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Effects of Cycle Length Cardiac Refractory Periods in Man The on By PABLO DENES, M.D., DELON RAYMOND J. PIETRAS, M.D, RAMESH DHINGRA, M.D., KENNETH M. ROSEN, M.D. WU, M.D., AND SUMMARY Downloaded from http://circ.ahajournals.org/ by guest on April 30, 2017 The effects of pacing-induced changes in cycle length on the refractory periods of the atrium, A-V node and His-Purkinje system were studied in 24 patients using the extra stimulus technique. Refractory period determinations were made at two or more cycle lengths in all patients. Slopes relating cycle length and refractory periods were calculated using the least squares method. Both the effective and functional refractory periods (ERP and FRP) of the atrium shortened with decreasing cycle lengths, with a mean slope of +0.155 and +0.129 respectively. A-V nodal ERP lengthened (mean slope, -0.177) while A-V nodal FRP shortened slightly (mean slope, +0.126). Bundle branch refractory periods as well as relative refractory periods of the His-Purkinje system also decreased, with mean slopes of +0.270 and +0.360, respectively. The ERP of the A-V node at any cycle length was related to the A-H at that cycle length (r = +0.646, P < 0.001). The responses of the human heart to changes in cycle length are generally similar to those previously described in the animal laboratory. Such information contributes to our understanding of electrocardiographic phenomena such as aberrant conduction. Additional Indexing Words: His bundle electrogram Functional refractorv period Premature atrial impulses Relative refractory period IN ISOLATED HEART TISSUE, as cycle length changes, action potential durations and refractory periods are altered.' Mendez et al., working with intact denervated canine hearts, noted that the functional refractory periods of the atrium, A-V node, His bundle, and bundle branches shortened as cycle length was decreased.2 These changes were least apparent in the A-V node and most striking in the His-Purkinje system. The purpose of the present study was to examine the effect of pacing-induced changes in cycle length Effective refractory period Aberrant conduction on the refractory periods of the atrium, A-V node, and His-Purkinje system in man. Methods Refractory periods were determined in 24 patients during diagnostic cardiac catheterization. All patients were in sinus rhythm and had normal QRS duration (0.10 sec or less) and normal conduction intervals as determined by His bundle recording technique.3 The mean age of the patients was 41 years (range 15-77), and there were 18 males and six females. Clinical and electrocardiographic data as well as control conduction intervals are summarized in table 1. Only two patients had received cardioactive drugs within the week prior to study (procaine amide in patient 4 and digoxin in patient 8). Both drugs were discontinued 48 hours prior to study in these latter two patients. His bundle electrograms were recorded with a tripolar catheter placed close to the tricuspid valve.4 Atrial electrograms were recorded through two electrodes of a quadripolar catheter positioned fluoroscopically against the lateral wall of the high right atrium. The remaining two electrodes were used for atrial pacing. Interelectrode distances were one centimeter. Recordings were obtained on a multichannel oscilloscopic recorder (Electronics for Medicine, DR-16, White Plains, New York) at paper speeds of 100 and 200 From the Section of Cardiology, Department of Medicine, Abraham Lincoln School of Medicine and the University of Illinois College of Medicine, and the West Side Veterans Administration Hospital, Chicago, Illinois. Supported in part by NIH contract 71-2478 under the Myocardial Infarction Program and West Side Veterans Administration Hospital BIS funds. Address for reprints: Kenneth M. Rosen, M.D., University of Illinois Hospital, P. 0. Box 6998, Chicago, Illinois 60680. Received May 4, 1973; revision accepted for publication August 30, 1973. 