Effects of intravenously administered propranolol on wall motion abnormalities

Effects of Intravenously Administered Propranolol on Wall Motion Abnormalities

PHILIP LUDBROOK, MBBS, MRACP. MRCP (UK) JOEL S. KARLINER, MD, FACC WILLIAM KOSTUK, MD, FRCP (C) RDBERT A. O’ROURKE, MD, FACC San Diego,

California

From the Cardiovascular Division, Department of Medicine, University of California, La Jolla, Calif. This study was supported in part by U. S. Public Health Service MIRU Contract PH 43-68NHLI-1332; National Heart Foundation of Australia (Dr. Ludbrook); and Ontario Training Fellowship, Ontario Heart Foundation and Royal College H. K. Detweiler Travel Fellowship (Dr. Kostuk). Manuscript received October 26, 1972, accepted Januarv 17. 1973. Address for reprints: Robert A. O’Fiourke, MD, University Hospital of San Diego County. 225 West Dickinson St., San Diego, Calif. 92103.

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Although propranolol is frequently utilized as therapy for angina pectoris in patients with previous myocardial infarction, its effects on wall motion abnormalities in such patients have not been adequately defined. Accordingly, using external wall motion video tracking, we studied 18 patients with previous myocardial infarction and wall motion disorders and 5 normal subjects before and after administration of propranolol, 5 mg intravenously. Systolic time intervals, heart rate and left heart size (measured by the distance between the mid-line and left heart border in an X-ray film triggered at end-diastole after a standard inspiration) were also measured before and after administration of propranolol. In each instance propranolol produced a reduction in the amplitude and velocity of wall motion in areas of normal movement, hypokinesis and paradox, resulting in decreased outward bulging. In the normal subjects, the amplitude and velocity of wall motion also decreased. In the patients with previous myocardial infarction, propranolol increased the ratio of the preejection period to the left ventricular ejection time from a mean of 0.377 f 0.03 (standard error of the mean) to 0.409 f 0.03 (P KO.001); decreased heart rate by an average of 7.5 beats/min (P
It has been suggested that local disturbances in left ventricular wall motion provide a functional basis for the impairment of cardiac performance in patients with chronic coronary artery disease.1 Whether or not cardioactive drugs administered to such patients affect wall motion abnormalities is of considerable clinical importance, especially in patients with impaired cardiac function. Although beta adrenergic blocking agents are being used with increasing frequency in treating angina pectoris, such therapy has the potential disadvantage of causing myocardial depression. It has previously been observed in a small group of patients that intravenously administered propranolol induces or exacerbates paradoxical wall motion.” Accordingly, the present study was designed to document the effects of propranolol on normal and abnormal wall motion by using the noninvasive technique of radarkymographic video tracking,as4 which permits continuous analysis of the movement of selected segments of the left ventricular wall.

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TABLE

AND WALL

MOTION

ABNORMALITIES-LUDBROOK

ET AL.

I

Clinical Data in 18 Patients

Months Since

Current Angina

Wall Motion Abnormality -

Electrocardiographic Site of Infarct

Case no.

Age (yr) & Sex

Infarct

1 2 3

58M 48M 30M

19

-

24 13

-

Ant sept; inf Ant sept; inf Ant sept; lat

4

45M

30

-

Ant; inf

5

53M

6

6

58M

24

Ant lat

7

73M

5

Ant lat

8 9 10

62M 67M 56M

5 24 6

Ant sept

11

60M

22

Ant lat

12

38M

2

-

Ant lat

13 14

59F 69M

8 3

+ +

Ant sept; apical Ant sept; lat

15

60M

6

-

Ant sept

16

38M

6

-

Ant

17 18

63F 57M

6 6.

-

Ant sept Ant lat; inf, apical

Ant lat = anterolateral;

Dyskinesis Hypokinesis Dyskinesis Hypokinesis Asynchrony Dyskinesis Hypokinesis Asynchrony Hypokinesis Asynchrony Dyskinesis Hypokinesis Hypokinesis

Ant sept; inf

Inf; apical Inf

+

ant sept = anteroseptal;

inf = inferior;

Methods Eighteen patients (mean age 55.2 years, range 30 to 67) who had had a documented myocardial infarction 2 to 30 months previously were studied in the supine basal state between 8 AM and 12 noon (Table I). All of these patients had wall motion abnormalities demonstrated either by prior left ventriculography or by video tracking (see later). Five subjects without cardiovascular disease (mean age 41.6 years, range 35 to 69) were also studied. Administration of digitalis, quinidine and propranolol was discontinued for at least 24 hours before the examination. Base-line scalar electrocardiogram, arterial blood pressure determined by cuff sphygomanometer and heart rate were recorded and subsequently monitored throughout the procedure. No patient had systemic hypertension or electrocardiographic evidence of left or right bundle branch block. Wall motion video tracking was performed as previously described334 with use of a commercially available device (Biotronix Heart Motion Video Tracker) with a frequency response, tested by means of a generated sine wave display, that decreased by 3 db at a frequency of 16 Hz. With use of a 23 cm image intensifier the fluoroscopic cardiac image was displayed on a Plumbicon television sys-

