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1 Department of Medicine, University of Alberta, Edmonton, Canada2 Department of Medicine, University of Calgary, Calgary, Canada
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Abstract |
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0 level of repolarization (MAP90), 95.4 ± 8.9 ms) to apex and epicardium to endocardium (longest MAP90, 110.77 ± 10.6 ms). The peak of phase 0 of the epicardial base MAP correlated with the return to baseline of the initial and usually dominant waveform of the QRS and the onset of the second usually smaller wave, which clearly occurred in early repolarization, thus establishing where depolarization ended and repolarization began on the murine ECG. This second waveform was similar to the J wave seen in larger animals. Despite temporal and spatial electrophysiological similarities, a T wave is frequently not seen on a murine ECG. There are several determinants of T wave morphology, including transmural activation time, slope of phase 3 repolarization and differences in epicardial, endocardial and M cell APDs. Experimental manipulation of murine transmural gradients by shortening epicardial MAP90 to 84% of endocardial MAP90 the epicardial/endocardial ratio in larger mammals when a positive T wave is present, resulted in a positive murine T wave. Thus, manipulation of the transmural gradients such that they are similar to larger mammals can result in T waves with similar morphology.
(Received 26 August 2003;
accepted after revision 14 November 2003;
first published online 21 November 2003)
Corresponding author K. M. Kavanagh: 2C2.32 Walter Mackenzie Centre, University of Alberta, Edmonton, Alberta, Canada T6G 2B7. Email: katherine.kavanagh{at}ualberta.ca
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Introduction |
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0 level of repolarization (APD75) of approximately 15 ms and APD90 of 25–40 ms (Baker et al. 2000; Knollmann et al. 2001; London, 2001). As a consequence it was suggested that, unlike other species, depolarization in some parts of the murine heart occurred simultaneously with repolarization in other parts; and the QRS in the mouse, which in the literature ranged from 7 to 30 ms, corresponded not to a spread of depolarization but to both the spread of depolarization and early repolarization across the myocardium (Berul et al. 1996; Chu et al. 2001; Knollmann et al. 2001; London, 2001). As a consequence of these differences, the usefulness of the mouse model in the study of arrhythmias has been questioned. Optimal use of a genetically altered murine heart requires an understanding of basic in vivo murine cardiac electrophysiology which is influenced by such factors as the nervous system, circulating humoral factors, metabolism and mechanical stretch. The purpose of this study was to assess the in vivo temporal and spatial distribution of ventricular depolarization and repolarization in the murine heart and to determine if manipulation of transmural action potential durations would result in a discernable repolarization wave or T wave on the mouse ECG. |
Methods |
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All studies were carried out according to Canadian Council on Animal Care guidelines and approved by the institutional Health Sciences Animal Welfare Committee of the University of Alberta. Twenty-eight BALB/c mice were anaesthetized with 0.033 mg g-1 of sodium pentobarbital via intraperitoneal injection. Reflex activity was monitored throughout the study and supplemental intraperitoneal injections of sodium pentobarbital were given as needed to maintain surgical plane anaesthesia. At the end of the study a lethal dose of sodium pentobarbital was administered. Intubation was achieved via tracheotomy and placement of a 20 gauge intravenous winged catheter (Becton Dickinson, Sandy, UT, USA) into the trachea. The mice were mechanically ventilated with a rodent respirator (Model 687, Harvard Apparatus, St-Laurent, PQ, Canada) at 120 breaths per minute and a tidal volume of 0.8 ml. A warming light was used to maintain body temperature at 37°C. Once surgical plane was achieved the chest was opened via a midline sternotomy approach. The pericardial sac was incised to expose the heart, and the cavity was kept moist with 37°C physiological saline. Once the heart was exposed, two bipolar epicardial pacing electrodes were sutured onto the right atrium.
Pacing, ECG and MAP electrodes
ECG electrodes. Custom-designed Ag–AgCl electrodes were positioned on the sole of each foot.
Pacing electrodes. Epicardial pacing electrodes were gold Teflon-coated wires 0.003 inches in diameter (A-M Systems, Inc., Carlsborg, WA, USA).
