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Effects of premature depolarization on refractoriness of ischemic canine myocardium
J. ELECTROCARDIOLOGY 15 (4), 1982, 335-344
Effects of Premature Depolarization on Refractoriness of Ischemic Canine Myocardium BY MARY Jo BURGESS,
M.D.
AND JOHN COYLE,
M.D.*
SUMMARY In 25 pentobarbital anesthetized dogs we measured refractory periods (RPs) of regularly driven complexes and premature ventricular depolarizations (PVDs) with a range of coupling intervals or of regularly driven complexes and the complex following the PVD, i.e, the postextrasystolic depolarization (PED). Measurements were made during control periods and during occlusion of a branch of the left anterior descending coronary artery. The difference in control and occlusion RPs was less following some PVDs with short coupling intervals than following other PVDs with longer coupling intervals. Variations in the coupling interval of PVDs had less effect on RPs of the PVDs in ischemic than in nonischemic tissue. RPs of PEDs were prolonged with respect to RPs of regularly driven complexes in both ischemic and nonischemic tissue, but the prolongation in ischemic tissue was significantly greater than that in nonischemic tissue, 8 ± 4 msec and 2 ± 2 msec respectively, p <.001. The difference in effect of PVDs on RPs of ischemic and nonischemic tissue results in greater disparity of refractoriness between ischemic and nonischemic tissue following some long coupling interval PVDs than following some PVDs with shorter coupling intervals. In addition the greater prolongation of RPs of PEDs in ischemic than in nonischemic tissue can result in increased disparity in RPs than the disparity between ischemic and nonischemic tissue present during regular drive.
Ventricular refractory periods are directly related to cardiac cycle length in nonischemic myocardium'. Dispersion of ventricular refractory periods is also directly related to cycle length in non-ischemic tissue 2 ,3 but inversely related to clycle length in ischemic tissue.! That is, dispersion of refractory periods in ischemic myocardium is greater at short cycle lengths than at long cycle lengths. The effects of single premature depolarizations (PVDs) on refractoriness of ischemic myocardium have not been defined. We
studied the effect of induced PVDs with a range of coupling intervals, on the refractory periods of the PVDs and their effect on the refractory periods of the first depolarization following the PVDs, i.e. the postextrasystolic depolarization (PED). The effects of PVDs on ventricular refractory periods differed in ischemic and nonischemic tissues, and the differences may playa role in the high incidence of ventricular tachyarrhythmias reported following long coupling interval PVDs in patients with ischemic heart disease.
From the Nora Eccles Harrison Cardiovascular Research and Training Institute and the Division of Cardiology, Department of Internal Medicine, University of Utah College of Medicine, Salt Lake City, Utah 84132. Supported, in part, by Research Grant NHL 12611 and Program ProjectGrant NHL 13480 from the National Institutes of Health, and American Heart Association Award #76-760. *Dr. Coyle's current address is: Suite 414, 1705 East 19th Street, Tulsa, Oklahoma 74104. Thecosts of publication of this article were defrayed in part by the payment of pagecharges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. § 1734 solely to indicate this fact. Reprint requests to: Mary Jo Burgess, M.D., Cardiology Division, Building 100, University of Utah, Salt Lake City, Utah 84112.
Experiments were done on 25 dogs, anesthetized with intravenous pentobarbital 30 mg/kgm. An additional slow intravenous drip of a solution of 120 mgm of pentobarbital in 1000 cc of saline was used to maintain anesthesia. The trachea was cannulated, and respiration maintained with a volume pump respirator. The chest was openedwith a sternal splitting incision, and the heart was suspended in a pericardialcradle. A branch of the anterior descendingcoronaryartery was dissected and umbilical tape placed beneath it to permit occlusion. The artery occluded produced a wedge shaped cyanotic region that extended from about the middleof the anterior surfaceof the left ventricle to the apex. The sinus node was crushed, and a bipolar stainless steel hook electrode was placed on the right
MATERIALS AND METHODS
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BURGESS AND COYLE
atrial appendage for pacing. In 14 experiments, RPs of regularly driven complexes and of PVDs were measured. In these experiments, a unipolar hook electrode was placed superficially in the subepicardium at a site that became cyanotic during coronary occlusion. The indifferent pole for the unipolar electrode was a needle inserted beneath the skin of the chest. In all but one experiment, the heart was paced at basic cycle lengths (8,-8 1 ) of 400 msec. The remaining dog had a fast junctional rhythm, and a 300 msec 8 ,·8, was required to control heart rate. The atrium was paced simultaneously with the ventricle to minimize the chances of retrograde conduction and reciprocating rhythms. Refractory periods were measured during regular drive and following PVDs with varying coupling intervals. Measurements were obtained during control periods and during coronary occlusion. In these 14 dogs, the coronary artery was occluded for up to eight minutes and RP measurements were started after two minutes of occlusion. In seven of these dogs, the PVDs were timed with respect to the basic driving stimuli. In seven other dogs, the PVDs were timed with respect to the refractory periods of the regularly driven cornplexes. This was done so the PVDs would occur as close to the end of the shortened RPs of the ischemic tissue as to the end of the RPs of nonischemic tissue. In 11 additional dogs, the effect of PVDs on RPs of the first cycle following the PVD, Le., the PED was studied. The PVD·PED interval equalled the 8,'S, cycle length in these experiments. The experimental set up was similar to that used in the animals ill which RPs of PVDs were measured. However, a unipolar electrode was placed at a site outside the distribution of the artery to be occluded as well as within the distribution of the artery. The coronary artery was permanently occluded, and RPs were measured at ischemic and nonischemic sites during regular drive and following the PEDs. The measurements at ischemic sites were made one or more hours after the occlusion. In six of these experiments, PVDs with a range of coupling Intervals were induced, and in five experiments, only short coupling interval PVDs were induced. RPs in all 25 experiments were measured by delivering cathodal stimuli to the same unipolar electrode used for ventricular drive. Driving and testing the same site eliminated activation time at the test site as a factor in the refractory period measurements. All stimuli were constant voltage, 2 msecs duration and two times diastolic threshold. Threshold was determined prior to each set of regular drive, PVD and PED measurements of RPs. The RP test stimuli (RPm) were delivered after every ninth or tenth 8 " after PVDs which were induced with stimuli (8 2) delivered after every ninth or tenth 81' or after the PED. The basic driving stimulus following 8 2 was reset from 8 2 so that 8 2.81 equalled the S,-S~ interval. RP(TI was first delivered early in the cycle at a time when it did not produce a propagated response, and was then delayed in 1 msec increments until a propagated response oc-
curred. An electrogram recorded from a bipolar hook electrode on the right ventricle and a vertical lead ECG were displayed on an oscilloscope to monitor responses to RP 1T )' RP measurements of regularly driven complexes and of PVDs or PEDs were alternated. Two to three measurements were made during each type of drive, and means and standard deviations were calculated. In the experiments in which RPs of PVDs were studied, control period measurements of RPs of regularly driven complexes and PVDs with a particular coupling interval were alternated with measurements of RPs of regularly driven complexes and PVDs with the same coupling interval during temporary coronary occlusion. The measurements during occlusion were started two minutes after the artery was occluded and continued for up to eight minutes of occlusion. The duration of temporary occlusions did not exceed eight minutes. During occlusions of this duration, it was possible to make two to three sets of measurements of RPs following regularly driven complexes and PVDs and to determine threshold prior to each set of measurements. It was not possible to make all observations during a single occlusion; therefore, control measurements with a specific set of coupling intervals for the PVDs were alternated with occlusion measurements of RPs of PVDs with the same coupling intervals. RP measurements following PVDs with other coupling intervals were made during subsequent occlusions. Measurements of basic drive refractory periods were alternated with measurements of PVD refractory periods and if the RPs of the basic drive were unstable the occlusion was released. At least ten minutes were allowed to elapse following each coronary occlusion before another set of control measurements was made. In the experiments in which RPs of PEDs were studied, the coronary artery was permanently occluded. RPs were measured at a site within and at a site outside the distribution of the occluded artery and thresholds were determined prior to each measurement. At each site, measurements of RPs of regularly driven complexes and of PEDs were alternated, and measurements at ischemic sites were begun one or more hours after coronary occlusion. Data were expressed as means and standard deviations of the means, and statistically analyzed with the paired t test.
RESULTS Refractory periods of PVDs in ischemic and nonischemic myocardium. In 13 of these 14 experiments, refractory periods measured while the heart was driven regularly were shorter during coronary occlusion than during control periods. During occlusion, refractory periods shortened an average of 10.2 ± 7.6 msec, p < .001. This average was determined from two to three measurements of RPs made
J. ELECTROCARDIOLOGY 15 (4), 1982
337
PVDS AND REFRACTORINESS IN ISCHEMIC TiSSUE
Fig. 1. Graphs of RPs measured in two dogs during control periods, solid lines, and coronary occlusion, boken lines. Measurements made during regular drive are shown in the top graphs. The numbers at the bottom of the upper graphs refer to repeated control and ocelusion periods during the course of the experiments. The lower graphs show RPs of PVDs during control and occlusian periods. In part A, RPs of PVDs with the coupling intervals indicated along the horizontal axis are shown directly beneath the RPs of regularly driven complexes measured during the corresponding control and occlusion periods. In part B, measurements of RPs of PVDs with coupling intervals of 220, 230 and 240 msec were alternated with measurements of RPs of regularly driven complexes during the fourth control and occlusion period. Measurements of RPs of PVDs with coupling intervals of 260, 280 and 300 msec were alternated with measurements of RPs of regularly driven complexes during the fifth control and occlusion period. The points on the graphs represent averages and the standard deviations of O. See text for further discussion.
