© 2001 by European Society of Cardiology
Copyright © 2000, European Society of Cardiology
Long-term electrophysiological effects of regional cardiac sympathetic denervation of the neonatal dog
Departments of Pharmacology and Pediatrics, Center for Molecular Therapeutics, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA
* Corresponding author. Department of Pharmacology, Center for Molecular Therapeutics, College of Physicians and Surgeons of Columbia University, 630 West 168 Street, PH 7 West-321, New York, NY 10032, USA. Tel.: +1-212-305-8754; fax: +1-212-305-8351 mrr1{at}columbia.edu
Received 28 February 2001; accepted 24 April 2001
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Abstract |
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Objective: In many cardiac arrhythmias, both a triggering factor and a favorable myocardial substrate are required. Whereas the sympathetic nervous system may trigger tachyarrhythmias, its function as a long-term modulator of the myocardial substrate is less well understood. Therefore, we tested the hypothesis that regional sympathetic denervation at birth would produce an abnormal myocardial substrate. The comparator was the substrate associated with inherited, lethal tachyarrhythmias at 5 months of age in German shepherd dogs with incomplete sympathetic innervation. Methods: Mongrel dogs underwent right cardiac stellectomy (RSX) within the first day of life and were terminally studied with control littermates at 5 months of age. Results: On days 1–21 of life, RSX animals manifested significant QT prolongation on ECG and sudden, asystolic death. Beyond this age, QT intervals normalized and deaths did not occur. At 5 months, action potentials (AP) were recorded from Purkinje fibers (PF) and midmyocardial preparations in anteroseptal (AS) and posterobasal (PB) left ventricle. Early afterdepolarizations occurred only in left ventricular PF from RSX dogs. Isoproterenol prolonged AP duration in AS and shortened it in PB of RSX but not control dogs. The incidence of isoproterenol-initiated triggered activity and the amplitude of delayed afterdepolarizations were greater in RSX than control dogs. Conclusion: Five months after RSX heterogeneous alterations of LV electrophysiological properties were similar to those previously observed in animals having inherited deficits in sympathetic innervation and sudden death. This implicates the sympathetic nerves as long-term modulators of an arrhythmogenic substrate. That 5-month-old RSX dogs did not experience tachyarrhythmias or sudden death indicates that further anomalies — beyond those explicable by the substrate change — must exist to induce sudden death.
KEYWORDS Arrhythmia (mechanisms); Autonomic nervous system; ECG; Membrane potential; Purkinje fiber; Ventricular arrhythmias
This article is referred to in the Editorial by R.F. Gilmour Jr. (pages 625–626) in this issue.
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1 Introduction |
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The sympathetic nervous system is a classic trigger of specific cardiac arrhythmias, as seen in conditions as diverse as catecholamine sensitive ventricular tachycardias and the KvLQT1 variant of the congenital long QT syndrome [1–5]. Less clear is whether the sympathetic nervous system also determines a potentially arrhythmogenic myocardial electrophysiological substrate. That long-term sympathetic modulation of ion channels and action potential characteristics is a likely event is suggested by experiments using nerve growth factor and its antibody to modulate sympathetic development in newborn rats. Here, acceleration or suppression of sympathetic neural development, respectively, sped or slowed phenotypic expression of the transient outward current, Ito, and altered repolarization [6,7]. A sympathetic effect to both provide a trigger and favorably modify substrate would increase the likelihood of arrhythmogenesis.
German shepherd dogs with an inherited tendency to develop lethal ventricular arrhythmias [8–12] have a deficit in sympathetic innervation of the anteroseptal left ventricle [13]. This suggests that lack of innervation may determine a heterogeneous myocardial substrate differing functionally from the normal. However, in the German shepherd model it is difficult to understand whether repolarization changes can be explained by the deficit in innervation.
