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1 Park Florio Hotel & Magaggiari Hotel Resort October 24th-27th, 2009
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

2 « A. Strano » Lecture Salvatore Novo Present: E. Bastounis
University of Palermo Faculty of Medicine and Surgery Department of Internal Medicine and Cardiovascular Diseases Chair of Cardiovascular Diseases, post-graduate School of Cardiology, Master of Vascular Diseases, Master of Echocardiography, Center for the Early Diagnosis of Preclinical and Multifocal Atherosclerosis and for the Secondary Prevention, Division of Cardiology University Hospital “P. Giaccone” of the University of Palermo Director: prof. Salvatore Novo Tuesday, October 27th, 2009 – « A. Strano » Lecture HOW DO PRECLINICAL ATHEROSCLEROSIS AND INFLAMMATION INFLUENCE GLOBAL CV RISK? Salvatore Novo Present: E. Bastounis

3

4 National Coordinator: R. Paoletti (Milan)
THE CIFTI4-GESCO-MURST PROJECT ON CARDIOVASCULAR AGING National Coordinator: R. Paoletti (Milan) Centre of Palermo: Strano, S. Novo From 1986……..

5 THE CONCEPT OF GLOBAL CARDIOVASCULAR RISK AND THE RISK CHARTS
5

6 INTERATION BETWEEN RISK FACTORS: THE MRFIT
Smokers Fatal Coronaric Events/10.000/year Not Smokers Quintiles of Diastolic Pressure (mmHg) Quintiles of Cholesterol mg/dl Quintiles of Cholesterol mg/dl Quintiles of Diastolic Pressure (mmHg) 6

7 RELATIVE RISK OF CORONARY EVENTS FOR EACH LEVEL
OF SBP ACCORDING TO THE ASSOCIATED RISK FACTORS 8 year - probability SBP Tot Chol. Diabetes Smoke LVH (ECG) 7

8 These mathematical algorithms, built up by using data coming from from
ALGORITHMS OF RISK 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 have a major CV event over the time. 8

9 FRAMINGHAM RISK CHART FOR
NON DIABETIC SUBJECTS MEN WOMEN Risk entity within 10 years Very High High Moderate Mild Low > 40% 20% - 40% 10% - 20% 5% - 10% < 5% 9

10 FRAMINGHAM RISK CHART FOR DIABETIC SUBJECTS
MEN Smokers Not Smokers Smokers Not Smokers WOMEN age age Risk entity within 10 years age age Very High High Moderate Mild Low > 40% 20% - 40% 10% - 20% 5% - 10% < 5% age age age age age age Cholesterol Cholesterol Cholesterol Cholesterol 10

11 ESC RISK CHART EUROSCORE 2003
High risk Low risk Women Men Women Men Non Smokers Smokers Non smokers Smokers Non Smokers Smokers Non Smokers Smokers (mg/dL) 150 200 250 300 150 200 250 300 150 200 250 300 150 200 250 300 150 200 250 300 150 200 250 300 150 200 250 300 150 200 250 300 180 70-79 years 160 140 120 180 60-69 years 160 140 120 180 50-59 years 160 Systolic Arterial Pressure (mmHg) 140 120 180 40-49 years 160 140 120 180 30-39 years 160 140 120 (mmoll) 4 5 6 7 8 4 5 6 7 8 4 5 6 7 8 4 5 6 7 8 4 5 6 7 8 4 5 6 7 8 4 5 6 7 8 4 5 6 7 8 Total Cholesterol: Percentage levels of risk <1% 1% 2% 3%-4% 5%-9% 10%-14% 15% and more Third Joint Task Force. Eur J of CV Prevention and Rehabilitation. 2003, 10: S1-S10 11

