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Significant prognostic impact of improvement in ventriculo-arterial coupling

induced by dobutamine stress on cardiovascular outcome for patients with
dilated cardiomyopathy

Article  in  European Heart Journal Cardiovascular Imaging · December 2015

DOI: 10.1093/ehjci/jev327

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 European Heart Journal – Cardiovascular Imaging (2016) 17, 1296–1304
doi:10.1093/ehjci/jev327

Significant prognostic impact of improvement

in ventriculo-arterial coupling induced by
dobutamine stress on cardiovascular outcome
for patients with dilated cardiomyopathy
Kensuke Matsumoto*, Hidekazu Tanaka, Junichi Ooka, Yoshiki Motoji, Takuma Sawa,
Yasuhide Mochizuki, Keiko Ryo, Kazuhiro Tatsumi, and Ken-ichi Hirata
Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan

Received 19 October 2015; accepted after revision 19 November 2015; online publish-ahead-of-print 24 December 2015

Aims The purpose of this study was to investigate the prognostic impact of the changes in ventriculo-arterial (VA) coupling
during dobutamine stress on the cardiovascular events for patients with dilated cardiomyopathy (DCM).
.....................................................................................................................................................................................
Methods For this study, 89 DCM patients with ejection fractions of 32 + 10% and 30 normal controls were recruited. Ees was
and results estimated with the non-invasive single-beat method using three-dimensional echocardiography at rest and during do-
butamine stress (20 mg/kg/min). Effective arterial elastance (Ea) was calculated as left ventricular (LV) end-systolic pres-
sure divided by stroke volume, and VA coupling was calculated as Ea/Ees. Event-free survival was then tracked for 32
months. At baseline, VA coupling was far from optimal in patients with DCM compared with controls (Ea/Ees:
2.49 + 1.02 vs. 1.04 + 0.21, P , 0.001). During the follow-up period, 22 patients developed adverse cardiovascular
events. During dobutamine stress, VA coupling was significantly improved in patients without cardiovascular events
(from 2.47 + 1.09 to 1.59 + 0.68, P , 0.001), but remained unchanged in those with cardiovascular events. A multi-
variate Cox proportional-hazards analysis revealed that age, NYHA functional class (.II), and the change in VA coup-
ling during dobutamine stress were the independent determinants of cardiovascular events (P , 0.05, ,0.01, and
,0.001, respectively). When patients were divided into two subgroups based on the finding of receiver operating char-
acteristic curve analysis, patients with good VA coupling reserve (cut-off: change in VA coupling. 0.29) showed signifi-
cantly favourable event-free survival than those with poor VA coupling reserve (P , 0.001).
.....................................................................................................................................................................................
Conclusions Improvement in VA coupling during dobutamine stress is an important determinant of cardiovascular outcome for
patients with DCM.
-----------------------------------------------------------------------------------------------------------------------------------------------------------
Keywords dilated cardiomyopathy † ventricular contractility † ventriculo-arterial coupling † dobutamine stress
echocardiography † cardiac work efficiency † left ventricular energetics

and effectively save the overall cost by focusing resources on the

Introduction
Although remarkable progress has been made in the development
of both pharmacological and non-pharmacological approaches to
treat heart failure (HF), the number of HF hospitalization and deaths
has increased steadily.1 It is thus important to identify HF patients
with poor prognosis who are likely to suffer clinical deterioration
to improve the effectiveness of care, optimize the patient outcomes,
high-risk patients.
Dobutamine stress echocardiography is being widely used to as-
sess left ventricular (LV) myocardial viability and patients’ prognosis,
and its safety and usefulness have been well established.2 – 7
Although the assessment of contractile reserve is well known to
be useful for the prognostic risk stratification of HF patients,2,5 ana-
lysis of wall motion, such as wall motion score index (WMSI),3

