Prolongation of conduction time during premature stimulation in the human atrium is primarily caused by local stimulus response latency

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1 European Heart Journal (1995) 16, Prolongation of conduction time during premature stimulation in the human atrium is primarily caused by local stimulus response latency B. S. KOLLER, P. E. KARASIK, A. J. SOLOMON AND M. R. FRANZ Georgetown University and VAMC, Washington, DC, U.S.A. KEY WORDS: Human atrium, extrastimulation, conduction time, stimulus response latency. Background: Conventional clinical electrophysiological techniques cannot accurately differentiate between local stimulus response latency and propagation time of the atrial response. The purpose of this study was to identify and distinguish local stimulus response latency from impulse propagation time in the human right atrium during programmed electrical stimulation. Methods: Pacing was performed from two atrial sites (high and low right atrium) in 19 patients, using monophasic action potential recording/pacing combination catheters (interelectrode distance <2 mm). Local stimulus response latency (interval between stimulus artifact and upstroke of the local monophasic action potential), and propagation time (interval between local and remote monophasic action potential upstroke) were evaluated at a basic cycle length (Sl-Sl) of 600 ms and as a function of the extrastimulus proximity (interval between extrastimulus and effective refractory period). Data are presented as means ± SEM. Results: During basic stimulation, local latency was very small (3-8 ± 1-7 ms). During premature extrastimulation (proximity <70 ms), local latency increased progressively with decreasing coupling intervals. Prolongation of local latency was most pronounced during stimulation close to the effective refractory period with local stimulus response latency increasing to 18-3 ±l-4ms (380 ± 7-9%) at 10 ms proximity (P<0002) and to 27-9 ±3-7 ms (630 ± 13-2%) at 5 ms proximity, respectively (P<00001). The impulse propagation time between the stimulation site and the remote recording site was on average 54-5 ± 14-3 ms during basic stimulation, and increased up to 621 ±13-5 ms (14-0 ± 8-4%), which was not significant. Conclusions: The intra-atrial impulse propagation remained essentially unchanged during the entire range of premature stimulation. Local stimulus response latency was negligible and constant during late coupling intervals but increased dramatically when extrastimulation approached the preceding repolarization phase. This has the following clinical impact: first, local stimulus response latency during premature extrastimulation curbs the targeted atrial response interval; second, local stimulus response latency, not propagation time, seems responsible for the greater functional than effective refractory period during electrical stimulation; third, local stimulus response latency should be considered in pace mapping for accurate comparison of conduction time before pacing with that during pacing. Introduction is difficult to accurately differentiate between the local Clinical electrophysiological atrial studies usually stimulus response latency and the propagation time of measure atrial conduction time as the interval between [ he. atnal resp? nse ; T 1 " 8 dlfficulty resu te fr T 7 the stimulus artifact and the atrial response at a denned l» tations in the design of conventional quadnpolar recording site. It has been shown during programmed <****** first ; a relatively ^ P a g thresho d which atrial stimulation that conduction time increases with ^"f s lar 8 e electrical stimulus artifacts partially masks prematurity of the extrastimulation"- 3 ]. However, the the local response and second, a relatively large distance specific factors that contribute to the increase in conducbet^een th f. dlsta P acm 8 electrode P air f d! he P roxi " mal tion time remain unclarified. An increased conduction rdm 8 e!^trode f ir makes the >. ' st ' nctlon time can be caused either by a local atrial response delay? e^een Xo f distant electrical responses uncertain, to the electrical stimulus (local stimulus response la- In this study, we examined the local and distant impulse tency) or by a slowing of the subsequent intra-atrial ProP^ion during electrical stimulation in the human impulse propagation. Using conventional clinical atnum with a monophasic action potential recording; electrophysiological pacing and recording techniques it pa? ng <f mbinat ' catheter wh.ch has closely spaced (<2mm) pacing and monophasic action potential Revision submitted 16 January 1995, and accepted 27 January recording electrodes and which produces a very Small.,, J..,..._ < tr- L stimulus artifact' 41. The specific objectives of this study Betuna S. Koller was supported by a fellowship from Deutsche Forschungs ,,,,.. gemeinschaft Bonn, Germany. were to: first, identify local latency during programmed Correspondence: Bettina Kolkr, MD, German Heart Center, Munich, electrical Stimulation; Second distinguish local Stimulus Lothstr. ii, Munich, Germany. response latency from propagation time, and third X/95/ S12.00/ The European Society of Cardiology

