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Dipartimento di Biologia Evolutiva e Funzionale-Sezione Fisiologia, Parco Area delle Scienze 11 A, 43100, Parma, Italy
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(Received 2 January 2004;
accepted after revision 23 March 2004; first published online 1 April 2004)
Corresponding author D. Stilli: Dipartimento di Biologia Evolutiva e Funzionale-Sezione Fisiologia, Parco Area delle Scienze 11 A, 43100, Parma, Italy. Email: stilli{at}biol.unipr.it
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Introduction |
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Changes in basic dispersion in the recovery of excitability in the heart have long been associated with the occurrence of severe ventricular arrhythmias, such as high-grade ventricular ectopy, ventricular tachycardia and ventricular fibrillation. Reentrant excitation and triggered activity from early (EAD) and delayed after depolarizations (DAD) are recognized as common mechanisms underlying ventricular tachyarrhythmias due to increased dispersion of repolarization (Tamargo et al. 1975; Amlie et al. 1985; Amlie, 1997; Kurz et al. 1993; Qin et al. 1996; Pastore & Rosenbaum, 2000; Antzelevitch & Fish, 2001; Yan et al. 2001a,b; Akar et al. 2002; Nerbonne & Guo, 2002; Akar & Rosenbaum, 2003). Important factors that alter the physiological dispersion of APD in the intact heart, with potentially arrhythmogenic effects, include various heart conditions such as myocardial ischaemia, infarction and hypertrophy (Qin et al. 1996; Amlie, 1997; Shipsey et al. 1997; Antzelevitch et al. 1999; Akar et al. 2000; Batur et al. 2000; Burton & Cobbe, 2001; Yan et al. 2001a; Li et al. 2002; Nerbonne & Guo, 2002; Akar & Rosenbaum 2003), sympathetic activation (Du & Dart, 1999; Pugsley et al. 1999; Obreztchikova et al. 2003), diabetes (Komukai et al. 2002), different kinds of anaesthesia and a number of pharmacological treatments (Balati et al. 1999; Merot et al. 1999; Weissenburger et al. 2000; Henderson et al. 2001). However in most heart diseases, in addition to the increased dispersion of repolarization, other morpho-functional alterations can contribute to arrhythmia development, including an increase in interstitial tissue with possible impairment of intercellular coupling. This may result in possible impairment of intercellular coupling, fibrosis, changes in gap junction expression or anisotropy, and alterations of calcium handling per se, or secondary to APD prolongation (Peters & Wit, 1998; Aimond et al. 1999; Armoundas et al. 2001; Viatchenko-Karpinski et al. 2004).
There is clinical and experimental evidence indicating that, under specific conditions such as emotional stimuli or exercise training, ventricular ectopy or more complex arrhythmic events can also occur in subjects without cardiac structural abnormalities or systemic disorders (Verrier & Lown, 1984; Sgoifo et al. 1999; Priori et al. 2002; Hart, 2003; Viatchenko-Karpinski et al. 2004). Although it has been suggested that ventricular arrhythmias can be the consequence of an altered dispersion of repolarization in trained normal subjects with a mild form of exercise-induced cardiac hypertrophy (Hart, 2003), the relationship between intrinsic spatial dispersion of APD and ventricular arrhythmogenesis, in the absence of definite myocardial morpho-functional alterations, is not yet completely understood.
