Transcript Summary Slides Presentation ( file, 10 MB)

New Indices of Endothelial Function
Measured by
Digital Thermal Monitoring of
Vascular Reactivity
Presenter:
Morteza Naghavi, M.D.
Chairman of Scientific Advisory Board
www.endothelix.com
Endothelial Function
is disturbed in various
diseases.
This slide shows the extent
of involvement of
endothelial dysfunction in
various diseases, much like a
high blood pressure
measurement or fever that is
indicative of different
problems.
There is a good argument for
adopting endothelial
function monitoring as part
of routine vital sign
monitoring along with blood
pressure.
Endothelial cells serve multiple functions.
(S)
The vascular endothelium serves multiple functions:
1)
2)
3)
4)
it regulates fluid and molecule traffic between blood and tissues
it is an anti-coagulant surface
it contributes to vascular homeostasis and repair
it plays a vital role in vascular tone and blood flow regulation ***
Assessing this function is the most practical way of measuring
endothelial function.
Endothelial and Vascular Dysfunction:
A “Barometer of Cardiovascular Risk”
• Marker of the inherent atherosclerotic risk
• An integrated index of both the overall CV risk
factor burden and the sum of all
vasculoprotective factors in an individual.
Aging
Smoking
Diabetes
↑ Blood Pressure
Genetics
Diet
Inactivity
↑ Cholesterol
Oxidative Stress
Medications
Brachial Artery Ultrasound with FMD
BASELINE
POST OCCLUSION
Reactive Hyperemia
Reactive hyperemia is the transient increase in organ blood flow that occurs following a
brief period of ischemia (e.g., arterial occlusion).
The left panel shows the effects of a 2 min arterial occlusion on blood flow. In this example, blood flow goes to zero
during arterial occlusion. When the occlusion is released, blood flow rapidly increases (i.e., hyperemia occurs) that lasts
for several minutes. The hyperemia occurs because during the period of occlusion, tissue hypoxia and a build up of
vasodilator metabolites (e.g., adenosine) dilate arterioles and decrease vascular resistance. Then when perfusion
pressure is restored (i.e., occlusion released), flow becomes elevated because of the reduced vascular resistance. During
the hyperemia, the tissue becomes reoxygenated and vasodilator metabolites are washed out of the tissue. This causes
the resistance vessels to regain their normal vascular tone, thereby returning flow to control.
http://www.cvphysiology.com/Blood%20Flow/BF006.htm
Endothelial Function
Basic Science to Clinical Practice Clinical practice
Discovery
of NO and the
role of the
endothelium
Endothelial
function with
exercise and
mental stress
First endothelial
function in
humans
1980
Noninvasive
endothelial
function
1989
1986
Basic
science
Comparison
peripheral and
coronary
endothelial
function
Endothelial
function and
myocardial
ischemia
Coronary
endothelial
function in
clinical practice
Association
between
endothelial
function and CV
events
19951997
1995
1992
FDA approved device
to assess endothelial
function
1996
Comparison
between the
PAT and
coronary
endothelial
function
2005
20002004
2006
2005
Clinical
practice
Moving Endothelial Function Testing out of the
Research Lab and into Doctors Offices
Brachial Artery Ultrasound FMD
• Ultrasound measurement of
brachial artery dilation
• 15-minute test
• Not automated
• Requires skilled operator
VENDYS® - Endothelix, Inc.
• Fingertip temperature changes
• 15-minute test
• Fully automated
• Operator independent
®
What is VENDYS technology?
®
How does VENDYS measure
vascular function?