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during each of several control and occlusion periods in all dogs. In the one experiment in which refractory periods prolonged during each of five temporary coronary occlusions, the prolongation averaged 10 ± 4.5 msec, p < .01. These changes RPs following coronary occlusion are comparable to those previously reported. As mentioned in the methods section, PVDs were timed respect to the basic driving stimuli, in seven experiments, and with respect to the refractory periods of the regularly driven complexes in seven experiments. The seven experiments in which PVDs were timed with respect to the basic driving stimuli will be described first. The results from two of these experiments are graphed in Fig. 1. Refractory periods of regularly driven comlexes measured during repeated control and occlusion periods are graphed in the upper panels. Although there was some variation in refractory periods during repeated control periods and during repeated coronary occlusions, these variations were small in comparison to the difference in refractory periods measured during the two states. Refractory periods of PVDs with various J. ELECTROCARDIOLOGY 15 (4), 1982
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coupling intervals are graphed in the lower panels of the figure. The solid lines indicate control period measurements and the broken lines indicate measurements during coronary occlusion. In both of the experiments there was a greater difference between control and occlusion refractory periods of the PVDs with longer coupling intervals than of the PVDs with shorter coupling intervals. For example, as seen in the lower panel of part A, the refractory period of PVDs with coupling intervals of 320 msec averaged 182 msec during the control period and 159 msec during coronary occlusion, a difference of 23 msec, The refractory period of PVDs with coupling intervals of 220 rnsec averaged 159 msec during control periods and 156 msec during coronary occlusion, a difference of only 3 msec. RPs of regularly driven complexes during the corresponding control and occlusion periods averaged 183 msec and 170 msec respectively, a difference of 13 msec. In this experiment there was less difference between control and occlusion RPs of PVDs with coupling intervals of 200, 220, 240 and 260 msec than between control and occlusion RPs of regularly
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Fig. 2. Graphs summarizing data from the seven experiments in which PVDs were timed with respect to the basic driving stimuli. The differences in RPs of PVDs in ischemic and control periods are plotted on the vertical axis and the coupling intervals of PVDs are plotted on the horizontal axis. The negative values, plotted beneath the horizontal lines in each graph, indicate that RPs of PVDs were longer during ischemia than during control periods. In five experiments (a, b, c, d and g)differences between controland coronaryocclusion RPs of PVDs at someshort coupling intervals wereless than the differences in RPs of PVDs at other longer coupling intervals. See text for further discussion. driven complexes. Similar findings from another experiment are shown in panel B. In all seven of these experiments the difference between control and occlusion RPs of PVDs at some coupling intervals was less than the difference between control and occlusion RPs of regularly driven complexes. In five of these seven experiments, control and occlusion RPs of PVDs with the shortest coupling intervals were more nearly equal than control and occlusion RPs of regularly driven complexes. The graphs in Fig. 2 summarize the results of these experiments. Each point on the graphs indicates the difference between control and occlusion RPs of PVDs at the coupling intervals indicated along the horizontal axis. The points plotted above the horizontal lines on the graphs indicate RPs of PVDs which were longer during the control period than during occlusion. Points plotted below the horizontal line indicate RPs of PVDs which were shorter during the control period than during occlusion. In five of the experiments (parts a, b, c, d, and g), there was a greater
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Fig. 3. Graph of ranges in control and occlusion durations of RPs measured following PVDs at all coupling intervals used. The range in durations of RPs measured during control periods are plotted on the left of the graph and averaged 28 ± 8.8 msec. The range in durations of RPs measured during coronary occlusion are plotted on the right of the graph and averaged 17 ± 7.6 msec, significantly less than the range during the control period, p < .05. J. ELECTROCARDIOLOGY 15 (4), 1982
PVDS AND REFRACTOR INESS IN ISCHEM iC TISSUE
(part fl, the RP of a PVD with a short coupling interval (81 - 8 2 = 195 msec) was less during ischemia than during the control period but the RP of a PVD with a longer coupling interval (81 - 8 2 = 275 msec) was longer during ischemia than during the control period. In one experiment (part d), RPs of PVDs at all coupling intervals had longer durations during coronary occlusion than during control periods. This was the same experiment in which RPs of regularly driven complexes were longer during repeated coronary occlusions than during the control periods. The range of duration of RPs of PVDs at all coupling intervals was also determined during control and occlusion periods in each experiment, and the results are graphed in Fig. 3. In five of the seven experiments, the range of RP durations of PVDs was less during coronary occlusions than during control periods. For all experiments, the range in durations of RPs of PVDs at all coupling int ervals during occlusion averaged 17 ± 7.6 msec, which was significantly less than the range in duration of RPs of PVDs during control periods (28 ± 8.8 msec, p < .05). This indicates that RPs of PVDs is ischemic tissue are more independent of abrupt shortening in cycle length than RPs of PVDs in nonischemic tissue. PVDs were timed with respect to RPs of regularly driven complexes during control periods and
during coronary occlusion in seven experiments. This was done because RPs of ischemic myocardium usually decreased during the first few minutes of coronary artery occlusion. In the group of experiments described above, premature ventricular complexes induced by stimuli timed with respect to the basic driving stimuli were, therefore, relatively earlier in the cardiac cycle with respect to RPs during control periods than during coronary occlusion. By timing the PVDs with respect to the RPs of regularly driven complexes, the PVDs had a similar temporal relationship to the RP of the regularly driven complexes during control and occlusion periods. The results of these experiments were similar to those found in the first group of experiments, and findings from two representative experiments are graphed in Fig. 4. The format of this figure is similar to that of Fig. 1 except that the coupling intervals of PVDs are expressed as a function of the RP of the regularly driven complex plu s 10 msec increments. In both experiments illustrated, there was less difference between control and occlusion RPs of some PVDs induced early in the cardiac cycle than the difference in refractory periods of some PVDs induced later in the cycle. For example, in the experiment graphed in part B, the RP of PVDs induced 70 msec after the refractory period of the regularly driven complexes were 9 msec
Fig. 4. Graphs of RPs measured in two dogs during control periods, solid lines, and coronary occlusion, broken lines. A 100 The points on the graphs are averages of two or three measurements and the ver1!lO tical bars indicate the standard devialeo tions. The points without vertical bars 170 had standard deviations of O. Measurements made during regular drive are r 12)4~'7 B shown in the top graphs and measure190 ments made following PVDs are shown in the bottom graphs. The numbers 110 f.. . - --t along the horizontal axis of the upper u 170 ,y-J, 'f graphs refer to repeat ed control and oc- ... r I clusion periods. In these experiments, .s 160 I I PVDs were timed with respect to the Q>• 1 RPs of regularly driven complexes. The Q. coupling intervals of the PVDs are In- 't5 Q. dicated on the horizontal axis of the a: - - - O"WJ'OM lower graphs and expressed as RP + 10 10 msec increments. The RPs of PVDs are RP 10 ~O ~O 70 90 110 plotted directly beneath RPs of regularly driven complexes measured during COUPLING INTERVAL OF PVO, the same control and occlusion periods. (meee) See text for further discussion.
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longer during occlusion than during the control period but there was no difference in control and occlusion RPs of PVDs induced 10 msec after the RP of the regularly driven complexes. In all seven of these experiments, refractory periods during regular drive, shortened during coronary artery occlusion, average 12.9 ± 5.0 msec, p < .001. In five experiments, control and occlusion RPs of PVDs at many coupling intervals were more nearly equal than control and occlusion RPs of regularly driven complexes. In five of the experiments, there was a greater difference between control and occlusion RPs of some PVDs with long coupling itervals than other PVDs with shorter coupling intervals. In five experiments, RPs of PVDs at some coupling intervals were
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longer during ischemia than during control periods even though the absolute duration of these coupling intervals which were timed with respect to the RP of the regularly driven complexes was less during coronary occlusion than during the control periods. Refractory periods of PEDs in ischemic and nonischemic myocardium.
In these 11 experiments, PVDs with short coupling intervals were induced following every tenth basic cycle length and RPs of PEDs were compared to those measured during regular drive. These experiments were done to further define differences in effects of PVDs on refractory periods of ischemic and nonischemic tissue. In six of these experiments, PVDs at several long cou-
Fig. 5. Vertical lead body surface ECG recorded during RP measurements. The recordings on the left were taken while measurements were made at a nonischemic site and those on the right were taken while measurements were made at an ischemic site. Parts A and B are recordings taken during RP measurements of regular driven complexes and parts C and D are recordings taken during RP measurements of PEDs. As shown on the left of part A and B, in nonischemic tissue the RP test pulse (RPm) failed to produce a response 216 msec after 8 1 but produced a response 217 msec after 8 1, As shown in parts C and D, when a PVD was induced with an 8 t - 8 2 interval 218 msec RPm failed to produce a response 218 msec after the PED but produced a response 219 msec after the PED. The RP of the PED was just 2 msec longer than the RP during regular drive. Parts A and B on the right show that at the ischemic site, during regular drive RPm failed to produce a response 211 msec after 8 1 but produced a response 212 msec after 8 1, As shown in part C when a PVD was induced 215 msec after 8 1, RP IT ) failed to produce a response 219 msec after the PED but as shown in part D, when RP'llwas delayed to 220 msec after the PED a response was induced. The S. - 8 2 interval was increased to 220 msec during the recording in part D because the RP increased during the irregular drive. At this ischemic site, the RP of the PED was 8 msec longer than the RP measured during regular drive.
