Electrocardiographic Effects of Isoprenaline in Normal Subjects and Patients with Coronary Atherosclerosis1

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Br Heart J: first published as 10.1136/hrt.33.5.759 on 1 September 1971. Downloaded from Britis h Heart Journal, 197I, 33, 759-764. Electrocardiographic effects of isoprenaline in normal subjects and patients with coronary atherosclerosis1

'Harold Wexler, Jafer Kuaity, and Ernst Simonson From Mount Sinai Hospital, 2215 Park Avenue, Minneapolis, Minnesota 55404, and the Laboratory of Physiological Hygiene, University of Minnesota, Minneapolis, Minnesota, U.S.A.

The intravenous infusion of isoprenaline in normal subjects causes no significant electrocardiographic abnormalities. This is in sharp contrast to the remarkably ischaemnic ST-T changes seen after infusing isoprenaline in patients with coronary artery disease. Limited experience thus far has been attended by no untoward reactions. In view of the simplicity and great sensitivity, we conclude that the isoprenaline infusion test is thus far a satisfactory method for differentiating normal subjects from coronary disease patients. It must be emphasized, however, that this is a preliminary report and further study of isoprenaline in patients with coronary disease is man- datory before advocating the routine employment of its use as a diagnostic tool.

During the past I5 years isoprenaline has Subjects gained a progressively important role in clini- Two age-matched groups of 14 clinically healthy cal medicine. Initially it was used to relieve subjects (io men, 4 women, age range from 40-75 W bronchospasm in obstructive lung disease and years, mean age 52) and I7 patients with coronary subsequently has gained a great deal of clinical heart disease (I2 men, 5 women, age range from

use in the treatment of cardiogenic shock, 4I-77 years, mean age 59-I) were investigated. http://heart.bmj.com/ incomplete and complete atrioventricular All patients had at least one well-documented block (Bluestone and Harris, I965; Bellet, myocardial infarction, but none had sustained a I963). Since isoprenaline is a myocardial infarction for at least 6 months before beta-adrenergic this study, none had taken any cardiac drugs, and stimulating agent with chronotropic, ino- none had undergone a recent change in the clinical tropic, and vasodilating properties, it has status oftheir angina. The electrocardiograms had been used extensively in haemodynamic and returned to normal in 6 of the coronary group, obiochemical research related to the cardio- while 7 had only QRS residual abnormalities. In

vascular system (Mendez and Kabela, I966; the remaining 3 patients, flattened or negative T on October 5, 2021 by guest. Protected copyright. Ahn and Vasko, I969; Lafontant, Feinberg, waves were also present in the baseline electro- and Katz, I962). Moreover, isoprenaline has cardiograms. None in the patient group had ST been used in the evaluation of cardiovascular changes before infusion of isoprenaline. In addi- effects in normal subjects, in patients with tion, a normal group of I5 subjects (8 women, 7 coronary artery disease, and in patients with men, age range from 2I to 35 years, mean age 27 4) and a group of io patients (2 women, 8 men, *congestive heart failure (Dodge, Lord, and age range from 40-65 years, mean age 53-4) with Sandler, I960; Eckstein and Hamilton, I957; suspected coronary artery disease, but with nor- Dodge and Murdaugh, 1957). In spite of its mal response to the 'Master two step' test, were wide use in clinical application and research investigated. However, these latter two groups (Krasnow et al., I964; Cohen et al., I966), no were not included in the statistical analysis. systematic study of its electrocardiographic effects, in normal subjects and in patients with Method ,coronary heart disease, has been reported. the of In all subjects a baseline standard i2-lead electro- Therefore, purpose this study is to cardiogram was taken. After an intravenous in- provide this information. fusion of about I0 to 20 ml 5 per cent glucose in Received 22 December I970. water, a second control electrocardiogram was 1 This work was supported in part by a grant from the taken, followed by intravenous infusion of o-2 mg Minnesota Heart Association and by a grant from the isoprenaline in 200 ml 5 per cent glucose in water National Heart Institute, Bethesda, Maryland, U.S.A. at a rate of I-2 ,±g/min, and continued until a heart Br Heart J: first published as 10.1136/hrt.33.5.759 on 1 September 1971. Downloaded from

760 Wexler, Kuaity, and Simonson

TABLE I Mean changes of ST segment and T wave before and after isoprenaline in 14 normal subjects and I7 patients with coronary heart disease

Normal controls Patients Lead ST SD* Ptt T SD Pt ST SD Pt T SD Pt Mean Mean Mean Mean

