e I CLINICAL INVFSTIGATIONS

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1 e I CLINICAL INVFSTIGATIONS Exercise-Induced Ventricular Tachycardia* Clinical Features, Relation to Chronic Ventricular Ectopy, and Prognosis David M. Mokotoff, M.D.; Miguel A. Quinones, M.D.; and Richard R. Miller, M.D. To determine the c6nlcal status, the occurrence of chronic ambulatory anbythmias, IUld the prognosis of patients with exercise-induced ventricular tachycardia, 26 Jiatients with ventricular tachycardia during or im mediately following exercise on a treadmill were evaluated. Of the 26 patients, 16 had coronary arterial disease, two had nonischemic cardiomyopathy, and eight had no other cardiac disease. Eleven (61 percent) of the 18 patients with heart disease developed ventricu lar tachycardia during exercise, in contrast to sb: (75 percent) of eight normal subjects who had ventricular tachycardia after exercise. In eight patients with repeat stress testing, four (5 percent) had reproducible ventricular tachycardia or malignant ventricular ectopic beats. In 19 (73 percent) of 26 patients, malignant ventricular ectopy occurred on nndom 24-hour E xercise-induced ventricufar tachycardia has generally been thought to occur consequent to severe ischemic heart disease.1-s Furthermore, this event has been regarded as a useful prognostic sign portending a grave clinical course; 1 u however, For editorial comment, see page 1 there are no previously reported ambulatory electrocardiographic monitoring data regarding the prevalence of chronic ventricular tachyarrhythmias in patients with exercise-induced ventricular tachycardia. Because of these important implications, the absence of data concerning a possible correlation with chronic ambulatory ventricular ectopy, and the relative paucity of objective data regarding the nature of underlying heart disease and clinical course, we investigated patients who developed ventricular From the Section of Cardiology, Deparbnent of Medicine, Baylor College of Medicine and the Methodist Hospital, Houston. Supported in part by grant HL from the National Heart, Lung, and Blood Institute. Presented in part at the 24th scientific session of the American College of Cardiology, March 6-8, 1978, Anaheim, Calif. Presently at the Mobile Heart Center, Mobile, Ala. Manuscript received March 26; revision accepted June 27. Reprint requests: Dr. Miller, Cardiologfl Section, 6516 Bettner Blod, HOUBton MOKOTOFF, QUINONES, MILLER electrocardiographic monitoring; ventricular tachycardia occurred in 5/26 (19 percent), and malignant ven tricular ectopic beats occurred in 14/26 (54 percent). Fifteen (83 percent) of 18 patients with cardiac disease vs 4 (5 percent) of eight normal subjects (P <.5) evidenced malignant ventricular ectopy during ambula tory monitoring. Only one episode of sudden cardiac death occurred in 24 patients followed for 21 months. Thus, 3 percent (eight) of the patients with exerciseinduced ventricular tachycardia had no evidence of heart disease. Furthermore, exercise-provoked ventricu lar tachycardia presaged sudden death in only one of 24 patients; however, ventricular tachycardia with ex erclse correctly predicts the presence of chronic ad vanced ventricular ectopic beats or ventricular tachy cardia in 73 percent (19/26) of the patients. tachycardia with maximal stress testing on a treadmill. The goals of the investigation were ( 1) to examine the incidence and type of heart disease present in patients with exercise-induced ventricular tachycardia, ( 2) to evaluate by 24-hour ambulatory electrocardiographic monitoring the incidence and nature of chronic ventricular ectopy in these potentially high-risk patients, and ( 3) to determine the prognosis. MATERIALS AND METHODS The population under study was comprised of 26 patients selected from a total group of 45 consecutive patients who developed ventricular tachycardia during or immediately following multistaged graded-treadmill stress testing utilizing Bruce's protocol. The criteria that determined selection of the 26 patients investigated were the acquisition of at least one 24-hour period of ambulatory electrocardiographic monitoring subsequent to the stress test and the ability to obtain detailed follow-up information. Ventricular tachycardia was defined as three or more successive ventricular ectopic beats during or within six minutes of completion of maximal stress testing on the treadmill. In seven patients, data were obtained prospectively, while analysis of data was performed retrospectively in the remaining 19. In every instance, followup information was obtained by direct communication with the patient or, in the event of death, with the oatient's immediate family and physician. Twenty-four-hour ambulatory electrocardiographic record- CHEST, 77: 1, JANUARY, 198

