Measuring Endothelial Function: A Key to Comprehensive CVD Risk Assessment and Monitoring Response to Therapy

Why Should We Measure Endothelial Function?
A review of State-of-the-Art in CVD Risk Assessment
Risk Factors vs. Structural vs. Functional Tests
www.endothelix.com
Presenter:
Morteza Naghavi, M.D.
Chairman of Scientific Advisory Board
For follow up and slides, please contact Linda Greif
Linda.greif@endothelix.com

Disclaimer:
Opinions presented in this presentation
solely reflect my personal views and should
not be attributed to Endothelix, SHAPE, or
any other organizations or individuals.

Let’s Begin with the End in Mind
Conclusion:
A comprehensive assessment of CVD risk requires 1)measuring risk factors,
2)evaluating the impact that risk factors had on arterial wall over years, and
3)evaluating the current status of vascular function.
Use all of the above for choosing type and intensity of therapy, and use vascular
function for monitoring response to therapy.

Naghavi et al US20100081941
A Comprehensive Assessment of CVD Risk in Asymptomatic Individuals

Naghavi et al. Am J Cardiol. 2006 Jul 17;98(2A):2H-15H

> 15 Million Heart Attacks Each Year
Source:
World
Heart
Federation
The Problem

CVD Is the Most Expensive Disease
Projected total costs of CVD, 2015 to 2030 in
the
United States.
$656
BILLION
$1,208
BILLION
2030
2015
- Company

CVD Is the Most Dangerous Disease

Because
in >50% of victims, the
first symptom of
asymptomatic
atherosclerosis is a
sudden cardiac death
or acute MI.

The real problem:
Not knowing
Who Is High Risk

Problem 1 – Inaccurate Individualized Assessment of
Cardiovascular Risk
Who Has Higher Cardiovascular Risk Based Only on Risk Factors?
Sir Winston Churchill, 91  Jim Fixx, 53 

Slide Source:
Lipids Online
www.lipidsonline.org
1998 – 2002. 222 patients with 1st acute MI, no prior
CAD, no DM. Men <55 y/o (75%), Women <65. 40%
hypertensive
10 yr risk >20%
Goal LDL<100 mg/dL
(optional < 70 mg/dL)
6% 6%
12%
8% 10%
18%
61%
9%
70%
would qualify for statin Rx
% of total
would not qualify for statin Rx
10 yr risk 10 - 20%
Goal LDL<130 mg/dL
(optional < 100 mg/dL)
10 yr risk <10%
Goal LDL<160 mg/dL
High Risk Lower / Moderate RiskModerately High Risk
What was NCEP risk before the MI? Would they have
received statin therapy or more intensive statin therapy?
Traditional Risk Factors Miss the Majority of
High Risk Patients
Akosah et al. JACC 2003:41 1475-9
> 70% the day before the event
would have been classified as low to
moderate risk!!!

Of 136,905 patients hospitalized with CAD, 77% had normal LDL levels
below 130 mg/dl
Modified from Sachdeva et al. AHJ, Vol 157, 111-117 Jan 2009
Chapter 1: Preventive Cardiology; the SHAPE of the Future in Naghavi et al. Asymptomatic Atherosclerosis: Pathophysiology,
Detection and Treatment. Humana Press, 2009

Of 136,905 patients hospitalized with CAD, 45.4% had normal HDL levels
above 40 mg/dl

Of 136,905 patients hospitalized with CAD, 61.8% had normal triglyceride
levels below 150 mg/dl

Problem 2 – Inadequate Monitoring of Vascular Response to
Treatments
Who is Not Responding to Therapy and Has High Residual Risk?

