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METABOLICMETABOLIC SYNDROMESYNDROME
Lajos Lajos SzollárSzollárProfessor of PathophysiologyProfessor of Pathophysiology
Semmelweis University, Semmelweis University, Faculty of MedicineFaculty of Medicine
Institute of PathophysiologyInstitute of Pathophysiology20072007
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The Metabolic Syndrome andThe Metabolic Syndrome andAssociated CVD Risk FactorsAssociated CVD Risk Factors
Insulin Resistance
AtherosclerosisAtherosclerosis
Endothelial Dysfunction
Hypertension
Abdominal obesity
Hyperinsulinaemia
Dyslipidaemia• high TGs
• small dense LDL• low HDL-C
Diabetes
Hypercoagulability
Deedwania PC. Am J Med 1998;105(1A);1S-3S.
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World Health Organization Clinical Criteria for Metabolic
Syndrome
Insulin resistance (T2DM, IFG, IGT, clamp)
+ any two of the following
BP > 140/90 mmHg or anti-HTN medicationPlasma TG > 1.7 mmol/L HDL-C < 0.9 mmol/L (M); < 1.0 mmol/L (F)BMI > 30 kg/m2 or W/H >0.9 (M) or > 0.85 (F)Urinary albumin > 20 mg/min
or Alb/Cr > 30 mg/g
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NCEP ATP III: The Metabolic SyndromeNCEP ATP III: The Metabolic Syndrome
<40 mg/dL (1.0 mmol/L)<40 mg/dL (1.0 mmol/L)<50 mg/dL (1.3 mmol/L)<50 mg/dL (1.3 mmol/L)
MenMenWomenWomen
>102 cm (>40 in)>102 cm (>40 in)>88 cm (>35 in)>88 cm (>35 in)
MenMenWomenWomen
110 mg/dL (6.0 mmol/L)110 mg/dL (6.0 mmol/L)Fasting glucoseFasting glucose
130/130/85 mm Hg85 mm HgBlood pressureBlood pressure
HDL-CHDL-C
150 mg/dL (1.7 mmol/L)150 mg/dL (1.7 mmol/L)TGTG
Abdominal obesity Abdominal obesity (Waist circumference)(Waist circumference)
Defining LevelDefining LevelRisk FactorRisk Factor
Recommends a diagnosis when 3 of these risk factors are present
NCEP, Adult Treatment Panel III, 2001. JAMA 2001:285;2486-2497.
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Updated ATPIII Criteria for Diagnosis of Metabolic Syndrome
Measure (any 3 of the following)Categorical cutpoints
Elevated waist circumference ≥102 cm men≥88 cm women
Elevated triglycerides ≥150 mg/dL (1.7 mmol/L) or on Rx for elevated TG
Reduced HDL-C <40 mg/dL (1.03 mmol/L) men<50 mg/dL (1.3mmol/L) women
or on Rx for reduced HDL-C
Elevated blood pressure ≥130 mm Hg systolic or ≥85 mm Hg diastolic or on
antihypertensive Rx with history of hypertension
Elevated fasting glucose ≥100 mg/dL or on Rx for elevated glucose
Grundy et al. Diagnosis and management of the metabolic syndrome. An AHA/NHLBI Scientific Statement Circulation 2005 112:2735-2752
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International Diabetes Federation definition of the metabolic syndrome
Central obesity (defined as waist circumference > 94cm for Europid men; > 80cm for Europid women; ethnicity specific values for other groups)
Plus any two of the following four factors:• Raised triglyceride level: > 150 mg/dL (1.7 mmol/L), or specific treatment
for this lipid abnormality• Reduced HDL cholesterol : < 40 mg/dL (1.03 mmol/L) in males and < 50
mg/dL (1.29 mmol/L) in females, or specific treatment for this lipid abnormality
• Raised blood pressure: systolic BP > 130 or diastolic BP > 85 mm Hg, or treatment of previously diagnosed hypertension
• Raised fasting plasma glucose > 100 mg/dL (5.6 mmol/L or previously diagnosed type 2 diabetes (if above 5.6 mmol/L, OGTT strongly recommended but not necessary to define presence of the syndrome)
International Diabetes Federation. Worldwide definition of the metabolic syndrome. Available at: http://www.idf.org/webdata/docs/IDF_Metasyndrome_definition.pdf.
