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PATHOPHYSIOLOGY AND NATURAL HISTORY ELECTROPHYSIOLOGY Inhibition in the human heart ERIC N. PRYSTOWSKY, M.D., AND DOUGLAS P. ZIPES, M.D. Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017 ABSTRACT Subthreshold electrotonic depolarizations have been shown to exert inhibitory actions on impulse conduction and generation in isolated cardiac tissues. We performed this study to determine whether inhibition occurs in human myocardium, and to investigate the effects of time and voltage, as well as distance, on myocardial inhibition. Sixteen subjects were studied in the clinical electrophysiology laboratory by standard techniques. Atrial and ventricular pacing were performed with the use of a quadripolar catheter. The basic drive train (S ) and premature stimulus (S2) were introduced at the distal bipolar electrode pair through one current output generator and the subthreshold conditioning stimulus (SC) was introduced before S2 at the distal or proximal bipolar pair through a separate current output generator. When SC was initiated at the distal electrodes 40 msec before S2 inhibition of S2 could always be demonstrated (atrium or ventriclej. Since SC was introduced progressively earlier than S29 Sc inhibited the response to S2 according to a curvilinear strength-interval relationship; increasing milliamperes of S from less than 1.0 to 10.0 increased the interval at which preceded S2 and still inhibited S2. With currents of of 10.0 mA or less, inhibited in the ventricle (n = 1 1) and atriumn (n = 5) when and 80 to 190 msec 40 to 160 msec 85 116 Sc SC preceded S2 by Sc SC S2 (mean msec) (mean msec), respectively. Ventricular inhibition attempted with Sc at the proximal bipolar pair and S a.t the distal pair was successful in three of nine patients. The effect of Sc on ventricular excitability threshold of S2 was determined in three patients. For all three patients the current threshold of S2 varied directly as a function of the magnitude of current used for S These data demonstrate that (1) subthreshold stimuli can prevent subsequent threshold stimuli from depolarizing human atrium and ventricle, (2) inhibition is both time and voltage dependent, and (3) inhibition is more effective if the inhibitory stimulus is applied close to the site of the threshold stimulus. Inhibition most likely occurs by Sc electronically affecting the response of the tissue to S29 possibly in part by modifying myocardial excitability threshold, thereby preventing S2 from initiating an active response. Circulation 68, No. 4, 707-713, 1983. . THAT AN electrical stimulus that does not completely depolarize myocardium has the ability to interact with a subsequent stimulus that activates myocardium has been known for some time. Drury and Love' showed in the frog ventricle that a subthreshold electrical stimulus initiated before a threshold stimulus could prevent the threshold stimulus from evoking a recordable ventricular depolarization. Lewis and Drury2 made similar observations in the dog atrium. Tamargo et al .3 demonstrated that subthreshold stimuli could inhibit threshold stimuli from activating canine ventricle. The phenomenon of inhibition and its properties From the Krannert Institute of Cardiology, the Department of Medicine, Indiana University School of Medicine, and from the Veterans Administration Medical Center, Indianapolis. Supported in part by the Herman C. Krannert Fund, Indianapolis, by grants HL-06308, HL-07182, and HL-18795 from the National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, and the American Heart Association, Indiana Affiliate, and the Veterans Administration, Indianapolis. Address for correspondence: Eric N. Prystowsky, M.D., Clinical Electrophysiology Laboratory, Indiana University School of Medicine, 1100 West Michigan St., Indianapolis, IN 46223. Received Feb. 21, 1983; revision accepted June 9, 1983. Vol. 68, No. 4, October 1983 have not been delineated in the human heart. The purpose of this investigation was to determine whether inhibition in human atrium and