(Circulation. 1999;100:1917-1922.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Antiarrhythmic Efficacy of Selective Blockade of the Cardiac Slowly Activating Delayed Rectifier Current, IKs, in Canine Models of Malignant Ischemic Ventricular Arrhythmia
From the Departments of Pharmacology, Laboratory Animal Medicine, Pharmaceutical Research and Development, and Medicinal Chemistry, Merck Research Laboratories, West Point, Pa, and the Department of Physiology, The Ohio State University, Columbus.
Correspondence to Dr Joseph J. Lynch, Jr, WP46-300, Merck Research Laboratories, West Point, PA 19486.
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Abstract |
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Background—To date, the lack of potent and selective inhibitors has hampered the physiological assessment of modulation of the cardiac slowly activating delayed rectifier current, IKs. The present study, using the IKs blocker L-768,673, represents the first in vivo assessment of the cardiac electrophysiological and antiarrhythmic effects of selective IKs blockade.
Methods and Results—In an anesthetized canine model of recent (8.5±0.4 days) anterior myocardial infarction, 0.003 to 0.03 mg/kg L-768,673 IV significantly suppressed electrically induced ventricular tachyarrhythmias and reduced the incidence of lethal arrhythmias precipitated by acute, thrombotically induced posterolateral myocardial ischemia. Antiarrhythmic protection afforded by L-768,673 was accompanied by modest 7% to 10% increases in noninfarct zone ventricular effective refractory period, 3% to 5% increases in infarct zone ventricular effective refractory period, and 4% to 6% increases in QTc interval. In a conscious canine model of healed (3 to 4 weeks) anterior myocardial infarction, ventricular fibrillation was provoked by transient occlusion of the left circumflex coronary artery during submaximal exercise. Pretreatment with 0.03 mg/kg L-768,673 IV elicited a modest 7% increase in QTc, prevented ventricular fibrillation in 5 of 6 animals, and suppressed arrhythmias in 2 additional animals.
Conclusions—The present findings suggest that selective blockade of IKs may be a potentially useful intervention for the prevention of malignant ischemic ventricular arrhythmias.
Key Words: antiarrhythmia agents • arrhythmia • myocardial infarction • fibrillation
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Introduction |
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In several mammalian species, including humans, cardiac delayed rectifier potassium current has been dissected into 2 kinetically distinct components: a rapidly activating current (IKr) that inwardly rectifies at depolarized membrane potentials and a slowly activating current (IKs) with a linear current-voltage relationship.1 2 3 4 5 Inhibition of IKr has been and continues to be explored as an antiarrhythmic mechanism. Selective inhibitors of IKr have been assessed clinically for the prevention of malignant ventricular arrhythmia as well as atrial arrhythmia.6 7 Although some clinical studies have demonstrated antiarrhythmic activity, proarrhythmic effects have also been reported. Specifically, torsade de pointes has been associated with IKr blockade, thereby limiting the therapeutic utility of these agents.8
To date, the antiarrhythmic potential of
IKs inhibition has not been vigorously
assessed because of the lack of potent and selective
inhibitors. Recently, the chemical synthesis and
preliminary cardiac electrophysiological
properties of a potent and selective IKs
blocker, L-768,673 (Figure 1
), were
described.9 The purpose of the present study was
to evaluate the cardiac
electrophysiological and antiarrhythmic
activities of L-768,673 in 2 canine models of malignant
ischemic ventricular arrhythmia. An
anesthetized canine model of recent anterior myocardial
infarction10 was used to assess the ability of L-768,673
to suppress ventricular tachyarrhythmia
induced by programmed ventricular stimulation (PVS)
as well as ventricular fibrillation precipitated by
thrombotically induced acute myocardial ischemia. A conscious
canine model of healed myocardial infarction11 12 was used
to investigate the effects of L-768,673 on ventricular
fibrillation provoked by transient myocardial ischemia against
a background of elevated sympathetic activity elicited by submaximal
exercise.
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Methods |
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Procedures related to the use of animals were approved by the Institutional Animal Care and Use Committees at Merck Research Laboratories at West Point, Pa, and at Ohio State University and conform to the Guide for the Care and Use of Laboratory Animals (Institute of Laboratory Animal Resources, Commission on Life Sciences, National Research Council, 1996).
