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Circulation. 1996;94:2526-2534

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(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

Peter Taggart, MD, FRCP; Peter M.I. Sutton, PhD; Mark R. Boyett, PhD; Max Lab, MD, PhD; Howard Swanton, MD, FRCP

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.


*    Abstract
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 *Abstract
down arrowIntroduction
 down arrowMethods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
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


*    Introduction
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 up arrowAbstract
 *Introduction
down arrowMethods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
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.


*    Methods
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 up arrowIntroduction
 *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 TableDown. The study protocol was approved by the hospital ethical committee, and written informed consent was obtained from each patient.


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  		Table 1. Patient Characteristics, LV Function, Coronary Anatomy, Medication, BCLs, Recording Sites, and Durations of Coronary Occlusions

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 (TableUp). 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 4CDown 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 4Down). 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 4CDown. 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 4DDown. In Fig 4A through 4CDown, 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 4DDown.






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  		Figure 4. A, B, C, Change in APD (APD of the test beat minus APD of preceding basic beat) plotted against change in diastolic interval (diastolic interval of test beat minus diastolic interval of preceding basic beat). Data from different patients are pooled. Plots for a control group (A), midseptum (B), and apex (C) before first balloon occlusion (control, first panel), during balloon occlusion [occlusion (1), second panel], after reflow (third panel), and during a second balloon occlusion [occlusion (2), fourth panel] are shown. Values for basic beat are shown as ringed circles. The correlation coefficient (r) for each of the graphs is as follows: control group, control (.90), occlusion 1 (.92), reflow (.91), occlusion 2 (.80); midseptum, control (.89), occlusion 1 (.13), reflow (.85), occlusion 2 (.46); apex, control (.87), occlusion 1 (.36), reflow (.81), occlusion 2 (.43). D, Slope (±SEM) of the electrical restitution curves in A, B, and C. For each group, values under control conditions, during the first occlusion, on reflow (control), and during the second occlusion are shown. *Slope during occlusion significantly different (P<.001) from the preceding control.

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.


*    Results
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 *Results
down arrowDiscussion
 down arrowReferences
 
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 1Down. The recordings were made from the midseptum. In Fig 1Down, 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 1Down, 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 1Down). 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 1Down, bottom. In this superimposition, the basic beat (S1) has the same APD as in Fig 1Down, top, ie, 288 ms, but the early test beat (S2) cycle length is slightly longer than for the test beat in Fig 1Down, 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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  		Figure 1. Superimposition of MAPs of basic beats (S1) (BB) and interposed test beats (S2) (TB) of shorter cycle length. The corresponding diastolic intervals (DI) between the basic beats and test beats and APD at 70% repolarization are shown at right. Before balloon occlusion of the artery (control), the APD of the premature test beat (S2) is shorter than its preceding basic beat (S1). During occlusion of the vessel, the APD of the premature beat (S2) does not shorten compared with its preceding basic beat (S1) (see text).

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 2Down (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 2ADown, 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 2ADown, 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 2BDown). 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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  		Figure 2. A, APD (mean±SEM) of basic beat before balloon occlusion of vessel (C) and during balloon occlusion before deflation and reflow (O). Values are shown separately for midseptum and apical recording sites during LAD occlusion and for midseptal recording sites during RCA occlusion (control group). I indicates first occlusion; II, second occlusion. Significance of change in APD between control and during occlusion is shown (see text). B, Comparison of time interval between first and second occlusions with APD expressed as percent of control, ie, percent of preocclusion values. Time 0 indicates end of first occlusion and start of reperfusion. Normalized control values are related to time -1 or -2 according to whether a 2- or 1-minute period of balloon occlusion (ischemia) preceded reflow. Regression analysis for relation between time and recovery of repolarization: r=.53, P<.003.

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 3ADown. 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 3ADown 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 3BDown. As in Fig 1Up, under control conditions the premature beat has a shorter APD. However, unlike Fig 1Up, during ischemia the premature beat is actually longer than the basic beat over a range of diastolic intervals.




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  		Figure 3. A, Data points for APD (ms) from 1 patient are shown to illustrate specific features. Top annotation indicates ischemia with time. Bottom axes are diastolic intervals at each period indicated at top. APD is plotted against its corresponding preceding diastolic interval. Basic beats (S1) are represented by a cross (x) and joined to subsequent (consecutive) test beat (S2), represented by a closed circle. Basic beats are joined by a dashed line as a visual aid. After balloon occlusion, the basic beat APD shortens and there is a flattening of the relationship between APD and diastolic interval. At 1 minute, APDs of test beats are longer than APD of basic beat. After balloon deflation, control relationship between APD and diastolic interval is rapidly restored, but basic APD is slower to recover. B, Superimposition of MAPs in same format as upper two panels in Fig 1Up illustrating "inverse restitution." During control, APD of premature beat (S2) is shorter than basic beat (S1). Lower panel, During occlusion, APD of premature beat (S2) is longer than basic beat (S1).

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 4AUp) and for the ischemic midseptal (Fig 4BUp) and apical (Fig 4CUp) 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 4AUp). At the midseptum, however (Fig 4BUp), 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 4CUp), 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 4DDown. 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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  		Figure 5. Plots of APDs against their respective diastolic intervals for each recording site before balloon occlusion (control) and during balloon occlusion. Midseptal sites during LAD occlusion (top) and for a control group during RCA occlusion (bottom). Flattening of the APD/diastolic-interval relationship during LAD occlusion is evident over a wide range of diastolic intervals and therefore cannot be attributed solely to interaction with a "hump" on restitution curve (see text).

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 {approx}50 and 100 ms.33 However, inspection of raw data plots (Fig 5Up) 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.


*    Discussion
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 *Discussion
down arrowReferences
 
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 {approx}50 to 100 ms. The hump, when present, would be expected to be located on the left edge of our data points in Fig 5Up. Indeed, there is a suggestion of this at several individual sites in the figure. It is clear from Fig 5Up 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.


*    Selected Abbreviations and Acronyms
 
APD = action potential duration
APD70 = APD measured at 70% repolarization
APD90 = APD measured at 90% repolarization
LAD = left anterior descending coronary artery
MAP = monophasic action potential
PTCA = percutaneous transluminal coronary angioplasty
RCA = right coronary artery


*    Acknowledgments
 
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.


*    References
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