Treadmill Arrhythmias in Patients with Idiopathic Hypertrophic Subaortic Stenosis* Robert E. Ingham, M.D.;oO Ronald M, Rossen, AI.D.; Daniel]. Goodman, ~l.D.;t and Donald G. Harrison, AI.D., F.G.G.P.

Treadmill tests were performed in 19 patients with previously documented idiopathic hypertrophic subaortic stenosis (IUSS). Arrhythmias occurred in 79 percent (IS) of the patients, and new arrhythmias not previously documented occurred in over SO percent (10) of the patients. Paroxysmal supraventricular tachycardia (PSVT), ventricular premature beats (VPBs) (two or more per minute) or atrial premature beats (APBs) (three or more per minute) occurred in 10 of 19 patients. There

was no association between treadmill arrhythmias and clinical symptoms, hemodynamic data, or electrocardiographic features. Propranolol administration resulted in failure of exercise to induce PSVT in one patient and had no effect on PSVT in two others, nor any effect on maximum frequency of APBs or VPBs. TreadmiD testing is more productive than retrospective analysis of ECGs for characterizing arrhythmias in IHSS.

Treadmill exercise testing has been reported to be an effective method for eliciting arrhythmias that are not demonstrated on a resting 12-lead electrocardiogram.!" These studies were performed in a population with known or suspected ischemic heart disease,1,2.5.6 and little has been done in other groups of patients at risk from arrhythmias. One such group at risk is patients with idiopathic hypertrophic subaortic stenosis (IHSS), a group which has received extensive study over the past decade in terms of clinical history, hemodynamic features, and effects of therapy."!' Moreover, patients with IHSS are reported to have a variety of electrocardiographic abnormalities, including supraventricular arrhythmias, and symptoms compatible with paroxysmal arrhythmias, such as palpitations, dizziness, and syncope.I!" Beta-adrenergic blockade provides symptomatic relief but has only minimal ('{feet on the obstructive features or the natural history of IHSS.lO.ll Accordingly, this study was carried out to characterize the arrhythmias induced by treadmill exercise in patients with IHSS and to determine the effects of propranolol on these arrhythmias.

METHODS

From the Cardiology Division, Stanford University School of Medicine, Stanford, Calif. This work was supported in part by National Institutes of Health grants HL-5866 and program project grant I-P01HL15833. Presented in part at the American College of Physicians Meetings, San Francisco, April 7-10, 1975. oOPresently at the Division of Cardiology, Naval Regional Medical Center, Oakland Calif. tPresently at Internal t\1edicine Associates, Hackensack, NJ. Manuscript received March 17; revision accepted May 15. o

Reprint requests: Ms. AlcCain, Cardiology Division, 701 Welch Road, Suite 3303, Palo Alto, California 94304

CHEST, 68: 6, DECEMBER, 1975

A group of 19 patients with IHSS diagnosed by clinical history and examination and proved at cardiac catheterization were studied by stress testing. Thirty-two treadmill tests were performed on these 19 patients, 13 of whom were men and six were women, ranging in age from 36 to 69 years. Thirteen patients were given two treadmill tests, one as a control and one while receiving propranolol. Additional tests were performed in six patients who were not receiving long-term propranolol therapy. The diagnosis of IHSS in each patient had been confirmed by previous cardiac catheterization in the Cardiovascular Laboratory at Stanford University Medical Center, Stanford, Calif. The hemodynamic data are presented in Table 1. Three patients (No.9, 14, and 15) tested had previously undergone cardiac myectomy 17 months, 53 months, and II years hefore this testing, respectively. One patient (No. 16) had the preexcitation syndrome. The number of standard 12-lead ECGs performed on each patient prior to treadmill testing ranged from 2 to 13 (average, five) over a period of one month to ten years. Each patient's previous ECGs were reviewed and examined with particular attention to the occurrence of any ectopic beats or arrhythmias occurring on these records. At the time of testing, each. patient's history was reviewed to determine whether they had ever experienced palpitations, dizziness, syncope, chest pain, shortness of hreath, or fatigue. No antiarrhythmic medications were taken during the control test, and if the patient had been receiving propranolol therapy, the medication was discontinued at least 48 hours prior to testing. The dose of propranolol taken during the propranolol test was the same dose the patient took on a regular outpatient basis and which had been determined previously on clinical and hemodynamic grounds. No other antiarrhythmic medications were being taken at the time of the propranolol test, and the doses of propranolol taken during the tests ranged from 40 to 160 mg/day. Silver electrodes were applied firmly to carefully prepared skin sites in the following five locations: the anterior chest wall just medial to both the right and left anterior axillary

