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Prognostic significance of ischemicelectrocardiographic changes during vasodilatorstress testing in patients with normal SPECT images Elizabeth Klodas, MD,a Todd D. Miller, MD,a Timothy F. Christian, MD,a David O.
Hodge, MS,b and Raymond J. Gibbons, MDa Background. Patients with ischemic electrocardiographic (ECG) findings during exercise
stress testing but normal perfusion images generally have a low risk of cardiac death or
myocardial infarction (<1% per year). During vasodilator stress testing, however, the prog-
nostic significance of the combination of normal perfusion images and ischemic ECG changes is
unknown.

Methods and Results. Among 5526 patients who underwent vasodilator stress single photon
emission computed tomography (SPECT), 49 (0.9%) had normal images but ischemic ECG
changes. A unique feature of this population was that 43 (88%) were women with a mean age
of 67
؎ 10 years. Ischemic ECG changes occurred at a mean heart rate of 101 ؎ 15 beats per
minute and persisted for 6.8
؎ 4.7 minutes after termination of drug infusion. During follow-up
of 28
؎ 20 months, cardiac death occurred in 2 patients and nonfatal myocardial infarction in
4 patients. The rate of cardiac death or nonfatal myocardial infarction was 4% at 1 year, 10%
at 2 years, and 14% at 3 years. Of the 12 patients who underwent coronary angiography or
autopsy during follow-up, 11 had multivessel coronary artery disease, indicating that these
patients likely had false-negative SPECT image results. Eight patients required coronary
revascularization.

Conclusions. The finding of ischemic ECG changes with normal SPECT images during
vasodilator infusion is uncommon, occurs primarily in older women, and is associated with a
higher subsequent cardiac event rate than is customarily associated with normal images. (J Nucl
Cardiol 2003;10:4-8.)

Key Words: Vasodilator stress • single photon emission • computed tomography •
electrocardiography • prognosis
modestly worse prognosis (annual risk of cardiac death See related article, p. 87
or myocardial infarction of 1.3%-2.3%).IschemicECG changes during adenosine or dipyridamole infusion Patients with normal exercise single photon emis- occur less commonly than during exercise but when sion computed tomography (SPECT) images generally present are predictive of 3-vessel or left main coronary have an excellent prognosis (annual risk of cardiac death artery disease (CAD) and/or worse prognosis.
or myocardial infarction Ͻ1%),even in the presence Perfusion images in such patients are usually abnormal, of ischemic electrocardiographic (ECG) changes.Pa- confirming the presence of CAD.The prognostic tients with normal vasodilator SPECT images have a significance of ischemic ECG changes during vasodilatorinfusion and normal SPECT images is unknown. This From the Divisions Cardiovascular Diseasesa, and Biostatistics,b Mayo study evaluates the prevalence and prognostic signifi- Clinic and Foundation, Rochester, Minn. Dr Klodas is currently cance of ischemic ECG changes and normal SPECT affiliated with the Center for Diagnostic Imaging, St Louis Park,Minn.
images during vasodilator stress testing.
No external funding was used to perform this study.
Received for publication Dec 10, 2001; final revision accepted June 18, Reprint requests: Todd D. Miller, MD, Mayo Clinic, 200 First St SW, Patients
Gonda 5, Rochester, MN 55905; miller.todd@mayo.edu. Between December 1986 and December 1993, 5526 Copyright 2003 by the American Society of Nuclear Cardiology.
1071-3581/2003/$30.00 patients underwent dipyridamole or adenosine thallium 201 or technetium 99m sestamibi SPECT in the nuclear cardiology Ischemic electrocardiography with normal SPECT images laboratory at the Mayo Clinic, Rochester, Minn. Of these, 49 Table 1. Patient characteristics (n ϭ 49)
patients (0.9%) who had ischemic ECG changes with normalSPECT images formed the study group. Exclusion criteria Variable
included digitalis use, an electrocardiogram showing pacing orleft bundle branch block, or SPECT images with mild fixed defects (thought to represent attenuation). Angina was graded according to the criteria of Diamond.Pretest probability of CAD was estimated with the use of published tables.The resting electrocardiogram was coded as normal or abnormal.
