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Circulation. 1995;92:120-129

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(Circulation. 1995;92:120-129.)
© 1995 American Heart Association, Inc.

Articles

Heterogeneities in [K+]o and TQ Potential and the Inducibility of Ventricular Fibrillation During Acute Regional Ischemia in the Isolated Perfused Porcine Heart

Ruben Coronel, MD; Francien J. G. Wilms-Schopman; Lukas R. C. Dekker, MD; Michiel J. Janse, MD

From the Department of Experimental Cardiology, Academic Medical Center, Amsterdam, and the Interuniversity Cardiology Institute, Utrecht, Netherlands.

Correspondence to R. Coronel, MD, Department of Experimental Cardiology, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, Netherlands.


*    Abstract
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 *Abstract
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Background The relation between the inducibility of ventricular fibrillation (VF) and heterogeneity of the extracellular potassium concentration ([K+]o) and of TQ potential is unknown.

Methods and Results Data from 78 epicardial DC electrodes or from up to 32 intramural K+ electrodes were acquired simultaneously. Induction of VF was attempted with one or two ventricular premature beats induced in normal myocardium in isolated porcine hearts during (1) regional perfusion of the left anterior descending artery (LAD) with a normoxic, hyperkalemic solution ([K+] 6 to 19.6 mmol/L), (2) simulated ischemia, ie, LAD perfusion with a glucose-free, hypoxic solution ([K+] 4 to 16 mmol/L, PO2 <5 mm Hg, pH 6.98), and (3) regional ischemia produced by stopping LAD flow. During normoxic, hyperkalemic LAD perfusion, no VF could be induced (12 interventions, 7 hearts). During simulated ischemia (27 interventions), VF could be induced only when [K+]o was between 8 and 13.5 mmol/L. After 5 minutes of true regional ischemia, more sites with [K+]o between 8 and 13.5 mmol/L were present than after 10 minutes. VF could be induced with 1 ventricular premature beat in 11 of 17 interventions after 5 minutes and in 0 of 14 interventions after 10 minutes of ischemia (P<.001). Regional simulated ischemia presents a relatively homogeneous condition compared with 5 minutes of regional ischemia (SD±SEM of TQ potential in LAD tissue, 0.9±0.05 versus 2.1±0.13 mV, respectively). True ischemia superimposed on regional simulated ischemia caused the rapid development of heterogeneities in [K+]o and TQ potential and caused VF after 45±7 seconds in all interventions. Activation maps of induction of VF suggest a different mechanism of unidirectional block during simulated ischemia from that in true ischemia.

Conclusions (1) In the presence of hypoxia and acidosis, [K+]o between 8 and 13.5 mmol/L provides the conditions necessary for the induction of VF; (2) after 5 minutes of ischemia, these conditions are present in a larger area and inducibility of VF is higher than after 10 minutes of ischemia; and (3) small heterogeneities within the intermediate K+–concentration domain (8 to 13.5 mmol/L) are associated with high inducibility of VF.


Key Words: fibrillation • ischemia • potassium


*    Introduction
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 up arrowAbstract
 *Introduction
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down arrowResults
down arrowDiscussion
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The most likely cause for ventricular fibrillation (VF) in the setting of acute ischemia is multiple wavelet reentry.1 For the initiation of a reentrant arrhythmia, a timely ventricular premature beat (VPB) should occur when the conditions for unidirectional activation block (the substrate2 ) are present. These conditions include regional differences in refractory period,3 4 a decrease in excitability, and slowing of conduction.5 6 7 Indeed, during the early phase of regional myocardial ischemia, heterogeneities in ventricular conduction velocity, excitability, and refractoriness precede ventricular tachycardias and fibrillation.3 4 8 9 10 11 These electrophysiological changes are mediated in large part by depolarization of the resting membrane caused by a rise of the extracellular potassium concentration ([K+]o).6 12 13 14 In the ischemic part of the heart, [K+]o is heterogeneous, with the largest [K+]o recorded from the center of the ischemic tissue.15 16 17 The electrophysiological effects of [K+]o are nonlinear: Up to about 8 mmol/L, an increase of conduction velocity and excitability occurs (which is potentially antiarrhythmic), whereas at higher concentrations, excitability and conduction velocity decrease and refractoriness increases until the myocardium becomes inexcitable at about 13.5 mmol/L, with a concomitant 30-mV depolarization of the resting membrane.6 12 13

It is unclear to what extent heterogeneities in [K+]o are related to arrhythmogenesis during ischemia. The aim of this study was to establish whether uniform depolarization of part of the ventricular muscle is sufficient as a basis for reentry or whether resting membrane potential differences within the ischemic tissue are a prerequisite. To detect the presence of the substrate for VF under these conditions, we applied closely coupled premature beats and observed whether they resulted in VF. The VPBs were provoked in myocardium at the normal side of the border, where spontaneous premature beats originate during ischemia.18 Thus, we determined the number of VPBs that induced VF during (1) hyperkalemic perfusion and (2) simulated regional ischemia as a function of [K+]o. Finally, VF induction was attempted at various times during the first two subsequent episodes of true regional myocardial ischemia. The first two ischemic episodes were selected because large differences in [K+]o occur between them.19 To assess the relation between inducibility of VF and [K+]o during these two subsequent episodes of ischemia, we also measured [K+]o in the ischemic tissue.

We conclude that the presence of myocardium with [K+]o between 8 and 13.5 mmol/L is a prerequisite for initiation of VF during both simulated and true ischemia and that small heterogeneities within the ischemic tissue are associated with increased inducibility of VF.