Hence in the present study we asked if interruption of regional sympathetic innervation to the neonatal canine heart is associated with long-term persistence of an abnormal electrophysiological substrate in myocardium. We report here results from animals subjected to right stellectomy at birth. We performed a right stellectomy because our preliminary studies indicated that portions of the left ventricle whose innervation is delayed by the procedure correspond to regions that have delayed innervation in the German shepherd model [13]. We performed a terminal study at 5 months because the expression of lethal arrhythmias in the German shepherds is maximal at this age [10]. As shall be demonstrated, abnormalities in cardiac action potentials and autonomic responsiveness analogous to those seen in the spontaneously occurring German shepherd model of inherited arrhythmias are clearly demonstrable in sympathectomized dogs, although tachyarrhythmias were not observed. In addition, the clinical course of the dogs through the first month of life provided information relevant to the cause of mortality seen in the setting of long QT intervals.
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2 Methods |
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2.1 Surgical procedure
All studies were performed per institutional guidelines for animal research. Mongrel dogs underwent a stellectomy within the first 24 h postpartum. Anesthesia was mask-induced with isoflurane, and animals were intubated and then maintained on isoflurane, 2%. A mid-line sternotomy was performed, the right lung reflected, and the pleura at the first interspace dissected to expose the stellate ganglion. The ganglion was removed along with 2 mm of thoracic chain. The sternum was approximated with a non-absorbable monofilament suture; muscle and subcuticular layers were closed with absorbable suture. Skin was closed with nylon sutures. Animals were extubated and maintained in a warmed intensive care unit until they could be returned to their mothers. Cefazilin, 25 mg, and gentamycin, 4 mg, were administered i.m. twice a day for 5 days. For the first 14 days of life, ECGs were recorded daily: thereafter they were recorded weekly. ECG recordings were made at 25 mm/s chart speed for determination of rhythm and 250 mm/s for measuring ECG variables (from 10 consecutive beats that were averaged). Data on RR, PR, QRS and QT intervals were tabulated. Rate correction of the QT interval was done using Bazett's formula. In selected animals 24-h recordings of the ECG were performed.
Animals were terminally studied at 22 weeks of age. Pilot experiments revealed no difference in electrophysiological properties of Purkinje fibers or ventricular tissue between sham-operated and unoperated dogs of the same litters at the age of 5 months. Therefore, age-matched littermates were used as a control group.
2.2 Cellular electrophysiological studies
Animals were anesthetized with sodium pentobarbital, 30 mg/kg i.v. The hearts were removed quickly through a left lateral thoracotomy and immersed in cold Tyrode's solution equilibrated with 95% O2–5% CO2 and containing (in mM): NaCl 131, NaHCO3 18, KCl 4, CaCl2 2.7, MgCl2 0.5, NaH2PO4 1.8, and dextrose 5.5. In experiments utilizing catecholamine, solutions were kept in dark bottles, and also contained EDTA 0.05 mM.
Transmural slabs (
1 mm thick) were filleted with surgical blades perpendicular to the surface of the anteroseptal and posterobasal left ventricular wall to permit impalement of midmyocardial (M) cells [14,15]. Similar preparations had previously been used in German shepherd dogs [12,16]. Free running Purkinje fibers were isolated from left and right ventricles. The preparations were placed in a tissue bath, superfused with Tyrode's solution warmed to 37°C (pH 7.3–7.4), and allowed to equilibrate at a cycle length (CL) of 1000 ms. Solutions were pumped through the tissue bath at a flow rate of 12 ml/min, with chamber content changed 3 times per min. The bath was connected to ground with a 3 M KCl/Ag/AgCl junction.
All preparations were impaled with 3 M KCl-filled glass capillary microelectrodes (tip resistances of 10–20 M
) coupled by an Ag/AgCl junction to an amplifier with high input impedance and input capacity neutralization. The maximum upstroke velocity of the action potential (Vmax) was obtained by electronic differentiation with an operational amplifier. Transmembrane action potentials and Vmax were displayed on a digital storage oscilloscope (model 4164, Gould) and stored in a personal computer for subsequent analysis. For stimulation of preparations, standard techniques were used to deliver 1–2-ms long square-wave pulses 2.0 times threshold through bipolar PTFE-coated silver electrodes. To investigate frequency-dependence, the preparations were driven at cycle lengths of 4000, 2000, 1000, 500 and 300 ms in sequence. Each frequency was maintained for 5 min before data were collected.
