Exercise Thallium Testing in Ventricular Preexcitation

STEPHEN ARCHER, MD, CHARLES GORNICK, MD, FRANK GRUND, MD, REX SHAFER, MD, and E. KENNETH WEIR, MD

Ventricular preexcitation, as seen in Wolff -Parkin- son-white syndrome, results in a high frequency of positive exercise electrocardiographic responses. Why this occurs is unknown but is not believed to reflect myocardial ischemia. Exercise thallium test- ing is often used for noninvasive assessment of cor- onary artery disease in patients with conditions known to result in false-positive electrocardiograph- ic responses. To assess the effects of ventricular preexcitation on exercise thallium testing, 8 men (aged 42 f 4 years) with this finding were studied. No subject had signs or symptoms of coronary ar- tery disease. Subjects exercised on a bicycle er- gometer to a double product of 28,000 f 2,000 (I!C standard error of mean). All but one of the subjects had at least 1 mm of ST-segment depression. Tests were terminated because of fatigue or dyspnea and no patient had chest pain. Thallium test results were

abnormal in 5 patients, 2 of whom had stress de- fects as well as abnormally delayed thallium wash- out. One of these subjects had normal coronary ar- teries on angiography with a negative ergonovine challenge, and both had normal exercise radionu- elide ventriculographic studies. Delayed thallium washout was noted in 3 of the subjects with ventric- ular preexcitation and normal stress images. This study suggests that exercise thallium testing is fre- quently abnormal in subjects with ventricular preex- citation. Ventricular preexcitation may cause dys- synergy of ventricular activation, which could alter myocardial thallium handling, much as occurs with left bundle branch block. Exercise radionuclide ven- triculography may be a better test for noninvasive assessment of coronary artery disease in patients with ventricular preexcitation.

(Am J Cardiol 1987;59:1103-1106)

V entricular preexcitation, as seen in Wolff-Parkin- son-white (WPW) syndrome, is known to result in a high frequency of positive exercise electrocardio- graphic results when standard criteria are used to evaluate exercise-associated ST-segment depression1 These positive results are not known to be predictive of coronary artery disease and have been assumed not to reflect myocardial ischemia. Exercise thallium test- ing is often used in noninvasive assessment of coro- nary artery disease in conditions known to cause false- positive exercise responses. To our knowledge, in no prior reports has exercise thallium testing been used to assess ischemic heart disease in patients with ventricu- lar preexcitation. The observation of a patient with WPW syndrome who had chest pain, a positive exer- cise thallium response (Fig. 1) and normal coronary angiographic findings (including a negative response to ergonovine challenge] stimulated a prospective study of exercise thallium testing in patients with ven- tricular preexcitation.

Methods All electrocardiograms recorded between 1980 and

1986 at the Minneapolis Veterans Administration Medical Center that revealed ventricular preexcita- tion were found by computer search and the original diagnosis was confirmed using standard diagnostic cri- teria.” Sixteen patients were found to have ventricular preexcitation on 1 or more U-lead electrocardiograms. The patients were informed about the experimental protocol, which had been approved by the human studies committee of the Minneapolis Veterans Ad- ministration Medical Center.

1103

Inclusion criteria: Patients 20 to 60 years old were eligible for inclusion in this study provided they had evidence of ventricular preexcitation on electrocar- diogram and gave informed consent for the study.

From the Veterans Administration Medical Center, Minneapo- lis, Minnesota. This study was support by an American College of Chest Physicians Fellowship, Park Ridge, Illinois, and the Veterans Administration, 54th Street and 48th Avenue South, Minneapolis, Minnesota. Manuscript received October 14,1986; revised manuscript received and accepted December 29, 1986.

Exclusion criteria: Exclusion criteria included evi- dence of the following conditions after careful assess- ment of the patient’s history, physical examination and echocardiogram: angina, coronary artery disease, his- tory of myocardial infarction, mitral valve prolapse, left bundle branch block, congestive heart failure, id- iopathic hypertrophic subaortic stenosis, aortic steno- sis and left ventricular hypertrophy.

Address for reprints: E. Kenneth Weir, MD, Veterans Ad- ministration (lllc], 54th Street and 48th Avenue South, Minne- apolis, Minnesota 55417.

