Endo-PAT2000 - Arterial Health

Transcription

Endo-PAT2000
Assessing
Endothelial
Overview
Function:
Itamar Medical
The Test
Endo-PAT tests can be carried out in both the office and hospital settings, with patients
positioned either sitting or supine. Endo-PAT bio-sensors are placed on the index
fingers of both arms. The test takes 15 minutes to complete, is very easy to perform,
and is both operator and interpreter independent. Thermo-neutral, quiet surroundings
are recommended.
Technology
Endo-PAT quantifies the endothelium-mediated changes in vascular tone, elicited by
a 5-minute occlusion of the brachial artery (using a standard blood pressure cuff).
When the cuff is released, the surge of blood flow causes an endothelium-dependent
Flow Mediated Dilatation (FMD). The dilatation, manifested as Reactive Hyperemia,
is captured by Endo-PAT as an increase in the PAT Signal amplitude. A post-occlusion
to pre-occlusion ratio is calculated by the Endo-PAT software, providing the EndoScore.
Automatic Analysis
Endo-PAT2000
Endo-PAT2000
Endo-PAT software is an integral part of the
Endo-PAT system. It is straight-forward and
easy to use. The software is used for both
on-line data acquisition as well as off-line
data analysis.
The online display allows real-time viewing
of events as they occur. The signals are
recorded on the computer for subsequent
review and automatic analysis. Since analysis
is performed by the software, inter- or intraoperator interpretation variability is avoided.
Analyzed test results can be exported to
an Excel spreadsheet that includes multiple
study parameters, calculated variables, and
measures of signal quality.
PAT Technology
Peripheral Arterial Tone (PAT) signal is a proprietary technology used
for non-invasively measuring arterial tone changes in peripheral arterial
beds1. The PAT Signal is measured from the fingertip by recording finger
arterial pulsatile volume changes. Based on PAT Technology, the noninvasive
Endo-PAT2000 system comprises a measurement apparatus that supports
a pair of modified plethysmographic bio-sensors. The unique feature
of the PAT bio-sensors is that they impart a uniform sub-diastolic pressure
field to the distal two thirds of the fingers including their tips. Applying
the pressure in this way is extremely important as it:
●
●
●
Air tubes
electric link
Sensing
region
Buffer
region
Anti-venous pooling region
Prevents distal venous blood pooling, that can induce a veno-arteriolar vasoconstriction reflex
Unloads arterial wall tension, which generates a greater dynamic range of the measured PAT Signal
Fixates the PAT bio-sensor to the finger, which reduces movement artifacts
REFERENCES
Medical Professionals with extensive experience in use and application of EndoPAT 2000:
These physicians are available for conversation regarding technology, use, application, results and
treatment options. Please contact your Arterial Health representative to schedule a convenient time to
speak with these individuals.
Dr. Perry Krichmar
Partner Elite Health in Pembroke Pines, FL
Board Certified Internal Medicine – practicing cardiologist
More than twenty-six years in practice
Dr. Steven Lamm
Faculty member New York University School of Medicine
Internal Medicine – Manhattan, NY
Published author, well-known speaker and media guest
Internist with tremendous experience with EndoPAT technology
Other well-known cardiologists who use the device (EndoPAT 2000) but are not generally available for
reference phone calls:
Dr. Arthur Agatston
Board Certified – Cardiology
Southeast Preventive Cardiology, Miami Beach, FL
Baptist Health Miami, FL
Author of the Agatston Scale to gauge coronary heart disease (EBT screening)
Creator of the South Beach Diet Plan, and accompanying series of books
Dr. Mark Houston, MS, ABAARM, FACP, FAHA, FASH
Board Certified Internal Medicine
Saint Thomas Medical Group Nashville, TN
Vascular Institute o f Saint Thomas Hospital, Nashville, TN
Vanderbilt University School of Medicine - Associate Professor
Hypertension Institute, Nashville, TN, - Director
Published author - “What Your Doctor May Not Be Telling You about Heart Disease” February 2012
Numerous lectures and published papers on CVD
Dr. John Cooke, MD, PhD
Stanford University - Professor of Cardiovascular Medicine
Stanford Cardiovascular Institute - Associate Director for Education and Training
Board Certified – Internal Medicine (1984)/Cardiovascular Disease (1986)
Prominent research professional targeting cardiovascular disease
3340 Peachtree Road, NE, Suite 1800 / Atlanta, GA 30326 / O: 877822.5232/ F: 888.814.1302
www.arterialhealth.net
Key Points on Endothelial Function and EndoPAT 2000
What is endothelial dysfunction?
The pathological state known as endothelial dysfunction is the earliest clinically detectable stage of cardiovascular disease
(which includes heart attacks, stroke, Peripheral Arterial Disease and many other diseases). The functioning of the
endothelial cells – endothelial function – is normally kept in balance. Atherosclerosis risk factors such as high cholesterol,
high blood sugar, high blood pressure, smoking, aging, obesity, chronic infection, and inflammation, can all disrupt this
balance and lead to endothelial dysfunction.
Endothelial dysfunction can be defined as reduced bio-availability of Nitric Oxide (NO) which plays many roles in maintaining
vascular health, most importantly its role in vasomotion. Hence, endothelial dysfunction is defined as an impairment of
endothelium dependent vasodilation. In their 2005 Circulation publication, Lerman et al. (1) defined endothelial dysfunction
as “ultimate risk of the risk factors” a summation of the integrated affects of cardiovascular risk factor.
(1) Lerman A and Zeiher A. Endothelial Function, Cardiac events, Circulation 2005, 111,363-368.
What are the consequences of endothelial dysfunction?
The main consequence of endothelial dysfunction is the initiation of an inflammatory process which leads to the formation
of atherosclerosis and its late sequel, cardiovascular morbidity and mortality. Endothelial dysfunction is involved in
numerous systemic disease processes such as: erectile dysfunction, metabolic syndrome, cerebrovascular diseases
(stroke/TIA), pre-eclampsia toxemia, renal failure, sleep apnea, claudication, and gangrene.
How does the EndoPAT™ measure endothelial function?
EndoPAT™ quantifies the endothelium-mediated changes in vascular tone, elicited by a 5-minute occlusion of the brachial
artery (using a standard blood pressure cuff). When the cuff is released, the surge of blood flow causes an endotheliumdependent. Flow Mediated Dilatation (FMD). The dilatation, manifested as Reactive Hyperemia, is captured by EndoPAT™ as
an increase in the PAT Signal amplitude. A post-occlusion to pre-occlusion ratio is calculated by the EndoPAT™ software,
providing the EndoPAT™ index.
1201 Main St, Suite 1980 | Columbia, SC 29201 | Phone: 803.748.1332 | Fax: 877.822.4632
What is the RHI and how it is calculated?
RHI stands for Reactive Hyperemia Index. This is the final concluded result of the EndoPAT™ test. It is a ratio of the post-topre occlusion PAT amplitude of the tested arm, divided by the post –to-pre occlusion ratio of the control arm.
A - Mean PAT amplitude between 90s-150s post occlusion of the occluded arm
B - Mean PAT amplitude from the baseline period of the occluded arm
C - Mean PAT amplitude between 90s-150s post occlusion of the control arm
D - Mean PAT amplitude from the baseline period of the control arm
Can the EndoPAT help predict endothelial dysfunction and cardiovascular events?
Results of a 2009 study conducted by researchers at the Mayo Clinic and Tufts reported that the EndoPAT test is “highly
predictive” of a major cardiac event, such as a heart attack or stroke, for people who are considered at low or moderate risk
based on their Framingham Risk Score (FRS).
The FRS is the commonly used risk predictor and was developed from the Framingham Heart Study, an ongoing longitudinal
study of heart disease.
In this Mayo Clinic study, published in the Journal of the American College of Cardiology, Amir Lerman, M.D., a cardiologist at
Mayo Clinic and senior author of the study, and other researchers, used an EndoPAT to measure the endothelial health of
270 patients between the ages of 42 and 66 and followed their progress between 1999 and 2007.
These patients already knew that they had low-to-medium risk of experiencing a major adverse cardiac event, or MACE,
based on their FRS. Some of their risk factors included high blood pressure, high cholesterol, obesity, and a family history of
heart disease.
The study results: The rate of MACE in patients who tested positive for endothelial dysfunction was 39% vs. normal
endothelial function 25% (p=0.024). The study showed that patients at low FRS risk but with endothelial dysfunction were
at a higher actual risk of future CV events than patients with high FRS but normal endothelial function.
Furthermore, endothelial dysfunction was found to be an independent risk factor for future MACE on multivariate
analysis (p=0.002).
* Rubinshtein R, Kuvin JT, Soffler M, Lennon RJ, Nelson RE, Pumper GM, Lerman LO, Lerman A. Assessment of Endothelial
Function by Peripheral Arterial Tonometry Predicts Cardiovascular Events Beyond the Framingham Risk Score. JACC 2009;
Suppl.
