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Journal of the American College of Cardiology
© 2006 by the American College of Cardiology Foundation
Published by Elsevier Inc.
Vol. 48, No. 6, 2006
ISSN 0735-1097/06/$32.00
doi:10.1016/j.jacc.2006.04.092
Attenuation of the Negative Inotropic Effects
of Metoprolol at Short Cycle Lengths in Humans
Comparison With Sotalol and Verapamil
Rebecca H. Ritchie, BSC(HONS), PHD,*† Christopher J. Zeitz, MBBS, PHD, FRACP,*
Ronald D. Wuttke, BSC,* John T. Y. Hii, BMBS, FRACP,* John D. Horowitz, MBBS, PHD, FRACP*
Adelaide and Melbourne, Australia
This study sought to compare the influence of changes in systolic interval on the negative
inotropic effects of metoprolol, sotalol, and verapamil in patients with ischemic heart disease.
BACKGROUND The long-term symptomatic and prognostic effects of antiarrhythmic agents are not easily
predicted on the basis of acute hemodynamic actions at rest, but may be unmasked during
tachycardia. However, this has not been studied extensively in vivo.
METHODS
The force-interval relationship of the intact human left ventricle was examined before and 10
min after intravenous bolus administration of the negatively inotropic agents metoprolol,
sotalol, or verapamil in patients undergoing diagnostic cardiac catheterization.
RESULTS
All three drugs similarly reduced maximal rate of increase of left ventricular pressures
(LV⫹dP/dtmax) by approximately 10%, but diversely modified the force-interval relationship.
The parameter c (the reduction in LV⫹dP/dtmax of a fixed premature stimulus on mechanical
restitution) was significantly reduced by metoprolol (by 9 ⫾ 4%, p ⬍ 0.05), was increased by
verapamil (by 6 ⫾ 2%, p ⬍ 0.05), and was not significantly changed by sotalol. Similarly,
metoprolol had a minimal effect on the extent of frequency potentiation, whereas sotalol and
verapamil attenuated frequency potentiation (the relative response to 10 s of rapid pacing was 1.19
⫾ 0.58-fold, 0.07 ⫾ 0.35-fold, and 0.03 ⫾ 0.17-fold of the baseline response after 10 min of
metoprolol, sotalol, or verapamil, respectively).
CONCLUSIONS These results show that the negative inotropic effects of metoprolol are attenuated and those
of verapamil are accentuated at short cycle lengths; sotalol is intermediate between the two.
These properties may contribute to the relative safety of these agents in patients prone to
hemodynamic deterioration during sustained tachycardia. (J Am Coll Cardiol 2006;48:
1234 – 41) © 2006 by the American College of Cardiology Foundation
OBJECTIVES
Onset of tachycardia in patients administered class I (sodiumchannel blocker) or class IV (calcium-channel antagonist)
antiarrhythmic drugs is associated with increased risk of
acute hemodynamic collapse, despite these agents being well
tolerated in sinus rhythm (1,2). Changes in heart rate may
thus unmask negative inotropic effects of cardioactive drugs
not apparent at rest, which may contribute to increased
mortality during treatment with such agents in patients with
impaired left ventricular systolic function (3,4). Conversely,
class II antiarrhythmic agents, beta-adrenoceptor antagonists, are not poorly tolerated at faster heart rates (5),
suggesting differential modulation of the force-frequency
relationship by antiarrhythmic agents.
The relationship between alterations in stimulation rate
and myocardial contractile performance can be studied
using either frequency potentiation and/or mechanical restitution. Frequency potentiation, also known as the staircase
or Treppe phenomenon, is commonly used in vitro (6,7),
From the *Cardiology Unit, The Queen Elizabeth Hospital, University of Adelaide, Adelaide, Australia; and the †Baker Heart Research Institute, Melbourne,
Australia. Supported by grants from the National Heart Foundation (Deakin,
ACT, Australia) and the Merck Foundation (South Granville, NSW, Australia).