ventricle occurs, and to analyze the effects of time and voltage as well as distance on inhibition in the human ventricle. Methods Sixteen patients in a postabsorptive nonsedated state and with a variety of arrhythmias (table 1) were studied in the electrophysiology laboratory. All patients gave informed written and verbal consent before entering the study. There were 14 men and two women in the study with a mean age of 52 + 14 years. Three to four electrode catheters were inserted percutaneously into the femoral and/or brachial veins and positioned under fluoroscopic guidance to multiple areas of the heart. In all patients ventricular pacing was performed with a quadripolar catheter (USCI) with 10 mm interelectrode distance. The right ventricular catheter for all studies was positioned at the apex. Atrial pacing was performed with a quadripolar catheter with 5 mm interelectrode distance (USCI) that was positioned in the high right atrial area. A second atrial catheter was positioned near the first atrial catheter to record the bipolar atrial electrogram. Pacing protocol. For the inhibition studies in the atrium or ventricle, the following protocol was used. A programmable custom-built stimulator (MECA) was used to pace the heart with 707 PRYSTOWSKY and ZIPES TABLE 1 Patient characteristics Patient No. Age Sex M M M M M M 10 77 61 63 59 48 56 40 46 56 16 11 50 12 13 14 15 16 57 48 59 61 38 M M M M M M 1 2 3 4 5 6 7 8 9 F F M M Structural heart disease Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017 CAD CAD CAD CM CAD None None None CAD CAD CAD None MVP CAD CAD CAD Clinical arrhythmia VT VT SSS VT VTI/VF VT Bradycardia AVN reentry VT VT/VF VT VT VT VT VT/VF VF AVN = atrioventricular node; CAD coronary artery disease; CM cardiomyopathy; MVP = mitral valve prolapse; SSS = sick sinus syndrome; VF = ventricular fibrillation; VT = ventricular tachycardia. rectangular pulses (WPI) delivered through an isolation unit for the basic drive train (SI) and the premature stimulus (S2). The pulse width of SI and S2 was 2.0 msec and the current used was twice late-diastolic threshold (1.0 to 1.4 mA). A second current output generator (WPI) that delivered 2 msec rectangular stimuli through an isolation transformer was used to introduce the conditioning stimulus (Sc). The SI, S2, and S, stimuli were bipolar and, regardless of whether the distal or proximal bipolar electrode pair on the quadripolar catheter were used for stimulation, the distal pole of the pair was always the cathode and the proximal pole the anode. Ventricular and atrial refractoriness were determined by stimulating the myocardium with a train of eight complexes and after each eighth complex a premature stimulus was introduced beginning in late diastole. The SIS2 interval was shortened progressively until S2 consistently failed to evoke a response. The longest SIS2 interval that did not result in myocardial depolarization on two consecutive attempts was defined as the effective refractory period of the tissue being tested. To test for ventricular inhibition, the stimulator delivering the basic train and premature interval was set at a fixed SISI and S1S2 interval. The SIS2 interval was 10 to 20 msec longer than the effective refractory period and S2 always produced a ventricular response. Then, with the use of a separate current generator, Sc was introduced beginning 20 msec before the occurrence of S2 and within the duration of the ventricular effective refractory period. The current of S, always was subthreshold and by itself Sc never produced a ventricular response. As the current of SC was increased, especially at levels of 6.0 mA or more, SC was periodically introduced without S2 to ensure that SC by itself did not result in myocardial depolarization. The current level of S, was increased in 0.1 to 0.3 mA increments until SC inhibited ventricular depolarization of S2. At this point, the current level of SC was kept constant but the S, stimulus was moved 10 msec earlier than the previous ScS2 interval. If SC failed to inhibit S2 then the mA was again increased progressively