Download Digitalis and Baroreceptor Reflexes in Man

Digitalis and Baroreceptor Reflexes in
Man
ALBERTO FERRARI, M.D., LUISA GREGORINI, M.D., MARIA CARLA FERRARI, M.D.,
LAURA PRETI, M.D., AND GIUSEPPE MANCIA, M.D.
SUMMARY Data in animals indicate that large amounts of digitalis potentiate arterial baroreflexes and
that this factor may be important for the cardiovascular effects of the drug. To determine if arterial baroreflex
potentiation also exists after administration of therapeutic doses of digitalis in man, we studied how stimulation and deactivation of arterial baroreceptors by phenylephrine and nitroglycerin injection affect heart rate
and how stimulation and deactivation of carotid baroreceptors by neck suction and pressure affects blood
pressure and heart rate. The study was performed in 29 normotensive or hypertensive subjects before and after
injection of Lanatoside C (0.8 mg i.v.). Baroreceptor stimulation reduced heart rate and blood pressure, while
baroreceptor deactivation increased both of these variables. The bradycardic and hypotensive effect of
baroreceptor stimulation increased significantly after digitalis both in normotensive and hypertensive subjects.
However, the tachycardic and hypertensive responses to baroreceptor deactivation were not affected by
digitalis. Thus, therapeutic doses of digitalis in man enhance baroreceptor reflexes, and both the heart rate and
the blood pressure reflex effects are involved. However, the enhancement occurs to a marked degree only with
baroreceptor stimulation and is not evident with baroreceptor deactivation.
Downloaded from http://circ.ahajournals.org/ by guest on June 14, 2017
EVIDENCE from experimental animals indicates
that digitalis increases the effectiveness of the arterial
baroreceptor reflexes and suggests that this may be
important in the clinical action of the drug. First, administration of ouabain in anesthetized cats and dogs
is followed by an increased firing of the aortic and the
carotid baroreceptors." 2 Second, injection of
acetylstrophantidin in anesthetized dogs increases the
depressor response that can be obtained by stimulation of baroreceptors in isolated carotid sinus
preparations.3', Third, the bradycardia induced by
digitalis in unanesthetized dogs is evident when the
baroreceptors are intact, but not after sinoaortic
denervation.'
However, most of the studies we have mentioned
have made use of doses of digitalis compounds that
are greater (and often markedly so) than the doses
used therapeutically. Most important, the only evidence on the effect of digitalis on baroreflexes in man
are reports that digitalis may potentiate the bradycardia induced by baroreceptor stimulation,6 but perhaps
only to a minor degree.7 The present study was undertaken to examine the effects of clinical doses of
digitalis on human baroreceptor reflexes. We examined the reflex effects induced by baroreceptor
stimulation and those resulting from baroreceptor
deactivation below the existing stimulus. By using
different techniques we studied both the heart
rate and the blood pressure influences of the baroreflex. Our results demonstrate that digitalis has a
major action on the cardiac and vascular component
of the baroreflexes in man. However, this action is
more complex than could be anticipated from the
animal studies, as it occurs when baroreceptors are
stimulated but not when they are deactivated.
Methods
We studied 29 subjects of both sexes (mean age
41.6 ± 2.5 years, range 21-59 years) who were hospital inpatients with either normal blood pressure or
with uncomplicated essential hypertension. None of
the subjects had signs of myocardial failure and none
had received antihypertensive or other cardiovascular
drugs in the preceding 3 weeks. Each gave free consent
to the study after its nature and purpose were explained.
Measurements
Pulsatile arterial blood pressure was measured by a
catheter (1.7 mm o.d., 11 cm long) placed percutaneously into a brachial artery and connected to a
strain-gauge transducer system with an optimal frequency response curve up to 20 Hz. Mean arterial
pressure was obtained by electronic damping of the
pulsatile signal and by integration of the pulsatile
trace over consecutive periods of 10 seconds. An ECG
trace (usually lead 2) was recorded throughout the
study for calculation of the RR intervals. Heart rate
was also continuously measured by a cardiotachometer, the signal for which was derived either from the
R wave or from the pulse-pressure signal.
