Published online before print August 9, 2004, doi: 10.1161/01.CIR.0000140258.09964.19
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(Circulation. 2004;110:1036-1041.)
© 2004 American Heart Association, Inc.
Original Articles |
Phase 2 Reentry as a Trigger to Initiate Ventricular Fibrillation During Early Acute Myocardial Ischemia
From Main Line Health Heart Center and Lankenau Institute for Medical Research, Wynnewood, Pa (G.X.Y., A.J., D.G., T.H., J.M., X.X., P.R.K.); The First Hospital of Xi’an Jiaotong University, Xi’an, China (G.X.Y.); and Lankenau Institute for Medical Research, Wynnewood, Pa (G.X.Y., P.R.K.).
Correspondence to Dr Gan-Xin Yan, Main Line Health Heart Center, 100 Lancaster Ave, Wynnewood, PA, 19096. E-mail yanganxin{at}mlhheart.org
Received September 17, 2003; de novo received March 2, 2004; revision received April 8, 2004; accepted April 12, 2004.
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Abstract |
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Background— Phase 2 reentry caused by heterogeneous loss of the transient outward potassium current (Ito)–mediated epicardial action potential (AP) dome can produce a closely coupled R-on-T extrasystole leading to ventricular fibrillation (VF) under conditions of ST-segment elevation unrelated to ischemia. The present study examined the role of phase 2 reentry in the initiation of VF during early myocardial ischemia.
Methods and Results— Regional myocardial ischemia was produced in an isolated, arterially perfused canine right ventricular wedge preparation. Transmembrane APs from 2 epicardial sites at each side of the ischemic border were simultaneously recorded together with measurements of extracellular potassium concentration ([K+]o) and a transmural ECG. Loss of the Ito-mediated epicardial AP dome in the ischemic zone but not in the perfused tissue resulted in phase 2 reentry and associated R-on-T extrasystoles capable of initiating VF in 7 of 15 preparations during the first 3 to 9 minutes of myocardial ischemia, with marked ST-segment elevation and [K+]o accumulation. The Ito and phase 1 magnitude of epicardium contributed importantly to the onset of VF. Phase 1 magnitude and Ito density at +30 mV in the group with phase 2 reentry–related R-on-T extrasystoles were 32.2±1.3 mV and 30.3±0.5 pA/pF (n=7), respectively, significantly greater than those (24.0±1.8 mV and 23.2±1.0 pA/pF) in the group without the extrasystoles (n=8, P<0.01).
Conclusions— Acute regional myocardial ischemia results in markedly heterogeneous loss of Ito-mediated epicardial AP domes across the ischemic border, leading to phase 2 reentry. Phase 2 reentry can in turn produce an R-on-T extrasystole capable of initiating VF.
Key Words: ischemia • arrhythmia • electrocardiography
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Introduction |
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Each year, about 1 million people in the United States have acute myocardial infarction (AMI), of whom approximately 20% to 25% die suddenly as the result of the development of ventricular fibrillation (VF) at an early stage of the event. Animal studies have shown that VF during the first 2 to 10 minutes (phase 1a) of acute ST-segment–elevation myocardial ischemia often emerges from tissue bordering the ischemic zone.1–3 However, cellular mechanisms underlying the first initiating beat capable of triggering VF, which invariably manifests as a closely coupled R-on-T extrasystole in the setting of ST-segment elevation on the ECG, is poorly understood.
Interestingly, the initiation of VF by an R-on-T extrasystole can be observed under conditions of ST-segment elevation unrelated to acute myocardial ischemia—for example, the Brugada syndrome or idiopathic VF.4,5 Our previous study has demonstrated that phase 2 reentry, a local reexcitation caused by heterogeneous loss of the transient outward potassium current (Ito)–mediated epicardial action potential (AP) dome and its transmural propagation can manifest as a closely coupled R-on-T extrasystole capable of initiating VF in the Brugada syndrome.6 The similarities between the ECG manifestations of the Brugada syndrome and those of acute myocardial ischemia indicate that the fundamental mechanism responsible for ST-segment elevation and the initiation of VF may be similar, although the pathogeneses differ.6,7 However, a direct demonstration of this mechanism in the intact wall of the ventricles during acute ST-segment–elevation myocardial ischemia has been lacking. The present study tested this hypothesis in an in vitro ischemic model consisting of an isolated, arterially perfused canine right ventricular wedge preparation in which epicardium exhibited a prominent Ito-mediated AP dome.
