Considerations for SphygmoCor radial artery pulse wave analysis: side selection and peripheral arterial blood pressure calibration

Page 1 Martin et al. Hypertension Research (In press). DOI: DOI: 10.1038/hr.2015.36

Text Word Count: 4064 1

Abstract Word Count: 250 2 Reference Word Count: 46 3

Table Count: 4 4

Figure Count: 3 5 Supplemental Figures: 2 6

7 Considerations for SphygmoCor Radial Artery Pulse Wave Analysis: Side Selection and 8

Peripheral Arterial Blood Pressure Calibration 9 10

Martin: Considerations for Pulse Wave Analysis 11 12

Jeffrey S. Martin1,2 13

Alexandra R. Borges1 14

John B. Christy IV3 15

Darren T. Beck3 16

17 1Department of Biomedical Sciences, Quinnipiac University, Hamden, CT USA 06518. 18

2Department of Cell Biology and Physiology, Edward Via College of Osteopathic Medicine- 19

Auburn Campus, Auburn, AL USA 36832 20 2Department of Kinesiology, University of Rhode Island, Kingston, RI USA 02881 21

22 23

Corresponding Author: 24

Jeffrey S. Martin, Ph.D. 25 Department of Cell Biology and Physiology 26

Edward Via College of Osteopathic Medicine – Auburn Campus 27 910 S. Donahue Dr. 28

Auburn, AL USA 36832 29 Tel: (203) 980-1322 30

Email: [email protected] 31

32

This is a pre-copyedited, author-produced PDF of an article accepted for publication in 33

Hypertension Research, the official journal of the Japanese Society of Hypertension. The 34

version of record (Martin JS, Borges AR, Christy IV and Beck DT. 2015. In press. DOI: 35

10.1038/hr.2015.36) is available online at: 36

http://www.nature.com/hr/journal/vaop/ncurrent/pdf/hr201536a.pdf 37

38

39

40

41

Disclosures/Conflicts of Interest: None 42

Keywords: applanation tonometry, augmentation index, bilateral blood pressure, pulse wave 43

analysis 44

http://www.nature.com/hr/journal/vaop/ncurrent/pdf/hr201536a.pdf


ABSTRACT 45

BACKGROUND: Methods employed for pulse wave analysis (PWA) and peripheral blood 46

pressure (PBP) calibration vary. The purpose of this study was to evaluate the agreement of 47

SphygmoCor PWA parameters derived from radial artery tonometry when considering 1) timing 48

(before vs. after tonometry) and side selection (ipsilateral vs. contralateral limb) for PBP 49

calibration and 2) side selection for tonometry (left vs. right arm). METHODS: In 34 subjects 50

(aged 21.9±2.3 years), bilateral radial artery tonometry was performed simultaneously at three 51

instances. PBP assessment via oscillometric sphygmomanometry in the left arm only and both 52

arms simultaneously occurred following the first and second instances of tonometry, 53

respectively. RESULTS: Significant within-arm differences in PWA parameters derived before 54

and after PBP measurement were observed in the right arm only (e.g. aortic systolic blood 55

pressure, Δ = 0.38±0.64 mmHg). Simultaneously captured bilateral PWA variables 56

demonstrated significant between-arm differences in 88% (14/16) and 56% (9/16) of outcome 57

variables when calibrated to within-arm and equivalent PBP, respectively. Moreover, the right 58

arm consistently demonstrated lower values for clinical PWA variables (e.g. Augmentation 59

Index, Bias = -2.79%). However, 26% (n=9) of participants presented with clinically significant 60

differences (>10 mmHg) in bilateral PBP and their exclusion from analysis abolished most 61

between-arm differences observed. CONCLUSIONS: SphygmoCor PWA in the right radial 62

artery results in greater variability independent of the timing of PBP measurement and 63

magnitude of calibration pressures in young subjects. Moreover, bilateral PBP measurement is 64

imperative to identify subjects in whom a significant difference in bilateral PWA outcomes may 65

exist. 66

67


INTRODUCTION 68

Several parameters of central arterial blood pressure and wave reflection characteristics 69

have demonstrated value as independent predictors of future cardiovascular morbidity and 70

mortality.1–5 Central blood pressures have also been shown to more strongly relate to vascular 71

disease than peripheral blood pressures.4 However, direct measurement of central aortic 72

pressures is invasive and expensive.6 As a result, methods for non-invasive assessment of central 73

hemodynamic indices have been increasingly employed in clinical and research settings for 74

evaluation and titration of treatments and/or interventions. 75

There are a number of methods currently available for the non-invasive assessment of 76

aortic wave reflection characteristics.7,8 At present, applanation tonometry in which high-fidelity 77

radial artery pressure waveforms are recorded using a ‘pencil’ type micromanometer are most 78

commonly performed,9 likely due in part to the strong validity and reliability of resultant 79

measures reported in the literature.10–12 Notably, the central hemodynamic indices derived from 80

radial artery pulse wave analysis (PWA) are dependent upon calibration to peripheral artery 81

blood pressure (PBP) measured at the brachial artery and based on the assumption that mean 82

blood pressure is constant throughout the arterial tree.13,14 Further, the importance of PBP in 83

PWA measures is emphasized by Shih et al who demonstrated that errors in PWA measurements 84

are equivalent to those associated with brachial cuff sphygmomanometry.15 85

Methods for PBP determination and calibration vary between PWA devices and are not 86

always standardized. In the case of the SphygmoCor system, the operations manual recommends 87

a rest period after brachial artery sphygmomanometry before radial pressure waveform 88

measurement due to supra-systolic pressures followed by a period of cuff deflation which 89

disrupts local and distal blood flow and brachial wave transmission. This would seem to suggest 90


that PBP measurement should be performed in the same arm at which PWA will occur. 91