Dr. Ritchie was a University of Adelaide (Adelaide, SA, Australia) and Queen
Elizabeth Hospital Research Foundation (Woodville, SA, Australia) Postgraduate
Scholar. Dr. Zeitz was a National Heart Foundation Postgraduate Scholar.
Manuscript received July 8, 2005; revised manuscript received February 23, 2006,
accepted April 4, 2006.
and is illustrated by the incremental reductions in calciumchannel current and contractile force induced by verapamil
in vitro with progressive increases in stimulation frequency
(8,9). However, the sustained tachycardia of frequency
potentiation in vivo may result in neurohumoral activation,
changed loading conditions, ischemia, or even hemodynamic deterioration (10 –13). Such effects could distort the
force-interval relationship, and thus limit utility of frequency potentiation.
The force-interval relationship can also be examined
(both in vitro and in vivo) using mechanical restitution
curves (MRC). Mechanical restitution is the recovery of
myocardial contractility after a non–steady-state beat (7).
We have recently described a mathematical model of the
MRC that has proven highly reproducible in patients under
investigation for ischemic heart disease (14,15). In the
current investigation, we studied the acute effects of 3 pharmacologically different antiarrhythmic agents on the forceinterval relationship, metoprolol (a selective ␤1-adrenoceptor
antagonist), d,l-sotalol (a nonselective ␤-adrenoceptor antagonist with additional outward delayed rectifier potassium
current blocking properties) and verapamil (an L-type
calcium-channel antagonist). All three drugs elicit negative
inotropic effects in sinus rhythm. Using both MRC construction and frequency potentiation analysis, we tested the
hypothesis that the negative inotropic effects of metoprolol,
JACC Vol. 48, No. 6, 2006
September 19, 2006:1234–41
Abbreviations and Acronyms
CI
⫽ confidence interval
ECG
⫽ electrocardiographic
LV⫹dP/dtmax ⫽ maximal rate of increase of left
ventricular pressures
MAP
⫽ mean arterial pressure
MRC
⫽ mechanical restitution curve
but not those of verapamil, were independent of changes in
R-R interval in patients with ischemic heart disease. Although
previous data have suggested that the negative inotropic effects
of verapamil might be accentuated at higher stimulation
frequencies (9,10), clinically based hemodynamic comparisons
of these agents have been lacking.
METHODS
Study population. Patients with stable symptoms were
selected from those undergoing routine diagnostic cardiac
catheterization and coronary arteriography for the investigation of chest pain. Exclusion criteria included unstable
angina pectoris, significant left main coronary artery stenosis, electrocardiographic (ECG) evidence of abnormal conduction intervals, clinically significant valvular disease, recent myocardial infarction (in the last 3 months), and severe
impairment of left ventricular systolic function (ejection
fraction ⬍30%), in addition to clinically significant renal or
hepatic disease. The protocol was approved by the Ethics of
Human Research Committee of The Queen Elizabeth
Hospital, and prior informed consent was obtained.
Catheterization protocol. Administration of all betaadrenoceptor and calcium-channel antagonists was ceased at
least 5 half-lives before the study. Oral diazepam and
diphenhydramine were administered approximately 30 min
before cardiac catheterization as premedication. Right and
left cardiac catheterization and coronary arteriography were
performed under local anesthesia (1% lidocaine) using the
Judkins approach via femoral arterial (16) and venous
sheaths. The research procedure commenced at the end of
the routine catheterization. A bipolar pacing lead was positioned in the right atrium, and a 4-F micromanometer-tipped
catheter (Millar Instruments, Houston, Texas) was inserted via
the femoral artery sheath into the left ventricle for measurement of left ventricular pressure and maximal rate of increase of
left ventricular pressures (LV⫹dP/dtmax). A 7-F Swan-Ganz
catheter was positioned in the pulmonary artery for determination of cardiac output via thermodilution. Incremental
radiation exposure associated with the research procedure
was minimal, limited to screening to check Millar catheter
position.
