18° MEETING OF THE EUROPEAN CHAPTER OF THE INTERNATIONAL UNION OF ANGIOLOGY JOINT

WITH THE XIX ANNUAL MEETING OF THE MEDITERRANEAN LEAGUE OF ANGIOLOGY AND

VASCULAR SURGERY

Park Florio Hotel & Magaggiari Hotel Resort

October 24th-27th, 2009

University of Palermo University of Palermo Faculty of Medicine and Surgery Faculty of Medicine and Surgery

Department of Internal Medicine and Cardiovascular Diseases Department of Internal Medicine and Cardiovascular Diseases Chair of Cardiovascular Diseases, post-graduate School of Cardiology, Chair of Cardiovascular Diseases, post-graduate School of Cardiology,

Master of Vascular Diseases, Master of Echocardiography, Master of Vascular Diseases, Master of Echocardiography, Center for the Early Diagnosis of Preclinical and Multifocal Center for the Early Diagnosis of Preclinical and Multifocal

Atherosclerosis and for the Secondary Prevention, Division of CardiologyAtherosclerosis and for the Secondary Prevention, Division of CardiologyUniversity Hospital University Hospital “P. Giaccone” of the University of Palermo “P. Giaccone” of the University of Palermo

Director: prof. Salvatore NovoDirector: prof. Salvatore Novo

Tuesday, October 27th, 2009 – 10.30-11.00

« A. Strano » Lecture

HOW DO PRECLINICAL ATHEROSCLEROSIS ANDINFLAMMATION INFLUENCE GLOBAL CV RISK?

Salvatore NovoSalvatore Novo

Present: E. Bastounis

THE CIFTI4-GESCO-MURST PROJECT ON

CARDIOVASCULAR AGING

National Coordinator: R. Paoletti (Milan)

Centre of Palermo: A. Strano, S. NovoFrom 1986……..

THE CONCEPT OF GLOBAL THE CONCEPT OF GLOBAL CARDIOVASCULAR RISK CARDIOVASCULAR RISK

AND THE RISK CHARTSAND THE RISK CHARTS

INTERATION BETWEEN RISK FACTORS: THE MRFIT

Not Smokers

Smokers

Quintiles of Cholesterol

mg/dl

Quintiles of Cholesterol

mg/dl

RELATIVE RISK OF CORONARY EVENTS FOR EACH LEVEL OF SBP ACCORDING TO THE ASSOCIATED RISK FACTORS

SBP

Tot Chol.

Diabetes

Smoke

LVH (ECG)

These mathematical algorithms, built up by using data coming from from large observational epidemiological studies,evaluating the main traditional RF.They aimed at stratifyng the risk to havea major CV event over the time.

ALGORITHMS OF RISK

FRAMINGHAM RISK CHART FOR NON DIABETIC SUBJECTS

WO

ME

N

Risk entity within 10 years

Very High

High

Moderate

Mild

Low

> 40%

20% - 40%

10% - 20%

5% - 10%

< 5%

FRAMINGHAM RISK CHART FOR DIABETIC SUBJECTS

Very High

High

Moderate

Mild

Low

> 40%

20% - 40%

10% - 20%

5% - 10%

< 5%

WO

ME

N

Risk entity within 10 years

Smokers Not Smokers Smokers Not Smokers

Cholesterol Cholesterol Cholesterol Cholesterol

age

age

age

age

age

age

age

age

age

age

ESC RISK CHART EUROSCORE 2003ESC RISK CHART EUROSCORE 2003 High risk Low risk High risk Low risk

Non Smokers Smokers Non smokers Smokers

WomenWomen MenMen

Systo

lic A

rteria

l Pre

ssu

re (m

mH

g)

70-79years

60-69years

50-59years

40-49years

30-39years

Third Joint Task Force. Eur J of CV Prevention and Rehabilitation. 2003, 10: S1-S10

(mmoll)

180

160

140

120

180

160

140

120

180

160

140

120

180

160

140

120

180

160

140

120

4 5 6 7 8

150 200 250 300(mg/dL)

4 5 6 7 8

150 200 250 300

<1% 2% 3%-4% 5%-9% 15% and more1% 10%-14%

300150 200 250 300

4 5 6 7 8

150 200 250

4 5 6 7 8

Non Smokers Smokers Non Smokers Smokers

4 5 6 7 8

150 200 250 300

4 5 6 7 8

150 200 250 300 300150 200 250 300

4 5 6 7 8

150 200 250

4 5 6 7 8

WomenWomen MenMen

Total Cholesterol: Percentage levels of risk

ITALIAN CHART OF CARDIOVASCULAR ITALIAN CHART OF CARDIOVASCULAR RISK: 10 – YEAR RISK IN NON DIABETIC RISK: 10 – YEAR RISK IN NON DIABETIC

MENMEN

ISS, 2004

60-69years

50-59years

40-49years

mmHg

200

170

150

130

130 174 213 252 291 320 130 174 213 252 291 320

90

200

170

150

130

90

200

170

150

130

90

mg/dL

Not smokers Smokers

20% - 30% Risk of CVD V

10% - 15% Risk of CVD III

Less then 5%Risk of CVD I

More then 30% Risk of CVD VI

15% - 20% Risk of CVD IV

5% - 10% Risk of CVD II

60-69years

50-59years

40-49years

mmHg

200

170

150

130

130 174 213 252 291 320 130 174 213 252 291 320

90

200

170

150

130

90

200

170

150

130

90

mg/dL

Non Smoking Smoking

20% - 30% Risk of CVD V

10% - 15% Risk of CVD III

Less then 5% Risk of CVD I

More then 30% Risk of CVD VI

15% - 20% Risk of CVD IV

5% - 10%Risk of

CVD II

ITALIAN CHART OF CARDIOVASCULAR ITALIAN CHART OF CARDIOVASCULAR RISK: RISK:

10 – YEAR RISK IN NON DIABETIC 10 – YEAR RISK IN NON DIABETIC WOMENWOMEN

ISS, 2004

ITALIAN CHART OF CARDIOVASCULAR RISK: ITALIAN CHART OF CARDIOVASCULAR RISK: 10 – YEAR RISK IN DIABETCS10 – YEAR RISK IN DIABETCS

mmHg

200

170

150

130

130 174 213252291320 130174213252291320

90

200

170

150

130

90

200

170

150

130

90

mg/dL

Not Smokers Fumatori

20% - 30% Rischio MCV V 10% - 15% Rischio MCV III meno 5% Rischio MCV I

oltre 30% Rischio MCV VI 15% - 20% Rischio MCV IV 5% - 10% Rischio MCV II

60-69anni

50-59anni

40-49anni

mmHg

200

170

150

130

130 174213252291320 130174213252291320

90

200

170

150

130

90

200

170

150

130

90

mg/dL

Non fumatrici Fumatrici

ISS, 2004

HIGH GLOBAL CARDIOVASCULAR HIGH GLOBAL CARDIOVASCULAR RISK AND THE ITALIAN NOTE 13 TO RISK AND THE ITALIAN NOTE 13 TO

WRIGHT STATINS IN CHARGE OF NHSWRIGHT STATINS IN CHARGE OF NHS

PATIENTS WITH CHD OR PREVIOUS ICTUS/TIA OR PAD OR DIABETES.

Hypercolesterolemia non susceptible to correction with diet in subjects with CV risk ≥ 20% in ten years.

NormalNormalFattyFatty

StreakStreakFibrousFibrousPlaquePlaque

Athero-Athero-scleroticscleroticPlaquePlaque

PlaquePlaqueRupture/Rupture/Fissure &Fissure &

ThrombosisThrombosis

MyocardialMyocardial InfarctionInfarction

Ischemic Ischemic StrokeStroke

Critical Critical Leg Leg

IschemiaIschemiaClinically SilentClinically Silent

Cardiovascular DeathCardiovascular Death

Increasing AgeIncreasing Age

Effort AnginaEffort AnginaTransient Ischemic AttackTransient Ischemic Attack

ClaudicationClaudication

ATHEROGENESIS, ATHEROTHROMBOSIS AND ATHEROGENESIS, ATHEROTHROMBOSIS AND MULTIFOCAL ATS: A PROGRESSIVE PROCESSMULTIFOCAL ATS: A PROGRESSIVE PROCESS

SOME METHODS TO DETECT SOME METHODS TO DETECT PRE-CLINICAL ATS:PRE-CLINICAL ATS:

• Evaluation of endothelial function

• IMT IMT • ABI < 0.90ABI < 0.90

• Multidetector coronary CTMultidetector coronary CT

MMETHOD FOR ETHOD FOR THE NON INVASIVE THE NON INVASIVE EVALUATIONEVALUATION OF ENDOTHELIAL FUNCTION OF ENDOTHELIAL FUNCTION

by the evaluation of flow mediated dilatation (FMD)

9,8

6,9

0

2

4

6

8

10

12

14

Without risk factors With risk factors

FM

D

FM

D

%%

ENDOTHELIAL FUNCTION, AS DETECTED BY ENDOTHELIAL FUNCTION, AS DETECTED BY FLOW MEDIATED VASODILATION, IN FLOW MEDIATED VASODILATION, IN

RELATION TO TRADITIONAL RISK FACTORSRELATION TO TRADITIONAL RISK FACTORS

p < 0,05p < 0,05

Corrado E, Muratori I, Coppola G, Strano A, Novo S Int Angiol 2005: 24: 52-8

IMT AND FMD: RELATIONSHIP WITH IMT AND FMD: RELATIONSHIP WITH EVENTS IN A 2 YEARS FOLLOW-UPEVENTS IN A 2 YEARS FOLLOW-UP IN IN 84 ASYMPTOMATIC SUBJECTS WITH A 84 ASYMPTOMATIC SUBJECTS WITH A

CLUSTER OF RFCLUSTER OF RF

84 PATIENTS84 PATIENTS

AGE = 60 AGE = 60 ± 11 YEARS± 11 YEARS

19

65

MALE FEMALE

Corrado E, Rizzo M, Carella M, Muratori I, Novo S, Coronary Artery Dis 2008; 19: 139-44

ENDOTHELIAL DYSFUNCTION AND CAROTID LESIONS STRONG ENDOTHELIAL DYSFUNCTION AND CAROTID LESIONS STRONG PREDICTORS OF CLINICAL EVENTS IN PATIENTS WITH EARLY PREDICTORS OF CLINICAL EVENTS IN PATIENTS WITH EARLY

STAGES OF ATS: A 24-MONTHS FOLLOW-UP STUDY STAGES OF ATS: A 24-MONTHS FOLLOW-UP STUDY

Patients without events (n = 60)

p= Patients with events (n = 24)

Logistic regression analysis (p=)

Age (years) 61±11 .02 66±8 ns Gender (male) (%) 73 .0001 87 2,5 (0,7-9,7); .001

Family history for CAD (%) 48 ns 50 ns Hypertension (%) 28 ns 33 ns

Diabetes (%) 15 ns 17 ns Active smoker (%) 25 ns 28 ns

Obesity (%) 16 ns 25 ns Waist circumference (cm) 100±6 ns 98±5 ns

Waist-to-hip ratio 0.92±0.03 ns 0.95±0.03 ns Glycaemia (mg/ dL) 100±34 ns 108±46 ns

