טרשת עורקים-מצגת מספר 2
TRANSCRIPT
H.Cohen 04-2009H.Cohen 04-2009 11
היפרליפידמיההיפרליפידמיה וטרשת עורקים וטרשת עורקים
22חלק חלק
היפרליפידמיההיפרליפידמיה וטרשת עורקים וטרשת עורקים
22חלק חלק דר' כהן חופיתדר' כהן חופית
מרכז הליפידים ע"ש ברוך שטרסבורגר ז"ל מרכז הליפידים ע"ש ברוך שטרסבורגר ז"ל
המרכז הרפואי ע”ש שיבא תל השומרהמרכז הרפואי ע”ש שיבא תל השומר
2009
H.Cohen 04-2009H.Cohen 04-2009 22
Pathogenesis Pathogenesis of of
AtherosclerosisAtherosclerosis
H.Cohen 04-2009H.Cohen 04-2009 33
חומר קריאה חומר קריאה דרך האתר של ספריית בית הספר לרפואה:דרך האתר של ספריית בית הספר לרפואה:להרצאותלהרצאות
Harrison's Principles of InternalHarrison's Principles of Internal MedicineMedicine 16th Edition / 16th Edition / Harrison's Online Chapter Harrison's Online Chapter
224.224. The Pathogenesis of Atherosclerosis The Pathogenesis of Atherosclerosis
Basic & Clinical EndocrinologyBasic & Clinical Endocrinology Francis S. Greenspan, David G. Gardner 7th Francis S. Greenspan, David G. Gardner 7th
edition 2004 edition 2004 chapter 19chapter 19
Immune and Inflammatory Mechanisms of Atherosclerosis. Annu. Rev. Immunol.
2009. 27:165–97
הטקסט של ההרצאה –מתחת לשקופיתהטקסט של ההרצאה –מתחת לשקופית
H.Cohen 04-2009H.Cohen 04-2009 44
AtheroscleroticAtherosclerotic plaqueplaque
Atherosclerosis-definition
H.Cohen 04-2009H.Cohen 04-2009 55
Coronary Heart Disease
Cerebro Vascular Disease
PVD
Atherosclerosis
BiologyInflammationCoagulation
Endothelial functionT cell
Macrophages
Risk Factors
DyslipidemiaDiabetes
HTNSmoking
FHx
clinical manifestations
H.Cohen 04-2009H.Cohen 04-2009 66
Major Vascular Manifestations of Major Vascular Manifestations of AtherothrombosisAtherothrombosis
Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6
Angina pectoris
Ischemicstroke
Myocardial infarction
Peripheral arterial disease:• Gangrene• Necrosis
Carotid vertebral
coronary
Femoral iliac
splanchnic circulation
renal artery stenosis
mesenteric ischemia
H.Cohen 04-2009H.Cohen 04-2009 77
Atherothrombosis is the Leading Cause Atherothrombosis is the Leading Cause of Death Worldwideof Death Worldwide
52%
5%
12%
14%
19%
24%
0 10 20 30 40 50 60
Atherothrombosis*
Cancer
Infectious Disease
Pulmonary disease
Violent death
AIDSMortality (%)
Cardiovascular disease, ischemic heart disease and cerebrovascular disease
World Health Organization. The World Health Report 2001. Geneva: WHO; 2001.
Cardiovascular disease is a leading cause of global mortality, accounting for almost 17 million deaths annually or
30% of all global mortality . 2007
H.Cohen 04-2009H.Cohen 04-2009 88
Atherothrombosis and Cause of Death in IsraelAtherothrombosis and Cause of Death in Israel ??? ???
1998-2004דו"ח משרד הבריאות
סיבות מוות בישראלסיבות מוות בישראל נפש100,000שיעור ל-
נשים גברים
146140סרטן
113113 119119מחלות לב מחלות לב
36364343 מחלות כלי דם במוחמחלות כלי דם במוח
3642סוכרת
H.Cohen 04-2009H.Cohen 04-2009 99
Slide 20. The arterial wall consists of three functionally separate layers: 1) the intima (composed of a single monolayer of endothelial cells, in contact with circulating blood), 2) the media (composed mainly of smooth muscle cells, embedded in extracellular matrix), and 3) the adventitia (harbours nutrient vessels, nerves and dense fibroelastic tissue). Reproduced with permission from Ross R, Glomset JA. The pathogenesis of atherosclerosis (part 1). N Engl J Med 1976; 295:369-377. © 1976 Massachusetts Medical Society. All rights reserved.