32 Circulaiiou, Volume XLlX, January 1974 CYCLE LENGTH AND CARDIAC REFRACTORY PERIODS 33 Table 1 Summary of Clinical Data, Electrocardiologic Data and Control Conduction Intervals for 24 Study Patients Downloaded from http://circ.ahajournals.org/ by guest on April 30, 2017 Patient number Age (years) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 67 35 19 42 54 26 13; 52 33 15 67 19 38 35 13 13 16 17 18 19 20 40 2'1 22 23 24 56 24 23 77 48 19 72 47 Sex M M M F M m M M F M M M m F M M F M M M F M M F Cardiovascular diagnosis HHD HHD No HI) ASHD ASHD JIHD ASD secundum ASHD R HD No HD PMI) ASD) secundtum No HD ASHD No HD ASHD Cale. peric. PDA Coarct. HHI) No HD No HD ASHD RHD Sinus rate QRS duration (beats/min) (sec) 90 74 75 58 103 96 94 72 78 65 0.09 0.09 0.08 0.09 35 78 85 110 92 87 84 81 86 64 73 75 5a6 93 0.08 0.10 0.08 0.08 0.08 0.10 0.09 0.10 0.08 0.08 0.06 0.06 0.07 0.09 0.09 0.09 0.09 0.07 0.09 0.08 Mean frontal QRS axis (degrees) -45 + 5 +30 +20 +20 +60 +80 +30 +60 +60 -20 +100 0 -15 +60 +40 +60 +45) +20 -10 +60 +60 +10 +50 ECG diagnosis LVH ST-T WNL ST-T ST-T LVH rr' in V1 ST-T LVH WNL LVH rr' in V1 WNL WNL ST-T WNL ST-T WNL LVH ST-T WNL WNL ST-T WNL P-A (msec) A-l- (msec) 20 65 53 1iO 19 40 15 20 20 100 92 90 130 6) 100 86 71 90 124 95 70 73 104 35 33 25 40 25 15 28 28 21 35 27 19 15 21 37 25 32 H-V (msec) 35 40 36 34 53 350 33 45 3.3 48 30 43 30 40 43 28 1]13 32 91 37 31 38 34 48 103 83 90 76 80 100 43 40 Abbreviations: P-A = interval between the beginning of the P wave and the atrial electrogram as recorded by the His bundle catheter; A-H = interval between the atrial electrogram and the His deflection; H-V = interval between the His bundle electrogram and initiation of ventricular depolarization; HHD = hypertensive heart disease; HD = heart disease; ASHD = arteriosclerotic heart disease; RHD = rheumatic heart disease; PDA = patent ductus arteriosus; ASD = atrial septal defect; PMD = primary myocardial disease; Coarct. = coarctation of the aorta; Calc. peric. = calcific pericarditis; WNL = within normal limits; LVH = left ventricular hypertrophy; ST-T = nonspecific ST and T wave changes. mm/ sec. Stimuli were approximately twice diastolic threshold, 2 msec in duration, and delivered by a programmable digital stimulator (manufactured by M. Bloom, Philadelphia, Pa.). Refractory periods were measured with the technique of extra stimulus. The extra stimulus (S2) was introduced after every tenth driven (S,) or spontaneous beat. S1-S2 intervals were decreased in 10-20 msec decrements in successive test cycles.5 Refractory periods were first determined during either sinus rhythm or at the slowest paced rate producing stable atrial capture. All patients had refractory periods determined at two or more cycle lengths. To examine the effect of cycle length on refractory periods, slopes were calculated by the least squares method for individual patients. Mean slopes (± SEM) were then calculated for refractory periods of the atria, A-V node, and His-Purkinje system. The term "significantly" was defined as a change in refractory period, statistically different from no change (zero slope). The relation between A-V nodal conduction time (A-H) and effective refractory period was analyzed using the correlation coefficient. Atrial and A-V nodal refractory periods were also Circulation, Volume XLIX, January 1974 analyzed by computing means and ranges for three absolute ranges of cycle length. These were 850 to 600 msec (heart rate of 70 to 100 beats/min), 599 to 460 msec (101 to 130 beats/min), and 459 to 330 msec (131 to 180 beats/min). A-H and H-V intervals were measured as previously described.5 A1, H1, and V1 represent the atrial, His bundle, and ventricular electrograms of either spontaneous or driven beats. A2, H2, and V2 represent the atrial, His bundle, and ventricular electrograms in response to the extra stimulus (S2). The atrial effective refractory period (ERP) was the longest S1-S2 interval in which atrial capture failed to occur. At times the coupling interval of the test stimulus was too long to determine the ERP. When this occurred, the atrial ERP was designated as being less than the shortest S1-S2 tested. Atrial functional refractory period (FRP) was the shortest attainable propagated A1-A2 interval. The