However, to our knowledge, there is no data available that examines the variability in PWA at 92

the radial artery prior to and following PBP assessment at the brachial artery via cuff 93

sphygmomanometry. 94

To circumvent the disruption in arterial blood flow that may occur downstream of cuff 95

sphygmomanometry, calibration could be performed using measurement of PBP in the 96

contralateral limb. However, PBP measurements made at the brachial artery have been shown to 97

vary significantly between arms.16,17 Given the reliance of PWA on PBP calibration, disparities 98

in bilateral PBP could further increase variability in clinical measures derived from PWA 99

depending on the arm selected for calibration. Indeed, calibration is based on the assumption 100

that mean blood pressure is constant throughout the large arteries.14 Moreover, it is unknown if 101

characteristics of the radial pulse pressure wave derived from PWA are also variable between 102

arms of measure, independent of arm selection for calibration. Importantly, validation studies 103

frequently use a single arm and/or exclude persons with unequal brachial pressures.11,12,18,19 As 104

PWA protocols are increasingly employed in clinical and research settings, it is imperative to 105

explore potential differences in bilateral PWA and to standardize evaluation methods for 106

continuity of patient monitoring and comparative value of PWA outcomes. 107

Therefore, the purpose of this study was to 1) evaluate the effect of PBP measurement on 108

subsequent PWA, 2) evaluate the difference in PWA between arms when calibrated to the same 109

PBP (i.e. left brachial artery), and 3) evaluate the difference in PWA between arms when 110

calibrated to within arm PBP in young, apparently healthy people using the SphygmoCor system. 111

METHODS 112

Study participants. 113


The study population was recruited via word of mouth from the greater Hamden, CT and 114

Kingston, RI areas with thirty-four subjects (17 male, 17 female; 21.9±2.3 years) enrolled. 115

Apparently healthy, young (aged <30 yrs), non-smokers without previously diagnosed 116

cardiovascular disease were included in this study and all participants maintained normal sinus 117

rhythm throughout the testing procedures. Subjects were asked to report to the laboratory in a 118

post-absorptive state and were instructed to abstain from exercise and the consumption of 119

alcohol and caffeine for at least 12 hours prior to testing. A random number generator was used 120

to create a list of 40, 4 digit codes that were assigned consecutively to each subject. All 121

measurements were made in the Cardiovascular Laboratories at Quinnipiac University and the 122

University of Rhode Island. This study was approved by the Institutional Review Boards at 123

Quinnipiac University and the University of Rhode Island and written informed consent was 124

obtained from all participants. 125

Subject Characteristics. 126

Height and weight were measured using standard techniques. Body fat was assessed via 127

bioelectrical impedance analysis (Omron HBF306C, Omron Corporation, Kyoto, Japan). Heart 128

rate (HR) brachial systolic (PSBP), diastolic (PDBP), and pulse blood pressure (PPP) 129

measurements were made in triplicate at the brachial artery of the right and left arms by 130

oscillometric blood pressure sphygmomanometry using an automated, non-invasive device 131

(Omron BP785, Omron Corporation, Kyoto, Japan). The Omron BP785 (HEM-7222) has been 132

declared as equivalent to the Omron M6 (HEM-7000) which has been previously validated 133

according to the international protocol20 and is required by manufacturing standards to be 134

accurate within 3 mmHg for pressure readings. In our hands, for triplicate measurements at the 135

same site, the overall intra-class correlation coefficient was 0.96 and 0.88 and the typical error 136


was 3.27 and 2.54 for PSBP and PDBP, respectively. HR and PBP measurements were made on 137

two occasions in the left arm, and on one occasion in the right arm with the second set of 138

measures in the left arm and thebsingular set of measures in the right arm occurring 139

simultaneously. Two automated oscillometric blood pressure sphygmomanometry devices 140

(Omron BP785) were used throughout the study with the arm measured by each device randomly 141

selected for each subject (i.e. odd/even first digit of subject code). The average of three HR and 142

BP measurements at each timepoint was used for resting values and hypertensive status was 143

determined by the mean of all left arm PBP measurements, unless right arm PBP was found to be 144

significantly higher (> 10 mmHg) than the left in which case the higher, right arm was used.21 145

Pulse wave analysis (PWA). 146

The assessment of arterial wave reflection characteristics was performed non-invasively 147

using identical SphygmoCor CPVH Pulse Wave Velocity systems and Research Version 9.0 148

software (AtCor Medical, Sydney, Australia). The SphygmoCor systems utilize a Medical 149

Electronics Module Model EM3, an AtCor Medical/Millar tipped pressure tonometer (Millar 150

Instruments, Houston, TX, USA) and a validated generalized mathematical transfer function to 151

synthesize a central aortic pressure waveform.13,14 The generalized transfer function has been 152

validated using both intra-arterially and noninvasively obtained radial pressure waves.12 153

Participants rested quietly in a supine position in a temperature controlled room for 15 154

minutes prior to initial radial artery pulse pressure waveform analysis. Consecutive pulse 155

pressure waveform measurements were then performed by two highly trained and experienced 156

technicians (JSM and DTB) simultaneously at the right and left radial artery on 3 occasions 157

interspersed by PBP assessment in the left arm only and in both arms simultaneously 158

(Supplemental Figure 1). Briefly, an initial set of pulse pressure waveform measurements was 159


performed (PWA 1), PBP was assessed in the left arm only, a second set of pulse pressure 160

waveform measurements commenced (PWA 2), PBP was assessed simultaneously in the right 161

and left arms, and, finally, a third set of pulse pressure waveform measurements was performed 162

(PWA 3). The arm evaluated for PWA by each of the two investigators was randomly selected 163

for each subject (i.e. odd/even last digit of subject code) and the average of the first three high 164

quality pulse pressure waveform recordings per subject and per tonometer were captured for 165

analysis. Pulse pressure waveforms were calibrated to the ipsilateral and/or contralateral limb 166

PSBP and PDBP as appropriate for the comparisons described below (see statistical analysis). 167

