Session 10 – Detection of Preclinical Atherosclerosis and Evaluation of

Cardiovascular Risk

Presidents: P.J. Touboul (France) – S. Novo (Italy)

Chirman: A. Kane (Sénégal)

Friday February 1st, 2013 - Hall Longchamp 1 – 16.30 – 17.15

METABOLIC SYNDROME, PRECLINICAL METABOLIC SYNDROME, PRECLINICAL ATHEROSCLEROSIS AND FUTURE ATHEROSCLEROSIS AND FUTURE

CARDIOVASCULAR EVENTSCARDIOVASCULAR EVENTS

Salvatore NovoSalvatore Novo2

University of Palermo - Faculty of Medicine University of Palermo - Faculty of Medicine Department of Internal Medicine and Department of Internal Medicine and

Cardiovascular Diseases Cardiovascular Diseases Section of CardioAngiology Section of CardioAngiology

Chair of Cardiovascular Diseases Chair of Cardiovascular Diseases Master of Echocardiography – Master of Vascular DiseaseMaster of Echocardiography – Master of Vascular Disease

Center for the Early Diagnosis of Preclinical and Center for the Early Diagnosis of Preclinical and Multifocal Atherosclerosis and for Secondary Prevention Multifocal Atherosclerosis and for Secondary Prevention

Division of Cardiology – University Hospital “P. Giaccone” - ItalyDivision of Cardiology – University Hospital “P. Giaccone” - ItalyDirector: Prof. Salvatore NovoDirector: Prof. Salvatore Novo

The metabolic syndrome (MetS) is a cluster of cardiovascular (CV) risk factors which includes abdominal obesity, abnormal glycemia, hypertension, low HDL-cholesterol (HDL-C), high triglycerides, insulin resistance, and proinflammatory and prothrombotic states.

The pathogenesis of the syndrome has multiple origins, but obesity and sedentary lifestyle coupled with diet and still largely unknown genetic factors clearly interact and may determine the syndrome.

3

METABOLIC SYNDROME

Criteri WHO 1999 EGIR 1999 ATP III 2001 AACE 2003

IDF 2005

A)Alterations of glucose metabolism

Diabetes Mellitus 2 o IFG o IGT

FPG 110-125 mg/dl

FPG ≥ 110 mg/dl IFG o IGT FPG ≥100 o Diabetes Mellitus 2

B) Hypertension

>140/90 ≥140/90 mmHg And/or pharmacological treatment

≥130/85 And/or pharmacological treatment

≥130/85 mmHg

≥130/85 and/or pharmacological treatment

C)Hypertriglyceridemia

≥150 ≥177 mg/dl ≥150 mg/dl and/or pharmacological treatment

≥150 mg/dland/or pharmacological treatment

≥150 mg/dl and/or pharmacological treatment

D) Low HDLc

<35 (M) mg/dl o <39 mg/dl (F)

<39 mg/dl <40 mg/dl (M) o <50 mg/dl(F)and/or pharmacological treatment

<40 mg/dl (M) o <50 (F)and/or pharmacological treatment

<40 mg/dl (M) o <50 (F) and/or pharmacological treatment

F)Obesity BMI >30 Kg/m o WHR >0,90 (M) O >0,85 (F)

Waist circunference ≥94 cm (M) o > 80 cm (F)

Weist circunference >102 cm (M) o >88 cm (F)

Weist circunference >94 cm (M)o >80 (F)

G)Mycroalbuminuria

AER >20 μg/min o Alb(u):Creat(u) ≥30 mg/gr

4

Alberti KG et al. Harmonizing the metabolic syndrome. A joint interim statement of the IDF Task Force on Epidemiology and Prevention; NHLBI; AHA; WHF; IAS; and International Association for the Study of Obesity. Circulation 2009; 120: 1640-5

The Italian Heart Project-Longitudinal Studies. Italian Heart J 2003; 4 (Suppl. 7): S13-S21 6

7

Decode Study,

PAMELA Study,

Galassi Meta-analysis,

Gami Meta-analysis,

Kuopio Ischemic Heart disease Risk factor

Study, Rotterdam Study, Cardiovascular

Health Study, Malmo Diet and Cancer

Study, Longitudinal Investigation for The

Longevity and Ageing in Hokkaido Country,

Carotid Atherosclerosis Progression Study e

Kitamura Study, …

Metabolic Syndrome and Risk of Cardiovascular Events and Death. A Systematic Review and Meta-Analysis of Longitudinal Studies

Impact of BMI and the Metabolic Syndrome on the risk of

cardiovascular rvents and death in Middle-Aged Men.

