HDL - C Factor de risc al aterosclerozei - Medikal.ro

<strong>HDL</strong> - C<strong>Factor</strong> <strong>de</strong> <strong>risc</strong> <strong>al</strong><strong>aterosclerozei</strong>Carmen Ginghina

T e r m e n u lF A C T O R D E R I S CDefineste o caracteristica prezenta laindividul sanatos dovedita in studiileepi<strong>de</strong>miologice a fi legata <strong>de</strong>APARITIA SUBSECVENTA A CI

Caracteristica person<strong>al</strong>aData fizicaFACTORI DERISCMasuratoare <strong>de</strong> laborator

MajoriFACTORIIDE RISC- dislipi<strong>de</strong>mia- HTA- fumatul- DZAdition<strong>al</strong>iPrimariFACTORIIDE RISC- dislipi<strong>de</strong>miaSecundari- dislipi<strong>de</strong>mia(SeveritateaBCI / functia VS / activareaneuro-endocrinaendocrina / <strong>risc</strong>ul aritmic …)

CLASIFICAREA FACTORILOR DE RISCTRADITIONALI- istoric famili<strong>al</strong> <strong>de</strong> CI- hipercolesterolemie- LDL ↑- <strong>HDL</strong> ↓- fumat- HTA- obezitate- DZ- inactivitate fizica- lipsa antioxidantelor- lipsa fibrelor in nutritie- lipsa pestelui- hiperuricemia- suferinta psihosoci<strong>al</strong>aTROMBOGENICI- fibrinogen- ↓ F VII- ↓ F VII la femei- lipsa F.V.Willebrand- activarea trombocitelor- PAI -1- TPA- lipsa AT-III- D-dimeri- homocisteina- Lp (a)- nivel ↓ estrogeniINFLAMATORI- leucocitoza- ↑ prot.C.reactive- ↑ vascozitatii plasmei- fibrinogen- infectie cr.ChlamydiaPneumoniaeCytomeg<strong>al</strong>o VirusHelicobacter Pylori- anticorpi la LDL oxidatCardiovascular diseases prevention, vol.1,nr.1, III, 1998The J.of the Internation<strong>al</strong> Society and Fe<strong>de</strong>ration of Card.

CLASIFICAREA FACTORILOR DE RISCMODUL DE VIATA- dieta bogata ingrasimi saturate,colesterol, c<strong>al</strong>orii- fumatul- consum excesiv<strong>de</strong> <strong>al</strong>cool- inactivitatea fizicaCARACTERISTICI BIOCHIMICESAU FIZIOLOGICE- MODIFICABILE -- ↑colesterolplasmatictot<strong>al</strong>;↑ LDL- ↓ <strong>HDL</strong> - colesterol- ↑ trigliceri<strong>de</strong>lor- HTA- DZ- obezitatea- factorii trombogeniciCARACTERISTICIPERSONALE- MODIFICABILE -- varsta- sexul- istoricul famili<strong>al</strong> <strong>de</strong>BCI sau vasculara ATSla varsta tanara (barbat< 55 ani, femeie < 65)- istoric person<strong>al</strong> <strong>de</strong> BCIsau vasculara ASCK.Pyor<strong>al</strong>aet <strong>al</strong>. “Prevention of CHD in clinic<strong>al</strong> practice”recommandation of the task force of the European Society ofCardiology; EHJ, 15, 1994

CLASIFICAREA FACTORILOR DE RISC<strong>Factor</strong>ii <strong>de</strong> <strong>risc</strong>pentru care s-asdovedit cainterventia reduceinci<strong>de</strong>nta BCI<strong>Factor</strong>ii <strong>de</strong> <strong>risc</strong>pentru care existaprobabilitatea cainterventia reduceinci<strong>de</strong>nta BCI<strong>Factor</strong>ii <strong>de</strong> <strong>risc</strong>pentru careinterventiapoate reduceinci<strong>de</strong>nta BCI<strong>Factor</strong>ii <strong>de</strong> <strong>risc</strong>nemodificabili- fumat- LDL - C- HTA- HVS- F.trombogenici- DZ- inactivitatea fizica- <strong>HDL</strong> - C- Obezitatea- status post-menopauza-fact.psihosoci<strong>al</strong>i- trigliceri<strong>de</strong>- Lp (a)- homocisteina- consum <strong>al</strong>cool- stress oxidativ- varsta- sex- rasa- greutateE.J.Topol“Textbook of cardiovascular medice”1997

