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(Circulation. 1995;91:2566-2572.)
© 1995 American Heart Association, Inc.

Articles

Dispersion of `Refractoriness' in Noninfarcted Myocardium of Patients With Ventricular Tachycardia or Ventricular Fibrillation After Myocardial Infarction

Anand R. Ramdat Misier, MD; Tobias Opthof, PhD; Norbert M. van Hemel, MD; Jessica T. Vermeulen, MD; Jacques M.T. de Bakker, PhD; Jo J.A.M. Defauw, MD; Frans J.L. van Capelle, PhD; Michiel J. Janse, MD

From the Academic Medical Center, University of Amsterdam, Department of Clinical and Experimental Cardiology, Amsterdam (A.R.R.M., T.O., J.T.V., J.M.T.d.B., F.J.L.v.C., M.J.J.); the Department of Cardiology, St Antonius Hospital, Nieuwegein (A.R.R.M., N.M.v.H., J.J.A.M.D.); and the Interuniversity Cardiology Institute, Utrecht (J.M.T.d.B.), the Netherlands.

Correspondence to Tobias Opthof, Academic Medical Center, University of Amsterdam, Department of Clinical and Experimental Cardiology, PO Box 22700, 1100 DE Amsterdam, Netherlands.

	Abstract

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Background Postinfarction ventricular tachycardias (VTs) may degenerate into ventricular fibrillation (VF), but this does not happen in all patients. The underlying mechanism is not exactly known, but dispersion of refractory periods is considered a major factor in both induction and persistence of reentrant arrhythmias in general. Hypertrophied, noninfarcted myocardium has altered electrophysiological characteristics. We hypothesized that noninfarcted ventricular tissue may provide the heterogeneities that cause the transition from VT into VF. Local fibrillation intervals, ie, the average interval between local activations during VF, have previously been shown to correlate well with local refractoriness in human and canine atrium and in porcine and canine ventricle and may therefore be used as an index of local refractoriness. This technique permits simultaneous assessment of refractoriness at multiple sites.

Methods and Results We measured local fibrillation intervals at 32 to 64 sites in the noninfarcted part of the left ventricle in patients undergoing antiarrhythmic surgery for symptomatic, drug-refractory, postinfarction ventricular tachyarrhythmias. The grid of electrodes (interelectrode distance, 7 mm) was attached to the epicardium of the left ventricle remote from the infarcted tissue. Group 1 consisted of 7 patients with hemodynamically tolerable sustained VT (VT group). Group 2 consisted of 7 patients with cardiac arrest and documented VF (VF group). With the patients on cardiopulmonary bypass, VF was induced by multiple premature stimulation. The VF interval was not significantly different in the two study groups (VT group, 136±5.5 ms; VF group, 129±3.4 ms, mean±SEM). However, spatial dispersion of the VF intervals (remote from the infarcted area) expressed as the coefficient of variation of VF intervals (SDx100/mean VF interval in each heart) was significantly larger in the VF group. It was 3.63±0.56 in the VF group and 1.55±0.40 in the VT group (mean±SEM; P<.01). Differences between the shortest and longest VF intervals in one and the same heart and the largest difference between two adjacent sites were also larger in the VF group (P<.02 and P<.05, respectively).

Conclusions This study shows larger dispersion in VF intervals and therefore suggests larger dispersion of refractory periods in parts of the myocardium remote from the infarction in patients with postinfarction VF than in patients with postinfarction VT.

Key Words: death, sudden • fibrillation • tachycardia

	Introduction

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Survivors of an acute myocardial infarction are at increased risk for cardiac death.^{1 2 3 4} Most of these deaths are sudden and are associated with ventricular tachycardia (VT) and ventricular fibrillation (VF).^{5 6 7 8} Surviving myocardial fibers within the infarction provide the arrhythmogenic substrate for reentrant VTs,^{9 10 11 12 13 14} which may degenerate into VF.^{5 6 8 15 16 17}

The degree of left ventricular dysfunction, ischemia, and rate and stability of the tachycardia are probably factors involved in the transition of VT into VF in postinfarction patients.^{18 19 20 21} Moreover, hypertrophied, noninfarcted myocardium has altered electrophysiological characteristics.²² We hypothesized that noninfarcted ventricular tissue may provide heterogeneities in refractory periods that contribute to the transition from VT into VF in postinfarction patients. However, the role of inhomogeneity of refractoriness in patients has not been defined because refractory periods can only be assessed with sequential and time-consuming measurements with the classical extrastimulus technique. Fibrillation intervals have been used as an index for local refractoriness.^{23 24 25 26 27 28} These fibrillation intervals have been shown to correlate well with local atrial and ventricular refractoriness in several species, including humans.^{23 24 25 26 27 28} This method allows assessment of "refractory periods" simultaneously at multiple sites. The purpose of this study was to determine spatial dispersion of ventricular refractoriness in patients referred for evaluation of postinfarction ventricular tachyarrhythmias.

