Published online before print August 25, 2003, doi: 10.1161/01.CIR.0000086461.86642.22
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(Circulation. 2003;108:1389.)
© 2003 American Heart Association, Inc.
Basic Science Reports |
Heterogeneous Ventricular Repolarization Provides a Substrate for Arrhythmias in a German Shepherd Model of Spontaneous Arrhythmic Death
From the Department of Pharmacology and Pediatrics, Center for Molecular Therapeutics, College of Physicians and Surgeons of Columbia University, New York, NY (M.N.O., E.A.S., E.P.A., R.B.R., M.R.R.), and the Department of Clinical Science, College of Veterinary Medicine of Cornell University, Ithaca, NY (N.S.M.).
Correspondence to Michael R. Rosen, MD, College of Physicians and Surgeons of Columbia University, Department of Pharmacology, 630 West 168 St, PH 7 West-321, New York, NY 10032. E-mail mrr1{at}columbia.edu
Received March 5, 2003; revision received May 8, 2003; accepted May 9, 2003.
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Abstract |
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Background— German shepherd dogs with inherited arrhythmias and sudden death appear to be a model for catecholamine-dependent ventricular tachycardias in human subjects. We tested the hypothesis that heterogeneity of left ventricular repolarization creates an arrhythmogenic substrate for pause-dependent ventricular tachycardia in these animals.
Methods and Results— We used microelectrode techniques to record action potentials (AP) from midmyocardial sections of anteroseptal, anterobasal, and posterobasal left ventricular (LV) wall of unafflicted and afflicted dogs. There were no differences in AP duration to 90% repolarization (APD) among LV regions in unafflicted dogs. In contrast, in afflicted dogs, there was significant heterogeneity, with the longest APD in anterobasal and shortest in anteroseptal regions. Isoproterenol did not affect repolarization in unafflicted dogs, whereas in afflicted dogs, it shortened APD anterobasally and prolonged APD anteroseptally. We studied the repolarizing currents, IKr and IKs, in single anteroseptal and anterobasal LV myocytes with the use of a whole-cell voltage clamp. There were no differences in IKr and IKs between anteroseptal and anterobasal regions in unafflicted dogs, whereas in afflicted dogs, IKr was smaller anterobasally (P<0.05). Isoproterenol produced a more prominent leftward shift in IKs voltage-dependent activation in anterobasal regions of afflicted than unafflicted dogs.
Conclusions— Spatial heterogeneity in expression and catecholamine responsiveness of IKr and IKs results in heterogeneous LV repolarization in afflicted German shepherd dogs, contributing importantly to the arrhythmogenic substrate.
Key Words: arrhythmia • death, sudden • electrophysiology • ion channels
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Introduction |
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A German shepherd model of spontaneously occurring ventricular arrhythmias and sudden death manifests similarities to catecholamine-induced tachycardias in human subjects.1–3 In this model, pause-dependent arrhythmias contribute to
80% of tachycardias.4–13 Their initiation has been attributed to early afterdepolarizations (EADs), inducing triggered activity that originates from left ventricular (LV) Purkinje fibers.7,8 However, the substrate contributing to maintenance of this ventricular tachycardia remains unknown. The pause dependence of the arrhythmias as well as the observations that in afflicted dogs (1) the QT interval is not prolonged,9,10 (2) LV sympathetic innervation is inhomogeneous,11 and (3) frequent T-wave notching occurs,10,12 raise the possibility that inhomogeneity of LV repolarization may constitute part of the arrhythmogenic substrate. Therefore, we studied action potential duration (APD) and isoproterenol responsiveness in multicellular sections from anterobasal, anteroseptal, and posterobasal LV midmyocardium, as well as epicardium and subendocardium of hearts from afflicted and unafflicted dogs. To elucidate ionic mechanisms of regional heterogeneity in APD, IKr and IKs and their responses to isoproterenol were examined as well. |
Methods |
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All experimental procedures conformed to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (publication No. 85-23).