2 Stimulus response latency in the human atrium 1921 evaluate the effects of premature stimulation on local latency and impulse propagation time. Methods PATIENTS The study was performed in 19 male patients aged 55 to 73 years (mean 57-5 ± 7-3 years) who underwent electrophysiological study for evaluation of documented or clinically suspected ventricular tachycardia, but without documented supraventricular arrhythmias. The underlying heart diseases were coronary artery disease in 13 patients and dilated left ventricular cardiomyopathy in two patients. In four patients, no organic heart disease could be documented. The mean left ventricular ejection fraction was 38-0 ± 12-5% (range 11 to 53%). No patients had right ventricular disease. All patients showed normal atrial dimensions in the echocardiograms. ELECTROPHYSIOLOGICAL STUDY The electrophysiological study was performed after all antiarrhythmic treatment had been discontinued for at least 5 half lives and patients had given informed written consent. Monophasic action potentials and surface electrocardiogram leads were recorded simultaneously on a multichannel recorder (Midas System 5000, PPG) at a paper speed of loomm.s" 1. Two monophasic action potential recording/pacing combination catheters were positioned, one in the high right atrium lateral, and one in the low right atrium. The monophasic action potential recordings were obtained with two nonpolarizable silver-silver chloride electrodes, one at the tip of the catheter (exploring electrode) and the other located 5 mm proximal to the tip (indifferent electrode). Simultaneous pacing was performed with two platinum electrodes which were mounted in an orthogonal Pacing electrodes Figure 1 Schematic illustration of the catheter design. position halfway between the distal (tip) and proximal (reference) MAP electrodes (Fig. 1) [4]. Stimulation in immediate vicinity to the monophasic action potential recording electrodes allowed us to clearly differentiate the local stimulus response latency, and the propagation time of the atrial response to the remote recording site (Fig. 2). The interval between the local stimulus artifact and the sharpest deflection of the local monophasic action potential upstroke was defined as the local stimulus response latency. The interval between the sharpest deflection of the monophasic action potential at the stimulation site and that at the distant recording site was defined as propagation time. Conduction time of the electrical impulse was the interval from the stimulus PR: 100 ms PR: 10 ms Figure 2 Simultaneous recordings of two monophasic action potential combination catheters from the high right atrium (HRA), and the low right atrium (LRA) during premature extrastimulation. Pacing is performed at the low right atrium; SI denotes the stimulus artifact during basic cycle length of 600 ms; S2 denotes the extrastimulus artifact. Proximity (PR) indicates the prematurity of the extrastimulus, which is referenced to the effective refractory period. At long coupling intervals (proximity 100 ms), local stimulus response latency (LL) is small, but increases progressively with decreasing coupling intervals (proximity 50 ms, and 10 ms, respectively), while the propagation time (PT) of the evoked atrial response from the stimulation site (LRA) to the remote recording site (HRA) remains essentially unchanged.

3 1922 B. S. Koller et al. artifact to the sharpest deflection of the monophasic action potential at the distant recording site (i.e. local stimulus response latency plus propagation time). Proximity of extrastimulation was defined as the difference between the actual extrastimulus coupling interval and the effective refractory period. The effective refractory period was defined as the longest coupling interval between the upstroke of the monophasic action potential preceding the extrastimulus artifact and the extrastimulus artifact that failed to produce a ventricular response. The effective refractory period was also referenced to the repolarization level of the preceding action potential. The functional refractory period was the shortest propagated atrial response interval during premature extrastimulation. superimposed onto the upstroke phase of the monophasic action potential recording (example Fig. 2). The propagation time of the electrical impulse from the stimulation site to the remote recording site at the basic cycle length of 600 ms was on average 54-5 ± 14-3 ms. EFFECTIVE REFRACTORY PERIOD The effective refractory period was determined with 5 ms precision in all 38 recordings and was ± 25-4 ms. The effective refractory period occurred at a repolarization level of 74-4 ± 12-2% of the preceding action potential. PACING PROTOCOL Pacing was performed at twice diastolic threshold strength and at 2 ms pulse duration. After a train of eight stimuli at the basic drive cycle length (SI SI) of 600 ms, an extrastimulus (S2) was introduced. The longest (S1-S2) coupling interval was 400 ms. With each train, the S1-S2 coupling interval was decreased in 5 ms steps until the effective refractory period was reached. The pause between the trains was 2 s. In all patients, pacing was performed from the high right atrium and from the low right atrium. The pacing sequences were randomized. Each pacing sequence was recorded twice. STATISTICAL ANALYSIS Data are presented as means ± SEM. Local stimulus response latency and propagation time during extrastimulation were normalized to local stimulus response latency and propagation time at the basic cycle length. Student's paired t-tests were performed to estimate the significance of differences between stimulation at the basic cycle length