Equilibrium Radionuclide Angiography in Evaluation of Left Ventricular Mechanical Dyssynchrony in Patients with Dilated Cardiomyopathy: Comparison with Electrocardiographic Parameters and Speckle-Tracking Echocardiography

Abstract

Purpose of the Study
The purpose of this study was to study the role of equilibrium radionuclide angiography (ERNA) in the assessment of left ventricular (LV) mechanical dyssynchrony in patients with dilated cardiomyopathy (DCM), by correlating the findings with electrocardiographic parameters and speckle-tracking echocardiography (STE).

Methods
This was a prospective observational study. A total of 55 patients with a mean age 42.5 ± 11 years (range: 19–61 years) diagnosed with DCM underwent ERNA and echocardiography sequentially. On ERNA, phase images of LV were obtained, and standard deviation of LV mean phase angle (SD LVmPA) was derived to quantify intra-LV mechanical dyssynchrony (ILVD). Similarly, on STE, “dyssynchrony index” was calculated as the standard deviation of time-to-peak systolic circumferential strain (SDCS) of the six mid-LV segments. The cutoff values used to define mechanical dyssynchrony were SD LVmPA >13.2° (or >27.1 ms) and SDCS >74 ms on ERNA and STE, respectively. The results obtained from the two modalities were then compared.

Results
Speckle-tracking analysis could be done on the echocardiographic data of only 42 patients. Paired data from ERNA and STE studies of these 42 patients (26 males and 16 females) were compared, which showed no significant difference in the detection of ILVD (P = 0.125). The two modalities showed good agreement with Cohen's kappa value of 0.78 (P < 0.0001). SD LVmPA and SDCS values showed moderately strong linear correlation (ρ = 0.69; P < 0.0001). No significant association of mechanical dyssynchrony on ERNA or STE was found with QRS duration and with the presence or absence of left bundle branch block. ILVD was also found to be negatively correlated with LV ejection fraction.

Conclusion
ERNA is comparable to STE for the assessment of LV mechanical dyssynchrony.

Full text

88 © 2019 Indian Journal of Nuclear Medicine | Published by Wolters Kluwer - Medknow
Address for correspondence:
Prof. Chetan Patel,
Department of Nuclear
Medicine, Cardiothoracic
Centre, All India Institute of
Medical Sciences, Ansari Nagar,
New Delhi ‑ 110 049, India.
E‑mail: cdpatel09@gmail.com
Access this article online
Website: www.ijnm.in
DOI: 10.4103/ijnm.IJNM_165_18
Quick Response Code:
Abstract
Purpose of the Study: The purpose of this study was to study the role of equilibrium radionuclide
angiography (ERNA) in the assessment of left ventricular (LV) mechanical dyssynchrony in
patients with dilated cardiomyopathy (DCM), by correlating the ndings with electrocardiographic
parameters and speckle‑tracking echocardiography (STE). Methods: This was a prospective
observational study.A total of 55 patients with a mean age 42.5 ± 11 years (range: 19–61 years)
diagnosedwithDCMunderwentERNAandechocardiographysequentially.OnERNA,phase images
of LV were obtained, and standard deviation of LV mean phase angle (SD LVmPA) was derived
to quantify intra‑LV mechanical dyssynchrony (ILVD). Similarly, on STE, “dyssynchrony index”
was calculated as the standard deviation of time‑to‑peak systolic circumferential strain (SDCS)
of the six mid‑LV segments. The cutoff values used to dene mechanical dyssynchrony were SD
LVmPA >13.2° (or >27.1 ms) and SDCS >74 ms on ERNA and STE, respectively. The results
obtained from the two modalities were then compared. Results: Speckle‑tracking analysis could be
doneonthe echocardiographic data ofonly42patients. Paired data from ERNAand STE studiesof
these42patients (26 males and16females) were compared, whichshowednosignicant difference
in the detection of ILVD (P = 0.125). The two modalities showed good agreement with Cohen’s
kappa value of 0.78 (P < 0.0001). SD LVmPA and SDCS values showed moderately strong linear
correlation(ρ =0.69; P <0.0001). No signicantassociationof mechanicaldyssynchronyon ERNA
orSTE was found withQRSdurationand with the presenceorabsence of left bundlebranchblock.
ILVD was also found to be negatively correlated with LV ejection fraction. Conclusion: ERNA is
comparableto STE fortheassessment of LVmechanicaldyssynchrony.
Keywords: Dilated cardiomyopathy, equilibrium radionuclide angiography, mechanical
dyssynchrony, speckle‑tracking echocardiography
Equilibrium Radionuclide Angiography in Evaluation of Left Ventricular
Mechanical Dyssynchrony in Patients with Dilated Cardiomyopathy:
Comparison with Electrocardiographic Parameters and Speckle‑Tracking
Echocardiography
Original Article
Abhinav Singhal1,2,
Bangkim Chandra
Khangembam1,2,
Sandeep Seth3,
Chetan Patel2
1Department of Nuclear
Medicine, Institute of Liver and
Biliary Sciences, Departments
of 2Nuclear Medicine and
3Cardiology, Cardiothoracic
Centre, All India Institute of
Medical Sciences, New Delhi,
India
How to cite this article: Singhal A, Khangembam BC,
Seth S, Patel C. Equilibrium radionuclide angiography
in evaluation of left ventricular mechanical
dyssynchrony in patients with dilated cardiomyopathy:
Comparison with electrocardiographic parameters and
speckle-tracking echocardiography. Indian J Nucl Med
2019;34:88-95.
