Differential Effects of Changes in Local Myocardial Refractoriness on Atrialand Ventricular Latency
Background Assessment of myocardial refractoriness and conduction properties, critical to development and propagation of reentrant arrhythmias, is an integral part of the investigation of atrial and ventricular tachycardias through the use of programmed electrical stimulation. Local conduction itself, however, may be affected by myocardial refractoriness.
Methods and Results We studied the effects of changes in myocardial refractoriness on local conduction in right atrial and ventricular myocardium in 19 patients. Changes in effective, functional, and relative refractoriness were accomplished with the use of four pacing protocols, including drive train pacing cycle lengths (PCLs) of 600 and 400 milliseconds (ms) and drive train durations (DTDs) of 8 and 50 stimuli. Unipolar cathodal stimulation was performed from the distal electrode, and unipolar electrograms were recorded from the proximal three poles of quadripolar catheters with 5-mm interelectrode spaces. Atrial and ventricular effective and relative refractory periods (ERPs and RRPs) were significantly shortened by both the reduction in PCL and the increase in DTD. The reduction in the PCL shortened atrial and ventricular refractory periods significantly more than did the increase in the DTD. Changes in ventricular refractory periods were significantly greater compared with atrial refractory periods. The ratio of RRP to ERP was reduced in the atrium but significantly increased in the ventricle with reduction in PCL and increase in DTD. For all premature intervals, the conduction interval from stimulus to the first recording electrode pole was significantly greater than conduction intervals measured between subsequent electrode poles. The greatest increase in conduction interval with closely coupled premature complexes occurred between the stimulus artifact and the first recording electrode pole. Reduction in ventricular but not atrial ERP was associated with significantly increased local conduction interval.
Conclusions First, most of the conduction delay after the stimulus artifact occurs within 5 mm from the pacing site. Second, closely coupled premature complexes delay conduction primarily by prolonging latency in the first 5 mm from the pacing site. Third, fundamental differences occur between the atrium and ventricle regarding changes in local conduction as a function of changes in ERP, suggesting that factors involved in sudden changes in refractoriness (eg, heart rate acceleration) could produce divergent effects on atrial and ventricular arrhythmogenesis.
The study of myocardial conduction and its relation to refractoriness in the human myocardium has important clinical relevance because many arrhythmias are due at least in part to abnormalities of conduction, refractoriness, or both. It is known that the ERP of atrial and ventricular myocardium can be shortened by several mechanisms, such as faster heart rate, longer DTD, or increases in stimulus intensity.1 2 3 4 However, shortening of ERP may lead to prolonged local conduction of closely coupled premature complexes and therefore increased conduction delay or latency from stimulus to electrogram. The purpose of the present study was to investigate the effect of changes in ERP on local conduction interval and to determine whether differences in conduction of premature complexes exist between atrial and ventricular myocardium.
Nineteen patients (13 men and 6 women; age, 53±21 years old) participated in the study, which was performed before electrophysiological evaluation for ventricular arrhythmias (n=12), syncope (n=4), cardiac arrest (n=1), AV conduction (n=1), or Wolff-Parkinson-White syndrome (n=1). Ten patients had coronary heart disease, 1 patient had dilated cardiomyopathy, and 1 patient had aortic valve disease. The remaining 7 patients had syncope or arrhythmias that were not related to significant hypertensive heart disease, coronary artery disease, valvular heart disease, or myocardial disease. All patients were in normal sinus rhythm, and the right atrium and right ventricle (sites of pacing) were believed to be normal. For example, none of the patients with ischemic heart disease had evidence of inferior myocardial infarction affecting the right ventricle. No patient had overt right heart failure.
Programmed Electrical Stimulation
Electrophysiological investigations were performed with the patient in the fasting, nonsedated state and in the absence of any cardioactive drugs, after informed written consent was obtained. Multiple electrode catheters were introduced percutaneously and advanced under fluoroscopic guidance to various areas of the heart, such as the high right atrium, His-bundle area, coronary sinus, and right ventricular apex. Quadripolar catheters with 5-mm interelectrode spaces positioned in the high lateral right atrium and right ventricular apex were used for the protocol study.