VENDYS® Vascular Function Monitoring
Blood Pressure “Occluding” Cuff on
Right Upper Arm
Fingertip
Temperature
Sensors on Both
Index Fingers
VENDYS® Vascular Function Monitoring
Addressing Problem 1:
Inaccurate Individualized Assessment of
Cardiovascular Risk
Lower Fingertip Temperature Rebound is Associated
with Higher Burden of Cardiovascular Risk Factors
Measured by Framingham Risk Score
Lower Fingertip Temperature Rebound is Associated
with Higher Coronary Plaque Burden
The Combination of Low Fingertip Temperature Rebound and High Framingham Risk
Score is Associated with High Risk Coronary Artery Calcium Score
VENDYS Improves Risk Stratification of High Risk Patients
(CAC ≥ 100) over Traditional Risk Factor Assessment
Variable
AUC ± S.D.
95% CI
P (compared to FRS)
VENDYS + FRS
0.89 (0.02)
0.79 (0.03)
0.66 (0.04)
0.84 - 0.93
0.72 - 0.84
0.57 - 0.77
0.001
0.001
---
VENDYS
FRS
Lower Fingertip Temperature Rebound is Associated with
the Presence of Cardiometabolic Disorders
Fingertip Temperature Rebound Decreases as the Number
of Cardiometabolic Risk Factors Increases
VENDYS Improves Identification of High Risk
Diabetic Patients (CAC ≥ 100)
DM – Diabetes Mellitus
AUC ± S.D.
95% CI
P
VENDYS + DM
0.91 (0.02)
0.87 - 0.95
0.0001
VENDYS
0.79 (0.03)
0.72 - 0.84
0.0001
DM
0.70 (0.03)
0.63 - 0.78
0.0001
Variable
Lower Fingertip Temperature Rebound is Associated with Increased
Insulin Resistance, Coronary Calcification, and Framingham Risk Score
In Patients with Chest pain, Lower Fingertip Temperature Rebound
is Associated with Myocardial Perfusion Defects
A Combination of VENDYS and Framingham Risk Score May Aid Detection of
Vaguely Symptomatic Patients (SSS ≥ 4) with Myocardial Perfusion Defects
Variable
VENDYS + FRS
VENDYS¥
FRS€
AUC ± S.D.
95% CI
P
0.84 (0.03)
0.75 (0.04)
0.65 (0.05)
0.77 - 0.91
0.65 - 0.84
0.56 - 0.77
0.0001
0.0001
0.004
SSS – Summed Stress Score
Comparison with
FRS
0.001
0.04
---
In Patients with Chest Pain, Lower Fingertip Temperature
Rebound is Associated with Coronary Artery Disease
A Combination of Low Fingertip Temperature Rebound and High Framingham
Risk Score is Associated with Obstructive Coronary Artery Disease
A Combination of VENDYS and Framingham Risk Score May Aid Clinical Risk
Assessment of Vaguely Symptomatic Patients Suspected of having Obstructive
Coronary Artery Disease
Variable
VENDYS + FRS + CAC
CACπ
VENDYS + FRS
VENDYS€
FRS¥
∏
AUC ± S.D.
95% CI
P
Comparison P with FRS
0.94 (0.03)
0.84 (0.04)
0.79 (0.04)
0.74 (0.04)
0.63 (0.05)
0.88 - 0.97
0.76 - 0. 90
0.72 - 0.85
0.65 - 0.82
0.54 - 0.72
0.0001
0.0001
0.0001
0.0001
0.0001
0.001
0.003
0.009
0.03
---
Coronary Artery Calcium Score: CAC: 0, 1-99, 100-399, ≥400
€ Fingertip Temperature Rebound: Tertiles of VENDYS TR
¥ Framingham 10 Year CHD Risk Score (FRS): <10%, 10-20%, >20%
Digital Thermal Monitoring of Vascular Function is Reproducible
Variable
D
SDD
CV (%)
CR (%)
ICC
P value
Heart Rate
0.47
0.054
11.4
10.6
0.7
0.01
Mean Arterial
Pressure
0.44
0.038
8.7
7.5
0.79
0.0005
Start Temperature
0.51
0.036
7.1
7.1
0.81
0.0001
DTM (VENDYS®) Indices of Vascular Function
TR (°C)
0.209
0.012
5.7
2.4
0.82
0.0001
AUC
0.292
0.014
4.8
2.8
0.83
0.0001
D: mean absolute difference; SDD: SD of mean differences; CV: coefficient of variability [(SDD /D)*100];
CR: coefficient of repeatability [(SDD *1.96)*100)]; ICC: Intra-class Correlation Coefficient.