Introduction
Cardiac resynchronization therapy (CRT)
has now become the standard of
care for drug refractory heart failure
patients.[1,2] The current clinical guidelines
mainly rely on QRS duration derived from
electrocardiogram (ECG) for the selection
of patients for CRT, with wide QRS
morphology (>120 ms) being regarded
as an essential criterion.[3] However, even
afterfollowingthe guidelines, 20%–30%of
patients fail to respond to CRT.[4‑6] Owing
to the high cost of CRT implantation and
possible procedural complications, it is
imperative to search for parameters which
can predict response to CRT with better
accuracy.
The presence of ventricular contractile
dyssynchronyis theoretically considered an
essentialsubstrate,whichcouldbecorrected
by CRT, leading to clinical improvement.
Conventionally, wide QRS duration has
been presumed to be a surrogate for
mechanical dyssynchrony of contractile
function.However,subsequent research has
pointedthat a wide QRS complex may just
be a marker of electrical dyssynchrony and
may not accurately reect the mechanical
dyssynchrony.[7] Emphasis has been
given to indentify the cardiac mechanical
dyssynchrony, which may be a better
predictor of response to device therapy.[8‑10]
Variousimagingtechniqueshavebeenused
to measure mechanical dyssynchrony
This is an open access journal, and arcles are
distributed under the terms of the Creave Commons
Aribuon‑NonCommercial‑ShareAlike 4.0 License, which
allows others to remix, tweak, and build upon the work
non‑commercially, as long as appropriate credit is given and
the new creaons are licensed under the idencal terms.
For reprints contact: reprints@medknow.com
[Downloaded free from http://www.ijnm.in on Thursday, May 2, 2019, IP: 91.234.79.75]

Singhal, et al.: Comparison of ERNA with echocardiography for left ventricular mechanical dyssynchrony
Indian Journal of Nuclear Medicine | Volume 34 | Issue 2 | April-June 2019 89
and response to CRT. These include echocardiography,
cardiac magnetic resonance, equilibrium radionuclide
angiography (ERNA), and gated myocardial perfusion
single‑photonemission computed tomography.[8‑16]
Echocardiography has been used most commonly
for this purpose as cardiologists are most familiar
with this method. Different echocardiography‑derived
dyssynchrony parameters have evolved over time,
with the tissue Doppler imaging (TDI) being the most
widely used technique. However, echocardiography is
largely operator dependent, so reproducibility is limited.
Moreover, data from PROSPECT trial do not support
the use of echocardiography‑derived dyssynchrony
parameters (including TDI) to be used in routine clinical
practice.[15] Speckle‑tracking echocardiography (STE) is
another novel technique which has shown promise in the
post‑PROSPECT era; however, the search for a more
reproducible method of measuring left ventricular (LV)
mechanicaldyssynchrony continues.
ERNA is a well‑established imaging modality to assess
ventricular function and wall motion.[17] Using phase
analysis, ERNA has also been investigated for the
assessmentofdyssynchronous cardiac contraction,anditis
proven to be highly reproducible.[18‑21] Being noninvasive,
highly reproducible, and relatively easy to perform, it
may be one of the most promising techniques to quantify
dyssynchrony.
Theprimary objective of our study was to evaluate ERNA
in the assessment of mechanical cardiac dyssynchrony in
patientsofdilatedcardiomyopathy(DCM)and compare its
resultswith STE.Thesecondaryobjectiveswere to testthe
associationof mechanical synchronyparametersderivedon
ERNAandSTEwithECGparametersofQRSduration and
morphology.
Methods
Fifty‑ve patients with DCM with low ejection
fraction (≤40%) were recruited in the study. Inclusion
criteria were (1) clinical heart failure with LV
ejection fraction (LVEF) ≤40%, (2) duration of
symptoms>1year,(3)age>12years,and(4)sinusrhythm.
Patients with a history of valvular heart disease and
arrhythmias were excluded. ERNA study was successfully
performed in all 55 patients. However, satisfactory
echocardiographic images required for speckle‑tracking
analysiscouldnotbe obtainedin13patients,due tolackof
properacousticwindowforimaging.Thus, 42 STE studies
wereavailablefor comparison withERNA.
Equilibrium radionuclide angiography acquisition and
processing
ERNA studies were done at rest with in vivo red
blood cell labeling with intravenous administration of
0.5–0.9mg(15µg/kgofbodyweight)ofstannouschloride,
followed 10–15 min later by 15–20 mCi (550–740 MBq)
of technetium‑99m pertechnetate. Acquisition was started
10–15 min later with a dual‑head gamma camera (Innia
Hawkeye 4; GE Medical Systems, Waukesha, WI, USA)
ttedwith alow‑energygeneral purposecollimator.Images
were acquired in left anterior oblique view (best septal
view). The projection was gated with the ECG to get 32
frames spanning the cardiac cycle. Images were acquired
in 64 × 64 matrix, with a zoom factor of 1.6; each view
acquiredfor approximately 500–600 kilo counts. The ECG
wasmonitoredcontinuouslyto ensureR‑wavegatingofthe
QRS complex. Elimination of ventricular premature beats
was obtained with a window threshold of 20% around the
meanR–R interval during acquisitionofprojections.
