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Hemodynamic effects of propranolol in coronary heart disease
Hemodynamic
Effects of Propranolol
Coronary JOHN 0.
Heart Disease*
PARKER, M.D., F.A.c.c., ROXROY 0. WEST, M.D. and SALVATORE DI GIORGI, M.D. Kingston,
Ontario,
T
Canada
surements of ventricular filling pressures or volume. The present study was designed to determine the hemodynamic changes induced by propran0101 at rest and during exercise in patients with coronary heart disease with and without exertional angina and in a control group of normal subjects.
HERE have been several reports on the use of the beta adrenergic blocking agent propranololt in patients with coronary heart disease and angina pectoris. While there is agreement that the oral administration of this drug in patients with angina pectoris is generally followed by a favorable therapeutic response,1-4 studies following the intravenous administration of propranolol have shown hemodynamic alterations that would suggest caution in the use of this drug. Most authors observed depression of cardiac performance at rest and during exercise as shown by elevation of right”*6 and left ventricular filling pressures,‘j increase in heart size,‘s8 prolongation of the systolic ejection period9 and subnormal increase in the velocity of shortening of myocardial fibers during exercise* with a fall in stroke volume.g Propranolol would also block the vasodilator effect of beta adrenergic stimulation on the coronary arteries. In contrast to these findings Wolfson and coworkerslO found a decrease in systolic and enddiastolic volumes of the left ventricle, decrease or unchanged left ventricular end-diastolic pressure, with insignificant changes in stroke volume, systolic ejection period and systolic ejection rate following the intravenous administration of propranolol. These workers found a reduction in coronary blood flow at rest after propranolol although in 1 patient when the drug was infused during spontaneous angina there was evidence of coronary vasodilatation. There is limited information on the effects of propranolol on the hemodynamic response to exercise in patients with coronary heart disease,g-*l and in these studies there were no mea-
MATERIAL AND METHODS Case Material: Three groups of patients were studied. Group f consisted of 10 patients with coronary heart disease who presented a typical angina1 syndrome. Eight had clinical and electrocardiographic evidence of myocardial infarction which had occurred from 6 to 24 months before the study. The remaining 2 patients had typical ischemic changes in the resting or postexercise electrocardiogram. Group 2 consisted of 12 patients with coronary heart disease who did not experience exertional angina. Eleven had clinical and electrocardiographic evidence of myocardial infarction which had occurred from 6 to 30 months before the study while the remaining patient had ischemic changes in the resting electrocardiogram but no clear evidence of previous myocardial infarction. Patients were not included if they had cardiac enlargement, ventricular aneurysm, congestive heart failure, atria1 fibrillation, valvular heart disease, or pulmonary disease; none was receiving digitalis or diuretics. Group 3 consisted of 5 subjects who had no demonstrable cardiac or pulmonary disease. Procedure: On the day prior to the investigation, the patients were brought to the laboratory where the procedure was explained, the resting ventilation recorded, and supine leg exercise on a bicycle ergometer practiced. In the patients with angina a work load was selected that would induce the pain of acute coronary insufficiency within the first three or four minutes of exercise but would not prevent the completion of steady exercise for seven minutes. The patients without angina and the normal subjects
t Propranolol (Inderal@) supplied by Ayerst Laboratories, Montreal, Quebec, Canada.
* From the Cardiopulmonary Laboratory, Department:of Medicine, Queen’s University, This study was supported in part by Grant 2-13 from the:Ontario Heart Foundation. VOLUME
21,
in
JANUARY
1968
11
Kingston,
Ontario.
12
Parker? West and 13 Giorgi
were cxerciscd at comparablc \*.ork loads ranging from 700 to 1000 kg.-M. ,‘min. Studies \vcre made in the l&tin: postahaorptivt. state without premeditation. Under local anesthesia, the right brachial artery and tllr: right median clll,ital vein \vert‘ isolated, and a doublr lumen No. ‘1 (:ournand catheter \vas inserted into the right side of tllc heart so that the tip lay in the pulmonary artc’r). .I No, 8 Sones cathrtcr was advanced from the. riqllt brachial artery into the left ventricle. and a C:ot~rnantl needle was imrrtccl into thr lrft t)r-achial ar‘tc~. Three or four rletrrminations \verr madc OP 1111.prt.;sures in the pulmonar)~ artery. right vcntriclt’. lt.lt ventricle and brachial artery during 3 i0 mimlte rest period, and the cardiac output I\ as measurrtl during the final t\vo minutex. Exercisr 12’as then pvrformed for seven minutes at the preclrtcrminecl work load. The intracardiac and intravascular prcssurrs were measured al the completion of thr first minuteof exercise and at t\ro minute intervals thrrcaftcr: the cardiac output \vas measured during thr final two minutes of exercise. Aftrr a rest period of 30 minutes, the intracardiac and intravascular prrssurt’s and cardiac output \vrre measured at rest. ant1 tllt.rl 0.15 mg.1 kg. of propranolol \vas rapidly injrctrtl into ‘I’ht~ pressures \vcrf‘ m?asurctI the pulmonary artery. at one, three, five, eight and twelvr minutes, and ttlc. cardiac output determined between the ninth and eleventh minute. -4 second period of exercise at tht‘ same work load was commenced from 12 to 14 minu tcs after the administration of this drug, and the tlcmodynamic data \vere recorded as during tllr initial
exercise period Hemo~ynami~~Studirs: ‘I‘hc prt’ssures were rccordtd by means of P23Db Statham strain-gauges from a zero .Sy+ reference Ievrl -5 cm. below thy sternal angle. tolic and diastolic pressures were calculated tq averaging individual systolic and diastolic points over at least 11~0 respirator! cycles. and the tnean pressures in the brachial artery and pulmonary arter) ‘l‘hc cardiac orltprlt \\;a~ were derived electronically. measured by thr indicator-dilution technic employing indocyaninc qrccn. ‘l‘he dye was injectrtl into thr right ventricle. and blood \vas withdra\\n rrom the. brachial artery needle through a Gilford densitornrtt-1 at a rate of 3X.5 ml. ‘min. with a Ijarvard apparatu\ pump. Pressures and dye curves were insrrilWtl on an Electronics for hfedicine DR-8 photograpllic, rccorcler. The oxygen consumption was determined IQ collecting expired air in a ‘Fissot spirometer for two minutes ancl analyzing the oxygen and carbon dioxide content by the micro-Scholander method. ‘l’his was determined lvith each measurement of cardiac output. The follozcirrg parameter.! were derived; Left uentricufar stroke worX Ade.v in gm.-M ./‘M .:! I+ using the formula: LvswI
=
(EJ$m
-
LVEDP)
1000
X SI X 13.0
\,vllrrc. B:\m
=
I.\.l
brachial
artery
mean
.\lrrrn .ix.rtolic Pjf(tion rate in nil. 111~ formlila: hZSER \\
pressure
in mm.
Hg = left ventricular end-diastolic pressurcr in mm. Hg = stroke index in ml., M.’ = conversion factor for the density of Hq sec.
M.’
bb-
using
= SJ,SEP
IIt‘l’f’ SI
= stroke
SEP
= systolic
index
in ml. ‘M.’
ejection
period
E:w~,~w fuctor calculated output in ml./!min. per oxygen consumption.
as the increase 100 ml.‘min.
