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Journal of Nuclear Cardiology
ISSN 1071-3581
J. Nucl. Cardiol.
DOI 10.1007/s12350-013-9765-4
The prognostic value of transient ischemic
dilatation with otherwise normal
SPECT myocardial perfusion imaging: A
cautionary note in patients with diabetes
and coronary artery disease
Rami Doukky, Nathan Frogge, Yohannes
A.Bayissa, Gautam Balakrishnan, Jacob
M.Skelton, Kara Confer, Kalindi Parikh
& Russell F.Kelly
1 23
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ORIGINAL ARTICLE
The prognostic value of transient ischemic
dilatation with otherwise normal SPECT
myocardial perfusion imaging: A cautionary
note in patients with diabetes and coronary
artery disease
Rami Doukky, MD, MSc, FACC,
a,b
Nathan Frogge, MBA,
a
Yohannes A. Bayissa,
MD,
b
Gautam Balakrishnan, MD,
c
Jacob M. Skelton, CNMT, RT(N),
d
Kara Confer,
BS,
a
Kalindi Parikh, MD,
a
and Russell F. Kelly, MD, FACC
a,b
Background. The prognostic implications of transient ischemic dilatation (TID) of the left
ventricle with otherwise normal single-photon emission computed tomography myocardial
perfusion imaging (MPI) remain controversial. Whether this finding may have prognostic
implications only in high-risk populations, such as patients with diabetes or manifest coronary
artery disease (CAD), is uncertain.
Methods. We conducted a prospective cohort study of 1,236 consecutive patients with
normal
99m
Tc-sestamibi MPI, defined as normal perfusion (summed stress score 5 0) and
normal left ventricle volume and function. TID was defined as >2 standard deviations above the
mean of patients with low likelihood of CAD.
Results. The study subjects were followed for 27 ± 9 months. The 76 (6%) patients with
TID had a greater rate of cardiac death or myocardial infarction (MI) [4 (5.3%) vs 11 (0.6%),
P 5 .003] independent of covariates [hazard ratio 5 6.4, P 5 .004]. This finding was entirely
derived from the subgroup of 294 patients with diabetes or CAD [4 (13.3%) with TID vs 1
(0.4%) without TID, P 5 .001] independent of covariates. However, TID was not predictive of
cardiac death or MI among the 941 patients without diabetes or CAD. Furthermore, TID was
not predictive of coronary revascularization.
Conclusions. This study confirms a benign prognosis of TID with otherwise normal MPI in
patients without diabetes or CAD, but cautions against extending this conclusion to high-risk
individuals, particularly those with diabetes or CAD. (J Nucl Cardiol 2013)
Key Words: SPECT
Æ
myocardial perfusion imaging (MPI)
Æ
transient ischemic dilatation
(TID)
Æ
diabetes mellitus
Æ
coronary artery disease (CAD)
Æ
prognosis
Æ
outcome
INTRODUCTION
Transient ischemic dilation (TID), as detected by
myocardial perfusion imaging (MPI) with single-pho-
ton emission computed tomography (SPECT), refers to
enlargement of the left ventricular (LV) cavity in the
post-stress scintigraphic images relative to the resting
images. Multiple studies have demonstrated that when
observed in patients with myocardial perfusion defects,
TID is a marker of severe and extensive coronary
artery disease (CAD) and a predictor of increased risk
for major adverse cardiac events (MACE).
1-4
However,
the prognostic value of TID in the setting of an
otherwise normal study is uncertain, as some studies
have shown increased risk, while others have not.
5-8
It
is possible that the clinical implications of this finding
may differ among patients with varying clinical charac-
teristics. In this study, we investigated the incremental
prognostic value of TID with otherwise normal myo-
cardial perfusion in patients within different clinical risk
strata.
From the Division of Cardiology,
a
Rush University Medical Center,
Chicago, IL; Division of Adult Cardiology,
b
John H. Stroger, Jr.
Hospital of Cook County, Chicago, IL; Department of Medicine
c
Iowa Methodist Medical Center, Des Moines, IA; and Medical
Outsourcing Solutions,
d
Midwest Imaging Consultants, Sycamore, IL
Received for publication May 4, 2013; final revision accepted Jul 24,
2013.
Reprint requests: Rami Doukky, MD, MSc, FACC, Division of Car-
diology, Rush University Medical Center, 1653 W. Congress Pkwy,
Chicago, IL 60612; rami_doukky@rush.edu.
1071-3581/$34.00
Copyright Ó 2013 American Society of Nuclear Cardiology.
doi:10.1007/s12350-013-9765-4
Author's personal copy
Design and Methods
We conducted a prospective cohort study of con-
secutive patients referred for a community-based,
outpatient, clinically indicated SPECT MPI performed
between August 15, 2007 and May 15, 2010 with a
2-year follow-up. Exclusion criteria from outcome analysis
were (1) missing or invalid address, telephone, or social
security numbers and (2) refusal of the referring physician
to provide the investigators access to patients’ health
records in order to conduct clinical follow-up.
