Prolonged left ventricular dysfunction following pharmacologic stress myocardial perfusion imaging: Should we be less stunned than in the past?
Prolonged left ventricular dysfunction following pharmacologic stress myocardial perfusion imaging: Should we be less stunned than in the past?
Andrew Van Tosh 0 3
Kenneth J. Nichols 0
0 Reprint requests: Andrew Van Tosh, MD, Noninvasive Imaging Laboratory, From the Research Department, St. Francis Hospital , 100 Port Washington Blvd., Roslyn, NY 11576-1348; J Nucl Cardiol 1071-3581/ $34.00 Copyright 2018 American Society of Nuclear Cardiology , USA
1 Department of Radiology, Donald and Barbra Zucker School of Medicine at Hofstra/Northwell , Hempstead, NY , USA
2 Division of Nuclear Medicine and Molecular Imaging, Northwell Health , New Hyde Park, NY , USA
3 Noninvasive Imaging Laboratory, From the Research Department, St. Francis Hospital , Roslyn, NY , USA
SPECT myocardial perfusion imaging (MPI) with
ECG-gated equilibrium wall motion analysis is the most
utilized non-invasive tool for the diagnosis and
management of coronary disease. It provides precise
localization of coronary stenoses, global left ventricular
(LV) function, regional wall motion, and asynchrony.
Recent analyses indicate that sensitivities for detecting
coronary disease are in the range of 76% to 81%, with
specificities as high as 71%.1 MPI also imparts
significant prognostic information. The extent of perfusion
defects and their degree of reversibility correlate with
adverse coronary events including MI and cardiac
death.2 This applies to MPI performed either with
exercise or pharmacologic stress.
One limitation of SPECT MPI has been that its
sensitivity for identifying multi-vessel coronary disease
(MVD) may be \ 50%.3–5 MVD strongly affects CAD
prognosis and, when accompanied by LV dysfunction, is
a primary indication for revascularization. This finding
has been attributed to several factors.6 The spatial
resolution of SPECT may limit its ability to separate
perfusion defects in neighboring territories, particularly
in small hearts.7 Certain perfusion defects, particularly
of the left main coronary artery, are not well detected on
SPECT MPI, limiting recognition of MVD affecting the
left main.8 Flow-dependent extraction fraction of
radionuclides may blunt regional differences in tracer
uptake at high cardiac outputs achieved in vasodilator
stress. Finally, qualitative or semi-quantitative diagnosis
of coronary disease requires comparison of relative
hypo-perfusion in one territory to a region which
appears normally perfused. In patients with MVD,
regions with ‘‘normal’’ perfusion may still be supplied
by stenotic arteries, resulting in under-diagnosis of CAD
Adjunctive scintigraphic parameters have been used
to improve the identification of MVD on perfusion
imaging. Lung tracer uptake, first quantified as a
lungto-heart ratio on anterior planar Tl-201 images, was
shown to correlate with LV dysfunction and extent of
CAD. The association of increased lung tracer uptake,
increased LV filling pressure, and MVD remains valid
for SPECT with Tc-99m tracers. Transient ischemic
dilation of the LV cavity (TID), caused by LV
enlargement, subendocardial ischemia, or systolic
dysfunction, was initially quantified as the area of the stress/
delayed images on planar Tl-201 studies.9 TID achieved
a 60% sensitivity for MVD (ratio 1.17),10 improving to
70% using an automated method on dual-isotope SPECT
studies. TID also predicts MACE11 and remains an
important prognostic parameter.
Braunwald first defined the concept of stunning in
1982 as a myocardial injury which may persist for up to
several days following an ischemic insult,12 and caused
by abnormal myocardial calcium accumulation or
liberation of oxidizing free radicals.13 Myocardial stunning
on SPECT MPI is evidenced by a decrease in LV
ejection fraction (LVEF) from rest to post-stress images
of [ 5%, based on the variability of gated LVEF
measurements in patients studied at rest on two successive
days.14 The most important determinant of myocardial
stunning is the extent of CAD. Hida et al. found that
myocardial stunning had a sensitivity of 66% for severe
CAD,2 while Druz et al. reported that coronary jeopardy
scores directly correlate with myocardial stunning.15 Its
prevalence varies from 3% to 36%, also dependent on
CAD severity.16 The time course of stunning has not
been established. When image acquisition is
simultaneous with the administration of stress agent, as in PET,
a decrease in LVEF vs rest may be seen immediately,
and correlates with severely reduced perfusion and
coronary steal.17,18 When image acquisition occurs in
the post-stress time period (SPECT), reduced LVEF can
be documented in ischemic patients at 4 minutes of
recovery, becoming less pronounced at nine minutes
through 21 minutes. The prevalence of myocardial
stunning decreases from 15 to 60 minutes of recovery.19
Ischemic LV dysfunction begins early after stress, with a
variable time course. However, the precise time
intervals for assessing myocardial stunning post stress have
not been defined.
