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ATEROSCLEROZA

FACTORI DE RISC
PREVENTIA
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 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.
NORMAL
DISFUNCTIONAL

Vasodilatie Vasoconstrictie
NO, EDHF (?), ET-1, ROS, TxA2,
PGI2 BK, C-NP A-II

Tromboliza Tromboza
tPA+anexina II, TF-I, PAR 1-2, TF, PAI-1,
trombomodulina,
Proteina S, R-proteina C, Tx-A2, vonWF,
Antiagregare Plachetara TAFI de Adeziune
Molecule
NO, PGI2 CAM, Selectine

Antiproliferare Factori de crestere


NO, PGI2, TGF-β , Hep ET-1, A-II, PDGF, ILGF,
Interleukine
Lipoliza Inflamatie
LPL ROS
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)
GUANIL-CICLAZA
(cel musculare netede)

4 HBP L-citrulina
NADPH
Calmodulina

• Vasodilatatie, regalarea
y+
L-argininina (i)/eNOS tonusului vascular bazal
ATP • Inhibă aderarea, activarea,

+ NO secreţia şi agregarea plachetară


• Sade expresia P selectinei la
nivelul membranei plachetare
• Inhibă aderarea leucocitară
↑ Ca 2+ • Inhibă migrarea şi proliferarea
celulelor musculare netede
• Blochează modificările
conformaţionale la nivelulul
•bradikinină, GP IIb/IIIa B
•substanţa P,
•ADP,
•agonişti muscarinici
•forţele mecanice generate de flux
-
4 HBP
NADPH
Calmodulina L-citrulina

L-argininina eNOS
aI
aI
I + NO ROS
ai gr
A
n
z gr
i ↑ Ca 2+
zanA ADMA
LDL–OXIDAT
L-ornitină, ROS
Uree

•bradikinină,
•substanţa P,
LDL–OXIDAT •ADP,
DIABET ZAHARAT •agonişti muscarinici
•forţele mecanice generate de flux
MODALITĂŢI DE EXPLORARE
A DISFUNCŢIEI
ENDOTELIALE
 Explorarea coronarografică directă:
 prima modalitate de evaluare a funcţiei endoteliale – prin
determinarea cantitativă, pe imaginea coronarografică a
răspunsului vasomotor al arterelor coronare epicardice la
injectarea de acetilcolină (si alte molecule cu ro in eliberarea
de NO)

Dezavantaje:
 Investigarea acestor vase de conductanţă, reprezentativă pentru
pacienţii cu boală coronariană documentată nu dă însă informaţii
despre disfuncţia endotelială la pacienţii aflaţi în etapele incipiente de
evoluţie ale aterosclerozei, când boala este subclinică.
 Instrumentarea coronarelor epicardice nu este relevantă pentru
statusul microcirculaţiei coronariene la nivelul vaselor de rezistenţă –
neafectată în mod obişnuit de ateroscleroză dar disfuncţională în
boala cardiacă ischemică
MODALITĂŢI DE EXPLORARE
A DISFUNCŢIEI
ENDOTELIALE
 Explorarea intracoronariană a fluxului prin
cateter Doppler:
 Se foloseste un cateter ghid de angiografie în
vârful căruia exista un transductor de 12 MHz, cu
semnal Doppler pulsat conectat la un sistem de
analiza spectrală a a fluxului care prin
transformare rapidă Fourier a furnizeaza imaginea
anvelopelor Doppler pulsat uzuale din ecografia
cardiacă/vasculară. Se calculeaza fluxul folosind o
formula bazată pe diametrul vasului măsurat pe
imaginea coronarografică şi pe valoarea măsurată
a integralei timp-velocitate maximă obţinută la
înregistrarea Doppler
 ESTE CONSIDERATA “GOLDEN STANDARD”
 Invaziva, costisitoare necesita tehnologie medicala
avansata – are aplicabilitate limitata.
“Brachial Artery Flow-
Mediated Vasodilation”
(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.
Leziunea 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.
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
AHA Classification of atherosclerosis