Circulation 2010; 121: 230-6

Impact of the Metabolic Syndrome on mortality from coronary heart disease, cardiovascular

disease and all causes of United States Adults.Circulation 2004; 110: 1245-50

Metabolic Syndrome and CV Risk

8

Results—Non modifiable risk factors include age, sex, low birth weight, race/ethnicity, and genetic predisposition. Well-documented

and modifiable risk factors include hypertension, exposure to cigarette smoke, diabetes, atrial fibrillation and certain other cardiac conditions, dyslipidemia, carotid artery stenosis, sickle cell disease, postmenopausal hormone therapy, poor diet, physical inactivity, and obesity and body fat distribution. Less well-documented or potentially modifiable risk factors include the metabolic syndrome, excessive alcohol consumption, drug abuse, use of oral contraceptives, sleep-disordered breathing, migraine, hyperhomocysteinemia, elevated lipoprotein(a), hypercoagulability, inflammation, and infection. Data on the use of aspirin for primary stroke prevention are reviewed.

Goldstein LB et al. Stroke 2011; 42: 517-84

Guidelines for the Primary Prevention of StrokeA Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association.

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

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

Matthias W et al. - Circulation 2007:115:459-467Circulation 2007:115:459-467

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

OF 18% FOR STROKE, SHOWING THAT OF 18% FOR STROKE, SHOWING THAT PRECOCIOUS ATS LESIONS OF CAROTID PRECOCIOUS ATS LESIONS OF CAROTID

ARTERIES ARE AN INDEPENDENT MARKER OF ARTERIES ARE AN INDEPENDENT MARKER OF CEREBRO- AND CV EVENTSCEREBRO- AND CV EVENTS

Nambi V et al. JACC 2010; 55 : 1660-7

Methods: Evaluate whether subclinical vascular damage adds significantly to Systemic Coronary Risk Evaluation (SCORE) risk stratification in 1968 subjects without CVD; follow-up of 12.8 years. Results: Risk of CV death was (independently of SCORE) associated with LV hypertrophy, plaques, PWV > 12 m/s for SCORE ≥ 5% and 7.3 for SCORE < 5%. Broaden primary prevention from subjects with SCORE ≥ 5% to include subjects with 1% ≤ SCORE < 5% together with subclinical organ damage increased sensitivity from 72 to 89% (P = 0.006), but reduced specificity from 75 to 57% (P < 0.002) and positive predictive value from 11 to 8% (P = 0.07). Conclusions: Subclinical organ damage predicted CV death independently of SCORE and the combination may improve risk prediction.

RISK PREDICTION IS IMPROVED BY ADDING MARKERS OF SUBCLINICAL DAMAGE TO SCORE

Sehestedt T et al. - Eur Heart J. 2010; 31: 883-91

8%

13%

15%

0%

2%

4%

6%

8%

10%

12%

14%

16%

Normal IMT ACP

Incid

en

ce o

f to

tal

Incid

en

ce o

f to

tal

eve

nts

%

eve

nts

%

p < 0.01p < 0.01

No fatal events in subjects No fatal events in subjects with normal carotid. 2 with normal carotid. 2 deaths for cardiac or deaths for cardiac or cerebrovascular cause in cerebrovascular cause in subjects with IMT or ACP subjects with IMT or ACP

INFLUENCE OF PRECLINICAL CAROTID ATHEROSCLEROSIS ON CEREBRO –

AND CV EVENTS IN 5-YEARS FOLLOW-UPNovo S, Carità P, Corrado E, Amorososo G, Muratori I, Pernice C, Tantillo R, Novo G.

Atherosclerosis 2010; 211: 287-90.

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 ADD TO PREDICTION OF CARDIOVASCULAR RISK: A TEN

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

G, Novo G Eur J Cardiovasc Prev & Rehabiltation 2010; 17: 514-8

Patient at very very high Risk

Metabolic syndrome (MetS) predicts cardio and cerebrovascular events in a twenty years follow-up. A prospective study.