Is the EndoPAT test used in cardiac-related research studies?
The EndoPAT has been used in dozens of clinical studies conducted at such renowned medical institutions as The Mayo
Clinic, Johns Hopkins Medicine, Harvard Medical School, Cleveland Clinic, the Framingham Heart Study, and Mount Sinai
Hospital (NY).
How well does the EndoPAT correlate with conventional cardiovascular risk factors (Framingham Risk Score)?
Since 2003, the Framingham Heart Study has included endothelial function measurements with EndoPAT. All three study
cohorts (the original study population, the offspring, and the third generation cohort) have been tested with EndoPAT,
totaling over 5,000 subjects.
Hamburg et al published A cross sectional analysis of 1,957 third generation subjects in 2008*. The study demonstrated a
significant inverse relation between EndoPAT index and multiple CV risk factors, including: male sex, body mass index,
total/HDL cholesterol, diabetes, smoking, and lipid-lowering treatment.
*Hamburg NM, Keyes MJ, Larson MG, Vasa RS, Schnabel R, Pride MM, Mitchell GF, Sheaf J, Vita JA, Benjamin EJ CrossSectional Relations of Digital Vascular Function to Cardiovascular Risk Factors in the Framingham Heart Study. Circulation
2008; 117: 2467-2474
Is there a threshold for a good EndoPAT™ result?
Yes, the threshold for a good EndoPAT™ result is an RHI of 1.67 and above. The threshold of 1.67 was determined following
the study of Bonetti et al(6) which was performed at the Mayo Clinic. In this study the EndoPAT™ was found to be correlated
with the coronary endothelial function using the gold standard method of assessment which is injection of ACH during
coronary catheterization.
(6) Bonetti PO, Pumper GM, Higano ST, Holmes DR Jr., Kuvin JT, Lerman A. Noninvasive Identification of Patients with Early
Coronary Atherosclerosis by Assessment of Digital Reactive Hyperemia. JACC 2004; 44: 2137-2141
What are treatment options for endothelium dysfunction?
General treatment options for endothelium dysfunction may include proper diet and exercise, and reducing or eliminating
smoking and excessive alcohol consumption. Several pharmacological choices include statins, angiotensin II receptor
blockers (ARB), angiotensin-converting enzymes (ACE) and β1 receptor blocker (Nebivolol) from various manufacturers.
(Please refer to pharmaceutical company and FDA guidelines when choosing treatment options for your patient)
Homeopathic remedies may include L-Argenine and Niacin. Treatment strategies must take into consideration the overall
medical profile of each patient, with due caution exercised as to dosage amounts and time periods for consumption.
How can EndoPAT, which measures changes in vascular function in a fingertip, ensure that the endothelium of the entire
vascular system has been checked?
The endothelium is the same throughout the body, and when damage is noted in the fingertip, it indicates that the
endothelium is damaged throughout the body—that it’s a systemic dysfunction. Endothelial dysfunction is involved in
numerous systemic disease processes, including: erectile dysfunction, metabolic syndrome, renal failure, sleep apnea, and
stroke.
In a study performed by Bonetti et al* at the Mayo Clinic, a group of 94 subjects underwent angiographic assessment of
coronary endothelial function and subsequent EndoPAT tests. Coronary endothelial function is quantified by injection of
acetylcholine during angiography.
The EndoPAT, which is a non-invasive test, was found to be highly correlative to the angiography results; it was this study
that helped EndoPAT receive final FDA clearance for the detection of coronary endothelial dysfunction. An EndoScore of
1.67 provides a sensitivity of 82% and a specificity of 77% and AUC 0.82 for diagnosing coronary endothelial function.
(*) Bonetti PO, Pumper GM, Higano ST, Holmes DR Jr., Kuvin JT, Lerman A. Noninvasive Identification of Patients with Early
Coronary Atherosclerosis by Assessment of Digital Reactive Hyperemia. JACC 2004; 44: 2137-2141
How reproducible are EndoPAT results?
The EndoPAT test is both operator and interpreter independent.
Selamet et al* tested prospectively the reproducibility and feasibility of the EndoPAT. EndoPAT tests were performed on two
different days separated by no more than seven days in 30 healthy fasting adolescents, ages 13 to 19 years. The authors
concluded, “In healthy adolescents, Endo-PAT is feasible and has excellent reproducibility.” Moreover, the authors stated,
“This technology may provide an easy and reliable means of assessing endothelial function in the pediatric population.”
* Selamet Tierney ES, Newburger JW, Gauvreau K, Geva J, Coogan E, Colan SD, Ferranti SD. Endothelial Pulse Amplitude
Testing: Feasibility and Reproducibility in Adolescents. J Pediatr. 2009; 154(6):901-5.
What is the association between the EndoPAT™ and BAUS (Brachial Artery Ultrasound)?
BAUS is a common research method for peripheral, noninvasive assessment of endothelial function. It differs from
EndoPAT™ in several ways. While the BAUS assesses a single conduit vessel, EndoPAT™ measures several vascular beds,
composed of small vessels and microcirculation. Furthermore, EndoPAT™ corrects for systemic changes by a simultaneous
measurement from the (un-occluded) contra-lateral arm. With minimal training necessary, EndoPAT™ is practically operator
independent, while BAUS requires a trained ultrasound technician and is highly user-dependent in both data acquisition and
analysis. Furthermore, the response measured with EndoPAT™ has a much larger dynamic range (hundreds of %) than the
miniscule changes assessed by BAUS (around 10% for a normal response). Several studies have simultaneously measured
Flow-Mediated Dilatation (FMD) with EndoPAT™ and BAUS. Kuvin et al.(8) at the Tufts Medical Center, Boston,
demonstrated a significant correlation between the two methods (r=0.55, p<0.0001) in a group of 89 adult patients suffering
from chest pain.
(8) Kuvin JT, Patel AR, Sliney KA, Pandian NG, Sheffy J, Schnall RP, Karas RH, Udelson JE. Assessment of Peripheral Vascular
Endothelial Function with Finger Arterial Pulse Wave Amplitude. AHJ 2003; 146: 168-74
Is the EndoPAT correlated to coronary endothelial function?
EndoPAT provides high degrees of sensitivity and specificity when compared to the assessment of coronary artery
endothelial function. Coronary endothelial function is quantified by measuring arterial diameter change and blood flow in
response to graded intra-coronary infusion of acetylcholine during angiography. In a study performed by Bonetti et al* at
the Mayo Clinic, a group of 94 subjects underwent angiographic assessment of coronary endothelial function and
subsequent EndoPAT tests. The results of this comparative study served as the basis for the FDA clearance of the EndoPAT in
the detection of coronary endothelial dysfunction. An EndoPAT index cutoff value of 1.67 provides a sensitivity of 82% and a
specificity of 77% and AUC 0.82 to diagnosing coronary endothelial function.
*Bonetti PO, Pumper GM, Higano ST, Holmes DR Jr., Kuvin JT, Lerman A. Noninvasive Identification of Patients with Early
Coronary Atherosclerosis by Assessment of Digital Reactive Hyperemia. JACC 2004; 44: 2137-2141.
What is the association between the EndoPAT and NO bioavailability?
Nohria and Gerhard et al* at the Brigham & Women’s Hospital, Boston, demonstrated the central role for nitric oxide (NO)
in the post-occlusion vasodilatory response measured by EndoPAT. EndoPAT index (EndoScore) was measured in a group of
nineteen healthy volunteers, before and after intra-arterial infusion of L-NAME (a specific inhibitor of endothelial nitric oxide
synthase). Fifteen matched controls were infused with saline or phenylephrine (an endothelium independent
vasoconstrictor). The study reported that L-NAME blocked 46% of the vasodilatory response (p=0.002). These results provide
direct confirmation that EndoPAT indeed measures a NO-mediated endothelial response.
*Nohria A, Gerhard-Herman M, Creager MA, Hurley S, MitraD, Ganz P. The Role of Nitric Oxide in the Regulation of Digital
Pulse Volume Amplitude in Humans. J Appl Physiol 2006; 101:545-8.
Why does the EndoPAT test require using both arms?
Think of the EndoPAT evaluation as a one-person clinical study with you comparing yourself to yourself. While endothelial
function is being tested in one arm with the blood pressure cuff and finger monitor, your other arm is being used to monitor
changes in blood flow that generally affects both arms. By then measuring both arms, EndoPAT automatically corrects for
any systemic changes that may occur during the course of the test and calculates a final EndoScore based on information
gathered from both finger monitors
Which arm should be used for occlusion/control?
The non-dominant arm is recommended as the tested (occluded) arm due to a lower mass of muscle and leads to easier
arterial occlusion
Does it matter which fingers are used for the test?
Any finger but the thumb may be used. Placement of the sensors on the index fingers is recommended. Due to variance
between fingers in blood supply, symmetrically-paired fingers on both arms should be used (i.e. either both index fingers or
both middle fingers). The thumb should be avoided.