12-month Treatment with Aged Garlic Extract was Associated with
Lower Coronary Calcium Progression and Higher Fingertip Temperature Rebound
Comparison with Competitor
VENDYS® - Endothelix, Inc.
• Fingertip temperature changes
• 15-minute test
• Fully automated
EndoPAT® - Itamar Medical Inc.
• Fingertip pressure changes
• 15-minute test
• Not automated
Infrared Imaging
Cuff inflated
Post cuff deflation
To schedule a free demo or learn more, send an email to
[email protected].
VENDYS® Portable
A complete system to perform automated, vascular function studies
• Cuff management module (CMM)
• Digital thermal monitoring (DTM) module
• VENDYS® fingertip probes
• Laptop computer with pre-installed software
– Data acquisition
– Report generation and data tabulation
Software Screenshots
The VENDYS Report
Software Screenshots
Report Viewer
Temperature Curves
The VENDYS® Report
Red = right finger
Blue = left finger
Flags help to notify user
of conditions that may
affect the technical
quality of the study.
A summary of
VENDYS indices is
shown here.
aTR is the primary
vascular reactivity
index.
Vascular Reactivity Gauge
Green = Good
Yellow = Intermediate
Red = Poor
Ambient room
temperature is recorded
throughout the study.
Sample Report Screen:
“Intermediate” Vascular Reactivity
Sample Report Screen:
“Poor” Vascular Reactivity
Digital Thermal Monitoring of Vascular Function is Reproducible
Variable
D
SDD
CV (%)
CR (%)
ICC
P value
Heart Rate
0.47
0.054
11.4
10.6
0.7
0.01
Mean Arterial
Pressure
0.44
0.038
8.7
7.5
0.79
0.0005
Start Temperature
0.51
0.036
7.1
7.1
0.81
0.0001
DTM (VENDYS®) Indices of Vascular Function
TR (°C)
0.209
0.012
5.7
2.4
0.82
0.0001
AUC
0.292
0.014
4.8
2.8
0.83
0.0001
D: mean absolute difference; SDD: SD of mean differences; CV: coefficient of variability [(SDD /D)*100];
CR: coefficient of repeatability [(SDD *1.96)*100)]; ICC: Intra-class Correlation Coefficient.
12-month Treatment with Aged Garlic Extract was Associated with
Lower Coronary Calcium Progression and Higher Fingertip Temperature Rebound
Comparison with Competitor
VENDYS® - Endothelix, Inc.
• Fingertip temperature changes
• 15-minute test
• Fully automated
EndoPAT® - Itamar Medical Inc.
• Fingertip pressure changes
• 15-minute test
• Not automated
1
Figure 1: Patient Setup and Sample VENDYS DTM Report
(Above) Illustration of patient setup, with temperature sensors affixed to both index fingers and blood pressure cuffs on both
arms.
(Below left) A sample report screen displays a right finger temperature curve (red), a left finger temperature curve (blue), and
a Zero Reactivity Curve (green).
(Below right) The software-generated, vascular reactivity curve is shown. The vascular reactivity index (VRI) is taken as the
maximum value of this temperature curve during the reactive hyperemic period.
Distribution of VRI
100%
900
90%
800
80%
700
70%
600
60%
500
50%
400
40%
300
30%
200
20%
100
10%
Vascular Reactivity Index
Figure 2A: Distribution of Vascular Reactivity Index (VRI)
A histogram and cumulative percentage curve are shown.