I,P~[ wntricular work in kg.-M.
LVW
in see.
= I,VS\,VI
/M.”
in cardiac increase in
by
tilt’
x HR
left ventricular stroke work M.” heart rate in beats,,‘min. ?br/Con-time index in mm. mula :
usinq
the
for-
= brachial artery mean pressure in mm. = heart rate in beats,‘min. = systolic ejection period in see.
Hg
‘l”L’1 = BAm
Hg/min.
in kg.-M.
X HR
using
X SEP
\vtlrrc H:Irn HR SEP
.We&v~ coronar~urteriography and left uentriculo,qaphj \vcrr carried out in all of the patients and in the control subjects following the completion of these hemocl!,namic studies. Significant obstructive disease was rlrmonstrated in at least two of the major coronary vc~rls in tile patients with coronary disease. and the coronary arteriograms \vere normal in the rontrol SLIbjKtY. KES~JLTS
.-\I1 of the perienced four
minutes
10 patients
pain
in the
of coronary which
angina
group
insufficiency
persisted
until
ex-
within
the
termina-
In 9 of the 10 chest pain developed during exercise after propranolol; 1 remained free of pain. In this patient (Case 9) the hernodynamic effects of propranolol at rest and during exercise were indistinguishable from those observed in other members of the group. None of the patients without tion
of the
first
exercise
‘I’HEAMERICAN
period.
JOURNAL
OF
CARDIOLOGY
Propranolol in Coronary Heart Disease .
CP’
.
.
Gp II
. f------f
R
Rp
E
EP
FIG. 1. Left mztricular end-diastolic pressure (mm. Hg) at rest (R) and during exercise (E) before and after administration of propranolol (p) in patients with angina (group l), those without angina (group 2) and in normal subjects (group 3).
angina and no control subject experienced chest pain during either exercise period. Table I* shows the hemodynamic findings in each of the three groups at rest and during exercise before and after the administration of propranolol. Multiple determinations were made of the various pressures, but those shown on the table were recorded at the time of the determination of the cardiac output. The data are summarized in Table II. Brachial Artery Mean Pressure: The resting mean pressure rose in each group after propran0101 was administered, but this change was significant only in the group without angina, in which the average brachial artery mean pressure rose from 98.2 to 103.2 mm. Hg C$ = 0.003). During exercise after propranolol the mean brachial artery pressure was significantly lower * This table, which tabulates the data for each case, is not included in the printed article but is available on request from the author. VOLUME
21,
JANUARY
1968
”
FIG. 2. Right ventricular end-diastolic pressure (mm. Hg) at rest and during exercise before and after propranolol in patients with angina (group l), those without angina (group 2) and in normal subjects (group 3).
in each group than during the first exercise period. The average values during exercise before and after propranolol were 121.0 and 112.1 mm. Hg (#J < 0.001) in group 1, 121.4 and 113.3 (JI = 0.003) in group 2 and 110.6 and 102.8 (p = 0.015) in group 3. Left Ventricular End-Diastolic Pressure (Fig. 1): The average level at rest increased significantly in each group after administration of propran0101, from 8.8 to 14.3 mm. Hg (p = 0.003) in group 1, from 10.3 to 13.5 (p =
14
Parker, of llemodynamic
Summar);
Rest
38.0
EX. Rec.
121.0 97.9 101.0 112.1 $3.3
R(P) E(P) A*% PI A,%
11.4 29.2 8.8 14.3 29.6 +62.5 0.003 f1.3
-7.3
Pz
Rest EX.
98.7 121.4 98.2 103.2 113.3 +5.0
Rec.
R(P) E(P) Al%
PI
0.003
PQ
EX. Rec. R(P) E(P) A,%
14.0 17.7 39.8 +20.4
-;:;
A*%
P2
0.015
136.6 580.0 139.7 134.6 584.4 -3.7
__..
_~~~__ .__ _
3.08 5.36 3.06 2.45 4.39 -20.1
.. .526
. 4;;.
.
0.003
14. I 4.5 26.3 ‘7 8 12.: 3.’ 15.3 5.7 32.5 13.5 t20.3 +54.0 ‘LO. OUl ,:(I. 001 j-23.9 b73.0 _=0 001 -C1).001 ~~.. __~. _._ .~~~~.__._-._._-
8.8 in.0 6.4 9.8 21 .o +53.1 0.045 +110.0 0.015
PI
at Rest and During Exercise
4.4 12.4 3 1; h 4 17.2 +77.7 -:o. 001 f38.7 c0.001
15.7
-____
86.4 110.6 89.4 90.6 102.8 fl.3
Rest
Elects of Propranolol
37.0
12.3 17.8 10.3 13.5 24.5 +31.0
-6.5 0.003
A,‘%
West and Di Giorgi
+0.;
-18.2
132.8 592.5 136.2 130.8 578.3 -3.9
3.15 6.26 3.09 2.77 5.22 -15.8 0.003 -16.6
-2.3 .
;;:1
.. 670
I. 5;s.
-_;4:5 . .
_._ _
12.4 23.4 11.6 12.8 29.4 t-10.3
‘i 2 6.8 3.2 4 (1 11.2 f43.7
135.4 618.4 150.2 143.2 588.6 -4.7
tzs’.c, u .04
+ k4’ 0.03
-4.; 0.05
3.47 7.06 4.12 3.13 5.52 -24.1 0.015 -21.9 0.015
744’
5i4’ . -j;:o 0.05
Rest = first rest period; Ex. = final 2 min. of first exrrcise prriod; Rec. = 30 min. after completion of exercise; R(P) = rest period 9-12 min. after propranolol; F,(P) = final 2 min. of second exercise period; A,?{, = per cent change between Rec. and R(P); pi = s@ifkancc of difference between Rec. and R(P); S,C;, = per cent change between E and E( P); p2 = significance ofdlff’wence brtwecn E and E(P) (only significant values ofll andp, are shown);
0.003) in group 2 and 10.0 and 21.0 (p = 0.015) 3. Pulmonary Artery Mean Pressure: Tllc average
in group mean
pressure
0101 in each cant gina.
only
The
in
rose group, the
significantly but
groups
average
the
change
with
values
after and
at
rest
propran-
was
signifi-
withorlt
an-
before
and
riod. and
‘l’he after
average
values
propranolol
The
=
0.015)
average
in
level
after
(i, < 0.001) in
group
in group
3.2 and
each
mean group
were
pressure than
was
during
significantly the
initial
higher exercise
in pe-
therapy
in each
nificant
only
gina.
The
group
at rest
artery
propranolol
exercise
37.0
before
and
39.8
26.3 23.4
and
mm.
32.5 (p
13% (p
14.0 and 17.7 I~III. Hg (p < 0.001) in group 1, 12.7 and 15.3 (p < 0.001) ingroup2and11.6and12.8ingroup3. During exercise after propranolol the pulmonaryafter
during
were
group,
rose
but
in the groups average
propranolol 2 and
after
this
propranolol
change
was
sig-
with
and
without
an-
at
rest
before
and
values were
1,
3.6
and
1, 3.7 and
6.4 5.7
4.6 in group
mm.
(Jo <
Hg
0.001)
3.