Images were analyzed using commercial
software (XT‑ERNA; GE Medical Systems, Waukesha,
WI, USA). Count‑based LVEF was then computed using
semiautomatic regions of interest (ROI) on two separate
regions (end diastolic and end systolic). ROI were drawn
automatically by the computer with adjustments of border
denition performed by the observer blinded to the state
of conduction. Phase images are computed using the rst
harmonic Fourier transform to display the mechanical
contraction time for all the ventricular pixels of the image
duringone composite cardiac cycle.
Phase image shows the areas of the heart whose change
in activity, on a pixel‑by‑pixel basis, occurs at the same
time. This, in effect, shows the progression of mechanical
systole through the heart over the R–R interval giving
information about the relative timing of contraction of
cardiac pixels, that is, the synchronicity. Phase images
weregeneratedforcardiac regionsusingacontinuouscolor
scale,corresponding tophaseangles from0°to360°.From
these histograms representing the distribution of the pixels
for each ventricle according to their phases, the mean
phaseand itsstandarddeviation werecalculated[Figure1].
Meanphaseangle(mPA)was computed for LVbloodpool
as the arithmetic mean of the phase angle for all pixels in
the corresponding ventricular ROI. The standard deviation
of the mPA of LV blood pool (SD LVmPA) represents
synchronicity of ventricular motion. SD LVmPA can be
expressed in units of degree/angle (°) or time, that is,
milliseconds (ms). Expressing SD of mPA in degrees is
considered more accurate for comparison across different
populations since it negates the effect of different heart
rates(andthus R–R interval) among individuals. However,
both units are analogous to each other and either can be
usedfor statistical analysis withinasample.
To dene intra‑LV mechanical dyssynchrony (ILVD),
we used cutoff values (mean + 2SD of SD LVmPA)
of ERNA which are already established in normal
Indian controls.[22] ILVD was thus diagnosed when SD
LVmPA value was >13.2° (or >27.1 ms), in the study
population.[22] Apart from quantitative analysis, qualitative
[Downloaded free from http://www.ijnm.in on Thursday, May 2, 2019, IP: 91.234.79.75]

Singhal, et al.: Comparison of ERNA with echocardiography for left ventricular mechanical dyssynchrony
90 Indian Journal of Nuclear Medicine | Volume 34 | Issue 2 | April-June 2019
visual assessment of the phase images was also done to
determineLVregionaldyssynchrony.
Speckle‑tracking echocardiography acquisition and
processing
Echocardiography was performed by an experienced
cardiologist in the left lateral decubitus position using
the commercially available equipment (Philips Inc.). Data
acquisition was performed with a 3‑MHz transducer at a
depthof15cmintheparasternalandapicalviews(standard
2‑ and 4‑chamber images). For speckle‑tracking analysis,
standard grayscale two‑dimensional (2D) images were
acquired in the parasternal short‑axis views at the level
of the papillary muscles. All of the images were recorded
with a frame rate of at least 50 fps to allow for reliable
operationof thesoftware(QLab; KoninklijkePhilipsN.V.).
Sector width was also adjusted to ensure that the whole
of the LV wall was included in the acquisition, while at
the same time, recording as narrow a sector as possible to
optimizetemporal resolution.
Ofine analysis was done on all the recordings, using the
vendor provided customized software package (QLab;
Koninklijke Philips N.V.). From an end‑systolic single
frame,ROIwere traced on the endocardial cavity interface
bya point‑and‑clickapproach.Then,anautomated tracking
algorithm followed the endocardium from this single
frame throughout the cardiac cycle. Further, adjustment
of the ROI was performed to ensure that all of the
myocardial regions were included. Next, acoustic markers,
the so‑called speckles, equally distributed in the ROI,
were followed throughout the entire cardiac cycle. The
distance between the speckles was measured as a function
of time, and parameters of myocardial deformation were
calculated. Circumferential strain (CS) was calculated
by dividing the myocardium into six segments, namely,
the mid‑anterior, mid‑anterolateral, mid‑inferolateral,
mid‑inferior, mid‑inferoseptal, and mid‑anteroseptal. The
different segments were color coded, and CS curves were
reconstitutedineachofthesixmid‑LVsegments[Figure2].
Parameters derived from speckle‑tracking
echocardiography
Using peak of the R wave as a reference, time to attain
the peak systolic CS was calculated for each segment. To
identifydyssynchrony,the“dyssynchronyindex” of the LV
was calculated as the standard deviation of time‑to‑peak
systolicCS(SDCS) of thesixsegments.
Tocalculate the upper limit of the normal value of SDCS,
STEwas preperformedon10apparently healthyvolunteers
with no history of cardiovascular symptoms and normal
ECGandroutine echocardiographic parameters. The cutoff
limit(mean+2SD) thus derived to dene ILVDfromSTE
wasSDCS >74 ms.
Each of the 55 patients rst underwent routine
2D echocardiographic examination. However, 2D
speckle‑tracking acquisition was only possible in
42 patients, in whom satisfactory and low‑noise LV
short‑axisimagescouldbeobtainedin theparasternalview.