until Sc inhibited S2. This process was repeated until an ScS2 interval was obtained at which an SC of 10 mA no longer inhibit708 ed S2. In 11 patients SI, S2, and S, were initiated at the distal bipolar pair and the proximal bipolar pair was used to record the local electrogram. In nine patients S I and S2 were initiated at the distal bipolar electrode pair but Sc was introduced at the proximal bipolar pair. For these patients the catheter was positioned so that late-diastolic pacing threshold was similar for the distal and proximal bipolar pair. For atrial inhibition a protocol similar to that detailed above for ventricular inhibition was used. Five patients underwent this protocol and for all five patients, SI, S2 and S, were initiated at the distal bipolar pair. A second electrode catheter positioned near the first catheter was used to record atrial potentials because the stimulus artifact often obscured atrial depolarization recorded from the same catheter that delivered the stimulus. The effect of Sc on threshold of S2 in the ventricle was investigated in patients 14 through 16. For each patient SI, S2, and Sc were delivered at the distal bipolar electrode pair. Stimuli for SI and S2 were initiated from a separate current output generator than stimuli for S, (see above). Pulse width for all stimuli was 2.0 msec. The SIS2 interval was 10 to 20 msec longer than the ventricular effective refractory period and S2 without Sc always depolarized the ventricle. The ScS2 interval was 50 msec and did not vary throughout the study. Initial current of S2 was twice late-diastolic threshold. Then, as the current of Sc was increased stepwise to inhibit S2, the current level of S2 was increased by 0.1 mA increments until S2 again produced a ventricular response. All Sc stimuli were subthreshold. In six patients we tested for summation in the ventricle. For all patients, SI, S2, and Sc stimuli were introduced at the distal bipolar pair, the pulse width of S, and S2 was 2.0 msec, and the current used was twice late-diastolic threshold. The stimulator used for the basic train and premature interval was set at a fixed SS5 and SIS2 interval. The SIS2 interval was always 10 msec less than the effective refractory period and S2 never produced a ventricular response when delivered alone. With a separate current generator, one or two subthreshold stimuli, each of 2.0 msec duration, were introduced up to 6 msec before S2. If ventricular depolarization occurred with S2 plus the subthreshold stimuli, S2 was tested again without Sc to ensure that S2 by itself still did not result in ventricular depolarization; similarly, the subthreshold stimuli were introduced without S2 to ensure that they did not institute ventricular depolarization. Summation was considered to be present when S2 plus subthreshold stimuli produced ventricular depolarization but S2 or subthreshold stimuli alone did not. Data from multiple surface and intracardiac leads were recorded on an oscilloscopic recorder (Electronics for Medicine VR12) at a paper speed of 100 mm/sec and stored on a tape recorder (Hewlett Packard No. 3968A). Electrocardiographic surface leads were filtered at 0.1 to 20 Hz and signals from intracardiac leads were filtered at 30 to 500 Hz. Results Ventricular inhibition. Eleven patients underwent ventricular inhibition testing and their data are listed in table 2. When the SI, S2, and SC were applied at the distal bipolar pair all patients demonstrated inhibition in the ventricle. For the entire group the maximum mean ScS2 interval at which inhibition still occurred at 10 mA or less was 85 msec, with a range of 40 to 150 msec. Figure 1 illustrates analog data from one patient. The S,S2 interval was 270 msec and this was held constant for the entire study. Figure 1, left demonCIRCULATION PATHOPHYSIOLOGY AND NATURAL HISTORY-ELECTROPHYSIOLOGY TABLE 2 Electrophysiologic parameters Longest S S2 interval (msec) at which S SS Patient PCL ERP No. (msec) (msec) (msec) Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017 Ventricle 1 500 290 300 2 500 240 250 3 500 240 