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Circulation. 1995;92:253-261

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(Circulation. 1995;92:253-261.)
© 1995 American Heart Association, Inc.

Articles

Arrhythmias and Death After Coronary Artery Occlusion in the Rat

Continuous Telemetric ECG Monitoring in Conscious, Untethered Rats

Christian F. Opitz, MD; Gary F. Mitchell, MD; Marc A. Pfeffer, MD, PhD; Janice M. Pfeffer, PhD

From the Cardiovascular Division, Department of Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, Mass.

Correspondence to Janice M. Pfeffer, PhD, Department of Medicine, Brigham & Women's Hospital, Harvard Medical School, 75 Francis St, Boston, MA 02115.


*    Abstract
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 *Abstract
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Background The onset of acute myocardial infarction (MI) is accompanied by a rapid increase in electrical instability and often fatal ventricular arrhythmias. The aim of this study was to assess the continuous arrhythmia profile during the initial 48 hours after coronary artery ligation in the rat in relation to time course, mortality, and infarct size.

Methods and Results Continuous ECG recordings were obtained in 26 conscious, untethered rats for 24 hours before and 48 hours after coronary ligation by use of an implantable telemetry system. All episodes of ventricular tachycardia and fibrillation were counted and their durations summed. Infarct size was measured at 48 hours after MI or after spontaneous death. After ligation, two distinctly active arrhythmogenic periods developed (A1, 0 to 0.5 hours; A2, 1.5 to 9 hours), each followed by a quiescent phase of low ectopy (Q1, 0.5 to 1.5 hours; Q2, 10 to 48 hours). The total mortality rate of 65% was found within the two active periods, with 13 of 15 deaths occurring in A2. Rats with larger infarcts (>=50%) and nonsurvivors tended to have increased arrhythmia frequency and duration compared with both animals with smaller MIs (<50%) and survivors.

Conclusions Two distinct arrhythmogenic periods occur in rats with acute MI that may be caused by different mechanisms and correspond to the bimodal arrhythmia time course seen in dogs and humans after acute MI. Telemetric monitoring of the ECG in the conscious rat after infarction will be useful in assessment of the differential effects of therapeutic interventions on these two arrhythmogenic periods and in the study of potential mechanisms for the spontaneous resolution of ventricular ectopy and risk of sudden death.


Key Words: myocardial infarction • fibrillation • tachycardia • arrhythmia


*    Introduction
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 up arrowAbstract
 *Introduction
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down arrowResults
down arrowDiscussion
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The acute occlusion of an epicardial coronary artery leading to myocardial ischemia and subsequent necrosis is accompanied by a rapid increase in electrical instability and often fatal ventricular arrhythmias.1 2 About two thirds of all patients with acute myocardial infarction (MI) die suddenly, often before receiving medical attention.3 However, the exact time course of these malignant arrhythmias in the hyperacute prehospitalization phase of MI is not well defined.

Various animal models have been used to evaluate the early arrhythmias associated with acute myocardial ischemia and MI.4 Occlusion of a coronary artery in experimental animals provides an opportunity to study the time-dependent occurrence of ischemia- or necrosis-induced arrhythmias and to relate these findings to the morphology of the infarct. Harris1 described the time-dependent occurrence of three arrhythmogenic periods in the dog model that were associated with a high rate of arrhythmic deaths after coronary artery occlusion. The rat has become an increasingly important model with which to explore the pathophysiological consequences of coronary artery occlusion. However, because of the requirements for persistent anesthesia or tethering during the entire observation period to obtain an ECG, the continuous arrhythmia profile has been described for only up to 4 hours in this animal model.5 Therefore, information on the incidence and severity of arrhythmias is limited to this brief, initial period after acute MI.

The aim of this study was to determine the complete time course for the density and severity of arrhythmias during the first 2 days after acute MI in the rat and to relate these findings to mortality and infarct morphology. For this purpose, an implantable telemetry system was used to obtain a continuous ECG recording over extended time periods in the conscious, unrestrained animal.


*    Methods
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 *Methods
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Experimental Procedure
Female Wistar rats (18±1 weeks old; range, 13 to 23 weeks; Charles River) weighing 292±6 g (range, 249 to 337 g) were used in these experiments, which were performed in accordance with protocols approved by the institutional animal management program.