12 ITALIAN CHART OF CARDIOVASCULAR RISK: 10 – YEAR RISK IN NON DIABETIC MEN
Not smokers Smokers 130 174 213 252 291 320 130 174 213 252 291 320 mg/dL 200 170 60-69 years 150 130 90 200 170 50-59 years 150 20% - 30% Risk of CVD V 10% - 15% III Less then 5% I More then 30% VI 15% - 20% IV 5% - 10% II 130 90 200 170 40-49 years 150 130 90 mmHg ISS, 2004 12 12

13 ITALIAN CHART OF CARDIOVASCULAR RISK: 10 – YEAR RISK IN NON DIABETIC WOMEN
Non Smoking Smoking 130 174 213 252 291 320 130 174 213 252 291 320 mg/dL 200 170 60-69 years 150 130 90 200 170 50-59 years 150 20% - 30% Risk of CVD V 10% - 15% III Less then 5% I More then 30% VI 15% - 20% IV 5% - 10% II 130 90 200 170 40-49 years 150 130 90 mmHg ISS, 2004 13 13

14 ITALIAN CHART OF CARDIOVASCULAR RISK: 10 – YEAR RISK IN DIABETCS
60-69 anni 50-59 anni 40-49 anni mmHg 200 170 150 130 174 213 252 291 320 90 mg/dL Non fumatrici Fumatrici mmHg 200 170 150 130 174 213 252 291 320 90 mg/dL Not Smokers Fumatori meno 5% Rischio MCV I 10% - 15% Rischio MCV III 20% - 30% Rischio MCV V 5% - 10% Rischio MCV II 15% - 20% Rischio MCV IV oltre 30% Rischio MCV VI ISS, 2004 14 14

15 HIGH GLOBAL CARDIOVASCULAR RISK AND THE ITALIAN NOTE 13 TO WRIGHT 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. 15 15

16 ATHEROGENESIS, ATHEROTHROMBOSIS AND MULTIFOCAL ATS: A PROGRESSIVE PROCESS
Plaque Rupture/ Fissure & Thrombosis Myocardial Infarction Athero- sclerotic Plaque Fatty Streak Fibrous Plaque Normal Ischemic Stroke Critical Leg Ischemia Clinically Silent Effort Angina Transient Ischemic Attack Claudication Cardiovascular Death Increasing Age 16

17 Evaluation of endothelial function Multidetector coronary CT
SOME METHODS TO DETECT PRE-CLINICAL ATS: Evaluation of endothelial function IMT ABI < 0.90 Multidetector coronary CT 17

18 METHOD FOR THE NON INVASIVE EVALUATION OF ENDOTHELIAL FUNCTION
by the evaluation of flow mediated dilatation (FMD) 18

19 ENDOTHELIAL FUNCTION, AS DETECTED BY FLOW MEDIATED VASODILATION, IN RELATION TO TRADITIONAL RISK FACTORS p < 0,05 FMD % Corrado E, Muratori I, Coppola G, Strano A, Novo S Int Angiol 2005: 24: 52-8 19

20 IMT AND FMD: RELATIONSHIP WITH EVENTS IN A 2 YEARS FOLLOW-UP IN 84 ASYMPTOMATIC SUBJECTS WITH A CLUSTER OF RF 84 PATIENTS AGE = 60 ± 11 YEARS Corrado E, Rizzo M, Carella M, Muratori I, Novo S, Coronary Artery Dis 2008; 19: 20

21 ENDOTHELIAL DYSFUNCTION AND CAROTID LESIONS STRONG PREDICTORS OF CLINICAL EVENTS IN PATIENTS WITH EARLY STAGES OF ATS: A 24-MONTHS FOLLOW-UP STUDY Corrado E, Rizzo M, Coppola G, Muratori I,, Novo S. Coronary Artery Disease 2008; 19:

