Relation Between Repolarization and Refractoriness During Programmed Electrical Stimulation in the Human Right Ventricle
Implications for Ventricular Tachycardia Induction
Background Although programmed electrical stimulation is widely used for provoking sustained ventricular tachycardia (VT), the mechanism by which repetitive extrastimulation evokes VT is still little understood. Specifically, it is not clear why several closely coupled extrastimuli are frequently required to induce VT. Although regularly paced human ventricular myocardium exhibits a near constant relation between myocardial repolarization and refractoriness, the effect of repetitive extrastimulation on the relation between repolarization and excitability in the human heart and its relevance for arrhythmia induction by programmed stimulation are unknown. We hypothesized that the induction of VT by repetitive extrastimulation is facilitated by an altered relation between repolarization and refractoriness, and this leads to disturbances in ventricular impulse propagation, which trigger the onset of VT.
Methods and Results Twenty-one patients undergoing routine electrophysiological study were paced from the right ventricular apex and outflow tract endocardium with monophasic action potential–pacing catheters placed at both sites simultaneously. Monophasic action potential durations (APDs) and effective refractory periods (ERPs) were measured simultaneously at each site, during regular stimulation (S1-S1) at 400-ms cycle length and during three consecutive extrastimuli (S2 through S4) at the closest coupling intervals at which all three extrastimuli still resulted in capture. Measurements further included the repolarization level at which the earliest capture occurred, the ratio between ERP and APD, and the propagation time between the pacing and distant recording site. APD and ERP both shortened progressively with each extrastimulus. APD at 90% repolarization decreased from a baseline (S1) of 238.1±19.7 ms by 14.9% at S2, 18.9% at S3, and 22.9% at S4 (P<.0001, S1 versus S4). ERP decreased from 233.1±19.7 ms (S1) to 180.0±41.9 ms (S3) (P<.0001, S1 versus S3). While ERP shortening occurred mainly on the basis of APD shortening, there was an additional factor that contributed to ERP shortening independent of APD shortening. Each consecutive extrastimulus was able to elicit a propagated response at earlier repolarization levels than the previous one: the earliest capture for S2 occurred at 85.5±10.2% of complete repolarization, for S3 at 83.9±10.5%, and for S4 at 78.4±11.2% (P<.05 for S2 versus S3; P<.05 for S3 versus S4; P<.01 for S2 versus S4). This progressive “encroachment” of the earliest capture stimulus onto the preceding repolarization phase (at progressively less repolarized levels) correlated with a progressive delay of impulse propagation between the pacing site and the second recording site: propagation time increased from baseline (S1) by 10.5±1.3% with S2 to 19.0±1.6% with S3 and to 22.5±2.8% with S4 (P<.05, S4 versus S1). VT was induced in 11 of 21 patients. Nine of these had VT induced only when significant encroachment of extrastimuli on the preceding repolarization phase (<81.3±7.0%) and associated conduction slowing (>16.6±1.8%) were present.
Conclusions Repetitive extrastimulation not only shortens APD and subsequently ERP but also alters the ERP/APD relation by allowing capture to occur at progressively less complete repolarization levels. This progressive encroachment onto the preceding repolarization phase is associated with impaired impulse propagation and a high incidence of VT induction. This may help explain how repetitive, closely coupled extrastimulation induces ventricular tachycardia in the human heart.
Programmed electrical stimulation of the right ventricle is widely used to provoke sustained ventricular tachycardia (VT) in patients who have had clinical events of VT, syncope, or sudden cardiac death. Although there is a large body of evidence relating clinically documented VT to artificially provoked ventricular arrhythmias,1 2 3 4 5 the mechanism by which repetitive right ventricular (RV) extrastimulation evokes such arrhythmias is still poorly understood. Specifically, it is not clear why programmed electrical stimulation must often reach a certain level of “aggressiveness” to induce sustained VT. It is empirically known but not yet scientifically explained that the probability of inducing VT in a patient increases with the number of electrical extrastimuli and with the closeness with which each consecutive extrastimulus is delivered to the myocardium.
