Original article 797
Pulse waveform characteristics predict cardiovascular events
and mortality in patients undergoing coronary angiography
Thomas Webera,b, Michael F. O’Rourkec,d, Elisabeth Lassniga,
Michael Porodkoa, Marcus Ammera, Martin Rammera and Bernd Ebera
Objectives Pulse waveform characteristics (Augmentation
Index – AIx and pulse wave transit time) are measures
of the timing and extent of arterial wave reflections.
Although previous studies reported an independent
association with cardiovascular morbidity, it remains to be
established that waveform characteristics, derived from
noninvasive pulse waveform analysis, predict
cardiovascular outcomes independent of and additional to
brachial blood pressure.
Methods We prospectively assessed AIx, heart-rate
corrected AIx, and pulse wave transit time, using radial
applanation tonometry and a validated transfer function to
generate the aortic pressure curve, in 520 male patients
undergoing coronary angiography. Primary endpoint was a
composite of all-cause mortality, myocardial infarction,
stroke, cardiac, cerebrovascular, and peripheral
revascularization.
Results During a follow-up of 49 months, 170 patients
reached the primary endpoint. On the basis of Cox
proportional hazards regression models, all pressure
waveform characteristics predicted the primary endpoint. A
10% increase of AIx and heart-rate corrected AIx was
associated with a 20.5% (95% confidence interval 6.5–36.4,
P U 0.003) and 31.4% (95% confidence interval 13.2–52.6,
P U 0.0004) increased risk of the primary endpoint,
respectively. A 10-ms increase of pulse wave transit time
was associated with a 20.8% (95% confidence interval
10.8–29.6, P U 0.0001) lower risk of the primary endpoint. In
Introduction
The technique of pulse waveform analysis (PWA), devel-
oped in the nineteenth century by Mahomed [1], but
largely ignored after introduction of the cuff sphygmo-
manometer, has recently experienced a revival. Using
accurate tonometric recording of the radial pressure
pulse, a computerized validated algorithm (the so-called
generalized transfer function [2]) provides the ascending
aortic waveform, whose different features can be ident-
ified automatically. Identification of the inflection point
facilitates the quantification of the timing and the extent
of pressure wave reflections from peripheral vessels in the
ascending aorta [3]. This information is thought to pro-
vide better insights into cardiovascular physiology and
disease than the mere extremes of the brachial blood
pressure (BP i.e. brachial SBP and DBP), measured with
conventional cuff sphygmomanometer [4]. Indeed, the
0263-6352 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
multiple adjusted models, AIx, heart-rate corrected AIx, and
pulse wave transit time were independently associated with
the combined endpoint even after adjustments for brachial
blood pressure, age, extent of coronary artery disease,
clinical characteristics, and medications.
Conclusion The study provides evidence that pulse
waveform characteristics consistently and independently
predict cardiovascular events in coronary patients.
J Hypertens 28:797–805 Q 2010 Wolters Kluwer Health |
Lippincott Williams & Wilkins.
Journal of Hypertension 2010, 28:797–805
Keywords: augmentation index, blood pressure, coronary artery disease,
pulse waveform analysis, wave reflections
Abbreviations: AIx, Augmentation Index; AIx@75, heart-rate corrected
Augmentation Index; CAD, coronary artery disease; CI, confidence
interval; MBP, mean blood pressure; MI, myocardial infarction; PCI,
percutaneous coronary interventions; PP, pulse pressure; PWA, pulse
waveform analysis
a
Cardiology Department, Klinikum Wels-Grieskirchen, Wels, bParacelsus Medical
University, Salzburg, Austria, cUniversity of New South Wales, Kensington and
d
St. Vincent’s Clinic, Darlinghurst, Sydney, New South Wales, Australia
Correspondence to Thomas Weber, MD, Associate Professor, Cardiology
Department, Klinikum Wels-Grieskirchen, Grieskirchnerstrasse 42, 4600 Wels,
Austria
Tel: +43 7242 415 2215; fax: +43 7242 415 3992;
e-mail: thomas.weber3@liwest.at
Received 1 August 2009 Revised 15 November 2009
Accepted 18 December 2009
Augmentation Index (AIx), a principal measure in PWA,
relating wave reflection to BP amplitude has been shown
to be closer associated with left ventricular hypertrophy
[5] and its regression [6], diastolic dysfunction [7,8],
presence and extent of coronary artery disease (CAD)
[9], and cardiovascular outcomes [10–12] than brachial
BPs. We have found recently [13] that increased arterial
wave reflections, determined with noninvasive PWA and
quantified as heart-rate corrected AIx (AIx@75), were
associated with adverse cardiovascular events in the
high-risk subgroup of CAD patients undergoing percu-
taneous coronary interventions (PCIs). Consequently, we
were interested in the prognostic value of PWA in the
entire range of CAD patients. Moreover, because of
sample size and follow-up duration, we had relatively
few patients suffering from myocardial infarction (MI) or
death in our previous study. An increased number of
DOI:10.1097/HJH.0b013e328336c8e9
 798 Journal of Hypertension 2010, Vol 28 No 4
endpoints would allow for more detailed statistical
analysis as well, in particular, regarding the potential
independency of PWA measures from conventional