2 ings were obtained in all 26 patients. The recorders utilized were two-channel recorders (Avionics 445 in 18 patients) or one-channel recorders (Avionics 4 in six patients), and each tape was scanned by an electromagnetic tape scanner (Avionics 66-A). In 16 patients, 24-hour ambulatory monitoring was performed within four days of the stress test during which ventricular tachycardia occurred. The remaining ten patients underwent monitoring an average of 15 months after exercise-induced ventricular tachycardia. A second treadmill stress test was performed in eight patients. Cardiac catheterization with selective coronary arteriograms was performed in 18 (69 percent) of the 26 patients. Ten patients had echocardiqgrams, and in no patient was there evidence of mitral valvular prolapse or hypertrophic cardiomyopathy. Only one of the 26 patients was receiving therapy with a digitalis glycoside or a diuretic at the time of treadmill stress testing, while two were receiving procainamide, six were receiving quinidine, and five were receiving propranolol. In the 16 patients undergoing ambulatory electrocardiograms within four days of stress testing, no change in therapy occurred between treadmill exercise testing and ambulatory monitoring. RESULTS The mean age of the 26 patients was 52 years (range, 28 to 68 years). The mean age of patients with and without heart disease was 5 and 55 years, respectively (P >.5). Twenty-two of the 26 patients were men. Sixteen ( 62 percent) of the 26 patients had coronary artery disease. In 12 of the 16 patients, coronary artery stenosis greater than or equal to 5 percent was documented by arteriograms; five had single-vessel disease, five had twovessel disease, and two demonstrated stenosis of each of the three major coronary arteries. Six ( 5 percent) of the 12 patients demonstrated systolic abnormalities of left ventricular wall motion; no left ventricular aneurysms were identified. In two of the 16 patients, coronary arterial disease was defined by the presence of myocardial infarction on the ECG. In the remaining two patients, coronary artery disease was defined by 1 mm or more of horizontal or downward-sloping electrocardiographic ST-segment depression persisting 8 msec after the J point on exercise stress testing and a history of typical angina pectoris. Two ( 8 percent) of the 26 patients had nonischemic cardiomyopathy by catheterization. Eight patients ( 3 percent) had no heart disease. Four of the eight normal subjects had normal findings on cardiac catheterization, while the remaining four were clinically normal, had no angina or ischemic ST-segment changes on stress testing, and achieved a mean maximal predicted heart rate of 94 percent {range, 88 to 99 percent). Thus, the majority of patients with exercise-induced ventricular tachycardia comprising this population had objectively documented heart disease. CHEST, 77: 1, JANUARY, 198 Minutes N No Heart Disease o Heart Disease 6 6' 1" ~ if A ' FIGURE 1. Duration of treadmill exercise for each of the 26 patients who developed ventricular tachycardia during or immediately following stress testing. Mean value was six minutes and ten seconds. Length of Stress Test and Maximal Heart Rate The mean duration of treadmill exercise was six minutes and ten seconds (Fig 1). There was no significant difference (P>.5) in the duration of exercise between patients with or without heart disease; however, there was a significant difference (P<.1) between the two groups in the mean maximal predicted heart rate achieved. The patients with heart disease achieved a mean heart rate of 76 percent of the predicted maximum vs 91 percent for those without heart disease. Heart Rate and Ventricular Tachycardia The mean heart rate at which ventricular tachycardia appeared for the 26 patients was 14 beats per minute (range, 18 to 175 beats per minute). The heart rate at the onset of ventricular tachycardia was significantly lower (P<.5) in patients with heart disease ( 134 beats per minute; range, 18 to 175 beats per minute), compared to normal subjects ( 154 beats per minute; range, 11 to 17 beats per minute). Onset and Length of Ventricular Tachycardia Thirteen ( 5 percent) of the 26 patients had short bursts of ventricular tachycardia ( ie, three successive ventricular ectopic beats), while the other 5 percent had more sustained episodes (Fig 2 and 3). Fifty percent ( 13 patients) of the group evidenced ventricular tachycardia during exercise, thereby necessitating termination of the test in these patients (Fig 2B). The remaining 13 patients each had ventricular tachycardia within three minutes of discon- UERCISE INDUCED VENTRICULAR TACHYCARDIA 11