Why does the occlusion last 5 minutes?
Five minutes is the optimal time needed to generate the forced stimulus response of the blood rushing through the vessels
in response to an occlusion. Faizi et al. (4) tested the effects of varying occlusion durations as well as the effects of occlusion
location in 30 apparently healthy adult volunteers. When comparing different occlusion times (1.5, 3, 5 and 8 minutes) with
the cuff placed on the forearm, they saw that the effective maximal response was reached at 5 minutes. The occlusions
shorter than 5 minutes had significantly lower responses. The response to a 5 minute occlusion did not differ significantly
from 8 minutes, but caused less discomfort.
Does having the blood pressure cuff inflated on the upper arm for five minutes cause any discomfort?
The five-minute blood pressure cuff inflation is an accepted standard test to cause reactive hyperemia (the increase of blood
flow after a temporary restriction in blood supply) for the assessment of endothelial function. While the occlusion may
cause some minor discomfort and tingling in the fingers, the test is absolutely harmless.
Where should we place the blood pressure cuff for the occlusion?
Optimal location is on the upper arm. Faizi et al. (5) tested twenty individuals with the cuff placed on their upper arm,
occluding the brachial artery for 5 minutes. These results were compared to their 5 minute forearm occlusion test, showing
an EndoPAT™ index of 1.88 (±0.55) for the forearm occlusion and 2.07 (±0.69) for the upper-arm occlusion (p=0.097).
Forearm occlusion was reported to cause less discomfort than the upper arm.
(5) Faizi AK, Kornmo DW, Agewall S. Evaluation of Endothelial Function Using Finger Plethysmography. Clin Physiol
FunctImaging 2009 Jun 22.
What are the clinical setting requirements for the EndoPAT™ test?
The EndoPAT™ is compact and can be used in almost any clinical setting. Since the PAT signal reflects autonomic nervous
system activity, it is recommended to create a stress free environment during the EndoPAT™ test. The room selected for the
study should be in a quiet area, thermo-neutral room temperature should be maintain 21oC-24oC (70oF-75oF) and dimmed
lights are preferred when performing the study. The test can be performed on a comfortable bed, exam table or armchair
which will enable placing both hands at heart level in a rested position.
What is the PAT signal?
The PAT (Peripheral Arterial Tone) signal is a proprietary technology used for non-invasively measuring arterial tone changes
in peripheral arterial beds. The PAT signal used in the EndoPAT is measured from the fingertip by recording finger arterial
pulse volume changes. Results of the 15-minute test are automatically calculated and an EndoScore is generated, which
indicates the present state of endothelial health.
EndoPAT is the only FDA-cleared device indicated for assessment of Endothelial Function. Clearance was obtained by
demonstrating equivalence of PAT Technology with an invasive catheterization procedure that directly assessed endothelial
dysfunction in coronary arteries. The clinical research was conducted at the Mayo Clinic.
Can the test be performed on children?
We rely on the medical judgment and expertise of the physician regarding the precise patient population. Although most of
the testing on EndoPAT has been done on adults, there are many ongoing and published studies with the EndoPAT on
children and adolescents. There is no special design of the biosensors for children, however. The length of the EndoPAT
biosensor is 5cm, thus the length of the finger of the child must be at least as the length of the biosensor.
Selamet et al* tested prospectively the reproducibility and feasibility of the EndoPAT in adolescents. EndoPAT tests were
performed on two different days separated by no more than seven days in 30 healthy fasting adolescents, ages 13 to 19
years. The authors concluded, “In healthy adolescents, Endo-PAT is feasible and has excellent reproducibility.” Moreover,
the authors stated, “This technology may provide an easy and reliable means of assessing endothelial function in the
pediatric population.”
* Selamet Tierney ES, Newburger JW, Gauvreau K, Geva J, Coogan E, Colan SD, Ferranti SD. Endothelial Pulse Amplitude
Testing: Feasibility and Reproducibility in Adolescents. J Pediatr. 2009; 154(6):901-5.
Mark C. Houston, MD, MS, ABAARM, FACP, FAHA, FASH
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Graduate of Vanderbilt Medical School
Associate Clinical Professor at Vanderbilt Medical School
Director, Hypertension Institute
Staff physician at Saint Thomas Medical Group
Saint Thomas Hospital, Nashville, TN
Has presented over 10,000 lectures on hypertension
More than 150 articles and scientific abstracts in peer-reviewed
journals, textbooks, handbooks and films
Key points from a revolutionary book
P. 4
‘OLD TRUTHS’ rebutted:
1. Abnormal cholesterol levels are not primary causes or indicators of
coronary heart disease
2. Consuming a high-cholesterol diet does not significantly raise blood
cholesterol levels for most people
3. All LDL “bad cholesterol” is not harmful and does not necessarily cause
4. All HDL “good” cholesterol is not protective - some types may promote
5. Blood pressure readings taken in office may not be an accurate
measurement of true blood pressure
6. A fasting morning blood sugar reading of 99 mgl/dL, is not safe or normal
7. A normal body weight..does not ensure heart health as it doesn’t reflect
the amount of risky visceral fat
‘NEW TRUTHS’ revealed:
P. 6
Coronary heart disease doesn’t come from cholesterol; it is the result of
inflammation, oxidative stress (free radical damage) and autoimmune damage to
coronary arteries and other arteries throughout the body.
These are the elements you should be attempting to control.
P. 18
For years we believed that heart disease began with atherosclerosis…That idea is
now obsolete. Today we understand that heart disease begins with an injury to
the endothelium. (Italics added)
P. 22-23
Tests to detect endothelial dysfunction:
Carotid Duplex Scans
Carotid Intima-Media Thickness
Ankle-Brachial Index
EndoPAT (measuring blood flow via Peripheral
Arterial Tonometry)
Journal of the American College of Cardiology
© 2004 by the American College of Cardiology Foundation
Published by Elsevier Inc.
Vol. 44, No. 11, 2004
ISSN 0735-1097/04/$30.00
doi:10.1016/j.jacc.2004.08.062
Coronary Artery Disease
Noninvasive Identification of Patients
With Early Coronary Atherosclerosis by
Assessment of Digital Reactive Hyperemia
Piero O. Bonetti, MD,* Geralyn M. Pumper, RN,* Stuart T. Higano, MD, FACC,*
David R. Holmes, JR, MD, FACC,* Jeffrey T. Kuvin, MD, FACC,† Amir Lerman, MD, FACC*
Rochester, Minnesota; and Boston, Massachusetts
We investigated the value of reactive hyperemia peripheral arterial tonometry (RH-PAT) as
a noninvasive tool to identify individuals with coronary microvascular endothelial dysfunction.
BACKGROUND Coronary endothelial dysfunction, a systemic disorder, represents an early stage of atherosclerosis; RH-PAT is a technique to assess peripheral microvascular endothelial function.
METHODS
Using RH-PAT, digital pulse volume changes during reactive hyperemia were assessed in 94
patients without obstructive coronary artery disease and either normal (n ⫽ 39) or abnormal
(n ⫽ 55) coronary microvascular endothelial function; RH-PAT index, a measure of reactive
hyperemia, was calculated as the ratio of the digital pulse volume during reactive hyperemia
divided by that at baseline.
RESULTS
Average RH-PAT index was lower in patients with coronary endothelial dysfunction
compared with those with normal coronary endothelial function (1.27 ⫾ 0.05 vs. 1.78 ⫾ 0.08:
p ⬍ 0.001). An RH-PAT index ⬍1.35 was found to have a sensitivity of 80% and a specificity
of 85% to identify patients with coronary endothelial dysfunction.
CONCLUSIONS Digital hyperemic response, as measured by RH-PAT, is attenuated in patients with coronary
microvascular endothelial dysfunction, suggesting a role for RH-PAT as a noninvasive test to
identify patients with this disorder. (J Am Coll Cardiol 2004;44:2137– 41) © 2004 by the
American College of Cardiology Foundation
OBJECTIVES
Endothelial dysfunction represents an early stage of coronary artery disease (CAD) (1). The presence of endothelial
dysfunction in coronary or peripheral vessels constitutes an
independent predictor of cardiovascular events (2). Given
that endothelial dysfunction is reversible, early detection of
this disorder may have therapeutic and prognostic implications (2).
Assessment of coronary endothelial function may be
considered the “gold standard” of endothelial function
testing (3). However, because endothelial dysfunction is not
confined to the coronary arteries, less invasive techniques for
the assessment of peripheral vascular endothelial function
have been developed (4,5). Although these methods are
widely used research tools, their operator dependency or
complexity preclude their use in clinical practice (2,5). Thus,
in order to promote endothelial function testing as a
screening method for individuals at increased cardiovascular
risk, techniques to easily assess endothelial function are
needed.
