1. Recent Findings of Endothelial Function Tests from FMDJ study
Hirofumi　Tomiyama　MD
Professor of Cardiology,
Tokyo Medical University

2. Why we need to assess endothelial function?

3. We have carotid ultrasound examination
NormaI
IMT
IMT：
Hypertrophy
IMT：
Plaque
IMT is the most common marker to assess the vascular damage morphologically.

4. The improvement of FMD by treatment is related to the improvement of the prognosis
Kitta　Y　et al . 83
J Am Coll Cardiol
2009
Coronary Artery disease 251
Suessenbacher A et al. 85
Vasc Med 2006
Coronary Artery disease 68
Modena 84
2002
Hypertension
400

5. Endothelial function　test　has　a　potential　to　be　a　marker　for　the　managements　(not only diagnosis) of　cardiovascular　disease/its risk　factors

6. Peripheral (brachial artery) Peripheral (finger microvasculature)
Method
Coronary or Peripheral artery
Vascular bed
Measurements
Stimulus
Invasive
Coronary epicardial vasoreactivity
Coronary
Conduit
Vessel diameter
Infusion of endothelial dependent vasodilator +
Coronary microvascular vasoreactivity
Resistance
Blood flow
FMD
Peripheral (brachial artery)
Reactive hyperemia −
RH-PAT
Peripheral (finger microvasculature)
Plethysmogram
Methods Used to Assess Endothelial Function

7. FMD & RH-PAT
FMD
RH-PAT

8. 2.5.4. Brachial/Peripheral Flow-Mediated Dilation （FMD）
Recommendation for Brachial/Peripheral Flow-Mediated Dilation
Class III: No Benefit
The technique requires a highly skilled sonographer,
highly standardized measurement conditions (including time of day, temperature, drug administration), and suitable ultrasound machine. Many examiners also use specialized computer software to semiautomatically quantitate the brachial artery diameter. Considerable variability exists for values of FMD determined by different investigators, even in similar patient populations, suggesting technical challenges with the measurement.
Circulation Dec 21;122(25):e
2010 ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.

9. Criteria for an Optimal Endothelial Function Test
Reflects disease state
Reversible with interventions
Mirrors coronary endothelial function
Improves risk stratification
Reproducible
Operator independent
Noninvasive (no or low risk for the patient)
Ease of use
Inexpensive
Criteria for an Optimal Endothelial Function TestCriteria for an Optimal Endothelial Function Test
Circulation Aug 7;126(6): doi: /CIRCULATIONAHA
The assessment of endothelial function: from research into clinical practice.
Flammer AJ1, Anderson T, Celermajer DS, Creager MA, Deanfield J, Ganz P, Hamburg NM, Lüscher TF, Shechter M, Taddei S, Vita JA, Lerman A.

10. Is data of FMD reliable ?

11. A multicenter study design to assess the clinical usefulness of semi-automatic measurement of flow-mediated vasodilatation of the brachial artery.
Tomiyama H, Kohro T, Higashi Y, Takase B, Suzuki T, Ishizu T, Ueda S, Yamazaki T, Furumoto T, Kario K, Inoue T, Koba S, Watanabe K, Takemoto Y, Hano T, Sata M, Ishibashi Y, Node K, Maemura K, Ohya Y, Furukawa T, Ito H, Yamashina A.
Int Heart J. 2012;53(3):170-5.

13. Training for FMD measurement in FMDJ study

14. To examine the reliability of FMD data analyzed in each institute
Send USB including the image of FMD without analyzing data
FMD data analyzed in each institute
Number of participating institutes was 19
Independent analysis of FMD image at core laboratory
Analyzing data was loaded on WEB site
Compare the results of both analyses

15. Are FMD and RH-PAT interchangeable?

16. Hyperemic Flow Velocity
Relation of Brachial and Digital Measures of Vascular Function in the Community: The Framingham Heart Study
Hypertension. 2011;57:390,
Adjustment
FMD Percent
Hyperemic Flow Velocity r* P
PAT ratio
    Unadjusted
0.094
<0.001
0.007
0.77
    Age and sex
−0.012
0.61
−0.052
0.03
    Multivariable†
−0.009
0.70
−0.026
0.27

