1. 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

2. University of Palermo - Faculty of Medicine
Department of Internal Medicine and
Cardiovascular Diseases
Section of CardioAngiology
Chair of Cardiovascular Diseases
Master of Echocardiography – Master of Vascular Disease
Center for the Early Diagnosis of Preclinical and
Multifocal Atherosclerosis and for Secondary Prevention
Division of Cardiology – University Hospital “P. Giaccone” - Italy
Director: Prof. Salvatore Novo
METABOLIC SYNDROME, PRECLINICAL
ATHEROSCLEROSIS AND FUTURE
CARDIOVASCULAR EVENTS
Salvatore Novo
2

3. METABOLIC SYNDROME
 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

4. Criteri WHO 1999 EGIR 1999 ATP III 2001 AACE IDF 2005
2003
A)Alterations Diabetes Mellitus 2 FPG 110-125 FPG ≥ 110 mg/dl IFG o IGT FPG ≥100 o Diabetes
of glucose o IFG o IGT mg/dl Mellitus 2
metabolism
B) >140/90 ≥140/90 mmHg ≥130/85 And/or ≥130/85 ≥130/85 and/or
Hypertension And/or pharmacological mmHg pharmacological
pharmacological treatment treatment
treatment
C)Hypertrigl ≥150 ≥177 mg/dl ≥150 mg/dl and/or ≥150 ≥150 mg/dl and/or
yceridemia pharmacological mg/dland/or pharmacological
treatment pharmacolo treatment
gical
treatment
D) Low <35 (M) mg/dl o <39 <39 mg/dl <40 mg/dl (M) o <40 mg/dl <40 mg/dl (M) o <50 (F)
HDLc mg/dl (F) <50 (M) o <50 and/or pharmacological
mg/dl(F)and/or (F)and/or treatment
pharmacological pharmacolo
treatment gical
treatment
F)Obesity BMI >30 Kg/m o Waist Weist Weist circunference >94
WHR >0,90 (M) O circunference ≥94 circunference cm (M)o >80 (F)
>0,85 (F) cm (M) o > 80 cm >102 cm (M) o
(F) >88 cm (F)
G)Mycroalbu AER >20 μg/min o
minuria Alb(u):Creat(u) ≥30 4
mg/gr

5. 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

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

7. Metabolic Syndrome and CV Risk
Decode Study,
PAMELA Study,
Metabolic Syndrome and Risk of
Galassi Meta-analysis,
Cardiovascular Events and Death.
Gami Meta-analysis, A Systematic Review and Meta-
Kuopio Ischemic Heart disease Risk factor Analysis of Longitudinal Studies
Study, Rotterdam Study, Cardiovascular
Health Study, Malmo Diet and Cancer
Impact of BMI and the Metabolic
Study, Longitudinal Investigation for The Syndrome on the risk of
Longevity and Ageing in Hokkaido Country, cardiovascular rvents and death
in Middle-Aged Men.
Carotid Atherosclerosis Progression Study e
Circulation 2010; 121: 230-6
Kitamura Study, …
Impact of the Metabolic Syndrome on mortality
from coronary heart disease, cardiovascular
disease and all causes of United States Adults.
7
Circulation 2004; 110: 1245-50

8. Guidelines for the Primary Prevention of Stroke
A Guideline for Healthcare Professionals From the American Heart
Association/American Stroke Association.
 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 8

9. A metanalysis 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 37197 subjects with a mean follow-
up of 5,5 years. Matthias W et al. Circulation 2007:115: 459-67

10. AN IMT INCREASE OF 0.1 MM WAS ASSOCIATED
WITH AN ENHANCED RISK OF 15% FOR AMI AND
OF 18% FOR STROKE, SHOWING THAT
PRECOCIOUS ATS LESIONS OF CAROTID
ARTERIES ARE AN INDEPENDENT MARKER OF
CEREBRO- AND CV EVENTS
Matthias W et al. - Circulation 2007:115:459-467

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

12. RISK PREDICTION IS IMPROVED BY ADDING
MARKERS OF SUBCLINICAL DAMAGE TO SCORE
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.
Sehestedt T et al. - Eur Heart J. 2010; 31: 883-91

