Download Is nuclear imaging a viable alternative technique to assess

Europace (2008) 10, iii101–iii105
doi:10.1093/europace/eun221
Is nuclear imaging a viable alternative technique to
assess dyssynchrony?
Ji Chen1*, Jeroen J. Bax2, Maureen M. Henneman2, Mark J. Boogers2, and Ernest V. Garcia1
1
2
Department of Radiology, Emory University School of Medicine, 1364 Clifton Road, Atlanta, GA 30322, USA; and
Department of Cardiology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands
KEYWORDS
Heart failure;
Cardiac resynchronization
therapy;
Left ventricular
dyssynchrony;
ECG-gated SPECT;
Myocardial perfusion imaging
Cardiac resynchronization therapy (CRT) has shown benefits in patients with end-stage heart failure (HF)
(NYHA class III or IV), depressed left ventricular (LV) ejection fraction, and prolonged QRS duration
(.120 ms). However, at least 30% of the patients who meet the above criteria show no response to CRT.
It has shown with echocardiography that the presence of LV mechanical dyssynchrony is an important predictor for response to CRT. However, echocardiography requires expertise to produce reproducible and
reliable results. The recent report from the Predictors of Response to Cardiac Resynchronization Therapy
trial showed that under ‘real-world’ conditions the current available echocardiographic techniques including tissue Doppler imaging (TDI) and myocardial strain-rate imaging are not ready for routine clinical practice to assess LV dyssynchrony. It suggested that there is a need for better standardization and refinements of
the echocardiographic screening tools currently used for the evaluation of LV dyssynchrony. This article
reviews a technique such as phase analysis that allows measuring LV dyssynchrony from conventional electrocardiogram-gated single-photon emission computed tomography myocardial perfusion imaging with no
additional procedure. Its advantages over TDI are its automation, repeatability, and reproducibility that are
very promising in improving prediction of CRT response in HF patients.
Introduction
Heart failure (HF) affects .5 million people in the USA.
Approximately 550 000 new cases are diagnosed annually
and acute decompensated HF accounts for over 1 million
hospital admissions per year.1 The estimated direct and
indirect cost for HF in 2006 is $29.6 billion.2
Cardiac resynchronization therapy (CRT) has shown
benefits in patients with severe HF.3 However, multiple CRT
trials using the conventional selection criteria—end-stage
HF (NYHA class III or IV), depressed left ventricular ejection
fraction (LVEF) (,35%), and prolonged QRS complex on the
surface electrocardiogram (ECG) (.120 ms)—have shown a
significant percentage of patients (20–40%) failing to benefit
from CRT.3–6 It has been recognized that electrical dyssynchrony as determined by QRS duration may not necessarily
represent mechanical dyssynchrony and, therefore, may not
represent the best predictor of CRT response.7–9 Assessment
of LV mechanical dyssynchrony has been attempted with
echocardiography, which shows promising results.10–14
However, the Predictors of Response to Cardiac Resynchronization Therapy (PROSPECT) study recently reported that
under ‘real-world’ conditions the current available echocardiographic techniques including tissue Doppler imaging
* Corresponding author. Tel: þ1 404 712 4024; fax: þ1 404 712 7961.
E-mail address: [email protected]
(TDI) and myocardial strain-rate imaging are not ready for
routine clinical practice to assess LV dyssynchrony.15 The
PROSPECT study suggests that there is a need for better
standardization and refinements of the echocardiographic
screening tools currently used for the evaluation of LV dyssynchrony. One of the major reasons of the unpleasant results
of the PROSPECT trial is that echocardiographic measurement
requires expertise to generate reliable and reproducible
results that are necessary in order to more accurately and
consistently predict CRT response.
Electrocardiogram-gated single-photon emission computed tomography (GSPECT) myocardial perfusion imaging
(MPI) is the most widely used nuclear imaging procedure
for diagnosis and management of coronary artery disease,
which is the most common cause of chronic HF.16 It is
widely available with superb standardization and reproducibility. Recently, a phase analysis technique has been developed to allow GSPECT MPI to assess LV mechanical
dyssynchrony.17 It is a mathematical algorithm that can be
applied to any conventional GSPECT MPI study and requires
no additional acquisition. This technique is very promising
in improving prediction of CRT response. In addition to its
superb automation and reproducibility, the prognostic information obtained from three-dimensional (3D) perfusion
images of the same patient can be very useful in the prediction of CRT response. For example, the presence and
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2008.
For permissions please email: [email protected].
iii102
location of myocardial scar tissue, which has recently been
shown to adversely affect response to CRT,18 may impact
site selection for LV pacing lead placement. In this article,
the phase analysis methodology is reviewed, and its clinical
validations are summarized.