Clinical Data
Baseline demographics, referral diagnosis, risk fac-
tors, cardiovascular history, indication for testing, and
medications were tabulated prior to stress MPI. Framing-
ham 10-year global coronary heart disease (CHD) risk
estimates were calculated.
9
History of CAD was defined
as having prior myocardial infarction (MI), coronary
artery bypass grafting (CABG) surgery, percutaneous
coronary intervention (PCI), or angiographically docu-
mented obstructive coronary stenosis. The likelihood of
obstructive CAD was tabulated in patients with ischemic-
equivalent symptoms based on age, gender, and chest pain
type (angina, atypical angina, non-anginal) according to
the Diamond and Forrester criteria.
10
Myocardial Perfusion Imaging
A one-day, rest/stress,
99m
Technetium-sestamibi
(MIBI-MIBI) protocol was implemented, conforming to
the American Society of Nuclear Cardiology guidelines.
11
One of three stress modalities was chosen as clinically
appropriate: exercise Bruce protocol, standard 6-minute
adenosine infusion, or adenosine stress with low-level
exercise.
12,13
All MPI studies were acquired using an
upright acquisition, dual-detector, dedicated cardiac
SPECT camera (MAIcam180
Ò
, Mid-Atlantic Imaging
Services, Inc., Columbia, MD). No attenuation correction
was applied. Images were uniformly processed by a
technologist blinded to clinical and outcome data.
Using QPS/QGS software (Cedars-Sinai Cardiac
Suite; Los Angeles, CA), MPI scans were semiquantita-
tively interpreted by a single expert nuclear cardiologist
(RD) who was blinded to patients’ clinical and outcome
data. On a 17-segment model, the segmental radiotracer
activity in the stress scans was scored according to the
standard 5-point scale (0: normal; 1: mild; 2: moderate; 3:
severe; 4: absent).
14
The segmental scores were summed to
generate summed stress score (SSS). Normal myocardial
perfusion was defined as SSS = 0 (rather than\4) in order
to evaluate the prognostic value of TID with ‘‘perfectly’’
normal perfusion. To ensure the reproducibility of the
semiquantitative assessment of the perfusion data, a
random subset of 151 scans (10% sample) were indepen-
dently interpreted by two board-certified nuclear
cardiologists who were blinded to the clinical and outcome
data. The inter-rater interpretation agreement (normal vs
abnormal) between the main reader and the two control
readers was excellent (kappa = 0.82 and 0.86; P val-
ues \.001). Furthermore, the post-stress LV end-diastolic
and end-systolic volumes were quantitatively tabulated and
indexed to the body surface area. Abnormal LV end-
diastolic volume index was defined as [2standarddevi-
ations (SD) above the mean of the study population with
normal perfusion (SSS = 0) and normal post-stress LV
ejection fraction (LVEF C 50%). We defined a normal
MPI as normal perfusion (SSS = 0), normal post-stress
LVEF C 50%, and normal LV end-diastolic volume index.
Definition of TID
TID values were determined quantitatively from the
ratio of the ungated (static) post-stress LV volume to the
resting LV volume. As no universally accepted definition
of TID for
99m
Tc-99m sestamibi MPI (MIBI-MIBI) with
adenosine stress protocols exists, we determined the
abnormal TID threshold internally for all three stress
modalities used (exercise, adenosine, and adenosine with
low-level exercise). Criteria for TID were prospectively
defined as [2SD above the mean of the study population
with low likelihood of CAD, normal perfusion (SSS = 0),
and normal LV end-diastolic volume index. Low likeli-
hood of CAD was defined, for the purpose of defining TID
threshold, as having no clinical history of diabetes or
CAD, Framingham 10-year global CHD risk \ 10%, and
achieving C85% of the maximum predicted heart rate
(only if exercise stress modality was used).
15
It is important to note that in the study patients, all
of whom had no perfusion abnormality, TID was not
documented in the official clinical report due to the
questionable clinical utility of this finding. Thus, it is
unlikely that TID data impacted the subsequent man-
agement and revascularization decisions in the clinical
setting of this cohort.
Outcome Determination
Subjects were prospectively followed for events of
death from any cause, cardiac death, MI, coronary
angiography, PCI, and CABG surgery. Outcome asses-
sors were blinded to MPI findings. Four methods for
ascertaining outcome events were uniformly applied: (1)
review of patient health records (from July 2011 through
February 2012) at the referring physician offices; (2) two
identical questionnaires mailed to patient residences
6 months apart (July 2011 and January 2012); (3)
Doukky et al Journal of Nuclear Cardiology
TID with normal MPI
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telephone interviews for subjects who did not complete
mail surveys; and (4) Social Security Death Index
(SSDI) search (April 2012) with cause of death deter-
mined from death certificates. MI events were defined
by the clinical determination of the treating cardiologist.
