Aterogeneza

Ateroscleroza
Athre: terci; skleros: dur boala cronica inflamatorie a peretelui arterial indusa de injurie endoteliala de cauze variate caracterizata prin: incarcare cu colesterol esterificat si liber recrutare focala subintimala de monocite si limfocite T circulante inducerea de fibroza locala prin proliferarea celulelor musculare

Pathogeneza placii aterosclerotice

The primary event in atherosclerosis is thought to be damage caused to the endothelium of arterial walls, resulting in endothelial dysfunction. This damage may be caused by a variety of factors; haemodynamic forces (shear stress caused by e.g. hypertension), a number of vasoactive substances, mediators (cytokines) from blood cells, cigarette smoke, atherogenic diet, elevated glucose levels and oxidised LDL-cholesterol.1 Initially, damage causes the endothelial cells to express cellular adhesion molecules such as cytokines (interleukin-1, IL1; IL-8) and growth factors (platelet-derived growth factor, PDGF; basic fibroblast growth factor, bFGF).1 This sticky surface encourages inflammatory cells such as monocytes and T lymphocytes to attach to the endothelial surface. Once attached they migrate through the intact endothelium into the subendothelial space. Many of the monocytes differentiate into macrophages and take up oxidised LDL, which is more atherogenic than native LDL; these macrophages then become foam cells.1 Oxidised LDL promotes death of endothelial cells and an inflammatory response resulting in impairment of normal function of the endothelium. In addition, it modifies the response to angiotensin II, resulting in vasodilatory impairment, and induces a prothrombic state by affecting platelets and coagulation factors. Thus, the endothelium responds to damage by inducing a protective response which will eventually lead to the formation of fibrofatty and fibrous lesions, the atherosclerotic plaque, preceded and accompanied by inflammation.2

MOLECULELE DE ADEZIUNE VASCULARA SI RISCUL ATEROGEN Aderarea leucocitelor circulante la celula endoteliala, cu migrarea transendoteliala a acestora, este mediata de moleculele de adeziune prezente pe celula endoteliala, ca raspuns la citokinele circulante. Concentratiile plasmatice ale ICAM-1 si selectinei-E, au fost gasite crescute cu ani de zile inaintea manifestarilor clinice de boala coronariana sau ateromatoza carotidiana.

Endothelial injury, or exposure to atherogenic stimuli, triggers endothelial cell inflammatory responses leading to recruitment of leukocytes and release of cellular adhesion molecules; cytokines, including tumour necrosis factor-1 (IL-1) and interferon gamma (IFNchemoattractant factor 1 (MCP-1) and interleukin-8 (IL-8), and growth factors, including platelet derived growth factor (PDGF) and fibroblast growth factor (FGF).1 The cytokines, in addition to amplifying the immune response, alter endothelial cell function towards a prothrombotic state, characterised by increased production of platelet activator inhibitor-1 (PAI-1), tissue factor expression (TFE) and activation of the extrinsic coagulation pathway), and release of PDGF. Disfunctia endoteliala in ateroscleroza

Endothelial dysfunction in atherosclerosis is characterised by a series of early changes that precede lesion formation. The changes include greater permeability of the endothelium, up-regulation of leucocyte and endothelial adhesion molecules and migration of leucocytes into the artery wall.1 Formarea striurilor grasoase in ateroscleroza

The fatty streak is the earliest recognisable lesion of atherosclerosis and is caused by the aggregation of lipidrich foam cells, derived from macrophages and T lymphocytes, within the intima, the inner most part of the artery wall. Later lesions include smooth muscle cells. A complicated series of steps is involved, including smooth-muscle migration, T cell activation, foam cell formation and platelet adherence and aggregation.1 Fatty streaks are common; they may increase in size, remain static or even disappear.1 Formarea placii aterosclerotice
The development of an atherosclerotic plaque indicates an advanced stage in the atherosclerotic process and results from death and rupture of the lipid-laden foam cells in the fatty streak. Migration of vascular smooth muscle cells (VSMCs) to the intima and laying down of collagen fibres results in the formation of a protective fibrous cap over the lipid core. The fibrous cap is a crucial component of the mature atherosclerotic plaque as it separates the highly thrombogenic lipid-rich core from circulating platelets and other coagulation factors. 4 Stable atherosclerotic plaques are characterised by a necrotic lipid core covered by a thick VSM-rich