Experiments were started after preparations had fully recovered and displayed stable electrophysiological characteristics. This required 60 min for Purkinje fibers and 3–4 h for transmural slabs. Before pharmacological interventions, control steady-state dependence of action potential parameters on CL of stimulation was determined. The CL was then returned to 1000 ms until the next data collection period. Graded concentrations of phenylephrine (10–8 to 10–6 mol/l) and isoproterenol (10–9 to 10–7 mol/l) were studied in each preparation with a 60-min washout between administration of agonists. The preparations stabilized within 10 min of exposure to each agonist concentration. To test the effect of isoproterenol to induce delayed afterdepolarizations (DAD) in transmural slabs they were stimulated for 1 min at a CL of 250 ms and then stimulation was discontinued.
2.3 Statistical analysis
Data are expressed as mean±S.E.M. Statistical analysis was via one- or two-way ANOVA for multiple groups or for repeated measures, with Bonferonni's test when the F value permitted this [17]. Microelectrode data were analyzed from impalements maintained throughout the course of each experiment. Significance of incidence of premature depolarizations was evaluated with Fisher's exact test. Significance was determined at P<0.05.
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3 Results |
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3.1 ECG and survival data
The ECG variables that changed importantly during the study were the R–R, QT and QTc intervals. R–R intervals prolonged through day 14 of life in the right stellectomy group (from 310±5 to 395±40 ms (P<0.05) (for n, see Fig. 1)), but not in controls (from 300±10 to 310±5 ms) (P>0.05). Thereafter, R–R intervals prolonged in both groups, and at 5 months they still differed significantly. Complete ECG data at 5 months are shown in Table 1. At this age variables other than R–R and QT intervals did not differ.
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During the first 21 days of life, QTc increased in all groups, and the increase was significantly greater in stellectomized animals (Fig. 1). After 21 days, QTc in the stellectomized group did not differ from sham and control and decreased gradually so that by day 154 the QTc was shorter than at birth. Although not shown, a left stellectomy was performed in 23 animals. This increased the QTc by a maximum of 6% on day 14 of life (P>0.05).
In the first 2–3 weeks of life, sinus pauses and ventricular ectopy (largely escape beats) were seen equally in control and sham groups, but their incidence was significantly higher in the right stellectomy group (Table 2). Moreover, the incidence of sudden death in the right stellectomy group was significantly higher than in the controls and shams (Table 2). Although not shown, mortality was 9% in the LSX group (P>0.05 cf. sham). Importantly, mortality was not tachyarrhythmia-related, but was the result of ventricular asystole, occurring in the setting of sinus bradycardia and/or AV block (e.g., Fig. 2). Beyond week 3 of life, no mortality occurred.
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3.2 Isolated tissue studies at 22 weeks
In the German shepherd model of ventricular arrhythmias, triggered activity induced by early afterdepolarizations (EAD) arising in left ventricular Purkinje fibers is considered responsible for pause-dependent ventricular tachycardias [11]. Therefore, we studied Purkinje fibers from the right and left ventricles of control and stellectomized dogs. The automatic rate of spontaneously beating Purkinje fibers was 16±6 beats/min in the right ventricle and 15±4 beats/min in the left ventricle of control dogs; in stellectomy dogs, the respective values were 12±4 and 18±5 beats/min (P>0.05 cf. one another and controls). EAD and EAD-induced triggered activity were observed in four of 11 left ventricular and none of six right ventricular fibers obtained from stellectomized dogs (Fig. 3A,B). There were no EAD in eight right and 13 left ventricular Purkinje fibers obtained from controls. In the presence of phenylephrine, 10–6 M, EAD occurred in six of 11 left and one of six right ventricular Purkinje fibers from stellectomized dogs and still were not seen in fibers from controls (Fig. 3C). Isoproterenol, 10–7 M, suppressed EAD and triggered activity (Fig. 3D). The suppression was, most likely, due to a significant (about 3-fold) increase of spontaneous rate from 15±4 to 40±3 beats/min in the left ventricular Purkinje fibers of stellectomized dogs.