Patients underwent continuous baseline atrial pacing at a
rate 7 ⫾ 1% above spontaneous heart rate to maintain a
constant heart rate throughout the procedure. Cardiac output
(the average of at least three readings at each time point), mean
arterial pressure (MAP), ECG parameters, and left ventricular
Ritchie et al.
Negative Inotropes Modulate the Force-Interval Relationship
1235
pressure and its first derivative LV⫹dP/dtmax were recorded
continuously. After acquisition of baseline data, including
MRC and frequency potentiation determination, patients
were sequentially allocated to receive metoprolol (4 mg; n ⫽
15), sotalol (20 mg; n ⫽ 15), or verapamil (4 mg; n ⫽ 17)
as a rapid intravenous bolus. Sodium nitroprusside was also
investigated in an additional subgroup of patients (10 to 20
␮g/min intravenous infusion until approximately a 10%
reduction in MAP was observed, n ⫽ 5) to determine the
influence, in isolation, of altered loading conditions on the
MRC. The dose of each agent was chosen from the lower
end of the dosage range used clinically. Hemodynamic
measurements and serial MRCs were obtained at frequent
intervals up to 10 min after administration. Frequency
potentiation was re-examined at 10 min.
Mechanical restitution. The MRCs were constructed as
previously described (14,15). Briefly, premature stimuli of
twice the threshold strength were inserted every 8 beats
during baseline pacing, at progressively shorter R-R intervals, until refractoriness prevented impulse conduction. The
contractile strength of each beat, LV⫹dP/dtmax, was plotted
as a function of the R-R interval. The LV⫹dP/dtmax was
expressed as a percent of that observed in the drug-free state
during baseline pacing, and R-R interval as a percent of the
cycle length of the baseline-pacing rate. This was then fitted to
one-half of a rectangular hyperbolic function, described by:
y ⫽ a ⫺ 关c (100 ⫺ d) (60 ⫺ d)兴 ⁄ 关40 (x ⫺ d)兴
where x is the R-R interval of the premature stimulus and y
is LV⫹dP/dtmax. The horizontal and vertical asymptotes are
represented by a and d, respectively. The parameter c, the
difference between the calculated values of LV⫹dP/dtmax
from the fitted curve when the R-R interval is 100%, and
Figure 1. A theoretical mechanical restitution curve (MRC): a (units are
percent baseline LV⫹dP/dtmax) and d (units are percent baseline R-R
interval) represent the horizontal and vertical asymptotes, respectively; the
parameter c (units are percent baseline LV⫹dP/dtmax) represents the
reduction in LV⫹dP/dtmax with a 40% reduction in R-R interval (13).
LV⫹dP/dtmax ⫽ maximal rate of increase of left ventricular pressures.
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Negative Inotropes Modulate the Force-Interval Relationship
60% (illustrated in Fig. 1), describes contractile sensitivity to
reductions in R-R interval for each patient (14). We then
calculated the change in the parameter c 10 min after
treatment by subtracting it from the pretreatment value, to
obtain ⌬-parameter c. Thus, an increase in c after drug
administration (i.e., positive ⌬-parameter c) would indicate
directly rate-dependent negative inotropic effects.
Frequency potentiation. The force-interval relationship
was also assessed using frequency potentiation by determining the influence of 1 min of rapid pacing (34 ⫾ 2% above
the rate of baseline pacing) on LV⫹dP/dtmax in 10-s
intervals. This protocol was not performed in patients with
severe angina pectoris, and was precluded by the development of atrioventricular block in some patients. We then
further analyzed the frequency potentiation response by
expressing the pacing-induced increase in LV⫹dP/dtmax
after drug administration in each patient as a ratio of the
response observed before treatment for each of metoprolol,
sotalol, and verapamil to calculate the relative frequency
potentiation response.
Statistical analyses. Results were expressed as mean ⫾ SE.
The goodness-of-fit of the MRC model for each individual
patient was determined using residual standard deviations.