J. ElECTROCARDIOlOGY 15 (4), 1982
PVDS AND REFRACTORINESS IN ISCHEMIC TISSUE
pling intervals were induced in addition to the PVDs with short coupling intervals. The coronary artery was occluded for at least one hour before RPs were measured at ischemic sites. In some experiments the RPs of the regularly driven complexes at ischemic sites were longer than those at nonischemic sites and in other experiments they were shortr. For all experiments, nonischemic site refractory periods averaged 198 ± 17 msec during regular drive (n = 39), and were not significantly different from those at ischemic sites, 199 ± 16 msec, (n = 37). At both ischemic and nonischemic sites, RPs of the PEDs were longer than RPs during regular drive. At ischemic sites, RPs of PEDs were 8 ± 4 msec (n = 37) longer than RPs during regular drive, and at nonischemic sites, RPs of PEDs were 2 ± 2 msec (n = 39) longer than RPs during regular drive. This prolongation of RPs of PEDs at ischemic sites was significantly greater than the prolongation of RPs of PEDs at nonischemic sites (p < .001). The greater prolongation of RPs of PEDs at ischemic sites than at nonischemic sites occurred whether the RPs during regular drive were longer or shorter at ischemic sites than at nonischemic sites. A dog's vertical lead ECG which was recorded during refractory period measurements is shown in Fig. 5. The recordings in the panel on the left were taken while measurements were made at a nonischemic site and the recordings on the right were taken while measurements were made at an ischemic site. Parts A and B were recorded during measurements of RPs of regularly driven complexes and parts C and D were recorded during measurements of RPs of PEDs. At the nonischemic site, during regular drive, RP(T) failed to produce a response when delivered 216 sec after 81' part A, left panel, but produced a response when delivered 217 msec after 8 1 , part B, left paneL When a PVD was induced 218 msec after every tenth 8 1, RP(T) 218 msec after the PED failed to induce a response, part C, left panel, but when RPm was delayed to 219 msec a response was induced, part D, left panel. The RP of the PED was just 2 msec longer than the RP of the regularly driven complex. At the ischemic site, during regular drive RP(T) failed to induce a response when delivered 211 msec after SI' part A, right panel, but produced a response when delivered 212 msec after 81' part B, right panel. PVDs were then induced after every tenth St' The PVD was 215 msec after 8 1 in the recording shown in part C, right panel, and 220 msec after 8 1 in that J. ELECTROCARDIOLOGY 15 (4), 1982
341
shown in part D, right paneL The coupling interval of the PVD had to be increased during this measurement because the RP increased during the irregular rhythm. RP 1T) 219 msec after the PED failed" to induce a response, part C, right panel, but when RPm was delayed to 220 msec after the PED a response was induced, part D, right paneL The RP of the PED was 8 msec longer than the RP during regular drive, The effect of longer coupling interval PVDs on the refractory periods of PEDs was studied in six of these experiments. As expected, when the coupling interval of the PVD was increased, the RP of the PED approached the duration of the RP of regularly driven complexes.
DISCUSSION A high incidence of ventricular tachyarrhythmias during the early phases of coronary artery occlusion has been well documented both in animal experiments 2,5'14 and in clinical studies 15·18. Han et aL2,3,19-2:J have defined a relationship between local dispersion of ventricular recovery properties and vulnerability to ventricular arrhythmias and fibrillation. Coronary occlusion alone and premature ventricular depolarization alone were two of the interventions they tested, and both were associated with increased dispersion of ventricular refractory periods. A relation of ventricular conduction defects to ventricular tachyarrhythmias has also been demonstra ted5,6,14,24-27. On the basis of these findings, it is reasonable to predict that in the setting of acute infarction early premature depolarizations would accentuate inhomogeneity of recovery properties and conduction defects present in ischemic tissue. The occurrence of a vulnerable period near the peak of the T wave, described by Wiggers and Wegria 28, also suggests a greater likelihood of inducing tachyarrhythmias with early premature depolarizations than the late ones. However, the literature contains conflicting data on whether tachyarrhythmias in patients with coronary artery disease are more likely to follow early or late premature ventricular depolarizations. In an early report, Smirk and Palmer 29 found that PVDs that fell within the T wave were frequently followed by a second PVD. Lawn et al. 30,31 also found that PVDs with short coupling intervals were the ones most likely to initiate ventricular fibrillation in patients with acute myocardial infarction. Induction of ventricular fibrilla-
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tion by artificial pacemaker stimuli falling on the T wave 32' 39 has also been reported. On the other hand, Bleifer et a1. 40 found that PVDs falling on the T wave did not induce tachyarrhythmias. De Soyza et a1. 41 found no statistically significant difference in the coupling intervals of PVDs that were followed by tachyarrhythmias and those that were not. Winkle et a1. 42 found that only 15% of episodes of ventricular tachycardia followed PVDs with the R on T phenomenon, and Lie et a1. 43 reported that ventricular fibrillation was almost as frequent when the coupling intervals of PVDs were long as when they were short. Roberts et a1. 44 found that majority of episodes of tachyarrhythmia in patients in the coronary care unit followed PVDs with relatively long coupling intervals. Other investigators have also noted that tachyarrhythrnias are frequently initiated by PVDs with long coupling intervals. 45-47 Similar findings have been observed in animal studies6,l4. The data from this study demonstrate a difference in cycle length dependent changes of RPs in ischemic as compared to normal myocardium. The RPs of PVDs with some coupling intervals had greater differences between control and coronary occlusion period measurements than RPs of PVDs with other coupling intervals. The timing of PVDs with the greatest and least difference in refractory periods between control and ischemic states varied from animal to animal, but the greatest difference was frequently found following long coupling interval PVDs. Differences in responses of refractory periods due to changes in cycle length in ischemic and nonischernic tissue have previously been reported by Lazarra et a1. 48• Those investigators found that action potentials of ischemic His fibers were longer at fast rates than at slow rates. Their report concerned only regularly driven complexes and not premature complexes. Gettes et a1. 49 demonstrated that the duration of premature ventricular action potentials did not shorten with respect to the duration of the preceding nonpremature action potential until the response arose within a critical range of the preceding repolarization, This phenomenon may have played a role in the difference in response of RPs of ischemic and nonischemic tissue we observed. It is, however, unlikely that it was the sole factor since differences in the response of RPs to changes in cycle length were observed in the experiments in which PVDs were timed with respect to the RP of the regularly driven complexes as well as in the
experiments in which the PVDs were timed with respect to 8 1" The effect of PVDs on the RPs of PEDs was also studied. In these experiments, RP measurements at ischemic sites were made one or more hours after coronary occlusion. Permanent coronary occlusions were used because the prolongation of refractory periods of PEDs did not reach a steady state for several minutes after initiating pacing with the irregular rhythm. It was therefore impossible to make the measurements during temporary coronary occlusion. One to one and a half hours after coronary occlusion, refractory periods were relatively stable and it was possible to compare refractory periods measured during regular drive to the refractory periods of the PEDs. Janse 60 reported that in nonischemic myocardium RPs of PEDs were longer than refractory periods during regular drive, but he did not study the effects of ischemia on refractory periods of PEDs. We found that in ischemic tissue refractory periods of PEDs prolonged more with respect to refractory periods during regular drive than the prolongation in nonischemic tissue. This effect was observed only in PEDs that followed short coupling interval PVDs and was observed whether the refractory periods during regular drive were longer or shorter in ischemic tissue than in nonischemic tissue. Therefore, inhomogeneity of RPs between ischemic and nonischemic tissue was sometimes greater and sometimes less after PEDs than during regular drive depending on whether the RPs during regular drive were longer or shorter in the ischemic tissue than in the nonischemic tissue. Our findings provide insight into the reason long coupling interval PVDs are frequently associated with tachyarrhythmias. Dispersion of refractoriness has been shown to enhance arrhythmia vulnerability2 3.19 22. In the majority of our experiments there was a greater difference between refractory periods in the control and ischemic states following some of the longer coupling interval PVDs than following other PVDs with shorter coupling intervals. In addition, the finding that refractory periods following PEDs prolong more in ischemic tissue than in nonischemic tissue may playa protective role at times during myocardial ischemia when refractory periods of ischemic tissue are short, but may enhance arrhythmia vulnerability at times when refractory periods of ischemic tissue are long. The greater difference in refractory periods during control and occlusion states following some PVDs with 0
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J. ELECTROCARDIOLOGY 15 (4), 1982
PVDS AND REFRACTORINESS IN ISCHEMIC TISSUE
long coupling intervals provides an electrophysiologic environment appropriate for the support of reentrant activity, and may be at least partially responsible for the high incidence of tachyarrhythmias associated with long coupling interval PVDs in patients with ischemic heart disease.