*    Methods
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 *Methods
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Handling of the experimental animals conformed to the guiding principles of the American Physiological Society. Pigs weighing 15 to 20 kg were anesthetized (sodium pentobarbital 20 mg/kg IV, Sanofi) after premedication with azaperone 200 mg IV (Stresnil, Janssen). After tracheal intubation, the animals were artificially ventilated. Heparin (1000 IU, Organon) was administered. A midsternal thoracotomy was performed, and 1500 mL of blood was collected from the superior vena cava and mixed with 1000 mL of a modified Tyrode's solution (composition in mmol/L: KCl 4.7, NaCl 128.5, CaCl2 1.5, MgCl2 0.7, NaHCO3 28, NaH2PO4 0.5, glucose 20, and dextran 4%). The heart was removed and connected to a Langendorff perfusion apparatus in which the mixture of blood and Tyrode's solution circulated. The perfusate was oxygenated (CO2 5%/O2 95%) and heated to 37°C. The pump pressure (40 to 50 mm Hg) and pH (7.35 to 7.45) were regulated. Total coronary flow was measured with an electromagnetic flow probe. The left anterior descending artery (LAD) was dissected free and cannulated. This led to arrest of LAD flow for a maximum of 2 minutes. Flow through the LAD could be deduced from the flow reduction when LAD flow was stopped. The cannula was connected to the perfusion apparatus. The heart or the LAD cannula could be connected to an identical perfusion system in which an alternative perfusate recirculated: (1) normoxic and hyperkalemic or (2) hypoxic (PO2 <5 mm Hg), acidotic (pH 6.98), and hyperkalemic. The average [K+] of the mixture of normal blood and Tyrode's solution was 4.0±0.6 mmol/L (mean±SD). In the alternative Tyrode's mixture, [K+] varied between 4.0 and 19.6 mmol/L. Perfusion pressure of the alternative perfusion system was regulated separately. Switching to this alternative perfusion system was used to calibrate the ion-selective electrodes or to regionally simulate ischemia. [K+] of the perfusate was measured by flame photometry. pH and PO2 were determined in blood samples with a commercially available blood gas analyzer (ABL-2, Radiometer).

The hearts were stimulated with rectangular current pulse (2-ms duration, twice diastolic stimulation threshold) at a cycle length of 450 ms. A bipolar stimulating electrode pair (interelectrode distance, 2 mm) was placed in the center of the tissue perfused by the left circumflex artery (LCx).

[K+]-sensitive electrodes consisted of pairs of silver wires (diameter, 0.2 mm) insulated except for a terminal 0.5-mm segment, which was chloridated. This segment was covered with a thin layer of liquid paper (Aspa). One of the two Ag/AgCl electrodes served as a reference electrode from which local DC electrograms could be recorded. On the other terminal, the [K+]-selective membrane was deposited as described before.17 20 The electrodes were calibrated before the experiment in two isotonic solutions ([K+] 1 and 10 mmol/L) at room temperature. Electrodes with a slope of >55 mV were selected for insertion into the heart.

Protocol 1
These experiments were performed to study the inducibility of VF. No [K+]-sensitive electrodes were present in this series of experiments so as to preclude the influence of tissue damage caused by the insertion of the electrodes. An epicardial DC electrode grid (78 wick electrodes in a 6x13 grid, interelectrode distance 3.6 mm) allowed the calculation of TQ inhomogeneity and the construction of activation maps. After cannulation of the LAD (above the first diagonal branch) and identification of the cyanotic region, the electrode grid was attached to the epicardium and partially covered the LAD-perfused tissue. An oxygen-sensing electrode was placed in the LAD cannula. After eight cycles (450 ms), first one, then two, and occasionally three ventricular premature stimuli with the shortest possible coupling interval were applied to the normal myocardium. The coupling intervals were determined before each intervention with an accuracy of 1 ms and did not change during the interventions. If the premature beats caused VF during control conditions, the protocol was aborted. During the interventions, an increasing number of premature stimuli were applied to the normal myocardium (the same amount of VPBs at least twice in sequence). On the basis of the expected electrophysiological effects (see introduction),6 12 13 the potassium concentrations were classified into three groups: [K+]o <8, between 8 and 13.5, and >13.5 mmol/L. Arrhythmias induced by the first two premature beat(s) were recorded during three conditions.

Protocol 1A, hyperkalemia. In 7 hearts (12 interventions), VF inducibility was tested during 4 minutes of regional perfusion with a normoxic, hyperkalemic blood–Tyrode's solution mixture ([K+] ranged from 6.0 to 19.6 mmol/L). Two interventions were performed in the low-[K+]o group, 7 in the intermediate, and 3 in the high-[K+]o group. VF inducibility was tested during control conditions immediately before each intervention (normal [K+]o, n=12).

Protocol 1B, simulated ischemia. In 10 hearts, VF inducibility was tested during 5 minutes of regional LAD perfusion with an acidotic (pH 6.98), hypoxic (PO2 <5 mm Hg), and hyperkalemic solution ([K+] ranged from 4.3 to 19.6 mmol/L, 27 interventions). Ten interventions were in the low-[K+]o group, 11 in the intermediate, and 6 in the high-[K+]o group. VF inducibility was also tested before each intervention. The hypoxic perfusion solution contained no erythrocytes and was infused at the same perfusion pressure as in the normal perfusion system. In 3 of these hearts, the LAD flow was interrupted for 2 minutes immediately after regional simulated ischemia. Again, VF induction was attempted as before. In 1 of these hearts, technical problems hampered DC recordings, and no TQ measurements were available.