Placa aterosclerotica instabila

An atherosclerotic plaque may cause complications as a result of its size, reducing lumen diameter and blood flow, its tendency to rupture, or following its erosion. Plaque erosion or rupture occur in plaques that are intrinsically vulnerable. Factors that may influence their vulnerability include hypertension, high turbulent blood flow, an increased number of inflammatory cells, a lipid-rich core and a thin fibrous cap with few smooth muscle cells or collagen fibres. Both erosion and rupture can lead to thrombus formation on the site of the plaque and vessel occlusion. Plaque formation can also cause hardening of the arteries, resulting in weakening and thinning of the vessel wall, leading to aneurysm and possibly haemorrhage.1 Regression of atherosclerotic plaques can occur with lipidmodifying therapy and with dietary and lifestyle changes.

Ruptura placii aterosclerotice si formarea trombului

Unstable fibrous plaques in atherosclerosis are prone to rupture and ulceration, followed by rapid development of thrombi. Rupture usually occurs at sites of thinning and is associated with regions where there is greater influx and activation of macrophages, accompanied by release of metalloproteinases.1 5

Pathological studies have shown that rupture of atherosclerotic plaques and subsequent luminal thrombosis underlies the aetiology of acute ischaemic coronary syndromes, including myocardial infarction and unstable angina. A lipid-rich core (particularly in the shoulder regions of lesions), abundance of inflammatory cells, a thin fibrous cap and dysfunctional overlying endothelium characterise morphological features of lesions prone to rupture. Dysfunctional endothelium may contribute to the propensity of plaque rupture owing to its proinflammatory, prothrombotic and vasoconstrictive properties that modulate lesion composition, growth responses, vascular tone and local shear stress.1

Leziunile AS dupa AHA

Tip I: monocite migrate subintimal Tip II: stria lipidica (celule spumoase) Tip III: acumulare de lipide extracelulare Tip IV: formarea miezului lipidic Tip V: formarea capsulei fibroase pidic + capison fibros

Tip VI: placa ulcerata, complicata cu tromboza luminala Evolutia procesului de aterogeneza

Placa stabila si cea vulnerabila

Markeri biologici de instabilitate Markeri serici de lezare miocardica Markeri de activitate inflamatorie ECG: Modificarile ST-T

Troponina CKMB, mioglobina, etc Proteina C reactiva (hsCRP), IL-6, sICAM, sVCAM sCD40L, SSA Fibrinogenul PAI-1, D-dimerii

Metode imagistice
Eco intravascular - Calcified areas are identified by their hyperechoic appearance and distal shadowing and may be associated with acoustic reverberation. Fibrous lesions yield homogeneous echo reflections without distal shadowing. However, the composition of lipid-containing and mixed (fibrous, lipid-calcified) plaques remains unknown in most of the cases. Elastografia intravasculara - The underlying principle is that soft material will strain more compared with hard material when a force is applied on the tissue.. Angioscopia Tomografia cu coerenta optica - OCT images of 3 different types of atherosclerotic plaques. A, Lipid-rich plaque (L) covered by thin fibrous cap (arrow, magnified inset). B, Another type of lipid-rich plaque, but with thick fibrous cap. C, Dense, eccentric fibrous plaque (F) with no lipid component. A signal-rich, homogeneous
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reflective pattern is typical for fibrous tissue. In regions with no plaque (between 7 and 10 oclock positions), intima, media, and adventitia are clearly visualized. Termografia intravasculara - Diamantopoulos et al. studied Thermosense thermography catheters (Thermocore Medical Ltd., Guildford, United Kingdom) in pigs and found that flow velocities above an average peak velocity of 9 cm/s do not affect temperature measurements. At flow velocities around 4 cm/s, the wall temperature began to rise by 0.015 0.005C, and further decrease in flow velocity causes a logarithmic increase in local wall temperature to a maximum of 0.188 0.023C, observed at total vessel occlusion. Importantly, in normal arteries, periodic oscillation in the flow velocity did not affect wall temperature. A mathematical simulation of a model of a coronary artery segment containing a heat source predicted that measured temperature is strongly affected by blood flow and also by cap thickness and source geometry Spectroscopia in infrarosu - can identify plaque composition and features associated with plaque vulnerability in postmortem human aortic specimens. These results support efforts to develop an NIR spectroscopy catheter system to detect vulnerable coronary plaques in living patients. NIR spectroscopy can identify cholesterol, HDL, and LDL in living arterial tissue through blood, without direct contact with the vessel wall. MARKERII SERICI SI RISCUL CORONARIAN Din punct de vedere epidemiologic , factorul de risc este definit ca o caracteristica a unui individ sau grup populational, prezenta timpuriu in cursul vietii si asociata cu un risc crescut pentru imbolnavire. PRINCIPALII MARKERI : -Dislipidemia -Statusul estrogenic -Factori recent diagnosticati * homocisteina * fibrinogenul * lipoproteina (a) -Parametri ai fibrinolizei * PAI -1 * t-PA * liza cheagului * d- dimerii -Markeri inflamatori * hs- CRP * ICAM1, VCAM-1 * IL-6, IL-10 * E-selectina, P- selectina * TNF-alfa DISLIPIDEMIA SI RISCUL CARDIOVASCULAR Cresterea colesterolului total TC si a LDL- colesterolului - cresterea cu 1% a TC, creste riscul coronarian cu 2-3% - cresterea cu 10% a TC, se asociaza cu o mortalitate coronariana crescuta (cu 38%)

