Effect of Oral Propranolol on Left Ventricular Performance in Patients with Ischemic Heart Disease

Effect of Oral Propranolol on Left Ventricular Performance in Patients with Ischemic Heart· Disease* Ear Densitographic Study during Uninterrupted Treadmill Exercise Tetsuro Sugiura, M.D.; Yoshinori L. Doi, M.D.; Bruce G. Haffty, M.S.; Thofntls Fitzgerald, B.S.; Richard L. Bishop, M.D.; and David H. Spodick, M.D., F.C.C.P. The effect of oral propranolol on left ventricalllr performance daring early upright exercise was evaluated by ear delllitography in patients with arteriograpbic coronary IU'tery disease (CAD). Measurements of systolic time intervals cWferentiated 10 unmedfcated patient& with CAD (group 1) and 15 patients with CAD taking propranolol (group 3). The padents in group 3 bad less lbortening of preejecdon period at 1 minute and 4 minutes of exercise than group 1 patients (p<0.001 and p
Leftpatients ventricular performance during exercise in with ischemic heart disease has been

actively investigated using various noninvasive methods. 1-' Radionuclide methods, for example, show decreased ejection fraction during exerciseinduced ischemia. 1.a Recently, systolic time intervals obtained by ear densitogram during continuous treadmill exercise demonstrated an abnormal fall in PEP I LVET (an inverse correlate of ejection fraction) in early exercise, followed by a rerise or no further decrease in patients with coronary artery disease (CAD), in sharp contrast to normal subjects who consistently showed continued decrease.• This was explained as rapid utilization of functional cardiac reserve followed by functional deterioration in the coronary patient. Although effects of oral ,8-blocking agents on LV performance during exercise have been extensively investigated, their effect on global LV function during acute ischemia remains poorly defined. 54 The present study was designed to ( 1) assess the effects of ,8-adrenergic blockade on LV function during •From the Cardiology Division, St. Vincent Hospital, and the University of Massachusetts Medical School, Worcester. Manuscript received November 20; revision accepted june 7. Reprint requests: Dr. S,odick, St. Vincent Hospifol. Worcuter, Massachusetts 01604

571

product both at rest and during exercise. Furthermore, PEP/LVET and percentage change in PEP/LVET &om control responses were similar to those of subjeds free of CAD (group l). These results indicate that propranolol effects a favorable change in LV performance by postponing early exhaustion of cardiac reserve, despite significant CAD. There was relatively large overlap in percentage change in PEP/LVET from control between group l and group 3 in contrast to the dear separation among unmedicated patients. Thus, the exceDent diagnostic accuracy of systoUc time intervals recorded during exercise is greatly reduced by tt-adrenoceptor blockade.

continuous exercise using ear densitographic systolic time intervals in patients with CAD, and ( 2) evaluate the diagnostic accuracy of this method in detecting CAD in patients receiving propranolol. MATERIAL AND METIIODS

Sub;ects

We investigated 15 men (mean age± SD, 50± 8 years) receiving long-term oral propranolol ( 80 to 320 mg/day) therapy with subsequent angiographic demonstration of significant CAD (more than 50 percent narrowing of at least one major coronary artery); ten patients were also taking low-dose oral isosorbide dinitrate (15 to 60 mg/day). No nitrates were taken at least four hours prior to the test. Since the response to exercise in this subgroup was indistinguishable from that of patients taking propranolol alone, it was not analyzed separately (Table 1) . The LV performance of the 15 patients was compared with that of unmedicated patients with coronary disease ( 15 angiogrampositive patients) and without coronary disease (seven angiogram-negative patients plus ten normal volunteers with indistinguishable exercise responses). Erercise Protocol and Measurements

The test was performed on a Quinton No. 18-54 treadmill without interruption at speeds of 1.7, 1.7, 2.5, 3.4, 4.2, and 5.0 mph; corresponding elevations, 5, 10, 12, 14, 16, and 18 percent (first stage, one minute; others, three minOral Propranolol and Left Ventricular Performanca (Sug/ura et a/)

Table 1--Com,.,U,n Be,.,een Patienu Receillir&« Propranolol-Nitratu (n 10) and Propranolol.4lone (n 5)•

=

PEP/LVET

,.------'-------,

Group

c

Group A Mean SD

51 4

36 5

Group B Mean SD

50 2

35

NS

NS

p

%-:~PEP/LVET ~

=

PEP

,.------'-----,

LVET

,.------'--------.