Holter monitoring was used to identify 28 arrhythmic (afflicted) German shepherd dogs (22 to 32 weeks of age) from a colony bred at Cornell University.4 In this age range, the expression of lethal arrhythmias is maximal.10 Arrhythmias included ventricular premature depolarizations and/or ventricular tachycardia (4 or more ventricular complexes in sequence). Twenty age-matched control (unafflicted) German shepherds were obtained from a commercial breeder and were determined to have no spontaneous arrhythmias.
Action Potentials in Multicellular Preparations
Animals were anesthetized with sodium pentobarbital (30 mg/kg IV). Hearts were removed through a left lateral thoracotomy and immersed in cold Tyrode’s solution equilibrated with 95% O2–5% CO2 and containing (mmol/L): NaCl 131, NaHCO3 18, KCl 4, CaCl2 2.7, MgCl2 0.5, NaH2PO4 1.8, and dextrose 5.5. Midmyocardial sections (0.5 to 1 mm thick) from anteroseptal, anterobasal, and posterobasal LV were filleted with surgical blades oriented parallel to the epicardium. To estimate the transmural gradient of repolarization, subendocardial and subepicardial strips of comparable thickness were filleted from the anterobasal LV. Preparations were placed in a 4-mL chamber, perfused with Tyrode’s solution (37°C, pH 7.3 to 7.4) at 12 mL/min, and were stimulated by Teflon-coated silver electrodes with 1- to 2-ms, rectangular, twice-threshold current pulses. Stabilization required 3 to 4 hours of stimulation at cycle length (CL)=1000 ms. Conventional microelectrode techniques were used to record transmembrane potentials.
Frequency dependence of APD was studied at CL=4000, 2000, 1000, 500, and 300 ms. Steady state was achieved by pacing at 3 minutes for each CL. After control records were obtained, some preparations were superfused with Tyrode’s solution containing isoproterenol (Sigma, 10-9 to 10-7 mol/L) and equilibrated for 10 minutes at each concentration before frequency dependence was studied.
Ion Channels in Single Myocytes
Midmyocardial myocytes were isolated by a collagenase perfusion method reported previously.14 Briefly, a wedge of LV free wall supplied by the left anterior descending (LAD) artery was dissected. The LAD or its first branch was cannulated and perfused with Ca2+-free Tyrode’s solution containing 0.2 mg/mL collagenase (Worthington, type 2, 198 U/mg) for 10 to 15 minutes. Thin tissue slices (2 to 7 mm from epicardial surface) were dissected from anteroseptal or anterobasal regions, minced, and incubated in fresh collagenase solution containing 0.3 mmol/L CaCl2 and agitated with 95% O2/5% CO2 for 5 to 15 minutes. Incubation was repeated 3 to 5 times, and the supernatant from each digestion was centrifuged. Isolated cells were stored at room temperature in buffer solution.
Myocytes were transferred to a bath (35°C) perfused with modified Tyrode’s solution containing (mmol/L): NaCl 140, KCl 5.4, CaCl2 1.8, MgCl2 1, HEPES 5, and glucose 10. pH was adjusted to 7.4 with NaOH. L-type Ca 2+ current was blocked with 10-6 mol/L nisoldipine (a gift of Bayer, Germany). Currents were recorded using a standard whole cell patch-clamp method. The pipette (1 to 3 M
) solution contained (mmol/L): aspartic acid 130, KOH 146, NaCl 10, EGTA 5, CaCl2 2, Mg-ATP 2, HEPES 10, with pH adjusted to 7.2 with KOH.
IKs and IKr were discriminated with a 2-tailed protocol.15 Cells were depolarized from a holding potential of -40 mV to +40 mV, repolarized first to 0 mV and then to -40 mV. The duration of each step was 6 seconds. The first repolarizing step to 0 mV generates mainly an IKs tail, whereas the final step to -40 mV results primarily in an IKr tail.15 Measurements were made before and 90 seconds after isoproterenol superfusion. In some experiments, the IKs/IKr blocker chromanol 293B (a gift of Aventis Pharma) was used.