smooth musclesmooth muscle
H.Cohen 04-2009H.Cohen 04-2009 1010
Cross section of an arteryCross section of an artery
sub-intimal space
H.Cohen 04-2009H.Cohen 04-2009 1111
Atherosclerosis Timeline
FoamFoamCellsCells
FattyFattyStreakStreak
IntermediateIntermediateLesionLesion AtheromaAtheroma
FibrousFibrousPlaquePlaque
ComplicatedComplicatedLesion/RuptureLesion/Rupture
Endothelial DysfunctionEndothelial Dysfunction
Smooth muscleand collagen
From first decade From third decade From fourth decade
Growth mainly by inflammation and lipid accumulation
Thrombosis,inflammation
Adapted from Stary HC et al. Circulation. 1995;92:1355-1374.
H.Cohen 04-2009H.Cohen 04-2009 1414
Initiation of Initiation of
AtherosclerosisAtherosclerosis
Localization of atherosclerosisLocalization of atherosclerosis
hemodynamic forces may influence cellular hemodynamic forces may influence cellular
eventsevents
provide an explanation for the localization provide an explanation for the localization
of atherosclerotic lesions of atherosclerotic lesions
at sites of disturbance to laminar shear at sites of disturbance to laminar shear
stress. stress. H.Cohen 04-2009H.Cohen 04-2009 1515
Fatty streakFatty streak• initial lesion of atherosclerosis
• arise from increases in the content of
lipoproteins inside the intima
H.Cohen 04-2009H.Cohen 04-2009 1717
Fatty streaksFatty streaks
Adventitia
Endothelial cells
Inflammation
Foam cells
H.Cohen 04-2009H.Cohen 04-2009 1818
Fatty streaksFatty streaksשלבים בהיווצרות שלבים בהיווצרות
( –( –LPLPהצטברות של ליפופרוטאינים- )הצטברות של ליפופרוטאינים- )1.1.
extracellular matrixextracellular matrixשנקשרים למרכיבי ה - שנקשרים למרכיבי ה -
((oxoxשינויים כימיים בהם-בעיקר חמצון )שינויים כימיים בהם-בעיקר חמצון )2.2.
.3.3LPLP oxox מעוררים תגובה דלקתית מעוררים תגובה דלקתית
Adventitia
Endothelial cells
Inflammation
Foam cells
H.Cohen 04-2009H.Cohen 04-2009 1919
Fatty streaksFatty streaksשלבים בהיווצרות שלבים בהיווצרות
LEUKOCYTE RECRUITMENTLEUKOCYTE RECRUITMENT
ADHESIONADHESIONהדבקות לאוקוציטים הדבקות לאוקוציטים 3.3.
PENETRATION PENETRATION--חדירת לאוקוציטים חדירת לאוקוציטים 4.4.Chemoattractant cytokines Chemoattractant cytokines : : monocyte chemoattractant protein 1monocyte chemoattractant protein 1
Adventitia
Endothelial cells
Inflammation
Foam cells
H.Cohen 04-2009H.Cohen 04-2009 2020
הדבקות לאוקוציטיםהדבקות לאוקוציטים•
ADHESIONADHESION לאוקוציטים לאוקוציטים חדירתחדירת•
PENETRATIONPENETRATION
monocyte chemotactic protein :
produced by vascular wall cells
in response to modified
lipoproteins
chemoattractant factors Intercellular
adhesion molecule-1
(ICAM-1)
vascular cell
adhesion molecule-
1(VCAM-1
H.Cohen 04-2009H.Cohen 04-2009 2121
macrophage macrophageהצטברות לאוקוציטיםהצטברות לאוקוציטים5.5.ACCUMULATIONACCUMULATION
NON REGULATEDNON REGULATEDקליטת כולסטרול קליטת כולסטרול 6.6.
תאי קצף תאי קצףהיווצרותהיווצרות7.7.
