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Exercise testing for arrhythmia
HENRY 6. WILES, M.D. Department of Pediatrics Medical University of South Carolina Charleston, South Carolina
Exercise testing is well established in the evaluation of arrhythmia in children and adolescents. The most important objective of the test is that the patients exert a maximal effort to uncover pathophysiologic effects. Either treadmill or bicycle ergometer techniques are appropriate. Special attention to safety is necessary because the induced rhythm disturbance may produce hemodynamic instability. in this review, arrhythmia is broadly defined as any rhythm or conduction abnormality other than normal sinus rhythm or the appropriate exercise increase in the sinus rate with 1:l atrioventricular node conduction (Figure 1). This includes bradycardia, supraventricular tachycardia (SVT), ventricular tachycardia (VT), atria1 ectopy, ventricular ectopy, or atrioventricular node block. Testing is appropriate in two groups of patients, those with primary arrhythmia or conduction disturbance and others with secondary arrhythmia associated with structural cardiovascular abnormalities, especially those who have had cardiac surgery.
GENERAL OVERVIEW Several studies have shown the general usefulness of exercise testing in children with arrhythmia. Testing to induce primary and secondary arrhythmia not seen at rest helps to direct management Address correspondence to Henry B. Wiles, M.D., South Carolina Children’s Heart Center, 171 Ashley Avenue, Charleston, SC 294254682.
and evaluate the effectiveness of therapy. Rozanski and coworkers’ studied the reproducibility of two exercise test measurements made an average of 3.1 months apart in 7 children with atria1 arrhythmia and 12 with ventricular arrhythmia. During both tests, 5 (71%) of the patients with atria1 arrhythmia had suppression of premature atria1 contractions (PAC). One patient had reproducible premature ventricular contractions (PVC), and another had runs of SVT during both tests. In patients with ventricular arrhythmia, 10 (83%) of 12 had suppression of the arrhythmia on both tests, 1 had nonsuppressed PVC and 1 with VT at rest continued to have VT. The results in each patient were exactly reproducible in follow-up tests. In 1991, Weigel et a1.2reported results of exercise testing in children with suspected or documented arrhythmia. Of the 49 patients with suspected arrhythmia, 10 (20%) had an arrhythmia during the test, prompting a change in therapy in 4 (8%) patients. In the other 39 children with a normal exercise test, another type of test demonstrated an arrhythmia in 8, indicating that in the 49 patients referred for a suspected a~hythmia, the arrhythmia was documented in 18 (37%). This provided an exercise test sensitivity of 56% and a negative predictive value of 79%. In 92 patients with known arrhythmia, 68 (74%) had an arrhythmia during the exercise test. Of the 35 patients who were referred for suppression of a ventricular arrhythmia, 25 (71%) demonstrated suppression during exercise testing. Among the 92 patients referred for known Prog Pediatr Cardioll993; 2(2):51-60 Copyright 0 1993 by Andover Medical
Progress in Pediatric Cardiology
52
FIGURE 1. This l&year-old boy with I-transposition of the great arteries showed asymptomatic second degree atrioventricular node block during the early stages of exercise. He had normal sinus rhythm at rest. A pacemaker was implanted when he began having symptoms.
arrhythmia, therapy was changed in 25 (27%) based on the exercise test results.
PRIMARY
ARRHYTHMIA
Supraventricular Tachycardia Although exercise testing rarely induces SVT in children, testing is an important adjunct in the management of patients with this common arrhythmia. Some patients do develop the arrhythmia during exercise testing,2 or a delta wave of WolffParkinson-White (WPW) conduction may change or disappear. Coelho et a1.3 evaluated 19 athletes with documented symptomatic arrhythmias: 5 with atria1 fibrillation, 5 with SVT, 8 with VT, and 1 with ventricular fibrillation. Ten (53%) of the patients had a cardiac abnormality: mitral valve prolapse in 9 and cardiomyopathy in 1. During testing, 8 (42%) of the 19 athletes developed an arrhythmia that resembled the one seen at rest. In children, SVT often may interfere with ordinary lifestyle needs or athletic participation but it is rarely life threatening. One exception to this benign natural history applies to patients who may be at risk for sudden death from atria1 fibrillation with WPW associated with a short antegrade refractory period of the bypass tract. The need to measure
the refractory period of the bypass tract in WPW is controversial, especially in asymptomatic patients. It is theorized that the tract may be sensitive to endogenous catecholamines. The significance of the disappearance of the WPW delta wave during exercise is not known; however, current information suggests that this indicates a relatively long 0220 ms) refractory period.4 Strasberg et al.s exercised 36 patients with manifest WPW and found that 18 (50%) lost the delta wave - 4 suddenly and 14 gradually. A partial change in the shape of the delta wave was found in 16 (44%), and the delta wave persisted in 2 (6%). Sudden loss of the delta wave with exercise was thought to indicate a block within the bypass tract. Gradual or partial loss was thought to be due to increased atrioventricular node conduction. The patients with sudden loss of the delta wave had significantly longer effective refractory periods (368 ms) than the others (314 ms). No patient had SVT induced during exercise. Bricker et a1.4 compared the results of invasive electrophysiologic (El?) studies and exercise tests in 17 children with WPW. In those in whom the delta wave disappeared, the measured refractory period ranged from 360 ms to 390 ms. Partial change in the delta wave was associated with a refractory period of 206 ms to 235 ms. Persistence of the delta
Arrhythmia
wave was associated with a refractory period of 180 ms to 290 ms. The investigators concluded that disappearance of the delta wave was a good predictor of a long refractory period and that a change or persistence was not. Gradual loss or change of the delta wave may simply indicate an improved conduction velocity through the atrioventricular node. At our institution every patient with WPW conduction undergoes an exercise test to evaluate induction of tachycardia, loss of the delta wave, and provocation of symptoms. In symptomatic patients, we do not rely solely on exercise changes in the delta wave but also performed EP studies to measure the refractory period directly. We believe that both of these tests help to identify all children with WPW who may be at risk of sudden death from a rapidly conducting (< 220 ms) bypass tract with atria1 fibrillation. Other mechanisms for producing SVT in children are much less common than those operating in WPW, and in these conditions information on exercise testing is limited. Ventricular Arrhythmia Exercise testing for evaluating abnormal ventricular rhythm is more valuable than for supraventricular arrhythmia. The induction, suppression, or nonsuppression of ventricular ectopy with exercise helps to identify the specific rhythm, define its significance or severity, guide choices of therapy, and evaluate drug effectiveness (Figure 2). Indications for exercise testing in children include suspected ventricular a~hythmia or demonstrated abnormalities such as PVC or VT (Figure 3). Benign PVC of childhood are defined as isolated uniform ventricular ectopics that are asymptomatic and disappear with exercise. This arrhythmia occurs in approximately 0.3% to 2.2% of children, has a benign natural history, and does not require therapy. On the other hand, further evaluation is required in children with multiform PVC, ventricular couplets or VT.” The induction of ventricular arrhythmia with exercise often indicates an abnormal heart. In a review of 2761 consecutive exercise tests at the Texas Children’s Hospital, VT was found in 22 tests (0.8%): during exercise in 14 and with recovery in 8.’ Sustained episodes of VT occurred in 5 children and in 17 VT was nonsustained. Only 5 of the 22 patients had a normal exercise test. In