Total cholesterol (mg/ dL) 195±44 ns 206±65 ns HDL-cholesterol (mg/ dL) 39±9 ns 39±8 ns LDL-cholesterol (mg/ dL) 134±92 ns 145±67 ns

Triglycerides (mg/ dL) 107±43 ns 106±43 ns Presence of carotid atherosclerosis 63 .0001 80 3,7 (1,3-10,1); .01

FMD% < median (13,5 %) 40 .02 66 3,0 (1,1-8,1); .03 Corrado E, Rizzo M, Coppola G, Muratori I,, Novo S. Coronary Artery Disease Corrado E, Rizzo M, Coppola G, Muratori I,, Novo S. Coronary Artery Disease 2008; 19: 139-44

ABI: INVERSE RELATIONSHIP WITH 5-ABI: INVERSE RELATIONSHIP WITH 5-YEAR RISK OF CV EVENTS AND DEATHYEAR RISK OF CV EVENTS AND DEATHABI: INVERSE RELATIONSHIP WITH 5-ABI: INVERSE RELATIONSHIP WITH 5-YEAR RISK OF CV EVENTS AND DEATHYEAR RISK OF CV EVENTS AND DEATH

Dormandy JA, Creager MA. Cerebrovasc Dis 1999; 9 (Suppl 1): 128 (Abstr 4)

10.2% relative risk increase

per 0.1 decrease in ABI

(p = 0.041)

1.00.80.60.40.20.01.0

1.5

2.0

2.5

ABI

Ris

k re

lativ

e to

AB

I

The ABI was a strong predictor of morbidity and mortality during4 years follow-up even in patients with no clinical symptoms of PAD

RESULTS FROM HOPE STUDY

Ostergren J et al. Eur Heart J 2004; 25, 17-24

HOT LINES AND CLINICAL TRIAL UPDATES - ESC HOT LINES AND CLINICAL TRIAL UPDATES - ESC CONGRESS 2007 - EXCESS CARDIOVASCULAR MORTALITY CONGRESS 2007 - EXCESS CARDIOVASCULAR MORTALITY

IN 6880 OLD PATIENTS WITH PAD IN PRIMARY CARE: 5-IN 6880 OLD PATIENTS WITH PAD IN PRIMARY CARE: 5-YEAR RESULTS OF THE GETABI STUDY BY K. DIEHM. YEAR RESULTS OF THE GETABI STUDY BY K. DIEHM.

12.1% of patients presented an ABI < 0.90, without symptoms, 12.1% of patients presented an ABI < 0.90, without symptoms, and 8.7% a symptomatic PAD. At the end of the follow-up the and 8.7% a symptomatic PAD. At the end of the follow-up the incidence of all cause of mortality was 24.1% in patients with incidence of all cause of mortality was 24.1% in patients with symptomatic PAD, 19.2% in patients with ABI < 0.90 and symptomatic PAD, 19.2% in patients with ABI < 0.90 and 9.5% in Controls 9.5% in Controls

24,1%

19,2%

9,5%

0,0%

5,0%

10,0%

15,0%

20,0%

25,0%

30,0%

Symptomatic PAD Asymptomatic PAD Controls

ABI COMBINED WITH FRAMINGHAM RISK SCORE TO PREDICT CV EVENTS AND MORTALITY

JAMA 2008; 300: 197-208

CAROTID B-MODE CAROTID B-MODE ULTRASONOGRAPHYULTRASONOGRAPHY

non invasiveless expensive no radiationcost-effective and easily

applied technique to screen for atherosclerosis

it is well-established as an indicator of cardiovascular event risk from epidemiologic studies

Kablak-Ziembicka et al., Heart 1997

0.4 0.6 0.8 1.0 1.2

Poredoš et al., Int Angiol 2002

Am J Cardiol 2007; 99: 1196-200Am J Cardiol 2007; 99: 1196-200

NORMAL(n= 212)

IMT(n= 162)

ACP(n= 294)

p=

Transient Ischemic Attack 2 2.5 4 .1

Ischemic stroke 0.5 2.5 3 .05

Effort or unstable angina 2 3 2 .9

Acute Myocardial Infarction 3 5.5 11 .0005

Peripheral arterial disease 1.5 4 7 .005

Cardiovascular or cerebrovascular death

0 2 3 .8

Total events %Patients with any event %

9.08.5

19.518.0

30.024.0

.0001

.0001

CLINICAL EVENTS REGISTERED DURING THE FOLLOW-UP IN 668 HIGH RISK ASYMPTOMATIC PATIENTS AS

RELATED WITH THE ULTRASONOGRAPHIC FINDINGS

Corrado E, Muratori I, Bonura F, Novo S, Stroke 2006; 37: 482-6

PLOTS OF HAZARD RATIOS FOR CV EVENTS AGAINST CCA-IMT (ADJUSTED FOR AGE AND SEX)

Myocardial infarction Stroke

Red ARIC blue line, CHS5; green line, MDCS10,11l "R11-180806; purple line, CAPS.12

Matthias W et al. Circulation 2007:115: 459-67

A meta-analysis of 8 popolation studies (Kuopio IHD-RF Study, A meta-analysis of 8 popolation studies (Kuopio IHD-RF Study, ARIC Study, Rotterdam Study, CVH Study, Malmo Diet and ARIC Study, Rotterdam Study, CVH Study, Malmo Diet and Cancer Study, Longitudinal Investigation for the Longevity and Cancer Study, Longitudinal Investigation for the Longevity and Aging in Hokkaido Country, CAPS and Kitamura Study) analysing Aging in Hokkaido Country, CAPS and Kitamura Study) analysing the the association between carotid IMT and cerebro and CV events in association between carotid IMT and cerebro and CV events in a total of 37197 subjects with a mean follow-up of 5,5 years. a total of 37197 subjects with a mean follow-up of 5,5 years.

