Download blocker with intrinsic sympathomimetic activity in

THERAPY AND PREVENTION
CARDIOMYOPATHY
Hemodynamic-inotropic response to [-blocker with
intrinsic sympathomimetic activity in patients with
congestive cardiomyopathy
PHILIP F. BINKLEY, M.D., ROBERT F. LEWE, JOHN J. LIMA, PHARM.D.,
ABDULKADER AL-AWWA, M.D., DONALD V. UNVERFERTH, M.D., AND CARL V. LEIER, M.D.
Downloaded from http://circ.ahajournals.org/ by guest on April 29, 2017
ABSTRACT The rest and exercise hemodynamic-inotropic response to administration of the l3blocker pindolol was evaluated in 10 patients with congestive cardiomyopathy to determine whether the
intrinsic sympathomimetic activity (ISA) of this agent may preserve ventricular function in the setting
of /3-blockade. A significant (p < .05) rise in systemic and pulmonary vascular resistance and a decline
in stroke volume and cardiac index was observed after a single 10 mg dose. The change in cardiac index
was negatively correlated with free drug concentration (r= - .59, p < .01); the change in pulmonary
and systemic vascular resistance showed a positive correlation with plasma concentration (r = .67,
r- .57, respectively; all p < .05). The response to exercise reflected a predominant /3-blocking effect,
with a significant decrease in peak heart rate and cardiac index and an increase in pulmonary vascular
resistance. There were no significant changes in variables of right or left ventricular inotropy after
administration of the drug. The mean baseline plasma norepinephrine concentration for the population
was 609 + 172 pg/ml (normal = 196 + 7 pg/ml) and was markedly elevated in two patients (931 and
2053 pg/ml) who developed severe pindolol-induced hypotension. Renin increased markedly in these
two patients, but decreased in each of the remaining eight patients. These data indicate that although
inotropy is not adversely affected by pindolol, increased afterload, which appears to be mediated by
peripheral /3-blockade, results in a reduction in ventricular performance. ISA may not protect against
possible adverse effects of /3-blockade in patients with congestive cardiomyopathy; the baseline
norepinephrine concentration and renin response to drug administration may define patients at highest
risk for hemodynamic compromise after administration of this /3-blocker.
Circulation 74, No. 6, 1390-1398, 1986
/3-BLOCKERS with intrinsic sympathomimetic activity (ISA) manifest /3-agonist as well as /3-blocking
effects in animal preparations and human subjects. ` It
has been postulated that ISA accounts for the difference in hemodynamic and inotropic effects of these
agents as compared with pure /3-blockers. Unlike the
latter, /3-blockers with ISA do not alter baseline cardiac index or systemic and pulmonary vascular resistances over the short term in normal subjects.2 A similar hemodynamic profile has been noted after
long-term administration of these agents in patients
with essential hypertension.' Examination of noninvaFrom the Division of Cardiology, The Ohio State University College
of Medicine, Columbus.
Supported by the Central Ohio Heart Chapter of the American Heart
Association, The William Davis Research Fund, and GCRC-34 of the
National Institutes of Health, Columbus, OH.
Address for correspondence: Philip F. Binkley, M.D., Assistant Professor of Medicine, Division of Cardiology, Ohio State University
Hospitals, 621 Means Hall, 1654 Upham Dr.. Columbus, OH 43210.
Received June 10, 1986; revision accepted Aug. 21, 1986.
1390
sive indexes of resting ventricular function has demonstrated that ISA /3-blockers do not reduce ventricular
contractility to the same degree as do pure /-blockers
and may in some populations improve resting ventricular function.46
These observations suggest that, in the setting of
normal ventricular function, the myocardial depressant
effects of ISA ,/-blockers are less than those of pure ,8blockers, perhaps as a result of their sympathomimetic
influence. Because the hemodynamic and inotropic
effects mediated by these agents in the setting of normal ventricular function would be desirable in those
with reduced ventricular contractility, it has been proposed that ISA /3-blockers would be preferable to pure
/3-blockers for use in a population with congestive
heart failure.7 This, however, has not yet been
verified.