* Corresponding author. Tel: +81 78 382 5846; Fax: +81 78 382 5859. E-mail: kenmatsu@med.kobe-u.ac.jp
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2015. For permissions please email: journals.permissions@oup.com.
Impact of changes in VA coupling during dobutamine stress
ejection fraction (EF),4,5 or even novel speckle-tracking strain6,7 is
highly load dependent. Thus, all of these measures of LV perform-
ance could lead to misleading results. On the other hand, end-
systolic ventricular elastance (Ees), the slope of the end-systolic
pressure– volume relationship, is thought to be a load-independent
index of myocardial contractility.8,9 And its coupling with the effect-
ive arterial elastance (Ea) is considered to be the principal determin-
ant of net cardiovascular performance.10 However, the potential
impact of LV contractile reserve assessed by entirely non-invasively
obtained Ees and ventriculo-arterial (VA) coupling on the patients’
prognosis has not been fully investigated.
The purpose of this study was therefore to investigate the prog-
nostic impact of the changes in VA coupling using non-invasive
single-beat method during dobutamine stress on the cardiovascular
outcome in patients with dilated cardiomyopathy (DCM).
Methods
Study population
This study is a substudy of our previous research investigating the rela-
tionship between bi-ventricular contractile reserve and cardiovascular
prognosis in patients with DCM using dobutamine stress echocardiog-
raphy.7 Among 120 patients recruited in the previous study, we retro-
spectively included 101 patients who underwent simultaneous
three-dimensional (3D) echocardiography during dobutamine stress
test, and 30 age- and gender-matched normal controls in this study.
Six of these subjects (6%) were excluded from all subsequent analyses
because of suboptimal quality of images as were six (6%) with atrial fib-
rillation. Exclusion criteria also included the presence of other major
cardiac arrhythmias and more than moderate organic valvular disease.
The final study population thus comprised 119 subjects (89 patients
with DCM and 30 normal controls). The diagnosis of DCM was estab-
lished on the basis of the following criteria: (i) the presence of LV dila-
tion (LV end-diastolic diameter ≥55 mm); (ii) reduced LV EF (all ≤45%);
(iii) coronary angiographic evidence of the absence of coronary artery
disease defined as .50% stenosis of a major epicardial vessel or a his-
tory of myocardial infarction; (iv) the absence of cardiac muscle disease
secondary to any known systemic diseases; and (v) no evidence of ex-
cessive alcohol intake, toxin exposure, or history of myocarditis. At the
time of enrolment, all patients were in clinically stable condition and
undergoing optimal and maximally tolerated pharmacological therapy.
This study was approved by the local ethics committee of our institu-
tion, and written informed consent was obtained from all subjects.
Echocardiographic examination
Transthoracic echocardiography was performed with a commercially
available ultrasound system (Aplio Artida; Toshiba Medical Systems,
Tochigi, Japan). Standard LV measurements were obtained in accord-
ance with the current guidelines of the American Society of Echocardi-
ography/European Association of Cardiovascular Imaging.11 LV ejection
flow waveform was acquired from apical long-axis view by positioning
the pulsed-wave Doppler sample volume just below the aortic annulus.
Isovolumic contraction time (ICT) was then measured as the time be-
tween the onset of QRS wave and the aortic valve opening, and ejection
time (ET) was defined as the time between the aortic valve opening and
the valve closure.
All 3D echocardiographic studies were performed in accordance
with the current guidelines of the American Society of Echocar-
diography/European Association of Cardiovascular Imaging12 using a
1297
2.5-MHz 3D matrix array transducer (Toshiba Medical Systems, Tochigi,
Japan). Digital 3D volume data were obtained from the apical view by
means of electrocardiogram-gated acquisition at baseline and during
peak dobutamine stress. After gain settings were optimized for endo-
cardial visualization, three to four data sets were acquired and stored
digitally for offline analysis. Based on the time – volume curve, LV
end-diastolic (EDV) and end-systolic volumes (ESV) and LVEF were
obtained. Blood pressure and heart rate were obtained continuously
throughout the echocardiographic examination.
Estimation of LV end-systolic elastance,
effective arterial elastance, and VA coupling
Ees was estimated by using the non-invasive single-beat technique as
previously described by Chen et al. 13 (determined from blood pressure,
stroke volume, pre-ejection and total systolic periods, LVEF, and an es-
timated normalized ventricular elastance at arterial end-diastole). The
effective arterial elastance (Ea) was calculated as the ratio of the end-
systolic pressure to the stroke volume10 (Ea ¼ ESP/SV). VA coupling
was then obtained as the ratio of arterial to ventricular elastance
(Ea/Ees), which is considered to be the principal determinant of net
cardiovascular performance. LV end-systolic pressure was estimated
from arterial systolic pressure × 0.9.14,15 Systemic vascular resistance
(SVR), the non-pulsatile component of afterload, was determined by
dividing (mean arterial pressure-5)/cardiac output × 80.
Estimate of LV energetics
For simplicity, we assumed that the PV loop could be regarded as a rect-
angle whose height was end-systolic pressure and whose width was
stroke volume16 (Figure 1). Under the simplifying assumption, stroke
work (SW) was approximated as the product of SV and end-systolic
pressure. In addition, the pressure – volume area (PVA) can be defined
as the sum of potential energy (PE) and SW, which has been defined
by Suga et al. 17 as the total mechanical energy required for ejection of
Figure 1 Schematic presentation of VA coupling on the pres-
sure – volume plane. The solid line represents the end-systolic
pressure – volume relationship and the slope of this line shows
the end-systolic LV elastance (Ees), while the dashed line shows
the effective arterial elastance (Ea). The brown rectangular area re-
presents the SW and the green triangular area shows the PE. EDV,
end-diastolic volume; ESV, end-systolic volume; ESP, end-systolic
pressure; V0, volume axis intercept of ventricular end-systolic
pressure– volume relation.
1298
the blood. As an index of the energy efficiency of ventricular contrac-
tion, cardiac work efficiency was calculated as the ratio of SW to the