Reactive hyperemia peripheral arterial tonometry (RH-PAT)
is a noninvasive technique to assess peripheral microvascular
From the *Center for Coronary Physiology and Imaging, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota; and the †Division of Cardiology,
New England Medical Center Hospitals, Tufts University School of Medicine,
Boston, Massachusetts. Supported by the National Institutes of Health (HL-63911
and HL-69840), the Mayo Foundation, and an unrestricted grant from Itamar
Medical Ltd.
Manuscript received April 22, 2004; revised manuscript received August 16, 2004,
accepted August 23, 2004.
endothelial function by measuring changes in digital pulse
volume during reactive hyperemia (6,7). This study was designed to investigate the relationship between coronary and
peripheral microvascular endothelial function and to assess the
value of RH-PAT as a tool to identify individuals with
coronary endothelial dysfunction.
METHODS
Patients. This study was approved by the Mayo Clinic
Institutional Review Board. Ninety-four consecutive patients, who were referred for coronary angiography to
exclude CAD and were found to have no significant
epicardial coronary stenoses (⬍30% diameter), were studied
prospectively. Exclusion criteria included prior myocardial
infarction; percutaneous coronary intervention; coronary
artery bypass graft surgery; unstable or variant angina; an
ejection fraction ⱕ50%; valvular heart disease; peripheral
vascular disease; uncontrolled arterial hypertension; allergy
to latex; and/or significant endocrine, hepatic, renal, or
inflammatory disease. Cardiovascular medications were
withheld for at least 48 h before cardiac catheterization.
Coronary and RH-PAT studies were performed in the
fasting state.
Assessment of coronary vasoreactivity. After diagnostic
coronary angiography and exclusion of significant CAD,
measurements of endothelium-dependent and endotheliumindependent coronary flow reserve were performed as previously described (3,8,9). According to previous studies,
2138
Bonetti et al.
Reactive Hyperemia and Endothelial Function
Abbreviations and Acronyms
CAD
⫽ coronary artery disease
CBF
⫽ coronary blood flow
L-NAME ⫽ N-nitro-L-arginine methyl ester
NO
⫽ nitric oxide
PAT
⫽ peripheral arterial tonometry
RH-PAT ⫽ reactive hyperemia peripheral arterial
tonometry
ROC
⫽ receiver operating characteristic
normal coronary endothelial function was defined as an
increase in coronary blood flow (CBF) of ⬎50% in response
to the maximum dose of acetylcholine (8,9).
RH-PAT. The principle of peripheral arterial tonometry
(PAT) has been recently described (6,7). Briefly, this system
(Itamar Medical Ltd., Caesarea, Israel) comprises a finger
probe to assess digital volume changes accompanying pulse
waves.
The RH-PAT measurements and cardiac catheterization
were performed on the same day; RH-PAT studies were
carried out at least 3 h after cardiac catheterization in a
thermoneutral environment. According to previous studies
(6), a blood pressure cuff was placed on one upper arm
(study arm), while the other arm served as a control (control
arm). Peripheral arterial tonometry probes were placed on
one finger of each hand for continuous recording of the
PAT signal. After a 10-min equilibration period, the blood
JACC Vol. 44, No. 11, 2004
December 7, 2004:2137–41
pressure cuff was inflated to suprasystolic pressures for 5
min. Then the cuff was deflated, while PAT recording
continued for 10 min (Fig. 1). A total of 19 patients with
normal coronary endothelial function and 17 patients with
coronary endothelial dysfunction agreed to take 0.4-mg
nitroglycerin sublingually to assess endothelium-independent
PAT response. In these patients nitroglycerin was given 10
min after cuff deflation, and 10 min later PAT recording
was stopped.
The RH-PAT data were analyzed by a computer in an
operator-independent manner as previously described (6).
As a measure of reactive hyperemia, RH-PAT index was
calculated as the ratio of the average amplitude of the PAT
signal over a 1-min time interval starting 1 min after cuff
deflation divided by the average amplitude of the PAT
signal of a 3.5-min time period before cuff inflation (baseline). Subsequently, RH-PAT index values from the study
arm were normalized to the control arm. The choice to use
the average 1-min PAT signal starting 1 min after cuff
deflation to describe the magnitude of reactive hyperemia
was based on the observation that this time interval provided the best information regarding detection of coronary
endothelial dysfunction as determined by receiver operating
characteristic (ROC) curve analysis as well as the best
correlation with CBF response to acetylcholine. Hyperemic
response to nitroglycerin was similarly assessed; average
PAT signal amplitude of four consecutive 1-min periods
starting at 5 min after administration of sublingual nitro-
Figure 1. Representative reactive hyperemia peripheral arterial tonometry recordings of subjects with normal and abnormal reactive hyperemic response.
Normal response is characterized by a distinct increase in the signal amplitude after cuff release compared with baseline.
JACC Vol. 44, No. 11, 2004
December 7, 2004:2137–41
glycerin was calculated. Peripheral arterial tonometry response to nitroglycerin was then calculated as the ratio of
the PAT amplitude of the 1-min interval during which peak
average PAT signal was recorded divided by the amplitude
of the baseline PAT signal (nitroglycerin-PAT index).
Determination of reproducibility of RH-PAT measurements was described earlier (6).
Statistical analysis. Results are expressed as mean values ⫾
SEM. Fisher exact test and unpaired t test or analysis of
variance was used to compare differences between groups.
The ROC curve analysis was done to identify the RH-PAT
index value for optimal discrimination between presence/
absence of coronary endothelial dysfunction. Simple linear
regression and multivariable analysis using a backward
stepwise regression model were utilized for evaluation of
possible associations between RH-PAT index and various
clinical variables and cardiovascular risk factors. Multivariable analysis included all variables that were tested in
univariable analysis. The ROC curve analysis was done by
SPSS statistical software (SPSS Inc., Chicago, Illinois). All
other analyses were done by StatView statistical data analysis software (SAS Institute, Cary, North Carolina). Statistical significance was accepted for p ⬍ 0.05.
RESULTS
A total of 94 patients were studied; 39 had normal coronary
endothelial function, and 55 had coronary endothelial dysfunction (Table 1).
Average RH-PAT index was higher in individuals with
normal coronary endothelial function than in those with
coronary endothelial dysfunction (1.78 ⫾ 0.08 vs. 1.27 ⫾
0.05; p ⬍ 0.001).
Linear regression analysis identified a significant relationship between RH-PAT index and CBF response to acetylcholine (r ⫽ 0.405, p ⬍ 0.001). In addition, univariable
analysis revealed significant relationships between RH-PAT
index and body mass index as well as high-density lipoprotein cholesterol levels (Table 2). However, multivariable
analysis identified CBF response to acetylcholine as the only
independent predictor of RH-PAT index (p ⫽ 0.006).
By ROC curve analysis, an RH-PAT index of 1.35 was
identified as the best discriminating value between individuals with normal and abnormal coronary endothelial function (Fig. 2). For an RH-PAT index value ⬍1.35, the
sensitivity and specificity for the detection of coronary
endothelial dysfunction were 80% and 85%, respectively.
When the patients were divided based on this cutoff value,
a significant difference in the average CBF response to
acetylcholine was found between patients with an RH-PAT
index of ⱖ1.35 and those with a value of ⬍1.35 (70.0 ⫾
11.9% vs. 6.5 ⫾ 8.7%; p ⬍ 0.001). In contrast, there was no
difference in the endothelium-independent coronary flow
reserve to adenosine between these two groups (3.0 ⫾ 0.1
vs. 3.1 ⫾ 0.1; p ⫽ 0.711); PAT response to nitroglycerin
was similar in patients with normal and abnormal coronary
Bonetti et al.
2139
Table 1. Clinical Characteristics of Patients With Normal and
Abnormal Coronary Endothelial Function
Age (yrs)
Male, n (%)
BMI (kg/m2)
Hypercholesterolemia, n (%)
Hypertension, n (%)
Diabetes, n (%)
Smoking, n (%)
Family history of CAD, n (%)
ACE inhibitor, n (%)
Beta-blocker, n (%)
Calcium channel blocker, n (%)
Nitrate, n (%)
Lipid-lowering medication, n (%)
Total cholesterol (mmol/l)
LDL cholesterol (mmol/l)
HDL cholesterol (mmol/l)
Triglycerides (mmol/l)
Fasting blood glucose (mmol/l)
Heart rate (beats/min)
Systolic blood pressure (mm Hg)
Diastolic blood pressure (mm Hg)
Pulse pressure (mm Hg)
LVEF (%)
⌬CBF (Ach), %
⌬CAD (Ach), %
CFR
⌬CBF (NTG), %
⌬CAD (NTG), %
Normal
Coronary
Endothelial
Function
(n ⴝ 39)
Abnormal
Coronary
Endothelial
Function
(n ⴝ 55)
50 ⫾ 2
16 (41)
28.2 ⫾ 0.8
19 (49)
21 (54)
2 (5)
15 (38)
30 (77)
7 (18)
13 (33)
19 (49)
19 (49)
11 (28)
4.8 ⫾ 0.2
2.8 ⫾ 0.1
1.4 ⫾ 0.1
1.4 ⫾ 0.2
5.5 ⫾ 0.2
69 ⫾ 2
128 ⫾ 3
75 ⫾ 2
53 ⫾ 3
64 ⫾ 1
107.3 ⫾ 8.8
0.7 ⫾ 1.9
2.9 ⫾ 0.1
22.7 ⫾ 10.4
13.3 ⫾ 2.7
49 ⫾ 2
23 (42)
29.5 ⫾ 0.9
31 (56)
20 (36)
6 (11)
23 (42)
41 (75)
10 (18)
17 (31)
23 (42)
29 (53)
22 (40)
4.7 ⫾ 0.2
2.8 ⫾ 0.1
1.3 ⫾ 0.1
1.5 ⫾ 0.2
5.7 ⫾ 0.2
67 ⫾ 1
126 ⫾ 2
73 ⫾ 1
53 ⫾ 2
63 ⫾ 1
⫺12.9 ⫾ 6.2*
⫺27.6 ⫾ 4.3*
3.1 ⫾ 0.1
15.4 ⫾ 8.9
14.8 ⫾ 2.4
Values are mean ⫾ SEM or n (%). *p ⬍ 0.001 vs. normal coronary endothelial
function group.