53
the other 17 (77%) patients, the VT was associated with underlying heart disease: long QT interval in 2, arrhythmogenic right ventricular dysplasia in 4, mitral valve prolapse in 2, cardiomyopathy in 3, and congenital heart disease in 6. No permanent complications of the VT occurred in these patients and none needed resuscitation. Rocchini et al8 performed exercise tests in 21 children with VT. Among 11 who were symptomatic, 8 (73%) had an increase in the amount of ventricular arrhythmia, and 9 (90%) of the 10 asymptomatic patients had partial or complete suppression of the ventricular ectopy. Ryujin et a1.9 evaluated 196 children who had PVC on electrocardiograms (ECG). With exercise testing, 29 (15%) had ventricular arrhythmias 8bad couplets, and 21 had VT. They found, however, that 24-hour ambulatory ECG recording was more sensitive than exercise testing in documenting episodes of VT. Noh et al.‘O described studies at our institution in 14 children with normal hearts who presented with VT. With exercise testing, 7 (SO%) patients had VT: 2 during exercise, 1 with recovery, and 4 throughout the test. Additional EP study of each child failed to show a correlation between the inducibility of VT with EP stimulation and the exercise test results. Ten of the patients were treated, 3 of them only briefly. There were no deaths in this group of children with normal hearts. Recently Wiles et a1.6 examined right ventricular endomyocardial biopsy samples from 33 children with normal hearts who had ventricular arrhythmia. Normal myocardial structure was found in 16 (48%) of them; 14 (42%) had changes similar to those of dilated cardiomyopathy, and 3 (9 % ) had lymphatic myocarditis. A maximal exercise test performed in 26 of these children induced ventricular arrhythmia in 4 (15% ), was associated with suppression of all arrhythmia in 11(42%), and demonstrated persistent ventricular arrhythmia in ll(42 8 1. There was no correlation between the biopsy results and whether the ventricular arrhythmia was induced, suppressed, or nonsuppressed by exercise. None of these patients died. The significance of these results of exercise testing in children with primary ventricular arrhythmia remain unclear. The findings appear similar to more extensive test results in children with SVT. If the ventricular arrhythmia is suppressed by exercise, the prognosis appears to be good, The signifi-
-
c
Arrhythmia
FIGURE 3. (A) This electrocardiogram shows nonsustained VT at rest in u 17year-old patient with a structurally normal heart. (B) At 3 minutes of exercise, the rhythm reverted to a normal sinus rhythm with suppression of all ectopic ventricular rhythm. He has received no medical treatment.
55
56
Progress in ~ediut~c Cardiology
cance of induced or nonsuppressed ventricular arrhythmia is not clear. The association of an abnormal heart and exercise-induced ventricular arrhythmia is significant, and patients with this association should be considered for drug therapy and undergo exercise retesting to evaluate its effectiveness. Sinus Node Dysfunction Sinus node dysfunction is uncommon in the normal heart. Because the sinus node is the primary structure for increasing heart rate and cardiac output during exercise, testing may be an important method for assessing sinus node function. Unfortunately, exercise testing is not specific for evaluating sinus node dysfunction. *i If it is used, it is essential that a maximal effort is produced. Most children develop a heart rate of at least 180 bpm during an exercise test. Sinus node dysfunction is demonstrated by rates below 180 bpm with a definite maximal effort, and it is suspected if a precipitous fall in heart rate occurs during the early postexercise recovery period. Bricker et al. compared sinus node recovery times and sinoatrial conduction times during exercise and El’ studies.” No correlations were found with several exercise parameters, including maximal heart rate, acceleration of heart rate, and workload. As with SVT and ventricular arrhythmia, exercise testing for sinus node dysfunction is useful mainly to confirm normal function (Fire 4). Atrioventricular Node Block Exercise testing is well established in patients with congenital complete heart block (CCHB). In 1977, tests in 12 patients showed PVC in 5 (42% ), causing cessation of the testsI The average atria1 rate of the group increased from 72 bpm to 156 bpm with exercise, and the average ventricular rate increased from 42 bpm to 95 bpm. The ventricular rate at rest was lower in the group who had ventricular arrhythmia. In 14 patients with CCHB without other cardiovascular abnormalities, significant ventricular arrhythmia occurred during exercise in 10 (71%).13 There was a strong association between ventricular arrhythmia and the age of these patients. Older patients had greater degrees and more complex ventricular arrhythmia than younger ones. None of these patients died. In evaluating exercise responses in 11 children with CCHB, Karpawich et al.14 found that exercise heart rates did not correlate with syncope. Only 3 (27%) of the children had ventricular arrhythmia
during exercise testing, and syncope was correlated only with resting heart rates below 50 bpm. The American Heart Association Committee on Pacemaker implantation recommends pacemakers for patients with symptomatic bradycardia caused by sinus bradycardia, second degree atrioventricular block, or third degree atrioventricular block. The only reference to the importance of exercise function is in the recommendation for pacemaker use in patients with advanced second or third degree atrioventricular block with “moderate to marked exercise intolerance.“ Moderate to marked exerciw intolerance was not defined. Currently, there are no standards or data that define the role of exercise testing in determining indications for pacemakers. At our institution, we believe that children with CCHB who have exercise-induced PVC or long corrected QT intervals (QT,) may benefit from pacemakers. Long QT Interval Syndrome In patients with presumed long QT interval syndrome, exercise testing may be useful to establish the diagnosis and judge its prognosis. In these patients, it is believed that the QT, interval does not shorten with exercise as it does normally. Measurement of the QT, interval during exercise is difficult and often inaccurate, but measurement 1 or 2 minutes after exercise can identify abnormalities in patients who have normal intervals at rest. In 16 children, Weintraub et al.15 found that the QTE was most prolonged 2 minutes after maximal exercise, and in 2 of the patients, the abnormal QT, was noted only during the recovery period. Only 2 of the patients had a major ventricular arrhythmia during the test and beta-blockade therapy abolished the ventricular arrhythmias on subsequent tests. Von Bemuth et all” found VT during exercise in only 1 of 23 children with long QT interval, and exercise testing was not sensitive in predicting the deaths that occurred in 5 of them. Exercise testing is useful, however, in evaluating the effectiventss of beta-blockade therapy in these patients. Blockade is effective if the maximal heart rate during exercise is below 150 bpm. Sudden Death Sudden unexpected death in children is a dramatic and tragic occurrence. Although this event may not be an appropriate consideration for discussion as a primary arrhythmia, many occurrences are most
Arrhythmia
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FIGURE 4. (A) This patient showed sinus brudycardiu with a junctional escape rhythm at rest 14 years after surgical closure of a ventricular septul defect. (J3) At I minute of exercise he had normal sinus pacing of his heart. (C) During exercise recovery he hud infrequent and isolated PVC. He hus received no treatment and remains asymptomatic.