Telemetry
Under ether anesthesia, a hermetically sealed transmitter (7 g, 3 cm3) with a pair of helically wound flexible stainless steel wires (0.6-mm diameter) insulated with silicone tubing except for the distal 1 to 2 cm (Data Sciences) was implanted subcutaneously. The transmitter was secured in the neck region, and the leads were tunneled under the skin to the recording sites and attached to the underlying tissue to prevent migration. The positive electrode was placed in a V4-V5 position; the negative electrode was secured over the right scapula. The biopotential signal was digitized, amplified, and continuously emitted with a radiofrequency carrier. The rat was then housed in an individual cage placed on a receiver that continuously captured the signal, independent of animal activity. After reconversion to analog format and filtering at 100 Hz, a continuous data stream was fed into a personal computer equipped with an analog-to-digital converter (AT-MIO-16x, National Instruments Corp). With a custom-made Windows program, the data were digitized with 16-bit precision and continuously processed and displayed in real-time with a sampling rate of 500 Hz. The data were simultaneously stored in a continuous binary data file for later analysis.

Study Protocol
Within 2 days after transmitter and lead placement, a 24-hour baseline ECG was recorded. At the end of the baseline period, the rat was removed from its cage, anesthetized with ether, and placed directly on the 9x13-in. signal-capturing receiver unit (moved to the operating table), which permitted the uninterrupted recording of the ECG during the infarction procedure. After a left-sided intercostal thoracotomy, the heart was briefly exteriorized, and the proximal left coronary artery was occluded by a previously described method.6 The rat was then transferred back into its individual cage for ambulatory monitoring, which was continued for 48 hours or until spontaneous death. No attempt was made to resuscitate animals with malignant rhythms. At 48 hours, all survivors were given an ether overdose to produce cardiac arrest, and the hearts were processed for the determination of infarct size. The control group of 6 noninfarcted animals included 2 rats found to have an infarct size of <5% after intended coronary ligation and 4 sham-operated rats.

Infarct Sizing
Two methods were used to estimate final infarct size: injection of alcian blue dye and histological staining with triphenyl tetrazolium chloride (TTC). The left ventricle was hand-cut into four to six slices after dye injection or before staining with TTC; the slices then were photographed. For infarcts <3 hours old, the tissue of which was not yet considered to be necrotic, alcian blue dye was injected into the coronary arteries through the ascending aorta to outline the area at risk of necrosis, or the nonperfused zone. Because on average 80% to 90% of this area will become necrotic in the rat model with time,7 8 the estimated infarct size for these early deaths was assessed as 0.8 times the nonperfused zone. Tissue slices from ventricles with infarcts >3 hours old that were considered necrotic were stained by incubation in 1% TTC for 10 to 15 minutes at 37°C and pH 7.8.9 The tissue was then bathed for 5 to 15 minutes in formal saline (4% formaldehyde) to enhance color contrast and then photographed. These TTC-stained tissue slices were also fixed in formalin and processed for routine histology.

The lengths of necrotic or nonperfused tissue and of noninfarcted or dye-perfused muscle for both the endocardial and epicardial surfaces of each slice were determined by planimetry of the projected and magnified (x10) photographic or histological slides. The length of infarcted tissue and the total circumference of each slice for the endocardial and epicardial surfaces were numerically summed separately. The ratio of these sums defined the infarct size for each of the myocardial surfaces. Total infarct size, expressed as a percentage, was defined as the average of the infarct sizes of the endocardial and epicardial surfaces times 100. The transmurality of an infarct was expressed as the ratio of epicardial to endocardial infarct sizes.

Arrhythmia Analysis
The acquired single-lead ECG tracings were displayed and analyzed off-line semiautomatically. Using a custom-designed R-wave detection and rate selection algorithm, the computer displayed questionable arrhythmias, noise, or other abnormalities for final visual classification and quantification by an investigator. The user can define the sensitivity of this detection algorithm by several rate and QRS-trigger-threshold criteria. With our standard settings, every single RR interval corresponding to a heart rate of <300 beats per minute (bpm) or every run of three or more RR intervals corresponding to a heart rate of >500 bpm was evaluated individually. These values were empirically found to result in a varying number of "false-positive" stops but were extremely sensitive for the arrhythmias of interest as defined below. The observer then classified all arrhythmic events according to the guidelines provided by The Lambeth Conventions.10 Ventricular tachycardia (VT) was defined as 4 or more consecutive ventricular premature beats (premature QRS complexes in relation to the P wave). Ventricular fibrillation (VF) was defined as a signal that changed from beat to beat in rate and morphology or a signal in which individual QRS deflections could not easily be distinguished from one another. As expected in this model,5 a high incidence of spontaneously reversible and nonfatal VF was found and could not be distinguished from sustained and fatal VF except by correlation with the condition of the animal.

Even with these guidelines, separating VF from VT was often difficult because both arrhythmias can convert several times to each other during one arrhythmic episode without a clear-cut interface. A tachycardia with a torsade de pointes morphology that degenerated into overt VF, reverted to "regular" VT, or terminated was classified as VT. Whenever possible, VT and VF were tabulated separately.