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Ischemic Model Including an Arterially Perfused Canine Right Ventricular Wedge
The Institutional Animal Care and Use Committee of the Lankenau Institute for Medical Research approved the study protocol for the use of dogs. The preparation of an isolated, arterially perfused ventricular wedge and the characterization of its viability and electrical stability have been detailed in previous studies.6,8 Briefly, a transmural wedge preparation was dissected from canine right ventricular free wall and cannulated through a coronary artery and perfused with Tyrode’s solution buffered with 95% O2 and 5% CO2 (36±0.3°C, Figure 1). The preparation was then suspended in a tissue chamber and surrounded by H2O-saturated atmosphere consisting of 95% O2 and 5% CO2 (36±0.3°C). The preparations were paced at a basic cycle length (BCL) of 2000 ms.
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Two types of acute myocardial ischemia (x10 minutes) were produced: global and regional ischemia. Global myocardial ischemia was induced by abrupt interruption of arterial flow to the entire preparation and change of the surrounding atmosphere within the chamber from a mix of 95% O2 and 5% CO2 to a mixture of 95% N2 and 5% CO2.9,10 The remaining PO2 in the atmosphere of the recording chamber during ischemia with the use of this method was usually <10 mm Hg.10 Acute regional myocardial ischemia was induced by ligation of one branch of the perfusion artery that supplied one third to one half of the preparation.
To examine the role of Ito-mediated epicardial AP dome in arrhythmogenesis during early myocardial ischemia, 4-aminopyridine (4-AP), a specific Ito blocker, was added into the perfusate 10 minutes before the onset of myocardial ischemia. Phase 1 magnitude was measured during normal perfusion with and without 4-AP (2 mmol/L).
Transmembrane APs from 2 epicardial sites (Epi1 and Epi2) and/or one endocardial site (Endo) were simultaneously recorded by using 2 or 3 separate floating glass microelectrodes (Figure 1). The locations of AP recording in epicardium were adjusted to obtain a large difference in AP spike and dome in the preparations with global myocardial ischemia. In the experiments of regional myocardial ischemia, Epi1 and Epi2 electrodes were placed on each side of the ischemic border, respectively. AP duration at 90% and 50% of repolarization (APD90 and APD50) between Epi1 and Epi2 electrodes on the epicardial surface was determined during normal perfusion and myocardial ischemia when epicardial AP dome was completely lost. A transmural ECG signal was recorded with the use of extracellular silver/silver chloride electrodes placed on 2 small sponges attached to epicardial and endocardial surfaces of the preparation. In 11 experiments, 2 extracellular K+-sensitive electrodes were used to monitor [K+]o at the epicardial sites close to transmembrane AP recordings, as described previously.11
Measurement of Transient Outward Potassium Current
The methods used for the isolation of single ventricular myocytes and measurement of ionic membrane currents have been detailed in our previous studies.12 In the present study, single ventricular myocytes were obtained from the same right ventricles in which the wedge preparations had been used. The technique of the wedge preparation was used to isolate right ventricular epicardial myocytes. Ito was recorded at 36±0.3°C by 180-ms pulses, stepping from a holding potential of –90 mV to test potentials of –20 to 30 mV in 10-mV increments. Ito amplitude was defined as the difference between the outward peak and the current at the end of pulses. Ito density was obtained by normalizing the amplitude with the corresponding cell membrane capacitance.