PVA.16
Dobutamine stress test
All patients underwent dobutamine stress echocardiography in incre-
mental stages lasting 5 min each. The initial dose was 5 mg/kg/min and
was increased first to 10 mg/kg/min and finally to the maximal dose of
20 mg/kg/min.18 LV contractile reserve was defined as the absolute dif-
ferences between baseline stroke volume index (SVI), cardiac index
(CI), LVEF, WMSI, Ees and VA coupling, and corresponding values ob-
tained at peak stress (DSVI, DCI, DLVEF, DWMSI, DEes, and DVA coup-
ling, respectively). Ongoing medical therapy including b-blockers
remained unchanged at the time of stress testing.
Long-term follow-up analysis
Unfavourable events were pre-specified as primary endpoints of death
from or hospitalization for deteriorating HF, and sudden cardiac death.
Follow-up was conducted for a median of 31.8 (16.8 – 52.6) months.
Statistical analyses
Continuous variables were expressed as mean values + SD or percen-
tages for normal distribution. For non-normally distributed data, the
median and inter-quartile ranges are shown. Group comparisons
were performed by using the unpaired t-test, and the paired t-test
was used for comparison of continuous variables. Proportional differ-
ences were evaluated by means of Fisher’s exact test or the x 2 test as
appropriate. Receiver operating characteristic (ROC) curves were com-
puted to determine the optimal cut-off points for predicting cardiovas-
cular events. The Kaplan – Meier curve was constructed to assess
cardiovascular event-free survival during the follow-up period, and
event rates were compared by means of the log-rank test. The associa-
tions of clinical and echocardiographic parameters with cardiovascular
events were identified by Cox proportional-hazards model for both uni-
variate and multivariate analyses. In the selection of the univariate vari-
ables, all the established clinical and echocardiographic prognostic
markers were selected as dependent variables regardless of the results
of the group comparisons. Variables with a univariate value of P , 0.10
were incorporated into the stepwise selection, while age and gender
were forced into the multivariate analysis regardless of their association
on univariate analysis. To avoid collinearity in situations where .2 vari-
ables measured a pathophysiological parameter (e.g. LV end-systolic vol-
ume index and LV EF as markers of LV contraction), clinically more
relevant parameter was entered into stepwise selection. The intra-class
correlation coefficient was used to determine inter- and intra-observer
reproducibilities from 10 randomly selected subjects. For all steps, a
P-value of ,0.05 was considered statistically significant. MedCalc
12.3.0 (MedCalc Software, Mariakerke, Belgium) was used for all statis-
tical analyses.
Results
Long-term follow-up
Of the 89 DCM patients who met all inclusion criteria, none were
lost to follow-up. During the median follow-up period of 31.8
months, 22 patients (25%) developed adverse cardiovascular events,
with 2 patients dying of HF, 4 of sudden cardiac death, and the re-
maining 16 being hospitalized due to worsening HF.
K. Matsumoto et al.
Baseline characteristics
The baseline clinical and echocardiographic characteristics of the 89
DCM patients and 30 age- and gender-matched normal controls are
summarized in Table 1. As expected, patients with DCM exhibited
significant global LV remodelling along with the reduced LV contrac-
tion in comparison with normal controls. With respect to the base-
line haemodynamic characteristics, baseline Ees was significantly
smaller for patients with DCM. Of note was that, Ees was nearly
equal to Ea in the normal control, while Ees was less than one-half
of Ea in patients with DCM (1.04 + 0.21 vs. 2.49 + 1.02, P , 0.001).
This coupling ratio resulted in increased PE (3181 + 1484 vs.
1742 + 514 mmHg mL/m2, P , 0.001) and decreased cardiac
work efficiency (46 + 9 vs. 66 + 9%, P , 0.001) for patients with
DCM.
Dobutamine stress echocardiography
Table 2 shows the comparisons of haemodynamic and echocardio-
graphic parameters between subgroups with and without cardiovas-
cular events, and changes in these parameters during dobutamine
stress. And group-averaged pressure – volume loops before and
after dobutamine stress are schematically presented in Figure 2. As
for the echocardiographic indices of LV contraction, in patients
without cardiovascular events both LVEF and WMSI improved sig-
nificantly along with a significant decrease in LV volumes in response
to dobutamine, while these responses were blunted in patients with
cardiovascular events. In terms of haemodynamic parameters, do-
butamine infusion significantly increased the total mechanical energy
consumption as evidenced by an increase in PVA (from 5937 +
2107 to 7542 + 3384 mmHg mL/m2; P , 0.001). On the other
hand, VA coupling improved significantly in patients without cardio-
vascular events (from 2.47 + 1.09 to 1.59 + 0.68, P , 0.001), so
that cardiac work efficiency improved significantly in response to
dobutamine (from 47 + 9 to 57 + 9%, P , 0.001) in these patients.
On the other hand, VA coupling did not change at all during dobu-
tamine stress in patients with cardiovascular events (from 2.55 +
0.82 to 2.39 + 0.99), so that total mechanical energy consumption
increased significantly but without improvement in cardiac work ef-
ficiency (from 45 + 8 to 47 + 10%) for this group.
Prognostic factor of cardiovascular events
Based on the findings of ROC curve analyses, we divided the pa-
tients into two subgroups according to LVEF (DLVEF: cut-off value
of 6.4%), Ees (DEes: cut-off value of 0.29 mmHg/mL), and VA coup-
ling response (DVA coupling: cut-off value of 0.86), respectively. Pa-
tients with good LVEF response showed significantly favourable
event-free survival than those with poor response (Figure 3A). Simi-
larly, patients with good Ees response and good VA coupling re-
sponse exhibited significantly favourable survival than the others,
respectively (Figure 3B and C). When adverse cardiovascular events
were restricted to only hard event (i.e. death from HF or sudden
cardiac death), patients with good VA coupling response experi-
enced significant favourable survival than the others (Figure 4A).
Similarly, when adverse cardiovascular events were restricted to
only soft event (i.e. hospitalization from HF), patients with good
VA coupling response showed significant favourable survival than
the others (Figure 4B).
Impact of changes in VA coupling during dobutamine stress 1299