The prevalence of VT and VF within a certain time period was defined as the percentage of rats affected by VT or VF relative to all rats alive at the beginning of this time period. For both VT and VF, the number of episodes was counted as a measure of arrhythmia incidence; the durations were measured for episodes that lasted longer than 1 second. The combined number and duration of all measured VT and VF episodes (VT+VF) were also calculated for each rat to obtain a parameter that is unaffected by the occasional problem of reliably distinguishing VT from VF. For VT, the rate was measured in beats per minutes whenever possible. Fatal VF was assigned a duration of 85 seconds, the longest observed nonfatal VF episode.

To compare arrhythmia density as a function of time from coronary artery occlusion, the number of episodes and the sum of the durations of VF and VT were expressed as mean values per hour. To account for the censoring effect associated with differential survival, we normalized the arrhythmia frequencies and durations by dividing the absolute number of episodes and their summed durations by the actual survival time or "time at risk" for experiencing an arrhythmia. We measured this time at risk in 30-minute increments to avoid overrepresentation of arrhythmia severity in animals that died after only a few minutes into the time period of interest. For analysis within each arrythmogenic or quiescent phase, the arrhythmia data for each animal were divided by the number of 30-minute blocks of time at risk within the period. The arrhythmia frequencies and durations were expressed in episodes per hour per rat and seconds per hour per rat, respectively.

Heart Rate
Because heart rate in the unrestrained, conscious rat can be highly variable if measured from short ECG segments, we calculated heart rate from continuous 10-minute ECG recordings from which nonsinus beats were excluded. The mean value of these RR intervals was used to determine the average heart rate.

Statistical Analysis
We used the {chi}2 test to compare categorical parameters between groups of animals. Because most of the continuous variables that describe arrhythmia frequency or duration are not normally distributed,5 8 10 we compared these end points between groups with the Mann-Whitney U test. Because the arrhythmias occurred in a time-dependent pattern and were concentrated primarily in the second active period between 1.5 and 9 hours after MI, we restricted the statistical comparison of arrhythmia end points between groups of animals to this time period. Without such a limit, the varying durations of the follow-up period created by the censoring effect of arrhythmic deaths would have led to a "dilution" of the arrhythmia data in the survivors and an overestimation of these end points in rats dying within the active periods. The comparison of heart rate over time between control and infarcted rats was done by ANOVA for repeated measures. For all comparisons, P<.05 was considered significant. All values are given as mean±SD unless otherwise specified.


*    Results
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*Results
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We studied 26 rats with MIs involving at least 23% of the left ventricle and the control group with 6 noninfarcted rats. Three infarcted rats that died within 12 minutes after coronary occlusion had unusually large perfusion defects (>60% on dye injection) that included large parts of the interventricular septum in addition to the intended and anticipated left ventricular free wall. This was due to the occlusion of the septal and the intended left descending coronary artery. These uncharacteristic multivessel occlusions were not included in the analysis.

Arrhythmias
Total Numbers and Durations
Analysis of the 24-hour baseline recordings before coronary artery occlusion revealed that an episode of VT or VF is exceptionally rare in conscious rats without coronary occlusion. During the cumulative 648 hours of baseline ECG recording (corresponding to a sample of about 15 million heart beats) from 27 rats before coronary occlusion, only two short runs of VT with durations of less than 2 seconds occurred, and no episodes of VF were found. Even during the 48-hour period after surgery in the 6 noninfarcted animals, no episodes of VF occurred, and 2 rats had one short run of VT, each <1 second long.

In sharp contrast, 96% (22 of 23) of the animals developed at least one episode of VT or VF after coronary occlusion, leaving only 1 animal completely unaffected during the 48-hour period. The majority of the rats (78%, 18 of 23) exhibited both types of arrhythmias, and only 17% (4 of 23) were exclusively affected by VT. No rat expressed VF without having an episode of VT. Overall, we found 4805 VT episodes in 22 rats, and in 18 (82%) of the rats, an additional 365 VF episodes were registered. On average, each affected rat had 218±285 (range, 1 to 1027) VT episodes and thereby spent >8 minutes (522±507 seconds; range, 3 to 1588 seconds) in VT during the first 2 days after acute MI. The average number of VF episodes was 20±19 (range, 1 to 60), with a total duration of >5 minutes (373±320 seconds; range, 20 to 1098 seconds) per affected animal. Of the total 4805 VT episodes, 1828 lasted more than 1 second, with an average rate of 740±161 bpm. The 672 episodes of monomorphic VT had a mean rate of 712±151 bpm, whereas the 108 episodes of VT with torsade de pointes morphology had a rate of 873±98 bpm.