Fig. 11.7
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-Aorta
Fatty 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
Process
 Multifactorial process (risk factors)
 Initiated by endothelial dysfunction
 Up regulation of endothelial and leukocyte
adhesion molecules
 Macrophage diapedesis
 LDL transcytosis
 LDL oxidation
 Foam cells
 Recruitment and proliferation of smooth
muscle cells (synthesis of connective tissue
proteins)
 Formation and organization of arterial thrombi
Disfunctie Boala Boala coronariana
coronariana
Endoteliala ocluziva
non-ocluziva
Boala coronariana sub-clinica

Boala coronariana clinica


DISFUNCTIA ENDOTELIALA
Three patterns of
arteriosclerosis
 Atherosclerosis
 The dominant pattern of arteriosclerosis
 Primarily affects the elastic (aorta, carotid,
iliac) and large to medium sized muscular
arteries (coronary, popliteal)
 Monckeberg medial calcific sclerosis
 Arteriolosclerosis –small arteries and
arterioles (hypertension and DM)
Is Atherosclerosis
Reversible
 Primate experiments
 High fat diet discontinued; atherosclerotic lesions
regress
 Humans
 Decrease fat and caloric intake (wars, famine,
wasting disease), atheromas decrease.
 Angiography after cholesterol lowering, plaque size
decreases
 What has to happen for plaques to regress?
 LDL lowered
 Mac ingest lipids
 Reverse cholesterol transport, depends on HDL
Consequences of plaque
formation
Generalized
 Narrowing/Occlusion

 Rupture

 Emboli

 Leading to specific problems:


 Myocardial and cerebral infarcts
 Aortic aneurysms

 Peripheral vascular disease


Altered Vessel Function

 Vessel change  Consequence


 Plaque narrows  Ischemia, turbulence
lumen  Aneurysms, vessel
 Wall weakened rupture
 Narrowing, ischemia,
 Thrombosis embolization
 Athero-embolization
 Breaking loose of
plaque  Increase systolic blood
 Loss of elasticity pressure
Late Changes
 Calcification
 An example of dystrophic calcification
 Cracking, ulceration, rupture
 Usually occurs at edge of plaque
 Thrombus formation
 Caused by endothelial injury,ulceration,
turbulence
 Organization of thrombus
 More thrombus
 Encroachment
 Weakens vessel wall
 Bleeding
 Ulceration, cracking and angiogenesis
ATHEROSCLEROSIS:
Pathology, Pathogenesis, Complications, Natural History
Hemorrhage into Plaque
Common Consequences
of Atherosclerosis in
Specific Vessels
Aorta

 Aneurysm
 Pulsatile abdominal mass
 Abdominal pain

 Bleeding

 Atheroembolization
 Narrowing of lumen
 Usually not a problem
Aortic Aneurysm
Aortic Aneurysm
Coronary Arteries

 Consequences of coronary artery


atherosclerosis: acute and chronic
ischemic heart disease
Coronary Artery Atherosclerosis
Coronary Artery Atherosclerosis
Carotids and Cerebral
Circulation
 Atherosclerosis with thrombosis can
lead to brain infarction
 Red or white
 Coagulative or liquefactive
 Can lead to transient ischemic
attacks (TIA), if narrowing is
aggravated by mural thrombus or
vasospasm
Celiac and Mesenteric
Arteries
 Narrowing primarily at aorta
bifurcation
 Ischemia uncommon because of
collateral circulation
 Ischemia can occur if more than 1
artery severely affected - ischemic
entercolitis
Renal Artery

 Progressive ischemic atrophy of


kidney leads to gradual kidney
failure (nephrosclerosis)
 Renal hypertension due to
decreased perfusion
Iliac and Femoral
Arteries
 Aneurysms
 Vessel occlusion by plaque and
thrombus
 Ischemia of leg muscles, especially
during exercise (intermittent
claudication)
 Ulcers of skin of legs and feet

 Gangrene of feet
CVD Prevention: The scope of
the problem
CVDs are the major causes of death and disability
in Europe - 4.35 million in Europe, 1.9 million in the
EU.
MORE women than men die from CVD -
2.3 million women, 2 million men.
10 fold regional differences, with reductions in the
West.
“Reductions” in age-specific CVD mortality
generally represent a transference of the problem
to older persons, with increasing heart failure.
Generally poor risk factor control (EuroAspire).
Improvements in smoking, BP and lipid control
offset by reduced activity, increasing obesity and
consequent diabetes.