BP. Finally, no information on the prognostic value of
pulse wave transit time and the height of the incident
pressure wave, other measures derived from PWA, has
been reported until now. Therefore, we aimed to clarify
the issues raised above, focusing on the question whether
PWA adds to the information already provided by
brachial BP.
Methods
Study population
This study was conducted in our invasive cardiology
department in a 1050-bed tertiary referral hospital in
Austria. We prospectively included 520 unselected male
patients undergoing coronary angiography for suspected
CAD between July 2001 and May 2002. One hundred and
seventy-four men undergoing PCI have been included in
a previous publication [13].
Exclusion criteria were atrial fibrillation, more than mild
valvular heart disease, or severely impaired systolic func-
tion (left ventricular ejection fraction < 35%). All patients
were studied while on regular medications (drugs were
not withheld before measurement) and gave written
informed consent. The study was approved by our local
ethics committee.
Hypertension was present with repeated measurements
of at least 140 mmHg SBP, at least 90 mmHg DBP, or
both or permanent antihypertensive drug treatment.
Diabetes mellitus was defined as a fasting blood glucose
concentration of at least 126 mg/dl or antihyperglycemic
drug treatment. Current smoking was defined as having
smoked the last cigarette less than 1 week before
coronary angiography.
Coronary angiography
Coronary angiography was performed using standard
techniques on a digitized monoplane or biplane coronary
angiography equipment (Cathcor; Siemens, Berlin/
Munich, Germany). All coronary angiograms were
visually assessed by at least three experienced angiogra-
phers (case load of more than 5000 angiograms each) and
a consensus was reached. The reviewers were blinded to
the results of PWA. The extent of CAD was defined as
one, two, or three-vessel disease, and by addition of a
modified stenosis score system (minimum score was 0,
maximum score was 27): 0, 1, 2, 3 points, respectively, for
less than 50, 50–70, 71–89, 90%, and more diameter
stenosis in one to three segments of the three main
coronary arteries (a total of nine segments). For this
study, we defined significant CAD as at least one 50%
or greater diameter stenosis in at least one coronary vessel
or prior percutaneous or surgical coronary revascular-
ization.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Pulse waveform analysis
PWA was performed noninvasively with the commer-
cially available SphygmoCor system (AtCor Medical,
Sydney, New South Wales, Australia) as previously
described [9]. In brief, peripheral pressure waveforms
were recorded from the radial artery at the wrist, using
applanation tonometry with a high-fidelity microman-
ometer. After 20 sequential waveforms had been
acquired, a validated [14] generalized transfer function
was used to generate the corresponding central aortic
pressure waveform. AIx and augmentation pressure were
derived from this with the technique of PWA [15]. The
merging point of the incident and the reflected wave (the
inflection point) was identified on the generated aortic
pressure waveform. Augmentation pressure was the
maximum systolic pressure subtracted from pressure at
the inflection point. The AIx was defined as the aug-
mentation pressure divided by pulse pressure (PP) and
expressed as a percentage. Larger values of AIx indicate
increased wave reflection from the periphery, earlier
return, or both of the reflected wave as a result of
increased pulse wave velocity (due to increased arterial
stiffness) and vice versa. In addition, as AIx is influenced
by heart rate (HR), an index normalized for HR 75/min
(AIx@75) was used in accordance to Wilkinson et al. [16].
Pulse wave transit time is the time from the beginning of
the derived aortic systolic pressure waveform to the
inflection point and has been shown to be related to
pulse wave velocity (a higher pulse wave velocity will
lead to a shorter pulse wave transit time) [17]. Finally, the
height of the incident pressure wave (the BP at the
inflection point) is related to aortic characteristic impe-
dance [18]. Only high-quality recordings, defined as an
in-device quality index of at least 80% (derived from an
algorithm including average pulse height, pulse height
variation, diastolic variation, and the maximum rate of
rise of the peripheral waveform) and acceptable curves on
visual inspection by one investigator (T.W.), were
included into the analysis. All PWA measurements were
taken in the sitting position in a quiet, temperature-
controlled room (22
18C) after a brief period (at least
5 min) of rest, most often on the day following PCI by
nurses not involved in performance or interpretation of
the angiograms. Repeatability of PWA was good, as
previously reported [9].
Blood pressure measurements
BP measurements were performed with a validated [19],
automated wrist BP monitor (Omron R3; Omron Health-
care, Tokyo, Japan), with the radial artery kept at heart
level during measurement.
Study endpoints
Primary endpoint was the combination of death, MI,
stroke, coronary, cerebrovascular, or peripheral revas-
cularization. Secondary endpoints were the combination
 Pulse waveform characteristics and outcome Weber et al. 799