REFERENCES 1. MENDEZ, C, GRUHZIT, C C AND MOE, G K: Influence of cycle length upon refractory periods of auricles, ventricles, and AV node in the dog. Am J Physiol 184:287, 1956 2. HAN, J AND MOE, G K: Non-uniform recovery of excitability in ventricular muscle. Circ Res 14:44, 1964 3. HAN, J, DETRAGLIA, J, MILLET, D AND MOE, G K: Incidence of ectopic beats as a function of basic rate in the ventricle. Am Heart J 72:632, 1966 4. KENT, K M, SMITH, E R, REDWOOD, D R AND EpSTEIN, S E : Electrical stability of acutely ischemic myocardium. Influences of heart rate and vagal stimulation. Circulation 47:291, 1973 5. EL-SHERIF, N, SCHERLAG, B AND LAZZARA, R: Electrode catheter recording during malignant ventricular arrhythmia following experimental acute myocardial ischemia. Evidence for re-entry due to conduction delay and block in ischemicmyocardium. Circulation 51:1003, 1975 6. FRIEDMAN, P L, STEWART, J R AND WIT, A L: Spontaneous and induced cardiac arrhythmias in subendocardial Purkinje fibers surviving extensive myocardial infarction in dogs. Circ Res 33:612, 1973 7. FRIEDMAN, P L, FENOGLIO, J J AND WIT, A L: Time course for reversal of electrophysiological and ultrastructural abnormalities in subendocardial Purkinje fibers surviving extensive myocardal infarction in dogs. Circ Res 36:127, 1975 8. HARRIS, A S AND ROJAS, G A: Initiation of ventricular fibrillation due to coronary occlusion. Exp. Med Surg 1:105, 1943 9. HARRIS, A S: Delayed development of ventricular ectopic rhythms following experimental coronary occlusion. Circulation 1:1318, 1950 10. LAZZARA, R, EL-SHERIF, NAND SCHERLAG, B: Electrophysiological properties of canine Purkinje cells in one day old myocardial infarction. Circ Res 33:722, 1973 11. LAZZARA, R, EL-SHERIF, NAND SCHERLAG, B J: Early and late effects of coronary occlusion on canine Purkinje fibers. Circ Res 35:391, 1974 12. SCHERLAG, B, HELFANT. R H. HAFT, J I AND DAMATO, A N: Electrophysiology underlying ventricular arrhythmias due to coronary ligation. Am J Physiol 219:1665, 1970 13. SCHERLAG, B J, EL-SHERIF, N, HOPE, R AND LAZZARA, R: Characterization and localization of ventricular arrhythmias resulting from myocardial
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ischemia and infarction. Circ Res 35:372, 1974 14. WILLIAMS, D 0, SCHERLAG, B J, HOPE, R R, ELSHERIF, N AND LAZZARA, R: The pathophysiology of malignant ventricular arrhythmias during acute myocardial ischemia. Circulation 50:1163, 1974 15. GRACE, W J AND CHADBOURN, J A: The first hours in acute myocardial infarction (AMI). Observations in 50 patients. Circulation 42:III :160, 1970 (Abstract) 16. LOWN, B, KLEIN, M D AND HERSHBERG, P I: Coronary and precoronary care. Am J Med 46:705, 1969 17. Moss, A J, GOLDSTEIN, 8, GREENE, W AND DE CAMILLA, J: Prehospital precursors of ventricular arrhythmias in acute myocardial infarction. Arch Intern Med 129:756, 1972 18. PANTRIDGE, J F, ADGEY, A A J, GEDDES, J SAND WEBB, S W: The Acute Coronary Attack. Grune and Stratton, New York, 1975, pp 27-42 19. HAN. J , GARCIA DE JALON, P AND MOE, G K: Adrenergic effects on ventricular vulnerability. Circ Res 14:516, 1965 20. HAN, J, GARCIA DE JALON, P D AND MOE, G K: Fibrillation threshold of premature ventricular responses. Circ Res 18:18, 1966 21. HAN, J: Mechanisms of ventricular arrhythmias associated with myocardial infarction. Am J Cardiol 24:800, 1969 22. HAN, J: Ventricular vulnerability during acute coronary occlusion. Am J Cardiol 24:857, 1969 23. HAN, J AND GOEL. B R: Electrophysiologic precursors of ventricular tachyarrhythmias. Arch Intern Med 129:749, 1972 24. BOINEAU, J P AND Cox, J L: Slowventricular activation in acute myocardial infarction: A source or reentrant premature ventricular contraction. Circulation 48:702, 1973 25. DURRER, D, VAN DAM, R TH, FREUD, G E AND JANSE, M J: Re-entry and ventricular arrhythmias in local ischemia and infarction of the intact dog heart. Proc K Ned Akad Wet (BioI Med) Ser C 73-4:321, 1971 26. HOPE, R R, WILLIAMS, D 0, EL-SHERIF, N, LAZZARA, RAND SCHERLAG, B J : The efficacyof antiarrhythmic agents during acute myocardial ischemia and the role of heart rate. Circulation 50:507, 1974 27. WALDO, A L AND KAISER, G A: A study of ventricular arrhythmias associated with acute myocardial infarction in the canine heart.' Circulation 47:1222, 1973 28. WIGGERS, C AND WEGRIA, R: Ventricular fibrillation due to single, localized inductionand condenser shocks applied during the vulnerable phase of ventricular systole. Am J PhysioI128:500, 1940 29. SMIRK. F H AND PALMER, D G: A myocardial syndrome. With particular reference to the occurrence of sudden death and of premature systoles interrupting antecedent T waves. Am J Cardiol 6:620, 1960 30. LOWN, B, KLEIN, M D AND HERSHBERG, P I: Coronary and precoronary care. Am J Med46:705, 1969
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31. LOWN, B, FAKHRO, A M, HOOD, W B JR AND THORN, J W: The coronary care unit. New perspectives and directions. JAMA 199:188, 1967 32. BILITCH, M, COSBY, R SAND CAFFERKY, E A: Ventricular fibrillation and competitive pacing. New Eng J Med 276:598, 1967 33. BURGESS, M J, GROSSMAN, M AND ABILDSKOV, J A: Fibrillation threshold of a patient with myocardial infarction treated with a fixed-rate pacemaker: Case report. Am Heart J 80:112, 1970 34. DITTMAN, H At FRIESE, G AND HOLDER, E: Erfahrungen uber die long fristige Reizung des Menschilchen Herzens. Z Kreislaufforsch, 51:66, 1962 35. DRESSLER, W, JONAS, S AND RUBIN, R: Observations in patients with implanted cardiac pacemaker, IV. Repetitive responses to electrical stimuli. Am J Cardiol 15:391, 1965 36. ELMQVIS'f, R, LANDEGREN, J, PETTERSSON, S 0, SENNIG, A AND WILLIAM·OLSSON, G: Artificial pacemaker for treatment of Adams-Stoke syndrome and slow heart rate. Am Heart J 65:731, 1963 37. GRONDIN, P, LEPAGE, G, KARAMEHMET, A, CASTONGUAY, Y AND MEERE, C: Pacemaker-induced repetitive firing: Report of two cases. Canad Med Assoc J 96:1477,1967 38. ROBINSON, D S, FALSETTI, H L, WHEELER, D H, MILLER, DB AND AMIDON, E L: Ventricular fibrillation associated with two functioning implanted cardiac pacemakers. Am J Cardio115:397, 1965 39. TAVEL, M E AND FISCH, C: Repetitive ventricular arrhythmia resulting from artificial internal pacemaker. Circulation 30:493, 1964 40. BLEIFER, S B, KARPMAN, H L, SHEPPARD, J J AND BLEIFER, D J: Relation between premature ventricular complexes and development of ventricular tachycardia. Am J Cardiol 31:400, 1973 41. DE SOYZA, N, BISSETT, J K, KANE, J J, MURPHY, M L AND DOHERTY, J E: Ectopic ventricular prematurity and its relationship to ventricular
42.
43.
44.
45.
46.
47.
48.
49.
50.
tachycardia in acute myocardial infarction in man. Circulation 50:529, 1974 WINKLE, R A, DERRINGTON, DC AND SCHROEDER, J S: Characteristics of ventricular tachycardia in ambulatory patients. Am J Cardiol 39:487, 1977 LIE, K I, WELLENS, H J J, DOWNAR, E AND DURRER: Observations on patients with primary ventricular fibrillation complicating acute myocardial infarction. Circulation 52:755, 1975 ROBERTS, R, AMBOS, H D, LOH,C W, AND SOBEL, B: Initiation of repetitive ventricular depolarizations by relatively late premature complexes in patients with acute myocardial infarction. Am J Cardiol 41:678, 1978 KLEIGER, R T, MARTIN, T F, MILLER, J P AND OLIVER, G C: Ventricular tachycardia and ventricular extrasystoles during the late recovery phase of myocardial infarction. Am J Cardiol 33:149, 1974 (Abstract) RUBERMAN, W, WEINBLA'l'T, E, GOLDBERG, J D, FRANK, C W AND SHAPIRO, S: Ventricular premature beats and mortality after myocardial infarction. New Eng J Med 297: 750, 1977 VAN DURME, J P AND PANNIER, R H: Prognostic significance of ventricular dysrhythmias one year after myocardial infarction. Am J Cardiol 37: 178, 1976 (Abstract) LAZZARA, R, EL·SHERIF, NAND SCHERLAG, B: Disorders of cellular electrophysiology produced by ischemia of the canine His bundle. Circ Res 36:444, 1975 GETTES, L S, MOREHOUSE, NAND SURAWICZ, B: Effect of premature depolarization on the duration of the action potentials in Purkinje and ventricular fibers of the moderator band of the pig heart: Role of proximity and the duration of the preceding action potential. Circ Res 30:55, 1972 JANSE, M J: The Effect of Changes in Heart Rate on the Refractory Period of the Heart. Mondeeloffsetdrukkerij, Amsterdam, 1971, pp 33-35
J. ELECTROCARDIOLOGY 15 (4), 1982
Effects of Premature Depolarization on Refractoriness of Ischemic Canine Myocardium BY MARY Jo BURGESS,
M.D.