A-V nodal ERP was the longest A1-A2 interval which did not propagate to the His bundle. A-V nodal FRP was the shortest propagated Hr-H2 interval. The ERP of the His-Purkinje system was the longest H1-H2 interval in which conduction to the ventricles DENES ET AL. 34 W Atr'i um 0350 400 F At r urm E 6 ° 350 (D °£300 0 0a ° 300 ,o U o 250 W:a 250 I-_ Si CL 150 Number of potients 11 Mean slope 4.1 29 D .045 S.E.M. .014 0 2 200 = c o f pa tients 11 ~~~~~~~~No. Mean slope +155 S. D. .06 S E.M. 062 L 400 500 700 600 800 Cycle length (msec) 900 u ~~~~S. 200 F a 400 1000 500 700 800 600 Cvele lenath (msec) 900 1000 Downloaded from http://circ.ahajournals.org/ by guest on April 30, 2017 Figure 1 Left) The atrial effective refractory period as a function of cycle length in 11 patients. Right) The atrial functional refractory period as a function of cycle length in 11 patients. Each patient is represented as a series of connected dots. failed to occur. This is identical to the ERP of the ventricular specialized conduction system as defined by Wit et al.5 The relative refractory period (RRP) of the His-Purkinje system was defined as the longest H1-H2 interval at which the H2-V2 interval becomes longer than HV1, interval of spontaneous or driven beats. Prolongation of H2-V2 could reflect conduction delays in the His bundle distal to the His bundle recording site and/or delays in both bundle branches. The refractory period of a bundle branch was considered the longest H1-H2 interval producing the appropriate electrocardiographic pattemn of complete bundle branch block. This refractory period could be either relative, with the critical degree of bundle branch delay necessary to produce a pattern of complete bundle branch block, or effective, with total failure of conduction in that bundle branch. All determinations could not be obtained in all patients or at every cycle length studied. Results Effect of Cycle Length on Refractory Periods Atrium. Atrial ERP was successfully measured at one or more cycle lengths in 23 patients (table 2). In patient nine, the extra stimulus was not brought 550 . 450- A V Node E0 Va 400 AV Node Number of patients 14 Mean slope - .177 S D .145 S. E.M. .040 No. of patients 15 Mean slope +.126 S D. .17 S.E.M. .045 en E 500 'V 10 <, 450 a- >, 350 a o 400 0 U 0 ,, 300 Si ° 350 l cc 0 00250- c WU U- 400 500 600 700 800 Cycle length ( msec) 900 1000 L 300, 400 1 1 500 600 -1~ - 700 800 - 9 900 000 1000 Cycle length (msec) Figure 2 Left) The A-V nodal effective refractory period as a function of cycle length in 14 patients. Right) The A-V nodal functional refractory period as a function of length in 15 patients. The crossed dots represent the atriad functional refractory period in those instances where this exceeded the A-V nodal effective refractory period. The actual value of the A-V nodal ERP can only be less than the atrial FRP at these points. Circulation, Volume XLIX, January 1974 CYCLE LENGTH AND CARDIAC REFRACTORY PERIODS 35 550r c) E 500r- a) His Purkinje System 0 -0 0. 0 Bundle Branches - ~Right BB . .Left BB 500F -o0 450- 4500- a) 4001 0 E, 0 a 0 3501 ,< . 0 300'L 400 Number ofpetients 6 ~~~Meon s lope + .27 S. D. .109 S. E. M. .044 1 500 600 700 Cycle length 4001- cr- Number of patients 7 350- Mean slope + .360 S.D. 300 L S. E. M. .065 IL4 800 900 (msec) .173 L 1000 500 400 600 700 Cycle length 800 900 (m sec) 10Z00 Downloaded from http://circ.ahajournals.org/ by guest on April 30, 2017 Figure 3 Left) Relative refractory period of the His-Purkinje system as a function of cycle length in six patients. Right) Refractory period of the bundle branches as a function of cycle length in seven patients. The crossed dots represent the A-V nodal functional refractory period in those instances where this exceeded the His-Purkinje system relative refractory period. in close enough to measure atrial ERP or FRP at cycle length. For purposes of analysis, slopes of the relationship of atrial ERP to cycle length were calculated for patients in whom four or more recordings over a cycle length range not less than 200 msec (11 patients) were made. The mean slope SEM was +0.155 0.020 msec (figs. 1 