The Metabolic Syndrome:

A Network of Atherogenic Factors

Glycemic disorders

Dyslipidemia
- Low HDL

Atherosclerosis
Insulin -Small, dense LDL
- Hypertriglyceridemia
Resistance - Postprandial lipemia
Visceral
Obesity ↑ Free Fatty Hypertension
Acids
Impaired thrombolysis
- ↑ PAI-1, fibrinogen

Endothelial dysfunction/
inflammation
Brunzell J, Hokanson J. Diabetes Care. 1999;22(Suppl 3):C10-C13.
McFarlane S, et al. J Clin Endocrinol Metab. 2001;86(2):713-718.
- ↑ CRP, MMP-9,
Frohlich M, et al. Diabetes Care. 2000;23(12):1835-1839. ↓adiponectin
Kuusisto J, et al. Circulation. 1995;91:831-837.
Parulkar AA, et al. Ann Intern Med. 2001;134:61-71.
Hseuh WA, et al. Diabetes Care. 2001;24(2):392-397.
Lebovitz H. Clin Chem. 1999;45(8B):1339-1345. Microalbuminuria
 Risk Factors and Defining Levels
of Metabolic Syndrome
Risk Factor Defining Level
Abdominal obesity Waist circumference
Men >102 cm (>40 in)
Women >88 cm (>35 in)
Triglycerides ≥150 mg/dL
HDL-C
Men <40 mg/dL
Women <50 mg/dL
Blood pressure ≥130/≥85 mm Hg
Fasting glucose ≥110 mg/dL

HDL-C = high-density lipoprotein cholesterol.

Reprinted with permission from NCEP ATP III. JAMA. 2001;285:2486-2497.
 Cardiovascular Mortality Associated
With Metabolic Syndrome

14
MS, 12
12
In cid en ce o f C V M o rtality

10

6 p < 0.001

4
No MS, 2.2
2

0
No MS MS

Diabetes Care 2001;24:683

 Cardiovascular Disease Mortality Is
Increased in the Metabolic Syndrome

15
Relative Risk = 3.55
Cumulative Hazard, %

10 Metabolic Syndrome

5 No Metabolic Syndrome

0 2 4 6 8 10 12
Follow-up, y

1209 Finnish men aged 42–60 y who were initially without cardiovascular disease, cancer, or diabetes.
Reprinted with permission from Lakka HM, et al. JAMA. 2002;288:2709-2716.
 y
negative impact on CV health and
mortality
No metabolic syndrome
25 Metabolic syndrome 25
* *p<0.001
20 20
*p<0.001 *

15 15

Mortality rate (%)

*
Prevalence (%)

10 * 10

5 * 5

0 0
CHD MI Stroke All-cause Cardiovascular
mortality mortality
Isomaa et al 2001
 Natural History of Insulin Resistance
y Age 15 – Acanthosis nigricans
y Age 23 – PCO insulin resistance, irregular period, hirsutism, obesity
y Age 25 – Dyslipidemia
y Age 30 – Gestational DM
y Age 35 – Hyperglycemia
y Age 40 – Diabetes
y Age 45 – HTN, DM, dyslipidemia, obesity
y Age 55 – Acute MI
y Age 58 – Renal insufficiency, renal failure
y Age 61 – Vision loss, neuropathy, toe amputation
y Age 62 – Claudication PVD, small CVAs
y Age 63 – CHF
 Prevalence of Metabolic
Syndrome in US Adults*
50 Men
45 W omen
40
35
Prevalence, %

30
25
20
15
10
5
0
20-29 30-39 40-49 50-59 60-69 ≥70
Age, y

* n=8814 US adults aged ≥20 years, by sex; National Health and Nutrition Examination
Survey III (NHANES III), 1988-1994. Overall prevalence is 24% (age-adjusted).
Reprinted with permission from Ford ES, et al. JAMA. 2002;287:356-359.
 Abdominal Adiposity:
The Critical Adipose Depot

