CP9929242

1
American Heart Association 2008
Emerging Role of Vascular Function Measurements
in Primary Prevention Clinics
Amir Lerman, MD Professor of Medicine Cardiovascul
ar DivisionMayo Clinic, Rochester, MN
CP992924-2
2
DISCLOSURE

• Relevant Financial Relationship(s)
• List Advisory Board Itamar medical
• Off Label Usage
• List None

3
In Search of Vulnerable Patients1,400,000 Annual
Heart Attacks (ACS SCD)
Vulnerable Patients
Vulnerable Patients
CP1131615-8
4
41 year old male with Ant. STEMIVulnerable
Patient vs. Plaque

• Presented 1 year ago with chest pain
• History of previous NQWMI
• NIDDM
• Hypertension
• BMI 30
• TMET positive
• Previous coronary angiograms

5
Coronary Artery Stenosis Before Acute Myocardial
Infarction
Patients()
Circulation, 1996 (data from four studies)
CP989561-1
6
ACS is a dynamic process that occurs at the inter
phase between the vascular wall and circulation

• Structural tests
• Functional test

7
Endothelial FunctionBasic Science to Clinical
Practice
CP1240167-10
8
Acetylcholine
100
NE
Smooth muscle cells
NO
0
Endothelium
CP1008137-5
9
Acetylcholine
100
NE
Smooth muscle cells
NO
0
Endothelium
Acetylcholine
CP1008137-5
10
Acetylcholine
100
NE
Smooth muscle cells
NO
0
Endothelium
Acetylcholine
CP1008137-5
11
Acetylcholine
100
NE
Smooth muscle cells
NO
0
Endothelium
CP1008137-5
12
Acetylcholine
100
NE
Smooth muscle cells
NO
0
Endothelium
Acetylcholine
NE
100
0
CP1008137-5
13
Acetylcholine
100
NE
Smooth muscle cells
NO
0
Endothelium
Acetylcholine
NE
100
0
CP1008137-5
14
(No Transcript)
15
The Multifunctional Nitric Oxide
Vascular smoothmuscle relaxation and decrease
permeability
SMC proliferation
NO
Leukocyteadhesion and Macrophages infiltration
Plateletreactivity
Down-regulation ofoxidative enzymes
Reduction inlipid peroxidation
16
Endothelial FunctionBasic Science to Clinical
Practice
Discovery of NO and the role of the endothelium
CP1240167-11
17
New England Journal of medicine 315 (17) 1986
CP990350-1
18
New England Journal of medicine 315 (17) 1986
CP990350-2
19
Shear stress reactive hyperemia
Acetylcholine
Bradykinin
Ca2
L-arg
Endothelium
NOS
NO
(Ca2)
GTP Cyclic GMP
Smooth muscle
sGC
Relaxation
20
Endothelial FunctionBasic Science to Clinical
Practice
Discovery of NO and the role of the endothelium
Endothelial function with exercise and mental
stress
First endothelial function in humans
CP1240167-13
21
Brachial Artery Flow-Mediated Vasodilation in a
Healthy Individual
CP1045482-12
22
Ultrasound Imaging of the Brachial Artery
Corretti et al JACC 39257, 2002
CP1147604-1
23
Flow-Mediated Dilatation in Control Subjects, FH
Children, Smokers and Subjects with CAD
Plt0.01
P0.01
Plt0.01
Plt0.01
Plt0.01
Flow-mediated dilatation ()
Subjects with homozygous FH
Control
FH
Control
CAD
Smokers
Control
CAD
Smokers
Celermajer et al Lancet 3401111, 1992
CP1240167-6
24
Endothelial FunctionBasic Science to Clinical
Practice
Discovery of NO and the role of the endothelium
Endothelial function with exercise and mental
stress
First endothelial function in humans
Noninvasive endothelial function
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Anderson et al
CP1176470-2
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? inbrachialarterydiameter()
P0.08
Plt0.001
n7
n26
n11
Anderson et al JACC 261238, 1995
CP1176470-4
27
Endothelial FunctionBasic Science to Clinical
Practice
Comparison peripheral and coronary endothelial
function
Discovery of NO and the role of the endothelium
Endothelial function with exercise and mental
stress
Coronary endothelial function in clinical practice
First endothelial function in humans
Noninvasive endothelial function
28
Coronary Blood Flow Function Protocol
Diagnostic angiography
Adenosine IC 24-36 µg
Endothelial
Ach 10-6
Ach 10-5
Ach 10-4
NTG
Hemodynamic data Doppler velocity Diagnostic
angiogram
IVUS
Infusion catheter Doppler wire
CP922798- 2
29
NS
Coronaryblood flowresponse()
Plt0.005
Plt0.01
Zeiher Circ, May 1995
CP990350-5
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CP990323-2