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Definitions of the Metabolic Syndrome
National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in
Adults (ATP III). Circulation. 2002;106:3143-3421.International Diabetes Federation. 2005. www.idf.orgGrundy SM, et al. Circulation. 2005;112:2735-2752.
* Based on a Chinese, Malay, and Asian-Indian population† Or on drug treatment
Metabolic syndrome ICD-9-CM code: 277.7
Components
NCEP ATP III
≥3
IDF
WC + ≥2
AHA-NHLBI
≥3
WC, cm >102 (m) >88 (f)
Europid ≥94 (m) ≥80 (f)
S. Asian* ≥90 (m) ≥80 (f)
Japanese ≥85 (m) ≥90 (f) >102 (m) >88 (f)‡
TG, mg/dL 150 150† 150†
HDL-C, mg/dL <40 (m) <50 (f) <40 (m) <50 (f)† <40 (m) <50 (f)†
BP, mm Hg 130/85 130 OR 85† 130 OR 85†
FPG, mg/dL 110 100† 100†
‡ ≥90cm (m) ≥80cm (f) for Asian Americans
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From Després JPAnn Med (2006) 38:52-63
From Després JPAnn Med (2006) 38:52-63
Metabolic syndrome : confusion between definition and screening tools Metabolic syndrome : confusion between definition and screening tools
CLINICAL TOOLS TO FIND PATIENTS WITH THE METABOLIC SYNDROME
NCEP-ATPIII• Waist girth• HDL-cholesterol• Triglycerides• Blood pressure• Glucose
AACE• Glucose• BMI• HDL-cholesterol• Triglycerides• Blood pressure• Other features of insulin resistance
EGIR• Insulin • Waist girth• Glucose• HDL-cholesterol• Triglycerides• Blood pressure
IDF• Waist girth• HDL-cholesterol• Triglycerides• Blood pressure• Glucose
HyperTG waist• Waist girth• Triglycerides
Others?
WHO• Insulin• Glucose• WHR, BMI• HDL-cholesterol• Triglycerides• Blood pressure• Microalbuminuria
B
• Proinflammatory profile
• Atherogenic dyslipidemia
• Prothrombotic profile
• Insulin resistance/ Glucose intolerance}may evolve to
type 2 diabetes
CONCEPTUAL DEFINITION OF THE MOST PREVALENT FORMOF THE METABOLIC SYNDROME: ABDOMINAL OBESITY
A
• Raised blood pressure (in about 50% of patients)
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RiskRiskRatioRatio
San Antonio Heart StudySan Antonio Heart StudyHunt KJ et al. Circ 2004; 110: 1251-1257Hunt KJ et al. Circ 2004; 110: 1251-1257
0
1.0
2.0
3.0
4.0
5.0
2.712.71
1.631.63
ATP IIIATP III
Metabolic Syndrome and CVD MortalityMetabolic Syndrome and CVD Mortality
WHOWHO
ATP III MS (3+)Abdominal obesityTG HDL-C BP Glucose
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MetS
CVDT2DM
5x 2x
3x
Relative Risk
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Prevalence of MI or Stroke and Components of the Metabolic Syndrome
Ninomiya et. al. NHANES III (Circulation, 2004;109:42-46.)
Abdominal obesity
High triglycerides
Low HDL-C
High blood pressure
Insulin resistance
Metabolic Syndrome
Odds Ratio 1.0
(P <0.001)
(P <0.0001)
(P <0.005)
(P <0.04)
2.0 3.0 4.0
MEN
Women
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MetS
CVDT2DM
Atherogenic dyslipidemia?Elevated BP?Impaired fasting glucose?Prothrombotic state?Proinflammatory state?
Abdominal obesityInsulin resistanceProinflammatory state?
What are themechanismsof higher risk?
Glycation?AGEs?
Glucose toxicity?Others?
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Kalff KG, et al. Aviat Space Environ Med. 1999 Dec;70(12):1223-1226.Hansen BC. Ann N Y Acad Sci. 1999 Nov 18;892:1-24.