Monophasic action potential electrodes. Ag–AgCl monophasic action potential electrodes included the 1.25 mm EPT MAP electrode catheter (EP Technologies, Boston Scientific, Ltd, Sunnyvale, CA, USA) as well as custom-designed 0.2 and 0.4 mm diameter Ag–AgCl MAP electrodes. Both the recording and reference electrodes were positioned in a 0.64 mm polyethylene tube. The recording electrode was centred in the tube and the reference electrode was positioned 1.8 mm proximal to the tip electrode to avoid simultaneous contact with the myocardium. To avoid DC drift, the MAP proximal and distal electrodes were shorted and soaked in saline for 30 min prior to experimental use. Both recording and ground electrodes were connected to an EP Technologies isolated DC-coupled MAP preamplifier (Boston Scientific Ltd, Sunnyvale, CA, USA). All MAP electrodes were calibrated in a saline bath using a square wave generated by a Hewlett Packard function generator (Model 3311A, Fotronic Corporation, Melrose, MA, USA) before use.
Signal acquisition
Standard five limb lead ECGs were simultaneously acquired from non-sedated mice by placing them in a custom-designed ECG recording chamber and positioning Ag–AgCl electrodes on the sole of each foot. The acquired signals were amplified at 0.5 mV cm-1 and filtered between 0.03 and 500 Hz using E for M ECG amplifiers (Torrance, CA, USA). MAP recordings were acquired from LV epicardial base and apex via the open chest cavity. Normal saline was dispensed into the pericardial cradle around the heart as a MAP reference electrode medium (as the chest cavity was not large enough to accommodate a saline-soaked sponge over the reference electrode). MAP recordings were acquired from LV endocardial apex via the left atrium. The flexible MAP electrodes were held in position using a micromanipulator to maintain continuous contact with the epicardium and endocardium. A DC-coupled MAP-preamplifier (Model 300, EP Technologies, Boston Scientific Ltd, Sunnyvale, CA, USA) with a gain of 100 was used to amplify the signal from the MAP recording electrode. A custom-designed computer acquisition program (Advanced Measurements, Calgary, AB, Canada) was used to acquire simultaneous ECG and MAP recordings. A calibration pulse of 5 mV was acquired at the beginning of each MAP acquisition. MAP recordings were considered stable if the baseline was constant and if the depolarization and repolarization phases were uniform throughout the experiment (30–60 min). To reduce the effect of respiratory motion the ventilator was briefly turned off during data acquisition.
Experimental protocols
MAP recordings were acquired simultaneously with ECG recordings. To eliminate rate-related variability, and in order to maximize the data collection from as many animals as possible, MAP recordings were always acquired during right atrial pacing at 400 beats min-1 (S1S1 pacing interval of 150 ms) with the exception of 10 mice that were paced to the shortest S1S1 interval that continued to have 1 : 1 atrioventricular (AV) conduction.
Ventricular effective refractory periods were determined at LV endocardial and epicardial sites by bipolar pacing at these sites at a basic cycle length of 150 ms and using the single extra stimulus (S2) technique and decrements of 2 ms.
In an attempt to shorten the epicardial action potential duration relative to the endocardial action potential duration, physiological and pharmacological interventions were undertaken. During the physiological intervention, the epicardial surface was progressively warmed by slowly dripping physiological saline at 39°C onto the surface of the heart and quickly suctioning it out of the chest cavity to prevent the endocardial surface from being equilibrated to the higher temperature. The pharmacological intervention involved dripping 37°C, 10 µmol pinacidil, an ATP-sensitive K+ channel (KATP) opener (Di Diego & Antzelevitch, 1993; Tang et al. 1999) onto the epicardial surface and quickly suctioning it out of the chest cavity to limit systemic effects. The vehicle (dimethyl sulfoxide (DMSO)) was similarly applied. During these procedures the hearts were paced at an S1S1 interval of 150 ms and epicardial and endocardial MAPs were recorded.