During regular pacing there is a close relation between the duration of the action potential (APD) and the effective refractory period (ERP) or, in other terms, between the level of repolarization and the return of excitability. In both animal6 7 8 9 and human ventricular myocardium,10 excitability recurs at a repolarization level of approximately 85%, and this relation is constant over a wide range of steady-state cycle lengths.8 10 Little is known, however, of the effect of repetitive extrastimulation on the relation between repolarization and excitability in the human heart. It has been suggested that repetitive extrastimulation decreases the APD and thereby the coupling interval to capture the myocardium,11 resulting in the greater inducibility of VT with repetitive extrastimulation.1 12 However, shortening of the APD or the ERP does not increase the susceptibility for reentrant tachycardia. For instance, sinus tachycardia, with its associated rate-dependent shortening of APD and ERP, is not a common cause of ventricular arrhythmias. Thus, additional mechanisms must facilitate VT induction by repetitive extrastimulation.
We hypothesized that the induction of VT by repetitive extrastimuli is facilitated by an altered relation between repolarization and refractoriness, and this leads to disturbances in ventricular impulse propagation, which trigger the onset of VT. The specific objectives of this study were (1) to determine the effects of repetitive closely coupled extrastimuli on the instantaneous relation between repolarization and excitability at two RV sites, (2) to assess the effects of an altered repolarization-excitability ratio on impulse propagation between the two RV sites, and (3) to assess the significance of such alterations for the inducibility of VT by programmed electrical stimulation.
The study was performed in 21 male patients 47 to 78 years old (mean, 58±6 years) who underwent electrophysiological testing for documented or clinically suspected VT. The underlying heart diseases were coronary artery disease (16 patients) and idiopathic dilated cardiomyopathy (5 patients). The mean left ventricular (LV) ejection fraction was 34.5% (range, 11% to 55%).
Electrophysiological studies were performed in the baseline state, with antiarrhythmic drugs withdrawn for at least 5 half-lives. All patients gave informed written consent to a protocol that had been approved by the institutional review board on human investigation. Two monophasic action potential (MAP)-pacing combination catheters were positioned in the RV, one in the apex and one in the outflow tract. Pacing was performed with a 2-ms pulse duration at precisely twice diastolic threshold strength with a programmable electrical stimulator (Bloom and Associates) and a custom-made constant-current isolation unit (EP Technologies) that allowed fine-tuning of stimulus output strength in the range <1 mA. The two MAPs and a six-lead surface ECG were recorded on a multichannel recorder (Midas System 5000, PPG) at a paper speed of 100 mm/s and also stored digitally on a BARD electrophysiology recording system.
Simultaneous Determination of APD and ERP
The technique for simultaneous determination of APD and ERP via the MAP-pacing combination catheter has been detailed earlier.9 13 Briefly, MAP recordings were obtained with two nonpolarizable silver–silver chloride electrodes, one at the tip of the catheter and the other located 5 mm proximal to the tip. Pacing was performed with two platinum electrodes mounted opposite each other at a 2-mm distance from the catheter tip. Because of the close spacing between the pacing dipole and the MAP recording electrode, the APD and the ERP could be measured at nearly identical myocardial sites. This helped avoid correlation errors that might result from the variability of both APD and ERP among separate ventricular sites.14 15 In addition, the short distance between recording and pacing electrodes results in minimal conduction delays between the pacing and recording site, as evident from the fact that the stimulus artifact coincides with the upstroke of the MAP (Fig 1⇓).
In all patients, pacing was performed from the RV apex and outflow tract; the pacing sequences were randomized. The hearts were paced at a basic (S1-S1) cycle length of 400 ms. After every eighth S1, an extrastimulus (S2) was introduced during early electrical diastole after the S1 response. The S1-S2 coupling interval was decreased in steps of 10 ms until the extrastimulus began to encroach onto the repolarization phase of the S1 response. At this point, the coupling interval was decreased in 5-ms steps until capture no longer occurred. The longest coupling interval between the basic (S1) MAP upstroke and the extrastimulus (S2) artifact that failed to produce a ventricular response was defined as the ERP. Next, the S1-S2 coupling interval was lengthened by 50 ms, and a second extrastimulus (S3) was introduced at a 50-ms delay from the preceding S2 response repolarization. Both the S1-S2 and the S2-S3 coupling intervals were then decreased until the shortest intervals that still resulted in capture were determined. This was verified by a 5-ms decrement resulting in refractoriness. Finally, a third extrastimulus (S4) was added, and the above procedure was repeated. Each eight-beat drive train and extrastimulus sequence was interrupted by a 2-second pause. This pacing protocol closely followed the routine procedure of electrophysiological testing. This was intended to make our arrhythmia inducibility data comparable to the existing literature.
