implications of vascular aging on cardiovascular disease risk“vascular endothelial...
TRANSCRIPT
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Implications of Vascular Aging
on Cardiovascular Disease Risk
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Outline
I. Significance and Relevance
II. Arterial Structure / Stiffness
III. Endothelial Function
IV. Integrated Vascular Control
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0
100
200
300
400
500
A B C D E A B D F E
Males
Females
CVD is the Leading Cause of Death in the U.S.
A Total CVD
B Cancer
C Accidents
D Chronic Lower Respiratory Diseases
E Diabetes Mellitus
F Alzheimer’s DiseaseSource: CDC/NCHS, 2002
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Lakatta E G , Levy D Circulation 2003;107:139-146
Age-related incidence of Hypertension, Stroke, and CAD
Stroke
CAD
Hypertension
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The Majority of CVD Deaths are
Attributable to Vascular Complications
18%
6%
5%
4%0%0%
13%
53%
Coronary Heart Disease
Stroke
Congestive Heart Failure
High Blood Pressure
Diseases of the Arteries
Rheumatic Fever/RheumaticHeart Disease
Congenital Cardiovascular Defects
Other
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Vascular Aging a Major Risk Factor
for Cardiovascular Disease
Lakatta EG Circulation 2003
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Aging Stats
• Population over 65 years of age will double from 12% to
22% from 2010-2040
• Prevalence of CVD will increase by 10% over the next 20
years
• Additional 20 million with hypertension
• 8 million with CHD
• 3 million more with heart failure
**Primarily due to increase in aging population
• Annual cost for people aged 65-79 years of age are
projected to increase by 238% from $135B to $457B
Heidenreich PA, et al. Circulation 2011
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Circulatory System
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Arterial Structure
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Structural Changes with Age
Najjar et al. Hypertension 2005
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Mechanisms of Arterial Wall Thickning
Spinetti, G. et al. Arterioscler Thromb Vasc Biol 2004
Other potential influences: Increased Blood Pressure
Increased growth factors
Endothelial function
Immune System Infiltration
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Lakatta E G , Levy D Circulation 2003;107:139-146
Aging is Associated with Elevated SBP and Pulse Pressure
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Aging and Aortic Stiffness
Lakatta EG Circulation 2003
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Aging and Large Artery ComplianceC
aro
tid
Art
ery
Co
mp
lian
ce (
U)
Tanaka et al. Circulation 2000
Sedentary Endurance-Trained
Young Middle Older Young Middle Older
0.10
0.15
0.20
0.25
**
* *
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Mechanisms of Arterial
Stiffness
Kass, D. A. et al. Circulation 2001
1 month 2 months
Hypertensives
Other potential influences:
Arterial Collagen Content
Arterial Elastin Content
Endothelial function
AGEs
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PHYSIOLOGICAL AGING
Mechanisms Effects Consequences
Large elastic SBP and PPartery remodeling systolic hypertension internal diameter aneurysms, stroke IMT
Elastin:fragmentationdensity
Collagen: concentration phenotype cross-linking
AGEs systolic pulse LV work, VO2VSM cell hypertrophy augmentation prolonged contraction growth factors ( carotid AI) early diastolic filling
Functional LV systolic reserve peak LV ESV peak LV EF VSM cell tone
Subclinicalatherosclerosis ( MCP-1, CCR2)
Age-gene interactions
Structural
aortic and carotidarterial compliance
( stiffness)
Endothelial damage atherosclerosis MI, thrombosis CAD, PAD, etc.