Confidence intervals (Cis) at 95% were derived for these
standard deviations. One-factor analysis of variance was
used to compare patient characteristics at baseline in the
four groups, and with repeated measures analysis (Dunnett),
to examine the time course of LV⫹dP/dtmax and c as
appropriate. Paired t tests were used to compare the
hemodynamic and ECG effects of the drugs studied, before
and 10 min after injection. The differential effects of the
three agents, metoprolol, verapamil, and sotalol, on MRC
analysis were examined via one-way analysis of variance of
⌬-parameter c across all three patient groups. To determine
whether the 3 agents attenuated the frequency potentiation
response, we compared the relative frequency potentiation
response across all three patient groups using a 1-way
analysis of variance. Statistical significance was accepted at
the p ⬍ 0.05 level.
RESULTS
Patient characteristics. The clinical characteristics before
drug injection of all 52 patients studied are summarized in
Table 1. The groups were generally well matched, with
predominantly normal left ventricular systolic function, and
JACC Vol. 48, No. 6, 2006
September 19, 2006:1234–41
Figure 2. Time course of changes in LV⫹dP/dtmax (percent baseline)
induced by metoprolol, sotalol, or verapamil during baseline pacing before
(open bars), 5 min after (hatched bars), and 10 min after (solid bars)
injection. Asterisks indicate statistical significance compared with baseline
(analysis of variance with repeated measures). Abbreviations as in Figure 1.
no significant differences in characteristics between the
groups. Clinically significant coronary artery disease (stenosis ⱖ50% in at least 1 major branch of a coronary artery) was
present in 36 patients. The procedure was well tolerated in
all patients.
Hemodynamic effects during baseline pacing. The doses
for each of metoprolol, sotalol, and verapamil used in the
present study were chosen with the intention of achieving
similar negative inotropic effects at baseline pacing: the
three negatively inotropic drugs induced approximately a
10% reduction in LV⫹dP/dtmax (Fig. 2). Table 2 summarizes the hemodynamic and ECG effects of all drugs studied
during baseline pacing, at the time of peak effect (10 min
after drug injection for metoprolol, sotalol, and verapamil,
and at the time of maximal hypotensive effect for sodium
nitroprusside). The MAP was significantly reduced by both
verapamil and sodium nitroprusside (as a requirement of the
length of the infusion period), but not by either metoprolol
or sotalol. Sodium nitroprusside had no additional hemodynamic effects, although pulmonary capillary wedge pressure also tended to decrease (from 13 ⫾ 2 mm Hg to 10 ⫾
1 mm Hg, p ⫽ NS).
Force-interval relationship. The influence of metoprolol,
sotalol, and verapamil on the MRC is shown in Figure 3
before and 10 min after injection (the time of peak effect).
The residual SDs of the model (the measure of goodnessof-fit) for these drugs were 4.9 (95% CI 3.3 to 6.4), 5.1
(95% CI 3.5 to 6.7), and 8.3 (95% CI 5.9 to 10.6; p ⬍ 0.05
vs. metoprolol and verapamil) for metoprolol, verapamil,
Table 1. Patient Characteristics at Baseline
Metoprolol Sotalol Verapamil Sodium Nitroprusside
(n ⴝ 15) (n ⴝ 15) (n ⴝ 17)
(n ⴝ 5)
Age (yrs)
Gender (male/female)
Coronary disease*
Left ventricular ejection fraction (%)
Pulmonary capillary wedge pressure (mm Hg)
Paced relative risk interval (ms)
56 ⫾ 2
11/4
10 (67%)
63 ⫾ 3
8⫾1
800 ⫾ 40
54 ⫾ 2
10/5
11 (73%)
72 ⫾ 2
7⫾1
780 ⫾ 30
61 ⫾ 3
9/8
12 (71%)
69 ⫾ 3
8⫾1
730 ⫾ 30
61 ⫾ 6
1/4
3 (60%)
65 ⫾ 3
13 ⫾ 1
710 ⫾ 40
*Greater than 50% stenosis in at least 1 coronary artery (left anterior descending, circumflex, or right coronary artery).
Ritchie et al.