and 4). Thus, atrial ERP decreased significantly as cycle length was shortened. The means and ranges of atrial ERP for all 23 patients are given in table 3. Atrial FRP was measured in 23 patients (table 2). Slopes were calculated for all patients in whom four or more recordings over a cycle length range not less than 200 msec (11 patients) were made. The mean slope SEM was +0.129 + 0.014 msec (figs. 1 and 4). Thus, atrial FRP decreased significantly as cycle length was shortened. The means and ranges for all 23 patients are given in table 3. A-V node. A-V node ERP could be determined in 18 patients (table 2). Slopes were calculated for all patients in whom three or more determinations over a cycle length range not less than 200 msec (14 patients) were made. The values at which atrial FRP exceeded the A-V nodal ERP at the initial (longest) cycle length were also computed (patients 8, 10, and 19) for calculation of the slopes, since A-V nodal ERP could only be less than the values indicated. The mean slope-+ SEM was -0.177 + 0.040 (figs. 2 and 4). Thus, A-V nodal ERP any Circulation, Volume XLIX, January 1974 < -02 -04 -E E:mean -06 ERF FRP ATRIUM ERP FRP RRP RP A-V NODE HPS BB. Figure 4 The effect of change in cycle length on the change in refractory periods of the atrium, A-V node, and His-Purkinje system. Each point represents the mean slope of change in refractory period related to change in cycle length for individual patients. A positive value indicates that as cycle length decreases refractory periods decrease. A negative value indicates that as cycle length decreases refractory period increases. A zero value indicates no change in refractory period despite change in cycle length. ARP = change in refractory period (msec); ACL = change in cycle length (msec); ERP = effective refractory period; FRP = functional refractory period; RRP = relative refractory period; RP.= refractory period; HPS = His-Purkinje system; BB = bundle branches. Mean SEM are indicated. 36 DENES ET AL. Table 2 Electrophysiological Data for 24 Patients* Patient CL A ERP A FRP 1 630 ;)20 430 240 210 200 640 480 667 043 462 85)0 AVN ERP AVN FRP 285 265 245 <28.5 < 265 <245 43 15 55 34,5 325 65) 65 270 305 < 305 < 3153) 345 390 430 435 120 150 265 265 <24.5 290 285 <270 300 335 320 440 500 445) 100 110 120 230 225 235 285 265 29,5 28 5 280 315 420 415 415) 105 125 165 390 360 190 180 180 190 265 24 5 255 2.50 < 265 <245 <25 5 t 335 330 330 90 100 100 6 600 450 400 <270 190 195 <270 225 25)0 275 275) 275 33i5 325 - 65 105 105 7 600 445 195 2 3 4 600 490 Downloaded from http://circ.ahajournals.org/ by guest on April 30, 2017 a 70 450 8t 9 10 210 215 280 325 415 41.5 80 200 -790 580 470 420 190 250 225) 200 200 265 235 225 235 < 265 310 75 100 110 110 667 4;5 <210 <245 <215 <245 350 375 360 350 430 7615 560 290 290 270 260 310 410 480 445 11 12 A-H 710 580 480 285 305 320 405 490 520 350 370 t 505 80 110 120 400 255 450 475 475 100 120 160 25)0 270 310 3653 270 295 <4225 405 425 330 370 365 390 180 2.50 260 260 480 440 360 190 190 210 215 180 205 t 6150 530 260 260 260 290 320 465 435 400 100 140 160 14 430 480 390 210 230 200 190 200 223 225 <2225 <225 <290 <305 70 100 1.5 480 <263 190 <26.3) 200 270 400 3,50 315 100 100 613) 52(0 445 215) 230 203 440 423 405 115 140 140 375 205 690 o60 510 13 16 230 22,5 275 300 280 275 265) 495 510 475 470 HPSRRP 355R <330 355 <330 470R 395 <360 425 380 <360 315R <305 - 115 128 <310 335 310 290 270 280 <42 5 460 BB RP 130 180 220 280 t- 250 340 3350 365 t - Circulaiion, Volume XLIX, January 1974 CYCLE LENGTH AND CARDIAC REFRACTORY PERIODS AVN ERP Patient CL A ERP A FRP 17 675 560 510 470 444 360 745 690 565 480 400 380 755 670 522 720 580 485 420 380 870 650 550 450 720 680 1000 640 480 420 620 560 470 353 230 280 310 230 230 195 300 260 240 240 230 300 275 280 275 275 240 230 195 195 365 365 340 330 330 310 295 260 260 200 190 390 340 305 295 250 210 210 195 360 405 420 18 19 Downloaded from http://circ.ahajournals.org/ by guest on April 30, 2017 20 21 22 23 24 190 180 220 220 210 205 205 165 150 160 160 34,5 335 290 285 265 230 200 185 190 190 170 360 300 250 230 220 190 180 170 37 AVN