Protocol 1C, ischemia. In 17 hearts, inducibility of VF during 2 subsequent episodes of 10 minutes' duration of regional myocardial ischemia was tested. Ischemia was produced by stopping flow through the cannula. The episodes were separated by 20 minutes of reperfusion.17 This interval was chosen because all electrophysiological changes had reverted to preischemic control values. VPBs were induced at three periods during ischemia: during the first 2 minutes of ischemia, between 4.5 and 5.5 minutes of ischemia, or between 9 and 10 minutes of ischemia. In these time windows, a single premature beat was given during the first 30 seconds and a second premature beat during the remainder of the period. Spontaneous VF occurred in 4 ischemic episodes (3 minutes 40 seconds, 4 minutes 30 seconds, 5 minutes, and 10 minutes of ischemia). If VF (spontaneous or induced) occurred, the heart was defibrillated with a DC shock and the period of ischemia was completed. After defibrillation, data acquisition was stopped. Reproducibility between the first and second occlusions was tested in 8 hearts (in 4 hearts starting after 4.5 minutes; in the other 4 hearts, after 9 minutes of ischemia). The difference in inducibility of VF between 5 and 10 minutes of ischemia was tested in 6 hearts (in 3 hearts, VPBs were given after 5 minutes in the first and after 10 minutes in the second occlusion, and in 3 hearts in reverse order). In the remaining 3 hearts, only a single ischemic episode was completed. Thus, in the first 2 minutes, VF inducibility was tested in 12 occlusions; between 4.5 and 5.5 minutes, in 17 occlusions; and between 9 and 10 minutes, in 14 occlusions.

To prevent preconditioning by simulated ischemia, protocol 1B preceded protocol 1C. The number of interventions tested in each heart (after ischemic episodes) was 2.2±0.3 (SEM) and ranged from 0 to 8. These interventions often belonged to both protocols 1A and 1B. The criterion to discontinue the experiment was the presence of activation block or induction of VF during control conditions.

Protocol 2
Protocol 2 was performed to relate VF inducibility (protocol 1C) to heterogeneity in [K+]o under the same conditions in a different set of hearts. In these hearts, in which VF induction was not attempted (see above), up to 32 [K+]-selective electrodes were inserted 2 to 5 mm from each other into the midmural portion of the left ventricular myocardium (13 hearts). The field of electrodes partially covered the myocardium perfused by the LCx artery. A map of the positions of the electrodes was drawn by hand. After calibration of the electrodes by perfusion of the heart with a medium with elevated [K+], the response of the individual electrodes was calculated. Electrodes with a response of >45 mV/decade were accepted. The average (±SEM) response of the [K+]-sensitive electrodes was 55.7±0.5 mV/decade (n=95). Data from electrodes were accepted if the DC offset was <20 mV and baseline drift was <10 mV/h. A large Ag/AgCl plate attached to the aortic root served as a common reference electrode.

Two sequential 10-minute occlusions of the LAD were performed, separated by 20 minutes of reperfusion. Data were collected at 1-minute intervals during ischemia and at 2- to 5-minute intervals during control perfusion. After identification of the electrophysiological border (the line separating tissue with TQ elevation from tissue with TQ depression during regional ischemia), only data from electrodes located inside the electrophysiological border were included in this study. The protocol could not be completed in all hearts because of intervening spontaneous VF or technical problems (baseline drift was larger at the beginning of the experiment). If spontaneous VF occurred, data from the entire ischemic episode were discarded. Therefore, the number of observations differed between the first and second episodes of ischemia (46 in the first and 63 in the second ischemic episode) and at different moments during ischemia.

In 3 other hearts (different from those in protocol 1), [K+]o and pHo were measured with intramural ion-sensitive electrodes during regional simulated ischemia followed by stopping flow through the cannulated artery. The construction of the pH-sensitive electrodes was similar to that of K+-sensitive electrodes. H+-sensitive membrane was applied as published previously.21

Data Acquisition
Signals from the reference electrodes and the differential signals from the ion-selective pairs were DC-amplified (32 and 8 times, respectively) against a common reference electrode placed on the aortic root and digitized (1 sample/4 ms). Registrations of 1.7 seconds' duration could be stored on disk at times indicated in the protocol. Selected signals were recorded on a polygraph (electrograms) and a slow-speed chart recorder (differential signals). [K+]o was calculated from the change of EK (mV), the voltage across the ion-selective membrane, with the Nernst equation. K+ data were normalized by use of the in vivo calibration factor.

Data are expressed as mean±SEM unless indicated otherwise. SDs were used as a measure of heterogeneity.16 Statistical analysis was performed with the paired Student's t test, the {chi}2 test, and the Kruskal-Wallis (KW) test (followed by the multiple-comparison protected rank-sum test) as appropriate. P<.05 was accepted as the level of significance.


*    Results
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 up arrowMethods
*Results
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[K+]o and Inducibility of VF
Increased [K+]o has been identified as a major factor in the genesis of reentrant arrhythmias during acute myocardial ischemia through its effect on the resting membrane potential.14 15 22 23 Because different levels of [K+] have qualitatively different effects on excitability, conduction velocity, and recovery of excitability (see the introduction),6 12 13 24 we divided interventions into three groups according to perfusate [K+]: <8 mmol/L, >13.5 mmol/L, and intermediate.