Table 1 Baseline clinical, haemodynamic, and echocardiographic characteristics

Variables DCM patients (n 5 89) Normal control (n 5 30) P

...............................................................................................................................................................................
Clinical characteristics
Age, years 56 + 16 60 + 17 0.38
Gender, M/F 58/31 18/12 0.61
BSA, m2 1.6 + 0.2 1.6 + 0.2 0.70
NYHA functional class
I 9 (10)
II 62 (70)
III 18 (20)
IV 0 (0)
Medications
Loop diuretics 53 (60)
b-Blockers 85 (96)
Spironolactone 51 (57)
ACE-I/ARBs 85 (96)
Haemodynamic characteristics
Systolic BP, mmHg 98 + 18 126 + 18 ,0.001
Diastolic BP, mmHg 56 + 14 73 + 10 ,0.001
Heart rate, bpm 65 + 14 65 + 13 0.87
Stroke volume index, mL/m2 39 + 12 43 + 12 0.42
SVR, dynes s/cm5 1323 + 441 1485 + 362 0.25
Cardiac index, L/min/m2 2.63 + 0.75 3.06 + 0.82 0.08
Ees, mmHg/mL 0.89 + 0.35 2.47 + 0.74 P , 0.001
Ea, mmHg/mL 2.02 + 0.85 2.48 + 0.61 P , 0.01
VA coupling, units 2.49 + 1.02 1.04 + 0.21 P , 0.001
SW, mmHg mL/m2 2706 + 1056 3388 + 847 P , 0.01
PE, mmHg mL/m2 3181 + 1484 1742 + 514 P , 0.001
PVA, mmHg mL/m2 5887 + 2262 5049 + 1200 0.06
Cardiac work efficiency, % 46 + 9 66 + 5 P , 0.001
Echocardiographic characteristics
LV volume index (mL/m2)
End-diastole 101 + 32 48 + 11 P , 0.001
End-systole 71 + 30 18 + 7 P , 0.001
LVEF, % 32 + 10 63 + 8 P , 0.001

