EXPERIMENTAL STUDY
Origin of ischemia-induced phase 1b ventricular arrhythmias in pig hearts
Ruben Coronel, MD, PhD*,*,
Francien J. G. Wilms-Schopman, MSc and
Joris R. deGroot, MD, PhD*
* Experimental and Molecular Cardiology Group, Cardiovascular Research Institute, Academic Medical Center, Amsterdam, The Netherlands
Interuniversity Cardiology Institute, Utrecht The Netherlands
Manuscript received April 26, 2001;
revised manuscript received September 17, 2001,
accepted September 20, 2001.
* Reprint requests and correspondence: Dr. Ruben Coronel, Department of Clinical and Experimental Cardiology, Academic Medical Center, M0-54, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
R.Coronel{at}amc.nl
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Abstract
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OBJECTIVES: The goal of this study was to establish the role of ventricular filling on the 1b phase of ischemia-induced arrhythmias.
BACKGROUND: Ischemia-induced ventricular arrhythmias occur in two phases. The mechanism of the initiation of delayed (1b) arrhythmias is unknown. The 1b arrhythmias (15 to 60 min of ischemia) are abundant in in situ hearts but scarce in isolated perfused hearts (with drained ventricles).
METHODS: Left ventricular (LV) epicardial mapping (11 x 11 matrix, 5 mm interelectrode distance) of the initiation of delayed arrhythmias was performed in open-chested pigs (group A, n = 7) and isolated pig hearts without (group B, n = 8) and with a filled intraventricular balloon (group C, n = 5).
RESULTS: There were no differences in ischemic zone size between groups. The ischemia-induced rise in tissue impedance was similar in groups A and B. Arrhythmias were less frequent and less severe in group B than in groups A or C, with no differences between groups A and C. An epicardial focal origin was detected in 26% of all first beats, significantly more from the ischemic border than from elsewhere. During a pacing protocol with a long pause (a separate group of four isolated hearts with a balloon), more premature beats occurred in the first postpause interval than in any other interval.
CONCLUSIONS: In isolated hearts 1b arrhythmias were less frequent and less severe than in working preparations. Focal activity was documented in 26% of arrhythmias and emerged from the ischemic border. Postpause contractile potentiation was associated with more arrhythmias. Our study suggests that the initiation of ischemia-induced 1b arrhythmias is related to LV wall stress.
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Abbreviations and Acronyms
| | EADs | | early afterdepolarizations | | KW | | Kruskall-Wallis | | LAD | | left anterior descending artery | | LV | | left ventricle, left ventricular | | MI | | myocardial infarction | | Rt | | tissue impedance | | VF | | ventricular fibrillation | | VPBs | | ventricular premature beats | | VT | | ventricular tachycardia |
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Ventricular arrhythmias after coronary occlusion constitute a major risk for sudden cardiac death (1). Study of these arrhythmias has focused on the first 10 to 15 min of regional myocardial ischemia (the 1a phase). However, a second—1b—phase of arrhythmias, 15 to 60 min after occlusion occurs in dogs (2) and in other species (3). The relative contribution of the delayed types of arrhythmias and the early arrhythmias to sudden cardiac death in humans is unknown, but animal experiments suggest that mortality in the 1b phase of arrhythmias is larger than in the 1a phase (2,4,5).
The mechanism of the origin of 1b arrhythmias is unclear. Kaplinsky et al. (2) proposed a non-reentrant mechanism on the basis of the absence of local continuous diastolic electrical activity (diastolic bridging) preceding a premature ventricular beat in in situ dog hearts, but indirect evidence for reentrant mechanisms is present as well (4).