22

23 ABI: INVERSE RELATIONSHIP WITH 5-YEAR RISK OF CV EVENTS AND DEATH
1.0 0.8 0.6 0.4 0.2 0.0 1.5 2.0 2.5 ABI 10.2% relative risk increase per 0.1 decrease in ABI (p = 0.041) Risk relative to ABI ABPI – inverse relationship with 5-year risk of cardiovascular events and death The CAPRIE trial, discussed previously, represents the largest prospective study of patients with symptomatic PAD. Data on entry ankle:brachial pressure index (ABPI) were available for 2180 of the patients who qualified with PAD. Analysis showed that there was a significant 10.2% increase in relative risk for major vascular ischaemic events (ischaemic stroke [IS], MI, vascular death) for every 0.1 decrease in ABPI.1 1Dormandy JA, Creager MA. Ankle:arm blood pressure index as a predictor of atherothrombotic events: evidence from CAPRIE. Cerebrovasc Dis 1999;9(Suppl 1):1 – 128 (Abstr 4). Dormandy JA, Creager MA. Cerebrovasc Dis 1999; 9 (Suppl 1): 128 (Abstr 4) 23

24 RESULTS FROM HOPE STUDY
The ABI was a strong predictor of morbidity and mortality during 4 years follow-up even in patients with no clinical symptoms of PAD Ostergren J et al. Eur Heart J 2004; 25, 17-24 24

25 HOT LINES AND CLINICAL TRIAL UPDATES - ESC CONGRESS EXCESS CARDIOVASCULAR MORTALITY IN 6880 OLD PATIENTS WITH PAD IN PRIMARY CARE: 5- YEAR RESULTS OF THE GETABI STUDY BY K. DIEHM. 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 incidence of all cause of mortality was 24.1% in patients with symptomatic PAD, 19.2% in patients with ABI < 0.90 and 9.5% in Controls 25

26 ABI COMBINED WITH FRAMINGHAM RISK SCORE
TO PREDICT CV EVENTS AND MORTALITY JAMA 2008; 300: 26

27 CAROTID B-MODE ULTRASONOGRAPHY
non invasive less expensive no radiation cost-effective and easily applied technique to screen for atherosclerosis it is well-established as an indicator of cardiovascular event risk from epidemiologic studies Measurement of carotid intimal medial thickness by carotid B-mode ultrasonography is non invasive, inexpensive and incurs no radiation, making it a cost-effective and easily applied technique to screen for atherosclerosis. 27

28 Poredoš et al., Int Angiol 2002
Poredoš et al., Int Angiol 2002 Kablak-Ziembicka et al., Heart 1997

29 29

30 Am J Cardiol 2007; 99: 30

31 CLINICAL EVENTS REGISTERED DURING THE FOLLOW-UP IN 668 HIGH RISK ASYMPTOMATIC PATIENTS AS RELATED WITH THE ULTRASONOGRAPHIC FINDINGS NORMAL (n= 212) IMT (n= 162) ACP (n= 294) p= Transient Ischemic Attack 2 2.5 4 .1 Ischemic stroke 0.5 3 .05 Effort or unstable angina .9 Acute Myocardial Infarction 5.5 11 .0005 Peripheral arterial disease 1.5 7 .005 Cardiovascular or cerebrovascular death .8 Total events % Patients with any event % 9.0 8.5 19.5 18.0 30.0 24.0 .0001 Corrado E, Muratori I, Bonura F, Novo S, Stroke 2006; 37: 482-6

32 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 "R ; purple line, CAPS.12 32

33 Matthias W et al. Circulation 2007:115: 459-67
A meta-analysis of 8 popolation studies (Kuopio IHD-RF Study, ARIC Study, Rotterdam Study, CVH Study, Malmo Diet and Cancer Study, Longitudinal Investigation for the Longevity and Aging in Hokkaido Country, CAPS and Kitamura Study) analysing the association between carotid IMT and cerebro and CV events in a total of subjects with a mean follow-up of 5,5 years. Matthias W et al. Circulation 2007:115:

34 Matthias W et al. - Circulation 2007: 115: 459-67
AN IMT INCREASE OF 0.1 mm WAS ASSOCIATED WITH AN ENHANCED RISK OF 15% FOR AMI AND OF 18% FOR STROKE, SO SHOWING THAT PRECOCIOUS ATS LESIONS OF CAROTID ARTERIES ARE AN INDEPENDENT MARKER OF CEREBRO- AND CV EVENTS Matthias W et al. - Circulation 2007: 115:

35 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

36 ITALIAN CHART OF CARDIOVASCULAR RISK: 10 – YEAR RISK IN NON DIABETIC MEN
Non fumatori Fumatori 130 174 213 252 291 320 130 174 213 252 291 320 CT mg/dL 200 170 60-69 anni 150 130 90 200 170 50-59 anni 150 20% - 30% Rischio MCV V 10% - 15% III meno 5% I oltre 30% VI 15% - 20% IV 5% - 10% II 130 90 200 170 40-49 anni 150 130 90 PAS mmHg ISS, 2004 36

37

38

39

40 Novo S, Visconti C, Amoroso GR, Corrado E, Muratori I, Fazio G, Novo G
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 PATIENTS Novo S, Visconti C, Amoroso GR, Corrado E, Muratori I, Fazio G, Novo G Eur J Cardiovasc Prev & Rehabiltation 2009; 16 (Suppl. 1): S48/P221 43 e 56% Non fatal events 3% e 7% Fatal events

41 PRECLINICAL ATHEROSCLEROSIS INCREASE THE GLOBAL CV RISK BEYOND THAT DETERMINED BY CHART OF RISK.

42 Recommendation 2 – Control of lipid pattern in PAD
TRANSATLANTIC INTERSOCIETY CONSENSUS FOR THE MANAGEMENT OF PAD (TASC II) 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, Lammer J, Liapis C, Novo S, Razavi M, Robbs J, Schaper N, Shigematsu H, Sapoval M, White C, White J. Eur J Vasc Endovasc Surg. 2007; 33 (Suppl 1): S1-75 & J Vasc Surg 2007; 45 (1 Suppl): S5-S67& Int Angiol 2007; 26: 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

43 NCEP ATP III: LDL-C GOALS (2004 PROPOSED MODIFICATIONS)
Lower Risk < 2 risk factors High Risk CHD or CHD risk equivalents Preclinical ATS ? (10-yr risk >20%) Moderately High Risk ≥ 2 risk factors (10-yr risk 10-20%) Moderate Risk ≥ 2 risk factors (10-yr risk <10%) 190 - Target 160 mg/dL 160 - Target 130 mg/dL Target 130 mg/dL LDL-C level 130 - Target 100 mg/dL or optional 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 100 - or optional 70 mg/dL* 70 - Grundy SM et al. Circulation 2004; 110: 43

44 HIGH GLOBAL CARDIOVASCULAR RISK AND THE ITALIAN NOTE 13 TO WRIGHT 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? 44 44

45

46 Illustration courtesy of Michael J. Davies
THROMBOSIS OF A DISRUPTED ATHEROMA, THE CAUSE OF MOST ACUTE CORONARY SYNDROMES, RESULTS FROM: Weakening of the fibrous cap Thrombogenicity of the lipid core Thrombosis of a disrupted atheroma: thrombogenicity of the lipid core In addition to the weakening of the fibrous cap, one must understand the thrombogenicity of the lipid core to appreciate fully the mechanisms of the acute coronary syndromes. Illustration courtesy of Michael J. Davies