FRP A-H 470 460 470 470 160 195 230 BB RP HPS RRP 425L <390 425 <390 460R 405 355 340 460 390 365 350 120 tt300 310 320 330 325 330 <230 270 265 <365 <365 <340 <330 <330 310 295 320 310 <200 <190 <390 <340 <305 <295 250 280 290 410 390 380 375 370 365 405 390 360 <395 <365 <350 <335 <335 385 360 330 335 425 370 <440 <390 <365 <380 405 400 390 95 100 105 130 130 140 105 110 125 100 115 145 155 150 80 120 135 125 100 115 95 135 155 460R 380 < 330 <335 410 370 <330 520L 400 <365 455 400 <365 <335 180 105 125 150 t *All values are expressed in msec. tCL at which type I second degree block proximal to H was present. tThe ERP of the HPS was 395 msec at the CL of 790 msec in this patient. The FRP of the A-V node exceeded the ERP of the HPS at a shorter CL. Abbreviations: CL = cycle length; A ERP = atrial effective refractory period; A FRP = atrial functional refractory period; AVN ERP = A-V nodal effective refractory period; AVN FRP = A-V nodal ftnctional refractory period; A-H = interval between the atrial electrogram and the His deflection recorded by the His bundle catheter; BB RP = Bundle branch refractory period; Ri = indicates right bundle; L indicates left bundle; anid HPS RRP = His-Purkinje System relative refractory period. lengthened significantly as cycle length was shortened. The means and ranges for all 18 patients are given in table 3. A-V nodal FRP could be measured in 21 patients (table 2). Slopes were calculated for all patients in whom three or more determinations over a cycle length range of more than 200 msec (15 patients) were made. The mean slope ± SEM was +0.126 ± 0.045 msec (figs. 2 and 4). Thus, A-V nodal FRP Circulation, Volume XLIX, January 1974 decreased as cycle length was shortened. Means and ranges for all 21 patients are given in table 3. A-V nodal conduction time (A,-H,) lengthened in all patients as cycle length was shortened. The relationship of A-V nodal conduction time to effective refractory period was examined by plotting A,-H1 intervals against the ERP of the A-V node for each patient at all cycle lengths in which both were measured. A statistically significant DENES ET AL. 38 Table 3 The Effective and Functional Refractory Period at Three Cycle Length Ranges for the Atrium and the A-V Node* 599-460 101-130 459-380 131-180 235 (150-360) 25 19 278 (190-390) 23 19 225 (160-335) 29 18 267 (195-365) 29 18 201 (165-285) 23 16 248 (195-330) 23 16 303 (250-365) 16 15 421 (350-495) 23 18 340 (265-425) 29 16 419 (330-520) 31 18 307 (275-365) 9 8 351 (313-415) 11 10 CL HR = = 850-600 70-100 ATRIUTM ERP mean (range) Number of observations Number of patients FRP mean (range) Number of observations Number of patients A-V NODE Downloaded from http://circ.ahajournals.org/ by guest on April 30, 2017 ERP mean (range) Number of observations Number of patients FRP mean (range) Number of observations Number of patients *All values are expressed in msec. Abbreviations: HR = heart rate, beats/mim; CL = cycle length in msec; ERP = effective refractory period; FRP = functional refractory period. correlation was found with an (r) value of +0.65 (fig. 5). No similar relationship was found between A,-Hi and A-V nodal FRP. His-Purkinfe system. The RRP of the HisPurkinje system could be measured in six patients (table 2). Slopes were calculated for all six patients. The values obtained at the longest cycle length in which A-V nodal FRP exceeded the RRP of the HisAH vs AVN-ERP r =+.646 300 SEE=34 D=< 001 0 0 250 0 @ 200 1) E */ 0 < 5 . 0 0 , 0* 0 Relationship between Refractory Periods of Different Cardiac Tissues 100 e* @* -: 0 * 7J 0 200 300 350 250 AVN- ERP( msec) Purkinje system were also computed from the recordings of all patients for calculation of the slopes, since the RRP of the His-Purkinje system could only be less than the values indicated. The mean slope ± SEM was +0.270 ± 0.044 (figs. 3 and 4). Thus, the RRP of the His-Purkinje system shortened significantly as cycle length was decreased. Bundle branch refractory periods could be measured in seven patients (left bundle branch in two and right bundle branch in five, table 2). Slopes were calculated as described for the HisPurkinje system for these patients. The mean slope + SEM was +0.36 ± 0.065 (figs. 3 and 4). Thus, bundle branch refractory periods decreased significantly as cycle length was shortened. The ERP of the His-Purkinje system could be measured in only one patient (patient 8) and was 395 msec at a cycle length of 790 msec (table 2). 