For spontaneous arrhythmias, the concurrence of a premature beat (a trigger) and a substrate (a preexisting proarrhythmic condition) is a prerequisite (6). We have previously characterized the substrate of 1b arrhythmias by repetitively applying a premature beat in Langendorff perfused pig hearts (7), where spontaneous 1b arrhythmias are scarce. The temporary presence of the arrhythmogenic substrate in this model closely corresponds to the 1b phase in in situ hearts and is probably caused by residual coupling of surviving tissue to severely depressed myocardium (7). The mechanism of the arrhythmogenic trigger in this phase of ischemia, however, is unknown, nor is it known why it is present in the in situ heart and not in the isolated perfused heart. The aim of this study is to elucidate the mechanism of the initiation of 1b arrhythmias.
According to Laplace’s law, wall stress is larger in in situ hearts than it is in perfused hearts with a drained left ventricle (LV). Previous publications support the notion that stretch causes ventricular premature beats (VPBs) (8) by altering refractory periods (9) and resting membrane potential (10). The development of rigor is closely associated with the 1b phase of arrhythmias (11), and regional abnormal wall motion is statistically associated with the occurrence of VPBs in patients (12). We therefore tested the hypotheses: 1) that a proarrhythmic factor related to LV filling is present during the 1b phase in in situ and not in isolated perfused hearts, and 2) that the first beat of 1b arrhythmias originates from tissue adjacent to the ischemic zone (which is in rigor at that time).
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Methods
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Animal preparation.
This study conformed to the institutional guidelines for animal research. Piglets (20 to 25 kg) of either gender were premedicated with ketamine 350 mg, azaperone 80 mg and atropin 0.5 mg (intramuscularly). After sedation, the animal was anaesthetized with 20 mg/kg pentobarbital intravenously, intubated and ventilated with room air and isoflurane. Heart rate, expiratory CO2 and body temperature were monitored. A venous drip was instituted, a midsternal thoracotomy was performed, and the heart was exposed. Heparin (5,000 IU) was injected intravenously.
Langendorff perfused hearts.
While 1 L of Tyrode’s solution (37°C) was infused, 2 L of blood-Tyrode’s mixture was collected from the superior caval vein (13). Ventricular fibrillation (VF) was induced by a DC current, and the heart was excised rapidly and submerged in ice cold Tyrode’s solution. The aorta was cannulated and connected to a Langendorff setup (13). Both ventricles were drained. Flow was measured continuously; pressure was regulated to obtain a flow of about 100 ml/min. Myocardial temperature was 37°C, and pH of the perfusate was between 7.35 and 7.45. In the working isolated preparations, a compliant plastic bag was introduced into the LV through the left atrium and connected to a vertical tube filled with saline (37°C). A clamp allowed control of the ejection resistance. A pressure transducer was connected to the tube. The saline level and the tube clamp were adjusted to obtain a diastolic pressure of 0 to 10 mm Hg and a systolic pressure of 30 to 50 mm Hg. In all cases systolic pressure was lower than perfusion pressure to prevent subendocardial ischemia.
Open-chested preparations.
The tip of a saline filled cannula was advanced through the right carotid artery to a position just above the aortic valves. Aortic pressure and a standard electrocardiogram lead were monitored. The animal was positioned on a heated pad and covered with a heated blanket. The wound was covered with a plastic sheet.
A short occlusion of left anterior descending coronary artery (LAD) below the first diagonal branch allowed identification of the ischemic zone. A ligature was left around the LAD.
Electrodes and data acquisition.
The multi-electrode consisted of 121 silver electrodes in an 11 x 11 matrix (interelectrode distance 5 mm) on a silicon sheet. Half of the electrode matrix was positioned over the prospective ischemic area. A bipolar stimulating electrode was placed in the nonischemic LV myocardium close to the multi-electrode. Bipolar recording electrodes were placed near the stimulating electrode and on the right ventricular outflow tract.
The multi-electrode was connected to a PC-based acquisition system. A virtual ground electrode was connected to the aortic root. Data from the preceding 1.8 s (sampling interval 0.5 ms) could be stored on disk. Signals from both bipolar electrode pairs and aortic pressure (or LV intra-balloon pressure) were written continuously on a Graphtec recorder for the detection of arrhythmias.