Adventitia
Endothelial cells
Inflammation
Foam cells
Accumulation of leukocytes characterizes the formation of early Accumulation of leukocytes characterizes the formation of early
atherosclerotic lesionsatherosclerotic lesions
H.Cohen 04-2009H.Cohen 04-2009 2222
tumor necrosis factor α (TNF-α) interleukin-1 (IL-1)
H.Cohen 04-2009H.Cohen 04-2009 2323
((11התהליך הטרשתי )התהליך הטרשתי )
The Postprandial State and Risk of Cardiovascular Disease. Diabetic Medicine. 1997;14: s50-s56
H.Cohen 04-2009H.Cohen 04-2009 2424
((22התהליך הטרשתי )התהליך הטרשתי )
..
The Postprandial State and Risk of Cardiovascular Disease. Diabetic Medicine. 1997;14: s50-s56
H.Cohen 04-2009H.Cohen 04-2009 2525
((33התהליך הטרשתי )התהליך הטרשתי )
The Postprandial State and Risk of Cardiovascular Disease. Diabetic Medicine. 1997;14: s50-s56
H.Cohen 04-2009H.Cohen 04-2009 2626
((44התהליך הטרשתי )התהליך הטרשתי )
The Postprandial State and Risk of Cardiovascular Disease. Diabetic Medicine. 1997;14: s50-s56
H.Cohen 04-2009H.Cohen 04-2009 2727
((55התהליך הטרשתי )התהליך הטרשתי )
The Postprandial State and Risk of Cardiovascular Disease. Diabetic Medicine. 1997;14: s50-s56
H.Cohen 04-2009H.Cohen 04-2009 2828
((66התהליך הטרשתי )התהליך הטרשתי )
The Postprandial State and Risk of Cardiovascular Disease. Diabetic Medicine. 1997;14: s50-s56
H.Cohen 04-2009H.Cohen 04-2009 2929
Foam CellsFoam Cellsmononuclear phagocytes ingest lipids and become foam cells,
represented by a cytoplasm filled with lipid droplets
H.Cohen 04-2009H.Cohen 04-2009 3030
FATTY STREAK
Not all fatty streaks progress to form complex atheromata
• Some lipid-laden macrophages leave the artery wall, exporting lipid in the process.
• Reverse cholesterol transport mediated by high-density lipoproteins (HDL), provides an
independent pathway for lipid removal from atheroma
Stable Stable atherosclerotic atherosclerotic
plaqueplaque• Fibrous plaque• evolves from the fatty streak • accumulation of connective tissue• increased number of smooth muscle cells • deeper extracellular lipid pool.
H.Cohen 04-2009H.Cohen 04-2009 3232
Characteristics of the stable atherosclerotic plaqueCharacteristics of the stable atherosclerotic plaque
Fibrous cap(VSMCs and matrix)
Lipid core
Adventitia
Endothelial cells
Intimal VSMCs
Medial VSMCs
Inflammation
Vascular Smooth
Muscle Cells
growth factors and cytokines produced
locally -stimulate the proliferation of
smooth-muscle cells in the intima +media
and stimulates interstitial collagen
production by smooth-muscle cells
Cytokines induce local production of growth factors
H.Cohen 04-2009H.Cohen 04-2009 3333
A stable atheroscleroticA stable atherosclerotic
plaque is at plaque is at lowlow risk of risk of rupturerupture
H.Cohen 04-2009H.Cohen 04-2009 3434
Features of stable plaquesFeatures of stable plaques
I.I. thick thick fibrous capfibrous cap of uniform density confers mechanical stability. of uniform density confers mechanical stability.
II.II. high VSMC and collagen contenthigh VSMC and collagen content in the fibrous cap. in the fibrous cap.
III.III. lipid-rich corelipid-rich core that occupies that occupies less less than 40%than 40% of the total volume of the total volume
of the plaqueof the plaque
IV.IV. low infiltration of inflammatory cellslow infiltration of inflammatory cells (macrophages and T-lymphocytes)(macrophages and T-lymphocytes)
H.Cohen 04-2009H.Cohen 04-2009 3535
The stable atherosclerotic plaqueThe stable atherosclerotic plaque
Thick, VSMC-rich fibrous cap
vascular remodelling
No reduction in the dimensions of the lumen
Vulnerable Vulnerable atherosclerotic plaqueatherosclerotic plaque
Plaques that are considered Plaques that are considered vulnerable vulnerable
arare e at at high risk of rupturehigh risk of rupture
H.Cohen 04-2009H.Cohen 04-2009 3737
PLAQUE EVOLUTIONPLAQUE EVOLUTION
• during the evolution of the atherosclerotic plaque
• there is a complex balance between :
• entry and way out of lipoproteins and leukocytes
• cell proliferation and cell death
•extracellular matrix production and remodeling
H.Cohen 04-2009H.Cohen 04-2009 3838
The vulnerable atherosclerotic plaqueThe vulnerable atherosclerotic plaque
Lipid core
Adventitia
Fibrous cap
Intimal VSMCs
InflammationT cell–derived cytokine IFN-inhibit collagen synthesis of vsmc
proteolytic enzymes-degrade the extracellular matrix.