250 4 600 230 250 5 500 260 270 6 500 240 250 7 600 250 260 S2 at: Sc site IC 1.0 IC 1.5 IC 2.0 IC 2.5 IC 3.0 IC 3.5 IC 4.0 IC 4.5 IC 5.0 IC 6.0 IC 7.0 IC 8.0 IC 9.0 IC 10.0 NI NI 40 NI 20 NI NI NI NI NI NI NI NI NI NI NI NI NI NI 10 NI NI 50 NI NI 60 30 40 60 60 40 70 90 40 70 90 40 70 90 40 80 90 50 80 90 60 80 90 60 90 90 60 120 90 80 130 100 80 140 30 50 60 60 70 80 80 80 80 80 80 80 80 20 20 20 20 20 20 20 30 30 40 40 40 40 30 20 NI 40 40 30 70 60 30 70 70 40 80 70 50 80 90 50 90 90 60 120 120 60 150 120 60 150 130 60 150 130 60 150 130 60 150 130 70 NI NI NI 40 NI 40 NI 30 40 NI 30 50 NI 30 50 20 40 50 20 50 50 20 50 70 90 90 - - - NI 40 NI NI 50 60 60 90 60 20 20 30 30 30 50 50 50 60 90 90 90 90 NI 10 NI 20 NI 20 NI 30 NI 30 NI 30 NI 30 NI 30 NI 50 40 50 50 50 50 50 50 60 NI NI NI NI NI NI NI NI NI NI NI 20 NI 20 NI NI 20 NI 20 NI 30 30 NI 30 30 40 30 NI 30 40 40 30 NI 30 40 50 40 NI 40 50 60 40 NI 50 60 70 70 NI 50 70 80 70 70 60 80 80 80 80 190 80 80 80 80 190 80 80 80 80 190 80 8 500 230 250 9 600 220 240 500 600 220 280 240 290 D P D P D P D P D P D P D P D P D P D D 600 500 500 600 600 250 210 220 260 250 270 220 230 280 270 D D D D D 10 11 Atrium 7 8 9 12 13 inhibited IC = inhibition current (mA of S,); PCL = pacing cycle length; ERP = effective refractory period; D = distal bipolar pair; P = proximal bipolar pair; NI = no inhibition. strates the maximum current for each Sc 2 interval at which the conditioning stimulus did not inhibit S2' while figure 1, right illustrates the minimum current at which Sc always inhibited S2. As shown, more current is needed for SC to inhibit S2 as S, precedes S2 at increasing intervals. The current of S, required to inhibit S2 plotted as a function of the time at which S, precedes S2 demonstrates a curvilinear relationship; the current required for Sc to inhibit S2 varies directly as the SCS2 interval increases (figure 2). The maximum ScS2 interval at which Sc inhibits S2 is 150 msec, achieved at a current of 6.4 mA. Currents of 6.6 to 10 mA did not produce any greater degree of inhibition. In fact, for the entire group of 11 patients, the maximum mean ScS2 interval at which Sc still inhibited S when currents for Sc were less than 5 mA was 56 msec, with a range of 0 to 110 msec. Therefore, approximately two-thirds of the maximum ScS2 interval at which SC still inhibited S2 occurred at current strengths for Sc of 5.0 mA or less. Vol. 68, No. 4, October 1983 In nine patients the conditioning stimulus was applied at the proximal ventricular pacing pair and the S, and S2 stimuli were applied at the distal pair. Six patients showed no inhibition at all during this pacing protocol, and for all nine patients the maximum mean ScS2 interval at which inhibition occurred with up to 10 mA current strength for S, was 26 msec, with a range of 0 to 130 msec. The maximum mean S S2 interval obtained with currents for Sc of 5.0 mA or less was 17 msec, with a range of 0 to 90 msec. As seen in figure 2, Sc delivered at the proximal bipolar electrode pair inhibited S2 delivered at the distal pair less effectively than when Sc and S2 were both delivered at the distal bipolar pair. This relationship is even more dramatically demonstrated in figure 3, in which almost the entire strength-interval inhibition curve using the proximal bipolar pair for Sc was shifted upward and to the right. We compared the effectiveness of inhibition of Sc delivered at the proximal and distal electrode pair in the three patients in whom inhibition occurred with the 709 PRYSTOWSKY and ZIPES SC initiated at either the proximal or distal bipolar electrode pair. The mean maximum ScS2 inhibition interval with currents of 10 mA or less for S was 113 msec (range 90 to 150) with Sc at the distal electrode pair vs 77 msec (range 20 to 130) with Sc at the proximal electrode pair. When S. was 5.0 mA or less, maximum mean S S2 inhibition interval was 83 msec (range 50 to 110) vs 50 msec (range 20 to 90) with Sc at the distal and proximal electrode pair, respectively. Thus, inhibition was much more effective when the Sc was applied nearer to