58
Progress in Pediat~c Cardiology
likely related to an arrhythmia. Furthermore, as many as 25% of sudden deaths in children occur during physical exertion. Syncope during exercise is a particularly worrisome symptom that should be evaluated by exercising testing. Most sudden cardiac deaths in children are due to congenital or acquired heart diseases, such as hypertrophic cardiomyopathy, anomalous origin of the left coronary artery from the right sinus of valsalva, myocarditis, or surgically repaired congenital heart disease. Drug, pacemaker, or surgical treatment of these conditions should be urgently considered if exercise testing is associated with arrhythmia. Pacemaker Function The atria1 electrogram changes with exercise in both animals and childrenI Thischange may affect atria1 sensing function in children with atria1 or dual chamber pacemakers. Other sensing artifacts, such as myopotential inhibition during exercise, can also affect pacemaker function. In children with permanent pacemakers, if upper rate limits are set too low cardiac output can be limited at maximal effort.
SECONDARY ARRHYTHMIA Secondary arrhythmias are those seen after surgical repair or with recognized acquired heart disease; they include sinus node dysfunction, atrioventricular node dysfunction, supraventricular arrhythmia, and ventricular arrhythmia. Only two postoperative lesions will be discussed in detail. Further information about exercise-related arrhythmia can be found elsewhere in this issue of the journal and in the next issue in sections dealing with each cardiovascular lesion. Tetralogy of Fallot More information is available on the significance of arrhythmia in patients who have had surgical repair of tetralogy of Fallot than for any other cardiovascular malformation. Previous reports indicate that 1% to 6% of surgically repaired patients with tetralogy die suddenly, presumably from ventricular arrhythmia.*” Characteristics that predict sudden death remain ambiguous; however, generally accepted risk factors are late ages at operation, poor hemodynamic results, and the presence of ventricular arrhythmia. Exercise testing is routinely included in the evaluation of tetralogy patients
after repair. In studies of 43 patients, James et a1.i9 found 9 (21%) with ventricular arrhythmia during exercise: 2 had VT, 1 had ventricular couplets, 2 had multiform PVC, and 4 had uniform PVC. They postulated that exercise testing was helpful in the management of tetralogy patients at risk for sudden death. In 1979, GarsorP reported follow-up results in 233 operated tetralogy patients. Seventeen of them had no ventricular arrhythmia during exercise. In 2 patients who had PVC before exercise, 1 had suppression of the PVC and 1 had nonsuppression. The number of patients who underwent exercise testing in this series was too small, however, to define the role of exercise testing accurately. In 1980, Garson et aLzOevaluated 104 patients who hadexercise testing after tetralogy repair. Ventricular arrhythmia occurred during or after exercise in 31 (30%), with isolated PVC in 21, multiform PVC in 4, couplets in 4, and VT in 2. Further analysis indicated that the 31 arrhythmia patients had longer postoperative intervals of time and higher right ventricular systolic and end-diastolic pressures than others without exercise ventricular arrhythmia. Late cardiac arrests occurred in 2 (6 %) of the 31 patients, both with poor hemodynamic results and multiform PVC on resting ECG. During exercise testing, one of these patients had suppression of PVC and the other had VT. The authors concluded that exercise testing was sensitive for detecting ventricular arrhythmia in tetralogy patients, and that ventricular arrhythmia was highly associated with poor hemodynamics and sudden death. However, the number of patients with cardiac arrest was too small to establish definitive prediction results. They noted that in documenting the ventricular arrhythmia in these tetralogy patients, the relative usefulness of the resting ECG versus the exercise testing remains uncertain. The incidence of ventricular arrhythmia with exercise testing was remarkably similar in studies of tetralogy patients by Wessel and colleagues.21 Of 91 operated patients who had an exercise test, 28 (31%) had PVC, which in most were suppressed during the exercise itself. None had VT. These 28 patients were older at the time of surgery, had increased heart sizes, and showed subnormal exercise endurance when compared to the 63 patients without PVC. Two patients died, neither of whom had ventricular arrhythmia with exercise testing. At our institution, an evaluation of surgically
A~kytkmia
treated tetralogy of Fallot included 40 patients who had exercise tests. Ventricular arrhythmia before or during the test occurred in 10 (25%), with suppression of PVC in 1, uniform PVC in 7, cou@b in 1, and VT in 1. There was no statistical correlation between the results of EP studies and the type or degree of ventricular arrhythmia with exercise testing. There have been no late deaths. We believe that aggressive drug therapy is appropriate in any operated tetralogy patients who have clinical, exerciseinduced, or EP-stimulated ventricular arrhythmia. The sensitivity and specificity of exercise testing to identify tetralogy patients at risk of sudden death remains unproven. There is some evidence that it does not have an independent prognostic value in the postoperative evaluation of an arrhythmia. The patient who has significant ventricular arrhythmia induced during exercise testing, however, should be strongly considered for therapy, Unfortunately, suppression of ventricular arrhythmia during exercise testing in these tetralogy patients is not as reliable a negative predictor of sudden death as it is in normal children or patients with CCHB. d-Transposition
of Great Arteries
The extensive surgery involved in the atrial switch (Mustard) operation for d-transposition of the great arteries (d-TGA) predisposes to atria1 bradyarrhythmias or tachyarrhythmias. The sick sinus node syndrome, a term used for some of these conditions, often requires pacemaker or drug therapy. Studies of the response to exercise in this group of children have found subnormal levels of maximal heart rate, oxygen consumption, exercise endurHesslein et al.” found ance, and cardiac output. *2~23 subnormal maximal heart rates in 24 (83 % ) of 29 d-TGA patients an average of 6.7 years after surgery. The maximal exercise heart rate did not correlate with clinical symptoms, clinical arrhythmia, or catheterization hemodynamics. Furthermore, EP studies identified sinus node dysfunction only in 56% of patients with abnormally low exercise heart rates. Mathews et a1.23evaluated 21 patients with d-TGA an average of 9 years after repair. Normal sinus rhythm was present at rest in 15 (71%) patients, but only 6 (40%) remained in sinus rhythm with exercise testing. The other patients had a variety arrhythmias, including PAC, junctional rhythm, and PVC. Six (29%) of the 21 remaining patients
59
had arrhythmias at rest that persisted through exercise. One patient with exercise-induced ventricular arrhythmia died suddenly 6 months after testing. Late sudden death, a recognized complication of d-TGA after an atria1 switch operation, has been considered to be more likely from tacharrhythmia than from bradycardia. A definite association between exercise test results and the risk of sudden death has not been established, however.