3 1 1 A B Percent Percent o~---~;;.a.a,... """'~"""- ouring Post- Exercise Exercise FIGURE 2. A (left), Percentage of patients with three successive ventricular ecotopic beats (VEBs ) vs those with more sustained ventricular tachycardia. B (right), Percentage of patients with ventricular tachycardia during vs immediately following exercise. 1'35" EX. FIGURE 3. Episode of ventricular tachycardia occurring during first stage of Bruce's protocol in patient without other evidence of heart disease. EX, exercise A Percent Percent FIGURE 4. A (left), Incidence of coronary artery disease (CAD) among patients developing ventricular tachycardia after exercise. B (right), Percentage of patients with ventricular ectopic beats preceding onset of ventricular tachycardia. CM, cardiomyopathy. 12 MOKOTOFF, QUINONES, MILL R CHEST, 77: l, JANUARY, 198

4 tinuing exercise for the usual clinical end points. Nine of the 13 patients with ventricular tachycardia during exercise had coronary arterial disease; two had nonischemic cardiomyopathy, and two were normal. Of the 13 patients who developed ventricular tachycardia following exercise, seven ( 54 percent) had coronary artery disease, while the other six ( 46 percent) were normal (Fig 4A). Sustained ventricular tachycardia and three-beat tachycardia during exercise occurred with similar (P>.5) frequency in patients with and without coronary arterial disease. Likewise, the number of complex ventricular ectopic beats and the incidence of ventricular tachycardia on ambulatory monitoring were the same (P>.5) in patients with brief as in those with more sustained exercise-provoked ventricular tachycardia. Preceding A"hythmias Ventricular ectopic beats preceding the onset of ventricular tachycardia and occurring either on the control resting ECG or during exercise occurred in 15 (58 percent) of the 26 patients (Fig 4B). Ten of the 16 patients with coronary arterial disease, both patients with cardiomyopathy, and three of the eight normal patients demonstrated ventricular ectopic beats preceding the development of ventricular tachycardia. Thus, ventricular ectopic beats occurring before ventricular tachycardia tended to be more common in patients with heart disease; however, this difference was not statistically significant (P>.5). Reproducibility of Exercise-Induced Tachycardia Eight of the 26 patients studied had more than one treadmill stress test performed, the mean interval between stress tests being 4.8 months. Of these eight patients, two developed a second episode of ventricular tachycardia on repeat exercise testing, and two other patients manifested complex grades of ventricular arrhythmia defined as paired beats or bigeminy (Fig 5). Neither patient with reproducible ventricular tachycardia had heart disease. Four patients had minimal or no ventrieular ectopic beats on repeat treadmill stress testing (Fig 5). Thus, the reproducibility of complex ventricular arrhythmias with treadmill exercise was 5 percent ( 4/8 ). In four of the patients, antiarrhythmic therapy was unchanged from the first to thcl second treadmill test; in one patient, therapy with propranolol was instituted, and in one, therapy with quinidine was started. The combination of quinidine and propranolol was given to one patient, and the final patient was changed from therapy with propranolol to procainamide. There was no relation between the CHEST, 77: l, JANUARY, 198 Percent O Advanced Insignificant VEBs f!3 or and VTIZI No VEBs F1cURE 5. Reproducibility of exercise-induced ventricular ectopic heats (VEBs) on repeat treadmill stress testing. VT, ventricular tachycardia. use of or change in antiarrhythmic therapy and exercise-provoked ventricular ectopy on repeat treadmill stress testing. Ambulatory ECGs In 19 ( 73 percent) of the 26 patients, malignant ventricular arrhythmias were identified on 24-hour ambulatory monitoring. In the 16 patients undergoing ambulatory monitoring within four days of treadmill stress testing, malignant ventricular ectopic beats were present in ten ( 63 percent), including three with ventricular tachycardia. Three patients had no ventricular ectopic beats. Considering the entire group of 26 patients, 15 ( 83 percent) of 18 patients with heart disease and exercise-provoked ventricular tachycardia manifested either ventricular tachycardia or