In the present study we tested the hypothesis that, in the normal heart, particular myocyte electrophysiological properties relating to intrinsic APD heterogeneity may provide a substrate favouring arrhythmia development. To this end, in a normal rat model, we analysed the relationship between incidence of arrhythmias occurring in healthy, freely moving rats chronically instrumented with a telemetry ECG system and intrinsic APD heterogeneity as measured in ventricular myocytes isolated from the same animals. Arrhythmias were naturally triggered by exposing the animals to an acute social challenge (social stress) (Martinez et al. 1998; Sgoifo et al. 1999) which is known to consistently induce an intense activation of the autonomic nervous system, with a shift of the sympatho-vagal balance towards a sympathetic predominance, affecting the threshold for cardiac electrical instability and resulting in arrhythmias even in normal animals (Martinez et al. 1998; Sgoifo et al. 1999). In the ischaemic canine intact heart, it has been demonstrated that adrenergic stimulation can induce EADs and enhance the inhomogeneity of repolarization (Zhang et al. 2002). In addition, studies performed on isolated normal ventricular myocytes have shown that adrenergic stimulation results in a dose-dependent prolongation of APD and induces EADs and DADs, suggesting a possible pathway for arrhythmogenesis following adrenergic stimulation in the intact heart (Priori & Corr, 1990).
The approach used in the present study, from the in vivo towards the cellular level, has never been adopted before to evaluate the arrhythmogenic action of dispersion of repolarization. The use of stress stimuli belonging to the everyday life of social animals to trigger arrhythmias via a natural activation constitutes an additional strength of the study.
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Methods |
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Animals and housing
The study population consisted of 29 6-month-old male Wistar rats (Rattus norvegicus), weighing 445 ± 11 g (mean ±S.E.M.), kept in unisexual groups of four individuals from weaning (1 month after birth) until the onset of the experiments, in a temperature-controlled room at 20–24 °C, with the light on between 7.00 h and 19.00 h. The bedding of the cages consisted of wood shavings, and food and water were freely available.
Chronic instrumentation for telemetry ECG recording
Each animal, at 6 months of age, was chronically instrumented with a miniaturized transmitter for telemetry ECG recording (model TA11CTA-F40, Data Sciences, St Paul, MN). The details of the surgical procedure have been published (Sgoifo et al. 1996b). Briefly, each animal was anaesthetized with droperidol plus fentanyl citrate (Leptofen, Pharmacia & Upjohn, Milan, Italy; 0.6 ml kg–1, I.M.). The body of the transmitter was placed in the abdominal cavity; one recording lead was fixed to the dorsal aspect of the xiphoid process, close to the apex of the heart, the other lead was located in the anterior mediastinum, close to the right atrium. After surgery, all animals were given antibiotic therapy with gentamicine sulphate (Aagent, Fatro, Milan, Italy; 0.2 ml kg–1, I.M.) for 3 days and individually housed for 3 weeks.
Social stress and ECG data acquisition and processing
All experimental sessions were performed during the light phase between 9.00 h and 13.00 h. As previously described (Sgoifo et al. 1996a), the social stress procedure consisted of introducing the instrumented animal (intruder) into the territory of an unfamiliar conspecific male (resident) belonging to an aggressive wild strain of rats (Rattus norvegicus, Wild Type Groningen, WTG) (resident–intruder test). High levels of aggression by the resident animal were achieved and maintained by cohabitation with a female and a training procedure performed in the 2 weeks preceding the intruder test. During the test, not only were the intruders threatened, but they also received biting attacks and finally displayed clear submissive postures (social defeat) (Sgoifo et al. 1996b).
Three successive 15-min telemetry ECG recordings were performed while the instrumented animal was, respectively: (i) left alone and undisturbed in its home cage (baseline conditions); (ii) exposed to the stress procedure (social stress); and (iii) back in its own home cage (recovery from stress). At each recording session, the telemetry ECG receiver (model CTR85-SA, Data Sciences) was placed under the experimental cage. The ECGs, provided as analog signals at the output of the receiver, were continuously monitored on an oscilloscope and simultaneously routed to a personal computer via an analog-to-digital conversion board (12 bits, 1000 Hz sampling rate). A real-time acquisition program allowed the digital data to be continuously recorded and stored on hard disk for off-line processing. The data were then analysed by using a software package developed by our group for measuring the average R–R intervals and interactively detecting ventricular rhythm disturbances during baseline, social stress and recovery periods.