Statistical analyses
Data are presented as mean with standard deviations or
median with ranges where appropriate. The Chi‑square
test/Fisher’s exact test was used for the comparison
of categorical (qualitative) data between groups. For
Figure 1: Results of Fourier phase analysis on equilibrium radionuclide
angiography study of a control participant showing synchronous
contraction. The phase image (a) and the phase histogram (b) are color
coded based on the phase angle of each pixel. R–R: R–R interval on
electrocardiogram, HR: Heart rate, SD: Standard deviation
ab
Figure 2: (a) Grayscale short‑axis image of the mid‑left ventricle at the
level of papillary muscles in a healthy control participant. Division of
myocardium into six segments is shown. (b) Software‑based strain
measurement by tracking of speckles. Amplitude of the strain is
color coded. (c) Circumferential strain curves of the six segments
traced over the cardiac cycle with the yellow dot placed at the nadir,
that is, peak strain. Standard deviation of the six time‑to‑peak strain
curves is below 74 ms, thus showing synchronous contraction. MA:
Mid‑anterior, MAL: Mid‑anterolateral, MIL: Mid‑inferolateral, MI: Mid‑inferior,
MIS: Mid‑inferoseptal, MAS: Mid‑anteroseptal
ab
c
[Downloaded free from http://www.ijnm.in on Thursday, May 2, 2019, IP: 91.234.79.75]

Singhal, et al.: Comparison of ERNA with echocardiography for left ventricular mechanical dyssynchrony
Indian Journal of Nuclear Medicine | Volume 34 | Issue 2 | April-June 2019 91
continuous variables, the Student’s t‑test/Mann–Whitney
U‑test was applied for comparison between the means
of two groups. Kappa analysis and McNemar’s test were
used to assess intermodality agreement. Pearson’s “r”/
Spearman’s ρ was used to assess the correlation between
quantitative variables where appropriate. Agreement
between representative quantitative measures of the two
imaging modalities was further tested by calculating
Cohen’skappa value and Bland–Altman analysis. P < 0.05
wasconsideredstatisticallysignicant.Allthedataanalyses
were performed using the statistical software packages
SPSS17(SPSS Inc., Chicago, Illinois, USA)andMedCalc
11.3(MedCalcSoftware,Mariakerke,Belgium).
Results
The baseline characteristics of the original sample of
55 patients who underwent ERNA and those of the
subset of 42 patients in whom STE acquisition could be
done for the comparison are summarized in Table 1. The
subset of 42 patients (26 males and 16 females) had a
mean age of 41.2 ± 10.5 years (range: 19–59 years). The
meanLVEF for the entire sample (n= 55) was 28% ± 8%
(range: 15%–40%) and that of the subset (n = 42) was
26%±7.7%(range:15%–40%).Theclinicalcharacteristics
of this subset (n = 42) were compared with the remaining
13 patients in whom STE could not be performed, and
no signicant differences were observed in age and
sex distribution, etiology of DCM, New York Heart
Association class, and presence of left bundle branch
block (LBBB) (P > 0.05 for all comparisons). However,
QRS duration was signicantly shorter (P = 0.01) and
LVEFrelativelybetter(P = 0.02) in patientsinwhomSTE
couldnot be performed.
Intermodality agreement
Since the reference upper limits to label dyssynchrony
for both modalities, that is, STE and ERNA were derived
fromtwoseparatecontrol groups,theirdemographicprole
was compared to the respective patient populations. No
signicantdifferencewasfoundinagedistributionsbetween
patients and STE controls (41.2 ± 10.5 vs. 41 ± 9 years,
P = 0.595) or patients and ERNA controls (42.5 ± 11 vs.
46.2±14.5 years, P = 0.109).
Using the above‑described cutoffs, out of 42 patients,
ILVD was found in 27 (64%) patients on speckle‑tracking
analysis and 31 (74%) patients on ERNA. ERNA identied
LV mechanical dyssynchrony in all 27 patients classied
as having dyssynchronous contraction on STE. The former
additionally detected dyssynchrony in four patients in
whom results of STE were normal. McNemar’s analysis
revealed no statistically signicant difference between
the mechanical dyssynchrony detection by STE and
ERNA (P = 0.125) [Table 2 and Figures 3, and 4]. The
results from the two modalities were further tested by
Cohen’s Kappa test for intermodality agreement. Kappa
value of 0.780 was derived (P < 0.0001), which indicated
goodagreement.
AShapiro–Wilktestshowedthatthequantitativeparameters
of dyssynchrony derived from ERNA (i.e., SD LVmPA)
and STE (i.e., SDCS) were not normally distributed in
the sample (test statistic 0.91; P < 0.05 and test statistic
0.94; P < 0.05, respectively). The association between the
two parameters was therefore tested by Spearman’s rank
correlation test. On analysis, the Spearman’s rho (ρ) value
wasderivedtobe0.690(P<0.0001),indicatingamoderately
strong linear correlation [Figure 5]. Bland–Altman plot
was also constructed to further test the agreement between
the above parameters, and the results are summarized in
Figure 6. The analysis revealed that differences between
almost all the paired measurements were contained within
two standard deviations of difference, indicating acceptable
agreement. Furthermore, a trend was observed that as the
Table 1: Patient characteristics
Clinical characteristics Value (n=55) Value (n=42)
Age(years) 42.5±11
(range:19‑61)
41.2±10.5
(range:19‑59)
Sex
Male 36(65.5) 26(61.9)
Female 19(34.5) 16(38.1)
LVEF(%) 28±8(range:
15‑40)
26±7.7(range:
15‑40)
NYHAclass
II 50(91) 38(90.4)
III 5(9) 4(9.6)
QRSduration(ms) 115±28.5
(range:72‑189)
121.4±30.0
(range:72‑189)
WideQRS(>120) 21(38) 20(47.6)
NarrowQRS(≤120) 34(62) 22(52.4)
LBBB
Present 11(20) 10(23.8)
Absent 44(80) 32(76.2)
DCM
Nonischemic(idiopathic) 43(78) 35(83.4)
Ischemic 12(22) 7(16.6)
Dataarepresentedasmean±SD(median,range),n(%).