Novo S, Peritore A, Guarneri FP, Corrado E, Macaione F, Evola S, Novo G. - Atherosclerosis 2012; 223: 468-72

From our registry of more than 9000 patients referred from 1985 to 1991 and in follow-up, we identified 529 asymptomatic subjects with Metabolic

Syndrome at baseline, 257 male and 272 female, aged between 25 and 85 years.

2007 Guidelines for the management of arterial hypertension. The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and

of the European Society of Cardiology (ESC). Task Force Members Eur Heart J 2007; 28: 1462–536

2007 Guidelines for the management of arterial hypertension. The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and

of the European Society of Cardiology (ESC). Task Force Members Eur Heart J 2007; 28: 1462–536

Cardiovascular endpoints were investigated in a 20 years follow up: CV death, myocardial infarction (MI),

angina pectoris, transient ischemic attack (TIA), ischemic stroke, admissions for

abdominal aortic aneurysm (AAA), coronary intervention (PCI), and carotid

thromboendarterectomy (TEA). Non fatal events were investigated in new controls

during the follow-up in hospital. Fatal events were ascertained through the interrogation

of family members or death certificates.

20 years follow-up20 years follow-up

529 patients

20

251 patients suffering

from MetS

278 healthy patients

199 CV adverse events

120 CV adverse

events

79 CV adverse

events

OR 2.3P < 0,0003

Free-events survival Free-events survival in patients suffering in patients suffering from MetS and not.from MetS and not.

Novo S, Peritore A, Guarneri FP, Evola S, Novo G, Atherosclerosis 2012; 223: 468-72

Metabolic syndrome

Control subjects

P value

Subclinical atherosclerosis OUI

68,12% 57,5% < 0,01

Subclinical atherosclerosis NON

31,87% 42,5% < 0,01

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Metabolic

Syndrome

(n=251)

Control Subjects

(n=278)

p-value

All CV events 144 98 < 0.0001

Fatal CV

events

24 19 (ns)

Not fatal CV

events

120 79 < 0.0001

Metabolic Syndrome

(n=251)

Control Subjects

(n=278)

p-value

ALL NOT FATAL CV EVENTS 120 79 < 0.0001

TIA 25 23 NS

Not fatal AMI 36 24 0.04

Angina pectoris 19 14 NS

Not fatal Ischemic Stroke 32 15 0.0049

Not fatal AAA 5 1 (ns)

TEA 3 2 (ns)

Metabolic Syndrome

(n=251)

Control Subjects

(n=278)

p-value

Total cerebrovascular events (TIA, not

fatal and fatal Stroke)

67 47 0.0086

Total AMI (fatal and not fatal) 47 33 0.0379

Variabile Regression Coefficient

standarderror

P value Relative Risk

CI (95%)

BMI -0,07659 0,02878 0,00778 0,9263 0,8757-0,9797

Fibrinogen 0,0001898 0,001097 0,8626 1,0002 0,9981-1,0023

CRP -0,4573 0,2367 0,05332 0,6330 0,3990-1,0042

MS -2,9124 0,5745 0,0000003992 0,0543 0,0177-0,1666

Weist circunference

-0,1486 0,2796 0,5951 0,8619 0,4997-1,4868

Preclinical atherosclerosis

-2,6772 0,4743 0,04343 0,0700 0,0373-0,1777

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In addition, the Multivariate Cox proportional-hazards analysis showed as independent predictors of cardiovascular events, in the whole population, subclinical Atherosclerosis (p < 0.04), MetS (p = 0.0000003992), BMI (p = 0.007), high C-reactive protein serum concentration (p < 0.005).

In addition, the Multivariate Cox proportional-hazards analysis showed as independent predictors of cardiovascular events, in the whole population, subclinical Atherosclerosis (p < 0.04), MetS (p = 0.0000003992), BMI (p = 0.007), high C-reactive protein serum concentration (p < 0.005).

SYNDROME METABOLIQUE, ATHÉROSCLÉROSE PRÉCLINIQUE ET

FUTURS ÉVÉNEMENTS CARDIOVASCULAIRES

Novo S. , Peritore A. , Trovato R.L. , Guarneri F.P. , Di Lisi D. , Novo G.

