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Am J Physiol Cell Physiol 278: C73-C80, 2000;
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Vol. 278, Issue 1, C73-C80, January 2000

Age-dependent response of the electrocardiogram to K+ channel blockers in mice

Li Wang, Shauni Swirp, and Henry Duff

Department of Medicine, University of Calgary, Calgary, Alberta, Canada T2N 4N1


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Developmental changes in electrocardiogram (ECG) and response to selective K+ channel blockers were assessed in conscious, unsedated neonatal (days 1, 7, 14) and adult male mice (>60 days of age). Mean sinus R-R interval decreased from 120 ± 3 ms in day 1 to 110 ± 3 ms in day 7, 97 ± 3 ms in day 14, and 81 ± 1 ms in adult mice (P < 0.001 by ANOVA; all 3 groups different from day 1). In parallel, the mean P-R interval progressively decreased during development. Similarly, the mean Q-T interval decreased from 62 ± 2 ms in day 1 to 50 ± 2 ms in day 7, 47 ± 8 ms in day 14 neonatal mice, and 46 ± 2 ms in adult mice (P < 0.001 by ANOVA; all 3 groups are significantly different from day 1). Q-Tc was calculated as Q-T/<RAD><RCD>R-R</RCD></RAD> interval. Q-Tc significantly shortened from 179 ± 4 ms in day 1 to 149 ± 5 ms in day 7 mice (P < 0.001). In addition, the J junction-S-T segment elevation observed in day 1 neonatal mice resolved by day 14. Dofetilide (0.5 mg/kg), the selective blocker of the rapid component of the delayed rectifier (IKr) abolished S-T segment elevation and prolonged Q-T and Q-Tc intervals in day 1 neonates but not in adult mice. In contrast, 4-aminopyridine (4-AP, 2.5 mg/kg) had no effect on day 1 neonates but in adults prolonged Q-T and Q-Tc intervals and specifically decreased the amplitude of a transiently repolarizing wave, which appears as an r' wave at the end of the apparent QRS in adult mice. In conclusion, ECG intervals and configuration change during normal postnatal development in the mouse. K+ channel blockers affect the mouse ECG differently depending on age. These data are consistent with the previous findings that the dofetilide-sensitive IKr is dominant in day 1 mice, whereas 4-AP-sensitive currents, the transiently repolarizing K+ current, and the rapidly activating, slowly inactivating K+ current are the dominant K+ currents in adult mice. This study provides background information useful for assessing abnormal development in transgenic mice.

mouse heart; development


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

PREVIOUS STUDIES have reviewed the electrocardiographic effects of dominant-negative functional knockouts of the mouse Kv4, Kv1.5, and human ether-a-go-go-related gene (HERG) K+ channel genes (1, 2, 13). The Kv4 functional knockout caused a decrease in the transiently repolarizing K+ current (Ito) (2), whereas the Kv1.5 functional knockout decreased the rapidly activating, slowly inactivating K+ current (Islow) (13). Both of these functional knockouts prolonged action potential duration (APD) and the Q-T interval in adult mice (2, 13). However, the HERG functional knockout did not prolong APD nor the Q-T interval in adult mice (1). These data indicate that the Kv4 and Kv1.5 K+ currents contribute substantially to repolarization in adult mice, whereas HERG K+ current does not. These data are also in keeping with previous in vitro studies, indicating that Ito and Islow are the dominant repolarizing K+ currents in adult mice, whereas the delayed rectifying K+ current (IKr) does not substantially contribute to repolarization in adult mice (20, 21). However, IKr is the dominant repolarizing K+ current in late fetal and early neonatal mice (19, 21). Thus we hypothesized that developmental changes in the densities and character of K+ currents could alter the surface electrocardiogram (ECG) characteristics of the mouse heart. Although previous studies have reported the character of the developmental changes in ECGs in rat (6), no previous study has examined the character of the developmental changes in mouse ECGs. Because the pattern of expression of various K+ channels varies even among closely related species, such as the mouse and rat, and because recombinant mice are being widely used to study structure-function relationships, the developmental changes in the mouse ECG and its response to pharmacological agents were assessed. These electrocardiographic data contribute information for detecting and understanding the alteration of ECGs in transgenic mice with ionic channel defects.


    METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

FVB mice at the following developmental stages were evaluated: days 1, 7, and 14 neonatal and male adults >60 days old. The mice were handled in accordance with our institutional guidelines for animal use in research. The mice were fed a standard rodent chow.

Recording ECGs. Previous studies have reported the character of ECGs in adult conscious, unsedated mice instrumented with a telemetry devise (15). However, implantation of the currently available telemetry devise in day 1 neonatal mice is not feasible because of its mass. Accordingly a method was devised to record ECGs in conscious, unsedated neonatal (1, 7, and 14 days old) and adult mice. Unsedated conscious mice were placed in a custom-designed restraining tube. Multiple perforations were cut in the tube so that the forelimbs and the hindlimbs would protrude through the perforations. The limbs were coated with electrocardiographic gel and electrodes were placed on the surface of the skin. Three standard leads of ECG were recorded using CV Soft (Calgary, Canada). To minimize stress, mice were accustomed to the restrainer by placing them in the restrainer for at least 15 min before obtaining the ECG. Because body temperature of day 1 neonatal mice drops rapidly toward ambient temperature, ECGs were recorded both at room temperature and in an Isolatte Infant Incubator (Healthdyne, Hatboro, PA). Thus ECG from all age groups could be recorded at a body temperature of 37°C. Measurements included sinus cycle length (R-R interval), P-R interval, and Q-T interval. The end of the T wave was measured as time when the repolarization process returns to the isoelectric point. The isoelectric point was defined as the position between the end of the P wave and the beginning of the QRS (5). The definition of the isoelectric point in this study is compatible with that used in human electrocardiography (5). Similarly, Mitchell et al. (15) assigned the end of the T wave as the isoelectric point, which follows a terminal negative T wave vector in the surface ECGs of mice. The Q-Tc interval was calculated as the Q-T/<RAD><RCD>R-R</RCD></RAD> interval (seconds). The P-R interval was defined as the interval from the beginning of the P wave to the onset of the QRS.

Statistics. All data are presented as means ± SE. Statistical significance among groups was determined using one-way ANOVA. P < 0.05 was considered significantly different. To define the difference between the subgroups compared within ANOVA, such as day 1 neonatal group vs. adult group, the Dunnett's multiple range test was used. All subgroups were compared.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Validation of measurements. One investigator made all initial electrocardiographic measurements. This investigator was blinded to the developmental stage of the ECG. Another investigator checked the validity of each measurement, and any measurement discrepancies were corrected by consensus.

To assess intraobserver variability, three sets of records from each developmental stage were measured on two separate occasions separated from each other by at least 48 h. The intraobserver variability was 2.3%.

Effect of temperature on age-dependent changes in ECGs. Figure 1A illustrates representative ECG leads I, II, and III recorded from conscious nonsedated day 1 neonatal mice at room temperature. We noted that the core body temperature of day 1 neonates progressively decreased when the neonatal mouse was separated from siblings and the maternal mouse and exposed to room temperature. In contrast, the body temperature of adult mice remained constantly at 37°C. Thus observed ECG difference between day 1 and adult mice may be simply due to temperature effect but not age. Therefore in all subsequent experiments neonatal mice were placed in an infant incubator set to control neonatal body temperature to 36.5 ± 0.5°C. Figure 1, B and C, displays the representative ECGs of day 1 neonatal mice recorded at a body temperature of approximately 37°C and adult mice, respectively.


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  		Fig. 1.   Representative electrocardiograms (ECGs) in leads I, II, and III recorded from conscious 1-day-old and adult mice at room temperature (RT) and 37°C. In day 1 neonates heart rate was 208 beats/min at room temperature (A) but increased to 432 beats/min with a significant shortening of P-R, R-R, and Q-T intervals at 37°C (B). However, changing body temperature did not alter configuration of day 1 neonatal ECGs (B), which was distinguished from adult mouse ECGs (C) in many aspects as described in text.

Progressive age-dependent changes in mouse ECGs. Figure 2A illustrates developmental changes in ECGs in lead I recorded at four developmental stages: neonatal days 1, 7, and 14 and adult mice, and the arrows indicate the end of the T waves for each example measurement. Progressive changes in the configuration of the J junction-S-T segment-T wave complex are shown in the boxes in Fig. 2A. Elevation of the J junction and the plateau portion of the S-T segment was observed in day 1 mice. The entire J junction-S-T segment-T wave complex shortens during development. In addition the elevation of the plateau portion of the S-T segment-T wave complex seen in day 1 animals resolves by day 14. In adult mice much of the repolarization process is truncated to a large transient repolarizing wave (TRW), which appears as an r' wave at the end of the apparent QRS. The TRW is evident in ECGs from day 14 mice but increases in magnitude and becomes shorter in duration in the adult mice.