Regional ischemia was simulated by perfusing the LAD with a hypoxic (PO2, 4.2±1.8 mm Hg), acidotic (pH, 6.98±0.01) perfusate in which no glucose was present and in which [K+] was varied. After the change to the alternative perfusate, the electrophysiological changes were steady in 35±1.8 seconds. One minute after start of regional perfusion, attempts were made to induce VF with a single premature beat, and after 2 minutes, with two premature beats. Fig 1Down shows the effect of the premature beats as a function of the [K+] during regional simulated ischemia (protocol 1B). Only in the intermediate group was VF inducible: by a single VPB at [K+] 9.0, 11.9, and 13.3 mmol/L and by two VPBs at [K+] 8.1, 8.3 (2 times), 9.3, and 10.8 mmol/L. In two other interventions ([K+] 9.0 and 9.3 mmol/L), no VF could be induced. The moment of onset of VF was 2.2±0.16 minutes after the perfusate was changed and was not statistically different between VF induced by one and by two VPBs. Inducibility of VF was significantly higher in the intermediate-[K+] than in the low- or high-[K+] groups (KW, P<.001). Above 13.5 mmol/L [K+], all electrograms from within the electrophysiological border were monophasic, indicating the absence of local activation.25 26 27



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  		Figure 1. Bar graph showing inducibility of ventricular fibrillation (VF) as a function of the prevailing extracellular potassium concentration ([K+]o) during regional perfusion with a hypoxic, acidotic, and glucose-deficient perfusate (simulated ischemia; PO2 <5 mm Hg; pH 6.98). The ordinate indicates the effect (VF or no VF) of one or two ventricular premature beats (VPBs): solid bars, VF, one VPB; stippled bars, VF, two VPBs; open bars, no VF, two VPBs, as a percentage of the number of interventions (total indicated inside the bars). During regionally simulated ischemia, VF can be induced only with [K+] between 8 and 13.5 mmol/L.

The blood flow through the LAD was derived from the reduction of total coronary flow upon occlusion of the LAD (during normokalemic perfusion). The calculated LAD flow was 23.9±1.1% of control flow. It was not significantly different in the intermediate-K+ group from that in the other two groups. Therefore, differences in the size of the perfused tissue cannot explain the differences in inducibility of VF.

Hyperkalemia in combination with hypoxia and acidosis more accurately simulates the electrophysiological consequences of ischemia than hyperkalemia alone.28 29 To study whether this is also true for the induction of VF, we tested the inducibility of VF during normoxic perfusion of the LAD with a mixture of blood and Tyrode's solution containing elevated [K+] varying from 6.0 to 19.6 mmol/L (7 hearts, 12 interventions). Up to two (in 6 interventions, three) closely coupled premature beats were induced in the normal myocardium after eight basic cycles. Seven interventions had perfusate with the intermediate [K+]. VF could not be induced during any of these interventions, lasting for 4 minutes, or during perfusion with control [K+].

[K+]o in Ischemia
[K+]o was measured simultaneously at multiple sites during two subsequent 10-minute episodes of ischemia produced by clamping the LAD (protocol 2). The TableDown summarizes the changes in [K+]o at electrode sites within the electrophysiological border at the three selected moments in ischemia at which VF inducibility was tested in a separate series of experiments. The SD of [K+]o, as a measure of the heterogeneity in [K+]o, in concert with the maximum value of [K+]o (at a particular time) increases during ischemia. However, the average [K+]o decreases between 5 and 10 minutes of ischemia. The secondary decrease in [K+]o was more pronounced in the first than in the second episode of ischemia. This resulted in a higher average [K+] after 10 minutes in the second than in the first ischemic episode (P<.001, t test). Fig 2Down shows the overall distribution of electrode sites over the three [K+]o ranges after 2, 5, and 10 minutes of ischemia (first and second episodes). The fraction of electrode sites with intermediate [K+]o was calculated in every heart. In the first ischemic episode, it was significantly larger after 5 than after 2 or 10 minutes of ischemia (KW, P<.05); in the second, the fraction after 5 minutes was larger than after 2 minutes (KW, P<.001) but not different compared with 10 minutes of ischemia. The decrease of this fraction between 5 and 10 minutes is caused by an increased number of sites with low [K+]o (as a result of normalization, Fig 2Down) in combination with an increased number of sites with [K+]o in the highest category (increase in range of values, see the TableDown).


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  		Table 1. Maximum, Mean, and SD of Extracellular Potassium Concentration ([K+]) Measured Inside the Electrophysiological Border of the Ischemic Myocardium after 2, 5, and 10 Minutes of Regional Ischemia (Occlusion)



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  		Figure 2. Bar graph showing the distribution of the number of sites (total indicated inside the bars) over three extracellular potassium concentration ([K+]o) ranges: solid bars, >13.5; stippled bars, 8 to 13.5; and open bars, 4 to 8 mmol/L, after 2, 5, and 10 minutes of a first and second episode of regional ischemia (occlusion) produced by occluding the left anterior descending artery. [K+]o was measured with multiple potassium-sensitive electrodes. More sites with intermediate [K+]o are present after 5 minutes than after 2 or 10 minutes of ischemia.

The fraction of electrode sites in the intermediate range after 2 and 5 minutes of ischemia is not significantly different between the two ischemic episodes. After 10 minutes of ischemia, more sites with [K+]o of 8 to 13.5 mmol/L were present in the second than in the first period of ischemia (KW, P<.05). The fraction of electrode sites in the 8- to 13.5-mmol/L range was calculated for other moments in ischemia as well. In both the first and second ischemic periods, it reached a maximum after 5 minutes. This was followed by an immediate decline in the first period. In the second ischemic episode, the decrease started after 7 minutes.