SYNDROME METABOLIQUE, ATHÉROSCLÉROSE PRÉCLINIQUE ET

FUTURS ÉVÉNEMENTS CARDIOVASCULAIRES

Novo S. , Peritore A. , Trovato R.L. , Guarneri F.P. , Di Lisi D. , Novo G.

MetS (n=250 patients)

Non MetS(n=277 patients)

P-value TOTAL(n=527 patients)

Normal 74 (29.6%)

118 (42.6%) P=0.0026 192 patients

Epaississement intima-média(IMT)/Plaque asymptomatique

176 (70.4%) 159 (57.4%) P=0.0026 335 patients

Répartition de la population de l'étude par rapport aux Mets et échographies carotidiennes Répartition de la population de l'étude par rapport aux Mets et échographies carotidiennes

Normal: IMT <0,9 mm; IMT: IMT> 0,9 mm et <1,5 mm; plaque asymptomatique: IMT> 1,5 mmNormal: IMT <0,9 mm; IMT: IMT> 0,9 mm et <1,5 mm; plaque asymptomatique: IMT> 1,5 mm

40,5%

25,4%

52%

33%

56%

39%

Normal IMT Plaque asymptomatique

MetS Sujets de contrôle

Répartition des patients atteints d'événements cardiovasculaires par rapport à l'athérosclérose subclinique et le syndrome métabolique

Répartition des patients atteints d'événements cardiovasculaires par rapport à l'athérosclérose subclinique et le syndrome métabolique

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Survie sans événement,

Kaplan Meyer fonction

Survie sans événement,

Kaplan Meyer fonction

Patients avec des

événements

Infarctus aigu du

myocarde N°

Angina N°

TIA N°

Stroke N°

Décès N°

Evénements

Normal (N°192) 60 (31.2%) 27 (14%) 11 (5.7%) 13 (6.7%) 22 (11.4%) 25 (13%) 98 (51.04%)

IMT/plaqueasymptomatique

(N°335)

152 (45.4%) 59 (17.6%) 19 (5.7%) 40 (12%) 37 (11%) 74 (22.1%) 229 (68.36%)

P-value P=0.0019 P=0.01 P=0.0001

Événements survenus chez des patients avec et sans lésions échographiques carotidiens Événements survenus chez des patients avec et sans lésions échographiques carotidiens

L'athérosclérose subclinique ajouté à des facteurs de risque traditionnels peut améliorer la prédiction du risque CV. Par ailleurs, selon les dernières CES 2012 des lignes directrices sur la prévention cardio-vasculaire, la détection d'une plaque carotidienne asymptomatique mis sujets dans la catégorie de risque très élevé. Nous vous proposons de rechercher la présence de l'athérosclérose subclinique chez tous les patients,> 45 ans, par un test de la carotide écho Doppler couleur, parce que dans la prévention primaire, la mesure IMT peut donner de plus amples informations pour une meilleure stratification des GCVR (risque cardiovasculaire global).

Nous recommandons également d'éviter l'apparition d'anomalies syndrome métabolique, en encourageant l'activité physique quotidienne et le régime alimentaire méditerranéen et de commencer tôt le traitement pharmacologique des facteurs de risque modifiables

L'athérosclérose subclinique ajouté à des facteurs de risque traditionnels peut améliorer la prédiction du risque CV. Par ailleurs, selon les dernières CES 2012 des lignes directrices sur la prévention cardio-vasculaire, la détection d'une plaque carotidienne asymptomatique mis sujets dans la catégorie de risque très élevé. Nous vous proposons de rechercher la présence de l'athérosclérose subclinique chez tous les patients,> 45 ans, par un test de la carotide écho Doppler couleur, parce que dans la prévention primaire, la mesure IMT peut donner de plus amples informations pour une meilleure stratification des GCVR (risque cardiovasculaire global).

Nous recommandons également d'éviter l'apparition d'anomalies syndrome métabolique, en encourageant l'activité physique quotidienne et le régime alimentaire méditerranéen et de commencer tôt le traitement pharmacologique des facteurs de risque modifiables

Palermo - Palais Chinoise

1799 – Ferdinando I de Bourbon

Palermo - Palais Chinoise

1799 – Ferdinando I de Bourbon

Merci pour votre attention Merci pour votre attention