In the rat with acute myocardial ischemia or MI, VF can frequently be a self-limited and nonfatal arrhythmia (Fig 1Down).5 Indeed, of the 365 VF episodes, only 11 (3%) were sustained and thereby fatal. All other episodes terminated spontaneously, typically followed by a pause and later by a phase of slowly accelerating ventricular escape rhythm in the presence of varying degrees of AV conduction block. The average duration of these nonsustained VF episodes was 16±16 seconds (range, 1 to 85 seconds).



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  		Figure 1. ECG recording showing nonsustained ventricular fibrillation (VF). Each row shows a 4-second ECG sample and the recording time relative to coronary ligation to the right. ECG 1, baseline (390 bpm); ECG 2, sinus rhythm and ST elevation at approximately 4:40 hours after occlusion (389 bpm); ECG 3, start of a polymorphic ventricular tachycardia that degenerated into VF and was associated with a loss of consciousness and a seizure after 12 seconds (ECG 4); ECGs 5 and 6, after a total duration of 59 seconds, spontaneous self-defibrillation followed by an escape rhythm with a ventricular rate of approximately 50 bpm. After a few ventricular beats, the rat regained consciousness, and after approximately 90 seconds (ECG 7), the heart rate was back to 359 bpm and the animal's condition was indistinguishable from that at 4:39:14.

Temporal Course
The observed arrhythmias and the associated mortality occurred in a distinct time-dependent fashion after coronary artery occlusion, disclosing two arrhythmogenic periods5 (Fig 2Down and the TableDown): an active phase 1 (A1) from 0 to 30 minutes followed by a first quiescent (Q1) period and an active phase 2 (A2) from 90 minutes to 9 hours after MI followed by a second quiescent (Q2) period from 10 to 48 hours. The rats were killed at the end of the Q2 period. These time windows were empirically chosen on the basis of the arrhythmia density within the recording period to clarify the time dependence of the observed arrhythmias.



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  		Figure 2. Graphs showing mortality and arrhythmia duration during the first 48 hours after occlusion. A, The cumulative mortality over time, with two arrhythmogenic (A1, 0 to 0.5 hours; A2, 1.5 to 9 hours) and two quiescent (Q1, 0.5 to 1.5 hours; Q2, 10 to 48 hours) periods. B, C, D, Arrhythmia durations for ventricular fibrillation (VF), ventricular tachycardia (VT), and VF+VT within each consecutive 30-minute block after occlusion, respectively (mean±SEM in s/30 min). Shown are only the first 14 hours after myocardial infarction because no deaths and only minimal ectopic activity were found during the remaining 34 hours.


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  		Table 1. Time-Dependent Arrhythmia Prevalence, Incidence, and Duration for VF, VT, and VF+VT

VT and VF frequently began within minutes after the occlusion of the coronary artery (Fig 2Up). During the first 30 minutes, 9 of 23 rats developed VT, and 4 had an episode of VF. The two deaths observed in this first arrhythmogenic period occurred within 10 minutes after occlusion.

From 30 to 90 minutes after occlusion, the arrhythmia density was greatly diminished (Fig 2Up). Although 8 of 21 rats were still affected by VT and 3 animals had VF, the frequency of both arrhythmias was markedly reduced (the TableUp), and no deaths occurred during this first quiescent phase.

A second arrhythmogenic period began 90 minutes after coronary occlusion with a steep increase in the frequency and duration of both VT and VF that progressed over the next 120 minutes toward a maximum during the third and fourth hour after occlusion (Fig 2Up, the TableUp). During this period, almost all (95%, 20 of 21) of the rats were affected by VT, with 81% (17 of 21) also manifesting VF. The 62% (13 of 21) mortality rate during this second active period closely paralleled the arrhythmia profile (Fig 2Up). All 13 deaths were related to an episode of VF and occurred between 2 and 8.5 hours after MI, with the majority of fatal arrhythmias (62%, 8 of 13) occurring between 2 and 3.5 hours after occlusion, the time of maximal ectopic activity.

After 10 hours, the 8 surviving rats exhibited a quiescent phase in which only a few episodes of VT and no VF occurred (Fig 2Up, the TableUp). These rats remained stable throughout the remaining monitoring period. Of the two active periods, the second one (1.5 to 9 hours) was clearly more arrhythmogenic, with more VT and VF episodes per hour and longer VT and VF durations per hour compared with the first 30 minutes of ischemia (Fig 2Up, the TableUp). Within both active phases, however, there was a marked variability among affected animals with respect to individual frequencies and durations of arrhythmias.