THE AMERICAN JOURNAL OF CARDIOLOGY
15
Propranolol in Coronary Heart Disease
Summary HR (beats/ min.)
of Hemodynamic
TABLE II (continued) Effects of Propranolol at Rest and During Exercise
SEP (sec.)
(2, M.2)
MSER (ml./sec./ M.*)
LVW (kg.-M./ min./M.2)
TTI (mm. Hg/ min.) -___
A. Group 1. Patients With Angina Rest EX. Rec. R(P)
EiP)
A,% Pi A,% Pz
80.6 127.5 84.9 71.9 108.9 -15.3
38.7 42.6 36.6 33.9 41.5 -7.3 1’2.5 ...
45.7 53.2 44.1 40.2 45.9 -8.8 - 1.3:7 0.003
0.330 0.308 0.316 0.323 0.322 +2.2 0.025 +4.5 0.045
117.5 138.7 115.5 105.1 127.3 -9.0 --8:2 0.02
3.45 6.52 3.59 2.84 4.35 -16.7 0.003 -33.3
2620 4957 2612 2396 3950 -8.24 0.008 -20.3 0.003
3.58 8.62 3.91 3.36 6.31 -14.0 0.007 -24.8 0.003
2209 4058 2241 2139 3485 -3.4
3.44 9.62 4.52 3.51 6.02 -22.4 0.05 -37.5 0.005
2027 4192 2469 2219 3596 -10.2
B. Group 2. Patients Without Angina Rest Ex. Rec. R(P) E(P) Ai% PI AZ’%
P2
65.4 113.0 69.1 61.0 97.8 -11.4
46.6 53.8 47.7 45.4 53.5 -4.8
54.3 75.6 56.7 54.9 64.4 -3.1
10.5
-14.8 0.015
0.341 0.316 0.331 0.339 0.342 $2.3 0.075 +8.2
136.4 169.0 143.4 133.7 156.2 -6.8 -i:5 0.04
-
ii.‘1
0.003
C. Groufi 3. Normal Patients Rest Ex. Rec. R(P) E(P) Al%’
PI A&:
Pz
68.0 120.4 82.6 69.8 101.4 -15.5 0.02 -15.8 0.01
48.0 58.4 50.0 44.8 54.2 -10.4 i-7.2
50.2 80.0 54.8 50.4 59.6 -9.2 -24.5
0.346 0.316 0.336 0.350 0.342 f4.1
139.2 185.0 149.6 128.4 156.6 -14.6
f&2
-;5:4 0.04
- 14.‘3 0.02
BAm = brachial artery mean pressure; LVEDP = left ventricular end-diastolic pressure; PAm = pulmonary artery mean pressure; RVEDP = right ventricular end-diastolic pressure; VO r = oxygen consumption (STPD); CI = cardiac index; EF = exercise factor; HR = heart rate; LVSWI = left ventricular stroke work index; SEP = systolic ejection period; MSER = mean systolic ejection rate; LVW = left ventricular work; TTI = tension-time index
During exercise after propranolol the right ventricular end-diastolic pressure was significantly higher in each group than during the initial exercise period. The average values during exercise before and after propranolol were 12.4 and 17.2 mm. Hg (‘J < 0.001) in group 1, 7.8 and 13.5 QJ < 0.001) in group 2 and 6.8 and 11.2 (p = 0.03) in group 3. Oxygen Consumption: The average oxygen consumption at rest fell slightly after propranolol therapy in each of the three groups, but the changes were not significant. During exercise after propranolol the oxygen consumption was VOLUME 21, JANUARY 1968
not significantly different from that during the initial exercise period in groups 1 and 2. In the normal subjects the oxygen consumption during exercise before and after propranolol was 618.4 and 588.6 ml./min./M.2. This decrease, although minimal, was statistically significant ($ = 0.03). Heart Rate: The resting heart rate fell in every subject after propranolol, and the average decrease was significant in each group. After propranolol the heart rate fell from 84.9 to 71.9 beats/min. (p < 0.001) in group 1, from 69.1 to 61.0 @ < 0.001) in group 2 and from 82.6 to 69.8 (p = 0.02) in group 3.
16
Parker,
WJ
West and IX Giorgi l-W
GpI
-60
60.
:-----AL .
40.
. 40
! -
20.
20
120.
120
100.
100
80.
80
.
60.
i 40 *
i
60
I
*
’
40
20
20 * 100
Gp
100
111
80
80
60
60
40
40
20 R
Rp
20
E
EP
L)uring excrclsf ufter /vokranolol tlic heart ratf: was lower than during the initial exercise period in each subject, and the a\.erage rccl~tctiotl was significant in each group. The a\magc Itc*ar-t rates during exercise before and after propran0101 were 127.5 and 108.9 brats ltttitt. (/I < 0.001) in group 1, 113.0 and 97.8 (,/I< 0.001) itt grOll[~ 3, and 120.4 and 101.4 (//= 0.01) it) ,group .3. Curdiar Index: The avemge cardiac indm a~ rest fell significantf!~ it) each group aftct propralt0101, from 3.00 to 2.45 L. ‘tttitt. ‘Lt.” (,/) = U.003) in group 1, frottt 3.00 to 2.77 (/I = 0.003) in grortp 2 and front 4.12 to 3.13 (@ = 0.015) in group 3. Durmg CXC~CISP after ,hopanolo/ the cardiac indcs was significantly lower in each ,grottp than dltring the initial exercise period. ‘Tfic a\.‘cragc values during exercise before and after propran0101 were 5.36 and 4.37 I,. ‘tnin./M.’ (/I < 0.001) in group 1, 6.26 and .5.22 (/I < 0.001) in grottp 2 and 7.06 and 5..52 (/j = 0.01 5) in group 3.
Stroke Index: ‘The stroke index at rest and during exercise after propranolol was lower than during the control study in each group, but rfme changes were not significant. I-
.7. ~\jstolic Ejection Period: ‘l’hc average at rest increased after propranolol in the three groups, bttt the change was significant only in the group with angina (/I = 0.025). During exercise after propranolol the systolic period was higher itt each group than during the initial exercise period, but the change was significant only in group 1 (j = 0.045) and group 2 (/ = 0.001). $stolic Ejection Kate (Fig. J): The average decreased in each group after propranolol was adtuinistered, but these changes were not significant. During exercise after propranoiol the systolic ejection rate was significantly lower in each THE AMERICAN
JOURNAL
OF
~:,\RUtOLOG\i
17
Propranolol in Coronary Heart Disease ‘X
200.
w)
.180
180.
,16NO
S.E.R.
‘* 1410
[ml~min~m~]lro.
1:!O
I(IO
,$.rtolic fjation rat?, IPftwntricuh tmsian-tzme index at rest and during exercise before and after propranolak in the patients with angina (continuous line), those without angina (interrupted line) and in normal subjects (dotted line). Flc.
4.
roori:
and
,l 0
101
8.
8. L.vW Kgm m,rnilr’r~Y’l~.
6
4
4
2
21
5000
5000
11’1: I. Imm
1
4OOO
4000
Hs; min I
3000
3000
I
2000
PROPRANOLOL
CON T ROL
FIG. 5. Left ventricular endpressure plotted diastolic against lefl ventricular stroke work index at rest and during exercise in each group of patients before and after propranolol.
-
ANGINA
,-,-fl.