Data analysis
Ventricular depolarization and repolarization intervals on the surface ECG were compared with the time course of depolarization and repolarization as determined from MAP recordings obtained from the epicardium and endocardium during constant rate atrial pacing. The methodology used to analyse MAP recordings was similar to that used for other mammals (Franz, 1983, 1991; Franz et al. 1986; Tande et al. 1991; Yuan et al. 1994). MAP durations were measured from the steepest part of the MAP upstroke to the 30, 50, 70 and 90% level of repolarization. The total action potential amplitude was defined as the distance from the diastolic baseline to the crest of the plateau (not the peak of the upstroke). Five consecutive complexes were averaged for each measurement. The activation time (ms) was defined as the time from the earliest QRS deflection, in any ECG lead, to the fastest rise time of the MAP upstroke. The ventricular effective refractory period was defined as the longest S1S2 interval at twice the diastolic pacing threshold that failed to evoke a propagated response.
Statistical analysis
SigmaStat (SPSS Science, Chicago, IL, USA) was used to perform statistical analysis. Data are presented as mean ±S.D. unless otherwise indicated. Mean values were compared with ANOVA followed by post hoc Student's paired t test analysis whenever significance was indicated by the ANOVA analysis. A value of P < 0.05 was considered statistically significant.
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Monophasic action potential recordings were acquired using three different size MAP electrodes (1.25 mm, 0.4 mm and 0.2 mm). The recordings from all three catheters demonstrated similar morphological characteristics including a sharp upstroke (phase 0), a rapid downstroke (phase 1), a prominent plateau (phase 2), and then a gradual downslope (phase 3) to the diastolic plateau (phase 4). The 0.4 mm tip recording electrode was selected because of the combination of size and durability especially for endocardial recordings. Figure 2 shows simultaneous ECG and MAP recordings. The onset of the apical endocardial MAP occurred with the onset of the QRS and was earlier than the epicardial MAP (Fig. 2A). Both epicardial and endocardial MAPs had a plateau phase. The epicardial MAP had a spike and dome appearance and the onset of the plateau occurred earlier in the epicardial MAP. Figure 2B shows that the epicardial apex activated before the epicardial base. The peak of the upstroke of the epicardial base occurred with the return to baseline of the QRS and the onset of the J wave. The onset of the J wave correlated significantly with the peak of the epicardial MAP (r2= 0.71, P= 0.001; Fig. 2C). The end of the J wave correlated significantly with the onset of the endocardial MAP plateau (r2= 0.72, P= 0.001; Fig. 2D). The subtraction of the endocardial and epicardial MAPs at the interval from the peak of the epicardial MAP and the onset of the endocardial plateau resulted in a waveform that was very similar to the J wave of the ECG (Fig. 2A, inset). Thus the J wave clearly occurs during early repolarization. No obvious repolarization wave was seen on the ECG during phase 3 of repolarization of the MAPs.
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In some mice it was possible to decrementally pace at S1S1 intervals from 150 ms to 90–100 ms (600–660 beats min-1) with 1 : 1 AV conduction. A spike and dome plateau phase was still clearly present at faster rates (Fig. 4A). APD90 was significantly shorter at faster pacing rates (Fig. 4B). There was a trend for both phase 1 and phase 3 to have increased repolarization rates at the faster pacing intervals; however, only phase 1 (Fig. 4C) had a significant increase in the mean rate of repolarization at S1S1 interval of 90 ms as compared to the S1S1 pacing interval of 150 ms (2.6 ± 0.62 mV ms-1versus 1.3 ± 0.85 mV ms-1P= 0.034). Only three mice conducted 1 : 1 at the S1S1 90 ms interval.
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Progressive warming of the epicardial surface with 39°C saline was carried out in nine mice. This resulted in a shortening of the epicardial MAP90 by 15.6 ± 7.4 ms. It also resulted in a positive wave during phase 3 of repolarization similar to T waves seen in ECGs of larger mammals, including humans. Figure 5 shows a typical simultaneous epicardial MAP and ECG recording at baseline (A) and during warming of the epicardial surface (B and C). The MAP90 was shortened by 12.8 ms and a positive waveform was present on the ECG recording during phase 3 of MAP repolarization. There was no change in the endocardial MAP90 (104.4 ± 14.3 ms versus 105.0 ± 15.0).
