ATEROSCLEROZAATEROSCLEROZAFACTORI DE RISCFACTORI DE RISC

PREVENTIAPREVENTIA

Ce este ?Ce este ? Ateroscleroza este prima cauză de mortalitate în lume, peste

jumătate din decesele înregistrate datorându-se complicaţiilor ei.

Efectele ei clinice se manifestă prin afectarea preponderentă a arterelor musculare de calibru mediu, precum coronarele, bazilarele, vertebralele, carotidele şi arterele membrelor inferioare.

Leziunile aterosclerotice nu sunt apananajul istoriei moderne, asociată stilului de viaţă contemporan, ci există încă din antichitate, fiind descrise ca entităţi patologice certe la mumiile egiptene.

Teoriile aterogenezei Primele încercări de explicitare a ateromatozei au fost făcute în 1852 de

Rudolf Virchow care considera că o leziune minimală a peretelui arterial produce o reacţie inflamatorie ce determină pasajul şi acumularea constituenţilor plasmatici în intima arterială.

În 1856, von Rokitansky elaborează o nouă teorie completată în 1946 de Duguid care susţine că ariile lezionale sunt acoperte de mici trombi, care se organizează prin creşterea celulelor musculare în interiorul lor, încorporându-i în leziune, pentru a deveni ulterior zonele de progresie ale acesteia.

O ipoteză complet diferită a fost lansată în 1973 – ipoteza monoclonală, ce sugerează că leziunile aterosclerotice pot să fie considerate ca o manifestare a unei forme de neoplazie.

Datele actuale explică aterogeneza prin ipoteza reacţiei la leziune (response-to-injury hypothesis of atherosclerosis) elaborată tot în 1973 şi revizuită prin rezultatele cercetărilor recente.

DISFUNCŢIA ENDOTELIALĂ 1983 Fudmer şi colab. care au demonstrat alterarea vasodilataţiei mediate de

endoteliu în boala coronariană şi au indicat legătura dintre endoteliul disfuncţional şi ateroscleroză

nu am găsit o definiţie consensuală a disfuncţiei endoteliale, probabil datorită naturii dinamice a subiectului, domeniul de cercetare ca şi aplicaţiile clinice ale acestuia aflându-se în plină evoluţie.

o afecţiune sistemică ce se regăseşte ca un numitor comun în fiziopatologia aterosclerozei, aterotrombozei şi remodelării vasculare cu determinări coronariene, carotidiene, perferice sau multiple, a insuficienţei cardiace, insuficenţei renale, diabetului şi hipertensiunii – fundamentând astfel conceptul actual de continuum cardiovascular.

viziunea actuală asupra funcţiei endoteliale o situează deasupra noţiunii clasice de factor de risc cardiovascular, fiind de fapt un summum al expresiei fenotipului vascular individual şi o integrală a tuturor factorilor lezionali / de protecţie vasculară.

ENDOTELIUL NORMALENDOTELIUL NORMAL

DISFUNCŢIA ENDOTELIALĂ

Disfuncţia endotelială se poate defini fiziopatologic ca un dezechilibru al activităţii endoteliului în sensul creşterii ”necompensate” a reacţiilor şi moleculelor în sensul promovării vasoconstricţiei, aderării celulare, trombozei, coagulării, inflamaţiei şi proliferării celulare la nivel vascular.

NORMALNORMAL DISFUNCTIONALDISFUNCTIONAL

Vasodilatie VasoconstrictieNO, EDHF (?), PGI2 BK, C-NP

ET-1, ROS, TxA2, A-II

Tromboliza Tromboza

Antiagregare Plachetara

NO, PGI2

Molecule de Adeziune

CAM, Selectine

Antiproliferare

NO, PGI2, TGF-, Hep

Factori de crestere

ET-1, A-II, PDGF, ILGF, Interleukine

Lipoliza InflamatieROS

PAR 1-2, TF, PAI-1, Tx-A2, vonWF, TAFI

tPA+anexina II, TF-I, trombomodulina,

Proteina S, R-proteina C,

LPL

Mecanisme fiziopatologice ale disfuncţiei endoteliale

Cea mai importantă verigă fiziopatologică, comună tuturor afecţiunilor în care apare disfuncţia endotelială, este alterarea sistemului de modularea a biologiei vasculare prin intermediul EDRF, studiile actuale concentrându-se asupra afectării lanţului biochimic al sintezei şi degradării acestuia.

Astfel, reducerea disponibilităţii NO poate fi determinată fie de reducerea producţiei, fie de inactivarea sa rapidă, după cum urmează: Diminuarea substratului necesar NO sintetazei Afectarea activităţii NO sintetazei Inactivarea NO de speciile reactive de oxigen (ROS)

L-argininina

L-citrulina4 HBPNADPHCalmodulina

(i)/eNOS

NO

•bradikinină,•substanţa P,•ADP,•agonişti muscarinici•forţele mecanice generate de flux

↑ Ca 2+

+

y+

ATP

• Vasodilatatie, regalarea tonusului vascular bazal• Inhibă aderarea, activarea,secreţia şi agregarea plachetară• Sade expresia P selectinei la nivelul membranei plachetare • Inhibă aderarea leucocitară • Inhibă migrarea şi proliferareacelulelor musculare netede• Blochează modificărileconformaţionale la nivelululGP IIb/IIIa B

GUANIL-CICLAZA (cel musculare netede)

L-argininina

L-citrulina

4 HBPNADPH

Calmodulina

eNOS

NO

•bradikinină,•substanţa P,•ADP,•agonişti muscarinici•forţele mecanice generate de flux

↑ Ca 2+

+Arg

inaza I

Arginaza

II

L-ornitină,Uree

ADMALDL–OXIDAT

ROS

LDL–OXIDATDIABET ZAHARAT

-

ROS

MODALITĂŢI DE MODALITĂŢI DE EXPLORARE A EXPLORARE A DISFUNCŢIEI DISFUNCŢIEI

ENDOTELIALEENDOTELIALE Explorarea coronarografică directăExplorarea coronarografică directă::

prima modalitate de evaluare a funcţiei endoteliale – prima modalitate de evaluare a funcţiei endoteliale – prin determinarea cantitativă, pe imaginea prin determinarea cantitativă, pe imaginea coronarografică a răspunsului vasomotor al arterelor coronarografică a răspunsului vasomotor al arterelor coronare epicardice la injectarea de acetilcolinăcoronare epicardice la injectarea de acetilcolină (si alte (si alte molecule cu ro in eliberarea de NO)molecule cu ro in eliberarea de NO)

Dezavantaje:Dezavantaje: Investigarea acestor vase de conductanţă, reprezentativă Investigarea acestor vase de conductanţă, reprezentativă

pentru pacienţii cu boală coronariană documentată nu dă pentru pacienţii cu boală coronariană documentată nu dă însă informaţii despre disfuncţia endotelială la pacienţii aflaţi însă informaţii despre disfuncţia endotelială la pacienţii aflaţi în etapele incipiente de evoluţie ale aterosclerozei, când în etapele incipiente de evoluţie ale aterosclerozei, când boala este subclinică.boala este subclinică.