13
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 developed
countries.
Falling in developed countries, rising fast
in developing ones.
2000- biggest cause of death worldwide.
1996- 15,000,000 deaths.
2020- 25,000,000 deaths.
(Source WHO)

14
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
CVD Deaths (all cohorts)

40

20

0
0 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
0 3 5 140 5 3 0
People who stay healthy tend
to have certain characteristics:
0 No tobacco
3 Walk 3 km daily, or 30 mins any
moderate activity
5 Portions of fruit and vegetables a day
140 Blood pressure less than 140 mm Hg
systolic
5 Total blood cholesterol <5 mmol/l
3 LDL cholesterol <3 mmol/l
0 Avoidance of overweight and diabetes

25
What are the PRIORITIES for
CVD prevention in clinical practice?
1. Patients with established atherosclerotic
CVD.
2. Asymptomatic individuals who are at
increased 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 premature


atherosclerotic CVD or of those at
particularly high risk.

26
What are the OBJECTIVES of
CVD prevention?
1. To assist those at low risk of CVD to maintain
this state lifelong, and to help those at
increased total CVD risk to reduce it.
2. To achieve the characteristics of people who
tend to stay healthy:
2.1 No smoking;
2.2 Healthy food choices;
2.3 Physical activity: 30 min of moderate activity a day;
2.4 BMI <25 kg/m2 and avoidance of central obesity;
2.5 BP <140/90 mmHg;
2.6 Total cholesterol <5 mmol/L (~190 mg/dL);
2.7 LDL cholesterol <3 mmol/L (~115 mg/dL);
2.8 Blood glucose <6mmo/L (~110 mg/dL).

27
What are the OBJECTIVES of
CVD prevention?
3. To achieve more rigorous risk factor control
in high risk subjects, especially those with
established 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) if
feasible;
3.3 LDL cholesterol <2.5 mmol/L (~100 mg/dL)
with an option of <2mmol/L (~80 mg/dL) if
feasible;
3.4 Fasting blood glucose <6 mmol/L (~110 mg/dL)
and HbA1c <6.5% if feasible.

4. To consider cardioprotective drug therapy in


these high risk subjects especially those with
established atherosclerotic CVD.

28
When do I assess
cardiovascular 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 assessed
but use of the SCORE chart is not necessary
as the person is already at high risk.

29
Why stress assessment of
total CVD risk ?
Multiple risk factors usually contribute
to the atherosclerosis that causes
CVD.
These risk factors interact, sometimes
multiplicatively.
Thus the aim should be to reduce
total risk; if a target cannot be
reached with one risk factor, total
risk can still be reduced by trying
harder with others.

30
Fig 2
The relationship of total cholesterol / HDL cholesterol ratio to 10 year fatal
CVD events in men and women aged 60 yrs with and without risk factors,
based on a risk function derived from the SCORE project.

30

25
Men, smoking,
10 yr risk of fatal CVD (%)

SBP=160 mmHg

20 Men, non-smoking,
SBP=120 mmHg
15
Women, smoking,
SBP=160 mmHg
10

Women, non-
5
smoking, SBP=120
mmHg

3 4 5 6 7

TC/HDL ratio

31
Table 1
Impact of combinations of risk
factors on 10 year risk of CVD death

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
How do I assess CVD risk
quickly 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 and
need management of all risk factors.
For all other people, the SCORE risk charts
can be used to estimate total risk-this is
critically important because many people
have mildly raised levels of several risk
factors that, in combination, can result in
unexpectedly high levels of total CVD risk.

33
Assessing cardiovascular risk:
What are the components?
History: Previous CVD or related diseases, family history
of 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), waist
circumference. Fundoscopy in severe hypertension.
Lab test: Urine for glucose and protein, microalbuminuria
in 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 hypertensive
persons.
Premature or aggressive CVD, especially with a family
history of premature CVD: Consider High sensitivity CRP,
lipoprotein (a), fibrinogen, homocysteine if feasible,
specialist referral.