Statistics
Statistical analysis of the differences between 2 groups was performed with the use of a Student’s t test for paired and unpaired data. The 
2 test was used for the comparison between 2 groups for event incidences. Data are presented as mean±SEM. In the present study, 2 or 3 wedge preparations could be obtained from a single canine right ventricle. In 21 of 24 dogs, the available wedge preparations from each dog were used for different types of experiments described above. In 3 of 24 dogs, 2 identical experiments in terms of experimental design were performed in the wedge preparations isolated from the same canine right ventricle. For these 3 dogs, the data obtained from 2 identical experiments in a single dog were then averaged and treated as those obtained from a single experiment. Therefore, the number (n) in this study represents the number of dogs that were used.
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ST-Segment Elevation and Phase 2 Reentry in Acute Myocardial Ischemia
During normal perfusion, right ventricular epicardium displayed prominent Ito-mediated AP dome, as reported previously (Figure 2, Control).6,13 Phase 1 magnitude was 27.8±1.0 mV at a BCL of 2000 ms in a total of 24 dogs during normal perfusion. There was no significant difference in preischemic phase 1 magnitude between the wedge preparations with subsequent global myocardial ischemia (27.6±1.4 mV, n=10) and those with subsequent regional myocardial ischemia (28.0±1.3 mV, n=15, P>0.05).
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Six minutes after the interruption of perfusion flow to the entire wedge preparation (acute global myocardial ischemia), complete loss of Ito-mediated epicardial AP dome occurred in all dogs (n=10), leading to prominent ST-segment elevation (Figure 2). At the same time, [K+]o increased from 4.2±0.2 to 8.1±0.3 mmol/L (n=7). Phase 2 reentry and resultant VF were observed only in 1 of 10 dogs during 10 minutes of acute global myocardial ischemia.
On the other hand, acute regional myocardial ischemia was associated with complete loss of Ito-mediated epicardial AP dome within the ischemic zone but not in the perfused side, leading to a marked difference in epicardial repolarization across the ischemic border (Figure 3A). As demonstrated in Figure 4, the difference in repolarization time on epicardial surface between Epi1 and Epi2 sites, particularly at AP phase 2 (ie, APD50, Figure 4B), was significantly greater during regional ischemia compared with that during global myocardial ischemia. In regional myocardial ischemia when Ito-mediated epicardial dome was lost within the ischemic zone, the repolarization gradient across the ischemic border (from the normal perfusion side to the ischemic zone) was 199±5 versus 151±7 ms in APD90 and 163±8 versus 52±4 ms in APD50 (n=15, P<0.01).
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Phase 2 reentry secondary to heterogeneous loss of the Ito-mediated epicardial AP dome across the ischemic border (ie, that the AP dome maintained at the perfused side but lost at the ischemic zone) resulted in frequent closely coupled R-on-T extrasystoles in 6 of 15 dogs compared with 1 of 10 during acute global ischemia (P<0.05) during the first 3 to 9 minutes of ischemia (5.2±0.5 minutes). The extrasystoles in turn initiated VF in 4 of 15 preparations (Figure 3).
Effect of Ito Density and Phase 1 Magnitude on Phase 2 Reentry and VF During Acute Myocardial Ischemia
Prominent Ito-mediated epicardial AP dome during normal perfusion was associated with a high incidence of phase 2 reentry and VF during myocardial ischemia, as shown in Figure 3. Phase 1 magnitude and Ito density at +30 mV in the group with ischemia-induced R-on-T extrasystoles and VF were 32.2±1.3 mV and 30.3±0.5 pA/pF (n=7), respectively, significantly greater than those (24.0±1.8 mV and 23.2±1.0 pA/pF) in the group without the extrasystoles (n=8, P<0.01). At a dose of 2 mmol/L, 4-AP reduced phase 1 magnitude from baseline 29.4±1.4 to 8.9±1.0 mV (n=6, P<0.01). No phase 2 reentry or resultant VF was observed in the presence of 4-AP during 10 minutes of acute regional myocardial ischemia.
