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ATHEROSCLEROSIS
Pavel Kraml
II. interní klinika 3. lékařské fakulty UKa Fakultní nemocnice Královské VinohradyPraha
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Mor
tali
ty /
100
000
ind
ivid
ual
s(M
en
35–
74 le
t)
International Cardiovascular Disease Statistics 2003: AHA.
0
500
1000
Romania
Poland
Scotla
nd USA
Germ
any
Sweden
Nether
lands
Austria Ja
pan
Cardiovasc. mortaloty
CVD mortaslity
Cardiovascular and CVD MortalityCardiovascular and CVD Mortality
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STANDARDIZED MORTALITY ČR, MEN, 1150 / 100 000
MALIGN.CVINJURIESOTHERS
28%49%
ZEMŘELÍ 2001, UZIS Praha
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PROCESS INITIATION
INJURY
ENDOTHELIAL DYSFUNCTION
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EARLY LESION
SMCmigration and proliferation
INFLAMMATIONFatty streak
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UNSTABLE PLAQUE
Plaque rupture
MMPElastase
Collagenase
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UNSTABLE PLAQUE
ThrombusFibrous plaque
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ATHEROSCLEROSIS – FIBROPROLIFERATIVE INFLAMM.
INSULT THEORY:
Process initiation- factors of injury:
Physical f.Chemical f.Biological f.
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AgeHyperlipidemiaHypertensionSmokingObesityDiabetes mellitusPhysical inactivityFamily history
TRADITIONAL RISK FACTORS Textbook of Internal Medicine (1988):
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Chron. renal failureHomocysteine
Dietary heme iron (meat)Uric acidAlcoholInfectionInflammation
NON-TRADITIONAL RISK FACTORS
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CHRI A ATS
Bias: HT, HL, anemia, sec. hyper - PTH, Hcy, chronic inflammation, oxidation stress
HOORN: CHRI in a independent RF of ATS !
Dimethylarginin – inhibts NO-synthase
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CHRI
GF 90 60 ml/min : 4 x RR KVO (HOORN)
creatinine > 133 µmol/l: 1,71 RR total mortal. (Cardiovascular Health Study)
MA < 300 mg/24 h: 1,83 RR KVO (HOPE)
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HOMOCYSTEINE
Metaanalyiss of 25 studies:Hcy correlates with ATS risk (esp. CVD)Hcy 20-30 % higher in CVD patientsAditive RF in : smokers, HL, HT
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HCY – MECHANISM OF ACTION
Induction of oxidative stress---ROS:endothelial damage, lipoperoxidationHcy + NO S-nitroso Hcy↓ NO ↓ HO-1Hcy ↑ f.V., ↓ protein C
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HYPER-HCY
Causes:Genetic defect MTHFR, CBSRI, hypothyreoidism, malignancies (leukemias),psoriasisDietary factors: ↑ animal fats, alkcohol,↓ foliate, B6, B12, (Zn)Drugs: methotrexate, INH
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Dg. HYPER-HCY
Fasting Hcy: 4 - 12 µmol/l
Methionine loading test: Met. 100 mg/kg weightPlasmy Hcy after 4 - 8 (6) h
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IRON AND ATHEROSCLEROSIS
Salonen (1992): ferritin > 200 µg/l 2,2 RR AMITuomainen (1998): ↓TfR/fer 3 RR AIMKiechl (1997):
↑ferritin IM thickness AC com. Drueke (2002):
i.v. subst. Fe (CHRI) IMT, oxid. stressMeyer (1999):
blood donation ↓ RR AIMRoest/Tuomainen:
Hered. hemochromatosis and CVD (Cys282Tyr 2,3 RR AIM)
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ELEVATED IRON STORES :
Dietary heme iron (red meat): (Klipstein-Grobusch et al., Snowdon et al.)Iron and insulin resistance?Physical inactivityGenetic faktors (hereditary hemochromatosis, beta-thalassemia, porphyria)
Sex difference – men vs. women
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IRON-MECHANISM OF ACTION
ROS production (Fentons reaction), LDL oxidation
Direct activation of macrophages --- foam cells
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URIC ACID AND ATS
1960-first mentioned as CVD risk factorIndependent RF ?Bias: obesity, IR, T2DM, renaI. insuff., diuretics
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URIC ACID AND ATS
Uric acid and oxidation stress?↑ SMC proliferation in arteriál mediaMCP-1, COX-2, NFkB, signal. molecules
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ALCOHOL AND ATS
„J-shape curve“ AMI, total mortality
1-2 drink – ekquvalents / D - lowest mortal.(1 DE: 0,33 l beer = 0,1 l wine = 0,04 l destil.)
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ALCOHOL AND ATS
Protective effect of alcohol:↑ HDL-C↓ coagul. factors, trombocytes
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ALCOHOL AND ATS
Regular consumption of high amounts,alcoholic excesses, alcohol between meals, on fasting
Alcohol as RF:HypertensionHyper TAG, ↑ small-dense LDLAD, MEOS, catalase --- ROS production---
--- endothelial dysfunctoion (↑ MMP-9, ↓ FL)
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INFLAMMATION IN GERERAL (IMMUNITY – AUTOIMUNITY)
Infections --- adhesive molecules, bact. endotoxin, hsp 60, CRPAuto-antobodies: anti-hsp, anti-oxLDL,anti-β2-GLPSLE, APS
Diagnostic role of CRP in atherosclerosis
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INFECTIOUS AGENTS
Chlamydia pneumoniae ???
CMV ???
Helicobacter pylori ??? Others ???
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SLE
Anti CL not assoc. with IMT ACCAnti-HDL-C ↓ HDL-C, PON activity, ↑ TAG, VLDL, LDLHT, DM
Alves et al., 2003
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APL
APL: anti-CL – independ.correlation with IMTAnti-CL, anti-β2-GP1↑ Anti-β2-GP1 ↓ PON activity
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TREATMENT OF ATHEROSCLEROSIS
Dietary and physical regimen: Weight reduction Smokling cessation Avoid alcohol in higher amounts
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TREATMENT OF ATHEROSCLEROSIS
Medication: Treatment of HT (ACE-I, AG2, BB, CCB, DU )
Treatment of HL (statins, fibrates, ezetimibe, niacin, resins …)
Treatment of DM
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Which arteries do we examine ?
• Coronary
Coronarography
EBCT
MRCA
• Extracoronary
Angiography
US – carotic art, (plaque, IMT), periph.art. (IKP),
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Possibilities of early diagnostics
Invasive• Angiography• IVUSNon-invasive• Structural changes: sono – carotid art.
(IMT, plaques), AIB, EBCT, MRCA • Functional tests: ergometry, Ratschow
test
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Eearly diagnostics ?
Endothel.dysfunction assessment ?
(not for routine diagnostics)
• EDV on brachial artery
• Laboratory markers of ED (vW f.
TPA/PAI1, cytokines , immunokines …
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Ankle-brachial index (ABI)
SBP ankle / SBP brach.art.
Measured by ultrasonography
Normal values ABI > 1,0
Severe pathology ABI < 0,9
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