Cellular electrophysiological studies
Within 1 week of ECG recording, each rat was anaesthetized with ether and killed by decapitation, the heart was rapidly excised, and single left ventricular myocytes were isolated, in accordance with a previously published procedure (Zaniboni et al. 2000). Briefly, the rat heart was removed and rapidly perfused at 37 °C by means of an aortic cannula with the following solutions (see below): a calcium-free solution for 5 min to remove the blood; a low calcium solution (0.1 mM) plus 1 mg ml–1 type 2 collagenase (Sigma, Milan, Italy) and 0.1 mg ml–1 type XIV protease (Sigma), for 20 min; an enzyme-free low calcium solution for 5 min. The left ventricle was then minced and shaken for 10 min in the low calcium solution. Myocytes were stored at room temperature in the control solution (see below). All experiments were performed within 8 h after isolation. All myocytes used in this study had well-defined striations and did not spontaneously contract.
Solutions. The isolation solution contained (mM): NaCl 126, dextrose 22, MgCl2 5.0, KCl 4.4, taurine 20, creatine 5, sodium pyruvate 5, NaH2PO4 1 and Hepes 24; pH adjusted to 7.4 with NaOH and equilibrated with 100% O2. Control solution for cell perfusion contained (mM): NaCl 126, dextrose 11, KCl 5.4, MgCl21.0, CaCl21.08 and Hepes 24; pH adjusted to 7.4 with NaOH. Normal pipette filling solution contained (mM): KCl 113, NaCl 10, dextrose 5.5, K2ATP 5, MgCl20.5 and Hepes 10; pH adjusted to 7.1 with KOH. The temperature of the solution in the cell bath was 36 ± 0.2 °C.
Electrophysiological methods and data analysis.
Suction pipettes were made from borosilicate capillary tubing (Harvard Apparatus, Edenbridge, UK) with an access resistance of 2–4 M
when filled. Transmembrane potential (Vm) was measured in whole-cell configuration using an Axoclamp 2B amplifier (Axon Instruments, Foster City, CA). Membrane capacitance (Cm) was derived by applying small hyperpolarizing constant current pulses (200-ms duration) and measuring the resulting membrane potential deflections.
Action potentials were elicited by means of brief (2–3 ms) depolarizing constant current pulses (
50% above current threshold) delivered via the suction pipette at a pacing rate of 5 Hz to approximate the baseline sinus rhythm in conscious rats. Signals were sampled at 2.5–5 kHz. After allowing repolarization to reach a steady-state configuration (usually within a few beats), 10 consecutive action potentials were recorded and automatically averaged. In addition, before and after 5 Hz measurements, sequences of action potentials elicited at 1 Hz were recorded and compared in order to verify that no irreversible changes had occurred in the action potential profile, due to the high pacing frequency.
For each action potential, APDn was calculated as the time between the maximum peak of dVm/dt and the time at which repolarizing Vm reached a given n value. Specifically, action potential duration was measured at –20 mV (APD-20 mV), –30 mV (APD-30 mV), –40 mV (APD-40 mV), –50 mV (APD-50 mV) and –60 mV (APD-60 mV).
In addition, at the same five potential values, the difference between the longest and the shortest action potential recorded in each animal was computed as an index of individual APD heterogeneity (APDh-20 mV, APDh-30 mV, APDh-40 mV, APDh-50 mV and APDh-60 mV) (Burton & Cobbe, 2001).
Statistical analysis
The SPSS statistical package was used (SPSS, Chicago, IL). Normal distribution of variables was checked by means of the Kolmogorov-Smirnov test. Statistics of variables normally distributed (all variables except the number of ventricular arrhythmias during baseline and recovery periods) included: means ±S.E.M., unpaired Student's t test, one-way analysis of variance (post hoc analysis: Games-Howell test), and linear correlation analysis. Non-parametric statistical analysis was used (Friedman test and Wilcoxon test) to compare data relating to the incidence of arrhythmias during baseline, social stress and recovery periods. Statistical significance was set at P < 0.05.
