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

Why we need to assess endothelial function?

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

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

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

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

FMD & RH-PAT FMD RH-PAT

2.5.4. Brachial/Peripheral Flow-Mediated Dilation （FMD） 2.5.4.1. 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. 2010 Dec 21;122(25):e584-636. 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.

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. 2012 Aug 7;126(6):753-67. doi: 10.1161/CIRCULATIONAHA.112.093245. 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.

Is data of FMD reliable ?

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.

Training for FMD measurement in FMDJ study

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

Are FMD and RH-PAT interchangeable?

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

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

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.

? 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

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

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

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

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

Scattergram①

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

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.