The Metabolic SyndromeThe Metabolic Syndrome
Approximately 20% to 30% of the middle-aged population in highly industrialized countries has the metabolic syndrome
By the year 2010, the number of people with the metabolic syndrome in the US could rise to between 50 and 75 million
PrevalencePrevalence
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NHANES III: Age-Specific Prevalence of the Metabolic Syndrome (ATP III)
Data are presented as percentage (SE).Age, y
50
45
40
35
30
25
20
15
10
5
0
Pre
va
len
ce
, %
Men
Women
Ford ES, et al. JAMA. 2002;287:356-359.
20-29 30-39 40-49 50-59 60-69 > 70
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NHANES III: Age-Adjusted Prevalence of NHANES III: Age-Adjusted Prevalence of 3 Risk Factors for the Metabolic Syndrome*3 Risk Factors for the Metabolic Syndrome*
*Criteria based on ATP III; diabetics were included in diagnosis; overall unadjusted prevalence was 21.8%.
Pre
vale
nce,
%
24.8
16.4
28.3
22.825.7
35.6
0
5
10
15
20
25
30
35
40
White
25.7% difference
African American Mexican American
Men
Women
56.7%difference
Ford ES, et al. JAMA. 2002;287:356-359.
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Epidemiology of the Metabolic Syndrome
0%
5%
10%
15%
20%
25%
30%
35%
40%
Obesity Low HDL HTN HypTrig IR
Age-Adjusted Prevalence of component risk factors
23.7% Overall23.7% Overall 47,000,000 US 47,000,000 US
residents have the residents have the syndromesyndrome
Ford et al: JAMA 2002:287
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Association of Multiple Risk Factor Clusteringwith Coronary Artery Disease (CAD)
Jpn Circ J 2001
0
10
20
30
40
0 1 2 3 4Number of Risk Factors
Mul
tiva
riat
e-a d
j ust
edO
dd
s R
atio
fo r
CA
D
1.05.1
9.7
31.3
Metabolic Syndrome
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Cardiovascular Disease Mortality Increased in the Metabolic Syndrome
Lakka HM, et al. JAMA. 2002;288:2709-2716.
15
10
5
0
0 2 4 6 8 10 12
Cardiovascular Disease Mortality
RR (95% Cl), 3.55 (1.98-6.43)
Metabolic SyndromeYesNo
Cumulative Hazard, %
Follow-up, y
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Prevalence of CHD risk factors: an evolving landscape
Smoking
Hypercholesterolemia
Hypertension
Type 2 diabetes
Abdominal obesity
Metabolic syndrome1950’ – 60’ 1990’ – 00’…
• StatinsStatins• HT medicationHT medication• Smoking cessationSmoking cessation
• SedentarinessSedentariness• Energy densityEnergy density of foodof food
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Metabolic Syndrome is an independent Metabolic Syndrome is an independent predictor of Coronary Heart Disease (CHD)predictor of Coronary Heart Disease (CHD)
Variable
Hazard Ratio
95% CI
Metabolic syndrome
1.7 1.4-2.1
Age (10 year) 1.8 1.5-2.1
LDL-C 1.3 1.1-1.5
Current smoking
1.6 1.3-1.8
WOSCOPS trial (n=6,447 males, aged 45-64)
0% 5% 10% 15%
+METS
-METS
P<.0001
5 yr CHD rate
• Prevalence of METS: 23.8%
*L’Italien et al: American College of Cardiology 2003
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Risk of ischemic heart disease (IHD) according to the cumulativenumber of “traditional” and “non-traditional” risk factors
The Québec Cardiovascular Study