Phase analysis of electrocardiogram-gated
single-photon emission computed tomography
myocardial perfusion imaging studies:
technical essentials
Processing and quantification
Phase analysis has been implemented in the Emory Cardiac
Toolbox (Emory University, Atlanta, GA, USA).19 Figure 1
illustrates its data flow. The input is a GSPECT MPI short-axis
image. Every temporal frame of this image is searched in 3D
to obtain regional maximal counts. These 3D samples can be
displayed as gated polar maps as shown in Figure 1. Once the
regional samples obtained from all temporal frames, the
regional maximal count variation over the cardiac cycle is
obtained. It has been shown that the variation of the
regional maximal counts is nearly proportional to the myocardial wall thickening of the region.20,21 Then, the firstharmonic Fourier function is used to approximate the
regional wall thickening curve to calculate a regional
phase, which is related to the time interval when the
region starts to contract [presumably, onset of mechanical
contraction (OMC)]. Repeating the Fourier analysis for all
regions over the left ventricle, an OMC phase distribution
is obtained and submitted to quantitative assessment of
J. Chen et al.
its uniformity or heterogeneity, i.e. a measure of LV synchronicity. Five quantitative indices (listed in Table 1) have been
used to assess LV dyssynchrony. Normal limits for these
indices have been generated from GSPECT MPI studies of
45 male and 45 female normal subjects.17
Reproducibility
Phase analysis is largely automatic. Intra-observer and
inter-observer reproducibility of this technique has been
evaluated in a recent study using 10 consecutive subjects
with LV dysfunction (LVEF 35%) and 10 normal controls.22
For phase standard deviation and histogram bandwidth,
the intra-observer correlation coefficients were 1.00 and
1.00, and the mean absolute differences between two
reads by the same observer in different occasions were
0.88 and 1.48, respectively. Inter-observer correlation coefficients were 0.99 and 0.99, and the mean absolute differences between two reads by two independent observers
were 2.08 and 5.48, respectively, for phase standard deviation and histogram bandwidth. The superior reproducibility
of phase analysis to echocardiography is a promising advantage that may improve prediction of CRT response, since the
20–40% of the poor CRT outcome is based on echocardiographic results, and in none of these studies, GSPECT MPI
was used.
Temporal resolution
Since GSPECT MPI studies are usually acquired as 8 or 16
frames/cardiac cycle, these data are perceived to have
low temporal resolution. It is important to note that phase
Figure 1 Illustration of using phase analysis to assess LV dyssynchrony. The points in the plots are the regional wall thickening data. The
first-harmonic approximation for 8 or 16 frames/cycle is shown as solid lines. The phase difference between 8 vs. 16 frames/cycle is very
small—0.58 (3608 corresponding to one cardiac cycle), demonstrating that Fourier harmonic approximation improves the temporal resolution
of the phase measurement. The phase polar map shows a significant phase delay (bright region) at the anterior and apical wall. The location
of the phase delay matches well with the perfusion defect shown in the perfusion polar map.
Nuclear imaging
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Table 1 Quantitative indices and their normal limits for
assessment of LV dyssynchrony
Male
Female
Indication
134.5 + 14.3
140.2 + 14.9
Phase SD
14.2 + 5.1
11.8 + 5.2
Bandwidth
38.7 + 11.8
30.6 + 9.6
Skewness
4.19 + 0.68
4.60 + 0.72
19.72 + 7.68
23.21 + 8.16
Peak of the phase
histogram
Standard deviation
of the phase
distribution
Width of the band
including 95% of
the elements in
the phase
distribution
Symmetry of the
phase histogram.
Positive skewness
indicates the
histogram with a
longer tail to the
right of the peak
Peakedness of the
phase histogram.
A histogram with
a higher peak
within a narrower
band has higher
kurtosis
Peak phase
Kurtosis
analysis uses continuous Fourier harmonic functions to
approximate the discrete wall thickening samples. As shown
in Figure 1, the phase difference between 8 vs. 16 frames/
cycle is very small—0.58 (3608 corresponding to one cardiac
cycle), demonstrating that Fourier harmonic approximation
improves the temporal resolution of the phase measurement.
A recent simulation study based on a digital phantom has
shown that in common clinical settings (10 counts/myocardial pixel) phase analysis can detect phase delays using
GSPECT MPI data acquired with 8 or 16 frames/cycle as well
as though it is acquired using 64 frames/cycle but processed
without Fourier analysis.23 This study indicated that the temporal resolution of phase analysis is equivalent to 1/64th
cardiac cycle, when there are enough counts in the image.
