Microsoft PowerPoint - A_Aterosklerosa_2012_IV.ro\350n\355k_A_MP

Attention
Atherosclerosis is NOT arteriosclerosis !!!
Atherosclerosis
Atherosclerosis is a systemic disease
affecting arterial blood vessels
(large and medium)
Is only a subgroup of arteriosclerosis
http://www.sciencephoto.com/media/108884/enlarge
http://www.teachpe.com/anatomy/arteries.php
Stěna tepny
Functions of parts
of the walls of arteries
• Adventicia
– Connection with its surroundings;
– autonomic nerve endings (varicosity –
synapse in passant, parietal plexus)
– vasa vasorum
• Media (blood pressure perpendicular to wall)
– Arteries elastic type (flexible)
– Muscular type arteries (TPR)
• Intima (longitudinal, shear blood pressure)
Lumen cévy je vpravo. Stěna je silnější než u žíly, převážnou část
tvoří svalová tunica media.
http://old.lf3.cuni.cz/histologie/Atlas0/fotka.php?fotka=219
– Endothelium contact with blood
Fig:: http://quizlet.com/10448592/bio446l-lecture-exam-2-flash-cards/
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Endothelium
Endothelial function
Endothelial cells:
Dynamic endocrine organ,
Regulates
• Not considered a true epithelium, as arise from
the mesenchyme. Create complex connections
with neighboring cells
• Stored von Willebrand factor(Weibel-Paladeova tělíska)
1. activity of vascular wall
(contractile, secretory and mitogenic)
2. homeostatic processes in the vessel lumen
•
Structural and functional integrity of the endothelial cells (=
endothelium) is essential for homeostasis of the vascular wall and
blood circulation
Besides participating in the formation of a blood clot (thrombus),
endothelial damage is a key moment in the development of
atherosclerosis, indirectly hypertension, and participates in a
number of diseases other organs.
Fig: http://www.jceionline.org/upload/sayi/12/301/02-AGurbet-1.htm
Endothelium
Keeps non-thrombogenic interface between the
blood and tissues, regulate thrombosis,
thrombolysis and adherence of platelets.
Modulates vascular tone and blood flow.
Metabolizes hormones.
Regulates immune and inflammatory responses
by acting on the interaction between the vessel
wall and leukocytes.
Modifies lipoproteins in the artery wall.
Regulates proliferation of other cells, especially
vascular smooth muscle.
Endothelial function I
Maintaining a permeability barriers
Modulation of blood flow
Vasoconstriction: ET1, Tx A2, ACE
vasodilatation: NO·, prostacyklin, „hyperpolarising
factor“ (activation ATP- a Ca2+ – dependent K+ channel)
Contractile (and mitogenic) activity of the vascular
smooth muscle
Red-ox balance
NOS
NOS
Katalýza L-arginin na L-citrulin
Kofaktors NOS:
Flavinmono(di)nukleotid
Tetrahydropterin
Calmodulin complex
They influence the effect
of NO
temporarily
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Endothelial function I I
Fluido – coagulation balance
Synthesis of anticoagulant and
antithrombotic molecules
prostacyclin
thrombomodulin
activator of plasminogen
molecules like heparin
Synthesis of prothrombotic molecules
von Willebrand factor
tissue factor (III)
plasminogen activator inhibitor
Endothelial function III
Regulation of inflammatory and
immune processes
IL 1, IL 6, IL 8
adhesion molecule (VCAM-1)
histocompatibility antigens
Regulation of cell growth
growth stimulators: PDGF, FGF, CSF
growth inhibitors: heparin, TGFb
Endothelial dysfunction
Endothelial function IV
Formation of extracellular matrix
(collagen, proteoglycans)
•
•
•
•
Vasoconstriction
Platelet aggregation
The proliferation of smooth muscle
Leukocyte adhesion (surface expression
of adhesion molecules)
• Bold: Key moments in the development of
atherosclerotic plaque
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Dysfunkční endotel
Vasodilatace
Vasokonstrikce
Antikoakulace
Prokoagulace
Protizánětový
efekt
Prozánětové
Antioxidační
Growth Fact.
cytokiny a adhezní
molekuly
Atherosclerosis
• Failure of intima !!! (chronic inflammation)
• Endothelial dysfunction
• Atheroma formation
• Impairment
of vascular wall
Tento a další
další obrá
obrázky s českým textem jsou z textu Prof. Masopusta: Aterosklerosa
How Artherosclerosis Develops
Cross Section of an Artery
•
Atherosclerosis begins
when white blood cells
called monocytes migrate
from the bloodstream into
the wall of the artery and
are transformed into cells
that accumulate fatty
materials. In time, a patchy
thickening (plaque)
develops in the inner
lining of the artery.
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Atherosclerosis
• Endothelial dysfunction
• Entry below endothelium:
– Oxid. LDL ( homocystein, ROS ….)
