European Journal of Heart Failure 10 (2008) 1192 1200

www.elsevier.com/locate/ejheart

Usefulness of systolic time intervals in the identification of abnormal

ventriculo-arterial coupling in stable heart failure patients
Hao-Min Cheng a , Wen-Chung Yu b , Shih-Hsien Sung b , Kang-Ling Wang b ,
Shao-Yuan Chuang c , Chen-Huan Chen a,d,e,f,
a
Department of Research and Education, Taiwan
b
Department of Medicine, Taipei Veterans General Hospital, Taiwan
c
Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
d
Cardiovascular Research Center, Taiwan
e
Department of Public Health, Taiwan
f
I-Lan University Hospital, National Yang-Ming University, Taipei, Taiwan
Received 13 November 2007; received in revised form 1 June 2008; accepted 8 September 2008

Abstract

Background: The ratio of effective arterial elastance (Ea) to ventricular end-systolic elastance (Ees) indicates the status of ventriculo-arterial
coupling.
Aims: We investigated if systolic time intervals (pre-ejection period, PEP; ejection time, ET; and their ratio, PEP/ET) can be used to identify
heart failure patients with abnormal ventriculo-arterial coupling.
Methods: Age and sex-matched study subjects included 54 apparently healthy subjects with normal left ventricular (LV) function, and
stable patients with LV diastolic (n = 54) and systolic dysfunction (n = 54). Ees and Ea were estimated non-invasively by echocardiography, and
abnormal ventriculo-arterial coupling was defined as Ea/Ees N 1.2. PEP, ET, and PEP/ET were measured automatically using electrocardiography,
phonocardiography, and brachial pulse volume recording.
Results: Ea/Ees N 1.2 was present in 48.1% of subjects with systolic dysfunction. The PEP/ET was significantly associated with most
parameters of LV structure and function, and Ea/Ees (r = 0.67, p b 0.001). Using PEP/ET 0.423 as cut point, the sensitivity and specificity to
identify patients with Ea/Ees N 1.2 were 85.7% and 84.3%, respectively for the whole population, and 84.6% and 78.6%, for patients with
systolic dysfunction.
Conclusion: Abnormal ventriculo-arterial coupling was present in almost half of stable patients with systolic dysfunction. PEP/ET was useful
in identifying such patients.
2008 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.

Keywords: Systolic time intervals; Ventricular-arterial coupling; Systolic heart failure