the point at which S. was delivered. Atrial inhibition. Atrial inhibition occurred in all five patients tested. The maximum mean S S. interval at which Sc still inhibited S, was 102 msec, with a range of 80 to 190 msec. The maximum mean Sc 2 interval at which Sc still inhibited S with S of 5.0 mA or less was 36 msec (range 0 to 50). In other words, a significant portion of inhibition (65%) could be obtained as the milliamperes of Sc exceeded 5.0 mA, in contrast to results for ventricular inhibition. Analog data from a typical experiment are shown in figure 4 in a format similar to figure 1. Figure 4, left illustrates, for each SCS2 interval, the maximum milliamperes of SC that still did not inhibit S2 and figure 4, right illustrates the minimum milliamperes of SC that always inhibited S2. Inhibition in this patient occurred up to an SC2 interval of 150 msec. Figure 5 illustrates graphically the relationship between milliamperes of SC and the' SS2 interval. III SCS2 = 30 RV S USc LS2 Sc=1 Ilm Sc = 1.4mA Sc RV =1.6mA SCS2=80 Sc=3.8mA Sc=3.6mA RV SCS2=130 Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017 Sc= 5.6mA Sc =5.4mA SCS2 =150 RV Sc=6.4mA Sc=6.2mA FIGURE 1. Inhibition of human ventricle (patient 5). The SI S2 interval for this patient was 270 msec. Left, For each ScS2 interval the highest S, (mA) at which no inhibition occurred. Right, The lowest Sc (mA) at which S2 was inhibited. As the Sc52 interval increases the current of S, needed to inhibit S2 increases. Time line intervals are 50 msec. RV right ventricle. 10- * 0 9- * 0 8- * 0 * 0 SlS2=270 msec 7- * Distal Sc o Proximal Sc 0 0 S E a822 5.- 0 co, 0 4- 0 3- *g 2 2- 0 i 1I E) %R- X I I I 170 160 150 140 I l 130 120 110 l I 100 90 80 70 -I l-II 60 50 40 I 30 I 20 SCS2 (msec) FIGURE 2. Inhibition strength-interval curve for patient 5. When the proximal bipolar electrode pair is used to initiate SC (unfilled circles) the maximum degree of inhibition of SC is 20 msec less than when the SC is initiated at the distal bipolar pair (filled circles). See text for details. 710 CIRCULATION PATHOPHYSIOLOGY AND NATURAL HISTORY-ELECTROPHYSIOLOGY 10-1 0 0 9- 0 0 S1S2=300 msec * Distal Sc 8- o Proximal 7- 6- E 5- co 4- Sc 0 0 0 * FIGURE 3. Ventricular inhibition as a function of the site of the inhibitory stimulus in patient 1. This curve demonstrates an upward and rightward shift when SC is initiated at the proximal bipolar electrode pair (unfilled circles) compared with at the distal pair (filled circles). c 3- * 0 8 * a OD 2- Iv. I* I 1 120 110 100 I I I I I I I I I 90 80 70 60 50 40 30 20 10 0 Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017 SC S2 (msec) VI S1 SC S2 SCS2 O HRA1 ScS2 =30 A2 N HRA2 Sc=3.OmA Sc=2.8mA SC Sc ScS2= 80 HRA2 Sc= 4.8mA Sc= 5.OmA SC SC Effects of SC on threshold. In patients 14 through 16 the effect of SC on threshold of S2 was investigated. For all patients, as the current of SC was increased to 10.0 mA or less to inhibit S29 inhibition could be overcome by the use of higher milliamperes for S2 (figure 6). Thus, the threshold of S2 appeared to vary directly as a function of the magnitude of current used for SC. Ventricular summation. Summation was present in only one of six patients. One subthreshold stimulus plus S2 never produced ventricular depolarization. In one patient, two subthreshold stimuli caused summation (figure 7). In figure 7, A, at an S,S2 interval of 230 msec, S2 did not result in ventricular depolarization. Figure 7, B shows no summation after two subthreshold stimuli initiated 6 msec (SIS3 224 msec) and 8 msec (SIS4 222 msec) before S2' Summation is illustrated in figure 7, C and it occurred when the second subthreshold stimulus was moved 1 msec closer to S2 (SIS4 223 msec). HRA1 Sc SCS2=120 HRA2 SC Sc Sc= 7.5mA Sc=7.7mA SC SC HRAl ScS2= 150 HRA2 I c Sc= 9.8mA Vol. 68, No. 4, October 1983 Sc= 10.0mA Discussion In this study we demonstrate that subthreshold stimuli can prevent subsequent threshold stimuli from depolarizing human atrium and ventricle, as noted earlier in animal investigations." We further show that inhibition is both time and voltage dependent, and is markedly more effective if the inhibitory stimulus is delivered at the same site as the S2' These properties of FIGURE 4. Inhibition of human atrium in patient 12. The format is; similar to that of figure 1. Since Sc occurs progressively earlier before S2 more current is required for S2 to inhibit the atrium. HRA = high right atrium. 