400 450 Figure 5 The relationship of A-V nodal conduction times (A-H) and effective refractory periods. The A-V nodal conduction times (A-H) of driven stimuli are plotted against A-V nodal effective refractory periods at the driven cycle length (AVNERP). Values of 54 cycle lengths from 18 patients are plotted. Atrial FRP vs A-V Nodal ERP. The A-V nodal effective refractory period could not be measured in six patients because the atrial FRP was longer at all cycle lengths. In eight of the remaining 18 patients, the atrial FRP was equal to or exceeded the A-V nodal ERP at the longest basic cycle length tested. In all eight cases this cycle length was greater than 600 msec. A-V Nodal FRP vs His-Purkinje System Refractory Periods. The RRP of the His-Purkinje system Circulation, Volume XLIX, January 1974 CYCLE LENGTH AND CARDIAC REFRACTORY PERIODS Downloaded from http://circ.ahajournals.org/ by guest on April 30, 2017 exceeded the A-V nodal FRP in five out of ten determinations (50%) at basic cycle lengths greater than 700 msee, in five out of 36 determinations (14%) between cycle lengths of 700 and 500 msec, and in two out of 25 determinations (7%) at cycle lengths less than 500 msec. The RP of the bundle branches exceeded the A-V nodal FRP in five out of ten determinations (50%) at basic cycle lengths greater than 700 msec, in five out of 36 determinations (14%) between 500 and 700 msec and in three out of 26 determinations (12%) at cycle lengths less than 500 msec. These relationships can be better visualized by examining the values from recording a typical patient. Values from patient 8 are shown in figure 6. At a cycle length of 790 msec, the shortest attainable interval between two atrial impulses that traverse the A-V node (H,-H2) was 350 msec (A-V nodal FRP). Impulses that propagated through the node J.G. REFRACTORY PERIODS 450 RBB -,' ARBB h U 0 0 X LUJ 350 AVFRP 0- AVERP o 300 U ` cc 250 AFRP 20C _ AERP,. _l400 600 700 500 LENGTH CYCLE (msec) 800 Figure 6 Refractory periods of the atrium, A-V node, and right bundle branch as a function of cycle length in one typical patient (patient 8). RBB =refractory period of the right bundle branch represented by open triangles and connected with interrupted lines. AVFRP= A-V nodal functional refractory period represented by open circles and connected with full lines. AVERP-A-V nodal effective refractory period represented by open circles and connected with interrupted lines. AFRP =atrial functional refractory period represented by closed circles and connected with full lines. AERP=atrial effective refractory period represented by closed circles and connected with interrupted lines. Circulation, Volume XLIX, January 1974 39 with an H,-H2 between 350 and 470 msec produced right bundle branch block pattern. At a cycle length of 580 msec, the A-V nodal FRP was 375 msec, and impulses with an H1-H. interval between 375 and 395 produced right bundle branch block. At a basic cycle length of 470 msec, the A-V nodal FRP exceeded the right bundle branch refractory period and functional right bundle branch block was not noted. At the longest cycle length (790 msec) the atrial FRP exceeded the A-V nodal ERP. Since these RP diverge at shorter cycle lengths, A-V nodal ERP exceeded atrial FRP at these cycle lengths. Discussion Effect of Cycle Length on Refractory Periods It has been demonstrated with microelectrode techniques in isolated cardiac tissues that action potential durations and refractory periods of atrial muscle, ventricular muscle, and His-Purkinje cells decrease with shortening of cycle length.' The A-V nodal cell differs in that recovery of excitability is delayed beyond complete repolarization. At higher driving rates, this gap between complete repolarization and recovery of excitability increases further.6 Mendez et al. examined the