Tissue impedance (Rt) was measured in eight separate hearts using the four-electrode technique described previously (7). In short, four parallel platinum pins (interelectrode distance 2 mm, length 5 mm, diameter 0.7 mm) were introduced into the myocardium (>1 cm within the prospective cyanotic border). The electrodes were isolated except at the terminal 1.5 mm. Alternating current (30 µA, 1 kHz) was delivered between the outer two electrodes, and the voltage was measured between the inner two electrodes. A custom-made recording system allowed for the calculation of Rt. Only recordings from the central ischemic zone showing a >100% rise during ischemia were accepted for analysis. The presence of the balloon precluded Rt measurement in group 3 (as described subsequently).
Protocol.
After an equilibrium period of 30 min following instrumentation, the ligature around the LAD was tied, and pacing was discontinued to reduce early (1a) ventricular arrhythmias. After 10 min of ischemia, ventricular pacing with a constant cycle length between 350 and 450 ms, slightly above the spontaneous sinus rate, was started. Spontaneous occurrence of ventricular arrhythmias was recorded during the observation period (15 until 60 min of ischemia or until VF). As many as possible onsets of arrhythmias were captured on disk.
The following groups were studied: 1) open-chested animals (in situ); 2) isolated perfused hearts; 3) isolated perfused hearts with intraventricular balloon; 4) same as group 3 but with a pacing protocol of nine basic beats and 700 to 750 ms pause.
After each experiment the heart was perfused with a solution containing black ink. The atria, the aorta and the pulmonary vessels were removed. The relative size of the ischemic zone was calculated as the ratio of the weight of unstained and total ventricular tissue.
Analysis of data.
Isochronal maps were constructed from all stored activation sequences if the total number of 1b arrhythmias was below 25. When more arrhythmias occurred, an equal fraction of arrhythmias in each 5-min bin of observation time was selected. Activation times were determined using an interactive analysis program that determined the moment of the maximum negative rate of rise (dV/dt) of each unipolar electrogram in a preselected time window.
Arrhythmia severity was graded 0 to 5 according to the most severe arrhythmia encountered in each heart: 0 = no arrhythmias; 1 = <30 VPBs; 2 =  30 VPBs; 3 = couplets; 4 = ventricular tachycardia (VT): (three or more consecutive VPBs); and 5 = VF.
Focal activity was defined as earliest electrical activity with surrounding delayed activation. In addition, at the site of earliest activation, an R wave should be absent. The line separating tissue with ST elevation from tissue with ST depression after 5 min of ischemia defined the electrophysiological border. To test the sensitivity of this method for detecting focal activity, we introduced a transmural multipolar needle in three Langendorff perfused pig hearts and stimulated at subsequent electrode terminals at 1 mm interelectrode distance. Epicardial activation patterns were reconstructed as described previously. The time difference of activation between the earliest and the second earliest electrode site was calculated. During intramural and subendocardial stimulation (at >6 mm from the epicardium), this time difference was significantly smaller (indicating a breakthrough pattern) than it was at subepicardial stimulation. Additionally, activation time differences in patterns from the experiments reported hereafter were significantly larger than those obtained at stimulation from >6 mm distance of the epicardium (Kruskal-Wallis test [KW], data not shown).
The time course of change in Rt was analyzed after differentiation of the curve of Rt rise at each electrode location. The onset of rise of Rt was defined as the time point where a positive inflection in the differentiated curve occurred, the time of maximum rise where the differentiated curve had a maximum. The end of the Rt rise was defined by the time point where the Rt curve had reached 95% of its value at 90 min of ischemia.
Data presentation.
Data are presented as mean ± SEM unless stated otherwise. The Z test was used for testing differences between proportions and the t test for differences between means. For nonparametric comparisons of multiple groups, KW followed by Dunn’s test was used; for parametric comparisons, analysis of variance (ANOVA) and Newman-Keuls test were used. A p value <0.05 was considered to be a statistically significant difference; NS indicates no statistically significant difference.