≥ 3.0
2.8 to < 3.0
2.6 to < 2.8
2.4 to < 2.6
2.2 to < 2.4
2.0 to < 2.2
1.8 to < 2.0
1.6 to < 1.8
1.4 to < 1.6
1.2 to < 1.4
1.0 to < 1.2
0.8 to < 1.0
0.6 to < 0.8
0.4 to < 0.6
0.2 to < 0.4
0%
< 0.2
0
Cumulative %
1000
Frequency (n)
2
A
2
B
80
70
Women
Men
60
% of Tests
50
40
30
20
10
0
0 to < 1
Poor
1 to < 2
Intermediate
≥≥ 222
>=
Good
Vascular Reactivity Index
Figure 2B: Distribution of Vascular Reactivity Index (VRI) by Gender
The percent of DTM tests falling into categories of poor, intermediate, and good vascular reactivity is shown for men (solid fill)
and women (hatch fill).
3
VRI vs. Age
4.5
4
Vascular Reactivity Index
3.5
3
2.5
2
1.5
r = - 0.21
P < 0.0001
1
0.5
0
0
20
40
60
80
100
120
Age (Yrs)
Figure 2C: Vascular Reactivity Index (VRI) and Age
A scatter plot, trend line, and Pearson’s r coefficient are shown. VRI was mildly and inversely correlated with age.
4
A
20%
18%
16%
% of tests with VRI < 1
14%
12%
10%
8%
6%
4%
2%
0%
< 50
50 to < 70
>≥=70
70
Age (Yrs)
Figure 2D: Prevalence of Poor VRI in Different Age Groups
The frequency of having a poor VRI score (VRI <1.0) is shown for the three age categories of age < 50y, age 50-70y, and age
>=70y.
4
Distribution of VRI scores for participants aged ≥ 70
B 80%
70%
60%
% of tests
50%
40%
30%
20%
10%
0%
0 to < 1
Poor
1 to < 2
Intermediate
≥2
Good
Vascular Reactivity Index
Figure 2E: Distribution of Vascular Reactivity Index (VRI) in Oldest Age
Group
Table 1: Selected Patient and Test
Characteristics
Variable
Mean ± SD or %(n)
Variable
Mean ± SD or %
Age (y)
65.5 ± 13.7
Cold Finger
5.8% (n=353)
Male / Female
54% / 46%
Sympathetic Response
4.8% (n=294)
Systolic blood pressure
(mmHg)
Diastolic blood
pressure (mmHg)
Heart rate (bpm)
138 ± 20
VRI score, overall
1.53 ± 0.53
77 ± 12
VRI score, women
1.56 ± 0.58
70 ± 13
VRI score, men
1.50 ± 0.49
Right finger t300 (°C)
32.1 ± 2.7
Left finger t300 (°C)
31.9 ± 2.8
Ambient temperature
(°C)
24.3 ± 1.9
Table 1: Selected Patient and Test Characteristics
Finger t300 = finger temperature at the onset of cuff occlusion (time300s); VRI = vascular reactivity index; NVRI =
neurovascular reactivity index; Cold Finger = a flagged condition in which right finger t300 is equal to or less than 27°C;
Sympathetic Response = a flagged condition in which left finger temperature continuously declines after right arm cuff
occlusion
Table 2: Multiple Linear Regression – Models for VRI, SBP, and DBP
VRI (Dependent)
R Square = 0.06, SE = 0.52
Intercept
Age
DBP
Male sex
β
1.885539
-0.00826
0.003341
-0.09741
p-value
< 0.001
< 0.001
0.002
< 0.001
SBP (Dependent)
R Square = 0.02, SE = 20.36
Intercept
VRI
Age
HR
Male sex
β
119.3615425
2.304075346
0.186886935
0.067271865
-0.412960283
p-value
< 0.001
0.001
< 0.001
0.018
0.560
DBP (Dependent)
R Square = 0.10, SE = 11.78
Intercept
VRI
Age
HR
Male sex
β
70.26680855
1.796063985
-0.150770023
0.1759533
3.509046088
p-value
< 0.001
< 0.001
< 0.001
< 0.001
< 0.001
Results are shown for four separate multiple linear regression models: VRI (vascular reactivity index), SBP
(systolic blood pressure) and DBP (diastolic blood pressure). β = β coefficient; R Square = R2; SE =
standard error. Units for variables were as follows: Age (y), HR (bpm), Sex (male = 1, female = 0), SBP and
DBP (mm Hg).