Traditional: Traditional: LDL-cholesterol, triglycerides and HDL-cholesterolLDL-cholesterol, triglycerides and HDL-cholesterolNon-traditional: Non-traditional: Insulin, apolipoprotein B and small, dense LDL particlesInsulin, apolipoprotein B and small, dense LDL particles
* Odds ratios are adjusted for systolic blood pressure, family history of IHD* Odds ratios are adjusted for systolic blood pressure, family history of IHD and medication useand medication use
1.0 1.0 1.84.7
2.8
9.1(0.01)
4.4(0.01)
20.8(<0.001)
Od
ds
ra
tio
*
0 1 2 3
Traditional risk factorsNon-traditional risk factors
15
10
5
0
20
25
30
From Lamarche B et al. JAMA (1998) 279:1955-1961
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InsulinResistance
Dysregulationof Risk Factor
Parameters
ElevatedBlood Pressure
AtherogenicDyslipidemia
ElevatedGlucose
Pro-thrombotic
State
Pro-inflammatory
State
Obesity
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MMetabolietabolicc s syyndrndroommee Android Android obesityobesity AtherogenAtherogenicic dyslipidaemia dyslipidaemia
TG > 1,7; HDL-C < 1 mmol/l ; „small-dense”, oxidized LDL ; apo B >TG > 1,7; HDL-C < 1 mmol/l ; „small-dense”, oxidized LDL ; apo B > 1,2 g/L1,2 g/L HypertensioHypertensionn Inzulin resistance / HyperinsulinaemiaInzulin resistance / Hyperinsulinaemia
(FG, IGT, „clamp”, inzulin level, HOMA(FG, IGT, „clamp”, inzulin level, HOMA
PPro-inflammatory state ro-inflammatory state ESR; WBC; hsCRP > 5 mg/LESR; WBC; hsCRP > 5 mg/L
Prothrombotic state Prothrombotic state Lp(a) > 40 mg/dL; fibr.:3,85 g/L; PAI-1, tPaLp(a) > 40 mg/dL; fibr.:3,85 g/L; PAI-1, tPa
MicroalbuminuriaMicroalbuminuria Microvascular anginaMicrovascular angina
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Sex-specified waist circumferences denoting Sex-specified waist circumferences denoting risk of metabolic complications with obesityrisk of metabolic complications with obesityBjorntop, Lancet 350:423, 1997Bjorntop, Lancet 350:423, 1997
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Central Obesity: The Metabolic Syndrome
(CETP)
VLDL-apoB Intra-abdominal fat
Insulin resistance
Free fatty acids Hepatic Lipase
TG
Small, dense LDL
HDL/HDL2
Brunzell 2001
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Obesity and CHD:26 -Year Incidence of CHD in Men
Inci
den
ce/1
,000
Adapted from Hubert HB et al. Circulation 1983;67:968-977. Metropolitan Relative Weight of 110 is a BMI of approximately 25.
177255
350333 366440
0
100
200
300
400
500
600
<25 25-<30 30+
<50 years 50+ years
BMI Level
Framingham Heart Study
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Intra-abdominal (visceral) fatIntra-abdominal (visceral) fatThe dangerous inner fat!
BackBack
Visceral AT
Subcutaneous AT
FrontFront
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Fat mass : 19.8 kg
VAT : 155 cm2
Fat mass : 19.8 kg
VAT : 96 cm2
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Assessment of accumulation of abdominal fatby measurement of waist at mid-distance between bottom of rib cage and iliac crest. Amount of visceral adipose tissue that can be assessed by CT canbe estimated by waist measurementDespres et al. BMJ 322:716,2001
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High visceral fat increases cardiovascular risk
