(Circulation. 1996;94:2526-2534.)
© 1996 American Heart Association, Inc.
Articles |
Human Ventricular Action Potential Duration During Short and Long Cycles
Rapid Modulation by Ischemia
the Department of Cardiology, The Middlesex Hospital, London (P.T., P.M.I.S., H.S.) and Hatter Institute for Cardiovascular Studies (P.T., P.M.I.S.), University College Hospital; the Department of Physiology, University of Leeds (M.R.B.); and the British Heart Foundation Cardiac Arrhythmia Group, Department of Physiology, Charing Cross and Westminster Hospital Medical School, London (M.L.).
Correspondence to Dr P. Taggart, Department of Cardiology, The Middlesex Hospital, Mortimer St, London W1N 8AA, UK.
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Abstract |
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Background Mechanisms underlying the initiation of ventricular arrhythmias in ischemia by a premature beat or after a pause remain unclear. The kinetics of electrical restitution, which is the modulation of action potential duration (APD) by an abrupt alteration in cycle length, may be important.
Methods and Results We recorded one or two simultaneous monophasic action potentials (MAPs) from the right ventricular septum during balloon occlusion of the left anterior descending coronary artery (LAD) (14 patients), which is expected to induce ischemia at the recording site, and during occlusion of the right coronary artery (RCA) (7 patients), which is not expected to induce ischemia at the recording area. The latter acted as a control. A test pulse sequence was incorporated whereby during steady-state pacing, test beats of altered cycle length were interposed. During LAD occlusion, APD for basic beats shortened from 260±4 to 236±4 ms (P<.0001), whereas the control group (RCA occlusion) showed no significant change (251±7 to 249±9 ms; P=NS). LAD occlusion resulted in flattening of the slope relating APD of test beats to diastolic interval (P=.001), whereas in the control group (RCA occlusion) the slope remained unchanged. Similar results were obtained during a second occlusion.
Conclusions LAD occlusion in patients during balloon angioplasty shortened MAP duration of basic beats and minimized, abolished, or reversed the normal APD/diastolic-interval relation of test beats of altered cycle length at sites served by the occluded vessel. The results suggest that ischemia flattens the electrical restitution curve in the human endocardium. These findings may have important implications in arrhythmogenesis.
Key Words: ischemia • action potentials • endocardium • electrophysiology
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Introduction |
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The elucidation of mechanisms underlying the initiation of serious or fatal ventricular arrhythmias in the ischemic human heart remains a major challenge for basic scientists and clinicians.1 Experimental studies continue to advance our knowledge of mechanisms of these arrhythmias and the associated cellular and ionic accompaniments of ischemia.2 3 However, data in the human heart that may relate directly to these experimental studies have been lacking owing to practical difficulties in developing appropriate models. We are investigating indirect approaches.
The interval dependence of the APD, often referred to as the electrical restitution curve, has been the subject of extensive experimental study in a variety of tissue types and species, including isolated ventricular muscle,4 5 6 7 8 Purkinje fibers,4 5 8 9 10 11 and single cells.12 These studies have included both a detailed appraisal of the mathematical relationship between APD and the preceding interbeat interval8 10 11 13 and the underlying cellular mechanisms involved.6 7 9 10 11 14 These observations not only provide a wealth of information on the physiological behavior of different cell types but also, since APD may be reliably measured in the in situ beating heart,15 16 17 18 19 provide a means of interfacing cellular events with whole-heart models, including human hearts. Several studies have used this approach, for example, to evaluate mechanisms of antiarrhythmic agents,20 neurohumoral influences,21 22 mechanical effects,23 and endocardial/epicardial differences.24 25 The interval dependence of APD may itself be directly relevant in the context of ischemic arrhythmias, since the latter are commonly initiated by a premature beat with a short coupling interval or after a pause.26 27 28 However, despite its potential importance, only one or two authors have addressed the APD/cycle-length relationship in the setting of ischemia,29 30 and we are unaware of any published data on the human heart.
The APD/cycle-length relationship may be readily determined in the human heart by use of MAP recordings.31 32 33 34 We have previously demonstrated the ability of the MAP catheter electrodes sited on the right ventricular septum to provide a reliable index of local ischemia in patients.35 36 37
PTCA provides the opportunity to monitor electrophysiological changes during short periods of controlled ischemia in the human heart. The evaluation of the entire range of interbeat intervals, ie, from the shortest to the longest possible diastolic interval, to establish a formal electrical restitution curve takes several minutes and is impractical in the early phase of ischemia during the PTCA procedure. We have therefore monitored APD during steady-state atrial pacing and confined our observations to just four test beats of altered cycle length introduced in a repeating sequence. Our results show that ischemia induces a rapid alteration in the interval dependence of the ventricular APD in the human heart.