The use of PSBP and PDBP to calibrate radial pressure waveforms omits a possible brachial-to-168

radial pressure amplification and may lead to underestimation of the central pressure.22–25 169

Despite this, PSBP and PDBP were used for radial artery waveform calibration, as recommended 170

by the manufacturer, as automated oscillometric blood pressure monitors are not required to 171

verify and validate mean arterial pressure (MAP),26 available estimation equations will produce 172

calibration errors,27 and the range of error in calibration was found to be less by Shih et al. when 173

utilizing PSBP and PDBP rather than MAP and PDBP.15 174

Optimal recording of the pressure wave was obtained when the hold-down force of the 175

transducer on the artery was such that the resulting waveform had a stable baseline for at least 10 176

cardiac cycles and resulted in a quality index QI of >90% (derived from an algorithm including 177

average pulse height variation, diastolic variation, and maximum rate of rise of the peripheral 178

waveform). This technique has been shown to be highly reproducible28 and, in our hands, 179

reproducibility in young, healthy men has previously been reported with a mean coefficient of 180

variation of 6.5%, 2.1%, 2.4% and 2.4% for aortic augmentation index (AIx), time to reflection 181

of the reflected pressure wave (T1r), central systolic and diastolic blood pressure, respectively.29 182


A typical aortic pressure waveform synthesized from radial pulse pressure using 183

applanation tonometry and the generalized transfer function is shown in Supplemental Figure 2. 184

Detailed description of PWA parameters have been described previously.30 185

Statistical Analysis. 186

Analyses included the following: 1) To evaluate the effect of PBP measurement on 187

subsequent PWA, comparisons of dependent variables within arm and calibrated to within arm 188

PBP (left arm: PWA 1 vs. PWA 2; right arm: PWA 2 vs. PWA 3) were performed; 2) To 189

evaluate the difference between arms in PWA, comparisons of dependent variables between 190

arms, calibrated to left arm PBP (PWA1 and PWA2) were performed; 3) To evaluate the effect 191

of calibrating to within arm PBP on between arm differences in PWA, comparisons of dependent 192

variables between arms, calibrated to within arm PBP (PWA3) were performed; 4) To explore 193

the impact of clinically significant differences in bilateral PBP (defined as a difference >10 194

mmHg) on the observed PWA differences between arms, comparisons of dependent variables at 195

PWA2 when calibrated to the same (left arm) PBP were made when subjects were clustered as 196

overall (overall group; n=34), those with (Clinical Difference, n=9) and those without (Normal, 197

n=25) a clinically significant difference in PBP; and 5) To determine the effect of not detecting a 198

clinically significant difference in PBP between arms with PWA, comparisons of left arm PWA2 199

dependent variables in the clinically different group when calibrated to the lower (left arm) and 200

higher (right arm) PBP observed were performed. 201

Nine subjects presented with a clinically significant difference in bilateral PBP with eight 202

demonstrating the higher pressure in the right arm. The subject with clinically significant higher 203

PBP in the left arm was excluded from analyses 4 and 5, described above, to more clearly define 204

the directional error associated with the traditional method of assessing PBP and PWA in only 205


the left arm. Inclusion/exclusion of this subject in the analysis did not affect any of the 206

significant outcomes. 207

All values are presented as mean ± SD. Kolmogorov-Smirnov tests were used to confirm 208

normality of the distributions of the variable differences. Comparisons of PWA primary and 209

secondary variables measured in the left and right arms via pencil-type tonometer were analyzed 210

using Student's paired t-tests for within and between arms differences. In the sub-analysis of 211

subjects with and without clinically significant difference in bilateral PBP, Satterwaite corrected 212

two sample t-tests were performed. Linear regression by the method of ordinary least squares 213

was used to define the correlation between tonometer values, with goodness of fit expressed by 214

Pearson's correlation coefficient (r). Further, agreement between the left and right arm 215

measurements were analyzed using Bland-Altman tests for agreement of clinical measurements 216

and defined as being within 10% of the overall mean for the studied variable as the maximal 217

tolerated difference.31 An alpha level of P < 0.05 was required for statistical significance. Based 218

on the reproducibility of augmentation index measured by PWA by Wilkinson et al28, we 219

determined that approximately 30 subjects would be required to give at least an 80% chance of 220

detecting a difference in AIx of 10% at an alpha level of 0.05. All statistical analyses were 221

performed using SPSS version 22.0 for Windows (SPSS, Chicago, IL, USA). 222

RESULTS 223

Subject characteristics are presented in Table 1. Study participants (n=34) included 22 224

normotensive, 11 prehypertensive, and 1 stage 1 hypertensive participants. Overall means of 225

PSBP, PDBP, and PMAP were calculated as the average of simultaneous bilateral measurements 226

resulting in PSBP, PDBP and PMAP means of 114.7 ± 13.7 mmHg, 65.6 ± 7.0 mmHg and 81.9 227

± 7.4, respectively. PSBP and PPP were significantly different in the right and left arms when 228


simultaneously measured (P<0.01). No significant differences in PBP were found between time 229

points in the left arm. 230

Effect of peripheral blood pressure measurement on subsequent pulse wave analysis 231

variables. 232

Comparisons of the within-arm difference before and after calibration to PBP via cuff 233

sphygmomanometry in PWA parameters are presented in Table 2. There were no significant 234

differences identified within the left arm. However, HR, ASBP, APP, PPA, TTI and AIx@75 235

were significantly different following PBP measurement in the right arm (P<0.05 for HR, PPA 236

and AIx@75; P<0.01 for ASBP, APP and TTI). 237

Evaluation of the difference in pulse wave analysis variables between arms. 238

Comparisons of between arms measures derived simultaneously from PWA at the 239

respective radial artery after calibration to the same PBP (i.e. left arm) demonstrated significant 240

differences in ED, AgBP, AgBP@75, ASBP, AMAP, APP, PPA, TTI, DTI, SEVR, AIx1, AIx2, 241

