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ATEROSCLEROZA FACTORI DE RISC PREVENTIA

Dr. Silviu I Dumitrescu, Medic specialist cardiolog, CCUBCVA Asistent universitar, UTM

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.

Princess Ahmose-Meryet-Amon of Egypt, 1500 IdHr

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

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

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

Tromboza
PAR 1-2, TF, PAI-1, Tx-A2, vonWF, TAFI Molecule de Adeziune CAM, Selectine Factori de crestere ET-1, A-II, PDGF, ILGF, Interleukine Inflamatie ROS

Antiagregare Plachetara NO, PGI2

Antiproliferare
NO, PGI2, TGF-, Hep Lipoliza LPL

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)

GUANIL-CICLAZA (cel musculare netede)

4 HBP NADPH
Calmodulina

L-citrulina

y+
ATP

L-argininina

(i)/eNOS

+
Ca 2+

NO

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
Calmodulina

L-citrulina

L-argininina

eNOS

+
Ca 2+
L-ornitin, Uree

NO
ADMA LDLOXIDAT ROS

ROS

LDLOXIDAT DIABET ZAHARAT

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

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 furnizeaza 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 Flow-Mediated Vasodilation (FMD)


50 mm Hg peste presiunea arteriala sistolica

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-over-ului. 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 LDLoxidat. 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 M-CSF. 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 LDL-oxidat. 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.

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

Endoteliala

Boala coronariana non-ocluziva

Boala coronariana 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


Decrease fat and caloric intake (wars, famine, wasting disease), atheromas decrease. Angiography after cholesterol lowering, plaque size decreases

Humans

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


Wall weakened Thrombosis

Ischemia, turbulence
Aneurysms, vessel rupture Narrowing, ischemia, embolization

Breaking loose of plaque

Athero-embolization
Increase systolic blood pressure

Loss of elasticity

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 3 5 140
No tobacco

Walk 3 km daily, or 30 mins any moderate activity Portions of fruit and vegetables a day
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

5 3 0

What are the PRIORITIES for CVD prevention in clinical practice?


1.

Patients with established atherosclerotic CVD. Asymptomatic individuals who are at increased risk of CVD because of :

2.

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.

30

10 yr risk of fatal CVD (%)

25

Men, smoking, SBP=160 mmHg Men, non-smoking, SBP=120 mmHg Women, smoking, SBP=160 mmHg Women, nonsmoking, SBP=120 mmHg

20

15

10

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 F M M

60 60 60 60

8 7 6 5

120 140 160 180

NO YES NO YES

2 5 8 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 Weight reduction if BMI 25 kg/m2 and especially if BMI 30 kg/m2 Healthy diet 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

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

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

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

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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. likely to have unhealthy lifestyles.

Social isolation: People living alone are more 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.

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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.
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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.
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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.
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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.

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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 Low <1% Moderate 14% Increased 5-9% Markedly increased 10%

Normal <130/85 Lifestyle advice Lifestyle advice Lifestyle advice Lifestyle advice

High Normal 130139/ 8589 Lifestyle advice Lifestyle advice +consider drug Rx +consider drug Rx

Grade 1 140159/ 9099 Lifestyle advice +consider drug Rx Drug Rx

Grade 2 160179/ 100109 Drug Rx if persists Drug Rx if persists Drug Rx

Grade 3 180/110 Drug Rx

Drug Rx

Drug Rx

Drug Rx

Drug Rx

Drug Rx

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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 raised lipid levels

Established CVD

Diabetes as above

SCORE risk 5%

SCORE risk < 5%

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.

Lifestyle advice for 3 months, then reassess SCORE and fasting lipids
SCORE now <5%
TC <5 mmol/l and LDL-C <3 mmol/l and

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

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

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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
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Treatment targets in patients with type 2 diabetes Unit Target

HbA (DCCT1c aligned) Plasma glucose

HbA (%)
1c

6.5 if feasible
<6.0 (110) if feasible

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

<7.5 (135) if feasible

Blood pressure
Total cholesterol LDL cholesterol

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

130/80
<4.5 (175) <4.0 (155) if feasible <2.5 (100) <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 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.
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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.

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JTF4 on CVD Prevention in Clinical Practice


16. NEW IMAGING METHODS TO DETECT ASYMPTOMATIC INDIVIDUALS AT HIGH RISK FOR CARDIOVASCULAR EVENTS
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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.
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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.
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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.
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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.
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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.
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