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Methods |
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Patients
Twenty-one patients were selected at random from the waiting list for angioplasty. Fourteen patients, 7 men and 7 women 36 to 73 years old (median, 60 years), undergoing PTCA of a proximal LAD lesion composed the study group. A control group consisted of 7 patients, 4 men and 3 women 48 to 72 years old (median, 58 years), undergoing PTCA of an RCA lesion. Patients with unstable angina or atrial fibrillation were excluded. Routine premedication was 10 mg diazepam 1 hour before the procedure. Individual patient details are shown in the Table
. The study protocol was approved by the hospital ethical committee, and written informed consent was obtained from each patient.
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MAP Recordings
MAPs were recorded with bipolar silver/silver chloride custom-built pressure contact electrodes (Cordis UK; 7F). The exploring electrode (1.0 mm2) was situated at the tip, and the reference electrode (1.0 mm2) was situated 5 mm back from the tip flush with the wall of the catheter. The MAP has been shown to provide a faithful representation of the time course of repolarization of the intracellular action potential.17 18 19 Signals without a smooth and stable diastolic baseline and amplitude of <10 mV were excluded from the analysis.
Signal Processing
The MAP signals were fed into a Gould isolated preamplifier (model 11-5407-58) to achieve patient isolation and then to a Gould universal amplifier (model 13-4615-58). The amplifiers were set to give an output of 1 V for 40-mV input with a frequency response of 300 Hz. A Gould chart recorder (model 3400-30-V8 404-12) was used for hard-copy recordings at a paper speed of 125 mm/s. Signals were calibrated with a DC millivolt source (model 404 S, Time Electronics). For patients 7 through 21, computer acquisition of data was included by use of a CED 1401-S for digitization at a sampling rate of 1000/s, Cambridge Electronic Design.
Pacing Protocol
A pacing protocol was used such that during atrial pacing at a basic cycle length (S1), four test beats or pulses (S2) of altered cycle length (S1-S2) were interposed in repeating sequence, with nine beats (S1) of the basic train between each S2: for example, the nine S1=750 ms, with the four S2 having S1-S2=300, 400, and 500 ms and a longer coupling interval of 900 ms (made possible because of the sinus node recovery time). S1 was determined by the patient's intrinsic heart rate (see below). The S2 intervals were chosen to span as wide a range of S1-S2 intervals as possible. From the data, an abbreviated electrical restitution curve may be constructed.
Procedure
After preliminary coronary arteriography, 0.6 mg atropine was administered. In the patients undergoing PTCA of the LAD, one or two MAP catheters were inserted via the right femoral vein and positioned on the right ventricular anterior septal wall in the midseptal region and/or toward the apex (Table
). In the control group, in patients undergoing PTCA of the RCA, one MAP catheter was positioned in the midseptal region. A 6F temporary pacing electrode was positioned for atrial pacing. A routine ECG was also monitored. The angioplasty balloon catheter (a Simpson ultralow-profile balloon catheter, Advanced Cardiovascular Systems, Inc) and guidewire (0.014-in flexible steering wire, USCI, CR Bond Inc) were advanced into the LAD. Atrial pacing was established at roughly 20 beats above the patient's intrinsic heart rate to maintain capture. After a 2-minute period to establish a steady state, control recordings were made of the MAP signals during the interpolation of test stimuli of altered cycle length as described above. The extrastimulus protocol was repeated serially during the first balloon occlusion (all patients) and before and during a second balloon occlusion (11 patients). The duration and number of balloon inflations were determined by the clinical circumstances. During the protocol, 9 of 14 patients in the study group developed ischemic ST changes on the routine ECG, and all but 1 experienced angina during the first balloon occlusion. During the second occlusion, 7 of the 11 patients showed ECG changes, and all but 1 developed angina. In the control group, 3 of 7 patients developed ST changes, and all but 1 developed angina during both the first and second runs.
Statistical analysis incorporated Student's t test with the Bonferroni method to correct for multiple comparisons as appropriate. The electrical restitution curves in Fig 4A through 4C were appraised as follows. Data were normalized (see figure legend for details), and data from different patients were pooled. It is well known that the electrical restitution curve can be described by an exponential function. To fit an exponential function to data with accuracy, it must be possible to identify the asymptotic value. Unfortunately, in our data this is not the case, for two reasons: first, there is scatter in the data (the result of patient-to-patient variability, possible errors in the measurement of APD from a MAP electrode recording, and the inability to repeat measurements during ischemia because of time constraints). Second, and more importantly, because of the technical limitations it is not possible to obtain data at very short and very long diastolic intervals; only if it were possible to obtain data at very long diastolic intervals (eg, 2 seconds) would it be possible to define the asymptote accurately. In the present study, the data were fitted with straight lines (y=mx+c; Fig 4). Although the data may be best fitted with an exponential function, a straight line is expected to be a reasonable fit to the data over a restricted range of diastolic intervals. In support of this, r ranged from .80 to .92 for the control data shown in Fig 4A through 4C. Fig. P (Fig. P Software Corp) was used to fit the data by a least-squares fitting method. The software returns both the slope of the straight line and the standard error of the slope. These are plotted in Fig 4D. In Fig 4A through 4C, an ANOVA was used to test whether the slope of the electrical restitution curve during occlusion is significantly different from the slope of the curve during the preceding control period. Two sets of data, eg, control and occlusion 1, were pooled to ensure that a common intercept (c) was fitted. An indicator column (I) was set up, ie, I was set to 0 or 1 depending on which of the two groups the data were from. The following model was used for the pooled data: y=(m+dI)x+c (ie, y=mx+c for one group and y=(m+d)x+c for the second group). Using an ANOVA, we tested the null hypothesis: d=0 versus the hypothesis: d
0 (two tailed). A significant difference is indicated by an asterisk in Fig 4D.
