1. health and fitness
2. disease

European Journal of Echocardiography (2009) 10, 106–111
doi:10.1093/ejechocard/jen184
Ventricular-arterial coupling in patients with heart
failure treated with cardiac resynchronization therapy:
may we predict the long-term clinical response?
Francesco Zanon1*, Silvio Aggio1, Enrico Baracca1, Gianni Pastore1, Giorgio Corbucci2,
Graziano Boaretto1, Gabriele Braggion1, Christian Piergentili1, Gianluca Rigatelli1,
and Loris Roncon1
1
Division of Cardiology, General Hospital, Rovigo, Italy; and 2Medtronic Italia, Sesto San Giovanni, Italy
Received 21 January 2008; accepted after revision 25 May 2008; online publish-ahead-of-print 18 June 2008
KEYWORDS
Objective To evaluate the effects of cardiac resynchronization therapy (CRT) on ventricular-arterial
coupling (VAC) in patients with refractory congestive heart failure (HF), left bundle brunch block,
and sinus rhythm.
Background The ratio between arterial elastance (Ea) and left ventricular end-systolic elastance (Ees),
the so-called VAC, defines the efficiency of the myocardium in pumping blood.
Methods Seventy-eight patients were studied with echocardiography before CRT, and 1 year later. Endsystolic elastance was calculated according to the method of Chen. Arterial elastance (ratio of the
systolic pressure to the stroke volume), end-systolic volume (ESV), and quality of life (QoL) (Minnesota
Living with Heart Failure Questionnaire) were assessed at the baseline and after 1 year. Patients with a
reduction .15% of ESV or a decrease .33% in QoL score were considered responders to CRT.
Results QRS duration and interventricular delay were significantly reduced with CRT compared with
baseline (156 + 2 vs. 195 + 3 ms, P , 0.001; and 25 + 2 vs. 55 + 3 ms, P , 0.001, respectively). Arterial
elastance/Ees decreased significantly on CRT (2.47 + 1.48 vs. 1.41 + 0.87, P , 0.0001). The lowering of
Ea/Ees was congruent to a decrease in intraventricular delay (83.1 + 55.7 vs. 28.4 + 49.5 ms, P ,
0.0001) and an increase in ejection fraction (26 + 6.3 vs. 36.9 + 8.0%, P , 0.0001). Responders to
CRT were 74 and 71% of the overall patient population, considering as endpoint QoL or ESV, respectively.
The analysis of VAC showed a baseline cut-off value of 2, above which 88% and 69% of patients responded
to CRT, considering as endpoint QoL or ESV, respectively.
Conclusions The non-invasive assessment of VAC may be proposed as an immediate, easy, and optimal
tool for quantifying the effect of CRT in patients with HF.
Introduction
The myocardial pump function and the performance of the
entire cardiovascular system are determined by preload,
afterload, and contractility.1 The best clinical measure of
preload is the end-diastolic volume of the heart. From a
clinical point of view, afterload can be estimated by measuring arterial blood pressure. In contrast, contractility is the
most difficult parameter to estimate in clinical practice,
since this would require invasive measurements of left
ventricular (LV) pressure–volume (PV) loops.
Left ventricular-arterial coupling (VAC) describes the ratio
between arterial elastance (Ea) and ventricular end-systolic
* Corresponding author. Tel: þ39 0425 394252; fax: þ39 0425 393597.
E-mail address: franc.zanon@iol.it
elastance (Ees). The mathematical ratio between these two
elastances, the so-called VAC, defines the efficiency of the
myocardium in pumping blood through the arteries, which
is the desired result of heart contraction. From a mechanical
point of view, the net flow and pressure output of a pump
depend on three interacting factors: the intrinsic properties, such as power and stroke capacity, the mass or
inertia of the fluid to be ejected, and the capacitance—
the resistance and inertial properties of the system receiving the ejected material.2 In the cardiovascular system,
the left ventricle is obviously the pump, the blood is the
fluid, and the arteries constitute the system receiving the
ejected blood. As blood viscosity is the only constant
factor in this energy transfer, the best performance of
the cardiovascular system is determined by the best fit
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2008.