Based on Fig 2Up, inducibility of VF is expected to be highest after 5 minutes of ischemia.

Inducibility of VF During Ischemia
The effects of VPBs in the first 2 minutes, between 4.5 and 5.5 minutes, and between 9 and 10 minutes of ischemia were studied in 17 hearts. In 14 of those hearts, two subsequent episodes of ischemia could be completed: The difference between the first and second ischemic periods was investigated in 8 hearts and the difference between 5 and 10 minutes of ischemia in 6 hearts (protocol 1C). Fig 3Down summarizes the results. No significant differences were detected between the first and second ischemic periods; therefore, the data from the same moment of ischemia were pooled. VF inducibility is higher after 5 minutes than after 2 or 10 minutes of ischemia (KW, P<.001). Moreover, VF was more easily inducible after 10 than after 2 minutes of ischemia (KW, P<.01).



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  		Figure 3. Bar graph showing inducibility of ventricular fibrillation (VF) during the first 2 minutes, between 4.5 and 5.5 minutes, and between 9 and 10 minutes of a first and second episode of regional ischemia (occlusion) produced by occluding the left anterior descending artery. The ordinate indicates the effect (VF or no VF) of one or two ventricular premature beats (VPBs) as a percentage of the number of periods of ischemia (indicated inside the bars): solid bars, VF, one VPB; stippled bars, VF, two VPBs; open bars, no VF, two VPBs. VF is more easily inducible between 4.5 and 5.5 minutes of ischemia than between 0 and 2 and between 9 and 10 minutes of ischemia.

Fig 2Up suggests that inexcitability ([K+]o >13.5 mmol/L) occurs in a larger part of the muscle after 10 than after 5 minutes of ischemia. Local absence of excitation is indicated by the appearance of monophasic electrograms.27 We determined the fraction of sites within the electrophysiological border displaying monophasic electrograms after the last basic stimulus before induction of VF. The fraction of sites with monophasic electrograms after the same duration of ischemia was not significantly different between the first and second episodes. Therefore, data from the same duration of ischemia in protocol 1C (epicardial measurements) were pooled. Monophasic electrograms were recorded from 5 of 676 sites (1%) after 5 minutes and from 82 of 725 sites (11%) after 10 minutes ({chi}2, P<.0001).

TQ Heterogeneities and Inducibility of VF
Fig 4ADown and 4BDown shows maps of distribution of TQ potential after 4 minutes of ischemia and after 2.5 minutes of simulated ischemia with a perfusate [K+] of 10 mmol/L. Depression of the TQ segment of local electrograms reflects local changes of the resting membrane potential.27 30 The amount of TQ depression within the LAD-perfused part of the muscle (left of the dotted line) is indicated by the numbers below each panel. It is similar in the two conditions, but the SD (a measure for spatial electrophysiological heterogeneity) is larger in ischemia. In this heart, a single VPB was capable of inducing VF during ischemia and not during perfusion with the "ischemic" solution.



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  		Figure 4. Maps of distribution of TQ potential after 4 minutes of regional ischemia achieved by occluding the left anterior descending artery (A), after 2.5 minutes of regional perfusion with a hyperkalemic ([K+] 10 mmol/L), hypoxic, acidotic, and glucose-free perfusate (B, simulated ischemia, sim. isch.), and after 1.25 minutes of ischemia (occl.) superimposed on simulated ischemia (C). TQ potential was measured at 78 electrode sites in a 6x13 grid with interelectrode distances of 3.6 mm. Individual measurements were classified according to the scale at lower left. Average±SD of the observations to the left of the dashed line are indicated below each panel. Dots in C indicate electrode sites at which reduction of TQ depression took place relative to B. One ventricular premature beat was capable of inducing ventricular fibrillation after 4 minutes of ischemia (A) and ischemia superimposed on simulated ischemia (C) but not after simulated ischemia alone (B). Note that heterogeneity in B is less than in A and C. After 4.5 minutes of sustained simulated ischemia in the same heart, no VF was inducible (not shown).

The SD of TQ potentials (±SEM) of tissue from within the electrophysiological border was calculated in all experiments. In protocol 1A (regional hyperkalemia), it was 1.1±0.5 mV (n=12) and in protocol 1B (regionally simulated ischemia), 0.9±0.05 mV (n=27 interventions, 9 hearts, not significantly different from 1A). The SD of TQ potentials during simulated ischemia was not statistically different in those interventions during which VF could be induced from those in which no VF occurred, indicating that the induction of VF under these circumstances depended on [K+]o rather than on heterogeneities. During true regional ischemia (5 minutes, 9 occlusions), in the same hearts as the 27 episodes of simulated ischemia, TQ variability was significantly larger (2.1±0.13 mV, P<.0001 against 1B, t test) than in simulated ischemia.