TREADMILL ARRHYTHMIAS IN IHSS 759

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(stage 3); 4.2 mph at a l6-percent grade (stage 4); and 5.0 mph at an l8-percent grade (stage 5). The endpoint of exercise for each test was severe breathlessness, fatigue, chest pain, dizziness, diaphoresis, or a heart rate of 160 beats per minute. Life-threatening arrhythmias, such as ventricular tachycardia or multifocal ventricular premature beats ( VPBs ), were also indications for discontinuing exercise. Exercise was not terminated upon development of VPBs, paroxysmal supraventricular tachycardia (PSVT), or atrial premature beats (APBs). The number of VPBs, APBs, and episodes of PSVT were noted during exercise and in a tenminute recovery period. "Significant" arrhythmias on treadmill testing were defined for the purposes of this study as two or more VPBs per minute, three or more APBs per minute, and tachyarrhythmias, such as PSVT, ventricular tachycardia, or bradyarrhythmias, with rates below 40 per minute. All tests were supervised by a physician experienced in stress testing. The exercise laboratory was fully equipped to respond to cardiac emergencies. Informed consent was obtained for all studies. Statistical analysis was performed using Fisher's exact test for one-tailed data. To compare the effects of propranolol on arrhythmias, Student's t test for matched data was used.

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lines in the second intercostal space, in the standard Vr. position, and on the abdomen on the right and left anterior axillary line just superior to the anterior iliac spine. Standard leads 2 and V 5 were recorded continuously on a two-channel electrocardiographic recorder (Hewlett-Packard model 7712) at paper speeds of 5 and 25 mm/sec. Electrocardiograms were also displayed on an oscilloscopic monitor. Prior to exercise, a standard 12-lead ECG with a one-minute strip was recorded. Patients were exercised in the postabsorptive nonsedated state. Exercise was performed on a motorized treadmill in accordance with the protocol of Doan et al.l~ The initial setting was 1.7 mph at a 10-percent grade elevation (stage I). Every three minutes, there was an increase in speed and grade, according to the following sequence: 2.5 mph at a 12percent grade (stage 2) 3.4 mph at a l4-percent grade

160 INGHAM ET AL

Arrhythmias Present on Treadmill Testing. Fifteen of 19 patients (79 percent) tested developed arrhythmias on treadmill testing (Table 2). Eleven patients had one type of arrhythmia, one patient had two different types, and three patients had several types of rhythm disturbance. Ten arrhythmias in nine patients were the same arrhythmias as previously documented by standard 12-lead ECGs. Twelve new arrhythmias not documented on previous ECGs occurred in ten of the patients tested (56 percent). These included PSVT in one patient, VPBs in four patients, and APBs in three patients. In two patients (No.2 and 8 ), stress testing resulted in two new arrhythmias which had not been previously documented (PSVT and VPBs in both cases) (Fig 1 ). Seven of these 12 arrhythmias in five of the ten patients occurred at a "significant" frequency. One patient had previously undocumented PSVT appear, one had two or more VPBs per minute appear, and one had three or more APBs .per minute appear. In the two patients with two treadmill-induced arrhythmias not previously documented, the arrhythmias were both "significant" by our criteria. No Arrhythmias Produced on Treadmill Testing. Only four patients failed to demonstrate arrhythmias on treadmill testing or during recovery. One of the four had a single VPB recorded on previous ECGs, and the remaining three had not had arrhythmias documented previously. Previously Documented Arrhythmias Not Reproduced on Treadmill Testing. Three patients failed to reproduce previously documented arrhythmias; one was the patient noted above who had a single VPB CHEST, 68: 6, DECEMBER, 1975