,.------'-------,

1 min

4min

c

32 4

30 6

37 5

133 11

99 12

87 13

261 277 14 19

270 20

63 6

84 9

97 11

76 114 13 19

141

32 2

30 2

35 4

125 8

95 4

86

251 270 16 11

265 10

64 6

86 11

95 8

80

125

7

11

148 12

NS

NS

NS

NS

NS

NS

NS

NS

NS

NS

1 min 4 min

1 min 4 min

3

c

HRxBPxlO-t

HR

,.------'-----,

NS

1 min 4min

NS

NS

c

1 min 4min

c

1 min 4 min

NS

22

NS

*Group A =Patients taking propranolol and nitrates; Group B=patients taking propranolol alone. C =resting control (standing); 4 min=four-minute exercise; HR=heart rate; HRxBS=heart rate-blood pressure product; LVET-left ventricular ejection time; n=number of patients; NS=not significant; 1 min=one-minute exercise; P=probability; PEP-pre-ejection period; %APEP/LVET=percent change in PEP/LVET from control; SD=standard deviation. utes each). The test was considered positive with 1 mm or more of horizontal or downsloping ST depression at 80 msec after the QRS in three consecutive beats. Data for systolic time intervals were recorded from an ear densitograph pulse derivative via Hewlett Packard No. 780-10 photoelectric earpiece according to previously reported methods. •,o·12 The systolic time intervals and heart rate were obtained by Summagraphics digitizer coupled to a DEC-10 computer and calculated from means of five consecutive beats. Statistical Analysis

Differences between the groups were tested by performing an analysis of variance followed by a multirange t test. The statistics were performed using the MBDP-1V statistical package developed at the UCLA.

fu:suLTS

The patients in this report constituted three groups for analysis: group 1, unmedicated patients with CAD ( n = 10); group 2, unmedicated subjects free of CAD (n=17); and group 3, CAD patients taking propranolol ( n = 15). Because two patients could only exercise for ~ minutes, we adopted common points of one and four minutes for measurement. Group 1 vs Group 3

The distribution of coronary lesions was comparable in the patients of group 1 and 15 patients of Table 2--DiHae (>50% Ocelwion) • of Major Coronary A.rteriu

No. of Vessels Involved Group

n

1

2

3

1

10

2t

6

2

3

15

2

10

3

*Twenty of 25 rami were over 75% occluded. tone was > 75% left main coronary occlusion.

group 3, with a preponderance of two-vessel disease in each (Table 2) . The very small numbers in each group with one- and three-vessel disease preclude any attempt to statistically associate individual exercise responses with extent of coronary narrowing. The effects of propranolol on heart rate and blood pressure (Table 3) showed that patients in group 3 had significantly slower heart rate than those in group 1 at rest, at one minute, and at four minutes of exercise ( p < 0.005, p < 0.005, and p < 0.01, respectively). The heart rate-blood pressure product in group 3 was significantly smaller at rest, at one minute, and at four minutes of exercise ( p < 0.005, p < 0.001, and p < 0.005, respectively) than in group 1. The effect of propranolol on systolic time intervals (Table 3) showed no significant differences in preejection period, LV ejection time index, and PEPI LVET ratio between the two groups at rest. The preejection period decreased in both groups, but at one minute and four minutes of exercise, the preejection period in group 3 was significantly longer than in group 1 ( p < 0.001 and p < 0.005, respectively). The LVET increased from standing control at one minute, then decreased toward control at four minutes in both groups, with no significant differences at one minute and four minutes. The left ventricular ejection time index ( LVET! = 1.2 X HR + LVET) 13 increased with exercise without significant differences between two groups. The PEP/LVET decreased with exercise, and at one minute it was greater in group 3 than in group 1 ( p < 0.05). Although the difference between the two groups did not reach statistical significance at four minutes (p = 0.057), the response of group 3 resembled that of group 2 ( p = 0.18) more than group 1. In group 3, the peak exercise PEP/LVET occurring between~ and 14 minutes in individual CHEST I 82 I 5 I NOVEMBER, 1982

577

=

Table 3---Com,_.._ Be,__ Urunediefdal (n 10) aJUl Itledleflled (n .;:: 15) p--.,. FWa CorOJUII'T .4rf.rr Dilleue* Group

HR

% 4PEP/LVET

PEP

LVET

LVETI

PEP/LVETx100

80±17 78±12 63±5 <0.005 NS

127±13 122±10 130±11 NS NS

237±27 244±22 258±15 <0.05 NS

333±14 338±13 334±13 NS NS

54±3 50±5 51±4 NS NS

One-minute exercise Group 1 103±17 Group2 98±14 Group 3 85±10 p (1 V8 3) <0.005 p (1 V8 2) NS