VF showed a tendency to be more easily inducible after 5 minutes of ischemia (17 of 17) than during simulated ischemia with [K+] 8 to 13.5 mmol/L (8 of 10) ({chi}2, P=.055). During true ischemia, however, less tissue is in the intermediate [K+] range (about 35%, Fig 3Up) than when the entire LAD region is perfused with a solution with [K+] in the intermediate range (compare with Fig 6Down). This suggests that heterogeneities may augment VF inducibility. We produced regional simulated ischemia ([K+] of 9, 10, and 10 mmol/L, 3 hearts, 7 interventions) for 2.5 to 4.5 minutes, during which 1 VPB was delivered repeatedly (after each train of eight basic stimuli). The VPB never induced VF. Immediately afterward, LAD perfusion was stopped while the pacing protocol continued. In all experiments, VF ensued 45±7.8 seconds (n=7; range, 21 to 75 seconds) after flow was stopped. Inducibility of VF was significantly higher than with simulated ischemia ([K+] 8 to 13.5 mmol/L) alone ({chi}2, P<.01). Heterogeneities in TQ potential and activation delay developed immediately before start of VF under these conditions. An example is shown in Fig 4CUp, which demonstrates that the development of heterogeneities is caused by a normalization of TQ depression at the border (sites indicated by dots) and a simultaneous increase in the central zone. Fig 5Down shows the changes in TQ dispersion and activation delay in the same experiment. During simulated ischemia ([K+] 10 mmol/L), activation delay slightly increases and TQ dispersion reaches a "steady state." After the arrest of flow, the development of heterogeneities in TQ potential is associated with a rapid increase of activation delay (of both the basic and the premature beats). This is evident also from the formation of R waves in the local electrograms recorded from the same site in the ischemic tissue (Fig 5Down, right panels). During sustained (4.5 minutes) simulated ischemia in the same heart, activation delay and TQ dispersion remained in a steady state and no VF was inducible (not shown).



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  		Figure 6. Graph showing distribution of [K+]o at different sites across the electrophysiological border (located at 0 mm) after 4 minutes of regional perfusion with a hyperkalemic ([K+] 10 mmol/L), hypoxic, and acidotic medium (simulated ischemia, {circ}) followed by 1.5 minutes of true ischemia (occlusion of the left anterior descending artery {bullet}). The graph represents one of three similar experiments. A normalization of changes takes place at border sites, while a small increase in [K+]o occurs at a larger distance from the border (more negative distance values).



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  		Figure 5. Graph showing changes in time of the SD of the TQ potential ({blacktriangleup}) as a measure of heterogeneity and of activation delay between normal and depolarized tissue ({bullet}) of the last basic and 1 premature beat (prem.). During 2.5 minutes, the left anterior descending artery (LAD) is subjected to simulated (sim.) ischemia ([K+] 10 mmol/L). Heterogeneities and changes of conduction times are relatively small and reach a "steady state." Subsequently, the LAD flow is interrupted (occl.), and activation delay increases rapidly in unison with an increase in TQ heterogeneity. One ventricular premature beat (VPB) is induced repeatedly from 1.5 minutes of simulated ischemia onward. The VPB causes ventricular fibrillation (VF) only after the development of heterogeneities. The panels on the right show the changes in a selected electrogram at the times indicated. Calibration bars relate to electrograms. Dashed lines indicate control TQ potential. Note the rapid development of TQ depression between A and B and of R waves between B and C (beginning of VF). The same experiment as in Fig 4Up (B and C).

In three separate experiments, measurements with [K+]- and proton-sensitive electrodes were made under the same conditions (anoxic perfusion with [K+] of 10 mmol/L, pH 6.95, followed by ischemia). Fig 6Up shows an example of one of these experiments. The open symbols indicate [K+]o at 11 sites spaced at various distances from the electrophysiological border after 4 minutes of regionally simulated ischemia. From the same sites, [K+]o was recorded after 1.5 minutes of ischemia immediately after these 4 minutes (closed symbols). In central zone sites, a small increase in [K+]o was recorded, while [K+]o decreased at sites closer to the border. Overall, [K+]o increased by 1.6±0.38 mmol/L (n=17), and pH decreased by 0.05±0.02 units (n=4) in central zone sites. Closer to the border, normalization of changes occurred, with a decrease of 3±1.5 mmol/L [K+] (n=4) and an increase in pH of 0.14±0.03 units (n=3). These changes were also recorded 1.5 minutes after arrest of flow.

Activation Patterns
Fig 7Down shows typical activation maps of the tissue underlying the epicardial electrode grid after the last basic and first premature stimulus. The patterns after 5 minutes of true ischemia (top panels) demonstrate that after a premature stimulus, activation block develops well inside the ischemic tissue. This is followed by VF. During 14 occlusions, similar activation patterns were observed, which were characterized by a distance of the site of earliest activation slowing (>30-ms activation delay between adjacent electrodes) during the last stimulated ventricular activation before VF of 9.8±1.9 mm (n=14) within the electrophysiological border. In the three remaining occlusions, activation delay did not exceed 30 ms.



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  		Figure 7. Activation maps of the last basic (B) and first (1) ventricular premature beat recorded after 5 minutes of ischemia (occlusion of the left anterior descending artery, top panels), after 4 minutes of simulated ischemia ([K+] 9 mmol/L, middle panels), and after 42 seconds of occlusion after simulated ischemia (bottom panels). Numbers indicate isochrone values with respect to the last basic stimulus artifact. Arrows signify gross sequence of activation. Dotted line in upper left panel indicates the position of the electrophysiological border. The result of premature stimulation is indicated at the right (VF, ventricular fibrillation). Shaded areas indicate activation block. In ischemia, after the premature stimulus, activation block lies well inside the electrophysiological border. During regionally simulated ischemia, activation is merely delayed at the interface between the two zones. Only 42 seconds of superimposed occlusion (bottom panels) creates activation block at about the same site as in the top panels and causes severe slowing of conduction and VF.