17. Abnormal PAT Ratio
Abnormal FMD Percent
OR* (95% CI) P
OR (95% CI)
Age
1.08 (0.87–1.33)
0.48
1.44 (1.28–1.63)
<0.0001
Female sex
1.41 (1.12–1.78)
<0.01
1.30 (1.10–1.54)
Systolic blood pressure
0.71 (0.63–0.81)
1.44 (1.33–1.56)
Diastolic blood pressure …
Heart rate
1.15 (1.04–1.28)
BMI
1.30 (1.17–1.44)
1.18 (1.09–1.27)
Total/HDL cholesterol ratio
1.36 (1.22–1.51)
Diabetes
1.73 (1.28–2.34)
<0.001
Current smoker
1.97 (1.48–2.60)
Lipid-lowering medication
1.43 (1.10–1.86)
FMD is particularly sensitive to being impaired by traditional risk factors (eg, age, hypertension), whereas the peripheral arterial tonometry reactive hyperemia index (microvasculature) is more sensitive to metabolic risk factors, especially body mass index and diabetes mellitus

18. Background ① ①Sympathetic activation markedly reduces endothelial
dependent flow mediated vasodilatation(FMD).
(J Am Coll Cardiol 2002; 39: 683-8)
②While the maneuver of reactive hyperemia in the assessment
　 of endothelial function is thought to affect sympathetic/
　 parasympathetic nerve activities, the details has not been
clarified.

19. ? Hypothesis Relationship of autonomic balance to endothelial function
by reactive hyperemia
Stress caused
by Reactive
Hyperemia
Sympathetic
Nerve
System
FMD ?
これは2006年のJACCからの抜粋です。Metsの進行と結果ですが、Metsは主として異常肥満から発生します。加齢と肥満増加で、Metsの危険因子は増悪します。Metsの多くは結果的に2型DMに進行します。Metsの進行は心血管危険性が高まり、合併症が増加します。このMetsと内皮機能障害は連関つまりお互いに影響しあっていると考えられています。
Microvascular
Endothelial
function

20. 115 treated hypertensive patients
Subjects
115 treated hypertensive patients
(75 men / 40 women)
Exclusion criteria
・Ankle/brachial systolic blood pressure index (ABI) <0.95
・Atrial fibrillation
・Undergoing regular hemodialysis
・Heart disease and/or stroke
・under beta-blocker medication
・patients with malignancy
・serious liver disease

21. FMD and EndoPAT and Heart rate variability
　　　Endo-PAT system
FMD
Heart rate viriability
monitor
FMD probe
Blood presure cuff
Heart rate variability system
Endo-PAT probe

22. Measurements FMD (flow mediated vasodilatation of brachial artery)
→ %FMD ＝(Maximal diameter-baseline diameter)×100/baseline diameter
RH-PAT (changes in skin blood flow by Endo- PAT in reactive
hyperemia）
HRV (Heart Rate Variability)
→　high frequency domain(HF),　Low frequency domain(LF)
LF/HF ,　delta HF,　delta LF, delta LF/HF

23. Methods (Heart Rate Variability)
Heart rate was continuously monitored throughout this reactive hyperemia,
and high frequency domain (HF), low frequency domain (LF) and their ratio
(LF/HF) were obtained in every 5 minutes’ interval.
① delta HF
　　 (HF value after the hyperemia – HF value before the hyperemia) x 100
= HF value before the hyperemia
② delta LF
(LF value after the hyperemia – LF value before the hyperemia) x 100
= LF value before the hyperemia
　③ delta LF/HF
(LF/HF value after the hyperemia – LF/HF value before the hyperemia) X100
= LF /HF value before the hyperemia

24. Scattergram①

25. Scattergram② RHI-PAT FMD Beta = 0.053 Beta = -0.222 P = 0.574

26. Summary of my presentation
When the analysis was limited to cases with clear FMD recordings, the reliability of the FMD assessment in each participant institution was acceptable.
Automatic nervous activation,　especially sympathetic nervous activation, induced by 5 minutes forearm clamping utilaized to induce reactive hyperemia may affect the RHI, but not FMD
in subjects with hypertension.
This difference may be one of explanations for the weak association between FMD and RHI.