The distal pole was used for cathodal unipolar stimulation; the anode was a skin electrode attached to the lateral aspect of the left thigh. The proximal three poles were used to record unipolar electrograms. Unipolar intracardiac recordings were filtered between 0.5 and 1000 kHz. Activation time for each unipolar electrogram was taken as the point of the first most rapid deflection of the electrogram. The intracardiac data were recorded simultaneously with five surface ECG leads with the use of an oscilloscopic recorder (VR 16, Electronics for Medicine) and a paper speed of 200 to 250 mm/s (Gould) and saved with a Teac tape deck.
Programmed electrical stimulation was performed with a custom-built constant current stimulator (Kassell) with the use of rectangular pulses of 2-ms duration and twice late diastolic threshold. For both the atrial and ventricular sites, ERP measurements were performed with four separate pacing protocols: PCL of 600 ms with DTD of 8 stimuli, PCL of 600 ms with DTD of 50 stimuli, PCL of 400 ms with DTD of 8 stimuli, and PCL of 400 ms with DTD of 50 stimuli. The order of testing was randomized. Premature stimuli were introduced, beginning in late diastole, and the coupling interval was shortened in 5-ms steps. A 30-second rest period was used between each pacing run. The atrial study was performed in 12 patients, and the ventricular study was performed in 12 patients. Because of time constraints, only 9 patients completed both the atrial and ventricular protocol studies.
Definition of Terms
Electrode poles a, b, and c represent the first, second, and third unipolar recording electrode poles, with pole a closest to the distal pacing electrode pole (p). Electrode pole p was used to determine ERP, FRP, and RRP. A and V represent the atrial and ventricular local electrograms. S1 and S2 represent the stimuli of basic drive and premature complex, respectively. ERP of the atrium or ventricle represents the longest S1S2 coupling interval that did not result in atrial or ventricular depolarization, respectively, on two consecutive attempts. RRP of the atrium or ventricle represents the longest S1S2 coupling interval with S2A2>S1A1 or S2V2>S1V1, respectively. FRP of the atrium or ventricle represents the shortest obtainable A1A2 or V1V2 interval, respectively. Basal conduction represents interpolar conduction intervals at basic drive cycle length. Maximum conduction represents interpolar conduction intervals recorded at S1S2 equal to ERP plus 5 ms. Latency represents conduction interval from stimulus artifact to specified electrogram.
Reproducibility of Measurements
The reproducibility for S2A2 and S2V2 determinations was excellent. The coefficient of intraobserver error for 22 duplicate maximum atrial latency intervals was 2%, and the correlation coefficient was .996 (P=.001). The coefficient of intraobserver error for 20 duplicate ventricular maximum latency intervals was 2%, and the correlation coefficient was .97 (P=.0001).
The data were expressed as mean±1 SD. The paired and unpaired Student's t tests and ANOVA with Bonferroni's correction for repeated comparisons were used to determine statistically significant differences (P<.05) between groups.
Atrial ERP: Effect of PCL
Reduction in PCL from 600 to 400 ms, at a DTD of 8 stimuli, shortened atrial ERP from 223±35 to 203±23 ms, or by 9% (P<.01). Similarly, a reduction in PCL from 600 to 400 ms, at a DTD of 50 stimuli, shortened the atrial ERP from 215±3l to 196±20 ms, or by 9% (P<.01) (Fig 1⇓).
Atrial ERP: Effect of DTD
Atrial ERP was also significantly shortened by an increase in DTD; an increase in DTD from 8 to 50 stimuli, at a PCL of 600 ms, decreased the atrial ERP from 223±35 to 215±31 ms, or by 4% (P<.01). Also, an increase in DTD from 8 to 50 stimuli, at a PCL of 400 ms, decreased the atrial ERP from 203±23 to 196±20 ms, or by 3% (P<.04) (Fig 1⇑).
Atrial RRP: Effect of PCL
A change in PCL from 600 to 400 ms, at a DTD of 8 stimuli, shortened atrial RRP from 267±43 to 251±33 ms, or by 6% (P=.04). Similarly, a reduction in PCL from 600 to 400 ms, at a DTD of 50 stimuli, shortened the atrial RRP from 247±38 to 237±28 ms, or by 4%. This change, however, did not reach statistical significance.