inflammatory mediators
processes that weaken the plaque's fibrous cap + enhance its vulnerability to ruptureprocesses that weaken the plaque's fibrous cap + enhance its vulnerability to rupture
H.Cohen 04-2009H.Cohen 04-2009 3939
Characteristics of vulnerable PlaquesCharacteristics of vulnerable Plaques
1.1. lipid corelipid core that that exceedsexceeds 40%40% of the total volume of the of the total volume of the plaqueplaque
2.2. high infiltrationhigh infiltration of macrophage and T- of macrophage and T-lymphocyte cells.lymphocyte cells.
3.3. thin, friable fibrousthin, friable fibrous cap with a reduced collagen and cap with a reduced collagen and VSMC content.VSMC content.
4.4. increased circumferential increased circumferential wall stresswall stress on the fibrous cap. on the fibrous cap.
H.Cohen 04-2009H.Cohen 04-2009 4040
Libby. Circulation. 1995;91:2844–2850.
– T lymphocyte
– Macrophage foam cell )tissue factor+(
– “Activated” intimal SMC
– Normal medial SMC
Fibrous cap
Media
LumenArea of detail
Lumen
Lipidcore
Lipidcore
Vulnerable Plaque
Stable Plaque
Characteristics of Vulnerable Characteristics of Vulnerable and Stable Plaquesand Stable Plaques
H.Cohen 04-2009H.Cohen 04-2009 4141
Thin Fibrous CapThin Fibrous CapLipid CoreLipid Core
Unstable PlaqueUnstable Plaque
H.Cohen 04-2009H.Cohen 04-2009 4242
The relation between atherosclerosis and The relation between atherosclerosis and acute cardiac eventsacute cardiac events
Vulnerable plaques are believed to Vulnerable plaques are believed to
account for only account for only 10–20%10–20% of all of all
coronary lesions.coronary lesions.
Responsible for the Responsible for the majoritymajority of of
acute clinical events !acute clinical events !
Plaque RupturePlaque Rupture
H.Cohen 04-2009H.Cohen 04-2009 4444
Disruption or erosion of an atherosclerotic Disruption or erosion of an atherosclerotic
plaqueplaque::
Allows circulating blood to contact the lesion Allows circulating blood to contact the lesion
and its and its highly thrombogenichighly thrombogenic, lipid-rich core. , lipid-rich core.
Adhesion and aggregation of Adhesion and aggregation of plateletsplatelets at the site at the site
of rupture.of rupture.
Formation of a partially occlusive, platelet-rich Formation of a partially occlusive, platelet-rich
thrombusthrombus..
H.Cohen 04-2009H.Cohen 04-2009 4545
Adventitia
lipid coreLipid core
Plaque RupturePlaque RupturePlatelets
aggregate at the site of rupture
/erosion
Weissberg, 1999Weissberg, 1999
H.Cohen 04-2009H.Cohen 04-2009 4646
Unstable Angina With Plaque DisruptionUnstable Angina With Plaque Disruption
Davies. Atlas of Coronary Artery Disease. Lippincott-Raven, Philadelphia, Pennsylvania: 1998:81
thrombus
fibrous cap is torn
H.Cohen 04-2009H.Cohen 04-2009 4747
Adventitia
lipid coreLipid core
Ruptured PlaqueRuptured PlaqueThrombus forms and
extends into the
lumen
Thrombus
arterial thrombosis by allowing blood
coagulant factors to contact thrombogenic
collagen of the extracellular matrix and
tissue factor produced by foam cells in the
lipid core of lesions
H.Cohen 04-2009H.Cohen 04-2009 4848
If the initial disruption of the plaque is If the initial disruption of the plaque is
superficialsuperficial, the thrombus will easily , the thrombus will easily
displaced.displaced.