ACE ⫽ angiotensin-converting enzyme; BMI ⫽ body mass index; CFR ⫽
endothelium-independent coronary flow reserve to adenosine; HDL ⫽ high-density
lipoprotein; LDL ⫽ low-density lipoprotein; LVEF ⫽ left ventricular ejection
fraction; ⌬CAD (Ach) ⫽ change in coronary artery diameter in response to
acetylcholine; ⌬CAD (NTG) ⫽ change in coronary artery diameter in response to
nitroglycerin; ⌬CBF (Ach) ⫽ change in coronary blood flow in response to
acetylcholine; ⌬CBF (NTG) ⫽ change in coronary blood flow in response to
nitroglycerin.
endothelial function (nitroglycerin-PAT index 1.42 ⫾ 0.13
and 1.33 ⫾ 0.13; p ⫽ 0.628).
DISCUSSION
This study demonstrates that patients with coronary microvascular endothelial dysfunction have a lower peripheral
hyperemic response, as measured by RH-PAT, than those
with normal coronary endothelial function, suggesting a
potential role for RH-PAT as a noninvasive test to identify
individuals with coronary endothelial dysfunction.
Reactive hyperemia peripheral arterial tonometry represents a noninvasive technique for measuring digital reactive
hyperemia, which is partly mediated by endotheliumderived nitric oxide (NO) (10). Thus, the magnitude of
reactive hyperemia may serve as an index of peripheral
microvascular endothelial function. Indeed, an excellent
correlation between forearm blood flow response to reactive
2140
Bonetti et al.
JACC Vol. 44, No. 11, 2004
December 7, 2004:2137–41
Table 2. Univariate Analysis of Potential Clinical Predictors of
the RH-PAT Index
Variables
r
p Value
⌬CBF (Ach)
Age
BMI
Height
Weight
Heart rate
Systolic blood pressure
Diastolic blood pressure
Pulse pressure
Total cholesterol
LDL cholesterol
HDL cholesterol
Triglycerides
Family history of CAD
Diabetes
Smoking
0.405
0.129
⫺0.238
0.091
⫺0.126
⫺0.128
0.105
0.179
0.048
0.212
⫺0.007
0.255
⫺0.055
0.040
0.032
0.040
⬍0.001
0.215
0.021
0.379
0.224
0.217
0.312
0.083
0.645
0.840
0.951
0.014
0.600
0.703
0.761
0.701
RH-PAT ⫽ reactive hyperemia peripheral arterial tonometry; other abbreviations as
in Table 1.
hyperemia and that to intra-arterial infusion of acetylcholine
was demonstrated (11).
Reactive hyperemia peripheral arterial tonometry measures digital pulse volume at rest and during reactive
hyperemia. Although digital pulse volume is modulated by
various local, systemic, and environmental factors, this
parameter is also affected by the bioavailability of NO and,
therefore, also depends on endothelial function (12). The
role of endothelium-derived NO in the RH-PAT response
was investigated in a preliminary study, in which RH-PAT
testing was performed before and during brachial artery
infusion of N-nitro-L-arginine methyl ester (L-NAME),
an inhibitor of NO synthesis, in healthy volunteers (7). In
this study, L-NAME reduced RH-PAT index significantly
Figure 2. Receiver operating characteristic curve for the reactive hyperemia
peripheral arterial tonometry (RH-PAT) index to identify patients with
normal coronary endothelial function. An RH-PAT index of 1.35 discriminates best between presence/absence of coronary endothelial dysfunction.
AUC ⫽ area under the curve.
by 61%. Taken together, measuring reactive hyperemia by
RH-PAT provides a noninvasive means for assessing peripheral microvascular endothelial function.
Average RH-PAT index was significantly lower in individuals with coronary endothelial dysfunction. Moreover,
and similar to a study by Anderson et al. (13), we found a
significant correlation between RH-PAT index and the
CBF response to acetylcholine. This moderate correlation
may be secondary to the differential response of vascular
beds to different stimuli. Therefore, defining a cutoff value
may represent a more accurate method to compare endothelial function between peripheral and coronary vessels.
Indeed, using ROC curve analysis, we found a sensitivity of
80% and a specificity of 85% for an RH-PAT index ⬍1.35
to identify patients with coronary endothelial dysfunction.
The similar PAT response to nitroglycerin in individuals
with normal and abnormal coronary endothelial function
supports the concept that the RH-PAT index represents a
measure of endothelial function. This is underscored by the
similar endothelium-independent coronary flow reserve in
both groups when patients were divided based on an
RH-PAT index of 1.35.
To minimize the impact of confounding factors on the
RH-PAT results, a two-pronged approach was used. First,
the reactive hyperemic response was referenced to a baseline
derived from the same finger in order to eliminate local
finger-related effects. Second, the effect of systemic factors
was minimized by normalizing the RH-PAT value of the
study arm to the corresponding PAT signal of the control
arm. Other factors affecting peripheral vascular tone, like
temperature, were less of a concern in our study because
environmental conditions during testing were kept equal for
all patients.
The present study has several limitations. Only patients
with chest pain undergoing cardiac catheterization were
included. Similar to a previous study (8), distribution of
traditional risk factors was similar among patients with
normal and abnormal coronary endothelial function. This
may explain the absence of a significant relationship between traditional risk factors and RH-PAT index and may
also suggests the possibility of a selection bias that may limit
translation of the results to a general population. Another
potential limitation pertains to the definition of coronary
endothelial dysfunction used. The role of coronary endothelial dysfunction as an independent risk factor for cardiovascular events is well established (2). Thus, our definition
of coronary endothelial dysfunction was based on previous
studies demonstrating the adverse prognostic impact of an
increase in CBF to acetylcholine of ⬍50% (8,9). Finally, our
results cannot be transferred to patients with heart failure or
autonomous nervous system dysfunction who may show
alterations of the peripheral circulation. Given these limitations, our results require independent confirmation and
further validation in different populations.
In summary, our study demonstrates that digital reactive
hyperemia, as measured by RH-PAT, is attenuated in
JACC Vol. 44, No. 11, 2004
December 7, 2004:2137–41
patients with coronary endothelial dysfunction compared
with individuals with normal coronary endothelial function.
This suggests a role for RH-PAT as a noninvasive tool to
identify patients during the early stage of CAD.
Reprint requests and correspondence: Dr. Amir Lerman, Division
of Cardiovascular Diseases, Mayo Clinic, 200 First Street SW,
Rochester, Minnesota 55905. E-mail: lerman.amir@mayo.edu.
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atherosclerotic coronary artery disease. Herz 1999;24:544 –7.
4. Anderson TJ, Gerhard MD, Meredith IT, et al. Systemic nature of
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71B– 4B.
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12. Noon JP, Haynes WG, Webb DJ, Shore AC. Local inhibition of nitric
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CLINICAL RESEARCH
European Heart Journal (2010) 31, 1142–1148
doi:10.1093/eurheartj/ehq010
Prevention
Assessment of endothelial function by
non-invasive peripheral arterial tonometry
predicts late cardiovascular adverse events
Ronen Rubinshtein 1, Jeffrey T. Kuvin 2, Morgan Soffler 2, Ryan J. Lennon 3, Shahar Lavi1,
Rebecca E. Nelson 1, Geralyn M. Pumper 1, Lilach O. Lerman 4, and Amir Lerman 1*
Received 11 May 2009; revised 2 November 2009; accepted 22 December 2009; online publish-ahead-of-print 24 February 2010
Aims
There is growing need for the identification of novel non-invasive methodologies for the identification of individuals
at risk for adverse cardiovascular (CV) events. We examined whether endothelial dysfunction, as detected by noninvasive peripheral arterial tonometry (EndoPAT), can predict late CV events.
