Why should we measure endothelial function
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This document discusses the importance of measuring endothelial function for cardiovascular risk assessment. It begins with background on cardiovascular disease being the leading cause of death globally and the problems with traditional risk assessment based only on risk factors. It then discusses how endothelial dysfunction underlies many disease states and can serve as an integrated measure of risk. The document reviews different techniques for measuring endothelial function, including flow-mediated dilation of the brachial artery. It argues that a comprehensive cardiovascular risk assessment should include measures of both subclinical disease and endothelial function.
![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](https://image.slidesharecdn.com/whyshouldwemeasureendothelialfunction-170531142613/85/Why-should-we-measure-endothelial-function-93-320.jpg)
Why should we measure endothelial function
- 1. 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
- 2. 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.
- 3. 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.
- 4. Naghavi et al US20100081941 A Comprehensive Assessment of CVD Risk in Asymptomatic Individuals
- 5. Naghavi et al. Am J Cardiol. 2006 Jul 17;98(2A):2H-15H
- 6. Background
- 7. > 15 Million Heart Attacks Each Year Source: World Heart Federation The Problem
- 8. 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
- 9. CVD Is the Most Dangerous Disease
- 10. Because in >50% of victims, the first symptom of asymptomatic atherosclerosis is a sudden cardiac death or acute MI.
- 11. The real problem: Not knowing Who Is High Risk
- 12. 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
- 13. 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!!!
- 14. 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
- 15. 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
- 16. Of 136,905 patients hospitalized with CAD, 61.8% had normal triglyceride levels below 150 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
- 17. Problem 2 – Inadequate Monitoring of Vascular Response to Treatments Who is Not Responding to Therapy and Has High Residual Risk?
- 18. In Search of the “Vulnerable Patient” Asymptomatic individuals at risk of a cardiovascular event within 12 months
- 19. CVD Genotyping? Naghavi et al. Circulation. 2003;108:1664 ~50% Apparently Healthy People (New) ~50% CHD Patients (Recurring)
- 20. CVD Genotyping? Naghavi et al. Circulation. 2003;108:1664 ~50% Apparently Healthy People (New) ~50% CHD Patients (Recurrent)
- 21. Naghavi et. al. Circulation Journal Vol108, No14; October 7, 2003 The Vulnerable Patient Consensus Statement Preceding the SHAPE Initiative
- 22. Naghavi et. al. Circulation Journal Vol108, No14; October 7, 2003 The Vulnerable Patient Consensus Statement Preceding the SHAPE Initiative
- 24. SHAPE Task Force Meeting
- 27. 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
- 28. 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.
- 29. Atherosclerosis is way too prevalent!
- 30. Atherosclerosis: A Very Prevalent Silent Disease About 60% of this asymptomatic study population had “polyvascular atherosclerosis”
- 31. 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?
- 32. 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
- 33. Risk Factors and Structural Assessment Are Not Enough Functional Assessment Is Needed!
- 34. Naghavi et al US20100081941 A Comprehensive Assessment of CVD Risk in Asymptomatic Individuals
- 39. 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
- 41. 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. CAC +FRS IMT+FRS Structural Risk Factors
- 43. 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. CAC +FRS IMT+FRS Structural Risk Factors Combined structural & functional?
- 45. What is Endothelial Function? “Endothelial Function” is a misnomer! Endothelial cells serve many functions.
- 46. (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.
- 47. 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.
- 48. 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.
- 49. Surface area > 3 tennis courts!
- 50. View the animated video http://www.endothelix.com/index.php/physicians/youtube-videos
- 51. 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
- 56. 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
- 57. 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
- 58. 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
- 59. New England Journal of Medicine 315 (17) 1986 Intracoronary Artery Injection of Acetylcholine
- 60. C1 10-9M Ach 10-8M Ach TNG New England Journal of Medicine 315 (17) 1986
- 61. 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
- 62. 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
- 63. BASELINE POST OCCLUSION Brachial Artery Ultrasound with FMD
- 64. 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.