1. Introduction

This work was supported in part by the intramural grants from the Taipei
Veterans General Hospital (Grant No. V95C1-052), and grants in aid from
the Research Foundation of Cardiovascular Medicine, (91-02-032, 93-02-
014), Taipei, Taiwan, ROC.
Corresponding author. No. 201, Sec. 2, Shih-Pai Road, Department of
Medical Research and Education, Taipei Veterans General Hospital, Taipei,
Taiwan. Tel.: +866 2 28712121x2073; fax: +886 2 28717431.
E-mail address: chench@vghtpe.gov.tw (C.-H. Chen).
1388-9842/$ - see front matter 2008 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.ejheart.2008.09.003
Heart failure is a major health problem worldwide [1,2].
Optimal treatment of this disabling and fatal condition may
require functional characterization of the failed left ventricle
(LV) and its interaction with the arterial system [3]. Most
LV performance indices, including ejection fraction, stroke
volume, and cardiac output, are load-dependent and are
 H.-M. Cheng et al. / European Journal of Heart Failure 10 (2008) 11921200
influenced by the functional coupling of the LV with the
arteries [4]. Ventriculo-arterial coupling is related to the
efficiency of mechanical energetic transfer from the heart to
the arteries [5]. The physiological significance has been
studied experimentally using the framework of the ratio of
effective arterial elastance (Ea) to end-systolic elastance
(Ees), which is relatively independent of the loading
conditions [6]. Although it has been shown that nitroprusside
significantly improved ventriculo-arterial coupling assessed
by the ratio of Ea to Ees (Ea/Ees) in patients with heart failure,
[3] it remains unclear how often the ventriculo-arterial
coupling is suboptimal in stable heart failure patients who
may benefit from vasodilator therapy on top of the standard
neurohormonal blockade [7].
The systolic time intervals, including pre-ejection period
(PEP), ejection time (ET), and their ratio (PEP/ET), is one
of the established non-invasive techniques for the quanti-
tative assessment of cardiac performance [8]. PEP is
prolonged and ET is shortened in patients with congestive
heart failure, and PEP/ET correlates with ejection fraction
[9]. Clinical values of the systolic time intervals in the
assessment of LV systolic function have been validated in
patients with severe heart failure and ischaemic heart
disease, [1012] and in patients receiving cardiac resyn-
chronization therapy [13]. Recently, Sunagawa et al.
proposed a framework linking Ees/Ea (the inverse of Ea/
Ees) with systolic time intervals and ventricular and aortic
pressure [14]. To our knowledge, the potential of systolic
time intervals in the assessment of ventriculo-arterial
coupling in patients with heart failure has not been
reported. Therefore, the purposes of the present study
were to investigate the prevalence of abnormal ventriculo-
arterial coupling in stable heart failure patients and the
usefulness of systolic time intervals in the identification of
such patients.
2. Methods
2.1. Study population
There were three groups of subjects in the present study.
The main patient group included 54 stable heart failure
patients with echocardiographic evidence of LV systolic
dysfunction. The second patient group consisted of 54 age-
and sex-matched stable patients with isolated LV diastolic
dysfunction. The third group comprised 54 age- and sex-
matched apparently healthy subjects with normal LV
function. Patients with LV systolic dysfunction were enrolled
consecutively for the study. Data for the age- and sex-
matched patients with LV diastolic dysfunction and the
normal controls were selected from previous studies [15].
None of the subjects had atrial fibrillation or bundle branch
block on their electrocardiograms or significant aortic valve
disease shown by echocardiography. All study subjects were
invited to undergo a two-hour comprehensive non-invasive
cardiovascular evaluation, including echocardiography and
1193
systolic time intervals, along with assessment of symptoms
and signs of heart failure according to the Framingham
criteria [16].
The study protocols were approved by our hospital insti-
tutional review board and all subjects gave informed consent
before entry into this study.
Heart rate was determined from the surface electrocardio-
gram, and the systolic blood pressure (SBP) and diastolic
blood pressure (DBP) were measured with an electronic
oscillometric sphygmomanometer.
2.2. Echocardiographic evaluation
Echocardiographic examination was performed using a
multi-frequency transducer incorporated in a SONOS 5500
echocardiograph (Hewlett Packard, Inc., Agilent Technolo-
gies, Andover, MA) according to the recommendations of
the American Society of Echocardiography [17]. All of the
following dimensions were measured online from the 2D-
guided M-mode echocardiography: aortic root diameter, left
atrial dimension, LV internal dimension at end-systole and
end-diastole, and thickness of the interventricular septum
and LV posterior wall. LV mass, LV end-systolic and end-
diastolic volumes, and LV ejection fraction were calculated
from the M-mode measurements. LV end-diastolic volume
index (LVEDVI) was LV end-diastolic volume divided by
body surface area.
Septal-to-posterior wall motion delay (SPWMD) is the
delay between the motion of the interventricular septum and
LV posterior wall, calculated as the shortest interval between
the maximal posterior displacement of the septum and the
maximal displacement of the LV posterior wall using a
mono-dimensional short-axis view at the papillary muscle
level [18].
Stroke volume (SV) was measured by pulsed-wave
Doppler echocardiography [19]. Mitral inflow profiles,
including the ratio of early to late diastolic transmitral velocity
(E/A) and the deceleration time (DT) of the early velocity
wave, were sampled between the tips of the anterior and
posterior mitral leaflets. Isovolumic relaxation time (IVRT)
was the interval between the aortic valve closing artifact and
the mitral valve opening artifact. Interventricular delay (IVD)
was measured as the time difference between the simulta-
neously recorded onset of the QRS interval to aortic and