Methods for Studying Arterial Baroreflexes
Two methods were used to study arterial baroreceptor reflexes. In the first, which is currently used, i.v.
phenylephrine and nitroglycerin are injected to increase and reduce arterial blood pressure, thus
stimulating and deactivating all arterial baroreceptors
and causing reflex increases and decreases in RR interval.8' 9 In our study we injected intravenously a
bolus of 50-100 ,g of phenylephrine, which induced a
progressive rise in systolic and diastolic pressures with
a maximal increase of 20-30 mm Hg above the
pressure values before the injection, and a bolus of
100-150 jig of nitroglycerin, which induced a
progressive fall in systolic and diastolic pressures, with
From the Istituto di Patologia Medica I dell'Universita di Milano
and Centro di Ricerche Cardiovascolari del CNR, Milano, Italy.
Address for correspondence: Professor Giuseppe Mancia, Istituto
Ricerche Cardiovascolari, Via F. Sforza 35, Policlinico 20122
Milano, Italy.
Received November 8, 1979; revision accepted June 11, 1980.
Circulation 63, No. 2, 1981.
279
280
CIRCULATION
Downloaded from http://circ.ahajournals.org/ by guest on June 14, 2017
a maximal reduction of 15-20 mm Hg below the
pressures before the injection.
The other method was the variable-pressure neck
chamber, which permits the study of reflex changes in
arterial blood pressure as well as in RR interval in
response to selective stimulation and deactivation of
the carotid sinus baroreceptors. We have given a
detailed description of this method elsewhere. 10-12
Briefly, it consists of a collar extending inferiorly to
the shoulders and superiorly to a plane intersecting the
chin, the ear lobe and the occiput. The pneumatic
pressure within the collar can be altered in a positive
and a negative direction, the alteration being transmitted to the neck tissues outside the carotid sinuses in
the respective amount of 86% and 64%.10 Thus, the
positive and negative neck pressure applications
cause, respectively, a reduction and an increase in
carotid transmural pressure, resulting in deactivation
and stimulation of the carotid sinus baroreceptors
with respect to the existing stimulus. In the present
study the alterations in pneumatic pressure were induced rapidly (90% of the change completed in less
than 1 second) and were maintained constant for 2
minutes. The increase and the decrease in neck tissue
pressure that were obtained were 30.8 ± 1.1 and
29.8 ± 1.1 mm Hg, respectively, before digitalis and
31.2 ± 1.2 and 29.2 ± 1.0 mm Hg after digitalis.
We investigated subjects with normal cardiac function because the injection of phenylephrine caused
similar increases in blood pressure before and after
administration of digitalis in these patients, achieving
comparable baroreceptor stimulation in the two conditions. In preliminary trials, this could not be obtained in patients with heart failure, in whom the
phenylephrine injection caused blood pressure to increase less before than after digitalis, probably
because in the former condition the heart had less
ability to sustain an increased afterload.
Protocol
The study was made with the subjects in a supine
position and began with the insertion of the arterial
and the venous catheters, which was made under local
anesthesia with 2% lidocaine. A 20-minute rest period
was allowed to reduce possible emotional factors involved in the cannulation and to achieve satisfactory
basal conditions. In 22 subjects arterial blood pressure
was increased by phenylephrine and decreased by
nitroglycerin, the two drugs being administered in a
random order and with an interval of 10 minutes.
Lanatoside C was subsequently injected intravenously at a dose of 0.8 mg, followed by an interval
of 40-45 minutes to allow the drug to have its effects,'3
after which phenylephrine and nitroglycerin were administered at the same doses.
In a separate group of seven subjects, the 20-minute
interval after the insertion of the catheters was
followed by application of one positive and one
negative neck pressure, performed in a random order
and separated by a 10-minute interval. Lanatoside C,
0.8 mg, was then injected intravenously and, after an
VOL 63, No 2, FEBRUARY 1981
interval of 40-45 minutes, the positive and negative
pressure applications were repeated at the same
magnitude and with the same sequence as before.
Throughout the study pulsatile arterial pressure,
mean arterial pressure, arterial pressure integrated
over consecutive periods of 10 seconds, heart rate and
ECG were continuously recorded on a Grass
polygraph. The recording was made at low speed (50
mm/min), except during the administration of
phenylephrine and nitroglycerin, when a high speed
(100 mm/sec) of recording was used to allow precise
calculation of systolic pressure values and RR intervals during the change in pressure induced by the
drugs.
Data Analysis
The data from the injection of phenylephrine and
nitroglycerin were analyzed as described by Smith et
al.8 and by Pickering et al.9 Systolic pressure was
measured during the increase or the decrease induced
by phenylephrine and nitroglycerin, each value being
related to the RR interval on the next cardiac cycle.