Atrial RRP: Effect of DTD
An increase in DTD from 8 to 50 stimuli, at a PCL of 600 ms, also shortened atrial RRP from 267±43 to 247±38 ms, or by 7.5% (P<.001). Likewise, an increase in DTD from 8 to 50 stimuli, at a PCL of 400 ms, shortened atrial RRP from 251±33 to 237±28 ms, or by 5.6% (P<.01).
Ventricular ERP: Effect of PCL
Reduction in PCL from 600 to 400 ms, at a DTD of 8 stimuli, shortened ventricular ERP from 238±14 to 210±20 ms, or by 11% (P<.01). Similarly, a reduction in PCL from 600 to 400 ms, at a DTD of 50 stimuli, shortened ventricular ERP from 226±17 to 193±20 ms, or by 15% (P=.005) (Fig 1⇑).
Ventricular ERP: Effect of DTD
Ventricular ERP was also significantly shortened by an increase in DTD: a change in DTD from 8 to 50 stimuli. At a PCL of 600 ms, ventricular ERP decreased from 238±14 to 226±17 ms, or by 5% (P<.01). An increase in DTD from 8 to 50 stimuli, at a PCL of 400 ms, shortened ventricular ERP from 210±20 to 193±20 ms, or by 8.5% (P<.005) (Fig 1⇑).
Ventricular RRP: Effect of PCL
Reduction in PCL from 600 to 400 ms, at a DTD of 8 stimuli, resulted in an 8.8% shortening of the ventricular RRP, from 272±17 to 248±21 ms (P<.0001). A reduction in PCL from 600 to 400 ms, at a DTD of 50 stimuli, shortened ventricular RRP by 11%, from 261±19 to 232±20 ms (P<.0001).
Ventricular RRP: Effect of DTD
An increase in DTD also reduced ventricular RRP; a change in DTD from 8 to 50 stimuli, at a PCL of 600 ms, shortened ventricular RRP by 4.4%, from 272±17 to 26l±19 ms (P<.001). Likewise, an increase in DTD from 8 to 50 stimuli, at a PCL of 400 ms, shortened ventricular RRP by 6%, from 248±21 to 232±20 ms (P<.001).
We have not excluded right ventricular disease in our patients. However, the changes in ventricular ERP and conduction times between the patients with ischemic heart disease or cardiomyopathy and the patients with normal ventricular function and morphology were similar.
Dissimilar Effects of Pacing Maneuvers on ARP and VRP Changes
It is noteworthy that the reduction in PCL from 600 ms to 400 ms shortened atrial ERP, ventricular ERP, and ventricular RRP more than the increase in DTD from 8 to 50 stimuli (Figs 1 and 2⇑⇓). In contrast, the increase in DTD shortened atrial FRP (Table⇓), atrial RRP, and ventricular FRP (Table⇓) more than did the reduction in PCL.
Decreases in ventricular ERP in response to the four pacing maneuvers were significantly greater compared with changes in atrial ERP (Fig 1⇑).
The effect of the pacing maneuvers on atrial ERP differed from that on ventricular ERP in one further important respect: increasing the DTD from 8 to 50 stimuli reduced significantly RRP:ERP in the atrium but significantly increased this ratio in the ventricle at a PCL of 400 ms (Fig 2⇑). However, reduction in PCL from 600 to 400 ms increased the ratio for both the atrium and ventricle (Fig 2⇑).
Atrial and Ventricular Conduction Intervals
Basal Atrial and Ventricular Conduction Intervals
Atrial and ventricular interpolar basal conduction intervals were unaffected by drive PCL or DTD (Fig 3⇓). Basal atrial interelectrode and basal ventricular interelectrode conduction intervals were similar (Fig 3⇓). Basal atrial and ventricular conduction intervals from the stimulus to pole a were significantly greater (≈15 ms) than conduction intervals from pole a to pole b (≈8 ms) and from pole b to pole c (≈10 ms) with each pacing sequence (Figs 3 through 5⇓⇓⇓). However, conduction intervals between pole a and pole b and between pole b and pole c were similar (Figs 3 through 5⇓⇓⇓).