34
How do I use the SCORE charts to
assess total CVD risk in
asymptomatic 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 for
Belgium, 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 higher
as the person approaches the next age, cholesterol or
BP 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 concea
a high relative risk; this may be explained to the person by
using the relative risk chart. As the person ages, a high
relative risk will translate into a high absolute risk. More
intensive lifestyle advice will be needed in such persons.
35
Risk estimation using SCORE: qualifiers
The charts should be used in the light of the clinician’s
knowledge and judgement, especially with regard to local
conditions.
As with all risk estimation systems, risk will be
overestimated in countries with a falling CVD mortality
rate, 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 men
die from CVD. Inspection of the charts shows that their risk
is merely deferred by 10 years.
Risk may be higher than indicated in the chart in:
~Sedentary or obese subjects, especially those with central
obesity;
~Those with a strong family history of premature CVD
~The socially deprived;
~Subjects with diabetes—risk may be 5-fold higher in women with
diabetes and 3-fold higher in men with diabetes compared with
those without diabetes;
~Those with low HDL cholesterol or high triglycerides;
~Asymptomatic subjects with evidence of pre-clinical
atherosclerosis, for example a reduced ankle-brachial index,
or on imaging such as carotid ultrasonography or CT scanning.
36
10 year risk of fatal CVD in
high risk regions of Europe

37
Relative Risk Chart
This chart may used to show younger people at low absolute
risk that, relative to others in their age group, their risk may
be many times higher than necessary. This may help to
motivate decisions about avoidance of smoking, healthy
nutrition and exercise, as well as flagging those who may
become candidates for medication

39
How do I manage the
components of total CVD risk?

The patient and the doctor agree


that a risk assessment is indicated,
and the patient is informed that the
result may lead to suggestions
regarding life style change and the
possibility of life long medication.
There are time and resources to
discuss and follow up advice and
treatment.
The doctor should be aware of and
respect the patients own values and
choices.

40
Total CVD risk management:
A key message

Management of the individual


components of risk such as smoking,
diet, exercise, blood pressure and
lipids impacts on total risk.
Thus, if perfect control of a risk factor
is difficult (for example, blood
pressure control in the elderly), total
CVD risk can still be reduced by
reducing other risk factors such as
smoking or blood cholesterol.

41
Lifestyle recommendations • Lifestyle advice
No smoking to maintain low risk
Healthy diet
status
Weight reduction if BMI ≥ 25 kg/m2 • Wide variety of foods
and especially if BMI ≥ 30 kg/m2 • Re-assess total
• Energy intake adjusted to avoid
risk at regular
No further weight gain if WC 80-88 overweight
intervals
cm in women and WC 94-102 cm • Encourage: fruits, vegetables,
in men. Advise weight loss if WC ≥ wholegrain cereals and bread, fish
88 cm in women and ≥ 102 cm in (especially oily), lean meat, low fat
men dairy products
• Replace saturated fat with
30 min of moderately vigorous monounsaturated and polyunsaturated
exercise on most days of the week; fats (vegetable and marine)
exercise and weight reduction can • Hypertensive subjects should reduce
prevent diabetes salt intake

Drug treatment
More likely as SCORE risk exceeds 5% and especially as it approaches 10%, or
if there is end-organ damage. In the elderly, drug treatment is generally not
recommended below 10% risk unless a specific indication exists

Consider BP-lowering drugs when BP ≥ 140/90


Consider statins when total cholesterol ≥ 5 or LDL ≥ 3
In patients with CVD: Aspirin. Statins for most
In patients with diabetes: consider glucose-lowering drugs
43
Managing total risk-
TIPS TO HELP BEHAVIOUR
CHANGE
Develop a sympathetic alliance with the patient.
Ensure the patient understands the relationship
between lifestyle and disease.
Use this to gain commitment to lifestyle change.
Involve the patient in identifying the risk factors
to change.
Explore potential barriers to change.
Help design a lifestyle change plan.
Be realistic and encouraging- “ANY increase in
exercise 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.

45
Managing total CVD risk:
Why do people find it hard to
change their lifestyle?
Socio-economic status: Low SES, including
low educational level and low income, impedes
the ability to adopt lifestyle change.
Social isolation: People living alone are more
likely to have unhealthy lifestyles.
Stress: Stress at work and at home makes it
more difficult for people to adopt and sustain a
healthy lifestyle.
Negative emotions: Depression, anxiety and
hostility impede lifestyle change.
Complex or confusing advice
Increased physician awareness of these factors
facilitates empathy, counselling, and the provision
of sympathetic, simple, and explicit advice.

