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ATEROSCLER

OZA
FACTORI DE
RISC
PREVENTIA
Dr. Silviu I Dumitrescu,
Medic specialist cardiolog,
CCUBCVA

Ce este ?

Ateroscleroza este prima cauz de mortalitate n


lume, peste jumtate din decesele nregistrate
datorndu-se complicaiilor ei.
Efectele ei clinice se manifest prin afectarea
preponderent a arterelor musculare de calibru
mediu, precum coronarele, bazilarele, vertebralele,
carotidele i arterele membrelor inferioare.
Leziunile aterosclerotice nu sunt apananajul istoriei
moderne, asociat stilului de via contemporan, ci
exist nc din antichitate, fiind descrise ca entiti
patologice certe la mumiile egiptene.

PrincessAhmoseMeryetAmonofEgypt,1500IdHr

Teoriile aterogenezei

Primele ncercri de explicitare a ateromatozei au fost


fcute n 1852 de Rudolf Virchow care considera c o
leziune minimal a peretelui arterial produce o reacie
inflamatorie ce determin pasajul i acumularea
constituenilor plasmatici n intima arterial.

Teoriile aterogenezei

n 1856, von Rokitansky elaboreaz o nou teorie completat


n 1946 de Duguid care susine c ariile lezionale sunt
acoperte de mici trombi, care se organizeaz prin creterea
celulelor musculare n interiorul lor, ncorporndu-i n leziune,
pentru a deveni ulterior zonele de progresie ale acesteia.

O ipotez complet diferit a fost lansat n 1973 ipoteza


monoclonal, ce sugereaz c leziunile aterosclerotice pot s
fie considerate ca o manifestare a unei forme de neoplazie.

Datele actuale explic aterogeneza prin ipoteza reaciei la


leziune (response-to-injury hypothesis of atherosclerosis)
elaborat tot n 1973 i revizuit prin rezultatele cercetrilor
recente.

DISFUNCIA
ENDOTELIAL

1983 Fudmer i colab. care au demonstrat alterarea vasodilataiei


mediate de endoteliu n boala coronarian i au indicat legtura
dintre endoteliul disfuncional i ateroscleroz

= o afeciune sistemic ce se regsete ca un numitor comun n


fiziopatologia aterosclerozei, aterotrombozei i remodelrii
vasculare cu determinri coronariene, carotidiene, perferice sau
multiple, a insuficienei cardiace, insuficenei renale, diabetului i
hipertensiunii fundamentnd astfel conceptul actual de
continuum cardiovascular.

viziunea actual asupra funciei endoteliale o situeaz deasupra


noiunii clasice de factor de risc cardiovascular, fiind de fapt un
summum al expresiei fenotipului vascular individual i o integral a
tuturor factorilor lezionali / de protecie vascular.

ENDOTELIUL NORMAL

DISFUNCIA
ENDOTELIAL

Disfuncia endotelial se poate defini


fiziopatologic ca un dezechilibru al activitii
endoteliului n sensul creterii necompensate
a reaciilor i moleculelor n sensul promovrii:

vasoconstriciei,
aderrii celulare,
trombozei,
coagulrii,
inflamaiei
proliferrii celulare la nivel vascular.

NORMAL
DISFUNCTIONAL
Vasodilatie
NO, EDHF (?),
PGI2 BK, C-NP

Tromboliza
tPA+anexina II, TF-I,
trombomodulina,
Proteina S, R-proteina C,

Vasoconstrictie
ET-1, ROS, TxA2,
A-II

Tromboza

Antiagregare Plachetara

PAR 1-2, TF, PAI-1,


Tx-A2, vonWF,
TAFI de Adeziune
Molecule

NO, PGI2

CAM, Selectine

Antiproliferare

Factori de crestere

NO, PGI2, TGF-, Hep

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


Interleukine

Lipoliza
LPL

Inflamatie

Mecanisme
fiziopatologice ale
disfunciei
endoteliale
Cea mai important verig fiziopatologic, comun
tuturor afeciunilor n care apare disfuncia
endotelial, este alterarea sistemului de modularea
a biologiei vasculare prin intermediul EDRF (NO),
studiile actuale concentrndu-se asupra afectrii
lanului biochimic al sintezei i degradrii acestuia.
Astfel, reducerea disponibilitii NO poate fi
determinat fie de reducerea produciei, fie de
inactivarea sa rapid, dup cum urmeaz:

Diminuarea substratului necesar NO sintetazei


Afectarea activitii NO sintetazei
Inactivarea NO de speciile reactive de oxigen (ROS)

GUANILCICLAZA
(celmuscularenetede)
4 HBP
NADPH

L-citrulina

Calmodulina

y+

ATP

L-argininina

(i)/eNOS

NO

Ca 2+
bradikinin,
substana P,
ADP,
agoniti muscarinici
forele mecanice generate de flux

Vasodilatatie,
Regalarea tonusului
vascular bazal
Inhib aderarea, activarea,
secreia i agregarea plachetar
Sade expresia P selectinei la
nivelul membranei plachetare
Inhib aderarea leucocitar
Inhib migrarea i proliferarea
celulelor musculare netede
Blocheaz modificrile
conformaionale la nivelulul
GP IIb/IIIa B

4 HBP
NADPH

L-citrulina

Calmodulina

L-argininina

za I I
a
in za
g
Ar ina
g
Ar

L-ornitin,
Uree

LDLOXIDAT
DIABET ZAHARAT

eNOS

+
Ca 2+

NO
ADMA
LDLOXIDAT
ROS

bradikinin,
substana P,
ADP,
agoniti muscarinici
forele mecanice generate de flux

ROS

MODALITI DE EXPLORARE
A DISFUNCIEI
ENDOTELIALE
Explorarea coronarografic direct:

prima modalitate de evaluare a funciei endoteliale prin


determinarea cantitativ, pe imaginea coronarografic a
rspunsului vasomotor al arterelor coronare epicardice la
injectarea de acetilcolin (si alte molecule cu rol in
eliberarea de NO)

Dezavantaje:
Investigarea acestor vase de conductan, reprezentativ pentru
pacienii cu boal coronarian documentat nu d ns informaii
despre disfuncia endotelial la pacienii aflai n etapele incipiente
de evoluie ale aterosclerozei, cnd boala este subclinic.
Instrumentarea coronarelor epicardice nu este relevant pentru
statusul microcirculaiei coronariene la nivelul vaselor de
rezisten neafectat n mod obinuit de ateroscleroz dar
disfuncional n boala cardiac ischemic

MODALITI DE EXPLORARE
A DISFUNCIEI
ENDOTELIALE

Explorarea intracoronarian a fluxului prin


cateter Doppler:

Se foloseste un cateter ghid de angiografie n


vrful cruia exista un transductor de 12 MHz, cu
semnal Doppler pulsat conectat la un sistem de
analiza spectral a a fluxului care prin
transformare rapid Fourier a furniz eaza
imaginea anvelopelor Doppler pulsat uzuale din
ecografia cardiac/vascular. Se calculeaza fluxul
folosind o formula bazat pe diametrul vasului
msurat pe imaginea coronarografic i pe
valoarea msurat a integralei timp-velocitate
maxim obinut la nregistrarea Doppler
ESTE CONSIDERATA GOLDEN STANDARD
Invaziva, costisitoare necesita tehnologie medicala
avansata are aplicabilitate limitata.

Brachial Artery FlowMediated Vasodilation


(FMD)
50mmHgpeste
presiunea
arterialasistolica

Leziunea endotelial

Leziunea endotelial este evenimentul cheie n dezvoltarea


ateromatozei.
Manifestrile ei sunt forme de disfuncie endotelial i includ
modificri ale proprietilor membranei celulare, ale expresiei
moleculelor de interaciune intercelular, ale eliberrii adecvate de
mediatori vasoactivi i factori de cretere i mrirea ratei turn-overului.
Aceasta duce la acumularea excesiv de colesterol la nivelul
membranei celulare endoteliale, cu alterarea consecutiv a
raportului colesterol/fofolipide, modificri de compoziie ce induc
rigidizarea acesteia.
Plasmalema rigid va reaciona n mod anormal la stressul
mecanic la care este supus de ctre fluxul sanguin mai ales n
locurile de producere a turbulenelor bifurcaii, zone n care se
formeaza striuri lipidice producndu-se disjuncia legturilor dintre
celulele endoteliale i retracie endotelial.