Anesthetized Canine Model of Recent Anterior
Myocardial Infarction
The canine model of recent anterior myocardial infarction
in which lethal ventricular arrhythmias are
precipitated by acute, thrombotically induced posterolateral myocardial
ischemia was described originally by Patterson et
al.10 Details of this preparation as used in this study
have been described previously.13 In brief,
anesthetized purpose-bred mongrel dogs (9.0±0.1 kg) were
studied at 8.5±0.4 days after anterior myocardial infarction. Four
groups of dogs were administered single intravenous doses
of L-768,673 (in a soybean oil–based microemulsion: 20.0% soybean
oil, 2.0% glycerin, 1.2% lecithin, and 76.8% water) as follows: (1)
0.0003 mg/kg (n=10), (2) 0.003 mg/kg (n=10), (3) 0.03 mg/kg (n=10), and
(4) microemulsion vehicle alone (n=10). Treatments were administered as
15-minute intravenous infusions.
Electrophysiological and PVS testing was conducted
before and 15 minutes after the termination of each treatment infusion.
After the completion of posttreatment
electrophysiological and PVS testing, an
anodal current of 200 µA was applied to the intimal surface of the
proximal left circumflex coronary artery, producing intimal
injury, thrombus formation, and acute posterolateral myocardial
ischemia. On the development of lethal ischemic
arrhythmias or 3 hours after the onset of posterolateral
myocardial ischemia in surviving animals, the hearts were
excised, thrombus mass was measured, and anterior myocardial infarct
size was determined by triphenyltetrazolium
chloride staining.
Conscious Canine Model of Healed Anterior Myocardial
Infarction
The conscious canine model of healed anterior myocardial
infarction in which ventricular fibrillation is
precipitated by transient acute myocardial ischemia during
exercise was described originally by Schwartz et al.11
Details of this preparation as used in this study have been described
previously.12 In brief, studies were conducted with
conscious mongrel dogs (19.8±0.4 kg) at 3 to 4 weeks after anterior
myocardial infarction. The animals were walked on a motor-driven
treadmill and adapted to the laboratory during this period.
Susceptibility to ventricular fibrillation was tested as
previously described.11 12 Ten animals developed
ventricular fibrillation (susceptible) during the
exercise-plus-ischemia test, and 7 did not (resistant).
Four susceptible animals were not successfully resuscitated. Thus,
studies were conducted with 6 susceptible and 7 resistant
animals. One week later, the exercise-plus-ischemia test was
repeated after administration of L-768,673. L-768,673 formulated as
described above was infused at a dose of 0.03 mg/kg IV over a period of
30 minutes. Thirty minutes after the end of the infusion, the
exercise-plus-ischemia test was performed (n=13; susceptible,
n=6; resistant, n=7). One week after these studies, a second
control exercise-plus-ischemia test was repeated after infusion
with the microemulsion vehicle (susceptible animals, n=5;
resistant dogs that had arrhythmias, n=2).
Statistical Analysis
Data are expressed as mean±SEM. For the anesthetized
canine model of recent infarction, pretreatment versus posttreatment
comparisons were made by use of a 2-tailed paired Student's
t test. Comparisons among treatment groups were made with a
single-factor ANOVA followed by Scheffé's post hoc test or
Fisher's exact test, as appropriate. Data obtained from the conscious
postinfarction animal studies were analyzed with a 2-factor
ANOVA with repeated measures. When the F value exceeded a critical
value (P<0.05), post hoc comparisons were made with
Scheffé's test. The effects of the interventions on mortality
were evaluated with Fisher's exact test.
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Results |
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Anesthetized Canine Model of Recent Anterior Myocardial Infarction
Table 1
summarizes the
effects of 0.0003, 0.003, and 0.03 mg/kg L-768,673 IV on heart rate,
mean arterial pressure, ECG intervals, and cardiac
electrophysiological parameters
in dogs with recent anterior myocardial infarction. The predominant
effects of L-768,673 in this preparation were modest but
consistent increases in noninfarct zone ventricular
effective refractory period (7.1±1.4% to 9.7±2.0%), infarct zone
ventricular effective refractory period (3.4±2.3% to
5.1±1.9%), and QTc interval (3.6±1.2% to 5.7±1.1%). L-768,673 had
no significant effects on heart rate, mean arterial
pressure, P-R interval, QRS interval, or ventricular
excitability.
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The effects of 0.0003, 0.003, and 0.03 mg/kg IV L-768,673 on the
induction of ventricular tachyarrhythmias
by PVS are summarized in Table 2.
