atherosclerosis pavel kraml ii. interní klinika 3. lékařské fakulty uk a fakultní nemocnice...
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ATHEROSCLEROSIS
Pavel Kraml
II. interní klinika 3. lékařské fakulty UKa Fakultní nemocnice Královské VinohradyPraha
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
STANDARDIZED MORTALITY ČR, MEN, 1150 / 100 000
MALIGN.CVINJURIESOTHERS
28%49%
ZEMŘELÍ 2001, UZIS Praha
PROCESS INITIATION
INJURY
ENDOTHELIAL DYSFUNCTION
EARLY LESION
SMCmigration and proliferation
INFLAMMATIONFatty streak
UNSTABLE PLAQUE
Plaque rupture
MMPElastase
Collagenase
UNSTABLE PLAQUE
ThrombusFibrous plaque
ATHEROSCLEROSIS – FIBROPROLIFERATIVE INFLAMM.
INSULT THEORY:
Process initiation- factors of injury:
Physical f.Chemical f.Biological f.
AgeHyperlipidemiaHypertensionSmokingObesityDiabetes mellitusPhysical inactivityFamily history
TRADITIONAL RISK FACTORS Textbook of Internal Medicine (1988):
Chron. renal failureHomocysteine
Dietary heme iron (meat)Uric acidAlcoholInfectionInflammation
NON-TRADITIONAL RISK FACTORS
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
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)
HOMOCYSTEINE
Metaanalyiss of 25 studies:Hcy correlates with ATS risk (esp. CVD)Hcy 20-30 % higher in CVD patientsAditive RF in : smokers, HL, HT
HCY – MECHANISM OF ACTION
Induction of oxidative stress---ROS:endothelial damage, lipoperoxidationHcy + NO S-nitroso Hcy↓ NO ↓ HO-1Hcy ↑ f.V., ↓ protein C
HYPER-HCY
Causes:Genetic defect MTHFR, CBSRI, hypothyreoidism, malignancies (leukemias),psoriasisDietary factors: ↑ animal fats, alkcohol,↓ foliate, B6, B12, (Zn)Drugs: methotrexate, INH
Dg. HYPER-HCY
Fasting Hcy: 4 - 12 µmol/l
Methionine loading test: Met. 100 mg/kg weightPlasmy Hcy after 4 - 8 (6) h
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)
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
IRON-MECHANISM OF ACTION
ROS production (Fentons reaction), LDL oxidation
Direct activation of macrophages --- foam cells
URIC ACID AND ATS
1960-first mentioned as CVD risk factorIndependent RF ?Bias: obesity, IR, T2DM, renaI. insuff., diuretics
URIC ACID AND ATS
Uric acid and oxidation stress?↑ SMC proliferation in arteriál mediaMCP-1, COX-2, NFkB, signal. molecules
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.)
ALCOHOL AND ATS
Protective effect of alcohol:↑ HDL-C↓ coagul. factors, trombocytes
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)
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
INFECTIOUS AGENTS
Chlamydia pneumoniae ???
CMV ???
Helicobacter pylori ??? Others ???
SLE
Anti CL not assoc. with IMT ACCAnti-HDL-C ↓ HDL-C, PON activity, ↑ TAG, VLDL, LDLHT, DM
Alves et al., 2003
APL
APL: anti-CL – independ.correlation with IMTAnti-CL, anti-β2-GP1↑ Anti-β2-GP1 ↓ PON activity
TREATMENT OF ATHEROSCLEROSIS
Dietary and physical regimen: Weight reduction Smokling cessation Avoid alcohol in higher amounts
TREATMENT OF ATHEROSCLEROSIS
Medication: Treatment of HT (ACE-I, AG2, BB, CCB, DU )
Treatment of HL (statins, fibrates, ezetimibe, niacin, resins …)
Treatment of DM
Which arteries do we examine ?
• Coronary
Coronarography
EBCT
MRCA
• Extracoronary
Angiography
US – carotic art, (plaque, IMT), periph.art. (IKP),
Possibilities of early diagnostics
Invasive• Angiography• IVUSNon-invasive• Structural changes: sono – carotid art.
(IMT, plaques), AIB, EBCT, MRCA • Functional tests: ergometry, Ratschow
test
Eearly diagnostics ?
Endothel.dysfunction assessment ?
(not for routine diagnostics)
• EDV on brachial artery
• Laboratory markers of ED (vW f.
TPA/PAI1, cytokines , immunokines …
Ankle-brachial index (ABI)
SBP ankle / SBP brach.art.
Measured by ultrasonography
Normal values ABI > 1,0
Severe pathology ABI < 0,9