Negative Inotropes Modulate the Force-Interval Relationship
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Table 2. Hemodynamic and Electrocardiographic Effects During Baseline Atrial Pacing of Each Drug Studied, at Time of Peak
Effect (10 Min After Injection for Metoprolol, Sotalol, and Verapamil; Approximately 5 Min After Infusion Stopped for
Sodium Nitroprusside)
Metoprolol
2
Cardiac index (l/min/m )
Mean arterial pressure (mm Hg)
PR interval (ms)
QT interval (ms)
LV⫹dP/dtmax (% baseline)
Sotalol
Verapamil
Sodium Nitroprusside
Before
After
Before
After
Before
After
Before
After
2.6 ⫾ 0.1
101 ⫾ 4
182 ⫾ 6
367 ⫾ 11
100 ⫾ 0
2.6 ⫾ 0.1
103 ⫾ 3
190 ⫾ 6*
365 ⫾ 10
88 ⫾ 3*
2.7 ⫾ 0.1
109 ⫾ 3
193 ⫾ 9
379 ⫾ 8
100 ⫾ 0
2.5 ⫾ 0.1
110 ⫾ 3
201 ⫾ 8*
386 ⫾ 7
89 ⫾ 3*
3.1 ⫾ 0.1
109 ⫾ 4
210 ⫾ 8
356 ⫾ 8
100 ⫾ 0
3.1 ⫾ 0.1
104 ⫾ 4*
215 ⫾ 9
360 ⫾ 6
93 ⫾ 2*
2.9 ⫾ 0.1
117 ⫾ 11
186 ⫾ 19
370 ⫾ 7
100 ⫾ 0
2.7 ⫾ 0.1
105 ⫾ 9*
182 ⫾ 18
370 ⫾ 9
95 ⫾ 4
*p ⬍ 0.05 vs. before drug.
LV⫹dP/dtmax ⫽ maximal rate of increase of left ventriclar pressures.
and sotalol, respectively. Although all three drugs exerted a
similar negative inotropic effect during baseline pacing (Fig.
2), these effects differed on MRC analysis. Metoprolol
decreased LV⫹dP/dtmax by 12 ⫾ 3% during baseline
pacing. However, this negative inotropic effect became less
marked at shorter R-R intervals, and was completely abolished
when the R-R interval was reduced to 60%. On the fitted
MRC, LV⫹dP/dtmax was 72 ⫾ 4% and 70 ⫾ 3% at an R-R
interval of 60% before and after metoprolol, respectively (Fig.
3A). This was reflected by a significant reduction in c from
28 ⫾ 4% to 21 ⫾ 3% (Fig. 4A; p ⬍ 0.05). In the group of
patients allocated to receive sotalol, LV⫹dP/dtmax was
reduced by 11 ⫾ 3% during baseline pacing. On MRC
analysis, the negative inotropic effect of sotalol was virtually
unchanged as the R-R interval decreased. The LV⫹dP/
dtmax on the fitted MRC was 72 ⫾ 6% and 59 ⫾ 7% at an
R-R interval of 60% before and after sotalol, respectively
(Fig. 3B), and c did not fluctuate significantly (from 29 ⫾
6% to 31 ⫾ 7%, p ⫽ NS) (Fig. 4B). In contrast with
metoprolol and sotalol, verapamil tended to induce a divergence of the MRC, with the negative inotropic effect (8 ⫾
2% reduction in LV⫹dP/dtmax at baseline) progressively
accentuated as the R-R interval decreased. On the fitted
MRC, LV⫹dP/dtmax was 81 ⫾ 4% and 67 ⫾ 5% at an R-R
interval of 60% before and after verapamil, respectively (Fig.
3C). This corresponded to an increase in c from 18 ⫾ 4% at
baseline to 24 ⫾ 4%, indicative of a rate-dependent effect (p
⬍ 0.05) (Fig. 4C). Moreover, when ⌬-parameter c after 10
Figure 3. Mechanical restitution curve (MRC) curve-fitting analysis for (A) metoprolol, (B) sotalol, and (C) verapamil. The left-hand panel shows
representative raw and fitted data obtained from one patient in each group, before (closed circles, solid curve) and 10 min after (open circles, dashed
curve) drug administration. The right-hand panel shows mean data from the fitted MRC before (closed circles) and after (open circles) drug
administration. Abbreviations as in Figure 1.