Matthias W et al. - Circulation 2007: 115: 459-67Circulation 2007: 115: 459-67

AN IMT INCREASE OF 0.1 mm WAS ASSOCIATED WITH AN IMT INCREASE OF 0.1 mm WAS ASSOCIATED WITH AN ENHANCED RISK OF 15% FOR AMI AND OF 18% AN ENHANCED RISK OF 15% FOR AMI AND OF 18%

FOR STROKE, SO SHOWING THAT PRECOCIOUS ATS FOR STROKE, SO SHOWING THAT PRECOCIOUS ATS LESIONS OF CAROTID ARTERIES ARE AN LESIONS OF CAROTID ARTERIES ARE AN

INDEPENDENT MARKER OF CEREBRO- AND CV INDEPENDENT MARKER OF CEREBRO- AND CV EVENTSEVENTS

CLINICAL CASE n. 1 - Male 57 years old, with elevated DBP, TC/TG, homocysteine and low HDL-C, IFG and smoker. Fibroadipose, echolucent, heterogeneous plaque of 2.4 mm

at the carotid bulb and 50% stenosis at the superficial femoral artery

ITALIAN CHART OF CARDIOVASCULAR ITALIAN CHART OF CARDIOVASCULAR RISK: 10 – YEAR RISK IN NON DIABETIC RISK: 10 – YEAR RISK IN NON DIABETIC

MENMEN

ISS, 2004

60-69anni

50-59anni

40-49anni

PAS mmHg

200

170

150

130

130 174 213 252 291 320 130 174 213 252 291 320

90

200

170

150

130

90

200

170

150

130

90

CT mg/dL

Non fumatori Fumatori

20% - 30% Rischio MCV V

10% - 15% Rischio MCV III

meno 5% Rischio MCV I

oltre 30% Rischio MCV VI

15% - 20% Rischio MCV IV

5% - 10% Rischio MCV II

4%

14%20%

35%

43%+3%

56%+7%

0

10

20

30

40

50

60

70 43 e 56% Non fatal events

3% e 7% Fatal events

PRECLINICAL ATHEROSCLEROSIS AND GLOBAL CV RISK: ROLE OF ASYMPTOMATIC CAROTID LESIONS IN THE RISK ASSESSMENT ESTIMATED ACCORDING TO THE ITALIAN ALGORHYTM “PROGETTO CUORE” IN

TEN YEARS FOLLOW-UP IN 558 PATIENTSNovo S, Visconti C, Amoroso GR, Corrado E, Muratori I, Fazio G, Novo G

Eur J Cardiovasc Prev & Rehabiltation 2009; 16 (Suppl. 1): S48/P221

PRECLINICAL ATHEROSCLEROSIS INCREASE THE GLOBAL CV RISK BEYOND THAT DETERMINED BY

CHART OF RISK.

TRANSATLANTIC ITRANSATLANTIC INTERSOCIETY CONSENSUS NTERSOCIETY CONSENSUS FOR THE MANAGEMENT OF PAD (TASC II)FOR THE MANAGEMENT OF PAD (TASC II)

Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FG Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FG

and TASC II Working Group; Bell K, Caporusso J, Durand-Zaleski I, Komori K, and TASC II Working Group; Bell K, Caporusso J, Durand-Zaleski I, Komori K,

Lammer J, Liapis C, Lammer J, Liapis C, Novo SNovo S,, Razavi M, Robbs J, Schaper N, Shigematsu H, Razavi M, Robbs J, Schaper N, Shigematsu H, Sapoval M, White C, White J. Eur J Vasc Endovasc Surg. 2007; 33 (Suppl 1): S1-Sapoval M, White C, White J. Eur J Vasc Endovasc Surg. 2007; 33 (Suppl 1): S1-

75 & J Vasc Surg 75 & J Vasc Surg 2007; 45 (1 Suppl): S5-S672007; 45 (1 Suppl): S5-S67& Int Angiol 2007; 26: 81-157& Int Angiol 2007; 26: 81-157

Recommendation 2 – Control of lipid pattern in PAD

All patients with Symptomatic PAD should have reduced their LDL-C < 100 mg/dL.

In patients with PAD and History of Multifocal Disease is suggested to reduce LDL-C < 70 mg/dL

All patients with Asymptomatic PAD, without other clinical evidence of CV disease, shoul have reduced their

LDL-C < 100 mg/dL

*Therapeutic option in very high-risk patients and in patients

with high TG, non-HDL-C<100 mg/dL;

**Therapeutic option; 70 mg/dL =1.8 mmol/L; 100 mg/dL = 2.6

mmol/L; 130 mg/dL = 3.4 mmol/L; 160 mg/dL = 4.1 mmol/L

High Risk

CHD or CHD risk

equivalents

Preclinical ATS ?

(10-yr risk >20%)

LD

L-C

level

100 -

160 -

130 -

190 -

Lower Risk

< 2 risk factors

Moderately High Risk

≥ 2 risk factors

(10-yr risk 10-20%)

Target 160

mg/dL

Target 130

mg/dL

70 -

Target 100

mg/dL

or optional

70 mg/dL*

Moderate Risk

≥ 2 risk factors

(10-yr risk <10%)

Target

130 mg/dLor

optional 100

mg/dL**

Grundy SM et al. Circulation 2004; 110:227-39.