Maximum Conduction Intervals
Atrial maximum conduction intervals, measured from stimulus to electrode pole a, were not significantly affected by changes in PCL or DTD (Fig 3⇑). In comparison, ventricular maximum conduction intervals from stimulus to electrode pole a were significantly increased, both by a reduction in PCL from 600 to 400 ms at DTD of 8 complexes (P<.01) and 50 complexes (P=.02) and by an increase in DTD from 8 complexes to 50 complexes at PCLs of 600 ms (P=.036) and 400 ms (P<.01, Figs 3 through 5⇑⇑⇑).
Of note, most of the atrial and ventricular conduction delay at the FRP of the myocardium was recorded within a distance of 5 mm from the pacing site (Fig 3⇑). Thus, on average, maximum atrial conduction interval from stimulus to electrode pole a was 41±16 ms compared with conduction intervals of 9±5 ms between electrode pole a and electrode pole b (P<.0001) and of 12±8 ms between electrode pole b and electrode pole c (P<.0001, Figs 3 and 4⇑⇑). Similarly, maximum ventricular conduction interval recorded from stimulus to electrode pole a was 44±10 ms compared with conduction intervals of 10±5 ms between electrode pole a and electrode pole b (P<.0001) and 12±4 ms between electrode pole b and electrode pole c (P<.0001, Figs 3 and 5⇑⇑).
Maximum atrial conduction intervals measured between electrode pole a and electrode pole b and between electrode pole b and electrode pole c were not significantly different (Figs 3 through 5⇑⇑⇑). Atrial conduction interval between electrode pole a and electrode pole c increased at the FRP of the myocardium compared with basal values, but this change did not reach statistical significance. In comparison, at a PCL of 600 ms (but not 400 ms) and at DTDs of 8 complexes and 50 complexes, ventricular conduction intervals between the distal electrode poles measured at the FRP did increase significantly compared with basal values (Fig 3⇑). The changes in ventricular conduction interval between the distal electrode poles were modest compared with the increases in conduction interval between stimulus and electrode pole a; on average, the conduction interval between stimulus and electrode pole a increased by 180% compared with only a 23% increase in conduction interval between the distal electrode poles.
Thus, changes in local atrial refractoriness induced by alterations in PCL and DTD were not associated with changes in local conduction. In contrast, changes in local ventricular refractoriness induced by identical pacing maneuvers were accompanied by altered local conduction.
The results of the present study elucidate important differences in accommodation of atrial and ventricular refractoriness and accompanying conduction delay to changes in stimulation rate and pulse train duration. Although both tissues display frequency-dependent decrements in effective and functional refractoriness, the change in ventricular tissue in response to a decrease in PCL was greater than in atrial tissue. In contrast, the decrease in atrial RRP exceeded that in ventricular tissue. This differential effect produced opposite effects on RRP:ERP—a decrease in atrial tissue and an increase in ventricular tissue with prolongation of the basic DTD. This study also documents a close relation between ERP and apparent conduction delay arising near the stimulus site. Given the observed changes in RRP:ERP in atrial tissue with alterations in basic DTD, the extrastimulus coupling window encompassing this conduction delay narrowed. In contrast, a decrease in basic drive PCL and an increase in pacing DTD in the ventricle expanded the vulnerable window, favoring greater local conduction delay.
Rate Dependence of Myocardial Refractoriness
The observation of rate-dependent refractoriness is consistent with results of previous in vitro and in vivo studies. A number of investigators have demonstrated that both APD1 2 3 4 5 6 7 8 9 10 and refractoriness11 12 13 14 15 16 17 18 decrease with declining PCLs. Although formal restitution curves relating APD and pacing coupling intervals were not derived, the findings of this decrease with the change in basic drive PCL from 600 to 400 ms in both atrial and ventricular tissue are analogous to the downward and leftward shift of previously observed in vitro APD restitution curves generated by faster PCLs.1 8 19 Such changes in refractoriness, typically paralleling that of APD,20 21 22 23 are most likely related to changes in intracellular and extracellular ionic activities. With rapid stimulation, several factors have been invoked to similarly explain a decrease in APD1 5 6 12 19 24 ; these include an accumulation of intracellular calcium, which may decrease the chemical gradient responsible for plateau-phase inward currents; an increase in extracellular cleft potassium, which may in turn reduce the APD; or an increase in intracellular calcium, triggering a calcium-activated outward current. Rate-dependent changes in specific ionic currents, such as Ito, may also be contributory.9 10 25 The disparate decrease in effective and relative refractoriness with changes in stimulus frequency or pulse train duration suggests greater changes in these factors in ventricular myocardium. In turn, the greater baseline effect of repolarizing K+ currents in atrial than in ventricular myocardium26 may mitigate appreciable changes in ERP in atrial tissue with changes in rate.