In another set of experiments, IKs was examined in myocytes pretreated with a selective IKr blocker, dofetilide (10-6 mol/L) (a gift of Helopharm). Currents were recorded during 5-second depolarizing test pulses from 0 to +70 mV in 10-mV increments and on repolarization to -10 mV. Pulses were applied from holding potential -40 mV at 10-second intervals to ensure deactivation of tail currents. The protocol was performed before and after 2 minutes of isoproterenol (10-8 mol/L) application.
Statistical Analysis
Microelectrode data were analyzed from impalements maintained throughout each experimental protocol. Data are expressed as mean±SEM. Statistical analysis was by 1- or 2-way ANOVA for multiple groups or for repeated measures, with the Bonferroni test when the F value permitted this. When 2 groups were compared, unpaired or paired t tests were used. Significance was determined at P<0.05.
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Results |
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Studies of Isolated Myocardium
Transmural dispersion of repolarization was examined in the anterobasal LV wall, where midmyocardial APD90 in afflicted dogs was the longest, suggesting a prominent transmural gradient of repolarization. In both groups of dogs, APD90 in midmyocardium was significantly longer than either in subepicardium or subendocardium, with a parallel upward shift of the curve for afflicted dogs (Figure 1). Accordingly, the expression of a transmural gradient of repolarization across the ventricular wall was about the same in both groups of animals and also similar to that of normal mongrel dogs.16 Given the comparability of differences across the LV wall, all subsequent studies were performed in midmyocardium only.
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Action potential parameters other than APD did not differ among the 3 regions of midmyocardium in unafflicted and afflicted dogs. At CL=1000 ms, maximum diastolic potential ranged from -88±1 to -90±1 mV across groups; AP amplitude from 116±2 to 119±1 mV and 
max from 248±12 to 267±19 V/s (n=38 to 55/group, all P>0.05). Figure 2A shows representative APs recorded in 3 LV midmyocardial regions of 1 unafflicted and 1 afflicted dog at CL=4000 ms. A notable difference between the two is evident with prominent heterogeneity of repolarization along the midmyocardium in the afflicted and minimum heterogeneity in the unafflicted dog. Whereas APD90 was not significantly different among LV regions in unafflicted dogs at all CLs, in afflicted dogs, and particularly at long CLs, APD90 was the longest in anterobasal and shortest in anteroseptal regions (Figure 2B).
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Figure 3A demonstrates that isoproterenol (10-7 mol/L) minimally affected repolarization in an unafflicted dog but reduced dispersion of repolarization among the LV regions of an afflicted dog. In unafflicted dogs, isoproterenol did not change APD90 significantly in any region (Figure 3B), whereas in afflicted dogs, it significantly shortened APD90 anterobasally (where predrug repolarization was the longest), prolonged APD90 anteroseptally (where predrug repolarization was the shortest), and had no significant effect posterobasally (compare Figure 3B with Figure 2B). As a result, isoproterenol minimized dispersion in different LV regions of afflicted dogs.
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Voltage Clamp Experiments
Figure 4 shows the separation of IKr and IKs by the 2-tailed protocol. When the repolarization step from +40 mV was subdivided in a step to 0 mV followed by a second step to -40 mV (Figure 4A), dofetilide had no significant effect on the tail at 0 mV but almost completely inhibited the tail at -40 mV (Figure 4B), designating the latter as IKr. The dofetilide-resistant component (the tail at 0 mV) was confirmed as IKs by blockade with chromanol 293B (Figure 4C). Residual current after chromanol ranged from 0.03 to .11 pA/pF.
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We used the 2-tailed protocol to compare IKr and IKs between anteroseptal and anterobasal regions in unafflicted and afflicted dogs since the maximum difference in APD90 in afflicted dogs occurred between these regions (Figure 2). Control values for IKs and IKr did not differ between regions in unafflicted dogs (Figure 5, left). In afflicted animals, control IKs was the same in both regions, but IKr was smaller anterobasally than anteroseptally (Figure 5, right).