NCEP ATP III: LDL-C GOALSNCEP ATP III: LDL-C GOALS(2004 PROPOSED (2004 PROPOSED MODIFICATIONS)MODIFICATIONS)

HIGH GLOBAL CARDIOVASCULAR HIGH GLOBAL CARDIOVASCULAR RISK AND THE ITALIAN NOTE 13 TO RISK AND THE ITALIAN NOTE 13 TO

WRIGHT STATINS IN CHARGE OF NHSWRIGHT STATINS IN CHARGE OF NHS

PATIENTS WITH CHD OR PREVIOUS ICTUS/TIA OR PAD OR DIABETES.

HYPERCOLESTEROLEMIA NON SUSCEPTIBLE TO CORRECTION WITH DIET IN SUBJECTS WITH A TEN-YEAR CV RISK ≥ 20%

PRECLINICAL ATS?

THROMBOSIS OF A DISRUPTED ATHEROMA, THE CAUSE OF MOST ACUTE CORONARY

SYNDROMES, RESULTS FROM:

Weakening of the fibrous cap

Thrombogenicity Thrombogenicity of the lipid coreof the lipid core

Illustration courtesy of Michael J. Davies

MATRIX METABOLISM AND INTEGRITY OF THE PLAQUE’S FIBROUS CAP

Libby P. Circulation. 1995; 91: 2844-50

+ + + +

++

–

Synthesis Breakdown

Lipid core

IL-1TNF-MCP-1M-CSF

FibrouscapIFN-IFN-

CD-40L

Collagen-degradingCollagen-degradingProteinasesProteinases

Tissue Tissue FactorFactorProcoagulantProcoagulant

INFLAMMATION CAN PROMOTE THROMBOSIS

PlatelePlatelett

CRP?CRP?

TissueTissueFactorFactor

FibrinogenFibrinogenVia gp Via gp llb/lllallb/llla

FibrinFibrinCD40LCD40LPlatelet-Platelet-

FibrinFibrinThrombusThrombus

FibrinopeptidesFibrinopeptides

PlatelePlatelett

PCR AND CAROTID PLAQUE IN THE FRAMINGHAM HEART STUDY

Methods:Methods: 3173 subjects underwent the echocolour Doppler study of carotid arteries and the PCR PCR measurementmeasurement. The presence of a . The presence of a stenosis > 25% has been reported in 24% of stenosis > 25% has been reported in 24% of men and 14% of women. In the patients of the men and 14% of women. In the patients of the upperupper quartile was registered a prevalence of quartile was registered a prevalence of carotid stenosis higher than in those of the lower carotid stenosis higher than in those of the lower quartile (after adjustment for the main traditional quartile (after adjustment for the main traditional FR).FR).

0

1

2

1 2 3 4

P< 0,001P< 0,001

OR

for

Caro

tid

ste

nosi

s O

R f

or

Caro

tid

ste

nosi

s (>

25%

)(>

25%

)

Quartili PCRQuartili PCR

Arterioscler Thromb Vasc Biol 2002: 22: 1662-67

INDEPENDENT RELATIONSHIP BETWEEN hsCRP AND BOTH IMTINDEPENDENT RELATIONSHIP BETWEEN hsCRP AND BOTH IMTAND ABI AS MEASURES OF SUBCLINICAL ATHEROSCLEROSISAND ABI AS MEASURES OF SUBCLINICAL ATHEROSCLEROSIS

ASSOCIATIONS OF INFLAMMATORY MARKERS AND CORONARY ARTERY CALCIFICATION (CAC):

THE MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS (MESA)

Jenny NS, Brown ER, Detrano R, Folsom AR, Saad MF, Shea S, Szklo M, Herrington DM, Jacobs DR Jr. - Atherosclerosis. 2009 Aug 28. [Epub ahead of print]

AIM:AIM: to evaluate the association of CRP, IL-6 and to evaluate the association of CRP, IL-6 and fibrinogen with CAC presence (Agatston score>0) fibrinogen with CAC presence (Agatston score>0) in in 6783 MESA participants. MESA participants.

RESULTS:RESULTS: all participants in the highest all participants in the highest quartile of quartile of CRPCRP had a RR of 1.13 for CAC had a RR of 1.13 for CAC than those in lowest than those in lowest quartilequartile. For highest versus lowest quartiles, RR . For highest versus lowest quartiles, RR were 1.22 for IL-6 and 1.18 for fibrinogen. RR for were 1.22 for IL-6 and 1.18 for fibrinogen. RR for CAC were 1.05 for CRP, 1.12 for IL-6 and 1.09 for CAC were 1.05 for CRP, 1.12 for IL-6 and 1.09 for fibrinogen in multivariate adjusted models. fibrinogen in multivariate adjusted models.

CONCLUSION:CONCLUSION: Inflammatory markers were weakly associated with CAC presence.