Time Dependence of Myocardial Refractoriness
The “use” dependence of APD has also been previously established in both in vitro and in vivo studies.27 28 29 30 Prior investigations demonstrated a progressive monoexponential decline in APD with repetitive stimulation. In some cases, more than 30 to 60 seconds of stimulation have been required for APD to reach a new steady-state value at a given pacing frequency.28 29 That refractoriness is similarly affected is suggested by the findings of Janse et al,30 who noted that a new steady-state duration of refractoriness in canine ventricular myocardium was reached only after several hundred complexes. Our finding of progressively shorter ERP with an increase in the basic drive train from 8 to 50 complexes in ventricular myocardium is consistent with these in vivo findings.
Differential Atrial and Ventricular Effects
Findings of the present study disclosed a differential response to the introduction of premature extrastimuli in atrial and ventricular myocardium. In general, atrial effective and relative refractoriness was less than that observed in ventricular myocardium. In addition, these findings were accompanied by the parallel observation that modulation of both effective and relative refractoriness in atrial myocardium with changes in basic drive PCL was less than that observed in the ventricle. These observations are likely related to differences in APD in atrial and ventricular myocardium. Previous studies have demonstrated that atrial APD tends to be shorter and phase 3 repolarization tends to be more gradual than in ventricular tissue. Some of this differential effect may be due to differences in the role of slow inward currents contributing to the maintenance of the plateau phase of the APD in ventricular cells and the greater presence of outward K+ currents in atrial tissue.26 31 32 33 34 35 The exception to this general finding was the greater decrease in atrial RRP with an increase in DTD than that seen in the ventricle.
Differences in the response of atrial and ventricular effective and relative refractoriness to changes in basic drive PCL or DTD resulted in contrasting effects on RRP:ERP and an accompanying conduction delay. In ventricular tissue, changes occurring with PCL and DTD increased RRP:ERP, whereas with a change in atrial basic drive PCL from 600 to 400 ms but not in DTD, RRP:ERP increased, because the decline in effective refractoriness was greater than that in relative refractoriness. This increase in RRP:ERP was accompanied by a conduction delay in the ventricular myocardium, suggesting an increased “vulnerable period” of progressive conduction delay in response to a VPC. Such an occurrence might explain the increase in inducibility of ventricular arrhythmias with the introduction of VPCs after shorter basic drive PCLs.36 37 38 39 The change in this RRP:ERP accompanying the abrupt decrease in basic PCL in atrial tissue may also account for the electric destabilization of the atrium of patients with rapid reciprocating tachycardia that leads to the generation of atrial fibrillation.40 41 Here, with the occurrence of reciprocating tachycardia, both ERP and RRP would be expected to shorten. The increase in the RRP:ERP so produced might increase the conduction delay encountered by an APC, leading to shorter wavelength of the reentrant circuits involved in atrial fibrillation.42 43
In clear contrast, with an increase in the basic DTD from 8 to 50 complexes, relative refractoriness decreased to a much greater extent than the ERP, producing a significant decline in this RRP:ERP and the diastolic or vulnerable period during which a premature impulse would be conducted with increased conduction delay. Little change in the near field conduction interval was observed with such step increases in basic DTD from 8 to 50 pulses in atrial tissue. These findings may be of relevance in explaining the effect of prolonged overdrive atrial pacing in decreasing the occurrence of atrial fibrillation/flutter as suggested by a recent study.44
Refractoriness-Dependent Conduction Delay
The finding of greater apparent refractoriness-related conduction delay in both atrial and ventricular tissue between the stimulus site and the first catheter recording pole suggests that “activation or capture delay” contributes to apparent conduction slowing generated by a VPC. At less negative membrane potentials related to incomplete repolarization from the previous impulse (in this case, the last complex of the paced drive train), a specific voltage-dependent proportion of Na+ channels remain in an inactivated state and are therefore unavailable to contribute to tissue activation. This decrease in excitability is manifested as capture delay due to the time required to activate sufficient tissue to propagate an impulse. Such stimulus delay has also been observed in atrial tissue.45
That conduction intervals between downstream electrode poles showed a lesser increase than observed at baseline indicates that near field activation delay allowed sufficient time for more complete repolarization ahead of the advancing depolarizing wave front. Therefore, no additional downstream conduction delay was noted in atrial tissue. This is also consistent with the change in RRP:ERP in atrial tissue. Because the RRP decreased to a greater extent than ERP in atrial tissue, additional conduction delay would not be expected.
