003;92:10K-16K.
Genetic dyslipidemias 1
Type II hyperlipidemia (familial hypercholesterolemia):
High LDL by a gene mutation of the LDL receptor
Prevalence: 1 / 250-500 in Caucasians
autosomal co-dominant hereditary transmission
Gerontoxon, xantelasma, tendinous xanthomas
High risk of early coronary disease (3rdrd and 4thth decade; 10 years delayed onset in F)

Type IV hyperlipidemia (familial hypertriglyceridemia):


Serum TG and VLDL markedly increased (200 500 mg/dl, post prandial 1000 mg/dl)
Unidentified genic anomaly
Prevalence between 1 / 100 and 1 / 50
Potentiated by alcohol and high carbohydrates diet
Low LDL, low HDL
Less prominent connection with coronary disease, vs high LDL
Gerontoxon
Xantelasma

Subcutaneous xanthomas
Secondary dyslipidemias
Metabolic Diabetes mellitus
Lipodystrophias Glicogenosis

Bad life style Sedentarism Rich saturated lipid diet


Obesity Alcohol abuse

Drug induced Cortisone and steroids Thiazide diuretics


Estrogen Beta-blockers
Testosterone cyclosporine
Anti-retroviral Anti-depressive drugs

Renal Chronic kidney disease


Glomerulonephritis; Nephrotic syndrome

Hepatic Ciroza hepatica

Endocrine disease Estrogen progesterone


Hypothyroidism Hypercorticism (Cushing Sdr)
Dyslipidemia and high BP: metabolic sdr
abdominal obesity (waist circumference):

Men > 102 cm

Women > 88 cm

Highly atherogenic dyslipidemia :

triglycerides

small LDL Type V


HDL hyperlipidemia
High blood pressure ( > 130/80 mmHg)

Glucose intolerance by insulin resistance)

Systemic pro-thrombotic status

Pro-inflammatory status

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.
2. Systemic HT
Increased incidence of:

Cerebrovascular disease - stroke

Atherogenesis

Coronary disease

independent risk factor for AS

ARS, catecholamines: cellular changes leading to AS

A-II: potent vasoconstrictor, activates Ca channels on SMCs

A-II: induce fenotypic expression of receptors for PDGF, TGF, FGF

Leads to focal endothelium lesions predisposing to plaque formation at bifurcations

Increases endothelial permeability to serum lipoproteins


3. Smoking
Very strong correlation with atherosclerosis:
Increases 2-3 x the risk for coronary disease

Increases CV mortality by 50%

CV risk increases with age and number of cigarettes

second hand smoking also increases CV risk

Pathogenesis:
Endothelial dysfunction (CO, nicotine)

Excessive vasoreactivity, vasoconstriction, increased BP

High serum levels of ox-LDL

Less protective role of HDL

High levels of plasma fibrinogen, increased platelet aggregation

Abstinence reduces AS complications and may induce lesion regression; irrespective of age
Smoking is the main preventable cause of death in USA
Produces 438.000 deaths every year
35% are due to cardiovascular causes
8% of deaths are due to second-hand smoking

Smoking leads to a total loss of 5 million years of life per year in the world

97
100 91 Non-smoking doctors
94 81 Smoking doctors
80
81
Survival at every

59
60 59
age (%)

10 years
40
24
20 26
2
4
0

40 50 60 70 80 90 100
Age (years)
Doll
Doll R
R et
et al. BMJ
BMJ 2004;328:151927.
2004;328:151927.
4. Diabetes mellitus
Increased risk for CAD: 2-3 x more in M, 3-5 x more in F

CAD: the main cause for death in DM

25% of ACS survivors have DM, > 50% have anomalies of glucose metabolism

Mechanisms for atherogenesis:

Increased Lp(a)

Increased LDL

Low HDL, high TG

Endothelial dysfunction

Increased platelet aggregation

Defective fibrinolysis (high PAI-1)

Proliferation of SMCs in the media

High prevalence of high BP (insulin resistance)


?
Stable plaque
vs
Ruptured plaque
Rupture of unstable plaque
- producing factors -
Intrinsic plaque vulnerability: thin-cap fibro-atheroma(TCFA)
Large lipid core
Thin fibrous cap
Rich inflammatory cells infiltrate

Bio-mechanical factors:
Sudden in BP
Sudden in HR
Vasospasm
Rupture of vulnerable plaque
The thickness of fibrous cap
Large lipid core, thin fibrous cap
Vulnerable plaque Stable plaque

Lipid core
lipid core

Abundant Miez lipidic Small

Thin < 150 m Capison fibros Thick

Numerous Macrofage, LT Few

Few Celule musculare netede Many

Numerous Numarul vasa vasorum la baza placii Few

Ruptured Lamina elastica interna Integer

Davies MJ et al. Circulation 1996;94:2013-20.


Vulnerable plaque
thrombosis

Erosion:
- 25% of lesions
- associated with smoking
- more frequent in F

Rupture:
- 75% of lesions; n = 298 pts
- abnormal lipid prophile

Arbustini E et al. Heart 1999;82:269.