– Macrophages ⇒ foam cells
– Lymphocytes
results ⇒ Atheroma mass
• Subsequently entry:
– smooth muscle cells from the media
Atherosclerosis
Fig.: Scheme of the initial phase of endothelial dysfunction
• Endothelial dysfunction
• Entry below endothelium:
– Oxid. LDL ( homocystein, ROS ….)
– Macrophages ⇒ foam cells
– Lymphocytes
results ⇒ Atheroma mass
• Subsequently entry:
– smooth muscle cells from the media
MCPMCP-1 monocytový chemoatraktantchemoatraktant-protein 1
Obr.: Schematic atheroma plaques
Smooth muscle
• Smooth muscle cells are also involved in
the formation of atherosclerotic lesions.
Together with monocytes accumulate in the
intima, particularly at the stage of fibrous
plaques. Into the intima they travel outside from
the media in response to various cytokines and
growth factors (eg. IL-1, TNF-alpha, PDGF).
Stable plaques vs. unstable plaques
• The atherosclerotic lesion is characterized by
change contractile phenotype of smooth muscle
cells in the synthetic phenotype.
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Transformed smooth muscle cells
Endothelial
dysfunction
• ↑ synthesis of extracellular matrix, mainly
collagen (type I, type II, and others)
• They form the core of lipid fibrous cap
(along with the components of the extracellular matrix)
• They can transform into foam cells
• ↑ masses of collagen ⇒ changes in the
mechanical properties of the vascular
wall.
Atherosclerosis
Chronic inflammatory process initiated and fostered by oxidative
stress
Risk factors for atherosclerosis
Known more than 200
The main 3:
1. Abnormal lipid metabolism
2. Hypertension
3. Smoking
Homocysteine teory
If reducing cholesterol levels, may be within 3-5 years
artery stenosis modify
Risk Factors
Atherosclerosis, risk factors
• Mechanical:
Mechanical hypertension, shear stress
• Plasmatic:
Plasmatic ↑glykémie, ↑LDL, ↑TAG, ↑acid uric, homocytein…
• Endothelial Red – ox balance: smoking ….
• Inflammatory:
Inflammatory cytomegalovirus,…
• Civilization:
stress, ↓ movement
Uncontrollable
Controllable
•Sex
•High blood pressure
•Hereditary
•High blood cholesterol
•Race
•Smoking
•Age
•Physical activity
•Obesity
•Diabetes
•Stress and anger
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Factors of atherogenesis
Risk Factors in Atherosclerosis
Minor Risk Factors:
Factors:
1. Environmental influences
2. Obesity
3. Hormones: Oestrogen deficiency, oral contracep.
4. Physical inactivity
5. Stressful life
6. Infections (C. pneumoniae, Herpes virus, CMV)
7. Homocystinuria
8. Role of Alcohol
•
•
•
•
•
LDL
Homocysteine (> 14 µmol/l, resp. 10,2 µmol/l)
Diabetes melitus (hyperglykémie, AGE), NF–Kapa B
Hypertension: AGT II
Infection (herpes virus, chlamydia pneumonie, ……
periodontitis)
• Inflammatory reaction (response to mechanical
damage to the blood stream– ICAM, VCAM for T-ly)
• Cigarette smoking (nicotine eg.
immunosuppression ....)
The emergence of various proinflammatory
factors such as the expression of endothelial
dysfunction
Cell metabolism
Endothelium, macrophages, lymphocytes, smooth
muscles
Activation of
• MAPK (mitogen-activated protein kinase)
• nuclear factor Kappa b
Results:
• inflammation, growth, differentiation and
apoptosis
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Early stage of development of plaque
The accumulation of lipids
Isolated foam cells derived from macrophages;
fatty streaks - accumulation of foam cells
containing intracellular lipid accumulation;
intermediate lesions - small amounts of
extracellularly stored lipids from dead foam cells;
atheroma - formation of lipid core, formed
extracellularly accumulated lipids.
Late stages of plaque development
Obr.: Schematic atheroma plaques
Intimal proliferation and thrombosis
fibroaterom - proliferation of smooth muscle cells
in the intima and increased synthesis of
extracellular matrix, including collagen and elastic
fibers, which creates a fibrous layer of lipid core
complicated lesions - calcification, rupture or
exulceration, bleeding in the atheroma, thrombus
formation.
Stable plaques vs. unstable plaques
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Atherosclerotic plaque
• Atherosclerotic plaque is formed:
– nucleus with abundant extracellularly stored lipids
and
– fibrous cover (cap, cap), consisting of connective
tissue with a predominance of collagen and
proteoglycans surrounding muscle cells.
• Stable plaque are characterized by strong
and intact fibrous cap. Conversely
vulnerable plates are placed in the core of
large amounts of lipids, foam cells and T
lymphocytes, whereas the thin fibrous cap
with a low content of collagen.
Atherosclerotic plaque, cont.
• Unstable plague are susceptible to rupture, which is
responsible for the majority of acute coronary events.