of death and MI and the single components of the Results

primary endpoint. Baseline characteristics of our patients are shown in
Table 1. Mean age was 64 (54–71.5) years, 66.7% had
Follow-up hypertension, 20% had diabetes, 79.2% were diagnosed
Patients were followed primarily by a written question- with significant CAD, 66.9% had normal systolic func-
naire, which was returned by almost two-thirds of patients. tion, and 33.5% underwent PCI at baseline.
The remaining patients were followed by a telephone
interview or, if not achievable, by information obtained After a follow-up of 49 months, 170 patients suffered from
from their general practitioners. If a patient reached an the primary combined endpoint, 55 patients died, 37
endpoint, the hospital record or – if the patient was not suffered from MI, 28 from stroke, 88 underwent coronary,
hospitalized – information from the general practitioner and 24 cerebrovascular or peripheral revascularization.
was obtained. All endpoints were adjudicated by two
investigators (T.W. and E.L.) independently.
Brachial blood pressures and outcomes
Statistical analysis We observed a direct relationship between brachial SBP
Data were analyzed using Statistica 6.0 (StatSoft Inc., and outcome: a 10-mmHg increase in brachial SBP was
Tulsa, Oklahoma, USA) as well as MedCalc 9.5.1 (Med- associated with a 10.9% increase in the risk of the
Calc Software, Mariakerke, Belgium) software packages. combined endpoint (Table 2). In contrast, there was
Values were expressed as numbers (percentages), as an inverse relationship between DBP and events: a
means (
SD) for normally distributed, and as medians 10-mmHg decrease in brachial DBP predicted a 28.9%
(interquartile range) for nonnormally distributed vari- higher risk of all-cause mortality and a 18.4% higher
ables. Normal distribution was evaluated with Kolmo- risk of all-cause mortality plus MI. MBP was not able
gorov–Smirnov test. Patients were divided into tertiles, to predict outcomes. A 10-mmHg increase in brachial
according to PWA parameters (AIx, AIx@75, augmenta- PP was associated with a 22.3% increased risk of the
tion pressure, and pulse wave transit time). To visualize
the relation between PWA parameters and outcomes, Table 1 Baseline characteristics
Kaplan–Meier plots were generated, and the log-rank n 520
test was used for comparison of the resulting survival Age [years (IQR)] 64.0 (54–71.5)
curves. Tertiles were 24 to 18, 19–29, and 30–60 for Prior MI (%) 94 (18.1)
Prior stroke (%) 31 (6.0)
AIx; 19 to 13, 14–21, and 22–52 for AIx@75; 9 to 6, 7– Peripheral arterial disease (%) 42 (8.1)
12, and 13–36 mmHg for augmentation pressure; and 227 Hypertension (%) 347 (66.7)
Diabetes (%) 104 (20)
to 144, 143 to 135, and 134 to 88 ms for pulse wave transit Current smoking (%) 111 (21.3)
time, respectively. Cox proportional hazards modeling Body height [cm (
SD)] 171.5 (
6.7)
was used for the determination of univariate and multi- Body weight [kg (
SD)] 81.7 (
11.6)
Total cholesterol [mg/dl (
SD)] 203 (
43)
variate predictors of the composite primary endpoint. LDL cholesterol [mg/dl (
SD)] 124 (
39)
PWA parameters were entered into the statistical models HDL cholesterol [mg/dl (
SD)] 44 (
11)
Triglycerides [mg/dl (IQR)] 150 (102–214)
as continuous variables. First, models for prediction of the
Creatinine [mg/dl (IQR)] 1.1 (1.0–1–3)
combined outcome were calculated, including age, PWA Coronary artery disease (%) 412 (79.2)
characteristics, brachial BPs as mean BP (MBP) and PP, Systolic function normal (%) 348 (66.9)
Angioscore (IQR) 4 (1–9)
as well as age and the extent of CAD (both have been PCI baseline (%) 174 (33.5)
shown to be associated with waveform characteristics) [9]. Heart rate [bpm (IQR)] 63 (56 – 71)
Then, age, MBP, brachial PP, prior MI, prior stroke, body SBP brachial [mmHg (
SD)] 133 (
20)
DBP brachial [mmHg (IQR)] 80 (70–86)
height, total cholesterol, presence of hypertension, pre- MBP [mmHg (IQR)] 96 (86–105)
sence of peripheral arterial disease, extent of CAD, HR, SBP aortic [mmHg (
SD)] 121 (
19)
DBP aortic [mmHg (IQR)] 80 (71–88)
left ventricular function, use of angiotensin-converting AIx (IQR) 24 (15–31)
enzyme inhibitors or angiotensin-receptor blockers, AIx@75 (IQR) 18 (11–24)
b-blockers, calcium channel blockers, and nitrates, per- Augmented pressure [mmHg (IQR)] 9 (5–14)
Pulse wave transit time [ms (IQR)] 139 (132–146)
formance of coronary interventions at baseline, and one Height of the incident pressure wave [mmHg (IQR)] 29 (25–35)
PWA parameter (AIx, AIx@75, augmentation pressure, Medications (%)
pulse wave transit time, or height of the incident pressure Nitrates (%) 131 (34.8)
ACEIs or ARBs (%) 256 (49.2)
wave) were entered into the final multivariable model for b-blockers (%) 377 (72.5)
prediction of the primary endpoint. Subgroup analysis CCBs (%) 67 (12.9)
Statins (%) 341 (65.6)
was performed, with patients stratified according to age,
left ventricular function, diabetes, performance of PCI at ACEI, angiotensin-converting enzyme inhibitor; AIx, Augmentation Index; AIx@75,
baseline, and on-treatment BP. All tests were two-tailed, heart-rate corrected Augmentation Index; ARB, angiotensin receptor blocker;
CCB, calcium channel blocker; HDL, high-density lipoprotein; IQR, interquartile
and a P value of less than 0.05 was considered to indicate range; LDL, low-density lipoprotein; MBP, mean blood pressure; MI, myocardial
statistical significance. infarction; PCI, percutaneous coronary interventions.