Protocol: Eight patients participated in this study and underwent the following assessment: history, physical examination, Z-dimensional and M-mode echocardiography, electrocardiography, chest roent- genography, and complete blood count, serum glucose,

1104 EXERCISE THALLIUM TESTING AND VENTRICULAR PREEXCITATION

FIGURE 1. Exercise thallium study of subject 1, which shows stress redistribution between the left panel (acquired immediately after exercise) and middle panel (acquired 3 hours later). The rig/H panel shows the computer’s graphic reconstruction of the defect.

electrolyte, cholesterol and triglyceride determina- thallium handling bv senaratinn the left ventricle into tions. The subjects, all of whom were fasting, then 60 segments (radii). Each segment originates from the underwent exercise thallium testing. The tests were center of the left ventricle and has a base of 6’. A stress done using the protocol of Garcia,3 Maddahi4 and co- defect was defined as one in which thallium uptake in workers. Patients performed bicycle ergometry while at least 3 contiguous sections (encompassing a total of seated. An electrocardiogram and blood pressure 18O) fell at least 2% standard deviations below the were recorded every 2 minutes during the protocol. normal values included in the Cedars-Sinai MDS-A2 Exercise was begun at 50 W and gradually increased to software package. Comparison with the normal popu- 200 W as tolerated. At peak exercise, 2.6 f 0.1 mCi of lation data in this program was matched for projection thallium-201 was injected into the left antecubital vein and time of acquisition. A delay of washout was simi- and then the intravenous catheter was flushed with 10 larly defined as being present when 3 or more contigu- ml of saline solution. No extravasation of thallium oc- ous sections (18’) had a rate of thallium washout more curred in any subject. Exercise was continued for 60 than 2% standard deviations below normal values. For more seconds. Images were acquired within 5 to 10 the test to be interpreted as abnormal, 2 or more 18O minutes of injection using a 128 X 128 byte mode ma- abnormalities had to be identified. All subsequent ref- trix. The MDS-A2 system [using the Cedars-Sinai erences to abnormal washout or stress defects are quantitative software for interpretation of thalli- based on the occurrence of 2 or more 18’ abnormali- um-201 myocardial images] was used for quantitative ties. Exercise radionuclide ventriculography was per- analysis of stress and delayed acquisitions. Details of formed in subjects who had stress defects using tech- this commercially available program have been de- netium-99rn labeling of red blood cells, as previously scribed.3-5 Stress images were acquired sequentially describede6 The exercise radionuclide ventriculo- (10 minutes/view) in the anterior, 45O left anterior graphic response was considered normal if the rest oblique and 85O left anterior oblique projections, De- ejection fraction was 50% or more and increased more layed imaging was done 3 to 4 hours after injection by than 5% with exercise with no evidence of wall motion the same protocol. The computer assesses myocardial abnormalities.

TABLE I Ventricular Preexcitation and Abnormal Exercise Thallium Test Results

Pt W

Location of Bypass Tract

54’ Right lateral SD, DW 59 Left paraseptal SD, DW 54 Right lateral DW 35’ Right lateral DW 37 Right lateral DW 41 Left lateral Normal 25 Right posterolateral Normal 34 Left lateral Normal

Stress Abn. Pattern of Double Product

Thallium Activation on Rest/ Test Echo (S,P,N,I)+ Exercise

11,000/19,000 11 1 mmlV, 8,400/22.000 7 1 mmlV,

10,000/20,000 6 2 mm/V, 9,100/26.000 10 2 mm/V,

13,000126,000 5 2 mm/V, 11.000/35,000 8 2 mm/V, 11,000/30,000 11 3 mm/V, 10,000/26,000 9 Normal

EX.

Time ECG EX. HR

ST Depression Nucleotide (beats/min) Lead VCG Rest/f%

Normal Normal

Normal

60/105 60/130 721122 581132 601135 68/145 67/160 801165

*Patient also had normal coronary angiogram with negative ergonovine challenge. tSite of abnormal pattern of activation on echocardiography (M-mode). fDiffuse abnormalities are those involving 3 or more of the following myocardial segments: inferior, apical, anterior, septal and posterior. DW = delayed washout of thallium; Ex. = exercise; HR = heart rate: I = inadequate study; N = no abnormality of activation; P = posterior wall; S =

septum: SD = stress defect; VCG = ventriculogram.