13. INFLUENCE OF PRECLINICAL CAROTID
ATHEROSCLEROSIS ON CEREBRO –
AND CV EVENTS IN 5-YEARS FOLLOW-UP
Novo S, Carità P, Corrado E, Amorososo G, Muratori I, Pernice C, Tantillo R, Novo G.
Atherosclerosis 2010; 211: 287-90.
Incidence of total events %
p < 0.01
15%
16%
14% 13% No fatal events in subjects
12% with normal carotid. 2
10%
8%
8%
deaths for cardiac or
6%
4%
cerebrovascular cause in
2% subjects with IMT or ACP
0%
Normal IMT ACP

14. PRECLINICAL ATHEROSCLEROSIS ADD TO
PREDICTION OF CARDIOVASCULAR RISK: A TEN
YEARS FOLLOW-UP STUDY IN 558 PATIENTS
Novo S, Visconti C, Amoroso GR, Corrado E, Muratori I, Fazio G, Novo G
Eur J Cardiovasc Prev & Rehabiltation 2010; 17: 514-8
70 56%+7% 43 e 56%
Non fatal
60 43%+3% events
3% e 7%
50
Fatal events
40 35%
30
20%
20 14%
10 4%
0

16. Patient at very very high Risk

17. 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

18. 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

19. 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. 20 years follow-up Free-events survival
Novo S, Peritore A, Guarneri FP, Evola in patients suffering
S, Novo G, Atherosclerosis 2012; 223:
468-72 from MetS and not.
529 patients
251 patients 278
suffering healthy
from MetS patients
199 CV
adverse
events
79
120
CV adverse
CV adverse
events
events
OR 2.3
P < 0,0003 20

21. Metabolic Control P value
syndrome subjects
Subclinical 68,12% 57,5% < 0,01
atherosclerosis OUI
Subclinical 31,87% 42,5% < 0,01
atherosclerosis NON
21

22. Metabolic Control Subjects p-value
Syndrome (n=278)
(n=251)
All CV events 144 98 < 0.0001
Fatal CV 24 19 (ns)
events
Not fatal CV 120 79 < 0.0001
events

23. Metabolic Syndrome Control Subjects p-value
(n=251) (n=278)
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 Control Subjects p-value
(n=251) (n=278)
Total cerebrovascular events (TIA, not 67 47 0.0086
fatal and fatal Stroke)
Total AMI (fatal and not fatal) 47 33 0.0379

24. Variabile Regression standard P value Relative CI (95%)
Coefficient error Risk
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 -0,1486 0,2796 0,5951 0,8619 0,4997-
circunference 1,4868
Preclinical -2,6772 0,4743 0,04343 0,0700 0,0373-
atherosclerosis 0,1777
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 serum24
concentration (p < 0.005).

25. SYNDROME METABOLIQUE,
ATHÉROSCLÉROSE PRÉCLINIQUE ET
FUTURS ÉVÉNEMENTS
CARDIOVASCULAIRES
Novo S. , Peritore A. , Trovato R.L. , Guarneri F.P. , Di Lisi D. , Novo G.

26. Répartition de la population de l'étude par
rapport aux Mets et échographies carotidiennes
MetS Non MetS P-value TOTAL
(n=250 (n=277 (n=527 patients)
patients) patients)
Normal 74 (29.6%) 118 (42.6%) P=0.0026 192 patients
Epaississement intima- 176 (70.4%) 159 (57.4%) P=0.0026 335 patients
média(IMT)/Plaqu
e asymptomatique
Normal: IMT <0,9 mm; IMT: IMT> 0,9 mm et <1,5 mm; plaque asymptomatique: IMT> 1,5 mm

27. Répartition des patients atteints d'événements
cardiovasculaires par rapport à l'athérosclérose
subclinique et le syndrome métabolique
MetS Sujets de contrôle
56%
52%
40,5%
39%
33%
25,4%
Normal IMT Plaque asymptomatique

28. Survie sans événement,
Kaplan Meyer fonction
28

29. Événements survenus chez des patients avec et
sans lésions échographiques carotidiens
Patients avec Infarctus Angina TIA Stroke Décès Evénements
des aigu N° N° N° N°
événeme du
nts myoca
rde N°
Normal (N°192) 60 (31.2%) 27 (14%) 11 (5.7%) 13 (6.7%) 22 (11.4%) 25 (13%) 98 (51.04%)
IMT/plaque 152 (45.4%) 59 (17.6%) 19 (5.7%) 40 (12%) 37 (11%) 74 (22.1%) 229 (68.36%)
asymptomatique
(N°335)
P-value P=0.0019 P=0.01 P=0.0001

30. 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

31. Merci pour votre attention
Palermo - Palais Chinoise
1799 – Ferdinando I de Bourbon