Metabolic syndrome (MetS) predicts cardiovascular and cerebrovascular events over 20 years of follow-up. A study of 529 asymptomatic patients with MetS at baseline found they experienced 199 cardiovascular adverse events, compared to 120 events for 278 healthy controls, with an odds ratio of 2.3. Multivariate analysis identified MetS, BMI, C-reactive protein levels, and preclinical atherosclerosis as independent predictors of cardiovascular events over the 20 year period. Subclinical atherosclerosis was more prevalent in patients with MetS compared to controls. MetS significantly increased the risk of total cardiovascular, cerebrovascular, myocardial infarction and angina events over the long term follow-up period.

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. METABOLIC SYNDROME, PRECLINICALMETABOLIC SYNDROME, PRECLINICAL
ATHEROSCLEROSIS AND FUTUREATHEROSCLEROSIS AND FUTURE
CARDIOVASCULAR EVENTSCARDIOVASCULAR EVENTS
Salvatore NovoSalvatore Novo
2
University of Palermo - Faculty of MedicineUniversity of Palermo - Faculty of Medicine
Department of Internal Medicine andDepartment of Internal Medicine and
Cardiovascular DiseasesCardiovascular Diseases
Section of CardioAngiologySection of CardioAngiology
Chair of Cardiovascular DiseasesChair of Cardiovascular Diseases
Master of Echocardiography – Master of Vascular DiseaseMaster of Echocardiography – Master of Vascular Disease
Center for the Early Diagnosis of Preclinical andCenter for the Early Diagnosis of Preclinical and
Multifocal Atherosclerosis and for Secondary PreventionMultifocal Atherosclerosis and for Secondary Prevention
Division of Cardiology – University Hospital “P. Giaccone” - ItalyDivision of Cardiology – University Hospital “P. Giaccone” - Italy
Director: Prof. Salvatore NovoDirector: Prof. Salvatore Novo

3.  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

4. 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)Hypertrigl
yceridemia
≥150 ≥177 mg/dl ≥150 mg/dl and/or
pharmacological
treatment
≥150
mg/dland/or
pharmacolo
gical
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
pharmacolo
gical
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)Mycroalbu
minuria
AER >20 μg/min o
Alb(u):Creat(u) ≥30
mg/gr
4

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. 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. 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 tocigarette
smoke, diabetes, atrial fibrillation and certain othercardiac conditions,
dyslipidemia, carotid artery stenosis, sicklecell disease,
postmenopausal hormone therapy, poor diet, physicalinactivity, and
obesity and body fat distribution. Less well-documentedor potentially
modifiable risk factors include the metabolicsyndrome, excessive
alcohol consumption, drug abuse, use oforal contraceptives, sleep-
disordered breathing, migraine, hyperhomocysteinemia,elevated
lipoprotein(a), hypercoagulability, inflammation, andinfection. Data
on the use of aspirin for primary stroke preventionare reviewed.
Goldstein LB et al. Stroke 2011; 42: 517-84
Guidelines for the Primary Prevention of Stroke
A Guideline for Healthcare Professionals From the American Heart
Association/American Stroke Association.

9. 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 andARIC Study, Rotterdam Study, CVH Study, Malmo Diet and
Cancer Study, Longitudinal Investigation for the LongevityCancer 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 theanalysing the association between carotid IMT and cerebroassociation 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.

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

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

12. 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

13. 8%
13%
15%
0%
2%
4%
6%
8%
10%
12%
14%
16%
Normal IMT ACP
Incidenceoftotalevents%Incidenceoftotalevents%
p < 0.01p < 0.01
No fatal events in subjectsNo fatal events in subjects
with normal carotid. 2with normal carotid. 2
deaths for cardiac ordeaths for cardiac or
cerebrovascular cause incerebrovascular cause in
subjects with IMT or ACPsubjects with IMT or ACP
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.

14. 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 PATIENTS
Novo S, Visconti C, Amoroso GR, Corrado E, Muratori I, Fazio G, Novo G
Eur J Cardiovasc Prev & Rehabiltation 2010; 17: 514-8

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-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 2.3
P < 0,0003
Free-events survivalFree-events survival
in patients sufferingin 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

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

22. 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

23. 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

24. Variabile Regression
Coefficient
standard
error
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
24
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).

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. 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)/Plaqu
e 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
Normal: IMT <0,9 mm; IMT: IMT> 0,9 mm et <1,5 mm; plaque asymptomatique: IMT> 1,5 mm

27. 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

28. 28
Survie sans événement,
Kaplan Meyer fonction

29. Patients avec
des
événeme
nts
Infarctus
aigu
du
myoca
rde 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/plaque
asymptomatique
(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

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