After 4 minutes of simulated ischemia (Fig 7Up, middle panels, [K+] 9 mmol/L), slight conduction slowing was present at the electrophysiological border and no VF occurred. Forty-two seconds after flow was stopped (bottom panels), VF was induced after the first premature stimulus, which caused conduction slowing and activation block at about the same sites as during true ischemia. The site of earliest activation slowing during the last stimulated ventricular activation before VF during simulated ischemia ([K+] 8 to 13.5 mmol/L) was 4.3±0.5 mm (n=8) inside the electrophysiological border (t test, P<.05 versus ischemia).

A particular example of the activation patterns of VF induction recorded during regional simulated ischemia is presented in Fig 8Down. The first VPB causes activation delay at the border between normal and ischemic tissue (compare with Fig 7Up). The second premature beat leads to activation block at the border between the myocardium subjected to simulated ischemia ([K+] 7.7 mmol/L) and the normally perfused tissue. Activation resumes after an apparent focal origin at the distal side of the band of activation block. A third premature stimulus generates apparent focal origin with a delay of 110 ms with respect to the approaching wave front. Activation then circles the activation block and reexcites proximal tissue. This is the start of VF. Fig 9Down shows selected electrograms recorded from sites indicated in Fig 8Down. It demonstrates the delay in activation (arrows) between adjacent sites. Activation of sites 60 and 48 after the third stimulus is preceded by large R waves (triangles). Note that the two sites display depression of the TQ segment. A similar unusual activation pattern of VF induction was recorded in another heart during simulated ischemia ([K+] 9.3 mmol/L).



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  		Figure 8. Activation maps of the last basic and three premature beats (VPBs) (B, 1, 2, 3) during regionally simulated ischemia with a [K+] of 7.7 mmol/L (3.5 minutes). Italic numbers are isochrone values relative to the basic stimulus artifact. Upper left panel schematically shows the placement of the electrode grid (rectangle) over the depolarized tissue (dotted area). The electrode grid is indicated in B (small open circles). The first VPB causes activation slowing at the border between normal and depolarized myocardium (dashed line in B) beyond which activation speeds up again. After the second VPB, a zone of activation block manifests itself at the interface between normal and depolarized myocardium (shaded area). Activation resumes with an apparent focal origin ({star}) distal to the site of activation block. The same is more clearly seen after the third VPB, which causes "delayed activation" after 110 ms. The activation wave then circles the area of block, reexcites proximal tissue, and leads to ventricular fibrillation. Electrograms recorded from the electrodes marked 48 and 60 through 63 in solid circles are shown in Fig 9Up.



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  		Figure 9. Induction of ventricular fibrillation. Local electrograms recorded from sites indicated in Fig 8BUp during regional simulated ischemia. The top trace schematically displays the stimulus protocol. Note that electrogram 61 is depicted twice. Sites 60 and 48 show depression of the TQ segment with respect to control TQ potential (lines near electrode numbers), indicating that they are in the depolarized tissue. After the second and third stimuli, activation is delayed over the electrophysiological border (arrowheads). Before local activation of sites 60 and 48, large R waves are recorded ({blacktriangleup}).


*    Discussion
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*Discussion
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Since Harris identified potassium as one of the major culprits in the genesis of arrhythmias in the setting of acute myocardial ischemia,23 much attention has been focused on the changes in [K+]o during ischemia. The development of [K+]-sensitive electrodes made multiple, simultaneous measurements possible.20 [K+]o rises inhomogeneously in a triphasic pattern.15 17 31 Small changes in [K+]o result in large changes in recovery of excitability12 13 and conduction velocity.6 Ischemia is associated with nonuniform recovery of excitability3 and decreased conduction velocity.29 Also, a decrease of the VF threshold was observed.9 32 However, the precise relation between [K+]o and the inducibility of VF, and whether heterogeneities within the ischemic tissue are necessary for the induction of VF, are unknown. In a recent article,33 a model of a selectively perfused rabbit heart was used to determine the role of potassium in arrhythmogenesis. Spontaneous arrhythmias were counted as a function of [K+] in one part of the heart. However, no conclusions can be drawn from that study about the role of [K+]o in the formation of the arrhythmogenic substrate. Previous studies have been performed with injection of a concentrated KCl solution directly into one of the coronary arteries.23 34 35 36 However, this does not uniformly depolarize the perfused region and causes large temporal variations in local [K+]o.35 Therefore, in this study, part of the heart was depolarized homogeneously by regional perfusion of the myocardium with a solution containing elevated [K+]. We tested the presence of conditions necessary for VF by providing the initiating VPB at the nondepolarized region and observing the subsequent onset of the arrhythmia.