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Results
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Incidence of arrhythmias: role of LV filling and potentiated beats.
Figure 1A shows the number of spontaneous arrhythmias during the first hour after occlusion in in situ hearts in 5-min bins. During the 1b phase of arrhythmias, VF occurred in five of seven animals. Figure 1B shows the spontaneous arrhythmias in the isolated perfused hearts. Although a 1b phase of arrhythmias is present, the incidence of arrhythmias is much lower.
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Figure 1 Average arrhythmias in 5-min bins after coronary occlusion (t = 0) in the three models used (A, B and C). Drawn line indicates number of surviving animals. Number of ventricular premature beat (VPBs) divided by 10. VF = ventricular fibrillation; VT = ventricular tachycardia.
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We introduced a filled balloon into the LV in five isolated perfused hearts. The average systolic pressure in the balloon was 41 ± 2.1 mm Hg during ischemia, always lower than perfusion pressure. More arrhythmias occurred during the 1b phase in these hearts (group 3) (Fig. 1C) than in hearts without an intraventricular balloon (Fig. 1B).
The severity of arrhythmias was significantly greater in groups 1 and 3 than in group 2 (Fig. 2, top panel, KW, both p < 0.05) and was not different between groups 1 and 3. The total duration of the grouped 1b phase was 145 (46% of observation time), 335 (93%) and 225 (100%) min in groups 1, 2 and 3, respectively, as a result of intervening VF. Figure 2 (lower panel) summarizes the average total number of single or primary VPBs per heart in the three groups of experiments, corrected for the differences in total duration of observation time. Groups 1 and 3 differ significantly from group 2 but not from each other (KW).
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Figure 2 Top: Hearts grouped according to the most severe arrhythmia in the 1b phase. Bottom: Number of first ventricular premature beat (VPBs) corrected for the differences in observation time. VF = ventricular fibrillation; VT = ventricular tachycardia.
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In four hearts (group 4) we tested whether more spontaneous premature ventricular beats occurred after the first (augmented) contraction after a pause. The systolic pressure in the LV balloon was deliberately chosen to be slightly lower than that in group 3 to enable the detection of a proarrhythmic effect of the pause protocol and was 31 ± 2 mm Hg.
Figure 3 is a recording of intraventricular pressure and bipolar electrograms during the 1b phase. Three premature beats occur in subsequent stimulation cycles after the potentiated beat after the pause.
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Figure 3 Pressure recording from the intraventricular balloon (19 min after occlusion). Left ventricular (LV) and right ventricular (RV) bipolar electrograms show ventricular premature beats after the postpause activation.
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Of 216 first premature beats during the 1b phase (15 to 60 min, four hearts), 76 (35%) occurred in the first interval after the stimulation pause (p < 0.01 vs. the expected 11%, Z test). The systolic pressure of the potentiated beat was 168 ± 7% of the last basic beat. The potentiated beat was followed by a pressure wave of lesser amplitude (82 ± 3.5% of a basic beat). After the second beat, only 14 (4.7%) premature beats occurred during the 1b phase. This was significantly less than the expected 11% (p < 0.05, Z test).
Isochronal mapping.
To investigate whether focal origin of 1b arrhythmias could be documented and to test whether the focus was located preferentially along the ischemic border, isochronal maps of the initiating beats of arrhythmias and the preceding stimulated beats were made. The number of isochronal maps made was 269, 117 and 283 for groups 1, 2 and 3, respectively.
The electrogram in Figure 4 shows the last two stimulated beats and the start of VF (group 1, 21 min after occlusion). The activation map of the last stimulated beat in panel A demonstrates a broad planar wave travelling from the site of stimulation into the ischemic area. The first premature beat (B and panel B) has a focal origin at the border between the ischemic and the normal tissue. An R wave is absent from the local electrogram (top panel). The second beat (panel C) does not originate from within the field of electrodes.