For permissions please email: journals.permissions@oxfordjournals.org.
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Cardiac resynchronization
therapy;
Ventricular arterial coupling;
Quality of life
VAC in patients with HF treated with CRT
between the factors characterizing the ventricles and the
arteries. The intrinsic properties of the myocardium are
strictly related to the end-systolic and -diastolic elastances,
which is the consequence of maximal and minimal chamber
stiffness. The blood per se determines the inertial load,
depending on the mass in the myocardium at the end of
the diastole. The arterial load depends on the dimensions
of the proximal vessels, the mean vascular resistance, and
the pulsatile components related to compliance and wave
reflections. The result of the complex interactions among
these factors is expressed by the relationship between Ees
and Ea, which describes the mechanical pumping function.
As the standard methods of evaluating Ees formerly involved
invasive techniques, the assessment of VAC was not feasible
in clinical practice. Efforts have been made to assess VAC
non-invasively,3–5 and a method has recently been developed and validated to estimate LV Ees in humans from noninvasive single-beat parameters.6 The method described by
Chen et al. requires five parameters obtained from noninvasive arm-cuff blood pressure, echo-Doppler echocardiography and ECG, thus making VAC assessment feasible in
clinical practice (see Appendix).
107
Lead implantation and device programming
The target veins for LV pacing were the basal posterior–lateral,
basal lateral, middle posterior–lateral, middle lateral, and
lateral-apical vein. The RV lead was placed in the apex of the
right ventricle, in accordance with standard procedure. A bipolar
atrial lead was implanted in the right atrial appendage, and the programmed mode was DDD with AV interval set at 130 ms to guarantee
constant capture of the ventricles. No additional procedure for AV
delay optimization was carried out and biventricular stimulation
was performed simultaneously in both ventricles.
Inclusion criteria
We considered eligible for enrolment all consecutive patients who
fulfilled the following inclusion criteria:
(i) cardiomyopathy of any aetiology;
(ii) end-stage HF refractory to drugs, including ACEinhibitors, b-blockers, and spironolactone;
(iii) NYHA class III or IV;
(iv) sinus rhythm;
(v) intraventricular delay with QRS duration .0.15 s and left
bundle branch block (LBBB) on ECG;
(vi) ejection fraction 35%;
(vii) end-diastolic diameter 65 mm.
Aim of the study
Methods
The study had the approval of the Ethics Committee and informed
consent to participate in the investigation was obtained from each
patient before enrolment.
All patients underwent a clinical examination and echocardiographic evaluation before CRT and after 1 year of follow-up (FU).
Echocardiography was performed by means of a commercially available imaging system (General Electric VIVID Five GE Medical System,
Milwaukee, WI, USA) equipped with a 2.5–3.6 MHz probe, with the
patient in the left lateral position. The LV volumes and ejection
fraction were measured by the biplane Simpson’s method.7,8 Left
ventricular Ees was calculated according to the method proposed
by Chen et al.6 Arterial elastance was measured as the ratio of
the systolic pressure to the stroke volume (SV). The latter was
obtained by subtracting the LV end-systolic volume (ESV) from the
LV end-diastolic volume.9 The cardiac output was calculated by
multiplying the - by the heart rate as measured during echocardiography. QRS duration was also collected. Quality of life (QoL) was
assessed by the Minnesota Living with Heart Failure Questionnaire.10
To avoid any influence on the patients, the questionnaire was selfadministered by them at enrolment and after 1 year of FU to identify responders to CRT. A patient was considered to be responder to
CRT if the following parameters significantly changed after 1 year of
FU, compared with their basal values: (i) 33% decrease in QoL and
(ii) 15% decrease in ESV.11 The decrease in QoL was considered a
marker to identify clinically responder patients. The decrease in
ESV was considered a marker of LV remodelling.