aortic PWV aortic impedance LV wall tension LV hypertrophy ( CHF)
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Healthy, Normally Functioning
Vascular Endothelium
Anti-Atherosclerotic Phenotype
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“Vascular Endothelial Dysfunction”: generalized alteration in
endothelial cell function
Atherosclerosis/CVD
Impaired vascular endothelium-dependent dilation (EDD),
characterized by the loss of endothelium-derived nitric oxide (NO)
production, is the central feature of endothelial dysfunction
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Aging and Endothelial Dependent Dilation
Taddei et al., Hypertension 1996
Brachial Artery
Celermajer et al., JACC 1994
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Aging and Endothelial Independent Dilation
Celermajer et al., JACC 1994
Taddei et al., Hypertension 1996
Brachial Artery
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Aging, Endothelial Dilation and NO
Taddei, S. et al. Circulation 2000
Age related EDD deficit is
explained by reduced NO
Endurance trained individuals
have augmented EDD via greater
NO
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Vascular endothelial dysfunction and risk of CVD with aging
Douglas R. Seals, Kristen L. Jablonski and Anthony J. Donato; Clinical Science 2011 120, 357-375
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Hypothesized Role of Reactive Oxygen
Species in Reduced NO
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Oxidative Stress a Mechanism Contributing to Endothelial Dysfunction with Aging
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Dilati
on
(%
)/∆
BF
(%)
Young Older OlderSedentary Sedentary Trained
FMD
*
Eskurza et al., J Physiol, 2004
FMD w/ Vitamin C
Young Older OlderSedentary Sedentary Trained
Acute Vitamin C Infusion Restores
Brachial Artery FMD in Older Sedentary Men
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Endothelial nitrotyrosine and EDD with aging in men
Donato et al., Circ Res 100:1659-66, 2007
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Taddei, S. et al. Hypertension 2001;38:274-279
Aging, Oxidative Stress and NO
1. Age-related
EDD deficit is
explained by
reduced NO
2. Older adults can
ameliorate NO
mediated EDD
by blocking
oxidative stress
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NADPH p47 phox, a subunit of a oxidant protien, is increased in endothelial cells from older sedentary adults
Donato et al., Circ Res 100:1659-66, 2007
No age-related changes in antioxidant protein expression
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Role of Reactive Oxygen Species in
Reduced NO with Aging
?
?
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Fibrinolysis - The Clot Buster
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Aging and Fibrinolysis
Smith et al. J Physiol 2002
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Risk Factors, Endothelial Dysfunction,
Atherogenesis, and Progression to
Cardiovascular Events
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Another Issue with Aging
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Percent of Elderly with Physical
Limitations
1992 1994 1996 1998
30
31
32
33
34
35
36
37
% o
f P
op
ula
tio
n o
ver
65
wit
h P
hysic
al L
imit
ati
on
s
Year
• With increasing life expectancy
physical limitations become more
prevalent
• This creates an expensive
burden on health care systems
and individual families
• The decline in cardiovascular
function with aging contributes
to these limitations
CDC NSDB 2003
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Blood Flow Regulation
• A delicate balance of
vasoconstrictor and
vasodilator influences
determines vessel
caliber and thereby
vascular resistance and
blood flow
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Aging and Resting Leg Blood
Flow
Dinenno et al. Circulation 1999
*
*
Young
Adults
Older
Adults
Young
Adults
Older
Adults
Femoral
Blood Flow
Femoral
Vascular Resistance
100
200
300
400
(ml/m
in)
0.1
0.2
0.3
0.4
0.5
(un
its
)
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Aging and Exercise Leg Blood Flow
Workload (Watts)
0 3 6 9Le
g B
loo
d F
low
(L
/min
)
0.0
0.5
1.0
1.5
2.0
2.5
3.0 Young
Old
Workload (Watts)
0 3 6 9
Le
g V
asc
ula
r C
on
du
cta
nc
e(m
l/m
mH
g)
0
5
10
15
20
25
30Young
Old
Workload (Watts)
0 3 6 9
Mean
Art
eri
al
Pre
ssu
re
(mm
Hg
)
94
96
98
100
102
104
106
108
110
112
114
116Young
Old
Leg
Blo
od
Flo
w
(L/m
in)
Donato et al. AJP Heart Circ. 2006
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Conclusions
Healthy Sedentary aging is associated with:
- Lumen enlargement
- Medial wall thickening
- Large artery stiffening
- Generalized endothelial dysfunction due to
-Decreased NO bioavailability
-Augmented oxidative stress
- A pro-constrictor resistance vasculature resulting in
an attenuated resting and exercise leg blood flow
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Questions??
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Structural Changes in
Resistance Arteries
Behnke, B. J. et al. J Physiol (Lond) 2006
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Aging and b-Adrenergic Dilation
[ISO] (log M)
PRE -9 -8 -7 -6 -5
% D
ilati
on
-40
-20
0
20
40
60YS
OSP < .05
1. Aging attenuates vasodilation
to isoproterenol in arterioles
without a functional
endothelium
2. The magnitude of vasodilation
is not reduced after denuding
the endothelium, thus
adrenergic vasodilation is due
to VSM-mediated dilation in
arterioles
Resistance artery
-endothelium
Donato et al. J physiol 2007
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Aging and cAMP Mediated
DilationSoleus
[FOR] (M)PRE
1e-93e-9
1e-83e-8
1e-73e-7
1e-63e-6
1e-53e-5
1e-4
% D
ilatio
n
-20
0
20
40
60
80
100 YS
OS
Donato et al. J physiol 2007
Resistance artery
-endothelium