Site

Type

lat = lateral;

Hypokinesis Hypokinesis Hypokinesis Asynchrony Dyskinesis Hypokinesis Asynchrony Dyskinesis Hypokinesis Hypokinesis Dyskinesis Hypokinesis Dyskinesis Hypokinesis Dyskinesis Hypokinesis Hypokinesis Dyskinesis Hypokinesis

Mid, low lat; apex Mid, low lat; inf Low lat; apex Mid lat Inf, post Mid; low lat Inf Apex Apex High, mid lat Apex Inf High, mid, low lat, apex Low lat, apex Mid low lat, inf Mid, low lat Low lat, apex Low lat, apex High lat Mid lat Apex Inf Apex Mid, low lat Inf Low lat Mid lat Low lat Apex Ant lat Low lat, apex High, mid lat

post = posterior,

tem and either recorded on video tape for later analysis or tracked directly during fluoroscopic studies. The analog video signal also was recorded on a Honeywell Visicorder photographic system for subsequent analysis. After a standard inspiration, recordings were made of the left ventricular free wall at selected high, mid and low sites in the posteroanterior and left anterior oblique projections*i ‘inferior and posterior wall movement was similarly recorded in the left anterior oblique and left lateral projections. In each patient the amplitude and velocity of wall motion were calculated at these selected sites before and after each intervention (Fig. 1). The value of the amplitude and velocity of wall motion in each patient was obtained by averaging at least 3 beats in which satisfactory tracings were recorded. Correction of these values for heart rate did not significantly alter them. Abnormal wall motion was classified according to a modification of the terminology employed by Herman and Gorlinl: Dyskinesis was defined as paradoxical systolic expansion; asynchrony was considered present when the temporal sequence of contraction was disturbed, early inward movement being followed by late paradoxical expansion or vice versa; and hypokinesis was defined as diminished wall motion (Table I).

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Normal Areas

ABNORMALITIES-LUDBROOK

Hypokinet ic Areas

ET AL.

Dyskinetic Areas

CONTROL a bJVF-q-+

c+-Jq~~~

PROPRANOLOL

?

Measurements of systolic time interuals were made from simultaneous recordings of a high-frequency phonocardiogram, the indirect carotid arterial pulse and the electrocardiogram on a multichannel recorder (Elena-schonander Mingograf) at a paper speed of 100 mm/set. Calculations of mean intervals were derived from measurements of 10 optimally recorded cardiac cycles. Observed time intervals were corrected for heart rate and sex according to the regression equations of Weissler et al.5 and were expressed as indexes. The ratio of preejection period to left ventricular ejection time was obtained by dividing the observed value for preejection period by the uncorrected value for left ventricular ejection time, since it has previously been shown that this ratio is independent of heart rate.5 The external left heart dimension was utilized as an index of left ventricular size.6 This value is obtained by measuring the distance from the mid-line to the widest point on the left heart border on a standard chest X-ray film exposed precisely at end-diastole by means of an electrocardiographic gating device after a measured inspiration of 1,000 ml from functional residual capacity. It has previously been shown that the external left heart dimension correlates well with cineangiographic measurements of left ventricular cavity size.6 After giving informed consent, the 18 patients and the 5 normal subjects underwent control measurements of systolic time intervals, left heart dimension and the amplitude and velocity of left ventricular wall motion at the selected sites indicated earlier. Twenty minutes after the intravenous administration of 5 mg of propranolol over 5 minutes, the same measurements were repeated. Neither significant bradycardia nor hypotension was observed after administration of propranolol.

Results Base-line wall movement: The types and sites of abnormal wall motion observed in the base-line re-

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L-L/J-

n

FIGURE 1. Representative radarkymographic recordings of normal (a), hypokinetic (b) and dyskinetic (c) areas of wall motion before and 20 minutes after administration of propranolol, 5 mg intravenously.

cording in each of 18 patients with coronary heart disease are listed in Table I. In 15 patients, all of whom had had an anterior or lateral wall infarction, areas of paradoxical wall motion were recorded at those sites. Seventeen patients had areas of reduced or inadequate wall motion (hypokinesis) recorded in the basal state, and in 5 patients areas of asynchrony were noted. Effects of propranolol on wall movement: In areas of normal wall motion in the patients with coronary heart disease, propranolol produced a significant reduction in both mean amplitude (34 percent) and velocity (41 percent) of movement (P
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after administration of propranolol (P 144 msec) in 2 patients. The average left ventricular ejection time index was 393.2 f 7.1 msec and was abnormal (C408 msec) in 11 patients. The ratio of preejection period to left ventricular ejection time averaged 0.377 f 0.03 and was abnormal (>0.417) in 4 patients.? After administration of propranolol, mean preejection period index increased by 7 percent to 139.7 l 5.0 msec (P
AND WALL

MOTION

ABNORMALITIES-LUDBROOK

WALL MOTION NORMAL AREAS (N=18)

+7

AMPLITUDE

HYPOKINETIC AREAS (N=17)

ET AL.