I -0-14 0.3I O0IO O039 o-9o O12 -i-85 0 55 O0OO0 I 0-22 197 o-68 aVF -0 43 0-5I o-oo6 0o36 o-82 0-12 -124 195 O002I OI5 2.55 o083 V2 -0-14 0o36 o-i6 12I o-96 0-0004 -2 35 I.65 O0OOOI 0o78 2 90 0.3I V6 -0-25 0 43 0-046 0-21 I0OI O045 -I.85 I0OI O0OOOI 0-78 2-25 O-I9

* SD = standard deviation. t Pt= statistical significance from zero change. rate of at least I3/min was obtained. At this point tical methods (xI; t test). Q, R, S, and T deflec- the infusion was discontinued and serial electro- tions were measured according to criteria of the cardiograms were taken immediately, 5 minutes, American Heart Association (I954). and IO minutes after the infusion was discontinued. Though 12 leads were taken, the ST-T Results changes were measured only in 4 (I, aVF, V2, V6) for statistical evaluation with standard statis- Table i shows the mean changes of the ST segment and of the T wave (differences TABLE 2 Mean differences in the response before and after isoprenaline), with standard of ST changes and T changes to isoprenaline deviation (SD), and statistical significance between normal controls and patients with (t test) in the normal control groups and in coronary heartdisease, and statistical significance the group of patients with coronary heart disease. A small, but statistically significant ST depression occurred in the normal control A Lead ST t A T t group only in aVF and V6, while in the - I1.71 9-98* -01-7 0°30 patients with ST depression it was much aVF -o-8i I *50 -0-2I o-i8 more pronounced and highly significant in all V2 -2-2I 469* -043 053 leads. The mean changes of the T wave do http://heart.bmj.com/ V6 -I-6o 5-28* -0.51 104 not show striking differences between the two groups, because the direction of T wave *=P==O-I. changes was not uniform. TABLE 3 Distribution in four leads of significant ST changes (>i mm) and T wave changes ( > 2 mm) after isoprenaline injection in normal controls and in patients with coronary heart disease on October 5, 2021 by guest. Protected copyright. >1 mm 2mm <2mm Total x2 Normal IO 46 56 IO 46 56 Patients 67 I 68 84.9I 42 23 65 26-83 Total 77 47 I24 P=O-OOOI 52 69 12I P=o-ooi

TABLE 4 Incidence of changes of T wave after isoprenaline in direction of negativity (lowering, inversion) or positivity (higher, less inverted, reversal of inversion) dependent on initial T wave (positive; flat or negative). All four leads are pooled. Significance (P), calculated with X2 test

Group - + Total P Group - + Total P Group - + Total P

I I 30 1 I 2 31

Group I-Normal controls; initial T positive. Group II-Coronary art. patients, initial T positive. Group III-Coronary art. patients, initial T flat or negative. Br Heart J: first published as 10.1136/hrt.33.5.759 on 1 September 1971. Downloaded from Electrocardiographic effects of isoprenaline 76I

The difference in the reaction of the ST T wave changes in either direction. All group segment between the normal control group comparisons show highly significant differ- and the group of patients was highly signifi- ences (x2). Nearly all changes in group I are cant except in aVF, while the differences of in the direction of greater positivity, and in T wave changes were not significant (Table 2). group II in the direction of greater negativity. In view of the differences in the direction In contrast to group II, the changes of group of ST-T changes in different patients, we III in the direction of positivity (i.e. reversal analysed the incidence of changes in either of T inversion) are about 24 times more fre- direction of the ST segment exceeding i mm, quent than greater inversion, but less frequent and of the T wave exceeding 2 mm in the than in the normal control. For this reason, pooled material of all four leads (Table 3). group III could obviously not be subjected The justification for this procedure is the to the type of statistical analysis employed in experience with the exercise test; reversal of Table 4. The typical change in the electro- an initially inverted T wave has been con- cardiogram after isoprenaline injection in a sidered since Master (1935) as an abnormal patient with initial T inversion is, therefore, 'response. The incidence of ST changes greater ST depression associated with reversal > i o mm and T changes over 2 mm was of the T wave. This pattern, typical for sub- much greater in the patients, and this differ- endocardial ischaemia, occurs in spontaneous ence, analysed by means of the x2 test, was coronary insufficiency and occasionally after highly significant. exercise, though sloping down ST depression The T wave changes were further analysed is more frequent. in regard to the initial (preinjection) direc- Fig. i illustrates the typically normal re- "tion; positive, flat, or inverted. Flat and in- sponse to isoprenaline with an increase in the verted initial T waves were combined, since T voltage in some of the leads but without any both are abnormal in the leads investigated. significant ST change. Fig. 2 and 3 depict The incidence of changes in the direction of the typical ST-T changes noted in an abnor- negativity or positivity was analysed in three mal isoprenaline response. A T wave reversal subgroups: I-normal controls; II-patients is noted in lead I of Fig. 3 after infusion of with coronary artery disease and positive T isoprenaline. It is of interest to note that 5 waves; III-patients with initially inverted minutes later the T wave has reverted to the or flat T waves. Since the incidence of no (or negative T wave seen in the baseline tracing. minor) changes was included in the analysis There was no essential difference in the of Table 3, Table 4 refers only to significant response to isoprenaline in the younger and http://heart.bmj.com/

FIG. i Normal response to isoprenaline.