In contrast, the additional delay between downstream electrode poles in the ventricular tissue parallels the differences in the observed change in RRP:ERP with increased DTDs. Given the relation between Na+ currents or Vmax and conduction velocity,46 47 48 the decrease in Na+ channel availability also translates into slowing of conduction and differences in action potential characteristics under these study conditions in atrial and ventricular tissue. In general, phase 3 of an atrial action potential shows a less steep repolarization slope compared with that observed in ventricular tissues. It may be reasonable to speculate that similar decrements in extrastimulus coupling intervals result in tissue activation at relatively less negative membrane potentials in ventricular versus atrial myocardium conduction delay, which might affect Na+ channel availability and, therefore, excitability. It could also be related to differences in the complexity of atrial versus ventricular tissue or resulting differences in excitability.
Several limitations should be considered in interpreting these data. First, by design, tissue refractoriness was used as a marker of repolarization, and monophasic APD recordings were not obtained. The focus on tissue repolarization was pursued to allow an investigation of the relation between changes in myocardial conduction and that of refractoriness as is relevant to the initiation of arrhythmias.
The use of intracardiac approach and a quadripolar catheter for recording impulse propagation also limited our ability to assess potential contributions of anisotropy or virtual cathode effects to the observed expression of conduction modulation. Unipolar pacing was used, in part, to eliminate the latter as a confounding consideration. With regard to anisotropy, the fiber orientation dependence of propagation could not be rigorously addressed with our approach, and conduction in an alternative direction to fiber orientation could have been fundamentally different.
With this study, only one atrial and ventricular site was used. As such, we were unable to consider the contribution of dispersions of conduction or refractoriness as a function of underlying tissue. Given the proposed apex-to-base gradient of APDs in ventricular tissue18 and recent findings of similar APD changes from the high lateral right atrium to the region of the AV node,49 50 we cannot necessarily extrapolate from these findings to all regions of the myocardium. The ventricular stimulation and recording sites also reflect impulse activation and propagation in endocardial/Purkinje network tissue. Given recent described differences in electrical properties of the subendocardium, midmyocardium, and epicardial tissue layers, it may not be possible to extrapolate from these data to full-thickness myocardium. Nevertheless, these findings are relevant to the elucidation of differences in local conduction and atrial and ventricular refractoriness near clinical stimulation sites that may contribute to arrhythmia induction.
Our study also did not take into consideration the potential effects of an altered autonomic nervous system on myocardial refractoriness and conduction. For example, pacing may cause increased local release of acetylcholine. It is also possible that during ventricular pacing, ventriculoatrial conduction/dissociation may have caused increased sympathetic nervous system activity. However, no pacing maneuver caused significant hypotension.
Selected Abbreviations and Acronyms
|APD||=||action potential duration|
|ARP||=||atrial refractory period|
|DTD||=||drive train duration|
|ERP||=||effective refractory period|
|FRP||=||functional refractory period|
|PCL||=||pacing cycle length|
|RRP||=||relative refractory period|
|RRP:ERP||=||ratio of RRP to ERP|
|VPC||=||ventricular premature complex|
|VRP||=||ventricular refractory period|
Reprint requests to Lameh Fananapazir, MD, FRCP, Co-Chief, Inherited Cardiac Diseases Section, Director, Clinical Electrophysiology Laboratory, Bldg 10, Rm 7B-14, Cardiology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, 10 Center Dr, MSC 1650, Bethesda, MD 20892-1650.