(mm)

DYSKINETIC AREAS (N=15)

+6 +5 +4

I =1SE

+3 +2 +1

c 0

c

P

P

-1 -2 p< .OOl p< .OOl +zL _ p< .OOl FIGURE 2. Average wall motion amplitude of normal and abnor-4

mal areas during control (C) measurements and after intravenous administration of propranoloi (P). 1SE = 1 standard error of the mean.

Discussion The deleterious effects of propranolol on both cardiac pump and muscle function have been well documented.8-10 For this reason, the presence of impaired cardiac function has frequently been considered a relative contraindication to the clinical administration of beta adrenergic blocking drugs. Since a high proportion of patients with chronic coronary artery disease, particularly those who have had a previous myocardial infarction, have some degree of abnormal wall motion,4 it is relevant to consider the possible effects of these drugs on such abnormal left ventricular wall movement. If propranolol induces dyskinesis or exacerbates preexistent aneurysmal bulging, deterioration in cardiac performance might be expected to occur regularly in patients with previous myocardial infarction who are treated with beta adrenergic blocking drugs. Our results indicated, however, that dyskinesis was not exaggerated by administration of propranol01 and new dyskinetic areas were not observed where none previously existed. These data appear to favor the use of propranolol when indicated in patients with coronary heart disease, even in the presence of wall motion abnormalities. That significant depression of cardiac performance was induced by the dose of propranolol used was reflected in the increases in the preejection period index and in the ratio of the

WALL NORMAL AREAS (N=18)

MOTION

VELOCITY

HYPOKINETIC AREAS (N=17)

(mmhc) DYSKINETIC AREAS (N=15)

+40

I =lSE

+30 +20 +I0

c

P

0 -10 -20 -30

L

F p< a01

p< .OOl

p<.ool

FIGURE 3. Average wall motion velocity of normal and abnormal area before (C) and after intravenous administration of propranolol (P). 1SE = 1 standard error of the mean.

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NON-INVASIVE

ABNORMALITIES-LUDBROOK

MEASUREMENTS

A HEART

BEFORE & AFTER PROPRANOLOL

A PEPI

A HEART RATE {beatdmin)

SIZE (mm)

ET AL.

A LVETI

A PEP/

LVET (m/see)

(m/set)

I =1‘%d

15

T

10

0.02 0.01

5 rl

-

-4 -8 p< .OOl

TABLE

0

-5 1J

-10

p‘C.001

p< .OOl

p< .OOl

II

Noninvasive Measurements Before and After Administration of Propranolol, 5 mg Intravenously

0-W

Heart Rate (beats/ min)

94.3 2.6 97.3 2.6 3.2

67.1 2.9 59.6 2.6 11.2



Heart Size

Control zk SEM Propranolol zt SEM y0 change P value __~

PEPI (msec)

LVETI (msec)

PEP/ LVET

130.6 4.7 139.7 4.9 7
393.2 7.1 387.3 7.7 2 <0.4(NS)

0.377 0.03 0.409 0.03 8.2
LVET = left ventricular ejection time; LVETI = left ventricular ejection time index; P = probability; PEP = preejection period; PEPI = preejection period index; SEM = standard error of the mean.

preejection period to left ventricular ejection time observed in the patients with coronary heart disease. Cardiac size as assessed by the left heart dimension also increased. Although heart rate slowed, it has been shown that there is no significant relation between the externally measured Lft heart dimension and cardiac rate between heart rates of 75 to 100 beats/min.G As indicated earlier, correction for heart rate of the alterations in mean amplitude and velocitv of the left ventricular wall did not alter the results. Beta adrenergic blockade produces a- number of of physiologic responses, including the diminution of myocardial contractility, both by direct depression

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FIGURE 4, Changes (A) in heart size, heart rate, preejection period index (PEPI), left ventricular ejection time index (LVETI) and ratio of preejection period to left ventricular ejection time (PEP/ LVET) after intravenous administration of propranolol. ISEd = standard error of the difference; p = probability.