Table 2-Patienta ",ith Treadmill Arrhythmia. * Patient

Previously Documented Arrhythmias

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Recovery

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*:\F, Atrial fibrillation; APB, atrial paroxysmal beats; PSVT, premature supraventricular tachycardia; and VPB, ventricular premature beats.

previously recorded, and the second was an additional patient with previously documented PSVT. A third patient (No. 14) had PSVT, atrial fibrillation, and APBs recorded prior to a myectomy. At the time of study, 11 years had passed since his myectomy, and only APBs had been documented on serial 12lead ECGs since his surgery. Exercise testing resulted in APBs only. Occurrence of Arrhythmias

The highest frequency of VPBs occurred during the recovery period in 13 (87 percent) of the 15 tests resulting in VPBs (Fig 2). Atrial premature beats occurred most frequently during recovery in ten (77 percent) of 13 tests resulting in APBs. Paroxysmal supraventricular tachycardia occurred only during recovery in two patients and during exercise as well as recovery in one. Correlation of Data uiit}: Treadmill Arrhythmias

No significant statistical correlation could be found between the presence of stress-induced arrhythmias and the hemodynamic data, symptomatology, or ECG data. Effects of Propranolol

Thirteen patients were tested while taking their usual dose of propranolol and again after having stopped propranolol therapy for at least 48 hours. The resting heart rate, the maximum heart rate achieved, and the change in heart rate (the maximum heart rate minus the resting heart rate) were all significantly lower in the propranolol test comCHEST, 68: 6, DECEMBER, 1975

pared to the control test. The maximum frequency of VPBs and the heart rate of their maximum frequency was not significantly affected by propranolol administration. Three patients had VPBs on the control test which were not seen on the propranolol test, while three other patients had VPBs only on the propranolol test and not on the control test. Similarly, the maximum frequency with which APBs occurred was not significantly different between the two tests. All patients who had APBs on the control test had APBs as well on the propranolol test. Three patients had PSVT on the control test, and two of these had PSVT on the propranolol test. The data are summarized in Table 3.

Other Observations On standing control tracings performed on the entire group of patients tested while not receiving propranolol, 14 demonstrated segmental ST depression or T wave abnormality. Nine of the 14 patients increased their ST depression by 1 mm or more with exercise. One patient who did not have ST or T wave abnormalities on his standing control had segmental ST depression of 1 mm after exercise. Six patients with resting ST or T wave abnormalities were retested while receiving propanolol and each again had 1 mm or larger ST depressions, comparable to the control test. The one patient without a resting abnormality who developed segmental ST depression of 1 mm on the control test showed the same abnormality on the propranolol test. None of the four patients with normal ST-T complexes on control testing developed abnormal ST-T complexes on propranolol testing.

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FII;um: 1. Contro l treadmill test of patient 2. A, Standing co nt ro l prior to exe rc ise. B, At tenn ination of exercise a fte r two minutes at sta ge 1 of Do an et al. l~ Maximum he art rate att ai ned was ISO heats per minute . C, Recovery period aft er one minute . Rhythm is PSVT at a rate of 230 . C arotid sinus massag e te rm inutecl thi s e pisode (not shown) , and patient re vert ed to sinus rh ythm at three m inutes of reco ver y ( D) .