From Pouliot MC et al.Diabetes (1992) 41:826-834
1
1
11
11,2
11
1 (mm
ol/l)
0.0
3.0
6.0
9.0
12.0
15.0
-30 0 30 60 90 120 150 180
Time (min)
1,2
Time (min)
0
200
400
800
1000
1200
6001,2
1,2
1,2 1,2
1,21,2
1,2
1,2
1
Are
a
1,2
Are
a
-30 0 30 60 90 120 150 180 (p
mol
/l)
InsulinGlucose
1 significantly different from Nonobese2 significantly different from Obese with low visceral AT levels
NonobeseObese low VATObese high VAT
VAT: visceral adipose tissueVAT: visceral adipose tissue
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300
250
200
150
100
50
0
r = 0.80
60 80 100 120
Waist circumference (cm)Waist circumference (cm)
Vis
cera
l AT
V
isce
ral A
T (
cm(cm
22)
Front
Back
WaistWaist
HipHipSubcutaneous AT
Visceral AT
Relationship between waist circumferenceRelationship between waist circumferenceand visceral adipose tissue accumulationand visceral adipose tissue accumulation
20
60
100
140
180
220
Waist girth (cm)Waist girth (cm)
Insu
lin
Insu
lin
(p
mo
l/L
)(p
mo
l/L
)
0,8
0,9
1
1,1
1,2
1,3
Waist girth (cmWaist girth (cm))
Ap
o B
(g
/L)
Ap
o B
(g
/L)
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Average apo B (A) and fasting insulin (B) levels among deciles of waist circumference.C LDL particle diameter among deciles of TGconcentration. Dotted lines mean apo B,fasting inslin and LDL peak particle diameter of overall cohort.Lemieux et al. Ciculation 102:179,2000
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MMetabolietabolicc s syyndrndroommee Android Android obesityobesity AtherogenAtherogenicic dyslipidaemia dyslipidaemia
TG > 1,7; HDL-C < 1 mmol/l ; „small-dense”, oxidized LDL ; apo B >TG > 1,7; HDL-C < 1 mmol/l ; „small-dense”, oxidized LDL ; apo B > 1,2 g/L1,2 g/L HypertensioHypertensionn Inzulin resistance / HyperinsulinaemiaInzulin resistance / Hyperinsulinaemia
(FG, IGT, „clamp”, inzulin level, HOMA(FG, IGT, „clamp”, inzulin level, HOMA
PPro-inflammatory state ro-inflammatory state ESR; WBC; hsCRP > 5 mg/LESR; WBC; hsCRP > 5 mg/L
Prothrombotic state Prothrombotic state Lp(a) > 40 mg/dL; fibr.:3,85 g/L; PAI-1, tPaLp(a) > 40 mg/dL; fibr.:3,85 g/L; PAI-1, tPa
MicroalbuminuriaMicroalbuminuria Microvascular anginaMicrovascular angina
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Events/1,000 in
8 yr
Assmann G et al. Am J Cardiol. 1992;70:733-737.
TG (mg/dL)
44
93
132
81
0
50
100
150
<200(157/3,593)
200-399(84/903)
400-799(14/106)
800(3/37)
Hypertriglyceridemia—An Independent Risk Factor for Hypertriglyceridemia—An Independent Risk Factor for CHD: PROCAM StudyCHD: PROCAM Study
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Triglyceride and CHD RiskPROCAM Study
Assmann G, Schulte H. Assmann G, Schulte H. Am J CardiolAm J Cardiol 1992;70:733–737. 1992;70:733–737.
2424 3131
116116
245245
00
5050
100100
150150
200200
250250
5.05.0 > 5.0> 5.0LDL-C/HDL-C ratioLDL-C/HDL-C ratio
Inci
denc
eIn
cide
nce
per
1,00
0 (in
6 y
ears
)pe
r 1,
000
(in 6
yea
rs)
TG < 200 mg/dLTG < 200 mg/dL
TG TG 200 mg/dL 200 mg/dL
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Cardiovascular Disease and HDL-C Levels
HDL Cholesterol, mg/dL
Rate per 1000
Kannel WB. Am J Cardiol. 1983;52:9B-12B.