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Data Analysis
Monophasic APD70 was measured. All measurements were made to the end of the repolarization phase, not to a terminal tangent. The first eight beats after a change in the pacing sequence were excluded so as to reestablish steady-state conditions for measurement of APD. Direct measurements were made (at a paper speed of 125 mm·s-1) to the nearest 4 ms and confirmed by a computer algorithm data-digitized at a sampling rate of 1000 Hz by a CED 1401-S, there being no statistical difference between the two methods of measurement.
APD is frequently analyzed at APD90. However, MAP recordings sometimes develop a small deflection at the terminal phase of repolarization resembling an afterdepolarization. The question is unresolved as to whether these are true afterdepolarizations or mechanical artifacts. In previous publications, we have included data for both APD90 and APD at earlier levels of repolarization, eg, APD70 and APD60. There has consistently been no difference in the overall interpretation of the results. We now avoid this problem by routinely reporting APD70, in line with many animal studies.
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Results |
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Superimpositions of test beats (S2) with their preceding basic beat (S1) are shown before balloon occlusion (control) and during balloon occlusion of the LAD (ischemia) in Fig 1
. The recordings were made from the midseptum. In Fig 1, top, APD of the basic beat (S1) is 288 ms during control conditions before occlusion of the vessel. An interposed beat of shorter cycle length (S2) has a shorter APD of 268 ms. In Fig 1, middle, during occlusion, the basic beat APD (S1) has shortened to 260 ms. An interposed early beat (S2) of the same short cycle length as at top now shows no shortening of APD compared with its basic beat. However, the shortening of the APD of the basic beat during occlusion results in a longer diastolic interval before the test beat compared with that under control conditions (ie, 252 ms compared with 216 ms as shown in Fig 1). Since the APD of the test beat would be expected to be governed primarily by the diastolic interval rather than the cycle length, we ideally should make the diastolic intervals comparable. This was impracticable during the occlusion, because it would require an even more premature beat in the face of ST segment changes and angina. It was also not practical to determine the new diastolic intervals during occlusion (which may be changing dynamically) and alter the drive runs to have fixed diastolic intervals. However, a second control example is shown in Fig 1, bottom. In this superimposition, the basic beat (S1) has the same APD as in Fig 1, top, ie, 288 ms, but the early test beat (S2) cycle length is slightly longer than for the test beat in Fig 1, top. This results in a longer diastolic interval that is now comparable to that during balloon occlusion. However, unlike during occlusion, the APD of the test beat during control is still clearly shorter than the preceding basic beat.
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The basic beat APD (S1) was shortened during balloon occlusion of the LAD that served the recording area. The mean values for MAP recording sites during LAD occlusion were 260±4 ms (mean±SEM) before occlusion of the vessel and 236±4 ms (P<.0001) during the first occlusion of the vessel. The corresponding values before and during a second balloon occlusion were 248±5 and 237±5 ms (P<.0001), respectively. Although mean APD was shorter before the second occlusion than before the first occlusion, this difference was not statistically different. However, the shortening of APD during the first occlusion of 22.4±3 ms was significantly greater than that during the second occlusion of 10.7±2.5 ms (P<.004). The mean values for APD before occlusion and during occlusion are shown separately in Fig 2 (top) for the midseptum and apical regions. The reason for separating the data obtained from the two regions is that we anticipated that occlusion of the proximal LAD would consistently induce ischemia in the midseptum and ischemia of a variable extent toward the apex dependent on collateralization (see "Discussion"). In Fig 2A, data for the first occlusion are shown on the left and data for the second occlusion on the right. There was, in fact, no significant difference in APD shortening between the two areas during the first occlusion. Control values before the second occlusion, after a period of reflow of between 0.5 and 5.5 minutes, show only partial recovery of APD (see also below). The APD subsequently shortens again during the second occlusion, although the shortening at the midseptum just fails to reach significance. Again, there was no significant difference in the changes between sites during occlusion 2 or between occlusion 1 and occlusion 2. In Fig 2A, bottom, mean values are similarly displayed for a control group of recordings from the midseptum during RCA occlusion. Occlusion of this vessel results in no significant change in APD during either the first or second occlusion. To provide some indication of the time required for the effects of ischemia (produced by LAD occlusion) on the basic beat APD to reverse, we have related the APD at the start of the second occlusion to the time interval between the first and second occlusions (Fig 2B). We have plotted APD at the end of the first occlusion and joined the points to the respective values at the start of the second occlusion to illustrate that the time course of recovery was not necessarily related to the extent of APD shortening during ischemia. Mean values for APD with respect to control were 90.5±1.3 ms at the end of the first occlusion and 93.9±1.3 ms for pooled values between the start of reperfusion and 3 minutes of reperfusion (P<.4) and 96.7±1.0 ms for pooled data between 3 and 6 minutes of reperfusion (P<.02) with respect to occlusion.