LVEF:Leftventricularejectionfraction,NYHA:NewYorkHeart
Association,LBBB:Leftbundlebranchblock,DCM:Dilated
cardiomyopathy,SD:Standarddeviation
Table 2: Contingency table for comparison between
equilibrium radionuclide angiography and
speckle‑tracking echocardiography
ILVD on
ERNA absent
ILVD on
ERNA present
Total
ILVDonSTEabsent 11 4 15
ILVDonSTEpresent 0 27 27
Total 11 31 42
ERNA:Equilibriumradionuclideangiography,STE:Speckle‑tracking
echocardiography,ILVD: Intra‑LV mechanical dyssynchrony,
LV:Leftventricle
[Downloaded free from http://www.ijnm.in on Thursday, May 2, 2019, IP: 91.234.79.75]

Singhal, et al.: Comparison of ERNA with echocardiography for left ventricular mechanical dyssynchrony
92 Indian Journal of Nuclear Medicine | Volume 34 | Issue 2 | April-June 2019
absolutemagnitudeofdyssynchronyincreases,thedifference
betweenSTEand ERNAmeasurementsincreases,indicating
thatinhighly dyssynchronous LVcontractions,eitherERNA
underestimates or STE overestimates the dyssynchrony.The
validation and explanation of this later nding however
require further research in future studies with larger sample
sizes.
Electrocardiogram versus imaging for mechanical
dyssynchrony
Among the study population (n = 55), 21 patients (38%)
had wide QRS (duration >120 ms). Eleven out of
these (20% of total) had LBBB, and two had right bundle
branchblockpattern. The remainingeightpatients(14%of
total) were classied as having nonspecic intraventricular
conduction defects. In patients with wide QRS, the mean
QRS duration was 148 ± 18 ms (range: 122–189 ms). The
relationship of electrical with mechanical dyssynchrony
was compared between wide QRS and narrow QRS group
using both ERNA (n = 55) and STE (n = 42). While
assessed by ERNA, 5 out of 21 patients (20%) with
wide QRS duration on ECG did not show mechanical
intra‑LV dyssynchrony. On the other hand, 21 out of
34 patients (62%) with otherwise narrow QRS showed
intra‑LV mechanical dyssynchrony. The Chi‑square test
did not show a signicant association of QRS duration
and ILVD (P = 0.268). When assessed with STE, again
no signicant association of QRS duration was noted with
ILVD(P= 0.167).
Effect of LBBB on mechanical dyssynchrony was also
assessed using ERNA and STE. Nine out of 11 (82%)
patientswithLBBB showed ILVDon ERNA; however, 28
outof44(64%)patientswithout LBBBalsoshowedILVD.
Figure 5: Scatter plot showing linear correlation between standard
deviation of left ventricular mean phase angle (ms) and standard deviation
of time‑to‑peak systolic circumferential strain (ms). SD LVmPA: Standard
deviation of left ventricular mean phase angle, SDCS: Standard deviation
of time‑to‑peak systolic circumferential strain
Figure 6: Bland and Altman plot for standard deviation of time‑to‑peak
systolic circumferential strain (ms) and standard deviation of left ventricular
mean phase angle (ms). SD LVmPA: Standard deviation of left ventricular
mean phase angle, SDCS: Standard deviation of time‑to‑peak systolic
circumferential strain
Figure 3: (a) A 25‑year‑old patient with left bundle branch block (QRS = 189 ms)
and left ventricular ejection fraction = 20%. Equilibrium radionuclide
angiography based phase image shows signicant dyssynchrony (wide
variation in timing of contraction among pixels on color scale). Phase
histogram is wide, and standard deviation of left ventricular mean phase
angle value is 31°. (b) Speckle‑tracking echocardiography analysis of the
same patient. Standard deviation of time‑to‑peak strain is 166 ms, that is,
higher than the upper limit of normal (see wide scattering of yellow dots)
consistent with intraleft ventricular dyssynchrony. R–R: R–R interval on
electrocardiogram, HR: Heart rate, SD: Standard deviation
ab
Figure 4: (a) A 38‑year‑old patient with QRS = 149 ms (intraventricular
conduction defect) and left ventricular ejection fraction = 38%. In spite
of wide QRS, equilibrium radionuclide angiography shows the absence
of dyssynchrony. Value of standard deviation of left ventricular mean
phase angle is 8°. (b) Speckle‑tracking echocardiography too, done for
the same patient, showing absence of intraleft ventricular dyssynchrony
with standard deviation of time‑to‑peak systolic circumferential strain
value of 63 ms. R–R: R–R interval on electrocardiogram, HR: Heart rate,
SD: Standard deviation
ab
[Downloaded free from http://www.ijnm.in on Thursday, May 2, 2019, IP: 91.234.79.75]

Singhal, et al.: Comparison of ERNA with echocardiography for left ventricular mechanical dyssynchrony
Indian Journal of Nuclear Medicine | Volume 34 | Issue 2 | April-June 2019 93
Overall, no signicant association was found between
the presence or absence of LBBB and ILVD (P = 0.429;
Chi‑square test with continuity correction). Similar results
are found with STE (P = 0.117; Chi‑square test with
continuitycorrection).
