Implications of Vascular Aging on Cardiovascular Disease Risk“Vascular Endothelial...
Transcript of Implications of Vascular Aging on Cardiovascular Disease Risk“Vascular Endothelial...
Implications of Vascular Aging
on Cardiovascular Disease Risk
Outline
I. Significance and Relevance
II. Arterial Structure / Stiffness
III. Endothelial Function
IV. Integrated Vascular Control
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
Lakatta E G , Levy D Circulation 2003;107:139-146
Age-related incidence of Hypertension, Stroke, and CAD
Stroke
CAD
Hypertension
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
Vascular Aging a Major Risk Factor
for Cardiovascular Disease
Lakatta EG Circulation 2003
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
Circulatory System
Arterial Structure
Structural Changes with Age
Najjar et al. Hypertension 2005
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
Lakatta E G , Levy D Circulation 2003;107:139-146
Aging is Associated with Elevated SBP and Pulse Pressure
Aging and Aortic Stiffness
Lakatta EG Circulation 2003
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
**
* *
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
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)
Healthy, Normally Functioning
Vascular Endothelium
Anti-Atherosclerotic Phenotype
“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
Aging and Endothelial Dependent Dilation
Taddei et al., Hypertension 1996
Brachial Artery
Celermajer et al., JACC 1994
Aging and Endothelial Independent Dilation
Celermajer et al., JACC 1994
Taddei et al., Hypertension 1996
Brachial Artery
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
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
Hypothesized Role of Reactive Oxygen
Species in Reduced NO
Oxidative Stress a Mechanism Contributing to Endothelial Dysfunction with Aging
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
Endothelial nitrotyrosine and EDD with aging in men
Donato et al., Circ Res 100:1659-66, 2007
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
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
Role of Reactive Oxygen Species in
Reduced NO with Aging
?
?
Fibrinolysis - The Clot Buster
Aging and Fibrinolysis
Smith et al. J Physiol 2002
Risk Factors, Endothelial Dysfunction,
Atherogenesis, and Progression to
Cardiovascular Events
Another Issue with Aging
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
Blood Flow Regulation
• A delicate balance of
vasoconstrictor and
vasodilator influences
determines vessel
caliber and thereby
vascular resistance and
blood flow
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
)
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
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
Questions??
Structural Changes in
Resistance Arteries
Behnke, B. J. et al. J Physiol (Lond) 2006
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
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