The primary endpoint was a composite endpoint of
cardiac death or nonfatal MI. The secondary endpoint
was coronary revascularization.
Statistical Analysis
We determined that the available sample size of
1,236 patients with 6% TID prevalence, followed for a
mean 27 months, was sufficient to attain 70% power to
detect a statistically significant difference in the rate of
cardiac death or MI using the Fisher’s exact test with a
two-tailed a = 0.05. Power analysis assumed a 0.4%
baseline annual event rate of cardiac death or MI and
6-fold increase in risk associated with TID.
4
The Fisher’s exact test was used to compare
dichotomous variables, which were expressed as fre-
quency (percentage). The relative likelihoods of events
were expressed as odds ratios (OR) with 95% confidence
intervals (CI). The 2-tailed Student’s t test was used to
compare normally distributed continuous variables,
which were expressed as mean ± SD. Cox proportional
hazards model method was used to compare event-free
survival adjusted for Framingham 10-year CHD risk,
exercise modality, and diabetic or CAD status. Although
the mean age was statistically different between the TID
study groups, we chose not to adjust for this covariate
since age is already accounted for in the Framingham
risk estimates. Proportionality of hazards assumption
was confirmed by demonstrating parallel log minus log
survival plots. The origin time in all survival analysis
plots was the MPI date. Stepwise multivariable logistic
regression was used to determine the gain in global chi-
square value as an indicator of the incremental predic-
tive value of sequentially added clinical and imaging
predictors. Two-tailed P values \ .05 were considered
significant. The PASW 18.0 software (SPSS, Inc.,
Chicago, IL) was used for statistical analyses.
The study was approved by the institutional review
board of Rush University Medical Center. A HIPAA
waiver was applied to the chart review aspect of the
methods. Subjects had the right to decline participation
in the study via the mailed questionnaire.
RESULTS
Cohort Definition
We identified 1,707 consecutive subjects referred
for an outpatient, one-day, rest/stress,
99m
Tc sestamibi
SPECT MPI. Among those, 182 subjects met one or
more exclusion criteria: 84 had no valid SSN, 172 were
missing a valid address or telephone number, and the
managing physician of 43 patients declined to collab-
orate with the study. Fourteen (0.9%) subjects were lost
to follow-up, none of whom were identified as deceased
by SSDI. The remaining 1,511 subjects (99.1%) had
complete follow-up.
A total of 275 subjects were excluded: 197 subjects
with SSS C 1; 31 with LVEF \ 50%; and 47 with LV
dilatation [end-diastolic volume index [ 2SD above the
mean (39.4 ± 10.8 mL/m
2
)]. Thus, 1,236 subjects were
included in the final analysis. The baseline characteris-
tics of the cohort were defined in Table 1.
Among the 196 patients who were excluded or lost to
follow-up, there were 162 with normal MPI. Compared to
the patients included in final analysis, those excluded were
younger (mean 54 ± 15 vs 58 ± 12 years, P = .003), but
had similar prevalence of male gender (58% vs 52%,
P = .16), diabetes (22% vs 20%, P = .60), and CAD
(6.2% vs 6.4%, P = 1.0). They also had similar 10-year
FraminghamCHDrisk(12±9%vs11±10%,P = .44)
and TID ratio (0.94 ± 0.135 vs 0.936 ± 0.137, P = .72).
Determination of Abnormal TID Thresholds
The mean TID in the population with low likelihood
of CAD and normal exercise stress MPI was
0.92 ± 0.12. The mean TID in the population with low
likelihood of CAD and a normal adenosine stress MPI
(with or without low-level exercise) was 1.01 ± 0.105,
which was significantly greater than the mean TID
associated with exercise stress MPI (P \ .001). The
mean TID for patients with low likelihood for CAD who
underwent the standard 6-minute adenosine stress and
for those who underwent adenosine infusion with low-
level exercise was nearly identical (1.01 ± 0.105 and
1.01 ± 0.106, respectively; P = .88). Using a
‘‘mean ? 2SD’’ cutoff, abnormal TID thresholds for
exercise and vasodilator stress MPI were, respectively,
defined as C1.16 and C1.22. Based on these values, the
study population was divided into TID? [76 (6%)] and
TID- [1,160 (94%)] groups. The baseline characteris-
tics of the study groups were similar, except that TID?
patients were older and had a higher Framingham
10-year CHD risk, prevalence of diabetes, and likeli-
hood of undergoing a vasodilator stress (Table 1).