Linear regression lines based on 12-17 values were obtained between these two variables, the regression
coefficients (i.e., the slope of the regression lines) indicating sensitivity of the reflex. Only subjects in
whom there was a close significant correlation
(p < 0.01) between the changes in systolic blood
pressure and in RR interval both before and after administration of digitalis were considered. This
happened in 18 of the 22 subjects with phenylephrine
and in 20 of the 22 subjects with nitroglycerin. This
technique has given reproducible results in short- and
long-term studies."- ' Within each subject the regression coefficients obtained with either phenylephrine or
nitroglycerin before and after administration of
digitalis were compared by covariant analysis.?6 For
the whole group, regression coefficients were compared by t test for paired observations.
The data obtained with the neck chamber were
analyzed as previously described."1 12 Mean arterial
pressure and RR intervals were calculated as follows.
A control period was obtained by averaging the values
occurring during the 30 seconds preceding the
alterations in neck chamber pressure and an early
response was considered which was the average of the
values occurring between the fifth and the fifteenth
second that followed the alterations in neck chamber
pressure. A late or steady-state response was also considered by averaging the values of the last 30 seconds
of the neck chamber pressure alterations. These two
responses allowed us to take into account both the initial and the late and steady-state effects of the changes
in carotid baroreceptor activity.", 12 Data from each
individual were pooled to obtain mean and standard
error values for the whole group of subjects. The t test
for paired observation was used to evaluate effects of
digitalis on the responses to stimulation and deactivation of carotid sinus baroreceptors. The early and the
steady-state responses were analyzed separately.
Values are mean ± SEM.
DIGITALIS AND BAROREFLEXES/Ferrari
Results
Phenylephrine (18 subjects)
Downloaded from http://circ.ahajournals.org/ by guest on June 14, 2017
These data are shown in table 1. In the control
period the average value for mean arterial pressure
was 112 mm Hg and the RR interval was 823 msec.
The rise in pressure induced by phenylephrine caused
a progressive lengthening of the RR interval in all subjects. The regression coefficient of RR interval on
systolic pressure (expressing the sensitivity of the
baroreflex) was on average 8.13 (range 2.67-15.40).
Digitalis had no significant effect on basal mean
arterial pressure but caused a significant increase in
basal RR interval (p < 0.001). There was no significant difference in the rate or magnitude of the rise in
blood pressure induced by the same dose of phenylephrine before and after digitalis. After digitalis, however, the sensitivity of the baroreflex was increased.
Covariant analysis showed that the magnitude of the
regression coefficient was significantly greater in 16 of
the 18 subjects (fig. 1) and a significant increase was
also found for the whole group by paired t test. The
average of the individual regression coefficients after
digitalis was 11.83, an increase of 43% over the value
before digitalis (fig. 2).
et
al.
281
Two further points were analyzed. First, a correlation was sought between the increase in RR interval
observed after digitalis in the basal period and the increased slope of the baroreflex response induced by the
drug. No significant correlation was found (r = 0.285;
NS). Thus, the bradycardic action of digitalis was not
related to the effect of the drug on the arterial baroreflexes.
Second, no significant correlation was found between the increase in the slope of the baroreflex response induced by digitalis and the value of the slope
before digitalis (r = 0.322; NS). Thus, the extent of
the baroreflex potentiation did not seem to depend on
having originally a more or less powerful baroreflex
function.
Nitroglycerin
Data for nitroglycerin are shown in table 2. In the
control period the average value for mean arterial
pressure was 106 mm Hg and the RR interval was 802
msec. The fall in pressure induced by nitroglycerin
caused a progressives shortening of the RR interval in
all subjects. The regression coefficient of RR interval
on systolic pressure (i.e., the baroreflex sensitivity)
was an average 4.93 (range 1.86-18.20).
TABLE 1. Reflex Increase in RR Interval Induced by Increasing Arterial Blood Pressure with Phenylephrine in 18 Subjects Studied
Before and After Administration of Digitalis
After digitalis
Before digitalis
Control Control
Control Control
Regr. coeff.
RR
MAP
Regr. coeff.