Significant suppression of PVS-induced ventricular
tachyarrhythmias was observed in the high-dose,
0.03-mg/kg L-768,673 IV group (9 of 10, 90% suppression). The effects
of L-768,673 on the incidence of lethal arrhythmias developing
in response to acute, thrombotically induced posterolateral myocardial
ischemia in dogs with recent anterior myocardial infarction
also are summarized in Table 2. In the microemulsion vehicle
group, the development of posterolateral ischemia resulted in
an 80% incidence (8 of 10) of ventricular fibrillation.
This control incidence of lethal ischemic arrhythmias
agrees well with the 85% incidence (34 of 40) reported previously for
aqueous vehicle controls.13 Figure 2 compares survival rates after the onset
of posterolateral ischemia for the microemulsion vehicle and
L-768,673 treatment groups. Compared with the microemulsion vehicle
group, the incidence of lethal ischemic arrhythmias was
reduced slightly but nonsignificantly by low-dose 0.0003-mg/kg
L-768,673 (6 of 10, 60%). However, the higher 0.003- and 0.03-mg/kg IV
doses of L-768,673 significantly reduced the incidence of lethal
arrhythmias (1 of 10, 10%, and 2 of 10, 20%, respectively,
all ventricular fibrillation). Left circumflex
coronary artery thrombus mass generally mirrored survival rate;
treatment groups with the lowest arrhythmic mortality and hence longer
survival times after the onset of ischemia possessed the
largest thrombus masses on postmortem analysis. Times to onset
of thrombotically induced posterolateral ischemia and
underlying anterior infarct size did not vary significantly among
treatment groups.
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Conscious Canine Model of Healed Anterior Myocardial
Infarction
As in previous studies,11 12 ventricular
flutter degenerating into ventricular fibrillation was
reproducibly induced with each presentation of the control
exercise-plus-ischemia test in susceptible animals. The average
time to ventricular fibrillation onset was 64.1±7.9
seconds (range, 37 to 94 seconds) for the first control occlusion and
63.7±9.5 seconds (range, 45.2 to 100 seconds) for the second control
occlusion. The control exercise-plus-ischemia tests also
elicited similar changes in heart rate (first occlusion: control,
202.0±9.3; occlusion, 210.8±12.8 bpm; second occlusion: control,
208.8±10.2; occlusion, 226.0±11.2 bpm).
Representative recordings obtained from the
same animal before and after pretreatment with L-768,673 are displayed
in Figure 3. In contrast to the control
occlusion, L-768,673 significantly reduced the incidence of
ventricular fibrillation, protecting 5 of 6 animals (83%
reduction, P=0.008). The arrhythmias were completely
suppressed in 2 animals, whereas the remaining 3 animals still had a
few single or coupled premature ventricular beats (6, 7,
and 27 beats, respectively). In addition, L-768,673 completely
suppressed arrhythmias in 2 resistant animals in which
multiple ventricular complexes were induced during the
control exercise-plus-ischemia test. Finally, the microemulsion
vehicle (n=5) failed to protect any animal from malignant
arrhythmias, nor did this treatment prevent arrhythmias
in resistant animals (n=2).
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The effects of L-768,673 on resting heart rate and ECG
parameters are displayed in Figure 4. L-768,673 significantly increased QTc
interval (control, 258.6±6.4 ms; L-768,673, 275.5±5.4 ms; change,
16.9±5.8 ms, 7.0±2.3%) but did not alter resting heart rate
(control, 109.7±3.0 bpm; L-768,673, 105.5±3.4 bpm). Likewise,
L-768,673 did not alter the heart rate response to exercise (Figure 5). Exercise significantly increased QTc
interval (control, 258.6±6.4 ms; exercise, 282.9±7.9 ms). The QTc
interval was not increased further with exercise in L-768,673–treated
animals (control, 275.5±5.4 ms; exercise, 284.9±8.9 ms). Finally,
L-768,673 did not alter the heart rate response to the coronary
artery occlusion (control, 202±9.3; occlusion, 210.8±12.8 bpm;
L-768,673, 211.7±9.8; occlusion, 214±15 bpm).