pulmonary flow. Motion of the mitral annulus was recorded in
the apical four-chamber view by tissue Doppler technique
[20]. The major negative myocardial velocity with the
movement of the annulus towards the base of the heart during
the early phase of diastole velocity was recorded (E). The
average of the velocities from the septal and lateral site of the
mitral annulus was used for calculation of the ratio of the early
diastolic transmitral velocity to early mitral annular diastolic
velocity ratio (E/E).
Patients with an LV ejection fraction b 50% were
considered to have systolic dysfunction [21]. Patients with
isolated diastolic dysfunction should have an LV ejection
1194 H.-M. Cheng et al. / European Journal of Heart Failure 10 (2008) 11921200
fraction N 50%, and the following echocardiographic char-
acteristics: 1) LVEDVI b 97 ml/m 2 and E/E N 15; or
2) LVEDVI b 97 ml/m2, 15 N E/E N 8, and abnormal LV
filling (E/AN 50year b 0.5, DTN 50year N 280 ms) [22].
2.3. Non-invasive estimation of Ees and Ea
Ees was estimated with a previously proposed single-
beat method employing SBP, DBP, SV, LV ejection fraction,
and an estimated normalized ventricular elastance at arte-
rial end-diastole [E(Nd)]: Ees = [DBP (E(Nd) SBP 0.9)] /
[E(Nd) SV], where E(Nd) was estimated from a group-
averaged value adjusted for individual contractile/loading
effects [19]. Ea was the ratio of LV end-systolic blood pres-
sure (Pes), which is approximated to value of SBP 2 / 3 +
DBP 1/3, to the value of SV [23]. Heart failure patients with a
value of Ea/Ees N 1.2 were considered as having abnormal
ventriculo-arterial coupling [24].
2.4. Systolic time intervals
A newly developed device (VP-1000, Colin Corporation,
Komaki, Japan) was used for fast evaluation of the cardiac
and arterial functions [25]. The device performed electro-
cardiography, phonocardiography, and pulse volume record-
ing on four extremities (ankles and arms). After completion
of preparation, the fully automatic data acquisition and
processing procedure started with the simultaneous measure-
ment of blood pressure over the four extremities by
oscillometric principle. This was followed by pulse volume
recording over the arms and ankles for 10 s, when the cuff
pressures were maintained at 60 mmHg.
The beat-by-beat total electromechanical systolic inter-
val (QS2) and LV ejection time (ET) were measured and
the pre-ejection period (PEP) was derived by subtracting
ET from QS2 automatically [26]. QS2 was measured from
the onset of the QRS complex to the first high frequency
vibrations of the aortic component of the second heart
sound. ET was measured from the beginning upstroke to
the dicrotic notch of the pulse volume trace of the right
brachial artery. ET and PEP were the averages of around
10 beats.
2.5. Estimation of Ea/Ees by systolic time intervals
A framework to estimate Ees/Ea using systolic time
intervals without measuring ventricular volume or altering
the loading condition has been proposed by Sunagawa et al.
[14] Using the concept of the pressurevolume relation-
ship, Ees/Ea is algebraically expressed as Ees/Ea = Pad / Pes
(1 + k ET/PEP) 1 [Eq. (1)], where Pad is aortic diastolic
pressure and can be approximated with DBP, and k is the slope
ratio of two straight lines that approximate the isovolumic
phase and the ejection phase of the time-varying elastance
curve, respectively [14]. Because k is empirically related
to Ees/Ea by the equation: k = 0.53 (Ees/Ea)0.51[Eq. (2)],
Ees/Ea can be solved from Eqs. (1) and (2) with known Pad,
Pes, ET, and PEP. Ea/Ees was simply a reciprocal of Ees/Ea.
2.6. Reproducibility of PEP and ET
Measurements of PEP and ET were repeated after 5 min in
20 randomly selected patients. The variability of the paired
measurements was calculated.
2.7. Statistical analysis
Between-group comparisons were performed by one
way ANOVA and Scheffe's method. Pearson's correla-
tion coefficients of systolic time intervals and Ea/Ees with
other parameters were provided with Bonferroni's correc-
tion. Determinants of Ea/Ees and PEP/ET were identified
by stepwise multiple linear regression analysis. Agree-
ment between Ea/Ees estimates was examined by Bland
Altman analysis. The Receiver operating characteristics
(ROC) analysis was performed to determine the optimal
cut-off value for PEP/ET in the prediction of abnormal
ventriculo-arterial coupling defined by Ea/Ees N 1.2. The
sensitivity, specificity, positive predictive value, negative
predictive value, and accuracy for either Ea/Ees estimated
from PEP/ET and blood pressure, or PEP/ET alone in
identifying abnormal ventriculo-arterial coupling were
calculated. All statistical significances were set at
p b 0.05 and all statistical analyses were carried out using
SAS 8.02.
3. Results
The characteristics of our study population are summar-
ized in Table 1. Of the patients with isolated diastolic
dysfunction, 70.4% were in New York Heart Association
Functional Classification (Fc) I and 29.6% in Fc II; 18.5%
had rales on chest auscultation, and 24.1% had peripheral
oedema. Of the patients with systolic dysfunction, 27.8%
were in Fc I, 59.3% in Fc II, and 13.0% in Fc III; 59.3% had
rales on chest auscultation, and 27.8% had peripheral
oedema. The percentages of smokers, and a history of
hypertension, diabetes, coronary artery disease, and chronic
renal failure were 9.1%, 67.3%, 22.9%, 9.8%, and 31.9% in
the diastolic dysfunction group, and 42.9%, 79.6%, 32.7%,
33.3%, and 31.3% in the systolic dysfunction group, respec-
tively. The percentages of patients receiving treatment with
-blockers, calcium channel blockers, angiotensin convert-
ing enzyme inhibitors, diuretics, and angiotensin receptor
blockers were 34.5%, 27.6%, 26.7%, 30.0%, and 20.0% in
the diastolic dysfunction group, and 49.0%, 8.3%, 22.9%,
47.9%, and 23.5% in the systolic dysfunction group,
respectively.
Patients with LV systolic dysfunction had increased LV
mass, LV end-diastolic volume, left atrial size, IVRT,
SPWMD, IVD, E/E, Ea, Ea/Ees, PEP, and PEP/ET, and
decreased LV ejection fraction, Ees, and ET; and patients
 H.-M. Cheng et al. / European Journal of Heart Failure 10 (2008) 11921200 1195