We also found that patients with ILVD on ERNA had
lower LVEF (24.3% ±6%; median 23%, range 15%–36%)
compared to patients without ILVD (34.2% ± 7%; median
37.5%,range16%–40%)andthedifferencewasstatistically
signicant (P < 0.001).A moderately negative Spearman’s
correlation(ρ =−0.672)wasobservedbetween SDLVmPA
andLVEF(P < 0.01)[Figure7].
Discussion
ERNA is a well‑established modality for evaluating
both global and regional cardiac functions. It is accurate,
reproducible, and simple to perform. Various studies have
assessed the feasibility of ERNA in assessing mechanical
synchrony and have also validated the accuracy of the
method.[19‑22] However, to make this technique proceed
fromthe bench tothebedside,we compared andcorrelated
ERNA with the modality, the cardiologist is most familiar
with, that is, the echocardiography. To the best of our
knowledge, this is the rst study comparing ERNA and
STEforthe assessment ofLVmechanicaldyssynchrony.
Outof55patientswithnormalsinusrhythminwhomERNA
was successfully performed, adequate parasternal view
echocardiographic recording for ofine speckle‑tracking
analysis was possible in only 42 (76%) patients. This
was attributed to poor acoustic window in the remaining
patients owing to thick chest wall (obesity), rib crowding
artifacts, obstructive airway disease, etc., Ofine speckle
tracking on the images of these patients was visually
found to be inconsistent, with poor reproducibility.This is
consistent with several previous studies that have reported
that lack of adequate imaging window is a limitation of
echocardiography in general, even more relevant when
performing STE which requires images with high spatial
resolution.[23‑25] In comparison, image degradation due to
overlying soft‑tissue attenuation is unlikely during ERNA
acquisition. In a subgroup analysis, we found that among
the clinical characteristics, QRS duration was signicantly
shorterandLVEFrelativelybetterin patientsin whomSTE
could not be performed. This may occur because patients
with coexisting obesity or obstructive airway disease
are more likely to be symptomatic and seek consultation
in heart failure clinic at earlier stages with relatively
preservedcardiacfunction.ILVDwasthus seriallyassessed
by both modalities in the subsample of 42 patients and
the agreement analysis for the detection of mechanical
dyssynchrony showed strong agreement between the two
modalities.
Compared to STE, ERNA identied ILVD in four
additional patients. Visual analysis of the phase images of
thesepatients revealedthattheregion ofdyssynchronywas
conned to the apical/inferoapical region. The signicance
ofthisndingremainsuncertainbutmayreecttheinherent
limitation of 2D nature of speckle tracking which may not
providecoverage ofadequatelongitudinal lengthoftheLV,
while dyssynchrony in itself is a 3D phenomenon.[26,27] 3D
speckle‑tracking technology can overcome the limitations
of2Dsampling.[27]
Inthis study,theQRS duration and LBBB status were not
found to have strong correlation with ILVD. Literature
review shows conicting data on the exact relationship of
QRSdurationwith ILVD.Fauchieret al.[16]reportedhigher
valuesof SDLVmPAinDCMpatients withQRS>120 ms,
while Marcassa etal.[28] reported only a weak correlation
between QRS duration and SD LVmPA (r = 0.51).
However,inthestudiesbyGhio etal.[29] andHaraetal.,[30]
no signicant relation was found between ILVD and wide
QRS. Our study supports the later studies. Although 76%
ofour patients with wide QRS had ILVD,62% of patients
with narrow QRS also have ILVD. Other authors have
reported the presence of ILVD in up to 50% of patients
withnormal QRS duration.[28,31]
Interestingly, not all patients with wide QRS show ILVD.
Previous studies[28‑30] have reported that up to 42% of
patientswithwideQRSmay not have ILVD.In this study,
24% of the patients did not show ILVD despite having
QRS width >120 ms. This percentage is very similar to
the proportion of nonresponders in the various CRT trials,
givingimpetusto the hypothesis thatthepresenceofILVD
maybe a necessary factorbehindtheresponse to CRT.
Ventricular synchrony and function are closely related.
Dyssynchronous contraction may have a signicant
detrimentaleffecton mechanical pumping efciency of the
ventricles. This is reected as reduced global ventricular
systolic function. Studies by several workers in the past
have supported this theory. Fauchier etal.[16] reported in
103 patients with idiopathic DCM that a degradation of
Figure 7: Scatter diagram showing negative correlation between intraleft
ventricular mechanical dyssynchrony and left ventricular ejection fraction.
SD LVmPA: Standard deviation of left ventricular mean phase angle,
LVEF: Left ventricular ejection fraction
[Downloaded free from http://www.ijnm.in on Thursday, May 2, 2019, IP: 91.234.79.75]

Singhal, et al.: Comparison of ERNA with echocardiography for left ventricular mechanical dyssynchrony
94 Indian Journal of Nuclear Medicine | Volume 34 | Issue 2 | April-June 2019
thehemodynamicstatuswasassociatedwith an increase in
ILVD. Among 13 univariate predictors of cardiac events,
the only independent predictors were an increased SD
LV mPA ( P= 0.0004)andanincreased pulmonary capillary
wedge pressure (P = 0.009). Marcassa etal.[28] reported in
130 DCM patients, a signicant nonlinear inverse relation
of LVEF with ILVD (r = −0.68, P < 0.0001) concordant
withourstudy.