myocardial function and by reduction of the sympathetic adrenergic “drive” to the myocardium.g This finding is convincingly demonstrated by the observed significant reduction in amplitude and velocity of both normal and abnormal wall motion. The following considerations may apply to the latter observations: As a result of the decreased contractility, the rate of rise of intraventricular systolic pressure is lessened, and the outward distending force on the ventricular wall is diminished, with consequent reduction in outward systolic bulging. In contrast to our results, the left ventriculographic studies of Helfant et al.2 showed that intravenously administered propranolol either induced or exaggerated asynergy in 5 subjects, 3 of whom had coronary heart disease. However, more recently, Pasternac and co-workers” demonstrated that wall motion abnormalities could be produced or intensified by atria1 pacing, an intervention that would be expected to increase myocardial oxygen demand.12.13 On the basis of the latter observation, it might be predicted that beta adrenergic blockade, which acts to decrease heart rate and myocardial oxygen consumption, should reduce the extent and severity of asynergy, which was the result we observed. Few data are available concerning the effects of beta blockade on systolic time intervals. After intravenous administration of 10 mg of propranolol in 37 normal resting subjects, Harris and associates documented an average increase of 10 msec in the preejection period uncorrected for heart rate.14 Hunt et al.15 noted an increase of 8 msec in the preejection period index in 3 of 5 normal resting male subjects, and a reduction of 8 and 3 msec, respectively, in the

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remaining 2 patients. We have shown that significant changes in systolic time intervals consistent with a reduction in left ventricular performance can be produced in patients with coronary artery disease after intravenous administration of 5 mg of propranolol. Thus, although it has been demonstrated that

namid status,la these meazkements do appear to be reliable for assessing changes produced by the dose of propranolol used in this study, especially when each patient is used as his own control.

systolic time intervals are tlot entirely reliable for the separation of groups of normal subjects from patients with coronary artery disease and normal hemody-

We are indebted to Joseph Byrne, CPT, and Mr. Wray Amon for expert technical assistance. We also acknowledge the invaluable assistance of Dr. Allan Simon.

Acknowledgmerit

References 1. Herman MV, Gorlin RG:. Implications of left ventricular asynergy. Amer J Cardiol23:538-547, 1989 of left ven2. Helfani RH, Herman MV, Gorlin R: Abnormalities tricular contraction induced by beta adrenergic blockade. Circulation 43:841-647, 1971 3. Schuette WH, Simon AL: A new device for recording cardiac motion. Med Res Eng 7:25-27.1988 4. Kazamias TN, Gander MP, Ross J Jr, et al: Detection of left ventricular wall motion disorders in coronary artery disease by radarkymugraphy. New Eng J Med 285,2:83-71, 1971 CD: Bedside tech5. Weissler AM, Harris WS, Schoenfeld niques for the evaluation of ventricular function in man. Amer J Cardiol23:577-583, 1989 TM, Gander MP, Gault JH, et al: Roentgeno8. Kazafnias graphic assessment of left ventricular size in man: a standardized method. J Appl Physiol 32, 8:881-884, 1972 7. Weissler AM, Garrard CL Jr: Systolic time intervals in cardiac disease. Mod Cone Cardiovasc Dis 40: l-4,1971 E: Clinical and hemodynamic ap8. Epstein SE, Braunwald praisal of beta adrenergic blocking drugs. Ann NY Acad Sci 139:952-987.1987 Amer J Car9. Stephen SH: Unwanted effects of propranolol. diol 18:483-488, 1988 10. Parmley WW, Braunwald E: Comparative myocardial de-

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12.

13.

14.

15.

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pressant and antiarrhythmic properties of d-propranolol, d-l propranolol and quinidine. J Pharm Exp Ther 158:11-21, 1987 Pasternac A, Gorlin R, Sonnenblick EH, et al: Abnormalities of ventricular motion induced by atrial pacing in coronary artery disease. Circulation 451195-l 205, 1972 Covell JW, Ross J Jr, Taylor R, et al: Effects of increasing frequency of contraction on the force velocity relation of left ventricle. Cardiovasc Res 1:2-8, 1987 Boerth RC, Covell JW; Pool PE, bt al: Increased myocardial oxygen consumption and contractile state associated ‘with increased heart rate in ddgs. Circ Res 24:7$5-734, 1989 Harris WS, Schoenfeld CD, Weissler AM: Effects of adrgnergic redeptor activation and blockade on the systolic preejection period, heart iate, and arterial pressure in man. J clin Invest 48:1704-1714, 1987 Hunt D, Sloman G, Clark RN, et al: Effects of beta adrenergic blockade on the systolic time intervals. Amer J Med Sci 259:97-l 13,197o MeConahav DR. Martin CM. Cheitlin MD: Resting and exercise systoic time intervals-correlations with ventricular performance in patients with cdronary artery disease. Circulation 45:592-801, 1972

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