Rizzo M, Corrado E, Coppola G, Muratori I, Novo G, Novo S - Coronary Artery Dis 2009; 20: 15-20Rizzo M, Corrado E, Coppola G, Muratori I, Novo G, Novo S - Coronary Artery Dis 2009; 20: 15-20

Methods:Methods: Our research group Our research group recently investigated recently investigated 127127 asymptomatic asymptomatic women in post-women in post-menopausal periodmenopausal period with echographic echographic preclinical atherosclerosis. All women preclinical atherosclerosis. All women underwent a five-years follow-upunderwent a five-years follow-up

MULTIVARIATE ANALYSIS OF RFs INDEPENDENTLY ASSOCIATED TO THE PRESENCE OF PRECLINICAL

ATHEROSCLEROSIS

OR (95% CI); p value

AgeAge 1.1 (1.1-1.2), 0.011.1 (1.1-1.2), 0.01ObesityObesity 1.5 (0.5-5.1), 0.51.5 (0.5-5.1), 0.5SmokeSmoke 2.1 (0.1-16),0.62.1 (0.1-16),0.6

Family history of CVDFamily history of CVD 0.5 (0.2-1.7), 0.3 0.5 (0.2-1.7), 0.3 DiabetesDiabetes 2.2 (0.6-8.7), 0.22.2 (0.6-8.7), 0.2

DyslipidemiaDyslipidemia 1.3 (0.3-5.2), 0.7 1.3 (0.3-5.2), 0.7 High values of CPR (> High values of CPR (>

3mg/L)3mg/L)3.2 (1.1–11.8), 3.2 (1.1–11.8),

0.03450.0345High values of fibrinogen (> High values of fibrinogen (>

350mg%)350mg%)6.2 (1.2–12.3), 6.2 (1.2–12.3),

0.02980.0298

Rizzo M, Corrado E, Coppola G, Muratori I, Novo G, Novo S, Coronary Artery Dis 2009; 20: 15-20

0 1.0 2.0 4.0 6.0 8.0 10.0

Hs-PCR [4.4 (1.4 – 13.7), .0096]Hs-PCR [4.4 (1.4 – 13.7), .0096]

Fibrinogen Fibrinogen [[6.0(2.0-18.1), .0014]6.0(2.0-18.1), .0014]

ASSOCIATION OF ELEVATED FIBRINOGEN AND ASSOCIATION OF ELEVATED FIBRINOGEN AND hsCRP LEVELS WITH CAROTID LESIONS IN hsCRP LEVELS WITH CAROTID LESIONS IN

PATIENTS WITH NEWLY DIAGNOSED PATIENTS WITH NEWLY DIAGNOSED HYPERTENSION OR TYPE II DIABETESHYPERTENSION OR TYPE II DIABETES

Corrado E, Rizzo M, Muratori I, Coppola G, Novo S. Arch Med Research 2006; 37:1004-9

AGING, INFLAMMATION AND ASYMPTOMATIC AGING, INFLAMMATION AND ASYMPTOMATIC CAROTID ATS ARE STRONG PREDICTORS OF CAROTID ATS ARE STRONG PREDICTORS OF

CLINICAL EVENTS IN POSTMENOPAUSAL WOMENCLINICAL EVENTS IN POSTMENOPAUSAL WOMEN

Corrado E, Rizzo M, Muratori I, Coppola G, Novo S. Menopause 2008; 15: 240-7 Corrado E, Rizzo M, Muratori I, Coppola G, Novo S. Menopause 2008; 15: 240-7

Methods: 250 asymptomatic postmenopausal women.Methods: 250 asymptomatic postmenopausal women.

A 5 years follow-upA 5 years follow-up

Age [1.7(1.3-2.2), <.0001]Age [1.7(1.3-2.2), <.0001]

Hs-PCR quintils [1.3(1.2-2.0),.0175]

Fibrinogen quintils [1.6(1.2-2.0),.001]

Carotid ATS [2.0(1.4-3.0),.0002]Carotid ATS [2.0(1.4-3.0),.0002]

Logistc regression analysis – Variables predittive of CV events ( OR (95% IC); P-valueLogistc regression analysis – Variables predittive of CV events ( OR (95% IC); P-value

Control subjects

Patients with MS*

P < No. of components of MS

%P <

Localisation of vascular disease 0 1 2 3 4 5

IMT or ACP 62% 74% 0.00

1 46 63 68 72 90100

0.002

CHD 2% 10% 0.001 6 7 12 8 15 40 0.001

CVD 4% 11% 0.001 2 2 6 11 15 40 0.001

PREVALENCE OF VASCULAR DISEASE IN THE WHOLE PREVALENCE OF VASCULAR DISEASE IN THE WHOLE SAMPLE AND IN RELATION WITH THE NUMBER OF SAMPLE AND IN RELATION WITH THE NUMBER OF

COMPONENTS OF THE M.S.COMPONENTS OF THE M.S. (n=163 on 568 high risk pts)(n=163 on 568 high risk pts)

Novo G, Corrado E, Novo S. et al. Int. Angiol 2007; Novo G, Corrado E, Novo S. et al. Int. Angiol 2007; 26: 26: 312-7

**Metabolic syndrome (M.S.) based on the ATP III criteria.Metabolic syndrome (M.S.) based on the ATP III criteria.

Metabolic Syndrome Yes No p =

hsCRP mg% 0.60.20 0.40.22 0.003

Fibrinogen mg% 33579 30598 0.03

0

100

200

300

400

500

600

700

0 1 2 3 4 5

Fib

rin

ogen

(m

g%)

Fib

rin

ogen

(m

g%)

0,00

0,20

0,40

0,60

0,80

0 1 2 3 4 5

Cluster of risk factors of the Metabolic Syndrome Cluster of risk factors of the Metabolic Syndrome

hs

CR

P (

mg%

)h

s C

RP

(m

g%)

5 components vs 0, 1, 2, 3, 4, p< 5 components vs 0, 1, 2, 3, 4, p< 0,0050,005

p < 0,05p < 0,05

p < 0,002p < 0,002

PLASMATIC LEVELS OF hsCRP AND FIBRINOGEN: RELATIONSHIP WITH THE CLUSTER OF RISK

FACTORS OF THE MS Novo G, Corrado E, Bellia A, Muratori I, Novo S, Int Angiol 2007: 26: 312-7

INCREASED LEVELS OF hsCRP AND FIBRINOGEN INFLUENCE THE RISK OF VASCULAR EVENTS IN A FIVE

YEARS FOLLOW-UP OF 156 PATIENTS WITH NIDDM r =r = p<p<

Associated to non fatal Associated to non fatal events. events.

