1. Evidence-Based Evaluation of Two Major Arterial Stiffness Measures in Japan: Brachial-ankle PWV and Cardio-Ankle Vascular Index Japan Labor health & Welfare Organization Tohoku Rosai Hospital MASANORI MUNAKATA M.D.,Ph.D. 2015 Pulse of Asia 1

2. 2 Changes in life expectancy in the world ↑ Universal health case system 1961

3. Aging Hypertension Diabetes Dyslipidemia Obesity Smoking etc. Vascular function tests could help our difficult task? Endothelial dysfunction Functional and organic changes in arterial system Abnormal central and peripheral hemodynamics Cardiovascular events large and small artery damage

4. ●endothelial function (FMD, plethysmography) ●PWV(cfPWV, baPWV, CAVI), Stiffness index β ●augmentation index, Central blood pressure, Photoplethysmogram waveform ●ABI Japanese Circulation Society Guidelines for non-invasive vascular function test 2013 4

5. Brachial-ankle PWVCardio Ankle Vascular Index Device nameVP-1000 (Omron colin)VS-1000 (Fukuda denshi) Sales start years19992002 Number on the Japan market in 2014 14000 5 Data on baPWV and CAVI There have been 8540 hospitals and 100528 clinics in Japan in 2013.

6. For a vascular biomarker 1.Logical mechanism 2. Reproducibility 3. Validation and generalization 4. Disease specific changes 5. Additional prognostic value 6. Role of surrogate marker 6

7. How to determine path length formula of baPWV? Length (b) ＝ 0.2195×height -2.0734 Length (c) ＝ 0.5643×height -18.381 Length (d) ＝ 0.2486×height +30.709 b :Heart-Brachial c :Heart-Femoral d :Femoral-Ankle Distance(ba) = 1.3×c + d - b ｄ b c Sternoclavicular joint Femoral position Middle point of sensor cuff Middle point of Cuff Height 7

8. FIGURE 1 Estimation errors of key arterial path lengths Lhb = path length from the heart to the brachial arterial pressure recording site; Lha = path length from the heart to the ankle arterial pressure recording site; Lba = Lha – Lhb. Data are mean ± SD. ∗ P < 0.05 vs. 19–34 years age group, ∗∗ P < 0.05 vs. 35–49 years age group, ∗∗∗ P < 0.05 vs. men. Copyright © 2014 Journal of Hypertension. Published by Lippincott Williams & Wilkins.8 Sugawara J et al. 32(4):881-889, 2014

9. FIGURE 2 A relation between brachial-ankle pulse wave velocity values derived from the height-based formulas (baPWVHt) and those recalculated using the MRI-based measurements of actual arterial path lengths (baPWVMRI) Copyright © 2014 Journal of Hypertension. Published by Lippincott Williams & Wilkins.9 Sugawara J et al. 32(4):881-889, 2014

10. B B A A A’ Brachial-radial PWV Femoral-tibial PWV Carotid-femoral PWV Brachial-ankle PWV T D AB PWV AB =D AB /T AB PWV AB =D AB /T AB =D AB /T A’B Munakata M Current Hypertens Rev 2014 a b 10

11. Figure 1 Artery Research 2011 5, 91-96DOI: (10.1016/j.artres.2011.03.005) Copyright © 2011 Association for Research into Arterial Structure and Physiology Terms and Conditions Terms and Conditions

12. 12 Limitations and strength of each methodology Limitations baPWV: assumption that pulse wave velocity to aorta and that to brachium is nearly equal. CAVI: assumption that systolic and diastolic blood pressures are nearly equal in all arterial portions. Strength Generality is guaranteed for both measures because only one formula is available to calculate baPWV and CAVI.

13. Level A: Multiple populations evaluated. Data from multiple randomized clinical trials or meta-analyses Ranking of evidence Level B: Limited populations evaluated. Data from a single randomized trial or nonrandomized studies Level C: Very limited populations evaluated. Only consensus opinion of experts, case studies or standard of care ACCF/AHA Practice Guideline 2010 13

14. Evidence level in disease specific changes hypertension diabetes Mets dyslipidemia diseasebaPWV Level A Level B Level C ESRD CKD CAD 14 CAVI

15. hypertension diabetes dyslipidemia diseaseCAVIbaPWV Level A Level B Level C ESRD CKD CAD Mets Evidence level as a surrogate marker 15