advanced grades of ventricular ectopy on 24-hour ambulatory electrocardiographic monitoring, in contrast (P<.5) to four ( 5 percent) of eight patients without evidence of heart disease. Ventricular tachycardia occurred in five ( 19 percent) of the 26 patients (Fig 6). Three of the five patients manifesting ventricular tachycardia had evidence of heart disease; two of the five were receiving standard antiarrhythmic agents. Fourteen ( 54 percent) had complex ventricular ectopic beats defined as a frequency of more than 1 percent of the total beats recorded, "R-on-1 phenomenon, multiform, or couplets. The remaining seven patients had either benign or no ventricular ectopic beats: three had heart disease, while four were normal. Thus 15 ( 83 percent) of 18 patients with heart disease and exercise-provoked ventricular tachycardia manifested either ventricular tachycard.ia or advanced grades of ventricular ectopy dur- EXERCISE-INDUCED VENTRICULAR TACHYCARDIA 13

5 75 Percent 5 25 o.._~~... _;;._-----~~~~~--~~_..~ Advanced VEBs t3 and VT ~ 7 Insignificant or No VEBs FIGURE 6. Results of 24-hour ambulatory electrocardiographic monitoring in 26 patients with exercise-induced ventricular tachycardia (VT). VEBs, ventricular ectopic beats. ing 24-hour ambulatory electrocardiographic monitoring, in contrast (P<.5) to four (5 percent) of the eight normal subjects. Follow-Up and Prognosis Twenty-four ( 92 percent) of the 26 patients were contacted for long-term follow-up. The mean interval from the index treadmill test to follow-up was 21 months (range, 1 to 65 months). Twenty-one ( 88 percent) of the 24 patients contacted were alive. One patient with a cardiomyopathy experienced sudden cardiac death 31' years after the stress test during which ventricular tachycardia occurred. A second patient died during coronary arterial bypass surgery from nonarrhythmogenic causes, and the third patient, with no evidence of heart disease by cardiac catheterization, died during a hospitalization for noncardiac disease. Thus, only one ( 4 percent) of 24 patients who developed treadmill exercise-induced ventricular tachycardia subsequently died suddenly of an apparent arrhythmia during an average followup of 21 months. None of the 16 patients with coronary arterial disease and exercise-related ventricular tachycardia experienced sudden death. DISCUSSION In 1927, Boume8 first suggested that an increase in or the appearance of ventricular premature beats after exercise was a sign of coronary arterial disease. Subsequently, there have been several reviews of exercise-induced ventricular ectopy,w.7-9 and of ventricular tachycardia;1-12 however, little attention has been given to the specific phenomenon of exercise-induced ventricular tachycardia.13 The ap- pearance of ventricular tachycardia with exercise testing has been thought to occur primarily in a setting of severe ischemic heart disease and to portend a grave prognosis; 1..s however, several reports have differed with these views In the present investigation, 62 percent ( 16) of the 26 patients with exercise-induced ventricular tachycardia had objective documentation of ischemic heart disease, while an additional 8 percent ( 2/ 26) had proven nonischemic cardiomyopathy. Interestingly, 15 percent (4/26) of our population had normal coronary arteries and left ventricular function confirmed by selective coronary arteriograms and left cardiac catheterization, while an additional 15 percent ( 4/26) had no evidence of coronary arterial disease or left ventricular dysfunction by extensive noninvasive evaluation. Importantly, in the present investigation the appearance of ventricular tachycardia during exercise strongly suggested heart disease ( 11/ 13; 85 percent); in contrast, this tachyarrhythmia occurring immediately after exercise was not useful in distinguishing between normal subjects and patients with heart disease. Goldschlager et al 2 observed that when all ventricular ectopy is considered, it more commonly occurs during the recovery period after exercise, and its occurrence at this time is more predictive of coronary arterial disease than the appearance of ventricular ectopy during exercise. It appears, therefore, that the onset of ventricular tachycardia occurring with exercise is more specific for underlying heart disease than the occurrence of ventricular premature contractions alone. The mechanism for exercise-induced tachycardia occurring in the "structurally normal heart" is not clear. Psychologic and neurophysiologic factors may predispose certain normal individuals to malignant 14 MOKOTOFF, QUINONES, MILLER CHEST, 77: l, JANUARY, 198

