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VASCULAR AGING
3
PLAN
1. Introduction
2. Normal vascular anatomy and physiology
3. What is vascular aging ?
4. What causes it ?
5. How to diagnose it ?
6. How to treat and prevent it ?
7. Take away
Aging : What matters?
45 yr IT professional
Arteries are 70 yr old
Chronological age is different from biological age
70 yr Athlete
Arteries are 45 yr old
Atherothrombosis Significantly
Shortens Life
Atherothrombosis reduces life expectancy by around
8-12 years in patients aged over 60 years1
Average Remaining Life Expectancy at Age 60 (Men)
20
-7.4
years
Years
16
12
-9.2
years
-12
years
8
4
0
Healthy
History of
History
Cardiovascular Disease of AMI
Analysis of data from the Framingham Heart Study.
Peeters A, et al. Eur Heart J. 2002;23:458-466.
History of
Stroke
Vascular age

Vascular age is the apparent age of the blood
vessels, particularly the arteries when compared
to what is normal for the healthy population

Vascular age is affected by genetic predisposition,
lifestyle choices and other factors
PLAN
1. Introduction
2. Normal vascular anatomy and physiology
3. What is vascular aging?
4. What causes it?
5. How to diagnose it?
6. How to treat and prevent it?
7. Takeaways
THE ARTERIAL SYSTEM

These are the main conducting vessels
carrying blood away from the heart

Can be muscular or elastic. There is a gradual
transition between these two types
Elastic Arteries





Are characterised by a predominance of elastin in
the tunica media and little smooth muscle
Are found just downstream from the heart
Undergo expansion with each systole of the heart
On relaxation of the heart the elastic recoil of the
wall helps propel blood through the blood vessels
Include the aorta, pulmonary, common carotid and
other major vessels
Muscular Arteries
These are medium sized to smaller arteries
 Are characterised by a predominance of smooth
muscle cells in the tunica media
 Make up the main distributing branches of the
arterial tree, eg. the femoral, radial, coronary and
cerebral arteries
 Remember, there is a gradual transition between
elastic and muscular arteries.

ARTERIES
ARTERIOLES
AORTA
ELASTIC
MUSCULAR
Normal Arterial Pulsation
Young compliant arteries : Normal PW velocity (8 m/sec)
Diastole
Systole
(1) Ventricular-Vascular coupling
(2)  coronary blood flow
Cushion
Conduit
Elderly stiff arteries with ISH : Increased PW velocity (12 m/sec)
Systole
Forward
wave
Reflected
(1) Ventricular-vascular mismatch
Wave central SBP during late systole:
(2) The reflected wave increases or “augments”






Increases vascular afterload with a propensity to develop LVH
Decreases coronary perfusion pressure
Increases myocardial oxygen demand and subendocardial ischemia
Increases flow turbulence, endothelial dysfunction and atherogenesis
Increases in pulsatile strain and chance of plaque rupture
All recognized by a wide brachial artery pulse pressure in the elderly
Pulsatile flow to Continuous
flow- Cushion effect
Conduit function – Role of Endothelium
Tunica adventitia
Tunica media
Tunica intima
Endothelium
Subendothelial
connective
tissue
Internal elastic
membrane
Smooth muscle cells
Elastic/collagen
Normal Endothelium
The endothelium is the gatekeeper of the vasculature and a major regulator of vascular tone and
hemostasis
It Provides a smooth, non-thrombogenic surface and a selectively permeability barrier between the
circulation and the vessel wall.
Regulates
vascular tone
and produces
• Endogenous vasodilators
and vasoconstrictors.
• Growth promoting and
growth inhibiting factors.
• Anticoagulants and
Procoagulants.
Retards platelet and
leucocyte adhesion
Inhibits VSMC migration
& proliferation
Adapted from Ormolgul and Dzau, J Vasc Med Biol., 1991, 282-301,
Pepine, C., et. al., “Vascular Health as as Therapeutic Target in Cardiovascular Disease,” VBW , University of Florida, 1998
Atomic force micrograph frpm Barbara et al, Am J Physiol [Heart Care Physiol.], 1995; 266: H1765-H1772
Barrier to LDL, degrade
VLDL & chylotriglyceride
Normal Arterial Function

