Normalization of Abnormal T-Waves During Stress Testing Does Not Identify Patients with Reversible Perfusion Defects

Clin. Cardiol. 30, 403 407 (2007) Normalization of Abnormal T-Waves During Stress Testing Does Not Identify Patients with Reversible Perfusion Defects Henry S. Loeb, M.D., Nicholas C. Friedman, M.D. Department of Cardiology, Edward Hines Jr. Veterans Affairs Hospital, Hines, Illinois; Department of Nuclear Medicine, Loyola University, Stritch School of Medicine, Chicago, Illinois, USA Summary Objective: To determine if T-wave normalization during exercise or dobutamine stress testing identified patients with myocardial ischemia as indicated by reversible perfusion defects. Methods: Exercise or dobutamine stress tests with perfusion scintigraphy were performed in 1,173 patients with abnormal T-waves on their baseline electrocardiograms. The results of perfusion scintigraphy were compared in patients with and without stress-induced T-wave normalization. Results: Only 33 of 270 patients with reversible perfusion defects (12.2%) had T-wave normalization during stress while 76.4% of 140 patients who had T-wave normalization during stress did not have a reversible perfusion defect. Results were similar for patients who did or did not reach 85% of their maximal predicted heart rate, for patients with and without Q-wave infarction on the baseline EKG and for patients who did or did not have ischemic ST-segment depression during stress. Conclusions: T-wave normalization during stress testing has low sensitivity and poor positive predictive value for stress-induced reversible myocardial ischemia. Address for reprints: Henry S. Loeb, M.D. Department of Cardiology Edward Hines Jr. Veterans Affairs Hospital 5th Ave. and Roosevelt Rd. Hines, Il, 60141, USA e-mail: HSL4134@yahoo.com Received: January 29, 2007 Accepted with revision: February 4, 2007 Published online in Wiley InterScience (www.interscience.wiley.com). DOI:10.1002/clc.20111 2007 Wiley Periodicals, Inc. Key words: T-wave normalization, exercise testing, perfusion scintigraphy, dobutamine stress, reversible ischemia Clin. Cardiol. 2007; 30: 403 407. 2007 Wiley Periodicals, Inc. Introduction The present study was undertaken to examine, in a large group of patients undergoing stress electrocardiography along with myocardial perfusion scintigraphy, whether or not T-wave normalization was useful in identifying patients with stress-induced ischemia as determined by reversible perfusion defects. Stress electrocardiography is widely used for detection of ischemia in patients suspected of having coronary artery disease. In patients with a normal baseline EKG horizontal or down sloping ST-segment depression equal or greater than 0.1 mv from baseline during stress is generally considered as a positive response 1 and often indicates the need for additional testing, whereas T- wave inversion alone, if not associated with ST-segment depression, is considered a nonspecific response. However when patients with abnormal T-waves on their resting EKG show normalization of the T-waves during stress the significance with regard to ischemia is less clear. 2 Methods Data was collected on 4,353 consecutive patients undergoing stress electrocardiography and myocardial perfusion scintigraphy between December 1997 and July 2006. This study only included patients (n = 1,173) whose baseline EKG showed abnormal T-waves (flat or inverted T-waves in leads where the T-wave should be upright). Exercise testing was performed on a graded treadmill in 887 patients using the Bruce protocol. Dobutamine infusion was used in 286 patients at increasing infusion

404 Clin. Cardiol. Vol. 30, August 2007 rates from 10 to 40 µg/min with atropine administered as needed to achieve a satisfactory heart rate response. Twelve-lead electrocardiograms were recorded before and every minute during stress. All EKGs were interpreted by a single cardiologist (HL) who had no knowledge of the imaging results. Likewise, interpretation of the imaging results was performed by nuclear medicine physicians who had no knowledge of the EKG findings. T-wave normalization was defined as a flat or inverted T-wave (Fig. 1) becoming upright during or immediately after stress (Fig. 2) in the absence of a new intraventricular conduction defect, which would be expected to alter T-wave polarity. Myocardial perfusion imaging was performed using a one-day rest/stress protocol or two-day protocol, with Tc-99m Sestamibi or Tc-99m Tetrofosmin acquired on a triple head or variable angle dual head gamma camera, using standard acquisition protocols with cardiac gating performed on the post-stress acquisition. SPECT images were reconstructed and realigned into a standard 3-view display without attenuation correction. Radiopharmaceutical dosage, camera step acquisition time and reconstruction filters were adjusted for patient weight. Images were interpreted over the 9-year time period with a variety of software systems, including 4D M SPECT, QGS, Autoquant and vendor specific software. Images were interpreted by one of three board certified nuclear medicine physicians. Imaging results were coded as being normal, showing only a fixed defect, or showing any reversible defect including those showing both fixed and reversible defects. FIG. 1 Data Analysis Continuous variables are expressed as mean ± SD and were compared using the Student t-test. Multiple regression analysis was applied to all 1,173 study patients with the dependent variable being the presence or absence of a reversible perfusion defect. The independent variables were: age, presence of Q-wave myocardial infarction on the baseline EKG, exercise or dobutamine stress, and T-wave normalization, maximal ST-segment depression, maximal heart rate and maximal systolic blood pressure during stress. Categorical variables of sub groups were compared with the chi-squared test. A p-value > 0.05 was considered nonsignificant (NS). Results The patients averaged 64.9 ± 10.5 years of age and 98% were male, reflecting the population served by our Veteran s Affairs Hospital. With exercise, (n = 887) baseline heart rate increased from 73.2 ± 14.8 beats/min to 135.5 ± 20.8 beats/min and systolic blood pressure increased from 137.7 ± 21.0 mmhg to 166.5 ± 25.8 mmhg. A similar hemodynamic response was seen during dobutamine infusion (n = 286) with baseline heart rate increasing from 74.9 ± 15.4 beats /min to 133.9 ± 19.6 beats/min, and systolic blood pressure increasing from 139.2 ± 24.0 mmhg to 164.2 ± 28.0 mmhg. Reversible perfusion defects were observed in 270 patients (23%) of the 1,173 patients included in our study. Of these 270 patients only 33 patients had T-wave normalization during stress for a sensitivity of 12.2%. Baseline 12-lead EKG showing abnormal T-waves in leads I, II, III, avf, and V3 V6.