Data are presented as n, mean + SD, n (%), or median (inter-quartile range).

BSA, body surface area; NYHA, New York Heart Association; ARB, angiotensin II receptor blocker; ACE-I, angiotensin-converting enzyme inhibitor; BP, blood pressure; Ees,
end-systolic elastance; Ea, arterial elastance; VA, ventriculo-arterial; SW, stroke work; PE, potential energy; PVA, pressure –volume area; LV, left ventricular; EF, ejection fraction.

The hazard ratio (HR) and 95% confidence interval (CI) for each
of the variables of the univariate and multivariate Cox proportional-
hazards analyses are shown in Table 3. An important finding of the
multivariate analysis was that not only age and NYHA functional
class but also DVA coupling (HR: 0.162, P , 0.001) were independ-
ently associated with cardiovascular events.
Feasibility and reproducibility of
measurements
The feasibility of the 3D echocardiography in our study was as high
as 94%. The intra-observer variability assessed in terms of intra-
class correlation coefficient was 0.993 (95% CI: 0.972 – 0.998)
for LVEF, 0.990 (95% CI: 0.959 – 0.998) for Ees, 0.993 (95%
CI: 0.973 – 0.998) for Ea, and 0.991 (95% CI: 0.965 – 0.998) for VA
coupling. The inter-observer variability for these measurements
was 0.979 (95% CI: 0.915 – 0.995), 0.973 (95% CI: 0.891 – 0.993),
and 0.991 (95% CI: 0.962 –0.998), respectively.
The additional time required for obtaining 3D images was mark-
edly short at 2.6 + 0.8 min for patient, and only 3.2 + 0.8 min was
needed to analyse 3D echocardiographic data during both resting
condition and during dobutamine infusion.
Discussion
The study reported here is the first to demonstrate the prognostic
capability of the assessment of changes in VA coupling using 3D
1300 K. Matsumoto et al.

Table 2 The comparisons of haemodynamic and echocardiographic parameters between subgroups with and without
cardiovascular events, and changes in these parameters during dobutamine stress

Event free (n 5 67) Event (n 5 22)

.................................................. ...................................................
Baseline Dobutamine Baseline Dobutamine
...............................................................................................................................................................................
Haemodynamics
Systolic BP, mmHg 98 + 16 128 + 31* 99 + 23 121 + 34†
Diastolic BP, mmHg 57 + 14 66 + 18* 55 + 11 65 + 18†
Heart rate, bpm 68 + 13 88 + 18* 68 + 13 85 + 18*
Stroke volume index, mL/m2 41 + 12 49 + 14* 36 + 11 42 + 16‡
2
Cardiac index, L/min/m 2.70 + 0.74 6.77 + 1.93* 2.44 + 0.75 5.49 + 2.25*
SVR, dynes s/cm5 1274 + 386 1024 + 340* 1473 + 563 1317 + 601
Ees, mmHg/mL 0.87 + 0.34 1.44 + 0.52* 0.95 + 0.41 1.15 + 0.53
Ea, mmHg/mL 1.91 + 0.62 2.06 + 0.55 2.36 + 1.29} 2.50 + 1.07
VA coupling, unit 2.47 + 1.09 1.59 + 0.68* 2.55 + 0.82 2.39 + 0.99
SW, mmHg mL/m2 2736 + 965 4306 + 1950* 2619 + 1317 3404 + 1790*
PE, mmHg mL/m2 3201 + 1463 3236 + 1723 3122 + 1582 3880 + 2205†
PVA, mmHg mL/m2 5937 + 2107 7542 + 3384* 5736 + 2730 7284 + 3721†
Cardiac work efficiency, % 47 + 9 57 + 9* 45 + 8 47 + 10
Echocardiographic indices
LV volume index, mL/m2
End-diastole 96 + 26 90 + 28‡ 118 + 41} 113 + 38
End-systole 65 + 23 54 + 25* 89 + 40§ 83 + 39
LVEF (%) 33 + 9 43 + 12* 27 + 13} 29 + 14
WMSI 1.99 + 0.22 1.71 + 0.39* 2.17 + 0.18|| 1.98 + 0.37‡

WMSI, wall motion score index. All other abbreviations as in Table 1.