The presence of ‘‘reversible’’ regional wall motion
abnormalities (RWMA), present on post-stress but not
rest imaging, has also been used to identify severe CAD
or MVD. Some patients decrease LVEF from rest to
stress, but do not meet the 5% criterion established by
Johnson.14 Worsening RWMA determined qualitatively
was specific for CAD and had a 90% positive predictive
value for severe stenoses and three vessel CAD.4,20
Reversible RWMA is prognostically important, and was
the strongest predictor of MACE in patients without MI,
in the study by Petix et al.21 RWMA may be a more
sensitive predictor than a DLVEF of 5% for identifying
severe CAD or predicting cardiac events.
Included in the approaches to assessing RWMA by
scintigraphic imaging is the quantification of LV wall
thickening (WT). The physical principles underlying the
use of LV WT, and the change in segmental WT from
rest to stress, were first described by Hoffman. Using
PET data,22 he noted that the partial volume effect—
decreased counts for structures smaller than twice the
spatial resolution of an imaging device—can be used to
measure myocardial wall thickening by way of
increasing myocardial counts from diastole to systole.
As demonstrated by Galt et al.,23 the typical 1-cm
transaxial spatial resolution of SPECT imaging lends
itself well to measure myocardial wall thickening, as
CMRI data demonstrate that the myocardial wall
thickness is typically 1 cm at diastole,24 so that the
change in maximum regional myocardial counts should
be adequately modeled as a linear relationship to the
change in myocardial wall thickness.25,26 Wall
thickening may be measured qualitatively, or by using
automated quantified algorithms. Visual wall thickening
analysis was used by Bestetti et al. to evaluate 138
patients with CAD. Wall thickening scores were
significantly higher (more abnormal), in patients with more
severe angiographic disease.27 Automated algorithms to
evaluate wall thickening were described by Germano
et al. who compared a wall thickening algorithm derived
from phantoms with qualitative visual assessment of
wall ‘‘brightening’’ in 79 patients with varying LVEF.
Concordance was 90%.28 Validity of these assumptions
and the limits of precision with which WT can be
measured by gated SPECT have been validated directly
against cardiac MRI.29 The QGS algorithms measure
wall thickening by tracking the endocardial and
epicardial borders encompassing the myocardial counts, while
incorporating count increases via the partial volume
effect with shape tracking, and constraining the overall
computed myocardial mass to be constant throughout all
segments of the R-R interval used to acquire the gated
SPECT data.30 Thus, regional WT values are among the
many parameters that are quantifiable by gated SPECT,
and additional features can be derived.
In the current issue of the Journal, Bestetti et al.
evaluate the utility of using change in wall thickening
from rest to stress as a marker of myocardial stunning
and severe CAD in 52 patients undergoing dipyridamole
Tc-99m stress MPI using a 2-day protocol. All patients
had inducible ischemia (SDS [ 5) and coronary
angiography within three months showing at least one
major vessel with [ 70% stenosis. QGS/QPS algorithms
were used to generate standard relative perfusion scores,
wall motion, LV volume, and LVEF. Automated wall
thickening SSS, SRS, and SDS were generated. The
principle results were that 60% of patients had MVD,
and LVEF decreased 2.4 units, and WT-SDS increased
(worsened) by 3.97. Patients with severe ischemia
(SDS [ 8) had significantly higher WT-SDS than those
with moderate ischemia (SDS 5 to 7), but DLVEF did
not differ. Regression analysis showed a moderate
correlation between WT-SDS and perfusion SDS and
The study is important in its attempt to establish the
parameter of wall thickening (rest vs stress) as an
analogue for myocardial stunning. In their hands WT-SDS
appears to be a more sensitive marker of CAD than
DLVEF, and changes significantly even when DLVEF
remains static. Among the positive aspects of this study
are that there were angiographic data establishing the
extent of CAD, and myocardial perfusion SDS and
WTSDS values were obtained quantitatively by automated
algorithms,31 rather than subjectively.
The changes in wall thickening noted in the study
were significant, but modest: 3.97 for the patient cohort
as a whole, and 5.97 for patients with severe ischemia.