Outcomes
The 1,236 study subjects were followed for a mean
of 27 ± 9 months for clinical events and 37 ± 8 months
for mortality (clinical or SSDI). During the entire
follow-up, there were 18 (1.5%) deaths, 5 (0.4%)
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cardiac deaths, and 6 (0.5%) nonfatal MIs. Additionally,
39 (3.2%) subjects underwent coronary angiography with
23 (1.9%) subsequent revascularizations (Table 2). The
rates of coronary angiography performed within 60 days
of the MPI study were similar in the TID? and TID-
groups [2 (2.6%) vs 13 (1.1%), respectively; P = .23].
The TID? group had higher rates of the primary
composite endpoint of cardiac death or MI, as well as
individual endpoints of cardiac death and nonfatal MI
(Table 2; Figure 1). The annualized event rate of death
or MI was 2.4% in the TID? group vs 0.4% in the TID-
group. Likewise, the TID? group had higher rates in
multiple composite endpoints, including death or MI;
death, MI, or revascularization; and cardiac death, MI,
or revascularization (Table 2; Figure 1). The hazard of
cardiac death or MI was significantly greater in the
TID? group [hazard ratio (HR) = 6.4 (CI 1.8-22.4),
P = .004] after adjusting for Framingham risk, stress
modality, and diabetic or CAD status, (Figure 2A). In
this analysis, vasodilator stress was also predictive of the
composite of cardiac death or MI, independent of TID
status and Framingham risk [HR = 5.1 (CI 1.4-18.7),
P = .01], whereas diabetic or CAD status was not
independently predictive (P = .76). On the other hand,
the rates of coronary revascularization (secondary end-
point) were not different between the TID groups
(Figure 1), irrespective of covariate adjustments
(Figure 3A). Only 2 revascularizations (PCIs) occurred
within 60 days of MPI, both in the TID- group.
Moreover, TID provided an incremental prognostic
value beyond Framingham risk, CAD ,and diabetic
status in predicting the composite of cardiac death or MI
and the composite of death or MI, but not coronary
revascularization (Figure 4).
Table 1. Baseline clinical and imaging characteristics
Entire cohort
N 5 1,236
TID1
N 5 76 (6)
TID2
N 5 1,160 (94) P value
TID ratio 0.94 ± 0.135 1.27 ± 0.14 0.92 ± 0.10 <.001
Age (years) 58 ± 12 62 ± 11 57 ± 12 .004
Male gender 642 (52) 36 (47) 606 (52) .48
Framingham 10-year CHD risk* (%) 12 ± 9 14 ± 12 12 ± 9 .047
Likelihood of obstructive CAD
(%) 17 ± 13 18 ± 7 17 ± 13 .33
Exercise stress 1,010 (82) 49 (64) 961 (83) <.001
Known CAD 79 (6) 8 (11) 71 (6) .14
Prior CABG 27 (2) 2 (3) 25 (2) .68
Prior PCI 47 (4) 5 (7) 42 (4) .21
Prior MI 10 (1) 1 (1) 9 (1) .47
Diabetes mellitus 244 (20) 26 (34) 218 (19) .003
Diabetes mellitus or CAD 295 (24) 30 (39) 265 (23) .002
Hypertension 660 (53) 45 (59) 615 (53) .34
Hypercholesterolemia 546 (44) 39 (51) 507 (44) .23
Tobacco use 139 (11) 7 (9) 132 (11) .71
Family history of CAD 449 (36) 21 (28) 428 (37) .11
Antiplatelet 259 (21) 23 (30) 236 (20) .06
Statin 431 (35) 31 (41) 400 (34) .27
b-Blocker 206 (17) 19 (25) 187 (16) .06
ACE-I or ARB 427 (35) 33 (43) 394 (34) .11
BMI (kg/m
2
) 30±6 30±7 29±5 .58
LVEF (%) 64 ± 8 64 ± 9 64 ± 7 .57
LV EDV index (mL/m
2
) 38±9 39±8 38±9 .31
LV ESV index (mL/m
2
) 18±6 18±5 18±6 .43
P values in bold indicate statistical significance.
SD, Standard deviation; CAD, coronary artery disease; CABG, coronary artery bypass grafting; PCI, percutaneous coronary
intervention; MI, myocardial infarction; ACE-I, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker, LVEF,
gated-SPECT, post-stress left ventricular ejection fraction; LV EDV, left ventricular end-diastolic volume; LV ESV, left ventricular
end-systolic volume.
a
Patients without CAD.
b
Patients with chest pain or dyspnea, but no CAD.(
10
).
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Subgroup Analyses
Notably, all four patients who experienced a
primary endpoint event (cardiac death or MI) were
elderly, with premorbid diabetes and/or CAD. Three out
the four patients were men or underwent vasodilator
stress (Table 3). Among patients with diabetes or CAD,
TID was associated with a significantly greater rate of
cardiac death or MI (Table 4; Figure 5B), which was
independent of covariates of Framingham risk and stress
modality (Figure 2B). The annualized event rate of
death or MI among patients with CAD or DM was 5.9%
in the TID? group vs 0.2% in the TID- group.