SUMMARY The physiologic effects of exercise alter the electrical conduction of the heart. Changes in intrinsic sympathetic and parasympathetic activity and in exogenous stimuli to the heart seem to change the substrate for rhythm disturbance. The major clinical use of any medical test is its predictive value, For primary rhythm disturbances, the main benefit of exercise testing appears to be its negative predictive value. More study is needed to determine its positive predictive value. The opposite appears to be the case with secondary arrhythmia. Induction of arrhythmia during exercise is more predictive than is noninduction or suppression.
REFERENCES 1. Rozanski JJ, Dimich I, Steinfeld L, Kupersmith J. Maximal exercise stress testing in evaluation of arrhythmias in children: results and reproducibility. Am 1 Cardiol. 1979;43:951-956. 2. Weigel TJ, Porter CJ, Mottram CD, Driscoll DJ. Detecting arrhythmia by exercise electrocardiography in pediatric patients: assessment of sensitivity and influence on clinical management. Mayo Clin Proc. 1991;46:379-386. 3. Coelho A, Palileo E, Ashley W, et al. Tachyarrhythmias in young athletes. J Am Co11 Cardiol. 1986;7: 237-243. 4. Bricker JT, Porter CJ, Garson A, et al. Exercise testing in children with Wolff-Parkinson-White syndrome. Am I Car&ol. 1985;55:1001-1004. 5. Strasberg B, Ashley WW, Wyndham CRC, et al. Treadmill exercise testing in the Wolff-ParkinsonWhite syndrome. Am 1 Cardiol. 1980;45:742-748. 6. Wiles HB, Gillette PC, Harley RA, Upshur JK. Cardiomyopathy and myocarditis in children with ventricular ectopic rhythm. J Am Co11 Cardiof. 1992; 20:359-362. 7. Bricker JT, Traweek MS, Smith RT, Moak JP, Vargo TA, Garson A Jr. Exercise-related ventricular tachy-
60
Progress in Pediatric Cardiology
cardia in children. Am Heart J. 1986;122:186-188. 8. Rocchini AI’, Chun PO, Dick M. Ventricular tachycardia in children. Am J Cardiol. 1981;47:10911097. 9. Ryujin Y, Arakaki Y, Takahashi 0, Kamiya T. Ventricular arrhythmias in children: the validity of exercise stress tests for their diagnoses and management. Jpn Circ J. 1984;48:1393-1398. 10. Noh CI, Gillette PC, Case CL, Zeigler VL. Clinical and electrophysiological characteristics of ventricular tachycardia in young individuals. Am Heart 1. 1990;120:1326-1333. 11. Bricker JT, Garson A, Paridon SM, Vargo TA. Exercise correlates of electrophysiologic assessment of sinus node function in young individuals. Pediatr Exer Sci. 1990;2:163-168. 12. Chawla K, Serratto M, Cruz J, et al. Response to maximal and submaximal exercise testing in patients with congenital complete heart block. Circulation. 1977;56:111-171. 13. Winkler RB, Freed MD, Nadas AS. Exercise-induced ectopy in children and young adults with complete heart block. Am Heart 1. 1980;99:87-92. 14. Karpawich PI’, Gillette PC, Garson A, Hesslein P, Porter C, McNamara D. Congenital complete atrioventricular block: clinical and electrophysiologic predictors of need for pacemaker insertion. Am ] Cardiol. 1981;48:1098-1102. 15. Weintraub RG, Gow RM, Wilkinson JL. The congenital long QT syndromes in childhood. J Am Coil Cardiol. 1990;16:674-680.
16. Von Bemuth G. Tachyarrhythmic syncopes in children with structurally normal hearts with and without Q-T prolongation in the electrocardiogram. Eur ] Pediatr. 1982;138:206-210. 17. Ross BA, Zeigler V, Zinner A, Woodall P, Gillette PC. The effect of exercise on the atria1 electrogram voltagein youngpatients. Pace. 1991;14:2092-2097. 18. Garson A, Nihill MR, McNamara DG, Cooley DA. Status of the adult and adolescent after repair of tetralogy of Fallot. Circulation. 1979;59:1232-1240. 19. James FW, Kaplan S, Schwartz DC, Chou T, Sandker MJ, Naylor V. Response to exercise in patients after total surgical correction of tetralogy of Fallot. Circulation. 1976;54:671-679. 20. Garson A Jr, Gillette PC, Gutgesell HP, McNamara DG. Stress-induced ventricular arrhythmia after repair of tetralogy of Fallot. Am 1 Cardiol. 1980;46: 1006-1012. 21. Wessel HU, Bastanier CK, Paul MH, Berry TE, Cole RB, Muster AJ. Prognostic significance of arrhythmia in tetralogy of Fallot after intracardiac repair. Am 1 Cardiol. 1980;46:843-848. 22. Hesslein PS, Gutgesell HP, Gillette PC, McNamara DG. Exercise assessment of sinoatrial node function following the Mustard operation. Am Heart]. 1982; 103:351-357. 23. Mathews RA, Fricker FJ, Beerman LB, et al. Exercise studies after the Mustard operation in transposition of the great arteries. Am J Cardiol. 1983;51:15261529.