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Comparison of MAP recordings
Accepted criteria for cardiac MAP recordings in both murine and larger mammals include: (i) stable MAP recordings with horizontal diastolic intervals and (ii) fast upstroke without a preceding undershoot. However, the recommended MAP criteria also differ between these two groups in a number of important features (Franz, 1983, 1991; Higuchi & Nakaya, 1984; Franz et al. 1986, 1990; Knollmann et al. 2001). In mice, it is recommended that amplitudes are measured from baseline to peak of the upstroke, and the 50% repolarization levels (MAP50) range between 3 and 11 ms. An inflection point below the 50% repolarization level is described but there is no plateau phase (Wickenden et al. 1999; Knollmann et al. 2001; Danik et al. 2002). In larger mammals there is a distinct plateau phase and the amplitude of MAP is defined as the distance from diastolic baseline to the crest of its plateau, not peak of upstroke as the upstroke of the MAP contains a biphasic notch (remnant of the intrinsic deflection) that cannot be reliably eliminated (Franz, 1983, 1991, 1999; Franz et al. 1986; Tande et al. 1991; Yuan et al. 1994). In the present study, similar morphology MAPs were obtained with three different recording catheters that ranged in size from 1.25 mm diameter, used in large animal models, to a custom-made MAP catheter with a 0.2 mm diameter contact electrode which was smaller than the one used by Knollmann et al. (2001). The catheter with a contact electrode diameter size of 0.4 mm was chosen for data acquisition because of its durability, especially for endocardial recordings. The mean amplitudes, assessed from baseline to peak of the upstroke, ranged from 14.6 mV (epicardial apex) to 22.4 mV (endocardial apex), as compared to baseline to peak mean amplitudes of 11 mV recorded by Knollmann et al. (2001). The mean baseline to plateau crest amplitudes in the present study ranged from 7.7 (epicardial apex) to 8.7 mV (epicardial base). These amplitudes (baseline to plateau crest) were less than the 10 mV amplitudes recorded from the ventricles of humans and dogs which are greater than 1000 times the size of a mouse heart (Yuan et al. 1994; Franz, 1999). The recording electrode was also about 30 times smaller than the one used in the larger mammals. With the exception of amplitude, the murine MAPs met all the criteria of larger mammals, therefore the analysis of action potential durations was performed as for larger mammal MAP analysis rather than developing special murine MAP criteria.
Short duration MAP recordings lacking a plateau have been accepted as typical of murine cardiac MAP recordings because of their close similarity to murine cardiac myocyte and transmembrane action potential (TAP) recordings. These recordings were confined to excised myocardial tissue preparations or single cell experiments (Wickenden et al. 1999; Baker et al. 2000; Knollmann et al. 2001; London, 2001). However, in vitro recordings may not be representative of in vivo recordings. In vivo electrophysiology, unlike in vitro electrophysiology, is influenced by such factors as the nervous system, circulating factors, metabolism, and mechanical stretch (DiFrancesco, 1995; Gillis et al. 1996; Shimoni, 1999; De Biasi, 2002; Shusterman et al. 2002; Stuyvers et al. 2002). Gillis et al. (1996) recorded longer monophasic action potential durations and ventricular effective refractory periods in blood-perfused working rabbit hearts compared to Langendorff-perfused hearts. Stuyvers et al. (2002) recently showed that physiological and electrophysiological parameters could be altered because of metabolic failure as stimulation rates increased, particularly in muscles thicker than 0.2 mm. Due to technical challenges, murine cellular action potentials have not been recorded in vivo to date.