Furthermore, among patients with diabetes or CAD, TID
was associated with higher rates of nonfatal MI; death
of any cause; death or MI; the composite of cardiac
death, MI, and revascularization; and the composite
endpoint of death, MI, and revascularization (Table 4;
Figure 5B). The greater risk observed in the subgroup
Table 2. Unadjusted risk of adverse car diac events
Entire cohort
1,236
TID1
76 (6)
TID2
1,160 (94)
Odds ratio
(95% CI) P value
Cardiac death or MI
a
11 (0.9) 4 (5.3) 7 (0.6) 9.2 (2.6–32.0) .003
Revascularization (CABG or PCI)
b
23 (1.9) 2 (2.6) 21 (1.8) 1.5 (0.34–6.4) .65
CABG 4 (0.3) 0 (0) 4 (0.3) NA 1.0
PCI 19 (1.5) 2 (2.6) 17 (1.5) 1.8 (0.4–8.0) .33
Cardiac death 5 (0.4) 2 (2.6) 3 (0.3) 10.4 (1.7–63.3) .03
Nonfatal MI 6 (0.5) 2 (2.6) 4 (0.3) 7.8 (1.4–43.3) .048
Death 18 (1.5) 3 (3.9) 15 (1.3) 3.1 (0.9–11.1) .09
Death or MI 24 (1.9) 5 (6.6) 19 (1.6) 4.2 (1.5–11.7) .01
Coronary angiography 39 (3.2) 4 (5.3) 35 (3.0) 1.8 (0.6–5.2) .30
Death, MI, revascularization 43 (3.5) 6 (7.9) 37 (3.2) 2.6 (1.1–6.4) .04
Cardiac death, MI, revascularization 30 (2.4) 5 (6.6) 25 (2.2) 3.2 (1.2–8.6) .03
Dichotomous variables: frequency (%). Continuous variables: mean ± SD.
The event rates reported are for the entire duration of follow-up (mean 27 months).
P values in bold indicate statistical significance.
OR, Unadjusted odds ratio of raw event rates; TID, transient ischemic dilatation; CI, confidence intervals; MI, myocardial infarction;
CABG, coronary artery bypass grafting; PCI, percutaneous coronary intervention.
a
Primary endpoint.
b
Secondary endpoint.
Figure 1. Adverse cardiac events based on TID.
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with diabetes or CAD was primarily derived from the
244 patients with diabetes mellitus (Table 4; Figure
5C). In contrast, among the 941 (76%) patients who
had no history of diabetes or CAD, there was no
significant difference in the adverse event rates based
on TID status (Table 4; Figure 5A), irrespective of
adjustment for covariates (Figure 2C). TID, on the
other hand, was not associated with increased revascu-
larization rate irrespective of diabetes or CAD status
(Figure 3).
Figure 2. Cox proportional hazards curves of survival free of death or MI. (A) Event-free survival
in the entire cohort, adjusted for Framingham 10-year CHD risk [HR = 1.01 (CI 0.95-1.1),
P = .86], vasodilator vs exercise stress modality [HR = 5.1 (CI 1.4-18.7), P = .01], and diabetic
or CAD status [HR = 1.2 (CI 0.3-4.8), P = .76]. (B) Event-free survival in the subgroup with
diabetes or CAD, adjusted for Framingham 10-year CHD risk [HR = 1.0 (CI 0.9-1.1), P = .98]
and vasodilator vs exercise stress modality [HR = 4.1 (CI 0.4-37.9), P = .21]. (C) Event-free
survival in the subgroup without diabetes or CAD, adjusted for Framingham 10-year CHD risk
[HR = 1.0 (CI 0.9-1.1), P = .51] and vasodilator vs exercise stress modality [HR = 6.4 (CI 1.3-
32.0), P = .02]. * There were no events in the TID? group.
Figure 3. Cox proportional hazards curves of survival free of coronary revascularization. (A)
Event-free survival in the entire cohort, adjusted for Framingham 10-year CHD risk [HR = 1.02
(CI 0.97-1.1), P = .47], vasodilator vs exercise stress modality [HR = 1.9 (CI 0.8-4.7), P = .16],
and diabetic or CAD status [HR = 0.86 (0.3-2.5), P = .79]. (B) Event-free survival in the
subgroups with diabetes or CAD, adjusted for Framingham 10-year CHD risk [HR = 1.0 (CI 0.9-
1.04), P = .28] and vasodilator vs exercise stress modality [HR = 0.6 (CI 0.1-3.2), P = .56]. (C)
Event-free survival in the subgroups without diabetes or CAD, adjusted for Framingham 10-year
CHD risk [HR = 1.06 (CI 1.004-1.1), P = .04] and vasodilator vs exercise stress modality
[HR = 3.2 (CI 1.2-9.1), P = .03].