83±8 92±10 98±10 <0.001 <0.05

262±26 259±23 275±17 NS NS

385±17 377±15 377±13 NS NS

32±2 36±4 36±4 <0.05 <0.005

41±4 29±4 30±5 <0.001 <0.001

151±17 141 ±12 139±14 <0.05 NS

Four-minute exercise Group 1 113±20 Group2 107±14 Group 3 96±10 p (1 V8 3) <0.01 p (I V8 2) NS

74±8 85±10 87±10 <0.005 <0.01

252±25 251 ±23 269±17 NS NS

388±16 379±14 384±13 NS NS

29±3 34±4 32±4 NS <0.005

45±5 32±4 36±4 <0.001 <0.001

165±17 154±18 150±14 <0.05 NS

BP

&sting control (standing)

Group 1 Group2 Group 3 p (1 V8 3) p (1 VB 2)

125±17 122±8 122±15 NS NS

•Group 1-Unmedicated patients with coronary artery di.seue; Group 2-Normalsubjects; Group a-Patients with coronary artery di.seue taking propranolol. BP-systolic blood pressure; LVETI -left ventricular ejection time index; other abbreviations as in Table 1.

patients compared with four-minute values showed both increases and decreases (Table 4). Percentage change from control in PEP I LVET (~M>EP I LVET) at one minute and four minutes was significantly smaller in group 3 than group 1 ( p < 0.001 and p < 0.001, respectively).

those without it.• In the present study, as compared with ten unmedicated patients with CAD (group 1), 15 patients with comparably extensive CAD who were treated with propranolol (group 3) showed sigTable 4.--PEP/LYET Re.pome. at Each Sta•e o/ E:rerciH (Group 3)•

Croup 2 and 3 ~APEPI LVET

The ~M>EPI LVET at one minute and four minutes in individual patients with CAD taking propranolol (group 3) were compared with that of normal subjects (group 2; Fig 1). Both groups were nearly identical at one minute. Although there were signiBcant differences between the two groups at four minutes (p < 0.05), there was considerable overlap. Exercise ECC

Among the 15 patients receiving propranolol therapy (group 3), live patients met the criteria for positive exercise test, three of whom also had angina pectoris. An additional patient had typical angina in the absence of diagnostic ECG abnormalities. The test was terminated in the remaining nine patients due to fatigue or dyspn
Measurement of systolic time intervals by ear densitography during continuous upright exercise was previously shown to clearly differentiate individuals with arteriographic coronary disease &om 178

Peak Exercise, ECG 1 min 4 min min Response

Patient

c

1

48

35

33

35

2

51

37

33

3

53

42

4

54

5

Angina

p

Yes

37 (8)

p

Yes

37

27

N

No

35

33

33 (7)

p

No

43

27

24

25 (8)

p

No

6

45

30

27

24 (8)

N

No

7

52

37

31

31

(6~)

N

Yes

8

57

39

35

28

(7~)

N

No

9

55

43

38

37 (8)

N

No

10

51

33

32

26 (5)

N

No

11

50

34

33

23 (14)

N

No

12

48

35

34

34

p

Yes

13

50

36

31

24 (11)

N

No

14

49

34

30

30 (10)

N

No

15

53

37

34

31 (10)

N

No

(4~)

(11~)

(4~)

•ECG-electrocardiogram; N -no significant ECG changes during exercise, P- positive exercise test. Other abbreviations as in Table 1. C-control Oral Propranolol and Left Ventricular Performance (SIIfllura et a/)

%AP%. LVET

e < O.OQI

P< 0.001

p < 0 .05

n.s.

(%)

P
60

I

I c

50 D

EP 40

~ aD

I

I

fc ~

A

p
0

ri EI 8

0

GROUP I

GROUP 2

!

GROUP 3

I

A

~I

tl r

0

go

20

I

0

GROUP

I MINUTE

nificant differences in systolic time intervals as well as reduction of heart rate. Although serum levels of propranolol were not measured in this study, significantly lower resting and exercise heart rates in the medicated patients indicate that the dosage was effective. There was less shortening of the preejection period in group 3 at one minute and four minutes compared with group 1; furthermore, group 3 had greater PEPILVET at one minute and four minutes. Therefore, .B-adrenergic blockade tended to abort the abnormal shortening of preejection period and decrease in PEP I LVET during early submaximal exercise. The major determinants of pre-ejection period are myocardial contractility (inotropic state ) , LV end-diastolic pressure, and aortic diastolic pressure.14-16 In a previous report, we postulated that abnormal shortening of preejection period in patients with CAD during early exercise was due to greater increase in left ventricular end-diastolic pressure or greater adrenergic stimulation or both. 4 The cardiac action of propranolol is attributable to ,8-adrenergic blockade, which would decrease sympathetic augmentation of function. It also indirectly increases LV compliance through its action on ischemic segments, which would reduce abnormally elevated LV end-diastolic pressure. 17•111 Both of these mechanisms could explain its favor-