I 1. II aVF Vi V2 VI V4 Vb

.l. -l .5.- .. l - .4 -% ..t ".. - lR BEFOREt I. .... et , ...i on October 5, 2021 by guest. Protected copyright. J ., -., I.,SA ,A * I\ th Il .., . I I ...'A

..i ztz .", AFTER .14, .'\ k ". - ,:,.,14., '..z GLUCOSE V A tit. ,

AFTER ISOPRENAIUNE t miduatei

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9 Br Heart J: first published as 10.1136/hrt.33.5.759 on 1 September 1971. Downloaded from 762 Wexler, Kuaity, and Simonson older normal control groups; therefore, the analysis was limited to the age-matched con- mmedtoteIy 5 minutes lOmninutes 50 minutes after ofter after ofter trol group. As anticipated, the incidence of Baselmne soprenaline sSoprenQ tne abnormal responses in the group of patients zsoprena line isoprenaline with suspected coronary disease was some- rK what in between that of the normal control .: A<.A.. group and that of patients with documented . ..^...... e .... s...: . . coronary artery disease. ..k *b~ ...,A;1Z. :. S j . Xi. . i . Discussion W: In io controls not included in the statistical analysis of the isoprenaline study an electro- 4*X;, ' cardiogram was taken after the infusion of c ... :.# . ^ ;0.1.Xq aVR I0 g glucose as 5 per cent glucose in water tL4L AA. over a 30-minute period, and in no instance was a change seen in a subsequent cardiogram. caVL _ ,,, f Less than i g glucose was infused in each of * ...... v S X . our test subjects. None of the subjects in either the normal or abnormal ., w. : j ...j..,..^.. groups s ,: j showed any change in the electrocardiographic H->i.... s.L response to infusing 5 per cent glucose and ... water. In 4 coronary disease patients vector- ...... f r.X-t cardiograms were taken before and after intravenous infusion of isoprenaline and in no case :. be .. ,., S 4, X ...... B could a change in the QRS demonstrated. ;L_t Catecholamines increase the myocardial V2 oxygen consumption and thus produce a .:... -,- fj -': |- [h }.--go stress situation similar to the effect of exercise ...... (Ferrans et al., I964; Raab et al., I962; Raab, I962). Holmberg showed that an increase in f\.0H9 the heart rate is the chief reason for the greater V3 j; If j S .fa. http://heart.bmj.com/ oxygen consumption and coronary blood ...... f ~~~~~~5I~~~~~~~~~~~~~~ AAA~~~~~~~~~~~~~~~~~.... o ..... flow in exercise (I967). It has also been shown '' ...... , ...... X : that catecholamines create an excessive and f .: wasteful consumption of oxygen by the myo- ...... -| 1 r . v * -1 ;.....t...... S . cardium independent of the presence or i absence of external work (Raab et al., I962). V4 .. t..A.S. , w M L\.s In patients with impairment of coronary .. (..: {0 circulation, the increased oxygen demand ..f;£' 1 .. on October 5, 2021 by guest. Protected copyright. cannot be met, resulting in myocardial jV iyr A .. ... hypoxaemia (Raab et al., I962)...... S o |: :! ::,'1:, .. ..s ...... *'..:1.:... '':'s ..:. The clinical corollary is angina produced ...... by physiological stimulation of catechol- ...... amines through excitement, smoking, and .i. , .. i , 4...... *... +k cold exposure (Raab, I962). In 1930, Levine, i ... ,-e1, Ernstene, and Jacobson noted that epine- i.X. i 1. phrine given for the relief of an asthma attack .s .4V :W4.Ia . in a coronary disease patient regularly pro- :< / > ^. .nC duced severe angina. They subsequently pro- .,.fe/ .t posed this as a diagnostic test for angina */ i g... pectoris. Pathological outpouring of cate- {1. : ; 1@ ; FIG. 2 Ischaemic response to isoprenaline with relatively slow return cholamines in cases of phaeochromocytoma to baseline in a patient with initial positive T wave in I, aVF, V6. frequently causes angina and subsequently ...... , .. even myocardial necrosis (Raab, I962). Pro- rauwolfia or guanethidine frequently produce pranolol, a beta-adrenergic blocking agent, is dramatic improvement of angina in cases of often helpful in decreasing the frequency of phaeochromocytoma or hyperthyroidism. angina attacks by counteracting the action of With this in mind one might also speculate catecholamines. Moreover, drugs that deplete about the genesis of the atypical variant form the body stores of catecholamines such as of angina characterized by frequent, almost Br Heart J: first published as 10.1136/hrt.33.5.759 on 1 September 1971. Downloaded from Electrocardiographic effects of isoprenaline 763