IInstrumentarea coronarelor epicardice nu este relevantă nstrumentarea coronarelor epicardice nu este relevantă pentru statusul microcirculaţiei coronariene la nivelul vaselor pentru statusul microcirculaţiei coronariene la nivelul vaselor de rezistenţă – neafectată în mod obişnuit de ateroscleroză de rezistenţă – neafectată în mod obişnuit de ateroscleroză dar disfuncţională în boala cardiacă ischemicădar disfuncţională în boala cardiacă ischemică

Explorarea intracoronariană a fluxului prin Explorarea intracoronariană a fluxului prin cateter Dopplercateter Doppler:: Se Se folosfolosesteeste un cateter ghid de angiografie în un cateter ghid de angiografie în

vârful căruia vârful căruia existaexista un transductor de 12 MHz, un transductor de 12 MHz, cu semnal Doppler pulsat conectat la un sistem cu semnal Doppler pulsat conectat la un sistem de analiza spectrală a a fluxului care prin de analiza spectrală a a fluxului care prin transformare rapidă Fourier a furniztransformare rapidă Fourier a furnizeazaeaza imaginea anvelopelor Doppler pulsat uzuale din imaginea anvelopelor Doppler pulsat uzuale din ecografia cardiacă/vasculară. ecografia cardiacă/vasculară. Se Se calculcalculeazaeaza fluxul fluxul folosind o formula folosind o formula bazată pe diametrul bazată pe diametrul vasului măsurat pe imaginea coronarografică şi vasului măsurat pe imaginea coronarografică şi pe valoarea măsurată a integralei timp-pe valoarea măsurată a integralei timp-velocitate maximă obţinută la înregistrarea velocitate maximă obţinută la înregistrarea DopplerDoppler

ESTE CONSIDERATA “GOLDEN STANDARD”ESTE CONSIDERATA “GOLDEN STANDARD” Invaziva, costisitoare necesita tehnologie medicala Invaziva, costisitoare necesita tehnologie medicala

avansata – are aplicabilitate limitata.avansata – are aplicabilitate limitata.

MODALITĂŢI DE MODALITĂŢI DE EXPLORARE A EXPLORARE A DISFUNCŢIEI DISFUNCŢIEI

ENDOTELIALEENDOTELIALE

““Brachial Artery Flow-Brachial Artery Flow-Mediated Vasodilation”Mediated Vasodilation”

(FMD)(FMD)50 mm Hg peste presiunea arteriala sistolica

Leziunea endotelială Leziunea endotelială este evenimentul cheie în dezvoltarea ateromatozei. Manifestările ei sunt forme de disfuncţie endotelială şi includ modificări

ale proprietăţilor membranei celulare, ale expresiei moleculelor de interacţiune intercelulară, ale eliberării adecvate de mediatori vasoactivi şi factori de creştere şi mărirea ratei turn-over-ului.

Aceasta duce la acumularea excesivă de colesterol la nivelul membranei celulare endoteliale, cu alterarea consecutivă a raportului colesterol/fofolipide, modificări de compoziţie ce induc rigidizarea acesteia.

Plasmalema rigidă va reacţiona în mod anormal la stressul mecanic la care este supusă de către fluxul sanguin mai ales în locurile de producere a turbulenţelor – bifurcaţii, zone în care se formeaza striuri lipidice producându-se disjuncţia legăturilor dintre celulele endoteliale şi retracţie endotelială.

Celulele endoteliale au receptori membranari pentru moleculele de LDL, care sunt apoi internalizate şi suferă un proces de “oxidare la nivel scăzut” transformându-se în LDL-oxidat.

În condiţiile existenţei unor nivele crescute, acesta este agentul agresor primordial – toxic atât pentru endoteliu cât şi pentru alte celule – ce induce cascada evenimentelor inflamatorii şi posibil autoimune asociate cu iniţierea şi dezvoltarea aterosclerozei.

LDL-ox determină expresia pe suprafaţa celulelor endoteliale a unui număr crescut de molecule de adeziune intercelulară în special pentru monocitele circulante.

Leziunea endotelială

Faza iniţială a aterogenezei Un număr important de leucocite (mai ales monocite) se ataşează la moleculele de adeziune

expuse de endoteliul lezat, după care trec prin spaţiile intercelulare şi migrează în spaţiul subendotelial.

Aici se transformă în macrofage şi acţionează ca celule gunoier (scavanger), încercând să îndepărteze moleculele de LDL-oxidat prin preluarea acestora de la celulele endoteliale pe calea receptorilor scavenger.

Macrofagele preiau şi molecule de LDL pe care îl transformă cu ajutorul unor enzime de tipul lipooxigenazei în LDL-oxidat, se supraîncarcă cu acesta şi se transformă în celule spumoase.

Macrofagele se pot replica, reprezentând cea mai importantă sursă de acumulare celulară la nivelul leziunii şi secretă pe lângă numeroşi mediatori intercelulari cel puţin 6 factori de creştere: PDGF, IL-1, FGF, EGF, TGF-β şi M-CSF. Aceştia acţionează şi asupra celulelor musculare cu fenotip secretor din medie, determinând migraţia acestora în spaţiul subintimal şi transformarea lor în celule spumoase.

Nu sunt complet elucidate relaţiile dintre limfocitele T CD8+ şi CD4+ (care au fost evidenţiate în toate fazele aterogenezei), macrofage şi LDL-oxidat care pare antigenul ce stimulează interacţiunea dintre acestea.

Fazele intermediară şi tardivă ale aterogenezei

în evoluţia leziunii se produce migrarea continuă a celulelor musculare netede din medie în spaţiul subintimal urmată de proliferarea acestora aici, leziunea devenind fibro-musculară proliferativă sub influenţa stimulării cu PDGF-B sintetizat de macrofage.