effects of changes in cycle length on the functional refractory periods of tissues in denervated canine hearts. They demonstrated that the functional refractory periods of the atria, ventricles, and A-V node were a curvilinear function of cycle length and shortened as cycle lengths decreased.2 Although our findings in man showed similar changes, the changes in refractory periods produced by changes in cycle length could not be described in terms of a single mathematical function. In this respect our results differ from those obtained in canine hearts. This difference can perhaps be explained by the fact that autonomic nervous systems were intact in our patients. In addition, the cycle length ranges we could study were limited since heart rates could not be slower than spontaneous sinus rhythm, or faster than the rate at which A-V nodal Wenckebach periods were observed. Atrial ERP and FRP had positive mean slopes when related to cycle length. The A-V nodal ERP had a negative mean slope when related to cycle length. In the recordings for all except one patient A-V nodal ERP increased when cycle length was decreased. In contrast, the FRP of the A-V node had a positive mean slope, although there vas a wide scatter of individual patients (fig. 4). Refractory periods in the His-Purkinje system showed the greatest decrease as eyele length shortened. DENES ET AL. 40 Relationship between Refractory Periods of the Cardiac Tissues The FRP of an excitable tissue at a given cycle length is the shortest attainable time interval between two impulses traversing that tissue, measured at a point distal to the stimulation site.2 The ERP of a tissue is the longest time interval between two impulses where the second fails to traverse it. If the FRP of the atrium is longer than the ERP of the A-V node, the A-V nodal ERP cannot be measured, Downloaded from http://circ.ahajournals.org/ by guest on April 30, 2017 since the atrium limits A-V conduction. The relationship between change in atrial FRP and A-V nodal ERP in response to variation in cycle length showed that the atrium might limit the determination of A-V nodal ERP at long cycle lengths, but this is less likely to occur at short cycle lengths (fig. 6 and table 2). A similar relationship between the A-V nodal FRP and the RP of the His-Purkinje system is possible. In long cycle lengths, the refractory period of the right bundle branch is frequently longer than the FRP of the A-V node. This allows a premature beat to be conducted with an 1-H2 interval shorter than the right bundle branch refractory period, producing functional right bundle branch block (aberrant conduction). At shorter cycle lengths the right bundle branch refractory period and the A-V nodal FRP converge, and aberrant conduction cannot occur. Aberrant conduction of a premature supraventricular beat is thus more likely during sinus bradycardia or when preceding R-R intervals are lengthened. Measurement of His-Purkinje system refractory periods with the atrial extra stimulus method is dependent upon three factors: 1) the A-V nodal FRP, 2) cycle length, and 3) the RP of the HisPurkinje system. In this study, those patients in whom determinations of His-Purkinje system refractory period could be obtained tended to have shorter A-V nodal FRP than those patients in whom His-Purkinje system refractory period could not be measured. Most determinations of His-Purkinje system refractory periods were obtained at cycle lengths greater than 600 msec. In two patients (5 and 14), both with sinus tachycardia, initial refractory period measurements could be obtained only at cycle lengths less than 600 msec. Moe et al. noted a similar relationship in denervated canine hearts.7 In his study, bundle branch refractory periods exceeded A-V nodal refractory periods at longer cycle lengths. Epinephrine reduced the refractory periods of the A-V node, His bundle, and bundle branches. However, the epinephrine effects were more pronounced in the A-V node than in the bundle branches. This might explain why bundle branch refractory periods could be obtained at cycle lengths less than 600 msec in the two patients with sinus