RR
MAP
p <
r
(msec/mm Hg)
(mm Hg) (msec)
r
(msec/mm Hg)
(mm Hg) (msec)
976
0.67
5.39
0.01
102
2.67
1
0.72
882
109
0.05
10.49
0.92
810
103
6.93
2
839
0.71
117
94
NS
6.23
0.98
833
3
97
789
0.88
7.15
0.01
16.69
0.84
682
109
4
10.96
0.83
594
113
0.05
7.29
0.91
882
123
6.29
0.91
789
123
5
0.01
7.75
0.92
845
89
3.59
6
0.81
828
96
NS
0.89
10.56
952
136
12.57
0.80
143
870
7
0.01
4.80
106
0.97
857
116
2.71
8
0.95
769
0.02
12.14
0.81
967
148
6.81
0.93
857
151
9
0.01
9.37
0.86
94
983
7.23
0.97
882
10
108
0.05
10.76
0.94
869
103
9.90
11
811
0.98
102
0.05
12.25
0.89
857
101
11.49
12
0.99
113
750
0.05
14.45
0.86
723
108
844
10.63
0.88
97
13
0.05
15.60
0.69
958
111
95
14
12.77
0.86
847
0.01
31.50
1000
0.64
13.40
78
15
79
860
0.84
0.01
3.98
0.85
779
122
2.70
0.86
733
138
16
0.01
0.88
19.90
1276
86
10.60
0.82
1190
89
17
0.01
822
13.70
0.92
18
100
114
6.03
0.89
676
11.83
106
893
823
8.13
0.01
-1.54
-4
±31
0.90
-4
--28
in
RR
interval
inData are expressed in each subject as linear relationships between rise in systolic pressure and lengthening
duced by the injection of phenylephrine, each systolic pressure value being related to the next RR interval value. p refers to the
difference between the regression coefficients before and after digitalis, estimated by covariant analysis in individuals and by t
test in the group as a whole.
Abbreviations: MAP = mean arterial pressure; RR = RR interval; regr. coeff. = regression coefficient.
Mean
SEM
112
282
CIRCULATION
VOL 63, No 2, FEBRUARY 1981
msec
mm Hg
1400-
0A after
A
digitalis
r - 0.92
b- 13.7
a = -1464
p < 0.001
A
1200-
msec
<c0.05
10
I
W
1.
z
a-+100-
l
mmHg
9z
digitalis
+100-
CL
z
W
a
-
1:
100-
z
b: 6.03
a: -350
p< 0.001
800-
X
I
100
o- C
czmse
4
o before
r = 0.89
cc
0z
(D
z
4x
IT
CU
Q
6
Downloaded from http://circ.ahajournals.org/ by guest on June 14, 2017
--
160
200
240 mmHg
SYSTOLIC PRESSURE
FIGURE 1. Effects of increasing systolic blood pressure by
phenylephrine on the RR interval before and after administration of digitalis. The increase in systolic pressure
caused a linearly related lengthening ofthe RR interval. The
slope of the relationship, i.e., the regression coefficient, is
significantly greater after than before digitalis administration.
As described in the previous section, administration
of digitalis was followed by no change in basal arterial
pressure and by an increase in basal RR interval
(p < 0.005). There was no significant difference in the
rate or magnitude of the fall in blood pressure induced
by the same dose of nitroglycerin before and after
digitalis. In contrast with the results with phenylephrine, however, the sensitivity of the baroreflex as
estimated by nitroglycerin was not affected by
PHENYLEPHRINE
n= 18
+
msec/+ mm Hg
n= 7
FIGURE 3. Hemodynamic changes induced by stimulating
(upper panel) and deactivating (lower panel) carotid sinus
baroreceptors by means of negative and positive neckchamber pressures. Data are average (± sEM) changes from
control values in seven subjects who were studied before
and after administration of digitalis. C = control values;
E = early response; and SS = steady-state responses. Basal
mean arterial pressure and basal RR interval were, respectively, 117.2 ± 6.1 mm Hg and 772 ± 29 msec before
digitalis and 114.3 ± 5 mm Hg and 833 ± 47 msec after
digitalis. The p values refer to differences in the responses
before and after digitalis. MAP = mean arterial pressure.
digitalis. In six subjects, the regression coefficient was
significantly increased, in six it was unchanged and in
eight it was significantly reduced. The average value
for the regression coefficient obtained with nitro-
TRINITROGLYCERINE
n= 20
14
T
12-
FIGURE 2. Effects of baroreceptor stimulation (phenylephrine) and baroreceptor
deactivation (nitroglycerin) on RR interval
in the control condition and after digitalis
administration. The histograms represent
the averages (± SEM) of the regression coefficients of each subject.
z
W
10-
<0
d01
IL
LL
W
0
86-
0
Vl)
(n
W
4-
it
WD
cc
S'S
before digitalis
after digitalis
- msec/- mmHg
14-
U
-%
010
-
0
.