Tot în acestă etapă se produce fenomenul de retracţie endotelială, menţionat anterior, care expune torentului circulator structurile subendoteliale.

Una din consecinţe este migrarea în fluxul sanguin, către splină şi ganglionii limfatici a macrofagelor încărcate cu LDL-oxidat.

Nici această etapă inflamatorie, posibil (auto)imună a reacţiei la leziune nu este deplin explicată.

Fazele intermediară şi tardivă ale aterogenezei

Altă consecinţă a denudării endoteliului prin disjuncţia celulelor endoteliale este pierderea proprietăţilor antitrombogenice şi aderarea plachetelor cu formarea unor microtrombi murali.

Trombocitul devine astfel, după celula endotelială şi macrofag, a treia celulă implicată în dezvoltarea leziunii aterosclerotice.

Plachetele agregate se vor degranula şi vor elibera 4 factori de creştere: PDGF, FGF, EGF şi TGF-β amplificând răspunsul proliferativ al ţesutului inflamator.

Se pare că la un interval relativ scurt leziunile aterosclerotice progresează, putând căpăta un înveliş fibros bine reprezentat.

Trebuie menţionat că agravarea ateromatozei poate surveni fără disjuncţia celulelor endoteliale şi interacţiunea plachetară consecutivă, întrucât endoteliul şi macrofagele reprezintă surse potente de factori de creştere.

Mediatorii aterogenezei Factorii de creştere implicaţi în aterogeneză sunt produşi de celulele endoteliale

(PDGF, FGF, TGF-β, IGF-1, IL-1), de macrofage (PDGF, FGF, EGF, TGF-β, IL-1, M-CSF) şi de trombocite (PDGF, FGF, EGF şi TGF-β). Un rol important au şi celulele musculare netede ce sintetizeză un singur factor de creştere: PDGF, la care răspund autocrin.

În mod normal există un echilbru între TGF-β (un stimulator potent al formării de ţesut conjunctiv şi totodată cel mai puternic inhibitor al proliferării celulelor musculare netede) şi PDGF (stimulator al migrării în subendoteliu şi al proliferării celulelor musculare netede) care atunci când se pierde, înclinând balanţa în favoarea PDGF, pare să reprezinte un moment critic în apariţia şi progresia leziunilor aterosclerotice. Cea mai importantă sursă de PDGF este reprezentată de macrofage, la aproximativ 20% dintre acestea – distribuite ubicuitar în leziune – evidenţiindu-se prezenţa intracitoplasmatică a lanţul proteic al acestuia.

PDGF este important şi datorită faptului că induce creşterea numărului de receptori pentru LDL, creşterea sintezei de colesterol, reorganizarea filamentelor actinice şi modificarea formei celulelor.

Normal Artery

Response to Injury

Endothelial Dysfunction

Initiation of Fatty Streak

Fatty Streak

Fibro-fatty Atheroma

                                                                                                   

  

                                               

Major components of plaque

• Cells (SMC, macrophages and other WBC)

• ECM (collagen, elastin, and PGs)

• Lipid = Cholesterol (Intra/extracellular)

• (Often calcification)

Two major processes in plaque formation

• Intimal thickening (SMC proliferation and ECM synthesis)

• Lipid accumulation

Fig. 11.7

                                                                         

AHA Classification of atherosclerosis

Striurile lipidice (Leziuni în fazele I, II, III): Apar în jurul vârstei de 10 ani, fiind constituite din macrofage încărcate cu

lipide, limfocite T, celule spumoase şi un număr redus de celule musculare netede migrate subendotelial şi care au acumulat şi ele lipide.

Celula de origine din care a provenit celula spumoasă este dificil de determinat chiar dacă se folsesc tehnici de microscopie electronică şi doar încercarea de identificare cu anticorpi monoclonali împotriva unui antigen citoplasmatic specific din macrofage şi a actinei α din celulele musculare netede a fost încununată de succes, dovedind că majoritatea celulelor spumoase provin din macrofage.

Aspectul macroscopic al striurilor lipidice este datorat acunulării de lipide, zonele respective părând ca arii bine delimitate de culoare galbenă.

Studiile anatomopatolgice au arătat că localizarea anatomică a striurilor lipidice la copii şi adulţi tineri este similară cu cea a leziunilor avansate, fibromusculare sau fibroase de la vârstnici. Acestă descoperire arată că striurile lipidice sunt formele precursoare ale leziunilor aterosclerotice ocluzive severe.

Fatty Streak-AortaFatty Streak-Aorta

Fatty Streak-Coronary ArteryFatty Streak-Coronary Artery

Îngroşarea intimală difuză (Leziuni faza IV)

Această fază a leziunii se caracterizează prin creşterea proporţiei celulelor musculare netede şi a ţesutului conjunctiv la nivelul leziunii aterosclerotice.

Se discută încă dacă acestă creştere a migrării celulelor musculare netede din medie în spaţiul subintimal şi hiperproliferarea lor este datorată stressului exercitat de flux asupra peretelui arterial sau este pur şi simplu consecinţa progresiei ateromatozei.

Deasemenea, la nivelul leziunii intimale difuze, se regăsesc elementele prezente în striurile lipdice: macrofage, limfocite T, celule spumoase.

Placa fibroasă (Leziuni în fazele V şi VI)

Leziunile ateroclerotice aflate în fazele avansate (V, VI) se numesc plăci fibroase şi macroscopic au culoare albă şi sunt protruzive în lumenul aterial.

Placa fibroasă prezintă aceleaşi elemente existente la nivelul îngroşării intimale difuze, existând însă o creştere foarte mare a numărului celulelor musculare netede şi a ţesutului conjunctiv.

Specificitatea plăcii fiboase constă în faptul că suprafaţa sa este acoperită de un înveliş fibros format din celule musculare netede cu o formă distinctă – subţiri şi plate, înconjurate de lamele numeroase de membrană bazală, proteoglicani şi fibre de colagen. Sub acest acoperiş fibros se găseşte o zonă cu celularitate bogată constituită din: celule musculare netede, macrofage, limfocite T CD8+ numeroase, un număr redus de limfocite T CD 4+ şi ţesut conjuctiv diferit de cel de la suprafaţă. Acesta este format din colagen, fibre elastice, cantităţi mari de proteoglicani şi lipide extracelulare într-o proporţie variabilă. Sub zona cu celule numeroase se află un strat profund alcătuit din celule spumoase mari şi numeroase, ţesut necrotic, resturi celulare, cristale de colesterol şi zone de calcificare.

