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ATHEROGENESIS_Risk Factors

ATHEROGENESIS_Risk Factors

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The Metabolic Syndrome: A Network of Atherogenic Factors

Glycemic disorders Dyslipidemia
- Low HDL

Atherosclerosis

Visceral Obesity

Insulin Resistance ↑ Free Fatty Acids

-Small, dense LDL - Hypertriglyceridemia - Postprandial lipemia

Hypertension 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. Frohlich M, et al. Diabetes Care. 2000;23(12):1835-1839. 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.

- ↑ CRP, MMP-9, ↓adiponectin

Microalbuminuria

Risk Factors and Defining Levels of Metabolic Syndrome
Risk Factor Abdominal obesity Men Women Triglycerides HDL-C Men Women Blood pressure Fasting glucose
HDL-C = high-density lipoprotein cholesterol. Reprinted with permission from NCEP ATP III. JAMA. 2001;285:2486-2497.

Defining Level Waist circumference >102 cm (>40 in) >88 cm (>35 in) ≥150 mg/dL <40 mg/dL <50 mg/dL ≥130/≥85 mm Hg ≥110 mg/dL

Cardiovascular Mortality Associated With Metabolic Syndrome
14 In cid en ce o f C V M o rtality 12 10 8 6 4 2 0 No MS MS
Diabetes Care 2001;24:683

MS, 12

p < 0.001
No MS, 2.2

Cardiovascular Disease Mortality Is Increased in the Metabolic Syndrome
15 Cumulative Hazard, %

Relative Risk = 3.55
10

Metabolic Syndrome

5

No Metabolic Syndrome

0 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.

negative impact on CV health and mortality
25
No metabolic syndrome Metabolic syndrome

25 20 15
*p<0.001

*
20 15
Prevalence (%) *p<0.001 Mortality rate (%)

*

*
10 5 0

10 5 0
CHD
Isomaa et al 2001

* *

MI

Stroke

All-cause mortality

Cardiovascular mortality

Natural History of Insulin Resistance
Age 15 – Acanthosis nigricans Age 23 – PCO insulin resistance, irregular period, hirsutism, obesity Age 25 – Dyslipidemia Age 30 – Gestational DM Age 35 – Hyperglycemia Age 40 – Diabetes Age 45 – HTN, DM, dyslipidemia, obesity Age 55 – Acute MI Age 58 – Renal insufficiency, renal failure Age 61 – Vision loss, neuropathy, toe amputation Age 62 – Claudication PVD, small CVAs Age 63 – CHF

Prevalence of Metabolic Syndrome in US Adults*
50 45 40 35 30 25 20 15 10 5 0 Men W omen

Prevalence, %

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

PAR (%)a

40

Abdominal obesity predicts the risk of CVD beyond BMI

20

20

18 10

0 Abn Lipids
aProportion

Abdom. Obesity

HTN

Diabetes

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 Triglycerides (≥ 1.7 mmol/L [150 mg/dL])‡ HDL cholesterol‡
– Men – Women < 1.0 mmol/L (40 mg/dL) < 1.3 mmol/L (50 mg/dL)

Blood pressure ≥ 130 / >85 mm Hg‡ 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

with multiple cardio vascular risk factors
US population age >20 years
30 Prevalence of high waist circumference associated with (%) 20 10 0

Low HDL-Ca

High TGb

High FPGc

High BPd
mg/dL;

>2 risk factorse

a<40 mg/dL (men) or <50 mg/dL (women); b>150 mg/dL; c>110 d>130/85 mmHg; eNCEP/ATP III metabolic syndrome

NHANES 1999–2000 cohort; data on file

Abdominal obesity and waist circumference thresholds
New IDF criteria:
Men
Europid South Asian Chinese Japanese >94 cm (37.0 in) >90 cm (35.4 in) >90 cm (35.4 in) >85 cm (33.5 in)

Women
>80 cm (31.5 in) >80 cm (31.5 in) >80 cm (31.5 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

Glycemic Disposal Rate (mmol/kg/min)

75 60 45 30 15 0 27 31 35 39

Glycemic Disposal Rate (mmol/kg/min)

Men (R=0.65)

90 75 60 45 30 15 0

Women (R=0.71)

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 Relative risk 16 12 8 4 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

tissue: an endocrine organ
Old View: inert storage depot
Fatty acids Glucose

Current View: secretory/endocrine organ

Fed Tg Tg
Fasted Fatty acids Glycerol
Multiple secretory products Muscle

Tg

Liver Pancreas

Vasculature

Lyon CJ et al 2003

Intra abdominal adiposity promotes insulin resistance and increased CV risk
Secretion of Hepatic FFA flux metabolically active (portal hypothesis) substances (adipokines) Intra-abdominal adiposity PAI-1 suppression of
lipolysis by insulin FFA

Adiponectin IL-6 TNFα Net result: Insulin resistance Inflammation

Insulin resistance Dyslipidaemia
Pro-atherogenic
Heilbronn et al 2004; Coppack 2001; Skurk & Hauner 2004

Adverse cardiometabolic effects of products of adipocytes
↑ Lipoprotein lipase

Hypertension
↑ Insulin

Inflammation
↑ TNFα

↑ IL-6

↑ Agiotensinogen ↑ FFA ↑ Resistin ↑ Leptin ↑ Lactate ↑ Plasminogen activator inhibitor-1 (PAI-1)