47 MATRIX METABOLISM AND INTEGRITY OF THE PLAQUE’S FIBROUS CAP
Synthesis Breakdown Collagen-degrading Proteinases Fibrous cap IFN- Matrix metabolism and integrity of the plaque's fibrous cap This slide depicts the current understanding of the dynamics of the plaque's stability and thrombogenicity. The inflammatory cells can send molecular messages to the smooth muscle cells (interferon-g) that inhibit the ability of this cell type to synthesize new collagen to strengthen the plaque's fibrous cap. In addition, the inflammatory cells can release proteolytic enzymes capable of degrading collagen and other structurally important constituents of the plaque's fibrous cap. Thus, when there is inflammation in the intima, the collagen responsible for the integrity of the plaque's fibrous cap is under double attack, subject to both decreased synthesis and increased degradation. This sets the stage for plaque disruption. The inflammatory cells also are responsible for signaling and producing increased quantities of tissue factor, a potent procoagulant deemed responsible for thrombosis of ruptured plaques. Reference: Libby P. Molecular bases of the acute coronary syndromes. Circulation 1995;91: IL-1 TNF- MCP-1 M-CSF CD-40L + + + + + + Tissue Factor Procoagulant Lipid core Libby P. Circulation. 1995; 91:

48 Platelet- Fibrin Thrombus
INFLAMMATION CAN PROMOTE THROMBOSIS Fibrinogen Via gp llb/llla Tissue Factor Platelet Inflammation can promote thrombosis The interactions between platelets and the coagulation system are complex. Platelets through CD40 ligation can increase tissue factor expression, which can accelerate blood coagulation. Platelet- Fibrin Thrombus Fibrin CD40L Platelet CRP? Fibrinopeptides

49 PCR AND CAROTID PLAQUE IN THE FRAMINGHAM HEART STUDY
Methods: 3173 subjects underwent the echocolour Doppler study of carotid arteries and the PCR measurement. The presence of a stenosis > 25% has been reported in 24% of men and 14% of women. In the patients of the upper quartile was registered a prevalence of carotid stenosis higher than in those of the lower quartile (after adjustment for the main traditional FR). P< 0,001 OR for Carotid stenosis (>25%) Quartili PCR Arterioscler Thromb Vasc Biol 2002: 22: 49

50 INDEPENDENT RELATIONSHIP BETWEEN hsCRP AND BOTH IMT
AND ABI AS MEASURES OF SUBCLINICAL ATHEROSCLEROSIS 50

51 THE MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS (MESA)
ASSOCIATIONS OF INFLAMMATORY MARKERS AND CORONARY ARTERY CALCIFICATION (CAC): THE MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS (MESA) AIM: to evaluate the association of CRP, IL-6 and fibrinogen with CAC presence (Agatston score>0) in 6783 MESA participants. RESULTS: all participants in the highest quartile of CRP had a RR of 1.13 for CAC than those in lowest quartile. For highest versus lowest quartiles, RR 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 fibrinogen in multivariate adjusted models. CONCLUSION: Inflammatory markers were weakly associated with CAC presence. Jenny NS, Brown ER, Detrano R, Folsom AR, Saad MF, Shea S, Szklo M, Herrington DM, Jacobs DR Jr. - Atherosclerosis Aug 28. [Epub ahead of print] 51

52 Methods: Our research group recently investigated 127 asymptomatic women in post-menopausal period with echographic preclinical atherosclerosis. All women underwent a five-years follow-up Rizzo M, Corrado E, Coppola G, Muratori I, Novo G, Novo S - Coronary Artery Dis 2009; 20: 15-20 52

53 MULTIVARIATE ANALYSIS OF RFs INDEPENDENTLY ASSOCIATED TO THE PRESENCE OF PRECLINICAL ATHEROSCLEROSIS
OR (95% CI); p value Age 1.1 ( ), 0.01 Obesity 1.5 ( ), 0.5 Smoke 2.1 (0.1-16),0.6 Family history of CVD 0.5 ( ), 0.3 Diabetes 2.2 ( ), 0.2 Dyslipidemia 1.3 ( ), 0.7 High values of CPR (> 3mg/L) 3.2 (1.1–11.8), High values of fibrinogen (> 350mg%) 6.2 (1.2–12.3), Rizzo M, Corrado E, Coppola G, Muratori I, Novo G, Novo S, Coronary Artery Dis 2009; 20: 15-20 53