Leziunea endotelial

Celulele endoteliale au receptori membranari pentru


moleculele de LDL, care sunt apoi internalizate i sufer
un proces de oxidare la nivel sczut transformndu-se
n LDL-oxidat.
n condiiile existenei unor nivele crescute, acesta este
agentul agresor primordial toxic att pentru
endoteliu ct i pentru alte celule ce induce cascada
evenimentelor inflamatorii i posibil autoimune asociate
cu iniierea i dezvoltarea aterosclerozei.
LDL-ox determin expresia pe suprafaa celulelor
endoteliale a unui numr crescut de molecule de
adeziune intercelular n special pentru monocitele
circulante.

Faza iniial a
aterogenezei

Un numr important de leucocite (mai ales monocite) se ataeaz la


moleculele de adeziune expuse de endoteliul lezat, dup care trec prin spaiile
intercelulare i migreaz n spaiul subendotelial.
Aici se transform n macrofage i acioneaz ca celule gunoier
(scavanger), ncercnd s ndeprteze moleculele de LDL-oxidat prin
preluarea acestora de la celulele endoteliale pe calea receptorilor scavenger.
Macrofagele preiau i molecule de LDL pe care l transform cu ajutorul unor
enzime de tipul lipooxigenazei n LDL-oxidat, se suprancarc cu acesta i
se transform n celule spumoase.
Macrofagele se pot replica, reprezentnd cea mai important surs de
acumulare celular la nivelul leziunii i secret pe lng numeroi mediatori
intercelulari cel puin 6 factori de cretere: PDGF, IL-1, FGF, EGF, TGF- i MCSF. Acetia acioneaz i asupra celulelor musculare cu fenotip secretor
din medie, determinnd migraia acestora n spaiul subintimal i
transformarea lor n celule spumoase.
Nu sunt complet elucidate relaiile dintre limfocitele T CD8+ i CD4+ (care au
fost evideniate n toate fazele aterogenezei), macrofage i LDL-oxidat care
pare antigenul ce stimuleaz interaciunea dintre acestea.

Fazele intermediar i
tardiv ale aterogenezei

n evoluia leziunii se produce migrarea continu a


celulelor musculare netede din medie n spaiul
subintimal urmat de proliferarea acestora aici, leziunea
devenind fibro-muscular proliferativ sub influena
stimulrii cu PDGF-B sintetizat de macrofage.
Tot n acest etap se produce fenomenul de retracie
endotelial, menionat anterior, care expune torentului
circulator structurile subendoteliale.
Una din consecine este migrarea n fluxul sanguin, ctre
splin i ganglionii limfatici a macrofagelor ncrcate cu LDLoxidat.
Nici aceast etap inflamatorie, posibil (auto)imun a reaciei
la leziune nu este deplin explicat.

Fazele intermediar i
tardiv ale aterogenezei

Alt consecin a denudrii endoteliului prin disjuncia celulelor


endoteliale este pierderea proprietilor antitrombogenice i
aderarea plachetelor cu formarea unor microtrombi murali.
Trombocitul devine astfel, dup celula endotelial, macrofag, si
celula musculara neteda, a patra celul implicat n
dezvoltarea leziunii aterosclerotice.
Plachetele agregate se vor degranula i vor elibera 4 factori de
cretere: PDGF, FGF, EGF i TGF- amplificnd rspunsul
proliferativ al esutului inflamator.
Se pare c la un interval relativ scurt leziunile aterosclerotice
progreseaz, putnd cpta un nveli fibros bine reprezentat.
Trebuie menionat c agravarea ateromatozei poate surveni fr
disjuncia celulelor endoteliale i interaciunea plachetar
consecutiv, ntruct endoteliul i macrofagele reprezint surse
potente de factori de cretere.

Mediatorii aterogenezei

Factorii de cretere implicai n aterogenez sunt produi de celulele


endoteliale (PDGF, FGF, TGF-, IGF-1, IL-1), de macrofage (PDGF, FGF,
EGF, TGF-, IL-1, M-CSF) i de trombocite (PDGF, FGF, EGF i TGF-). Un
rol important au i celulele musculare netede ce sintetizez un singur
factor de cretere: PDGF, la care rspund autocrin.
n mod normal exist un echilbru ntre TGF- (un stimulator potent al
formrii de esut conjunctiv i totodat cel mai puternic inhibitor al
proliferrii celulelor musculare netede) i PDGF (stimulator al migrrii n
subendoteliu i al proliferrii celulelor musculare netede) care atunci cnd
se pierde, nclinnd balana n favoarea PDGF, pare s reprezinte un
moment critic n apariia i progresia leziunilor aterosclerotice. Cea mai
important surs de PDGF este reprezentat de macrofage, la aproximativ
20% dintre acestea distribuite ubicuitar n leziune evideniindu-se
prezena intracitoplasmatic a lanul proteic al acestuia.
PDGF este important i datorit faptului c induce creterea numrului de
receptori pentru LDL, creterea sintezei de colesterol, reorganizarea
filamentelor actinice i 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 n fazele I, II, III):