Electrophysiology of the mouse heart versus other mammals
Structurally, the sinus node, AV node and His-Purkinje network are very similar in the hearts of mice and other mammals including humans (Rentschler et al. 2001). Additionally, many of the ionic channels and currents have been found to be present in both mice and larger mammals; however, the magnitude of these ionic currents have been demonstrated to be very different in the various species (Nerbonne, 2000; London, 2001; Pond & Nerbonne, 2001). In adult mice Ito is the major repolarization current with delayed rectifying current (IKr) and slowly activating delayed rectifier (IKs) having a diminished role, while in larger mammals IKr and IKs are the major repolarization currents (Nerbonne, 2000; Wang et al. 2000; London, 2001; Pond & Nerbonne, 2001). In the canine heart, which is approximately 5.5 mm thick, it required about 9.0 ms for excitation to travel from endocardium to epicardium (Higuchi & Nakaya, 1984). In the mouse, transmural excitation required 3.0 ms at the apex, which was 1.7 ± 0.3 mm thick. Thus the transmural conduction velocity in both canine and murine hearts was 0.6 mm ms-1. Larger mammalian hearts activated from endocardium to epicardium and from apex to base, and they repolarized from epicardium to endocardium and from base to apex (Burgess et al. 1972; Toyoshima et al. 1981; Higuchi & Nakaya, 1984; Yan & Antzelevitch, 1996; Antzelevitch et al. 1998; Yan & Antzelevitch, 1998). The present study indicated that the sequence of depolarization and repolarization in mice was qualitatively similar to most other mammals. There was also a negative correlation between activation time and action potential duration as in other mammals. The transmural differences in MAPs in this study suggested that there was a transmural gradient for Ito in the murine ventricle similar to other mammals. This finding was compatible with the recent findings of Kuo et al. (2001) who demonstrated differential expression of Ito across the murine ventricular wall. While the sequence of depolarization and repolarization is qualitatively similar in mouse and larger mammals there are important quantitative differences. Ito is such a dominant repolarization current in mouse that the plateau of the action potential duration is less distinct and it occurs at more negative potentials. Moreover, in humans and dogs Ito is a minor component in determining action potential duration and its directional influence is dependent on heart rate.
The murine ECG
Despite electrophysiological similarities, murine ECGs are markedly different from those of larger mammals and there is considerable controversy in the mouse as to where ventricular depolarization ends and where repolarization begins and ends (Koller et al. 1995; Rosen, 2000; London, 2001; Nuyens et al. 2001; Danik et al. 2002; Mohler et al. 2003).
The results of the present study showed that the onset of the QRS complex coincided with the onset of phase 0 of the endocardial MAP. The peak of phase 0 of the epicardial base MAP coincided with the return to baseline of the initial and usually dominant waveform of the QRS complex and the onset of the second usually smaller amplitude wave, which clearly occurred in early repolarization, thus establishing where depolarization ended and repolarization began on the murine ECG. In the murine literature this second ECG wave is referred to as a depolarization repolarization wave (London, 2001), a J wave (Rosen, 2000), a TRW wave (transiently repolarization wave) (Wang et al. 2000), a b wave (Danik et al. 2002), and a T wave (Kirchhoff et al. 1998; Mohler et al. 2003). This second wave, referred to as the J wave in this study, clearly occurred during early repolarization and was very similar in appearance and timing to the ‘late delta wave’ or small secondary R wave (R') seen in humans and larger mammals in which it is referred to as a J wave. As in larger mammals, it is most likely the result of the transmural voltage gradient that results from the transmural variation in the Ito gradient (Yan & Antzelevitch, 1996).
In larger mammals including humans, the T wave is a late repolarization phenomenon. The polarity of this wave is determined predominantly by transmural gradients that occur as a consequence of transmural activation times and differences in the action potential durations of cells in the epicardium, M region and endocardium (Higuchi & Nakaya, 1984; Franz et al. 1987, 1991; Liu & Antzelevitch, 1995; Yan & Antzelevitch, 1998; Yan et al. 1998). Differences in action potential durations are determined by rates of phase 3 repolarization. This phase of repolarization is governed by the properties of the particular ion channels and currents that are active in the myocytes in the various myocardial regions during this time period (Litovsky & Antzelevitch, 1988; Liu & Antzelevitch, 1995; Yan & Antzelevitch, 1998; Yan et al. 1998). Phase 3 repolarization is also governed by electrotonic coupling of myocytes which results in electrical gradients between the various myocardial regions (Toyoshima et al. 1981; Yan & Antzelevitch, 1998; Yan et al. 1998). The action potential of M cells is significantly longer than that of either epicardial or endocardial myocytes because of a reduced IKs current and a larger late sodium current. In humans and larger mammals it is the vector summation of opposing currents flowing down voltage gradients on either side of the M region that determines the morphology of the T wave (Yan & Antzelevitch, 