Table 1
Clinical characteristics of the study population
Variable Normal controls Diastolic dysfunction Systolic dysfunction Significant between-group comparisons
(n = 54) (A) (n = 54) (B) (n = 54) (C)
Age, years 66.5 17.2 66.3 14.8 66.6 15.0
Sex, men (%) 44 (81.5) 44 (81.5) 44 (81.5)
Height, cm 162.6 9.6 163.6 7.9 163.6 7.3
Weight, kg 62.2 10.6 64.4 9.6 62.5 11.9
Body mass index, kg/m2 23.4 2.7 24.0 3.2 23.3 3.7
SBP, mmHg 122 15 128 20 123 22
DBP, mmHg 67 11 68 11 67 13
Heart rate, beats per minute 71 11 71 11 76 14
Cardiac structure
LV mass, g 135 30 195 64 275 97 AB, AC, BC
LV end-diastolic volume, ml 99 21 109 29 194 63 AC, BC
Left arterial size, cm 31.3 4.7 34.9 4.7 41.8 7.4 AB, AC, BC
Cardiac function
LVEF, % 76 6 71 9 36 10 AB, AC, BC
Ees, mmHg/ml 3.5 1.1 3.3 1.1 1.9 0.8 AC, BC
IVRT, ms 84 12 124 21 115 31 AB, AC
Peak E/A 1.2 0.4 0.8 0.3 1.0 0.6 AB
E/E 7.4 1.5 9.0 2.1 11.3 5.0 AB, AB AC
SPWMD, ms 52 22 66 49 79 50 AC
IVD, ms 11 9 15 13 26 22 AC
Arterial function
Ea, mmHg/l 2.1 0.5 2.1 0.6 2.4 1.0 AC
Ventriculo-arterial coupling
Ea/Ees 0.6 0.2 0.7 0.2 1.4 0.7 AC, BC
Systolic time intervals
PEP, ms 93 16 104 17 116 25 AB, AC, BC
ET, ms 290 20 280 39 262 28 AC, BC
PEP/ET 0.32 0.06 0.38 0.09 0.45 0.12 AB, AC, BC
Values are shown as mean SD or percentage.
DBP = diastolic blood pressure; E/A = ratio of the early to late diastolic transmitral velocity; E/E = ratio of the early diastolic transmitral velocity to early mitral
annular diastolic velocity; Ea = effective arterial elastance; Ees = End-systolic elastance; Ea/Ees = ratio of Ea to Ees; EF = ejection fraction; ET = ejection time;
IVD = interventricular delay assessed by Doppler echocardiography; IVRT = isovolumic relaxation time; LV = left ventricle; PEP = pre-ejection period; PEP/
ET = ratio of PEP to ET; SBP = systolic blood pressure; SPWMD = septal- to-posterior wall motion delay.