Heart Rate
The mean heart rate of all rats studied at the end of the 24-hour baseline period was 384±49 bpm. After coronary artery occlusion, heart rate increased to 461±44 bpm at 24 hours and subsequently decreased to 431±53 bpm at 47 hours after MI. However, this increase cannot be attributed to the infarction itself because operated but noninfarcted rats showed a comparable heart rate response, with 447±23 bpm at 24 hours and 438±30 bpm at 47 hours after surgery. Statistically, both groups were not different, whereas the time effect was significant (P<.001).

Infarct Size
MI sizes ranged from 23% to 67% of the left ventricular circumference, averaging 46±11%; 18 of the 23 rats had MI sizes between 40% and 60%, and only 3 rats had infarcts <30%. Endocardial and epicardial MI sizes were 51±12% and 42±14%, respectively, yielding a transmurality ratio of 0.83±0.22. Because of the limited number of rats in the low infarct size range, a correlation between infarct size and arrhythmia severity was not performed. Instead, we compared the animals with infarcts above and below the median infarct size (50%) with respect to their arrhythmia profile during the main arrhythmogenic period between 1.5 and 9 hours after occlusion (Fig 3Down). For VT, VF, and VT+VF, the number of episodes and their summed durations were higher in the group with the larger infarcts, although this difference was significant only for VT duration (187.0±143.5 versus 59.6±45.7 s/h, P<.05). Acute mortality did not differ in this relatively small sample with a limited range of MI sizes.



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  		Figure 3. Bar graphs showing arrhythmia incidence (episodes/h) and duration (sec/h) for ventricular fibrillation (VF), ventricular tachycardia (VT), and VF+VT in rats with myocardial infarction (MI) sizes below (white bars, n=11) and above (shaded bars, n=12) the median MI size (50%) during the second arrhythmogenic period (A2, 1.5 to 9 hours after MI), respectively. Values are mean±SEM. *P<.05 versus MI size <50%.


*    Discussion
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*Discussion
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Despite continued improvements in the treatment of acute MI, an estimated 50% of patients die suddenly in the first hours before receiving medical attention.3 The majority of these early deaths are caused by complex ventricular arrhythmias, particularly VF. Surprisingly little is known, however, about the exact time course of these early malignant arrhythmias or their underlying mechanisms.11 12 13 14 15 16 17 18 Animal models of abrupt coronary artery occlusion provide an opportunity to explore these issues in a controlled environment. Although major contributions have come from studies in dogs,1 2 19 20 21 22 23 24 25 26 27 28 the canine model has a highly variable coronary anatomy, with large variations in collateral flow resulting in a wide range of infarct sizes and transmurality.21 22 23 25 29 Coronary artery ligation in the rat more consistently produces a large transmural MI, representing another end of the spectrum observed in MI. This model has provided relevant information on the long-term consequences of transmural myocardial necrosis on ventricular function and dilatation.30 Ischemia- and necrosis-induced arrhythmias have also been studied in the rat, although primarily under in vitro conditions or in short-term preparations under anesthesia.5 8 31 Continuous ECG data in conscious rats after coronary occlusion have been obtained for up to 4 hours by use of cable recordings.5 Miniature telemetry systems now make it possible to record continuous ECG for longer periods in the untethered rat. This study details the uninterrupted time course of VT and VF during the first 2 days after abrupt coronary occlusion in conscious, unrestrained rats in relation to the associated mortality and the infarct morphology and provides new information about the arrhythmia profile during the acute phase of MI.

After a baseline recording in which ventricular ectopic beats were exceedingly rare, an abrupt change in arrhythmia frequency began within minutes after the coronary artery occlusion. A distinct time-dependent arrhythmia profile occurred with severe and frequent episodes of VT and VF concentrated primarily in two discrete arrhythmogenic periods. More than 95% of the rats were affected by VT or VF, and in individual rats, we found up to several hundred VT episodes and >20 occurrences of VF during the first 2 days after MI. This relatively uniform arrhythmia profile was paralleled by a mortality time course in which all deaths during the first 48 hours occurred within the combined 8-hour duration of the two arrhythmogenic periods. This distinct arrhythmia and mortality profile reflected the evolution of the infarct over time and may be related to the progression of the ischemic tissue injury32 and the coexisting electrophysiological alterations2 19 and to the marked neurohormonal activation.