The plaque instability contributes to the inflammatory
process that occurs in places of accumulation of
macrophages and T lymphocytes. Macrophages are
a source of proteolytic enzymes (metalloproteinases)
collagenase, stromelysin, which may weaken the fibrous
cap. On the contrary, T cells present in plaque produce
interferon gamma suppresses collagen synthesis of
smooth muscle cells, and CD40 stimulating the synthesis
of metalloproteinases.
• Plaque rupture is a reason to hemorrhage into a plaque
and the creation of thrombus.
FIGURE 1 DEVELOPMENT OF ATHEROSCLEROSIS
Adapted from Koenig W, Khuseyinova N. Biomarkers of
atherosclerotic plaque instability and rupture. Arterioscler Thromb
Vasc Biol. 2007;27:15-26, with permission.
http://www.arteriograf.hu/sk/arteriograf/o_arteriografe_pre_vsetkych/co_je_to_ateroskleroza
http://www.jfponline.com/pages.asp?id=8085
FIGURE 3 INTRAVASCULAR ULTRASOUND OF PLAQUE AT BASELINE (LEFT
PANEL) AND OF PLAQUE REGRESSION WITH DECREASED ATHEROMA
VOLUME AFTER 24 MONTHS OF INTENSIVE ROSUVASTATIN THERAPY (RIGHT
PANEL) IN A PATIENT WITH CORONARY ARTERY DISEASE IN THE ASTEROID
TRIAL
Reprinted from Sipahi I, Nicholls SJ, Tuzcu EM, et al. Coronary
atherosclerosis can regress with very intensive statin therapy.
Cleve Clin J Med. 2006;73:937-944, with permission. Copyright ©
2006 Cleveland Clinic. All rights reserved.
http://www.jfponline.com/pages.asp?id=8085
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Ultrazvuk normální cévy
Aterosklerotický plát v obrazu
intravaskulárního ultrazvuku.
Žlutá barva
– linie lamina elastica externa,
modrá linie – lumen tepny,
plocha mezi liniemi
http://medicalmyths.wordpress.com/atherosclerosis/
– aterosklerotický plát
http://www.brown.edu/Courses/Digital_Path/systemic_path/cardio/atherosclerosis-ca.html
A cross-section of
coronary artery that has
significant luminal
obstruction by an
atheroma. A lipid-rich
core can be seen in the
center of the lesion.
Shown is a typical eccentric atherosclerotic plaque. A central necrotic core
shows dystrophic calcification. Note the fibrous cap and that the media is
thinned throughout most of the circumference.
Remember:
Atherosclerosis is a chronic inflammatory
process of arterial wall (Intima)
• Risk factors
• Activation and endothelial dysfunction
• Changes in the endothelium, intima
• Consequence of the changes of arterial of
hemodynamics ⇒ difficulties during exertion
http://medicalmyths.wordpress.com/atherosclerosis/
The consequences of atherosclerosis
• Synthesis of predominantly vasoconstrictive
substances and reducing synthesis vasodilators
⇒ reduced ability vasodilatation
• Narrowing of the lumen of blood vessels ⇒ change in
blood flow and endothelial dysfunction potentiation ⇒
atherosclerosis
• Procoagulant activation cascade ⇒ easy creation of
thrombus and vessel closure ⇒ ischemia (angina,
heart attack)
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Case report
Anamnesis
Physical examination
• BP: 180/90 mm Hg; HR: 70/min;
• 76-year-old man complains on pain in the left
lower limb while walking. He also complains on
crushing substernal pain after climbing the
stairs, which subsides with rest.
• Past medical history: diabetes and hypertension
• Abuse: smoking
• The patient notes that he has taken many
different medications on hypertension but with
little or no effect
• Auscultation:
– murmur over the left carotid artery
– chest sounds are clean
– heart: increased apex beat, the first and second heart sounds
are clean, third sound is audible; all sounds are without murmurs
• Abdomen: soft without resistance, on auscultation –
presence of murmur in the center of abdomen
• Lower limbs: murmurs are heard over both of femoral
arteries; pulse is weakly palpable on the left dorsal pedal
artery
• ECG: in chest leads V3 – V6 = T wave inversion
Laboratory findings:
Patient
Normal
Total
cholesterol
7.8 mmol/l
< 5.2 mmol/l
LDL
4.91 mmol/l
< 3.0 mmo/l
HDL
0.8mmol/l
> 1.6 mmo/l
Questions
• Briefly describe the patient's state.
• What causes patient’s leg pain? Is there specific name
for this type of pain? How would you confirm your
diagnosis?
• What causes patient’s chest pain? Is there specific name
for this type of pain?
• What causes the murmurs over the arteries?
• Is there one cause for most of the patient's symptoms?
If yes, briefly describe it.
• How do you explain the patient's hypertension that has
not responded to most drugs?
• Could you unify patient’s signs and symptoms to single
nosological unit?
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Which stage the patient probably has ?
Thank you for your attention
http://www.scientific-art.com/portfolio%20medicine%20pages/atherosclerosis.htm
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