46
Smoking and CVD
Smoking is a strong and independent
causal risk factor for both first and
subsequent CVD events, as well as for
multiple other diseases.
Passive smoking also increases risk.
Smoking greatly increases the risks
associated with other risk factors.
Those who stop smoking after a CHD
event have half the mortality of those
who continue. No drug is so effective.

48
Managing total CVD risk:
SMOKING
All smokers should be professionally encouraged to
permanently stop smoking all forms of tobacco
The 5 As can help-
A- ASK systematically identify all smokers at
every opportunity.
A- ASSESS: Determine the person’s degree of
addiction and his/her readiness to cease
smoking.
A- ADVISE: Unequivocally urge all smokers to
quit.
A- ASSIST: Agree on a smoking cessation
strategy including behavioural counselling,
nicotine replacement therapy, and/or
pharmacological intervention.
A- ARRANGE a schedule of follow-up visits.
49
Managing total CVD risk:
HEALTHY FOOD CHOICES
All individuals should be advised about food choices that are
associated with a lower CVD risk. High risk persons should
receive 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 and
bread, fish (especially oily), lean meat, low fat dairy
products
Replace saturated fats with the above foods and with
monounsaturated and polyunsaturated fats from
vegetable 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 avoiding
table salt and salt in cooking, and by choosing fresh or
frozen unsalted foods. Many processed and prepared
foods, including bread, are high in salt.
51
Managing total CVD risk:
BODY WEIGHT
Increasing body weight is associated with increased
total and CVD mortality and morbidity, mediated in
part through increases in blood pressure and blood
cholesterol, reduced HDL cholesterol, and an
increased likelihood of diabetes.
Weight reduction is recommended for obese people
(BMI ≥30 kg/m2) and should be considered for those
who are overweight (BMI ≥25 and <30 kg/m2).
Men with a waist circumference of 94—102 cm and
women with a waist circumference of 80—88 cm are
advised not to increase their weight. Men above 102
cm and women above 88 cm are advised to lose
weight.
Restriction of total calorie intake and regular physical
exercise are the cornerstones of weight control. It is
likely that improvements in central fat metabolism
occur with exercise even before weight reduction
occurs.

52
Managing total CVD risk:
PHYSICAL ACTIVITY
Stress that positive health benefits occur with
almost any increase in activity; small amounts of
exercise have an additive effect; exercise
opportunities exist in the workplace, for example by
using stairs instead of the lift.
Try to find leisure activities that are positively
enjoyable.
30 min of moderately vigorous exercise on most
days of the week will reduce risk and increase
fitness.
Exercising with family or friends tends to improve
motivation.
Added benefits include a sense of well-being,
weight reduction, and better self-esteem.
Continued physician encouragement and support
may help in the long term.
54
JTF4 Blood pressure
Risk factor for all atherosclerotic CVDs, heart failure and
renal failure, cognitive impairment.
Risk rises progressively from <120/80 on.
Other RFs such as diabetes and dyslipidaemia are more
likely in hypertensives, and interact to greatly increase risk.
Direct association with body weight- 5 KG reduction
reduces 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 fat
and salt.
Benefits of BP reduction apply to both sexes, up to at least
age 80, and to CHD, stroke, heart failure, renal function and
possibly to cognitive impairment.
Effective BP control is more important than the choice of
agent.

56
Managing total CVD risk:
Blood Pressure
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 is
desirable if feasible. For all other people, check SCORE risk. Those with target organ
damage are managed as ‘increased risk’.

SCORE Normal High Normal Grade 1 Grade 2 Grade 3


CVD risk <130/85 130—139/ 140—159/ 160—179/
85—89 90—99 100—109 ≥180/110
Low Lifestyle Lifestyle Lifestyle Drug Rx Drug Rx
<1% advice advice advice if persists