Plaque healing and growth will ensue.Plaque healing and growth will ensue.
The thrombotic episode will pass either The thrombotic episode will pass either
silently or with transient symptomssilently or with transient symptoms. .
H.Cohen 04-2009H.Cohen 04-2009 4949
ThrombThrombusus
ThrombThrombusus
InflammatInflammatory ory CellsCellsFewFew
SMCSMCss
ActivatedActivatedMacrophagMacrophageses
Ruptured PlaqueRuptured Plaque
H.Cohen 04-2009H.Cohen 04-2009 5050
Clinical correlation Clinical correlation
Occlusion that is Occlusion that is partial or intermittentpartial or intermittent -symptoms -symptoms
of Unstable Angina.of Unstable Angina.
Myocardial Infarction is the result of either a more Myocardial Infarction is the result of either a more
persistent partial occlusionpersistent partial occlusion or or total occlusiontotal occlusion..
H.Cohen 04-2009H.Cohen 04-2009 5151
Whether the attack is diagnosed as an Whether the attack is diagnosed as an
episode of Unstable Angina or episode of Unstable Angina or
Myocardial Infarction will depend Myocardial Infarction will depend
upon:upon:
the duration and extent of the duration and extent of
occlusion caused by the occlusion caused by the
thrombus:thrombus:
H.Cohen 04-2009H.Cohen 04-2009 5252
אבל.....יש לזה גם צד חיובי אבל.....יש לזה גם צד חיובי כלשהואכלשהוא
In some cases, the thrombus may lyse without occluding the In some cases, the thrombus may lyse without occluding the
vessel - vessel - fibrinolytic or antithrombotic mechanismsfibrinolytic or antithrombotic mechanisms. .
Such instances may be clinically silent.Such instances may be clinically silent.
The healing process in arteries, as in skin wounds, involves The healing process in arteries, as in skin wounds, involves
the laying down of new extracellular matrix and fibrosisthe laying down of new extracellular matrix and fibrosis
healing process in arterieshealing process in arteries The subsequent The subsequent fibrosis and healing fibrosis and healing causes a causes a
fibroproliferative responsefibroproliferative response that can lead to a more fibrous that can lead to a more fibrous
lesionlesion
"vulnerable" atheroma with a thin fibrous cap prone to rupture "vulnerable" atheroma with a thin fibrous cap prone to rupture
turns into a more "stable" fibrous plaque with a reinforced cap. turns into a more "stable" fibrous plaque with a reinforced cap.
Angioplasty of unstable coronary lesions may "stabilize" the Angioplasty of unstable coronary lesions may "stabilize" the
lesions by a similar mechanism, producing a wound followed by lesions by a similar mechanism, producing a wound followed by
healing.healing.
H.Cohen 04-2009H.Cohen 04-2009 5353
H.Cohen 04-2009H.Cohen 04-2009 5454
• A. Arterial remodeling -
•compensatory enlargement
accounts for coronary
arteriography to underestimate
atherosclerosis.
• B. Rupture of the plaque's
fibrous cap+thrombosis.
Blood coagulant factors contact
with thrombogenic collagen of the
extracellular matrix .
• C. arterial occlusion.
• D. fibrosis and healing
causes a more fibrous lesion-Plaque rupture, thrombosis, and healing
Harrison’s 2008
H.Cohen 04-2009H.Cohen 04-2009 5555
Not all atheromata
exhibit the same
propensity to
rupture
H.Cohen 04-2009H.Cohen 04-2009 5656
InflammationInflammation RepairRepair
Unstable plaqueUnstable plaque
Increased lipids Lipid oxidationImmune –response
Genetic susceptibility
Increased lipids Lipid oxidationImmune –response
Genetic susceptibility
Lipid-lowering drugs Antioxidants?
??????
Lipid-lowering drugs Antioxidants?
??????
Stable plaqueStable plaque
Weissberg, 1999Weissberg, 1999
Balancing the Stability EquationBalancing the Stability Equation
H.Cohen 04-2009H.Cohen 04-2009 5757
Progression of AtherosclerosisProgression of Atherosclerosis
Adapted from Stary, in Fuster et al, eds. Adapted from Stary, in Fuster et al, eds. Atherosclerosis and Coronary Artery Disease.Atherosclerosis and Coronary Artery Disease. 1996. 1996.