AIx@75 and LVEW (Table 3). The most striking differences between arms were observed in 242

AgBP, AIx1, AIx@75 and LVEW at 0.8 mmHg, 2.8%, 2.7% and 79.26 dynes•s/cm-1, 243

respectively. When comparing simultaneous measurements between arms before calibration to 244

the same PBP, the same parameters were significantly different, with the exceptions of AMP, 245

TTI and SEVR (P=0.298, 0.570 and 0.973, respectively; data not shown). 246

Figures 1 and 2 show Pearson correlations and Bland-Altman tests for agreement of 247

clinical measurements. PWA measurements in the right arm produced a negative bias in SEVR, 248

AgBP, AIx1, AIx2, AIx@75 and LVEW whereas DTI demonstrated a positive bias which was 249

expected given its reciprocal relationship with TTI. In persons that presented with clinically 250

different bilateral PBP, the difference between arms was significantly higher when compared to 251


‘normal’ subjects for AgBP, AgBP@75, TTI, DTI, SVI, AIx1, AIx2, AIx@75 and LVEW despite 252

being calibrated to the same PBP. Moreover, in all cases except for DTI, the significant 253

difference between arms in simultaneous PWA measurements was abolished when considering 254

only the ‘normal’ subjects (Figure 3). 255

Effect of calibration to within arm peripheral blood pressure on differences in between 256

arm pulse wave analysis variables. 257

Between arms measures derived simultaneously from PWA at the respective radial artery 258

after calibration to within arm PBP are shown in Table 4. Simultaneous measurements 259

calibrated to within arm PBP no longer demonstrated statistical differences in ASBP, AMAP, 260

TTI, DTI, and SEVR. Although the difference in ASBP increased (-0.4 vs. +1.96; PWA2 vs. 261

PWA3) when calibrated to within arm PBP, it only approached statistical significance (P=0.065). 262

Differences in ASBP, ED, AgBP, AgBP@75, APP, PPA, AIx1, AIx2, AIx@75 and LVEW 263

between arms were still found to vary significantly between sides. 264

Effect of not detecting a clinically significant difference in bilateral peripheral blood 265

pressure measurement on pulse wave analysis variables. 266

Correcting for the higher PBP (re-calibration) with the same radial artery pulse pressure 267

waveform measurements in the clinically different group resulted in significant increases in TTI 268

(182.5 ± 73.4, P<0.01), DTI (246.0 ± 149.5, P<0.01), CSP (10.8 ± 3.5, P<0.01), CDP (4.1 ± 4.3, 269

P<0.05), CPP (6.7 ± 4.6, P<0.01) and CMP (7.1 ± 3.3, P<0.01). 270

DISCUSSION 271

The present study sought to evaluate the agreement in variables derived from bilateral 272

radial artery PWA and the effects of timing and side selection for PBP measurement using the 273

SphygmoCor system. The principle findings are that, in young subjects 1) there was no 274


significant effect of PBP measurement on repeated PWA in the left arm; 2) there is a significant 275

difference in simultaneously captured bilateral PWA in which the right arm variables associated 276

with wave reflection characteristics are lower; and 3) a significant portion of the negative bias in 277

the right arm was associated with subjects who presented with clinically significant differences 278

in PBP. 279

It has been suggested that peripheral vasodilation caused by arterial obstruction alters 280

brachial wave transmission,32 and this may need to be considered in the assessment of PBP prior 281

to PWA. Indeed, the SphygmoCor operator’s manual suggests that a period of at least two 282

minutes elapse following cuff sphygmomanometry before radial pressure waveform recordings. 283

However, to our knowledge, no data are available that documents the magnitude or time course 284

of the effect(s) of PBP assessment via cuff sphygmomanometer on indices derived from PWA. 285

Here we employed radial artery PWA before and two minutes after PBP measurement in the left 286

arm and found no significant effect of standard brachial artery sphygmomanometry on any 287

variables (P>0.10 for all dependent variables). Interestingly, significant differences were 288

observed in ASBP, APP, PPA, TTI and AIx@75 measurements prior to and following PBP 289

assessment in the right arm (Table 2). Although the absolute difference between measurements 290

is modest, it does suggest greater variability in the right arm with consecutive PWA 291

measurements surrounding PBP assessment may exist. Indeed, greater variability in right arm 292

PBP has been reported previously33 and may extend to differences in radial pressure waveforms. 293

Several investigations have reported differences in PBP between arms with 294

approximately 20% exhibiting clinically significant bilateral differences (defined as a >10 295

mmHg difference).17,34 In the present study, we observed a significant difference in PSBP and 296

PPP between arms (Table 1) and nine subjects (26.5%) presented with clinically significant 297


differences between arms. Current recommendations for the assessment of PBP include 298

measurement in both arms at first examination,21,35,36 and when a consistent inter-arm difference 299

is observed that the higher pressure should be used to determine hypertensive status.21 Strict 300

adherence to these guidelines is not routinely reported in PWA studies and clinical adherence is 301

sub-optimal.37 Frequently, PWA and PBP are measured in the same arm (e.g. left arm), and may 302

not detect a difference in bilateral PBP. Of the 9 subjects in our study that presented with 303

clinically significant differences in PBP, comparative analysis of the effect of calibration to each 304

limb for the same radial artery PWA measurements demonstrated markedly lower values for 305

clinically relevant variables, TTI (10%), DTI (8%), ASBP (11%), ADBP (6%), APP (24%), and 306

AMAP (9%), when calibrated to the lower pressure. Given the clinical implications of these 307

markers, this discrepancy cannot be ignored. For example, it has been reported that there is a 7 308

and 15% increase in cardiovascular risk for every 10 mmHg increase in ASBP and APP, 309

respectively.38 Importantly, 8 of 9 participants exhibited significantly higher PBP in the right 310

arm. 311

Comparisons of simultaneous bilateral PWA parameters revealed significant differences 312

between sides whether calibrated to the ipsilateral or contralateral limb. Nearly all (HR, T1r and 313

