Hispanics

African Americans

Caucasians

Whole

0 10 20 30 40 50 60WomenMen Prevalence of CVD (%)

Prevalence of Cardiovascular Disease by Race

American Heart Association

2002 200532

33

34

35

36

37

38

MenWomen

Year

Prev

alen

ce o

f CVD

(%)

Prevalence of Cardiovascular Disease

American Heart Association

CleanArteryCleanArtery

Fatty SteaksFatty

Steaks

Fibrous PlaqueFibrous Plaque

Clinical LesionClinical Lesion

NATURAL HISTORY OF ATHEROSCLEROSISNATURAL HISTORY OF ATHEROSCLEROSIS

Lumen

Subendothelial Space

NOL-arginineO2

NADPH

Lumen

↑NO

↑NO

Subendothelial Space

eNOS

BH4

PI-3 kinase

Blood FlowInsulinAcetylcholine

Anti-AdhesionAnti-CoagulationFibrinolysis

Vasodilation

Nitric Oxide

NOL-arginineO2

NADPH

Lumen

↑NO

↑NO

Subendothelial Space

eNOS

BH4

PI-3 kinase

Blood FlowInsulinAcetylcholine

Anti-AdhesionAnti-CoagulationFibrinolysis

Vasodilation

Oxidative Stress

O2-

ONOO-

NOL-arginineO2

NADPH

↓NO

Subendothelial Space

eNOS

BH4

PI-3 kinase

Blood FlowInsulinAcetylcholine

Anti-AdhesionAnti-CoagulationFibrinolysis

Vasodilation

Oxidative Stress

O2-

↓NO

ONOO-

NOL-arginineO2

NADPH

↓NO

Subendothelial Space

eNOS

BH4

PI-3 kinase

Blood FlowInsulinAcetylcholine

Anti-AdhesionAnti-CoagulationFibrinolysis

Vasoconstriction

Oxidative Stress

O2-

↓NO

ONOO-

NOL-arginineO2

NADPH

↓NO

Subendothelial Space

eNOS

BH4

PI-3 kinase

Blood FlowInsulinAcetylcholine

Anti-AdhesionAnti-CoagulationFibrinolysis

Vasoconstriction

Oxidative Stress

O2-

↓NO

ONOO-

O2-

ENDOTHELIAL FUNCTIONENDOTHELIAL FUNCTIONVASODILATIONVASODILATION

VASODILATIONVASODILATION

VASODILATIONVASODILATION

Shear Stress

PI-3-KinasePI-3-Kinase

OxygenL-ArginineNADPH

OxygenL-ArginineNADPH

Nitric

Oxide

Nitric

Oxide

eNOSeNOS

CofactorsCofactors

VASODILATIONVASODILATION

Shear Stress

PI-3-KinasePI-3-Kinase

OxygenL-ArginineNADPH

OxygenL-ArginineNADPH

Nitric

Oxide

Nitric

Oxide

eNOSeNOS

CofactorsCofactors

NONO

i

cGMP

↓Ca++

ARTERIAL HEALTHARTERIAL HEALTH

Flow-Mediated DilationFlow-Mediated Dilation

Pre

ARTERIAL HEALTHARTERIAL HEALTH

Flow-Mediated Dilation = 8%Flow-Mediated Dilation = 8%

PrePre Post

4.1 mm4.1 mm 4.7 mm4.7 mm

Series10

1

2

3

4

5

6

7

8

9

10

Healthy

Aging

Heart Disease

Visceral Fat

Diabetes

HypertensionFM

D (

%)

Faulx, et al, American Heart Journal 145:943-951, 2003

Iiyama, et al. American Heart Journal 132:779-782, 1996

Hashimoto, et al. International Journal of Obesity: Relar Metab Disord 22:477-484, 1998.

Caballero, A.E., Obesity Research 11:1278-1289, 2003.

Celermajer,et al. J Am Coll Cardiol 24:471-476, 1994.

Faulx, et al, American Heart Journal 145:943-951, 2003

Iiyama, et al. American Heart Journal 132:779-782, 1996

Hashimoto, et al. International Journal of Obesity: Relar Metab Disord 22:477-484, 1998.

Caballero, A.E., Obesity Research 11:1278-1289, 2003.

Celermajer,et al. J Am Coll Cardiol 24:471-476, 1994.

02468

1012141618

FMD (%)

Men

Women

Children

Hasimoto, et al. Circulation 92:3431-3435, 1995.Hasimoto, et al. Circulation 92:3431-3435, 1995.

Apparently HealthyApparently Healthy

0

2

4

6

8

10

12

FMD (%)Normal Weight

Obese

Woo, et al, International Journal of Obesity 28:852-857, 2004Woo, et al, International Journal of Obesity 28:852-857, 2004

ChildrenChildren

0

2

4

6

8

10

12

20 30 40 50 60 65 70

Years

FMD (%)Men

Women

Celermajer,et al. J Am Coll Cardiol 24:471-476, 1994.Celermajer,et al. J Am Coll Cardiol 24:471-476, 1994.

AgingAging

0123456789

FMD (%)Normal

Subcutaneuous

Visceral Fat

Hashimoto, et al. International Journal of Obesity: Relar Metab Disord 22:477-484, 1998. Hashimoto, et al. International Journal of Obesity: Relar Metab Disord 22:477-484, 1998.

Overweight & ObesityOverweight & Obesity

0

5

10

15

20

Normal BloodPressure

High BloodPressure

Iiyama, et al. American Heart Journal 132:779-782, 1996Iiyama, et al. American Heart Journal 132:779-782, 1996

HypertensionHypertension

0

2

4

6

8

10

12

14

FMD (%)

Normal

GlucoseIntolerance

Diabetes

Caballero, A.E., Obesity Research 11:1278-1289, 2003.Caballero, A.E., Obesity Research 11:1278-1289, 2003.