Among the 5526 patients, 1440 had a normal resting electro- Vasodilator Stress Testing
The methods for vasodilator stress testing have been described previously.Patients were instructed not to con- sume caffeine for 12 hours before the test. Dipyridamole (n ϭ 25) was infused continuously for 4 minutes at a constant rate of 0.14 mg ⅐ kg–1 ⅐ min–1. Adenosine (n ϭ 24) was infused continuously for 6 minutes at a constant rate of 140 ␮g ⅐ kg–1 ⅐ min–1. Tl-201, 3 to 4 mCi, or Tc-99m sestamibi, 20 to 30 mCi, was injected intravenously, either 3 to 4 minutes after the termination of the dipyridamole infusion or at 3 minutes (midpoint) during the adenosine infusion. ECG rhythm strips were monitored continuously, and a 12-lead electrocardiogram was obtained at each minute. The stress electrocardiogram wasinterpreted by the physician or nurse supervising the test. An *Numbers are percentages unless otherwise stated.
ischemic ECG response was defined as 1.0-mm or greaterhorizontal or downsloping ST-segment depression 80 millisec-onds after the J point compared with baseline. The magnitude Statistical Analysis
of ST-segment depression was categorized as 1.0 to 1.4 mm, Estimation of event-free survival was completed with the 1.5 to 1.9 mm, 2.0 to 2.4 mm, and 2.5 mm or greater.
Stress SPECT began 10 to 15 minutes after Tl-201 injection and 30 to 60 minutes after Tc-99m sestamibi injec-tion. Resting Tl-201 studies were acquired 3 to 4 hours after the stress study. Patients studied after January 1, 1990, underwentreinjection with 1 mCi of Tl-201 before delayed imaging.
Characteristics
Patients studied with sestamibi underwent rest imaging on aseparate day. SPECT image processing was performed as Clinical variables are summarized in Most previously reported.Stress and rest images were graded by of the patients were women (88% in the study group vs consensus of 2 experienced observers using a 24-segment 44% in the overall population referred for testing, P Ͻ model and a 5-point scale (0, absent uptake; 1, severely .001) who were postmenopausal and not undergoing decreased uptake; 2, moderately decreased uptake; 3, mildly estrogen therapy. Risk factors for CAD and use of decreased uptake; and 4, normal uptake).
antianginal medications were common. Pretest probabil-ity of CAD was estimated to be low in 16% of patients,intermediate in 55%, and high in 29%. One patient had a Follow-up
history of myocardial infarction and five patients had ahistory of coronary angioplasty.
Follow-up was performed by chart review or contact by letter or telephone with patients or their physicians. Significantcardiac events were defined as death, nonfatal myocardial Rest and Stress Electrocardiograms
infarction, or coronary revascularization. Events were con-firmed by review of hospital records and/or death certificates.
The resting electrocardiogram was normal in 26 Deaths were coded as cardiac or noncardiac by a reviewer patients (53%) and showed minor ST-T abnormalities in blinded to other data. The mean follow-up for the study was 28 23 (47%). During stress, 38 patients (78%) had ST- Ϯ 20 months. Of those patients who were alive at follow-up, segment depression of 1.0 to 1.4 mm develop, 7 (14%) 78% had follow-up of at least 1 year.
had 1.5 to 1.9 mm, and 4 (8%) had 2.0 mm or greater.
Ischemic electrocardiography with normal SPECT images (slightly Ͻ1% of patients referred for vasodilatorSPECT) and predominantly affects older women withatypical chest pain. The annual risk of cardiac death ormyocardial infarction in these patients is approximately5%. The general tendency with discrepant ECG andSPECT findings is to rely primarily on the image resultsand to consider the ECG findings as likely representing afalse-positive result. In this particular subset of patients,however, the electrocardiogram appears to identify somehigh-risk patients who escape detection by SPECT.