Exercise testing is well established in the evaluation of arrhythmia in children and adolescents. The most important objective of the test is that the patients exert a maximal effort to uncover pathophysiologic effects. Either treadmill or bicycle ergometer techniques are appropriate. Special attention to safety is necessary because the induced rhythm disturbance may produce hemodynamic instability. in this review, arrhythmia is broadly defined as any rhythm or conduction abnormality other than normal sinus rhythm or the appropriate exercise increase in the sinus rate with 1:l atrioventricular node conduction (Figure 1). This includes bradycardia, supraventricular tachycardia (SVT), ventricular tachycardia (VT), atria1 ectopy, ventricular ectopy, or atrioventricular node block. Testing is appropriate in two groups of patients, those with primary arrhythmia or conduction disturbance and others with secondary arrhythmia associated with structural cardiovascular abnormalities, especially those who have had cardiac surgery.
GENERAL OVERVIEW Several studies have shown the general usefulness of exercise testing in children with arrhythmia. Testing to induce primary and secondary arrhythmia not seen at rest helps to direct management Address correspondence to Henry B. Wiles, M.D., South Carolina Children’s Heart Center, 171 Ashley Avenue, Charleston, SC 294254682.
and evaluate the effectiveness of therapy. Rozanski and coworkers’ studied the reproducibility of two exercise test measurements made an average of 3.1 months apart in 7 children with atria1 arrhythmia and 12 with ventricular arrhythmia. During both tests, 5 (71%) of the patients with atria1 arrhythmia had suppression of premature atria1 contractions (PAC). One patient had reproducible premature ventricular contractions (PVC), and another had runs of SVT during both tests. In patients with ventricular arrhythmia, 10 (83%) of 12 had suppression of the arrhythmia on both tests, 1 had nonsuppressed PVC and 1 with VT at rest continued to have VT. The results in each patient were exactly reproducible in follow-up tests. In 1991, Weigel et a1.2reported results of exercise testing in children with suspected or documented arrhythmia. Of the 49 patients with suspected arrhythmia, 10 (20%) had an arrhythmia during the test, prompting a change in therapy in 4 (8%) patients. In the other 39 children with a normal exercise test, another type of test demonstrated an arrhythmia in 8, indicating that in the 49 patients referred for a suspected a~hythmia, the arrhythmia was documented in 18 (37%). This provided an exercise test sensitivity of 56% and a negative predictive value of 79%. In 92 patients with known arrhythmia, 68 (74%) had an arrhythmia during the exercise test. Of the 35 patients who were referred for suppression of a ventricular arrhythmia, 25 (71%) demonstrated suppression during exercise testing. Among the 92 patients referred for known Prog Pediatr Cardioll993; 2(2):51-60 Copyright 0 1993 by Andover Medical
Progress in Pediatric Cardiology
52
FIGURE 1. This l&year-old boy with I-transposition of the great arteries showed asymptomatic second degree atrioventricular node block during the early stages of exercise. He had normal sinus rhythm at rest. A pacemaker was implanted when he began having symptoms.
arrhythmia, therapy was changed in 25 (27%) based on the exercise test results.
PRIMARY
ARRHYTHMIA
Supraventricular Tachycardia Although exercise testing rarely induces SVT in children, testing is an important adjunct in the management of patients with this common arrhythmia. Some patients do develop the arrhythmia during exercise testing,2 or a delta wave of WolffParkinson-White (WPW) conduction may change or disappear. Coelho et a1.3 evaluated 19 athletes with documented symptomatic arrhythmias: 5 with atria1 fibrillation, 5 with SVT, 8 with VT, and 1 with ventricular fibrillation. Ten (53%) of the patients had a cardiac abnormality: mitral valve prolapse in 9 and cardiomyopathy in 1. During testing, 8 (42%) of the 19 athletes developed an arrhythmia that resembled the one seen at rest. In children, SVT often may interfere with ordinary lifestyle needs or athletic participation but it is rarely life threatening. One exception to this benign natural history applies to patients who may be at risk for sudden death from atria1 fibrillation with WPW associated with a short antegrade refractory period of the bypass tract. The need to measure
the refractory period of the bypass tract in WPW is controversial, especially in asymptomatic patients. It is theorized that the tract may be sensitive to endogenous catecholamines. The significance of the disappearance of the WPW delta wave during exercise is not known; however, current information suggests that this indicates a relatively long 0220 ms) refractory period.4 Strasberg et al.s exercised 36 patients with manifest WPW and found that 18 (50%) lost the delta wave - 4 suddenly and 14 gradually. A partial change in the shape of the delta wave was found in 16 (44%), and the delta wave persisted in 2 (6%). Sudden loss of the delta wave with exercise was thought to indicate a block within the bypass tract. Gradual or partial loss was thought to be due to increased atrioventricular node conduction. The patients with sudden loss of the delta wave had significantly longer effective refractory periods (368 ms) than the others (314 ms). No patient had SVT induced during exercise. Bricker et a1.4 compared the results of invasive electrophysiologic (El?) studies and exercise tests in 17 children with WPW. In those in whom the delta wave disappeared, the measured refractory period ranged from 360 ms to 390 ms. Partial change in the delta wave was associated with a refractory period of 206 ms to 235 ms. Persistence of the delta
Arrhythmia
wave was associated with a refractory period of 180 ms to 290 ms. The investigators concluded that disappearance of the delta wave was a good predictor of a long refractory period and that a change or persistence was not. Gradual loss or change of the delta wave may simply indicate an improved conduction velocity through the atrioventricular node. At our institution every patient with WPW conduction undergoes an exercise test to evaluate induction of tachycardia, loss of the delta wave, and provocation of symptoms. In symptomatic patients, we do not rely solely on exercise changes in the delta wave but also performed EP studies to measure the refractory period directly. We believe that both of these tests help to identify all children with WPW who may be at risk of sudden death from a rapidly conducting (< 220 ms) bypass tract with atria1 fibrillation. Other mechanisms for producing SVT in children are much less common than those operating in WPW, and in these conditions information on exercise testing is limited. Ventricular Arrhythmia Exercise testing for evaluating abnormal ventricular rhythm is more valuable than for supraventricular arrhythmia. The induction, suppression, or nonsuppression of ventricular ectopy with exercise helps to identify the specific rhythm, define its significance or severity, guide choices of therapy, and evaluate drug effectiveness (Figure 2). Indications for exercise testing in children include suspected ventricular a~hythmia or demonstrated abnormalities such as PVC or VT (Figure 3). Benign PVC of childhood are defined as isolated uniform ventricular ectopics that are asymptomatic and disappear with exercise. This arrhythmia occurs in approximately 0.3% to 2.2% of children, has a benign natural history, and does not require therapy. On the other hand, further evaluation is required in children with multiform PVC, ventricular couplets or VT.” The induction of ventricular arrhythmia with exercise often indicates an abnormal heart. In a review of 2761 consecutive exercise tests at the Texas Children’s Hospital, VT was found in 22 tests (0.8%): during exercise in 14 and with recovery in 8.’ Sustained episodes of VT occurred in 5 children and in 17 VT was nonsustained. Only 5 of the 22 patients had a normal exercise test. In