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  		Fig. 2.   Representative ECGs of lead I recorded from conscious mice at 4 developmental stages: days 1, 7, 14 neonatal and adult mice. A: ECGs illustrate representative examples of ECGs recorded in days 1, 7, 14 neonatal and adult mice. Arrows indicate end of Q-T intervals for each developmental stage. Expanded view of J junction-S-T segment-T wave complex is shown in boxes. Day 1 mouse shows elevation of J junction and elevation of plateau portion of S-T segment. J junction-S-T segment-T wave complex in day 14 and adult mice shows resolution of elevation of plateau phase of S-T segment to near isoelectric values. B: progressive developmental shortening of mean R-R, P-R, Q-T, and Q-Tc intervals (n >=  8 for each group). * Significant difference compared with day 1 by ANOVA and Dunnett's multiple range test.

The mean R-R, P-R, Q-T and Q-Tc intervals observed during normal development are shown in Fig. 2B. Progressive and significant shortening of R-R interval was observed comparing measurements at day 1 to measurements at all other developmental stages (P < 0.01). However, there was no significant difference comparing R-R intervals at 14 days old to adult mice. In parallel with the changes in R-R intervals, there were significant changes in the P-R intervals during normal development (Fig. 2B). Although significant differences were noted comparing day 1 to adult mice, no significant decrease was observed comparing data from day 14 to adult mice. In addition the mean Q-T intervals significantly decreased comparing data from day 1 mice to any other developmental stage; however, there was no difference comparing Q-T interval in day 7 and 14 to adult mice (Fig. 2B). The Q-Tc interval significantly decreased comparing day 1 and day 7 mice; however, there was no subsequent significant developmental change. Specifically the Q-Tc interval was not significantly different comparing values in days 7 and 14 and adult mice.

Q-T intervals at matched R-R intervals in neonatal and adult mice. To assess whether developmental changes in P-R and Q-T intervals were predominantly due to the slower mean heart rate of the early neonates, we compared neonatal mice with unusually fast sinus rates (cycle length less than 100 ms) to adult mice with comparable sinus cycle lengths. Figure 3 shows an example of ECG records from such a day 1 neonate and an adult mouse. At a similar sinus cycle length, the Q-T interval was longer in day 1 (n = 2) vs. adult (n = 2). In addition, the morphological differences as previously described were still present comparing neonatal and adult mice. These data indicate that the developmental changes in Q-T intervals are present even at matched cycle lengths. These data also parallel the changes in Q-Tc interval, which is another method to correct for changes in R-R interval. These data indicate that developmental changes in Q-T interval occur independent of changes in heart rate.


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  		Fig. 3.   ECGs obtained from day 1 neonatal and adult mice with similar heart rates. Examples of ECGs recorded in day 1 neonatal mouse with unusually rapid heart rate is compared with ECG of adult mouse at virtually matched sinus heart rates. P-R and Q-T intervals were longer in day 1 neonate even at heart rates equivalent to that of adult. Ends of the Q-T intervals are shown by arrows.

Effects of selective K+ channel blockers on ECGs in neonatal and adult mice. Previous in vitro studies have reported that IKr is the dominant repolarizing current in fetal and early neonatal mice, whereas Ito and Islow are the dominant repolarizing currents in adult mice (19-21). To assess the functional role of these K+ currents on cardiac electrical activities in vivo, we treated day 1 and adult mice with the selective IKr blocker dofetilide (7) and the selective Ito and Islow blocker 4-aminopyridine (4-AP) (22).

