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

Changes in life expectancy in the world

↑Universal health case system 1961

AgingHypertension DiabetesDyslipidemiaObesitySmoking 　 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

●endothelial function (FMD, plethysmography)●PWV(cfPWV, baPWV, CAVI), Stiffness index β●augmentation index, Central blood pressure, Photoplethysmogram waveform●ABI

Japanese Circulation SocietyGuidelines for non-invasive vascular function test

2013

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Brachial-ankle PWV Cardio Ankle Vascular Index

Device name VP-1000 (Omron colin) VS-1000 (Fukuda denshi)

Sales start years 1999 2002

Number on the Japan market　 in 2014

14000 14000

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Data on baPWV and CAVI

There have been 8540 hospitals and 100528 clinics in Japan in 2013.

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 marker6

How to determine path length formula of baPWV?

Length (b) ＝ 0.2195×height -2.0734Length (c) ＝ 0.5643×height -18.381Length (d) ＝ 0.2486×height +30.709

b :Heart-Brachialc :Heart-Femorald :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

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Copyright © 2014 Journal of Hypertension. Published by Lippincott Williams & Wilkins.

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.

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Sugawara J et al. 32(4):881-889, 2014

Copyright © 2014 Journal of Hypertension. Published by Lippincott Williams & Wilkins.

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)

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Sugawara J et al. 32(4):881-889, 2014

B

B

A

A

A’

Brachial-radial PWVFemoral-tibial PWV

Carotid-femoral PWVBrachial-ankle PWV

T

D

AB

AB

PWVAB=DAB/TAB

PWVAB=DAB/TAB=DAB/TA’B

Munakata M Current Hypertens Rev 2014

a

b

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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

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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.

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

Evidence level in disease specific changes

hypertension

diabetes

Mets

dyslipidemia

disease baPWV

Level A

Level B

Level C

ESRD

CKD

CAD

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CAVI

hypertension

diabetes

dyslipidemia

disease CAVIbaPWV

Level A

Level B

Level C

ESRD

CKD

CAD

Mets

Evidence level as a surrogate marker

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CAVI as a sarrogate marker

16

Otsuka T et al. Hypertens Res 37:1014-1020, 2014

hypertension

diabetes

Mets

dyslipidemia

disease baPWV

Level A

Level B

Level C

ESRD

CKD

CAD

Evidence level in prognostic value

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CAVI

NO Report Subjects Mean age follow-up Outcome Prognostic value

1 Kitahara T et al.2005

785 hemodialysis patients 60 34 months Total death　 131

CV death　 85Significant

2 Tomiyama H et al.2005

215 acute coronary syndrome No data 26 month CV events　 18 Significant

3 Morimoto S et al.2009

199 hemodialysis patients 61 43.2 month Total death　 24

CV death　 10Significant

4 Meguro T et al. 2009

72 CHF 68 14 month Readmission due to CHF　１７

Cardiac death　 9

Significant

5 Miyano I et al. 2010

530 elderly general population 76 3 yrs Total death　 30

CV death　 10

Significant

6 Nakamura N et al. 2010

191 diabetic patients with CAD No data 25.4 months Composite CV events 59 Significant

7 Turin TC et al. 2010

2480 general population men　 61

women　 57

6.5 yrs Total death　 59 Significant

8 Kato A et al. 2010

194 hemodialysis patients 64 39 months Total death　 39

CV events　 39

Not significant

9 Tanaka M et al. 2011

445 hemodialysis patients 63 43 months CV events 206CV death　 36

Not significant

10 Yoshida M et al.

2012 783 diabetic patients No data 5.4 yrs CV events　 85 Not significant

11 Munakata M et al2012

662 hypertensive patients 60 3 yrs CV events　 24 Significant

12 Inoue T et al.2012

197 hemodialysis patients 66 69 months CV events 89 Significant

13 Ninomiya T et al. 2013

2916 general population 60 7.1 yrs CV events　 126 Significant

14 Takashima N et al.2013

4164 general population 58.9 6.5 yrs CV events 40 Significant

15 Kawai T et al.2013

440 hypertension patients 61 6.3 CV events 62 Significant

16 Ishisone T et al.2013

972 general population 59 7.8 years CV events 37 Significant

17 Maeda Y et al.2014

3628 diabetic patients 61.0 3.2 yrs Total death 207CV events 298

significant

18 Katakami N2014

1040 diabetic patients 59 7.5 years CV events 113 Significant

19 Sugamata W et al.2014

923 CAD patients 65 64 months 116 coronary events Significant

Studies on prognostic significance of baPWV in Japan

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NO Report Subjects Mean age follow-up Outcome Prognostic value

1 Chang LH et al.2014

(Taiwan)

452 diabetic patients 67 5.8 years Total death 17Composite

cardiovascular events 64

Significant

2 Yoon HE at al.(Korea)

241 CKD patients 53 367 days CV events 12 significant

3 Kim J et al.2014

(Korea)

1765 acute ischemic stroke patients

65 3.3 years Total death 228Vascular death 143

significant

4 Sheng C et al. 2014

(China)

3876 general population 68 5.9 years Total death 316 significant

Studies on prognostic significance of baPWV outside Japan

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.

Subjects in theTop Decile(n=385)

Top Decile ofBrachial –Ankle 　 PWV vs

Whole Study Population

Outcome No. ofDeaths

Rate per 1000Person-Years

　HR (95% CI) P 　 Value

All-cause mortality 75 39.9 1.56 (1.16-2.08) 　　 0.003

Cardiovascularmortality 43 22.9 1.46 (0.90-2.05) 0.15

Stroke mortality 13 6.9 1.49 (0.69-3.20) 0.31

Noncardiovascularmortality

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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

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Sheng C et al. Hypertension. 2014;64:1124-1130

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.

Table2. Association Between baPWV and Long-Term mortality in Acute Stroke

All –Cause 　 Mortality Vascular 　 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. Ref. Ref. 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/s 4.27 (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, currentsmoking, 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 arteryAtherosclerosis, previous stroke subtype , white blood cell count,hemoglobin,cholesterol,triglyceride,albumin,creatinine,anddiastolic 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

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NO Report Subjects Mean age follow-up Outcome Prognostic value

1 Kubota Y et al.2011

400 patients with lifestyle-related diseases

68.7 27.2 months CV events 47 Significant

Study on prognostic significance of CAVI in Japan

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

The cumulative incidence of coronary artery diseases and strokes in 3 groups of CAVIcategory

Kubota Y et al. Artery Res 2011

Group A

Group B

Group C

Hazard ratio for cardiovascular diseases

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Group A Group B Group C P value for trend

<9.0 9.0-10.0 ≤10.0

Person-years of follow-up 154 132 114

Number of cardiovascular diseases 13 16 20

Adjusted HR (95% CI)a 1 1.47 (0.70-3.08) 2.11 (1.02-4.38) 0.04

Multivariate HR (95% CI)b 1 1.38 (0.65-2.97) 2.25 (1.02-4.95) 0.04

CI, confidence interval; HR, hazard ratioaAdjusted for sex and agebAdjusted for sex, age, hypertension, diabetes, dyslipidemia and CKD

Kubota Y et al. Artery Res 2011

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.

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ACCF/AHA Practice Guideline 2010

Evidence of classification of recommendation

hypertension

diabetes

Mets

dyslipidemia

disease CAVIbaPWV

ESRD

CKD

CAD

Class I

Class IIa

Class IIb

Class III

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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.

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conclusion

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