16. CAVI as a sarrogate marker 16 Otsuka T et al. Hypertens Res 37:1014-1020, 2014

17. hypertension diabetes Mets dyslipidemia diseasebaPWV Level A Level B Level C ESRD CKD CAD Evidence level in prognostic value 17 CAVI

18. NOReportSubjectsMean age follow-upOutcomePrognostic value 1Kitahara T et al. 2005 785 hemodialysis patients 60 34 months Total death 131 CV death 85 Significant 2Tomiyama H et al. 2005 215 acute coronary syndromeNo data26 month CV events 18 Significant 3Morimoto S et al. 2009 199 hemodialysis patients6143.2 month Total death 24 CV death 10 Significant 4Meguro T et al. 2009 72 CHF6814 month Readmission due to CHF １７ Cardiac death 9 Significant 5Miyano I et al. 2010 530 elderly general population763 yrs Total death 30 CV death 10 Significant 6Nakamura N et al. 2010 191 diabetic patients with CADNo data25.4 monthsComposite CV events 59Significant 7Turin TC et al. 2010 2480 general population men 61 women 57 6.5 yrs Total death 59 Significant 8Kato A et al. 2010 194 hemodialysis patients6439 months Total death 39 CV events 39 Not significant 9Tanaka M et al. 2011 445 hemodialysis patients6343 monthsCV events 206 CV death 36 Not significant 10Yoshida M et al. 2012 783 diabetic patientsNo data5.4 yrs CV events 85 Not significant 11Munakata M et al 2012 662 hypertensive patients603 yrs CV events 24 Significant 12Inoue T et al. 2012 197 hemodialysis patients6669 monthsCV events 89Significant 13Ninomiya T et al. 2013 2916 general population607.1 yrs CV events 126 Significant 14Takashima N et al. 2013 4164 general population58.96.5 yrsCV events 40Significant 15Kawai T et al. 2013 440 hypertension patients616.3CV events 62Significant 16Ishisone T et al. 2013 972 general population597.8 yearsCV events 37Significant 17Maeda Y et al. 2014 3628 diabetic patients61.03.2 yrsTotal death 207 CV events 298 significant 18Katakami N 2014 1040 diabetic patients597.5 yearsCV events 113Significant 19Sugamata W et al. 2014 923 CAD patients6564 months116 coronary eventsSignificant Studies on prognostic significance of baPWV in Japan 18

19. 19 NOReportSubjectsMean age follow-upOutcomePrognostic value 1Chang LH et al. 2014 (Taiwan) 452 diabetic patients675.8 yearsTotal death 17 Composite cardiovascular events 64 Significant 2Yoon HE at al. (Korea) 241 CKD patients53367 daysCV events 12significant 3Kim J et al. 2014 (Korea) 1765 acute ischemic stroke patients 653.3 yearsTotal death 228 Vascular death 143 significant 4Sheng C et al. 2014 (China) 3876 general population685.9 yearsTotal death 316significant Studies on prognostic significance of baPWV outside Japan

20. Adjusted hazard ratios (HR; 95% confidence intervals [CIs]) for all-cause mortality according to the decile distributions of brachial-ankle pulse wave velocity in all (left) and hypertensive subjects (right). Sheng C et al. Hypertension. 2014;64:1124-1130 Copyright © American Heart Association, Inc. All rights reserved.

21. Subjects in the Top Decile(n=385) Top Decile of Brachial –Ankle PWV vs Whole Study Population Outcome No. of Deaths Rate per 1000 Person-Years HR (95% CI) P Value All-cause mortality 7539.9 1.56 (1.16-2.08) 0.003 Cardiovascular mortality 4322.91.46 (0.90-2.05) 0.15 Stroke mortality 13 6.91.49 (0.69-3.20) 0.31 Noncardiovascular mortality 32 17.0 1.60 (1.18-2.75) 0.006 Adjusted Analyses on the Risk of Mortality in Subjects in the Top Decile of Brachial-Ankle PWV Relative to the Whole Study Population 21 Sheng C et al. Hypertension. 2014;64:1124-1130

22. Stacked cumulative incidence curves of patients with stroke according to the brachial-ankle pulse wave velocity (baPWV). Kim J et al. Hypertension. 2014;64:240-246 Copyright © American Heart Association, Inc. All rights reserved.