Cushion function – mainly by Aorta; prevents
transmission of systolic pressure to the periphery ,
slows systolic velocity and maintains continuous
flow in distributing arteries and arterioles

Conduit function – Mainly by arteries and their
endothelium ; prevents atheroma, plaque,
thrombus formation to provide continuous and
uninterrupted blood flow to the organs
PLAN
1.Introduction
2.Normal vascular anatomy and physiology
3.What is the mechanism of vascular aging ?
4.What causes it ?
5.How to diagnose it ?
6.How to treat and prevent it ?
7.Takeaways
Mechanism
 Loss
or reduction of Cushion and
Conduit functions of the blood
vessels
YOUNG
NORMAL SIZE
NORMAL RELAXATION
OLD
DILATED
STIFF
Aortic Stiffening and Early Wave
Reflection
Young compliant arteries : Normal PW velocity (8 m/sec)
Systole
Diastole
(1) Ventricular-Vascular coupling
(2)  coronary blood flow
Elderly stiff arteries with ISH : Increased PW velocity (12 m/sec)
Systole
(1) Ventricular-vascular mismatch
(2) The reflected wave increases or “augments” central SBP during late systole:
Abnormal cushion function
LV systolic,diastolic
dysfunction
Abnormal Conduit Function
Abnormal Endothelium
LDL-C Hypertension
Endothelial
dysfunction sets the
stage for
atherosclerosis
Angiotensin II Homocysteine
Diabetes
Smoking
Oxidative stress
Oestrogen
deficiency
Dysfunction
Formation of
superoxide anion
with inactivation of
NO & stimulation
of vascular
oxidase system
 platelet and
leucocyte
adhesion
VSMC
migration &
proliferation
 LDL deposition 
lipid clearance
Adapted from Ormolgul and Dzau, J Vasc Med Biol., 1991, 282-301
Griendling, K. et.al., “Oxidative Stress and Cardiovascular Disease,”Circulation, 1007; 96: 3264-3265.
Atomic force micrograph frpm Barbara et al, Am J Physiol [Heart Care Physiol.], 1995; 266: H1765-H1772
The Evolution of Atherosclerosis
Foam
Cells
Fatty
Streak
Intermediate
Lesion
Atheroma
Fibrous
Plaque
Complicated
Lesion/Rupture
Endothelial Dysfunction
From 1st Decade
From 3rd Decade
Growth Mainly by Lipid Accumulation
Adapted From Stary HC et al. Circulation. 1995;92:1355-1374
From 4th Decade
Smooth Muscle Thrombosis,
& Collagen
Hematoma
Abnormal conduit
function
Abnormal cushion
function
VASCULAR
AGING
PLAN
1. Introduction
2. Normal vascular anatomy and physiology
3. What is the mechanism of vascular aging ?
4. What causes it ?
5. How to diagnose it ?
6. How to treat and prevent it ?
7. Takeaways
Midsegment obesity
FAMILY HISTORY
LARGE ARTERIES
HYPERGLYCEMIA,OTHER RF
AGES
PROTEIN GLYCATION
IN VESSEL WALL
ATHEROMA
LESS DISTENSIBLE
COLLAGEN
HIGH SYSTOLIC BP
LOSS OF ARTERIAL
COMPLIANCE
LOW DIASTOLIC BP
HIGH PULSE PRESSURE
Factors contributing to Abnormal
conduit function
LDL-C
Hypertension
Angiotensin II
Homocysteine
Diabetes
Smoking
Oxidative stress
Endothelial dysfunction
 NO +  Local mediators +  Tissue ACE, Angiotensin II
PAI-1
VCAM, ICAM,
Cytokines- NF-kB
Thrombosis Inflammation
Endothelin
Growth factors,
matrix
Vasoconstriction
Proteolysis
Vascular lesion
and remodelling
Plaque
rupture
Clinical Sequelae
Gibbons GH, Dzau VJ, New England J Med,1994; 330: 1431-1438
ATHEROSCLEROSIS