AND JOHN COYLE,
M.D.*
SUMMARY In 25 pentobarbital anesthetized dogs we measured refractory periods (RPs) of regularly driven complexes and premature ventricular depolarizations (PVDs) with a range of coupling intervals or of regularly driven complexes and the complex following the PVD, i.e, the postextrasystolic depolarization (PED). Measurements were made during control periods and during occlusion of a branch of the left anterior descending coronary artery. The difference in control and occlusion RPs was less following some PVDs with short coupling intervals than following other PVDs with longer coupling intervals. Variations in the coupling interval of PVDs had less effect on RPs of the PVDs in ischemic than in nonischemic tissue. RPs of PEDs were prolonged with respect to RPs of regularly driven complexes in both ischemic and nonischemic tissue, but the prolongation in ischemic tissue was significantly greater than that in nonischemic tissue, 8 ± 4 msec and 2 ± 2 msec respectively, p <.001. The difference in effect of PVDs on RPs of ischemic and nonischemic tissue results in greater disparity of refractoriness between ischemic and nonischemic tissue following some long coupling interval PVDs than following some PVDs with shorter coupling intervals. In addition the greater prolongation of RPs of PEDs in ischemic than in nonischemic tissue can result in increased disparity in RPs than the disparity between ischemic and nonischemic tissue present during regular drive.
Ventricular refractory periods are directly related to cardiac cycle length in nonischemic myocardium'. Dispersion of ventricular refractory periods is also directly related to cycle length in non-ischemic tissue 2 ,3 but inversely related to clycle length in ischemic tissue.! That is, dispersion of refractory periods in ischemic myocardium is greater at short cycle lengths than at long cycle lengths. The effects of single premature depolarizations (PVDs) on refractoriness of ischemic myocardium have not been defined. We
studied the effect of induced PVDs with a range of coupling intervals, on the refractory periods of the PVDs and their effect on the refractory periods of the first depolarization following the PVDs, i.e. the postextrasystolic depolarization (PED). The effects of PVDs on ventricular refractory periods differed in ischemic and nonischemic tissues, and the differences may playa role in the high incidence of ventricular tachyarrhythmias reported following long coupling interval PVDs in patients with ischemic heart disease.
From the Nora Eccles Harrison Cardiovascular Research and Training Institute and the Division of Cardiology, Department of Internal Medicine, University of Utah College of Medicine, Salt Lake City, Utah 84132. Supported, in part, by Research Grant NHL 12611 and Program ProjectGrant NHL 13480 from the National Institutes of Health, and American Heart Association Award #76-760. *Dr. Coyle's current address is: Suite 414, 1705 East 19th Street, Tulsa, Oklahoma 74104. Thecosts of publication of this article were defrayed in part by the payment of pagecharges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. § 1734 solely to indicate this fact. Reprint requests to: Mary Jo Burgess, M.D., Cardiology Division, Building 100, University of Utah, Salt Lake City, Utah 84112.
Experiments were done on 25 dogs, anesthetized with intravenous pentobarbital 30 mg/kgm. An additional slow intravenous drip of a solution of 120 mgm of pentobarbital in 1000 cc of saline was used to maintain anesthesia. The trachea was cannulated, and respiration maintained with a volume pump respirator. The chest was openedwith a sternal splitting incision, and the heart was suspended in a pericardialcradle. A branch of the anterior descendingcoronaryartery was dissected and umbilical tape placed beneath it to permit occlusion. The artery occluded produced a wedge shaped cyanotic region that extended from about the middleof the anterior surfaceof the left ventricle to the apex. The sinus node was crushed, and a bipolar stainless steel hook electrode was placed on the right
MATERIALS AND METHODS
335
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BURGESS AND COYLE
atrial appendage for pacing. In 14 experiments, RPs of regularly driven complexes and of PVDs were measured. In these experiments, a unipolar hook electrode was placed superficially in the subepicardium at a site that became cyanotic during coronary occlusion. The indifferent pole for the unipolar electrode was a needle inserted beneath the skin of the chest. In all but one experiment, the heart was paced at basic cycle lengths (8,-8 1 ) of 400 msec. The remaining dog had a fast junctional rhythm, and a 300 msec 8 ,·8, was required to control heart rate. The atrium was paced simultaneously with the ventricle to minimize the chances of retrograde conduction and reciprocating rhythms. Refractory periods were measured during regular drive and following PVDs with varying coupling intervals. Measurements were obtained during control periods and during coronary occlusion. In these 14 dogs, the coronary artery was occluded for up to eight minutes and RP measurements were started after two minutes of occlusion. In seven of these dogs, the PVDs were timed with respect to the basic driving stimuli. In seven other dogs, the PVDs were timed with respect to the refractory periods of the regularly driven cornplexes. This was done so the PVDs would occur as close to the end of the shortened RPs of the ischemic tissue as to the end of the RPs of nonischemic tissue. In 11 additional dogs, the effect of PVDs on RPs of the first cycle following the PVD, Le., the PED was studied. The PVD·PED interval equalled the 8,'S, cycle length in these experiments. The experimental set up was similar to that used in the animals ill which RPs of PVDs were measured. However, a unipolar electrode was placed at a site outside the distribution of the artery to be occluded as well as within the distribution of the artery. The coronary artery was permanently occluded, and RPs were measured at ischemic and nonischemic sites during regular drive and following the PEDs. The measurements at ischemic sites were made one or more hours after the occlusion. In six of these experiments, PVDs with a range of coupling Intervals were induced, and in five experiments, only short coupling interval PVDs were induced. RPs in all 25 experiments were measured by delivering cathodal stimuli to the same unipolar electrode used for ventricular drive. Driving and testing the same site eliminated activation time at the test site as a factor in the refractory period measurements. All stimuli were constant voltage, 2 msecs duration and two times diastolic threshold. Threshold was determined prior to each set of regular drive, PVD and PED measurements of RPs. The RP test stimuli (RPm) were delivered after every ninth or tenth 8 " after PVDs which were induced with stimuli (8 2) delivered after every ninth or tenth 81' or after the PED. The basic driving stimulus following 8 2 was reset from 8 2 so that 8 2.81 equalled the S,-S~ interval. RP(TI was first delivered early in the cycle at a time when it did not produce a propagated response, and was then delayed in 1 msec increments until a propagated response oc-
curred. An electrogram recorded from a bipolar hook electrode on the right ventricle and a vertical lead ECG were displayed on an oscilloscope to monitor responses to RP 1T )' RP measurements of regularly driven complexes and of PVDs or PEDs were alternated. Two to three measurements were made during each type of drive, and means and standard deviations were calculated. In the experiments in which RPs of PVDs were studied, control period measurements of RPs of regularly driven complexes and PVDs with a particular coupling interval were alternated with measurements of RPs of regularly driven complexes and PVDs with the same coupling interval during temporary coronary occlusion. The measurements during occlusion were started two minutes after the artery was occluded and continued for up to eight minutes of occlusion. The duration of temporary occlusions did not exceed eight minutes. During occlusions of this duration, it was possible to make two to three sets of measurements of RPs following regularly driven complexes and PVDs and to determine threshold prior to each set of measurements. It was not possible to make all observations during a single occlusion; therefore, control measurements with a specific set of coupling intervals for the PVDs were alternated with occlusion measurements of RPs of PVDs with the same coupling intervals. RP measurements following PVDs with other coupling intervals were made during subsequent occlusions. Measurements of basic drive refractory periods were alternated with measurements of PVD refractory periods and if the RPs of the basic drive were unstable the occlusion was released. At least ten minutes were allowed to elapse following each coronary occlusion before another set of control measurements was made. In the experiments in which RPs of PEDs were studied, the coronary artery was permanently occluded. RPs were measured at a site within and at a site outside the distribution of the occluded artery and thresholds were determined prior to each measurement. At each site, measurements of RPs of regularly driven complexes and of PEDs were alternated, and measurements at ischemic sites were begun one or more hours after coronary occlusion. Data were expressed as means and standard deviations of the means, and statistically analyzed with the paired t test.
RESULTS Refractory periods of PVDs in ischemic and nonischemic myocardium. In 13 of these 14 experiments, refractory periods measured while the heart was driven regularly were shorter during coronary occlusion than during control periods. During occlusion, refractory periods shortened an average of 10.2 ± 7.6 msec, p < .001. This average was determined from two to three measurements of RPs made
J. ELECTROCARDIOLOGY 15 (4), 1982
337
PVDS AND REFRACTORINESS IN ISCHEMIC TiSSUE
Fig. 1. Graphs of RPs measured in two dogs during control periods, solid lines, and coronary occlusion, boken lines. Measurements made during regular drive are shown in the top graphs. The numbers at the bottom of the upper graphs refer to repeated control and ocelusion periods during the course of the experiments. The lower graphs show RPs of PVDs during control and occlusian periods. In part A, RPs of PVDs with the coupling intervals indicated along the horizontal axis are shown directly beneath the RPs of regularly driven complexes measured during the corresponding control and occlusion periods. In part B, measurements of RPs of PVDs with coupling intervals of 220, 230 and 240 msec were alternated with measurements of RPs of regularly driven complexes during the fourth control and occlusion period. Measurements of RPs of PVDs with coupling intervals of 260, 280 and 300 msec were alternated with measurements of RPs of regularly driven complexes during the fifth control and occlusion period. The points on the graphs represent averages and the standard deviations of O. See text for further discussion.