53
the other 17 (77%) patients, the VT was associated with underlying heart disease: long QT interval in 2, arrhythmogenic right ventricular dysplasia in 4, mitral valve prolapse in 2, cardiomyopathy in 3, and congenital heart disease in 6. No permanent complications of the VT occurred in these patients and none needed resuscitation. Rocchini et al8 performed exercise tests in 21 children with VT. Among 11 who were symptomatic, 8 (73%) had an increase in the amount of ventricular arrhythmia, and 9 (90%) of the 10 asymptomatic patients had partial or complete suppression of the ventricular ectopy. Ryujin et a1.9 evaluated 196 children who had PVC on electrocardiograms (ECG). With exercise testing, 29 (15%) had ventricular arrhythmias 8bad couplets, and 21 had VT. They found, however, that 24-hour ambulatory ECG recording was more sensitive than exercise testing in documenting episodes of VT. Noh et al.‘O described studies at our institution in 14 children with normal hearts who presented with VT. With exercise testing, 7 (SO%) patients had VT: 2 during exercise, 1 with recovery, and 4 throughout the test. Additional EP study of each child failed to show a correlation between the inducibility of VT with EP stimulation and the exercise test results. Ten of the patients were treated, 3 of them only briefly. There were no deaths in this group of children with normal hearts. Recently Wiles et a1.6 examined right ventricular endomyocardial biopsy samples from 33 children with normal hearts who had ventricular arrhythmia. Normal myocardial structure was found in 16 (48%) of them; 14 (42%) had changes similar to those of dilated cardiomyopathy, and 3 (9 % ) had lymphatic myocarditis. A maximal exercise test performed in 26 of these children induced ventricular arrhythmia in 4 (15% ), was associated with suppression of all arrhythmia in 11(42%), and demonstrated persistent ventricular arrhythmia in ll(42 8 1. There was no correlation between the biopsy results and whether the ventricular arrhythmia was induced, suppressed, or nonsuppressed by exercise. None of these patients died. The significance of these results of exercise testing in children with primary ventricular arrhythmia remain unclear. The findings appear similar to more extensive test results in children with SVT. If the ventricular arrhythmia is suppressed by exercise, the prognosis appears to be good, The signifi-
-
c
Arrhythmia
FIGURE 3. (A) This electrocardiogram shows nonsustained VT at rest in u 17year-old patient with a structurally normal heart. (B) At 3 minutes of exercise, the rhythm reverted to a normal sinus rhythm with suppression of all ectopic ventricular rhythm. He has received no medical treatment.
55
56
Progress in ~ediut~c Cardiology
cance of induced or nonsuppressed ventricular arrhythmia is not clear. The association of an abnormal heart and exercise-induced ventricular arrhythmia is significant, and patients with this association should be considered for drug therapy and undergo exercise retesting to evaluate its effectiveness. Sinus Node Dysfunction Sinus node dysfunction is uncommon in the normal heart. Because the sinus node is the primary structure for increasing heart rate and cardiac output during exercise, testing may be an important method for assessing sinus node function. Unfortunately, exercise testing is not specific for evaluating sinus node dysfunction. *i If it is used, it is essential that a maximal effort is produced. Most children develop a heart rate of at least 180 bpm during an exercise test. Sinus node dysfunction is demonstrated by rates below 180 bpm with a definite maximal effort, and it is suspected if a precipitous fall in heart rate occurs during the early postexercise recovery period. Bricker et al. compared sinus node recovery times and sinoatrial conduction times during exercise and El’ studies.” No correlations were found with several exercise parameters, including maximal heart rate, acceleration of heart rate, and workload. As with SVT and ventricular arrhythmia, exercise testing for sinus node dysfunction is useful mainly to confirm normal function (Fire 4). Atrioventricular Node Block Exercise testing is well established in patients with congenital complete heart block (CCHB). In 1977, tests in 12 patients showed PVC in 5 (42% ), causing cessation of the testsI The average atria1 rate of the group increased from 72 bpm to 156 bpm with exercise, and the average ventricular rate increased from 42 bpm to 95 bpm. The ventricular rate at rest was lower in the group who had ventricular arrhythmia. In 14 patients with CCHB without other cardiovascular abnormalities, significant ventricular arrhythmia occurred during exercise in 10 (71%).13 There was a strong association between ventricular arrhythmia and the age of these patients. Older patients had greater degrees and more complex ventricular arrhythmia than younger ones. None of these patients died. In evaluating exercise responses in 11 children with CCHB, Karpawich et al.14 found that exercise heart rates did not correlate with syncope. Only 3 (27%) of the children had ventricular arrhythmia
during exercise testing, and syncope was correlated only with resting heart rates below 50 bpm. The American Heart Association Committee on Pacemaker implantation recommends pacemakers for patients with symptomatic bradycardia caused by sinus bradycardia, second degree atrioventricular block, or third degree atrioventricular block. The only reference to the importance of exercise function is in the recommendation for pacemaker use in patients with advanced second or third degree atrioventricular block with “moderate to marked exercise intolerance.“ Moderate to marked exerciw intolerance was not defined. Currently, there are no standards or data that define the role of exercise testing in determining indications for pacemakers. At our institution, we believe that children with CCHB who have exercise-induced PVC or long corrected QT intervals (QT,) may benefit from pacemakers. Long QT Interval Syndrome In patients with presumed long QT interval syndrome, exercise testing may be useful to establish the diagnosis and judge its prognosis. In these patients, it is believed that the QT, interval does not shorten with exercise as it does normally. Measurement of the QT, interval during exercise is difficult and often inaccurate, but measurement 1 or 2 minutes after exercise can identify abnormalities in patients who have normal intervals at rest. In 16 children, Weintraub et al.15 found that the QTE was most prolonged 2 minutes after maximal exercise, and in 2 of the patients, the abnormal QT, was noted only during the recovery period. Only 2 of the patients had a major ventricular arrhythmia during the test and beta-blockade therapy abolished the ventricular arrhythmias on subsequent tests. Von Bemuth et all” found VT during exercise in only 1 of 23 children with long QT interval, and exercise testing was not sensitive in predicting the deaths that occurred in 5 of them. Exercise testing is useful, however, in evaluating the effectiventss of beta-blockade therapy in these patients. Blockade is effective if the maximal heart rate during exercise is below 150 bpm. Sudden Death Sudden unexpected death in children is a dramatic and tragic occurrence. Although this event may not be an appropriate consideration for discussion as a primary arrhythmia, many occurrences are most
Arrhythmia
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FIGURE 4. (A) This patient showed sinus brudycardiu with a junctional escape rhythm at rest 14 years after surgical closure of a ventricular septul defect. (J3) At I minute of exercise he had normal sinus pacing of his heart. (C) During exercise recovery he hud infrequent and isolated PVC. He hus received no treatment and remains asymptomatic.