23. Table2. Association Between baPWV and Long-Term mortality in Acute Stroke All –Cause MortalityVascular Mortality* baPWV Unadjusted HR (95% Cl) Adjusted HR (95% Cl)† Unadjusted HR (95% Cl) Adjusted HR (95%Cl)‡ As categorical variables Tertiles of baPWV T1;<17.79m/s Ref. T2;17.79-22.63m/s 2.15 (1.43-3.24) 1.46 (0.95-2.26 ） 2.42 (1.39-4.20 ） 1.56 (0.88-2.78) T3;>22.63m/s4.27 (2.92-6.25 ） 1.97 (1.25-3.08) 5.30 (3.18-8.82 ） 2.39 (1.33-4.29 ） baPWV>optimal cut-off§3.87 (2.92-5.15 ） 2.22 (1.59-3.09)4.44 (3.07-6.40)2.41 (1.57-3.70) As continuous variable baPWV,per10m/s ‖ 2.24 (1.95-2.57 ） 1.54 (1.27-1.87) 2.32 (1.97-2.74 ） 1.62 (1.28-2.04) baPWV indicated brachial–ankle pulse wave velocity ; Cl, confidence interval;and HR, hazard ratio. *Derived from cause-specific Cox hazard regression model (nonvascular death is censored at the event time). †Adjusted for sex, age, National Institutes of Health Stroke Scale (NIHSS) score at admission,Hypertension, diabetes mellitus, current smoking, cardiac disease, peripheral artery disease, cerebral artery atherosclerosis, previous stroke,stroke subtype, hemoglobin, Cholesterol, low-density lipoprotein, triglyceride,albumin, glucose, creatinine,and diastolic arterial pressure. ‡Adjusted for sex, age,NHSS score at admission,current smoking, cardiac disease, peripheral artery disease, cerebral artery Atherosclerosis, previous stroke subtype, white blood cell count,hemoglobin,cholesterol,triglyceride,albumin,creatinine,and diastolic arterial pressure. ‡HR in patients with baPWV above the optimal cut-off point (>27.48m/s for all-cause mortality and>28.56m/s for vascular mortality) compared with those with baPWV less than the cut-off point. ‖ HR per increase in 10m/s of baPWV. Kim J et al. Hypertension. 2014;64:240-246

24. 24 NOReportSubjectsMean age follow-upOutcomePrognostic value 1Kubota Y et al. 2011 400 patients with lifestyle-related diseases 68.727.2 monthsCV events 47Significant Study on prognostic significance of CAVI in Japan

25. Figure 4 Artery Research 2011 5, 91-96DOI: (10.1016/j.artres.2011.03.005) Copyright © 2011 Association for Research into Arterial Structure and Physiology Terms and Conditions Terms and Conditions The cumulative incidence of coronary artery diseases and strokes in 3 groups of CAVI category Kubota Y et al. Artery Res 2011 Group A Group B Group C

26. Hazard ratio for cardiovascular diseases 26 Group AGroup BGroup CP value for trend <9.09.0-10.0≤10.0 Person-years of follow-up154132114 Number of cardiovascular diseases131620 Adjusted HR (95% CI) a 11.47 (0.70-3.08)2.11 (1.02-4.38)0.04 Multivariate HR (95% CI) b 11.38 (0.65-2.97)2.25 (1.02-4.95)0.04 CI, confidence interval; HR, hazard ratio a Adjusted for sex and age b Adjusted for sex, age, hypertension, diabetes, dyslipidemia and CKD Kubota Y et al. Artery Res 2011

27. Class I: Recommendation that procedure or treatment is useful/effective (benefit>>>risk). Classification of recommendation Class IIa: Recommendation in favor of treatment or procedure being useful/effective (benefit>>risk). Class IIb: Recommendation’s usefulness/efficacy less well established (benefit≥risk). Class III: Recommendation that procedure or treatment is not useful/effective and may be harmful. 27 ACCF/AHA Practice Guideline 2010

28. Evidence of classification of recommendation hypertension diabetes Mets dyslipidemia diseaseCAVIbaPWV ESRD CKD CAD Class I Class IIa Class IIb Class III 28

29. 29 Summary Prognostic significance has been broadly confirmed in the general population, hypertension, diabetes and other high risk populations for brachial-ankle PWV while only limited evidence exists for CAVI. We fairly compared all available evidence between brachial-ankle PWV and CAVI, both are most frequently used arterial stiffness measures in Japan. Cross sectional studies showed that both measures demonstrated an increase in major life style-related diseases and cardiovascular diseases.

30. 30 conclusion Current evidence strongly suggests that brachial-ankle PWV might be a better vascular biomarker than CAVI.