NON ANGINA
II~~~~*II*~I~DI NORMAL 10
20
30
L.V. E. D.P. VOLUME 21, JANUARY
1968
4
0
10
[mm
Hg 1
20
18
Parker,
West and Di Giorgi
group than during the initial exercise period. The average values during exercise before and after propranolol were 138.7 and 127.3 ml./sec./M.* (p = 0.02) in group 1, 169.0 and 156.2 (J = 0.04) in group 2 and 185.0 and 156.6 (p = 0.04) in group 3.
The present study shows evidence of depression of myocardial function at rest and during exercise after propranolol therapy, as indicated by the relation between left ventricular stroke work and left ventricular end-diastolic pressure (Fig. 5). After propranolol the left ventricular end-diastolic pressure was higher at rest and during exercise in most patients in the presence of decreased or unchanged left ventricular stroke work. The impairment of tnyocardial contractility during exercise is also suggested b). the lower mean systolic ejection rate during exercise after propranolol. The mean systolic ejection rate is determined by the velocity of shortening of the myocardial fibers and the ventricular volrenlains ume.12 If the velocity of shortening constant, an increase or decrease in ventricular volume will determine respectively a rise or fall In the presin the mean systolic ejection rate. ent study the decrease in lnean systolic ejection rate during exercise after propranolol in the presence of unchanged or increased left ventricular volume, as suggested by the level of left vcntricular end-diastolic pressure, indicates a decrease in the velocity of contraction of the left ventricle. These observations arr in agreement with most reports but are contrary to the findings of Wolfson and co-workers’” that the adrninistration of propranolol is followed at rest by a rrduction in left \.entricular vohnnc with constant or decreased left ventricular end-diastolic pressures. Their studies were done with smaller doses of propranolol, and the nzasurements lnadc 20 minutes after its administration : thrsc‘ factors could explain the discrepancies. It has been suggested that the beneficial effects of propranolol may be secondary to a reduction The in myocardial oxygen requirerllents.“‘,” oxygen consulllption of the left ventricle is related to the external left ventricular work,‘” thr velocity of left ventricltlar contraction“’ and the tension within the wall of the left ventricle.15 The latter is related to the systolic pressure generated by the left ventricle per minute and to the volume of the left \.entricnlar chamber.‘” During exercise after propranolol the tension-
the
index, systolic ejection rate and left ventricular work were significantly lower than during the initial exercise period, and such changes would be expected to reduce myocardial oxygen requirements. In the normal subjects and those without angina, the higher left ventricular end-diastolic pressure during exercise after propranolol would suggest a larger left ventricular \,olunle. The resulting increase in left ventricular tension, according to Laplace’s law, would increase myocardial oxygen consumption.16 In the patients with exertional angina the left ventricular oxygen consumption during exercise must have decreased after propranolol since the decrease in tension-time index, systolic ejection rate and left ventricular work was not associated with any further elevation of left ventricular end-diastolic pressure. In the cases where exertional angina was pre\cnted by propranolol, the reduction in myocardial oxygen consumption may have been sufficient to prevent or relieve rllyocardial ischemia. We cannot, however, exclude the possibility that propranolol increased coronary blood flow. It is possible that the poor results with propranolol in our studies as compared to other reports are related to the level of exercise emIf a work load had been selected that ployed. was just sllfficient to induce exertional angina, the redlrction in Inyocardial oxygen consumption after propranolol might have been adequate to prevent the development of rnyocardial ischernia in more of the patients. SUMMAR\
of intravelious propranolol have brcn studied in 10 patients with coronary heart disease and angina pectoris, 12 patients with as).mptonlatic coronary heart disease and 5 norrllal subjects. In all three groups there was evidence of depression of myocardial function both at rest and during exercise after beta adrenergic blockade as shown by increased left ventricular rnd-diastolic pressure with no increase in stroke The mean systolic ejection rate was also work. IOWCY~ both at rest and during exercise after adIn spite of hemorlCnistration of propranolol. dynalnic evidence suggesting a reduction in nlyocardial oxygen requirements, in only 1 of the 10 patients with angina pectoris was chest pain prevented by this agent. l‘tir
effects
REFERENCES 1.
(hIJAM,
I’.
propranolol
hf.
S.
and
,?HICHARD,
in angina
pu2toris.
‘I‘IIE AMERICAN
JOURSAL
337, 1965.
B. N. (:. Brit.
OF
Use of 2:
M. J.,
(:ARDIOLOGY
Propranolol in Coronary Heart Disease 2. KEELAN, P. A. A double-blind trial of propranolol (Inderal) in angina pectoris. &it. M. J., I: 897, 1965. 3. RABKIN, R., STABLES, D. P., LEVIN, N. W. and SUZMAN, M. M. The prophylactic value of propranolol in angina pectoris. Am. J. Curdiol., 18: 370, 1966. 4. GRANT, R. H. E. et al. Multicenter trial of propranolol in angina pectoris. Am. J. Cizrdiol., 18: 361, 1966. 5. EPSTEIN,S. E., ROBINSON,B. F., KAHLER, R. L. and BRAUNWALD,E. Effect of beta-adrenergic blockade on the cardiac response to maximal and submaximal exercise in man. J. Gin. Invest., 44: 1745, 1965. 6. RING, R. J. Technique for measurement of the coronary circulation. Presented at Symposium on Advances in Coronary Heart Disease, Los Angeles, Calif., Mar. IO, 1967. 7. CHAMBERLAIN,D. A. Effects of beta adrenergic blockade on heart size. Am. J. Cardiol., 18: 321, 1966. 8. SONNENBLICK,E. H., BRAUNWALD, E., WILLIAMS, J. F., JR. and GLICK, G. Effects of exercise on myocardial force-velocity relations in intact unanesthetized man: Relative roles of changes in heart rate, sympathetic activity, and ventricular
VOLUME 21, JANUARY I968
19
dimensions. J. Clin. Invest., 44: 2051, 1965. 9. SOWTON, E. and HAMER, J. Hemodynamic changes after beta adrenergic blockade. Am. J. Card& 18: 317, 1966. IO. WOLFSON, S. et al. Propranolol and angina pectoris. Am. J. Cardiol., 18: 345, 1966. II. HAMER, J. and SOMPTON,E. Cardiac output after beta-adrenergic blockade in ischaemic heart disease. Brit. Heart J., 27: 892, 1965. 12. LEVINE, J. H., NEILL, W. A., WAGMAN, R. J., KRASNOW, N. and GORLIN, R. The effect of exercise on mean left ventricular ejection rate in man. J. Clin. Invest., 41: 1050, 1962. 13. GORLIN, R., COHEN, L. S., ELLIOTT, W. C., KLEIN, M. D. and LANE, F. J. Effect of supine exercise on left ventricular volume and oxygen consumption in man. Ctrculation, 32: 361, 1965. 14. SONNENBLICK, E. H., Ross, J., JR., CO~ELL, J. W., KAISER, G. A. and BRAUNWALD,E. Velocity of contraction as a determinant of myocardial oxygen consumption. Am. J. Physiol., 209: 919, 1965. 15. SARNOFF, S. J. et al. Hemodynamic determinants of oxygen consumption of the heart with special reference to the tension-time index. Am. J. Physiol., 192: 148, 1958. 16. LEVINE, J. H. and WAGMAN, R. J. Energetics of the human heart. Am. J. Cardiol., 9: 372, 1962.