	Methods

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Study Group
The study groups consisted of patients who were selected to undergo mapping-guided antiarrhythmic surgery for symptomatic, drug-refractory, postinfarction VT (Table 1). Group 1 consisted of 7 patients with hemodynamically tolerable sustained VT, and group 2 consisted of 7 patients with cardiac arrest and documented VF. The index arrhythmia occurred between 2 weeks and 9 years after myocardial infarction. In none of the patients was the ventricular tachyarrhythmia secondary to an acute myocardial infarction, electrolyte disturbance, QT prolongation, or heart failure. At the time of the spontaneously occurring ventricular tachyarrhythmias, all patients were free of antiarrhythmic drugs.

View this table: [in this window] [in a new window]   Table 1. Clinical and Angiographic Characteristics

A detailed clinical and physical examination was obtained from all patients. Cardiac catheterization had been performed according to standard techniques. Significant coronary artery disease was defined as a >50% reduction in luminal diameter of the left main coronary artery or a >75% reduction in luminal diameter of any other major coronary artery. An aneurysm was defined as a dyskinetic segment of myocardium producing a distinct distortion of the diastolic left ventricular contour. The location of an infarction required an akinetic or dyskinetic area supplied by a major coronary artery with a >70% stenosis and corresponding pathological Q waves on the 12-lead ECG. Left ventricular ejection fraction at rest was quantified during sinus rhythm using radionuclide ventriculography. All antiarrhythmic drugs had been discontinued for at least five drug half-lives before programmed ventricular stimulation or surgery. All patients underwent programmed ventricular stimulation according to a previously described protocol.²⁹ The end point of the electrophysiological study was completion of the pacing protocol, the induction of a ventricular arrhythmia requiring DC countershock, or the reproducible initiation of a sustained ventricular arrhythmia that did not require countershock. The diagnosis of VT was made according to standard criteria.^{30 31} VT was defined as sustained if it lasted more than 30 seconds or if hemodynamic deterioration necessitated termination; VT was defined as nonsustained if it ended spontaneously within 30 seconds and did not provoke hemodynamic compromise. VF was defined as a rapid ventricular rhythm with totally disorganized electrical activity in the surface ECG leads without recognizable QRS complexes.^{32 33} The protocol of this study was approved by the institutional committee on human research. All patients gave informed consent to the study protocol.

Epicardial Signal Acquisition
A multiterminal grid electrode was used for simultaneous recording of epicardial electrograms. The grid electrode consisted of rectangular sheets of silicone rubber on which terminals (stainless steel hemispheres, 2-mm diameter) were fixed and arranged in a square lattice of either 8 columns and 4 rows or 8 columns and 8 rows. The interelectrode distance was 7 mm. The grid electrode was always placed remote from the infarcted myocardium of the left ventricle, as judged by means of the cineangiogram and by visual inspection during the operation. Recordings were made in the unipolar mode, with the signal of a needle in the left shoulder as reference. A hook electrode attached to either the right or left ventricle was used to induce VF by multiple premature stimulation. All measurements were made at least 1 minute after the induction of VF during normothermia on cardiopulmonary bypass. Epicardial electrograms were filtered (low cutoff, 1 Hz; high cutoff, 1 kHz) and amplified (x200) together with surface ECG leads I, II, and III. Subsequently, these signals were fed into an LS 11–based computer system by means of an 80-channel multiplexing analog-to-digital converter. Samples were taken every 4 ms. Twelve epicardial signals, the surface ECG leads, and a stimulation marker were continuously registered on a 16-channel recorder. With each registration, a 4-second period of VF was stored. Data were transmitted to and stored in a PDP-11/73 computer for analysis.