A subanalysis of ischaemic and non-ischaemic patients was also
performed. Ischaemic CHF was defined as LV systolic dysfunction
associated with at least 75% narrowing of at least one of the three
major coronary arteries (marked stenosis) or a documented
history of a myocardial infarction. Non-ischaemic CHF was defined
as LV systolic dysfunction without marked stenosis.12
Echo-Doppler parameters
The following echo-Doppler parameters were measured at any FU
(enrolment and after 1 year):
(i) End-diastolic volume index, measured at the onset of the QRS
complex.13
(ii) End-systolic volume index, referred to the smallest LV
cavity.13
(iii) Left ventricular ejection fraction (EF).13
(iv) Stroke volume, measured from proximal aorta pulse-wave
Doppler-flow and aortic cross-sectional area.
(v) Arterial elastance.14
(vi) Left ventricular Ees.6
(vii) VAC expressed as the Ea/Ees ratio
(viii) Intraventricular delay: Colour tissue Doppler imaging was
acquired in 2D mode from the apical four-chamber and twochamber views to assess myocardial regional function. The
mean velocity profile was determined for the interventricular
septum and the lateral, inferior, and anterior walls at the
level of the basal and medial segments. The regional preejection period was measured for all segments from the
onset of QRS to the beginning of the positive component of
the regional systolic velocity, defined by zero-crossing or,
when this was not possible, as the beginning of the
upstroke of the velocity curve after the isovolumic contraction
phase.13
(ix) Interventricular delay: the difference between the aortic
and pulmonary pre-ejection time. The pre-ejection time is
calculated as the interval from the onset of QRS to the
beginning of the aortic or pulmonary flow velocity curve
recorded by pulsed-wave Doppler in the apical five-chamber
view.13
In the first 20 patients, the inter-observer and intra-observer variability of EDV, ESV, EF, and SV was tested to evaluate reproducibility
of the data. The inter-observer variability was ,4.2% and the
intra-observer variability ,3.4%.
Each patient was kept at rest for at least half an hour before
measuring any echo parameter.
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The aim of the study was to prospectively evaluate the longterm effects of cardiac resynchronization therapy (CRT) on
VAC, in patients with refractory congestive heart failure
(HF), left bundle branch block, and sinus rhythm.
108
F. Zanon et al.
Statistical analysis
All data are expressed as mean + SD. An intra-patient analysis was
performed, and the data were compared by means of paired Student’s t-test. A P-value of 0.05 was regarded as significant.
according to the QoL criterion (Figure 3A). When ESV is
the endpoint, responders are 50% if VAC , 4, rising up to
100% when VAC . 4 (Figure 3B).
Discussion
Results
Table 1. The echo-Doppler parameters and indexes 1 year after CRT
End-diastolic volume index (mL/mq)
End-systolic volume index (mL/mq)
EF (%)
Stroke volume (mL/b)
Ea (mmHg/mL)
Ees (mmHg/mL/mq)
Ea/Ees
Intrav.Delay (ms)
QoL score
Before CRT_Baseline
CRT on_1 Year
P 1 Year vs. baseline
157.76 + 47.88
118.21 + 41.82
25.96 + 6.30
49.71 + 19.23
2.74 + 1.11
1.25 + 0.47
2.47 + 1.48
83.09 + 55.72
58 + 13
139.90 + 51.44
88.95 + 40.43
38.15 + 8.20
66.09 + 19.37
2.02 + 0.59
1.97 + 1.09
1.31 + 0.71
23.00 + 46.58
34 + 8
0.0002
,0.0001
,0.0001
,0.0001
,0.0001
,0.0001
,0.0001
,0.0001
,0.0001
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Seventy-eight patients (61 male) entered the study. The
mean age was 72 + 9 years (range 44–88): 42% were
affected by ischaemic cardiomyopathy. The mean NYHA
class was 3.1 + 0.6, the Minnesota quality life score was
62 + 12, and the mean EF was 26 + 7%. Ninety-five per
cent of patients were on treatment with ACE-inhibitors,
61% with b-blockers and 67% with spironolactone. At the
end of the study, 94 and 63% of the patients were treated
with ACE-inhibitors and beta-blockers, respectively.