*P , 0.001 vs. baseline.
†
P , 0.01 vs. baseline.
‡
P , 0.05 vs. baseline.
§
P , 0.001 vs. patients without events.
||
P , 0.01 vs. patients without events.
}
P , 0.05 vs. patients without events.

non-invasive single-beat method during dobutamine stress for pa-
tients with DCM. Left ventricle and vasculature were found to be ef-
fectively coupled to maximize SW (i.e. Ea ¼ Ees) in the normal heart,
while in patients with DCM, coupling ratio was far from ideal condi-
tion, which could no longer maintain SW properly and resulted in the
mechanical uncoupling. In response to low-dose dobutamine, Ees, VA
coupling and cardiac work efficiency improved significantly in patients
without cardiovascular events, but total mechanical energy increased
without improvement in cardiac work efficiency in those with cardio-
vascular events. Moreover, the quantitative assessment of changes in
VA coupling proved to be highly effective for prognostic risk stratifi-
cation for patients with DCM.
Assessment of ventricular contractility
and its inotropic reserve
Dobutamine stress echocardiography is used to assess the progno-
sis for HF patients and its usefulness is well recognized.2 – 7 Pratali
et al. 3 studied 184 patients with DCM with high-dose dobutamine
stress echocardiography and found the contractile reserve assessed
in terms of change in the WMSI was the independent predictor of
cardiac death. On the other hand, Ramahi et al. 4 have shown that
an increase in LVEF during high-dose dobutamine echocardiography
is a strong predictor of survival for patients with DCM, independent
of the baseline value of LVEF. However, analysis of wall motion, such
as WMSI3 and LVEF4,5 during dobutamine infusion, is subjective as
well as highly load dependent, and its accuracy depends largely on
the experience of the operators. On the other hand, we recently re-
ported the prognostic utility of contractile reserve assessed by
means of quantitative speckle-tracking strain in patients with
DCM, and that contractile reserve assessed on 3D global circumfer-
ential strain was found to be a more robust prognostic parameter
than that assessed by WMSI or LVEF to predict adverse cardiovas-
cular events.6 Thus, the application of quantitative speckle-tracking
echocardiography to the arena of dobutamine stress test was ex-
pected to remove the subjective nature associated with visual assess-
ment during stress testing. In patients with HF, however, it is known
that dobutamine stress has varied effects on afterload depending on
the severity of HF.19 Actually, dobutamine infusion showed the het-
erogeneous effects on the vasculature with this relatively low-dose
protocol in this study. Although SVR decreased during dobutamine
stress from 1323 + 441 to 1096 + 434 dynes s/cm5 in the entire
Impact of changes in VA coupling during dobutamine stress
Figure 2 Schematic presentation of group-averaged pressure – volume loops before and after dobutamine stress for patients without (A) and
with (B) cardiovascular events. The black line shows baseline pressure – volume loop trajectories, and the coloured line shows those obtained
during dobutamine stress.
group of the patients, dobutamine infusion reduced SVR . 10% in 57
(64%), remained unchanged in 16 (18%), and increased .10% in 16
patients (18%), respectively. Thus, conventional measures of LV con-
tractile reserve including LVEF, WMSI, and even novel speckle-
tracking strain, which are highly dependent on loading conditions,
may not accurately reflect the changes in ventricular contractility dur-
ing dobutamine stress.
On the other hand, the concept of contractility is an intrinsic
property of ventricular contraction relatively independent of
preload and afterload. 8,9 Thus, one can speculate that the
changes in ventricular contractility may be a more robust and re-
liable marker to assess true inotropic reserve. In the 1970s, Suga
et al. 8 and Sagawa9 established the concept of end-systolic ela-
stance as a reliable marker of ventricular contractility. Although
Ees is considered to be the theoretical gold standard of LV con-
tractility, its clinical applicability has been limited due to its inva-
siveness and complex measurement procedure. To resolve these
problems, several investigators have proposed single-beat esti-
mation of end-systolic elastance without changing the loading
conditions.20,21 More recently, by using two-dimensional echo-
cardiography, completely non-invasive single-beat estimation of
Ees has been advocated and validated against invasive measure-
ments both at rest and during dobutamine stress.13,22 When
an entirely non-invasive single-beat Ees is obtained, we can quan-
tify LV end-systolic elastance and LV energetics by measuring
only several easily obtainable echocardiographic parameters. In
this regard, accurate and reproducible quantitative assessment
of LV volumes and function are pivotal for the assessment of