and extrastimulation. A P value <005 was considered significant. Results After having placed the two monophasic action potential catheters in stable contact with the high and low right atrial myocardium, monophasic action potentials were recorded continuously from both sites during the entire study period (30-50 min). The diastolic threshold for pacing through the monophasic action potential combination catheter was less than 0-4 ma in all patients. The pacing threshold was confirmed frequently throughout the protocol and pacing was performed precisely at twice diastolic threshold strength. STIMULATION AT THE BASIC CYCLE LENGTH During regular pacing at a cycle length of 600 ms, local latency in all recordings (n=38) was very small (3-8 ± 1-7 ms). This was documented by the fact that the stimulus artifact either immediately preceded or was EFFECT OF EXTRASTIMULATION ON LOCAL STIMULUS RESPONSE LATENCY AND PROPAGATION TIME During extrastimulation at long coupling intervals (proximity ^ 70 ms), the local stimulus response latency did not change significantly, with a maximal increase to 4-58 ±0-2 ms (200±4-8%) CP=ns), compared to local stimulus response latency at the basic cycle length. With extrastimulation at tighter coupling intervals (proximity <70 ms), local latency increased progressively. The most pronounced prolongation of local latency occurred with stimulation in close vicinity to the effective refractory period, with local stimulus response latency increasing to 18-3 ± 1-4 ms (380 ±7-9%) at 10 ms proximity (/><0-002) and to 27-9 ± 3-7 ms (630 ±13-2%) proximity, respectively (/ > <00001) (Figs 3 and 4). Atrial propagation time remained essentially constant throughout the entire range of extrastimulus intervals. The maximal increase of the propagation time was 140±8-4%, which was not significant (Figs 3 and 4). DIVERGENCE BETWEEN STIMULUS INTERVALS AND FUNCTIONAL ATRIAL RESPONSE INTERVALS The extrastimulus coupling intervals and the corresponding atrial response intervals differed by the amount of the local stimulus response latency. As local stimulus response latency increased progressively with premature extrastimulation, the difference between the extrastimulus coupling intervals and the atrial response coupling intervals became more pronounced, i.e. the progressive shortening of the extrastimulus intervals was not paralleled by an equal shortening of the corresponding atrial response intervals (Fig. 5). Discussion This study demonstrates that the local stimulus response latency may represent a substantial part of what is usually considered conduction time in the human atrium. It also shows that local latency increases progressively with extrastimulation at successively decreasing coupling intervals while the propagation time between the elicited monophasic action potential and the

4 Stimulus response latency in the human atrium a s & A Proximity (ma) Figure 3 Local stimulus response latency ( ) and propagation time ( ) as a function of the extrastimulus proximity to the effective refractory period. n = 38; SEM not shown for clarity Proximity (ms) Figure 4 Effect of premature extrastimulation (referenced as proximity to the effective refractory period) on changes of local stimulus response latency ( ) and intra-atrial propagation time (A), n = 38. remote monophasic action potential remains essentially unchanged during the entire range of premature stimulation. SIMULTANEOUS DETERMINATION OF LOCAL LATENCY AND PROPAGATION TIME We could separate the contributions of local latency and propagation time by using a monophasic action potential recording/pacing combination catheter technique. With this technique, stimulation and recording occur at nearby myocardial sites' 4 " 6 '. The pacing electrodes are specifically configured which provides S2 (ms) 320 Figure 5 With progressively premature extrastimulation (S1-S2), local latency at the stimulation site increased. As a result, the shortening of the premature extrastimulus coupling interval (Sl- S2) was not paralleled by an equal shortening of the corresponding atrial response interval (MAP1-MAP2); i.e. local stimulus response latency during premature extrastimulation curbed the targeted atrial response interval (shaded area). extremely low pacing thresholds' 41, and consequently, minimal stimulus artifacts. The stimulus artifacts did not interfere with the simultaneously recorded monophasic action potentials, which allowed us to make a clear distinction between the stimulus pulse and the evoked local myocardial response. Thus, the local stimulus response latency could be evaluated precisely and distinguished from the propagation time of the impulse to the remote recording site. LOCAL STIMULUS RESPONSE LATENCY DURING PREMATURE STIMULATION In clinical studies, a delay in the myocardial response to early premature stimulation commonly is considered to be due to intra-atrial slowing of impulse propagation' 1 ' 2 '. This study shows that it is not the intra-atrial propagation delay, but the local stimulus response latency which is mainly responsible for a delayed myocardial response during premature stimulation. This was reflected in a 630% prolongation of the local stimulus response latency during premature extrastimulation, which was much greater than the 14% prolongation of the propagation time. The most pronounced delay of the stimulus response occurred during incomplete repolarization of the preceding atrial repolarization phase. This suggests that the local stimulus response latency results from incomplete recovery of excitability of the tissue adjacent to the stimulation electrodes. Application of an extrastimulus early during the repolarization phase where excitability is only partially recovered causes a delay of the evoked stimulus response until the recovery process is more complete. The amount of local stimulus response latency depends on the incompleteness of the