In the study of Xu et al., the variability of wall
thickening scores was 5%, within the same order of
magnitude of as the difference in WT in moderate vs
severe ischemic patients in the present study.32
This limitation in measurement precision
contributes to the difficulty in appreciating the importance
of the results, but there are additional factors as well.
First, the number of patients in the two subgroups,
moderate vs severe ischemia, is not given. Whether
there was sufficient sample size to be reliable or
meaningful is uncertain, a problem that could have been
addressed with power analysis.
Second, the study fails to establish the authors’ own
variability of the WT parameter, such as was performed
in the study of Johnson et al.14 This could have been
accomplished by reporting the results of WT-SDS in a
control group without ischemia or with mild ischemia.
Alternatively, a test/re-test protocol could have been
carried out in a small subgroup of the cohort. Such
analyses would have provided a gauge of the magnitude
of noise in the data and an indication of the limits of
WT-SDS measurement precision. Also, in comparing
WT-SDS among groups, the paired t test was applied,
but this would only have been valid if the distribution
was normally distributed. Otherwise, the Mann-Whitney
test should have been applied, and the significance of the
results might have been affected.
Third, the study leaves unanswered the question of
what wall thickening criteria are to be used to define
myocardial stunning. In part, this is due to the lack of
information on measurement reproducibility, as noted
above. However, the authors used a regression equation
(Figure 1A) to indicate that a WT-SDS score of 10 was
required to cause a DLVEF of - 5%, suggesting that
these parameters be considered equivalent. Inspection of
the graph data, though, reveals at least 6 to 7 patients
with WT-SDS \ 10 had DLVEF decrease of more than
5%, invalidating this concept. The authors do not relate
WT-SDS to coronary anatomy, presumably because of
the small numbers involved, but this would have been
another mechanism with which to separate limits of
normal and abnormal.
When myocardial stunning was originally described
on gated SPECT data by Johnson, et al,14 a prevalence
of 36% of patients was reported. However, over the last
two decades, changes in practice patterns and referral
bias have led to a reduction in the percentage of
abnormal and severely abnormal SPECT MPI studies
seen in most laboratories, so the expected prevalence of
stunning would now be less. The current paper does not
specifically detail how many patients would fulfill the
DLVEF decrease of 5%. Estimating from Figure 1A, the
number is approximately 13 to 14, for a prevalence of 25
to 27%, less than previously, but within a similar range.
Requiring the subjects to have a perfusion SDS [ 5 has
resulted in a higher risk group than most laboratories’
current referral populations. The true prevalence of
stunning in a laboratory population typical of 2018,
whether defined by DLVEF or WT-SDS, will need
further study in a non-selected group.
The pathophysiology of patients with myocardial
stunning, particularly following vasodilator stress, may
be further characterized using rest-stress PET perfusion
imaging. The gated list mode stress data for an 82Rb
PET protocol are acquired, in their entirety,
simultaneous with peak pharmacologic stress. Doing so has shown
that global and regional LV function changes during
stress can be related to abnormal global and regional
myocardial blood flow, flow reserve, and coronary
resistance.33 Changes in LV asynchrony, quantified as
the phase of regional wall contraction, correspond to
quantified arteriographic findings.34
The advent of newer solid-state detectors that
acquire data from 180 simultaneously, and that have
count sensitivities 3 to 5 greater than those of
conventional Anger detectors,35 enables continuous data
collection over 30 to 60 minutes, which could then be
re-binned into sequential time segments during and after
pharmacologic stress. By these means, the time course
of change in LV function and myocardial stunning may
be defined in greater detail, documenting the sequence
by which a patient’s ventricular function transforms
back to a resting state. The study of Brodov et al.
examined more precisely the time sequence of ischemic
myocardial dysfunction using solid-state technology.36
Fifty patients underwent regadenoson rest/stress MPI.
Two-minute post-stress acquisitions were performed at
four minute intervals beginning one minute after stressor
and isotope injection. Patients with significant ischemia
had a drop in LVEF of 4.6% at 5 through 9 minutes,
gradually returning toward normal at 21 minutes. Those
with mild or no ischemia had increased LVEF. This pilot
study was the first to examine in this degree of detail the
time course of post-stress LV functional changes.36
Further studies need to be performed to evaluate
relationships to coronary anatomy, and to regional
function and asynchrony, if adequate signal-to-noise
ratios can be obtained. Such data would provide a
clearer picture of the prevalence and time course of
transient myocardial stunning, potentially enabling more
refined risk stratification of patients.
Andrew Van Tosh serves as a consultant to Astellas
Pharma Global Development, Inc; Kenneth Nichols
participates in royalties from Syntermed, Inc.
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