Fibrous Plaques Complicated Lesions

Complicated Lesions

Summary of Atherosclerotic ProcessSummary of Atherosclerotic Process

Multifactorial process (risk factors)Multifactorial process (risk factors) Initiated by endothelial dysfunctionInitiated by endothelial dysfunction Up regulation of endothelial and leukocyte adhesion Up regulation of endothelial and leukocyte adhesion

moleculesmolecules Macrophage diapedesisMacrophage diapedesis LDL transcytosisLDL transcytosis LDL oxidationLDL oxidation Foam cellsFoam cells Recruitment and proliferation of smooth muscle cells Recruitment and proliferation of smooth muscle cells

(synthesis of connective tissue proteins)(synthesis of connective tissue proteins) Formation and organization of arterial thrombiFormation and organization of arterial thrombi

Disfunctie

Endoteliala

Boala coronariana non-ocluziva

Boala coronariana ocluziva

Boala coronariana sub-clinica

Boala coronariana clinica

DISFUNCTIA ENDOTELIALA

Three patterns of arteriosclerosisThree patterns of arteriosclerosis

AtherosclerosisAtherosclerosis The The dominant patterndominant pattern of arteriosclerosis of arteriosclerosis Primarily affects the elastic (aorta, carotid, iliac) Primarily affects the elastic (aorta, carotid, iliac)

and large to medium sized muscular arteries and large to medium sized muscular arteries (coronary, popliteal)(coronary, popliteal)

Monckeberg medial calcific sclerosisMonckeberg medial calcific sclerosis ArteriolosclerosisArteriolosclerosis –small arteries and –small arteries and

arterioles (hypertension and DM)arterioles (hypertension and DM)

Is Atherosclerosis ReversibleIs Atherosclerosis Reversible Primate experimentsPrimate experiments

High fat diet discontinued; atherosclerotic lesions High fat diet discontinued; atherosclerotic lesions regressregress

HumansHumans Decrease fat and caloric intake (wars, famine, wasting Decrease fat and caloric intake (wars, famine, wasting

disease), atheromas decrease.disease), atheromas decrease. Angiography after cholesterol lowering, plaque size Angiography after cholesterol lowering, plaque size

decreases decreases What has to happen for plaques to regress?What has to happen for plaques to regress?

LDL loweredLDL lowered Mac ingest lipidsMac ingest lipids Reverse cholesterol transport, depends on HDLReverse cholesterol transport, depends on HDL

Consequences of plaque Consequences of plaque formationformation

GeneralizedGeneralized

Narrowing/OcclusionNarrowing/Occlusion RuptureRupture EmboliEmboli

Leading to specific problems:Leading to specific problems: Myocardial and cerebral infarctsMyocardial and cerebral infarcts Aortic aneurysmsAortic aneurysms Peripheral vascular diseasePeripheral vascular disease

Altered Vessel FunctionAltered Vessel Function

Vessel changeVessel change Plaque narrows lumenPlaque narrows lumen Wall weakenedWall weakened

ThrombosisThrombosis

Breaking loose of Breaking loose of plaqueplaque

Loss of elasticityLoss of elasticity

ConsequenceConsequence Ischemia, turbulenceIschemia, turbulence Aneurysms, vessel Aneurysms, vessel

rupturerupture Narrowing, ischemia, Narrowing, ischemia,

embolizationembolization Athero-embolizationAthero-embolization

Increase systolic blood Increase systolic blood pressurepressure

Late ChangesLate Changes CalcificationCalcification

An example of dystrophic calcificationAn example of dystrophic calcification Cracking, ulceration, ruptureCracking, ulceration, rupture

Usually occurs at edge of plaqueUsually occurs at edge of plaque Thrombus formationThrombus formation

Caused by endothelial injury,ulceration, turbulenceCaused by endothelial injury,ulceration, turbulence Organization of thrombusOrganization of thrombus More thrombusMore thrombus

EncroachmentEncroachment Weakens vessel wallWeakens vessel wall

BleedingBleeding Ulceration, cracking and angiogenesisUlceration, cracking and angiogenesis

ATHEROSCLEROSIS:Pathology, Pathogenesis, Complications, Natural History

Hemorrhage into Plaque

Common Consequences of Common Consequences of Atherosclerosis in Specific Atherosclerosis in Specific

VesselsVessels

AortaAorta

AneurysmAneurysm Pulsatile abdominal massPulsatile abdominal mass Abdominal painAbdominal pain BleedingBleeding

AtheroembolizationAtheroembolization Narrowing of lumenNarrowing of lumen

Usually not a problemUsually not a problem

Aortic Aneurysm

Aortic Aneurysm

Coronary ArteriesCoronary Arteries

Consequences of coronary artery Consequences of coronary artery atherosclerosis: acute and chronic ischemic atherosclerosis: acute and chronic ischemic heart diseaseheart disease

Coronary Artery Atherosclerosis

Coronary Artery Atherosclerosis

Carotids and Cerebral CirculationCarotids and Cerebral Circulation

Atherosclerosis with thrombosis can lead to Atherosclerosis with thrombosis can lead to brain infarctionbrain infarction

Red or whiteRed or white Coagulative or liquefactiveCoagulative or liquefactive Can lead to transient ischemic attacks (TIA), Can lead to transient ischemic attacks (TIA),

if narrowing is aggravated by mural if narrowing is aggravated by mural thrombus or vasospasmthrombus or vasospasm

Celiac and Mesenteric ArteriesCeliac and Mesenteric Arteries

Narrowing primarily at aorta bifurcationNarrowing primarily at aorta bifurcation Ischemia uncommon because of collateral Ischemia uncommon because of collateral

circulationcirculation Ischemia can occur if more than 1 artery Ischemia can occur if more than 1 artery

severely affected - ischemic entercolitisseverely affected - ischemic entercolitis

Renal ArteryRenal Artery

Progressive ischemic atrophy of kidney Progressive ischemic atrophy of kidney leads to gradual kidney failure leads to gradual kidney failure (nephrosclerosis)(nephrosclerosis)

Renal hypertension due to decreased Renal hypertension due to decreased perfusionperfusion

Iliac and Femoral ArteriesIliac and Femoral Arteries

AneurysmsAneurysms Vessel occlusion by plaque and thrombusVessel occlusion by plaque and thrombus

Ischemia of leg muscles, especially during Ischemia of leg muscles, especially during exercise (intermittent claudication)exercise (intermittent claudication)

Ulcers of skin of legs and feetUlcers of skin of legs and feet Gangrene of feetGangrene of feet

13

CVD Prevention: The scope ofthe problem

CVDs are the major causes of death and disabilityin Europe - 4.35 million in Europe, 1.9 million in theEU.