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In this population with normal MPI, the rate of the
primary endpoint of cardiac death or MI among subjects
undergoing vasodilator stress was greater than that of
subjects undergoing exercise stress (3.1% vs 0.4%;
P = .001). Moreover, among the 226 patients who
underwent vasodilator stress, TID was associated with a
greater rate of cardiac death or MI (11.1% vs 2.0%,
P = .04), even after adjusting for Framingham risk,
CAD, and diabetic status [HR = 5.6 (CI 1.24-25.1);
P = .03]. However, the revascularization rates were
similar (Figure 5D). In the exercise stress subgroup, TID
was not associated with an increase in adverse cardiac
events.
DISCUSSION
TID is generally accepted as a marker for severe
multi-vessel CAD and a predictor of poor clinical
outcome when seen in the presence of perfusion
defects.
1-4
Possible mechanisms for TID include
actual ischemia-induced LV dilatation, subendocardial
ischemia with a decrease in subendocardial tracer
uptake leading to an appearance of LV dilatation, and
post-stress stunning of the left ventricle.
15-18
How-
ever, the significance of TID in patients with
otherwise normal perfusion remains the subject of
controversy.
5-7
Figure 4. The incremental prognostic value of TID. Stepwise multivariable logistic regression
models in which outcome predictors were incrementally introduced in a stepwise fashion: 10-year
Framingham CHD risk, coronary disease status, diabetic status, and TID status (present or absent).
The gain in the global chi-square (v
2
) value was used to determine whether each sequentially
introduced predictor provides an incremental predictive value for adverse cardiac events. The
goodness of fit at the final step of the regression models for all three endpoints depicted was
acceptable (Hosmer and Lemeshow test P values C .32).
Table 3. Characteristics of the four patients with TID who experienced cardiac death or MI events
Age—gender Stress type TID DM CAD LVEF Indication Event
Time to
event
80—male Vasodilator 1.25 Yes No C60% Dyspnea Cardiac death 12 months
80—male Exercise
a
1.16 Yes Yes C60% CAD assessment Nonfatal MI 22 months
65—male Vasodilator 1.49 Yes No C60% Preoperative assessment Nonfatal MI 31 months
68—female Vasodilator 1.65 No Yes C60% Preoperative assessment Cardiac death 32 months
TID, Transient ischemic dilatation; DM, diabetes mellitus; CAD, coronary artery disease; MI, myocardial infarction.
a
Duke treadmill score = 8 (low-risk), no ECG changes.
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In this prospective study, we found that TID did
predict clinical outcomes in subjects with TID with an
otherwise normal
99m
Tc-sestamibi SPECT MPI, defined
as normal myocardial perfusion (SSS = 0), LVEF, and
LV volume. To put this finding in perspective, the
relative risk of TID? to the TID- patients (HR = 6.4)
was similar to the relative risk of patients who received
vasodilator stress compared to those who underwent
exercise stress (HR = 5.1). Furthermore, the predictive
value of TID depended on individual patient character-
istics. TID was independently associated with a
multifold increase in MACE (cardiac death or MI) in
patients with diabetes or previously manifested CAD,
but was not predictive in patients without these high-risk
features. In fact, subjects without prior diabetes or CAD
had a very low MACE risk, regardless of TID. Further-
more, TID was also associated with increased MACE
risk among patients who underwent pharmacologic
stress, another clinically high-risk group. We identified
that all four patients who experienced cardiac death or
MI were elderly and three out of four were men
(Table 3). Age and gender, however, are heavily
weighted in the Framingham CHD risk, which was
adjusted for in the Cox regression models (Figure 2).
Thus, the impact of TID on the outcome of patients with
diabetes or CAD seems to be independent of age and
gender. These findings should be interpreted with
caution given the limited number of events observed.
Many physicians interpret a normal MPI as a
‘‘warranty’’ with less than 1% annual event rate.
However, this low event rate is not applicable to all
patients. Hachamovitch et al
19
demonstrated that normal
MPI in clinically high-risk patients (CAD, diabetes,
pharmacologic stress, etc.) is associated with a hard
event rate as high as 1.8% yearly. Therefore, it is
clinically useful if TID can separate clinically high-risk
patients into higher risk groups (5.9% annual event rate
in our study) from those with ultralow risk (\1%)
without TID, hence providing an incremental prognostic
value beyond clinical and other perfusion parameters.