ARTERIOSCLEROSIS
Focal, Occlusive
Intimal disease
Inflammatory
Endothelial
dysfunction
Related to LDL
cholesterol oxidation
“Inside-out”
Sensitive to A II and
other substances
(Increased vascular stiffness
Decreased vascular compliance)







Diffuse, Dilatory
Medial disease
Fibrotic (elastin
breakdown, collagen
increase)
Adventitial and medial
hypertrophy
Related to age and BP
“Outside-in”
Sensitive to A II and
other substances
PLAN
1.Introduction
2.Normal vascular anatomy and physiology
3.What is the mechanism of vascular aging ?
4.What causes it ?
5.How to diagnose it ?
6.How to treat and prevent it ?
7.Takeaways
(CUSHION)
(CONDUIT)
PULSE WAVE FORM ANALYSISTONOMETRY
TONOMETRY-PULSE WAVE FORM ANALYSIS
MAP
Identification of Arterial Aging
ABNORMAL CUSHION EFFECT
NORMAL CUSHION EFFECT
Normal systolic,diastolic
And pulse pressure
High systolic,low
Diastolic and high
Pulse pressure
Effect of SBP and DBP on
Age-Adjusted CAD Mortality: MRFIT
CAD Death Rate per 10,000 Person-years
80.6
48.3
43.8
37.4
31.0
25.8
38.1
34.7
25.3
24.6
25.2
24.9
23.8
16.9
20.6
10.3
13.9
11.8
100+
90-99
80-89
Diastolic BP (mmHg)
12.6
12.8
8.8
75-79
High systolic and low diastolic pressure is dangerous
8.5
70-74
11.8
9.2
<70
160+
140-159
120-139
Systolic BP
<120
(mmHg)
PULSE WAVE VELOCITY
What is Central Aortic Pressure ?

Blood pressure in the aorta, closer to the vital organs
Central aortic
pressure
Peripheral brachial
pressure
RISK FACTORS AND MARKERS
 RISK








FACTORS
PREDICT DISEASE
DM,DUR.
LIPIDS
HBP
SMOKING
MET SYN
MENTAL STRESS
FAMILY HISTORY
 RISK






MARKERS
INDICATE PRESENCE
MICROALB.,ED,CKD,
FMD
CIMT, AB INDEX,PW
VELOCITY
MSCT, STRESS TEST
Hs CRP
ECHO – DD,E/E’
INDIVIDUAL ASSESSMENT FOR EARLY
VASCULAR AGING (EVA)? AT 30 YRS
RISK FACTOR AND RISK MARKER ASSESSMENT
RISK FACTORS +
RISK MARKERS +
ALREADY EVA +
RISK FACTORS +
RISK MARKERS --
LIKELY TO DEVELOP EVA
RISK FACTORS –
RISK MARKERS --
PREVENT EVA
PLAN
1.Introduction
2.Normal vascular anatomy and physiology
3.What is the mechanism of vascular aging ?
4.What causes it ?
5.How to diagnose it ?
6.How to treat and prevent it ?
7.Takeaways
To reverse and prevent vascular aging