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In control conditions, before occlusion of the artery, test beats with diastolic intervals shorter than the basic beat had APD shorter than the basic beat, and test beats with diastolic intervals longer than the basic beat had APD longer than the basic beat. These findings are consistent with the kinetics of restitution of APD. However, during balloon occlusion of the coronary artery supplying the recording site, this relationship was altered. In the midseptal region, the area potentially the most vulnerable to ischemia, the response of APD to abrupt alteration in diastolic interval was largely lost. At the apical recording sites, the overall effect was similar to the midseptal region, resulting in a substantial diminution of the response of APD to change in diastolic interval. However, in this region the effect was less clear-cut, several test beats tending to retain the control relationship. Data plots to illustrate specific features of basic beats (S1) and test beats (S2) are shown in Fig 3A. Values for APD of the basic beats are shown as crosses and the test beats as circles. Data points for the basic beats are joined with a dashed line as a visual aid to the overall and relative changes in APD. Fig 3A shows APD measurements during a 2-minute occlusion of the vessel and 5 minutes of reflow. The APD of the basic beat shortens during the occlusion. In control recordings, the APDs of test beats with shorter diastolic intervals are shorter than the APD of the basic beats. This relationship is lost after balloon inflation, and at 1 minute in this example, the relationship is actually reversed such that the test beats with diastolic intervals shorter than the basic beat now have APDs longer than the basic beat. During reflow, the control relationship of the test beat to the basic beat is rapidly restored, whereas the APD of the basic beat itself is slower to recover. An example of "inverse restitution" is shown in Fig 3B. As in Fig 1, under control conditions the premature beat has a shorter APD. However, unlike Fig 1, during ischemia the premature beat is actually longer than the basic beat over a range of diastolic intervals.
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Our overall results suggest a flattening of the electrical restitution curve in response to early ischemia. To demonstrate this for the group as a whole, we have normalized the data for the control group (ie, nonischemic recording site, Fig 4A) and for the ischemic midseptal (Fig 4B) and apical (Fig 4C) regions. The control values for all three groups show a positive relation between APD and diastolic interval. For the control group, balloon occlusion of the vessel not supplying the recording site results in no alteration of the APD/diastolic-interval relationship (Fig 4A). At the midseptum, however (Fig 4B), there is a dramatic change with a flattening of the relationship during balloon inflation, an equally dramatic return to control configuration during the reflow, and a further flattening during a second occlusion of the artery. At the apical region (Fig 4C), an effect is seen that is similar to that at the midseptum. The scatter about the line at the shorter diastolic intervals during the first occlusion is created by two recording sites, which showed little change from control. The slopes (and standard errors of the mean) of the electrical restitution data are summarized in Fig 4D. An ANOVA was carried out to compare the slopes under ischemic conditions with those during the preceding control period (see "Methods" for further details). An asterisk indicates a significant difference (P
.001) between ischemia and the preceding control period.
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Our observations are confined to only a few beats at each recording site. Consequently, the possibility must be considered that the changes that we observed in APD of the test beats relative to the basic beats could have been due to the presence of a hump related to a "supernormal period" on the electrical restitution curve. Such a hump has been demonstrated in the human heart at diastolic intervals of between 
50 and 100 ms.33 However, inspection of raw data plots (Fig 5) shows that although what could be described as a hump in some of the records may have exerted some influence on the results, it is by no means the explanation for our findings.
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Discussion |
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Angioplasty of the LAD in patients undergoing balloon angioplasty shortened APD at two right ventricular endocardial sites, mid anterior septum and low septum/apex. When beats of shorter or longer cycle length were interposed during steady-state atrial pacing before balloon occlusion of the artery, the overall effect was a shortening of APD after the shorter intervals and a lengthening of APD after the longer intervals. During periods of ischemia created by balloon inflation, the relationship between abrupt alteration in cycle length and APD seen in control conditions was minimized, absent, or reversed.