Interestingly, Ito-mediated epicardial phase 1 magnitude became significantly smaller during reperfusion after 10 minutes of global myocardial ischemia (Figure 5). Phase 1 magnitude was 27.5±1.6 mV in control perfusion and decreased to 22.9±1.5 mV during reperfusion after a brief episode of ischemia (n=8, P<0.01). Attenuation of epicardial phase 1 magnitude was associated with a reduction in phase 2 reentry and associated R-on-T ectopic beats in subsequent regional ischemic insult (0/8, P<0.05).
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Discussion |
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Early ventricular arrhythmias during the first 30 minutes of myocardial ischemia occur in a biphasic temporal distribution, that is, phase 1a ("immediate") and phase 1b ("delayed"). The phase 1a VF occurs during the first 2 to 10 minutes, with a peak incidence at 5 to 6 minutes after the acute interruption of coronary flow, when [K+]o approaches close to its plateau phase and ST-segment elevation becomes prominent.2,3 The onset of VF is almost always initiated by a closely coupled R-on-T extrasystole under conditions of ST-segment elevation. The present study provides the first direct evidence that acute myocardial ischemia can lead to loss of Ito-mediated epicardial AP dome, contributing in part to the development of ST-segment elevation mechanistically similar to that observed in the Brugada syndrome.6,7 More importantly, heterogeneous loss of Ito-mediated epicardial AP dome across the ischemic border during regional myocardial ischemia facilitates the development of phase 2 reentry that manifests as a closely coupled R-on-T extrasystole on the ECG. The extrasystole in turn is capable of initiating VF.
An outward shift in the balance of currents active in AP phases 1 and 2 caused by a decrease in inward currents (principally INa and ICa) and/or an increase in outward currents (principally K+ currents) predisposes to the loss of Ito-mediated epicardial AP dome.6,7,13 Abrupt arrest of coronary flow to the myocardium deprives ventricular myocytes of O2 and causes the cessation of delivery of metabolites, resulting in a cascade of pathophysiological events that are associated with a decrease in inward currents of INa and ICa and a significant increase in outward currents such as IK-ATP and IKAA.3,14 Our data indicate that these ischemia-related changes in membrane currents can lead to the loss of AP dome in epicardium, in which Ito is prominent. Loss of Ito-mediated epicardial dome with relatively maintained plateau phase and AP duration in endocardium (Figure 2) can generate a transmural voltage gradient that leads to ST-segment elevation on the ECG. From a mechanistic viewpoint, this is similar to the early observations by Kléber et al1,15: Loss of AP amplitude and AP shortening in the ischemic core is responsible for ST-segment elevation during systole. The so-called "injury current" caused by the difference in resting membrane potentials contributes to only a moderate TQ- (or TP)-segment depression when the ECG signal is input through DC coupling (ie, high-pass filter frequency=0 Hz).15 In clinical practice, the frequency for the high-pass filter in an ordinary ECG recorder is often set to the 0.1- to 0.5-Hz range to avoid direct current drift. Under this condition, the TP depression is transformed to apparent "ST-segment upward deviation" that contributes partially to the overall ST-segment elevation.7
On the other hand, complete loss of Ito-mediated epicardial AP dome occurs at some sites but not at others during myocardial ischemia, resulting in a marked heterogeneity in ventricular repolarization on the epicardial surface. This is particularly exaggerated during regional myocardial ischemia, in which an ischemic border is created. Heterogeneous loss of Ito-mediated epicardial AP dome across the ischemic border facilitates the development of phase 2 reentry, that is, a local reexcitation secondary to the dome propagating from the sites where the dome is maintained to the other sites where the dome is completely lost. Phase 2 reentry on the epicardial surface adjacent to the ischemic boarder and, probably, its transmural propagation, likely is responsible for R-on-T extrasystoles on the ECG (Figure 3). This might explain why a trigger initiating phase 1a VF often originates from the perfused tissue bordering ischemic tissue.1–3,16 Additionally, loss of epicardial AP dome may also generate a transmural repolarization gradient that manifests as ST-segment elevation on the ECG (Figure 2), which may serve as a reentrant substrate for the maintenance of VF.6