.....................................................................................................................................................................................
Methods
Reactive hyperaemia (RH) was induced following upper arm occlusion of systolic blood pressure in 270 outpatients
and results
(54 + 12 years, 48% female). The natural logarithmic scaled RH index (L_RHI) was calculated from the ratio between
the digital pulse volume during RH and at baseline. The patients were followed for CV adverse events (AE: cardiac
death, myocardial infarction, revascularization or cardiac hospitalization) during a 7-year follow-up (inter-quartile
range ¼ 4.4 –8). Cox models were used to estimate the association of EndoPAT results with AE adjusted for age.
During the follow-up, AE occurred in 86 patients (31%). Seven-year AE rate was 48% in patients with
L_RHI , 0.4 vs. 28% in those with L_RHI 0.4 (P ¼ 0.03). Additional univariate predictors of AE were advancing
age (P ¼ 0.02) and prior coronary bypass surgery (P ¼ 0.01). The traditional Framingham risk score was not
higher in patients with AE. Multivariate analysis identified L_RHI , 0.4 as an independent predictor of AE (P ¼ 0.03).
.....................................................................................................................................................................................
Conclusion
A low RH signal detected by EndoPAT, consistent with endothelial dysfunction, was associated with higher AE rate
during follow-up. L_RHI was an independent predictor of AE. Non-invasive assessment of peripheral vascular function may be useful for the identification of patients at risk for cardiac AEs.
----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords
Endothelial function † Outcome † Peripheral arterial tonometry † Reactive hyperaemia
Background
Coronary heart disease is the leading cause of morbidity and mortality in most industrialized societies.1 In spite of comprehensive
treatment and modification of conventional risk factors, there is
still high incidence of cardiovascular (CV) events rate.2 Thus,
there is a need to identify a more individualized functional risk
profile in order to personalize treatment.3
It has been suggested that cardiac risk factors can cause impairment of coronary vasomotor function of both the epicardial
arteries and the microcirculation,4 – 8 which is considered an
important phase in atherogenesis.9 – 11 It has been demonstrated
that coronary endothelial dysfunction in humans may be associated
with myocardial ischaemia.12,13
Coronary endothelial dysfunction is considered an early stage of
atherosclerosis14 and has been shown to be associated with an
increased risk of ischaemic CV outcome events and stroke.15 – 18
Assessment of coronary microcirculatory vasomotor function
(especially in patients without obstructive coronary artery
disease) may therefore allow the identification of patients in the
early stages of coronary atherosclerosis and at risk for CV events.
However, one of the main obstacles in using peripheral endothelial function for individualized assessment of CV risk is the
lack of standardization of these tests.3,19
* Corresponding author. Tel: þ1 507 255 4152, Fax: þ1 507 255 2550, Email: lerman.amir@mayo.edu
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2010. For permissions please email: journals.permissions@oxfordjournals.org.
Downloaded from eurheartj.oxfordjournals.org at Mayo Clinic Library on May 8, 2010
1
Division of Cardiovascular Diseases, Center of Coronary Physiology and Imaging, Mayo College of Medicine, MB4 523, 200 First Street SW, Rochester, MN 55905, USA; 2Division
of Cardiology, Tufts Medical Center, Boston, MA, USA; 3Division of Biomedical Statistics and Informatics, Mayo College of Medicine, Rochester, MN, USA; and 4Division of
Nephrology and Hypertension, Mayo College of Medicine, Rochester, MN, USA
1143
Assessment by EndoPAT predicts late CV AEs
Methods
Patient selection
Between August 1999 and August 2007, 329 symptomatic outpatients
(with unexplained chest pain (low-risk findings during stress testing)
and/or the absence of new obstructive lesions by an invasive coronary
angiogram) underwent evaluation of endothelial function using RH
with non-invasive PAT at the centres for coronary physiology at
Mayo Clinic in Rochester, MN, and in Tufts Medical Center in
Boston, MA. Five patients were excluded from the current investigation on the basis of poor quality signal (n ¼ 3) or lack of research
authorization as required by Minnesota law (n ¼ 2). In 54 patients
(17%), the follow-up and phone interview could not be completed.
The final study group consisted of 270 patients.
Reactive hyperaemia by peripheral arterial
tonometry
All vasoactive medications were discontinued at least 24 h prior to
testing.
Peripheral arterial tonometry signals were obtained using the
EndoPAT 2000 device (Itamar Medical Inc., Caesarea, Israel), which
has been validated and used previously to assess peripheral arterial
tone in other populations.25 – 29 Specially designed finger probes
were placed on the middle finger of each subject’s hand. These
probes comprised a system of inflatable latex air cuffs connected by
pneumatic tubes to an inflating device controlled through a computer
algorithm. A constant counter pressure (pre-determined by baseline
diastolic blood pressure) was applied through the air cushions. This
prevented venous pooling thus avoiding venoarteriolar reflex vasoconstriction. There was no occlusion of arterial blood flow.
Pulsatile volume changes of the distal digit induced pressure alterations in the finger cuff, which were sensed by pressure transducers and
transmitted to and recorded by the EndoPAT 2000 device. A decrease
in the arterial blood volume in the distal finger tip caused a decrease in
pulsatile arterial column changes, reflected as a decrease in the
measured PAT signal, and vice versa. Blood pressure and heart rate
were measured using an automated blood pressure monitor
(Omron Healthcare Inc., Kyoto, Japan; model # HEM-907XL).
Endothelial function was measured via an RH– PAT index. The RH –
PAT set-up has been previously described.23,24,26 An RH protocol consists of a 5 min baseline measurement, after which a blood pressure
cuff on the test arm was inflated to 60 mmHg above baseline systolic
blood pressure or at least 200 mmHg for 5 min. Occlusion of pulsatile
arterial flow was confirmed by the reduction of the PAT tracing to
zero. After 5 min, the cuff was deflated, and the PAT tracing was
recorded for a further 6 min. The ratio of the PAT signal after cuff
release compared with baseline was calculated through a computer
algorithm automatically normalizing for baseline signal and indexed
to the contra lateral arm. The calculated ratio reflects the RHI.
The natural logarithmic scaled RHI (L_RHI) was calculated from the
same ratio between the digital pulse volume during RH and at baseline.
Assessment of clinical status and outcome
events
Vital status was determined by review of medical records, social security death index, and reviews of death certificates supplemented by a
phone interview to determine patients’ clinical status and occurrence
of CV outcome events since PAT examination date. Clinical data
were determined by an investigator blinded to PAT data. The following
clinical parameters were assessed.
Baseline characteristics
Baseline characteristics including risk factors status during the week in
which PAT was performed: (i) Hypertension (blood pressure of .140/
90 or treatment with anti-hypertensive medications), (ii) diabetes mellitus (patient history and/or treatment with insulin or oral hypoglycaemic agents), (iii) family history of coronary artery disease in first-degree
relatives ,55 (male) or ,65 (female) years of age, (iv) hyperlipidaemia (total serum cholesterol level .240 mg/dL or treatment with
lipid-lowering drugs), (v) smoking history (previous or current cigarette smoking), (vi) coronary artery disease, which was defined as
diameter stenosis .50% diagnosed by coronary angiography or documented prior myocardial infarction (MI) [defined according to standard
definition (serum cardiac biomarker elevation with symptoms of
ischaemia and/or ECG changes indicative of new ischaemia/infarction)],
(vii) angiographically diagnosed peripheral vascular disease, and (viii)
patient medications (at baseline).
We also collected the arterial blood pressure measurements and
lipid profile (total, HDL and LDL cholesterol and level of triglycerides,
all expressed in mg/dL) at the time of PAT study. The data from the
risk factors in conjunction with the level of total and HDL cholesterol
and the systolic blood pressure were then used to calculate the
Framingham risk score (FRS) which presented as 10 years risk
(in per cent).
Assessment of subsequent interventions
and outcome events during follow-up
Analysis of the patient medical records which were supplemented by
phone interview (as mentioned above) was performed to detect the
occurrence of any of the following outcome events: (i) all-cause
death, (ii) CV death (all death not known to be definitely non-CV),
(iii) MI, (iv) percutaneous coronary intervention, (v) coronary artery
bypass grafting, (vi) diagnosed ischaemic or haemorrhagic stroke or
transient ischaemic attack (TIA). All cerebrovascular events were confirmed by neurologists to meet the criteria for stroke or TIA through
appropriate combination of medical history, examination, and/or neuroimaging, and (vii) hospitalization for any cardiac cause, defined as
hospitalization for any of the following symptoms: chest pain, dyspnoea, palpitations, or syncope. The number of cardiac hospitalizations
Measurement of peripheral vasodilator response as a measure
for endothelial dysfunction is correlated with adverse outcome
events20 and measurements of this response using fingertip pulse
amplitude tonometry (peripheral arterial tonometry-PAT) may
emerge as a useful method for non-invasive assessment of vascular
health.21,22 Impairment of pulse amplitude hyperemic response is
associated with the presence of coronary artery endothelial dysfunction, and we have previously reported the correlation
between abnormal PAT results and coronary microvascular endothelial dysfunction as detected by invasive evaluation of the coronary endothelial function.23 Reactive hyperaemia (RH) response
(with PAT) as detected by the RH index (RHI) has recently been
shown to be related to multiple traditional and metabolic risk
factors.24 However, it is unknown whether this non-invasive
approach can predict adverse CV outcome events beyond the traditional risk assessment.