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Results |
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In all intruder rats, the exposure to the social challenge provoked a pronounced decrease in the mean R–R interval as compared with baseline conditions (approximately –30%, P < 0.01) followed by a partial recovery during the post-stress period (–20% compared to baseline values, P < 0.01) (Fig. 1).
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Average values of membrane capacitance (Cm) and resting potential (Vm) were 152 ± 5.2 pF and –72 ± 0.3 mV, respectively, (total number of cells n= 149).
According to previous data (Shipsey et al. 1997), recorded action potentials could be ascribed to three main types of waveforms, as shown in Fig. 3. Specifically, following the upstroke, the three action potential configurations, recorded at the pacing frequency of 5 Hz, were characterized by: (a) brief early and late repolarization phases, without a well defined plateau (13% of the recorded action potentials, Fig. 3a); (b) relatively short early repolarization phase, a clearly detectable plateau and a relatively long late repolarization phase (53%, Fig. 3b); or (c) relatively long early and late repolarization phases (34%, Fig. 3c).
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Discussion |
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The intrinsic higher APD heterogeneity found in rats prone to sympathetic-induced ventricular arrhythmias might be due to accentuated regional differences in the expression and/or properties of some ion channel or regulatory proteins involved in the recovery of excitability. These changes might create a substrate with electrophysiological properties at the border of the normal range, leading to arrhythmia vulnerability under specific conditions, such as sympathetic activation. Indeed, sympathetic stimulation can further increase the transmural dispersion of repolarization in more than one way. The dose-dependent effects of catecholamines on ventricular APD observed in isolated normal ventricular myocytes (Priori & Corr, 1990) may have important implications in the intact heart, due to the possibility that different concentrations of noradrenaline (norepinephrine) are simultaneously present at the receptor level in different regions of the myocardium, mainly as a consequence of the non-uniform innervation, thus contributing to inhomogeneity of repolarization. In addition, sympathetic activation induces APD changes by affecting cellular electrophysiological properties (Bers, 2001) which are not homogeneously distributed in the different layers of the ventricular myocardium (Clark et al. 1993; Volk et al. 1999; Nerbonne & Guo, 2002). Finally, experimental studies in intact hearts have demonstrated that sympathetic stimulation does increase the transmural dispersion of repolarization (Zhang et al. 2002). In these conditions, a potential mechanism underlying an isolated premature beat is the occurrence of an EAD generated in myocardial regions with longer APDs capable of inducing a new action potential in myocardial areas with shorter APDs (Yan et al. 2001a,b; Li et al. 2002). As an alternative, it has been proposed that the marked spatial inhomogeneity of APDs may contribute to enhance the disparities in the voltage level between closely adjacent regions such that an already depolarized region produces a premature activation in the neighbouring polarized cells (Priori & Corr, 1990). The increase in heart rate during social stress can also contribute to arrhythmogenesis by affecting APD heterogeneity. It has been demonstrated that in rat ventricular myocytes, unlike other species (Ravens & Wettwer, 1998), the increase in heart rate leads to an average prolongation of APD that is not homogeneous in the different myocardial layers (Shigematsu et al. 1997; Fauconnier et al. 2003).
The increased incidence of ventricular arrhythmias and the associated increased heart rate during exposure to social stress could be reasonably attributed to the sympathetic activation. This is in agreement with previous studies performed on different rat models, with and without heart diseases, showing that social challenges induce a significant activation of the sympathetic adrenomedullary system and the hypothalamo-pituitary-adrenocortical axis, as measured by means of plasma catecholamine and corticosterone concentrations, respectively (Sgoifo et al. 1996a).