Only 5 minutes after the onset of ischemia, frequent episodes of VT were found, together with several episodes of VF. This first and reversible phase of ischemia is characterized by a marked spatial heterogeneity of slowed conduction and activation delay in the epicardial segments of the underperfused zone.2 20 24 At this time, the extracellular potassium concentration increases while pHi falls, and the cells in the center of the ischemic zone become less excitable.2 These conditions favor reentry of activation wave fronts as the most likely mechanism underlying these very early, or "phase 1a," arrhythmias.2 24 At this time, no severe structural damage occurs within the myocardium, and on reperfusion, ischemic cells generally survive and eventually regain function. This first burst of severe ventricular arrhythmias has been found to cause a high early mortality rate in several species.4 33 The two early deaths observed in our study occurred during this first maximum of ectopic activity. Cardiogenic shock as a consequence of extensive ischemia is another important cause of cardiac death in this early phase after occlusion; the 3 excluded rats with suspected multivessel occlusions probably belonged in this category. With ischemia durations of >10 minutes, irreversible tissue damage begins in the rat myocardium.32 These functional and electrophysiological alterations are modulated by the onset of structural changes and the loss of cell integrity. At this point, we found frequent ventricular arrhythmias that may be correlated with the local release of catecholamines,34 which may act in concert with the elevated potassium concentration as a powerful arrhythmogenic stimulus.35 However, there were no deaths during these "phase 1b" arrhythmias24 for which abnormal automaticity has been proposed as an important arrhythmogenic mechanism.2 The significant decrease in arrhythmia frequency and duration by 30 minutes after occlusion may be related to the final loss of excitability in most of the cells within the core of the ischemic zone.2 However, it is not entirely clear which mechanisms underlie the quiescent phase between 30 and 90 minutes after occlusion, when the necrotic wave front is expanding within the area of underperfusion and myocytes are constantly undergoing irreversible cell damage.

The second, much more severe phase of ectopic activity associated with arrhythmic deaths began at approximately 90 minutes after occlusion, by which time the necrotic wave front of irreversible cell damage had penetrated most of the ischemic area.36 The arrhythmias increased in frequency and duration over the next 1 to 2 hours and reached a maximum 3 to 4 hours after occlusion, by which time final infarct size is established in the rat and reperfusion can no longer reduce the amount of myocardial damage.36 The origin of these arrhythmias may be at the interface between dead and still viable, but ischemic, myocardium where depolarized myocytes can develop abnormal automaticity.19 In this study, 87% of all arrhythmia-related deaths occurred within this most lethal 7.5-hour time period. Eight of 13 (62%) arrhythmic deaths occurred within the 1.5 hours of maximal ectopic activity beginning 2 hours after occlusion, a time period that is not commonly studied in the infarcted rat because of the technical difficulties of monitoring a continuous ECG for many hours. The disappearance of these severe and often fatal arrhythmias between 8 and 10 hours after MI again is difficult to explain. In the dog, in which sinus rhythm is usually restored by 48 to 72 hours after MI,1 it has been shown that the surviving Purkinje fibers, which are thought to be a primary source of the delayed arrhythmias, have almost regained their normal electrophysiological properties by this time.37 Our finding of a quiescent phase from 10 hours on suggests that the death of myocytes more than the evolving inflammatory response plays a crucial role for the genesis of these arrhythmias.

As another potentially arrhythmogenic mechanism, myocardial ischemia evokes alterations in the autonomic regulation of the heart.38 The reflective increase in heart rate after ischemia of the anterior wall has been attributed to enhanced cardiac sympathetic activity, although the role of this effect with respect to arrhythmogenesis is not entirely understood. An increase in heart rate has been linked to acceleration of ischemic cell injury, and in anesthetized dogs with acute MI, the occurrence of VT and VF has been positively correlated with heart rate.21 However, in conscious rats with acute MI, the occurrence of VT and VF was found to be independent of heart rate response.8 Although we did find a significant increase in heart rate after MI, it was unrelated to mortality or arrhythmia severity and also occurred in noninfarcted control rats. Nevertheless, the autonomic innervation of the heart plays an important role in arrhythmogenesis.39 The rat ventricle is innervated by chemical- and mechanical-sensitive C fibers that are activated by locally released mediators, such as prostaglandins and oxygen-derived free radicals, within minutes after the onset of ischemia.40 With the progression of ischemic cell damage, a combination of functional and structural alterations of autonomic cardiac innervation develops that can differentially affect the vagal and sympathetic components and thereby promote the occurrence of spontaneous arrhythmias in a time-dependent manner.38 This time-dependent local cardiac denervation might be involved in the facilitation of arrhythmias during both active periods and in the emergence of the two quiescent phases.

Others have studied the incidence of arrhythmias in anesthetized or conscious rats during the first 30 minutes after coronary occlusion and found 73% to 100% to have VT and 57% to 89% to have VF.5 The associated mortality ranged from 10% to 30% in anesthetized and 50% to 82% in conscious animals.5 Like previous investigators,5 8 we found VF to occur frequently as a self-limited and thereby nonfatal arrhythmia (Fig 1Up). This phenomenon has been related to the size of the heart and its physiological properties, the age of the animal, and the status of the autonomic nervous system.41 VF in the rat heart might involve only a limited number of circulating activation wave fronts with an increased chance of spontaneous self-defibrillation.42 In this study, 78% of the animals suffered from VF during the first 2 days after MI, with 20 such episodes on average per affected rat. However, the individual VF episode was a self-limited and nonfatal arrhythmia in 97% of all incidents.

