METABOLIC SYNDROME Lajos Szollár Professor of Pathophysiology Semmelweis University, Faculty of...

METABOLICMETABOLIC SYNDROMESYNDROME

Lajos Lajos SzollárSzollárProfessor of PathophysiologyProfessor of Pathophysiology

Semmelweis University, Semmelweis University, Faculty of MedicineFaculty of Medicine

Institute of PathophysiologyInstitute of Pathophysiology20072007

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.

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

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.

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

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.

http://www.idf.org/webdata/docs/IDF_Metasyndrome_definition.pdf.%20Accessed%20February%2026

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

http://www.idf.org/

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)

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

MetS

CVDT2DM

5x 2x

3x

Relative Risk

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

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?

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

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

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.

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

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

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

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

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

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

InsulinResistance

Dysregulationof Risk Factor

Parameters

ElevatedBlood Pressure

AtherogenicDyslipidemia

ElevatedGlucose

Pro-thrombotic

State

Pro-inflammatory

State

Obesity

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

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

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

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

Intra-abdominal (visceral) fatIntra-abdominal (visceral) fatThe dangerous inner fat!

BackBack

Visceral AT

Subcutaneous AT

FrontFront

Fat mass : 19.8 kg

VAT : 155 cm2

Fat mass : 19.8 kg

VAT : 96 cm2

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

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

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)

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

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

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

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

Metabolic abnormalities associated with Metabolic abnormalities associated with abdominal obesityabdominal obesity

• Insulin resistanceInsulin resistance• DyslipidaemiaDyslipidaemia• Mild hypertensionMild hypertension• InflammationInflammation

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

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

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%

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

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

The small dense LDL is a key component of the metabolic syndrome

The small dense LDL is a key component of the metabolic syndrome

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

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

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



(FG, IGT, „clamp”, inzulin level, HOMA)(FG, IGT, „clamp”, inzulin level, HOMA)





(CETP)


Insulin resistance


TG

Small, dense LDL

HDL/HDL2

Brunzell 2001

Obesity

Primary (Genetic)Insulin Resistance

ElevatedBlood Pressure

AtherogenicDyslipidemia

ElevatedGlucose

Pro-thrombotic

State

Pro-inflammatory

State

PhysicalInactivity

WHO

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.


(CETP)


Insulin resistance


TG

Small, dense LDL

HDL/HDL2

Brunzell 2001

Ser/Thr phosphorylation of the IRS molecules induces insulin resistanceLe Roith et al., Diabetes Care 24:588 (2001)

Mechanism of fatty acid-induced insulin resistance in skeletal muscle

as proposed by Randle et al.Shulman, J Clin Invest

106:171, 2000

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.

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

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

IRS and StressIRS and Stress

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)

Hopelessness in a healthy population (Kuopio)

Everson SA & al Psychosom Med 1996;58:113

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

AdiposeAdiposeTissueTissue LiverLiver

CytokinesCytokinesUnstableUnstable PlaquesPlaques

CRPCRP

Proinflammatory State

Apo BHDL Prothrombotic

State

Diabetes

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- ↑

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

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:

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

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

METABOLIC SYNDROME Lajos Szollár Professor of Pathophysiology Semmelweis University, Faculty of...

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Transcript of METABOLIC SYNDROME Lajos Szollár Professor of Pathophysiology Semmelweis University, Faculty of...