The current study tests the hypothesis that the beneficial effects of ISA /3-blockers noted in patients with
normal ventricular function will also be expressed in a
CIRCULATION
THERAPY AND PREVENTION-CARDIOMYOPATHY
population with reduced ventricular contractility. The
rest and exercise hemodynamic-inotropic response to
administration of the potent ISA ,f-blocker pindolol is
described in a population with idiopathic congestive
cardiomyopathy. The observed changes in these variables are correlated with neurohumoral factors and free
drug concentrations to provide insight into the mechanism of action of this complex class of fl-blockers.
Methods
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Patient population (table 1). Ten patients with idiopathic
congestive cardiomyopathy (ages 28 to 57 years) comprised the
study population. Each had a reduced ejection fraction (all <
30%) as determined by contrast or radionuclide angiography.
Criteria for exclusion included evidence of pulmonary, renal, or
hepatic dysfunction and high-grade sinus node or atrioventricular conduction abnormalities. All vasodilator drugs were
discontinued at least 48 hr before entry into the protocol. Informed consent was obtained before the study from all patients
in accordance with the Human Rights Review Committee of the
Ohio State University, which reviewed and approved this inves-
tigation.
Hemodynamic monitoring and drug administration. All
patients were admitted to the cardiovascular monitoring section
of the Clinical Research Center of the Ohio State University
Hospitals. Shortly after admission a balloon-tipped flow-directed catheter was inserted via the subclavian or internal jugular
vein (Seldinger technique) and advanced until the distal tip was
positioned in the pulmonary artery.
On the moming after catheter placement, baseline standard
hemodynamic measurements were made. Calculated variables
derived from these measurements included cardiac index (liters!
min/m2) = cardiac output/body surface area; stroke volume
index (ml/beat/m2) = cardiac index x 1000/heart rate; mean
systemic blood pressure (mm Hg) = (systolic - diastolic pressure)/3 + diastolic pressure; total systemic vascular resistance
(dynes-sec-cm-5) = (mean systemic blood pressure x 80)/cardiac output; total pulmonary vascular resistance (dynes-seccm-5) = (mean pulmonary arterial pressure X 80)/cardiac output. Cardiac outputs were determined by the thermodilution
technique and were taken as the mean of at least three measureTABLE 1
Characteristics of study population
Patient
No.
Age
(years)
1
2
3
4
5
6
7
8
9
10
Mean+SD
44
67
46
38
50
47
30
28
47
59
46±12
Ejection
fraction
(%)
15
18
29
25
23
22
29
22
15
29
23+5
Functional
class
II
II
II
III
III
IV
II
III
III
1I
2.6+0.7
Functional class is according to New York Heart Association classification.
Vol. 74, No. 6, December 1986
ments (six measurements if variation was >10%). Systemic
blood pressures were measured by cuff auscultation.
After duplicate baseline measurements were obtained, a 5 mg
oral dose of pindolol was administered and hemodynamic variables were measured at 15 and 30 min and 1, 2, 4, 6 and 8 hr after
dosing. In the absence of an adverse response to the drug, a 10
mg oral dose of pindolol was given 24 hr after the first dose and
hemodynamic variables were measured at intervals corresponding to those after the 5 mg dose. A second, third, and fourth 10
mg dose were given at eight hr intervals after the first 10 mg
dose. Hemodynamic variables were measured through the 8 hr
after the fourth dose.
Inotropic indexes. Indexes of the inotropic state of the right
and left ventricles were obtained in subjects in the supine posture. These measurements were acquired immediately before
and 2 hr after the 5 mg dose, the first 10 mg dose, and the fourth
10 mg dose. The inotropic indexes were derived from the M
mode echocardiogram, carotid pulse tracing, phonocardiogram,
apexcardiogram, right atrial pressure, pulmonary arterial pressure, pulmonary capillary wedge pressure, and electrocardiogram. Left ventricular inotropic variables consisted of (1) percent fractional shortening = (EDD - ESD)/EDD x 100%,
where EDD and ESD are the end-diastolic and end-systolic
minor-axis dimensions of the left ventricle, respectively,8 (2)
systolic time intervals, consisting of total electromechanical
systole (QS2), preejection period (PEP), left ventricular ejection time (LVET), and the ratio PEP/LVET,9 (3) mean velocity
of circumferential fiber shortening defined as (EDD ESD)/(EDD x LVET),8 and (4) isovolumetric developed pressure/isovolumetric contraction time (AP/AT) = (systemic diastolic pressure-pulmonary capillary wedge pressure)/(PEP EMCP), where EMCP is the electrical-mechanical coupling
interval defined as the interval from the onset of the Q wave of
the electrocardiogram to the onset of the rapid upstroke of the
apexcardiogram. 10 Right ventricular inotropic indexes were (1)
systolic time intervals, including right ventricular electromechanical systole (QP2), right ventricular PEP (RV-PEP), and
right ventricular ejection time (RVET) derived from the pulmonary arterial pulse tracing, and (2) AP/AT of the right ventricle
(RV-AP/AT) = (pulmonary arterial diastolic pressure - right
atrial pressure)/RV-PEP. All determinations represent the mean
of measurements obtained from 10 consecutive cardiac cycles.