5 1924 B. S. Roller et al. recovery process at the time of extrastimulation and therefore increases with the prematurity of stimulation. Our hypothesis is consistent with results from previous basic and clinical studies' 3 ' 7 " 91, which demonstrated a close relationship between conduction time increase and premature extrastimulation or stimulation during the relative refractory period. Basic research 181 suggested first that this increase was due mainly to changes in the stimulus response latency and that the subsequent impulse propagation was only slightly affected. Early experimental cellular studies' 71 found that cathodal stimulation during phase 3 repolarization prolonged the stimulus response interval between the stimulation cathode and close bipolar recording electrodes. Transmembrane recordings demonstrated that the electrical impulse propagated extremely slowly next to the stimulation site but propagated with normal conduction velocity at more distant sites 171. A more recent study on recovery of excitability using microelectrodes and voltage clamp techniques in pig ventricular myocytes showed that prolongation of the intracellular stimulus response interval was associated with partial recovery of the repolarizing currents' 101. This experimental 'in vitro' finding is consistent with our clinical results, which showed that the local stimulus response latency was most pronounced during incomplete repolarization of the preceding monophasic action potential. The contact electrode catheter technique cannot elucidate whether local latency in the human atrium is an intracellular delay phenomenon or a localized slowing of impulse propagation in the immediate vicinity (<2 mm) of the stimulation site. Such 'slow local propagation', if it exists, is probably caused by the same cellular mechanisms i.e. incomplete recovery of repolarizing currents. PROPAGATION OF THE MYOCARDIAL RESPONSE DURING EXTRASTIMULATION The propagation time in our study was much less affected by premature stimulation. According to the described theoretical basis, this result is understandable. Atrial repolarization continues during the period of local latency; therefore, by the time the atrial stimulus response occurs, intra-atrial impulse propagation is less affected because myocardial repolarization is more complete. showed that local latency increases progressively with premature extrastimulation, whereas propagation time remains essentially unchanged. This has several important clinical implications. First, the increasing local latency during premature stimulation causes the atrial response coupling intervals to exceed the corresponding extrastimulus intervals, i.e. local latency curbs the targeted response interval. Second, local latency, and not an increase in propagation time, seems to be the main cause for differences between the functional refractory period and the effective refractory period during programmed stimulation in the human atrium. Finally, local stimulus response latency should be considered in pace mapping to avoid misinterpretations of slow conduction'" 1. References [1] Cosio F, Palacios J, Vidal J el al. Electrophysiologic studies in atrial fibrillation. Am J Cardiol 1982; 51: [2] Simpson R, Amara I, Foster et al. Thresholds, refractory periods, and conduction times of the normal and diseased human atrium. Am Heart J 1988; 116: [3] Buxton A, Waxman H, Marchlinski F el al. Atrial conduction: Effects of extrastimuli with and without atnal dysrhythmias. Am J Cardiol 1984; 54: [4] Franz MR, Chin MC, Sharkey HR et al. A new single catheter technique for simultaneous measurement of action potential duration and refractory period in vivo. J Am Coll Cardiol 1990; 16: [5] Franz MR. Long-term recording of monophasic action potentials from human endocardium. Am J Cardiol 1983; 51: [6] Franz MR, Burkhoff D, Spurgeon H et al. In vitro validation of a new cardiac catheter technique for recording monophasic action potentials. Eur Heart J 1986; 7: [7] Kao C, Hoffman B. Graded and decremental response in heart muscle fibers. Am J Physiol 1958; 194: [8] Brooks C, Hoffman B, Suckling E et al. Excitability of the heart. New York: Grune & Stratton, [9] Spach M, Dolber P, Heigage J. Influence of the passive anisotopic properties on directional differences in propagation following modification of the sodium conductance in human atrial muscle. A model of reentry based on anisotropic discontinuous propagation. Circ Res 1988; 62: [10] Delmar M, Michels D, Jalife J. Slow recovery of excitability and the Wenckebach phenomenon in the single pig ventricular myocyte. Circ Res 1989; 65: [II] Stevenson W, Weiss J, Wiener I et al. Fractionated endocardial electrograms are associated with slow conduction in humans: evidence from pace-mapping. J Am Coll Cardiol 1989; 13: CLINICAL IMPACT OF DISTINCTION BETWEEN LOCAL STIMULUS RESPONSE LATENCY AND PROPAGATION TIME The distinction between local stimulus response latency and propagation time in the human atrium