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 800 Journal of Hypertension 2010, Vol 28 No 4

Table 2 Brachial blood pressure and outcomes, expressed as unadjusted hazard ratios (95% confidence interval)
SBP brachial per 10 mmHg DBP brachial per 10 mmHg MBP per 10 mmHg PP brachial per 10 mmHg
#
Total mortality 1.054 (0.927–1.197) 0.711 (0.574–0.881) 0.843 (0.699–1.017) 1.249 (1.117–1.396) $
MI 1.052 (0.899–1.229) 1.009 (0.795–1.280) 1.042 (0.839–1.296) 1.074 (0.889–1.298)
Death þ MI 1.045 (0.939–1.163) 0.816 (0.687–0.968)M 0.908 (0.780–1.058) 1.185 (1.066–1.318)#
Stroke 1.140 (0.964–1.349) 0.839 (0.628–1.120) 0.995 (0.771–1.285) 1.271 (1.091–1.481)#
Coronary revascularization 1.142 (1.031–1.265)M 1.109 (0.956–1.288) 1.147 (0.999–1.317) 1.145 (1.008–1.301)M
Peripheral and cerebrovascular revascularization 1.099 (0.908–1.330) 1.038 (0.773–1.395) 1.107 (0.846–1.450) 1.122 (0.899–1.400)
Combined endpoint 1.109 (1.030–1.194)$ 0.942 (0.842–1.054) 1.024 (0.925–1.134) 1.223 (1.122–1.333)$

#
MBP, mean blood pressure; MI, myocardial infarction; PP, pulse pressure. M
P < 0.05. P < 0.01. $ P < 0.001.

combined endpoint and a 24.9% increased risk of total in AIx and AIx@75 was associated with a 20.5% [95%
mortality. confidence interval (CI) 6.5–36.4, P ¼ 0.003] and 31.4%
(95% CI 13.2–52.6, P ¼ 0.0004) increased risk of the
Pulse waveform characteristics and combined endpoint primary endpoint, respectively. A 10-mmHg increase
When divided into tertiles, all waveform characteristics of augmentation pressure and height of the incident
were statistically significant predictors of the combined pressure wave was associated with a 50.7% (95% CI
endpoint. The corresponding Kaplan–Meier curves are 23.7–83.5, P ¼ 0.00005) and 36.5% (95% CI 17.3–58.8,
shown in Fig. 1. P < 0.00001) higher risk of the primary endpoint, respec-
tively. A 10 ms longer pulse wave transit time was associ-
When PWA parameters were analyzed as continuous ated with a 20.8% (95% CI 10.8–29.6, P ¼ 0.0001) lower
variables, findings were similar (Table 3). A 10% increase risk of the primary endpoint.

Fig. 1

100 100
Eventfree survival probability (%)

Eventfree survival probability (%)

90 90
80
80
70 AIx tertiles AIx@75 tertules
70
60 AIx T1 AIx 75 T1
AIx T2 60 AIx 75 T2
50 AIx T3 AIx 75 T3
50
40
30 40

20 30

10 20
0 20 40 60 80 0 20 40 60 80
Time (months) Time (months)

100 100
Eventfree survival probability (%)

Eventfree survival probability (%)

90 90

80
80
Ap tertiles 70 Tr tertiles
70 AP T1 Tr T1
AP T2 60 Tr T2
60 AP T3 Tr T3
50
50
40
40 30

30 20
0 20 40 60 80 0 20 40 60 80
Time (months) Time (months)

Kaplan–Meier curves showing the association between Augmentation Index, heart-rate corrected Augmentation Index, augmented pressure, and
pulse wave transit time, and the risk of the combined endpoint. All relationships were statistically significant, corresponding P values are 0.008,
0.003, 0.0003, and 0.0003, respectively (log-rank test). AIx, Augmentation Index; AIx@75, heart-rate corrected AIx; AP, augmented pressure; Tr,
pulse wave transit time.

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 Pulse waveform characteristics and outcome Weber et al. 801

Table 3 Pulse waveform characteristics and the risk of the combined endpoint (death, myocardial infarction, stroke, coronary,
cerebrovascular, and peripheral revascularization), expressed as univariate and adjusted hazard ratios
Covariates Hazard ratio 95% CI P

AIx per 10% None 1.205 1.065–1.364 0.003

Age 1.168 1.029–1.325 0.02
MBP 1.216 1.069–1.384 0.003
PP brachial 1.175 1.036–1.333 0.01
Age, angioscore 1.162 1.025–1.318 0.02
Age, angioscore, MBP 1.185 1.042–1.348 0.01
MBP, PP brachial 1.209 1.061–1.378 0.005
Age, MBP, PP brachial 1.159 1.013–1.327 0.03
Age, angioscore, MBP, PP brachial 1.150 1.006–1.316 0.04
AIx@75 per 10% None 1.314 1.132–1.526 0.0004
Age 1.258 1.081–1.463 0.003
MBP 1.352 1.153–1.585 0.0002
PP brachial 1.271 1.092–1.479 0.002
MBP, PP brachial 1.346 1.147–1.580 0.0003
Age, angioscore 1.243 1.069–1.445 0.005
Age, angioscore, MBP 1.233 1.046–1.453 0.01
Age, MBP, PP brachial 1.270 1.077–1.498 0.005
Age, angioscore, MBP, PP brachial 1.247 1.056–1.471 0.009
Augmentation pressure per 10 mmHg None 1.507 1.237–1.835 0.00005
Age 1.348 1.100–1.653 0.004
MBP 1.574 1.273–1.946 < 0.00001
PP brachial 1.257 0.996–1.588 0.056
MBP, PP brachial 1.317 1.033–1.679 0.03
Age, angioscore 1.343 1.092–1.653 0.0055
Age, angioscore, MBP 1.319 1.049–1.660 0.02
Age, MBP, PP brachial 1.204 0.937–1.547 0.13
Age, angioscore, MBP, PP brachial 1.208 0.939–1.553 0.14
Pulse wave transit time per 10 ms None 0.792 0.704–0.892 0.0001
Age 0.834 0.741–0.939 0.003
MBP 0.793 0.704–0.892 0.0001
PP brachial 0.813 0.721–0.917 0.0008
Age, angioscore 0.849 0.756–0.954 0.006
Age, angioscore, MBP 0.856 0.761–0.963 0.01
Age, MBP, PP brachial 0.845 0.749–0.953 0.006
Age, angioscore, MBP, PP brachial 0.859 0.763–0.968 0.01
Height of the incident pressure wave per 10 mmHg None 1.365 1.173–1.588 <0.0001
Age 1.253 1.065–1.474 0.007
MBP 1.373 1.175–1.604 <0.0001
PP brachial 0.728 0.371–1.425 0.36
MBP, PP brachial 0.702 0.357–1.383 0.31
Age, angioscore 1.219 1.034–1.437 0.02
Age, angioscore, MBP 1.194 1.008–1.416 0.04
Age, MBP, PP brachial 0.747 0.375–1.488 0.41
Age, angioscore, MBP, PP brachial 0.730 0.371–1.437 0.36