May 1, 1987 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 59 1105

Statistics and test analysis: All values are ex- pressed as mean f standard error of the mean. Inter- pretation of the Z-dimensional and M-mode echocar- diograms as well as electrocardiographic localization of the accessory pathways was done by personnel blinded to the results of the exercise thallium studies. The technique of electrocardiographic localization of accessory pathways using the initial 40 ms of delta wave vectors has been described.;JJ Thallium images were assessed by 2 physicians visually and also by using quantitative computer analysis.

Results The results are summarized in ‘Table I. Mean age of

the 8 participants was 42 f 4 years (range 25 to 59). None had a history of coronary artery disease and all had normal echocardiographic findings (except for septal and posterior wall activation abnormalities at- tributable to preexcitation of the ventricle by the ac- cessory conduction pathways). Only patients 1 and 4 had documented episodes of tachycardia. Subjects ex- ercised to a heart rate-blood pressure product of 26,000 f 2,000 over 9 f 1 minutes. All subjects stopped exercising because of fatigue: no subject had chest discomfort. Only 1 subject (no. 4) had been taking a /3- blocking drug in the 48 hours before this study, and this subject exercised to a heart rate of 15~1 beats/min, sug- gesting that p blockade was not effective. The P-block- ing drug had been prescribed for rate control. Seven of the 8 subjects (nos. 1 through 7) had at least 1 mm of ST- segment depression on their exercise electrocardio- gram. All patients were in sinus rhythm at rest, and in no patient did arrhythmias develop during exercise. A typical positive exercise stress test result is shown in Figure 2.

Two subjects (nos. 1 and 2) had stress defects, which were reversed by the time of the delayed image (Fig. 1). They also had at least 1 area of delayed thallium wash- out. Subject 1 had normal coronary arteriographic findings without evidence of spasm, even after in- fusion of ergonovine, during the same week as the exercise thallium test. Left ventricular end-diastolic pressure was normal. The exercise radionuclide ven- triculographic study was normal in subjects 1 and 2, with an appropriate increase in ejection fraction dur- ing exercise and absence of wall motion abnormalities both at rest and during exercise. Subjects 3,4 and 5 had multiple areas of delayed thallium washout despite normal stress images. Subjects 6, 7 and 8 had normal exercise thallium test results and subject 8 had a nor- mal exercise electrocardiogram. Electrocardiographic localization of accessory connections is summarized in Table I.7,” Subjects 4 and 8 had little evidence of ante- rograde conduction down the bypass tract at the time of exercise thallium testing. There was no obvious as- sociation between the location of the bypass tract and the result of thallium testing; abnormal results oc- curred with both left- and right-sided accessory tracts.

Discussion This prospective study of subjects with ventricular

preexcitation who had no evidence of coronary artery

disease yielded a high frequency of abnormal thallium perfusion or washout during exercise testing. Although coronary angiography was done only in subject 1, it is unlikely that occult coronary artery disease accounts for the 627~~ frequencv of abnormal thallium test re- sults. This contention” is supported by the relatively young age of the subjects, absence of angina or equiva- lent symptoms, and the normal exercise radionuclide ventriculographic responses in patients 1, 2 and 6.

Explanation of abnormal thallium images in the presence of normal coronary arteries requires under- standing of the causes that determine the delivery, uptake and removal of the ion from the circulation by the heart. Thallium distribution within the cell occurs by mechanisms similar to those used by the potassium cation.“,1n Unlike angiographic contrast media, thalli- um uptake requires more than vascular patency. Thal- lium distribution may be affected by the activity of the sodium/potassium ATPase pump, the microvascular function of the myocardium, or the anatomy of the epicardial arteries. lo Therefore, it is not surprising that positive thallium study results occur under con- ditions in which the coronary arteries are normal by angiography.