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Figure 4 Top: Electrogram of the onset of ventricular fibrillation 21 min after occlusion. The shaded area (diagram) designates ischemic tissue; the pulse shows the site of stimulation. Dots in the enlarged multi-electrode represent electrode positions; the circle represents the site of focal origin. The dotted line indicates the electrophysiological border. A, B and C are activation maps of the corresponding beats. Lines indicate 5 ms isochrones; arrows indicate gross activation sequence; numbers indicate times relative to the last stimulus artefact; the asterisk indicates the site of origin. Note the absence of R wave in local electrogram recorded from the site of origin (top).
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All first mapped premature beats (273) were classified as focal or not focal: 72 (26.4%) had a focal origin (p = NS between groups, ANOVA). In none of the cases was the site of origin of the arrhythmias adjacent to the latest site of activation of the previous beat. Preceding deeply negative T waves were not observed.
The shortest distance of focal origins to the electrophysiological border is shown in 5-mm bins in Figure 5A (in situ experiments). A predominance of focal activity is observed around the electrophysiological border. Figure 5B shows that the grouped occurrence of focal activity in groups 1 to 3 is significantly larger inside than outside the border region (1 cm at either side of the electrophysiological border, Z test). The multi-electrode was placed over the ischemic borders resulting in a total number of electrode sites inside and outside the border region of 572 and 724, respectively. The distance to the electrophysiological border was 0.4 ± 1.4, –3.5 ± 0.9 and –4.4 ± 1.1 mm in groups 1, 2 and 3, respectively (p < 0.05 between groups 1 and 2, and groups 1 and 3, p = NS between groups 2 and 3, ANOVA).
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Figure 5 (A) Number of foci (in situ experiments) in 5-mm bins distance from the electrophysiological border (0 mm). Negative values indicate the ischemic side. Dotted lines indicate the border region. (B) Number of foci (all experiments) inside and outside the border region.
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Figure 6 shows a premature beat recorded after 26 min of ischemia. The activation map shows that two sites underlying the multi-electrode demonstrated early activity, that at both sites local electrograms had an initial negative deflection and that activation spread in a centrifugal fashion. Both early foci were close to the electrophysiological border. Of the 72 focal activation patterns, 21 demonstrated a secondary origin.
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Figure 6 Top: Electrograms (recorded from marked sites) 26 min after occlusion. Activation map from the ventricular premature beat shows two foci (asterisks). Details as in Figure 4.
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When more than a single VPB was recorded (all three experimental groups), focal activity was recorded in the second beat in 18 of 86 cases, in the third in 9 of 37 cases. Sequential focal activity (focal activity in beats 1 and 2 or beats 2 and 3) was recorded in 11 cases. Figure 7 shows an example (group 3) in which focal activity was documented in two consecutive beats after 34 min of ischemia. The isochronal maps demonstrate that the foci were disparate, but both were located near the electrophysiological border.
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Figure 7 Top: Electrograms of a short run of ventricular tachycardia 26 min after occlusion. Activation maps are of subsequent beats. Details as in Figure 4. The first and second beats have a focal origin (A and B, circles in middle left panel) close to the border. No R waves occur at the sites of origin (see electrograms).
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Confounding factors.
Figure 8 (upper panels) shows representative examples of the rise in Rt initiated by ischemia in the central ischemic zone of an in situ heart and an isolated perfused heart, respectively. The lower panel indicates no statistically significant differences in onset, maximum and end of Rt rise between the in situ and isolated hearts (four hearts in each group, number of recording sites 19 and 14, respectively). Therefore, a difference in time course of ischemia between the models cannot explain the difference in number of arrhythmias between the groups.
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Figure 8 Example of the time course of relative rise of tissue impedance (Rt) in an isolated perfused heart and a heart in situ (top). Both electrodes are from the central ischemic zone and displayed a more than twofold rise in absolute Rt. 100% indicates the value at 90 min of ischemia. Bottom: Onset, time of maximum rise and time of 95% rise of Rt compared between isolated hearts and in situ hearts.