ADBP being the exceptions) PWA variables were significantly different between arms when 314

measured simultaneously and calibrated to the same (left arm) PBP with the right arm 315

consistently indicating lesser results of wave reflection and central pressure augmentation (Table 316

3). Moreover, independent of PBP calibration, ED and PPA were consistently higher in the right 317

arm while AgBP, AgBP@75, AIx1, AIx2, AIx@75 and LVEW were consistently lower in the 318

right arm at all timepoints (Table 4). To further explore these differences, Pearson correlations 319

and Bland-Altman agreement analyses were evaluated to demonstrate the bias between arms. 320


Selected variables presented in Figures 1 and 2 illustrate the negative bias in parameters of wave 321

reflection and central pressure augmentation. Despite modest bias in measures known to have a 322

considerable variability (TTI, DTI and SEVR; Figure 2),39 underestimation in clinical 323

populations (e.g. coronary artery disease) is less than desirable. The present study included 324

young, apparently healthy male and female participants representing a relatively homogenous 325

population. Therefore, further studies should be conducted to evaluate the bilateral PWA 326

relationship in aged and clinical populations as age associated increases in vascular resistance 327

and/or asymmetrical vascular disease may contribute to disparities in PWA characteristics.17,40 328

Nevertheless, as can be appreciated from Figure 1, there was a moderate negative bias associated 329

with central pressure augmentation (i.e. AgBP, AIx1) and resultant LVEW, an index of 330

myocardial oxygen demand and LV work.41 In our study, six (18%) of the participants 331

demonstrated absolute differences of greater than 10% for AIx and, on average, the bias for AIx 332

was 3% lower in the right arm. The clinical significance of the observed difference is 333

demonstrated by reports that the relative risk of LV hypertrophy, and independent predictor of 334

cardiovascular events,42 has been reported as 1.99 for each 10% increase in AIx.43 335

Upon review of our data, we hypothesized that the bias in bilateral PWA assessment may 336

be driven by those that presented with clinically significant differences in bilateral PBP. 337

Identification of those subjects on the Pearson correlation and Bland-Altman agreement analyses 338

plots (represented by closed circles, Figures 1 and 2) demonstrated a clear pattern of greater 339

variability in those subjects. When grouped separately, the difference in bilateral PWA measures 340

is amplified in those with a clinically significant difference in bilateral PBP and abolished in 341

those without for all variables except DTI (Figure 3). 342

Limitations 343


The prevalence of clinically significant differences in bilateral blood pressure among 344

young, apparently healthy, non-obese subjects in the present study was unexpected. Although 345

inter-arm differences in PBP can suggest underlying pathophysiology (e.g. vascular disease), 346

Grossman et al. recently reported a prevalence of 13% and 9% for inter-arm systolic and 347

diastolic blood pressures, respectively, in a large cohort of young, healthy subjects.44 348

Importantly, the prevalence was not related to age, body mass index or heart rate. In addition, 349

the automated oscillometric blood pressure devices employed in the present study feature a 350

calibration check system which runs immediately prior to each measurement, were used within 3 351

months of initial manufacturer calibration, and are similar to those commonly used in clinical 352

and research settings. Ideally, aortic pressure waveforms should be measured directly via arterial 353

angiography as a gold standard for reference. However, the purpose of the present study was to 354

evaluate bilateral differences in variables derived from unilateral radial artery PWA methods that 355

have previously been validated invasively. Regardless, further studies should be conducted to 356

further explore the differences in bilateral PWA in a larger, more heterogeneous population (e.g. 357

disease, aging, etc.) as considerable variability in wave reflection characteristics can be attributed 358

to age and gender.45,46 In the present study, we did not observe significant gender differences in 359

the bilateral PWA discrepancies, but our study was not sufficiently powered to appropriately 360

evaluate this point and should be further characterized. Finally, we used the SphygmoCor 361

system and the findings may not be applicable to different devices and transfer functions. 362

Although methods should be optimized for each PWA system, consideration of the findings 363

herein and inter-system variability should be given for evaluation and titration of treatments 364

and/or interventions. 365

Conclusions 366


With respect to the aforementioned variability in bilateral radial artery PWA measures 367

using the SphygmoCor system and the prevalence of clinically different PBP, standard 368

recommendations for PWA are needed for longitudinal clinical monitoring and research 369

comparisons. Here we present novel evidence that SphygmoCor PWA in the right radial artery 370

results in significantly more variability than the left radial artery independent of the order of 371

PWA and PBP measurement and calibration pressures. Moreover, our data suggest that bilateral 372

PBP should be evaluated prior to tonometry measurements and PWA in order to identify subjects 373

in whom 1) there may be a significant difference in bilateral PWA outcomes and 2) markedly 374

different reports of aortic blood pressure estimates would be generated depending on the limb 375

selected for PBP calibration if a clinically significant difference in PBP exists. Therefore, when 376

possible, we suggest simultaneous assessment of PBP prior to radial artery tonometry and that 377

the left arm be utilized for SphygmoCor tonometry measurements. Moreover, when a clinically 378

significant difference in bilateral PBP is observed several things should be considered, including, 379

but not limited to, exclusion from research studies or bilateral assessment of PWA with careful 380

analytical consideration of treatment effects. As our findings highlight, future studies should 381

invasively determine the most accurate method for assessing radial artery PWA in these persons. 382

