SHAPE Society

1. The Role of Endothelial Function
Testing and Arterial Elasticity
Jay N. Cohn, M.D.
Professor of Medicine
University of Minnesota Medical School
Minneapolis, Minnesota

2. Faculty Disclosure Statement
I have received honoraria, study grants, consultation
fees and/or hold stock options in the following:
Novartis Pharmaceuticals Acorn Cardiovascular Abbott Labs
Bristol-Myers Squibb Biosite Diagnostics Amgen
SmithKline Beecham Medtronic Inc. Intercure Inc.
Forest Laboratories NitroMed Inc. Pfizer
Hypertension Diagnostics Solvay Guidant
AstraZeneca Pharmaceia

3. Arterial Vascular Bed
Capacitive Function
(large artery elasticity)
Oscillatory/Reflective
Function
(small artery elasticity)
Systemic
Vascular Resistance

4. Femoral Artery

6. Impaired NO Release
– Platelet aggregation
– Increased vascular tone (decreased
compliance)
– VSM hypertrophy / hyperplasia
– Atherosclerosis
Endothelium
Lumen
Media
NO
NO

7. Vicious Circle of Hypertension
↑SVR
Atherosclerotic
Events
Endothelial
Dysfunction
↑ Arterial
Pressure

8. Simple, Non-Invasive,
FDA-Cleared, Reimbursable

9. Blood Pressure Waveform
Analysis Methodology

10. Pre Post

11. Vascular Effects of L-NAME
in 10 Normal Subjects
Control L-NAME P
•BP mmHg 112/65 122/75 <0.01
•MAP mmHg 80 90 <0.01
•PWV m/sec 8.25 8.98 0.04
•BA@100 mmHg cm2
10.8 11.0 NS
•BAC@100 mmHg cm2
/mmHg .0027 .0049 0.07
•FMV% 5.29 4.47 0.06
•C1 ml/mmHg 16.9 18.5 NS
•C2 ml/mmHg 9.9 6.9 <0.001
•SVR dynes-sec-cm-5
1200 1487 <0.001

12. Hi-Normal
(n = 1794)
130 – 139/ 85 – 89
Normal*
(n = 2185)
120 – 129/ 80 – 84
Optimal
(n = 2880)
< 120/80
Hazard
Ratio
*P < 0.001 for trend across categories.
2.5
1.5
1.0
Impact of High-Normal Blood
Pressure
on the Risk of Cardiovascular
Disease
CumulativeCVDIncidence,%
Time, years
Normal
Optimal
Hi-Normal
Women
Vasan RS, et al. N Engl J Med. 2001;345:1291–1297.

13. •ENDOTHELIAL DYSFUNCTION
FUNCTION STRUCTURE
Small Artery Constriction Large Art Remodeling
↓C1 ↑Pulse Plaques
Pressure
Clots
↓C2 ↑SVR Small Art Remodeling
↓↓C2 ↓Flow Organ
Reserve Dysfunction
“HYPERTENSION”
HYPERTENSION

14. C1 and C2 with Age
0
0.5
1
1.5
2
2.5
20 40 60 75
C1 C2
.08
.01
1.6
McVeigh et al Hypertens. 1999;33:1392McVeigh et al Hypertens. 1999;33:1392
C1 and C2 decreased with age,, the slope of C2C1 and C2 decreased with age,, the slope of C2
being greater. The change in BP with agebeing greater. The change in BP with age
independently contributed to the decrease in C1 butindependently contributed to the decrease in C1 but
not in C2not in C2

15. MAP
**
C2
**
C1
*
SVR
*
Vascular Measurement in Normotensive
and Hypertensive Subjects
150
100 –
50 –
0
N Hyp
n = 32
n =
38
*P<0.01, **P<0.001
N Hyp N Hyp N Hyp
2000
1000 –
0
dyne•sec •cm-5mm Hg mL/mm Hg mL/mm Hg
2.0
1.0 –
0
.08
.06 –
.04 –
.02 –
0