Reeves, I965). Both false negative and false immediately 5 minutes Onminutes after after fter positive responses to exercise are frequent. It Baseline isoprenaline ssoprencihne solprenaine is of interest that three of our coronary disease patients with an abnormal response to isoprenaline had normal responses to a double Master's test; however, a progressive exercise test was not performed. The exercise test also requires that the test subject not only be IV 1__ J 7- ambulatory but also quite active physically in R rV order to get a valid test. In the isoprenaline test the subject lies quietly in bed. If T 'Atrial pacing', i.e. increasing the heart rate by electrical stimulation with an electrode in the right atrium, is an excellent test to pro- 7., :.. .. I.: duce myocardial ischaemia (Linhart et al., I969; Lau et al., I968). The physiological ,~.:...:.:~~~~~ ~ ~ ~ ~ ~ ~~~~~~~~~~~~~ ~... basis for this test is the high correlation between heart rate and myocardial oxygen con- I V X sumption (Holmberg, I967). Therefore, when an individual with coronary atherosclerosis J<4#. reaches a critical heart rate, ischaemic ST-T V2~~~~~~~~~~~~~j changes will develop. Unfortunately, the need for cardiac catheterization limits the

A potential application of this procedure. 4 ;, The isoprenaline test itself is simple to per- form. The entire procedure generally did not take longer than 20 minutes. In most instances was done on V4 the study outpatients. The

.~~~~~~~~~~~~~~~~~~~~~~~J...... amount of isoprenaline infused is significantly less than the 5 to 6 [Lg infused intravenously per minute for therapeutic purposes. As a V5H result of the minimal dose side

used, effects, http://heart.bmj.com/ ~~~~~r such as apprehension, tremor, headache, facial flushing, extrasystoles, and sweating, pre- vbj sented little or no problem in our study. The vast majority of the patients noted only an increase in heart rate and in no instance did a FIG. 3 Ischaemic response to isoprenaline in paroxysmal arrhythmia develop. Of greater a patient with initial diphasic or negative T importance is the fact that even though the wave patients in the coronary artery disease group in I, V2, and V6. on October 5, 2021 by guest. Protected copyright. had abnormal electrocardiographic responses, rhythmic, episodes of chest pain seemingly none of the patients had any chest pain or unrelated to physical exertion. Many of these dyspnoea during or after the isoprenaline subjects have a normal electrocardiographic infusion. This is in contrast to the experience response to exercise yet show dramatic ST-T with the exercise and hypoxaemia test. It must shanges during an attack, not unlike those be emphasized that normal subjects respond individuals with phaeochromocytoma. It is to the drug simply by developing a sinus therefore difficult to escape the possibility of tachycardia, but abnormal subjects have a catecholamines playing a prominent role in typically ischaemic ST-T response. In one the production of this type of angina. instance only (Fig. 2) the electrocardiogram Currently the exercise tolerance test is the did not return to the preinfusion baseline I0 most frequently employed stress test for the minutes after discontinuing isoprenaline. In ,arly recognition of coronary artery disease all cases, once the cardiogram returned to the (Master and Rosenfeld, I96i); however, the baseline level it did not subsequently change. test does carry a small risk of precipitating Therefore, it is reasonable to assume that one severe coronary insufficiency. Furthermore, may discontinue the test after the electro- the performance and interpretation of the cardiogram has returned to the baseline level. exercise tolerance test has been and continues Hypoxaemia and drug tests (pitressin, to be the subject of much discussion and con- adrenaline, ergonovine) have been suggested troversy (Mattingly, I962; Sheffield and as diagnostic tests (Levy, Bruenn, and Russell, Br Heart J: first published as 10.1136/hrt.33.5.759 on 1 September 1971. Downloaded from 764 Wexler, Kuaity, and Simonson