In Search of the
“Vulnerable Patient”
Asymptomatic individuals at risk of a cardiovascular event within 12 months

CVD Genotyping?
Naghavi et al. Circulation. 2003;108:1664
~50%
Apparently
Healthy
People
(New)
~50%
CHD
Patients
(Recurring)

CVD Genotyping?
Naghavi et al. Circulation. 2003;108:1664
~50%
Apparently
Healthy
People
(New)
~50%
CHD
Patients
(Recurrent)

Naghavi et. al. Circulation Journal Vol108, No14; October 7, 2003
The Vulnerable Patient Consensus Statement Preceding the
SHAPE Initiative

Atherosclerosis Test
Negative Positive
No Risk Factors + Risk Factors
Step 1
Test for
Presence of the
Disease
Step 2
Stratify based on the
Severity of the Disease and
Presence of Risk Factors
Step 3
Treat based on
the Level of
Risk
Lower
Risk
Moderate
Risk
Moderately
High Risk
High
Risk
Very
High Risk
Apparently Healthy At-Risk Population
The 1st S.H.A.P.E. Guideline
Conceptual Flow Chart
<75th
Percentile
75th-90th
Percentile
≥90th
Percentile

Atherosclerosis Test
Very Low Risk3
Negative Test
• CACS =0
• CIMT <50th percentile
Lower
Risk
Moderate
Risk
Positive Test
• CACS ≥1
• CIMT 50th percentile or Carotid Plaque
Moderately
High Risk
High
Risk
Very
High Risk
No Risk Factors5 + Risk Factors • CACS <100 & <75th%
• CIMT <1mm & <75th%
& no Carotid Plaque
• Coronary Artery Calcium Score (CACS)
or
• Carotid IMT (CIMT) & Carotid Plaque4
• CACS 100-399 or >75th%
• CIMT 1mm or >75th%
or <50% Stenotic Plaque
• CACS >100 & >90th%
or CACS 400
• 50% Stenotic Plaque6
LDL
Target
<160 mg/dl <130 mg/dl <130 mg/dl
<100 Optional
<100 mg/dl
<70 Optional
<70 mg/dl
Re-test Interval 5-10 years 5-10 years Individualized Individualized Individualized
All >75y receive unconditional treatment2
Apparently Healthy Population Men>45y Women>55y1
ExitExit
Myocardial
IschemiaTest
NoAngiography
Follow Existing
Guidelines
Yes
The 1st SHAPE Guidelines
Step 1
Step 2
Step 3
Optional
CRP>4mg
ABI<0.9
1: No history of angina, heart attack, stroke, or peripheral arterial disease.
2: Population over age 75y is considered high risk and must receive therapy without testing for
atherosclerosis.
3: Must not have any of the following: Chol>200 mg/dl, blood pressure >120/80 mmHg, diabetes,
smoking, family history, metabolic syndrome.
4: Pending the development of standard practice guidelines.
5: High cholesterol, high blood pressure, diabetes, smoking, family history, metabolic syndrome.
6: For stroke prevention, follow existing guidelines.

Atherosclerosis is way too prevalent!

Atherosclerosis: A Very Prevalent Silent Disease
About 60% of this asymptomatic study population had “polyvascular atherosclerosis”

Existing Guidelines (Status Quo):
• Screen for Risk Factors of Atherosclerosis
• Treat Risk Factors of Atherosclerosis
The SHAPE Guidelines:
• Screen for Atherosclerosis (the Disease)
Regardless of Risk Factors
• Treat based on the Severity of the Disease
and its Risk Factors
SHAPE v.s. the Status Quo?

The new ACC/AHA
Guidelines are still
inaccurate because the
recommendation is based
on epidemiological
“normal” cu off points
from a mixed population
of different ethnicities not
personalized structural
and physiological
assessment of
atherosclerosis.
Population-based vs. Individual-based (Personalized) Medicine

Risk Factors and
Structural Assessment
Are Not Enough
Functional Assessment Is
Needed!

Based on the paper by Pepe e. al. Am J Epidemiol 2004; 159:882-890.
ROC Curve, its AUC and Corresponding Odds Ratio
hs-CRP LDL
HDL Smoking
HypertensionD
iabetes etc.
Risk Factors

hs-CRP LDL
HDL Smoking
HypertensionD
iabetes etc.
CAC +FRS
IMT+FRS
Structural
Risk Factors

hs-CRP LDL
HDL Smoking
HypertensionD
iabetes etc.
CAC +FRS
IMT+FRS
Structural
Risk Factors
Combined structural & functional?

What is Endothelial Function?
“Endothelial Function” is a misnomer!
Endothelial cells serve many functions.