0
20
40
60
80
100
120
140
160
<34 35-54 >55 <34 35-54 >55
Men Women
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Metabolic abnormalities associated with Metabolic abnormalities associated with abdominal obesityabdominal obesity
• Insulin resistanceInsulin resistance• DyslipidaemiaDyslipidaemia• Mild hypertensionMild hypertension• InflammationInflammation
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Dyslipidemia associated with abdominal obesity
Increased plasma triglycerideIncreased plasma triglyceride
Increased plasma apoBIncreased plasma apoB
LDL fraction characterized by and small, dense particlesLDL fraction characterized by and small, dense particles
Decreased HDL cholesterolDecreased HDL cholesterol
HDL fraction characterized by and small, dense particlesHDL fraction characterized by and small, dense particles
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Atherogenic Apo B-containing LPs
• VLDL• VLDL Remnants• IDL• LDL; Dense LDL
• Enhanced Arterial Cholesterol Deposition • Attenuated Reverse Cholesterol Transport
• Accelerated Atherogenesis
Anti-atherogenicHDL
Atherogenic DyslipidaemiaAtherogenic Dyslipidaemia Metabolic Syndrome Hypercholesterolaemia Type II Diabetes Mixed Hyperlipidaemia
Hypertriglyceridaemia
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Relationship Between Changes in LDL-C and HDL-C Levels and CHD Risk
1% decrease1% decreasein LDL-C reduces in LDL-C reduces
CHD risk byCHD risk by1%1%
1% increase1% increasein HDL-C reduces in HDL-C reduces
CHD risk byCHD risk by1%1%
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High visceral fat increases cardiovascular riskHigh visceral fat increases cardiovascular risk
From Pouliot MC et al.From Pouliot MC et al.Diabetes (1992) 41:826-834Diabetes (1992) 41:826-834
310
248
186
124
62
0
60
45
30
(mg/
dl)
(mg/
dl)
HDL-cholesterol
(mg/
dl)
(mg/
dl)
Triglycerides
NonobeseNonobese NonobeseNonobeseObeseObese ObeseObese
LowVAT
HighVAT
LowVAT
HighVAT
VAT: visceral adipose tissueVAT: visceral adipose tissue
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Relationships between LDL particle size vs triglycerides,HDL cholesterol and cholesterol/HDL cholesterol ratio
LDL particle size (Å)
235 240 245 250 255 260 265 270
Triglycerides(mmol/l)
0
1.0
2.0
3.0
4.0
5.0r=-0.52p<0.0001p<0.0001
235 240 245 250 255 260 265 270 235 240 245 250 255 260 265 270
Chol/HDL chol
2.0
4.0
6.0
8.0
10.0
0
0.5
1.0
1.5
2.0
2.5
HDL cholesterol(mmol/l)
r=0.44p<0.0001p<0.0001
r=-0.45p<0.0001p<0.0001
LDL particle size (Å) LDL particle size (Å)
From Després JPFrom Després JPAnn Med (2001) 33:534-541Ann Med (2001) 33:534-541
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The small dense LDL is a key component of the metabolic syndrome
The small dense LDL is a key component of the metabolic syndrome
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ApoB, proportion of small LDL and the risk of IHD
ApoB, proportion of small LDL and the risk of IHD
3.9(<0.001)
3.9(<0.001)
5.9(<0.001)
5.9(<0.001)
1.01.02.0
(0.12)2.0
(0.12)
< 116< 116 > 116> 116< 40%< 40%
> 40%> 40%1.01.0
2.02.0
3.03.0
4.04.0
5.05.0
6.06.0
ApoB (mg/dl)ApoB (mg/dl)
RR of IHDRR of IHD
LDL < 255 ALDL < 255 A
St-Pierre et al, Circulation 2001St-Pierre et al, Circulation 2001
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Apo B, LDL Diameter and CHD Risk Quebec Apo B, LDL Diameter and CHD Risk Quebec Cardiovascular StudyCardiovascular Study
2.00
0
1
2
3
4
5
6
7
>25.64 25.64
<120 mg/dL
120 mg/dLLDL peak particle
diameter (nm)
Odds Ratio for CHD
Apo B
6.20
Lamarche B, et al. Circulation. 1997;95:69-75.