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Discussion |
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Two distinct components of cardiac delayed rectifier current, IKr and IKs, have been identified in multiple mammalian species, including humans.1 2 3 4 5 IKr is a rapidly activating current that exhibits prominent inward rectification at depolarized membrane potentials, whereas IKs is a more slowly activating and deactivating current with a linear current-voltage relationship.14 It is noteworthy, however, that the biophysical characteristics of IKs may vary among species, with the rate of deactivation of IKs reported to be more rapid in dog than in guinea pig myocytes.5 IKr and IKs are differentially modulated in varied experimental conditions that mimic physiological or pathological states. During rapid heart rate, the contribution of IKr to repolarization is functionally diminished because of the enhanced contribution of other currents, including IKs, which accumulates at faster rates as a result of incomplete deactivation.15 This differential rate-dependence of the delayed rectifier subtypes has been proposed to underlie the diminished activities of IKr blockers at faster heart rates and exaggerated activity at slower heart rates (ie, reverse frequency–dependence).15 16 IKr is unaffected per se by ß-adrenergic receptor stimulation, whereas IKs is enhanced; however, the functional contribution of IKr to repolarization is diminished during ß-adrenergic receptor stimulation.17 18 19 The differential modulation of IKr and IKs, particularly the maintained or enhanced activity of IKs relative to IKr with faster heart rate and enhanced sympathetic tone, has led to the speculation that IKs may represent the more effective target current for therapeutic modulation of cardiac action potential duration (APD).18 19 20
The in vivo assessment of the antiarrhythmic potential of IKs blockade has been hampered by the lack of potent and selective inhibitors. Chromanol 293B has been reported to block IKs selectively with IC50=2.0 to 9.9 µmol/L in guinea pig myocytes, Xenopus oocytes, and COS-7 cells.21 22 Chromanol 293B produces frequency-independent prolongations of cardiac APD in guinea pig and human ventricular myocytes, in contrast to the strong reverse frequency–dependent profile displayed by the IKr blocker E-4031.23 Chromanol 293B has been used to evaluate the contribution of IKs to action potential morphology and arrhythmogenesis in isolated canine cardiac preparations.24 25 26 The exposure of canine epicardial, midmyocardial, and endocardial ventricular myocytes to chromanol 293B resulted in no afterdepolarization-type activity, whereas combined exposures to either 293B and the IKr blocker E-4031 or 293B and isoproterenol resulted in early and delayed afterdepolarizations, respectively, suggesting arrhythmogenic risk with simultaneous IKr and IKs blockade as well as with IKs blockade in the setting of high sympathetic tone.24 25 In an isolated canine ventricular wedge preparation, perfusion with chromanol 293B homogeneously prolonged QT interval and APD of epicardial, midmyocardial, and endocardial myocytes but did not widen the T wave, increase transmural dispersion of repolarization, or induce torsade de pointes. However, combined perfusion with chromanol 293B and isoproterenol widened the T wave, accentuated transmural dispersion of repolarization, and elicited torsade de pointes, again suggesting arrhythmogenic risk with IKs blockade in the setting of high sympathetic tone.26
L-768,673 is a recently described benzodiazepine blocker of IKs.9 In guinea pig ventricular myocytes, L-768,673 blocks IKs selectively and potently (IC50=6 nmol/L) and elicits a self-limiting, maximal 30% prolongation of APD.9 No early afterdepolarizations were noted with exposure of guinea pig ventricular myocytes to L-768,673, whereas comparable lengthening of APD with IKr blockade resulted in the development of early afterdepolarizations.9 L-768,673 was used in the present studies to assess the antiarrhythmic efficacy of selective IKs blockade in 2 canine models of ischemically induced malignant ventricular arrhythmias. In anesthetized dogs with recent anterior myocardial infarction, L-768,673 suppressed both electrically induced ventricular tachyarrhythmia and ventricular fibrillation precipitated by thrombotically induced posterolateral myocardial ischemia. Efficacy in this preparation was associated with modest 3% to 10% increases in ventricular refractory periods and 4% to 6% increases in QTc interval measured before the acute ischemic triggering event. Significant antiarrhythmic efficacy with only modest increases in ventricular refractoriness and QTc interval with L-768,673 contrasts with the profiles observed in previous studies with the selective IKr blockers d-sotalol, dofetilide, E-4031, and MK-499. These IKr blockers required 12% to 27% increases in ventricular refractoriness and 12% to 17% increases in QTc interval to achieve >50% reductions in the incidence of malignant ventricular arrhythmias in previous studies using conscious and anesthetized versions of this canine model.13 27 28 29 The greater increase in ventricular refractoriness and QTc interval required by selective IKr blockers for significant suppression of ischemic ventricular arrhythmias may be necessary to offset reduced IKr in the settings of elevated heart rate and high sympathetic tone such as occur during acute myocardial ischemia. Conversely, the modest effects on ventricular refractoriness and QTc interval required for antiarrhythmic activity with L-768,673 are consistent with a maintenance, if not enhancement, of IKs activity during acute myocardial ischemia.