The following variables were analyzed during the closest S1-to-S4 stimulation sequence: (1) APD at the level of 90% repolarization (APD90)10 at the stimulation site and at the distant recording site (RV apex and outflow tract); (2) the ERP for S1, S2, and S3; (3) the repolarization level at which each extrastimulus (S2, S3, S4) captured with the closest possible coupling interval (the basic MAP served as the reference); and (4) the propagation time between the two pacing/recording sites (either RV apex to outflow tract or vice versa). This was determined as the interval between the upstrokes of the two MAPs. Sustained VT was defined as inducible when it lasted for at least 15 seconds. VT inducibility was related both to the degree of incomplete repolarization levels at which extrastimuli produced propagated responses and to the increase in propagation time between the RV pacing and distant RV recording site.
Data are presented as mean±SD. One-way ANOVA was used to estimate the significance of differences for APD, ERP, closest repolarization capture level, and propagation time between the two pacing/recording sites during basic S1 stimulation and S2 through S4 extrastimulation. A value of P<.05 was considered significant. The statistical analyses were done with jmp software from SAS Institute, Cary, NC.
Both MAP-pacing combination catheters maintained a stable position in the RV apex and outflow tract, respectively, during the entire study protocol. The MAP signals had initial amplitudes ranging from 12 to 35 mV (mean, 15±9 mV). A 15% to 25% loss in amplitude was seen over the course of the study protocol. Despite this decline in amplitude, the MAP signals retained a smooth configuration with sharp upstrokes, a convex plateau phase and final repolarization phase, and flat diastolic intervals, known to be hallmarks of high-fidelity MAP recordings.13 The diastolic pacing thresholds averaged 0.12±0.05 mA at both sites in all patients and, although frequently interrogated, rarely required adjustment.
APD90 and ERP Changes During Maximally Close Repetitive Extrastimulation
There was a cumulative shortening of both APD90 and ERP with each extrastimulus. The APD90 and ERP shortening was observed at both the pacing site and the distant recording site. At the pacing site, APD90 was 238.1±19.7 ms at S1 and decreased 14.9% at S2, 18.9% at S3, and 22.9% at S4 extrastimulation (P<.0001, S1 versus S4). At the distant recording site, APD90 was 228.7±24.1 ms at S1 and shortened 7.4% at S2, 15.7% at S3, and 17.9% at S4 (P<.0001, S1 versus S4) (Fig 2⇓). The ERP shortened from 233.1±19.7 ms at S1 to 180.0±41.9 ms at S3 (P<.0001, S1 versus S3) (Fig 3⇓). Because only three extrastimuli were introduced, the ERP associated with the last (S4) action potential could not be determined.
Relation Between APD and ERP During Repetitive Extrastimulation
The MAP recordings demonstrated that the shortening of the ERP during repetitive extrastimulation was due to two mechanisms: the first was the progressive decrease (up to 22.9%) of the APD during repetitive extrastimulation. Second, repetitive extrastimulation decreased the ratio between the ERP and the APD progressively. As shown in Fig 1⇑, the repolarization level at which premature extrastimulation of twice diastolic threshold strength produced the earliest propagated response (“takeoff” potential) shifted upward, to less complete repolarization levels, with each additional extrastimulus. Earliest capture for S2 was possible when the preceding action potential was repolarized to a level of 85.5±10.2%; earliest capture for S3 occurred at 83.9±10.3% of the preceding repolarization phase (P<.05, S2 versus S3) and for S4 at a repolarization level of 78.4±11.2% (P<.05, S3 versus S4; P<.01, S2 versus S4) (Fig 4⇓). Thus, each additional extrastimulus that still captured the myocardium could do so at progressively less complete repolarization levels.