H. S. Loeb and N. C. Friedman: T-wave normalization and myocardial ischemia 405 FIG. 2 12-lead EKG during exercise showing normalization of the abnormal T-waves in leads II, II, avf and V4 V6 with flattening of the T-wave in lead I. TABLE 1 Multiple regression analysis of all 1,173 patients Dependent variable = reversible perfusion defect during stress Independent variable Age MI on baseline EKG Exercise or dobutamine T-wave normalization Maximal ST depression Maximal heart rate Maximal systolic BP P LCI 0.69 0.03 0.97 0.002 0.007 0.060 0.003 0.141 0.058 0.59 0.054 0.096 0.04 0.002 0.23 0.0006 0.003 0.001 UCI 0.018 0.001 0.0004 predictors of a reversible perfusion defect during stress were the presence of myocardial infarction on the baseline EKG, the maximal heart rate achieved during stress and the extent of ST-segment depression during stress. Neither the type of stress (exercise vs. dobutamine) nor the presence of T-wave normalization during stress were predictors of a reversible perfusion defect. Table 2 shows the frequency of T-wave normalization in patients with and without the predictors of a reversible perfusion defect. As can be seen, the frequency of T-wave normalization was similar in patients who did and did not reach 85% of maximal predicted heart rate, in patients with and without myocardial infarction on their baseline EKG, and in patients with and without 0.1 mv or greater ST-segment depression during stress. Discussion Similarly, of the 140 patients with T-wave normalization only 33 patients a had reversible perfusion defect yielding a positive predictive value of only 23.6%. The determinants of a reversible perfusion defect are shown in Table 1. For all 1,173 patients the independent Our data show that stress-induced T-wave normalization has a very low sensitivity and poor positive predictive value for stress-induced myocardial ischemia, as defined by a reversible perfusion defect.