6 ventricular arrhythmias. 15 Another possibility relates to changes in electrophysiologic properties of conduction which favor reentry and occur during maximal exercise. It has been well documented that of patients who demonstrate exercise-induced ventricular ectopy, the frequency of premature ventricular beats increase proportionally to the heart rate achieved with maximal exercise. 5 That the malignant character of ventricular ectopy may increase with faster heart rates is less clear; however, this possibility must be considered in the present group of normal subjects who achieved a mean maximal predicted heart rate at the time of onset of ventricular tachycardia of 154 beats per minute (range, 11 to 17 beats per minute), compared with a mean of 134 beats per minute (range, 18 to 175 beats per minq.te) (P<.1) in the group of 18 patients with heart disease. Digitalis intoxication or diuretic-related hypokalemia cannot be implicated as a precipitating factor in this study, as only one patient was receiving these agents at the time of the index exercise test. The extent of coronary arterial disease encountered in the present population differs somewhat from that previously reported in patients with malignant ventricular arrhythmias with exercise. In this regard, we found a surprisingly large percentage of patients with one-vessel and two-vessel disease. Only two of the 18 patients studied had three-vessel disease; however, interestingly, abnormal wall motion was present in 5 percent ( 6/ 12) of the coronary patients, although no patient had a left ventricular aneurysm. The average heart rate at the time of the occurrence of the ventricular tachycardia was 14 beats per minute; however, this rate was significantly (P<.5) higher in the group of normal subjects ( 154 beats per minute) than in those with heart disease ( 135 beats per minute). This finding is in agreement with the already recognized relationship between the level of exercise and the appearance of ventricular arrhythmias;5 that is, with increasing heart rates, more ventricular ectopic beats are seen, even in normal patients. 5 Also, it has been established that patients with heart disease develop ventricular arrhythmias at lower levels of exercise, compared to normal subjects. a Warning ventricular ectopic beats ( ie, ventricular ectopic beats appearing in the control ECG at rest or during exercise, but before the appearance of ventricular tachycardia) tended to be more common in those patients with heart disease. These preceding ventricular arrhythmias occurred in 58 percent ( 15/ 26) of the total group. Thus, in 42 percent (11/26) of exercise tests, there was no warning when ven- CHEST, 77: l, JANUARY, 198 tricular tachycardia appeared. This differs somewhat from what has been described previously. 18 Of the 16 patients with coronary artery disease in the present series, only five ( 31 percent) developed ischemic ST-segment changes before the appearance of ventricular tachycardia. Ventricular arrhythmias appeared with exercise in 34 patients with heart disease in the series reported by Gooch and McConnell, 7 yet only 21 percent (7/34) had concomittant ST-segment changes diagnostic of ischemia. Goldschlager et al2 also found that exercise-induced ventricular arrhythmias often occur in the absence of ischemic ST-segment changes or angina. Thus, exercise-induced ventricular tachycardia in patients with coronary disease appears to often precede electrocardiographic evidence of ischemia. With regard to the reproducibility of exercise-related ventricular ectopy, in the present investigation, 5 percent (four) of eight patients undergoing repeat treadmill stress testing demonstrated advanced grades of ventricular premature beats. Only two patients had ventricular tachycardia again with exercise. Reproducibility of serious ventricular arrhythmias therefore was 5 percent ( 4/ 8). This is in close agreement with the reproducibility of serious exercise-induced ventricular arrhythmias found by others In the present investigation, 24-hour electrocardiographic ambulatory monitoring performed at variable intervals following treadmill stress testing indicated a close relation between exercise-induced ventricular tachycardia and malignant grades of ventricular ectopy. Thus, 73 percent ( 19/26) of the total population demonstrated malignant forms of ventricular ectopy; and, moreover, approximately 2 percent ( 3/ 16) of our patients manifested one or more episodes of ventricular tachycardia during ambulatory monitoring. Of the 18 patients with heart disease in this investigation, 