Studies in anesthetized31 or conscious8 rats monitored continuously for up to 4 hours after MI also showed an early arrhythmogenic period during the first 15 to 30 minutes and a second phase between 1.5 and 4 hours. These data suggested that the second arrhythmogenic phase continued beyond 4 hours after occlusion. For conscious Wistar rats, there was an overall incidence of VT and VF of 73% and 68%, respectively, with 28% having irreversible VF that did not terminate on attempted mechanical defibrillation. The mortality rates at 4 and 24 hours after MI were 34% and 46%, respectively. From these findings, most investigators believe that the initial 30-minute period was the most critical phase during the evolution of acute MI in the rat with respect to the occurrence of malignant and potentially fatal arrhythmias. Our study extends this time window to 48 hours after MI and thereby discloses the entire second arrhythmogenic phase between 1.5 and 9 hours, the time interval in which 87% of the overall mortality occurred. In addition, the existence of a quiet phase between 10 and 48 hours was documented. Our findings during the first 4 hours after MI are in agreement with most of the earlier reports, despite marked variations in the actual number and duration of VT and VF episodes and the associated mortality. Most of this variability can be explained by differences in the protocols used, the range of MI sizes studied, and the use of mechanical defibrillation techniques that can significantly raise the survival rate.5 Even the rat strain can be important; in Sprague-Dawley rats, the size of the occluded zone and the mortality and arrhythmia incidence have been found to be significantly higher compared with those of Wistar rats.5 However, within a given laboratory using standardized techniques, the observed arrhythmias and the average mortality rate remained constant and highly reproducible over time.5 The slightly higher mortality rate in the current series (65%) than in our prior experience43 probably reflects the protocol directive to ascertain the time to spontaneous death without attempted resuscitation. Despite these dissimilarities, the occurrence of a time-dependent arrhythmia and mortality profile after coronary artery occlusion with two distinct arrhythmogenic periods and a high rate of arrhythmic deaths is a consistent finding.

In analogy to the clinical definition, it might be important to separate primary VF from arrhythmias that occur in the presence of acute heart failure. Data obtained by continuous ECG and blood pressure monitoring in conscious rats after acute MI suggested that VF was the primary lethal event in 90% of all deaths, whereas 10% were preceded by overt pump failure with hypotension.8 The incidence of pump-failure deaths increased with very large ischemic zones.44 Arrhythmic deaths were invariably associated with a sudden loss of consciousness and a convulsive-type behavior; pump-failure deaths with hypotension were preceded by a phase of morbidity. Most of our witnessed deaths demonstrated convulsive-type behavior (Fig 1Up), supporting the classification as a primary arrhythmic event. Nevertheless, we frequently observed clinical signs of morbidity during normal sinus rhythm before the final arrhythmia. Therefore, it might be erroneous to classify all VF episodes as primary arrhythmias.

Infarct Size
Ischemia- and necrosis-induced arrhythmias, arrhythmic deaths, and total mortality have been shown to be related to the size of the ischemic or infarcted area.5 8 21 22 23 26 45 Yet in the acute clinical setting, it is difficult to ascertain the duration and extent of ischemia and the collateral flow to that area, all of which contribute to the observed variability in MI size.46 Experimental studies of acute MI in the dog are also affected by a highly variable coronary anatomy with different levels of collateral flow to the ischemic area.21 22 23 25 29 Indeed, even small differences in collateral flow can override the impact of ischemic zone size on the genesis of arrhythmias.21 Thus, the incidence of VF after coronary artery occlusion in the dog can range from 0% to 100%, depending on the degree of collateral flow.21 25 27 Nonetheless, by controlling for differences in collateral flow, a positive correlation has been found between the size of the ischemic area and the incidence and frequency of ventricular arrhythmias in the dog model.21

In our study with a range of MI sizes between 23% and 67%, it is noteworthy that 3 of the 4 rats that never developed VF were found at the lower end of our range of MI sizes, supporting the concept that the risk of VF increases substantially once a certain amount of myocardium becomes ischemic, whereas VT might occur in a wider range of infarct sizes.21 Infarct size, mortality, arrhythmia score, and the occurrence of VT and VF were shown in conscious rats to be positively correlated with the size of the ischemic area.8 The best correlation was found between the size of the occluded zone and the arrhythmia score, suggesting that the interface area between the ischemic and normal myocardium plays a major role in arrhythmia generation.8 47 Furthermore, over a wide range of MI sizes, comparable values were obtained for the arrhythmia score when corrected for the size of the occluded zone.48