non-invasive single-beat method. Three-dimensional echocardi-
ography allows more accurate quantification of LV volumes
1301
than with two-dimensional method and has an accuracy that is
similar to magnetic resonance imaging.23
Importance of VA coupling and
LV energetics
The conditions for coupling of ventricular contractility with arterial
load have been predicted theoretically and validated experimental-
ly.15,24 Previous investigators clearly showed that SW is maximized
when effective arterial elastance equals end-systolic elastance15 (i.e.
Ees ¼ Ea), whereas cardiac work efficiency is maximized when ef-
fective arterial elastance is approximately one-half of end-systolic
elastance (i.e. Ees ¼ 2Ea).24 In this study, the left ventricle and
vasculature were observed to be effectively coupled to maximize
the SW (i.e. Ees ¼ Ea) in the normal heart, while coupling ratio
was far from ideal condition, which could no longer maintain SW
properly and resulted in the mechanical uncoupling in the failing
heart.
During dobutamine stress, improvement in VA coupling was
found to be important determinants of cardiovascular outcome
for HF patients, while change in Ees and LVEF was not an independ-
ent determinant of adverse cardiovascular events. Thus, when one
considers the compensatory mechanisms of the cardiovascular sys-
tem, the ability to adjust VA coupling may be more important for
maintaining a stable compensated condition in patients with chronic
HF than the ability to augment the LV contractility in response to
sympathetic stimulation. On the other hand, in patients with cardio-
vascular events, VA coupling did not change during dobutamine
stress. As a result, dobutamine stress significantly increased total
mechanical energy consumption without improvement in cardiac
1302
Figure 3 Shown are Kaplan– Meier curves of event-free survival from the primary endpoint according to ejection fraction (LVEF) (A), Ees (B),
and VA coupling response (C) during dobutamine stress.
work efficiency (i.e. ‘energy wasting effect’) in this group. This indicates
that cardiac oxygen consumption would increase without improve-
ment in cardiac work efficiency in the setting of haemodynamic stress
or exertion without effective increase in cardiac output. This may be a
reason why patients without VA coupling reserve experienced more
cardiovascular events in this patient population.
Previous investigators used end-systolic pressure – volume ratio
(i.e. ESP/ESV), as a simplified surrogate of LV end-systolic elastance,
and have reported that inotropic reserve assessed by pressure – vol-
ume ratio and VA coupling can be used as a robust surrogate of LV
contractile reserve and used for the risk stratification of the patients
with various heart diseases.25,26 Bombardini et al. 25 studied 51 pa-
tients with systolic HF who underwent exercise stress radionuclide
angiography and observed LV functional reserve during stress test-
ing. The patients who were able to increase SV during stress testing
showed a decrease in arterial elastance during exercise, which lead
to better VA coupling and improved cardiac efficiency. Further-
more, they also reported that event-free survival was significantly
better in these patients than the others. More recently, same
authors26 expanded these results to study 891 patients with nega-
tive stress echocardiography results. They demonstrated that LV
K. Matsumoto et al.
end-systolic elastance assessed by pressure – volume ratio and VA
coupling reserve could predict cardiac events even in patients
with negative stress echocardiography. At a glance, these results ap-
pear to be similar to ours, but both the absolute values of LV end-
systolic elastance and arterial elastance are more than two times
higher than previously reported values27,28 for patients with systolic
HF. Using invasive haemodynamic study, Ishihara et al. 27 reported
the changes in Ees, Ea, and VA coupling ratio during low-dose dobu-
tamine stress for 23 patients with idiopathic DCM (mean EF 33 +
2%). During dobutamine infusion, Ees increased from 0.80 + 0.12 to
1.31 + 0.13 mmHg/mL, Ea remained relatively unchanged from
2.14 + 0.19 to 2.33 + 0.22 mmHg/mL, and Ea/Ees ratio significantly
decreased from 3.12 + 0.43 to 1.86 + 0.15. Although these results
are quite similar to ours, it appears that pressure–volume ratio (i.e.
ESP/ESV ratio) apparently overestimates the LV contractility. The
reason of this overestimation of ventricular contractility may be
based on the concept of pressure – volume ratio, which assumes
V0, the volume axis intercept at zero pressure, is negligibly small.
However, as shown in the invasive haemodynamic study, V0 was
not negligibly small especially in HF patients with dilated failing
heart.29 These results indicate that pressure – volume ratio can
Impact of changes in VA coupling during dobutamine stress 1303