762 INGHAM ET AL

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DISCUSSION

Analysis of routine ECGs has formed the basis of past reports associating IHSS with arrhythmias and particularly supraventricular arrhythmias."!" Frank and Braunwald's" large series reported an 8 percent incidence of atrial fihrillation in a group of patients followed an average of 33 months. This series also reported that during the observation period, one-third of the patients had rhythm changes, the majority of which consisted of the appearance or disappearance of ectopic beats. Other studies report similar incidences of atrial fibrillation! " or supraventricular arrhythmias.'! On the other hand, Marriott'! has stated that arrhythmias and atrioventricular conduction disturbances are conspicuously absent in IHSS. More recent observations report that atrial arrhythmias, particularly atrial fibrillation , are associated with clinical deterioration, presumably because of the lack of an effective atrial contribution to the filling of a thickened, noncompliant ventricle.":" While the occurrence of preexcitation syndromes with IHSS has offered some explanation for the frequency of the supraventricular arrhythmias which occur, clearly there are many patients without the diagnostic criteria for preexcitation who develop atrial tachycardias.

CHEST, 68: 6, DECEMBER, 1975

The association of sudden death with IHSS has been suspected, although poorly documented, to be on an arrhythmic basis. Palpitations, however, which are presumably on an arrhythmic basis , have not been correlated with sudden death.P In a recent multicenter study of the natural history of IHSS, neither the presenting symptom nor the clinical class correlated with the occurrence of sudden death." Propranolol administration, in doses which should have some antiarrhythmic effect, similarly has been reported not to protect from sudden death. 13 Retrospective analysis of ECGs to characterize arrhythmias with a given pathologic entity is fraught with difficulties. The lack of sensitivity which a 30second 12-lead ECG has in detecting arrhythmias is well known, even when a number of standard ECGs are performed, as in our patients. While treadmill testing has been widely applied as both a diagnostic and prognostic tool for detecting arrhythmias in patients with known and suspected coronary artery disease,':" there has been relatively little application of this technique for arrhythmia detection to other pathologic entities. The present study demonstrates the feasibility of using treadmill testing for eliciting arrhythmias in patients with IHSS. In 79 percent (15) of the pa-

TREADMILL ARRHYTHMIAS IN IHSS 763

tients, a rhythm disturbance was elicited, and this was a newly documented arrhythmia not apparent on previous ECGs in approximately 50 percent of the patients tested. We attempted to discriminate between the fact that an arrhythmia is present and whether or not it is present with some frequency by defining a "significant" arrhythmia as two or more VPBs per minute, three or more APBs per minute, PSVT, ventricular tachycardia, or other tachyarrhythmias or bradyarrhythmias. When this discriminate analysis is applied to rhythm disturbances induced by treadmill testing, five patients (21 percent) had "significant" arrhythmias not previously documented on various ECGs. Exercise appeared to be particularly effective in eliciting VPBs which had not been previously recorded on routine ECGs. Exercise also resulted in PSVT in three patients in whom it had not been previously documented. Interestingly, PSVT could not be provoked in the one patient tested who had electrocardiographic evidence of a preexcitation syndrome; however, psvr had not been previously documented in this patient. The absence of any significant correlation (albeit with small numbers) between symptoms of palpitations, dizziness, or syncope and treadmill arrhythmias is interesting. Only one of our tested patients complained of palpitations at the time of PSVT. None of the other patients with PSVT or frequent VPBs had any specific symptoms during the testing. Though the numbers are small and the hemodynamic data were obtained some time before exercise testing, the lack of statistical correlation between the hemodynamic data and treadmill arrhythmias suggests that the arrhythmias in patients with IHSS are not related to the severity of outflow obstruction or the degree of left ventricular dysfunction. Alternatively, these arrhythmias may be related to a primary myocardial cellular abnormality, to the characteristic random alignment of myocardial fibers seen on microscopy," the abnormal electrophysiology which these fibers display," or a combination of these factors. While propranolol administration significantly lowered resting, as well as the maximal, heart rates in the patients tested, we were unable to demonstrate any significant effect of propranolol on the maximal frequency of ectopic beats. In those patients in whom the same arrhythmia occurred in both the control and propranolol tests, the heart rate at which the maximum frequency of this arrhythmia occurred tended to be slower in the propranolol test, but these differences were not significant (P < 0.05). Two of three patients with PSVT while not receiving propranolol had PSVT while receiving