Exercise evaluation. A baseline, upright, bicycle exercise
study using a Quinton model 845 Uniwork ergometer was performed on all patients on the day before administration of the
first dose of pindolol at least 2 hr after insertion of the pulmonary arterial catheter. The exercise protocol consisted of 3 min
stages at an initial workload of 100 kilopond-meters per minute
(kpm) with increments of 100 kpm per stage to maximal exercise. Maximal bicycle ergometry was repeated 2 hr after the last
dose of pindolol. Values for hemodynamic variables were obtained at baseline, during the last 30 sec of each 3 min stage, and
at maximal exercise.
Neurohumoral variables. Blood for the determination of
plasma norepinephrine and renin concentration was obtained
after 12 hr of bed rest preceding administration of the 5 mg dose
and the first 10.mg dose. Blood samples for determination of
these variables were again obtained 2 hr after the 5 mg dose and
the first 10 mg dose. The neurohumoral determinations, performed by radioimmunassay in the core laboratory of the Clinical Research Center of the Ohio State University, have the
following coefficients of variation: norepinephrine, 4.2% (CatA-KIT Upjohn Diagnostics); renin, 5.2% (Rianen Assay System, New England Nuclear).
Determination of plasma concentrations of pindolol.
Blood samples for- determination of total (unbound plus bound)
plasma concentrations of pindolol were obtained before dosing
1391
BINKLEY et al.
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and at 15 min, 30 min, and hourly intervals for 12 hr after the 5
mg dose. Samples were obtained before dosing and at 1, 2, 4,
and 8 hr after each 10 mg dose. Analysis for pindolol concentration was performed by reversed-phase liquid chromatography
with ultraviolet detection at a wavelength of 220 nm.12 The
plasma protein binding of pindolol was determined by equilibrium dialysis with use of '4C-pindolol.i3 Quenching was controlled for by internal standardization with '4C-toluene. The
unbound fraction of pindolol in plasma was determined by calculation of the ratio of the concentration of disintegrations per
minute in buffer to disintegrations per minute in plasma after
equilibrium. Unbound concentrations of pindolol were determined by calculating the product of the unbound fraction and
total plasma concentrations of pindolol. Details on the method
used and the plasma protein binding and pharmacokinetics of
pindolol have been published. 4
Statistical analysis. Data were analyzed by the CLINFO
Data Management and Analysis system of the Ohio State University (GCRC RR-34). Analysis of variance for repeated measures was used to test significant differences between hemodynamic-inotropic variables and neurohumoral factors at baseline
and after administration of drug. Correlations between free drug
concentrations and hemodynamic and inotropic indexes were
sought by linear regression analysis with Pearson's correlation
coefficient.