Subcutaneous fat

Abdominal muscle
layer
Intra-abdominal fat

Is this correct?
Abdominal obesity: a major underlying
cause of acute myocardial infarction
Cardiometabolic risk factors in the InterHeart Study
60
49
Abdominal obesity predicts the
risk of CVD beyond BMI
PAR (%)a

40

20
18
20
10

0
Abn Lipids Abdom. HTN Diabetes
Obesity
aProportion of MI in the total population attributable to a specific risk factor
Yusuf et al 2004
 Abdominal obesity: required for
diagnosing the metabolic syndrome
IDF criteria of the metabolic syndrome
High waist circumference
Plus any two of
Ï Triglycerides (≥ 1.7 mmol/L [150 mg/dL])‡
Ð HDL cholesterol‡
– Men < 1.0 mmol/L (40 mg/dL)
– Women < 1.3 mmol/L (50 mg/dL)
Ï Blood pressure ≥ 130 / >85 mm Hg‡
Ï FPG (≥ 5.6 mmol/L [100 mg/dL]), or diabetes
‡or specific treatment for these conditions

International Diabetes Federation (2005)

 Unmet clinical need associated
with abdominal obesity
CV risk factors in a typical patient with abdominal obesity

Patients with
abdominal obesity
(high waist
circumference) often
present with one or
more additional
CV risk factors
 g
with multiple cardio vascular risk
factors
US population age >20 years
30
Prevalence of high waist

associated with (%)

20
circumference

10

0
Low High High High >2 risk
HDL-Ca TGb FPGc BPd factorse
a<40 mg/dL (men) or <50 mg/dL (women); b>150 mg/dL; c>110 mg/dL;
d>130/85 mmHg; eNCEP/ATP III metabolic syndrome

NHANES 1999–2000 cohort; data on file

 Abdominal obesity and waist
circumference thresholds
y New IDF criteria:

Men Women
Europid >94 cm (37.0 in) >80 cm (31.5 in)
South Asian >90 cm (35.4 in) >80 cm (31.5 in)
Chinese >90 cm (35.4 in) >80 cm (31.5 in)
Japanese >85 cm (33.5 in) >90 cm (35.4 in)

Current NCEP ATP-III criteria

>102 cm (>40 in) in men, >88 cm (>35 in) in women

NCEP 2002; International Diabetes Federation (2005)

 Effect of Waist Circumference
on Insulin Sensitivity
90 90 Women
Men

Glycemic Disposal Rate

Glycemic Disposal Rate

(R=0.65) (R=0.71)
75 75

(mmol/kg/min)
(mmol/kg/min)

60 60

45 45

30 30

15 15

0 0
27 31 35 39 43 47 23 27 31 35 39 43 47

Waist Circumference (inches) Waist Circumference (inches)

Diabetes 42: 273-281, 1993

 Abdominal obesity increases the
risk of developing type 2 diabetes
24

20

16
Relative risk

12

0
<71 71–75.9 76–81 81.1–86 86.1–91 91.1–96.3 >96.3
Waist circumference (cm)

Carey et al 1997
Central Adiposity
Insulin Resistance:
Associated Conditions
 g p
tissue:
an endocrine organ
Old View: inert storage depot Current View: secretory/endocrine organ

Fatty acids Glucose

Fed

Tg Multiple secretory
Tg products
Tg
Fasted Muscle

Fatty acids Glycerol

Liver Vasculature

Pancreas

Lyon CJ et al 2003
 Intra abdominal adiposity promotes
insulin resistance and increased CV
risk
Ï Secretion of
Ï Hepatic FFA flux metabolically active
(portal hypothesis) substances (adipokines)
Ï Intra-abdominal
Ð suppression of adiposity Ï PAI-1
lipolysis by insulin
Ð Adiponectin
Ï FFA
Ï IL-6
Ï TNFα
Ï Insulin resistance
Ï Dyslipidaemia Net result:
Ï Insulin resistance
Pro-atherogenic
Ï Inflammation