All patients were successfully implanted with CRT devices,
defibrillators (34 patients, 44%) or pacemakers depending on
the indication. The target veins into which the LV lead was
implanted were: basal posterior–lateral in 6 patients (8%),
basal lateral in 8 (10%), middle posterior–lateral in 5 (6%),
middle lateral in 45 (58%), and lateral-apical in 14 (18%).
The mean time of the procedure was 85 + 34 min, of
which 9 + 10 min were required for LV lead positioning and
17 + 12 min for fluoroscopy.
QRS duration and interventricular delay were significantly
reduced with CRT: 195 + 32 vs. 156 + 17 ms, P , 0.001, and
55 + 33 vs. 25 + 19 ms, P , 0.001, respectively.
Table 1 summarizes the echo-Doppler parameters and
indexes 1 year after CRT, in comparison with the baseline.
On CRT, all values significantly improved.
According to the improvement of the QoL score, 74% of
the overall patient population responded to CRT. According
to the improvement of ESV, 71% of patients were classified
as responders. The analysis of VAC showed a baseline
cut-off value of 2, above which at least 88 and 69% of
patients responded to CRT, considering as endpoint QoL or
ESV, respectively (Figure 1A and B).
A subanalysis of ischaemic and non-ischaemic patients is
showed in Figures 2 and 3. At least 75% of all non-ischaemic
patients (Figure 2A) are responders to CRT independently of
VAC and the percentage becomes very high when VAC 1.5.
When the endpoint is ESV (Figure 2B) responders range
around 50% if VAC 2, but they rise to 81 and 100% with
higher values of VAC.
In the case of ischaemic patients, on average 75%
responded to CRT when VAC was .2 (range 69–100%),
Our study, for the first time, evaluated the long-term effects
of CRT on VAC in patients with HF and sinus rhythm. The
main result is the positive effect that CRT has on VAC and,
moreover, the potential of VAC for identifying patients
responder to this therapy.
Ea/Ees ratio in normal subjects is generally between 0.7
and 1.0: the range of optimal function.15,16 In patients
with congestive HF, this ratio typically rises to as high as
4.0, owing to the relative decline in ventricular contractile
function (lower Ees) and concomitant rise in Ea.17–19 Such
coupling is detrimental from the standpoint of ventricular
performance and metabolic efficiency.
In their non-invasive analysis, Chen et al. demonstrated
the feasibility of using a single PV point, timed at the
onset of ejection (end of the isovolumic period). This
method requires five accurately measured parameters
obtained from non-invasive arm-cuff blood pressures, echoDoppler, and the electrocardiogram. Correlations between
measured and estimated VAC, both at rest and with acute
contractility change(s), were generally good, and the reproducibility of measurements over time proved reasonable,
making this method applicable in clinical practice.6
The proposed method offers a new tool for a complete
estimation of the cardiac network with regard to the final
result of the heart: the efficiency of the mechanical
pumping function. This method is relatively fast, requiring
the evaluation of few parameters and is based on the standard parameters evaluated by echocardiography, plus blood
pressure. Ventricular-arterial coupling is calculated immediately by means of a software formula, and the result is a
single index that summarizes the mechanical efficiency of
the myocardium in pumping blood.
Cardiac resynchronization therapy has recently been
introduced to improve haemodynamics and symptoms in
patients with advanced HF.20–23 Much of the information
regarding the clinical benefits of CRT derives from clinical
trials,20,24 which together demonstrate that CRT improves
symptoms and exercise tolerance in medically treated
patients with persistent, moderate-to-severe symptoms
of HF, poor LV function, and intraventricular conduction
delay.25 Nevertheless, the identification of responders to
CRT is still matter of debate. The measurement of VAC
VAC in patients with HF treated with CRT
109
Figure 1 Patients responding to CRT in the overall population, as a function of the basal value of VAC: a cut-off value of 2 may identify 88% of
responders to CRT as evaluated through the QoL and 69% of responders as defined through ESV.