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During superfusion with control Tyrode's solution at a drive CL of 1000 ms, there were no significant differences in action potential characteristics among all groups of Purkinje fibers (Table 3). Fig. 4 depicts the effects of phenylephrine on action potential duration (APD). There was a tendency for phenylephrine to prolong APD in all groups, however this effect was prominent and significant only in left ventricular Purkinje fibers obtained from stellectomized dogs (Fig. 4C,D).
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Because triggered activity induced by DAD in midmyocardial cells of the left ventricle can account for tachycardia-dependent triggered arrhythmias in the German shepherd model [12], we also studied myocardium from anteroseptal and posterobasal regions of the left ventricle. At long cycle lengths APD was greater in the anteroseptal region of the stellectomy group (Fig. 5). There were no significant differences between control anteroseptal and posterobasal regions and the stellectomized posterobasal region. Other action potential parameters did not differ significantly among all regions in both groups with the exception of action potential plateau amplitude which was higher in stellectomized (14±1 mV) than control (10±1 mV, P<0.05) anteroseptal regions (data not shown).
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Fig. 6 illustrates the effects of isoproterenol on representative M cell transmembrane potentials. Isoproterenol had no significant effects on MDP, action potential amplitude and Vmax in all preparations (data not shown). Plateau potential was increased by isoproterenol in all preparations, whereas APD was changed only in preparations from stellectomized animals. Importantly, the effects on APD of stellectomized dogs differed regionally: i.e., isoproterenol shortened APD in posterobasal regions and prolonged APD anteroseptally (Figs. 6 and 7
) while having no effect on APD in controls. As a result, a significant regional difference in APD was seen in stellectomized dogs in the presence of isoproterenol. Phenylephrine had no effects on APD in all groups of preparations (data not shown).
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To study the effect of isoproterenol to induce DAD and triggered activity, preparations were stimulated at a CL of 250 ms for 1 min and then stimulation was discontinued. In the absence of isoproterenol, there were no DAD or ectopic activity in all preparations. In the presence of isoproterenol, 10–7 M, DAD and triggered activity were observed in preparations from both regions of both groups of dogs (Fig. 8). However, the maximal incidence of triggered activity was in the anteroseptal region of stellectomized animals (Fig. 8B). Similar results were obtained with regard to those DADs that did not reach threshold potential: DAD amplitude was significantly greater in both the anteroseptal and posterobasal regions of stellectomized dogs than in control (Fig. 8C).
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4 Discussion |
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The sympathetic nervous system provides an important trigger for cardiac arrhythmias, as seen in catecholamine-dependent ventricular tachycardias, and the KvLQT1 variant of the congenital long QT syndrome [1–5]. Each of these conditions also incorporates an important abnormality in the myocardial substrate. For catecholamine-dependent ventricular tachycardias, this resides in the RyR2 receptors on the sarcoplasmic reticulum [18], and for KvLQT1 variant of the long QT syndrome, in the co-assembled KvLQT1 and minK genes that determine the current, IKs [19].
Research in the 1970s implicated a ‘sympathetic imbalance’ in the causality of the congenital long QT syndrome (see Ref. [20] for review). This idea was supported by the observations that β-blockade or left stellectomy conferred benefit in terms of reduced syncope and increased survival in populations of LQTS patients. The idea of sympathetic imbalance as the source of the lethal arrhythmias was supplanted by understanding of the primary role of ion channel mutations, although a triggering effect of the sympathetics remains unquestioned.
Data from the present study are relevant to the above information. First, we have confirmed that unilateral stellectomy is associated with QT prolongation. This is far more extensive with right than left stellectomy and is consistent with the idea of a sympathetic imbalance. We can question whether the ‘imbalance’ is a primary and immediate effect of denervation or a deficit in cell and ion channel machinery secondary to long-term deprivation of innervation. It is clear, however, that the QT prolongation is of limited duration (through 21–28 days of life — see Fig. 1). Whether the normalization of the QT is a sign of reestablishment of a critical extent of innervation is not certain, as there was still a slower sinus rate in the stellectomized animals. Moreover, whether the mechanisms responsible for QT prolongation in these animals are in any way referable to human subjects with QT prolongation remains to be determined.