CRT, by means of correcting dyssynchrony, may help in
the improvement of LVEF which may be linked with the
overall clinical response. It is pertinent thus to investigate
the parameter of ventricular synchrony which has the
greatestimpact on ventricularfunctionmeasuredasLVEF.
The above ndings suggest that ILVD might be more
important than QRS duration in determining LV function
and the subsequent prognosis and should, therefore, be the
target of resynchronization therapy. The fact that ERNA
has high accuracy and reproducibility in the assessment of
ILVDunderlinesitspotentialapplicabilityintheassessment
of patients with heart failure who are potential candidates
forresynchronizationtherapy.
Conclusion
ERNA as a modality for the assessment of cardiac
mechanical dyssynchrony compares favorably with the
current standard of care echocardiographic technique for
this purpose, that is, STE. The former also overcomes
the inherent limitations of the latter in being operator
independent and thus being more reproducible and also in
beingapplicable to a widersubsetofpatients.
Financial support and sponsorship
Nil.
Conicts of interest
Thereare no conicts ofinterest.
References
1. Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D,
Kappenberger L, et al. The effect of cardiac resynchronization
on morbidity and mortality in heart failure. N Engl J Med
2005;352:1539‑49.
2. Abraham WT, Fisher WG, Smith AL, Delurgio DB, LeonAR,
Loh E, et al. Cardiac resynchronization in chronic heart failure.
NEngl J Med2002;346:1845‑53.
3. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr.
Drazner MH, et al. 2013 ACCF/AHA guideline for the
management of heart failure: A report of the American College
ofCardiology Foundation/AmericanHeartAssociationtaskforce
onpractice guidelines. JAmCollCardiol 2013;62:e147‑239.
4. Fox DJ, Fitzpatrick AP, Davidson NC. Optimisation of
cardiac resynchronisation therapy: Addressing the problem of
“non‑responders”.Heart 2005;91:1000‑2.
5. Reuter S, Garrigue S, Barold SS, Jais P, Hocini M,
Haissaguerre M, et al. Comparison of characteristics in
responders versus nonresponders with biventricular pacing
for drug‑resistant congestive heart failure. Am J Cardiol
2002;89:346‑50.
6. Epstein AE, DiMarco JP, Ellenbogen KA, Estes NA 3rd,
FreedmanRA, GettesLS, et al.ACC/AHA/HRS2008 guidelines
for device‑based therapy of cardiac rhythm abnormalities:
Areport oftheAmerican CollegeofCardiology/American Heart
AssociationTaskforceonpracticeguidelines(Writingcommittee
to revise the ACC/AHA/NASPE 2002 guideline update for
implantationofcardiac pacemakers and antiarrhythmia devices):
Developed in collaboration with the American Association for
Thoracic Surgery and society of thoracic surgeons. Circulation
2008;117:e350‑408.
7. AuricchioA,YuCM.Beyondthe measurementofQRS complex
toward mechanical dyssynchrony: Cardiac resynchronisation
therapy in heart failure patients with a normal QRS duration.
Heart2004;90:479‑81.
8. Pitzalis MV, Iacoviello M, Romito R, Massari F, Rizzon B,
Luzzi G, et al. Cardiac resynchronization therapy tailored by
echocardiographic evaluation of ventricular asynchrony. J Am
CollCardiol 2002;40:1615‑22.
9. MukherjeeA,PatelCD, NaikN,Sharma G,RoyA.Quantitative
assessment of cardiac mechanical dyssynchrony and prediction
of response to cardiac resynchronization therapy in patients
with non‑ischaemic dilated cardiomyopathy using equilibrium
radionuclideangiography.Europace 2016;18:851‑7.
10. MukherjeeA,PatelCD, NaikN,Sharma G,RoyA.Quantitative
assessment of cardiac mechanical dyssynchrony and prediction
ofresponseto cardiac resynchronization therapy in patients with
nonischaemic dilated cardiomyopathy using gated myocardial
perfusionSPECT.Nucl Med Commun2015;36:494‑501.
11. Yu CM, Fung JW, Zhang Q, Chan CK, Chan YS, Lin H, et al.
Tissue Doppler imaging is superior to strain rate imaging and
postsystolic shortening on the prediction of reverse remodeling
in both ischemic and nonischemic heart failure after cardiac
resynchronizationtherapy.Circulation 2004;110:66‑73.
12. Koos R, Neizel M, Schummers G, Krombach GA, Stanzel S,
Günther RW, et al. Feasibility and initial experience of
assessment of mechanical dyssynchrony using cardiovascular
magnetic resonance and semi‑automatic border detection.
JCardiovasc Magn Reson2008;10:49.
13. Chen J, Garcia EV,Folks RD, Cooke CD, Faber TL, TauxeEL,
et al. Onset of left ventricular mechanical contraction as
determined by phase analysis of ECG‑gated myocardial
perfusionSPECTimaging: Development of a diagnostic tool for
assessment of cardiac mechanical dyssynchrony.J Nucl Cardiol
2005;12:687‑95.