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Results
Adverse responses. Three patients did not complete
the protocol due to adverse responses to the drug. In
patient 9, systolic and diastolic blood pressure fell
from a baseline of 104/88 mm Hg to 80/0 mm Hg 2 hr
after the 5 mg dose. In patient 6, systolic and diastolic
blood pressure declined from a baseline of 92/60 mm
Hg to 70/0 mm Hg 6 hr after the first 10 mg dose; only
a mild decline in blood pressure was observed after the
5 mg dose in this patient. In both patients, administration of a vasopressor (dopamine) was required for 12 to
18 hr. Patient 7 developed frequent (20/min) premature ventricular contractions, one to three ventricular
couplets per hour, and salvos of ventricular tachycardia (occurring one to three times per hour) starting 15
min after the first 10 mg dose and persisting for 10 hr
after the administration of the drug. Further details on
this adverse response have been reported."5
Hemodynamic responses. Significant changes in cardiac index, stroke volume index, systemic vascular
resistance, and pulmonary vascular resistance (PVR)
were noted after the first 10 mg dose of pindolol (figure
1). A significant decrease in cardiac index (p < .05)
was observed 30 min after this dose (2.50 + 0.56 to
2.27 ± 0.45 liters/min/m2) and remained significantly
depressed throughout the 2 hr after dosing. Similarly, a
significant (p < .05) decline in stroke volume index
was observed 30 min after the first 10 mg dose (34.2 ±
7.9 to 31.2 ± 6.5 ml/beat/m2). Systemic and pulmonary vascular resistance both increased significantly (p
< .05) over those at baseline during this period. Sys-
w
temic vascular resistance returned to baseline within 2
hr after dosing, but pulmonary vascular resistance
tended to remain elevated through the 8 hr after dosing. No significant changes in any of these variables
were noted after the 5 or the last 10 mg dose. There
were no significant differences in these measures during the baseline periods preceding each dosing
interval.
Significant decreases in heart rate were noted after
the 5 mg dose and the first and last 10 mg doses (all p <
-
0
.5
2
4
6
1
8
HOURS POST PI NDOiLOL ( 1 0 mg )
FIGURE 1. From top to bottom: heart rate, cardiac index (CI), stroke
index (SI), systemic vascular resistance (SVR), and pulmonary vascular
resistance (PVR) at predose baseline and after the first 10 mg dose of
pindolol. A significant (p < .05) decline in heart rate, Cl, and SI was
noted coincident with significant increases in SVR and PVR.
CIRCULATION
THERAPY AND PREVENTION-CARDIoMYOPATHY
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.05). The decline in heart rate was observed within 2 hr
after dosing and returned to baseline 4 to 6 hr after
dosing. A significant (p < .05) decline in mean blood
pressure was observed within 1 hr after the 5 mg dose
(96 ± 18 to 89 + 20 mm Hg) and persisted for 8 hr.
No significant changes in mean systemic pressure were
noted after the first or fourth 10 mg dose. There was no
significant deviation in pulmonary capillary wedge
pressure from the mean baseline value of 19 ± 1 1 mm
Hg after any of the drug doses.
Exercise hemodynamics. The mean baseline exercise
duration of 11.4 + 3.4 min tended to decline (to 10.1
± 3.0 min) after pindolol, but this change was not
statistically significant. Changes in hemodynamic variables at peak exercise before drug and 2 hr after the
last 10 mg dose are illustrated in figure 2. Peak heart
rate fell from 127 ± 61 to 93 ± 11 beats/min (p <
.0001). Peak cardiac index fell from 4.46 ± 0.67 to
3.44 ± 0.96 liters/min/m2 (p < .05), but stroke volume index did not change. Peak mean blood pressure
declined significantly from 123 ± 13 to 107 ± 16 mm
Hg (p < .005); peak exercise systemic vascular resistance was unchanged before and after dosing. A significant (p < .05) increase in peak pulmonary vascular
resistance was noted (375 ± 211 to 500 ± 287 dynessec-cm~5). Pulmonary capillary wedge pressure at peak
exercise was not changed after administration of pindolol.
Inotropic indexes (table 2). QS2I shortened slightly,
but significantly (p < .005), from 565 ± 50 to 560 ±
52 msec after the first 10 mg dose of pindolol. Significant changes in QS2J were not observed after the 5 or
the last 10 mg dose. There were no significant changes
compared with the predose baseline values for any of
the remaining left ventricular inotropic indexes. A significant trend toward an increase in mean right ventricular AP/AT was noted after the 5 mg dose (p = .08)
and a decrease in mean RV-AP/AT that did not attain
statistical significance was observed after the final 10
mg dose.
Neurohumoral response. Mean baseline plasma norepinephrine was 609 ± 171 pg/ml (normal in our
laboratory = 196 + 7 pg/ml). Norepinephrine level at
baseline in patients 6 and 9 (the two patients developing hypotension after receiving the drug) was 2053
pg/ml and 931 pg/ml, respectively, and exceeded the
range of 247 to 475 pg/ml in the remaining patients.