Effects of Propranolol
Coronary JOHN 0.
Heart Disease*
PARKER, M.D., F.A.c.c., ROXROY 0. WEST, M.D. and SALVATORE DI GIORGI, M.D. Kingston,
Ontario,
T
Canada
surements of ventricular filling pressures or volume. The present study was designed to determine the hemodynamic changes induced by propran0101 at rest and during exercise in patients with coronary heart disease with and without exertional angina and in a control group of normal subjects.
HERE have been several reports on the use of the beta adrenergic blocking agent propranololt in patients with coronary heart disease and angina pectoris. While there is agreement that the oral administration of this drug in patients with angina pectoris is generally followed by a favorable therapeutic response,1-4 studies following the intravenous administration of propranolol have shown hemodynamic alterations that would suggest caution in the use of this drug. Most authors observed depression of cardiac performance at rest and during exercise as shown by elevation of right”*6 and left ventricular filling pressures,‘j increase in heart size,‘s8 prolongation of the systolic ejection period9 and subnormal increase in the velocity of shortening of myocardial fibers during exercise* with a fall in stroke volume.g Propranolol would also block the vasodilator effect of beta adrenergic stimulation on the coronary arteries. In contrast to these findings Wolfson and coworkerslO found a decrease in systolic and enddiastolic volumes of the left ventricle, decrease or unchanged left ventricular end-diastolic pressure, with insignificant changes in stroke volume, systolic ejection period and systolic ejection rate following the intravenous administration of propranolol. These workers found a reduction in coronary blood flow at rest after propranolol although in 1 patient when the drug was infused during spontaneous angina there was evidence of coronary vasodilatation. There is limited information on the effects of propranolol on the hemodynamic response to exercise in patients with coronary heart disease,g-*l and in these studies there were no mea-
MATERIAL AND METHODS Case Material: Three groups of patients were studied. Group f consisted of 10 patients with coronary heart disease who presented a typical angina1 syndrome. Eight had clinical and electrocardiographic evidence of myocardial infarction which had occurred from 6 to 24 months before the study. The remaining 2 patients had typical ischemic changes in the resting or postexercise electrocardiogram. Group 2 consisted of 12 patients with coronary heart disease who did not experience exertional angina. Eleven had clinical and electrocardiographic evidence of myocardial infarction which had occurred from 6 to 30 months before the study while the remaining patient had ischemic changes in the resting electrocardiogram but no clear evidence of previous myocardial infarction. Patients were not included if they had cardiac enlargement, ventricular aneurysm, congestive heart failure, atria1 fibrillation, valvular heart disease, or pulmonary disease; none was receiving digitalis or diuretics. Group 3 consisted of 5 subjects who had no demonstrable cardiac or pulmonary disease. Procedure: On the day prior to the investigation, the patients were brought to the laboratory where the procedure was explained, the resting ventilation recorded, and supine leg exercise on a bicycle ergometer practiced. In the patients with angina a work load was selected that would induce the pain of acute coronary insufficiency within the first three or four minutes of exercise but would not prevent the completion of steady exercise for seven minutes. The patients without angina and the normal subjects
t Propranolol (Inderal@) supplied by Ayerst Laboratories, Montreal, Quebec, Canada.
* From the Cardiopulmonary Laboratory, Department:of Medicine, Queen’s University, This study was supported in part by Grant 2-13 from the:Ontario Heart Foundation. VOLUME
21,
in
JANUARY
1968
11
Kingston,
Ontario.
12
Parker? West and 13 Giorgi
were cxerciscd at comparablc \*.ork loads ranging from 700 to 1000 kg.-M. ,‘min. Studies \vcre made in the l&tin: postahaorptivt. state without premeditation. Under local anesthesia, the right brachial artery and tllr: right median clll,ital vein \vert‘ isolated, and a doublr lumen No. ‘1 (:ournand catheter \vas inserted into the right side of tllc heart so that the tip lay in the pulmonary artc’r). .I No, 8 Sones cathrtcr was advanced from the. riqllt brachial artery into the left ventricle. and a C:ot~rnantl needle was imrrtccl into thr lrft t)r-achial ar‘tc~. Three or four rletrrminations \verr madc OP 1111.prt.;sures in the pulmonar)~ artery. right vcntriclt’. lt.lt ventricle and brachial artery during 3 i0 mimlte rest period, and the cardiac output I\ as measurrtl during the final t\vo minutex. Exercisr 12’as then pvrformed for seven minutes at the preclrtcrminecl work load. The intracardiac and intravascular prcssurrs were measured al the completion of thr first minuteof exercise and at t\ro minute intervals thrrcaftcr: the cardiac output \vas measured during thr final two minutes of exercise. Aftrr a rest period of 30 minutes, the intracardiac and intravascular prrssurt’s and cardiac output \vrre measured at rest. ant1 tllt.rl 0.15 mg.1 kg. of propranolol \vas rapidly injrctrtl into ‘I’ht~ pressures \vcrf‘ m?asurctI the pulmonary artery. at one, three, five, eight and twelvr minutes, and ttlc. cardiac output determined between the ninth and eleventh minute. -4 second period of exercise at tht‘ same work load was commenced from 12 to 14 minu tcs after the administration of this drug, and the tlcmodynamic data \vere recorded as during tllr initial
exercise period Hemo~ynami~~Studirs: ‘I‘hc prt’ssures were rccordtd by means of P23Db Statham strain-gauges from a zero .Sy+ reference Ievrl -5 cm. below thy sternal angle. tolic and diastolic pressures were calculated tq averaging individual systolic and diastolic points over at least 11~0 respirator! cycles. and the tnean pressures in the brachial artery and pulmonary arter) ‘l‘hc cardiac orltprlt \\;a~ were derived electronically. measured by thr indicator-dilution technic employing indocyaninc qrccn. ‘l‘he dye was injectrtl into thr right ventricle. and blood \vas withdra\\n rrom the. brachial artery needle through a Gilford densitornrtt-1 at a rate of 3X.5 ml. ‘min. with a Ijarvard apparatu\ pump. Pressures and dye curves were insrrilWtl on an Electronics for hfedicine DR-8 photograpllic, rccorcler. The oxygen consumption was determined IQ collecting expired air in a ‘Fissot spirometer for two minutes ancl analyzing the oxygen and carbon dioxide content by the micro-Scholander method. ‘l’his was determined lvith each measurement of cardiac output. The follozcirrg parameter.! were derived; Left uentricufar stroke worX Ade.v in gm.-M ./‘M .:! I+ using the formula: LvswI
=
(EJ$m
-
LVEDP)
1000
X SI X 13.0
\,vllrrc. B:\m
=
I.\.l
brachial
artery
mean
.\lrrrn .ix.rtolic Pjf(tion rate in nil. 111~ formlila: hZSER \\
pressure
in mm.
Hg = left ventricular end-diastolic pressurcr in mm. Hg = stroke index in ml., M.’ = conversion factor for the density of Hq sec.
M.’
bb-
using
= SJ,SEP
IIt‘l’f’ SI
= stroke
SEP
= systolic
index
in ml. ‘M.’
ejection
period
E:w~,~w fuctor calculated output in ml./!min. per oxygen consumption.
as the increase 100 ml.‘min.