In the interim, when non-invasive estimates of central pressure are primary outcomes of interest 383

in persons with a clinically significant difference in bilateral PBP, the higher PBP observed 384

should be used for calibration as this is more consistent with guidelines for determination of 385

hypertensive status using brachial artery PBP.21 386

387

388

389


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538

539

540

541

542

543

544

545

546

547


FIGURE LEGENDS 548

549

Figure 1. Correlation coefficients and Bland-Altman plots for right and left arm measurement 550

agreement in PWA derived measures of central augmented blood pressure (AgBP), the central 551

augmentation index (AIx1), and wasted left ventricular energy (LVEw) at PWA 2. Closed circles 552

represent subjects who presented with a clinically significant difference in bilateral peripheral 553

blood pressure (n=9), whereas open circles represent those without a clinically significant 554

difference in peripheral blood pressure (n=25). 555

556

Figure 2. Correlation coefficients and Bland-Altman plots for right and left arm measurement 557

agreement in PWA derived measures of the tension-time index (TTI), diastolic-time index (DTI) 558

and sub-endocardial viability ration (SEVR) at PWA 2. Closed circles represent subjects who 559

presented with a clinically significant difference in bilateral peripheral blood pressure (n=9), 560

whereas open circles represent those without a clinically significant difference in peripheral 561

blood pressure (n=25). 562

563

Figure 3. Between arm differences (right arm - left arm) in PWA derived characteristics of 564

central arterial blood pressure and wave reflection characteristics at PWA2. TTI, tension-time 565

index; DTI, diastolic time index; SEVR, sub-endocardial viability ratio; AgBP, central 566

augmented blood pressure AIx1, augmentation index 1, LVEW, wasted left ventricular energy. 567

Data are mean ± SD. Paired t-tests were performed to determine significant differences between 568

arms and Satterthwaite corrected two sample t-tests were performed to determine differences 569

between groups. Clinically different bilateral blood pressure was defined as > 10mmHg. 570


*Significantly different between arms (P<0.05), †significantly different between groups 571

(P<0.05). 572


SUPPLEMENTAL FIGURE LEGENDS

Supplemental Figure 1. Timeline for measurement of radial artery pulse pressure waveforms

(PWA) and brachial artery blood pressure (PBP)

Supplemental Figure 2. A typical central aortic pressure waveform synthesized from the radial

artery pressure waveform using applanation tonometry. The dotted line is representative of the

theoretical aortic pressure waveform independent of wave reflection. Augmentation index (AIX),

expressed as a percentage, is the ratio of augmented pressure (ASBP – Pi) and central aortic

pulse pressure (ASBP – ADBP). Wasted left ventricular pressure energy (LVEW) is defined as

the portion of area under the pulse pressure curve attributed to amplitude and duration of wave

reflection where, even though there is an increased systolic pressure, blood flow through the

aorta decreases. LVEW, expressed in dynes·sec/cm2, is directly related to augmented pressure

(AP; calculated as ASBP – Pi) and to the time duration of the reflected aortic pressure wave, ∆tr.

ASBP = central aortic systolic blood pressure; Pi = pressure at the first inflection point marking

the onset of reflected aortic pressure wave return from the periphery; ADBP = central aortic

diastolic blood pressure; ∆tp = time to arrival of the reflected pressure wave; ∆tr = systolic

duration of the reflected aortic pressure wave; ED = ejection duration; ESP = end systolic

pressure.


Table 1. Subject characteristics and comparison of resting brachial artery blood pressures.

Variable M ± SD Range

Number of males 17 - Number of females 17 -

Age (yrs) 21.9 ± 2.3 19.1 - 29.1

Height (cm) 169.4 ± 9.3 154.9 - 188.0 Body mass (kg) 68.6 ± 13.5 48.6 - 106.8

BMI (kg/m2) 23.6 ± 2.8 18.3 - 31.0

Body fat (%) 17.0 ± 6.1 6.3 - 30.6

Left Arm 1 Left Arm 2 Right Arm

M ± SD M ± SD P-value M ± SD P-value

PSBP (mmHg) 113.29 ± 13.72 112.44 ± 13.09 0.193 116.88 ± 15.42 0.005** PDBP (mmHg) 65.56 ± 8.49 65.66 ± 7.31 0.204 65.53 ± 6.94 0.833

PPP (mmHg) 46.74 ± 11.60 46.78 ± 12.35 0.807 51.35 ± 15.15 0.001**

Values are mean ± SD. BMI indicate body mass index; PSBP, peripheral (i.e. brachial artery)

systolic blood pressure; PDBP, peripheral diastolic blood pressure; PMAP, peripheral mean

arterial pressure; PPP, peripheral pulse pressure. Significance is reported from paired t-tests of

simultaneous bilateral PBP measurement (Right Arm vs. Left Arm 2; *P<0.05, **P<0.01).


Table 2. Within arm differences in resting pulse wave analysis variables measured pre and post peripheral blood pressure

measurement and calibrated to within arm blood pressure.

Left Arm (PWA 2 – PWA 1) Right Arm (PWA 3 – PWA 2)

M ± SD CV ± SD P-value M ± SD CV ± SD P-value

HR (bpm) 0.74 ± 2.72 0.023 ± 0.022 0.121 1.39 ± 3.18 0.030 ± 0.022 0.016* ED (ms) -1.45 ± 7.27 0.010 ± 0.012 0.255 -0.15 ± 8.30 0.012 ± 0.014 0.918

T1r (ms) 2.63 ± 8.89 0.030 ± 0.030 0.094 0.42 ± 7.96 0.026 ± 0.026 0.759

AgBP (mmHg) 0.14 ± 1.46 nda 0.585 0.24 ± 1.29 nda 0.286

AgBP@75 (mmHg) 0.26 ± 1.57 nda 0.339 0.40 ± 1.31 nda 0.082

ASBP (mmHg) 0.20 ± 0.86 0.005 ± 0.004 0.192 0.38 ± 0.64 0.004 ± 0.004 0.002**

ADBP (mmHg) -0.02 ± 0.42 0.003 ± 0.003 0.838 0.03 ± 0.48 0.004 ± 0.004 0.720

AMAP (mmHg) 0.15 ± 0.97 0.006 ± 0.006 0.364 0.41 ± 1.13 0.008 ± 0.008 0.043

APP (mmHg) 0.21 ± 0.79 0.017 ± 0.013 0.126 0.35 ± 0.64 0.014 ± 0.013 0.003**

PPA (AU) -0.47 ± 4.30 0.015 ± 0.011 0.529 -1.20 ± 3.31 0.011 ± 0.010 0.042* TTI (mmHg•s•min