The purpose of this study was to examine whether endothelial
dysfunction, as detected by non-invasive PAT, may have a role in
predicting late adverse CV events.
1144
during follow-up period was also recorded. The combined endpoint of
cardiac adverse event (AE) was defined as the occurrence of CV death,
MI, revascularization, or cardiac hospitalizations.
Death certificates were reviewed to verify the date and cause of all
death events occurred during the follow-up period.
Statistical analysis
Results
As mentioned above, a detailed follow-up including a telephone
interview was completed in 270 patients (83%). Baseline characteristics are presented in Table 1. There were missing laboratory data
on the following parameters: creatinine (n ¼ 4), total and HDL
cholesterol (n ¼ 39), triglycerides (n ¼ 38), LDL cholesterol
(n ¼ 31), systolic BP (n ¼ 12), diastolic BP (n ¼ 14).
Analysis of reactive hyperaemia –
peripheral arterial tonometry
Reactive hyperaemia index was calculated from the ratio of the
digital pulse volume during RH and baseline in 270 patients, and
the mean (natural logarithmic) L_RHI was 0.5 + 0.4 (range 20.7
to 1.8).
Clinical outcome
Patients were followed for a mean follow-up of 5.8 years
(median ¼ 5.8 years, IQR 4.4, 8.0) during which 98 patients had
Table 1 Baseline characteristics of 270 patients
undergoing reactive hyperaemia –peripheral arterial
tonometry
Age (mean + SD)
53.7 + 12.4 years
Females
Hypertension
130 (48%)
123 (46%)
Diabetes mellitus
Smoking history
Hyperlipidaemia
Family history of coronary artery disease
Proven peripheral vascular disease
Body mass index (kg/m2) (mean + SD)
32 (11.9%)
60 (22%)
178 (66%)
75 (28%)
6 (2%)
30.5 + 6.6
10 years Framingham risk in % (range)
7.2 + 6.65 (1– 53)
History of prior myocardial infarction
Known coronary artery disease (previous
MI or revascularization)
37 (14%)
43 (16%)
................................................................................
Discharge medications
Beta-blockers
117 (44%)
Calcium channel blockers
107 (40%)
Anti-platelet medications
ACE-inhibitors or ARBs
126 (47%)
123 (46%)
Lipid-lowering drugs
169 (63%)
Nitrates
119 (44%)
................................................................................
Total cholesterol (mg/dL) (mean + SD)
HDL cholesterol (mg/dL) (mean + SD)
182 + 41
51 + 18
LDL cholesterol (mg/dL) (mean + SD)
103 + 34
Triglycerides (mg/dL) (mean + SD)
Systolic BP in mmHg (mean + SD) (range)
147 + 109
126 + 18 (90– 190)
Diastolic BP in mmHg (mean + SD) (range)
76 + 11 (50– 109)
Mean L_RHI
0.5 + 0.4
an AE. Adverse event as defined (CV death/MI/revascularization
or CV hospitalization) occurred in 86 patients.
Nine patients died during follow-up: three died from a definite
CV cause (two patients who died of MI and one patient due to
heart failure). Eight patients experienced MI during the follow-up
period (and two of them died later as mentioned above).
Twenty-eight patients underwent a coronary revascularization procedure (18 percutaneous intervention and 10 coronary artery
bypass surgery). Definite stroke was diagnosed in 10 patients.
Sixty-nine patients overall were hospitalized for a cardiac cause
during the follow-up period. Careful assessment of all cardiac hospitalizations identified exacerbation of chest pain (angina) and suspected acute coronary syndrome as the most frequent admission
diagnosis (in .90% of cases).
Outcome events in relation to peripheral
arterial tonometry results
Adverse event rates differed according to RH-PAT results, as
patients with lower L_RHI had higher event rates during the
follow-up period, and the most useful cut-off point was with an
L_RHI of 0.4. The difference was due to CV death events which
occurred only in the group with an L_RHI , 0.4, but especially
The statistical analysis was performed by an independent observer
(R.J.L.). Continuous variables are summarized as mean + SD, unless
otherwise specified. Discrete variables are summarized as frequency
(percentage). Kaplan– Meier methods were used to estimate survival
and event-free survival rates. Cox proportional hazards models were
used to estimate unadjusted and adjusted hazard ratios with corresponding 95% confidence intervals and P-values. Multiple Cox
regression models were computed to estimate the partial effect of
L_RHI. Three covariate sets were investigated: (1) age, (2) age and
prior CABG, (3) the FRS (modelled as a three-degree-of-freedom
spline). Sets 1 and 2 were chosen because they were significantly
associated with AE. However, both gave similar results. The FRS
was chosen for clinical relevance (and incorporates age into its
calculation).
The best cut-off points for the PAT results for predicting future outcomes was identified and P-values were adjusted for the multiple tests
done to identify the cut-off point.30 The ability of the cut-point to discriminate between high- and low-risk patients was estimated by a
modified c-index statistic,31 similar to the traditional area under the
ROC curve, but specifically for time-to-event endpoints which preclude ROC calculations.
One thousand bootstrap samples were created to estimate the optimism31 in the estimated association between L_RHI and follow-up AE.
The optimism measure indicates how much better the model (or cutpoint) works in the data set on which it was derived vs. other similar
data sets. In each bootstrap sample, the best cut-off for L_RHI was
determined as in the observed sample. The optimism measure was
subtracted from the observed estimate to get a corrected measure
of the effect. The same standard error was used to generate confidence intervals about the corrected point estimate, and a Wald test
was used to calculate a corrected P-value.
R. Rubinshtein et al.
1145
Table 2 Estimated 7 years clinical cardiac adverse event rates in patients undergoing reactive hyperaemia –peripheral
arterial tonometry in relation to natural logarithmic scaled reactive hyperaemia index
Parameter
Patients with L_RHI < 0.4 (n 5 130)
Patients with L_RHI 0.4 (n 5 140)
HR (95% CI)
P-value
0.032
0.93
...............................................................................................................................................................................
3.9%
3.4%
0.0%
3.7%
1 (1.32, 1)
1.06 (0.27, 4.27)
Revascularization
12.7%
11.4%
1.21 (0.55, 2.65)
0.64
Stroke
CV hospitalizations
5.3%
30.5%
3.1%
18.7%
1.6 (0.45, 5.68)
2.06 (1.26, 3.38)
0.46
0.018a
AE
48 %
28 %
1.83 (1.18, 2.81)
0.030a
CV death
Myocardial infarction
a
P-values adjusted for the multiple tests done to identify the optimal cut-point.
Figure 1 Cardiovascular adverse events: a combination of
cardiac death/myocardial infarction/coronary revascularization
and cardiac hospitalizations in patients with and without low
L_RHI (,0.4).
Most baseline characteristics were not different between the
two groups. The mean FRS was also similar in both groups
(Table 3).
Multivariate analysis showed that, for the observed data set,
L_RHI , 0.4 was independently associated with increased AE
rate (HR ¼ 1.79, 95% CI 1.16–2.76, P ¼ 0.008) during follow-up
and identified advancing age as a predictor of AE (HR¼1.2, 95%
CI 1.013–1.45, P ¼ 0.035). L_RHI remained an independent predictor of AE even when included in a model with the FRS
(HR¼1.68, 95% CI 1.02–2.78, P ¼ 0.043) (Table 4).
Discussion
The main finding of our study was that low RH value derived from
the EndoPAT signal was associated with a higher incidence of AEs
during the follow-up period and especially was predictive of significant symptoms (mostly chest pain) during follow-up, requiring
repeated hospitalizations for suspected acute coronary syndrome.
The combined endpoint of CV death, MI, revascularization, and CV
hospitalizations was not only more frequent during follow-up in
Figure 2 Plot of the (inverted) P-values vs. the L_RHI cutpoints comparing the usefulness of the cut-point of L_RHI 0.4
vs. other cut-points to risk stratify patients for adverse events.
due to a significantly higher rate (.50% increased rate) of CV hospitalizations (Table 2). Patients with L_RHI , 0.4 were not only
more likely to be hospitalized but were more likely to experience
repeated hospitalizations. Thus, the total number of hospitalizations during the follow-up period was significantly higher in
patients with L_RHI , 0.4, with an incidence estimate of 0.19/
year (135 hospitalizations during a total of 718.8 follow-up years
in this group), when compared with 0.05/year (overall 44 hospitalizations during a total of 826.4 follow-up years) in the group with
L_RHI 0.4.