tachycardia who were probably not under basal conditions during the period of the study. Conduction Time and Refractory Periods A-V nodal conduction time (A-H interval) increases as cycle length shortens. This increase has been attributed to the low amplitude of the A-V nodal action potential, the low A-V nodal resting membrane potential, and the decreased rate of depolarization of the A-V nodal cells in response to shortening of cycle length.' Merideth et al.6 have shown in rabbit hearts that the frequency-related depression of A-V nodal conductivity is associated with both an increase in diastolic threshold and delays between full repolarization and recovery of excitability. Van Capelle et al.,8 working with rat heart, suggested that A-V nodal conduction time (A-H) could determine A-V nodal refractoriness for a subsequent impulse. Our study suggests that A-H interval might be a partial determinant of A-V nodal ERP. No such relationship was found for A-H and A-V nodal FRP. Experimental Limitations Several limitations should be considered in the interpretation of our results. First, most of the patients had evidence of organic heart disease. It is possible that cycle length-refractory period relationships might have been slightly different in a group of patients without heart disease. However, findings in our six normal patients were similar to the findings in the 18 patients with heart disease. Second, since autonomic nervous system influences were intact, reflex responses to paced changes in cycle length could have influenced our results. Third, the results of this study probably are not applicable to changes in refractory periods induced by spontaneous changes in heart rates, as occurring with exercise or change in posture. Spontaneous changes in rate are generally mediated by changes in sympathetic and/or parasympathetic tone, which have direct effects on conduction. Similarly, the changes described in this study would not apply to cycle length changes induced by drugs with direct effects on the conduction system. This study therefore describes changes in refractory periods related to paced changes in cycle length and are of value in understanding cardiac electrophysiological responses in man. These results Circulation, Volume XLIX, January 1974 CYCLE LENGTH AND CARDIAC REFRACTORY PERIODS may be directly applicable to changes in rate not mediated by the autonomic nervous system, as occur in some paroxysmal arrhythmias or in A-V block. References 1. HOFFMAN BC, CRANEFIELD PF: Electrophysiology of the heart. New York, McCraw-Hill Book Company, 1960 2. MENDEZ C, GAUHZIT CC, MOE GK: Influence of cycle length upon refractory periods of auricles, ventricles and A-V node in the dog. Am J Physiol 184: 287, 1956 3. DHINGRA RC, ROSEN KM, RAMMTOOLA SH: Normal conduction intervals and responses in 61 patients using His bundle recording and atrial pacing. Chest 64: 55, 1973 Downloaded from http://circ.ahajournals.org/ by guest on April 30, 2017 Circulation, Volume XLIX, January 1974 41 4. SCHERLAG BJ, LAU SH, HELFANT RM, STEIN E, BERKOWITZ WD, DAMATO AN: Catheter technique for recording His bundle activity in man. Circulation 39: 13, 1969 5. WIT AL, WEISS MB, BERKOWITZ WD, ROSEN KM, STEINER C, DAMATO AN: Patterns of atrioventricular conduction in the human heart. Circ Res 27: 345, 1970 6. MERIDETH J, MENDEZ C, MUELLER WJ, CORDON GK: Electrical excitability of atrioventricular nodal cells. Circ Res 23: 69, 1968 7. MOE GK, MENDEZ C, HAN J: Aberrant A-V impulse propagation in the dog heart: A study of functional bundle branch block. Circ Res 15: 261, 1955 8. VAN CAPELLE FJL, DUPERRON JC, DUPBER D: Atrioventricular conduction in isolated rat heart. Am J Physiol 221: 284, 1971 The Effects of Cycle Length on Cardiac Refractory Periods in Man PABLO DENES, DELON WU, RAMESH DHINGRA, RAYMOND J. PIETRAS and KENNETH M. ROSEN Downloaded from http://circ.ahajournals.org/ by guest on April 30, 2017 Circulation. 1974;49:32-41 doi: 10.1161/01.CIR.49.1.32 Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 1974 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7322. 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