atherosclerosis pavel kraml ii. interní klinika 3. lékařské fakulty uk a fakultní nemocnice...

ATHEROSCLEROSIS

Pavel Kraml

II. interní klinika 3. lékařské fakulty UKa Fakultní nemocnice Královské VinohradyPraha

Mor

tali

ty /

100

000

ind

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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