Our study shows that the initiation of a reentrant arrhythmia is possible when tissue with a [K+]o between 8 and 13.5 mmol/L is present (Fig 1Up), but only in hypoxic, acidotic conditions. At higher concentrations, the myocardium is permanently inexcitable.14 Differences in the maximum value (and thus the range) of [K+]o between the first and second periods of ischemia (as demonstrated previously19 ) do not lead to differences in VF inducibility. Also, the SD of [K+]o is larger after 10 minutes (TableUp), whereas VF is induced more easily after 5 minutes (Fig 3Up) of ischemia. This demonstrates that neither the maximum value nor heterogeneity of [K+]o (expressed as SD) is a reliable measure for the inducibility of VF. Rather, combining Figs 1Up, 2Up, and 3Up implies that the amount of tissue within the critical intermediate range of [K+]o more accurately determines whether VF can be induced. The easy inducibility of VF after 5 minutes of ischemia suggests that heterogeneities within the ischemic tissue augment the substrate for VF. Indeed, if small heterogeneities are superimposed on the relatively homogeneous conditions of simulated ischemia, VF could be induced with a single VPB in 7 of 7 interventions. The earliest case of VF could be induced 21 seconds after arrest of flow. VF occurred during the evolution from an abrupt to a gradual transition between normal and depolarized tissue and in the absence of a large increase in [K+]o or a decrease in pH (Fig 6Up). The development of heterogeneities was associated with a rapid decrease in conduction velocity. This probably is caused by decremental "uphill" conduction of the activation wave, whereby the wave progressively loses the ability to excite the resting myocardium.37 However, this study does not provide direct evidence for a causal relation between heterogeneities and conduction slowing.

In true ischemia, factors other than [K+]o, such as pH, catecholamines, oxygen free radicals, and lysophosphatidylcholines, may influence the electrophysiological substrate of VF. During simulated ischemia, the extracellular accumulation of these factors was prevented by perfusion and only [K+]o was varied. When simulated ischemia was followed by true ischemia (Fig 5Up), VF occurred as early as 21 seconds after flow was stopped. This makes the role of the above-mentioned factors in the genesis of VF improbable, because during true ischemia, VF can be induced only after about 3 minutes.

At moderately elevated [K+] (up to about 8 mmol/L), increased conduction velocity6 29 38 and excitability10 24 probably antagonize arrhythmogenesis. A concomitant regionally decreased refractory period39 may preclude unidirectional block when premature beats are induced in myocardium with a longer refractory period (the normal zone).

The mechanism of initiation of VF during regionally simulated ischemia seems to be different from that observed in ischemia (Figs 7 through 9UpUpUp). Whereas in ischemia, activation delays gradually increase when the activation wave penetrates the ischemic segment, simulated ischemia shows an abrupt slowing of the wave at the interface between the two vascular beds. Activation block is located well within the ischemic tissue during true ischemia (Fig 7Up) and at the border between normal and depolarized tissue in regionally simulated ischemia (Figs 8Up and 9Up). The abrupt transition between normal and depressed tissue in simulated ischemia presents a large current load to the approaching wave front and may lead to failure of conduction. The apparent focal emergence of activity at the distal side of the zone of activation block is an exceptional feature and has never been described in true ischemia. In true ischemia, activation propagates slowly around an area of block to activate the area distal to the block with delay and then to retrogradely invade the region of unidirectional block and to reexcite the tissue proximal to it. With the techniques used in our study, we cannot exclude that conduction circumvented the area of block in a transmural plane. However, it may be expected that the abrupt transition was present throughout the ventricular wall. The large R waves preceding "focal" activation suggest that a large electrotonic current flowed intracellularly from the normal toward the still refractory depressed tissue. After termination of the refractory period, this current might have led to delayed activation of the depolarized tissue (Fig 10Down). Reexcitation of the tissue proximal to the block may have been caused by reflection.40 Other focal mechanisms are not likely in ischemic tissue: Early afterdepolarizations do not occur after short action potentials, and delayed afterdepolarizations are counteracted by elevated [K+]o.



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  		Figure 10. Schematic of transmembrane potentials from adjacent sites. N is from the normal myocardium, and "I" from myocardium subjected to simulated ischemia. The gradient between the two sites is abrupt. The heart is stimulated from the normal side. Bars indicate the effective refractory periods from the two locations. A premature stimulus activates normal myocardium. However, conduction toward the "ischemic" tissue is blocked. A large systolic electrotonic current (arrows) flows intracellularly from N to "I," resulting in a large R wave in the extracellular space of the "ischemic" segment. After termination of refractoriness, "I" is activated with a considerable delay. This activation is associated with (retrogradely) unidirectional block and may lead to reentry.

Spontaneous VF during acute myocardial ischemia is usually initiated by a premature beat originating in the normal zone.1 18 41 42 For the initiation of a reentrant arrhythmia, the occurrence of a VPB should coincide with conditions favorable for the emergence of unidirectional block.2 7 43 Kaplinsky et al44 described the occurrence of two distinct periods of spontaneous arrhythmias during the early phase of ischemia. The surge of reentrant arrhythmias (VT/VF) between 3 and 8 minutes demonstrates that the substrate for reentry was present, but the initiating VPBs were also increased during the same period. The current of injury, which is held responsible for the genesis of premature beats during regional ischemia,1 24 is largest during deep negative T waves. The incidence of these deep negative T waves is largest between 3 and 5 minutes of regional ischemia.1 Therefore, both the substrate and the initiating factor for VF are simultaneously present, most prominently around 5 minutes of ischemia. Based on the present study, the phase of relative arrhythmogenic quiescence after the first period of arrhythmias can be explained in terms of a decline of the mass of tissue with intermediate [K+]o. The critical value of the fraction of ischemic tissue with intermediate [K+]o (8 to 13.5 mmol/L) for the induction of VF by a single premature beat is between 20% and 35% (Figs 2Up and 3Up). Between about 3 and 8 minutes of ischemia, this critical value is exceeded, corresponding to the phase of immediate ventricular arrhythmias.44 Clinical interventions aimed at reducing the mass of tissue with dangerous intermediate [K+]o are to be considered in addition to those that reduce the amount of VPBs.

Received December 1, 1994; accepted December 20, 1994.


*    References
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*References
 

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