DISLIPIDEMIA SI RISCUL CORONARIAN Valorile scazute ale HDL-colesterolului -riscul coronarian scade cu 2-3% pentru cresterea cu 1 mg/dl a HDL- col. -trialul VA-HIT a constatat pentru o crestere cu 6% a HDL- col. sub gemfibrozil, o scadere cu 22% a mortalitatii prin boala coronariana, cu 11% a mortalitatii globale, cu 25% a AVC, 59% a AIT. -in trialul Lopid Coronary Angiography, pe barbati cu valori scazute ale HDL-col. ,terapia cu fibrati a incetinit progresia ateromatozei coronariene si pe by-pass. -Helsinki Heart Study,Lipoprotein and Coronary Atherosclerosis Study au constatat la pacientii cu valori scazute ale HDL- col. tratati cu statine, o ameliorare clinica si angiografica semnificativa. Hipertrigliceridemia- factor de risc independent pentru boala coronariana Studii recente ( Copenhagen Male Study, Prospective Cardiovascular Munster Study), constata un risc cardiovascular cu 50 200% crescut in functie de valorile TGL. Cresterea cu 88.5mg/dl a TG, s-a asociat cu o crestere a incidentei bolii coronariene cu 32% pentru barbati, respectiv 76% pentru femei ( metaanaliza a 17 studii prospective). ECAT Angina Pectoris Study a constatat o corelatie semnificativa intre valorile TG si severitatea- numarul de artere coronare stenozate. Mai aterogene sunt IDL, small VLDL. Mai putin aterogene sunt chilomicronii si large VLDL. Riscul de boala coronariana este mai mare in hiperTG asociate hiperlipidemiei familiale combinate, diabetului zaharat, obezitatii, si mai redus pentru unele hiperTG genetice. Unele studii nu constata o reducere semnificativa a riscului cardiovascular secundara terapiei de scadere a valorilor TG ( 4S, WOSCOPS) Non-HDL col. Definit ca suma LDL-col si VLDL col este un factor predictiv superior LDL col privind mortalitatea cardiovasculara ( include toate lipoproteinele aterogene). Conform ghidului ATPIII, reducerea non-HDL col, reprezinta obiectiv terapeutic esential la pacienti cu TG >200mg/dl. TC/HDL-col LDL-col/HDL-col Reprezinta factori predictivi superiori conf. studiilor Framingham si PROCAM. Persoane cu valori scazute ale colesterolului total ( < 200 mg/dl) dar si ale HDL-C ( < 40 mg/ dl ) au acelasi risc coronarian crescut ca si cele cu valori crescute ale colesterolului ( 260 mg/dl). Valori crescute ale HDL-col nu confera insa protectie pentru colesterolemii crescute.