Apar n jurul vrstei de 10 ani, fiind constituite din macrofage ncrcate cu


lipide, limfocite T, celule spumoase i un numr redus de celule musculare
netede migrate subendotelial i care au acumulat i ele lipide.
Celula de origine din care a provenit celula spumoas este dificil de
determinat chiar dac se folsesc tehnici de microscopie electronic i
doar ncercarea de identificare cu anticorpi monoclonali mpotriva unui
antigen citoplasmatic specific din macrofage i a actinei din celulele
musculare netede a fost ncununat de succes, dovedind c majoritatea
celulelor spumoase provin din macrofage.
Aspectul macroscopic al striurilor lipidice este datorat acunulrii de lipide,
zonele respective prnd ca arii bine delimitate de culoare galben.
Studiile anatomopatolgice au artat c localizarea anatomic a striurilor
lipidice la copii i aduli tineri este similar cu cea a leziunilor avansate,
fibromusculare sau fibroase de la vrstnici. Acest descoperire arat c
striurile lipidice sunt formele precursoare ale leziunilor aterosclerotice
ocluzive severe.

Fatty Streak-Aorta

Fatty Streak-Coronary
Artery

ngroarea intimal difuz


(Leziuni faza IV)

Aceast faz a leziunii se caracterizeaz prin creterea


proporiei celulelor musculare netede i a esutului
conjunctiv la nivelul leziunii aterosclerotice precum si
cresterea acumularii de lipide extracelulare.
Se discut nc dac acest cretere a migrrii
celulelor musculare netede din medie n spaiul
subintimal i hiperproliferarea lor este datorat
stressului exercitat de flux asupra peretelui arterial sau
este pur i simplu consecina progresiei ateromatozei.
Deasemenea, la nivelul leziunii intimale difuze, se
regsesc elementele prezente n striurile lipdice:
macrofage, limfocite T, celule spumoase.

Placa fibroas
(Leziuni n fazele V i VI)

Leziunile ateroclerotice aflate n fazele avansate (V, VI) se numesc


plci fibroase i macroscopic au culoare alb i sunt protruzive n
lumenul aterial.
Placa fibroas prezint aceleai elemente existente la nivelul
ngrorii intimale difuze, existnd ns o cretere foarte mare a
numrului celulelor musculare netede i a esutului conjunctiv.
Specificitatea plcii fiboase const n faptul c suprafaa sa este
acoperit de un nveli fibros format din celule musculare netede cu o
form distinct subiri i plate, nconjurate de lamele numeroase de
membran bazal, proteoglicani i fibre de colagen. Sub acest
acoperi fibros se gsete o zon cu celularitate bogat constituit
din: celule musculare netede, macrofage, limfocite T CD8+
numeroase, un numr redus de limfocite T CD 4+ i esut conjuctiv.
Sub zona cu celule numeroase se afl un strat profund alctuit din
celule spumoase mari i numeroase, esut necrotic, resturi celulare,
cristale de colesterol i zone de calcificare.

FibrousPlaques

ComplicatedLesions

ComplicatedLesions

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
Endoteliala

Boala
coronariana
non-ocluziva

Boalacoronariana
ocluziva

Boala coronariana sub-clinica

Boala coronariana clinica

DISFUNCTIAENDOTELIALA

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

Humans

High fat diet discontinued; atherosclerotic lesions


regress
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 lumen

Ischemia, turbulence

Wall weakened

Thrombosis

Aneurysms, vessel
rupture
Narrowing, ischemia,
embolization

Breaking loose of plaque

Athero-embolization

Increase systolic blood


pressure

Loss of elasticity

HemorrhageintoPlaque

Common
Consequences of
Atherosclerosis
in Specific
Vessels

Aorta

Aneurysm
Pulsatile abdominal mass
Abdominal pain
Bleeding

Atheroembolization
Narrowing of lumen

Usually not a problem

AorticAneurysm

AorticAneurysm

Coronary Arteries

Consequences of coronary artery


atherosclerosis: acute and chronic
ischemic heart disease

CoronaryArteryAtherosclerosis

CoronaryArteryAtherosclerosis

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

CVD Deaths (all cohorts)