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during each of several control and occlusion periods in all dogs. In the one experiment in which refractory periods prolonged during each of five temporary coronary occlusions, the prolongation averaged 10 ± 4.5 msec, p < .01. These changes RPs following coronary occlusion are comparable to those previously reported. As mentioned in the methods section, PVDs were timed respect to the basic driving stimuli, in seven experiments, and with respect to the refractory periods of the regularly driven complexes in seven experiments. The seven experiments in which PVDs were timed with respect to the basic driving stimuli will be described first. The results from two of these experiments are graphed in Fig. 1. Refractory periods of regularly driven comlexes measured during repeated control and occlusion periods are graphed in the upper panels. Although there was some variation in refractory periods during repeated control periods and during repeated coronary occlusions, these variations were small in comparison to the difference in refractory periods measured during the two states. Refractory periods of PVDs with various J. ELECTROCARDIOLOGY 15 (4), 1982
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coupling intervals are graphed in the lower panels of the figure. The solid lines indicate control period measurements and the broken lines indicate measurements during coronary occlusion. In both of the experiments there was a greater difference between control and occlusion refractory periods of the PVDs with longer coupling intervals than of the PVDs with shorter coupling intervals. For example, as seen in the lower panel of part A, the refractory period of PVDs with coupling intervals of 320 msec averaged 182 msec during the control period and 159 msec during coronary occlusion, a difference of 23 msec, The refractory period of PVDs with coupling intervals of 220 rnsec averaged 159 msec during control periods and 156 msec during coronary occlusion, a difference of only 3 msec. RPs of regularly driven complexes during the corresponding control and occlusion periods averaged 183 msec and 170 msec respectively, a difference of 13 msec. In this experiment there was less difference between control and occlusion RPs of PVDs with coupling intervals of 200, 220, 240 and 260 msec than between control and occlusion RPs of regularly
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Fig. 2. Graphs summarizing data from the seven experiments in which PVDs were timed with respect to the basic driving stimuli. The differences in RPs of PVDs in ischemic and control periods are plotted on the vertical axis and the coupling intervals of PVDs are plotted on the horizontal axis. The negative values, plotted beneath the horizontal lines in each graph, indicate that RPs of PVDs were longer during ischemia than during control periods. In five experiments (a, b, c, d and g)differences between controland coronaryocclusion RPs of PVDs at someshort coupling intervals wereless than the differences in RPs of PVDs at other longer coupling intervals. See text for further discussion. driven complexes. Similar findings from another experiment are shown in panel B. In all seven of these experiments the difference between control and occlusion RPs of PVDs at some coupling intervals was less than the difference between control and occlusion RPs of regularly driven complexes. In five of these seven experiments, control and occlusion RPs of PVDs with the shortest coupling intervals were more nearly equal than control and occlusion RPs of regularly driven complexes. The graphs in Fig. 2 summarize the results of these experiments. Each point on the graphs indicates the difference between control and occlusion RPs of PVDs at the coupling intervals indicated along the horizontal axis. The points plotted above the horizontal lines on the graphs indicate RPs of PVDs which were longer during the control period than during occlusion. Points plotted below the horizontal line indicate RPs of PVDs which were shorter during the control period than during occlusion. In five of the experiments (parts a, b, c, d, and g), there was a greater
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PVDS AND REFRACTOR INESS IN ISCHEM iC TISSUE
(part fl, the RP of a PVD with a short coupling interval (81 - 8 2 = 195 msec) was less during ischemia than during the control period but the RP of a PVD with a longer coupling interval (81 - 8 2 = 275 msec) was longer during ischemia than during the control period. In one experiment (part d), RPs of PVDs at all coupling intervals had longer durations during coronary occlusion than during control periods. This was the same experiment in which RPs of regularly driven complexes were longer during repeated coronary occlusions than during the control periods. The range of duration of RPs of PVDs at all coupling intervals was also determined during control and occlusion periods in each experiment, and the results are graphed in Fig. 3. In five of the seven experiments, the range of RP durations of PVDs was less during coronary occlusions than during control periods. For all experiments, the range in durations of RPs of PVDs at all coupling int ervals during occlusion averaged 17 ± 7.6 msec, which was significantly less than the range in duration of RPs of PVDs during control periods (28 ± 8.8 msec, p < .05). This indicates that RPs of PVDs is ischemic tissue are more independent of abrupt shortening in cycle length than RPs of PVDs in nonischemic tissue. PVDs were timed with respect to RPs of regularly driven complexes during control periods and
during coronary occlusion in seven experiments. This was done because RPs of ischemic myocardium usually decreased during the first few minutes of coronary artery occlusion. In the group of experiments described above, premature ventricular complexes induced by stimuli timed with respect to the basic driving stimuli were, therefore, relatively earlier in the cardiac cycle with respect to RPs during control periods than during coronary occlusion. By timing the PVDs with respect to the RPs of regularly driven complexes, the PVDs had a similar temporal relationship to the RP of the regularly driven complexes during control and occlusion periods. The results of these experiments were similar to those found in the first group of experiments, and findings from two representative experiments are graphed in Fig. 4. The format of this figure is similar to that of Fig. 1 except that the coupling intervals of PVDs are expressed as a function of the RP of the regularly driven complex plu s 10 msec increments. In both experiments illustrated, there was less difference between control and occlusion RPs of some PVDs induced early in the cardiac cycle than the difference in refractory periods of some PVDs induced later in the cycle. For example, in the experiment graphed in part B, the RP of PVDs induced 70 msec after the refractory period of the regularly driven complexes were 9 msec
Fig. 4. Graphs of RPs measured in two dogs during control periods, solid lines, and coronary occlusion, broken lines. A 100 The points on the graphs are averages of two or three measurements and the ver1!lO tical bars indicate the standard devialeo tions. The points without vertical bars 170 had standard deviations of O. Measurements made during regular drive are r 12)4~'7 B shown in the top graphs and measure190 ments made following PVDs are shown in the bottom graphs. The numbers 110 f.. . - --t along the horizontal axis of the upper u 170 ,y-J, 'f graphs refer to repeat ed control and oc- ... r I clusion periods. In these experiments, .s 160 I I PVDs were timed with respect to the Q>• 1 RPs of regularly driven complexes. The Q. coupling intervals of the PVDs are In- 't5 Q. dicated on the horizontal axis of the a: - - - O"WJ'OM lower graphs and expressed as RP + 10 10 msec increments. The RPs of PVDs are RP 10 ~O ~O 70 90 110 plotted directly beneath RPs of regularly driven complexes measured during COUPLING INTERVAL OF PVO, the same control and occlusion periods. (meee) See text for further discussion.
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longer during occlusion than during the control period but there was no difference in control and occlusion RPs of PVDs induced 10 msec after the RP of the regularly driven complexes. In all seven of these experiments, refractory periods during regular drive, shortened during coronary artery occlusion, average 12.9 ± 5.0 msec, p < .001. In five experiments, control and occlusion RPs of PVDs at many coupling intervals were more nearly equal than control and occlusion RPs of regularly driven complexes. In five of the experiments, there was a greater difference between control and occlusion RPs of some PVDs with long coupling itervals than other PVDs with shorter coupling intervals. In five experiments, RPs of PVDs at some coupling intervals were
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longer during ischemia than during control periods even though the absolute duration of these coupling intervals which were timed with respect to the RP of the regularly driven complexes was less during coronary occlusion than during the control periods. Refractory periods of PEDs in ischemic and nonischemic myocardium.
In these 11 experiments, PVDs with short coupling intervals were induced following every tenth basic cycle length and RPs of PEDs were compared to those measured during regular drive. These experiments were done to further define differences in effects of PVDs on refractory periods of ischemic and nonischemic tissue. In six of these experiments, PVDs at several long cou-
Fig. 5. Vertical lead body surface ECG recorded during RP measurements. The recordings on the left were taken while measurements were made at a nonischemic site and those on the right were taken while measurements were made at an ischemic site. Parts A and B are recordings taken during RP measurements of regular driven complexes and parts C and D are recordings taken during RP measurements of PEDs. As shown on the left of part A and B, in nonischemic tissue the RP test pulse (RPm) failed to produce a response 216 msec after 8 1 but produced a response 217 msec after 8 1, As shown in parts C and D, when a PVD was induced with an 8 t - 8 2 interval 218 msec RPm failed to produce a response 218 msec after the PED but produced a response 219 msec after the PED. The RP of the PED was just 2 msec longer than the RP during regular drive. Parts A and B on the right show that at the ischemic site, during regular drive RPm failed to produce a response 211 msec after 8 1 but produced a response 212 msec after 8 1, As shown in part C when a PVD was induced 215 msec after 8 1, RP IT ) failed to produce a response 219 msec after the PED but as shown in part D, when RP'llwas delayed to 220 msec after the PED a response was induced. The S. - 8 2 interval was increased to 220 msec during the recording in part D because the RP increased during the irregular drive. At this ischemic site, the RP of the PED was 8 msec longer than the RP measured during regular drive.