MORE women than men die from CVD -2.3 million women, 2 million men.

10 fold regional differences, with reductions in theWest.

“Reductions” in age-specific CVD mortalitygenerally represent a transference of the problemto older persons, with increasing heart failure.

Generally poor risk factor control (EuroAspire).

Improvements in smoking, BP and lipid controloffset by reduced activity, increasing obesity andconsequent diabetes.

14

CVD - the size of the problem

Current life expectancy 65 (45-80) yrs.1900- <10% deaths due to CVD.1970- biggest cause of death in developedcountries.Falling in developed countries, rising fastin developing ones.2000- biggest cause of death worldwide.1996- 15,000,000 deaths.2020- 25,000,000 deaths.

(Source WHO)

CV

D D

eath

s (a

ll c

ohor

ts)

00 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

Predicted Risk (Men aged 50-59 )

18

Fig. 1 - The expected number of CVD deaths at increasing levels of predicted risk.Illustration of the fact that most events occur in low risk subjects with few deaths

among high risk subjects.

80

60

40

20

0 3 5 140 5 3 0People who stay healthy tend

to have certain characteristics:03

5140

530

No tobacco

Walk 3 km daily, or 30 mins anymoderate activity

Portions of fruit and vegetables a day

Blood pressure less than 140 mm Hgsystolic

Total blood cholesterol <5 mmol/l

LDL cholesterol <3 mmol/l

Avoidance of overweight and diabetes

25

What are the PRIORITIES forCVD prevention in clinical practice?

1.

2.

Patients with established atheroscleroticCVD.

Asymptomatic individuals who are atincreased risk of CVD because of :

2.1 Multiple risk factors resulting in raised total CVD risk(≥5% 10-year risk of CVD death);

2.2 Diabetes type 2 and type 1 with microalbuminuria;2.3 Markedly increased single risk factors especially if

associated with end-organ damage.

3 Close relatives of subjects with prematureatherosclerotic CVD or of those atparticularly high risk.

26

What are the OBJECTIVES ofCVD prevention?

1.

2.

To assist those at low risk of CVD to maintainthis state lifelong, and to help those atincreased total CVD risk to reduce it.

To achieve the characteristics of people whotend to stay healthy:

2.12.22.32.42.52.62.72.8

No smoking;Healthy food choices;Physical activity: 30 min of moderate activity a day;BMI <25 kg/m2 and avoidance of central obesity;BP <140/90 mmHg;Total cholesterol <5 mmol/L (~190 mg/dL);LDL cholesterol <3 mmol/L (~115 mg/dL);Blood glucose <6mmo/L (~110 mg/dL).

27

3.

4.

To achieve more rigorous risk factor controlin high risk subjects, especially those withestablished CVD or diabetes:

3.1 Blood pressure under 130/80 mmHg if feasible;3.2 Total cholesterol <4.5 mmol/L (~175 mg/dL)

with an option of <4 mmol/L (~155 mg/dL) iffeasible;

3.3 LDL cholesterol <2.5 mmol/L (~100 mg/dL)with an option of <2mmol/L (~80 mg/dL) iffeasible;

3.4 Fasting blood glucose <6 mmol/L (~110 mg/dL)and HbA1c <6.5% if feasible.

To consider cardioprotective drug therapy inthese high risk subjects especially those withestablished atherosclerotic CVD.

28

What are the OBJECTIVES ofCVD prevention?

29

When do I assesscardiovascular risk?

If the patient asks for it.If, during a consultation:

- The person is a middle aged smoker.

- There is obesity, especially abdominal.- One or more risk factors such as blood

pressure, lipids or glucose is raised.- There is a family history of premature CVD

or of other risk factors.- There are symptoms suggestive of CVD. If

confirmed, risk factors should be assessedbut use of the SCORE chart is not necessaryas the person is already at high risk.

30

Why stress assessment oftotal CVD risk ?

Multiple risk factors usually contributeto the atherosclerosis that causesCVD.

These risk factors interact, sometimesmultiplicatively.

Thus the aim should be to reducetotal risk; if a target cannot bereached with one risk factor, totalrisk can still be reduced by tryingharder with others.

10

yr

risk

of

fata

l C

VD

(%

)

5

0

25

20

15

Fig 2

The relationship of total cholesterol / HDL cholesterol ratio to 10 year fatalCVD events in men and women aged 60 yrs with and without risk factors,

based on a risk function derived from the SCORE project.

30

Men, smoking,SBP=160 mmHg

Men, non-smoking,SBP=120 mmHg

Women, smoking,SBP=160 mmHg

10

Women, non-smoking, SBP=120mmHg

3 4 5 6 7

TC/HDL ratio

31

SEX AGE CHOL BP SMOKE RISK %

F 60 8 120 NO 2

F 60 7 140 YES 5

M 60 6 160 NO 8

M 60 5 180 YES 21

32

Table 1

Impact of combinations of riskfactors on 10 year risk of CVD death

33

How do I assess CVD riskquickly and easily?

Those with-

~known CVD;~type 2 diabetes or type 1 diabetes with

microalbuminuria;~ very high levels of individual risk factors.

are already at INCREASED CVD RISK andneed management of all risk factors.

For all other people, the SCORE risk chartscan be used to estimate total risk-this iscritically important because many peoplehave mildly raised levels of several riskfactors that, in combination, can result inunexpectedly high levels of total CVD risk.

34

Assessing cardiovascular risk:What are the components?

History: Previous CVD or related diseases, family historyof premature CVD, smoking, exercise and dietary habits,social and educational status.

Examination: BP, heart rate, heart and lung auscultation,foot pulses, height, weight, (Body mass index), waistcircumference. Fundoscopy in severe hypertension.

Lab test: Urine for glucose and protein, microalbuminuriain diabetics. Cholesterol and if practicable, fasting lipids(LDL and HDL cholesterol, triglycerides) glucose,creatinine.

ECG and exercise ECG if angina suspected.

ECG and consider echocardiogram in hypertensivepersons.