Pozitivi- varsta- istoricul famili<strong>al</strong> <strong>de</strong> BCI precoceFACTORIIDE RISC- fumatul- HTA- colesterol LDL > 160 mg / dl- ↓<strong>HDL</strong>- C < 35 mg / dl- DZNegativi- ↓<strong>HDL</strong>- C ≥ 60 mg / dl

↓ <strong>HDL</strong> (< 35 mg / dl)- este i<strong>de</strong>ntificata ca factor major <strong>de</strong> <strong>risc</strong>- <strong>HDL</strong> - C poate fi masurata pentru stabilireainiti<strong>al</strong>a a <strong>risc</strong>ului↑ <strong>HDL</strong> - C ≥ 60 mg / dl- este consi<strong>de</strong>rata factor negativ <strong>de</strong> <strong>risc</strong>- efectul in<strong>de</strong>pen<strong>de</strong>nt <strong>al</strong> ↑ <strong>HDL</strong> asupra <strong>risc</strong>ului<strong>de</strong> morbiditate si mort<strong>al</strong>itate c-v nu a fost<strong>de</strong>terminatThe Expert Panel. Summary of second report of the Nation<strong>al</strong>Cholesterol Education Program - JAMA, 1993; 269 (23): 3015-3023

Ev<strong>al</strong>uarea multifactori<strong>al</strong>a a <strong>risc</strong>uluiEstimarea <strong>risc</strong>ului luand in consi<strong>de</strong>ratie toti factorii <strong>de</strong><strong>risc</strong> simultan (v<strong>al</strong>oare multiplicativa, nu aditiva)Element comun, unic, , <strong>al</strong> fact.<strong>risc</strong>“Mo<strong>de</strong>lul unificator”Ipoteze- SNS …- element genetic …- disfunctia endoteli<strong>al</strong>a- stress oxidativ

Studiul FraminghamRiscul CI prin LDH si <strong>HDL</strong> - C- <strong>HDL</strong>-C scazut este un factor <strong>de</strong> <strong>risc</strong> in<strong>de</strong>pen<strong>de</strong>ntpentru BCI precoce- pentru indivizii cu <strong>HDL</strong> ≤ 45 mg/DL <strong>risc</strong>ul CI ↑ cu↑LDL- pentru indivizii cu <strong>HDL</strong> ↑ exista protectie- protectia este intensa la 65 si 85 mg/DL cand chiarLDL ↑ creste <strong>risc</strong>ul putin- <strong>HDL</strong> ↑ sca<strong>de</strong> <strong>risc</strong>ul <strong>de</strong> boli vasculare

<strong>HDL</strong>-C permite o mai bunaseparare (discriminare)) asubiectilor cu sau fara BCI<strong>de</strong>cat LDL-CDistributia LDL-C si <strong>HDL</strong>-C C la barbatii cu si faraBCI.Subiectii cu BCI au ASC coronariana doveditaangiograficS.Robins “Low <strong>HDL</strong>-C C and coronary heart disease” Clinician,vol.18,nr.3, august 2000

Tri<strong>al</strong>NoLDL-C(mg/dl)<strong>HDL</strong>-C(mg/dl)EvenimenteNo%LIPIDCAREVA-HIT4.5022.0781.26715013911137393271527427515,813,221,7Subiectii cu ↓<strong>HDL</strong>-C si ↓LDL-CAu un <strong>risc</strong> mai mare <strong>de</strong> evenimente coronariene (IMA si<strong>de</strong>ces prin BCI) fata <strong>de</strong> cei care asociaza mo<strong>de</strong>rata crestere aLDL-C(Tri<strong>al</strong>uriLIPID, CARE si VA-HIT)

Frecventadislipoproteinemiilor geneticela b.cu CI constituita67% din b. cu IMA precoce auDIS.L.P.genetice42% au <strong>HDL</strong>-C ↓15% au TG ↑ si <strong>HDL</strong> ↓