Propagation Time During Repetitive Extrastimulation
The propagation time from the upstroke of the directly paced MAP response to the distantly recorded MAP upstroke was constant during regular pacing as well as during extrastimulation, so long as extrastimuli were applied after complete repolarization. As extrastimuli began to encroach upon the repolarization phase of the preceding action potential, propagation time between the pacing site and the distant recording site increased. This prolongation in propagation time increased with the degree by which each additional capturing extrastimulus was able to further encroach onto the preceding repolarization phase. Compared with baseline S1-S1 pacing, propagation time between the pacing site increased by 10.5±1.3% with the closest S2, by 19.0±1.6% with the closest S3, and by 22.5±2.8% with the closest S4 (P<.05, S1 versus S4) (Fig 5⇓).
Induction of VT
Sustained VT was induced in 11 of 21 patients (52.4%). The VT was monomorphic in 8 of 11 patients (72.7%) and polymorphic in 3 of 11 patients (27.3%). In all but 2 patients with monomorphic VT, the VT was induced only when extrastimuli encroached onto the preceding repolarization phase at levels of <90%. All polymorphic VT followed significant encroachment of the extrastimuli. There were no significant differences in the APD90, the ERP, the ERP/APD ratio, and the propagation time between the monomorphic and polymorphic VTs. All patients who had encroachment of extrastimuli and VT inducibility required more than 1 extrastimulus for VT induction; 2 patients were inducible with 2 extrastimuli, and 7 patients were inducible only when 3 extrastimuli were introduced (Fig 6⇓). At the VT induction drive, S2 encroached onto 85.9±9.5% of the preceding repolarization phase, S3 onto 81.3±8.0%, and S4 onto 79.6±6.4%. The encroaching extrastimulation was associated with slowing of impulse conduction by 9.4±1.5% with S2 to 16.6±1.8% with S3 and to 29.4±1.6% with S4 preceding VT induction.
There were several major findings in this prospective study. First, during repetitive extrastimulation, both APD and ERP shortened progressively with each additional extrastimulus. Second, each additional extrastimulus was able to capture the myocardium earlier during repolarization than the preceding extrastimulus. Third, this progressive encroachment of successive extrastimuli onto the preceding action potential’s repolarization phase was associated with a slowing of impulse propagation from the paced to a distant recording site. Finally, VT occurred in 82% of inducible patients only when extrastimuli encroached onto the preceding repolarization phase.
Recording and Stimulation Technique
The effect of repetitive, closely coupled extrastimuli on the relation between local repolarization and refractoriness has not been studied systematically in the human heart. Standard electrophysiological catheter techniques depict unipolar or bipolar differential electrograms, which identify local capture but not the true time course of local myocardial repolarization. In this study, we used a MAP-pacing combination catheter9 that allowed us to record MAPs in the immediate vicinity of the pacing site and thereby analyze simultaneously the instantaneous relation between the local repolarization time course and the recurrence of excitability in the human heart. In addition, the activation times at two different ventricular sites were readily determined by the sharp upstrokes of the MAPs at either site (uncluttered by pacing artifacts), and thus the propagation time between the two sites could be determined with greater accuracy than with standard electrode catheters.13 16 17
Relation of APD to Extrastimulus Cycle Length
The shortening of the APD90 correlated closely (r=.80) with the decrease of the coupling interval during repetitive extrastimulation. Although no comparable data during repetitive extrastimulation exist, a close relation between the APD and the preceding cycle length is well established for steady-state pacing18 19 20 and during single extrastimulation with decreasing coupling intervals.11 21 22 The successive APD shortening during maximally close repetitive stimulation can be explained by two mechanisms: First, a closely coupled extrastimulus decreases the subsequent APD, which in turn allows the next extrastimulus to capture with a shorter coupling interval, which in turn causes further APD shortening, and so forth. Second, the progressive encroachment of earliest capture onto the preceding repolarization phase during repetitive extrastimulation additionally decreases the coupling interval and shortens the APD.