60

40

20

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
3

No tobacco

5
140

Portions of fruit and vegetables a day

5
3
0

Walk 3 km daily, or 30 mins any


moderate activity
Blood pressure less than 140 mm Hg
systolic
Total blood cholesterol <5 mmol/l
LDL cholesterol <3 mmol/l
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
2.2
2.3
2.4
2.5
2.6
2.7
2.8

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

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.

10 yr risk of fatal CVD (%)

30

Men, smoking,
SBP=160 mmHg

25

Men, non-smoking,
SBP=120 mmHg

20

15

Women, smoking,
SBP=160 mmHg

10

Women, nonsmoking, SBP=120


mmHg

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 %

60

120

NO

60

140

YES

60

160

NO

60

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 persons 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 conceal


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 clinicians
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 diabetesrisk 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
No smoking

Healthy diet

Weight reduction if BMI 25 kg/m2


and especially if BMI 30 kg/m2

Wide variety of foods


Energy intake adjusted to avoid
overweight
Encourage: fruits, vegetables,
wholegrain cereals and bread, fish
(especially oily), lean meat, low fat
dairy products
Replace saturated fat with
monounsaturated and polyunsaturated
fats (vegetable and marine)
Hypertensive subjects should reduce
salt intake

No further weight gain if WC 80-88


cm in women and WC 94-102 cm
in men. Advise weight loss if WC
88 cm in women and 102 cm in
men
30 min of moderately vigorous
exercise on most days of the week;
exercise and weight reduction can
prevent diabetes

Lifestyle advice
to maintain low risk
status
Re-assess total
risk at regular
intervals

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 riskTIPS 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 patients 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 persons 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 94102 cm and
women with a waist circumference of 8088 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
CVD risk

Normal
<130/85

High Normal
130139/
8589

Grade 1
140159/
9099

Grade 2
160179/
100109

Grade 3
180/110

Low
<1%

Lifestyle
advice

Lifestyle
advice

Lifestyle
advice

Drug Rx
if persists

Drug Rx

Moderate
14%

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

Markedly
increased
10%

Lifestyle
advice

+consider
drug Rx

Drug Rx

Drug Rx

Drug Rx

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

Established
CVD

Diabetes as
above

Dietary and exercise advice together


with attention to all risk factors comes
first.
Aim to reduce total cholesterol to <4.5
mmol/L (~175 mg/dL) or <4 mmol/L
(~155 mg/dL) if feasible, and LDLcholesterol to <2.5 mmol/L (~100
mg/dL) or <2 mmol/L (~80 mg/dL) if
feasible.
This will require statin treatment in
many. Some recommend statins for all
CVD and most diabetic patients
regardless of baseline levels.

Markedly
raised lipid
levels

SCORE risk 5%

SCORE risk < 5%

Lifestyle advice for 3


months, then reassess
SCORE and fasting lipids
SCORE now <5%
SCORE risk
still 5%

Treatment goals are not defined for HDL cholesterol and triglycerides, but
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

TC <5 mmol/l
and LDL-C <3
mmol/l and

Lifestyle
advice to
reduce
total chol
<5
mmol/L
(~190
mg/dL)
and LDL-C
<3
mmol/L
(~115
mg/dL)
Regular
follow-up

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 (DCCTaligned)
Plasma glucose

HbA 1c(%)

6.5 if feasible

Fasting/pre-prandial
mmol/L (mg/dL)

<6.0 (110) if feasible

Post-prandial
mmol/L (mg/dL)

<7.5 (135) if feasible

Blood pressure

mmHg

130/80

Total cholesterol

mmol/L (mg/dL)
mmol/L (mg/dL)
mmol/L (mg/dL)
mmol/L (mg/dL)

<4.5 (175)
<4.0 (155) if feasible
<2.5 (100)
<2.0 (80) if feasible

LDL cholesterol

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 followup; 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.
-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

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