The Cardiovascular System and Aging- Is it Built to Fail? · PDF fileThe Cardiovascular System and Aging- ... Regulate CV Function Change with Age ... Obtain measurements of left ventricular

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

Circulation 113

2089-2096, 2006

900

1050

1200

1350

1500

Control

without

HTN

* #

Control

with

HTN

LVH

without

DHF

LVH

with

DHF

* = p<0.05 vs Control

# = p<0.05 vs LVH without DHF

TIM

P-1

(n

g/m

L)

TIMP-1 Identifies and Predicts Development of HF

Circulation 113

2089-2096, 2006

1.5

2.0

2.5T

IMP

-4 (

ng

/mL

)

Control

without

HTN

Control

with

HTN

LVH

without

CHF

LVH

with

CHF

P < 0.04

Mean = 1.87 ± 0.10

TIMP-4 Identifies and Predicts Development of HF

-Occurs as a function of age

-A blood test can be used to

identify and predict presence

and risk

Myocardial Remodeling and

Hypertensive Heart Disease….

What can we do with

this blood test?

-Screen

-Manage

-Test New Treatments

Myocardial Remodeling and

Hypertensive Heart Disease….

Cardiovascular Remodeling with Aging

Is there a meter running?