Studiul Helsinki- reducerea CI este asociata cu ↑<strong>HDL</strong>-C si ↓LDL-C C in timpul a 5 ani<strong>de</strong> tratament cu Gemfibrozil- o ↓ importanta a trigliceri<strong>de</strong>lor (35%) nu are semnificatiein<strong>de</strong>pen<strong>de</strong>nta

Structura lipoproteinelor chilomicroni, , VLDL, LDL, <strong>HDL</strong>Diferentele constau in:- dimensiunea nucleului <strong>de</strong> lipi<strong>de</strong> neutre (trigliceri<strong>de</strong>, colesterol esterificat)- compozitia lipidica a nucleului- compozitia APO- colesterolul neesterificat se gaseste pred.inmonostratul fosfolipidic

Lipoproteinele si apolipoproteinele<strong>HDL</strong> sunt bogate in apolipoproteine AI si AII

Mo<strong>de</strong>lul schematic <strong>al</strong> particulei plasmatice <strong>HDL</strong>- suprafata este acoperita cu cap polar interactionand cu mediul apos. - Apolipoproteinele sicolesterolul sunt interc<strong>al</strong>ate intre capetele polare <strong>al</strong>e fosfolipi<strong>de</strong>lor. - Miezul (“core”) cuprin<strong>de</strong>lipi<strong>de</strong> neutre, esteri <strong>de</strong> colesterol si trigliceri<strong>de</strong>. - Diverse apolipoproteine sunt prezente peparticulele lipoproteice(ele functioneaza careceptori pentru liganzi, cofactori pentruenzime, proteine structur<strong>al</strong>e pentru sinteza lipoproteinelor.

Rolul lipoproteinelor plasmatice in <strong>de</strong>zvoltarea leziunilor ateroclerotice⇒ <strong>HDL</strong> - lipoproteina antiaterogenica majora - protejeaza <strong>de</strong> ATS prin mecanisme multiple:→ Major: inversarea transportului c.facilitand in<strong>de</strong>partarea c.din celulele spumoase sitransportand c.afaradin peretele vascular si inapoi in ficat.→ In plus: protejeaza LDL <strong>de</strong> oxidare in peretele vascular.

Mecanisme <strong>de</strong> protectieH D LInversareatransportuluicolesteroluluiActivitateaantioxidanta- scoate colesteroluldin peretelearteri<strong>al</strong>e- inhiba cresterea,<strong>de</strong>zvoltareaplacilor noi- crestestabilitateaplacilorpreexistente- inhiba rupereaplacilor- protejeazaLDL <strong>de</strong>oxidare- sca<strong>de</strong> expresiamoleculelor <strong>de</strong>a<strong>de</strong>ziune- mentine integritateaendoteliuluivascular

Diagrama venin ilustrand relatia <strong>HDL</strong>-ASCASC-transport C.Asociatia inversa a <strong>HDL</strong> cu ateroscleroza poate fi datorata, cel putinparti<strong>al</strong>, procesului in<strong>de</strong>pen<strong>de</strong>nt <strong>de</strong> inversare a transportuluicolesterolului

<strong>HDL</strong> si inversarea transportului colesterolului- <strong>HDL</strong> s (in curs <strong>de</strong> formare, secretat <strong>de</strong> intestin si ficat) capteaza excesul <strong>de</strong>colesterol din celulele periferice- <strong>HDL</strong>-2 transfera <strong>HDL</strong>-C C la hepatocite, un<strong>de</strong> poate fi convertit in acizi biliari sisecretat in bila ca si colesterol si in<strong>de</strong>partat din organism

Excesul <strong>de</strong> colesterol in celulele peretelui vascular exista subforma <strong>de</strong> colesterol-esterificat esterificat hidrofobic. Numai colesterolulliber poate fi scos din celule <strong>de</strong>ci este necesara hidrolizaesterilor <strong>de</strong> colesterol intracelulari<strong>HDL</strong> in formare se leaga <strong>de</strong> receptorul transportatorului ABC-1 caretransfera colesteroluldinceluleinlipoproteine.Colesterolul difuzeaza prin membrana celulara in corpul preβ<strong>HDL</strong>Colesterolul este reesterificat si inmagazinathidrofob <strong>HDL</strong>3inmiezulAcest colesterol inglobat in <strong>HDL</strong> este transportat la ficat sieliberat