711 PRYSTOWSKY and ZIPES 10- . 9- S1S2= 240 msec 80 0 7- 60-1. E 0 5- 0 0 0 co, 40 3- 0 0 0 0 21- 0 fl. I I I I I I Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017 170 160 150 140 130 120 110 . I I I 100 90 I 80 I 70 60 50 -| I I 40 I 30 20 SCS2 (msec) FIGURE 5. Inhibition strength-interval relationship in atrium of patient 12. Please note that in addition to an increased current of SC required to inhibit S2 as the ScS2 interval progressively increases, a significant amount of inhibition occurs with currents for Sc of more than 5 mA. inhibition may be explained by several mechanisms but are cc insistent with the possibility that S, electronically affe cts the response of the tissue to S2, thereby preventin g S2 from initiating an active response. Severa 1 studies5-'0 have shown that subthreshold electrotor Pic depolarizations can exert inhibitory actions on iimpulse conduction as well as impulse generation in is(olated cardiac tissues. The inhibitory effects on impulsse generation include the ability of subthreshold depol .arization to delay the scheduled discharge of a spontanieous pacemaker' and the ability to annihilate or terminate pacemaker cycling.8 In a more recent study'0 it was demonstrated that electrotonic interac4.0Patient Number 0 A 3.0- 14 16 a*16 CO) - E 2.0 - 1.0 . 10.0 8.0 6.0 mA 4.0 2.0 0 (Sc) FIGURE 6. Threshold of S2 as a function of current for Sc. For each patient, the points plotted represent the milliamperes of S2 needed to depolarize tI he ventricle at various milliamperes of Sc. See text for more detail. 712 tions resulting from a nonconducted response could impair the transmission of an impulse arriving later in time at a zone of depressed conductivity. Electrotonic depolarizations exerted a graded voltage and time-dependent inhibitory effect on the conduction of subsequent beats. Specifically, a subthreshold stimulus more effectively inhibited a threshold stimulus from producing a response if it occurred closer in timing to the threshold stimulus. At a fixed ScS2 interval, higher voltage of the Sc stimulus caused more effective inhibition. Our observations in human myocardium parallel these results. As noted in table 2 and figures 2, 3, and 5, the current of SC required to inhibit S2 is related to the ScS2 interval. Furthermore, at a constant ScS2 interval, the amount of current of S2 needed to depolarize the ventricle increases as the milliamperes of SC increase. Thus, it appears that S, inhibits S2 in part by modifying myocardial excitability threshold. Inhibition has also been demonstrated in branched Purkinje fibers, the branch points of which were encased in high-K agar. II Under these conditions, excitation of the branch by a wave front arriving from one end of the preparation could be inhibited by appropriately timed stimulation of the opposite end of the preparation. To explain this phenomenon of spatial inhibition it was suggested that stimulation of the inhibitory end gives rise to an action potential that may invade and die out in some fibers of the bundle. Those fibers would then be unable to participate in the excitatory response to which they would normally have contribut- CIRCULATION PATHOPHYSIOLOGY AND NATURAL HISTORY-ELECTROPHYSIOLOGY c B VI' HBE' RV- i I {E I I 11 1 FIGURE 7. Summation in the ventricle. Premature interval (S1S2) of 230 msec never by itself resulted in ventricular depolarization (A). Subthreshold stimuli 6 msec (SIS3) and 8 msec (S S4) before S2 plus S2 do not cause ventricular depolarization (B), but when SIS4 is moved 1 msec closer to S2 ventricular activation occurs. Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017 ed. This mechanism, however, cannot adequately explain our observations since Sc stimuli well within the refractory period of the myocardium tested were able to inhibit S2 (figures 1 and 4). Under these conditions, electrotonic displacement of membrane potential by Sc is more likely than active invasion of surrounding tissue. Further work is needed to define the mechanism(s) responsible for electrotonic inhibition in myocardium. Additionally, our patients had a variety of arrhythmias and most, but not all, had structural heart disease; it is not known whether the results of this study can be extrapolated to the general population. Although inhibition occurred in all patients tested, summation could be demonstrated in only one patient. In this patient a total of three stimuli were necessary to evoke a ventricular response, a finding noted earlier by Tamargo et al.3 The findings in this study suggest potential clinical applications for the use of subthreshold stimuli to prevent tachyarrhythmias in humans. It is possible that atrial or ventricular arrhythmias may be prevented by applying subthreshold stimuli to one or more areas of the heart after a threshold depolarization (induced or spontaneous) has occurred. For example, a patient with a tachyarrhythmia may have the arrhythmogenic focus identified during epicardial or endocardial mapping. A single electrode or an array of electrodes could then be permanently placed at or near the focus, and a pacemaker generator could deliver one or more subthreshold stimuli at a predetermined time after normal Vol. 68, No. 4, October 1983 and/or premature complexes. Other investigators4 have demonstrated a protective zone for ventricular fibrillation. In their studies a second stimulus delivered during a critical interval after a fibrillatory stimulus was shown to protect against ventricular fibrillation. Our data suggest that a similar protective zone may precede the precipitating event. References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. Drury AN, Love WS: The supposed lengthening of the absolute refractory period of frog's ventricular muscle by veratrine. Heart 13: 77, 1926 Lewis T, Drury AN: Revised views of the refractory period in relation to drugs reputed to prolong it, and in relation to circus movement. Heart 13: 95, 1926 Tamargo J, Moe B, Moe GK: Interaction of sequential stimuli applied during the relative refractory period in relation to determination of fibrillation threshold in the canine ventricle. Circ Res 37: 534, 1975 Verrier RL, Lown B: Prevention of ventricular fibrillation by use of low-intensity electrical stimuli. Ann NY Acad Sci 382: 355, 1982 Weidman S: Effect of current flow on membrane potential of cardiac muscle. J Physiol (Lond) 115: 227, 1951 Wennemark JR, Ruesta VJ, Brody DA: Microelectrode study of delayed conduction in the canine right bundle branch. Circ Res 23: 753, 1968 Jalife J, Moe GK: Effect of electrotonic potentials on pacemaker activity of canine Purkinje fibers in relation to parasystole. Circ Res 39: 801, 1976 Jalife J, Antzelevitch C: Phase resetting and annihilation of pacemaker activity in cardiac tissue. Science 206: 695, 1979 Antzelevitch C, Moe GK: Electrotonically mediated delayed conduction and reentry in relation to "slow responses" in mammalian ventricular conducting tissue. Circ Res 49: 1129, 1981 Antzelevitch C, Moe GK: Electrotonic inhibition of impulse transmission across inexcitable segments of cardiac tissue. Circulation 66 (suppl II): 11-358, 1982 (abst) Cranefield PF, Hoffman BF: Conduction of the cardiac impulse. II. Summation and inhibition. Circ Res 28: 220, 1971 713 Inhibition in the human heart. E N Prystowsky and D P Zipes Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017 Circulation. 1983;68:707-713 doi: 10.1161/01.CIR.68.4.707 Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 1983 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7322. Online ISSN: 1524-4539 The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circ.ahajournals.org/content/68/4/707.citation Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. 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