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Negative Inotropes Modulate the Force-Interval Relationship
JACC Vol. 48, No. 6, 2006
September 19, 2006:1234–41
Figure 4. Time course of changes in the parameter c from mechanical restitution curve (MRC) curve-fitting analysis (the decrease in LV⫹dP/dtmax with
a 40% reduction in R-R interval from the fitted MRC model) for each of (A) metoprolol, (B) sotalol, and (C) verapamil. Asterisks indicate statistical
significance compared with baseline (analysis of variance with repeated measures). (D) The increment in parameter c after drug treatment. Verapamil
induces a significantly different response to metoprolol (analysis of variance). Abbreviations as in Figure 1.
min was compared among metoprolol, sotalol, and verapamil, the MRC response to metoprolol was significantly
different than that obtained with verapamil (p ⬍ 0.05) (Fig.
4B). The significant decrease in MAP induced by sodium
nitroprusside, however, was not accompanied by significant
alterations in LV⫹dP/dtmax either during baseline pacing (⫺5
⫾ 4% vs. baseline, p ⫽ NS) or at shorter R-R intervals. No
significant fluctuations in the parameter c were observed
(from 43 ⫾ 6% to 43 ⫾ 7%, p ⫽ NS, results not shown).
Frequency potentiation. The force-interval relationship
was also investigated using frequency potentiation analysis
before and 10 min after administration of each of the three
negatively inotropic drugs. Figure 5 shows the time course
of LV⫹dP/dtmax during rapid pacing. Before drug administration, the effects of rapid pacing were comparable in the
3 treatment groups, showing an initial increase of approximately 20% in LV⫹dP/dtmax, which was preserved for the
full minute. As with MRC analysis, all three agents examined showed different effects on the extent of frequency
potentiation (Fig. 5), especially evident after 10 s of rapid
pacing. Metoprolol did not affect the frequency potentiation
response: the pacing-induced increases in LV⫹dP/dtmax
before and after the drug were maintained (Fig. 5A). This
was not the case for verapamil: the pacing-induced increase
in LV⫹dP/dtmax seemed to be markedly suppressed during
the 1 min of rapid pacing (Fig. 5C). The results for sotalol
were intermediate between those of metoprolol and verapamil (Fig. 5C). As shown in Figure 5D, the relative
frequency potentiation response after metoprolol was un-
changed after 10 s of rapid pacing; conversely, both sotalol
and verapamil significantly attenuated the relative frequency
potentiation response (p ⬍ 0.005). After 60 s of rapid
pacing (at which time ischemia and/or neurohumoral activation may be evident [10,12]), sotalol, however, no longer
the attenuated the frequency potentiation response (results
not shown).
DISCUSSION
The results of the current study show that the negative
inotropic effects during tachycardia of a pharmacologically
heterogeneous group of antiarrhythmic drugs cannot be
predicted on the basis of their observed effects in the resting
state. Metoprolol, sotalol and verapamil were administered
acutely at doses that elicited comparable negative inotropic
effects at rest (Fig. 2) and minimal changes in pulmonary
capillary wedge pressure. However, these three agents exerted markedly different negative inotropic effects at shorter
R-R intervals, as determined from both MRC (Figs. 3 and
4) and frequency potentiation analysis (Fig. 5). The negative
inotropic effects of metoprolol were markedly attenuated at
short cycle lengths on MRC analysis, and metoprolol did
not attenuate the inotropic response associated with frequency potentiation. Conversely, verapamil exerted directly
rate-dependent negative inotropic effects, virtually ablating
the frequency potentiation response; accentuation of verapamil’s negative inotropy was also evident at short R-R
intervals on MRC analysis. The effects of sotalol were
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Negative Inotropes Modulate the Force-Interval Relationship
1239
Figure 5. Influence of negatively inotropic agents on frequency potentiation for each of (A) metoprolol, (B) sotalol, and (C) verapamil. Time course of
LV⫹dP/dtmax during rapid pacing before (closed circles) and after (open circles) drug injection. Results are expressed as a percent of LV⫹dP/dtmax
observed immediately before the onset of rapid pacing. (D) The relative frequency potentiation (FP) response after drug treatment (the increase in
LV⫹dP/dtmax after 10-s rapid pacing, observed 10 min after treatment as a ratio of the response observed previously). Both sotalol and verapamil (but not
metoprolol) significantly attenuated the frequency potentiation response (analysis of variance). Abbreviations as in Figure 1.