After dofetilide (0.5 mg/kg ip) was given, ECGs were recorded from day 1 and adult mice at 5, 10, 15, and 20 min. Figure 4, A and B, shows representative ECGs recorded from day 1 neonatal mice and Fig. 4C is adult mice at baseline and after exposure to dofetilide. Before dofetilide treatment, an elevation of the baseline J junction-S-T segment-T wave complex is shown as the striped area in the top box in Fig. 4A. Dofetilide treatment reversed the elevation of the plateau portion of the S-T segment to an isoelectric position as shown in the bottom box of Fig. 4A. This dofetilide-induced change in configuration appeared 5 min after treatment, persisted for more than 2 h, and fully recovered within 16 h. In addition, Mobitz 1, Wenckebach block was observed in some day 1 neonates treated with dofetilide (in 25% of records, Fig. 4B). Dofetilide did not substantially change the ECG configuration and intervals in adult mice (Fig. 4C). Figure 5 shows the effect of dofetilide on mean ECG intervals. Dofetilide prolonged R-R, Q-T and Q-Tc intervals in day 1 neonates (Fig. 5A) but not in adult mice (Fig. 5B). In day 1 mice, dofetilide prolonged Q-Tc interval from 181 ± 4 ms at baseline to 196 ± 6 ms (n = 6, P < 0.05).


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  		Fig. 4.   Effects of dofetilide, a selective delayed rectifying K+ current (IKr) channel blocker on ECGs recorded from day 1 and adult mice. A: representative ECG before and after dofetilide (0.5 mg/kg ip) in day 1 neonatal mouse. Dofetilide substantially suppressed plateau of S-T segment in day 1 mouse as shown in boxes. B: illustrative example of dofetilide-induced Wenckebach in day 1 neonatal mice. However dofetilide at same dose did not affect ECGs in adult mice (C).



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  		Fig. 5.   Effects of dofetilide on mean ECG intervals in day 1 neonatal and adult mice. Mean R-R, P-R, Q-T, and Q-Tc intervals before and after treatment with dofetilide (0.5 mg/kg ip) are shown for day 1 neonates (A) and for adults (B). * Change that is significantly different from control (n = 4 for each group).

Figure 6 shows representative examples of the effects of 4-AP (2.5 mg/kg ip) on ECGs of both day 1 and adult mice. ECGs were recorded at 5, 10, 15, and 20 min after 4-AP treatment. In day 1 neonatal mice, 4-AP had no significant effect on the configuration of the QRS-T complex (Fig. 6A) for up to 20 min following injection. In contrast, 4-AP changed the configuration of the QRS-T complex in adult mice (Fig. 6B). Specifically, 4-AP reduced the amplitude and widened the duration of the TRW shown in the striped area (Fig. 6B, bottom box). These data indicate that 4-AP-sensitive currents contribute to TRW. The effect of 4-AP on mean electrocardiographic intervals is shown in Fig. 7A for day 1 neonatal mice and in Fig. 7B for adult mice. 4-AP prolonged Q-T and Q-Tc intervals in adult animals but had no effect on neonatal day 1 mice. In adult mice, 4-AP prolonged Q-Tc interval from 155 ± 4 ms at baseline to 177 ± 4 ms (P < 0.05, n = 6).


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  		Fig. 6.   Effects of 4-aminopyridine (4-AP), a selective transiently repolarizing K+ current and slowly inactivating K+ current channel blocker on ECGs recorded from day 1 neonate and adult mice. Effects of 4-AP (2.5 mg/kg) on representative ECGs in day 1 neonate and adult mice are shown. 4-AP had no effect on ECG configuration in day 1 neonatal mice (A). In contrast, in adult mice 4-AP decreased amplitude of transient repolarizing wave as shown in boxes (B).



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  		Fig. 7.   Effects of 4-AP on mean ECG intervals in day 1 neonatal and adult mice. Mean R-R, P-R, Q-T, and Q-Tc intervals during control and after treatment with 4-AP are shown for day 1 neonates (A) and for adults (B). * Change that is significantly different from control (n = 4 for each group).

We cannot exclude that developmental differences in absorption, distribution, and metabolism of the dofetilide and 4-AP could contribute to differences in the pharmacological response.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

The new findings of this study include 1) a method was devised that allows noninvasive measurements of ECGs in conscious, unsedated mice at various ages of development; 2) significant changes in the configuration of the J junction-S-T segment-T wave complex, and the R-R, P-R, Q-T, and Q-Tc intervals were observed during normal postnatal development; 3) a dofetilide-sensitive current, likely IKr, appears to contribute to spatial gradients that result in elevation of the plateau portion of the S-T segment in day 1 neonatal mice; 4) 4-AP-sensitive currents appear to contribute to the TRW in adult mice.