Heilbronn et al 2004; Coppack 2001;

Skurk & Hauner 2004
 Adverse cardiometabolic effects of
products of adipocytes
↑ Lipoprotein lipase Hypertension
↑ IL-6 ↑ Agiotensinogen
Inflammation
↑ Insulin Atherogenic
↑ FFA dyslipidaemia
↑ TNFα
Adipose
↑ Resistin
tissue
↑ Leptin
↑ Adipsin
(Complement D) ↑ Lactate
Type
↑ Plasminogen 2 diabetes
↓ Adiponectin
activator inhibitor-1
(PAI-1)
Atherosclerosis
Thrombosis
Lyon 2003; Trayhurn et al 2004; Eckel et al 2005
 Properties of key adipokines
Anti-atherogenic/antidiabetic:
Adiponectin
↓ in IAA ↓ foam cells ↓ vascular remodelling
↑ insulin sensitivity ↓ hepatic glucose output
Pro-atherogenic/pro-diabetic:
IL-6
↑ in IAA ↑ vascular inflammation ↓ insulin signalling

Pro-atherogenic/pro-diabetic:
TNFα
↑ in IAA ↓ insulin sensitivity in adipocytes (paracrine)

PAI-1 Pro-atherogenic:
↑ in IAA ↑ atherothrombotic risk

IAA: intra-abdominal adiposity

Marette 2002
 gg
adiposity and FFA in insulin
resistance
Ï Hepatic Ï Hepatic
Ï Small,
Intra insulin glucose
output dense
abdominal resistance Lipolysis
adiposity LDL-C

Ï TG-rich
Portal
circulation
Ï FFA VLDL-C
CETP, Low
lipolysis HDL-C

Systemic
circulation Ð Glucose utilisation
FFA: free fatty acids
CETP: cholesteryl ester Ï Insulin resistance
transfer protein

Lam et al 2003; Carr et al 2004; Eckel et al 2005

 Intra abdominal adiposity impairs
pancreatic β-cell function
Ï FFA
Splanchnic & systemic
circulation

Intra abdominal
adiposity

Short-term Long-term damage

stimulation to β-cells
of insulin Decreased insulin
secretion secretion
FFA: Free fatty acids
Haber et al 2003; Zraika et al 2002
 Intra-abdominal adiposity and
dyslipidaemia
Triglycerides HDL-cholesterol
310 60
248
186
45
124

62
mg/dL
mg/dL

0 30
Lean Low High Lean Low High
Visceral fat Visceral fat
(obese subjects) (obese subjects)

Pouliot et al 1992
Lipoprotein Subclasses
 Same LDL-C Levels,
Different Cardiovascular Risk
Large LDL Small, Dense LDL
LDL=
130 mg/dL
Apo B More Apo B

Cholesterol
Ester

Fewer Particles More Particles

Correlates with: Correlates with:
TC 198 mg/dL TC 210 mg/dL
LDL-C 130 mg/dL LDL-C 130 mg/dL
TG 90 mg/dL TG 250 mg/dL
HDL-C 50 mg/dL HDL-C 30 mg/dL
Non-HDL-C 148 mg/dL Non-HDL-C 180 mg/dL
Otvos JD, et al. Am J Cardiol. 2002;90:22i-29i.
LDL Particle Size and Concentration
 Meta-analysis: Predictive Value of
HDL Cholesterol
CPPT: Coronary Primary Prevention Trial
LRCF: Lipid Research Clinics Prevalence Mortality
Follow-up Study
MRFIT: Multiple Risk Factor Intervention Trial
FHS: Framingham Heart Study

2% risk 3% risk
1 mg/dl
in men in women
decrease
FHS
FHS, CPPT, MRFIT in HDL-C
 Intra-abdominal adiposity and
glucose metabolism
Glucose Insulin
1 1,2
15 1200 1,2 1,2