These findings are clinically significant, as identifying
TID with otherwise normal perfusion, in certain high-
Table 4. Unadjusted risk of adverse car diac events: subgroups of CAD and/or diabetes
Diabetes or CAD present
295 (24)
Diabetes or CAD absent
941 (76)
TID1
30 (10)
TID2
265 (90) P value
TID1
46 (5)
TID2
895 (95) P value
Cardiac death or MI
a
4 (13.3) 1 (0.4) <.001 0 (0) 6 (0.7) 1.0
Revascularization
b
1 (3.3) 6 (2.3) .53 1 (2.2) 15 (1.7) .55
Cardiac Death 2 (6.7) 1 (0.4) .03 0 (0) 2 (0.2) 1.0
Nonfatal MI 2 (6.7) 0 (0) .01 0 (0) 4 (0.4) 1.0
Death 3 (10.0) 6 (2.3) .05 0 (0) 9 (1.0) 1.0
Death or MI 5 (16.7) 6 (2.3) .002 0 (0) 13 (1.5) 1.0
Cardiac Death, MI, Revasc 4 (13.3) 7 (2.6) .02 1 (2.2) 18 (2.0) .62
Death, MI, Revasc 5 (16.7) 12 (4.5) .02 1 (2.2) 25 (2.8) 1.0
Diabetes present
244 (20)
Diabetes absent
992 (80)
TID1
26 (11)
TID2
218 (89) P value
TID1
50 (5)
TID2
942 (95) P value
Cardiac death or MI
a
3 (11.5) 0 (0) .001 1 (2.0) 7 (0.7) .34
Revascularization
b
1 (3.8) 2 (0.9) .29 1 (2.0) 19 (2.0) 1.0
Cardiac Death 1 (3.8) 0 (0) .11 1 (2.0) 3 (0.3) .19
Nonfatal MI 2 (7.7) 0 (0) .01 0 (0) 4 (0.4) 1.0
Death 2 (7.7) 1 (0.5) .03 1 (2.0) 14 (1.5) .54
Death or MI 4 (15.4) 1 (0.5) <.001 1 (2.0) 18 (1.9) 1.0
Cardiac death, MI, Revasc 3 (11.5) 2 (0.9) .009 2 (4.0) 23 (2.4) .36
Death, MI, Revasc 4 (15.4) 3 (1.4) .003 2 (4.0) 34 (3.6) .70
The event rates reported are for the entire duration of follow-up (mean 27 months).
P values in bold indicate statistical significance.
TID, Transient ischemic dilatation; MI, myocardial infarction; Revasc, coronary revascularization.
Doukky et al Journal of Nuclear Cardiology
TID with normal MPI
Author's personal copy
risk groups, may prompt the managing physician to
aggressively pursue secondary risk prevention goals and
consider coronary angiography in some patients.
To the best of our knowledge, this is the only large
outcome study of TID in otherwise normal MPI con-
ducted with a one-day
99m
Tc single-isotope (Tc-Tc)
protocol, the most commonly implemented one in
current practice.
Previous Studies
Our findings are similar to those reported in a
landmark study by Abidov et al,
5
who followed 1,560
patients with normal MPI for 2.3 years, of whom 390
had TID, and found an increase in both hard events of
MI or cardiac death and soft events of coronary
revascularization. The concordance between our find-
ings and theirs is not surprising given the similarities in
methods and definition of normal perfusion (SSS = 0),
inclusion of patients with CAD and diabetes, and
identical endpoints. In their study, however, they defined
TID with dual-isotope protocol (rest
201
Tl/stress
99m
Tc-
sestamibi) as C1.21 (the top quartile of the study
population). Moreover, their findings were primarily
driven by revascularization events, whereas our findings
were primarily determined by a higher rate of cardiac
death or MI. In fact, we did not find a significant
difference in revascularization rate between the TID
groups. It is likely that the higher revascularization rate
observed in their study is in part biased by the TID
finding itself.
5
In our study, however, TID with normal
perfusion was not reported to the managing physician,
explaining the non-significant effect of TID on revas-
cularization rate.
More recently, a study by Valdiviezo et al
6
reported
that 28 patients with TID, but otherwise normal MPI,
had a similar CAD burden to a cohort without TID,
suggesting that TID noted on SPECT scans without any
concomitant perfusion defects does not predict multi-
vessel CAD. These investigators also followed a cohort
of 593 patients with TID, but otherwise normal MPI for
an average of 3.6 years and did not find any difference
in survival compared to patients without TID.
6
There are
a few possibilities to account for the discordant results.
In the study by Valdiviezo et al, dual isotope was the
protocol implemented in a majority of the patients. Use
Figure 5. Adverse cardiac events based on TID in study subgroups.
Journal of Nuclear Cardiology Doukky et al
TID with normal MPI
Author's personal copy
of
201
Tl with its poor endocardial definition and low
signal-to-noise ratio could have led to small statistically
random changes in the cavity size on the resting scan,
thus yielding high TID ratios in patients with small left
ventricles.