Table 3: Comparison between CVD Risk Assessment Methods
Method
Type
(Structural,
Functional,
Risk Factors)
Independen
t of Age
Predictive
Value
Response to
Therapy
Ease of Use and
Applicability in
Primary Care
Setting
Intra- and Inter Observer
Reproducibility
Self-Monitoring
by Patients at
Home
Coronary Artery
Calcium
Structural
-
+++
-
+
+++
-
Carotid IMT and
Plaque
Structural
-
++
+
++
+
-
Ankle Brachial
Index
Structural
-
++
-
+++
++
-
Arterial Stiffness
(e.g., PWV, AI,
C1/C2)
Risk FactorBased Risk
Calculators
(e.g.,FRS,
SCORE, QRISK2)
FMD
Structural/
-
++
+
++
++
-
Risk Factors
-
++
n/a
+++
++
++
Functional
+
++
++
-
-
-
PAT (RHI)
Functional
+
++
++
+++
++
++
PPG (RI)
Functional
+
++
++
+++
++
++
DTM (VRI)
Functional
+
++
++
+++
++
+++
Functional
Table 3: Comparison between CVD Risk Assessment Methods
Carotid IMT = carotid intima-media thickness; PWV = pulse wave velocity; AI = augmentation index; C1/C2 = indices of large and small
artery compliance (elasticity); FRS = Framingham Risk Score; SCORE = Systematic Coronary Risk Evaluation risk score system published by
The European Society of Cardiology; QRISK2 = risk calculator developed by UK National Health Service; FMD = flow mediated dilatation;
PAT = peripheral arterial tonometry; RHI = reactive hyperemia index; PPG = photoplethysmography for digital pulse waveform analysis;
RI = reflection index; DTM = digital thermal monitoring; VRI = vascular reactivity
VENDYS Publications
DTM Clinical Papers:
•Association of coronary artery calcium score and vascular dysfunction in long-term hemodialysis patients. Hemodialysis International,
International Society for Hemodialysis (2013). PDF
•Beneficial effects of aged garlic extract and coenzyme Q10 on vascular elasticity and endothelial function: The FAITH randomized clinical trial
Nutrition / Elsevier (2013). PDF
•Evaluation of Digital Thermal Monitoring as a Tool to Assess Perioperative Vascular Reactivity J Atheroscler Thromb (2013). PDF
•A Novel Technique for the Assessment of Preoperative Cardiovascular Risk: Reactive Hyperemic Response to Short-Term Exercise BioMed
Research International (2013). PDF
•Fingertip Digital Thermal Monitoring: A Fingerprint for Cardiovascular Disease? Int J Cardiovasc Imaging (2010). PDF
•Aged garlic extract supplemented with B vitamins, folic acid and L-arginine retards the progression of subclinical atherosclerosis: A randomized
clinical trial. Preventive Medicine (2009). PDF
•Low fingertip temperature rebound measured by digital thermal monitoring strongly correlates with the presence and extent of coronary artery
disease diagnosed by 64-slice multi-detector computed tomography. Int. J Cardiovasc Imaging (2009). PDF
Accompanying Editorial: Digital thermal monitoring of vascular function: a novel tool to improve cardiovascular risk assessment. Vascular
Medicine (2009). PDF
•Concomitant insulin resistance and impaired vascular function is associated with increased coronary artery calcification. Int. Journal of
Cardiology (2009). PDF
•Vascular dysfunction measured by fingertip thermal monitoring is associated with the extent of myocardial perfusion defect. JNC (2009). PDF
•Vascular function measured by fingertip thermal reactivity is impaired in patients with metabolic syndrome and diabetes. J Clin Hypertens
(2009). PDF
•Relations between digital thermal monitoring of vascular function, the Framingham risk score, and coronary artery calcium score. JCCT (2008).