AIx, Augmentation Index; AIx@75, heart-rate corrected Augmentation Index; CI, confidence interval; MBP, mean blood pressure; PP, pulse pressure.

AIx, AIx@75, and pulse wave transit time predicted the
combined endpoint even after adjustments for brachial
BP, age, and extent of CAD, although the hazard ratios
were lowered (Table 3). Augmentation pressure lost its
predictive value after full adjustment for age, MBP, and
brachial PP. Height of the incident pressure wave was no
longer associated with the risk of the combined endpoint
after adjustment for brachial PP.
In the final multivariable models, adjusted for brachial
PP, MBP, and a large number of clinically relevant
covariates as well as medications, AIx, AIx@75, and
pulse wave transit time still added significant prognostic
information to that already provided by the brachial BP
(Table 4). A 10% increase in AIx and AIx@75 was
associated with a 26.4% (95% CI 5.8–50.9, P ¼ 0.01)
and 27.4% (95% CI 6.5–52.5, P ¼ 0.009) increased risk
of the primary endpoint, respectively. Augmentation
pressure tended to predict the combined endpoint as
well (P ¼ 0.06). A 10-ms shorter pulse wave transit time
was associated with a 15.2% (95% CI 3.7–25.3, P ¼ 0.01)
lower risk of the combined endpoint. In contrast, height
of the incident pressure wave was not independently
associated with the primary endpoint.
Subgroup analysis
The results with respect to the primary endpoint were
consistent across important clinical subgroups: younger
(<65 years) and older (66þ years) patients, patients
undergoing PCI at baseline or not, patients with normal
(ejection fraction 60%) and mildly to moderately
impaired systolic function (ejection fraction 35–59%),
and patients with and without diabetes (Fig. 2). When
stratified according to achieved BP, the predictive value
of waveform characteristics tended to be higher with BPs
in the normal or prehypertensive range.

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 802 Journal of Hypertension 2010, Vol 28 No 4

Table 4 Multivariable models for prediction of the combined important information that cannot be inferred from
endpoint (P < 0.0001 for the total models)
knowledge of the simple extremes of the brachial (cuff)
Covariate Hazard ratio 95% CI P value BP, that is, SBP and DBP.
(a)
AIx per 10% 1.264 1.058–1.509 0.01 The most relevant information derived from PWA is
Age per year 1.020 1.003–1.038 0.02
PP brachial per 10 mmHg 1.113 1.006–1.231 0.04
related to the wave reflection phenomenon. The magni-
Angioscore 1.068 1.027–1.110 0.0009 tude and timing of wave reflection from peripheral arter-
Peripheral arterial disease 2.710 1.748–4.202 <0.0001 ial sites can be gauged, using AIx, AIx@75, augmentation
(yes ¼ 1, no ¼ 0)
PCI baseline (yes ¼ 1, no ¼ 0) 1.482 1.069–2.055 0.02 pressure, and pulse wave transit time. Very recently, the
CCBs (yes ¼ 1, no ¼ 0) 1.804 1.828–2.752 0.006 importance of wave reflection across the human life span
(b)
AIx@75 per 10% 1.274 1.065–1.525 0.009
has been assessed [20]. Increased/premature wave reflec-
Age per year 1.020 1.002–1.037 0.03 tions (a higher AIx, AIx@75, augmentation pressure, and
PP brachial per 10 mmHg 1.114 1.007–1.232 0.04 a shorter pulse wave transit time) have been shown to
Angioscore 1.070 1.029–1.112 0.0007
Peripheral arterial disease 2.677 1.726–4.150 <0.0001 occur with age, cardiovascular risk factors [21], and risk
(yes ¼ 1, no ¼ 0) scores [22]. Previously, we [9] and others [23,24] found an
PCI baseline (yes ¼ 1, no ¼ 0) 1.458 1.051–2.032 0.02 association between cardiac structure (presence and
CCBs (yes ¼ 1, no ¼ 0) 1.792 1.176–2.731 0.007
(c) extent of CAD) and wave reflection. In addition, a func-
Pulse wave transit time per 10 ms 0.848 0.747–0.963 0.01 tional link has been described as well: increased and
Age per year 1.022 1.005–1.040 0.01
PP brachial per 10 mmHg 1.093 0.987–1.209 0.09
higher wave reflection in the central aorta rise central
Angioscore 1.075 1.034–1.118 0.0003 SBP (thus increasing myocardial oxygen demand) and
Peripheral arterial disease 2.579 1.646–4.042 <0.0001 decrease central DBP (thus impeding coronary blood
(yes ¼ 1, no ¼ 0)
PCI baseline (yes ¼ 1, no ¼ 0) 1.520 1.094–2.113 0.01 flow), both contributing to an imbalance between oxygen
CCBs (yes ¼ 1, no ¼ 0) 1.819 1.193–2.773 0.006 demand and supply, and, hence, ischemia [3]. Supporting
this view, an inverse relationship between AIx and exer-
Waveform characteristics entered into the models were AIx (a), AIx@75 (b), and
pulse wave transit time (c). In all models, MBP, prior MI, prior stroke, body height, cise time [25] as well as a decreased coronary flow in
total cholesterol, hypertension, heart rate, systolic function, use of nitrates, ACEIs, association with a stiffer aorta [26] and an increased AIx
and b-blockers did not reach statistical significance. ACEI, angiotensin-converting
enzyme inhibitor; AIx, Augmentation Index; AIx@75, heart-rate corrected Augmen-
[27] has been observed. These findings may possibly
tation Index; ARB, angiotensin receptor blocker; CCBs, calcium channel blockers; explain our findings regarding wave reflections and out-
CI, confidence interval; MBP, mean blood pressure; MI, myocardial infarction; PCI, comes, even more in our population of coronary patients.
percutaneous coronary interventions; PP, pulse pressure.