with LV diastolic dysfunction had increased LV mass, left
atrial size, IVRT, E/E, PEP, and PEP/ET, and decreased E/A,
respectively, in comparison with the normal controls. In
particular, patients with diastolic dysfunction had Ea, Ees, and
Ea/Ees values similar to those in the normal controls. On the
other hand, patients with systolic dysfunction had a higher
percentage of smokers and coronary artery disease, greater LV
mass, LV end-diastolic volume, left atrial size, Ea/Ees, PEP,
and PEP/ET, and a lower use of calcium channel blockers, and
lower LV ejection fraction, Ees, and ET, than patients with
diastolic dysfunction. PEP, ET, and PEP/ET were not
significantly different in patients with systolic or diastolic
dysfunction who were or were not receiving -blockers (data
not shown).
The prevalence of abnormal ventriculo-arterial coupling
defined by echocardiographic Ea/Ees N 1.2 was 0% in
normal controls, 3.7% in patients with diastolic dysfunction,
48.1% in patients with systolic dysfunction, and 17.3% in
patients with either diastolic or systolic dysfunction.
Characteristics of patients with systolic dysfunction and
abnormal ventriculo-arterial coupling are shown in Table 2.
Although they were 10 years younger, the patients with
systolic dysfunction and abnormal ventriculo-arterial cou-
pling had even greater heart size (increased LV mass and LV
end-diastolic volume), more depressed systolic function
(increased E/E and decreased Ees and LV ejection fraction),
and more prominent changes in systolic time intervals
(prolonged PEP, shortened ET, and increased PEP/ET),
compared with patients with systolic dysfunction and normal
ventriculo-arterial coupling.
3.1. Correlates of Ea/Ees and systolic time intervals
With Bonferroni's correction for the multiple variables
examined, the threshold of P values for the correlation
coefficients was set at 0.003. Ea/Ees was significantly
associated with LV mass (r = 0.56), LV end-diastolic
volume (r = 0.75), left atrial size (r = 0.41), LV ejection
fraction (r = 0.72), Ees (r = 0.62), E/E (r = 0.37),
SPWMD (r = 0.40), IVD (r = 0.56), Ea (r = 0.30), and PEP/
ET(r = 0.68). By stepwise multiple linear regression analysis
(model r2 = 0.77, p b 0.001), the independent determinants of
Ea/Ees were LV ejection fraction (partial r2 = 0.15), PEP/ET
(partial r2 = 0.58), and IVD (partial r2 = 0.04).
1196 H.-M. Cheng et al. / European Journal of Heart Failure 10 (2008) 11921200