I,P~[ wntricular work in kg.-M.
LVW
in see.
= I,VS\,VI
/M.”
in cardiac increase in
by
tilt’
x HR
left ventricular stroke work M.” heart rate in beats,,‘min. ?br/Con-time index in mm. mula :
usinq
the
for-
= brachial artery mean pressure in mm. = heart rate in beats,‘min. = systolic ejection period in see.
Hg
‘l”L’1 = BAm
Hg/min.
in kg.-M.
X HR
using
X SEP
\vtlrrc H:Irn HR SEP
.We&v~ coronar~urteriography and left uentriculo,qaphj \vcrr carried out in all of the patients and in the control subjects following the completion of these hemocl!,namic studies. Significant obstructive disease was rlrmonstrated in at least two of the major coronary vc~rls in tile patients with coronary disease. and the coronary arteriograms \vere normal in the rontrol SLIbjKtY. KES~JLTS
.-\I1 of the perienced four
minutes
10 patients
pain
in the
of coronary which
angina
group
insufficiency
persisted
until
ex-
within
the
termina-
In 9 of the 10 chest pain developed during exercise after propranolol; 1 remained free of pain. In this patient (Case 9) the hernodynamic effects of propranolol at rest and during exercise were indistinguishable from those observed in other members of the group. None of the patients without tion
of the
first
exercise
‘I’HEAMERICAN
period.
JOURNAL
OF
CARDIOLOGY
Propranolol in Coronary Heart Disease .
CP’
.
.
Gp II
. f------f
R
Rp
E
EP
FIG. 1. Left mztricular end-diastolic pressure (mm. Hg) at rest (R) and during exercise (E) before and after administration of propranolol (p) in patients with angina (group l), those without angina (group 2) and in normal subjects (group 3).
angina and no control subject experienced chest pain during either exercise period. Table I* shows the hemodynamic findings in each of the three groups at rest and during exercise before and after the administration of propranolol. Multiple determinations were made of the various pressures, but those shown on the table were recorded at the time of the determination of the cardiac output. The data are summarized in Table II. Brachial Artery Mean Pressure: The resting mean pressure rose in each group after propran0101 was administered, but this change was significant only in the group without angina, in which the average brachial artery mean pressure rose from 98.2 to 103.2 mm. Hg C$ = 0.003). During exercise after propranolol the mean brachial artery pressure was significantly lower * This table, which tabulates the data for each case, is not included in the printed article but is available on request from the author. VOLUME
21,
JANUARY
1968
”
FIG. 2. Right ventricular end-diastolic pressure (mm. Hg) at rest and during exercise before and after propranolol in patients with angina (group l), those without angina (group 2) and in normal subjects (group 3).
in each group than during the first exercise period. The average values during exercise before and after propranolol were 121.0 and 112.1 mm. Hg (#J < 0.001) in group 1, 121.4 and 113.3 (JI = 0.003) in group 2 and 110.6 and 102.8 (p = 0.015) in group 3. Left Ventricular End-Diastolic Pressure (Fig. 1): The average level at rest increased significantly in each group after administration of propran0101, from 8.8 to 14.3 mm. Hg (p = 0.003) in group 1, from 10.3 to 13.5 (p =
14
Parker, of llemodynamic
Summar);
Rest
38.0
EX. Rec.
121.0 97.9 101.0 112.1 $3.3
R(P) E(P) A*% PI A,%
11.4 29.2 8.8 14.3 29.6 +62.5 0.003 f1.3
-7.3
Pz
Rest EX.
98.7 121.4 98.2 103.2 113.3 +5.0
Rec.
R(P) E(P) Al%
PI
0.003
PQ
EX. Rec. R(P) E(P) A,%
14.0 17.7 39.8 +20.4
-;:;
A*%
P2
0.015
136.6 580.0 139.7 134.6 584.4 -3.7
__..
_~~~__ .__ _
3.08 5.36 3.06 2.45 4.39 -20.1
.. .526
. 4;;.
.
0.003
14. I 4.5 26.3 ‘7 8 12.: 3.’ 15.3 5.7 32.5 13.5 t20.3 +54.0 ‘LO. OUl ,:(I. 001 j-23.9 b73.0 _=0 001 -C1).001 ~~.. __~. _._ .~~~~.__._-._._-
8.8 in.0 6.4 9.8 21 .o +53.1 0.045 +110.0 0.015
PI
at Rest and During Exercise
4.4 12.4 3 1; h 4 17.2 +77.7 -:o. 001 f38.7 c0.001
15.7
-____
86.4 110.6 89.4 90.6 102.8 fl.3
Rest
Elects of Propranolol
37.0
12.3 17.8 10.3 13.5 24.5 +31.0
-6.5 0.003
A,‘%
West and Di Giorgi
+0.;
-18.2
132.8 592.5 136.2 130.8 578.3 -3.9
3.15 6.26 3.09 2.77 5.22 -15.8 0.003 -16.6
-2.3 .
;;:1
.. 670
I. 5;s.
-_;4:5 . .
_._ _
12.4 23.4 11.6 12.8 29.4 t-10.3
‘i 2 6.8 3.2 4 (1 11.2 f43.7
135.4 618.4 150.2 143.2 588.6 -4.7
tzs’.c, u .04
+ k4’ 0.03
-4.; 0.05
3.47 7.06 4.12 3.13 5.52 -24.1 0.015 -21.9 0.015
744’
5i4’ . -j;:o 0.05
Rest = first rest period; Ex. = final 2 min. of first exrrcise prriod; Rec. = 30 min. after completion of exercise; R(P) = rest period 9-12 min. after propranolol; F,(P) = final 2 min. of second exercise period; A,?{, = per cent change between Rec. and R(P); pi = s@ifkancc of difference between Rec. and R(P); S,C;, = per cent change between E and E( P); p2 = significance ofdlff’wence brtwecn E and E(P) (only significant values ofll andp, are shown);
0.003) in group 2 and 10.0 and 21.0 (p = 0.015) 3. Pulmonary Artery Mean Pressure: Tllc average
in group mean
pressure
0101 in each cant gina.
only
The
in
rose group, the
significantly but
groups
average
the
change
with
values
after and
at
rest
propran-
was
signifi-
withorlt
an-
before
and
riod. and
‘l’he after
average
values
propranolol
The
=
0.015)
average
in
level
after
(i, < 0.001) in
group
in group
3.2 and
each
mean group
were
pressure than
was
during
significantly the
initial
higher exercise
in pe-
therapy
in each
nificant
only
gina.
The
group
at rest
artery
propranolol
exercise
37.0
before
and
39.8
26.3 23.4
and
mm.
32.5 (p
13% (p
14.0 and 17.7 I~III. Hg (p < 0.001) in group 1, 12.7 and 15.3 (p < 0.001) ingroup2and11.6and12.8ingroup3. During exercise after propranolol the pulmonaryafter
during
were
group,
rose
but
in the groups average
propranolol 2 and
after
this
propranolol
change
was
sig-
with
and
without
an-
at
rest
before
and
values were
1,
3.6
and
1, 3.7 and
6.4 5.7
4.6 in group
mm.
(Jo <
Hg
0.001)
3.