lead to the significant overestimation of LV end-systolic elastance

and can lead to misleading results especially in the patients with re-
modelled heart.

Clinical implications
In the assessment of the HF patients, the quantitative evaluation of
haemodynamic condition, including the ventricular contractility, vas-
cular tone, and also its interaction will be needed for the treatment
of individual HF patients. By using non-invasive single-beat method,
we can repeatedly assess the changes in LV contractility in a short
time at bedside due to its fully non-invasive nature. And based on
the quantitative assessment of coupling condition and LV energetics,
comprehensive tailored treatment approach could serve to opti-
mize the VA coupling to stabilize acute exacerbation, reduce re-
admission, enhance quality of life, and optimize HF therapy.

Figure 4 Shown are Kaplan– Meier curves of event-free survival
from hard events (death from heart failure or sudden cardiac
death) (A) and soft events (HF hospitalization) (B) in patients
with good or poor VA coupling response during dobutamine
stress, respectively.
Study limitations
There are certain limitations to this study. First, this pilot study cov-
ered a relatively small number of patients in a single centre, so that
further studies with larger patient populations in multicentre basis
will be needed to validate our findings. Second, simultaneous inva-
sive haemodynamic study was not performed, but the assessment of
non-invasive single-beat method was previously validated in com-
parison with invasive measurement both at rest and during dobuta-
mine stress.13 Third, we enrolled chronic HF patients with reduced
EF using the arbitrary cut-off point of LVEF ≤45% in this study.
Although the cut-off of LVEF 40% or less is generally applied in
the majority of similar studies dealing with HF with reduced EF,
there is no consensus about the optimal cut-off value of LVEF for
the diagnosis of this group of patients. We believe that cut-off value
of LVEF for patient enrolment would not have a significant effect on
the overall results of this study. Finally, b-blockers were left un-
changed in all patients during dobutamine stress. Although this
may have affected the response to dobutamine infusion, ethical

Table 3 Univariate and multivariate Cox proportional-hazards analysis

Variables Univariate analysis Multivariate analysis

.................................................... ....................................................
HR 95% CI P HR 95% CI P
...............................................................................................................................................................................
Clinical variables
Age (years) 1.036 1.006–1.066 ,0.05 1.038 1.007– 1.069 ,0.05
Gender (female) 0.487 0.180–1.314 0.16
NYHA functional class (.II) 3.315 1.418–7.753 ,0.01 4.205 1.617– 10.93 ,0.01
Serum BNP concentration (pg/mL) 5.609 2.676–11.76 ,0.001
Echocardiographic variables
LV end-diastolic volume index (mL/m2) 1.017 1.017–1.028 ,0.01
LVEF (%) 0.942 0.902–0.984 ,0.01
E/e′ ratio 1.036 0.996–1.078 0.08
Variables under dobutamine stress
DSVI (mL/m2) 0.965 0.922–1.009 0.12
DLVEF (%) 0.890 0.840–0.942 ,0.001
DWMSI 0.376 0.082–1.732 0.21
DEes (mmHg/mL) 0.010 0.002–0.063 ,0.001
DVA coupling 0.128 0.057–0.287 ,0.001 0.162 0.078– 1.192 ,0.001

HR, hazard ratio; CI, confidential interval.

All other abbreviations as in Table 1.
1304
reasons prevented us from interrupting administration of these key
drugs for HF therapy.
Conclusions
Improvement in VA coupling during dobutamine stress was identi-
fied as an important determinant of cardiovascular outcome for pa-
tients with DCM. The quantitative assessment of VA coupling
reserve using 3D non-invasive single-beat method may thus lead
to better management of these patients.
Conflict of interest: none declared.
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