ERP/APD Ratio and Encroachment of Reexcitability
As described in detail previously,8 9 10 the single-site recording and pacing method demonstrates a close correlation between APD and ERP. We showed in a previous canine8 and human9 10 heart study that at a given site, the ERP/APD ratio during steady-state pacing is constant and independent of the cycle length; refractoriness for a single extrastimulus (S2) at twice diastolic threshold ceased and excitability recurred at a repolarization level of 82±5% regardless of the prior pacing cycle length.6 7 This correlation is comparable to in vitro findings in single cells.1 2 The present human heart study corroborates these findings by confirming that a single S2 extrastimulus was able to capture the local myocardium when the preceding response had repolarized to, on average, 85.5%.
This relatively fixed relation between repolarization and refractoriness during regular pacing changed during closely coupled repetitive extrastimulation. With each additional extrastimulus, earliest capture occurred at progressively less complete repolarization levels. Neither experimental animal nor clinical human studies have yet reported that successive, maximally close extrastimuli are able to capture the myocardium at progressively earlier repolarization levels. Basic investigators, measuring transmembrane action potentials in excised myocardial tissue preparations, had little reason to apply programmed repetitive extrastimulation, whose purpose is to induce sustained ventricular arrhythmias. In the clinical arena, standard electrode catheters do not provide direct images of the local myocardial repolarization time course and therefore cannot be used to identify the direct relation between repolarization and excitability in the human heart.
Because of this lack of directly applicable basic or clinical data on the effects of repetitive, closely coupled extrastimulation, an explanation for the progressively earlier capture takeoff level must remain speculative at the present time. We propose two hypothetical explanations. (1) Myocardial responsiveness to premature electrical stimuli is governed by both voltage- and time-dependent recovery processes from inactivation of sodium channel conductance after a prior myocardial response.23 24 The earlier repolarization level at which each additional extrastimulus captures the myocardium could be due to an as yet undescribed phenomenon of “facilitation” that allows for earlier recovery of a subgroup of sodium channels during the course of repolarization when stimulated repetitively at close coupling intervals. This could be verified by intracellular action potential recordings in isolated cardiac cells during repetitive stimulation. (2) The phenomenon of progressive encroachment of repetitive extrastimuli could also be interpreted as a tissue phenomenon. Unlike single-cell, intracellular action potential recordings, the MAP catheter is known to simultaneously record the electrical activity from a multitude of cells in close proximity to the recording electrode.13 16 It is conceivable that the repolarization time courses of neighboring cells (and of their associated refractoriness) do not exactly coincide and that dispersion of repolarization and refractoriness in this cell population increases with each additional extrastimulus. A progressive divergence in electrical restitution curves with repetitive extrastimulation recently has been demonstrated for canine ventricular muscle fibers.25 If repolarization in the cell group underneath the MAP recording and stimulating electrode is dispersed in time and space, some cells may be captured early while others are still refractory. The discordance between the responsiveness of individual cells and the average (recorded) repolarization level may increase with repetitive extrastimulation. This would displace the average capture level to earlier repolarization.
Conduction Delay During Repetitive Close Extrastimulation
Regardless of whether the “facilitation of excitability” phenomenon is based on single-channel dynamics or tissue properties, a dyssynergy of cellular activation is bound to diminish the electrical energy of the wave front and subsequently to reduce the initial propagation velocity of the cardiac impulse.26 27 In keeping with this hypothesis, the propagation time of the electrical impulse between the stimulation and the recording site increased with the first, closely coupled premature extrastimulus (S2) compared with stimulation at the basic cycle length (S1-S1). Each additional closely coupled extrastimulus (S3, S4) created further conduction delay of the electrical impulse. This is in accordance with previous experimental data that showed marked slowing of myocardial conduction properties during incomplete repolarization or at more depolarized transmembrane potentials.28 29
Impact of Encroachment and Conduction Slowing on VT Inducibility
VT was induced in 82% of inducible patients only when the repetitive extrastimuli captured the myocardium before 90% of the preceding repolarization phase. In all cases, this was associated with a delay in impulse conduction between the RV pacing and distant RV recording sites. Several explanations might be hypothesized. Encroachment of an electrical impulse onto the preceding repolarization phase would encounter only a minority of sodium channels available for activation and thus result in slowed impulse propagation through the myocardium. Slowed conduction of the propagating electrical impulse is associated with an increased probability of VT induction by two mechanisms. First, slowing of conduction augments the dispersion of activation times in the ventricles, which may increase the probability that the electrical wave front initiates the reentry circuit during its excitable gap. Second, progressive conduction slowing of the electrical impulse results in an increased dispersion of the diastolic interval between the stimulation site and recording sites, with longer diastolic intervals at sites distant from the stimulation site.30 The increased range of diastolic intervals increases the dispersion of ventricular repolarization (APD).30 31 Our clinical data support these experimental findings. Shortening of APD90 during repetitive, encroaching extrastimulation was more pronounced at the electrically paced site (55 ms from S1 to S4) compared with simultaneous APD90 shortening at the distant recording site (42 ms, P<.05), which was activated by impulse propagation with delayed conduction and increased diastolic intervals. The different electrophysiological effects of encroaching extrastimulation might also explain that we could induce both monomorphic and polymorphic VT with repetitive closely coupled extrastimulation. The explanations provided for VT induction account for a high percentage (82%) of VT in our patients. In the remaining 18% of VTs that were inducible without encroachment on repolarization, other electrophysiological mechanisms may have prevailed.