- Received August 21, 1995.
- Revision received December 18, 1995.
- Accepted December 21, 1995.
- Copyright © 1996 by American Heart Association
Miller JP, Wallace AG, Feezor MD. A quantitative comparison of the relation between the shape of the action potential and the pattern of stimulation in canine ventricular muscle and Purkinje fibers. J Mol Cell Cardiol. 1971;9:3-29.
Carmeliet E. Repolarization and frequency in cardiac cells. J Physiol. 1977;73:903-923.
Elharrar V, Surawicz B. Cycle length effect on restitution of action potential duration in dog cardiac fibers. Am J Physiol. 1983;244:782-792.
Robinson RB, Boyden PA, Hoffman BF, Hewett KW. Electrical restitution process in dispersed canine cardiac Purkinje and ventricular cells. Am J Physiol. 1987;253:1018-1025.
Elharrar V, Atarashi H, Surawicz B. Cycle length-dependent action potential duration in canine cardiac Purkinje fibers. Am J Physiol. 1984;247:H936-H945.
Antzelevitch C, Sicouri S, Litovsky SH, Lukas A, Krishnan SC, DiDiego JM, Gintant GA, Liu D-W. Heterogeneity within the ventricular wall: electrophysiology and pharmacology of epicardial, endocardial, and M cells. Circ Res. 1991;69:1427-1449.
Mendez C, Gruhzit CC, Moe GK. Influence of cycle length upon refractory period of auricles, ventricles, and A-V node in the dog. Am J Physiol. 1956;84:287-295.
Moore EN, Preston JB, Moe GK. Durations of transmembrane action potentials and functional refractory periods of canine false tendon and ventricular myocardium: comparisons in single fibers. Circ Res. 1965;27:259-273.
Denes P, Wu D, Dhingra R, Pietras RJ, Rosen KM. The effects of cycle length on cardiac refractory periods in man. Circulation. 1974;49:32-41.
Guss SB, Kastor JA, Josephson ME, Scharf DL. Human ventricular refractoriness: effects of cycle length, pacing site and atropine. Circulation. 1976;53:45S5.
Strobel RE, Fisher JD, Katz G, Kim SG, Mercando AD. Time dependence of ventricular refractory periods: implications for electrophysiologic protocols. J Am Coll Cardiol. 1990;19:614-618.
Rosenbaum DS, Kaplan DT, Kanai A, Jackson L, Garan H, Cohen RJ, Salama G. Repolarization inhomogeneities in ventricular myocardium change dynamically with abrupt cycle length shortening. Circulation. 1991;84:1333-1345.
Lerman BB, Burkhoff D, Yue DT, Sagakawa K. Mechanoelectric feedback: independent role of preload and contractility in modulation of canine ventricular excitability. J Clin Invest. 1985;76:1843-1850.
Dean JW, Lab MJ. The effect of changes in afterload on the absolute refractory period of the pig heart. PACE. 1987;10:986.
Zhu WX, Johnson S, Packer D. Potential mechanism of ventricular arrhythmias in dogs with pacing-induced heart failure. PACE. 1994;17:793. Abstract.
Kunze DL. Rate-dependent changes in extracellular potassium in the rabbit atrium. Circ Res. 1977;41:122-127.
Sicouri S, Antzelevitch C. A subpopulation of cells with unique electrophysiologic properties with the deep subepicardium of the canine ventricle: the M cell. Circ Res. 1991;68:1729-1741.
Kanaan N, Jenkins J, Childs K, Ge Y-Z, Kadish A. Monophasic action potential duration during programmed electrical stimulation. PACE. 1991;14:1049-1059.
Seed WA, Noble MIM, Oldershaw P, Wanless RB, Drake-Holland AJ, Redwood D, Pugh S, Mills C. Relation of human cardiac action potential duration to the interval between beats: implications for the validity of rate corrected QT interval (QTc). Br Heart J. 1987;57:32-37.
