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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
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