S-T segment elevation in neonatal day 1 mouse ECG. The surface ECG is a useful, nontraumatic method to obtain information about depolarization and repolarization of the heart in intact animals and humans. During depolarization of the heart an activation wave propagates through the heart, creating a potential difference between depolarized and not-yet-depolarized areas of the heart. The potential differences seen during activation of the heart have been represented as a moving depolarizing dipole vector of variable magnitude and direction. After depolarization the cells repolarize, again as a propagation wave, creating a repolarizing dipole vector. The direction and magnitude of the repolarization vector are determined by the spatial gradients of action potential configurations (4-8). Action potential is shorter in the epicardium than the endocardium in many species, resulting in a upright T wave (4-8). S-T segment elevation can result from multiple causes, including congenital abnormalities of the sodium channel such as the Brugada syndrome (8, 9) and some class 1C drugs (12) and transmural ischemia (10, 16). The available data suggest that loss of the action potential dome in right ventricular epicardium but not endocardium underlies the S-T segment elevation associated with Brugada syndrome. Similarly, using simulations Wohlfart (23) reconstructed S-T segment elevation by calculating differences between subendocardial and epicardial action potentials. Indeed spatial heterogeneity of action potential configurations appears to be the common underlying mechanism of S-T segment elevation.

Day 1 neonatal mice manifest elevation of the J junction and a plateau phase of the S-T segment-T wave complex. One possible mechanism of S-T segment elevation in day 1 neonatal mouse heart is the presence of a gradient of unopposed depolarizing forces early during the action potential. In day 1 neonatal mouse, IKr is the dominant repolarizing current. However, IKr characteristically manifests a substantial latency to activation. Therefore early in the action potential the depolarizing currents are unopposed by any substantial repolarizing forces. During the first 2 wk of normal development a progressive resolution of this elevation in the J junction-S-T segment-T wave complex occurs. Over this same time the density of Ito increases progressively. The Ito activates very rapidly and thus can oppose the depolarizing forces. Thus the S-T segment elevation in day 1 neonates may result from gradients of unopposed depolarizing forces and developmental resolution of the S-T segment elevation may result from a greater balance of repolarizing and depolarizing forces early in the action potential. However this mechanism cannot explain how dofetilide resolves the S-T segment elevation in day 1 neonatal heart. Indeed, pharmacologically inhibiting IKr might be expected to leave more of the initial depolarizing forces unopposed and thus might be expected to exaggerate S-T segment elevation.

Our working hypothesis is that spatial gradients in the balance of depolarizing versus repolarizing currents likely contributes to the elevation of the J junction-S-T segment complex and may explain the response to dofetilide. Suppose that dofetilide is the dominant repolarizing current in most day 1 neonatal ventricular myocytes but not in one particular region of the mouse heart (say the endocardium). Indeed we have reported that the dofetilide-sensitive IKr is the dominant repolarizing current in most ventricular cardiac myocytes but that the APD of some endocardial cells are substantially different, suggesting a different balance of depolarizing and repolarizing currents in these cells (19, 21). When dofetilide blocks IKr in most of the day 1 neonatal myocytes it may spatially homogenize action potential repolarization and thus decrease the spatial voltage gradient that leads to J junction-S-T segment elevation. However, no experimental study has evaluated spatial heterogeneity of action potentials in neonatal heart, so this explanation is speculative.

Transiently repolarizing wave in adult mouse ECG. A transiently repolarizing wave appears as an r' wave at the end of the apparent QRS complex and is a dominant repolarizing vector in the ECGs of adult mice. The evidence that the TRW is a part of the repolarization includes 1) the timing of the TRW would temporally align with phase 1 repolarization and Ito is responsible for phase 1 repolarization in many species and is the dominant repolarizing current in adult mice (22); 2) 4-AP blocks Ito and Islow in vitro (21) and decreases the magnitude and slows the time course of the TRW in vivo; 3) our conviction that Ito contributes to the TRW is supported by the data in Fig. 5 of the study by Barry et al. (2) that shows that the Kv4 functional knockout results in a decrease in the amplitude and slowing of the time constant of the TRW. From these data we conclude that the Ito contributes to the TRW in vivo.