- 66. 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
- 67. 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
- 68. 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
- 69. Takese B, Am J Cardiol 1998:82:1535 Comparison of Brachial and Coronary Flow-Mediated Vasodilation
- 70. 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
- 71. 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
- 72. The following slides describe Endothelix’s VENDYS technology for assessment of vascular reactivity and endothelial function.
- 73. 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
- 75. 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.
- 76. VENDYS® Vascular Function Monitoring Fingertip Temperature Sensors on Both Index Fingers Blood Pressure “Occluding” Cuff on Right Upper Arm
- 79. Addressing Problem 1: Inaccurate Individualized Assessment of Cardiovascular Risk
- 80. Lower Fingertip Temperature Rebound is Associated with Higher Burden of Cardiovascular Risk Factors Measured by Framingham Risk Score
- 81. Lower Fingertip Temperature Rebound is Associated with Higher Coronary Plaque Burden
- 82. The Combination of Low Fingertip Temperature Rebound and High Framingham Risk Score is Associated with High Risk Coronary Artery Calcium Score
- 83. 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 - - -
- 84. Lower Fingertip Temperature Rebound is Associated with the Presence of Cardiometabolic Disorders
- 85. Fingertip Temperature Rebound Decreases as the Number of Cardiometabolic Risk Factors Increases
- 86. 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
- 87. Lower Fingertip Temperature Rebound is Associated with Increased Insulin Resistance, Coronary Calcification, and Framingham Risk Score
- 88. In Patients with Chest pain, Lower Fingertip Temperature Rebound is Associated with Myocardial Perfusion Defects
- 89. 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
- 90. In Patients with Chest Pain, Lower Fingertip Temperature Rebound is Associated with Coronary Artery Disease
- 91. A Combination of Low Fingertip Temperature Rebound and High Framingham Risk Score is Associated with Obstructive Coronary Artery Disease
- 92. 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%
- 93. 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
- 94. 12-month Treatment with Aged Garlic Extract was Associated with Lower Coronary Calcium Progression and Higher Fingertip Temperature Rebound
- 95. 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
- 98. New Generation VENDYS: VENDYS-II
- 99. 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.
- 100. The New VENDYS-II® Report
- 101. VENDYS-II® Sample Report (Good VRI)
- 102. VENDYS-II® Sample Report (Good VRI)
- 103. VENDYS-II® Sample Report (Good VRI)
- 104. VENDYS-II® Sample Report (High Borderline VRI)
- 105. VENDYS-II® Sample Report (Borderline VRI)
- 106. VENDYS-II® Sample Report (Borderline VRI)
- 107. VENDYS-II® Sample Report (Low Borderline VRI)
- 108. VENDYS-II® Sample Report (Low Borderline VRI)
- 109. VENDYS-II® Sample Report (Low Borderline VRI)
- 110. VENDYS-II® Sample Report (Low Borderline VRI)
- 111. VENDYS-II® Sample Report (Low Borderline VRI)
- 112. VENDYS-II® Sample Report (Poor VRI)
- 113. VENDYS-II® Sample Report (Poor VRI)
- 114. VENDYS-II® Sample Report (Poor VRI)
- 115. Infrared Imaging Cuff inflated Post cuff deflation View Video: https://youtu.be/54mlLxXKjgk
- 116. VENDYS Digital Thermal monitoring of Neurovascular Reactivity NVRI
- 117. VENDYS Registry Data
- 119. 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
- 120. 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
- 121. 0 10 20 30 40 50 60 70 80 0 to < 1 Poor 1 to < 2 Intermediate >= 2 Good %ofTests Vascular Reactivity Index ≥ 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
- 122. 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
- 123. 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
- 124. 0% 10% 20% 30% 40% 50% 60% 70% 80% 0 to < 1 Poor 1 to < 2 Intermediate ≥ 2 Good %oftests Vascular Reactivity Index 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
- 125. 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
- 126. 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) R Square = 0.02, SE = 20.36 β p-value 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) R Square = 0.10, SE = 11.78 β p-value 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).
- 127. 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 + ++ ++ +++ ++ +++
- 128. 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
- 129. •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
- 130. 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