The height of the incident pressure wave, strongly

Secondary endpoints
Pulse waveform characteristics predicted most com-
ponents of the primary endpoint (Table 5). A 10%
increase of AIx@75 was associated with a 37.8% (95%
CI 5.1–80.7, P ¼ 0.02) increased risk of all-cause
mortality. A 10-mmHg increase of augmentation pressure
and height of the incident pressure wave was associated
with a 56.3% (95% CI 10.7–120.5, P ¼ 0.01) and 43.9%
(95% CI 18.9–74.1, P ¼ 0.0002) higher risk of all-cause
mortality, respectively. A 10-ms longer pulse wave transit
time was associated with a 36.7% (95% CI 18.8–50.7,
P ¼ 0.02) lower risk of MIs. AIx, AIx@75, augmentation
pressure, pulse wave transit time, and height of the
incident pressure wave were significant predictors of
the endpoint all-cause mortality plus MI.
Discussion
In our cohort of patients, most of them suffering from
CAD, we found that arterial pulse waveform character-
istics, calculated with automated analysis of the transfer–
function-derived central aortic pressure curve, were sig-
nificant predictors of cardiovascular outcomes, including
all-cause mortality and MI. Moreover, the prognostic
value was additional to and, largely, independent of
brachial BPs, strongly supporting the view that a com-
prehensive analysis of the arterial pressure curve reveals
related to aortic characteristic impedance and its increase
with age [20], was a strong predictor of a worse outcome as
well. However, in contrast to the wave reflection-related
parameters, its independent predictive value diminished
after adjustments for brachial BPs were made.
Of note, the predictive value of AIx and related
parameters was not limited to younger patients, and even
the hazard ratios were similar between younger and
elderly patients. This seems to contradict previous
opinions, in which a more prominent increase in AIx in
younger persons and a plateau effect [28] or even a
decline of the AIx [29] after the age of 60 years has been
taken as an argument that the AIx might be a more
sensitive risk marker in younger individuals. Our results
are more in keeping with very recent findings that wave
reflection is important across the whole life span by
contributing predominantly (before 60 years of age) or
equally with the incident pressure wave to the age-
related increase in aortic PP [20].
Interestingly, the predictive value of waveform charac-
teristics tended to be higher with lower achieved brachial
BPs. This may indicate that normalization of brachial BP
alone may not be sufficient to optimally reduce cardio-
vascular risk, and resembles previous findings that a

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 Pulse waveform characteristics and outcome Weber et al. 803

Fig. 2

All All

Age - 65 Age - 65

Age 66 + Age 66 +

EF normal EF normal

EF impaired EF impaired

Diabetes Diabetes

No diabetes No diabetes

PCI PCI

No PCI No PCI

Normal BP Normal BP

Prehypertension Prehypertension

Isolated systolic hypertension Isolated systolic hypertension

Systolic-diastolic hypertension Systolic-diastolic hypertension

2.5 2 1.5 1 0.5 0 2 1.5 1 0.5 0

HR (95% Cl) per 10 % increase in AIx@75 HR (95% Cl) per 10 ms increase in transit time

Association between the risk of the combined endpoint and heart-rate corrected Augmentation Index (left) and pulse wave transit time (right),
expressed as hazard ratio and 95% confidence interval, in various subgroups. BP, blood pressure; CI, confidence interval; EF, ejection fraction; HR,
hazard ratio; PCI, percutaneous coronary intervention.

lowering of BP should be accompanied by a decrease in
arterial stiffness to improve prognosis [30].
The timing and extent of arterial wave reflections may be
of particular prognostic relevance in CAD patients, that
is, in patients with impaired coronary circulation, due to
the pathophysiological links outlined above. As increased
and premature wave reflections are invariably linked with
a higher SBP, but a lower DBP, this may be the major
reason for the recently much discussed J-curve phenom-
enon [31]. Indeed, in our study, a lower DBP was associ-
ated with a worse prognosis. In the multiple-adjusted
models, however, wave reflection parameters, but not
brachial BPs, remained significant predictors of outcome,
suggesting that the increased risk of coronary patients
with lower DBP may be better explained by increased

Table 5 Waveform characteristics and outcomes, expressed as unadjusted hazard ratios (95% confidence interval)
Augmented pressure Height of the incident Pulse wave transit
AIx per 10% AIx@75 per 10% per 10 mmHg pressure wave per 10 mmHg time per 10 ms