1
0
LU
-
_-4
0
ox
X
C-) -20-
W
1
-
.1
z
_
<0.05
''\<005 0.05
2
z
20-
0-
control
digitalis
control
digitalis
DIGITALIS AND BAROREFLEXES/Ferrari et al.
283
Downloaded from http://circ.ahajournals.org/ by guest on June 14, 2017
TABLEJ 2. Reflex Reduction in RR Interval by Reducing Arterial Blood Pressure with Nitroglycerin in 20 Subjects During Control
and After Administration of Digitalis
After digitalis
Before digitalis
RR
MAP
RR
MAP
Regr. coeff.
Regr. coeff.
r
(mm Hg) (msec)
r
p <
(msec/mm Hg)
(msec/mm Hg)
(mm Hg) (msec)
1
109
0.70
882
1.86
102
NS
967
0.65
1.29
810
2
839
2.30
103
0.97
117
0.97
3.21
0.05
94
3
833
97
789
0.97
4.61
0.96
3.22
0.01
682
4
113
594
0.94
3.55
109
0.96
2.98
0.05
5
101
682
6.36
100
952
0.97
0.83
3.79
0.01
123
789
0.88
2.42
123
882
0.85
6
1.98
0.05
96
7
827
845
0.95
3.03
89
0.89
4.19
0.05
143
136
869
8
0.74
3.15
952
0.96
5.59
0.01
106
116
769
2.84
0.97
857
0.97
9
2.37
NS
94
10
882
108
0.98
3.64
983
0.93
3.87
NS
11
102
810
0.92
103
3.28
869
0.89
3.03
NS
12
113
750
3.58
101
0.96
857
0.94
4.20
0.05
722
13
97
843
0.97
3.17
108
0.98
3.00
NS
111
95
958
12.36
0.05
14
847
0.90
10.32
0.92
1001
15
79
869
0.79
3.92
78
0.92
7.44
0.01
16
72
829
0.97
780
9.77
78
0.75
2.55
0.01
122
732
761
17
138
0.92
3.50
0.88
2.81
0.05
18
121
923
114
0.87
903
5.80
0.98
NS
5.09
92
0.92
19
852
18.20
78
1081
0.92
0.01
5.20
114
20
676
100
0.98
3.30
819
0.97
2.21
0.05
106
Mean
802
101
875
4.93
4.02
NS
3
-SE
018
-22
-3
0.86
-0.54
Data are expressed in each subject as linear relationships between fall in systolic pressure and shortening in RR interval induced by the injection of nitroglycerin, each systolic pressure value being related to the next Rlt interval value.
Abbreviations: MAP = mean arterial pressure; RR = RR interval; regr. coeff. = regression coefficient.
glycerin was 4.02, which did not differ significantly
from the average value before digitalis.
Neck Chamber
The effects of digitalis on basal blood pressure and
basal RR interval were similar to those previously
described (no significant pressure change and a significant RR interval -lengthening).
In the control condition, reducing the tissue pressure outside the carotid sinuses (i.e., increasing carotid
transmural pressure and stimulating carotid sinus
baroreceptors) caused a clear-cut reduction in arterial
blood pressure (fig. 3), whereas increasing the tissue
pressure outside the carotid sinuses (i.e., reducing
carotid transmural pressure and deactivating the
carotid sinus baroreceptors) caused a clear-cut increase in arterial pressure. The early and the steadystate responses to these maneuvers (see Methods) were
similar. After digitalis, the hypotensive responses to
carotid baroreceptor stimulation were significantly
greater, whereas the pressor responses to carotid baroreceptor deactivation were not significantly altered.
The effects of carotid baroreceptor stimulation and
deactivation on RR interval are shown in figure 3.
Confirming previous findings,"' 12 these responses
were modest and variable. On average, RR interval
was reduced slightly in response to carotid baroreceptor deactivation, while no significant change was
observed when the carotid baroreceptors were
stimulated. The only effect of digitalis was on the early
response to baroreceptor stimulation, which consisted
of a significant increase in RR interval.