Significant changes in norepinephrine levels were not
seen after the 5 mg dose, but a trend toward an increase
was seen after the first 10 mg dose (p < .1).
Plasma renin increased in patients 6 and 9 after the 5
mg dose (figure 3). In the remaining eight patients,
Vol. 74, No. 6, December 1986
mean renin level decreased significantly (p < .05) and
individual renin concentrations decreased in each subject after dosing. No significant change in mean renin
level was noted after the 10 mg dose.
Relationship of drug concentration to hemodynamic and
inotropic responses. Mean free plasma concentrations of
pindolol after the 5 mg and the first and fourth 10 mg
doses are shown in figure 4. Peak drug concentration
was noted from 1.5 to 2 hr after administration of drug.
With respect to the hemodynamic variables measured, the mean cardiac index declined from baseline
with increasing drug concentration (r = - .59, r2 =
A.
140
B.
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950
to
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2
4
30
a:
4
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10
BASELINE
POST
DOSING
l
BASELINE
POST
DOSING
FIGURE 2. Peak exercise hemodynamic variables measured before
the first dose of pindolol and 2 hr after the fourth 10 mg dose. A
significant decline was noted in peak exercise heart rate (A), cardiac
index (B), and mean blood pressure (C). Peak exercise pulmonary
vascular resistance was significantly increased over that noted at peak
exercise in the baseline period (D).
1393
BINKLEY et al.
TABLE 2
Values for inotropic indexes at baseline and 2 hr after pindolol
10 mg pindolol
5 mg pindolol
Baseline
(n = 10)
ADMYo
Vcf (msec)
AP/AT (mm Hg/sec)
16.1
+1.5
0.70
+0.07
776
+124
QS2I (msec)
PEP/LVET
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RV-AKP/AT
567
+15
0.62
0.04
72.1
After
dose
1 0)
(n
16.4
1.7
0.70
+0.07
707
-128
Baseline
(n = 9)
16.8
+1.4
0.69
0.07
927
+209
4th dose
After
dose
(n = 9)
Baseline
(n = 7)
18.6
17.8
+1.8
+1.8
After
dose
(n = 7)
18.2
--24
0.76
0.70
0.71
0.07
+0.07
+0.09
862
+184
560A
+17
817
921
+148
+161
0.57
0.60
0.57
0.56
+0.05
+0.06
±0.04
+0.07
68.1
± 18.8
0.73
75.9
± 17.8
0.57
83.1
0.67
564
+17
0.63
+0.06
104. IB
39.3
0.65
0.65
60.3
+ 24.6
0.68
±0.10
±0.08
+0.16
±0.07
+0.14
±0.12
±27.3
RV-PEP/RVET
1st dose
565
+17
566
568
+19
-20
±27.1
Data are the mean ± SEM. AD% = percent fractional shortening; Vcf velocity of circumferential shortening; other
abbreviations are as under "Inotropic indexes" in the Methods section.
Ap < .05 change from predose baseline; Bp < 1 change from predose baseline.
.35, p < .01). There was no correlation between the
change in heart rate and drug concentration. A positive
correlation between free pindolol concentration and
mean change from baseline in pulmonary (r = .67,
66 1
62
* p c.05
7
58
54
50
46
strated in figure 5, A.
A positive correlation (figure 5, B) between free
drug concentration and mean change in percent fractional shortening was demonstrated (r
.82, r<
.67, p
.05). The change in QS2I was negatively
correlated with free drug plasma concentration (r
- .79, r2 - .63, p < .05). There was a significant
trend toward a positive correlation between pindolol
concentration and mean change in circumferential fiber shortening (r - .70, r2 - .49, p - .1).
Discussion
This study demonstrates that, in patients with congestive cardiomyopathy, the hemodynamic response
to the ISA /3-blocker pindolol differs from that observed in subjects with normal ventricular function.
42
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38
z
2 34
wL
30
26
16
14
12
8
4
0
BASELINE
1394
.45, p < .005) and systemic (r - .57, r = .32. p
< .05) vascular resistances was observed, as demon-
r2
POST DOSE
FIGURE 3. Plasma renin concentrations at baseline and 2 hr after the 5
mg dose of pindolol. A marked increase in renin concentration was
noted after pindolol in the two patients having the highest baseline
plasma concentrations of norepinephrine and who did not tolerate the
drug due to drug-induced hypotension (open circles). In the remaining
patients, baseline plasma renin concentration declined after dosing
(closed circles). An increase in mean plasma renin, which did not attain
statistical significance, was noted for the entire population (open triangles). Excluding the two patients who became hypotensive, a modest,
but significant, decrease in mean plasma renin (X) was observed.