Total mortality 1.173 (0.938–1.466) 1.378 (1.051–1.807)M 1.563 (1.107–2.205)M 1.439 (1.189–1.741)$ 0.841 (0.681–1.037)
MI 1.309 (0.995–1.721) 1.366 (0.985–1.894) 1.382 (0.898–2.127) 1.006 (0.703–1.441) 0.633 (0.493–0.812)$
Death þ MI 1.226 (1.019–1.476)M 1.365 (1.093–1.706)# 1.495 (1.121–1.992)# 1.280 (1.057–1.549)M 0.737 (0.618–0.879)$
Stroke 1.263 (0.919–1.734) 1.319 (0.900–1.933) 1.956 (1.225–3.124)# 1.488 (1.149–1.928)# 0.899 (0.671–1.206)
Coronary revascularization 1.168 (0.982–1.388) 1.221 (0.992–1.503) 1.366 (1.032–1.807)M 1.228 (0.983–1.535) 0.778 (0.661–0.916)#
Peripheral and cerebrovascular 1.268 (0.899–1.786) 1.494 (0.983–2.269) 1.463 (0.848–2.523) 1.199 (0.820–1.753) 0.815 (0.596–1.116)
revascularization
Combined endpoint 1.205 (1.065–1.364)# 1.314 (1.132–1.526)$ 1.507 (1.237–1.835)$ 1.365 (1.173–1.588)$ 0.792 (0.704–0.892)$

#
AIx, Augmentation Index; AIx@75, Augmentation Index corrected for heart rate 75/min; MI, myocardial infarction. M
P < 0.05. P < 0.01. $ P < 0.001.