The bradycardic
Discussion
response to stimulation of arterial
baroreceptors by phenylephrine and the hypotensive
response to stimulation of carotid sinus baroreceptors
by neck suction were greater after than before injection of 0.8 mg of Lanatoside C, which is within the
therapeutic range adopted in man. Therefore,
administration of clinical doses of digitalis in man
augments the reflex effects of arterial baroreceptor
stimulation, and the augmentation is evident with
regard both to the heart rate and to the blood
pressure. This potentiation may have beneficial
effects.'7 For example, enhancement of the inhibitory
influence of baroreceptors on the sinoatrial and atrioventricular node'8 may reduce the ventricular rate,
284
CIRCULATION
Downloaded from http://circ.ahajournals.org/ by guest on June 14, 2017
thus improving cardiac filling, stroke volume and coronary flow in conditions such as heart failure and
atrial fibrillation if baroreflex potentiation occurs in
these pathologic conditions as it does in normal subjects.
Our results also show that in man, only one side of
the baroreflex is enhanced. When the opposite side of
the reflex was studied, i.e., when the baroreceptors
were deactivated below the existing level of stimulus
by nitroglycerin and positive neck pressure, the reflex
tachycardic and pressor responses were not significantly different before and after administration of
digitalis. Thus, in man, the augmentation of the
arterial baroreceptor function by this drug is limited
to the effects of the baroreceptor stimulation and cannot be demonstrated for the effects of a baroreceptor
deactivation below the level set tonically by the existing arterial pressure. This indicates a difference with
animal studies using large doses of digitalis, in which
the hemodynamic responses to deactivation of carotid
baroreceptors by common carotid occlusion is also
enhanced.3
We do not know why digitalis only potentiates the
effects of baroreceptor stimulation and not those of
baroreceptor deactivation. However, data from experimental animals suggest at least two explanations.
The first is that digitalis stimulates vagal efferent
fibers by an action at the central level and possibly at
the nerve terminals.'7 The second is that besides augmenting baroreceptor responses to increase in blood
pressure (a "sensitization," which may account for the
potentiation of the reflex that we observed), digitalis
causes a direct pharmacologic stimulation of the
receptors independent of any pressure stimulus.2' 1'
These factors might oppose the tachycardic and
pressor responses either by supporting cardiac vagal
influence and by limiting the degree of baroreceptor
deactivation that can be obtained by a fall in blood
pressure or carotid transmural pressure. Whatever the
mechanism involved, that digitalis does not potentiate
the response to baroreceptor deactivation may be
therapeutically beneficial because excessive tachycardia is avoided during reductions in blood pressure.
Several other aspects of our study should be discussed. First, our subjects showed widely different
degrees of baroreceptor control of heart rate in the
basal condition, consistent with their wide range of
age and blood pressure.'4' 20, 21 Yet digitalis enhanced
the heart rate response to baroreceptor stimulation to
the same degree in the subjects with lesser and in those
with greater baroreflex sensitivity. One of the conditions in which the baroreflex has a reduced sensitivity is heart failure,15' 21 which is often preceded
and caused by hypertension.22 Therefore, the effect of
digitalis on the baroreflex may operate in the clinical
conditions in which digitalis is used.
Second, we found a lack of correlation between the
extent of the bradycardia induced by digitalis and the
increase in baroreflex sensitivity caused by the drug.
This finding suggests that arterial baroreflex potentiation by digitalis is just one of the many factors responsible for the effect of digitalis on heart rate, the others
VOL 63, No 2, FEBRUARY 1981
being the well-known influence of digitalis on cardiovagal centers and vagal nerve terminals'7 and possibly
also the effect of this drug on reflexes originating in
the heart.23
Third, we noted greater blood pressure responses to
carotid baroreceptor stimulation after digitalis. Heart
rate effects of baroreceptor manipulation are entirely
mediated via the vagus,'Il 24 but blood pressure effects
depend mainly on the baroreceptor modulation of
noradrenergic sympathetic tone.25 26 Thus, our observations indicate that the baroreflex potentiation
caused by digitalis in man is not limited to the cardiovagal component of the reflex, but involves its sym-
pathetic efferent pathways.
Acknowledgment
We thank Paola Boccaccini for typing the manuscript, Riccardo
Sarri for photography and Carla Zanchetti for preparing illustrations.