CIRCULATION
THERAPY AND PREVENTION-CARDIoMYOPATHY
100
6
-
80
0
-J
6
0
z
60
6
40
-J
LL
20
FIGURE 4. Mean and SD free plasma drug concentrations (in ng/ml) after the 5 mg and the first and
fourth 10 mg doses of pindolol. Numerals indicate
the number of patients for whom interference-free
concentrations were available at each time point.
Peak concentrations were noted at 1.5 to 2 hr after
dosing.
6
6
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0
0
4
8
12
16 20 24
t
t
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48 52 56 60
10mg
lOmqX4
TIME- HOURS
Unlike previous reports in subjects with normal or
mildly reduced ventricular contractility,2'4 a significant decline in cardiac index and stroke volume index
associated with an increase in systemic and pulmonary
vascular resistance was noted after administration of
drug in this study. Moreover, pulmonary and systemic
vascular resistance increased and cardiac index decreased with increasing drug concentration.
Neurohumoral profile of the study population. The dif-
ferences from the response in normal subjects that we
noted may in part be attributable to the markedly abnormal neurohumoral profiles characteristic of patients
with congestive cardiomyopathy. 6' 17 Elevated plasma
norepinephrine levels were noted in the study population. Remarkable was the greatly increased baseline
plasma norepinephrine in the two patients who developed severe hypotension after the administration of
pindolol. Evidence suggests that there is an inverse
correlation between the plasma level of norepinephrine
and the degree of hemodynamic compensation in the
patient with heart failure.18 These two patients, having
the highest levels of norepinephrine, may represent a
subset of patients with minimal hemodynamic reserve
and a greater dependence on endogenous catecholamines for the central inotropic and/or chronotropic
stimulation necessary for maintenance of cardiac
output.
That peripheral and pulmonary vascular resistance
increased after pindolol suggests that the /3-agonist
Vol. 74, No. 6, December 1986
effects of pindolol, which are known to mediate vasodilation in normal and hypertensive subjects,1 7 are not
expressed in a heart failure population. This may indicate that (1) the intrinsic sympathomimetic activity of
pindolol contributes little above the near maximal
stimulation of receptors by elevated endogenous catecholamines, or (2) responsiveness of peripheral /3-receptors to agonist stimulation is reduced due to mechanisms such as receptor downregulation. In either case,
the /3-blocking rather than /3-agonist properties of pindolol would predominate, leading to an "unmasking"
of a-receptor-mediated effects'9 20 and subsequent
elevation of systemic and pulmonary vascular resistance.
The renin profile of the study population is a second
neurohumoral characteristic that appears to distinguish
patients most sensitive to /3-blockade (figure 3). The
two patients who did not tolerate pindolol hemodynamically had the highest baseline renin levels. Also,
in these two patients, renin concentration increased
after the 5 mg dose of pindolol, whereas renin decreased in each of the remaining eight patients (figure
3). Similar to the case for norepinephrine, baseline
renin levels appear to be inversely related to the degree
of hemodynamic compensation in the patients with
congestive heart failure.21 22 Second, in normal subjects, /3-blockade decreases resting renin concentration
and attenuates the rise in renin associated with hemodynamic stress such as upright tilt.23 In patients 6 and
1395
BINKLEY et al.
A
B.
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20
30
40
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0*
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p: .05
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0
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20
30
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50
FIGURE 5. Correlations between mean free drug concentration and mean changes from predose baseline in hemodynamicinotropic variables. A, A significant negative correlation was noted between change in cardiac index (CI in liters/min/m2) and
free plasma pindolol concentration. Changes in systemic vascular resistance (SVR in dynes-sec-cm-5), and pulmonary vascular
resistance (PVR in dynes-sec-cm-5) were positively correlated with plasma drug concentration. B, Change in QS2I (in msec) was
negatively correlated and change in percent fractional shortening (,AD%) was positively correlated with plasma pindolol
concentration. See text for discussion.