Coronary artery atCoronary artery atlesion-prone locationlesion-prone location Type II lesionType II lesion Type IIIType III
)preatheroma()preatheroma(
Type IVType IV)atheroma()atheroma(
Type VaType Va)fibroatheroma()fibroatheroma(
Type VIType VI)complicated lesion()complicated lesion(
Adaptivethickening)smooth muscle(
Intima
Media
Macrophagefoam cells
Small pools ofextracellularlipid
Fibrousthickening
Core ofextracellularlipid
Thrombus
Fissure andhematoma
H.Cohen 04-2009H.Cohen 04-2009 5858
IVUS -documents the IVUS -documents the thickness and composition of plaquethickness and composition of plaque in the in the
arterial wall. IVUS is compared with angiography to show that arterial wall. IVUS is compared with angiography to show that tight tight
stenosisstenosis is is notnot necessarilynecessarily the site of an active plaque the site of an active plaque
Intravascular ultrasound (IVUS)Intravascular ultrasound (IVUS)
H.Cohen 04-2009H.Cohen 04-2009 5959
AAAA
BBBB
BBBB
AAAA
AAAA
The Tight Stenosis Is The Tight Stenosis Is NotNot the Active Lesion the Active Lesion
Images supplied by Steven E. Nissen, MD, Cleveland Clinic.Images supplied by Steven E. Nissen, MD, Cleveland Clinic.
BBBB Rupture Rupture SiteSite
Lipid CoreLipid Core
Atheroma
LumenLumen
H.Cohen 04-2009H.Cohen 04-2009 6060
Most Acute MIs Are Associated Most Acute MIs Are Associated With Less Severe StenosesWith Less Severe Stenoses
0
10
20
30
40
50
60
70
80
<50 50-70 >70
% Diameter Stenosis% Diameter Stenosis
Smith. Smith. CirculationCirculation. 1996;93:2205-. 1996;93:2205-2211.2211.
%
% P
atie
nts
Pat
ien
ts
Severity of Coronary ArterySeverity of Coronary ArteryStenosis Before Acute MI )n=195(Stenosis Before Acute MI )n=195(
=MIאוטם שריר הלב
PreventionPrevention and and
TreatmentTreatment
H.Cohen 04-2009H.Cohen 04-2009 6262
סיכון סיכון למחלת לבלמחלת לב
LDL-C LDL-C רמתרמת
הקשר בין ערכי הכולסטרול בדם הקשר בין ערכי הכולסטרול בדם והסיכון למחלות לב וכלי דם והסיכון למחלות לב וכלי דם
Correlation of Heart Disease with Cholesterol LevelsCorrelation of Heart Disease with Cholesterol Levels
H.Cohen 04-2009H.Cohen 04-2009 6363
H.Cohen 04-2009H.Cohen 04-2009 6464
Treatment of HyperlipidemiaTreatment of Hyperlipidemia
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.
High LDL-CHigh LDL-CHigh LDL-CHigh LDL-C
Therapeutic Lifestyle ChangeTherapeutic Lifestyle ChangeTherapeutic Lifestyle ChangeTherapeutic Lifestyle Change
Drug TherapyDrug TherapyDrug TherapyDrug Therapy
H.Cohen 04-2009H.Cohen 04-2009 6565
H.Cohen 04-2009H.Cohen 04-2009 6666
diet and
exercise
H.Cohen 04-2009H.Cohen 04-2009 6767
H.Cohen 04-2009H.Cohen 04-2009 6868
30 % Fat30 % Fat
Low transLow trans
Low saturated Low saturated
50% Carb50% Carb
10-15% protein10-15% protein
300 mg 300 mg CholesterolCholesterol
H.Cohen 04-2009H.Cohen 04-2009 6969
drugs in the treatment of hypercholesterolemia
H.Cohen 04-2009H.Cohen 04-2009 7070MEVASTATINMEVASTATIN CC2323HH3636OO66
HMG HMG CoA CoA
InhibitorsInhibitors
H.Cohen 04-2009H.Cohen 04-2009 7171
Statins: Mechanism of Action
LDL receptor–mediated hepatic
uptake of LDL and VLDL remnants
Serum VLDL remnants
Serum LDL-C
Cholesterol synthesis
LDL receptor synthesis
Intracellular Cholesterol
Systemic CirculationHepatocyte
LDLLDL
Serum IDL
VLDLRVLDLR
VLDL
H.Cohen 04-2009H.Cohen 04-2009 7272
Pleiotropic Effects of Statin Pleiotropic Effects of Statin
TherapyTherapyNon lipid-lowering effects of statin Non lipid-lowering effects of statin
therapytherapy
Most of the benefits of statin therapy are owing to the Most of the benefits of statin therapy are owing to the
lowering of serum cholesterol levels. lowering of serum cholesterol levels.
