jay cohn md aha 04 aeha conf

The Role of Endothelial Function Testing and Arterial Elasticity

Jay N. Cohn, M.D.Professor of Medicine

University of Minnesota Medical SchoolMinneapolis, Minnesota

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

Arterial Vascular Bed

Capacitive Function(large artery elasticity)

Oscillatory/ReflectiveFunction

(small artery elasticity)

Systemic Vascular Resistance

Femoral Artery

Impaired NO Release

– Platelet aggregation– Increased vascular tone (decreased

compliance)– VSM hypertrophy / hyperplasia– Atherosclerosis

Endothelium

Lumen

Media

NO

NO

Vicious Circle of Hypertension

SVR

Atherosclerotic Events

EndothelialDysfunction

ArterialPressure

Simple, Non-Invasive, FDA-Cleared, Reimbursable

Blood Pressure Waveform Analysis Methodology

Pre Post

Vascular Effects of L-NAMEin 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

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

Cum

ula t

ive

CVD

Inc i

denc

e , %

Time, years

Normal

Optimal

Hi-Normal

Women

Vasan RS, et al. N Engl J Med. 2001;345:1291–1297.

•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

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 C2 C1 and C2 decreased with age,, the slope of C2 being greater. The change in BP with age being greater. The change in BP with age independently contributed to the decrease in C1 but independently contributed to the decrease in C1 but not in C2not in C2

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 Hg2.0

1.0 –

0

.08

.06 –

.04 –

.02 –

0

VariableC2

Age

Odds Ratio0.071.04

Lower0.53531.02

Upper0.841.05

pp Value Value<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 the Artery Elasticity Index, there is a 33% increase in the odds ratio for cardiovascular events.odds ratio for cardiovascular events.

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

BP

C2 normal C2 lowFundi normal Funduscopic changesNo LVH LVH No microalbuminuria

Microalbuminuria

C2 normal C2 lowNo sign of vascular disease Signs of vascular disease

• LDL / HDL

Follow Treat aggressively

Natural History of Vascular Disease

GenesPressureLipidsSmoking

InflammationOxidative StressAging


AtherosclerosisVascular Aging Events

PlaquesCAC

Small artery complianceFM dilationBP

IMTRetinopathyMicroalbuminuriaBPLarge artery compliancePulse pressure

M.I.AnginaHeart failureSudden deathStrokeRenal failurePVDDementiaHealth care costs

Natural History of CVD ProgressionElevated BP Target Organ Damage

More Recent Paradigm

A Proposed Future Paradigm

Elevated BP Target Organ DamageVascular Dysfunction

Elevated BP Target Organ Damage

Vascular Dysfunction


Early Paradigm

Angina PectorisStroke

MIRenal Damage

LVH

Hypertension: The Disease Continuum

R A S M U S S E NC E N T E R

forCARDIOVASCULAR

DISEASE PREVENTION

RASMUSSEN CENTERScreening 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


DetectionCardiac Evaluation

• Electrocardiogram• Cardiac ultrasound (LVID, LVWT, mass )• Plasma BNP (Biosite)


Detection

Modifiable Disease Contributors• Fasting lipids (LDL, HDL, Trig)• Fasting blood sugar• hsCRP• Homocysteine

Results of Rasmussen Center Screening

0

20

40

60

80

100

120

140

0 2 4 6 8 10 12 14 16

3-D Column 1

Freq

uenc

y

Rasmussen Score

Low Risk

33%

Modest Risk

36%

High Risk

31%

Age-Dependent Progression of Vascular Disease

Vasc

ular

Rem

odel

ing/

Ath

eros

cler

osis

Death

Morbid Events

Age 20 40 60 80 100

Therapy to Prevent Progression

• Statin drugs• ACE inhibitors/AT1 blockers• Antihypertensive drugs• Beta blockers• Antioxidants (?)• Hormone replacement (?)• Exercise (?)• Potassium (?)• Diet

Risk FactorsBiomarkers

Cardiac and VascularStructural Abnormalities

DeathNon-Fatal

MorbidEvents

RecurrenceProgression

Primary Prevention

Secondary Prevention

Tertiary Prevention

jay cohn md aha 04 aeha conf

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