March 2012 The Cardiovascular System and Aging- Is it Built to Fail? Francis G. Spinale, MD, PhD Professor of Surgery and Cell Biology and Anatomy University of South Carolina School of Medicine Veterans Affairs Medical Centers, Columbia, South Carolina
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March 2012
The Cardiovascular System and Aging-
Is it Built to Fail?
Francis G. Spinale, MD, PhD
Professor of Surgery and Cell Biology and Anatomy
University of South Carolina School of Medicine
Veterans Affairs Medical Centers, Columbia, South Carolina
OUTLINE -Review the Causes of HF in the Elderly
-Identify Factors Causing HF in the Elderly
-Demonstrate that Enzyme Systems that
Regulate CV Function Change with Age
-Report on New Blood Tests and
Approaches
Concentric
Remodeling
Normal Left Ventricle
Eccentric
Remodeling
Hypertension Coronary Artery
Disease
Concentric
Remodeling
Normal Left Ventricle
Eccentric
Remodeling
Hypertension Coronary Artery
Disease
AGING
Prevalence of Hypertension and MI by Age and Sex
CDC/NCHS and NHLBI 1999-2002.1
0
10
20
30
40
50
60
70
80
90
20-34 35-44 45-54 55-64 65-74 75+
Ages
Per
cen
t o
f P
op
ula
tio
n
0
100
200
300
400
29-44 45-64 65+Ages
Heart
Att
acks (
x 1
000)
HYPERTENSION
CORONARY
ARTERY
DISEASE
Perc
en
t o
f P
op
ula
tio
n
Heart
Att
acks (
x 1
000)
0
10
20
30
40
50
60
70
80
90
20-34 35-44 45-54 55-64 65-74 75+
Ages
Per
cen
t o
f P
op
ula
tio
n
Men Women
Burden of Disease:
Transition of Hypertension to Failure H
ealt
h S
tatu
s/Q
OL
Time (Years)
Normotensive Elevated Blood
Pressure
Left Ventricular Dysfunction
Heart Failure
Lo
wer
Hig
her
Death
Aging and the Vasculature
• Central vessel wall thickening
• Endothelial dysfunction
• Smooth Muscle cell proliferation
• Changes in the Matrix
• Impaired distensibility-
• “Stiffening of Vasculature”
Aging and the Heart
Structural Changes – Heart Weight
– Cardiomyocyte dimensions
– Matrix Composition
– Cardiac sympathetic nerve supply
Aging and the Heart
Structural Changes – Heart Weight
– Cardiomyocyte dimensions
– Matrix Composition
– Cardiac sympathetic nerve supply
•Influences LV Geometry
•Coordinates Contraction
•Interface for Integrins-
Intracellular Signaling
•Reservoir of Bioactive
Signaling Molecules
•Dynamic Changes Following
Mechanical/Biological Stimuli
Myocardial Collagen Matrix -2012
Robinson et al, Lab Invest, 1983
Rossi et al, Circulation, 1998
DHF P = 1.5 x e 0.034V
Normal P = 2.3 x e 0.010V
0
5
10
15
20
25
30
0 20 40 60 80 100 120
LV
Dia
sto
lic
Pre
ss
ure
(m
mH
g)
LV Diastolic Volume (mL)
Structure
Diastolic Heart Failure
Substrate
Increased
Stiffness
Normal DHF
Function
The Aging Heart and Fibrosis
Increased Collagen
Normal
MMP
Matrix metalloproteinases (MMPs)
Family of zinc-dependent
enzymes responsible for
turnover of the ECM, facilitating
tissue remodeling.
A. Deschamps ‘02 Endogenous inhibitors that
regulate activity of MMPs by
binding to their active site.
Tissue inhibitors of MMPs (TIMPs)
TIMP
Matrix Remodeling
Golgi Apparatus
Pro MMPs Serine Proteases
Nucleus
Integrin
Pro-Peptides
Golgi Apparatus
Pro-MMPs Serine Proteases
Nucleus
Integrin
Pro-Peptides Active MMPs
TIMPS
Microdialysis Probe
Active MMP
Substrate
Cleaved
Substrate Interstitial Space
Inlet Tubing
Outlet
Tubing 4 mm Membrane
Patent pending: 60/855,419
Microfluidics Detection System
Time (seconds) 0 10 20 30 40 50 60 70
Flu
ore
scen
ce
Em
issio
n
1800
2000
2200
2400
2600
2800
3000
Active MMP
Substrate
Cleaved
Substrate
Interstitial Space
Steady State MMP Activity
Patent pending: 60/855,419
Microdialysis Instrumentation
LV LAD
Interstitial MMP Activity
Cross
Clamp on
Cross
Clamp off
Flu
ore
sc
en
ce
Em
iss
ion
(3
60
nm
)
1400
1600
1800
2000
2200
2400
2600
Myocardial
Arrest
Myocardial
Reperfusion
#
MM
P A
cti
vit
y (
ng
/hr)
0
1
2
3
4
5
6
7
MM
P A
cti
vit
y (
ng
/hr)
0
1
2
3
4
5
6
7
Myocardial
Arrest
Myocardial
Reperfusion
p < 0.05 vs. Myocardial Arrest #
Steady
State
Dynamic changes in MMP
activity occur within the human
heart and is a continuous
process….