Table 2 controls, 0.27 0.26 (p b 0.001) in patients with diastolic

Clinical characteristics of patients with LV systolic dysfunction stratified by dysfunction, and 0.11 0.54 (p = 0.165) in patients with
status of ventriculo-arterial coupling
systolic dysfunction, respectively. The agreement between
Variable Ea/Ees 1.2 Ea/Ees N 1.2 p Ea/Ees values estimated by the singe-beat method and those
(n = 28) (n = 26) values
estimated from the systolic time intervals and blood pressure
Age, years 71.8 11.3 61.0 16.6 0.008 in the whole study population are shown in Fig. 1 and in
Sex, men, n (%) 25 (89) 20 (77) NS
patients with systolic dysfunction in Fig. 2.
Height, cm 164.0 8.0 163.1 6.7 NS
Weight, kg 62.3 10.7 62.6 13.2 NS
Body mass index, kg/m2 23.2 3.6 23.4 3.8 NS 3.3. Identification of patients with abnormal ventriculo-arterial
SBP, mmHg 125 20 121 25 NS coupling
DBP, mmHg 67 11 67 15 NS
Heart rate, beats per minute 73 11 79 17 NS
The sensitivity, specificity, positive predictive value,
Cardiac structure
LV mass, g 245 83 307 102 0.02 negative predictive value, and accuracy of Ea/Ees estimated
LV end-diastolic volume, 168 48 223 65 0.001 by systolic time intervals and blood pressure in identifying
ml patients with abnormal ventriculo-arterial coupling in the
Left arterial size, cm 42.2 7.9 41.3 6.9 NS whole study population and in patients with LV systolic
Cardiac function
dysfunction, respectively, are shown in Table 3.
LVEF, % 39 9 33 11 0.04
Ees, mmHg/ml 2.4 0.7 1.4 0.6 b0.001
IVRT, ms 113.1 30.5 118.2 31.4 NS
E/A 1.0 0.7 0.9 0.4 NS
E/E 9.6 3.6 11.7 6.5 0.02
SPWMD, ms 70 40 89 59 NS
IVD, ms 15 13 37 23 0.001
Arterial function
Ea, mmHg/l 2.4 0.7 2.5 1.2 NS
Ventricular-arterial coupling
Ea/Ees 1.0 0.1 1.9 0.9 b0.001
Systolic time intervals
PEP, ms 105 18 128 26 0.001
ET, ms 274 23 250 28 0.002
PEP/ET 0.38 0.07 0.52 0.13 b0.001
Values are shown as mean SD or percentage.
DBP= diastolic blood pressure; E/A = ratio of the early to late diastolic
transmitral velocity; E/E = ratio of the early diastolic transmitral velocity to
early mitral annular diastolic velocity; Ea = effective arterial elastance;
Ees = end-systolic elastance; Ea/Ees = ratio of Ea to Ees; EF= ejection fraction;
ET= ejection time; IVD = interventricular delay assessed by Doppler echo-
cardiography; IVRT = isovolumic relaxation time; LV = left ventricle;
PEP = pre-ejection period; PEP/ET= ratio of PEP to ET; SBP = systolic blood
pressure; SPWMD = septal- to-posterior wall motion delay.