1.001.00
Larger
LDLSmaller
LDL
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MMetabolietabolicc s syyndrndroommee Android Android obesityobesity AtherogenAtherogenicic dyslipidaemia dyslipidaemia
TG > 1,7; HDL-C < 1 mmol/l ; „small-dense”, oxidized LDL ; apo B >TG > 1,7; HDL-C < 1 mmol/l ; „small-dense”, oxidized LDL ; apo B > 1,2 g/L1,2 g/L HypertensioHypertensionn Inzulin resistance / HyperinsulinaemiaInzulin resistance / Hyperinsulinaemia
(FG, IGT, „clamp”, inzulin level, HOMA(FG, IGT, „clamp”, inzulin level, HOMA
PPro-inflammatory state ro-inflammatory state ESR; WBC; hsCRP > 5 mg/LESR; WBC; hsCRP > 5 mg/L
Prothrombotic state Prothrombotic state Lp(a) > 40 mg/dL; fibr.:3,85 g/L; PAI-1, tPaLp(a) > 40 mg/dL; fibr.:3,85 g/L; PAI-1, tPa
MicroalbuminuriaMicroalbuminuria Microvascular anginaMicrovascular angina
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DCEM/2001DCEM/2001
OBESITY
volumeoverload
pressureoverload
ARTERIALHYPERTENSION
sympatheticactivity
vascularhypertrophy
Na+
retention
peripheralinsulin-resistance
abdominal fat
insulin secretion
release of Free Fatty Acids
type 2diabetes
dyslipidemiahyperinsulinemiahyperinsulinemia
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MMetabolietabolicc s syyndrndroommee Android Android obesityobesity AtherogenAtherogenicic dyslipidaemia dyslipidaemia
TG > 1,7; HDL-C < 1 mmol/l ; „small-dense”, oxidized LDL ; apo B >TG > 1,7; HDL-C < 1 mmol/l ; „small-dense”, oxidized LDL ; apo B > 1,2 g/L1,2 g/L HypertensioHypertensionn Inzulin resistance / HyperinsulinaemiaInzulin resistance / Hyperinsulinaemia
(FG, IGT, „clamp”, inzulin level, HOMA)(FG, IGT, „clamp”, inzulin level, HOMA)
PPro-inflammatory state ro-inflammatory state ESR; WBC; hsCRP > 5 mg/LESR; WBC; hsCRP > 5 mg/L
Prothrombotic state Prothrombotic state Lp(a) > 40 mg/dL; fibr.:3,85 g/L; PAI-1, tPaLp(a) > 40 mg/dL; fibr.:3,85 g/L; PAI-1, tPa
MicroalbuminuriaMicroalbuminuria Microvascular anginaMicrovascular angina
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Central Obesity: The Metabolic Syndrome
(CETP)
VLDL-apoB Intra-abdominal fat
Insulin resistance
Free fatty acids Hepatic Lipase
TG
Small, dense LDL
HDL/HDL2
Brunzell 2001
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Obesity
Primary (Genetic)Insulin Resistance
ElevatedBlood Pressure
AtherogenicDyslipidemia
ElevatedGlucose
Pro-thrombotic
State
Pro-inflammatory
State
PhysicalInactivity
WHO
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Risk of Major CHD Event Associated with High Risk of Major CHD Event Associated with High Insulin Levels in Non-diabetic MenInsulin Levels in Non-diabetic Men
Q1 to Q5 = quintiles of area under the curve (AUC) insulin (Q1=lowest quintile; Q5=highest quintile).
Years
Proportion with a major CHD
event
00
5
0.05
0.10
0.15
0.20
0.25
1.00
10 15 20 25
Log rank:Overall P = .001Q5 vs Q1 P < .001
Q1
Q2
Q3Q4Q5
Pyörälä M et al. Circulation 1998;98:398–404.
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Central Obesity: The Metabolic Syndrome
(CETP)
VLDL-apoB Intra-abdominal fat
Insulin resistance
Free fatty acids Hepatic Lipase
TG
Small, dense LDL
HDL/HDL2
Brunzell 2001
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Ser/Thr phosphorylation of the IRS molecules induces insulin resistanceLe Roith et al., Diabetes Care 24:588 (2001)
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Mechanism of fatty acid-induced insulin resistance in skeletal muscle
as proposed by Randle et al.Shulman, J Clin Invest
106:171, 2000
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FFA
FA
VLDL
DNL
Adipose tissue
Muscle
Liver
Intestine
TG mobilizationby tissue lipases
TG, CEApoB
Cytosolic TGstores
Oxidation
Lipases
LPL
Mechanisms of VLDL-apoB overproduction Mechanisms of VLDL-apoB overproduction in Insulin Resistancein Insulin Resistance
Hepatic Insulin Resistance
Adeli K. et al. (2000) J. Biol. Chem. 275: 8416-8425.Adeli K. et al. (2002) J. Biol. Chem. 277:793-803.