The antiarrhythmic potential of IKs blockade with L-768,673 was further evaluated in the conscious canine model of healed anterior myocardial infarction. In this model, ventricular fibrillation was induced by the reversible occlusion of the left circumflex coronary artery during submaximal exercise to increase cardiac sympathetic activity. This model differs in several respects from the preceding preparation, including study in the conscious versus anesthetized state, healed versus recent anterior infarction, production of secondary ischemic insult by mechanical versus thrombotic coronary occlusion, and most notably the occurrence of the secondary ischemic insult in the setting of high sympathetic tone and elevated heart rate elicited by exercise. Pharmacologically, IKr blockers, including d-sotalol, have demonstrated efficacy in suppressing lethal ventricular arrhythmias provoked by thrombotic coronary artery occlusion in the setting of recent myocardial infarction studied in either the anesthetized or conscious state.13 27 29 In contrast, d-sotalol was ineffective in preventing the provocation of malignant ventricular arrhythmias by transient coronary artery occlusion during exercise in the setting of healed myocardial infarction, presumably because of an attenuation of the effects of IKr blockade in the setting of high heart rate and high sympathetic tone.19 20 In this conscious model of healed anterior myocardial infarction, pretreatment with L-768,673 prevented malignant arrhythmias provoked by coronary artery occlusion in the setting of exercise-induced high sympathetic tone in 5 of 6 animals previously susceptible to ventricular fibrillation. Efficacy in this preparation was accompanied by a modest 7% increase in preexercise QTc interval, whereas QTc was not further increased during exercise. The lack of overt proarrhythmia with IKs blockade with L-768,673 in the present in vivo study apparently contrasts with the arrhythmogenic risk of combined exposure to isoproterenol and chromanol 293B in canine ventricular myocytes and in the canine ventricular wedge preparation.26 26 The demonstration of proarrhythmia in preclinical models is highly preparation-dependent, however; therefore, further studies are required to determine whether the observed differences are compound- or preparation-specific.
The question remains whether or not selective
IKs blockade may have proarrhythmic
activity in humans. This is a particularly important question, given
the discouraging results from large clinical studies using
IKr blockers (ie, SWORD and
DIAMOND).6 7 Recent genetic linkage and molecular
biological studies of patients with congenital long-QT syndrome (a rare
cardiac disorder characterized by prolonged ventricular
repolarization, long QT interval, and a high risk for sudden death)
have identified multiple mutations of several genes encoding cardiac
ion channels, including KvLQT1, encoding the
IKs 
-subunit, and KCNE1, encoding IsK,
thought to be an IKs
ß-subunit.30 The incidence of cardiac
arrhythmia and sudden death are reportedly more likely to be
associated with adrenergic factors (eg, physical or emotional stress)
in long-QT syndrome patients with KvLQT1 mutations compared with other
mutations.31 Whether these associations between specific
genetic defects in KvLQT1 and IsK proteins and congenital long-QT
syndrome identify a small high-risk population for which class III
therapy would be absolutely contraindicated or, conversely, constitute
genetic evidence that IKs blockade
represents an inherently unacceptable risk for the general
population is at present unknown. Therefore, although the
present studies with the IKs blocker
L-768,673 indicate antiarrhythmic activity in preclinical models, it is
probable that under appropriate conditions,
IKs blockade could be arrhythmogenic.
Further preclinical and clinical studies are required to better assess
the overall antiarrhythmic potential and arrhythmogenic risk of
selective IKs blockade.
Received October 29, 1998; revision received June 11, 1999; accepted June 22, 1999.
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J. Kang, X.-L. Chen, L. Wang, and D. Rampe Interactions of the Antimalarial Drug Mefloquine with the Human Cardiac Potassium Channels KvLQT1/minK and HERG J. Pharmacol. Exp. Ther., October 1, 2001; 299(1): 290 - 296. [Abstract] [Full Text] [PDF]
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X. Xu, S. J. Rials, Y. Wu, J. J. Salata, T. Liu, D. B. Bharucha, R. A. Marinchak, and P. R. Kowey Left Ventricular Hypertrophy Decreases Slowly but Not Rapidly Activating Delayed Rectifier Potassium Currents of Epicardial and Endocardial Myocytes in Rabbits Circulation, March 20, 2001; 103(11): 1585 - 1590. [Abstract] [Full Text] [PDF]
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