Regarding the mechanism for QT prolongation, it is known that sympathetic innervation modulates the evolution of both specific adrenergic pathways [21] and specific ion channels [7,22]. For example, sympathetic innervation of rat and dog heart as well as of myocytes in tissue culture induces the maturation of 
1B-adrenergic receptor–effector coupling [23] and induces the maturation of the transient outward potassium current, Ito [7]. The result is the evolution of the phase 1 notch in the canine ventricular action potential [24] and the acceleration of repolarization in the rat action potential [6]. Interestingly, Ito density was reduced in a study of the German shepherd model of inherited arrhythmias [25], in which innervation is absent in regions of left ventricle [13], a finding in keeping with the effect of innervation to induce maturation of the current. A variety of studies suggest that when Ito is reduced there may be prolongation of action potential duration [26]. Whether this is the cause of the longer action potential duration of myocardial fibers from stellectomized dogs is not certain.
Of interest, as well, in the sympathectomized dogs are the arrhythmias that occur and their relationship to sudden death. It had long been assumed that the prolonged QT intervals characteristic of congenital long QT syndrome (and of sympathetic imbalance) would result in tachyarrhythmias such as torsades de pointes. Yet, as seen in the young animals that died in this study, the mechanism was not a tachyarrhythmia, but ventricular asystole (e.g., Fig. 2). The origin of the sinus bradycardia (Table 1) and sinus pauses (Table 2) in these animals is likely reduced sympathetic input. Whether increased vagotonia occurred and might have played a role here was not tested.
The failure of ventricular escape pacemakers to emerge and drive the asystolic heart is difficult to fathom in light of the fact that the threshold for activation of the pacemaker current, If, in ventricular myocytes of newborns is far more positive than that in adults [27]. One possibility is that the magnitude of IK1, in maintaining a negative membrane potential is sufficient to prevent onset of automatic rhythms. In any event, despite the occurrence of a long QT interval in these animals, their deaths are attributable at least in part to lack of sympathetic drive at the level of the sinus node (sinus pauses) and ventricle (asystole).
Very importantly, differences in the myocardial substrate of the sympathectomized animals persisted throughout the 5 months of the present study. This permitted comparison of the effects of unilateral sympathectomy in the present study with results of studies in the German shepherd model of lethal arrhythmias. In the German shepherds EAD and triggered activity occurred spontaneously in all left ventricular Purkinje fibers obtained from afflicted dogs but were never seen in Purkinje fibers isolated from the right ventricles of afflicted dogs or from either ventricle of unafflicted dogs [11,12]. In the present study, about 40% of left ventricular Purkinje fibers from stellectomized dogs displayed EAD and triggered activity, whereas EAD were not observed in the right ventricular Purkinje fibers from stellectomized dogs and in the Purkinje fibers from both ventricles of control dogs. Furthermore, -adrenergic stimulation with phenylephrine induced significantly greater APD prolongation in Purkinje fibers from afflicted as opposed to unafflicted German shepherds [11,12], and the same was true for left ventricular Purkinje fibers from stellectomized dogs. A similar pattern emerged with respect to incidence and magnitude of EAD. Hence, in Purkinje fibers, right sympathectomy produces changes completely consistent with those seen with the inherited arrhythmia.
With regard to myocardial tissue, afflicted German shepherds have longer APD than normal controls [16]. Similarly, in the present study, APD of myocardium of stellectomized dogs was longer than in controls. The largest difference was found in the anteroseptal region. That differences in APD are found in both models despite the fact that QT prolongation is not seen indicates that the in vitro environment, while permitting evolution of mechanistic factors in common does not replicate all conditions that contribute to the in vivo setting.