83 percent ( 15 ) evidenced serious forms of ventricular ectopy, while 5 percent (four) of eight patients without heart disease had absent or less malignant grades of ventricular ectopy. Therefore, exercise-induced ventricular tachycardia predicts a high likelihood of serious ventricular premature beats or ventricular tachycardia (or both) during 24-hour ambulatory monitoring in patients with heart disease. The most surprising finding in the present investigation was the relatively good prognosis, even in the patients with coronary arterial disease. Of our 26 patients followed for a mean duration of 21 months, only one patient could be found with well-documented sudden cardiac death. Several factors may have affected this surprisingly good outcome. The majority of patients with coronary disease had one- DERCISE-INDUCED VENTRICULAR TACHYCARDIA 15

7 vessel or two-vessel disease, in contrast to a predominance of two-vessel and three-vessel coronary arterial stenoses in patients previously reported with exercise-precipitated ventricular arrhythmias Additionally, with the exception of the two patients with cardiomyopathy, one of whom experienced sudden death, none of our population had evidence of severe left ventricular dysfunction. Furthermore, one-half of the normal patients in the present study had no malignant ectopy on 24-hour monitoring, suggesting that the episode of exercise-provoked ventricular tachycardia was a very transient and brief electrophysiologic event, perhaps related to maximal and unusual exercise. Finally, it is unknown if ventricular tachycardia of longer duration than three beats relates to a greater likelihood of sudden death. Nevertheless, our data indicate that the occurrence of ventricular tachycardia with exercise does not necessarily portend a grave prognosis, even in patients with coronary arterial disease. ACKNOWLEDGMENT: We are grateful for the technical assistance of Ms. Gay McAllister, the statistical support of George Terrell, Ph.D., and the secretarial skills of Ms. Kathy Cullen. 1 Ellestad MH: Stress Testing: Principles and Practices. Philadelphia, F. A. Davis, 1975, p Goldschlager N, Cake D, Cohn K: Exercise-induced ventricular arrhythmias in patients with coronary artery disease: Their relation to angiographic 6ndings. Am J Cardiol 31:434-44, McHenry PL, Morris SN, Kavalier N, et al: Comparative study of exercise-induced ventricular-arrhythmias in normal subjects and patients with documented coronary artery disease. Am J Cardiol 37 :69-615, Udall JA, Ellestad MH: Predictive implications of ventricular premature contractions associated with treadmill stress testing. Circulation 56: , Blackburn H, Taylor HL, Damrell B, et al: Premature ventricular complexes induced by stress testing. Am J Cardiol 31:441-45, Bourne G: Attempt at the clinical classification of premature ventricular beats. QJ Med 2: , Gooch AS, McConnell D: Analysis of transient arrhythmias and conduction disturbances occurring during submaximal treadmill exercise testing. Prog Cardiovasc Dis 13:293-37, Lown B, Graboys TB: Management of patients with malignant ventricular arrhythmias. Am J Cardiol 39:91-918, Jelinek MV, Lown B: Exercise stress testing for exposure of cardiac arrhythmias. Prog Cardiovasc Dis 16: , Lown B: Ventricular tachyarrhythmia: Clinical aspects. Circulation 47 : , Lesch M, Lewis E, Humphries JD, et al: Paroxysmal ventricular tachycardia in the absence of organic heart disease: Report of a case and review of the literature. Ann Intern Med 66:95-96, Chapman JH, Shrank JP, Crampton RS: Idiapathic ventricular tachycardia: An intracardiac electrical, hemodynamic and angiographic assessment of six patients. Am J Med 59:479-48, Forker AD, Wilson CS, Weaver WF: Exercise-induced "benign" paroxysmal ventricular tachycardia with normal coronary arteries. Nebr Med J 58: , Kosowsky BD, Lown B, Whiting R, et al: Occurrence of ventricular arrhythmias with exercise as compared to monitoring. Circulation 44: , Lown B, Temte JV, Reich P, et al: Basis for recurring ventricular fibrillation in the absence of coronary heart disease and its management. N Engl J Med 294: , Gooch AS: Exercise testing for detecting changes in cardiac rhythm and conduction. Am J cardiol 3: , Cantwell JD, Fletcher GF: Instant electrocardiography: Use in cardiac exercise program. Circulation 5: , Crawford M, O'Rourke RA, Ramakrishna WR, et al: Comparative effectiveness of exercise testing and continuous monitoring for detecting arrhythmias in patients with previous myocardial infarction. Circulation 5:31-35, MOKOTOFF, QUINONES, MILLER CHEST, 77: l, JANUARY, 198