THE AMERICAN JOURNAL OF CARDIOLOGY
15
Propranolol in Coronary Heart Disease
Summary HR (beats/ min.)
of Hemodynamic
TABLE II (continued) Effects of Propranolol at Rest and During Exercise
SEP (sec.)
(2, M.2)
MSER (ml./sec./ M.*)
LVW (kg.-M./ min./M.2)
TTI (mm. Hg/ min.) -___
A. Group 1. Patients With Angina Rest EX. Rec. R(P)
EiP)
A,% Pi A,% Pz
80.6 127.5 84.9 71.9 108.9 -15.3
38.7 42.6 36.6 33.9 41.5 -7.3 1’2.5 ...
45.7 53.2 44.1 40.2 45.9 -8.8 - 1.3:7 0.003
0.330 0.308 0.316 0.323 0.322 +2.2 0.025 +4.5 0.045
117.5 138.7 115.5 105.1 127.3 -9.0 --8:2 0.02
3.45 6.52 3.59 2.84 4.35 -16.7 0.003 -33.3
2620 4957 2612 2396 3950 -8.24 0.008 -20.3 0.003
3.58 8.62 3.91 3.36 6.31 -14.0 0.007 -24.8 0.003
2209 4058 2241 2139 3485 -3.4
3.44 9.62 4.52 3.51 6.02 -22.4 0.05 -37.5 0.005
2027 4192 2469 2219 3596 -10.2
B. Group 2. Patients Without Angina Rest Ex. Rec. R(P) E(P) Ai% PI AZ’%
P2
65.4 113.0 69.1 61.0 97.8 -11.4
46.6 53.8 47.7 45.4 53.5 -4.8
54.3 75.6 56.7 54.9 64.4 -3.1
10.5
-14.8 0.015
0.341 0.316 0.331 0.339 0.342 $2.3 0.075 +8.2
136.4 169.0 143.4 133.7 156.2 -6.8 -i:5 0.04
-
ii.‘1
0.003
C. Groufi 3. Normal Patients Rest Ex. Rec. R(P) E(P) Al%’
PI A&:
Pz
68.0 120.4 82.6 69.8 101.4 -15.5 0.02 -15.8 0.01
48.0 58.4 50.0 44.8 54.2 -10.4 i-7.2
50.2 80.0 54.8 50.4 59.6 -9.2 -24.5
0.346 0.316 0.336 0.350 0.342 f4.1
139.2 185.0 149.6 128.4 156.6 -14.6
f&2
-;5:4 0.04
- 14.‘3 0.02
BAm = brachial artery mean pressure; LVEDP = left ventricular end-diastolic pressure; PAm = pulmonary artery mean pressure; RVEDP = right ventricular end-diastolic pressure; VO r = oxygen consumption (STPD); CI = cardiac index; EF = exercise factor; HR = heart rate; LVSWI = left ventricular stroke work index; SEP = systolic ejection period; MSER = mean systolic ejection rate; LVW = left ventricular work; TTI = tension-time index
During exercise after propranolol the right ventricular end-diastolic pressure was significantly higher in each group than during the initial exercise period. The average values during exercise before and after propranolol were 12.4 and 17.2 mm. Hg (‘J < 0.001) in group 1, 7.8 and 13.5 QJ < 0.001) in group 2 and 6.8 and 11.2 (p = 0.03) in group 3. Oxygen Consumption: The average oxygen consumption at rest fell slightly after propranolol therapy in each of the three groups, but the changes were not significant. During exercise after propranolol the oxygen consumption was VOLUME 21, JANUARY 1968
not significantly different from that during the initial exercise period in groups 1 and 2. In the normal subjects the oxygen consumption during exercise before and after propranolol was 618.4 and 588.6 ml./min./M.2. This decrease, although minimal, was statistically significant ($ = 0.03). Heart Rate: The resting heart rate fell in every subject after propranolol, and the average decrease was significant in each group. After propranolol the heart rate fell from 84.9 to 71.9 beats/min. (p < 0.001) in group 1, from 69.1 to 61.0 @ < 0.001) in group 2 and from 82.6 to 69.8 (p = 0.02) in group 3.
16
Parker,
WJ
West and IX Giorgi l-W
GpI
-60
60.
:-----AL .
40.
. 40
! -
20.
20
120.
120
100.
100
80.
80
.
60.
i 40 *
i
60
I
*
’
40
20
20 * 100
Gp
100
111
80
80
60
60
40
40
20 R
Rp
20
E
EP
L)uring excrclsf ufter /vokranolol tlic heart ratf: was lower than during the initial exercise period in each subject, and the a\.erage rccl~tctiotl was significant in each group. The a\magc Itc*ar-t rates during exercise before and after propran0101 were 127.5 and 108.9 brats ltttitt. (/I < 0.001) in group 1, 113.0 and 97.8 (,/I< 0.001) itt grOll[~ 3, and 120.4 and 101.4 (//= 0.01) it) ,group .3. Curdiar Index: The avemge cardiac indm a~ rest fell significantf!~ it) each group aftct propralt0101, from 3.00 to 2.45 L. ‘tttitt. ‘Lt.” (,/) = U.003) in group 1, frottt 3.00 to 2.77 (/I = 0.003) in grortp 2 and front 4.12 to 3.13 (@ = 0.015) in group 3. Durmg CXC~CISP after ,hopanolo/ the cardiac indcs was significantly lower in each ,grottp than dltring the initial exercise period. ‘Tfic a\.‘cragc values during exercise before and after propran0101 were 5.36 and 4.37 I,. ‘tnin./M.’ (/I < 0.001) in group 1, 6.26 and .5.22 (/I < 0.001) in grottp 2 and 7.06 and 5..52 (/j = 0.01 5) in group 3.
Stroke Index: ‘The stroke index at rest and during exercise after propranolol was lower than during the control study in each group, but rfme changes were not significant. I-
.7. ~\jstolic Ejection Period: ‘l’hc average at rest increased after propranolol in the three groups, bttt the change was significant only in the group with angina (/I = 0.025). During exercise after propranolol the systolic period was higher itt each group than during the initial exercise period, but the change was significant only in group 1 (j = 0.045) and group 2 (/ = 0.001). $stolic Ejection Kate (Fig. J): The average decreased in each group after propranolol was adtuinistered, but these changes were not significant. During exercise after propranoiol the systolic ejection rate was significantly lower in each THE AMERICAN
JOURNAL
OF
~:,\RUtOLOG\i
17
Propranolol in Coronary Heart Disease ‘X
200.
w)
.180
180.
,16NO
S.E.R.
‘* 1410
[ml~min~m~]lro.
1:!O
I(IO
,$.rtolic fjation rat?, IPftwntricuh tmsian-tzme index at rest and during exercise before and after propranolak in the patients with angina (continuous line), those without angina (interrupted line) and in normal subjects (dotted line). Flc.
4.
roori:
and
,l 0
101
8.
8. L.vW Kgm m,rnilr’r~Y’l~.
6
4
4
2
21
5000
5000
11’1: I. Imm
1
4OOO
4000
Hs; min I
3000
3000
I
2000
PROPRANOLOL
CON T ROL
FIG. 5. Left ventricular endpressure plotted diastolic against lefl ventricular stroke work index at rest and during exercise in each group of patients before and after propranolol.
-
ANGINA
,-,-fl.