Premature or aggressive CVD, especially with a familyhistory of premature CVD: Consider High sensitivity CRP,lipoprotein (a), fibrinogen, homocysteine if feasible,specialist referral.

35

How do I use the SCORE charts toassess total CVD risk inasymptomatic persons?

1. Use the low risk chart in Belgium*, France, Greece*,Italy, Luxembourg, Spain*, Switzerland, and Portugal;use the high risk chart in other countries of Europe

* Updated, re-calibrated charts are now available forBelgium, Germany, Greece, The Netherlands, Poland,Spain, and Sweden.

2. Find the cell nearest to the person’s age, cholesterol,and BP values, bearing in mind that risk will be higheras the person approaches the next age, cholesterol orBP category.

3. Check the qualifiers.4. Establish the absolute 10-year risk for fatal CVD.

Note that a low absolute risk in a young person may conceala high relative risk; this may be explained to the person byusing the relative risk chart. As the person ages, a highrelative risk will translate into a high absolute risk. Moreintensive lifestyle advice will be needed in such persons.

36

Risk estimation using SCORE: qualifiersThe charts should be used in the light of the clinician’sknowledge and judgement, especially with regard to localconditions.As with all risk estimation systems, risk will beoverestimated in countries with a falling CVD mortalityrate, and underestimated if it is rising.At any given age, risk appears lower for women than men.This is misleading since, ultimately, more women than mendie from CVD. Inspection of the charts shows that their riskis merely deferred by 10 years.Risk may be higher than indicated in the chart in:

~Sedentary or obese subjects, especially those with centralobesity;

~Those with a strong family history of premature CVD~The socially deprived;~Subjects with diabetes—risk may be 5-fold higher in women withdiabetes and 3-fold higher in men with diabetes compared withthose without diabetes;

~Those with low HDL cholesterol or high triglycerides;~Asymptomatic subjects with evidence of pre-clinicalatherosclerosis, for example a reduced ankle-brachial index,or on imaging such as carotid ultrasonography or CT scanning.

37

10 year risk of fatal CVD inhigh risk regions of Europe

39

This chart may used to show younger people at low absoluterisk that, relative to others in their age group, their risk maybe many times higher than necessary. This may help tomotivate decisions about avoidance of smoking, healthynutrition and exercise, as well as flagging those who maybecome candidates for medication

Relative Risk Chart

40

How do I manage thecomponents of total CVD risk?

The patient and the doctor agreethat a risk assessment is indicated,and the patient is informed that theresult may lead to suggestionsregarding life style change and thepossibility of life long medication.

There are time and resources todiscuss and follow up advice andtreatment.

The doctor should be aware of andrespect the patients own values andchoices.

41

Total CVD risk management:A key message

Management of the individualcomponents of risk such as smoking,diet, exercise, blood pressure andlipids impacts on total risk.

Thus, if perfect control of a risk factoris difficult (for example, bloodpressure control in the elderly), totalCVD risk can still be reduced byreducing other risk factors such assmoking or blood cholesterol.

Lifestyle recommendationsNo smoking

Weight reduction if BMI ≥ 25 kg/m2

and especially if BMI ≥ 30 kg/m2

No further weight gain if WC 80-88cm in women and WC 94-102 cmin men. Advise weight loss if WC ≥88 cm in women and ≥ 102 cm inmen

30 min of moderately vigorousexercise on most days of the week;exercise and weight reduction canprevent diabetes

Healthy diet

• Wide variety of foods• Energy intake adjusted to avoidoverweight• Encourage: fruits, vegetables,wholegrain cereals and bread, fish(especially oily), lean meat, low fatdairy products• Replace saturated fat withmonounsaturated and polyunsaturatedfats (vegetable and marine)• Hypertensive subjects should reducesalt intake

Drug treatmentMore likely as SCORE risk exceeds 5% and especially as it approaches 10%, orif there is end-organ damage. In the elderly, drug treatment is generally notrecommended below 10% risk unless a specific indication exists

Consider BP-lowering drugs when BP ≥ 140/90Consider statins when total cholesterol ≥ 5 or LDL ≥ 3In patients with CVD: Aspirin. Statins for mostIn patients with diabetes: consider glucose-lowering drugs

43

• Lifestyle adviceto maintain low riskstatus

• Re-assess totalrisk at regularintervals

45

Managing total risk-TIPS TO HELP BEHAVIOUR

CHANGE

Develop a sympathetic alliance with the patient.Ensure the patient understands the relationshipbetween lifestyle and disease.

Use this to gain commitment to lifestyle change.Involve the patient in identifying the risk factorsto change.

Explore potential barriers to change.Help design a lifestyle change plan.Be realistic and encouraging- “ANY increase inexercise is good and can be built on”.Reinforce the patient’s efforts to change.Monitor progress through follow-up contacts.Involve other health care staff wherever possible.

46

Managing total CVD risk:Why do people find it hard to

change their lifestyle?Socio-economic status: Low SES, includinglow educational level and low income, impedesthe ability to adopt lifestyle change.

Social isolation: People living alone are morelikely to have unhealthy lifestyles.

Stress: Stress at work and at home makes itmore difficult for people to adopt and sustain ahealthy lifestyle.

Negative emotions: Depression, anxiety andhostility impede lifestyle change.

Complex or confusing adviceIncreased physician awareness of these factorsfacilitates empathy, counselling, and the provisionof sympathetic, simple, and explicit advice.

48

Smoking and CVD

Smoking is a strong and independentcausal risk factor for both first andsubsequent CVD events, as well as formultiple other diseases.

Passive smoking also increases risk.

Smoking greatly increases the risksassociated with other risk factors.

Those who stop smoking after a CHDevent have half the mortality of thosewho continue. No drug is so effective.

49

Managing total CVD risk:SMOKING

A- ASK systematically identify all smokers atevery opportunity.

A- ASSESS: Determine the person’s degree ofaddiction and his/her readiness to ceasesmoking.

A- ADVISE: Unequivocally urge all smokers toquit.

A- ASSIST: Agree on a smoking cessationstrategy including behavioural counselling,nicotine replacement therapy, and/orpharmacological intervention.

A- ARRANGE a schedule of follow-up visits.

All smokers should be professionally encouraged topermanently stop smoking all forms of tobacco

The 5 As can help-

51

Managing total CVD risk:HEALTHY FOOD CHOICES

All individuals should be advised about food choices that areassociated with a lower CVD risk. High risk persons shouldreceive specialist dietary advice if feasible

General recommendations should suit the local culture

A wide variety of foods should be eaten

Energy intake should be adjusted to avoid overweight.