58
Progress in Pediat~c Cardiology
likely related to an arrhythmia. Furthermore, as many as 25% of sudden deaths in children occur during physical exertion. Syncope during exercise is a particularly worrisome symptom that should be evaluated by exercising testing. Most sudden cardiac deaths in children are due to congenital or acquired heart diseases, such as hypertrophic cardiomyopathy, anomalous origin of the left coronary artery from the right sinus of valsalva, myocarditis, or surgically repaired congenital heart disease. Drug, pacemaker, or surgical treatment of these conditions should be urgently considered if exercise testing is associated with arrhythmia. Pacemaker Function The atria1 electrogram changes with exercise in both animals and childrenI Thischange may affect atria1 sensing function in children with atria1 or dual chamber pacemakers. Other sensing artifacts, such as myopotential inhibition during exercise, can also affect pacemaker function. In children with permanent pacemakers, if upper rate limits are set too low cardiac output can be limited at maximal effort.
SECONDARY ARRHYTHMIA Secondary arrhythmias are those seen after surgical repair or with recognized acquired heart disease; they include sinus node dysfunction, atrioventricular node dysfunction, supraventricular arrhythmia, and ventricular arrhythmia. Only two postoperative lesions will be discussed in detail. Further information about exercise-related arrhythmia can be found elsewhere in this issue of the journal and in the next issue in sections dealing with each cardiovascular lesion. Tetralogy of Fallot More information is available on the significance of arrhythmia in patients who have had surgical repair of tetralogy of Fallot than for any other cardiovascular malformation. Previous reports indicate that 1% to 6% of surgically repaired patients with tetralogy die suddenly, presumably from ventricular arrhythmia.*” Characteristics that predict sudden death remain ambiguous; however, generally accepted risk factors are late ages at operation, poor hemodynamic results, and the presence of ventricular arrhythmia. Exercise testing is routinely included in the evaluation of tetralogy patients
after repair. In studies of 43 patients, James et a1.i9 found 9 (21%) with ventricular arrhythmia during exercise: 2 had VT, 1 had ventricular couplets, 2 had multiform PVC, and 4 had uniform PVC. They postulated that exercise testing was helpful in the management of tetralogy patients at risk for sudden death. In 1979, GarsorP reported follow-up results in 233 operated tetralogy patients. Seventeen of them had no ventricular arrhythmia during exercise. In 2 patients who had PVC before exercise, 1 had suppression of the PVC and 1 had nonsuppression. The number of patients who underwent exercise testing in this series was too small, however, to define the role of exercise testing accurately. In 1980, Garson et aLzOevaluated 104 patients who hadexercise testing after tetralogy repair. Ventricular arrhythmia occurred during or after exercise in 31 (30%), with isolated PVC in 21, multiform PVC in 4, couplets in 4, and VT in 2. Further analysis indicated that the 31 arrhythmia patients had longer postoperative intervals of time and higher right ventricular systolic and end-diastolic pressures than others without exercise ventricular arrhythmia. Late cardiac arrests occurred in 2 (6 %) of the 31 patients, both with poor hemodynamic results and multiform PVC on resting ECG. During exercise testing, one of these patients had suppression of PVC and the other had VT. The authors concluded that exercise testing was sensitive for detecting ventricular arrhythmia in tetralogy patients, and that ventricular arrhythmia was highly associated with poor hemodynamics and sudden death. However, the number of patients with cardiac arrest was too small to establish definitive prediction results. They noted that in documenting the ventricular arrhythmia in these tetralogy patients, the relative usefulness of the resting ECG versus the exercise testing remains uncertain. The incidence of ventricular arrhythmia with exercise testing was remarkably similar in studies of tetralogy patients by Wessel and colleagues.21 Of 91 operated patients who had an exercise test, 28 (31%) had PVC, which in most were suppressed during the exercise itself. None had VT. These 28 patients were older at the time of surgery, had increased heart sizes, and showed subnormal exercise endurance when compared to the 63 patients without PVC. Two patients died, neither of whom had ventricular arrhythmia with exercise testing. At our institution, an evaluation of surgically
A~kytkmia
treated tetralogy of Fallot included 40 patients who had exercise tests. Ventricular arrhythmia before or during the test occurred in 10 (25%), with suppression of PVC in 1, uniform PVC in 7, cou@b in 1, and VT in 1. There was no statistical correlation between the results of EP studies and the type or degree of ventricular arrhythmia with exercise testing. There have been no late deaths. We believe that aggressive drug therapy is appropriate in any operated tetralogy patients who have clinical, exerciseinduced, or EP-stimulated ventricular arrhythmia. The sensitivity and specificity of exercise testing to identify tetralogy patients at risk of sudden death remains unproven. There is some evidence that it does not have an independent prognostic value in the postoperative evaluation of an arrhythmia. The patient who has significant ventricular arrhythmia induced during exercise testing, however, should be strongly considered for therapy, Unfortunately, suppression of ventricular arrhythmia during exercise testing in these tetralogy patients is not as reliable a negative predictor of sudden death as it is in normal children or patients with CCHB. d-Transposition
of Great Arteries
The extensive surgery involved in the atrial switch (Mustard) operation for d-transposition of the great arteries (d-TGA) predisposes to atria1 bradyarrhythmias or tachyarrhythmias. The sick sinus node syndrome, a term used for some of these conditions, often requires pacemaker or drug therapy. Studies of the response to exercise in this group of children have found subnormal levels of maximal heart rate, oxygen consumption, exercise endurHesslein et al.” found ance, and cardiac output. *2~23 subnormal maximal heart rates in 24 (83 % ) of 29 d-TGA patients an average of 6.7 years after surgery. The maximal exercise heart rate did not correlate with clinical symptoms, clinical arrhythmia, or catheterization hemodynamics. Furthermore, EP studies identified sinus node dysfunction only in 56% of patients with abnormally low exercise heart rates. Mathews et a1.23evaluated 21 patients with d-TGA an average of 9 years after repair. Normal sinus rhythm was present at rest in 15 (71%) patients, but only 6 (40%) remained in sinus rhythm with exercise testing. The other patients had a variety arrhythmias, including PAC, junctional rhythm, and PVC. Six (29%) of the 21 remaining patients
59
had arrhythmias at rest that persisted through exercise. One patient with exercise-induced ventricular arrhythmia died suddenly 6 months after testing. Late sudden death, a recognized complication of d-TGA after an atria1 switch operation, has been considered to be more likely from tacharrhythmia than from bradycardia. A definite association between exercise test results and the risk of sudden death has not been established, however.