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Coronary Endothelial Function Protocol
NIH grant 1994 Clinical practice 1997
Diagnostic angiography
Adenosine IC
NTG
Acetylcholine
Hemodynamic data
Infusion catheter Doppler wire
CP922798- 2
32
Endothelial FunctionBasic Science to Clinical
Practice
Comparison peripheral and coronary endothelial
function
Discovery of NO and the role of the endothelium
Endothelial function with exercise and mental
stress
Endothelial function and myocardial ischemia
Coronary endothelial function in clinical practice
First endothelial function in humans
Noninvasive endothelial function
CP1240167-17
33
CP1120037-4
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Risk for Stroke or TIA Multivariable Logistic
Regression
Variable
4.1 (1.2-1.4)
Endothelial dysfunction
1.0 (1.0-1.1)
Age
3.7 (1.2-11.2)
Diabetes
Odds ratio and 95 CI
Circulation 2003
CP1045482-14
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CP1045482-20
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CV Events During Follow-Up (53 Months)
Plt0.001
Forearm blood flow (mL/100 mL/min)
No events Events
ACh-induced vasodilation
Heitzer et al Circulation 104, 2001
CP1045482-5
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Endothelial Dysfunction and CV Events
Meta-analysis of 15 studies
Coronary (N5)
Brachial (N10)
Overall
Risk Ratio
CP1137788-1
Lerman and Zeiher Circulation 2004
38
CAD Risk Factors
CP949994-1
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Systemic Manifestation of Endothelial Dysfunction
Sleep apnea
Stroke/TIAs
Dementia
Renal failure
Myocardial infarction Sudden Death
Metabolic Syndrome
Stem cells/EPCs
Erectile dysfunction
Claudication
CP1136207-1
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r0.4, P0.002
changeCBF(Ach 10-4mol/L)
IIEF score
CP1192551-14
41
Conclusions In patients with minimally
symptomatic OSA, diverse properties of
endothelial function are impaired and arterial
stiffness is increased. Although this was not
associated with a significantly increased ABP,
the findings suggest that patients with minimally
symptomatic OSA are at increased cardiovascular
risk.
CP1333354-5
42
Relationship of 1-Year Change in Endothelial
Function with Development of Cognitive
ImpairmentAmong Baseline Cognitively Normal
Elderly Age 60-100 Years (n150)
Score change gt0 worsening from baseline
PAT score change from baseline at 1-year
follow-up
Average 1-yr change -13 from baseline
Score change lt0 worsening from baseline
MMSE ?28 cognitively normal
MMSE score at 1-year follow-up
Lerman A
CP1328553-1
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Relation Between the Number of Endothelial
Progenitor Cells and Endothelial Function
Endothelial progenitor cells(colony-forming
units)
r-0.59 Plt0.001
Change in brachial reactivity ()
Hill et al NEJM 348(7)597, 2003
CP1099981-3
44
CP1333354-29
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Endothelium-Dependent Dilation at Baseline and
After 6 Weeks of Intervention
Plt0.001
Plt0.001
Endothelium-dependentdilation ()
Endothelium-dependentdilation ()
Diet only
Diet exercise
Woo KS et al Circ 1091981, 2004
CP1333354-30
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Endothelium-Dependent Dilation at Baseline and
After 6 Weeks and 1 Year of Intervention
Detraining After 6 Weeks
Continued Training
EDD ()
EDD ()
P0.001
P0.104
Plt0.0001
P0.044
Woo KS et al Circ 1091981, 2004
CP1333354-31
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CP1333354-29
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Endothelial FunctionBasic Science to Clinical
Practice
Comparison peripheral and coronary endothelial
function
Discovery of NO and the role of the endothelium
Endothelial function with exercise and mental
stress
Endothelial function and myocardial ischemia
FDA approved device to assess endothelial function
Comparison between the PAT and coronary
endothelial function
Association between endothelial function and CV
events
Coronary endothelial function in clinical practice
First endothelial function in humans
Noninvasive endothelial function
49