Adipose

Atherogenic dyslipidaemia

tissue

↑ Adipsin (Complement D) ↓ Adiponectin

Type 2 diabetes

Atherosclerosis

Thrombosis

Lyon 2003; Trayhurn et al 2004; Eckel et al 2005

Properties of key adipokines
Adiponectin
↓ in IAA

Anti-atherogenic/antidiabetic:
↓ foam cells ↓ vascular remodelling ↑ insulin sensitivity ↓ hepatic glucose output

IL-6
↑ in IAA

Pro-atherogenic/pro-diabetic:
↑ vascular inflammation ↓ insulin signalling

TNFα
↑ in IAA

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

PAI-1
↑ in IAA

Pro-atherogenic:
↑ atherothrombotic risk

IAA: intra-abdominal adiposity Marette 2002

adiposity and FFA in insulin resistance
Intra abdominal adiposity
Portal circulation

Hepatic insulin resistance

Hepatic glucose output

Lipolysis

Small, dense LDL-C

FFA

TG-rich VLDL-C
CETP, lipolysis

Low HDL-C

Systemic circulation FFA: free fatty acids CETP: cholesteryl ester transfer protein

Glucose utilisation

Insulin resistance

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

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

Short-term stimulation of insulin secretion
FFA: Free fatty acids Haber et al 2003; Zraika et al 2002

Long-term damage to β-cells Decreased insulin secretion

Intra-abdominal adiposity and dyslipidaemia
Triglycerides
310 248 186 124 45 60

HDL-cholesterol

mg/dL

mg/dL

62 0

30

Lean

Low High Visceral fat (obese subjects)

Lean

Low High Visceral fat (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 Cholesterol Ester More Apo B

Fewer Particles
Correlates with: TC 198 mg/dL LDL-C 130 mg/dL TG 90 mg/dL HDL-C 50 mg/dL Non-HDL-C 148 mg/dL

More Particles
Correlates with: TC 210 mg/dL LDL-C 130 mg/dL TG 250 mg/dL HDL-C 30 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 1 mg/dl decrease in HDL-C 3% risk in women
FHS

2% risk in men
FHS, CPPT, MRFIT

Intra-abdominal adiposity and glucose metabolism
Glucose
12 9 mmol/L 6 3 0 0 60 120 Time (min)
Non-obese
1 1

Insulin
1

1

1

Area

1
1,2

1

800 pmol/L
1 1

1,2

1,2

1,2 1,2 1,2

1,2

400
1,2

180
Obese low IAA

0
0 60 120 Time (min) 180

OObese high IAA

IAA: intra-abdominal adiposity Significantly different from 1non-obese, 2obese with low intra-abdominal adiposity levels Pouliot et al 1992

Area

15

1200

1,2 1,2

1,2

Blood Pressure and CVD
Age-adjusted CV Event Rate/1,000
174

Age-adjusted CV Event Rate/1,000

180 160 140 120 100 80 60 40 20 0
50 24

Men

Women

180 160 140 120 100 80 60 40 20 0

113

119 90 77 59 38

74 48 31 15 105 36 23 56

105

135

165

195

135

165

195

Systolic BP (mmHg)

Systolic BP (mmHg)

No Glucose Intolerance Glucose Intolerance

Am Heart J 121: 1268-1273, 1991

JNC VII

Cardiovascular Disease Mortality

Multiple cardiovascular risk factors drive adverse clinical outcomes
Increased Cardiometabolic Risk

Dyslipidaemia Hypertension

Abdominal obesity

Glucose intolerance Insulin resistance

Metabolic Syndrome

Metabolism of homocysteine
Doshi, S. N. et al. Cardiovasc Res 1999 42:578-582

Obesity

Metabolic Derangement

Other Causes

Cardiovascular Disease
Coronary heart disease Stroke Peripheral arterial disease Congestive heart failure Chronic renal disease Arrhythmia

Metabolic Disease
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
2.8 1.3 1.1

Relative risk of MI

4 3 2 1 0

3.4

2.5

2.8

1.0
Low

1.2
Medium High

High Medium RP Low s-C h

Cholesterol/HDL cholesterol ratio
Ridker et al 1998

Visceral obesity Insulin resistance

↑ Insulin

Cardiometabolic Risk (ADA MCR Initiative)

↑ ApoB Dense LDL

↑ TG ↓ HDL

Insulin InflamResistance mation Syndrome
Thrombosis
↑ BP

IFG

Diabetes

LDL HDL

Hyper tension*

Smoking

Age Male sex

GLOBAL CARDIOMETABOLIC RISK
Diabetes Cardiovascular disease

Insulin resistance and CHD: Proposed relationships
Genetic influences
Insulin resistance

Environmental influences

Glucose metabolism Glucose intolerance

Lipid metabolism • ↑ TG • ↑ PP lipemia • ↓ HDL-cholesterol • Small, dense LDL

Hypertension

Hemostatic

• ↑ SNS activity • ↑ Na retention • Hypertension

• ↑ PAI-1 • ↑ Fibrinogen

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
Oxidative stress Diabetes Smoking

Endothelial dysfunction

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

PAI-1

VCAM ICAM cytokines

Endothelin

Growth factors matrix

Proteolysis

Thrombosis

Inflammation

Vasoconstriction

Vascular lesion and remodeling

Plaque rupture

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

THANK YOU
KNOW TO PREVENT DISEASE DEATH AND SUFFERING

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