I

4

GROUP

2

GROUP

MINUTES

3

FiGURE 1. Percentage fall ( $4) in PEP/LVET from control in each subject at one minute and four minutes. Squares represent unmedicated subjects with CAD (group 1), circles, unmedicated subjects free of CAD ( group 2), and triangles, subjects with CAD taking propranolol (group 3). Values are mean± SD.

able effect on the preejection period. Our results show identical LVET and heart ratecorrected LVET (ejection time index) in the two groups during exercise, suggesting that the effects of ,8-blockade on the basic deterniinants of LVET, stroke volume, and ejection rate are approximately balanced. The ratio PEP I L VET is a well-accepted and widely used correlate of another expression of LV function, ejection fraction.19•20 The patients receiving propranolol (group 3) showed PEP I L VET and %.:1PEP I LVET response similar to that of normal subjects (group 2) during early exercise. Thus, in contrast with unmedicated patients with CAD (group 1), they could postpone the early exhaustion of cardiac reserve despite their significant CAD. Along with the heart rate-blood pressure product, which is highly correlated with myocardial oxygen requirement, 21 this behavior of PEPILVET suggests that propranolol favorably changes LV performance during early treadmill exercise. In this connection, it has been shown that at submaximal exercise, ejection fraction may increase in patients with coronary disease before a final decrease at maximum stress. 22 In six patients, we terminated the test because of positive ECG changes or typical angina or both. Interestingly, at peak exercise, the PEPILVET in all six patients showed no further decrease from four-minute values. The remaining nine patients CHEST I 82 I 5 I NOVEMBER, 1882

579

terminated the test without ECG or subjective signs of ischemia. In this group, eight of nine patients showed improvement of PEPILVET at peak exercise. This variability of the effect of propranolol on LV performance at peak exercise may be due to differences in the degree of exercise-induced ischemia. It has been reported that propranolol affects the diagnostic accuracy of exercise radionuclide angiography in patients with CAD. 7 Our previous studies demonstrated percentage change from control in PEP I L VET ( %aPEP I L VET) to be an accurate indication of angiographic CAD in unmedicated patients. The present study shows a great overlap between CAD patients taking propranolol (group 3) and unmedicated subjects free of CAD (group 2). Thus, propranolol appears to shift the responses of patients with CAD toward normal. Indeed, propranolol thus produces "false-negative" responses. Propranolol evidently protects patients from the effect of ischemia at the cost of reducing the diagnostic accuracy of systolic time intervals in detecting CAD. ACKNOWLEDGMENT: We gratefully acknowledge Kathleen Moreau, L.P.N., Delores Paladino, R.N., and Linda Cook, L.P.N., for technical assistance, and Mary Ellen DeSantis for secretarial assistance. REFERENCES

1 Borer JS, Bacharach SL, Green MV, Kent KM, Epstein SE, Johnston GS. Real-time radionuclide cineangiography in the noninvasive evaluation of global and regional left ventricular function at rest and during exercise in patients with coronary-artery disease. N Eng) J Med 1977; 296 :839-44 2 Jengo JA, Oren V, Conant R, Brizendine M, Nelson T , Uszler JM, et al. Effects of maximal exercise stress on left ventricular function in patients with coronary artery disease using first pass radionuclide angiocardiography: a rapid, noninvasive technique for determining ejection fraction and segmental wall motion. Circulation 1979; 59:60-65 3 Slutsky R, Karliner J, Ricci D, Schuler G, Pfisterer M, Peterson K, et al. Response of left ventricular volume to exercise in man assessed by radionuclide equilibrium angiography. Circulation 1979; 60:565-71 4 Sugiura T, Doi YL, HaHty BG, Moreau KA, Bishop RL, Spodick DH, et al. Noninvasive assessment of left ventricular performance in patients with ischemic heart disease: ear densitographic study during uninterrupted treadmill exercise. Am J Cardiol 1981; 48 :101-05 5 Frishman W, Smithen C, Befler B, Kligfield P, Killip T. Noninvasive assessment of clinical response to oral propranolol therapy. Am J Cardiol 1975; 35:635-44 6 Pine M, Favrot L, Smith S, McDonald K, Chidsey CA. Correlation of plasma propranolol concentration with

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7

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9 10 11 12 13 14

15 16 17 18

19

20

21

22

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Oral Propranolol and Left Ventricular Performance (Sug/ura et a/)