APD of the Basic Beat
During balloon occlusion of the artery, APD of the basic beat shortened, consistent with the well-known effects of both true and simulated ischemia in a wide variety of tissue types and species.2 3 The shortening is likely to be the result of a decrease of the L-type Ca2+ current (ICa) and an increase in the extracellular K+ concentration (and the consequent increase in the inward rectifier K+ current, IK1)38 and possibly activation of the ATP-sensitive K+ current (IKATP). The extent of the APD shortening was similar to our previous observations on the human endocardium in patients with coronary artery disease undergoing PTCA,35 pacing to the angina threshold,39 and vasodilator perfusion imaging.36 Myocardial perfusion scintigraphy was incorporated into two of these studies and demonstrated a good correlation between the APD changes and the location of the ischemic territory.36 39
APD of the Test Beats
In control recordings before balloon inflation, interposed test beats of shorter cycle length had a shorter APD and test beats of longer cycle length had a longer APD. During balloon inflation of the LAD, striking differences were apparent at the midseptal and apical sites, at which the majority of test beats now showed little or no change in APD compared with the basic beat or even a change in the opposite direction (ie, test beats with shorter coupling intervals had APD longer than the APD of the preceding basic beat). We consider it reasonable to equate these findings with the effects of ischemia, for various reasons: (1) The APD shortening of the basic beat is characteristic of ischemia; (2) the basic-beat APD changes were comparable to our previous observations with MAP electrodes on the human endocardium when we verified the position of the MAP in an ischemic zone by nuclear scintigraphy36 37 39 ; (3) all patients except 1 experienced angina during balloon inflation and the recordings; (4) 9 of the 14 patients showed ischemic ECG changes in the routine ECG during both occlusion periods; (5) the MAP electrodes for the midseptal and apical recordings were located in the area served by the balloon-occluded segment of the artery; and (6) in the control group, MAP recordings from one of the same regions as the study group (midseptum) during occlusion of the RCA (which does not supply the recording site) showed no change in basic-beat APD consistent with the absence of ischemia, and the APD/diastolic-interval relation was unchanged.
Consideration of the Model and Limitations
To appraise interval-dependent changes of APD during ischemia in the human heart, it is necessary to use a model that is both practical in terms of time constraints and safe. Construction of formal electrical restitution curves with multiple test points spanning from the refractory period to the longest intervals permitted by the sinus node recovery time takes several minutes. This is clearly not practical in the context of angioplasty, in which the balloon occlusion times are usually between 1 and 3 minutes. We therefore used a protocol incorporating just four test beats, three shorter and one longer than the basic beat, each separated by nine basic beats. Repeated sequences suggested that during ischemia, the electrical restitution curve in humans moves downward and flattens in line with observations on the porcine epicardium.30
In these studies, we opted for atrial rather than ventricular pacing because the increased dispersion inherent in ventricular pacing might make the introduction of premature stimuli during ischemia, even in the right ventricle, hazardous. Consequently, AV nodal refractoriness, despite atropine, limited the range of prematurity obtainable. As a result, our observations are limited to the middle part of the electrical restitution curve and provide no information on the initial steep rising phase. It is likely that many of the premature beats that initiate ventricular tachycardia impinge on partially refractory tissue at very short or even negative diastolic intervals, as recognized clinically as the R on T phenomenon (ie, when the R wave in the ECG of the premature beat falls on the T wave of the preceding beat). However, the results of Dilly and Lab30 suggest that the initial steep rising phase of the electrical restitution curve may also flatten during ischemia.
In many isolated experimental preparations, the curve relating APD to the electrical diastolic interval follows a smooth exponential time course from the shortest APD at the shortest diastolic interval to the longer APDs at the longer diastolic intervals. However, in several species, including humans,31 33 34 a biphasic time course has been observed, resulting in a hump on the early phase of the curve (see Franz et al33 for references and discussion). The hump is not always present, but when it occurs, it occurs between diastolic intervals of 50 to 100 ms. The hump, when present, would be expected to be located on the left edge of our data points in Fig 5. Indeed, there is a suggestion of this at several individual sites in the figure. It is clear from Fig 5 that our results could not be explained by APD at short diastolic intervals falling on the early rising phase or trough after the hump and subsequently falling on the summit during ischemia. It is possible that these slight deviations may have influenced our data, although this should be minor. The hump could not have been responsible for the effect at longer cycle lengths. The possibility exists that ischemia may produce a generalized increase in the hump, but this would be tantamount to a generalized alteration in the time course of electrical restitution.