-1) 15.63 ± 79.17 0.024 ± 0.019 0.258 45.94 ± 95.26 0.030 ± 0.025 0.008**

DTI (mmHg•s•min-1

) -5.88 ± 69.73 0.012 ± 0.010 0.626 -26.14 ± 96.05 0.019 ± 0.017 0.122

SEVR (%) -0.93 ± 12.71 0.035 ± 0.029 0.674 -4.53 ± 14.69 0.050 ± 0.042 0.081

AIx1 (%) 0.46 ± 5.05 nda 0.597 0.98 ± 4.32 nda 0.195

AIx2 (%) 0.56 ± 5.52 0.028 ± 0.027 0.559 0.95 ± 4.24 0.024 ± 0.020 0.202 AIx@75 (%) 0.98 ± 5.34 nda 0.292 1.57 ± 4.46 nda 0.049*

LVEW (dynes•s/cm2) 13.11 ± 148.32 nda 0.126 28.78 ± 138.46 nda 0.234

Data are presented as difference in pulse wave analysis variables pre and post peripheral blood pressure measurement for the left

and right arm (PWA 2 – PWA 1 and PWA 3 – PWA 2, respectively). Values are mean difference ± SD and coefficients of

variation (CV) ± SD. HR, heart rate; ED, Ejection duration; T1r, time of the start of the reflected wave; AgBP, central

augmented blood pressure; AgBP@75, augmented blood pressure normalized to 75 beats per minutes; ASBP, aortic systolic

pressure; ADBP, aortic diastolic pressure; AMAP, aortic mean arterial pressure; APP, aortic pulse pressure; PPA, pulse pressure

amplification ratio; TTI, tension-time index; DTI, diastolic time index; SEVR, sub-endocardial viability ratio; AIx1,

augmentation index 1; AIx2, augmentation index 2; AIx@75, augmentation index normalized to 75 beats per minute; LVEW, wasted left ventricular energy; nda, no data available. Significance values are reported from paired t-tests (* P<0.05, ** P<0.01).


Table 3. Comparison of resting pulse wave analysis variables measured between arms, post left arm peripheral blood pressure

measurement, and calibrated to left arm peripheral blood pressure

Left Arm Right Arm

M ± SD M ± SD CV ± SD P-value

HR (bpm) 64.83 ± 12.38 64.47 ± 12.06 0.020 ± 0.018 0.111 ED (ms) 325.06 ± 13.54 327.93 ± 14.44 0.010 ± 0.007 0.001**

T1r (ms) 149.40 ± 16.62 152.56 ± 11.11 0.049 ± 0.062 0.332

AgBP (mmHg) 0.23 ± 3.22 -0.54 ± 2.82 nda 0.015*

AgBP@75 (mmHg) -1.38 ± 3.38 -2.05 ± 3.05 nda 0.034*

ASBP (mmHg) 95.48 ± 10.96 95.04 ± 10.56 0.007 ± 0.006 0.030*

ADBP (mmHg) 67.26 ± 8.72 67.24 ± 8.70 0.002 ± 0.003 0.697

AMAP (mmHg) 80.08 ± 9.53 79.69 ± 9.48 0.007 ± 0.005 0.009**

APP (mmHg) 28.22 ± 6.83 27.80 ± 6.74 0.020 ± 0.018 0.024* PPA (AU) 165.57 ± 11.49 168.27 ± 10.23 0.022 ± 0.018 0.013* TTI (mmHg•s•min

-1) 1836 ± 388.2 1858 ± 387.4 0.021 ± 0.017 0.046*


) 2969 ± 408.6 2925 ± 397.4 0.014 ± 0.012 0.001**

SEVR (%) 169.05 ± 40.95 164.37 ± 39.58 0.033 ± 0.026 0.007**

AIx1 (%) 1.44 ± 10.63 -1.34 ± 9.87 nda 0.022*

AIx2 (%) 102.69 ± 11.24 100.39 ± 9.65 0.042 ± 0.033 0.018* AIx@75 (%) -3.95 ± 12.40 -6.60 ± 11.08 nda 0.030*

LVEW (dynes•s/cm2) 31.80 ± 331.97 -47.46 ± 275.87 nda 0.016*

Values are representative of the mean ± SD and coefficients of variation (CV) ± SD in pulse wave analysis variables at PWA 2 in the

left and right arms. HR, heart rate; ED, Ejection duration; T1r, time of the start of the reflected wave; AgBP, central augmented blood

pressure; AgBP@75, augmented blood pressure normalized to 75 beats per minutes; ASBP, aortic systolic pressure; ADBP, aortic

diastolic pressure; AMAP, aortic mean arterial pressure; APP, aortic pulse pressure; PPA, pulse pressure amplification ration; TTI,

tension-time index; DTI, diastolic time index; SEVR, sub-endocardial viability ratio; AIx1, augmentation index 1; AIx2, augmentation

index 2; AIx@75, augmentation index normalized to 75 beats per minute; LVEW, wasted left ventricular energy; nda, no data available. Significance values are reported from paired t-tests (* P<0.05, ** P<0.01).