Rupture

Erosion
Treatment of dyslipidemias: drugs
Mechanism of
Drug Adverse effects Clinical trials results
action
Atorvastatin (10-80 mg)
Fluvastatin (20-80 mg)
HMG CoA reductase Liver enzymes, Major coronary events,
Lovastatin (20-80 mg)
Statins inhibition in myopathy, rash, digestive coronary mortality,
Pravastatin (20-40 mg) hepatocytes disturbances AVC
Rosuvastatin (10-40 mg)
Simvastatin (20-80 mg)

Cholestyramine (4-16 g) Inhibits intestinal Constipation, digestive


Bile acid Major coronary events,
Cholestypol (5-20 g) reabsorption of bile disturbances, drug
chelation acids absorbtion coronary mortality
Colsevelam (2.6-3.8 g)

Crystalline (1.5 3g) Rash, hyperuricemia,


Nicotinic Decreases hepatic abnormal OGTT, gastritis,
Major coronary events,
Long acting (1-2g)
acid VLDL production
Liver enzymes
Global mortality
sustained release (1-2g)

Clofibrate (1g x 2) Stimulation of a nuclear Rash, digestive


transcription factor: disturbances, myopathy, No influence on major
Fibrates Gemfibrosil (600 mg x 2)
PPAR- for LPL, apo cholelitiasis, Liver coronary events
Phenofibrat (200 mg) CII and Apo AI enzymese, ED

Cholesterol
Selective block of Major coronary events
absorbtion Ezetimibe (10 mg)
NPC1L1 in enterocytes
Idem statins
(over statins)
inhibitors

National
National Cholesterol
Cholesterol Education
Education Program.
Program. Adult
Adult Treatment
Treatment Panel
Panel III.
III. JAMA
JAMA 2001;285:2486-97.
2001;285:2486-97.
THE THERAPEUTIC EFFECTS OF THE MAIN
DRUGS USED TO TREAT DYSLIPIDEMIA

Drug class LDL TG HDL

STATINS 18 55% 7 30% 5 15%

FIBRATES 5 20% 20 50% 10 20%

RESINS 15 30% - 3 5%

NICOTINIC 5 25% 20 50% 15 35%


ACID
NCEP Adult Treatment Panel III. JAMA. 2001;285:2486-2497.
LDL
LDL reduction
reduction with
with statins
statins is
is different
different
depending
depending on
on molecular
molecular structure
structure
2431 adult pts with LDL > 160 mg/dl; TG < 400 mg/dl

Dose (mg)
10 20 40 80
0

Rosuvastatin
10
LDL-C reduction vs

Atorvastatin
baseline (%)

20 Simvastatin
X
X Pravastatin
30 n=485
X
40 X
FU = 6
X n=648
weeks
50 * n=634
n=473
60

Jones
Jones PH
PH et
et al.
al. STELLAR
STELLAR Study.
Study. Am
Am JJ Cardiol
Cardiol 2003;92:15260.
2003;92:15260.
PCSK-9 inhibitors: the new kids on the block

Lambert G, et al. J Lipid Res. 2012;53(12):2515-24.


The role of PCSK-9 to regulate LDL receptor
expression

Lambert G, et al. J Lipid Res. 2012;53(12):2515-24.


Role of PCSK9 inhibitors (monoclonal
antibodies) to increase LDL expression

Lambert G, et al. J Lipid Res. 2012;53(12):2515-24.


Pharmacokinetics and pharmacodynamics of
evolocumab: changes in PCSK9 and LDL-C

FOURIER trial results with clinical end-points eagerly expected in 2017


Stein EA & RaalFJ Annu. Rev. Med. 2014. 65:41731.
Clinical variables that assess CV risk in PRIMARY
prevention (no definite CV disease is present)

High risk defined by


the risk of fatal CVD
at 10 years 5%

Used in European countries


with the exception of those at
low risk (Belgium, France,
Greece, Italy, Luxembourg,
Spain, Switzerland, Portugal)

Catapano AL et al. Eur Heart J 2016;37:2999-3058.


Lipid fractions as treatment targets in the prevention of
CV disease

Catapano AL et al. Eur Heart J 2016;37:2999-3058.


Clinical variables that influence decision for cholesterol
reduction and LDL goals with medication

Catapano AL et al. Eur Heart J 2016;37:2999-3058.


Clinical variables that influence decision for cholesterol
reduction and LDL goals with medication

Catapano AL et al. Eur Heart J 2016;37:2999-3058.


Treatment goals for LDL-cholesterol depend on baseline
risk of fatal CV disease at 10 years

Catapano AL et al. Eur Heart J 2016;37:2999-3058.


Treatment targets and goals for CV disease prevention

Catapano AL et al. Eur Heart J


2016;37:2999-3058.
Recommended reading

Catapano AL et al. 2016 ESC/EAS Guidelines for the management of


dysllipidemias. Eur Heart J 2016;37:2999-3058.
available for free download at:
http://www.escardio.org/Guidelines/Clinical-Practice-Guidelines/Dyslipidaemias-
Management-of