The physiological and pathophysiological significance of a prominent Ito has been long recognized.6,7,13,17,18 Similar to observations under other pathophysiological conditions,6,7,13 a prominent preexisting Ito is essential to the development of phase 2 reentry during early myocardial ischemia. Because Ito in epicardium is much more prominent in the right ventricle than in the left,7 one may expect that the incidence of primary VF in humans would be higher in the MI location involving or having a border with right ventricle. Conflicting observations have been reported, however.19–22 In the Grupo Italiano per lo Studio della Streptochinasi nell’Infarto miocardico (GISSI) trial (11 712 patients), the incidence of VF caused by AMI in the posteroinferior wall, in which the right ventricle may be more likely to be involved, was significantly higher than that in anterolateral area (3.7% versus 2.5%).19 This was further supported by the Thrombolysis In Myocardial Infarction II data (2546 patients).20 In contrast, Gheeraert et al21 recently reported that acute anterior MI caused by occlusion of the left coronary artery was associated with greater risk of primary VF compared with the right coronary artery, according to angiographic findings of 72 patients who survived out-of-hospital VF. In a more recent clinical trial (Collaborative Organization for RheothRx Evaluation [CORE] trial, with 2100 patients), the incidence of primary VF was higher in patients with acute inferior MI who had right ventricular involvement (8.4%) than in those with inferior MI without right ventricular involvement (2.7%) or anterior MI (5.0%).22 Despite a higher incidence of VF, the patients with inferior MI who had right ventricular involvement showed lower peak creatine kinase level, smaller infarct size, and greater left ventricular ejection fraction compared with patients with anterior MI.22 Another clinical observation that favors the important implication of Ito in arrhythmogenesis of coronary heart disease is the sex-related difference in sudden cardiac death. In men and women who had coronary heart disease, the incidence of sudden death in men was significantly higher than that in women.23,24 In the Myocardial Infarction Triage Registry study, for example, the hazard ratio for sudden cardiac death was 0.78 in women compared with men.24 This is probably in part due to a more prominent Ito in men versus women, which has been thought to be responsible for the predominance of the Brugada syndrome or idiopathic VF in men.13
Another interesting phenomenon in the present study is that a brief episode of ischemia, that is, ischemic preconditioning, reduces Ito-mediated epicardial phase 1 magnitude and arrhythmogenesis during subsequent myocardial ischemia. It is well known that ischemic preconditioning exhibits a powerful cardioprotective effect.25 Ito may play an important role in ischemic preconditioning.
Limitations of the Study
The relative contribution of "injury current" caused by a regional difference in the resting membrane potentials could not be determined in the present study. This was largely because of the difficulty in simultaneously obtaining resting membrane potentials in both epicardium and endocardium. The measurement of TP depression, which may serve as a surrogate of the injury current,7 was also technically limited because of direct current drift. This probably was due to our experimental setup, in which the small ventricular wedge preparations were suspended in the tissue chamber with a high flow of N2 and CO2 gases for preventing O2 contamination. The fact that prominent ST elevation coincides with the loss of Ito-mediated epicardial AP dome indicates that the difference in AP plateau phase between epicardium and endocardium plays an important role in ST-segment elevation during early acute myocardial ischemia.
In this study, the wedge preparations were paced at a BCL of 2000 ms. Therefore, the effect of a faster pacing rate on the onset of VF in our experimental model is unknown. However, it has been recognized that the development of VF during acute myocardial ischemia in humans as well as animals is often preceded by bradycardia or a pause.26,27 This is consistent with the properties of Ito, such that bradycardia or pause exaggerates the Ito-mediated epicardial AP dome and facilitates the development of phase 2 reentry.6,7,13,17
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Acknowledgments |
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This study was supported by the American Heart Association, the W.W. Smith Charitable Trust, the John S. Sharpe Foundation, and the Adolph Rose Levis Foundation.
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