1998; Yan et al. 1998). The lack of a distinct repolarization wave or T wave in the mouse despite similarities in temporal and spatial repolarization properties suggests that repolarization gradients and hence vectors are different in mice. The difference in the repolarization gradients may relate to species differences in repolarization currents. Ito is the dominant repolarization current in the mouse heart, whereas IKr and IKs are the dominant repolarization currents in dog and man (Yan & Antzelevitch, 1998; Yan et al. 1998; Guo et al. 1999; Wang et al. 2000; Nerbonne et al. 2001). To date it is not known if an M region exists in the murine myocardium. In the canine model, Higuchi & Nakaya (1984) demonstrated that by manipulating the difference in action potential durations between epicardium and endocardium he was able to affect the polarity of the T wave. The T wave was negative when the endocardial action potential was 14 ms longer than the epicardial action potential, isoelectric when the difference was 30 ms and positive when the difference was 48 ms. Assuming a similar relation between the murine and canine models, an endocardium to epicardium MAP90 difference of at least 16 ms would be required for a positive T wave. A negative T wave would require an endocardium to epicardium difference of 5 ms and an isoelectric T wave a difference of approximately 10 ms. The difference between MAP90 endocardium and MAP90 epicardium in this study was 8.2 ms. Additionally in the Higuchi & Nakaya study when the T wave was isoelectric, the ratio of MAP90 epicardium to endocardium in dogs was approximately 93%, which was identical to the MAP90 epicardium to endocardium ratio at the murine apex in the present study when isoelectric T waves were also seen. Positive T waves were seen in the canine model when the epicardial MAP90 was shortened to 84% of endocardial MAP90. This suggested that the epicardial MAP90 of the mouse heart would have to shorten by approximately 10 ms for a positive T wave to occur. When the epicardial MAP90 was shortened, by an average of 15.6 ± 7.4 ms with epicardial warming and 12.8 ± 9.3 ms with epicardial application of pinacidil, a positive T wave similar to that of larger mammals was observed. Thus manipulation of murine transmural repolarization gradients to resemble those of larger mammals yields similar results in the murine model.
Limitations
BALB/c mice, which are one of the three most common strains used in transgenic experiments, were used in this study. Interstrain differences can impact electrophysiological parameters in mice (Shusterman et al. 2002); however, the lack of a distinct repolarization wave in non-sedated mice has been documented in numerous other species (Xu et al. 1999a; Rosen, 2000; Mohler et al. 2003). Sedation was required in this study as this was an in vivo open chest procedure. It has been previously documented that sodium pentobarbital can have an effect on ion channels (Nattel et al. 1990; Bachmann et al. 2002). However, this anaesthetic agent is commonly used during electrophysiological studies in animals, including mice (Toyoshima et al. 1981; Levine et al. 1986; Tande et al. 1991; Berul et al. 1996; Danik et al. 2002). ECGs in sedated and anaesthetized mice were compared and were virtually identical under both conditions. Certainly in the open chest mechanically ventilated mouse, the respiratory cycle can change the position of the heart with respect to the ECG recording leads thus affecting recorded signals and baseline stability. Noise artefact is often a problem with such preparations. Every effort was made to record signals during the same phase of the respiratory cycle and to keep the surface of the heart moist and at 37°C. Unfortunately, at the present time, there is no way of recording epicardial monophasic action potentials other than using an open chest procedure. There are also inherent problems with monophasic action potential recordings. Compared with transmembrane action potential recordings monophasic action potential recordings cannot provide information on resting membrane potentials, action potential amplitude or upstroke velocity (Franz, 1991; Yuan et al. 1994). Comparison of relative MAP amplitudes is also questionable because of the short-circuiting of conductance between the recording and the indifferent electrode. Conductance may vary even within an individual action potential because of motion artefacts caused by the beating heart. Systolic contraction and diastolic relaxation may increase or decrease the contact pressure of the monophasic action potential catheter. However, monophasic action potential recordings have been extensively used in in vivo preparations and are the only method of simultaneously recording action potential durations from the epicardium and endocardium. MAP recordings do provide precise information regarding local activation and repolarization (Franz, 1991; Yuan et al. 1994). The pacing rate of 400 beats min-1 that was used in this study was slower than the non-sedated sinus rates of 600–700 beats min-1. This rate was chosen in order to ensure atrial pacing with 1 : 1 conduction through the AV node. In animals that could tolerate higher pacing rates with 1 : 1 AV node conduction the MAP recordings demonstrated the same morphology with a distinct plateau phase.
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0.001). D, the correlation between the end of the J wave on the ECG and the onset of the endocardial MAP plateau (r2= 0.72, P