Underlying Mechanisms
The electrical restitution curve reflects the time-dependent restitution of a variety of membrane currents. Incomplete restitution of the transient outward K+ current (Ito) and Ca2+-dependent transient Cl- outward current [ICl(Ca)] will tend to prolong an extrasystolic action potential, and presumably these processes are normally masked by the incomplete restitution of ICa and Na+-Ca2+ exchange current (INa,Ca) and delayed rectifier K+ currents (IK,r and IK,s), which will tend to shorten an extrasystolic action potential. The flattening of the electrical restitution curve in ischemia could result from a decline in the importance of ICa, INa,Ca, IK,r, and IK,s in relation to Ito and ICl(Ca); for example, ICa is known to be depressed by metabolic inhibition.38 It is also possible that the flattening of the electrical restitution curve is the result of a shortening of the action potential as a result of the activation of IK,ATP (the shorter action potential will result in less inactivation and, thus, less restitution of ICa, for example).
Clinical Implications
Despite the short duration of ischemia over which our observations were made, these findings may have important clinical implications in the initiation of arrhythmia after a premature beat. The most common mode of sudden death in patients with coronary heart disease is the initiation of ventricular tachycardia by a premature beat and its degeneration into ventricular fibrillation.27 28 How flattening of the restitution curve in these circumstances would influence arrhythmia is not clear. It has been suggested that the converse, a steepening of the curve, is proarrhythmic or leads to "chaos."40 Moreover, Winfree41 has suggested through his modeling that steepening of restitution breaks spiral waves (reentry) into smaller ones, the spiral breakup being the equivalent of fibrillation. One could therefore argue that flattening of the restitution curve is protective. On the other hand, even in the presence of postrepolarization refractoriness, the APD will in part determine the refractory period. It is well known that dispersion of APD enhances arrhythmogenesis by reentrant mechanisms.2 It has also been shown that APD may have a significant effect on a reentrant circuit.42 43 Therefore, flattening of restitution within the ischemic zone, by enhancing dispersion of repolarization after a premature beat between the ischemic and normal zones, could cause dispersion of refractoriness and subsequent reentry. Our results may also be relevant to the initiation of the arrhythmia by local current flow.44 45 46 An increase in extracellular potassium that occurs early in ischemia may result in regions of inexcitability, thereby facilitating the juxtaposition of action potentials of different durations.47 48 Flattening of the electrical restitution curve in the ischemic region may alter the local voltage gradients during premature activation or after a pause. This could then reexcite across the border zone.
Finally, other mechanisms whereby flattening of restitution of APD during myocardial ischemia may be proarrhythmic would include reentry at Purkinje fiber muscle junctions.42 Recent work has demonstrated the critical importance of interval-related local differences in APD (coupled with effects on latency). Furthermore, small differences in membrane voltage were shown to have potentially significant effects on macroscopic wave fronts, which in an anisotropic system could be proarrhythmic in regions other than the Purkinje-muscle junction.
Conclusions
Occlusion of the mid LAD in patients undergoing balloon angioplasty shortened monophasic APD of the basic beat and minimized, abolished, or reversed the normal APD/cycle-length relation at endocardial sites served by the occluded vessel. These results suggest that ischemia rapidly alters the APD/cycle length relationship and flattens the electrical restitution curve. These findings during premature activation may have important implications in arrhythmogenesis.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by the British Heart Foundation. We are grateful to Professor M.J. Janse and Dr Tobias Opthof for critical reading of the manuscript. We thank Angela Scott for medical artwork.
Received March 26, 1996; revision received June 11, 1996; accepted June 17, 1996.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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1. Task Force of the Working Group on Arrhythmias of the European Society of Cardiology. The Sicilian gambit: a new approach to the classification of antiarrhythmic drugs based on their actions on arrhythmogenic mechanisms. Circulation. 1991;84:1831-1851.
2.
Janse MJ, Wit AL. Electrophysiological mechanisms of ventricular arrhythmias resulting from myocardial ischemia and infarction. Physiol Rev. 1989;69:1049-1169.
3. Gettes LS, Cascio WE. Effect of acute ischemia on cardiac electrophysiology. In: Fozzard HA, Harber E, Jennings RB, Katz AM, Morgan HE, eds. The Heart and Cardiovascular System. 2nd ed. New York, NY: Raven Press Ltd; 1992:2021-2054.
4. Greenspan K, Edwards RE, Fisch C. Effects of cycle length alteration on canine cardiac action potentials. Am J Physiol. 1967;212:1416-1420.
5.
Gettes LS, Marchanse N, Surawicz B. Effect of premature depolarization on the duration of 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. 1972;30:55-60.
6. Bass BG. Restitution of the action potential in cat papillary muscle. Am J Physiol. 1975;228:1717-1724.
7.
Boyett MR, Jewell BR. A study of the factors responsible for rate dependent shortening of the action potential in mammalian ventricular muscle. J Physiol (Lond). 1978;285:359-380.