Developmental changes in Q-Tc intervals and Q-T intervals at matched R-R intervals in neonates and adults. Previous studies have reported developmental shortening of APD at matched cycle lengths (20, 21). In the present study, developmental shortening in mean sinus R-R interval is a confounding factor to an assessment of whether developmental Q-T interval shortening was due to an intrinsic shortening of APD or due to more rapid heart rates. To address this issue we calculated the rate-corrected Q-T interval (Q-Tc) and compared the ECGs of day 1 neonatal mice with unusually rapid heart rates to adult mice at matched rates. The two methods for rate correction provide similar results. Q-T interval in adults was shorter than in neonates even at matched sinus R-R intervals. Similarly the Q-Tc interval was significantly shorter in adults than neonates. These data provide evidence that the developmental shortening of the Q-T interval is at least in part related to intrinsic shortening of APD.

Relevance of these data to K+ channel knockout mice. Transgenic and knockout mouse models allow an assessment of the physiological sequelae of over- or underexpression of gene products or the sequelae of changes in the structure of a protein. Transgenic knockout mice may provide insights into the contribution of ion channels to normal growth and development. Before a study of transgenic mice, it is necessary to understand the correspondence between the currents underlying the action potential and the ECG waves recorded from the body surface. The method reported herein will allow recording of ECGs in conscious, unsedated mice and thus can avoid the potential confounding effects of anesthetic drugs, instrumentation, or signal averaging on the ECG. The present study provides insights for studying transgenic mouse with altered K+ channel expression in the heart. For example, 4-AP-mediated reductions in Ito and Islow result in a reduction in the amplitude of the TRW. This information may be helpful for recognizing phenotypes of appropriate functional knockouts.

In conclusion, changes in the ECG morphology and changes in R-R, P-R, Q-T, and Q-Tc intervals occur during normal development in mice. Electrocardiographic responses to K+ channel blockers differ dependent on developmental age in mice.


    ACKNOWLEDGEMENTS

We thank Dr. H. E. D. J. ter Keurs and Alan Davidoff for helpful suggestions.


    FOOTNOTES

This work was funded by the Medical Research Council of Canada Grant CBBA-18083 and by the Canadian Heart and Stroke Foundation and the Andrew's Family Professorship for Cardiovascular Research .

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Address for reprint requests and other correspondence: H. J. Duff, Dept. of Medicine, Univ. of Calgary, 3330 Hospital Dr., NW, Calgary, Alberta, Canada, T2N 4N1 (E-mail: hduff{at}ucalgary.ca).

Received 29 April 1999; accepted in final form 27 August 1999.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

1.   Babij, P., R. Askew, B. Nieuwenhuijsen, C. M. Su, T. R. Bridal, B. Jow, T. M. Argentieri, J. Kulik, L. J. Degennaro, W. Spinelli, and T. J. Colatsky. Inhibition of cardiac IKr induced by overexpression of the long QT syndrome HERG G628S mutation in transgenic mice. Circ. Res. 83: 668-678, 1998[Abstract/Free Full Text].

2.   Barry, D. M., X. Haodong, R. B. Schuessler, and J. M. Nerbonee. Functional knockout of the transient outward current, long-QT syndrome and cardiac remodelling in mice expressing a dominant negative Kv4alpha subunit. Circ. Res. 83: 560-567, 1998[Abstract/Free Full Text].

3.   Berul, C. I., M. J. Aronovitz, P. J. Wang, and M. E. Mendelsohn. In vivo cardiac electrophysiology studies in mouse. Circulation 94: 2641-2648, 1996[Abstract/Free Full Text].

4.   Brand, P. I. L., R. A. van Lingen, F. Brus, M. D. Talsma, and N. J. Elzeng. Hypertrophic cardiomyopathy as a side effect of dexamethasone treatment for bronchopulmonary dysplasia. Acta Paediatr. 82: 614-617, 1993[ISI][Medline].

5.   Chou, T.-C. Electrocardiography in Clinical Practice. New York: Grune and Stratton, 1985.

6.   Diez, U., and H. Schwartze. Quantitative electrocardiography in postnatally developing rats. J. Electrocardiol. 24: 53-62, 1991[ISI][Medline].

7.   Duff, H. J., Z. P. Feng, and R. S. Sheldon. High and low affinity site for 3H-dofetilide binding to guinea pig myocytes. Circ. Res. 77: 718-725, 1995[Abstract/Free Full Text].