Study Limitations
Surgery and anesthesia may influence ischemia- and necrosis-induced arrhythmias8 through their effects on the plasma concentration of potassium (increase) and the autonomic nervous system. Indeed, the incidence of ischemia- and necrosis-induced VF has been shown to be decreased in acutely prepared compared with chronically instrumented rats.5 Although our finding of an early arrhythmogenic period followed by a relatively quiet phase may have been influenced by the recovery from anesthesia and surgery, it is consistent with the extensive experiences in which coronary artery occlusion was induced in conscious rats.8

The use of a single-lead Holter system for the diagnosis of ventricular arrhythmias can lead to erroneous results with respect to the separation of ventricular from supraventricular arrhythmias, so our VT data may be contaminated by mislabeled supraventricular arrhythmias. On the other hand, it is unlikely that the correct diagnosis of VF is affected by the number of available ECG leads. Occasionally, it can be difficult to separate coarse VF from VT with a torsade de pointes morphology. However, we tended to classify these arrhythmias as torsade de pointes VT as long as we could measure a rate in the presence of oscillating QRS morphology. Our empirical decision to set the tachycardia threshold to 500 bpm limited the detection of occasional episodes of idioventricular rhythm that occur at rates close to the underlying sinus rhythm.

Clinical Implications
In patients with acute MI, clinically important arrhythmias also occur as a time-dependent phenomenon, although this arrhythmia profile has not been well described. During the first 24 hours after the onset of symptoms, VT and VF were found in up to 39% and 36%, respectively, of all patients with acute MI.11 12 13 14 15 16 17 18 A recent meta-analysis49 of 15 placebo-controlled randomized trials of thrombolytic therapy that included approximately 10 000 patients showed a VF incidence of 3% during the first day and a VT incidence of 7.5% during hospitalization in the placebo-treated group. The varying numbers in different studies are most likely related to differences in monitoring techniques, the initiation of arrhythmia monitoring with respect to symptom onset, and to differences in MI size. Another confounding factor can be a "stuttering" MI with recurrent spontaneous reperfusion and reocclusion. However, only a few studies assessed the detailed time course of VT and VF during the first hours of acute MI.11 14 15 16 17 18 These trials also excluded the large number of patients who die before receiving medical attention.3 Whereas VF was observed early after the onset of ischemia with a steadily declining incidence over time,11 14 the frequency of VT followed a more bimodal time course with an early peak and a delayed arrhythmogenic phase between 7 and 14 hours after an interspersed quiescent period.11 15 17 18 It has been proposed that these data support the hypothesis that the time course and the underlying mechanisms of arrhythmogenesis are comparable with those observed in the canine model of acute MI.19 Interestingly, the onset of the delayed arrhythmogenic phases, which start in dogs1 28 and humans18 between 4 and 6 hours after MI, coincides with the completion of the necrotic wave front phenomenon of ischemic cell death, when most of the ischemic tissue is irreversibly damaged and the final infarct size is established.50 For the first time, it is possible to explore this phenomenon in the rat model of acute MI. Despite significant anatomic and electrophysiological differences among rats, dogs, and humans, there are obvious analogies with respect to ischemia- and necrosis-induced arrhythmias. In the rat, the area of necrosis approaches the final infarct size between 90 minutes and 2 hours after occlusion.36 Thus, in analogy to the canine model, the onset of the delayed phase of arrhythmias at 90 minutes after occlusion in the rat also occurs at a time when the final infarct size is established and most of the ischemic tissue is irreversibly damaged.

In summary, two distinct periods of frequent malignant and fatal arrhythmias, which are probably caused by different underlying mechanisms, were found in conscious, untethered rats after acute MI. The two periods were followed by quiescent phases of low ectopy. The extension of continuous monitoring disclosed the previously unknown duration of the second, more malignant arrhythmogenic period in which 87% of the arrhythmic deaths were found and the subsequent appearance of a long, uneventful quiescent phase despite the continuing inflammatory response. Because the rat exhibits a high frequency of malignant arrhythmias in response to myocardial ischemia and necrosis (even VF can be observed repeatedly in the same individual), this model provides the opportunity to assess the differential effects of therapeutic interventions on these two dissimilar arrhythmogenic periods beyond the commonly studied time window.


*    Acknowledgments
 
The assistance of Peter Finn, MD, and Joseph Gannon on the technical aspects of this study is gratefully acknowledged. Dr Opitz is a recipient of a Physician Investigator Award from the Massachusetts Affiliate of the American Heart Association.

Received October 27, 1994; revision received January 4, 1995; accepted January 9, 1995.


*    References
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*References
 

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