8. Elharrar V, Surawicz B. Cycle length effect on restitution of action potential duration in dog cardiac fibers. Am J Physiol. 1983;244:H782-H792.
9.
Hauswirth O, Noble D, Tsien RW. The dependence of plateau currents in cardiac Purkinje fibres on the interval location between action potentials. J Physiol (Lond). 1972;222:27-49.
10. Elharrar V, Atarashi H, Surawicz B. Cycle length dependent action potential duration in canine cardiac Purkinje fibres. Am J Physiol. 1984;247:H936-H945.
11.
Boyett MR, Fedida D. Changes in the electrical activity of dog cardiac Purkinje fibres at high heart rates. J Physiol (Lond). 1984;350:461-491.
12.
Robinson RB, Boyden PA, Hoffman BF, Hewett KW. Electrical restitution process in dispersed canine cardiac Purkinje and ventricular cells. Am J Physiol. 1987;253:H1018-H1025.
13. Boyett MR, Jewell BR. Analysis of the effects of changes in rate and rhythm upon the electrical activity in the heart. Prog Biophys Mol Biol. 1980;36:1-52.[Medline] [Order article via Infotrieve]
14.
Gettes LS, Reuter H. Slow recovery from inactivation of inward currents in mammalian myocardial fibres. J Physiol (Lond). 1974;240:703-724.
15. Franz MR. Long-term recording of monophasic action potentials from human endocardium. Am J Cardiol. 1983;51:1629-1634.[Medline] [Order article via Infotrieve]
16. Runnalls ME, Sutton PMI, Taggart P, Treasure T. Modifications of electrode design for recording monophasic action potentials in animals and humans. Am J Physiol. 1987;253:H315-H320.
17. Hoffman BF, Cranefield PF, Lepeschkin E, Surawicz B, Herrlich HC. Comparison of cardiac monophasic action potentials recorded by intracellular and suction electrodes. Am J Physiol. 1959;196:1297-1301.
18. Ino T, Karagueuzian HS, Hong K, Meesman M, Mandel WJ, Peter T. Relation of monophasic action potentials recorded with contact electrode to underlying transmembrane action potential properties in isolated cardiac tissues: a systematic microelectrode validation study. Cardiovasc Res. 1988;22:255-264.[Medline] [Order article via Infotrieve]
19.
Franz MR, Burkhoff D, Spurgeon H, Weisfeldt ML, Lakatta EG. In vitro validation of a new cardiac catheter technique for recording monophasic action potentials. Eur Heart J. 1986;7:34-41.
20.
Varro A, Elharrar V, Surawicz B. Effect of antiarrhythmic drugs on the premature action potential duration in canine cardiac Purkinje fibers. J Pharmacol Exp Ther. 1985;233:304-311.
21. Taggart P, Sutton P, Lab M, Dean J, Harrison F. Interplay between adrenaline and interbeat interval on ventricular repolarisation in intact heart in vivo. Cardiovasc Res. 1990;24:884-895.[Medline] [Order article via Infotrieve]
22.
Munakata K, Dominic JA, Surawicz B. Variable effects of isoproterenol on action potential duration in guinea-pig papillary muscle: differences between nonsteady and steady state: role of extracellular calcium concentration. J Pharmacol Exp Ther. 1982;221:806-814.
23.
Elzinga G, Lab MJ, Noble MIM, Papadoyannis DE, Pidgeon J, Seed A, Wohlfart B. The action-potential duration and contractile response of the intact heart related to the preceding interval and the preceding beat in the dog and cat. J Physiol (Lond). 1981;314:481-500.
24.
Tande PM, Mortensen E, Refsum H. Rate-dependent differences in dog epi- and endocardial monophasic action potential configuration in vivo. Am J Physiol. 1991;261:H1387-H1391.
25. Litovsky S, Antzelevitch C. Rate dependence of action potential duration and refractoriness in canine endocardium differs from that of epicardium: role of a transient outward current. J Am Coll Cardiol. 1989;14:1053-1066.[Abstract]
26.
Lown B, Wolf M. Approaches to sudden death from coronary heart disease. Circulation. 1971;44:130-142.
27.
Janse MJ. The premature beat. Cardiovasc Res. 1992;26:89-100.
28. Bayes de Luna A, Coumel P, Leclerq JF. Ambulatory sudden cardiac death: mechanisms of production of fatal arrhythmia on the basis of data from 157 cases. Am Heart J. 1989;117:151-159.[Medline] [Order article via Infotrieve]
29.
Lukas A, Antzelevitch C. Differences in the electrophysiological response of canine ventricular epicardium and endocardium to ischemia: role of the transient outward current. Circulation. 1993;88:2903-2915.
30.
Dilly SG, Lab MJ. Electrophysiological alternans and restitution during acute regional ischaemia in myocardium of anaesthetized pig. J Physiol (Lond). 1988;402:315-333.