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Isoproterenol increased IKs but did not affect IKr in either region of unafflicted dogs. Isoproterenol increased IKs as well in both regions of afflicted animals. However, in contrast to unafflicted dogs, isoproterenol also appeared to increase IKr (second tail amplitude) in the anterobasal region of afflicted animals. Because we could not be certain if the apparent effect of isoproterenol on IKr was in fact exerted on this current or alternatively resulted from a shift in the IKs-voltage relation, we studied this further in anterobasal LV of unafflicted and afflicted dogs. In these experiments, cells were pretreated with 10-6 mol/L dofetilide to eliminate IKr. Control IKs I-V curves did not differ between groups over the entire range of voltages (Figure 6, A andB). Isoproterenol increased IKs significantly in cells from unafflicted dogs in the voltage range of +30 through +70 mV and in cells from afflicted dogs at voltages of +30 through +50 mV. The percent change in current induced by isoproterenol did not differ between groups.
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Voltage-dependent activation curves for IKs were obtained based on I-V relation data (Figure 6C). Isoproterenol produced a leftward shift in activation in both groups but more prominently in afflicted dogs (control-isoproterenol difference in V1/2=14.1±2.1mV, afflicted versus 8.5±1.1 mV, unafflicted P<0.05). The greater shift induced by isoproterenol in cells from afflicted dogs can lead to a larger change in IKs at threshold values near 0 mV. This can account for the isoproterenol effect observed on the second tail in figure 5.
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Discussion |
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Heterogeneity of repolarization may occur along and across the LV wall, with both contributing to T-wave morphology and arrhythmogenesis.17,18 Therefore, we analyzed both types of heterogeneity. We found that at low pacing rates (CL=2000 to 4000 ms), there is significant spatial inhomogeneity of repolarization along the LV wall of afflicted but not unafflicted dogs, whereas transmural dispersion of repolarization does not differ between the 2 groups. Although 4000 ms represents a long cycle length, it is pathophysiologically relevant, given the long pauses that have been recorded during sinus rhythm in afflicted animals.4,9 Such heterogeneity of repolarization can provide a substrate for reentry and pause-dependent ventricular tachycardia and might account for the abnormal T-wave morphology in afflicted dogs.10,12 Our voltage-clamp data pinpoint the ionic basis of this heterogeneity. In afflicted animals, IKs was significantly larger and IKr significantly smaller anterobasally than anteroseptally whereas no differences in these currents occurred across the 2 LV regions in unafflicted dogs. For most action potentials we recorded, plateau potential was in the range of 0 to +10mV. At these potentials, IKr is fully activated, whereas IKs is relatively small. This indicates a greater dependence for repolarization on IKr and the smaller IKr can account for the long APD recorded anterobasally in afflicted dogs.
The occurrence of pause-dependent ventricular tachycardia at complete rest or in sleep1,9 is in a setting of low sympathetic tone. We therefore anticipated that any dispersion of repolarization in these animals should be maximal in the absence of catecholamine and should diminish in a setting of increased sympathetic tone. We simulated this using isoproterenol. Whereas isoproterenol had minor effects on repolarization in all regions of unafflicted dogs, it shortened APD anterobasally and prolonged it anteroseptally in afflicted animals, thereby equalizing LV repolarization. Thus, ß-adrenergic stimulation would appear to eliminate the arrhythmogenic substrate for pause-dependent arrhythmias in afflicted dogs.