(S)
The vascular endothelium serves multiple functions:
1) it regulates fluid and molecule traffic between blood and tissues
2) it is an anti-coagulant surface
3) it contributes to vascular homeostasis and repair
4) it plays a vital role in vascular tone and blood flow regulation ***
Endothelial cells serve multiple functions.
Assessing this function is the most practical way of measuring
endothelial function.

Endothelial Dysfunction
(Vascular Dysfunction)
and 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.
This is why we
believe endothelial
function monitoring
will be adopted as
part of routine vital
sign monitoring.

Most people don’t realize that our
body is a giant network of vessels
(OVER 60,000 MILES) and 99.99% of it
is microvascular and barely visible.
These microvessels function very
similarly and their endothelial function
is the most important part of the
vascular health.

Surface area > 3 tennis courts!

View the animated video http://www.endothelix.com/index.php/physicians/youtube-videos

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 Diet
Smoking Inactivity
Diabetes ↑ Cholesterol
↑ Blood Pressure Oxidative Stress
Genetics Medications

Secondary Prevention
Strategy of
Cardiovascular
Disease
Using Endothelial
Function Testing
Yasushi Matsuzawa,
MD, PhD; Raviteja R.
Guddeti, MD; Taek-
Geun
Circulation Journal
Official Journal of the
Japanese Circulation
Society
http://www.j-circ.or.jp

Comparison
between
dingertip and
coronary
endothelial
function
Association
between
endothelial
function and CV
events
First endothelial
function in
humans
1986
Discovery
of NO and the
role of the
endothelium
1980
Endothelial
function with
exercise and
mental stress
1989
Noninvasive
endothelial
function
1992
Comparison
peripheral and
coronary
endothelial
function
1995
Coronary
endothelial
function in
clinical practice
1996
Endothelial
function and
myocardial
ischemia
1995-
1997
2000-
2004
2005
2006
2010
Clinical practice
Endothelial Function
Basic Science to Clinical Practice
Clinical
practice
Basic
science

Acetylcholine Bradykinin
Shear stress
reactive hyperemia
Ca2
Endothelium
Smooth muscle
(Ca2+)
L-arg
NO
NOS
sGC GTP
Cyclic GMP
Relaxation
Lumen of Artery
Endothelial cells, in response to shear stress or other stimuli, release
nitric oxide and other compounds that elicit relaxation of nearby
smooth muscle cells and result in vasodilation.
Blood flow

New England Journal of Medicine 315 (17) 1986
Intracoronary Artery Injection of Acetylcholine

C1 10-9M Ach
10-8M Ach TNG
New England Journal of Medicine 315 (17) 1986

Halcox JPJ et al, Circulation 2002;106:653
CVE’s over 4 Years in 176 Subjects without CAD
According to CVR and CA Diameters Changes
with ACh
0%
5%
10%
15%
20%
25%
30%
Cor Vasc Res
Change Ach
CA Diameter
Change Ach
vasodil or T1 CVR
vasocon or T2,3 CVR

Al Suwaidi J et al. Circulation 2000;101:948
Cardiac Events in 157 CAD Patients over 28
Months Stratified by CBF Responses to ACh
0
0.5
1
1.5
2
2.5
3
Normal Mild Dysfunction Severe Dysfunction
CHD Death
MI
CHF
CABG
PCI

BASELINE POST OCCLUSION
Brachial Artery Ultrasound with FMD

http://www.cvphysiology.com/Blood%20Flow/BF006.htm
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.

Brachial Artery Ultrasound with FMD
BASELINE
5 minute
cuff occlusion
The resulting
reactive
hyperemia
creates
increased
shear
stress in the
brachial artery,
which
stimulates the
release of NO
and causes
vasodilation.
POST OCCLUSION

Corretti et al: JACC 39:257, 2002
Baseline
4-5 mm
45-60 sec after
cuff release
5.0 mm, FMD = 11%
Ultrasound Imaging of the Brachial Artery

Brachial Artery Flow-Mediated Vasodilation
in a Healthy Individual
Time after cuff release (sec)
Brachial
diameter
(mm)
5.2
5.0
4.8
Pre 30 60 90 120