intermediate between those of metoprolol and verapamil,
relatively independent of R-R interval on MRC analysis and
some attenuation of the frequency potentiation response.
Construction of MRCs was the primary methodology
used in the current study for the quantitative examination of
drug effects on the force-interval relationship. We have
previously shown that this is highly reproducible, with
significant determinants of the parameter c including R-R
interval (held constant in the present investigation) and left
ventricular ejection fraction (14,15). Sodium nitroprusside,
used in part because of the known insensitivity of the
force-frequency relationship to nitric oxide (17), exerted no
significant effects on mechanical restitution, suggesting that
the parameter c is relatively independent of small changes in
preload and afterload. Nevertheless, it remains possible that
differential effects on preload might have influenced some of
the observed differences between verapamil and metoprolol/
sotalol. The use of additional measures of the inotropic
state, and in particular the simultaneous measurement of left
ventricular pressure and volume, would have provided more
load-independent assessment of drug effect. The reductions
in LV⫹dP/dtmax induced by metoprolol and sotalol in the
present study are consistent with previous investigations in
humans (18 –21). However, we now show that the negative
inotropic effect of metoprolol is reverse rate-dependent on
MRC analysis. These data are consistent with recent suggestions that metoprolol normalizes the ventricular forcefrequency relationship in patients with heart failure (5).
Conversely, sotalol did not significantly influence MRC.
Also on MRC analysis, we quantitatively showed that the
negative inotropic effect of verapamil was accentuated at
shorter R-R intervals in humans in vivo. The ratedependent nature of this negative inotropic effect has been
clearly defined in animal models in vitro (8,9). However, no
evidence of this type for verapamil or any other calcium
antagonist in humans was previously available. Clinical
experience with the acute administration of verapamil has
suggested the potential for acute hypotensive and negative
inotropic sequelae (2,4), a complication that is rarely observed in the absence of tachyarrhythmias.
The most appropriate examination of the effects of all
three agents on frequency potentiation is after 10 s of rapid
pacing (Fig. 5D) because more prolonged tachycardia may
induce ischemia (12) and/or neurohumoral activation (10)
in some patients. Nevertheless, the three agents examined
disparate effects on frequency potentiation irrespective of
the period of rapid pacing considered. Metoprolol had no
detectable effect, whereas verapamil significantly (and sotalol to a lesser extent) impaired the frequency potentiation
response. These disparate effects of the agents examined
may reflect the underlying physiological changes involved in
mechanical restitution and frequency potentiation. Frequency potentiation in an intact circulation represents a
complex model comprising both negative (mechanical
restitution-like) and positive inotropic (Treppe-like) components. The cellular correlates of this model cannot be
ascertained in the current setting. Nevertheless, the rank
order of rate-related negative inotropic effects (verapamil ⬎
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Negative Inotropes Modulate the Force-Interval Relationship
sotalol ⬎ metoprolol) was identical to that seen with MRC
analysis. The incomplete MRC, the principal measure of
the force-interval relationship used in the present study,
reflects availability of calcium for contractile performance.
Conventionally it has been regarded that a major determinant of mechanical restitution at low stimulation frequencies is calcium release from the sarcoplasmic reticulum,
whereas trans-sarcolemmal calcium flux becomes increasingly important at high stimulation frequencies (8,9,22,23).