9, this attenuation was not observed, perhaps reflecting deterioration of marginal hemodynamic compensation and a reduction in renal perfusion pressure of a
magnitude sufficient to override the influence of ,3blockade.24
Response to exercise. Previous reports in hypertensive
subjects have noted an increase in peak exercise stroke
volume after administration of an ISA /3-blocker.25 It
has been proposed that ISA may account for this improvement through a beneficial inotropic effect on the
myocardium. Such an increase in exercise stroke volume was not seen in the current study, suggesting that
an effect of ISA is not present during exercise in a
population with congestive cardiomyopathy. The significant reduction in peak cardiac index and peak heart
rate as well as the increase in pulmonary vascular resistance at peak exercise would further imply that the
sympathomimetic properties of pindolol are not expressed to an observable degree under these condi1396
tions. Reduction of peak heart rate has been previously
noted after pindolol in patients with ischemic heart
disease and normal ventricular function.4 26 In the
study reported by Frishman et al.4 the reduction in
maximal heart rate after pindolol was equivalent to that
observed after propranolol, even though there was no
reduction in resting heart rate with pindolol. It was
hypothesized that the marked increase in endogenous
catecholamines known to occur during exercise
outweighed the intrinsic sympathomimetic activity of
the drug, thus eliminating effects of ISA with exercise.4 It is known that catecholamine levels increase
markedly during exercise in patients with congestive
heart failure,27 and thus, as in the resting state, ISA
appears to be masked in the environment of increased
catecholamines encountered during exercise in a heart
failure population.
Inotropic
no
response
to drug administration. There were
significant changes in right
or
left ventricular inoCIRCULATION
THERAPY AND PREVENTION-cARDIOMYOPATHY
Downloaded from http://circ.ahajournals.org/ by guest on April 29, 2017
tropic variables after dosing other than a modest improvement in QS2J, and correlation of changes in these
variables with drug level did not reveal an adverse
inotropic effect. The observed correlation between
drug level and change in circumferential fiber shortening, percent fractional shortening, and QS2I are in fact
consistent with an improvement rather than a decline in
left ventricular contractility.9' 28, 29
Thus, the negative influence of pindolol on overall
ventricular performance would appear to result predominantly from a disadvantageous elevation in right
and left ventricular afterload mediated through peripheral fl-blockade, rather than a primary alteration in
ventricular inotropy. Whether the intrinsic sympathomimetic activity of pindolol is responsible for preservation of contractility, as has been suggested by studies in normal subjects, remains speculative.5
In conclusion, in the setting of greatly elevated levels of catecholamines characteristic of congestive heart
failure and exercise, the potent intrinsic sympathomimetic activity of a drug such as pindolol may not be
expressed in the peripheral vasculature due to the already marked stimulation of lP-receptors by endogenous norepinephrine. The result is a profile that resembles that after administration of pure f-blockers to
subjects with normal ventricular function.30 However,
there does not appear to be a significant decline in left
or right ventricular inotropic state after pindolol. The
net response in this population appears to be determined by the effects of systemic and pulmonary vascular fl-blockade and the consequent rise in ventricular
afterload. Thus, the intrinsic sympathomimetic activity of agents such as pindolol may not protect against
the potential adverse effects of f-blockade in patients
with congestive heart failure. Markedly elevated baseline levels of plasma norepinephrine and increases in
renin levels after the administration of drug appear to
identify patients at increased risk for a potential adverse hemodynamic response to this ISA fl-blocker.
The response to long-term administration of ISA
blockers in patients with congestive heart failure may
differ from the hemodynamic-inotropic profile after
short-term use, as suggested by findings after repeated
drug dosing, and requires further study.
fi-
We thank Terri Mason for her assistance in the preparation of
this manuscript and Mitzi Prosser for her technical assistance.
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1398
CIRCULATION
Hemodynamic-inotropic response to beta-blocker with intrinsic sympathomimetic
activity in patients with congestive cardiomyopathy.
P F Binkley, R F Lewe, J J Lima, A Al-Awwa, D V Unverferth and C V Leier
Downloaded from http://circ.ahajournals.org/ by guest on April 29, 2017
Circulation. 1986;74:1390-1398
doi: 10.1161/01.CIR.74.6.1390
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