Carmaliet E. Influence du rhythme sur la duree du potential d'action ventriculaire cardiaque. Arch Int Physiol Biochim. 1955;58:222-232.
Janse MJ, van der Steen ABM, van Dam RH, Durrer D. Refractory period of the dog's ventricular myocardium following sudden changes in frequency. Circ Res. 1969;24:251-262.
Tamkun MM, Knoth KM, Walbridge JA, Kroemer H, Roden DM, Glover DM. Molecular cloning and characterization of two voltage-gated K+ channel cDNAs from human ventricle. FASEB J. 1991;5:331-337.
Snyders J, Knoth KM, Roberds SL, Tamkun MM. Time-, voltage-, and state-dependent block by quinidine of a cloned human cardiac potassium channel. Mol Pharmacol. 1992;41:322-330.
Escande D, Coulombe A, Faivre J-F, Deroubaix E, Coraboeuf E. Two types of transient outward currents in adult human atrial cells. Am J Physiol. 1987;252:H142-H148.
Shibata EF, Drury T, Refsum H, Aldrete V, Giles W. Contributions of a transient outward current to repolarization in human atrium. Am J Physiol. 1989;257:H1773-H1781.
Wang Z, Fermini B, Nattel S. Delayed rectifier outward current and repolarization in human atrial myocytes. Circ Res. 1993;73:276-285.
Sousa J. Prospective comparison of a conventional and an accelerated protocol for programmed ventricular stimulation in patients with coronary artery disease. Circulation. 1991;83:764-773.
Morady F, Kou WH, Kadish AH, Schmaltz S, Summitt J, Rosenheck S. Effect of basic drive train cycle length on induction of ventricular tachycardia by a single extrastimulus. J Electrophysiol. 1989;3:111-116.
Summitt J, Rosenheck S, Kou W, Schmaltz S, Kadish AH, Morady F. Effect of basic drive cycle length on the yield of ventricular tachycardia during programmed ventricular stimulation. Am J Cardiol. 1990;64:49-52.
Sung RJ, Castellanos A, Mallon SM, Bloom MG, Gelband H, Myerburg RJ. Mechanisms of spontaneous alternation between reciprocating tachycardia and atrial flutter-fibrillation in the Wolff-Parkinson-White syndrome. Circulation. 1977;56:409-416.
Rensma PL, Alessie JA, 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.
Allessie MA, Rensma PL, Brugada J, Smeets JLRM, Penn O, Kirchhof CJHJ. In: Zipes D, Jalife J, eds. Cardiac Electrophysiology: From Cell to Bedside. Philadelphia, Pa: WB Saunders; 1990:548-559.
Sgarbossa EB, Pinski SL, Maloney JD, Simmons TW, Wilhoff BL, Castle LW, Trohman RG. Chronic atrial fibrillation and stroke in paced patients with sick sinus syndrome: relevance of clinical characteristics and pacing modalities. Circulation. 1993;88:1045-1053.
Franz MR, Koller B, Solomon AJ, Fletcher RD. Local stimulus response latency is the main contributor to conduction time increase during premature stimulation in the human atrium. J Am Coll Cardiol. 1993;21:355A. Abstract.
Packer DL, Grant AO, Strauss HC, Starmer CF. Characterization of concentration- and use-dependent effects of quinidine from conduction delay and declining conduction velocity in canine Purkinje fibers. J Clin Invest. 1989;83:2109-2119.
Buchanan JW, Saito T, Gettes LS. The effects of antiarrhythmic drugs, stimulation frequency, and potassium-induced resting membrane potential changes on conduction velocity and dV/dtmax in guinea pig myocardium. Circ Res. 1985;56:696-703.
Spach MS, Dolber PC, Anderson PAW. Multiple regional difference in cellular properties that regulate repolarization and contraction in the right atrium of adult and newborn dogs. Circ Res. 1989;65:1595-1611.
Spach MS, Dolber PC, Heidlage JF. Interaction of inhomogeneities of repolarization with anisotropic propagation in dog atria: a mechanism for both preventing and initiating reentry. Circ Res. 1989;65:1612-1631.