Area
Area
12 1 1,2
1 1 1,2 1,2
9 1,2 800
1 1
1 1,2
mmol/L

1 1 1,2
6

pmol/L
400 1,2
3 1,2

0 0
0 60 120 180 0 60 120 180
Time (min) Time (min)

Non-obese Obese low IAA OObese high IAA

IAA: intra-abdominal adiposity

Significantly different from 1non-obese, 2obese with low intra-abdominal adiposity
levels
Pouliot et al 1992
 Blood Pressure and CVD
Women
180 Men

Age-adjusted CV Event Rate/1,000

174 113
180
Age-adjusted CV Event Rate/1,000

160
160
140 140
119 74
120 120
100 90 100 56
77 48
80 80
59 36
60 50 60 31
38 23
40 24 40 15
20 20
0 0
105 135 165 195 105 135 165 195

Systolic BP (mmHg) Systolic BP (mmHg)

No Glucose Intolerance
Glucose Intolerance

Am Heart J 121: 1268-1273, 1991

JNC VII
 p
Cardiovascular Disease
Mortality
 Multiple cardiovascular risk factors
drive adverse clinical outcomes

Increased Cardiometabolic Risk

Dyslipidaemia Abdominal Glucose intolerance

Hypertension obesity Insulin resistance

Metabolic Syndrome
 Metabolism of
homocysteine
Doshi, S. N. et al. Cardiovasc Res 1999 42:578-582
 Metabolic Other
Obesity Derangement Causes

Cardiovascular Disease Metabolic Disease

Coronary heart disease
Stroke
Peripheral arterial disease
Congestive heart failure
Chronic renal disease
Arrhythmia
Diabetes
Prediabetes
Fatty liver disease
Cholesterol gallstones
Polycystic ovarian
syndrome
Obstructive sleep apnea
 Systemic inflammation and
adverse cardiovascular outcomes
Physicians' Health Study: 9-year follow-up

5
4.4
Relative risk of MI

4
2.8
3.4
3
2.5 2.8
2 1.3
1.1
1 1.2
1.0 High
0 Medium
Low C RP
Low Medium High -
hs
Cholesterol/HDL cholesterol ratio

Ridker et al 1998
 Cardiometabolic
Visceral
↑ Insulin Risk
obesity
Insulin
resistance
(ADA MCR Initiative)
↑ ApoB
↑ TG
Dense
↓ HDL
LDL
Insulin ÇLDL Hyper Age
Inflam- Diabetes Smoking Male sex
Resistance IFG ÈHDL tension*
mation
Syndrome

Thromb- ↑ BP
osis

GLOBAL CARDIOMETABOLIC RISK

Diabetes Cardiovascular disease
 Insulin resistance and CHD:
Proposed relationships
Genetic Environmental
influences Insulin resistance influences

Glucose Lipid
Hypertension Hemostatic
metabolism metabolism

Glucose • ↑ TG • ↑ SNS activity • ↑ PAI-1

intolerance • ↑ PP lipemia • ↑ Na retention • ↑ Fibrinogen
• ↓ HDL-cholesterol • Hypertension
• Small, dense LDL

Coronary heart disease Adapted from Reaven GM.

N Engl J Med. 1996;334:374-381..

TG = triglycerides; PP = postprandial; SNS = sympathetic nervous system;

Na = sodium; PAI-1 = plasminogen activator inhibitor type 1
 Unifying model:
Endothelial dysfunction to CVD
Risk factors: Dyslipidemia ↑ BP Diabetes Smoking

Oxidative stress

Endothelial dysfunction

↓ NO • ↑ Local mediators • ↑ Tissue ACE leading to ↑ Angiotensin II

PAI-1 VCAM Endothelin Growth Proteolysis

ICAM cytokines factors matrix

Thrombosis Inflammation Vasoconstriction Vascular lesion Plaque rupture

and remodeling

Clinical sequelae
Gibbons GH, Dzau VJ. N Engl J Med. 1994;330:1431-1438.
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