Prior Studies
Patients with normal exercise perfusion scans, in- Figure 1. Kaplan-Meier plot of survival free of cardiac death or
cluding those with a positive exercise electrocardiogram, myocardial infarction. The risk of cardiac death or nonfatalmyocardial infarction was 4% at 1 year, 10% at 2 years, and have an annual risk of cardiac death or myocardial 14% at 3 years. Thinner lines indicate 95% confidence inter- infarction of less than 1%.In patients with normal vasodilator images, the annual rate is still low butslightly higher, at 1.3% to 2.3%.None of thesestudies analyzed prognosis in the specific subset of These ECG changes occurred at a heart rate of 101 Ϯ 15 patients with ischemic ECG changes and normal images.
beats per minute and persisted for 6.8 Ϯ 4.7 minutes after We did not collect follow-up data on the entire group of 5526 patients who underwent vasodilator SPECT be-tween 1986 and 1993 from whom the study group wasidentified. In a previous study,we identified 225 Follow-up
patients with normal vasodilator SPECT and a normal Eleven patients had significant cardiac events, in- electrocardiogram whose annual risk of cardiac death or cluding 2 cardiac deaths, 4 nonfatal myocardial infarc- myocardial infarction was 2%, significantly lower than in tions, and 5 revascularization procedures. One patient this study’s population of patients with an ischemic died from malignancy. Of the 11 patients with cardiac electrocardiogram (log-rank statistic, P ϭ .02). The events, 9 were women. The annual rate of cardiac death significance of ST-segment changes during pharmaco- or myocardial infarction was approximately 5% logic stress is controversial. Ischemic ECG changes were , and the annual rate of any cardiac event was 9% associated with angiographic 3-vessel and/or left main There were no differences in event rates for patients undergoing dipyridamole versus adenosine similarly identified patients at higher risk in some prog- stress (log-rank test, P ϭ .77 for the endpoint cardiac nostic studiesbut not in others.Analyzing death or myocardial infarction). The magnitude of ST- coronary anatomy in patients with ischemic ECG segment depression (1.0-1.4, 1.5-1.9, and Ն2.0) was changes and normal images is difficult. Few patients with modestly worse in patients with events (73%, 9%, and normal SPECT images are referred for angiography.
18%, respectively) versus those without events (79%, The only practical method of studying these patients is to 16%, and 5%, respectively) (P ϭ .02). Of the 12 patients who underwent coronary angiography or autopsy duringfollow-up, 7 had 3-vessel CAD and 4 had 2-vessel CAD, Potential Explanations for Study Results
consistent with false-negative SPECT studies. Only 1patient had no significant CAD. Of the remaining 36 Balanced hypoperfusion is commonly cited as a patients, 18 (50%) continued to have the same symp- reason for normal images in the presence of 3-vessel CAD. In this study many of the patients with angio-graphic or necroscopic evaluation of their coronaryarteries had 3-vessel disease. Animal models of severe DISCUSSION
coronary stenoses have shown that vasodilators canresult in shifts in the endocardial-epicardial flow ratio, Clinical Importance of Study Results
a finding that conceivably could result in ischemic ECG The combination of normal images and ischemic changes but not a perfusion defect. Magnetic resonance ECG changes during vasodilator SPECT is uncommon imaging may be able to more accurately address this Ischemic electrocardiography with normal SPECT images underwent vasodilator SPECT and coronary angiogra-phy, the magnitude of ST-segment depression was thestrongest among all clinical and stress SPECT variablesfor predicting the high-risk anatomic endpoint of leftmain/3-vessel CAD.
Implications
Patients with ischemic ECG changes but normal SPECT images during vasodilator stress testing are athigher risk than is usually expected for patients withnormal images. Some of these patients probably havenormal coronary arteries and a good prognosis. How-ever, in other patients the ischemic ECG changes appear Figure 2. Kaplan-Meier plot of survival free of cardiac death,
myocardial infarction, or revascularization. The risk of cardiac
to identify patients with prognostically important CAD.
death, nonfatal myocardial infarction, or revascularization was Coronary angiography should be strongly considered in 11% at 1 year, 19% at 2 years, and 28% at 3 years. Thinner these patients to resolve the prognostic uncertainty raised lines indicate 95% confidence intervals.
issue. Another potential but clearly speculative explana- Acknowledgment
tion is that some patients may have abnormal flowreserve that is manifested as an ECG abnormality but not We thank Lisa VanDeWalker and Pam McCabe for as a perfusion defect for unknown reasons. Patients with secretarial preparation of the manuscript and Tammy Hudson insignificant CAD and endothelial dysfunction are at for collection of follow-up data. The authors have indicated higher risk than patients with normal endothelial func- they have no financial conflicts of interest. tion.The preponderance of women in the study groupis not readily explainable. During exercise testing, References
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