Encourage: Fruits, vegetables, wholegrain cereals andbread, fish (especially oily), lean meat, low fat dairyproducts

Replace saturated fats with the above foods and withmonounsaturated and polyunsaturated fats fromvegetable and marine sources to reduce total fat to<30% of energy, of which less than 1/3 is saturated.

Reduce salt intake if blood pressure is raised by avoidingtable salt and salt in cooking, and by choosing fresh orfrozen unsalted foods. Many processed and preparedfoods, including bread, are high in salt.

52

Managing total CVD risk:BODY WEIGHT

Increasing body weight is associated with increasedtotal and CVD mortality and morbidity, mediated inpart through increases in blood pressure and bloodcholesterol, reduced HDL cholesterol, and anincreased likelihood of diabetes.

Weight reduction is recommended for obese people(BMI ≥30 kg/m2) and should be considered for thosewho are overweight (BMI ≥25 and <30 kg/m2).

Men with a waist circumference of 94—102 cm andwomen with a waist circumference of 80—88 cm areadvised not to increase their weight. Men above 102cm and women above 88 cm are advised to loseweight.

Restriction of total calorie intake and regular physicalexercise are the cornerstones of weight control. It islikely that improvements in central fat metabolismoccur with exercise even before weight reductionoccurs.

54

Managing total CVD risk:PHYSICAL ACTIVITY

Stress that positive health benefits occur withalmost any increase in activity; small amounts ofexercise have an additive effect; exerciseopportunities exist in the workplace, for example byusing stairs instead of the lift.

Try to find leisure activities that are positivelyenjoyable.

30 min of moderately vigorous exercise on mostdays of the week will reduce risk and increasefitness.

Exercising with family or friends tends to improvemotivation.

Added benefits include a sense of well-being,weight reduction, and better self-esteem.

Continued physician encouragement and supportmay help in the long term.

56

JTF4 Blood pressure

Risk factor for all atherosclerotic CVDs, heart failure andrenal failure, cognitive impairment.

Risk rises progressively from <120/80 on.

Other RFs such as diabetes and dyslipidaemia are morelikely in hypertensives, and interact to greatly increase risk.

Direct association with body weight- 5 KG reductionreduces BP by 4.4/3.6 mm Hg.

Physical training can reduce BP by 3.5/3.2 mm Hg.

Multiple nutritional factors affect BP- encourage fruit,vegetables, low-fat dairy products, reduced saturated fatand salt.

Benefits of BP reduction apply to both sexes, up to at leastage 80, and to CHD, stroke, heart failure, renal function andpossibly to cognitive impairment.

Effective BP control is more important than the choice ofagent.

SCORE

CVD risk

Normal

<130/85

High Normal

130—139/

85—89

Grade 1

140—159/

90—99

Grade 2

160—179/

100—109

Grade 3

≥180/110

Low

<1%

Lifestyle

advice

Lifestyle

advice

Lifestyle

advice

Drug Rx

if persists

Drug Rx

Moderate

1—4%

Lifestyle

advice

Lifestyle

advice

+consider

drug Rx

Drug Rx

if persists

Drug Rx

Increased

5-9%

Lifestyle

advice

+consider

drug Rx

Drug Rx Drug Rx Drug Rx

Markedlyincreased

≥10%

Lifestyle

advice

+consider

drug Rx

Drug Rx Drug Rx Drug Rx

57

In ALL cases, look for and manage all risk factors. Those with established CVD,diabetes or renal disease are at markedly increased risk, and a BP of <130/80 isdesirable if feasible. For all other people, check SCORE risk. Those with target organdamage are managed as ‘increased risk’.

Managing total CVD risk:Blood Pressure

59

JTF4 LipidsTotal and LDL cholesterol relate to CVD risk causally,strongly, independently and progressively and are the primaryfocus of management. Reduction unequivocally reduces CVDrisk, including stroke.Moderately raised triglycerides (>1.7 mmol/l, ~150 mg/dl)relate to risk; may relate to particle size; inverse associationwith HDL cholesterol; associations with abdominal obesity &blood sugar and possible thrombogenic effects- LOOK forthese!HDL cholesterol relates inversely to CVD risk. HDL isantiatherogenic, anti-inflammatory and anti-thrombotic, and isinvolved in reverse cholesterol transport. <1 mmol/l (~40mg/dl) in men and <1.2 mmol/l (~45 mg/dl) in womendenotes increased risk.Total cholesterol:HDL ratio relates to risk but better riskestimation may be possible if they are considered separately.Apo B/A1 ratio relates strongly to risk but it is not known ifit should be a treatment goal.Lp(a) relates to risk, is genetically determined, but resistantto modification.

Lifestyle advice for 3months, then reassessSCORE and fasting lipids

mg/dL) or <2 mmol/L (~80 mg/dL) iffeasible.This will require statin treatment in still ≥ 5%

EstablishedCVD

Diabetes asabove

Markedly

raised lipidlevels

SCORE risk ≥ 5% SCORE risk < 5%

Lifestyleadvice toreducetotal chol<5mmol/L(~190mg/dL)and LDL-C<3mmol/L(~115mg/dL)Regularfollow-up

Managing total CVD risk: LipidsIn ALL cases, look for and manage all risk factors. Those with established CVD, diabetestype 2 or type 1 with microalbuminuria, or with severe hyperlipidaemia are already at highrisk. For all other people, the SCORE charts can be used to estimate total risk

Dietary and exercise advice togetherwith attention to all risk factors comesfirst.Aim to reduce total cholesterol to <4.5mmol/L (~175 mg/dL) or <4 mmol/L(~155 mg/dL) if feasible, and LDL-cholesterol to <2.5 mmol/L (~100

TC <5 mmol/lSCORE risk and LDL-C <3

mmol/l andmany. Some recommend statins for all

CVD and most diabetic patients regardless of baseline levels.