31. Endresen K, Amlie JP, Forfang K, Simonsen S, Jensen Ø. Monophasic action potentials in patients with coronary artery disease: reproducibility and electrical restitution and conduction at different stimulation rates. Cardiovasc Res. 1987;21:696-702.[Medline] [Order article via Infotrieve]
32.
Seed WA, Noble MIM, Oldershaw P, Wanless RB, Drake-Holland AJ, Redwood D, Pugh S, Mills C. Relation of human cardiac action potential duration to the interval between beats: implications for the validity of rate corrected QT interval (QTc). Br Heart J. 1987;57:32-37.
33. Franz MR, Swerdlow CD, Liem LB, Schaefer J. Cycle length dependence of human action potential duration in vivo: effects of single extrastimuli, sudden sustained rate acceleration and deceleration, and different steady-state frequencies. J Clin Invest. 1988;82:972-979.
34. Morgan JM, Cunningham D, Rowland E. Dispersion of monophasic action potential duration: demonstrable in humans after premature ventricular extrastimulation but not in steady state. J Am Coll Cardiol. 1992;19:1244-1253.[Abstract]
35.
Taggart P, Sutton P, John R, Hayward R, Swanton H. The epicardial electrogram: a quantitative assessment during balloon angioplasty incorporating monophasic action potential recordings. Br Heart J. 1989;62:342-352.
36.
John RM, Taggart PI, Sutton PM, Costa DC, Ell PJ, Swanton H. Vasodilator myocardial perfusion imaging: demonstration of local electrophysiological changes of ischaemia. Br Heart J. 1992;68:21-30.
37. John RM, Taggart PI, Sutton PM, Ell PJ, Swanton H. Direct effect of dobutamine on action potential duration in ischemic compared with normal areas in the human ventricle. J Am Coll Cardiol. 1992;20:896-903.[Abstract]
38.
Lederer WJ, Nichols CG, Smith GL. The mechanism of early contractile failure of isolated rat ventricular myocytes subjected to complete metabolic inhibition. J Physiol (Lond). 1989;413:329-349.
39. John RM, Taggart PI, Sutton PM, Costa DC, Ell PJ, Swanton H. Endocardial monophasic action potential recordings for the detection of myocardial ischemia in man: a study using atrial pacing stress and myocardial perfusion scintigraphy. Am Heart J. 1991;122:1599-1609.[Medline] [Order article via Infotrieve]
40.
Chilvo DR, Michaels DC, Jalife J. Supernormal excitability as a mechanism of chaotic dynamics of activation of cardiac Purkinje fibers. Circ Res. 1990;66:525-545.
41. Winfree AT. How does ventricular tachycardia decay into ventricular fibrillation. In: Shanasa M, Borggrefe M, Breithardt G, eds. Cardiac Mapping. Mount Kisco, NY: Futura Publishing Co Inc; 1993.
42.
Gilmour RF, Watanabe M. Dynamics of circus movement reentry across canine Purkinje fibre-muscle junctions. J Physiol (Lond). 1994;476:473-485.
43.
Starmer CF, Romashko DN, Reddy RS, Zilberter YI, Starobin J, Grant AO, Krinsky VI. Proarrhythmic response to potassium channel blockade: numerical studies of polymorphic tachyarrhythmias. Circulation. 1995;92:595-605.
44.
Janse MJ, Van Capelle FJL, Morsink H, Kleber AG, Wilms-Schopman F, Cardinal R, Nauman d'Alnocoust C, Durrer D. Flow of `injury' current and patterns of excitation during early ventricular arrhythmias in acute regional myocardial ischemia in isolated porcine and canine hearts: evidence for two different arrhythmogenic mechanisms. Circ Res. 1980;47:151-165.
45.
Janse MJ, Kleber AG. Electrophysiological changes and ventricular arrhythmias in the early phase of regional myocardial ischemia. Circ Res. 1981;49:1069-1081.
46.
Coronel R, Wilms-Schlopman FJG, Opthof T, Van Capelle FJL, Janse MJ. Injury current and gradients of diastolic stimulation threshold, TQ potential, and extracellular potassium concentration during acute regional ischemia in the isolated perfused pig heart. Circ Res. 1991;68:1241-1249.
47. Kodama I, Wilde AAM, Janse MJ, Durrer D, Yamada K. Combined effects of hypoxia, hyperkalaemia and acidosis on membrane action potential and excitability of guinea pig ventricular muscle. J Mol Cell Cardiol. 1984;16:247-259.[Medline] [Order article via Infotrieve]
48. Opthof T, Coronel R, Shander GS, Wilms-Schlopman FJG, Janse MJ. Electrophysiological changes and ventricular fibrillation in acute regional myocardial ischemia in the porcine heart: the concept of wavelength. J Cardiovasc Electrophysiol. 1992;3:128-140.
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