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pling intervals were induced in addition to the PVDs with short coupling intervals. The coronary artery was occluded for at least one hour before RPs were measured at ischemic sites. In some experiments the RPs of the regularly driven complexes at ischemic sites were longer than those at nonischemic sites and in other experiments they were shortr. For all experiments, nonischemic site refractory periods averaged 198 ± 17 msec during regular drive (n = 39), and were not significantly different from those at ischemic sites, 199 ± 16 msec, (n = 37). At both ischemic and nonischemic sites, RPs of the PEDs were longer than RPs during regular drive. At ischemic sites, RPs of PEDs were 8 ± 4 msec (n = 37) longer than RPs during regular drive, and at nonischemic sites, RPs of PEDs were 2 ± 2 msec (n = 39) longer than RPs during regular drive. This prolongation of RPs of PEDs at ischemic sites was significantly greater than the prolongation of RPs of PEDs at nonischemic sites (p < .001). The greater prolongation of RPs of PEDs at ischemic sites than at nonischemic sites occurred whether the RPs during regular drive were longer or shorter at ischemic sites than at nonischemic sites. A dog's vertical lead ECG which was recorded during refractory period measurements is shown in Fig. 5. The recordings in the panel on the left were taken while measurements were made at a nonischemic site and the recordings on the right were taken while measurements were made at an ischemic site. Parts A and B were recorded during measurements of RPs of regularly driven complexes and parts C and D were recorded during measurements of RPs of PEDs. At the nonischemic site, during regular drive, RP(T) failed to produce a response when delivered 216 sec after 81' part A, left panel, but produced a response when delivered 217 msec after 8 1 , part B, left paneL When a PVD was induced 218 msec after every tenth 8 1, RP(T) 218 msec after the PED failed to induce a response, part C, left panel, but when RPm was delayed to 219 msec a response was induced, part D, left panel. The RP of the PED was just 2 msec longer than the RP of the regularly driven complex. At the ischemic site, during regular drive RP(T) failed to induce a response when delivered 211 msec after SI' part A, right panel, but produced a response when delivered 212 msec after 81' part B, right panel. PVDs were then induced after every tenth St' The PVD was 215 msec after 8 1 in the recording shown in part C, right panel, and 220 msec after 8 1 in that J. ELECTROCARDIOLOGY 15 (4), 1982
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shown in part D, right paneL The coupling interval of the PVD had to be increased during this measurement because the RP increased during the irregular rhythm. RP 1T) 219 msec after the PED failed" to induce a response, part C, right panel, but when RPm was delayed to 220 msec after the PED a response was induced, part D, right paneL The RP of the PED was 8 msec longer than the RP during regular drive, The effect of longer coupling interval PVDs on the refractory periods of PEDs was studied in six of these experiments. As expected, when the coupling interval of the PVD was increased, the RP of the PED approached the duration of the RP of regularly driven complexes.
DISCUSSION A high incidence of ventricular tachyarrhythmias during the early phases of coronary artery occlusion has been well documented both in animal experiments 2,5'14 and in clinical studies 15·18. Han et aL2,3,19-2:J have defined a relationship between local dispersion of ventricular recovery properties and vulnerability to ventricular arrhythmias and fibrillation. Coronary occlusion alone and premature ventricular depolarization alone were two of the interventions they tested, and both were associated with increased dispersion of ventricular refractory periods. A relation of ventricular conduction defects to ventricular tachyarrhythmias has also been demonstra ted5,6,14,24-27. On the basis of these findings, it is reasonable to predict that in the setting of acute infarction early premature depolarizations would accentuate inhomogeneity of recovery properties and conduction defects present in ischemic tissue. The occurrence of a vulnerable period near the peak of the T wave, described by Wiggers and Wegria 28, also suggests a greater likelihood of inducing tachyarrhythmias with early premature depolarizations than the late ones. However, the literature contains conflicting data on whether tachyarrhythmias in patients with coronary artery disease are more likely to follow early or late premature ventricular depolarizations. In an early report, Smirk and Palmer 29 found that PVDs that fell within the T wave were frequently followed by a second PVD. Lawn et al. 30,31 also found that PVDs with short coupling intervals were the ones most likely to initiate ventricular fibrillation in patients with acute myocardial infarction. Induction of ventricular fibrilla-
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tion by artificial pacemaker stimuli falling on the T wave 32' 39 has also been reported. On the other hand, Bleifer et a1. 40 found that PVDs falling on the T wave did not induce tachyarrhythmias. De Soyza et a1. 41 found no statistically significant difference in the coupling intervals of PVDs that were followed by tachyarrhythmias and those that were not. Winkle et a1. 42 found that only 15% of episodes of ventricular tachycardia followed PVDs with the R on T phenomenon, and Lie et a1. 43 reported that ventricular fibrillation was almost as frequent when the coupling intervals of PVDs were long as when they were short. Roberts et a1. 44 found that majority of episodes of tachyarrhythmia in patients in the coronary care unit followed PVDs with relatively long coupling intervals. Other investigators have also noted that tachyarrhythrnias are frequently initiated by PVDs with long coupling intervals. 45-47 Similar findings have been observed in animal studies6,l4. The data from this study demonstrate a difference in cycle length dependent changes of RPs in ischemic as compared to normal myocardium. The RPs of PVDs with some coupling intervals had greater differences between control and coronary occlusion period measurements than RPs of PVDs with other coupling intervals. The timing of PVDs with the greatest and least difference in refractory periods between control and ischemic states varied from animal to animal, but the greatest difference was frequently found following long coupling interval PVDs. Differences in responses of refractory periods due to changes in cycle length in ischemic and nonischernic tissue have previously been reported by Lazarra et a1. 48• Those investigators found that action potentials of ischemic His fibers were longer at fast rates than at slow rates. Their report concerned only regularly driven complexes and not premature complexes. Gettes et a1. 49 demonstrated that the duration of premature ventricular action potentials did not shorten with respect to the duration of the preceding nonpremature action potential until the response arose within a critical range of the preceding repolarization, This phenomenon may have played a role in the difference in response of RPs of ischemic and nonischemic tissue we observed. It is, however, unlikely that it was the sole factor since differences in the response of RPs to changes in cycle length were observed in the experiments in which PVDs were timed with respect to the RP of the regularly driven complexes as well as in the
experiments in which the PVDs were timed with respect to 8 1" The effect of PVDs on the RPs of PEDs was also studied. In these experiments, RP measurements at ischemic sites were made one or more hours after coronary occlusion. Permanent coronary occlusions were used because the prolongation of refractory periods of PEDs did not reach a steady state for several minutes after initiating pacing with the irregular rhythm. It was therefore impossible to make the measurements during temporary coronary occlusion. One to one and a half hours after coronary occlusion, refractory periods were relatively stable and it was possible to compare refractory periods measured during regular drive to the refractory periods of the PEDs. Janse 60 reported that in nonischemic myocardium RPs of PEDs were longer than refractory periods during regular drive, but he did not study the effects of ischemia on refractory periods of PEDs. We found that in ischemic tissue refractory periods of PEDs prolonged more with respect to refractory periods during regular drive than the prolongation in nonischemic tissue. This effect was observed only in PEDs that followed short coupling interval PVDs and was observed whether the refractory periods during regular drive were longer or shorter in ischemic tissue than in nonischemic tissue. Therefore, inhomogeneity of RPs between ischemic and nonischemic tissue was sometimes greater and sometimes less after PEDs than during regular drive depending on whether the RPs during regular drive were longer or shorter in the ischemic tissue than in the nonischemic tissue. Our findings provide insight into the reason long coupling interval PVDs are frequently associated with tachyarrhythmias. Dispersion of refractoriness has been shown to enhance arrhythmia vulnerability2 3.19 22. In the majority of our experiments there was a greater difference between refractory periods in the control and ischemic states following some of the longer coupling interval PVDs than following other PVDs with shorter coupling intervals. In addition, the finding that refractory periods following PEDs prolong more in ischemic tissue than in nonischemic tissue may playa protective role at times during myocardial ischemia when refractory periods of ischemic tissue are short, but may enhance arrhythmia vulnerability at times when refractory periods of ischemic tissue are long. The greater difference in refractory periods during control and occlusion states following some PVDs with 0
o
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long coupling intervals provides an electrophysiologic environment appropriate for the support of reentrant activity, and may be at least partially responsible for the high incidence of tachyarrhythmias associated with long coupling interval PVDs in patients with ischemic heart disease.