Treatment goals are not defined for HDL cholesterol and triglycerides, butHDL-C <1.0 mmol/L (~40 mg/dL) for men and <1.2 mmol/L (~45 mg/dL)for women and fasting triglycerides of >1.7 mmol/L (~150 mg/dL) aremarkers of increased cardiovascular risk

60

SCORE now <5%

62

JTF4 Diabetes and themetabolic syndrome

Linear, graded relationship between glucose and CVD risk,especially for 2 hour post load glucose and for HbA1cfrom levels well within the “normal” rangeRelative risk of CVD for impaired glucose tolerance isapprox 1.5, for diabetes 2-4, maybe more in womenRisk relates to both the diabetic state and related factors,and to associated conventional, modifiable risk factorsThe ideal is to prevent the occurrence of diabetes ifpossible

Good metabolic control prevents microvascularcomplicationsLipid targets are total cholesterol < 4.5 mmol/l (~175mg/dl), or <4.0 mmol/l (~155 mg/dl), if feasible, and LDLchol <2.5 mmol/l (~100 mg/dl) or < 2.0 mol/l (~80mg/dl) if feasibleBP target is < 130/80 mm Hg if feasible

Treatment targets in patients with type 2 diabetes

Unit Target

HbA (DCCT-1c

aligned)HbA (%)1c ≤6.5 if feasible

Plasma glucose Fasting/pre-prandialmmol/L (mg/dL)

<6.0 (110) if feasible

Post-prandialmmol/L (mg/dL)

<7.5 (135) if feasible

Blood pressure mmHg ≤130/80

Total cholesterol mmol/L (mg/dL)mmol/L (mg/dL)

<4.5 (175)<4.0 (155) if feasible

LDL cholesterol mmol/L (mg/dL)mmol/L (mg/dL)

<2.5 (100)<2.0 (80) if feasible

63

64

The Metabolic Syndrome

The term ‘metabolic syndrome’ refers tothe combination of several factors thattend to cluster together- central obesity,hypertension, low HDL cholesterol, raisedtriglycerides, and raised blood sugar- toincrease risk of diabetes and CVD.This implies that, if one component isidentified, a systematic search for the

others is indicated, together with an activeapproach to managing all of these riskfactors.

Physical activity and weight control canradically reduce the risk of developingdiabetes in those with the metabolicsyndrome.

66

JTF4 Psychosocial factors

Appear to contribute independently to CVDrisk- both of developing CVD and forprognosis thereafter.

Also act as barriers to achieving lifestylechange and to adhering to treatment.

Factors include low socio-economic status,social isolation, poor social support, workstress (high demand, low control; higheffort, low reward) domestic stress,hostility, depression.

Hard to quantify the benefits ofinterventions. Stress management programsmay improve well-being, risk factor levelsand CVD outcomes.

68

Inflammation markers andhaemostatic factors

Criteria for evaluation include applicabilityto all relevant CVD events; ability to predictin short, intermediate and long-term follow-up; standardised measurements;examination of variability; degree ofcorrelation with established risk factors;improvement in overall prediction of events.

Reverse causality may be a problem- subclinical disease my increase the factor.

Incorporation of CRP, fibrinogen and otheremerging risk factors for the estimation ofCVD risk may be premature.

70

Genetic factors

A family history of CVD in a first degreerelative aged <55 (male) or 65 (female)carries an independent relative risk of 1.5-1.7.

Heritability of lipid phenotypes is 40-60%,>90% for Lp(a).

Dominant genotypes such as familialhypercholesterolaemia exert large effects butare infrequent. Screening for multiplepoymorphisms with small but cumulativeeffects on risk is not yet realistic.

Close relatives of persons with premature CVDshould have risk assessments; some will have,for example, familial hyperlipidaemia. Otherswill share high risk lifestyles.

71

JTF4 on CVD Preventionin Clinical Practice

16. NEW IMAGING METHODSTO DETECT ASYMPTOMATIC

INDIVIDUALS AT HIGH RISKFOR CARDIOVASCULAR

EVENTS

72

New imaging methodsAtherosclerosis in often advanced before the first clinicalmanifestation such as sudden death, myocardial infarctionor stroke. Therefore it is logical to seek easy and reliablemethods to detect sub clinical disease.Criteria for accepting the clinical utility of new imagingtechniques have been defined; clinical benefit withoutharm is required.MR imaging of carotid and coronary plaque is possible butremains a research tool thus far.Multi-slice CT coronary arteriography has a high negativepredictive value. The presence of coronary calcium seemsto add independent prognostic information, especially inmedium risk subjects, but may also lead to unnecessarytests and interventions.Ultrasound carotid intima-media thickness appears toallow a modest improvement in risk estimation afterallowing for conventional risk factors; the hazard ratiomay be greater in women. Meticulous technique isrequired.Ankle-brachial index is easy, cheap and inexpensive andrelates strongly to future CVD. It deserves further studyto define its role in risk estimation.

74

Gender issues: cardiovasculardisease in women

Ultimately, more women (55%) die of CVDthan men (45%), particularly of stroke. Cf3% breast cancer deaths in women.The apparent lower risk in women in SCOREreflects the fact that women develop CVD 10years later.The evidenced base for risk factor advice,especially regarding drug treatments ishampered by under-representation of womenin clinical trials.Women are disadvantaged at all stages in theevolution of CVD- they are less likely to beoffered risk assessment, to have chest painevaluated or investigated, and to be offeredtherapy and interventions.Mortality from acute coronary syndromes andafter CABG is frequently higher in women.

76

CVD in women:Management implications II

3. The principles of total risk estimationand management are the same forboth sexes. In women, emphasise theevaluation of smoking, weight,glucose tolerance and oralcontraceptive use.

4. A low absolute risk in a youngerwoman may conceal a very highrelative risk. Detailed lifestyle advicemay prevent this from changing into ahigh absolute risk in later life.

78

Renal impairment andcardiovascular risk

Risk of CVD rises progressively frommicroalbuminuria with preserved GFR toend-stage renal disease, when it is 20—30x that of the general population.

Applies to apparently healthy people andto those with hypertension, CVD, andheart failure.

Associated with high blood pressure,hyperlipidaemia, metabolic syndrome,uric acid, homocysteine, and anaemia.Particularly vigorous risk factor controlneeded.

80

When to prescribe cardioprotective drugsin addition to those used to treat blood

pressure, lipids, and diabetes

Aspirin for virtually all with established CVD,and in persons at >10% SCORE risk onceblood pressure has been controlled.

β-blockers after myocardial infarction and,in carefully titrated doses, in those withheart failure.

ACE inhibitors in those with left ventriculardysfunction and in diabetic subjects withhypertension or nephropathy.

Anticoagulants in those at increased risk ofthromboembolic events, particularly atrialfibrillation.