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The relative weight of the ischemic myocardium between groups 1, 2 and 3 was not different between the three groups (30.6 ± 2.0, 31.9 ± 2.7% and 29.8 ± 1.5, ANOVA).
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Discussion
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This study demonstrates that more 1b arrhythmias occur in in situ hearts than in isolated perfused hearts (Fig. 2), while the time course of ischemic changes is identical (Fig. 8). In isolated perfused hearts without a balloon, we have demonstrated that the substrate for delayed ischemia-induced arrhythmias is present (7). Thus, the paucity of initiating premature beats rather than the absence of a substrate causes the relative arrhythmogenic quiescence during the 1b phase in these isolated hearts. Isolated perfused hearts do develop 1b arrhythmias similar to those in in situ hearts when intraventricular pressure is increased. If a focal origin of the 1b arrhythmias was documented, the foci clustered over the ischemic border supporting the notion of interaction between the ischemic and the nonischemic tissue. After a potentiated beat induced by a pause, more arrhythmias occurred.
Wall stress.
Previous publications have indicated that stretch is arrhythmogenic, either experimentally by imposing a sudden volume load on the ventricles or indirectly by the observation that wall motion abnormalities rather than a previous myocardial infarction (MI) are related to VPBs (8,9). Horner et al. (14) have documented that a sudden increase in LV load is arrhythmogenic during ischemia of up to 30-min duration. Franz et al. (10) have suggested that myocardium experiencing greater relative stretch may act as "focus" of arrhythmias. Acute volume load in infarcted canine hearts increases inducibility of tachyarrhythmias (15,16).
We describe a role for stretch-induced arrhythmias in the 1b phase of myocardial ischemia under conditions that occur in clinical practice where hearts are performing work and where a sudden increase of wall stress can occur during a potentiated beat.
The onset of 1b arrhythmias cannot be solely attributed to stretch activated channels on the basis of this study because mechanical effects persist after termination of arrhythmogenesis. Other arrhythmogenic factors play a role as well.
Other arrhythmogenic mechanisms.
Signs of the end systolic injury current (deeply negative T waves) (17) were absent in this phase of ischemia. Therefore, large regional differences in the transmembrane potential related to depolarization and activation delay, which are responsible for the initiation of 1a arrhythmias are not the direct cause for 1b arrhythmias. The injury current, however, may play a facilitory role by depolarizing tissue at the normal side of the ischemic border (18). In support of this is the observation that 1b arrhythmias cease when intercellular uncoupling is complete (and the electrotonic influence stops) while mechanical interaction across the ischemic border continues (4,5,7,11).
It could be argued that the potentiated beat after a pause is associated with a prolonged action potential, suggesting early afterdepolarizations (EADs) as the triggering mechanism. However, the pause was not longer than 700 ms and was slightly shorter than the spontaneous cycle length. A similar pacing protocol did not elicit EADs in ischemic myocardium, nor in normal myocardium (19). For triggered arrhythmias based on EADs, longer cycle lengths are a prerequisite (20). In addition, the second beat after the pause was associated with smaller contractility and a less than expected number of premature beats. Note also that changes in the QT interval after the pause are minimal (Fig. 3).
A reentrant origin of the arrhythmia was not detected in the tissue under the electrode. Although our methods do not exclude the possibility that microreentry is the underlying mechanism of the first beat of an arrhythmia, we have demonstrated that intramural electrical activity is absent in this phase of arrhythmias (7) and that epicardial conduction velocity and refractoriness would yield a reentrant circuit that, if present, would be detectable with our methods (21).
Purkinje fibers have been documented to constitute the site of earliest ectopic activity in models of prolonged ischemia (22–26). However, the involvement of Purkinje fibers has only been demonstrated in the Harris phase 3 type of arrhythmias, beginning after about 20 h following MI (Harris phase 2 represents a period relatively free of arrhythmias after phase 1). These arrhythmias are primarily characterized by monomorphic VTs. Indeed, from the subendocardial Purkinje fibers, spontaneous activity could be recorded (23). The 1b phase, however, occurs much earlier and does not show monomorphic ventricular rhythms but rather multiform VPBs that may degenerate into VF. This suggests that a different mechanism is operative in this phase of ischemia. Also, it should be noted that, unlike the canine model, the Purkinje system of pigs is located primarily intramurally (27,28). This makes the role of Purkinje fibers less likely, although our methods do not exclude the possible participation of the subendocardial Purkinje system in arrhythmogenesis.