REFERENCES 1. MENDEZ, C, GRUHZIT, C C AND MOE, G K: Influence of cycle length upon refractory periods of auricles, ventricles, and AV node in the dog. Am J Physiol 184:287, 1956 2. HAN, J AND MOE, G K: Non-uniform recovery of excitability in ventricular muscle. Circ Res 14:44, 1964 3. HAN, J, DETRAGLIA, J, MILLET, D AND MOE, G K: Incidence of ectopic beats as a function of basic rate in the ventricle. Am Heart J 72:632, 1966 4. KENT, K M, SMITH, E R, REDWOOD, D R AND EpSTEIN, S E : Electrical stability of acutely ischemic myocardium. Influences of heart rate and vagal stimulation. Circulation 47:291, 1973 5. EL-SHERIF, N, SCHERLAG, B AND LAZZARA, R: Electrode catheter recording during malignant ventricular arrhythmia following experimental acute myocardial ischemia. Evidence for re-entry due to conduction delay and block in ischemicmyocardium. Circulation 51:1003, 1975 6. FRIEDMAN, P L, STEWART, J R AND WIT, A L: Spontaneous and induced cardiac arrhythmias in subendocardial Purkinje fibers surviving extensive myocardial infarction in dogs. Circ Res 33:612, 1973 7. FRIEDMAN, P L, FENOGLIO, J J AND WIT, A L: Time course for reversal of electrophysiological and ultrastructural abnormalities in subendocardial Purkinje fibers surviving extensive myocardal infarction in dogs. Circ Res 36:127, 1975 8. HARRIS, A S AND ROJAS, G A: Initiation of ventricular fibrillation due to coronary occlusion. Exp. Med Surg 1:105, 1943 9. HARRIS, A S: Delayed development of ventricular ectopic rhythms following experimental coronary occlusion. Circulation 1:1318, 1950 10. LAZZARA, R, EL-SHERIF, NAND SCHERLAG, B: Electrophysiological properties of canine Purkinje cells in one day old myocardial infarction. Circ Res 33:722, 1973 11. LAZZARA, R, EL-SHERIF, NAND SCHERLAG, B J: Early and late effects of coronary occlusion on canine Purkinje fibers. Circ Res 35:391, 1974 12. SCHERLAG, B, HELFANT. R H. HAFT, J I AND DAMATO, A N: Electrophysiology underlying ventricular arrhythmias due to coronary ligation. Am J Physiol 219:1665, 1970 13. SCHERLAG, B J, EL-SHERIF, N, HOPE, R AND LAZZARA, R: Characterization and localization of ventricular arrhythmias resulting from myocardial
J. ELECTROCARDIOLOGY 15 (4), 1982
343
ischemia and infarction. Circ Res 35:372, 1974 14. WILLIAMS, D 0, SCHERLAG, B J, HOPE, R R, ELSHERIF, N AND LAZZARA, R: The pathophysiology of malignant ventricular arrhythmias during acute myocardial ischemia. Circulation 50:1163, 1974 15. GRACE, W J AND CHADBOURN, J A: The first hours in acute myocardial infarction (AMI). Observations in 50 patients. Circulation 42:III :160, 1970 (Abstract) 16. LOWN, B, KLEIN, M D AND HERSHBERG, P I: Coronary and precoronary care. Am J Med 46:705, 1969 17. Moss, A J, GOLDSTEIN, 8, GREENE, W AND DE CAMILLA, J: Prehospital precursors of ventricular arrhythmias in acute myocardial infarction. Arch Intern Med 129:756, 1972 18. PANTRIDGE, J F, ADGEY, A A J, GEDDES, J SAND WEBB, S W: The Acute Coronary Attack. Grune and Stratton, New York, 1975, pp 27-42 19. HAN. J , GARCIA DE JALON, P AND MOE, G K: Adrenergic effects on ventricular vulnerability. Circ Res 14:516, 1965 20. HAN, J, GARCIA DE JALON, P D AND MOE, G K: Fibrillation threshold of premature ventricular responses. Circ Res 18:18, 1966 21. HAN, J: Mechanisms of ventricular arrhythmias associated with myocardial infarction. Am J Cardiol 24:800, 1969 22. HAN, J: Ventricular vulnerability during acute coronary occlusion. Am J Cardiol 24:857, 1969 23. HAN, J AND GOEL. B R: Electrophysiologic precursors of ventricular tachyarrhythmias. Arch Intern Med 129:749, 1972 24. BOINEAU, J P AND Cox, J L: Slowventricular activation in acute myocardial infarction: A source or reentrant premature ventricular contraction. Circulation 48:702, 1973 25. DURRER, D, VAN DAM, R TH, FREUD, G E AND JANSE, M J: Re-entry and ventricular arrhythmias in local ischemia and infarction of the intact dog heart. Proc K Ned Akad Wet (BioI Med) Ser C 73-4:321, 1971 26. HOPE, R R, WILLIAMS, D 0, EL-SHERIF, N, LAZZARA, RAND SCHERLAG, B J : The efficacyof antiarrhythmic agents during acute myocardial ischemia and the role of heart rate. Circulation 50:507, 1974 27. WALDO, A L AND KAISER, G A: A study of ventricular arrhythmias associated with acute myocardial infarction in the canine heart.' Circulation 47:1222, 1973 28. WIGGERS, C AND WEGRIA, R: Ventricular fibrillation due to single, localized inductionand condenser shocks applied during the vulnerable phase of ventricular systole. Am J PhysioI128:500, 1940 29. SMIRK. F H AND PALMER, D G: A myocardial syndrome. With particular reference to the occurrence of sudden death and of premature systoles interrupting antecedent T waves. Am J Cardiol 6:620, 1960 30. LOWN, B, KLEIN, M D AND HERSHBERG, P I: Coronary and precoronary care. Am J Med46:705, 1969
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31. LOWN, B, FAKHRO, A M, HOOD, W B JR AND THORN, J W: The coronary care unit. New perspectives and directions. JAMA 199:188, 1967 32. BILITCH, M, COSBY, R SAND CAFFERKY, E A: Ventricular fibrillation and competitive pacing. New Eng J Med 276:598, 1967 33. BURGESS, M J, GROSSMAN, M AND ABILDSKOV, J A: Fibrillation threshold of a patient with myocardial infarction treated with a fixed-rate pacemaker: Case report. Am Heart J 80:112, 1970 34. DITTMAN, H At FRIESE, G AND HOLDER, E: Erfahrungen uber die long fristige Reizung des Menschilchen Herzens. Z Kreislaufforsch, 51:66, 1962 35. DRESSLER, W, JONAS, S AND RUBIN, R: Observations in patients with implanted cardiac pacemaker, IV. Repetitive responses to electrical stimuli. Am J Cardiol 15:391, 1965 36. ELMQVIS'f, R, LANDEGREN, J, PETTERSSON, S 0, SENNIG, A AND WILLIAM·OLSSON, G: Artificial pacemaker for treatment of Adams-Stoke syndrome and slow heart rate. Am Heart J 65:731, 1963 37. GRONDIN, P, LEPAGE, G, KARAMEHMET, A, CASTONGUAY, Y AND MEERE, C: Pacemaker-induced repetitive firing: Report of two cases. Canad Med Assoc J 96:1477,1967 38. ROBINSON, D S, FALSETTI, H L, WHEELER, D H, MILLER, DB AND AMIDON, E L: Ventricular fibrillation associated with two functioning implanted cardiac pacemakers. Am J Cardio115:397, 1965 39. TAVEL, M E AND FISCH, C: Repetitive ventricular arrhythmia resulting from artificial internal pacemaker. Circulation 30:493, 1964 40. BLEIFER, S B, KARPMAN, H L, SHEPPARD, J J AND BLEIFER, D J: Relation between premature ventricular complexes and development of ventricular tachycardia. Am J Cardiol 31:400, 1973 41. DE SOYZA, N, BISSETT, J K, KANE, J J, MURPHY, M L AND DOHERTY, J E: Ectopic ventricular prematurity and its relationship to ventricular
42.
43.
44.
45.
46.
47.
48.
49.
50.
tachycardia in acute myocardial infarction in man. Circulation 50:529, 1974 WINKLE, R A, DERRINGTON, DC AND SCHROEDER, J S: Characteristics of ventricular tachycardia in ambulatory patients. Am J Cardiol 39:487, 1977 LIE, K I, WELLENS, H J J, DOWNAR, E AND DURRER: Observations on patients with primary ventricular fibrillation complicating acute myocardial infarction. Circulation 52:755, 1975 ROBERTS, R, AMBOS, H D, LOH,C W, AND SOBEL, B: Initiation of repetitive ventricular depolarizations by relatively late premature complexes in patients with acute myocardial infarction. Am J Cardiol 41:678, 1978 KLEIGER, R T, MARTIN, T F, MILLER, J P AND OLIVER, G C: Ventricular tachycardia and ventricular extrasystoles during the late recovery phase of myocardial infarction. Am J Cardiol 33:149, 1974 (Abstract) RUBERMAN, W, WEINBLA'l'T, E, GOLDBERG, J D, FRANK, C W AND SHAPIRO, S: Ventricular premature beats and mortality after myocardial infarction. New Eng J Med 297: 750, 1977 VAN DURME, J P AND PANNIER, R H: Prognostic significance of ventricular dysrhythmias one year after myocardial infarction. Am J Cardiol 37: 178, 1976 (Abstract) LAZZARA, R, EL·SHERIF, NAND SCHERLAG, B: Disorders of cellular electrophysiology produced by ischemia of the canine His bundle. Circ Res 36:444, 1975 GETTES, L S, MOREHOUSE, NAND SURAWICZ, B: Effect of premature depolarization on the duration of the action potentials in Purkinje and ventricular fibers of the moderator band of the pig heart: Role of proximity and the duration of the preceding action potential. Circ Res 30:55, 1972 JANSE, M J: The Effect of Changes in Heart Rate on the Refractory Period of the Heart. Mondeeloffsetdrukkerij, Amsterdam, 1971, pp 33-35
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