764 INGHAM ET AL

propranolol as well. These observations would be in agreement with those of Hardarson et al 13 that propranolol in small doses does not protect the patient from sudden death, if sudden death is on an arrhythmic basis. Similarly, the occurrence of palpitations which are presumably on an arrhythmic basis does not correlate in this study with the presence or absence of arrhythmias induced by stress. REFERENCES

2 3

4

5 6

7

8 9 10

11

12

13

14

15

16

17 18

Kosowsky BD, Lown B, Whiting R, et al: Occurrence of ventricular arrhythmias with exercise as compared to monitoring. Circulation 44:826-832, 1971 Jelenik MV, Lown B: Exercise stress testing for exposure of cardiac arrhythmias. Progr Cardiovasc Dis 16:497-522, 1974 Gooch AS, McConnell D: Analysis of transient arrhythmias and conduction disturbances occurring during submaximal treadmill exercise testing. Prog Cardiovasc Dis 13: 293-307, 1970 McHenry PL, Fisch C, Jordan JW, et al: Cardiac arrhythmias observed during maximal treadmill exercise testing in clinically normal men. Am J Cardiol 29: 331-336, 1972 Anderson MT, Lee GB, Campion BC, et aI: Cardiac arrhythmias associated with exercise stress testing. Am J CardioI30:763-767, 1972 DeMaria AN, Vera Z, Amsterdam EA, et al: Disturbances of cardiac rhythm and conduction induced by exercise. Am J Cardiol 33:732-736, 1974 Braunwald E, Lambrew CT, Rockoff SD, et al: Idiopathic hypertrophic subaortic stenosis: 1. A description of the disease based upon analysis of 64 patients. Circulation 2930 (suppl 4) :IV-213, 1964 Frank S, Braunwald E: Idiopathic hypertrophic subaortic stenosis: Clinical analysis of 126 patients with emphasis on the natural history. Circulation 37 :759-788, 1968 Goodwin JR: Congestive and hypertrophic cardiomyopathies: A decade of study. Lancet 1:731-738, 1970 Swan DA, Bell B, Oakley CM, et al: Analysis of symptomatic course and prognosis and treatment of hypertrophic obstructive cardiomyopathy. Br Heart J 33: 671685, 1971 Stenson RE, Flamm MD, Harrison DC, et aI: Clinical and hemodynamic effects of long-term propranolol therapy. Am J Cardiol 31:763-773, 1973 Doan AE, Peterson DR, Blackmon JR, et a1: Myocardial ischemia after maximal exercise in healthy man. Am Heart J 69: 11-21, 1965 Hardarson T, de la Calzada CS, Curiel R, et al: Progress, prognosis and mortality of hypertrophic obstructive cardiomyopathy. Lancet 2: 1462-1467, 1973 Adelman AG, Wigle ED, Ranganathan N, et al: The clinical course in muscular subaortic stenosis. Ann Intern Med 77 :515-525, 1972 Marriott HJL: Electrocardiographic abnonnaIities, conduction disorders and arrhythmias in primary myocardial disease. Prog Cardiovasc Dis 7 :99-111, 1964 Shah PM, Adelman AG, Wigle ED, et al: The natural and unnatural history of hypertrophic obstructive cardiomyopathy. Circ Res 35 (suppl 2) : 179-186, 1974 Teare RD: CIBA Foundation Symposium: Cardiomyopathies. London, Churchill, 1964, p 11 Coltart DJ, Meldrum 5J: Hypertrophic cardiomyopathy: An electrophysiologic study. Br t\fed J 4:217-218, 1970

CHEST, 68: 6, DECEMBER, 1975