Autonomic nervous system.
The incidence of premature beats was similar in isolated perfused working hearts and in situ hearts, whereas VF occurred more often in the in situ model. This suggests that in the in situ experiments the intact autonomic nervous system may have influenced arrhythmogenesis and that it, although not relevant for the triggering mechanism, acts on the substrate of the arrhythmia possibly by creating heterogeneities by local release of catecholamines (29,30). The topic of this study relates to the origin of the arrhythmia only.
The trigger during the 1b phase may be formed by the release of endogenous catecholamines from nerve endings located in the ischemic myocardium (31,32). This release of catecholamines occurs in severely depressed tissue and is also observed in isolated hearts (31). Contrary to our findings, it would cause an arrhythmogenic focus in the central ischemic zone and would be equally present in the isolated hearts without a balloon. Also, the occurrence of repetitive focal activity was rare and was documented maximally up to two beats. Nevertheless, we cannot exclude that interplay between the release of catecholamines from the ischemic nerve endings (31) and increased wall stress may play a role in the 1b arrhythmias.
Methodologic considerations.
It was not our objective to discern whether a focal mechanism or a reentrant mechanism caused 1b arrhythmias. For that purpose, complete and three-dimensional mapping is required. We wished to test the hypothesis that if a focal origin was documented, the origin or the site of epicardial breakthrough was overlying the ischemic border. We found that a focal origin within the field of epicardial electrodes occurred in about 25% of cases and that most of the sites of origin were situated directly over the ischemic border. This observation should be seen in the light that we only performed activation mapping over part of the LV epicardial border, whereas the right ventricular epicardial and the endocardial borders including those of the interventricular septum were not covered by multi-electrode. Ischemia-induced changes of the surviving epicardial layer would have caused a preferential arrhythmic origin over the ischemic zone. Intramural stimulation experiments at varying distances from the epicardium support the finding that our methods permit us to detect a focal origin up to 6 mm from the epicardium.
Differences in the size of the ischemic zone may have caused differences in the number of arrhythmias. However, collateral vascularization is scarce in pig hearts, and the size of the ischemic tissue was not different between the groups (33).
Rather than suddenly inflating an intraventricular balloon, we induced a physiological stimulus to increase LV systolic pressure by using a stimulus protocol incorporating a pause. This prevented a direct mechanical arrhythmogenic effect and the occurrence of subendocardial ischemia.
Clinical significance.
This paper points to the potentially important contribution of the 1b phase of arrhythmias to mortality after coronary occlusion. In clinical practice coronary occlusion is gradual rather than abrupt, and the 1a and 1b phases are probably not as clearly separated as they are in acute coronary occlusion models. Also, myocardial ischemia in hearts from rabbits with heart failure leads to an earlier onset of cellular uncoupling than in normal hearts (34), which contributes to overlap between the two phases.
Our study also implies that increasing myocardial contractility or increasing afterload may be arrhythmogenic. In view of Laplace’s law, it can be inferred that regional ischemia in dilated hearts is more arrhythmogenic than it is in normal myocardium, also because hypertrophied myocytes are more susceptible to stretch than normal myocardium (35). Afterload reduction with nitroprusside results in an abolition of severe ventricular arrhythmias in patients with acute MI (36).
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Acknowledgments
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The authors thank Charly N. W. Belterman, Wim L. ter Smitte and Carel Kools for their excellent support of this study and Dr. Opthof for critical reading of the manuscript.
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Footnotes
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Supported by the Netherlands Heart Foundation (NHS, grant 2000.D020).
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References
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