14. Chen J, Henneman MM, Trimble MA, Bax JJ, Borges‑Neto S,
Iskandrian AE, et al. Assessment of left ventricular mechanical
dyssynchrony by phase analysis of ECG‑gated SPECT
myocardialperfusion imaging. JNucl Cardiol 2008;15:127‑36.
15. Chung ES, Leon AR, Tavazzi L, Sun JP, Nihoyannopoulos P,
Merlino J, et al. Results of the predictors of response to
CRT(PROSPECT)trial. Circulation2008;117:2608‑16.
16. Fauchier L, Marie O, Casset‑Senon D, Babuty D, Cosnay P,
Fauchier JP, et al. Interventricular and intraventricular
dyssynchrony in idiopathic dilated cardiomyopathy:
A prognostic study with Fourier phase analysis of radionuclide
angioscintigraphy.JAmCollCardiol 2002;40:2022‑30.
17. Strauss HW, Zaret BL, Hurley PJ, Natarajan TK, Pitt B.
A scintiphotographic method for measuring left ventricular
ejection fraction in man without cardiac catheterization. Am J
Cardiol1971;28:575‑80.
18. FraisM,Botvinick E,ShosaD,O’ConnellW,PachecoAlvarezJ,
Dae M, et al. Phase image characterization of localized and
generalized left ventricular contraction abnormalities. JAm Coll
[Downloaded free from http://www.ijnm.in on Thursday, May 2, 2019, IP: 91.234.79.75]

Singhal, et al.: Comparison of ERNA with echocardiography for left ventricular mechanical dyssynchrony
Indian Journal of Nuclear Medicine | Volume 34 | Issue 2 | April-June 2019 95
Cardiol1984;4:987‑98.
19. Vallejo E, Jiménez L, Rodríguez G, Roffe F, Bialostozky D.
Evaluation of ventricular synchrony with equilibrium
radionuclide angiography: Assessment of variability and
accuracy.ArchMedRes2010;41:83‑91.
20. Dormehl I, Burow R, Hugo N, Maree M, Van Zandwijk C,
Van Vuuren C, et al. Phase mapping from left ventricular
radionuclide ventriculograms: Interobserver reliability and
accuracyof the programme.Nucl Med Commun1987;8:805‑13.
21. Toussaint JF, Peix A, Lavergne T, Vicente FP, Froissart M,
Alonso C, et al. Reproducibility of the ventricular
synchronization parameters assessed by multiharmonic phase
analysis of radionuclide angiography in the normal heart. Int J
CardiovascImaging 2002;18:187‑94.
22. Singh H, Singhal A, Sharma P, Patel CD, Seth S, Malhotra A,
et al. Quantitative assessment of cardiac mechanical synchrony
using equilibrium radionuclide angiography. J Nucl Cardiol
2013;20:415‑25.
23. Suffoletto MS, Dohi K, Cannesson M, Saba S, Gorcsan J 3rd.
Novelspeckle‑trackingradialstrainfrom routineblack‑and‑white
echocardiographic images to quantify dyssynchrony and predict
response to cardiac resynchronization therapy. Circulation
2006;113:960‑8.
24. Gorcsan J 3rd, Tanabe M, Bleeker GB, Suffoletto MS,
Thomas NC, Saba S, et al. Combined longitudinal and
radial dyssynchrony predicts ventricular response after
resynchronizationtherapy.JAmColl Cardiol2007;50:1476‑83.
25. DelgadoV,YpenburgC,vanBommelRJ,TopsLF,MollemaSA,
Marsan NA, et al. Assessment of left ventricular dyssynchrony
by speckle tracking strain imaging comparison between
longitudinal, circumferential, and radial strain in cardiac
resynchronizationtherapy.JAmColl Cardiol2008;51:1944‑52.
26. Tanaka H, Hara H, Adelstein EC, Schwartzman D, Saba S,
GorcsanJ3rd, et al. Comparative mechanical activationmapping
of RV pacing to LBBB by 2D and 3D speckle tracking and
association with response to resynchronization therapy. JACC
CardiovascImaging 2010;3:461‑71.
27. Tanaka H, Hara H, Saba S, Gorcsan J 3rd. Usefulness
of three‑dimensional speckle tracking strain to quantify
dyssynchrony and the site of latest mechanical activation.Am J
Cardiol2010;105:235‑42.
28. Marcassa C, Campini R, Verna E, Ceriani L, Giannuzzi P.
Assessment of cardiac asynchrony by radionuclide phase
analysis: Correlation with ventricular function in patients
with narrow or prolonged QRS interval. Eur J Heart Fail
2007;9:484‑90.
29. GhioS,ConstantinC,KlersyC,SerioA,FontanaA,CampanaC,
et al. Interventricular and intraventricular dyssynchrony are
common in heart failure patients, regardless of QRS duration.
EurHeart J 2004;25:571‑8.
30. Hara H, Oyenuga OA, Tanaka H, Adelstein EC, Onishi T,
McNamara DM, et al. The relationship of QRS morphology
and mechanical dyssynchrony to long‑term outcome following
cardiacresynchronization therapy.Eur HeartJ2012;33:2680‑91.
31. BaderH, GarrigueS, LatteS,ReuterS,Jaïs P,HaïssaguerreM,
et al. Intra‑left ventricular electromechanical asynchrony.Anew
independent predictor of severe cardiac events in heart failure
patients.JAmColl Cardiol2004;43:248‑56.
[Downloaded free from http://www.ijnm.in on Thursday, May 2, 2019, IP: 91.234.79.75]