8.   Fujiki, A., M. Usui, H. Nagasawa, K. Mizumaki, H. Hayahi, and H. Inoue. ST segment elevation in the right precordial leads induced with class 1C antiarrhythmic drugs: insights into the mechanisms of Brugada syndrome. J. Cardiovasc. Electrophysiol. 10: 214-218, 1999[ISI][Medline].

9.   Gussak, I., C. Antzelevitch, P. Bjerregaard, J. A. Towbin, and B. R. Chaitman. The Brugada syndrome: clinical, electrophysiologic and genetic aspects. J. Am. Coll. Cardiol. 33: 5-15, 1999[Abstract/Free Full Text].

10.   Holland, R. P., and H. Brooks. Precordial and epicardial surface potentials during myocardial ischemia in the pig. Circ. Res. 37: 471-480, 1975[Abstract/Free Full Text].

11.   Jedeikin, R., A. Primhak, A. T. Shennan, P. R. Swyer, and R. D. Rowe. Serial electrocardiographic changes in healthy and stressed neonates. Arch. Dis. Child. 58: 605-611, 1983[Abstract].

12.   Krishnan, S. C., and M. E. Josephson. ST segment elevation induced by class 1C antiarrhythmic agents: underlying electrophysiologic mechanisms and insights into drug-induced proarrhythmia. J. Cardiovasc. Electrophysiol. 9: 1167-1172, 1998[ISI][Medline].

13.   London, B., A. Jeron, J. Zhou, P. Buckett, X. Han, G. F. Mitchell, and G. Koren. Long QT and ventricular arrhythmias in transgenic mice expression the N terminus and first transmembrane segment of a voltage-gated potassium channel. Proc. Natl. Acad. Sci. USA 95: 2926-2931, 1998[Abstract/Free Full Text].

14.   Mena, J. S., and E. C. de Frias. Electrocardiographic changes in the first two weeks of life of premature infants. Acta Cardiol. 2: 95-110, 1979.

15.   Mitchell, G. F., A. Geron, and G. Koren. Measurement of heart rate and Q-T interval in the conscious mouse. Am. J. Physiol. Heart Circ. Physiol. 274: H747-H751, 1998[Abstract/Free Full Text].

16.   Ross, J. Electrocardiographic ST-segment analysis in the characterisation of myocardial ischemia and infarction. Circulation 53: 173-181, 1976.

17.   Sreenivasan, V. V., B. J. Fisher, J. Liebman, and T. Downs. Longitudinal study of the standard electrocardiogram in healthy premature infant during the first year of life. Am. J. Cardiol. 31: 57-63, 1973[ISI][Medline].

18.   Thomaisis, C., G. Varlamis, and S. Karamperis. Comparative study of electrocardiogram of healty full-term and premature newborns. Acta Paediatr. Scand. 77: 653-657, 1988[ISI][Medline].

19.   Wang, L., and H. J. Duff. Identification and characteristics of the delayed rectifier K+ current in fetal mouse ventricular myocytes. Am. J. Physiol. Heart Circ. Physiol. 270: H2088-H2093, 1996[Abstract/Free Full Text].

20.   Wang, L., and H. J. Duff. Developmental changes in transient outward current in mouse ventricle. Circ. Res. 81: 120-127, 1997[Abstract/Free Full Text].

21.   Wang, L., Z. P. Feng, C. S. Kondo, R. S. Sheldon, and H. J. Duff. Developmental changes in the delayed rectifier K+ channels (IKr) in mouse heart. Circ. Res. 79: 79-85, 1996[Abstract/Free Full Text].

22.   Wang, Z., B. Fermini, and S. Nattel. Effects of flecainide, quinidine and 4-aminopyridine on transient outward and ultrarapid delayed rectifier currents in human atrial myocytes. J. Pharmacol. Exp. Ther. 272: 184-196, 1995[Abstract/Free Full Text].

23.   Wohlfart, B. A simple model for demonstration of STT-changes in ECG. Eur. Heart J. 8: 409-416, 1987[Abstract/Free Full Text].

Am J Physiol Cell Physiol 278(1):C73-C80
0363-6143/00 $5.00 Copyright © 2000 the American Physiological Society


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