The diverse effects of metoprolol and verapamil at shorter
R-R intervals observed in the current study may simply
reflect different sites of action on frequency-dependent
cellular physiology. The interaction between verapamil and
the L-type calcium channel per se is frequency-dependent:
the drug binds preferentially to its receptor when the
channel is in the open state (8). No analogous cellular
phenomenon has been observed for beta-adrenoceptor ligands. The major finding of attenuation of the negative
inotropic effect of metoprolol at short cycle lengths is of
great interest. Superficially, this is a somewhat paradoxical
observation because previous studies in a range of myocardial preparations (24) have suggested that the positive
inotropic response to beta-adrenoceptor agonists increases
with stimulation frequency. Available data for betaadrenoceptor antagonists, however, are consistent with our
observations: both chronic therapy of heart failure patients
with metoprolol and acute propranolol treatment in intact
canine ventricles are associated with attenuated negative
inotropic effects at increased heart rates (5,25).
The effects of sotalol on MRC and frequency potentiation clearly differed from those of metoprolol in the present
study. The only previously reported investigation of sotalol
effects in human ventricular myocardium (26) failed to show
any effect of either d,l-sotalol or of d-sotalol (which lacks
effects at the beta-adrenoceptor while retaining potassiumchannel blockade), but the potential for rate-related inotropic interactions was not examined. The results of the current
study imply that the potassium-channel blocking actions of
sotalol modulate its inotropic effects, resulting in incremental negative inotropy during tachycardia.
Study limitations. This was essentially a study of patients
with intact left ventricular systolic function (by nature of the
selection criteria). It is possible that studying patients with
impaired systolic function would produce different results
with respect to the relationship between MRC and frequency potentiation data: such patients might show an
underlying defect of intracellular calcium availability
(27,28), the consequences of which would increase progressively as heart rate increased (29). Furthermore, we did not
investigate the mechanisms underlying the attenuation of
frequency potentiation effects (attributed to progressive
induction of ischemia and counter-regulatory neurohumoral
activation). The use of a pacing regimen that was sufficiently
brief as to be associated with no overt ischemia in any
patient clearly does not preclude the possibility that some
patients might have developed subclinical ischemia during the
JACC Vol. 48, No. 6, 2006
September 19, 2006:1234–41
latter stages of the frequency potentiation protocol. On the
other hand, it is unlikely that the abolition of bradycardiarelated anti-ischemic effects (in the cases especially of metoprolol and sotalol) would have differentially influenced the
current results. Lastly, the potential for a correlation between changes in the force-interval relationship and simultaneous evaluation of cellular electrophysiology, difficult to
accurately obtain in vivo, was not sought. Nevertheless, such
information might have provided additional insight, particularly in the case of sotalol.
Conclusions. In summary, we have shown that the negative inotropic effects of metoprolol are attenuated at short
cycle lengths. This would in theory be a salutary effect as
regards maintenance of hemodynamic status during tachycardia, especially in the presence of impaired ventricular
function, but might limit the effectiveness of the drug as an
antianginal agent. Conversely, verapamil shows the potential for hemodynamic deterioration during tachycardia in
susceptible individuals. This may limit its utility in patients
with angina plus left ventricular dysfunction (30). Heterogeneity between effects of metoprolol and sotalol may also
be important, illustrated by the deleterious effects of
d-sotalol (31). Furthermore, the methodology used in this
study might well prove useful both during preclinical studies
and in phase 1 human investigations of new cardioactive
agents to identify potential for hemodynamic deterioration
during tachycardia.
Acknowledgments
The authors acknowledge the assistance of Professor Richard
Jarrett, Department of Statistics, The University of Adelaide.
The authors thank the staff of the Cardiac Catheterization
Laboratory, The Queen Elizabeth Hospital, for assistance
with the experimental procedure, and Mr. J. Pearce and Mr.
B. Braysher for assistance with the mathematical mechanical restitution curve model.
Reprint requests and correspondence: Dr. John D. Horowitz,
Cardiology Unit, The Queen Elizabeth Hospital, 28 Woodville
Road, Woodville, SA 5011, Australia. E-mail: jhorowitz@
medicine.adelaide.edu.au.
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