Takese B, Am J Cardiol 1998:82:1535
Comparison of Brachial and Coronary
Flow-Mediated Vasodilation

Figure 5. Hazard ratio (95% CI) for cardiovascular event for brachial diameter (BD)/unit SD (height adjusted) in univariate and
4 multivariable models. *FRS indicates Framingham Risk Score. **Full model was adjusted for age, sex, diabetes mellitus,
cigarette smoking, systolic blood pressure, blood pressure medication use, HDL cholesterol, LDL cholesterol, triglycerides,
heart rate, and statin use.
Yeboah J et al. Circulation. 2009;120:502-509
Copyright © American Heart Association, Inc. All rights reserved.
From MESA Study

Figure 1 A Kaplan-Meier survival curve showing survival until the first composite adverse CV end point (cardiac mortality, nonfatal
myocardial infarction, hospitalization for heart failure or angina pectoris, stroke, coronary artery bypass grafting, and percutaneous
coronary interventions) in subjects with FMD above (dashed line) and below (solid line) the median value of 11.3%, after controlling
for traditional risk factors (age, gender, lipoproteins, diabetes, hypertension, and BMI). Patients with FMD below the median had
lower survival rate compared with those with FMD above the median (p <0.001).
Michael Shechter , Alon Shechter , Nira Koren-Morag , Micha S. Feinberg , Liran Hiersch
Usefulness of Brachial Artery Flow-Mediated Dilation to Predict Long-Term Cardiovascular Events in Subjects Without
Heart Disease
The American Journal of Cardiology, Volume 113, Issue 1, 2014, 162 - 167
http://dx.doi.org/10.1016/j.amjcard.2013.08.051

The following slides describe
Endothelix’s VENDYS technology for
assessment of vascular reactivity and
endothelial function.

Moving Endothelial Function Testing out of the
Research Lab and into Doctors Offices
VENDYS® - Endothelix, Inc.Brachial Artery Ultrasound FMD
• Fingertip temperature changes
• 15-minute test
• Fully automated
• Operator independent
• Ultrasound measurement of
brachial artery dilation
• 15-minute test
• Not automated
• Requires skilled operator

How does VENDYS®
measure
vascular function?
VENDYS® measures vascular function using small temperature sensors attached
to the fingertips. It detects blood flow during a standard 5-minute arm-cuff
reactive hyperemia test.

VENDYS® Vascular Function Monitoring
Fingertip
Temperature
Sensors on Both
Index Fingers
Blood Pressure “Occluding” Cuff on
Right Upper Arm

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) 0.84 - 0.93 0.001
VENDYS 0.79 (0.03) 0.72 - 0.84 0.001
FRS 0.66 (0.04) 0.57 - 0.77 - - -

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)
Variable 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
DM – Diabetes Mellitus

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 AUC ± S.D. 95% CI P
Comparison with
FRS
VENDYS + FRS 0.84 (0.03) 0.77 - 0.91 0.0001 0.001
VENDYS¥ 0.75 (0.04) 0.65 - 0.84 0.0001 0.04
FRS€ 0.65 (0.05) 0.56 - 0.77 0.004 - - -
SSS – Summed Stress Score

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 AUC ± S.D. 95% CI P Comparison P with FRS
VENDYS + FRS + CAC 0.94 (0.03) 0.88 - 0.97 0.0001 0.001
CACπ
0.84 (0.04) 0.76 - 0. 90 0.0001 0.003
VENDYS + FRS 0.79 (0.04) 0.72 - 0.85 0.0001 0.009
VENDYS€
0.74 (0.04) 0.65 - 0.82 0.0001 0.03
FRS¥
0.63 (0.05) 0.54 - 0.72 0.0001 - - -
∏ 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
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.
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

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. EndoPAT® - Itamar Medical Inc.
• Fingertip temperature changes
• 15-minute test
• Fully automated
• Fingertip pressure changes
• 15-minute test
• Not automated

New Generation VENDYS: VENDYS-II

The VENDYS® ReportTemperature Curves
Red = right finger
Blue = left finger
Vascular Reactivity Gauge
Green = Good
Yellow = Intermediate
Red = Poor
Flags help to notify user
of conditions that may
affect the technical
quality of the study.
A summary of
VENDYS indices is
shown here.
VRI is calculated
based on adjusted
temperature
rebound (aTR)
Ambient room
temperature is recorded
throughout the study.