it is possible that statins exert cholesterol-independent it is possible that statins exert cholesterol-independent
or 'pleiotropic' effectsor 'pleiotropic' effects
H.Cohen 04-2009H.Cohen 04-2009 7373
Pleiotropic Effects of StatinsPleiotropic Effects of Statins
H.Cohen 04-2009H.Cohen 04-2009 7474
• serum inflammatory markers• plaque stabilization + thrombogenicity
H.Cohen 04-2009H.Cohen 04-2009 7575
Potential Time Course of Statin Effects
Days Years
LDL-C lowered
Inflammationreduced
Vulnerableplaques
stabilized
Endothelialfunctionrestored
Ischemicepisodesreduced
(12)
Cardiacevents
reduced
Months
ההשפעה של מתן סטאטין על ההשפעה של מתן סטאטין על
תחלואה ותמותה הקשורה למחלות תחלואה ותמותה הקשורה למחלות
לב וכלי דםלב וכלי דם
Reduction in LDL cholesterol levels,
reduces the incidence of major coronary
events, coronary revascularization, and
strokeLancet 2005
H.Cohen 04-2009H.Cohen 04-2009 7777
Coronary Heart Disease Risk Reduction with Statin TherapyCoronary Heart Disease Risk Reduction with Statin Therapy
La Rosa JC et al. JAMA 1999;282:2340-2346. | Crouse JR III et al. Arch Intern Med 1997;157:1305-1310. | Pedersen TR et al. Am J Cardiol 1998;81:333-335.
+20 –35–30–250 –5 –10–15–20
Risk Reduction (%)Risk Reduction (%)
–40–45–50
Major coronary events
Coronary deaths
Total mortality
Strokes
Intermittent claudication
STATINS REDUCE NONFATAL EVENTS + REDUCE TOTAL MORTALITY
כמה נמוך כמה נמוך עלינו לרדת עלינו לרדת
בערכי בערכי הכולסטרול ?הכולסטרול ?
כמה נמוך כמה נמוך עלינו לרדת עלינו לרדת
בערכי בערכי הכולסטרול ?הכולסטרול ?
ובכן.....ובכן.....איש אינו יודעאיש אינו יודע
ובכן.....ובכן.....איש אינו יודעאיש אינו יודע
H.Cohen 04-2009H.Cohen 04-2009 7979
RegressionRegression of atherosclerosis with statin of atherosclerosis with statin
מתן סטאטיןלפנילפני
מתן אחריאחרישנתיים סטאטין
Atheroma Area10.16 mm2
Lumen Area6.19 mm2
Atheroma Area5.81 mm2
Lumen Area5.96 mm2
Ref: Nissen S et al. JAMA 2006; 295
אחרי שנתיים של טיפול להורדת ערכי כולסטרול ישנה נסיגה אחרי שנתיים של טיפול להורדת ערכי כולסטרול ישנה נסיגה בהיקף טרשת העורקיםבהיקף טרשת העורקים
חלל העורקחלל העורק
–טרשת עורקיםטרשת עורקיםהצטברות כולסטרול
טרשת עורקים –טרשת עורקים –הצטברות כולסטרול
חלל העורקחלל העורק
H.Cohen 04-2009H.Cohen 04-2009 8080
ASTEROID rosuvastatin
50 60 80 90 100 110
0.6
1.2
1.8
LDL-C levels and change in atheroma volumeLDL-C levels and change in atheroma volume
Median
change in
Percent
Atheroma
Volume
(%)
Mean LDL-C (mg/dL)
0
-1.2
-0.6
7070 120
A-Plus placebo
CAMELOT placebo
REVERSAL pravastatin
REVERSAL atorvastatin Progression
Regression
Ref: Nissen S et al. JAMA 2006; 295