Dislipidemiile genetice 1
Hiperlipidemia tip II (hipercolesterolemia familiala): - LDL crescut prin mutatia genei receptorului LDL - Incidenta: 1 / 500 - Autozomal co-dominanta - Gerontoxon, xantelasma, xantoame tendinoase - Risc crescut de boala coronara precoce decada 3 si 4 (debut mai tardiv cu 10 ani la F) Hiperlipidemia tip IV (hipertrigliceridemia familiala):
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- TG plasmatice si VLDL crescute marcat (200 500 mg/dl, post prandial 1000 mg/dl) - Anomalia genica neidentificata - Incidenta intre 1 / 100 si 1 / 50 - Potentata de alcool si exces de carbohidrati - LDL scazut, HDL scazut - Relatie mai redusa cu boala coronariana, decat in cazul LDL

Dislipidemiile genetice 2
Hiperlipidemia tip I (hiperchilomicronemia familiala): -Cresterea TG > 1000 mg/dl a jeun - Reducerea activitatii lipoprotein-lipazei sau lipsa activatorului ei, apo CII - Cp 60 mutatii genice dau defecte de LPL - Acumulare de chilomicroni si VLDL - Plasma lactescenta - Pancreatita acuta si xantoame eruptive; defect de crestere; xerostomie, xeroftalmie - Restrictie severe in dieta; plasmafereza Hiperlipidemia tip III (disbeta-lipoproteinemia): - Acumulare de VLDL, IDL si LDL (broad beta disease) - Crestere de colesterol si trigliceride cu HDL mic - Anomalie de apoE (se cupleaza cu receptor hepatic) - Xantoame tuberoase; xantoame palmare striate HOMOCISTEINA FACTOR DE RISC PENTRU BOALA ISCHEMICA CORONARIANA Aminoacid sulfhidrilic, derivat prin demetilarea metioninei din alimente. Mecanismul de actiune: efect toxic pe endoteliu, oxidare excesiva a LDL-C, alterare a vasodilatatiei arteriale. Hiperhomocisteinemia ( >15 mol/l) -in anomalii ereditare al metabolismului metioninei -anomalii ale genei MTHFR -aport insuficient de acid folic, terapie cu metotrexat - in hipotiroidism, insuficienta renala Studii populationale, au constatat un risc crescut pentru boala coronariana ( de 1,5 , 2 X) pentru indivizii cu nivele plasmatice de peste 15 mol/l AHA si ACC nu recomanda actualmente screening populational pentru dozarea homocisteinei. Nu exista studii care sa demonstreze o reducere a riscului coronarian, secundar scaderii nivelului de homocisteina serica. FIBRINOGENUL- FACTOR DE RISC CORONARIAN Valori crescute ale fibrinogenului plasmatic reprezinta un factor de risc independent pentru boala coronariana la sanatosi, dar si pentru mortalitatea si morbiditatea prin ateromatoza coronariana la pacienti cunoscuti cu cardiopatie ischemica. Este un factor predictiv asemanator colesterolemiei pentru evenimente cardiovasculare. ( Eur.Heart J.1998,19,H11) Este un factor predictiv pentru AVC. Cresterea acuta sau cronica a fibrinogenului conduce la morbiditate cardiovasculara prin mai multe mecanisme: - infiltrarea peretelui arterial - cresterea vascozitatii sangelui - cresterea agregabilitatii plachetare
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- productie crescuta de fibrina Tratamentul cu fibrati realizeaza o scadere a fibrinogenului plasmatic. LIPOPROTEINA(a) SI RISCUL CARDIOVASCULAR Consta dintr-o particula LDL-C, legata prin punti disulfidice de apo(a), proteina cu o structura asemanatoare plasminogenului. Exista peste 25 de isoforme de Lp(a). Diferite studii au semnalat prezenta Lp(a) alaturi de fibrina in placile de aterom la pacienti cu sindroame coronariene ( angina pectorala). -Nivelul plasmatic de Lp(a) creste consecutiv ischemiei miocardice. -Rolul predictiv al Lp(a) este insuficient precizat pentru diferitele rase, pentru sexul feminin, etc -Reducerea LDL-C, anihileaza eventualele efecte aterogene ale Lp(a) MARKERI AI FIBRINOLIZEI SI RISCUL CARDIOVASCULAR

MARKERI AI INFLAMATIEI SI RISCUL CARDIOVASCULAR

Hs-CRP cea mai usor de determinat clinic. Predictiva la ambele sexe, la varstnici, la sanatosi sau coronarieni Predictiva pentru riscul vascular chiar pentru valori ale LDL-col < 130 mg/dl ( ATP-2) Nu este foarte semnificativa in primele 2-3 sapt. Postinfectii IL-6 crescuta in angina instabila, risc cardiovascular IL-6 marker al riscului de restenoza post PTCA Amiloidul A seric , marker inflamator. Legarea sa de HDL- col. le face mai putin eficiente.