MAPs were of different magnitudes at different endocardial sites or in different patients and exhibited a gradual decline in amplitude over the course of the study. However, this is of little concern for the purpose of our study, which was not aimed at measuring the true transmembrane potential but rather at depicting the proportions between the relative time course of repolarization and its relation to reexcitability. MAPs have been validated to provide this information.16 The gradual decrease in MAP amplitude that occurred without significant loss in MAP morphology is most likely due to a decline in electrode contact pressure over time.13
We collected our data from only two pacing and recording sites, both located at the RV endocardium. Therefore, we cannot predict the effects of repetitive RV extrastimulation on impulse propagation toward and within the LV myocardium and on the reentry substrate, which is most commonly located in the LV myocardium. The pathway within the RV is shorter than that anticipated for impulse propagation between an RV pacing site and an LV recording site. Both from a geometrical point of view and by considering the probable lack of myocardial disease in the RV, the conduction delay measured between two RV sites is likely to have underestimated the conduction delay from the RV to the LV myocardium. The fact that we found a significant prolongation in propagation time from one RV site to another corroborates rather than defeats our hypothesis that closely coupled extrastimuli are able to prolong impulse propagation within the myocardium.
Although our approach could not deliver local information about electrophysiological variables in the LV, we adhered to an RV pacing protocol because this is the one generally used in electrophysiological testing. We feel that information derived from this approach is most readily comparable to the published clinical database concerning VT induction by programmed electrical stimulation.
Using a catheter technique that allows simultaneous pacing and recording of MAPs in the human heart, we found that closely coupled repetitive extrastimuli progressively shortened the local repolarization time and, more importantly, altered the instantaneous relation between repolarization and refractoriness. The latter allowed earliest capture by consecutive extrastimuli to occur at progressively less complete repolarization levels. Progressive encroachment of earliest capture toward more incompletely repolarized potentials was associated with a progressive slowing of impulse propagation. This observation may help us to understand the mechanism by which programmed stimulation induces VT in patients with reentry substrates. It would be of interest to learn how antiarrhythmic drugs modulate this relation, especially those drugs that successfully suppress VT induction by altering the ERP/APD relation. Such a study is currently under way in our laboratory.
Bettina S. Koller was supported by a fellowship from the Deutsche Forschungsgemeinschaft, Bonn, Germany. We appreciate the technical assistance of Frankie Hayes, RN, and Mary Chavez.
Reprint requests to Michael R. Franz, MD, PhD, Cardiology Division, Veterans Administration Medical Center, 50 Irving St NW, Washington, DC 20422.
Dr Franz was a consultant for EP Technologies.
- Received August 29, 1994.
- Revision received November 17, 1994.
- Accepted November 26, 1994.
- Copyright © 1995 by American Heart Association
Wellens HJJ, Brugada P, Stevenson WG. Programmed electrical stimulation of the heart in patients with life-threatening ventricular arrhythmias: what is the significance of induced arrhythmias and what is the correct stimulation protocol? Circulation. 1985;72:1-7.
Berger MD, Waxman HL, Buxton AE, Marchlinski FE, Josephson ME. Spontaneous compared with induced onset of sustained ventricular tachycardia. Circulation. 1988;78:885-892.