Do changes in this proteolytic
cascade change as a function
of age?
Are these changes
independent of hypertension or
coronary artery disease?
Enroll subjects with a wide age range without
evidence of CV disease.
Obtain measurements of left ventricular structure
and function.
Measure plasma MMP/TIMP profiles.
MMPs/TIMPs and Aging
Developing a Sensitive Blood Test
for MMPs/TIMPs
Antibody Coated
Flourescent Beads
Dual Lasers Excite Coated Beads
Robotics Handle
and Dilute Plasma
Samples
MMP-2 (pg/mL)
0.1 1 10 100 1000 10000
Flu
ore
sce
nt
Un
its
0
2000
4000
6000
8000
10000
12000
14000
16000
Standards
Samples
Standards
Samples
MMP-2
High Sensitivity-High
Throughput System for
MMP/TIMP
Measurements
Developed and Validated
0.60
0.65
0.70
0.75
0.80
0.85
0.90
22 - 29 30 - 48 49 - 56 57 - 64 65 - 90
Age Group
LV
Vo
lum
e/M
ass
(mL
/gra
m)
LV Remodeling with Age
p<0.05 vs quintile 22-29
LV
Vo
lum
e/M
ass (
mL
/gra
m)
0.6
0.8
1.0
1.2
1.4
1.6
1.8
2.0
22 - 29 30 - 48 49 - 56 57 - 64 65 - 90
Age Group
E/A
Rati
oImpaired Diastolic Filling with Age
p<0.05 vs quintile 22-29
E / A
Rati
o
700
800
900
1000
1100
1200
22 - 29 30 - 48 49 - 56 57 - 64 65 - 90
Age Group
TIMPs vs Age
30
40
50
60
70
22 - 29 30 - 48 49 - 56 57 - 64 65 - 90
Age Group
TIM
P 1
(n
g/m
L)
TIM
P 2
(n
g/m
L)
p<0.05 vs quintile 22-29
Reduce Degree of Continuous MMP Activity
Reduce Normal Collagen Matrix Turnover
Cause Increased Collagen Accumulation
Changes in Collagen
Turnover With Age
TIMPs with Aging
DHF P = 1.5 x e 0.034V
Normal P = 2.3 x e 0.010V
0
5
10
15
20
25
30
0 20 40 60 80 100 120
LV
Dia
sto
lic
Pre
ss
ure
(m
mH
g)
LV Diastolic Volume (mL)
Structure
Diastolic Heart Failure
Substrate
Increased
Stiffness
Normal DHF
Function
The Aging Heart and Fibrosis
Increased Collagen
Normal
Prevalence of Hypertension and MI by Age and Sex
CDC/NCHS and NHLBI 1999-2002.1
0
10
20
30
40
50
60
70
80
90
20-34 35-44 45-54 55-64 65-74 75+
Ages
Per
cen
t o
f P
op
ula
tio
n
0
100
200
300
400
29-44 45-64 65+Ages
Heart
Att
acks (
x 1
000)
HYPERTENSION
CORONARY
ARTERY
DISEASE
Perc
en
t o
f P
op
ula
tio
n
Heart
Att
acks (
x 1
000)
0
10
20
30
40
50
60
70
80
90
20-34 35-44 45-54 55-64 65-74 75+
Ages
Per
cen
t o
f P
op
ula
tio
n
Men Women
The Heart of The Matter in
Hypertensive Heart Disease
Normal
The Heart of The Matter in
Hypertensive Heart Disease
Normal Hypertensive
Heart Disease
Myocardial Remodeling and
Hypertensive Heart Disease
Heart Wall Remodeling in
Hypertensive Heart Disease
Myocardial Remodeling and
Hypertensive Heart Disease
What Does Heart
Failure Look Like?
How does it happen? (Changes in MMP/TIMPs)
Can we predict it?
Myocardial Remodeling and
Hypertensive Heart Disease….
Non Detectable
Detectable
Control LV Hypertrophy
53% 47%
15%
85%
PLASMA MMP-13
(2 = 17.89, p<0.001)
Detectable Non Detectable Detectable Non Detectable