NON ANGINA
II~~~~*II*~I~DI NORMAL 10
20
30
L.V. E. D.P. VOLUME 21, JANUARY
1968
4
0
10
[mm
Hg 1
20
18
Parker,
West and Di Giorgi
group than during the initial exercise period. The average values during exercise before and after propranolol were 138.7 and 127.3 ml./sec./M.* (p = 0.02) in group 1, 169.0 and 156.2 (J = 0.04) in group 2 and 185.0 and 156.6 (p = 0.04) in group 3.
The present study shows evidence of depression of myocardial function at rest and during exercise after propranolol therapy, as indicated by the relation between left ventricular stroke work and left ventricular end-diastolic pressure (Fig. 5). After propranolol the left ventricular end-diastolic pressure was higher at rest and during exercise in most patients in the presence of decreased or unchanged left ventricular stroke work. The impairment of tnyocardial contractility during exercise is also suggested b). the lower mean systolic ejection rate during exercise after propranolol. The mean systolic ejection rate is determined by the velocity of shortening of the myocardial fibers and the ventricular volrenlains ume.12 If the velocity of shortening constant, an increase or decrease in ventricular volume will determine respectively a rise or fall In the presin the mean systolic ejection rate. ent study the decrease in lnean systolic ejection rate during exercise after propranolol in the presence of unchanged or increased left ventricular volume, as suggested by the level of left vcntricular end-diastolic pressure, indicates a decrease in the velocity of contraction of the left ventricle. These observations arr in agreement with most reports but are contrary to the findings of Wolfson and co-workers’” that the adrninistration of propranolol is followed at rest by a rrduction in left \.entricular vohnnc with constant or decreased left ventricular end-diastolic pressures. Their studies were done with smaller doses of propranolol, and the nzasurements lnadc 20 minutes after its administration : thrsc‘ factors could explain the discrepancies. It has been suggested that the beneficial effects of propranolol may be secondary to a reduction The in myocardial oxygen requirerllents.“‘,” oxygen consulllption of the left ventricle is related to the external left ventricular work,‘” thr velocity of left ventricltlar contraction“’ and the tension within the wall of the left ventricle.15 The latter is related to the systolic pressure generated by the left ventricle per minute and to the volume of the left \.entricnlar chamber.‘” During exercise after propranolol the tension-
the
index, systolic ejection rate and left ventricular work were significantly lower than during the initial exercise period, and such changes would be expected to reduce myocardial oxygen requirements. In the normal subjects and those without angina, the higher left ventricular end-diastolic pressure during exercise after propranolol would suggest a larger left ventricular \,olunle. The resulting increase in left ventricular tension, according to Laplace’s law, would increase myocardial oxygen consumption.16 In the patients with exertional angina the left ventricular oxygen consumption during exercise must have decreased after propranolol since the decrease in tension-time index, systolic ejection rate and left ventricular work was not associated with any further elevation of left ventricular end-diastolic pressure. In the cases where exertional angina was pre\cnted by propranolol, the reduction in myocardial oxygen consumption may have been sufficient to prevent or relieve rllyocardial ischemia. We cannot, however, exclude the possibility that propranolol increased coronary blood flow. It is possible that the poor results with propranolol in our studies as compared to other reports are related to the level of exercise emIf a work load had been selected that ployed. was just sllfficient to induce exertional angina, the redlrction in Inyocardial oxygen consumption after propranolol might have been adequate to prevent the development of rnyocardial ischernia in more of the patients. SUMMAR\
of intravelious propranolol have brcn studied in 10 patients with coronary heart disease and angina pectoris, 12 patients with as).mptonlatic coronary heart disease and 5 norrllal subjects. In all three groups there was evidence of depression of myocardial function both at rest and during exercise after beta adrenergic blockade as shown by increased left ventricular rnd-diastolic pressure with no increase in stroke The mean systolic ejection rate was also work. IOWCY~ both at rest and during exercise after adIn spite of hemorlCnistration of propranolol. dynalnic evidence suggesting a reduction in nlyocardial oxygen requirements, in only 1 of the 10 patients with angina pectoris was chest pain prevented by this agent. l‘tir
effects
REFERENCES 1.
(hIJAM,
I’.
propranolol
hf.
S.
and
,?HICHARD,
in angina
pu2toris.
‘I‘IIE AMERICAN
JOURSAL
337, 1965.
B. N. (:. Brit.
OF
Use of 2:
M. J.,
(:ARDIOLOGY
Propranolol in Coronary Heart Disease 2. KEELAN, P. A. A double-blind trial of propranolol (Inderal) in angina pectoris. &it. M. J., I: 897, 1965. 3. RABKIN, R., STABLES, D. P., LEVIN, N. W. and SUZMAN, M. M. The prophylactic value of propranolol in angina pectoris. Am. J. Curdiol., 18: 370, 1966. 4. GRANT, R. H. E. et al. Multicenter trial of propranolol in angina pectoris. Am. J. Cizrdiol., 18: 361, 1966. 5. EPSTEIN,S. E., ROBINSON,B. F., KAHLER, R. L. and BRAUNWALD,E. Effect of beta-adrenergic blockade on the cardiac response to maximal and submaximal exercise in man. J. Gin. Invest., 44: 1745, 1965. 6. RING, R. J. Technique for measurement of the coronary circulation. Presented at Symposium on Advances in Coronary Heart Disease, Los Angeles, Calif., Mar. IO, 1967. 7. CHAMBERLAIN,D. A. Effects of beta adrenergic blockade on heart size. Am. J. Cardiol., 18: 321, 1966. 8. SONNENBLICK,E. H., BRAUNWALD, E., WILLIAMS, J. F., JR. and GLICK, G. Effects of exercise on myocardial force-velocity relations in intact unanesthetized man: Relative roles of changes in heart rate, sympathetic activity, and ventricular
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19
dimensions. J. Clin. Invest., 44: 2051, 1965. 9. SOWTON, E. and HAMER, J. Hemodynamic changes after beta adrenergic blockade. Am. J. Card& 18: 317, 1966. IO. WOLFSON, S. et al. Propranolol and angina pectoris. Am. J. Cardiol., 18: 345, 1966. II. HAMER, J. and SOMPTON,E. Cardiac output after beta-adrenergic blockade in ischaemic heart disease. Brit. Heart J., 27: 892, 1965. 12. LEVINE, J. H., NEILL, W. A., WAGMAN, R. J., KRASNOW, N. and GORLIN, R. The effect of exercise on mean left ventricular ejection rate in man. J. Clin. Invest., 41: 1050, 1962. 13. GORLIN, R., COHEN, L. S., ELLIOTT, W. C., KLEIN, M. D. and LANE, F. J. Effect of supine exercise on left ventricular volume and oxygen consumption in man. Ctrculation, 32: 361, 1965. 14. SONNENBLICK, E. H., Ross, J., JR., CO~ELL, J. W., KAISER, G. A. and BRAUNWALD,E. Velocity of contraction as a determinant of myocardial oxygen consumption. Am. J. Physiol., 209: 919, 1965. 15. SARNOFF, S. J. et al. Hemodynamic determinants of oxygen consumption of the heart with special reference to the tension-time index. Am. J. Physiol., 192: 148, 1958. 16. LEVINE, J. H. and WAGMAN, R. J. Energetics of the human heart. Am. J. Cardiol., 9: 372, 1962.