DiabetesDiabetes

NOL-arginineO2

NADPH

Lumen

↑NO

↑NO

Subendothelial Space

eNOS

BH4

PI-3 kinase

Blood FlowInsulin ResistanceAcetylcholine

Anti-AdhesionAnti-CoagulationFibrinolysis

Vasodilation

NOL-arginineO2

NADPH

Lumen

Subendothelial Space

eNOS

BH4

PI-3 kinase

Blood FlowInsulinAcetylcholine ↓NO

Anti-AdhesionAnti-CoagulationFibrinolysis

↑NO

Vasodilation

NOL-arginineO2

NADPH

Lumen

Subendothelial Space

eNOS

BH4

PI-3 kinase

Blood FlowInsulinAcetylcholine ↓NO

↓NO

Anti-AdhesionAnti-CoagulationFibrinolysis

Vasoconstriction

Non-Smokers Current Smokers Past Smokers0

2

4

6

8

10

12FM

D (%

)

Celemajer, D, et al Circulation 88:2149-2155, 1999

Endothelial Function of Smokers

Non-Smokers

1-4 yrs 5-8 yrs 10-19 yrs >20 yrs0

2

4

6

8

10

12FM

D (%

)

Celemajer, D, et al Circulation 88:2149-2155, 1999

Endothelial Function of Smokers

0

100

200

300

400

500

600

NonobeseGynoid ObesityAndriod Obesity

8 PG

F2al

pha

(pg/

ml)

OXIDATIVE STRESS IN OBESITY

Davi, et al. JAMA 288:2008-2014, 2002

Non Obese Obese0

0.5

1

1.5

2

2.5

3

3.5

PrePost

Lipi

d H

ydro

pero

xide

s (n

mol

/ml)

*

OXIDATIVE STRESS FOLLOWING MAXIMAL EXERCISE

Vincent, et al. Med Sci Sport Sci, 37:213-219, 2005.

Triglyceride Storage Triglyceride Release

Resistin

TNF - α

AdiponectinPlasminogen activator inhibitor

Leptin

Agiotensin

Adipocyte

Exercise

0123456789

10

Pre-Meal Post-Meal

Bra

chia

l Art

ery

FM

D (

%)

Healthy

Healthy

Diabetes

Tsai, et al. Clinical Science 106:315-319, 2004Anderson, et al, Atherosclerosis 154:475-483, 2001Ceriello, et al, Circulation 106:1211-1218, 2002

Tsai, et al. Clinical Science 106:315-319, 2004Anderson, et al, Atherosclerosis 154:475-483, 2001Ceriello, et al, Circulation 106:1211-1218, 2002

0

1

2

3

4

5

6

7

8

9

10

Series 1

FMD

(%)

0

1

2

3

4

5

6

7

8

9

10

Series 1

FMD

(%)

Β Oxidation

↑Electron Donors

Electron Transport Chain

↑FADH2

↑ O2-

TCA Cycle

↑FFA

↑ NADH+H+NAD+

e-

Complex I

Complex IIIComplex II

Complex IVQ-

e-

e-

e-

FAD

0

2

4

6

8

10

12

14

FMD (%)O

W

Ob C

hld

Met S

ynd

Dia

bete

s

Heart D

is

Pre-Training

Post-Training

Hamby et al, Diabetes Care 26:2119-2125, 2003Watts, et al, Journal Pediatrics 144:620-625, 2004Walsh, et al, JAP 95:20-25, 2003

Hamby et al, Diabetes Care 26:2119-2125, 2003Watts, et al, Journal Pediatrics 144:620-625, 2004Walsh, et al, JAP 95:20-25, 2003

EXERCISE IMPROVES ENDOTHELIAL FUNCTIONEXERCISE IMPROVES ENDOTHELIAL FUNCTION

NITRIC OXIDENITRIC OXIDE

i

Eight weeks of training in healthy adults

Maeda, et al. Life Sciences 69:1005-1016, 2001

0

2

4

6

8

10

12

Before After

Art

eria

l Hea

lth (F

MD

)

High Fat

Low Fat

HFM &Exercise

Padilla, et al., European Journal of Applied Physiology, 98:256-262, 2006 Padilla, et al., European Journal of Applied Physiology, 98:256-262, 2006

Johnson, B. et al.

ACTIVE vs. INACTIVE

Johnson, B. et al.

ACTIVE vs. INACTIVE

Johnson, B. et al.

ACTIVE vs. INACTIVE

Johnson, B. et al.

ACTIVE vs. INACTIVE

Johnson, B. et al.

ACTIVE vs. INACTIVE

3

4

5

6

7

8

9

Baseline Post Exercise

FMD (%)Sedentary

Active

Harris, et al, Obesity, 2008Harris, et al, Obesity, 2008

Active & Inactive

Overweight Men

Active & Inactive

Overweight MenFMD

ResponseFMD

ResponseTreadmillExerciseTreadmillExercise

Oxidative Source

Oxidative Stress( 8 PG F2alpha)

Endothelial Function

Single Physical Activity Session

NO bioavailability Blood Flow

Anti-inflammatory

Myokine( IL-6)

Inflammatory Stress( TNF-alpha)

Antioxidant Defense(SOD)

Insulin Resistance

Visceral Fat ( TNF-alpha)

SystemicInflammation

( CRP)

Habitual Physical Activity

Insulin Resistance