54 ASSOCIATION OF ELEVATED FIBRINOGEN AND hsCRP LEVELS WITH CAROTID LESIONS IN PATIENTS WITH NEWLY DIAGNOSED HYPERTENSION OR TYPE II DIABETES Hs-PCR [4.4 (1.4 – 13.7), .0096] Fibrinogen [6.0( ), .0014] Corrado E, Rizzo M, Muratori I, Coppola G, Novo S. Arch Med Research 2006; 37:1004-9 54

55 Methods: 250 asymptomatic postmenopausal women.
AGING, INFLAMMATION AND ASYMPTOMATIC CAROTID ATS ARE STRONG PREDICTORS OF CLINICAL EVENTS IN POSTMENOPAUSAL WOMEN Methods: 250 asymptomatic postmenopausal women. A 5 years follow-up Logistc regression analysis – Variables predittive of CV events ( OR (95% IC); P-value Age [1.7( ), <.0001] Hs-PCR quintils [1.3( ),.0175] Fibrinogen quintils [1.6( ),.001] Carotid ATS [2.0( ),.0002] Corrado E, Rizzo M, Muratori I, Coppola G, Novo S. Menopause 2008; 15: 240-7 55

56 *Metabolic syndrome (M.S.) based on the ATP III criteria.
PREVALENCE OF VASCULAR DISEASE IN THE WHOLE SAMPLE AND IN RELATION WITH THE NUMBER OF COMPONENTS OF THE M.S. (n=163 on 568 high risk pts) Control subjects Patients with MS* P < No. of components of MS % Localisation of vascular disease 1 2 3 4 5 IMT or ACP 62% 74% 0.001 46 63 68 72 90 100 0.002 CHD 2% 10% 6 7 12 8 15 40 CVD 4% 11% 11 *Metabolic syndrome (M.S.) based on the ATP III criteria. Novo G, Corrado E, Novo S. et al. Int. Angiol 2007; 26: 312-7 56

57 Cluster of risk factors of the Metabolic Syndrome
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 5 components vs 0, 1, 2, 3, 4, p< 0,005 p < 0,002 p < 0,05 Fibrinogen (mg%) hs CRP (mg%) Cluster of risk factors of the Metabolic Syndrome 57

58 Associated to non fatal events. Fibrinogen Preclinical atherosclerosis
INCREASED LEVELS OF hsCRP AND FIBRINOGEN INFLUENCE THE RISK OF VASCULAR EVENTS IN A FIVE YEARS FOLLOW-UP OF 156 PATIENTS WITH NIDDM p< r = Associated to non fatal events. Fibrinogen Preclinical atherosclerosis Obesity hsCRP > 0.3 mg% +.393 .0001 +.169 .005 +.128 .05 +.121 .05 Associated to fatal events Fibrinogen > 350 mg% Age hsCRP > 0.3 mg% +.263 .0001 +.132 .05 .05 +.117 Coppola G, Corrado E, Muratori I, Lo Coco L, Novo S. Int J Cardiol 2006; 106: 16-20 58

59 Clinical Events (in percent) Quintiles of hs-PCR (in mg/dL)
THE PREDICTIVE ROLE OF C-REACTIVE PROTEIN IN 472 SUBJECTS WITH HYPERTENSION AND SUBCLINICAL ATHEROSCLEROSIS p < 40% 0.780.05 0.680.01 30% Clinical Events (in percent) 20% 0.620.04 0.490.05 0.220.11 10% 0% 1 2 3 4 5 Quintiles of hs-PCR (in mg/dL) Rizzo M, Corrado E, Coppola G, Muratori I, Novo G, Novo S. Internal Med J 2009; 39: 539–45 59