By stepwise multiple linear regression analysis (model

r2 = 0.62, P b 0.001), the independent determinants of PEP/ET
were Ea/Ees (partial r2 = 0.56) and IVRT (partial r2 = 0.03).
None of the medications were significant determinants for
PEP/ET in the multivariate model.

3.2. Estimation of Ea/Ees by PEP/ET and blood pressure

Ea/Ees values estimated from PEP/ET and blood pressure

according to the framework proposed by Sunagawa et al.
for normal controls, patients with diastolic dysfunction, and
patients with systolic dysfunction were 0.7 0.2, 0.9 0.3,
and 1.3 0.7, respectively. As compared with the reference
Ea/Ees values estimated by the echocardiographic single-
beat method (Table 1), Sunagawa's framework significantly
overestimated the Ea/Ees values with a mean difference of
0.08 0.37 (p = 0.009) in the whole study population. The
mean differences were 0.09 0.16 (p b 0.001) in normal
Fig. 1. BlandAltman analysis of estimated Ea/Ees by PEP/ET and blood
pressure (Sunagawa's framework) versus reference Ea/Ees by echocardio-
graphic single-beat method in the whole study population. Dashed line
indicates line of identity. Ea = effective arterial elastance; Ees = end-systolic
elastance; Ea/Ees = ratio of Ea to Ees; ET = ejection time; PEP = pre-ejection
period; PEP/ET = ratio of PEP to ET.
 H.-M. Cheng et al. / European Journal of Heart Failure 10 (2008) 11921200 1197

Fig. 3. Receiver operating characteristic curve (ROC) analysis of PEP/ET

discriminating between study subjects with and without ventriculo-arterial
mismatch. AUC = area under curve. PEP = Pre-ejection period; PEP/
ET = ratio of PEP to ET.

coupling in the whole study population and in patients with

LV systolic dysfunction, respectively, are shown in Table 3
and Fig. 3.

3.4. Reproducibility of PEP and ET

There was no significant difference between the means

Fig. 2. BlandAltman analysis of estimated Ea/Ees by PEP/ET and blood
pressure (Sunagawa's framework) versus reference Ea/Ees by echocardio-
graphic single-beat method in patients with systolic dysfunction. Dashed
line indicates line of identity. Ea = effective arterial elastance; Ees = end-
systolic elastance; Ea/Ees = ratio of Ea to Ees; ET = ejection time; PEP = pre-
ejection period; PEP/ET = ratio of PEP to ET.
The sensitivity, specificity, positive predictive value,
negative predictive value, and accuracy of PEP/ET N 0.423
in identifying patients with abnormal ventriculo-arterial
of the two measurements for PEP and ET in the 20
randomly selected subjects. The mean and standard
deviation of the difference between the two measurements
repeated in 5 min were 0.3 4.9 ms for PEP and 0.8 5.8 ms
for ET (95% confidence intervals were 2.0 to 2.6 ms,
p = 0.787, for PEP, and 2.0 to 3.5 ms, p = 0.569, for ET).
The variability of the paired measurements (the difference
divided by the mean value of the repeated two measure-
ments) accounted for 0.1 4.3% and 0.2 2.0% of the mean
values of the paired measurements of PEP and ET,
respectively. The correlation coefficient between the two
measurements were 0.946 and 0.982 for PEP and ET,
respectively (p b 0.001).