<strong>HDL</strong> si scoaterea colesterolului din peretele arteri<strong>al</strong>

<strong>HDL</strong> - efectul antioxidant2 enzime antioxidante asociate <strong>HDL</strong>PARAOXONAZATransportata <strong>de</strong> <strong>HDL</strong> cu 2 apolipoproteine <strong>de</strong>suprafata APO AI si APO J = clusterinaPAFAHPlatelet activating factoracetylhydroxilaza

<strong>HDL</strong> - efectul antioxidantProtejeaza LDL <strong>de</strong> oxidare<strong>HDL</strong> transporta paraoxonaza in peretele arteri<strong>al</strong>un<strong>de</strong> protejeaza LDL <strong>de</strong> oxidarePAFAH completeaza aceasta actiune,catabolizand lipoproteinele oxidate si fractiunilelipoproteice

<strong>HDL</strong> protejand LDL <strong>de</strong> oxidare reduce inductiasi expresiaMoleculelor <strong>de</strong> a<strong>de</strong>ziuneVCAM “Vascular cell adhesion molecule”ChemokineMCP-1 “Monocyte chemotactic protein 1” 1Care atrag leucocitele in peretele arteri<strong>al</strong> si suntcaracteristic active in celulele endoteli<strong>al</strong>ein aria placii ASC in formare

Mecanisme <strong>de</strong> protectieH D LInversareatransportuluicolesteroluluiActivitateaantioxidanta- scoate colesteroluldin peretelearteri<strong>al</strong>e- inhiba cresterea,<strong>de</strong>zvoltareaplacilor noi- crestestabilitateaplacilorpreexistente- inhiba rupereaplacilor- protejeazaLDL <strong>de</strong>oxidare- sca<strong>de</strong> expresiamoleculelor <strong>de</strong>a<strong>de</strong>ziune- mentineintegritateaendoteliuluivascular

Ghidul <strong>de</strong> tratament <strong>al</strong> dislipi<strong>de</strong>miilor

C r e s t e r e a n i v e l u l u iH D L - CScop propusin tratamentul dislipi<strong>de</strong>miilor

Statinele cresc <strong>HDL</strong>-CPe langa ↓ CT, LDL-C,ApoB, , TG la bolnavii cu hipercolesterolemie primara(familiara heterozigota sau nonfamili<strong>al</strong>a) si hiperlipemie combinata (Fre<strong>de</strong>ricksontip IIa si IIb)

Statinele cresc <strong>HDL</strong>-CPe langa ↓ CT, LDL-C, TG - in tri<strong>al</strong>urile <strong>de</strong> prevenire secundara 4S, CARE, LIPIDBeneficiul clinic reflecta si efectele favorabile nonlipidice

Activarea PPAR αPeroxisome proliferator activator receptor= receptor nuclear implicat in translatia semn<strong>al</strong>ului nutrition<strong>al</strong> inexpresia genica= mesagerul care dirijeaza mecanismele moleculare <strong>al</strong>ehiperlipi<strong>de</strong>miilor si ASC si <strong>de</strong>termina fenotipul lipidicAdreneaza transcriptia ARNm a apolipoproteinelorA I si A II constituenti esenti<strong>al</strong>i ai <strong>HDL</strong>-CDiminua expresia APO C III(↓ trigliceri<strong>de</strong>le)

Medicatia hipolipemianta - fibratii si statinele - activeaza PPARα, ↑transcriptiaARNm a APO AI si AII, ↓<strong>HDL</strong>-C;↓expresiaAPOC III si ↓trigl(asociat celorl<strong>al</strong>teactiuni…)

C O N C L U Z I I<strong>HDL</strong>-C ↓ = factor <strong>de</strong> <strong>risc</strong> c-v v majormodificarea <strong>HDL</strong> - C trebuie sa <strong>de</strong>vinaun scop <strong>al</strong> tratamentului la fel <strong>de</strong>important ca si sca<strong>de</strong>rea LDL-C