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