• FibrinogenFibrinogen

• Preclinical Preclinical atherosclerosis atherosclerosis

•ObesityObesity

• hsCRP > 0.3 mg%hsCRP > 0.3 mg%

+.3+.39393

.000.00011+.1+.1

6969+.1+.12828+.1+.12121

.05.05

.005.005

.05.05

Associated to fatal Associated to fatal eventsevents

• Fibrinogen > 350 mgFibrinogen > 350 mg%%

• AgeAge

• hsCRP > 0.3 mg%hsCRP > 0.3 mg%

+.1+.13232

+.2+.26363 .05.05

.000.00011

+.11+.1177

.05.05

Coppola G, Corrado E, Muratori I, Lo Coco L, Novo S. Int J Cardiol 2006; 106: 16-20

Quintiles of hs-PCR (in mg/dL)Quintiles of hs-PCR (in mg/dL)

Clin

ical

Eve

nts

(in

per

cen

t)C

linic

al E

ven

ts (

in p

erce

nt)

0.220.220.110.110.490.490.050.05

0.620.620.040.04

0.680.680.010.01

0.780.780.050.05

p < 0.0001p < 0.0001

0%0%

10%10%

20%20%

30%30%

40%40%

11 22 33 44 55

THE PREDICTIVE ROLE OF C-REACTIVE PROTEIN IN 472 SUBJECTS WITH HYPERTENSION AND

SUBCLINICAL ATHEROSCLEROSIS

Rizzo M, Corrado E, Coppola G, Muratori I, Novo G, Novo S. Internal Med J 2009; 39: 539–45

Patients withoutevents

p=Patients with

events

Logistic Regression Analysis

OR (95% IC); P-value

High Fibrinogen (>350 mg/dL) 9 <.0001 45 9.1 (5.5-14.7), <.0001

High hs-CRP (>3 mg/L) 80 .01 91 1.9 (1.1-4.2), .014

HP IgG+ (%) 78 .4 82 1.3 (0.7-2.1); .4

HP CTX+ (%) 18 .0009 34 2.3 (1.4-3.7), .001

CMP IgG+ (%) 39 .03 50 1.6 (1.1-2.5), .026

CMV IgG+ (%) 34 .4 39 1.2 (0.8-1.9); .4

Total burden of infection (%) 4 <.0001 32 10.9 (6.2-19.5), <.0001

Presence of baseline carotid lesions (%)

65 <.0001 89 4.4 (2.4-8.1), <.0001

BASELINE CLINICAL CHARACTERISTICS AND BASELINE CLINICAL CHARACTERISTICS AND BIOCHEMISTERY PLASMA VALUES IN RELATION BIOCHEMISTERY PLASMA VALUES IN RELATION TO THE OCCURRENCE OF THE TO THE OCCURRENCE OF THE CLINICAL CLINICAL EVENTS EVENTS

AFTER 5-YEARS OF FOLLOW-UPAFTER 5-YEARS OF FOLLOW-UP

Corrado E, Rizzo M, Muratori I, Bonura F, Vitale G, Novo S. Stroke, 2006;37: 482-6

10%

49%

17%

30%

71%

39%

0%

10%

20%

30%

40%

50%

60%

70%

80%

Fumo Familiarità perMCV

Fibrinogeno >400 mg/ dl

Senza Eventi Con Eventi

.02.02

PREDICTION OF CARDIO- AND CEREBRO-VASCULAR EVENTS IN PATIENTS WITH SUBCLINICAL CAROTID ATHEROSCLEROSIS AND LOW HDL-CHOLESTEROL

.03.03

.008.008

Rizzo M, Corrado E, Coppola G, Muratori I, Novo G, Novo S. Atherosclerosis. 2008; 200: 389-95

Smoke Family history of CVD

smoke Fibrinogen >

Without events With events

Methods: From the original population of From the original population of 5888 5888 subjects, without baseline CVD,subjects, without baseline CVD, of the CHS of the CHS (an observational study of adults aged 65 (an observational study of adults aged 65 years), years), 5020 subjects 5020 subjects were sampled. They were were sampled. They were followed up for as long as 12 years for followed up for as long as 12 years for incidence of CVD and all-cause mortality incidence of CVD and all-cause mortality after baseline ultrasound and CRP after baseline ultrasound and CRP measurementmeasurement

KAPLAN-MEIER PLOTS OF CUMULATIVE CV EVENTS (A) AND ALL CAUSE OF MORTALITY (B) OVER 12-YEAR FOLLOW-UP STRATIFIED BY CAROTID ATS AND CRP LEVEL (LOW LEVEL ≤ 3 MG/L VS HIGH LEVEL > 3 MG/L)

AA BB

0.0.00

0.0.44

0.0.66

22 66 1010 1212

High CRP, high High CRP, high atheroatheroHigh CRP, low atheroHigh CRP, low athero

Low CRP, High Low CRP, High atheroatheroLow CRP, low atheroLow CRP, low athero

yearsyears0.0.00

0.0.44

0.0.66

22 66 1010 1212

yearsyears

Cao JJ et al - Circulation 2007; 116: 32-8Cao JJ et al - Circulation 2007; 116: 32-8