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 804 Journal of Hypertension 2010, Vol 28 No 4
and premature wave reflections and better expressed by a
higher AIx and a shorter pulse wave transit time than by
the ‘simple’ brachial DBP value.
Our findings, together with previous invasive studies
[11,12] in a similar patient group, as well as French study
[10] in end-stage renal patients (a population with a high
proportion of CAD), strongly support the independent
and additive prognostic value of wave reflection markers
in high-risk coronary patients. If this applies to other
patient groups (hypertensive and diabetic) or to the
general population as well, remains to be shown. In
the conduit artery function evaluation study [32], CAD
(a previous MI or treated angina) was an exclusion
criterion, and consequently event rates were much lower
than in our study. In that study, augmentation pressure,
but not AIx, was independently associated with the
primary (composite) outcome. Our results may not apply
to patients with severely impaired systolic function, as
waveforms undergo dramatic changes with loss of con-
tractile function of the left ventricle [33], nor may they
apply to patients with valvular heart disease [34]. Next, as
women have higher values of AIx throughout their life
[27], we limited this analysis to men only. Finally, the
predictive value of brachial BP measurements may have
been improved by ambulatory BP measurement. How-
ever, this may be the case for waveform characteristics
as well.
In summary, measuring AIx and pulse wave transit time,
both related to the timing and extent of arterial wave
reflections from the periphery to the central aorta, and
derived from noninvasive analysis of the pressure pulse
waveform, improves our ability to identify high-risk
patients beyond brachial BP. Because of physiology, this
may be particularly true for patients suffering from CAD.
Consequently, a strategy to reduce increased arterial
wave reflections in these high-risk individuals in order
to improve prognosis should be tested in a clinical trial.
Acknowledgements
M.F.O’R. is a director of AtCor Medical, manufacturer of
systems for pulse wave analysis and pulse wave velocity
measurements. The other authors have no potential
conflicts of interest.
References
1 Mahomed FA. The physiology and clinical use of the sphygmograph. Med
Times Gazette 1972; 1:62–64.
2 Karamanoglu M, O’Rourke MF, Avolio AP, Kelly RP. An analysis of the
relationship between central aortic and peripheral upper limb pressure
waves in man. Eur Heart J 1993; 14:160–167.
3 Nichols WW, O’Rourke M. Pressure pulse waveform analysis. In: Nichols
WW, O’Rourke MF, editors. McDonald’s blood flow in arteries: theoretical,
experimental and clinical principles, 5th ed. London, UK: Hodder Arnold.
pp. 463–502.
4 O’Rourke MF, Pauca A, Jiang XJ. Pulse wave analysis. Br J Clin Pharmacol
2001; 51:507–522.
5 Saba PS, Roman MJ, Pini R, Spitzer M, Ganau A, Devereux R. Relation of
arterial pressure waveform to left ventricular and carotid anatomy in
normotensive subjects. J Am Coll Cardiol 1993; 22:1873–1880.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
6 Hashimoto J, Imai Y, O’Rourke MF. Monitoring of antihypertensive therapy
for reduction in left ventricular mass. Am J Hypertens 2007; 20:1229–
1233.
7 Weber T, Auer J, O’Rourke MF, Punzengruber C, Kvas E, Eber B.
Prolonged mechanical systole and increased arterial wave reflections in
diastolic dysfunction. Heart 2006; 92:1616–1622.
8 Borlaug B, Melenovsky V, Redfield MM, Kessler K, Chang HJ, Abraham TP,
Kass DA. Impact of arterial load and loading sequence on left ventricular
tissue velocities in humans. J Am Coll Cardiol 2007; 50:1570–1577.
9 Weber T, Auer J, O’Rourke MF, Kvas E, Lassnig E, Berent R, Eber B. Arterial
stiffness, wave reflections and the risk of coronary artery disease.
Circulation 2004; 109:184–198.
10 London GM, Blacher J, Pannier B, Guerin AP, Marchais SJ, Safar ME.
Arterial wave reflections and survival in end-stage renal failure.
Hypertension 2001; 38:434–438.
11 Chirinos JA, Zambrano JP, Chakko S, Veerani A, Schob A, Willens H, et al.
Aortic pressure augmentation predicts adverse cardiovascular events in
patients with established coronary artery disease. Hypertension 2005;
45:980–985.
12 Ueda H, Hayashi T, Tsumura K, Yoshimaru K, Nakayama Y, Yoshikawa J.
The timing of the reflected wave in the ascending aortic pressure predicts
restenosis after coronary stent placement. Hypertension Res 2004;
27:535–540.
13 Weber T, Auer J, O’Rourke MF, Kvas E, Lassnig E, Lamm G, et al. Increased
arterial wave reflections predict severe cardiovascular events in patients
undergoing percutaneous coronary interventions. Eur Heart J 2005;
26:2657–2663.
14 Pauca AL, O’Rourke MF, Kon ND. Prospective evaluation of a method for
estimating ascending aortic pressure from the radial artery pressure
waveform. Hypertension 2001; 38:932–937.
15 O’Rourke MF, Gallagher DE. Pulse wave analysis. J Hypertens 1996;
14:147–157.
16 Wilkinson IB, MacCallum H, Flint L, Cockcroft JR, Newby DE, Webb DJ.
The influence of heart rate on augmentation index and central arterial
pressure in humans. J Physiol 2000; 525:263–270.
17 London G, Guerin A, Pannier B, Marchais S, Benetos A, Safar M. Increased
systolic pressure in chronic uremia. Role of arterial wave reflections.
Hypertension 1992; 20:10–19.
18 Weber T, O‘Rourke MF, Ammer M, Kvas E, Punzengruber C, Eber B.
Arterial stiffness and arterial wave reflections are associated with systolic
and diastolic function in patients with normal ejection fraction. Am J
Hypertens 2008; 21:1194–1202.
19 Eckert S, Gleichmann U, Zagorski O, Klapp A. Validation of the Omron R3
blood pressure self-measuring device through simultaneous comparative
invasive measurements according to protocol 58130 of the German
Institute of Validation. Blood Press Monit 1997; 2:189–192.
20 Namasivayam M, McDonnel BJ, McEniery CM, O’Rourke MF. Does wave
reflection dominate age-related change in aortic blood pressure across the
human life span? Hypertension 2009; 53:979–985.
21 Wilkinson IB, Prasad K, Hall IR, Thomas A, MacCallum H, Webb DJ, et al.
Increased central pulse pressure and augmentation index in subjects with
hypercholesterolemia. J Am Coll Cardiol 2002; 39:1005–1011.
22 Nürnberger J, Keflioglu-Scheiber A, Opazo Saez AM, Wenzel RR, Philipp T,
Schäfers RF. Augmentation index is associated with cardiovascular risk.
J Hypertens 2002; 20:2407–2414.
23 Hayashi T, Nakayama Y, Tsumura K, Yoshimaru K, Ueda H. Reflection in the
arterial system and the risk of coronary heart disease. Am J Hypertens
2002; 15:405–409.
24 Covic A, Haydar AA, Bhamra-Ariza P, Gusbeth-Tatomir P, Goldsmith DJ.
Aortic pulse wave velocity and arterial wave reflections predict the extent
and severity of coronary artery disease in chronic kidney disease patients.
J Nephrol 2005; 18:388–396.
25 Kingwell BA, Waddell TK, Medley TL, Cameron JD, Dart AM. Large artery
stiffness predicts ischemic threshold in patients with coronary artery
disease. J Am Coll Cardiol 2002; 40:773–779.
26 Leung MCH, Meredith IT, Cameron JD. Aortic stiffness affects the coronary
blood flow response to percutaneous coronary intervention. Am J Physiol
Heart Circ Physiol 2006; 290:H624–H630.
27 Saito M, Okayama H, Nishimura K, Ogimoto A, Ohtsuka T, Inoue K, et al.
Possible link between large artery stiffness and coronary flow velocity
reserve. Heart 2008; 94:e20.
28 McEniery CM, Yasmin, Hall IR, Qasem A, Wilkinson IB, Cockcroft JR.
Normal vascular aging: Differential effects on wave reflection and aortic
pulse wave velocity. J Am Coll Cardiol 2005; 46:1753–1760.
29 Mitchell GF, Parise H, Benjamin EJ, Larson MG, Keyes MJ, Vita JA, et al.
Changes in arterial stiffness and wave reflection with advancing age in
healthy men and women: the Framingham Heart study. Hypertension 2004;
43:1239–1245.
 Pulse waveform characteristics and outcome Weber et al. 805

30 Guerin AP, Blacher J, Pannier B, Marchais SJ, Safar ME, London GM.
Impact of aortic siffness attenuation on survival of patients in end-stage
renal disease. Circulation 2001; 103:987–992.
31 Messerli FH, Mancia G, Conti R, Hewkin AC, Kupfer S, Champion A, et al.
Dogma disputed: can aggressively lowering blood pressure in hypertensive
patients with coronary artery disease be dangerous? Ann Intern Med
2006; 144:884–893.
32 Williams B, Lacy PS, Thom SM, Cruickshank K, Stanton A, Collier D, et al.
The CAFÉ investigators. Differential impact of blood pressure-lowering
drugs on central aortic pressure and clinical outcomes: principal results of
the conduit artery function evaluation (CAFÉ) study. Circulation 2006;
113:1213–1225.
33 Weber T, Auer J, Lamm G, O’Rourke MF, Eber B. Arterial stiffness, central
blood pressures, and wave reflections in cardiomyopathy: implications for
risk stratification. J Card Fail 2007; 13:353–359.
34 O’Rourke MF. The aortic pressure wave in aortic stenosis. J Hypertens
2009; 27:1104.

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