• Be simple, noninvasive, and widely applicable
• Be reproducible, with low interobserver error
• Be standardizable between laboratories and have
  population normal data to inform interpretation
• Be able to predict risk
• Add to the predictive value of established risk
  factor measurement, particularly in
  intermediate-risk subjects
• Be able to demonstrate that improvement with the
  new test predicts a reduction in subsequent
  cardiovascular risk

Celermajer Circ 1172428, 2008
CP1333354-28
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Brachial Artery Ultrasound with FMD
POST OCCLUSION
BASELINE
51
PAT Reactive Hyperemia Protocol
5 - 10 min
5 min
5 - 10 min
Cuff inflation
Cuff deflation
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Example of the Systemic Correction
Occluded Arm
Control Arm
Dilated
Constricted
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Coronary and Peripheral Endothelial Function
Abnormal Endothelial Function
Normal Endothelial Function
Baseline
Acetylcholine
Baseline
Acetylcholine
Angio
Flow
PAT
CP989904-6
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ROC AnalysisNormal Coronary Endothelial Function
N94
Sensitivity ()
AUC 0.834 (0.747-0.921) Plt0.0001
1-specificity ()
Bonetti Lerman JACC 2004
55
MACE During Follow-Up in Relation to F_RHI
F_RHI lt0.42
P0.024
F_RHI ?0.42
Cardiac death MI/Revasc/C. Hosp., ()
Years from EndoPAT study
F_RHI ?0.42
137 121 113 102 85 65 54 43
F_RHI lt0.42
132 112 103 86 71 58 38 27
CP1330116-2
56
Incremental Benefit of Vascular Markers in
Addition to FRS for Coronary Risk Prediction
Lau et al The University of Hong Kong,
57
CP1326653-2
58
Receiver Operating Characteristic (ROC) Curves to
Illustrate the Incremental Benefit Achieved by
Adding Presence of Carotid Plaque or an Impaired
Flow-Mediated Dilatation
Sensitivity
FRS, AUC 0.66
FRS carotid plaque, AUC 0.72 (P0.008 vs FRS)
FRS FMD ?4.75AUC 0.78 (P0.007 vs FRS)
1-specificity
Lau et al Postgrad Med J 84153, 2008
CP1326653-4
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CP1326653-2
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Vulnerable plaque
Endothelial dysfunction
Vulnerable patient
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Correlations Between Flow-Mediated Dilatation
r-0.246 P0.016
FMD()
FRS
Lau et al Postgrad Med J 84153, 2008
CP1326653-3
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Multivariate Predictors of an Acute Coronary Event
P
FRS Hypercholesterolaemia FMD ?4.75
0.034 0.003 lt0.001
Lau et al Postgrad Med J 84153, 2008
CP1326653-5
63
CP1326653-6
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Study of Flow-Mediated Vasodilation in Patients
with and Without Cardiovascular Risk Factors
FMD
IMT
CFR
n
P0.000
P0.000
P0.000
Campuzano et al J Hypertens 241581, 2006
CP1326653-7
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Multiple Linear Regression Model of the Variable
Cardiovascular Risk Score by Framingham
r0.658 P0.000
Framinghamrisk
IMT
Campuzano et al J Hypertens 241581, 2006
CP1326653-8