Moderate Lifestyle Lifestyle +consider Drug Rx Drug Rx


1—4% advice advice drug Rx if persists

Increased Lifestyle +consider Drug Rx Drug Rx Drug Rx


5-9% advice drug Rx

Markedly Lifestyle +consider Drug Rx Drug Rx Drug Rx


increased advice drug Rx
≥10%

57
JTF4 Lipids
Total and LDL cholesterol relate to CVD risk causally,
strongly, independently and progressively and are the primary
focus of management. Reduction unequivocally reduces CVD
risk, including stroke.
Moderately raised triglycerides (>1.7 mmol/l, ~150 mg/dl)
relate to risk; may relate to particle size; inverse association
with HDL cholesterol; associations with abdominal obesity &
blood sugar and possible thrombogenic effects- LOOK for
these!
HDL cholesterol relates inversely to CVD risk. HDL is
antiatherogenic, anti-inflammatory and anti-thrombotic, and is
involved in reverse cholesterol transport. <1 mmol/l (~40
mg/dl) in men and <1.2 mmol/l (~45 mg/dl) in women
denotes increased risk.
Total cholesterol:HDL ratio relates to risk but better risk
estimation may be possible if they are considered separately.
Apo B/A1 ratio relates strongly to risk but it is not known if
it should be a treatment goal.
Lp(a) relates to risk, is genetically determined, but resistant
to modification.

59
Managing total CVD risk: Lipids
In ALL cases, look for and manage all risk factors. Those with established CVD, diabetes
type 2 or type 1 with microalbuminuria, or with severe hyperlipidaemia are already at high
risk. For all other people, the SCORE charts can be used to estimate total risk

Markedly
Established Diabetes as raised lipid SCORE risk ≥ 5% SCORE risk < 5%
CVD above levels

Dietary and exercise advice together Lifestyle


Lifestyle advice for 3
with attention to all risk factors comes months, then reassess advice to
first. SCORE and fasting lipids reduce
Aim to reduce total cholesterol to <4.5 total chol
mmol/L (~175 mg/dL) or <4 mmol/L <5
(~155 mg/dL) if feasible, and LDL- SCORE now <5% mmol/L
cholesterol to <2.5 mmol/L (~100 (~190
mg/dL) or <2 mmol/L (~80 mg/dL) if TC <5 mmol/l mg/dL)
feasible. SCORE risk and LDL-C <3
and LDL-C
This will require statin treatment in mmol/l and <3
many. Some recommend statins for all still ≥ 5% mmol/L
CVD and most diabetic patients (~115
regardless of baseline levels. mg/dL)
Regular
Treatment goals are not defined for HDL cholesterol and triglycerides, but follow-up
HDL-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) are
markers of increased cardiovascular risk
60
JTF4 Diabetes and the
metabolic syndrome
Linear, graded relationship between glucose and CVD risk,
especially for 2 hour post load glucose and for HbA1c
from levels well within the “normal” range
Relative risk of CVD for impaired glucose tolerance is
approx 1.5, for diabetes 2-4, maybe more in women
Risk relates to both the diabetic state and related factors,
and to associated conventional, modifiable risk factors
The ideal is to prevent the occurrence of diabetes if
possible
Good metabolic control prevents microvascular
complications
Lipid targets are total cholesterol < 4.5 mmol/l (~175
mg/dl), or <4.0 mmol/l (~155 mg/dl), if feasible, and LDL
chol <2.5 mmol/l (~100 mg/dl) or < 2.0 mol/l (~80
mg/dl) if feasible
BP target is < 130/80 mm Hg if feasible

62
Treatment targets in patients with type 2 diabetes
Unit Target
HbA 1c (DCCT- HbA 1c(%) ≤6.5 if feasible
aligned)
Plasma glucose Fasting/pre-prandial <6.0 (110) if feasible
mmol/L (mg/dL)

Post-prandial <7.5 (135) if feasible


mmol/L (mg/dL)

Blood pressure mmHg ≤130/80


Total cholesterol mmol/L (mg/dL) <4.5 (175)
mmol/L (mg/dL) <4.0 (155) if feasible
LDL cholesterol mmol/L (mg/dL) <2.5 (100)
mmol/L (mg/dL) <2.0 (80) if feasible

63
The Metabolic Syndrome
The term ‘metabolic syndrome’ refers to
the combination of several factors that
tend to cluster together- central obesity,
hypertension, low HDL cholesterol, raised
triglycerides, and raised blood sugar- to
increase risk of diabetes and CVD.
This implies that, if one component is
identified, a systematic search for the
others is indicated, together with an active
approach to managing all of these risk
factors.
Physical activity and weight control can
radically reduce the risk of developing
diabetes in those with the metabolic
syndrome.