60 BASELINE CLINICAL CHARACTERISTICS AND BIOCHEMISTERY PLASMA VALUES IN RELATION TO THE OCCURRENCE OF THE CLINICAL EVENTS AFTER 5-YEARS OF FOLLOW-UP Patients without events p= Patients with Logistic Regression Analysis OR (95% IC); P-value High Fibrinogen (>350 mg/dL) 9 <.0001 45 9.1 ( ), <.0001 High hs-CRP (>3 mg/L) 80 .01 91 1.9 ( ), .014 HP IgG+ (%) 78 .4 82 1.3 ( ); .4 HP CTX+ (%) 18 .0009 34 2.3 ( ), .001 CMP IgG+ (%) 39 .03 50 1.6 ( ), .026 CMV IgG+ (%) 1.2 ( ); .4 Total burden of infection (%) 4 32 10.9 ( ), <.0001 Presence of baseline carotid lesions (%) 65 89 4.4 ( ), <.0001 Corrado E, Rizzo M, Muratori I, Bonura F, Vitale G, Novo S. Stroke, 2006;37: 482-6 60

61 PREDICTION OF CARDIO- AND CEREBRO-VASCULAR EVENTS IN PATIENTS WITH SUBCLINICAL CAROTID ATHEROSCLEROSIS AND LOW HDL-CHOLESTEROL Without events With events .03 .008 .02 Fibrinogen > smoke Smoke Family history of CVD Rizzo M, Corrado E, Coppola G, Muratori I, Novo G, Novo S. Atherosclerosis. 2008; 200: 61

62 Methods: From the original population of 5888 subjects, without baseline CVD, of the CHS (an observational study of adults aged 65 years), 5020 subjects were sampled. They were followed up for as long as 12 years for incidence of CVD and all-cause mortality after baseline ultrasound and CRP measurement 62

63 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) Cao JJ et al - Circulation 2007; 116: 32-8 B A 0.6 0.6 0.4 0.4 years years 0.0 0.0 2 6 10 12 2 6 10 12 High CRP, high athero Low CRP, High athero High CRP, low athero Low CRP, low athero 63

64 64

65 HS-CRP ADDS PROGNOSTIC INFORMATION AT ALL LEVELS OF LDL-C AND AT ALL LEVELS OF THE FRAMINGHAM RISK SCORE <1.0 >3.0 <1.0 >3.0 25 C-Reactive Protein (mg/L) 3 C-Reactive Protein (mg/L) 20 2 15 Relative risk Multivariable relative risk 10 1 This slide depicts two additional important analysis from the WHS database which establish that CRP levels independently add predictive information above and beyond traditional approaches. The data on the right indicate that at all levels of LDL, knowledge of CRP adds important risk information, even after multivariate adjustment for all available traditional risk factors. The data on the left indicate that at all levels of the Framingham Risk Score, knowledge of CRP also adds important prognostic information. This information is most important for those at intermediate risk, that is between a 5 percent and 20 percent 10-year risk of developing coronary artery disease. This latter group is exactly the group to be recruited for the JUPITER trial. 5 0-1 2-4 5-9 10-20 <130 >160 Framingham estimate of 10-year risk (%) LDL cholesterol (mg/dL) Ridker et al, N Engl J Med. 2002; 347: 65

66 Elevated CRP levels and coronary microvascular
dysfunction in patients with coronary artery disease. Tomai et al. Eur Heart J 2009; /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: CRP enhances TF expression by vascular smooth muscle cells: mechanisms and in vivo significance. Wu J et al. Arterioscler Thromb Vasc Biol. 2008; 28:

67 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: 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: Lp-APA2: an independent predictor of CV risk and a novel target for immunomodulation therapy. Khakpour H et al. Cardiol Rev. 2009; 17:

68 JUPITER - PRIMARY ENDPOINT Time to first occurrence of a CV death, non-fatal stroke, non-fatal MI, UA or revascularization 0.08 Placebo Hazard Ratio 0.56 (95% CI ) P < 0.06 Cumulative Incidence Rosuvastatin 20 mg 0.04 NNT for 2y = 95 5y* = 25 Results: At the time of study termination (median follow-up 1.9 years, maximal follow up 5.0 years), 142 first major cardiovascular events had occurred in the rosuvastatin group and 251 in the placebo group which represented a 44% relative risk reduction (HR 0.56; 95% CI: 0.46 to 0.69; p< ). The rates of the primary endpoint were 0.77 and per 100 person-years of follow-up in the rosuvastatin and placebo groups, respectively. The number of patients who would need to be treated with rosuvastatin for 2 years to prevent one primary endpoint event is 95, the number needed to treat (NNT) for 4 years is 31. If this figure is projected out to 5 years based on the model proposed by Altman and Andersen then the NNT is 25. Reference Ridker P et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008; 359: NOTE: COPYRIGHT PERMISSIONS REQUIRED FOR THIS SLIDE 0.02 0.00 1 2 3 4 Follow-up (years) Number at Risk Rosuvastatin 8,901 8,631 8,412 6,540 3,893 1,958 1,353 983 544 157 Placebo 8,901 8,621 8,353 6,508 3,872 1,963 1,333 955 534 174 Ridker P et al. N Eng J Med 2008;359: 68

69 JUPITER - TOTAL MORTALITY Death from any cause
0.06 Hazard Ratio 0.80 (95% CI ) p=0.02 Placebo 0.05 Rosuvastatin 20mg 0.04 Cumulative Incidence 0.03 0.02 Results: Looking now at total mortality, there were 198 deaths in the rosuvastatin group compared to 247 deaths in the placebo group – HR 0.80; 95% CI: 0.67 to 0.97; p=0.02. Significantly reducing the risk of death from any cause is a unique finding for statins in a patient population without established coronary heart disease. The rates of death from any cause were 1.00 and 1.25 per 100 person- years of follow-up in the rosuvastatin and placebo groups, respectively. Reference Ridker P et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008; 359: NOTE: COPYRIGHT PERMISSIONS REQUIRED FOR THIS SLIDE 0.01 0.00 1 2 3 4 Follow-up (years) Number at Risk Rosuvastatin 8,901 8,847 8,787 6,999 4,312 2,268 1,602 1,192 683 227 Placebo 8,901 8,852 8,775 6,987 4,319 2,295 1,614 1,196 684 246 Ridker P et al. N Eng J Med 2008;359: 69

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71 INFLAMMATION PARTICIPATES IN ALL PHASES OF ATHEROTHROMBOTIC DISEASE
Lesion initiation Lesion progression Thrombotic complications Inflammation participates in all phases of atherothrombotic disease In conclusion, inflammation participates in all phases of atherothrombotic disease as demonstrated by the data presented in this slide collection. Libby P. Circulation. 1995; 91: 71

72 INFLAMMATION IN THE FUTURE Possible clinical implications:
The inflammation has an important role in the determinism of atherosclerotic process. The CRP is able to guide the clinical practice and is currently an important field of research. Possible clinical implications: Primary prevention: the CRP is an independent marker of CVD and its evaluation could provide further informations for the assessment of GCVR in patients with dyslipidemia and MS. Secondary prevention: nevertheless the possible CRP usefulness is uncertain, a more aggressive pharmacological treatments should be warrented. 72

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74 ADHERENCE TO MD AND CARDIOVASCULAR INCIDENCE AND/OR MORTALITY
Study Weight (%) RR (95% CI) Trichopoulou et al. 2003 4.29 0.95 (0.90–1.00) Knoops et al. 2004 27.73 0.89 (0.77–1.03) Lagiou et al. 2006 12.21 0.91 (0.82–1.01) Fung et al. 2006 3.78 0.94 (0.91–0.97) Mitrou et al (males) -9% 34.11 0.96 (0.92–1.00) Mitrou et al (females) 17.88 0.88 (0.81–0.96) 0.91 ( ) Total (95% CI) 100 0.1 0.2 0.5 1 2 Decreased risk Increased risk Sofi et al., BMJ 2008 74


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