406 Clin. Cardiol. Vol. 30, August 2007 TABLE 2 Frequency of reversible perfusion defects in patients with and without T-wave normalization during stress TWN No TWN P LCI UCI MHR < 85% predicted 15/53 (28.3) 88/348 (25.3) 0.64 0.10 0.16 MHR => 85% predicted 18/87 (20.7) 150/685 (21.9) 0.80 0.10 0.08 MI on baseline EKG 5/22 (22.7) 48/156 (30.8) 0.43 0.29 0.13 No MI on baseline EKG 28/118 (23.7) 190/877 (21.7) 0.61 0.06 0.10 ST depression => 0.1 mv 3/13 (23.1) 108/320 (33.8) 0.42 0.37 0.16 No ST depression => 0.1 mv 30/127 (23.6) 130/713 (18.2) 0.15 0.02 0.13 Abbreviations: TWN = T-wave normalization, P = probability, LCI = lower confidence interval, UCI = upper confidence interval, MHR = maximal heart rate during stress, MI = myocardial infarction, ST = ST-segment depression during stress. Numbers are as follows: patients with reversible defects/total patients and (percentage of patients with reversible defects). In patients with normal resting electrocardiograms STsegment depression either during spontaneous angina or induced by stress is generally considered suggestive of myocardial ischemia. 1 Unlike ST-segment changes which are related to potential differences during phase 2 of the ventricular action potential, the T-wave reflects potential differences during rapid repolarization (phase 3). T-wave changes during stress are usually independent from ST-segment changes and alone are of little value in identifying patients with myocardial ischemia. 3 However, in patients with abnormal T-waves on their resting EKG, normalization of the T-wave either at rest or during stress has been reported to indicate myocardial ischemia. Noble and coworkers 2 described normalization of inverted T-waves in 38 patients either during spontaneous angina, exercise stress or during isoproteranol infusion. The presence of significant coronary disease was confirmed in all 29 of their patients who underwent angiography. Since the patients reported by Noble all had clinical evidence of myocardial ischemia the specificity of stressinduced T-wave normalization for ischemia could not be determined. However, an earlier study by Daoud 4 suggested that T-wave normalization could be induced by isoproterenol infusion in patients both with and without heart disease. T-wave normalization has been investigated in patients with recent myocardial infarction. Several reports suggest that normalization of T-waves either spontaneously over time 5,6 or during stress 7 11 in leads demonstrating prior infarction is indicative of ischemic but viable myocardium in the peri-infarction region. Elhendy and associates 12 studied 36 patients with non-q-wave infarction and abnormal T-waves at rest. During dobutamine, stress patients having T-wave normalization were significantly more likely to have reversible ischemia than patients without T-wave normalization. Contrary to the above, Hahalis and coworkers 13 studied ST-segment and T-wave changes in 101 patients with Q-wave myocardial infarction who underwent stress testing prior to discharge. Although ST-segment elevation during stress was associated with larger infarcts, neither ST-segment elevation nor T-wave normalization were predictive of viable or ischemic myocardium. Similarly, Kim and associates 14 found no relationship between stress-induced T-wave normalization and myocardial viability in 30 infarct patients who had undergone successful revascularization and stress testing 10 14 days following the infarct. Ho and coworkers 15 studied 119 postinfarct patients using dobutamine stress echocardiography and perfusion scintigraphy. They found ST-segment elevation or T-wave normalization to be associated with poor left ventricular function but not with myocardial ischemia or residual viability. Stress-related T-wave normalization has also been reported to be associated with both increased 16 and reduced 17 risk of future coronary events in patients with unstable angina, or following myocardial infarction. It seems, therefore, that the significance of stress-induced T-wave normalization remains uncertain in patients with established coronary artery disease. The significance of stress-induced T-wave normalization in patients both with and without myocardial infarction has been studied by Frais and Hoeschen. 18 These investigators found T-wave normalization during stress in 22 of 319 consecutive patients being evaluated for chest pain with thallium stress-perfusion scintigraphy. In 12 patients with T-wave normalization the baseline EKG had abnormal T-waves but did not have Q-waves, and none of these patients had a reversible perfusion defect. The remaining 10 patients with T-wave normalization had Q-waves on their baseline EKG and 7 of these patients (70%) also had reversible perfusion defects during stress. However, reversible defects were also found in 34 of 47 pts (72%) who did not have T-wave normalization during stress but had Q-waves on the baseline EKG. In our study, we found the presence of MI on the baseline EKG, a lower heart rate during stress and the presence of ST-segment depression to be predictive of

H. S. Loeb and N. C. Friedman: T-wave normalization and myocardial ischemia 407 reversible perfusion defects. On the other hand, for all of our patients as well as for each of the subgroups, analyzed T-wave normalization was not a predictor of reversible perfusion defects. Similar to what was reported by Frais and Hoeschen the majority of our patients showing normalization of abnormal T-waves during stress did not have reversible perfusion defects. The incidence of reversible defects in our 1,173 patients with abnormal T-waves on the baseline EKG was rather low, being only 23%. Most patients included in our study underwent stress testing because of atypical or infrequent symptoms, equivocal EKG changes on a prior exercise EKG, or increased coronary risk factors. Patients considered to be at high risk usually underwent coronary angiography without first undergoing stressperfusion scintigrapy. Therefore, the patients included in our study should be considered to have been at relatively low risk for having severe coronary disease. Conclusions In conclusion, the data suggests that in a relatively low-risk male population, T-wave normalization during stress can be expected in 10 15% of patients with abnormal T-waves on their baseline EKG, but has both a low sensitivity and poor positive predictive value for reversible myocardial ischemia. Although the mechanisms for T-wave normalization are uncertain approximately half of our patients who had T-wave normalization had normal myocardial perfusion scans suggesting that neither myocardial ischemia nor prior myocardial infarction are necessary for stress-induced normalization of abnormal T-waves. Study Limitations This study was virtually limited to males and thus the results may not be applicable to females. Since this study was retrospective, the presence or absence of abnormal T-waves at rest, as well as the presence or absence of T-wave normalization during stress was based upon a binary (yes/no) code entered at the time of EKG interpretation. It was, therefore, not possible to determine if there were additional features of the T-wave at rest or during stress, which might have a stronger correlation with reversible perfusion defects. Since only relatively low-risk patients undergoing myocardial imaging were included, it is possible that T-wave normalization (either spontaneously or during stress) might be more strongly associated with myocardial ischemia in patients with severe angina, recent MI, or with a markedly abnormal stress EKG. Only 15% of our study patients underwent coronary arteriography within 60 days prior to or following the stress test, and thus we relied on the results of myocardial imaging to identify stress-induced myocardial ischemia. References 1. 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