64
JTF4 Psychosocial factors
Appear to contribute independently to CVD
risk- both of developing CVD and for
prognosis thereafter.
Also act as barriers to achieving lifestyle
change and to adhering to treatment.
Factors include low socio-economic status,
social isolation, poor social support, work
stress (high demand, low control; high
effort, low reward) domestic stress,
hostility, depression.
Hard to quantify the benefits of
interventions. Stress management programs
may improve well-being, risk factor levels
and CVD outcomes.

66
Inflammation markers and
haemostatic factors
Criteria for evaluation include applicability
to all relevant CVD events; ability to predict
in short, intermediate and long-term follow-
up; standardised measurements;
examination of variability; degree of
correlation with established risk factors;
improvement in overall prediction of events.
Reverse causality may be a problem- sub
clinical disease my increase the factor.
Incorporation of CRP, fibrinogen and other
emerging risk factors for the estimation of
CVD risk may be premature.

68
Genetic factors
A family history of CVD in a first degree
relative 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 familial
hypercholesterolaemia exert large effects but
are infrequent. Screening for multiple
poymorphisms with small but cumulative
effects on risk is not yet realistic.
Close relatives of persons with premature CVD
should have risk assessments; some will have,
for example, familial hyperlipidaemia. Others
will share high risk lifestyles.

70
JTF4 on CVD Prevention
in Clinical Practice

16. NEW IMAGING METHODS


TO DETECT ASYMPTOMATIC
INDIVIDUALS AT HIGH RISK
FOR CARDIOVASCULAR
EVENTS

71
New imaging methods
Atherosclerosis in often advanced before the first clinical
manifestation such as sudden death, myocardial infarction
or stroke. Therefore it is logical to seek easy and reliable
methods to detect sub clinical disease.
Criteria for accepting the clinical utility of new imaging
techniques have been defined; clinical benefit without
harm is required.
MR imaging of carotid and coronary plaque is possible but
remains a research tool thus far.
Multi-slice CT coronary arteriography has a high negative
predictive value. The presence of coronary calcium seems
to add independent prognostic information, especially in
medium risk subjects, but may also lead to unnecessary
tests and interventions.
Ultrasound carotid intima-media thickness appears to
allow a modest improvement in risk estimation after
allowing for conventional risk factors; the hazard ratio
may be greater in women. Meticulous technique is
required.
Ankle-brachial index is easy, cheap and inexpensive and
relates strongly to future CVD. It deserves further study
to define its role in risk estimation.
72
Gender issues: cardiovascular
disease in women
Ultimately, more women (55%) die of CVD
than men (45%), particularly of stroke. Cf
3% breast cancer deaths in women.
The apparent lower risk in women in SCORE
reflects the fact that women develop CVD 10
years later.
The evidenced base for risk factor advice,
especially regarding drug treatments is
hampered by under-representation of women
in clinical trials.
Women are disadvantaged at all stages in the
evolution of CVD- they are less likely to be
offered risk assessment, to have chest pain
evaluated or investigated, and to be offered
therapy and interventions.
Mortality from acute coronary syndromes and
after CABG is frequently higher in women.
74
CVD in women:
Management implications II
3. The principles of total risk estimation
and management are the same for
both sexes. In women, emphasise the
evaluation of smoking, weight,
glucose tolerance and oral
contraceptive use.
4. A low absolute risk in a younger
woman may conceal a very high
relative risk. Detailed lifestyle advice
may prevent this from changing into a
high absolute risk in later life.
76
Renal impairment and
cardiovascular risk
Risk of CVD rises progressively from
microalbuminuria with preserved GFR to
end-stage renal disease, when it is 20—
30x that of the general population.
Applies to apparently healthy people and
to those with hypertension, CVD, and
heart failure.
Associated with high blood pressure,
hyperlipidaemia, metabolic syndrome,
uric acid, homocysteine, and anaemia.
Particularly vigorous risk factor control
needed.

78
When to prescribe cardioprotective drugs
in 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 once
blood pressure has been controlled.
β-blockers after myocardial infarction and,
in carefully titrated doses, in those with
heart failure.
ACE inhibitors in those with left ventricular
dysfunction and in diabetic subjects with
hypertension or nephropathy.
Anticoagulants in those at increased risk of
thromboembolic events, particularly atrial
fibrillation.

80