I939), but have not gained wide clinical use Krasnow, N., Rolett, E. L., Yurchak, P. M., Hood, because of side slow W. B., Jr., and Gorlin, R. (I964). Isoproterenol and probably effects, reversi- cardiovascular performance. American J7ournal of bility, and possible medical-legal implications. Medicine, 37, 514. The absence of side effects and prompt Lafontant, R. R., Feinberg, H., and Katz, L. N. reversibility in our admittedly small series, (I962). Partition of coronary flow and cardiac oxy- together with the wide therapeutic use in gen extraction between coronary sinus and other coronary drainage channels. Circulation Rcsearch, much higher dosage, is encouraging for con- ii, 686. tinuing the study of isoprenaline as a tool in Lau, S. H., Cohen, S. I., Stein, E., Haft, J. I., Kinney, the early diagnosis of ischaemic heart disease. M. J., Young, M. W., Helfant, R. H., and Damato, A. N. (I968). Controlled heart rate by atrial pacing References in angina pectoris. Circulation, 38, 711. Ahn, C., and Vasko, J. S. (I969). Influences of coron- Levine, S. A., Ernstene, A. C., and Jacobson, B. M. ary blood flow and hypoxia upon the cardiac re- (1930). The use of epinephrine as a diagnostic test sponses to isoproterenol. Annals of Thoracic for angina pectoris. Archives of Internal Medicine, Surgery, 7, 500. 45, 19I. American Heart Association, Committee on Electro- Levy, R. L., Bruenn, H. G., and Russell, N. G., Jr. cardiography (I954). Report: Recommendations (1939). The use of electrocardiographic changes for standardization of electrocardiographic and caused by induced anoxemia as a test for coronary vectorcardiographic leads. Circulation, I0, 564. insufficiency. American Journal of the Medical Bellet, S. (I963). Clinical Disorders of the Heart Beat, Sciences, 197, 241. 2nd ed. Lea and Febiger, Philadelphia. Linhart, J. W., Hildner, F. J., Barold, S. S., Lister, Bluestone, R., and Harris, A. (I965). Treatment of J. W., and Samet, P. (I969). Left heart hemo- heart-block with long-acting isoprenaline. Lancet, dynamics during angina pectoris induced by atrial I, 1299. pacing. Circulation, 40, 483. Cohen, L. S., Elliott, W. C., Klein, M. D., and Gorlin, Master, A. M. (1935). The two-step test of myocardial R. (1966). Coronary heart disease. Clinical, cine- function. American HeartJournal, 10, 495. arteriographic and metabolic correlations. American Master, A. M., and Rosenfeld, I. (I96I). Criteria for the Journal of Cardiology, 17, I53. clinical application of the 'two-step' exercise test. Dodge, H. T., Lord, J. D., and Sandier, H. (I960). Journal of the American Medical Association, 178, Cardiovascular effects of isoproterenol in normal 283. subjects and subjects with congestive heart failure. American Heart Journal, 60, 94. Mattingly, T. W. (I962). The postexercise electro- Dodge, H. T., and Murdaugh, H., Jr. (I957). Cardio- cardiogram. Its value in the diagnosis and prognosis vascular-renal effects of isoproterenol in congestive of coronary arterial disease. American Journal of heart failure. Circulation, I6, 873. Cardiology, 9, 395. Eckstein, J. W., and Hamilton, W. K. (I957). Effects of Mendez, R., and Kabela, E. (I966). Beta-recepters in sympathomimetic amines on forearm venous dis- coronary vessels. Lancet, I, 907. tensibility, pressure and Raab, W. (I962). The sympathogenic biochemical volume. Circulation, I6, http://heart.bmj.com/ 875. trigger mechanism of angina pectoris. Its thera- Ferrans, V. J., Hibbs, R. G., Black, W. C., and Weil- peutic suppression and long-range prevention. baecher, D. G. (I964). Isoproterenol-induced myo- American Journal of Cardiology, 9, 576. cardial necrosis. A histochemical and electron Raab, W., Van Lith, P., Lepeschkin, E., and Herrlich, microscopic study. American Heart,Journal, 68, 71. H. C. (I962). Catecholamine-induced myocardial Holmberg, S. (I967). Effect of severe muscular work hypoxia in the presence ofimpaired coronary dilata- on total and coronary circulation in man in relation bility independent of external cardiac work. to findings in the coronary arteriogram. In Coronary American Journal of Cardiology, 9, 455. Circulation and Energetics of the Myocardium. Ed. Sheffield, L. T., and Reeves, T. J. (I965). Graded by G. Marchetti and B. Taccardia. Karger, New exercise in the diagnosis of angina pectoris. York. Modern Concepts of Cardiovascular Disease, 34, I. on October 5, 2021 by guest. Protected copyright.