VENDYS-II® Sample Report (Good VRI)

VENDYS-II® Sample Report (High Borderline VRI)

VENDYS-II® Sample Report (Borderline VRI)

VENDYS-II® Sample Report (Low Borderline VRI)

VENDYS-II® Sample Report (Poor VRI)

Infrared Imaging
Cuff inflated Post cuff deflation
View Video: https://youtu.be/54mlLxXKjgk

VENDYS Digital Thermal monitoring of Neurovascular Reactivity
NVRI

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.
1

Figure 2A: Distribution of Vascular Reactivity Index (VRI)
A histogram and cumulative percentage curve are shown.
2A
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
0
100
200
300
400
500
600
700
800
900
1000
<0.2
0.2to<0.4
0.4to<0.6
0.6to<0.8
0.8to<1.0
1.0to<1.2
1.2to<1.4
1.4to<1.6
1.6to<1.8
1.8to<2.0
2.0to<2.2
2.2to<2.4
2.4to<2.6
2.6to<2.8
2.8to<3.0
≥3.0
Cumulative%
Frequency(n)
Vascular Reactivity Index
Distribution of VRI

0
10
20
30
40
50
60
70
80
0 to < 1
Poor
1 to < 2
Intermediate
>= 2
Good
%ofTests
≥ 2
Women
Men
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).
2B
≥ 2

0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
0 20 40 60 80 100 120
VascularReactivityIndex
Age (Yrs)
VRI vs. Age
r = - 0.21
P < 0.0001
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.
3

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.
4A
0%
2%
4%
6%
8%
10%
12%
14%
16%
18%
20%
< 50 50 to < 70 > = 70
%oftestswithVRI<1
Age (Yrs)
≥ 70

0%
10%
20%
30%
40%
50%
60%
70%
80%
0 to < 1
Poor
1 to < 2
Intermediate
≥ 2
Good
%oftests
Distribution of VRI scores for participants aged ≥ 70
Figure 2E: Distribution of Vascular Reactivity Index (VRI) in Oldest Age Group
The percent of tests falling into categories of poor, intermediate, and good vascular reactivity is shown for patients age >= 70 years.
4B

Table 1: Selected Patient and Test Characteristics
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
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)
138 ± 20 VRI score, overall 1.53 ± 0.53
Diastolic blood
pressure (mmHg)
77 ± 12 VRI score, women 1.56 ± 0.58
Heart rate (bpm) 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 2: Multiple Linear Regression – Models for VRI, SBP, and DBP
VRI (Dependent)
R Square = 0.06, SE = 0.52 β p-value
Intercept 1.885539 < 0.001
Age -0.00826 < 0.001
DBP 0.003341 0.002
Male sex -0.09741 < 0.001
SBP (Dependent)
Intercept 119.3615425 < 0.001
VRI 2.304075346 0.001
Age 0.186886935 < 0.001
HR 0.067271865 0.018
Male sex -0.412960283 0.560
DBP (Dependent)
Intercept 70.26680855 < 0.001
VRI 1.796063985 < 0.001
Age -0.150770023 < 0.001
HR 0.1759533 < 0.001
Male sex 3.509046088 < 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
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
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)
Structural/
Functional
- ++ + ++ ++ -
Risk Factor-
Based Risk
Calculators
(e.g.,FRS,
SCORE, QRISK2)
Risk Factors - ++ n/a +++ ++ ++
FMD Functional + ++ ++ - - -
PAT (RHI) Functional + ++ ++ +++ ++ ++
PPG (RI) Functional + ++ ++ +++ ++ ++
DTM (VRI) Functional + ++ ++ +++ ++ +++

DTM Clinical Papers:
Effect of Tai Chi on Vascular Function among Patients with Peripheral Neuropathy PDF
New Indices of Endothelial Function Measured by Digital Thermal Monitoring of Vascular Reactivity: Data from 6084 Patients
Registry (2016) PDF VENDYS Registry Data
•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
VENDYS Publications

•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 Mar-
Apr;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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