ATEROSCLEROZA- BOALA INFLAMATORIE SAU AUTOIMUNA?

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Nivelele plasmatice ale IL-6 si ale CRP produse intrahepatic reflecta inflamatia si riscul de ruptura al placii de aterom. Consecinta este screening-ul populational si tratament antiinflamator ( antiagregante, inhibitori de HMG-CoA reductaza, IEC ), pentru cei cu risc crescut, utilizand CRP ca marker superior LDL- col. Daca agenti agentii fibrinolitici au dominat anii 80 90, antiplachetarele anii 90- 2000, decada urmatoare va fi a terapiei modulatoare leucocitare. ( Niall A Herity)

HTA
Asociata cu incidenta crescuta a: - Bolilor cerebrovasculare - Aterogenezei - Bolii coronariene Factor de risc independent ptr AS SRA, catecolii: modificari celulare care duc la AS -A II: VC puternic, activeaza canalele de Ca de pe CMN - A II induce expresia fenotipica a receptorilor ptr PDGF, TGF, FGF Duce la leziuni focale ale endoteliului care predispun la AS la bifurcatii Creste permeabilitatea endoteliului ptr lipoproteine serice

Fumatul
Corelatie puternica cu ateroscleroza: -creste de 2-3 x riscul ptr boala coronara - Creste mortalitatea CV cu 50% - Riscul CV creste cu varsta si cu numarul tigarilor fumate Fumatul pasiv creste riscul de boala coronara Mecanisme patogenice: - Leziune endoteliala (CO, nicotina) - Vasoreactivitate excesiva, cresterea TA - Nivele crescute de ox LDL - Scade rolul protector al HDL - Nivele crescute de fibrinogen, agregare plachetara crescuta Oprirea fumatului reduce complicatiile AS si duce la regresia leziunilor Fumatul este principala principala cauza prevenibila de deces in SUA Determina 438.000 decese anual 35% din acestea sunt cardiovasculare 8% din decese sunt determinate de fumat pasiv

Diabetul zaharat
Risc de CAD de 2-3 ori mai mare la M, de 3-5 ori mai mare la F CAD principala cauza de deces in DZ 25% din supravietuitorii IMA au DZ, > 50% au anomalii de metabolism glucidic Mecanisme de aterogeneza: - Cresterea Lp(a) Cresterea LDL Crestera TG si scaderea HDL Disfunctie endoteliala Cresterea agregarii plachetare Fibrinoliza deficitara (PAI-1 redus) Proliferarea CMN din medie Incidenta crescuta a HTA (asociata hiperglicemiei)
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Diabetul -a 4-a cauza de mortalitate in lume -peste 177 milioane indivizi cu diabet -incidenta va creste la 300 de milioane in 2025 ( se va dubla in Europa, SUA si tripla in alte tari) Complicatii macrovasculare - cardiomiopatia ( mortalitatea creste de 2 4 ori ) Complicatii microvasculare Evolutie severa in infarctul miocardic asociat, postbypass, angioplastie, etc. SINDROMUL METABOLIC 3 sau mai multi factori de risc: -intoleranta la glucoza, diabet, rezistenta la insulina -TA > 160/90 -Dislipidemie -Obezitate centrala -Microalbuminurie, insuf. renala -Hipercoagulare, disfunctie endoteliala NCEP ATP III: Sindromul metabolic

WHO: Sindromul metabolic Intoleranta la glucoza, diabet sau rezistenta la insulina asociate cu 2 sau mai multe: r low HDL-C (men <0.9 mmol/L, 35 mg/dl; women <1.0 mmol/L, 39 mg/dL) Central obesity

Alti factori de risc

SEDENTARISMUL G, TA, lipide OBEZITATEA: abdominala, toracica AGLOMERAREA FAMILIALA STRESS TIPUL PERSONALITATE ALCOOL INFECTIA CU C PNEUMONIAE STATUSUL HORMONAL estrogenii cresc HDL, scad LDL Cu, Zn din alimente, duritatea apei hiperCa transplantul de cord
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