Hoffman BF, Cranefield PF. Electrophysiology of the Heart. Mount Kisco, NY: Futura Publishing Co; 1960:222-227.
Davidenko JM, Antzelevitch C. Electrophysiological mechanisms underlying rate-dependent changes of refractoriness in normal and segmentally depressed canine Purkinje fibers: the characteristics of post-repolarization refractoriness. Circ Res. 1986;58:257-268.
Franz MR, Costard A. Frequency-dependent effects of quinidine on the relation between action potential duration and refractoriness in the canine heart in situ. Circulation. 1988;77:1177-1184.
Gottlieb C, Josephson ME. The preference of programmed stimulation-guided therapy for sustained ventricular arrhythmias. In: Brugada P, Wellens HJJ, eds. Cardiac Arrhythmias: Where to Go From Here? Mount Kisco, NY: Futura Publishing Co; 1987:421-434.
Franz MR, Bargheer K, Rafflenbeul W, Haverich A, Lichtlen PR. Monophasic action potential mapping in human subjects with normal electrocardiograms: direct evidence for the genesis of the T wave. Circulation. 1987;75:379-385.
Watanabe T, Rautaharju PM, McDonald TF. Ventricular action potentials, ventricular extracellular potentials, and the guinea-pig. Circ Res. 1985;57:362-370.
Franz MR, Burkhoff D, Spurgeon H, Weisfeldt ML, Lakatta EG. In vitro validation of a new catheter technique for recording monophasic action potentials. Eur Heart J. 1986;7:34-41.
Franz MR, Flaherty JT, Platia EV, Bulkley BH, Weisfeldt ML. Localization of regional myocardial ischemia by recording of monophasic action potentials. Circulation. 1984;69:593-604.
Franz MR, Schaefer J, Schottler M, Seed WA, Noble MI. Electrical and mechanical restitution of the human heart at different rates of stimulation. Circ Res. 1983;53:815-822.
Franz MR, Swerdlow CD, Liem LB, Schaefer J. Cycle length dependence of human action potential duration in vivo: effects of single extrastimuli, sudden sustained rate acceleration and deceleration, and different steady-state frequencies. J Clin Invest. 1988;82:972-979.
Dangman KH, Hoffman BF. In vivo and in vitro antiarrhythmic and arrhythmogenic effects of N-acetyl procainamide. J Pharmacol Exp Ther. 1981;217:851-862.
Thompson KA, Blair IA, Woosley RL, Roden DM. Comparative in vitro electrophysiology of quinidine, its major metabolites and dihydroquinidine. J Pharmacol Exp Ther. 1987;241:84-90.
Weidmann S. The effect of the cardiac membrane potential on the rapid availability of the sodium-carrying system. J Physiol. 1955;127:213-224.
Kobayashi Y, Peters W, Khan SS, Mandel WJ, Karagueuzian HS. Cellular mechanisms of differential action potential restitution in canine ventricular muscle cells during single versus double premature stimuli. Circulation. 1992;86:955-967.
Han J, Moe GK. Nonuniform recovery of excitability in ventricular muscle. Circ Res. 1964;14:44-60.
Rensma PL, Allessie MA, Lammers WJEP, Bonke FIM, Schalij MJ. Length of excitation wave and susceptibility to reentrant atrial arrhythmias in normal conscious dogs. Circ Res. 1988;62:395-410.
Peon J, Ferrier GR, Moe GK. The relationship of excitability to conduction velocity in canine Purkinje tissue. Circ Res. 1978;43:125-135.
Van Dam RT, Moore NE, Hoffman BF. Initiation and conduction of impulses in partially depolarized cardiac fibers. Am J Physiol. 1963;204:1133-1144.
Kuo CS, Atarashi H, Reddy CP, Surawicz B. Dispersion of ventricular repolarization and arrhythmia: study of two consecutive ventricular premature complexes. Circulation. 1985;72:370-376.
Avitall B, McKinnie J, Jazayeri M, Akhtar M, Anderson A, Tchou P. Induction of ventricular fibrillation versus monomorphic ventricular tachycardia during programmed stimulation: role of premature beat conduction delay. Circulation. 1992;85:1271-1278.