16. Variable
C2
Age
Odds Ratio
0.07
1.04
Lower
0.5353
1.02
Upper
0.84
1.05
pp ValueValue
<0.01<0.01
<0.001<0.001
95% CI
Loss of Arterial Elasticity is Predictive of
Cardiovascular Events
N=419 subjects, C1 - Large Artery Elasticity and C2 - Small Artery Elasticity
measured at baseline by radial artery PulseWave Analysis
1 to 7 year follow-up (contacted and returned questionnaires)
End points: MI, stroke, TIA, angina, coronary or peripheral angioplasty, coronary
artery or peripheral bypass graft, death
Occurrence of Events as a Function of Baseline Arterial Compliance*Occurrence of Events as a Function of Baseline Arterial Compliance*
Grey E et al. Am J Hypertens. 2000;13 (part 2). Abstract.
Presented at the 15th
Scientific Meeting of the American Society of Hypertension.
*C1 was associated with age but not outcome
For each 2 ml/mmHg x 100 of lowered CFor each 2 ml/mmHg x 100 of lowered C22 - Small- Small
Artery Elasticity Index, there is a 33% increase in theArtery Elasticity Index, there is a 33% increase in the
odds ratio for cardiovascular events.odds ratio for cardiovascular events.

17. Small Artery Elasticity Predicts
Cardiovascular Events
Reduced Small Artery Elasticity was
predictive of cardiovascular events
Events increase as Small Artery Elasticity
decreases
Large Artery Elasticity related to age, not
independently predictive of events
Grey et al, Am J Hypertension. In Press

18. ↑ BP
C2 normal C2 low
Fundi normal Funduscopic
changes
No LVH LVH
No microalbuminuria
Microalbuminuria
C2 normal C2 low
No sign of vascular disease Signs of vascular
disease
Follow
Treat aggressively

19. Natural History of Vascular Disease
Genes
Pressure
Lipids
Smoking
Inflammation
Oxidative
Stress
Aging
Endothelial
Dysfunction
Atherosclerosis
Vascular Aging Events
Plaques
CAC
↓Small artery
compliance
↓FM dilation
↑BP
↑IMT
Retinopathy
Microalbuminuria
↑↑BP
↓Large artery
compliance
↑Pulse pressure
M.I.
Angina
Heart failure
Sudden death
Stroke
Renal failure
PVD
Dementia
Health care
costs

20. Natural History of CVD Progression
Elevated BP Target Organ Damage
More Recent Paradigm
A Proposed Future Paradigm
Elevated BP Target Organ DamageVascular Dysfunction
Elevated BP Target Organ
Damage
Vascular
Dysfunction
Endothelial
Dysfunction
Early Paradigm
Angina
Pectoris
Stroke
MIRenal
Damage
LVH
Hypertension: The Disease
Continuum

21. R A S M U S S E N
C E N T E R
for
CARDIOVASCULAR
DISEASE PREVENTION

22. RASMUSSEN CENTER
Screening Tests for Early Detection
• Arterial Elasticity (Pulse Contour Analysis)
- Small Artery (C2)
- Large Artery (C1)
• Rest and exercise BP (3-minute treadmill)
• Retinal digital photograph
• Urine for microalbumin/creatinine ratio
• Carotid intimal-medial thickness
Vascular Evaluation

23. RASMUSSEN CENTER
Screening Tests for Early Detection
Cardiac Evaluation
• Electrocardiogram
• Cardiac ultrasound (LVID, LVWT, mass )
• Plasma BNP (Biosite)

24. RASMUSSEN CENTER
Screening Tests for Early Detection
Modifiable Disease Contributors
• Fasting lipids (LDL, HDL, Trig)
• Fasting blood sugar
• hsCRP
• Homocysteine

25. Results of Rasmussen Center Screening
0
20
40
60
80
100
120
140
0 2 4 6 8 10 12 14 16
3-
Frequency
Rasmussen Score
Low Risk
33%
Modest Risk
36%
High Risk
31%

26. Age-Dependent Progression of Vascular
Disease
VascularRemodeling/
Atherosclerosis Death
Morbid Events
Age 20 40 60 80 100

27. Therapy to Prevent
Progression• Statin drugs
• ACE inhibitors/AT1 blockers
• Antihypertensive drugs
• Beta blockers
• Antioxidants (?)
• Hormone replacement (?)
• Exercise (?)
• Potassium (?)
• Diet

28. Risk Factors
Biomarkers
Cardiac and Vascular
Structural Abnormalities
Death
Non-Fatal
Morbid
Events
Recurrence
Progression
Primary Prevention
Secondary Prevention
Tertiary Prevention