Life style modification – Diet/ Exercise /
Good habits / Mental relaxation

Block Renin- Angiotensin system

Control Blood pressure

Reduce Lipids

Control Blood sugar
Local Angiotensin System in Macrophages
and Role in Atherosclerosis
circulating
monocytes
ACE
ACE
Y Y Y
adhesion- Y
molecules
endothelial
damage
+ Angiotensin II
LDL
+
Y
infiltration
+
ACE
smooth muscle cells
Y Y
Y
endothelium
oxidative stress
oxLDL/eLDL
subintima
differentiation
(activation)
Macrophages
lumen
fatty streak, plaque
ACE
Ang II
Mod. from Diaz et al., N Engl J Med 337 (1997)
ACE
Ang II
Foam-cells
+
Growth factors
Cytokines
media
ACE I OR ARB?
WHICH ACEI,ARB?
Evidence base in diabetic subjects
Surrogate vascular structure
& function trials
Post MI
patients
High risk without LVF
Stroke
ACEIs
ARBs


TELMISARTAN
(SECURE)
NIL


(AIRE,TRACE,SAVE)

(HOPE/MICRO HOPE)

(HOPE, PROGRESS)
Preventing Heart failure
Heart failure
Diabetes & hypertension
Renal disease
(OPTIMAAL)

NIL

(SCOPE)
LIFE



?
(HOPE)
(CONSENSUS, SOLVD,HOPE)

(CAPP,ABCD, FACET)

(LEWIS II)
NIL
(ELITE II,Val-HeFT)
Charm

(LIFE)

(IDNT,RENAAL,IRMA2)
Renin-Angiotensin Systems (III)
Distribution of ACE:
10%
RAS
90%
circulating (plasma)
local (tissue)
Acute and short-term effects
cardiovascular/
renal homeostasis
Long-term effects
Mod. from Dzau V, Arch Intern Med 153 (1993)
local "organ adaptation"
renal-independent activation
Potential Pharmacological Actions of
ACE Inhibitors in Atherosclerosis
Putative role of 10 mg ramipril:
in hypertension
RAS
(Plasma-ACE)
RAS
(Plaque-ACE)
Ramipril
Metalloproteinases
(fibrous cap of plaque)
Other targets?
VSMC = vascular smooth muscle cells
adapt. from Dzau et al., Drugs 47 (1994)
Angiotensin II
Bradykinin
NO
Collagen
Elastin etc.
Blood pressure
VSMC-Contraction
VSMC-Growth
VSMC-Migration
Platelet aggregation
PAI-1
t-PA
Matrix-Stability
(CUSHION)
Plaque rupture
(CONDUIT)
ACE I
Total CV events and procedures
18.0
Atenolol  thiazide
(No. of events 1602)
16.0
14.0
12.0
Amlodipine  perindopril
(No. of events 1362)
10.0
8.0
6.0
4.0
HR = 0.84 (0.780.90)
p < 0.0001
2.0
0.0
Number at risk
Amlodipine  perindopril
Atenolol  thiazide
0.0
1.0
2.0
3.0
4.0
5.0
9639
9618
9277
9210
8957
8848
8646
8465
8353
8121
7207
6977
Years
Effects of Statins and ACE Inhibitors
Agostino Faggiotto et al,Hypertension. 1999;34[part 2]:987-996.
55
Antiatherosclerotic Effect of
ACE Inhibitors in the Vasculature (HOPE)
Scheme of "plaque deactivation":
ACE activity
in plaques
State-of-the-art
therapy
State-of-the-art
therapy+ACE
inhibitor
(incl. ASA, Amlo, Statins)
(e.g. 10 mg Ramipril)
ACE activity
in plaques
Activated Plaque
ACE activity
in plaques
Deactivated Plaque
So, to reverse and prevent Vascular
Aging






Life style modification
Block RAS-ACEI (Ramipril, Perindopril-Max.
tolerated dose)
Control BP- Calcium blockers Amlodepin
Control lipids- Statins
Control sugar – emerging drugsDPP4
inhibitors
Logical combination of above
PLAN
1. Introduction
2. Normal vascular anatomy and physiology
3. What is the mechanism of vascular aging?
4. What causes it?
5. How to diagnose it?
6. How to treat and prevent it?
7. Takeaways
Vascular Age - Approach
Reverse
Vascular
aging
KEEPING THE ARTERIES YOUNGER