Inhibition in the human heart.

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 Sc preceded S2 and still inhibited S2. With currents of SC of 10.0 mA or less, SC inhibited S2 in the ventricle (n = 1 1) and atriumn (n = 5) when Sc preceded S2 by 40 to 160 msec (mean 85 msec) and 80 to 190 msec (mean 116 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 Structural Patient heart Clinical No. Age Sex disease arrhythmia 1 77 M CAD VT 2 61 M CAD VT 3 63 M CAD SSS 4 59 M CM VT 5 48 M CAD VTI/VF 6 56 M None VT 7 40 F None Bradycardia 8 46 F None AVN reentry 9 56 M CAD VT 10 16 M CAD VT/VF 11 50 M CAD VT 12 57 M None VT 13 48 M MVP VT 14 59 M CAD VT 15 61 M CAD VT/VF 16 38 M CAD 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