Table 3
Sensitivity, specificity, positive and negative predictive values, and accuracy in predicting echocardiographic Ea/Ees N 1.2
Variable Total population (n = 162) Systolic dysfunction (n = 54)
By estimated By By estimated By
Ea/Ees PEP/ET N 0.423 Ea/Ees PEP/ET N 0.423
Sensitivity (%) 75.0 85.7 73.1 84.6
Specificity (%) 85.1 84.3 67.9 78.6
PPV (%) 51.2 53.3 67.9 78.6
NPV (%) 94.2 96.6 73.1 84.6
Accuracy (%) 83.3 84.6 70.4 81.5
Ea= effective arterial elastance; Ees = end-systolic elastance; Ea/Ees = ratio of Ea to Ees; ET = ejection time; NPV= negative predictive value; PEP = pre-ejection
period; PEP/ET = ratio of PEP to ET; PPV= positive predictive value.
1198 H.-M. Cheng et al. / European Journal of Heart Failure 10 (2008) 11921200
4. Discussion
Our study demonstrated that abnormal ventriculo-arterial
coupling defined by Ea/Ees N 1.2 was rare in patients with
diastolic dysfunction and was present in almost half of the
patients with systolic dysfunction. Systolic time intervals,
PEP/ET in particular, correlated well with Ea/Ees and PEP/
ET was the major independent determinant of Ea/Ees. Based
on the framework proposed by Sunagawa et al, Ea/Ees could
also be estimated from PEP/ET and oscillometric brachial
blood pressure. Using PEP/ET (N0.423) alone, heart failure
patients with ventriculo-arterial mismatch could be identified
with reasonable accuracy.
4.1. Ventriculo-arterial mismatch in heart failure
The normal LV operates efficiently with an Ea/Ees ratio
around 0.6 [27]. The ratio increases as the pump function
deteriorates with concomitant peripheral vasoconstriction
resulting partly from enhanced sympathetic stimulation and
altered baroreceptor gain. The increased Ea/Ees can be
significantly reduced by vasodilator therapy which may
optimize mechanoenergetic performance of the LV in heart
failure subjects through lowering peripheral vessel resistance
[28,21].
To our knowledge, the prevalence of ventriculo-arterial
mismatch in heart failure patients has not been well defined,
probably because of the difficulty in estimating Ees non-
invasively. In the present study, abnormal ventriculo-arterial
coupling was present in 48.1% of stable patients with
systolic dysfunction, in contrast to only 3.7% of those with
LV diastolic dysfunction. It is thus apparent that ventriculo-
arterial mismatch is mainly a problem in patients with
systolic dysfunction.
In 1050 black patients who had New York Heart
Association class III or IV heart failure with dilated ventricles,
a fixed dose of isosorbide dinitrate plus hydralazine in addition
to standard therapy for heart failure significantly improved the
rate of death from any cause, the rate of first hospitalisation for
heart failure, and the quality of life [7]. The clinical benefits of
vasodilator therapy may partly result from its favourable effect
on LV function and ventriculo-arterial coupling [3,28]. If
confirmed, the identification of patients with systolic dys-
function and abnormal ventriculo-arterial coupling may be
clinically important since they represent a substantial propor-
tion of heart failure patients and may benefit from additional
vasodilator therapy.
With the development of the single-beat method, Ea/Ees
can be estimated non-invasively using echocardiographic
measurements, oscillometric blood pressures, and a universal
transfer function [19]. The non-invasive single-beat method
for the estimation of Ea/Ees may still be too cumbersome for
daily practice. The present study proposed a much simpler
method for the assessment of ventriculo-arterial coupling in
stable heart failure patients. Using PEP/ET and oscillometric
brachial blood pressures, both can be automatically and
rapidly obtained in one device, Ea/Ees can be estimated at
the point of care. In addition, using PEP/ET alone, patients
with abnormal ventriculo-arterial coupling could be identi-
fied with a negative predictive value of 96.5% for the whole
study population including normal controls and patients with
diastolic and systolic dysfunction, and a positive predictive
value of 77.8% for patients with known systolic dysfunction.
The reasonably good predictive values may suggest that the
automated measurement of PEP/ET could be used as a
screening tool to identify patients with abnormal ventriculo-
arterial coupling in an unselected population and patients
with known systolic dysfunction. Further studies are
warranted to confirm the usefulness of PEP/ET in the identi-
fication and optimization of abnormal ventriculo-arterial
coupling in patients with known systolic dysfunction.
4.2. The link between Ea/Ees and PEP/ET
Sunagawa ea al. proposed the single-beat estimate of
ventricular-arterial coupling [14] using the equation: Ees/
Ea = Pad / Pes (1 + k ET / PEP) 1. The rationale is that the
approximation of time-varying elastance curve could be
made with two straight lines, one for the isovolumic phase
(PEP) and the other for the ejection phase (ET). The slope
ratio k of these two lines quantitatively depended on the
ventriculo-arterial coupling state. Using this approximation,
Ees/Ea can be estimated from Pes, Pad, and PEP/ET over
wide ranges of contractility and loading conditions. Other
approaches have been proposed for estimating Ees without
loading interventions, and these are generally referred to as
single-beat methods based primarily on the similarities
between the amplitude and time-normalized human LV time-
varying elastance curves during early isovolumic contraction
[29]. The fact that E(Nd), the normalized ventricular
elastance at arterial end-diastole, can be estimated by
identification of the timing of normalized ventricular ejection
(PEP divided by PEP+ET) on the universal normalized time-
varying elastance curve [19,29] supports that systolic time
intervals are major determinants of Ees and Ea/Ees.
The framework proposed by Sunagawa et al. was based
on a study in 11 anesthetized dogs and has never been
validated in humans. It has been shown that the slope ratio k
and Ees/Ea are mutually dependent on each other and k may
be affected by ET/PEP and Pad/Pes [14]. It is not known if
the empirical k value is the same between dogs and humans.
The use of the dog empirical k value may partly explain the
small but significant discrepancies between the reference
values of echocardiographic Ea/Ees and those derived from
ET/PEP, Pad/Pes, and k. However, remarkable similarity of
the normalized time-varying elastance curves among
animals, and in patients with various cardiac diseases has
been demonstrated previously [30]. Although in the present
study we did not collect invasive haemodynamic data in
order to produce a human empirical k value, our results
suggest that the framework may also be valid in humans and
patients with various degrees of LV dysfunction, by showing
 H.-M. Cheng et al. / European Journal of Heart Failure 10 (2008) 11921200
the high correlation between Ea/Ees and PEP/ET (r = 0.68),
and the improvement of the correlation by adding blood
pressure variables into the framework (r = 0.77, Fig. 1).
4.3. Subjects with LV diastolic dysfunction
Patients with diastolic heart failure are characterized by
older age, female gender, diabetes and obesity, arterial hyper-
tension, and LV hypertrophy [22]. In the present study,
patients with LV diastolic dysfunction defined by the
echocardiographic criteria proposed by the Heart Failure
and Echocardiography Associations of the European Society
of Cardiology [22] had normal blood pressure and Ea.
Because 67.3% of the patients had history of hypertension, it
was likely that their blood pressure and Ea had been
normalized by effective antihypertensive treatment. In
hypertensive patients, optimal antihypertensive treatment
may favourably shift ventriculo-arterial coupling from
cardiac output maximization to ventricular mechanical
efficiency optimization [31]. The low prevalence of abnormal
ventriculo-arterial coupling in patients with diastolic dys-
function found in this study may partly result from successful
antihypertensive treatment.
4.4. Limitations of the present study
Our study used a case-control design that precludes the
investigation of causal effects. Our results may further be
confounded by the use of multiple cardiovascular medica-
tions in heart failure patients, since the systolic time intervals
and echocardiographic measurements are subject to pharma-
cological manipulation. However, the significant correla-
tions between systolic time intervals and echocardiographic
measurements of cardiovascular structure and function,
indicated the existence of a tight mechanistic link between
time intervals and cardiovascular structure and function and
ventriculo-arterial coupling. Lastly, the accuracy of several
proposed single-beat methods for non-invasive estimation of
Ees has been questioned [3234]. In general, some of the
inaccuracy is from the inherent limitations of Ees, such as
curvilinearity of the end-systolic pressure volume relation-
ship, relative afterload dependence, and inconstant V0 [34].
Specifically, the single-beat method used in the current study
was based on the assumptions of linear end-systolic pressure
volume relationship, constant V0, and the similarity of the
normalized elastance function curves among normal subjects
and patients with various heart diseases [30]. Although later
studies have confirmed that the individual normalized
elastance function curves were similar but not identical,
[34] we have modified and validated the methodology for
human use by accounting for the potential variation of the
generalized normalized elastance function curve with
individual contractile and loading effects [19].
In conclusion, abnormal ventriculo-arterial coupling was
present in almost half of our stable patients with systolic
dysfunction. PEP/ET was useful in identifying such patients.
1199
Acknowledgement
We thank the Colin Corporation Japan for free loan of the
VP-1000 apparatus.
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