2,3
Another source for the discrepancy may be
the definition of normal perfusion, which they defined as
SSS \ 4 (rather than 0). This could have increased the
event rate in the TID- group, biasing the study toward
the null. Unlike our study, Valdiveizo et al did not study
cardiac specific endpoints. Thus, noncardiac deaths
could have, in part, offset an association between TID
and cardiac deaths. We do not believe that including
patients with CAD in the present investigation, but
excluding them in the study by Valdiviezo et al, can
explain the difference in the results. Having excluded
CAD patients in the current study would not change its
overall conclusions.
Pathophysiology
There are multiple potential explanations for
increased MACE risk associated with TID among
patients with CAD and diabetes. A frequently cited
hypothesis is ‘‘balanced’’ myocardial ischemia due to
diffuse CAD leading to homogenously reduced radio-
isotope uptake with subendocardial ischemia and/or
post-stress stunning manifesting as TID on the ungated
SPECT images. This hypothesis is supported by data
from Fallahi et al, who demonstrated that, among
diabetics with otherwise normal MPI, TID strongly
correlated with severe and extensive CAD. This corre-
lation was not found among non-diabetics.
8
Furthermore,
a recent report by Petretta et al
20
demonstrated the
incremental value of TID in predicting severe CAD in
diabetics. A second plausible explanation is that TID in
the setting of otherwise normal perfusion is a manifes-
tation of diffuse microvascular disease, which may
render patients more vulnerable to adverse events. A
third reason, which seems most likely, is that the
increased risk observed among patients with diabetes
or CAD is simply a manifestation of Bayes’ theorem,
analogous to the diagnostic value of stress testing in
groups with different disease prevalence. Therefore, TID
identifies a significant increase in MACE risk in a
population with high prevalence of severe CAD and
greater baseline MACE rate despite normal perfusion.
4
In a low-risk group, however, TID fails to predict a
significant increase in MACE rate due to very low
baseline risk.
Methodological Considerations
We prospectively defined abnormal TID ratio as
[2SD above the mean of the study population with low
likelihood of CAD, normal myocardial perfusion, normal
LV function and volume, and achieved 85% of the
maximum predicted heart rate (if exercise Bruce protocol
was used). Although a recent report defined abnormal
TID threshold with rest/exercise stress
99m
Tc-sestamibi
protocol,
15
no published study established a cutoff for
adenosine stress modality. Clearly, exercise stress TID
thresholds are not applicable to adenosine stress.
1,3,21
Therefore, we had to internally define thresholds for all
three stress modalities used in the study, applying
uniform methodology. We defined a TID threshold for
rest/exercise stress
99m
Tc-sestamibi protocol at 1.16,
which is significantly lower than associated with aden-
osine stress (1.22), mirroring a similar observation with
dual-isotope protocols (1.36 and 1.22, respectively).
3,21
It is important to note that defining TID thresholds in the
present study was for the sole purpose of dichotomizing
the cohort into two TID groups. Pending external
validation, these thresholds are not to be used outside
the context of this investigation. Furthermore, the inclu-
sion of the subjects from whom these thresholds were
derived in subsequent analyses may have provided more
optimistic results than would be accomplished if exter-
nally validated TID thresholds were used.
Secondly, this study was designed as an outcome
study. Thus, angiography results were not collected.
However, coronary revascularization events provide an
insight into subsequently identified ‘‘revascularization
anatomy’’ CAD. In this regard, it is unique to the current
study that TID with otherwise normal perfusion was not
noted in the official clinical report. Therefore, it is
unlikely that TID data triggered any of the subsequent
medical or procedural interventions. This proposition
was confirmed as all revascularizations in the TID?
group occurred late ([60 days) post-MPI, suggesting
that clinical events were their trigger. This cohort,
therefore, provides a unique opportunity to evaluate the
unmodified impact of TID with otherwise normal MPI
on a patient’s outcome and subsequent coronary
revascularization.
Limitations
This study is primarily limited by the low number of
events. After all, only 11 cardiac deaths or MI events
were recorded, 4 of which were in the TID? group. This
limitation leaves uncertainty as to the exact expected
event rate associated with TID, which is evident in the
wide CI shown in Figures 1 and 4. Furthermore, the low
number of hard events limited our ability to adjust for
multiple covariates. Despite that, the findings were
significant and consistent with prior reports.
5,8
Thus, the
study cautions from dismissing TID with otherwise
normal perfusion in high-risk groups. Certainly, a
Doukky et al Journal of Nuclear Cardiology
TID with normal MPI
Author's personal copy
dedicated study to evaluate the prognostic value of this
imaging finding in high-risk population is warranted.
CONCLUSIONS
This investigation confirms a benign prognosis of
TID with otherwise normal MPI in patients without
high-risk clinical features such as diabetes or CAD.
However, the study cautions against extending this
conclusion to high-risk individuals.
Conflicts of interest
Rami Doukky served on the advisory board of Astellas
Pharma US and received past funding investigator-initiated
grant support from Astellas Pharma US.
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