Isoproterenol significantly prolonged APD in the anteroseptal regions of afflicted German shepherds [12] and of right stellectomized dogs. Moreover, rapid pacing in the presence of isoproterenol induced DAD and triggered activity in myocardial tissue of afflicted German shepherd dogs [12] and stellectomized dogs. Hence, even at 5 months of age there are persistent abnormalities in the electrophysiology of stellectomized dogs that are consistent with German shepherds with lethal arrhythmias. This implicates the sympathetic nerves as long-term modulators of both the arrhythmogenic substrate (heterogeneity of repolarization) and triggers (EAD and DAD) for lethal arrhythmias. However, it should be emphasized that the stellectomized animals did not have arrhythmias or die at 4–5 months of age, a range in which the German shepherd model experiences pleomorphic ventricular tachycardias. Hence, there are critical differences in these models, likely involving aspects of substrate and trigger that have not yet been determined.
Although uncertainty remains about the mechanisms whereby reduced sympathetic input alters electrophysiological properties of cardiac tissues and creates arrhythmogenic substrates and triggers, the following should be taken into account: first, the interruption of sympathetic innervation can affect all components of the adrenergic receptor signaling cascade. For example, increased β-receptor density and β-adrenergic stimulation of adenylyl cyclase have been demonstrated in the anteroseptal left ventricle, which has reduced sympathetic innervation, in afflicted German shepherds [12]. As a result, the tissue responds in an exaggerated fashion to agonists, as might be seen with denervation supersensitivity [28]. Second, chronically reduced sympathetic innervation can inhibit the functional expression of repolarizing ionic currents and expression of adrenergic pathways to activate ionic channels in the ventricle [7,29], as noted above with respect to the transient outward potassium current (Ito).
With respect to ventricular tissue, β-adrenergic agonists can activate delayed rectifier potassium current (IK) [30] which shortens APD, and inward calcium current (ICa,L) [31] which elevates the plateau and prolongs duration. It has been shown that in neonatal heart prior to innervation, IK is unaffected by isoproterenol and ICa,L is increased by isoproterenol [29]. The fact that in the sympathectomized and control animals there is a uniform elevation in the plateau, while APD prolongs regionally in the sympathectomized animals only, is consistent with an action uniquely on ICa, here, and not IK. Hence, the absence of sympathetic innervation may delay or prevent expression of both IK channels and the β-adrenergic pathway that activates IK, such that β-receptor stimulation would increase APD in the anteroseptal (non-innervated) but not the posterobasal (innervated) left ventricle.
Another possible explanation for the effects of isoproterenol to prolong the anteroseptal APD of stellectomized animals would involve IKs. The explanation is based on several observations, as follows: (1) in both canine [32] and guinea pig [33] ventricles in which pharmacological blockade of IKs was induced, isoproterenol increased APD and induced DAD; (2) prolongation of repolarization with isoproterenol in the setting of IKs block was described in perfused canine myocardial wedge preparations [34]; (3) patients with the LQT1 variant of the congenital long QT syndrome manifested a long QT interval in response to isoproterenol [35]. These observations imply that a defect in evolution of IKs, possibly secondary to impaired or delayed sympathetic innervation, contributes to the repolarization abnormality in the stellectomized canine model. In fact, the roles of IKs and IKr in contributing to the substrate in this and the German shepherd model are currently being investigated.
In conclusion, right stellectomy in newborn mongrels induces long-term heterogeneous alterations of left ventricular electrophysiological properties. Twenty-two weeks after stellectomy, abnormal activity of Purkinje fibers and the responses of myocardial tissue to isoproterenol are similar to those observed in dogs of the same age with an inherited risk for sudden death. These results strongly implicate the sympathetic nerves as a source for evolution of the arrhythmogenic substrate.
Time for primary review 28 days.
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Acknowledgements |
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The authors express their gratitude to Dr. Natalia Egorova and to Sarah Mary-Rabine and Steven Friezema for assisting in the performance of the experiments. We thank as well Ms Eileen Franey for her careful attention to the preparation of the manuscript.
These studies were supported by USPHS-NHLBI grant HL-28958.
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