Table 4. Comparison of resting pulse wave analysis variables measured between arms, post simultaneous bilateral peripheral blood

pressure measurement, and calibrated to within arm peripheral blood pressure

Left Arm Right Arm

M ± SD M ± SD CV ± SD P-value

HR (bpm) 63.86 ± 11.56 63.06 ± 11.89 0.021 ± 0.021 0.111 ED (ms) 324.26 ± 12.65 327.12 ± 14.10 0.011 ± 0.009 0.006**

T1r (ms) 150.87 ± 9.62 152.25 ± 11.40 0.037 ± 0.032 0.457

AgBP (mmHg) 0.10 ± 3.30 -0.95 ± 3.08 nda 0.002**

AgBP@75 (mmHg) -1.65 ± 3.28 -2.81 ± 3.17 nda 0.000**

ASBP (mmHg) 94.43 ± 9.69 96.39 ± 10.09 0.033 ± 0.031 0.065

ADBP (mmHg) 66.32 ± 7.54 66.19 ± 7.13 0.029 ± 0.025 0.832

AMAP (mmHg) 79.19 ± 8.14 79.56 ± 7.94 0.029 ± 0.025 0.625

APP (mmHg) 28.10 ± 7.29 30.20 ± 8.54 0.095 ± 0.054 0.010**

PPA (AU) 166.74 ± 12.31 169.50 ± 10.60 0.020 ± 0.017 0.004**

TTI (mmHg•s•min-1

) 1812 ± 352.4 1829 ± 372.0 0.034 ± 0.031 0.423


) 2935 ± 337.9 2945 ± 321.9 0.029 ± 0.028 0.735

SEVR (%) 168.11 ± 36.79 167.78 ± 38.08 0.028 ± 0.025 0.832

AIx1 (%) 0.60 ± 10.88 -2.16 ± 9.81 nda 0.012*

AIx2 (%) 101.51 ± 12.18 98.27 ± 10.33 0.039 ± 0.032 0.007** AIx@75 (%)

LVEW (dynes•s/cm2)

-4.74 ± 11.79 12.22 ± 320.71

-8.03 ± 10.07 -89.58 ± 301.57

nda

nda

0.005** 0.002**

Values are representative of the mean ± SD and coefficients of variation (CV) ± SD in pulse wave analysis variables at PWA 3 in the left and right arms. HR, heart rate; ED, Ejection duration; T1r, time of the start of the reflected wave; AgBP, central augmented blood

pressure; AgBP@75, augmented blood pressure normalized to 75 beats per minutes; ASBP, aortic systolic pressure; ADBP, aortic

diastolic pressure; AMAP, aortic mean arterial pressure; APP, aortic pulse pressure; PPA, pulse pressure amplification ration; TTI,

tension-time index; DTI, diastolic time index; SEVR, sub-endocardial viability ratio; AIx1, augmentation index 1; AIx2, augmentation

index 2; AIx@75, augmentation index normalized to 75 beats per minute; LVEW, wasted left ventricular energy; nda, no data available. Significance values are reported from paired t-tests (* P<0.05, ** P<0.01).


Figure 1. Correlation coefficients and Bland-Altman plots for right and left arm measurement

agreement in PWA derived measures of central augmented blood pressure (AgBP), the central

augmentation index (AIx1), and wasted left ventricular energy (LVEw) at PWA 2. Closed circles

represent subjects who presented with a clinically significant difference in bilateral peripheral

blood pressure (n=9), whereas open circles represent those without a clinically significant

difference in peripheral blood pressure (n=25).


Figure 2. Correlation coefficients and Bland-Altman plots for right and left arm

measurement agreement in PWA derived measures of the tension-time index (TTI),

diastolic-time index (DTI) and sub-endocardial viability ration (SEVR) at PWA 2.

Closed circles represent subjects who presented with a clinically significant difference

in bilateral peripheral blood pressure (n=9), whereas open circles represent those

without a clinically significant difference in peripheral blood pressure (n=25).


Figure 3. Between arm differences (right arm - left arm) in PWA derived characteristics of central

arterial blood pressure and wave reflection characteristics at PWA2. TTI, tension-time index; DTI,

diastolic time index; SEVR, sub-endocardial viability ratio; AgBP, central augmented blood pressure

AIx1, augmentation index 1, LVEW, wasted left ventricular energy. Data are mean ± SD. Paired t-

tests were performed to determine significant differences between arms and Satterthwaite corrected

two sample t-tests were performed to determine differences between groups. Clinically different

bilateral blood pressure was defined as > 10mmHg. *Significantly different between arms (P<0.05),

†significantly different between groups (P<0.05).


1

2

3

4

5

6

Supplemental Figure 1. Timeline for measurement of radial 7

artery pulse pressure waveforms (PWA) and brachial artery 8

blood pressure (PBP) 9


10

Supplemental Figure 2. A typical central aortic pressure waveform synthesized from the radial 11

artery pressure waveform using applanation tonometry. The dotted line is representative of the 12

theoretical aortic pressure waveform independent of wave reflection. Augmentation index 13

(AIX), expressed as a percentage, is the ratio of augmented pressure (ASBP – Pi) and central 14

aortic pulse pressure (ASBP – ADBP). Wasted left ventricular pressure energy (LVEW) is 15

defined as the portion of area under the pulse pressure curve attributed to amplitude and 16

duration of wave reflection where, even though there is an increased systolic pressure, blood 17

flow through the aorta decreases. LVEW, expressed in dynes•sec/cm2, is directly related to 18

augmented pressure (AP; calculated as ASBP – Pi) and to the time duration of the reflected 19

aortic pressure wave, ∆tr. ASBP = central aortic systolic blood pressure; Pi = pressure at the 20

first inflection point marking the onset of reflected aortic pressure wave return from the 21

periphery; ADBP = central aortic diastolic blood pressure; ∆tp = time to arrival of the reflected 22

pressure wave; ∆tr = systolic duration of the reflected aorticpressure wave; ED = ejection 23

duration; ESP = end systolic pressure. 24

25

Considerations for SphygmoCor radial artery pulse wave analysis: side selection and peripheral arterial blood pressure calibration

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