References
1. McLain PL: Effects of ouabain on spontaneous afferent activity
in the aortic and carotid sinus nerves of cats. Neuropharmacol
9: 399, 1970
2. Quest JA, Gillis RA: Effect of digitalis on carotid sinus baroreceptor activity. Circ Res 35: 247, 1974
3. Quest JA, Gillis RA: Carotid sinus reflex changes produced by
digitalis. J Pharmacol Exp Ther 177: 650, 1971
4. Reing CM, Thibodeaux H, Gillis RA, Kot PA: Influence of
baroreceptor reflexes on cardiovascular responses of the dog to
acetylstrophantidin. J Pharmacol Exp Ther 184: 641, 1973
5. McRitchie RJ, Vatner SF: The role of arterial baroreceptors in
mediating the cardiovascular response to a cardiac glycoside in
conscious dogs. Circ Res 38: 321, 1976
6. Cokkinos DV, Haralambakis G, Thalassinos C, Heimanas ET,
Demopoulos J, Voridis N, Gardikas C: Effect of digitalis on
diminished baroreceptor sensitivity in diabetics. Angiology 30:
549, 1979
7. Thompson MA, Eckberg DL: Effects of ouabain upon the
carotid baroreceptor reflex in normal man. (abstr) Circulation
54 (suppl II): 11-224, 1976
8. Smith HS, Sleight P, Pickering GW: The reflex regulation of
arterial pressure during sleep in man: a quantitative method of
assessing baroreflex sensitivity. Circ Res 24: 109, 1969
9. Pickering TG, Gribbin B, Sleight P: Comparison of reflex heart
rate response to rising and falling arterial pressure in man. Cardiovasc Res 6: 277, 1972
10. Ludbrook J, Mancia G, Ferrari A, Zanchetti A: The variablepressure neck-chamber method for studying the carotid baroreflex in man. Clin Sci Mol Med 53: 165, 1977
11. Mancia G, Ferrari A, Gregorini L, Valentini R, Ludbrook J,
Zanchetti A: Circulatory reflexes from carotid and extracarotid baroreceptor areas in man. Circ Res 41: 309, 1977
12. Mancia G, Ludbrook J, Ferrari A, Gregorini L, Zanchetti A:
Baroreceptor reflexes in human hypertension. Circ Res 43: 170,
1978
13. Moe GK, Farah AE: Digitalis and allied cardiac glycosides. In
The Pharmacological Basis of Therapeutics, edited by Goodman LS, Gilman A. New York, MacMillan, 1974, p 653
14. Gribbin B, Pickering TG, Sleight P, Peto R: Effect of age and
high blood pressure on baroreflex sensitivity in man. Circ Res
29: 424, 1971
15. Higgins CB, Vatner JF, Eckberg DL, Braunwald E: Alteration
in the baroreceptor reflex in conscious dogs with heart failure. J
Clin Invest 51: 715, 1972
16. Snedecor GW, Cochran WG: Statistical Methods. Ames, Iowa,
Iowa University Press, 1967
17. Gillis RA, Pearle DL, Levitt 0: Digitalis: a neuroexcitatory
drug. Circulation 52: 739, 1975
18. Mancia G, Bonazzi 0, Pozzoni L, Ferrari A, Gregorini L,
CORONARY SCORE AND CAD/Leaman et al.
19.
20.
21.
22.
Perondi R: Baroreceptor control of atrioventricular conduction
in man. Circ Res 44: 752, 1979
Saum WR, Brown AM, Tuley FM: An electrogenic sodium
pump and baroreceptor function in normotensive and spontaneously hypertensive rats. Circ Res 39: 497, 1976
Bristow JD, Honour AS, Pickering GW, Sleight P, Smyth HS:
Diminished baroreflex sensitivity in high blood pressure. Circulation 39: 48, 1969
Eckberg DL, Drabinsky M, Braunwald E: Defective parasympathetic control in patients with heart disease. N Engl J
Med 285: 87, 1971
Kannel WB: Importance of hypertension as a major risk factor
in cardiovascular disease. In Hypertension, edited by Genest J,
285
Koiw E, Kuchel 0. New York, McGraw-Hill, 1977, p 888
23. Thames MD: Acetylstrophantidin-induced reflex inhibition of
canine renal sympathetic nerve activity mediated by cardiac
receptors with vagal afferents. Circ Res 44: 8, 1979
24. Eckberg DL, Abboud FM, Mark AL: Modulation of carotid
baroreflex responsiveness in man: effects of posture and
propranolol. J Appl Physiol 41: 383, 1976
25. Mancia G, Ferrari A, Gregorini L, Parati G, Ferrari MC,
Pomidossi G, Zanchetti A: Control of blood pressure by carotid
sinus baroreceptors in human beings. Am J Cardiol 44: 895,
1979
26. Kirchheim H R: Systemic arterial baroreceptor reflexes. Physiol
Rev 56: 100, 1976
Coronary Artery Atherosclerosis: Severity
of the Disease, Severity of Angina Pectoris
and Compromised Left Ventricular Function
Downloaded from http://circ.ahajournals.org/ by guest on June 14, 2017
DAVID M. LEAMAN, M.D., RONALD W. BROWER, PH.D., GEERT T. MEESTER, M.D.,
PATRICK SERRUYS, M.D., AND MARCEL VAN DEN BRAND, M.D.