Phase analysis of electrocardiogram-gated
single-photon emission computed tomography
myocardial perfusion imaging:
clinical validations
Validation with tissue Doppler imaging
Left ventricular dyssynchrony assessed by phase analysis has
been compared with that assessed by 2D TDI in 75 patients
with HF (NYHA function class III or IV), depressed LVEF
(,35%), and wide QRS duration (.120 ms).24 These patients
underwent 2D TDI and resting GSPECT MPI. The TDI data
were evaluated by consensus by two experienced cardiologists who were blinded to the GSPECT MPI data. Peak systolic velocities and time-to-peak systolic velocities were
obtained from the basal portions of the septal, inferior,
anterior, and lateral wall, respectively. The delay in peak
velocity between the earliest and latest activated segments
was calculated as LV dyssynchrony. Phase standard deviation, histogram bandwidth, histogram skewness, and histogram kurtosis, measured by phase analysis of the GSPECT
MPI data, were compared with LV dyssynchrony measured
by 2D TDI. Good correlations were obtained for phase
standard deviation vs. TDI LV dyssynchrony (r ¼ 0.80,
P , 0.0001) and histogram bandwidth vs. TDI LV dyssynchrony (r ¼ 0.89, P , 0.0001).24
Left ventricular dyssynchrony assessed by phase analysis
has also been compared with LV dyssynchrony measured
by 3D TDI in 40 consecutive patients with end-stage HF
(NYHA class III or IV), depressed LVEF (,35%), and prolonged QRS duration (.120 ms).25 These patients underwent 3D TDI and resting GSPECT MPI. The TDI data were
processed by two experienced cardiologists who were
blinded to the MPI data. Times to peak systolic velocity
(Ts) are obtained from 12 segments based on a 12segment model introduced by Yu et al.26 Then, the standard
deviation of these times (Ts-SD) is calculated as an indicator
of LV dyssynchrony. Correlation analyses showed good correlation for both phase standard deviation vs. Ts-SD (r ¼ 0.74,
P , 0.0001) and histogram bandwidth vs. Ts-SD (r ¼ 0.77,
P , 0.0001). When dividing the 40 patients into two
groups according to Ts-SD (33 vs. ,33 ms), both phase
standard deviation (55.38 + 13.68 vs. 25.18 + 7.68, P ,
0.0001) and histogram bandwidth (1868 + 528 vs. 748 +
248, P , 0.0001) were significantly different between the
two groups.25
These validation studies demonstrate that LV dyssynchrony assessed by phase analysis of GSPECT MPI is comparable to that assessed by TDI. They support the feasibility
of evaluating LV dyssynchrony by GSPECT MPI and its applicability in a clinical setting.
Prediction of cardiac resynchronization therapy
responses
Left ventricular dyssynchrony assessed by phase analysis has
been evaluated to study whether it can predict response to
CRT.27 Forty-two patients with severe HF (NYHA HF class III
or IV), depressed LVEF (,35%), and prolonged QRS duration
(.120 ms) were included. Thirty of the 42 patients were
defined as responders according to improvement greater
than one NYHA HF class after 6-month follow-up, and 12
were defined as non-responders (Figure 2). At baseline
(pre-CRT), there were no significant differences in clinical
characteristics between responders and non-responders
except for the histogram bandwidth and phase standard
deviation, which were significantly larger in responders
when compared with non-responders. As determined by
receiver operating characteristic (ROC) analysis, the
optimal sensitivity and specificity of 70% was obtained for
histogram bandwidth at a cut-off value of 1358, and those
of 74% obtained for phase standard deviation at a cut-off
value of 438. The areas under the ROC curves were 0.78
and 0.81 for histogram bandwidth and phase standard
deviation, respectively, indicating good predictive values.
This study demonstrates that clinical response to CRT is
related to the presence of LV dyssynchrony assessed by
phase analysis of GSPECT MPI studies. The LV dyssynchrony
quantification (histogram bandwidth and phase standard
deviation) can be used to predict response to CRT.
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J. Chen et al.
Figure 2 Example phase analyses in a non-responder (A) and a responder (B) to CRT. Both patients had NYHA functional class III, depressed
left ventricular ejection fraction (LVEF) (,35%), and prolonged QRS duration (.120 ms). Left ventricular dyssynchrony with phase analysis
was not present in the non-responder, but present in the responder. Six month after cardiac resynchronization therapy (CRT), the nonresponder deteriorated in NYHA functional class from III to IV, whereas the responder improved in NYHA functional class from III to II. The
change in LVEF post-CRT was minimal for both patients (non-responder: from 32% to 33%; responder: from 27% to 33%).
Conclusion
Phase analysis is a novel technique to measure LV dyssynchrony and predict response to CRT. It yields comparable
results to TDI, and it appears that it may be superior to
the current mostly echocardiographic techniques available
because of its higher reproducibility, and more importantly,
its potential for integrated assessment of myocardial
ischaemia, infarction, viability, LV dysfunction, and LV
dyssynchrony from the same GSPECT MPI study.
Conflict of interest: J.C. and E.V.G. receive royalties from the
sale of Phase Analysis tool with the Emory Cardiac Toolbox. The
terms of this arrangement have been reviewed and approved by
Emory University in accordance with its conflict-of-interest practice. No conflict of interest is declared for the other authors
(J.J.B., M.M.H., and M.J.B.).
Funding
This work was supported in part by the 2006–2007 American
Society of Nuclear Cardiology Foundation/GE Healthcare
Research Award.
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