PDF
Accompanying Editorial: Anatomy, physiology, or epidemiology: Which is the best target for assessing vascular health? JCCT (2008). Abstract
•Flow mediated change of finger tip temperature in patients with high cardiovascular risk. Cardiologia Hungarica (2005). PDF English summary
PDF Graphical Data
•Post-Exercise Reactive Hyperemia: A Novel Preoperative Risk Assessment Tool Poster Abstract
•Digital Thermal Monitoring: Non-Invasive Assessment of Perioperative Microvascular Function Poster Abstract
DTM Technical Papers:
Reproducibility and variability of digital thermal monitoring of vascular reactivity. Clin Physiol Funct Imaging
(2011). PDF
Use of temperature alterations to characterize vascular reactivity. Clin Physiol Funct Imaging (2011). PDF
Sensitivity of Digital Thermal Monitoring Parameters to Reactive Hyperemia. Journal of Biomechanical
Engineering, ASME (2010). PDF
Digital Thermal Monitoring (DTM) of Vascular Reactivity Closely Correlates with Doppler Flow Velocity. Conf Proc
IEEE Eng Med Biol Soc (2009). PDF
Lumped parameter thermal model for the study of vascular reactivity in the fingertip. J Biomech Eng (2008).
Abstract
Interrelationships among noninvasive measures of postischemic macro- and microvascular reactivity J Appl Physiol
(2008). PDF
Review Articles about Vascular/Endothelial Dysfunction Measurement:
Endothelial dysfunction over the course of coronary artery disease. Eur Heart J (2013). PDF
The Assessment of Endothelial Function: From Research Into Clinical Practice. Circulation (2012). PDF
The Endothelial Cell in Health and Disease: Its Function, Dysfunction, Measurement and Therapy. Int J Impot Res
(2010). PDF
Endothelial function as a functional expression of cardiovascular risk factors. Biomark Med (2010). PDF
Additional Publications
1. Schier R, Hinkelbein J, Marcus H, Smallwood A, Correa AM, Mehran R, El-Zein R, Riedel B. A
novel technique for the assessment of preoperative cardiovascular risk: reactive hyperemic
response to short-term exercise. Biomed Res Int. 2013;2013:837130. PMID: 23691513
2. Schier R, Marcus HE, Mansur E, Lei X, El-Zein R, Mehran R, Purugganan R, Heir JS, Riedel B,
Gottumukkala V. Evaluation of digital thermal monitoring as a tool to assess perioperative
vascular reactivity J Atheroscler Thromb. 2013;20(3):277-86. PMID: 23197179
3. Ahmadi N, McQuilkin GL, Akhtar MW, Hajsadeghi F, Kleis SJ, Hecht H, Naghavi M, Budoff M.
Reproducibility and variability of digital thermal monitoring of vascular reactivity. Clin Physiol
Funct Imaging. 2011 Nov;31(6):422-8. PMID: 21981452
4. Akhtar MW, Kleis SJ, Metcalfe RW, Naghavi M. Sensitivity of digital thermal monitoring
parameters to reactive hyperemia. J Biomech Eng. 2010 May;132(5):051005. PMID: 20459206
5. Schwartz BG, Economides C, Mayeda GS, Burstein S, Kloner RA. The endothelial cell in health
and disease: its function, dysfunction, measurement and therapy. Int J Impot Res. 2010 MarApr;22(2):77-90. Review. PMID: 20032988
6. van der Wall EE, Schuijf JD, Bax JJ, Jukema JW, Schalij MJ. Fingertip digital thermal monitoring:
a fingerprint for cardiovascular disease? Int J Cardiovasc Imaging. 2010 Feb;26(2):249-52. PMID:
20012695
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