SUMMARY The physiologic effects of exercise alter the electrical conduction of the heart. Changes in intrinsic sympathetic and parasympathetic activity and in exogenous stimuli to the heart seem to change the substrate for rhythm disturbance. The major clinical use of any medical test is its predictive value, For primary rhythm disturbances, the main benefit of exercise testing appears to be its negative predictive value. More study is needed to determine its positive predictive value. The opposite appears to be the case with secondary arrhythmia. Induction of arrhythmia during exercise is more predictive than is noninduction or suppression.
REFERENCES 1. Rozanski JJ, Dimich I, Steinfeld L, Kupersmith J. Maximal exercise stress testing in evaluation of arrhythmias in children: results and reproducibility. Am 1 Cardiol. 1979;43:951-956. 2. Weigel TJ, Porter CJ, Mottram CD, Driscoll DJ. Detecting arrhythmia by exercise electrocardiography in pediatric patients: assessment of sensitivity and influence on clinical management. Mayo Clin Proc. 1991;46:379-386. 3. Coelho A, Palileo E, Ashley W, et al. Tachyarrhythmias in young athletes. J Am Co11 Cardiol. 1986;7: 237-243. 4. Bricker JT, Porter CJ, Garson A, et al. Exercise testing in children with Wolff-Parkinson-White syndrome. Am I Car&ol. 1985;55:1001-1004. 5. Strasberg B, Ashley WW, Wyndham CRC, et al. Treadmill exercise testing in the Wolff-ParkinsonWhite syndrome. Am 1 Cardiol. 1980;45:742-748. 6. Wiles HB, Gillette PC, Harley RA, Upshur JK. Cardiomyopathy and myocarditis in children with ventricular ectopic rhythm. J Am Co11 Cardiof. 1992; 20:359-362. 7. Bricker JT, Traweek MS, Smith RT, Moak JP, Vargo TA, Garson A Jr. Exercise-related ventricular tachy-
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Progress in Pediatric Cardiology
cardia in children. Am Heart J. 1986;122:186-188. 8. Rocchini AI’, Chun PO, Dick M. Ventricular tachycardia in children. Am J Cardiol. 1981;47:10911097. 9. Ryujin Y, Arakaki Y, Takahashi 0, Kamiya T. Ventricular arrhythmias in children: the validity of exercise stress tests for their diagnoses and management. Jpn Circ J. 1984;48:1393-1398. 10. Noh CI, Gillette PC, Case CL, Zeigler VL. Clinical and electrophysiological characteristics of ventricular tachycardia in young individuals. Am Heart 1. 1990;120:1326-1333. 11. Bricker JT, Garson A, Paridon SM, Vargo TA. Exercise correlates of electrophysiologic assessment of sinus node function in young individuals. Pediatr Exer Sci. 1990;2:163-168. 12. Chawla K, Serratto M, Cruz J, et al. Response to maximal and submaximal exercise testing in patients with congenital complete heart block. Circulation. 1977;56:111-171. 13. Winkler RB, Freed MD, Nadas AS. Exercise-induced ectopy in children and young adults with complete heart block. Am Heart 1. 1980;99:87-92. 14. Karpawich PI’, Gillette PC, Garson A, Hesslein P, Porter C, McNamara D. Congenital complete atrioventricular block: clinical and electrophysiologic predictors of need for pacemaker insertion. Am ] Cardiol. 1981;48:1098-1102. 15. Weintraub RG, Gow RM, Wilkinson JL. The congenital long QT syndromes in childhood. J Am Coil Cardiol. 1990;16:674-680.
16. Von Bemuth G. Tachyarrhythmic syncopes in children with structurally normal hearts with and without Q-T prolongation in the electrocardiogram. Eur ] Pediatr. 1982;138:206-210. 17. Ross BA, Zeigler V, Zinner A, Woodall P, Gillette PC. The effect of exercise on the atria1 electrogram voltagein youngpatients. Pace. 1991;14:2092-2097. 18. Garson A, Nihill MR, McNamara DG, Cooley DA. Status of the adult and adolescent after repair of tetralogy of Fallot. Circulation. 1979;59:1232-1240. 19. James FW, Kaplan S, Schwartz DC, Chou T, Sandker MJ, Naylor V. Response to exercise in patients after total surgical correction of tetralogy of Fallot. Circulation. 1976;54:671-679. 20. Garson A Jr, Gillette PC, Gutgesell HP, McNamara DG. Stress-induced ventricular arrhythmia after repair of tetralogy of Fallot. Am 1 Cardiol. 1980;46: 1006-1012. 21. Wessel HU, Bastanier CK, Paul MH, Berry TE, Cole RB, Muster AJ. Prognostic significance of arrhythmia in tetralogy of Fallot after intracardiac repair. Am 1 Cardiol. 1980;46:843-848. 22. Hesslein PS, Gutgesell HP, Gillette PC, McNamara DG. Exercise assessment of sinoatrial node function following the Mustard operation. Am Heart]. 1982; 103:351-357. 23. Mathews RA, Fricker FJ, Beerman LB, et al. Exercise studies after the Mustard operation in transposition of the great arteries. Am J Cardiol. 1983;51:15261529.