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Atherogenic LipoproteinPhenotype
Predisposing factors
Atherogenicpotential
CentralobesityMalesex
LiverfatInsulinresistanceLowadiponectinDiet
VLDL
Chylos
Chyloremnants
Small,denseLDL
OxidisedLDL
Small,denseHDL
HDL
Highhepatic lipase
Thrombosis
Macrophagecholesterol
Inflammation
Artery wallretention
Reverse cholesteroltransportAnti-inflammatoryactions
Dyslipidemia in Metabolic Syndrome
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Insulin resistance related to dyslipidemia Insulin resistance related to dyslipidemia and cardiovascular diseaseand cardiovascular diseaseGinsberg, J Clin Invest 106:453, 2000Ginsberg, J Clin Invest 106:453, 2000
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IRS and StressIRS and Stress
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Fatty acid-level elevating psychosocial stressors: Type A personality, anxiety, Fatty acid-level elevating psychosocial stressors: Type A personality, anxiety, depression, hostility, job demand, vital exhaustion, differences in income depression, hostility, job demand, vital exhaustion, differences in income
HemHemingway et al.,BMJ 318:1460 (1999)ingway et al.,BMJ 318:1460 (1999)
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Hopelessness in a healthy population (Kuopio)
Everson SA & al Psychosom Med 1996;58:113
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Degree of depression and CHD mortality
Lespérance F & al.Circulation 2002;105:1049
BDI=Beck Depression Inventory
P=0.01
P<0.001
P<0.001
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AdiposeAdiposeTissueTissue LiverLiver
CytokinesCytokinesUnstableUnstable PlaquesPlaques
CRPCRP
Proinflammatory State
Apo BHDL Prothrombotic
State
Diabetes
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The Metabolic Syndrome
Dysregulation of adipocytokinesPortal FFA↑ Adiponectin↓
Insulin resistanceLipoprotein synthesis ↑
PAI-1 ↑Adiponectin↓
HypertensionImpaired glucose tolerance
Hyperlipidemia
?
Environmental Factors Genetic Factors
Atherosclerosis
Visceral Fat Accumulation
TNF- ↑
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Atherogenic dyslipidemia Triglycerides
HDL-cholesterol Cholesterol/HDL-cholesterol ratio
«Normal» LDL-cholesterol but apo BSmall, dense LDL and HDLPostprandial hyperlipidemia
Insulin resistanceInsulin resistanceHyperinsulinemiaHyperglycemiaType 2 diabetes
Thrombotic state PAI-1
Fibrinogen
Inflammatory state CRP
Cytokinesrisk of acute
coronary syndromeMetabolic risk factorsAbdominal obesity
Inflammation
Lipid coreThin fibrous cap
CORONARY ATHEROSCLEROSISUNSTABLE PLAQUE
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The metabolic syndrome … close to a consensusThe metabolic syndrome … close to a consensus
Visceral obesity Insulin
resistance
Insulin
TG HDL
Adiponectin
Small, dense LDL CRP
The core componentsPathophysiology
The common form of themetabolic syndrome: high-risk visceral obesity
The common form of themetabolic syndrome: high-risk visceral obesity
CVDCVDDiabetesDiabetes
HypertensionHypertension
The definition:
The corescreening tools
+• NCEP-ATP III• AHA, ADA, EASD• IDF• Hypertriglyceridemic waist
• NCEP-ATP III• AHA, ADA, EASD• IDF• Hypertriglyceridemic waist
The clinical identification:
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Visceral obesity Insulin
resistance
Insulin
METABOLICSYNDROME
Thrombosis
Inflam-mation
ApoBDense LDL
TG HDL
Blood pressure
GLOBAL CARDIOMETABOLIC RISKGLOBAL CARDIOMETABOLIC RISK
Smoking
Dyslipidemicstates not
related to MS* Hypertension*Age
Male sex
DiabetesDiabetes Cardiovascular diseaseCardiovascular disease
Diabetes Impaired fastingglucose
Global Cardiometabolic Risk:Total Long-Term and
Short Term (10-yr) Risk forT2DM and CVD
LDL HDL
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Deteriorated
Impaired
Impaired
Improved
Improved
Improved
Lipid profile
Insulin sensitivityInsulinemiaGlycemia
Susceptibilityto thrombosis
Inflammationmarkers
Endothelialfunction
CHD Risk LowHigh
DietPhysical activity
Pharmacotherapy
AbdominallyobeseHigh waist
Reducedobese
Low waist
~10% Weight loss~ 30 Visceral AT loss
Visceraladiposetissue
Visceraladiposetissue
Subcutaneous AT
Adapted from Després et al.BMJ (2001) 322:716-720
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