That these tests are better regarded as “positive tests of unknown significance” is illustrated by the results of investigations of thallium testing in patients with left bundle branch block. Hirzel et all’ found septal perfusion defects in 100% of patients with left bundle branch block. Only 4 of the 19 patients report- ed by this group had coronary stenosis in the subtend- ing artery.l’ Other studies have documented a high frequency of positive exercise thallium test results in patients with left bundle branch block who have nor- mal coronary arteries. l2 Hirzel et al also showed, using the dog, that rapid right ventricular pacing (resulting in a functional left bundle branch block) caused focal perfusion defects on thallium scintigraphy. Regional blood flow in 7 of the 8 dogs, as measured by micro-

FIGURE 2. Typical electrocardiographic response to exercise in patients with ventricular preexcitation (subject 3). This recording shows the sequential change in ST-segment level in lead V5 during a Bruce protocol exercise test. This tracing is comprised of computer-

generated “composite” beats.

1106 EXERCISE THALLIUM TESTING AND VENTRICULAR PREEXCITATION

sphere studies, was decreased in myocardial segments that showed diminished thallium uptake. The 1 dog with pacing-induced left bundle branch block that had a normal thallium scan also had normal microsphere levels in the septum.ll

The similarities between patients with ventricular preexcitation and those with bundle branch block are considerable. The original report of the entity of Wolff-Parkinson-White syndrome described this con- duction abnormality as a functional bundle branch block.13 Patients with ventricular preexcitation, simi- lar to those with left bundle branch block, have evi- dence of abnormal wall motion on echocardiography. In a study by Francis et a1,14 septal motion abnormali- ties occurred in all patients with evidence of right- sided preexcitation pathways. In the current study, 5 of 8 patients showed abnormal activation of the septum or posterior wall. Four of these patients had positive thallium scans. The abnormal patterns of myocardial activation noted on echocardiography may reflect dys- synergy of ventricular contraction, which could alter the uptake and washout of thallium. Tomographic phase analysis studies of intracavitary flow vectors during rest radionuclide ventriculographic studies showed altered patterns of blood ejection in patients with WPW syndrome .15,16 These studies also suggest that ventricular preexcitation can result in dyssynergy of ventricular contractions.

Other circumstances under which ventricular pre- excitation could be associated with abnormal exercise thallium results are the presence of occult cardiomy- opathy or failure to achieve an adequate exercise lev- el. None of these patients had evidence of cardiac failure and all had normal left ventricular function on &dimensional echocardiography. In addition, the 2 patients with stress defects had normal exercise radio- nuclide ventriculography studies.

Inadequate exercise can cause delayed thallium washout, presumably by failing to adequately increase coronary blood flow, with resultant stagnation of thal- lium washout.17 All patients in this study exercised to fatigue, and the increase in double product (from 10,000 f 1,000 to 26,000 f 2,000) suggests that an ade- quate exercise level was achieved. Rest and exercise heart rates of study subjects are shown in Table I. The subjects with normal exercise thallium responses had the highest heart rates, although they also tended to be younger. Submaximal heart rate responses might ex- plain the abnormal thallium washout. However, the stress defects cannot be attributed to failure to achieve target heart rate. Other technical problems can cause false-positive thallium test results, such as hangup of thallium in peripheral veins, extravasation of thallium and improper image acquisition.18v1g None of these problems occurred during this study.

Perhaps the best noninvasive test for ischemic disease in patients with ventricular preexcitation syndrome is exercise radionuclide ventriculography. Greenland et alzO reported a patient with Wolff-Par- kinson-white syndrome who had atypical chest pain and a positive exercise electrocardiographic response. This patient had no evidence of coronary artery dis-

ease as assessed by exercise radionuclide ventricu- lography and confirmed by angiography. Because ejection fraction measured by radionuclide ventricu- lography reflects net changes in chamber volume rath- er than subtle, subsegmental abnormalities of the pat- tern of ventricular activation, it presumably would not be influenced by such preexcitation-induced changes. In this study, exercise radionuclide ventriculographic findings were normal in the 2 patients with abnormal exercise thallium tests.

Acknowledgment: We gratefully acknowledge the assistance of Dr. Bert Larson in performing the exer- cise thallium tests and Dr. Gary Francis in interpreting the echocardiograms. The excellent support provided by Jill Bonfe, Lisa Berskow and Vicki Hayle in the preparation of this manuscript is greatly appreciated.

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