Action potentials were elicited in isolated ventricular myocytes at a relatively high pacing rate (5 Hz) in order to approximate the baseline sinus rhythm usually observed in the rat. In several mammalian species, marked spatial APD differences have been described within the left ventricle mainly reflecting the differential expression of multiple types of voltage-gated K+ channels (Watanabe et al. 1983; Antzelevitch et al. 1991, 1998; Clark et al. 1993; Shipsey et al. 1997; Li et al. 1998; Volk et al. 1999; Stankovicova et al. 2000; Antzelevitch & Fish, 2001; Burton & Cobbe, 2001; Volk et al. 2001; Nerbonne & Guo, 2002). Specifically, in the rat left ventricle, regional differences in transient outward K+ current (Ito) density are generally considered to be the most important ionic mechanism responsible for heterogeneity of APD (Clark et al. 1993; Volk et al. 1999). We emphasize here that we did not isolate cardiomyocytes specifically from different regions of the ventricular wall, but from the entire left ventricle. Nevertheless, different action potential waveforms could be clearly recognized similar to those previously described in normal rats, indicating that in the cell population under study (149 in number) each of the three main action potential subforms described in the literature (subendocardial, mid-myocardial and subepicardial types) were largely represented (Shipsey et al. 1997; Volk et al. 1999, 2001).
A degree of non-uniformity in ventricular recovery properties resulting in spatial dispersion of APD is physiological and plays an important role in the maintenance of normal ventricular recovery gradient and electrical stability of ventricular myocardium in healthy hearts (Burton & Cobbe, 2001). On the other hand, it is well established that myocardial remodelling associated with various heart diseases can contribute to the modification of APD heterogeneity, with potentially arrhythmogenic effects (Kurz et al. 1993; Qin et al. 1996; Amlie, 1997; Gomez et al. 1997; Shipsey et al. 1997; Aimond et al. 1999; Antzelevitch et al. 1999; Bryant et al. 1999; Akar et al. 2000; Batur et al. 2000; Burton & Cobbe, 2001; Yan et al. 2001a; Kaprielian et al. 2002; Li et al. 2002; Nerbonne & Guo, 2002; Akar, 2003). The data reported in the present study indicate that vulnerability to ventricular arrhythmias triggered by social stress is higher in animals with a normal myocardial substrate but exhibiting longer average APD associated with larger potential gradients throughout repolarization resulting from marked intrinsic APD dispersion. The presence of a normal myocardial substrate is supported by the behaviour of ECG parameters in baseline conditions and previous ECG and morphological data obtained by our group in the same normal rat model (Stilli et al. 2001). Theoretically, the large APD heterogeneity could be either an intrinsic characteristic of animals prone to stress-induced arrhythmias or the effect of the exposure to the social stress itself. However, the first hypothesis is supported by the fact that APD measurements obtained in the present study are comparable with those reported in previous studies on normal unstressed rats of the same strain (Shipsey et al. 1997).
We cannot provide a definite explanation of the mechanism triggering arrhythmias during social stress, as we did not directly analyse the specific action of autonomic stimulation on the different action potential waveforms. However, as mentioned above, it is conceivable that the increased sympathetic activity induced by social stress, acting on a myocardium with a particularly large APD heterogeneity, further emphasizes the spatial dispersion of APDs favouring abnormal impulse initiation, consequent to increased local potential gradients or occurrence of afterdepolarizations (Priori & Corr, 1990; Spear & Moore, 2000; Viswanathan & Rudy, 2000; Yan et al. 2001a,b; Zhang et al. 2002, Obreztchikova et al. 2003). It is not surprising that in the normal rat population reported here, this focal ectopic activity does not initiate more complex ventricular tachyarrhythmias due to the absence of morpho-functional myocardial alterations.
In conclusion, in the present study we showed that in normal hearts a large intrinsic APD heterogeneity, resulting from particular electrophysiological properties of isolated ventricular myocytes, is not in itself arrhythmogenic, but can predispose towards arrhythmia development under specific conditions. These data are clinically relevant and warrant further investigations on the molecular bases underlying a particularly large repolarization heterogeneity in normal hearts. This approach from ‘in vivo’ to the molecular level may be suitable to achieve genotype–phenotype correlation data and identify a genetic predisposition to ventricular arrhythmias.
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significant differences compared with SS (one-way analysis of variance, post hoc analysis: Games-Howell test).