SUMMARY To determine if the severity of angina pectoris and the degree of altered left ventricular function correlated with the severity and extent of the underlying coronary artery disease, a coronary scoring
system was derived. The system was based on the severity of luminal diameter narrowing and weighted according to the usual flow to the left ventricle in each coronary vessel. Thus, the most weight was given to the left
main coronary artery, followed by the left anterior descending, circumflex, and right coronary arteries. The
resultant number was an indicator of the overall severity of the obstructive coronary artery disease. A coronary
arterial system with no obstructive disease was scored as zero and the greater the degree of obstructive disease
coronary
present, the higher the coronary score. From 202 subjects, four groups were evaluated: group 1
coronary score = 17.5score = 0.5-4.5 (n = 10); group 2- coronary score = 10.5-12.5 (n = 11); group 3
20.5 (n = 11); and group 4 coronary score = 25.0-36.0 (n = 11). All subjects had coronary artery bypass
surgery and had preoperative and l-year postoperative cardiac catheterization, including atrial pacing to maximal heart rate. The groups could not be separated on the basis of angina frequency, resting heart rate, cardiac
index, left ventricular end-diastolic pressure, peak paced left ventricular end-diastolic pressure, dP/dt, V max,
left ventricular end-diastolic volume index, left ventricular end-systolic volume index, stroke volume index,
ejection fraction or mean circumferential fiber shortening velocity. Thus, based on this study, the severity of
coronary artery disease does not statistically correlate with the frequency of angina pectoris or produce a
predictable degree of altered left ventricular function. The frequency of angina pectoris cannot be used to
predict prognosis or the adequacy of myocardial revascularization.
-
IF THE SEVERITY of angina pectoris correlated
with the severity of the underlying coronary artery
atherosclerosis, one could better judge the appropriate
time for invasive diagnostic and therapeutic interventions. One could also ascertain the prognosis of the
disease, as it has been adequately shown that
prognosis is in part dependent on the severity of coroFrom the Erasmus University, Thoraxcentrum, The Interuniversity Cardiology Institute, Rotterdam, The Netherlands, and the
Department of Cardiology, The Milton S. Hershey Medical Center
of the Pennsylvania State University, Hershey, Pennsylvania.
Address for correspondence: David M. Leaman, M.D., Department of Medicine, Division of Cardiology, The Hershey Medical
Center, Hershey, Pennsylvania 17033.
Received August 21, 1979; revision accepted June 26, 1980.
Circulation 63, No. 2, 1981.
nary artery disease (CAD).1-10 It would also be helpful
if the severity of the CAD correlated with the degree
of abnormal left ventricular function. This would be
especially helpful in the postoperative state, when one
could very simply ascertain the adequacy of the operation and judge the state of left ventricular function.
To evaluate these possibilities, a coronary score was
derived to assess the degree of CAD. The coronary
score was then related to the frequency of angina pectoris to determine if the extent of CAD could be
predicted based on the clinical presentation of angina
pectoris. It was also compared with resting and paced
left ventricular function measurements to determine if
the severity of CAD had a predictably deleterious
effect on left ventricular function. The coronary score
was also determined at 1 year after coronary bypass
surgery and was again compared with the frequency of
Digitalis and baroreceptor reflexes in man.
A Ferrari, L Gregorini, M C Ferrari, L Preti and G Mancia
Downloaded from http://circ.ahajournals.org/ by guest on June 14, 2017
Circulation. 1981;63:279-285
doi: 10.1161/01.CIR.63.2.279
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 1981 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539
The online version of this article, along with updated information and services, is located on
the World Wide Web at:
http://circ.ahajournals.org/content/63/2/279
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally
published in Circulation can be obtained via RightsLink, a service of the Copyright Clearance Center, not the
Editorial Office. Once the online version of the published article for which permission is being requested is
located, click Request Permissions in the middle column of the Web page under Services. Further
information about this process is available in the Permissions and Rights Question and Answer document.
Reprints: Information about reprints can be found online at:
http://www.lww.com/reprints
Subscriptions: Information about subscribing to Circulation is online at:
http://circ.ahajournals.org//subscriptions/