HS-CRP ADDS PROGNOSTIC INFORMATION AT ALL LEVELS OF LDL-C AND AT ALL LEVELS OF

THE FRAMINGHAM RISK SCORE

0-0-11

2525

2020

1515

1010

55

00

Rela

tive

ris

kR

ela

tive

ris

k

Mu

ltiv

ari

ab

le r

ela

tive

M

ult

ivari

ab

le r

ela

tive

ri

skri

sk2-2-44

5-5-99

10-10-2020 130-130-

160160<130<130 >160>160

Framingham estimate of 10-year risk (%)Framingham estimate of 10-year risk (%) LDL cholesterol (mg/dL)LDL cholesterol (mg/dL)

C-Reactive Protein (mg/L)C-Reactive Protein (mg/L)C-Reactive Protein (mg/L)C-Reactive Protein (mg/L)

11

00

22

33

<1.0<1.0 1.0-3.01.0-3.0 >3.0>3.0

Ridker et al, N Engl J Med. 2002; 347:1557-63

<1.0<1.0 1.0-3.01.0-3.0 >3.>3.00

Elevated CRP levels and coronary microvascular dysfunction in patients with coronary artery disease. Tomai et al. Eur Heart J 2009; 10.1093/eurheartj/ehi356

CRP regulates the expression and activity of TF as well as TFPI via NF-kappaB and ERK 1/2 MAPK pathway.Chen Y et al. FEBS (Letter) 2009; 583: 2811-8

CRP enhances TF expression by vascular smooth muscle cells: mechanisms and in vivo significance.Wu J et al. Arterioscler Thromb Vasc Biol. 2008; 28: 698-704

Release of CRP as well as activity of MMP-9 from unstable atherosclerotic plaques during PCI.Robertson L et a. J Intern Med. 2007; 262: 659-67Lp-APA2: an independent predictor of CV risk and a novel target for immunomodulation therapy.Khakpour H et al. Cardiol Rev. 2009; 17: 222-9.

CRP stimulates superoxide anion release and TF activity in vivo.Devaraj S et al. Atherosclerosis 2009; 203: 67-74 Atherothrombosis: role of TF: link between diabetes, obesity and inflammation.Meerarani P et al. Indian J Exp Biol. 2007; 45: 103-10

Placebo

Rosuvastatin 20 mg

JUPITER - PRIMARY ENDPOINT Time to first occurrence of a CV death, non-fatal

stroke, non-fatal MI, UA or revascularization

Hazard Ratio 0.56 (95% CI 0.46-0.69)P < 0.00001

Ridker P et al. N Eng J Med 2008;359: 2195-207

NNT for 2y = 95 5y* = 25

0 1 2 3 4

0.00

0.02

0.04

0.06

0.08

Cu

mu

lati

ve I

nci

den

ce

Follow-up (years)Number at RiskRosuvastatinPlacebo

8,901 8,631 8,412 6,540 3,893 1,958 1,353 983 544 1578,901 8,621 8,353 6,508 3,872 1,963 1,333 955 534 174

Placebo

Rosuvastatin 20mg

JUPITER - TOTAL MORTALITY Death from any cause

Hazard Ratio 0.80 (95% CI 0.67-0.97)p=0.02

Ridker P et al. N Eng J Med 2008;359: 2195-207

0 1 2 3 4

0.00

0.01

0.02

0.03

0.04

0.05

0.06

Cu

mu

lati

ve I

nci

den

ce

Number at Risk Follow-up (years)RosuvastatinPlacebo

8,901 8,847 8,787 6,999 4,312 2,268 1,602 1,192 683 2278,901 8,852 8,775 6,987 4,319 2,295 1,614 1,196 684 246

INFLAMMATION PARTICIPATES IN ALL PHASES OF ATHEROTHROMBOTIC

DISEASE

Lesion initiation

Lesion progression

Thrombotic complications

Libby P. Circulation. 1995; 91: 2844-50

The inflammation has an important role in The inflammation has an important role in the determinism of atherosclerotic the determinism of atherosclerotic

process. The CRP is able to guide the process. The CRP is able to guide the clinical practiceclinical practice and is currently an and is currently an

important field of research.important field of research.

Possible clinical implications: Possible clinical implications:

Primary prevention: Primary prevention: the CRP is an the CRP is an independent marker of CVD and its independent marker of CVD and its

evaluation could provide further evaluation could provide further informations for the assessment of GCVR informations for the assessment of GCVR

in patients with dyslipidemia and MS. in patients with dyslipidemia and MS.

Secondary prevention: Secondary prevention: nevertheless the nevertheless the possible CRP usefulness is uncertain, a possible CRP usefulness is uncertain, a

more aggressive pharmacological more aggressive pharmacological treatments should be warrented.treatments should be warrented.

INFLAMMATION IN THE FUTURE

Study RR (95% CI)Weight (%)

Trichopoulou et al. 2003

Knoops et al. 2004

Lagiou et al. 2006

Mitrou et al. 2007 (males)

Mitrou et al. 2007 (females)

0.1 0.2 1 2

34.11

3.78

17.88

0.96 (0.92–1.00)

0.88 (0.81–0.96)

Total (95% CI) 100 0.91 (0.90-0.96)

Increased risk

Fung et al. 2006 0.94 (0.91–0.97)

12.21 0.91 (0.82–1.01)

27.73 0.89 (0.77–1.03)

4.29 0.95 (0.90–1.00)

Decreased risk

ADHERENCE TO MD AND CARDIOVASCULAR INCIDENCE AND/OR MORTALITY

0.5

-9%

Sofi et al., BMJ 2008