The estimated 7-year AE rate was 48% in patients with L_RHI ,
0.4 vs. 28% of patients with L_RHI 0.4 (P ¼ 0.030; c-index ¼
0.57; corrected c-index ¼ 0.55) and the Kaplan– Meier curves continued to separate during the follow-up period (Figure 1).
MI, revascularization, and stroke rates were not significantly
higher in the patient group with L_RHI , 0.4. The comparison
of the significance of this cut-point vs. others to differentiate
patients by risk of AE is shown in Figure 2 as the relation
between the (inverted) P-values and the L_RHI.
1146
Table 3 Selected baseline characteristics and
laboratory values in relation to the natural logarithmic
scaled reactive hyperaemia index
Parameter
L_RHI 0.4
(n 5 140)
L_RHI < 0.4
(n 5 130)
P-value
................................................................................
Age (years)
53 + 12
Total cholesterol (mg/dL) 185 + 36
54 + 13
178 + 45
0.28
0.14
55 + 18
46 + 17
LDL cholesterol (mg/dL)
Systolic blood pressure
(mmHg)
Diastolic blood pressure
(mmHg)
Framingham risk (10
years, %)
L_RHI
104 + 31
127 + 17
103 + 36
125 + 18
0.57
0.57
76 + 10
75 + 12
0.4
6.3 + 4.7
8.3 + 8.3
0.28
0.8 + 0.3
0.1 + 0.2
,0.0001
0.0001
Table 4 Hazard ratios for adverse event from
multiple Cox regression models
Variable
Estimate
Hazard
ratio
95% CI
P-value
................................................................................
Model 1: no adjustment (corrected c-statistic 0.55)
................................................................................
L_RHI , 0.40
Correcteda
0.6004
0.4472
1.82
1.56
(1.18, 2.81)
(1.01, 2.41)
0.007
0.030b
Model 2: adjusted for age (corrected c-statistic 0.57)
................................................................................
L_RHI , 0.40
0.5831
1.79
(1.16, 2.76)
0.008
0.4301
1.54
(1.00, 2.37) 0.052
Correcteda
Age, per
0.1918
1.21
(1.01, 1.45) 0.036
decade
Model 3: adjusted for Framingham risk (corrected c-statistic 0.59)
................................................................................
L_RHI , 0.40
0.5197
1.68
(1.02, 2.78)
0.043
Correcteda
0.3420
1.41
(0.85, 2.33)
0.18
a
Corrected for bias in choosing a cut-point that fits the observed data best via a
bootstrap algorithm.31
b
Corrected P-value according to Contal and O’Quigley.30
patients with a low L_RHI than in patients with higher L_RHI, but
also was able to predict future AE (as defined) beyond the traditional FRS. This may suggest a role for individualized risk assessment using non-invasive evaluation of the endothelial function
by PAT.
Endothelial cells dysfunction is a key component of atherogenesis and contributes to the development of clinical CV diseases.32
In the presence of known vascular risk factors, endothelial cells
undergo phenotypic changes resulting in decreased nitric oxide
bioactivity, thereby promoting vasoconstriction, inflammation,
and thrombosis.33 In human studies, CV risk factors have been
associated with impaired vasomotor function, and individuals
with abnormal vasodilator function were shown to have higher
Study limitations
The study may be influenced by selection bias as the patients
referred for tertiary centres may be a selected group, perhaps
with more significant symptoms but with less overt obstructive
coronary disease. The inclusion of patients with known coronary
HDL cholesterol (mg/dL)
rate of CV events.20 Furthermore, modifications of CV risk
factors that contribute to endothelial dysfunction improve
patient clinical outcomes disproportionately to the improvement
in coronary atherosclerosis,34 thus implying that these beneficial
effects may be mediated in part through improvement in endothelial function.
A key player in the endothelial cells response to various stimuli
is nitric oxide.
Nitric oxide has been shown to be an important factor contributing to the augmentation of the PAT pulse amplitude after
ischaemia, and administration of an endothelial nitric oxide inhibitor blunted the hyperaemic response as detected by PAT.35
Hence, the hypaeremic response detected by PAT reflects endothelial function.
Coronary endothelial dysfunction as evaluated by invasive
methods predict CV events and stroke14 – 17 and correlate with
abnormal PAT results and coronary endothelial dysfunction as
detected by the invasive evaluation of coronary endothelial function.23 Brachial artery flow-mediated dilation was also shown
recently to predict future adverse outcome events in patients
with diagnosed obstructive coronary artery disease.36 The
current study shows that PAT has a similar predictive power.
Overall, PAT is becoming a useful method to evaluate vascular
health in various disease states. For example, PAT detected
improved endothelial function following treatment with enhanced
external counter pulsation in patients with refractory angina pectoris.26 Abnormal endothelial function by PAT was also shown
to be prevalent in adolescents with type 1 diabetes mellitus.37
Thus, the concept of using a non-invasive method to evaluate
endothelial function in an office based manner is an appealing
concept in primary (or secondary) prevention. The potential significance of the assessment of endothelial function is underscored
by previous studies that demonstrated that lack of improvement of
endothelial function by conventional therapy is associated with CV
events.36,38 Therefore, the non-invasive evaluation of endothelial
function may serve as a clinical tool, not only for prediction of
events but also for the assessment of therapy.36 While the main
limitation of peripheral endothelial testing was reproducibility of
the results, PAT may have improved reproducibility, especially
because of ongoing monitoring allowing for complete arterial
occlusion and indexing the RH score to the contralateral arm.39
Our finding that PAT results were predictive of outcome events
beyond the traditional FRS is encouraging given the established
predictive value of the FRS. However, in selected groups such as
young adults and females, the FRS may have a lower predictive
value, and its usefulness for risk stratification in the individual
patient may still be limited.40 – 43 Thus, there is a dire need for
better risk prediction tools, and individualized evaluation of endothelial dysfunction may allow a more personalized risk assessment.3
PAT may therefore be an important risk stratification tool in
addition to the traditional FRS.
Conclusions
In conclusion, a low RH signal as detected by the EndoPAT, and
consistent with endothelial dysfunction, was associated with
higher AE rate during follow-up. L_RHI was an independent predictor of AE beyond the traditional FRS. Non-invasive assessment
of peripheral vascular function in addition to the FRS may be useful
for individualized identification of patients at risk for cardiac AEs.
Supplementary material
Supplementary material is available at European Heart Journal
online.
Conflict of interest: A.L. is a member of the advisory board of
Itamar Medical. All other authors have no conflicts of interest to
disclose.
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doi:10.1093/eurheartj/ehp582
Online publish-ahead-of-print 17 December 2009
.............................................................................................................................................................................
Contrast echocardiography guidance for alcohol septal ablation of
hypertrophic obstructive cardiomyopathy
Dominique Himbert*, Eric Brochet, Gregory Ducrocq, and Alec Vahanian
Department of Cardiology, AP-HP, Bichat-Claude Bernard Hospital, 46 rue Henri Huchard, Paris 75018, France
* Corresponding author. Tel: þ33 1 40 25 66 01, Fax: þ33 1 40 25 88 65, Email: dominique.himbert@bch.aphp.fr
A 63-year-old man was admitted due to worsening dyspnoea and faintness related to hypertrophic obstructive cardiomyopathy. Resting
left ventricular outflow tract obstruction on
echocardiography was 100 mmHg. Angiography
showed normal coronary arteries, with one
main septal perforator artery suitable for
alcohol ablation (Panel A, black arrow). After
installation of a 0.014 in. wire, a 1.5 mm
over-the-wire angioplasty balloon was placed
and inflated (Panel B, black arrow). Injection of
the echographic contrast agent (Sonovuew,
Bracco Imaging) through the catheter showed
that the septal artery supplied a myocardial
area distal to the subaortic bulge, extending to
the tricuspid subvalvular apparatus (Panel C,
white arrow). Thus, ablation of this septal
artery was given up. Careful review of the baseline angiogram showed the presence of another
small, hardly visible, septal perforator artery, 1 cm proximal to the previous one (Panel A, white arrow). It was catheterized by a wire
and a balloon was installed (Panel D, white arrow). Contrast injection opacified the septal bulge (Panel E), confirming that it was the
target vessel for ablation. Two millilitres of pure ethanol were infused over a period of 15 min. Immediate haemodynamic result was
good, with disappearance of either resting or provoked left ventricular outflow tract gradient. Clinical outcome was uneventful.
Alcohol septal ablation has emerged as an effective method to treat symptomatic hypertrophic obstructive cardiomyopathy refractory to medical therapy. However, questions about its acute and long-term safety are still pending. Guidance of the procedure by
contrast echocardiography can avoid acute complications which cannot be anticipated by angiography.
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org
CARDIOVASCULAR FLASHLIGHT

Endo-PAT2000 - Arterial Health

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