Figure 3 Patients responding to CRT in the ischaemic group, as a function of the basal value of VAC: a cut-off value of 2 may identify 69% of
patients responders to CRT as evaluated through the QoL and a cut-off value of 4 may identify 100% of responders defined through ESV.
Responders range to 50% when VAC , 4, if ESV is considered the endpoint.
not only may allow to estimate the baseline condition and
the improvement of the patient submitted to therapeutic
actions, but it probably may be of help in the selection of
responders. Of course a larger scale, prospective and
long-term trial should be designed for this purpose.
To define responders and non-responders, we assumed
both a clinical criterion based on QoL and a functional parameter of remodelling based on ESV. This is in accordance
with the objectives of standard clinical practice. Although
different approaches have been proposed to select patients
for CRT, there is no unifying definition of responders.26–29
Our proposal is not only coherent with clinical practice,
but also coherent with the results of large-scale trials like
MUSTIC21 and MIRACLE,20 which first validated CRT on the
basis of clinical response. In these two trials, CRT failed to
improve clinical status in up to 30% of patients, with a corresponding success rate of 70%. Similarly, we obtained a 74%
response with the QoL criterion and 71% with ESV. When ESV
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Figure 2 Patients responding to CRT in the non-ischaemic group, as a function of the basal value of VAC: a cut-off value of 1.5 may identify
89% of responders to CRT as evaluated through the QoL and a cut-off value of 2 may identify 81% of responders defined through ESV.
110
Study limitations
We only used non-invasive methods to estimate all cardiovascular parameters used in the study.
Conclusions
Cardiac resynchronization therapy increases Ees, which is a
main determinant of LV systolic performance, reduces Ea,
and improves VAC. The improvement in VAC may suggest
an improved mechanical efficiency of the myocardium in
pumping blood.
The selection of responders to CRT on the basis of the
basal value of VAC is promising, but it should be further
investigated in a prospective, large-scale, and long-term
trial.
Acknowledgements
We would like to acknowledge the contributions of Paola Raffagnato
RN and Antonella Tiribello RN, who provided valuable support for
implantation and data collection, and Mrs Giovanna Zucchi, who
provided secretarial support.
Conflict of interest: In connection with the submitted article, there
are no financial associations that might pose a conflict of interest.
Appendix
The formula proposed and validated by Chen for the estimation of
Ees is reported below:
Ees ¼ ½Pd ðENdPs0:9Þ=½SVEnd
where Pd is the brachial diastolic pressure, Ps the brachial systolic
pressure, SV the stroke volume, and ENd the predicted normalized
LV elastance at the onset of ejection. The estimate is described
by the following formula:
ENd ¼ 0:0275 0:165EF þ 0:3656ðPd=PesÞ þ 0:515ENdðavgÞ
where Pes=Ps 0.9 and EF is the basal ejection fraction.
ENdðavgÞ ¼ 0:35695 7:2266tNd þ 74:249tNd2 307:39tNd3
þ 684:54tNd4 856:92tNd5 þ 571:95tNd6
159:1tNd7
where tNd was determined by the ratio of pre-ejection period
(R-wave!flow-onset) to total systolic period (R-wave!end-flow),
with the time at onset and termination of flow defined noninvasively from the aortic-Doppler waveform.
Once these formulas are implemented on an automatic algorithm,
the determination of non-invasive parameters like Ps, Pd, SV, EF,
and tNd allows the immediate calculation.
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Differences are also evident between ischaemic and nonischaemic patients. Probably, ischaemic patients have nonhomogeneous myocardial tissue, and pacing may result in
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