Our voltage-clamp data with isoproterenol explain these isolated tissue findings. The effects of isoproterenol were about the same in both LV regions of unafflicted dogs, increasing IKs and not changing IKr. In afflicted animals, isoproterenol increased IKs similarly in both regions, whereas what appeared to be IKr in the 2-tailed protocol was significantly elevated anteroseptally. The latter result was somewhat unexpected because IKs is recognized to be regulated by ß-adrenoreceptor stimulation,19 but controversy exists regarding the effects of ß-adrenoreceptor activation on IKr: No changes,19 stimulation20 or inhibition21 have been reported. Because isoproterenol enhancement of what appeared to be IKr occurred only anterobasally, we compared isoproterenol effects on the voltage dependence of IKs activation in this region. The more prominent leftward shift of activation in afflicted than unafflicted animals significantly increased normalized IKs at 0 mV, thereby verifying that the isoproterenol-induced increase in what appeared to be IKr in the 2-tailed protocol was actually due to an enhanced contribution of IKs at this potential. The consequence of this IKs contribution to repolarization in the plateau voltage would be significant APD shortening by isoproterenol.
The heterogeneity in LV repolarization and isoproterenol effects derives most likely from a regional delay in the development of sympathetic innervation to the LV in afflicted dogs.11 There is considerable literature concerning the potential for delayed, incomplete, or asymmetric development of cardiac sympathetic nerves to be arrhythmogenic (see References 2222 and 2323). Moreover, sympathetic innervation is known to modulate the functional expression of repolarizing ionic currents in the developing heart.24,25 Reduced Ito density in LV regions having decreased innervation was demonstrated in afflicted German shepherds.26 Also favoring a role for sympathetic nerves as long-term modulators of the LV substrate are the observation that right-sided stellectomy to make regional sympathetic denervation at birth results in 4 to 5 months of altered LV electrophysiological properties similar to those observed in German shepherds afflicted with arrhythmias.27
The present study strengthens the hypothesis that the mechanisms of pause-dependent and tachycardia-dependent lethal arrhythmias in afflicted German shepherds are different.8 Pause-dependent arrhythmias are most marked when the animals are lying quietly or are asleep.9 Ventricular tachycardia in these animals typically is initiated by a premature complex coupled to a sinus complex that follows a long pause. These arrhythmias are attributed to triggering by EADs originating in LV Purkinje fibers.7,8 The present study suggests a substrate for maintenance of these arrhythmias. In the absence of sympathetic stimulation and at a low heart rate, there is significant dispersion of repolarization in the LV of afflicted animals which may facilitate reentry.28 Increased sympathetic tone (ß-adrenoreceptor stimulation) inhibits EADs in Purkinje fibers of afflicted animals7 and, as per the present study, equalizes LV repolarization, thus reducing both trigger and substrate for pause-dependent arrhythmias. Limiting the interpretation of our findings is that studies using MIBG to estimate extent and location of innervation, while implicating the regions to have studied here, were performed in different animals.11 Also, complicating the situation, isoproterenol-induced delayed afterdepolarizations (DAD) and DAD-induced triggered activity have recently been documented in LV sympathetic innervation in afflicted dogs.8 These DADs may underlie catecholamine-sensitive and exercise-induced ventricular tachycardias.
In conclusion, our data demonstrate significant spatial dispersion of repolarization in the LV of German shepherd dogs afflicted with arrhythmias. This finding is an important component relating the German shepherd model of lethal arrhythmias to human disease because heterogeneity of ventricular repolarization is also important in some inherited arrhythmias in human subjects.28 Moreover, as in afflicted dogs, abnormal sympathetic innervation has been identified in patients with Brugada syndrome29 and in some patients with congenital long QT syndrome.30 With regard to the latter patient group, although ion channelopathies are recognized as determining the arrhythmogenic substrate (eg, Reference 3131), the role of sympathetic nerves as a trigger remains an attractive hypothesis. Thus, the German shepherd model of inherited lethal arrhythmias mimics certain conditions (heterogeneity of ventricular sympathetic innervation and repolarization) important in humans, which makes its further investigation both important and promising.
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Acknowledgments |
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These studies were supported in part by USPHS-NHLBI grant HL-28958. The authors express their gratitude to Nimee Bhat for her assistance in performing certain of the studies and to Eileen Franey for her careful attention to the preparation of the manuscript.
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