Signal Analysis
Stored signals were displayed on a graphic display. An interactive computer program indicated local activation times in each electrogram. The intrinsic deflection of the unipolar electrogram, indicating local activation during VF, was arbitrarily defined as a negative deflection with a steepness of at least 0.5 V/s over two consecutive 4-ms periods. Subsequently, histograms of the intervals between local activations were made. The "VF interval" was defined as the mean of the first (or only) peak of the histogram.^{24 28} A VF interval was assigned to a site only if the SEM was <2.5 ms.^{24 28} The reason for exclusion of sites with VF intervals with SEM values >2.5 ms was as follows. Local mean VF intervals are correlated with local refractory periods. This relation has been established in canine atrium,²³ in canine ventricle,²⁴ in porcine ventricle,²⁵ and in human atrium.²⁶ Obviously, the local VF interval needs to be accurate to serve as an index for local refractoriness. Sites with mean local VF intervals with large SEM values are observed during prolonged periods of acute ischemia. They probably are the reflection of large excitable gaps during fibrillation. In another series of patients (not described in this study; see also "Discussion"), we observed that measurements from the infarcted area always led to wide histograms of local VF intervals with, as a consequence, mean local VF intervals with large SEM values. Although it is easily possible to measure these intervals, it is hard to assign a meaningful physiological significance to them. Therefore, we restricted ourselves to the myocardium remote from the infarcted region. All data were analyzed by observers unaware of the index arrhythmia.

Statistics
Data are mean±SEM unless SD values are indicated. Differences in patient characteristics were tested by Student's t test. Spatial dispersion in refractoriness was assessed by three (comparable) parameters. We calculated the coefficient of variation (SDx100/mean) of the mean VF intervals at all sites in each heart. Further, we calculated the difference between the site with the longest mean local VF interval and the site with the shortest mean local VF interval in each heart. Finally, we measured the largest difference in mean local VF interval at adjacent sites in each heart. The spatial dispersion in refractoriness in both groups was compared by the nonparametric Wilcoxon test applied to data from the two patient groups.

	Results

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Patient Characteristics
There were no differences between the VT and the aborted sudden death (VF) group in age, sex, and time interval from myocardial infarction to initial episode of arrhythmia (Table 1). The number of coronary arteries with a >70% stenosis was similar in both groups (2.6±0.7 VT versus 2.4±0.9 VF group [mean±SD]). There was no difference in the distribution of one-, two-, or three-vessel disease between the two groups. The majority of patients had anterior infarctions. One patient with VT and 2 patients with VF had two separate sites of infarction. The overall ejection fraction was 32±10% (SD) in the VT group and 35±10% (SD) in the VF group. The difference was not statistically significant.

Electrophysiological Data Before Surgery
During electrophysiological study, before surgery, sustained monomorphic VT was induced in all 14 patients (Table 1). The mean cycle length of the VT was 300±80 ms in the VT and 255±34 ms in the VF group (mean±SD). This difference was not statistically significant.

Induction of VF During Surgery
In all 14 patients who had developed either VT or VF spontaneously after myocardial infarction (the index arrhythmia) that had occurred between 2 weeks and 9 years before the operation, VF was induced during antiarrhythmic surgery with programmed ventricular stimulation. Fig 1A shows a 4-second recording of surface leads I and II during VF induced in a patient from the VT group. Figs 1B through 1D show maps (8x8 grid electrode) of three consecutive cycles and provide evidence that hearts of patients from the VT group indeed fibrillated during our measurements during antiarrhythmic surgery, because of the presence of multiple wave fronts.³⁴

View larger version (21K): [in this window] [in a new window]   Figure 1. A, Tracings are surface ECG leads I and II during a 4-second period of ventricular fibrillation induced in a patient from the ventricular tachycardia group during antiarrhythmic surgery. B, C, and D, Epicardial activation maps of three consecutive cycles. Isochrones are in milliseconds and timed with respect to the vertical line (t=0 ms). Arrows indicate main spread of activation. t indicates time. Zone of block in B and D is indicated.

VF Interval as an Index of Refractoriness
Fig 2 shows a 4-second recording of an electrogram during VF (Fig 2A) with the activation moments determined by an interactive computer program superimposed (Fig 2B; see "Methods"). Fig 2C shows the corresponding histogram. The VF interval at this particular site was 151.7±1.63 ms. This procedure was performed at all recording sites.

View larger version (31K): [in this window] [in a new window]   Figure 2. A, Local electrogram during a 4-second period of ventricular fibrillation (VF) in one patient from the ventricular tachycardia group. B, Same signal as in A with the activation moments superimposed. These were determined by an interactive computer program. C, Histogram of the intervals indicated in B. The mean of the peak of the histogram was 151.7±1.63 (SEM) ms, and it was considered to be the VF interval of this particular site. This procedure was followed at all 32 or 64 sites in each heart. Only VF intervals with SEM values 2.5 ms were accepted, because only the mean local VF interval at a given site was used for the calculation of the parameters for spatial dispersion of VF intervals. Therefore, this mean value should be as accurate as possible. In the case of collision of two wave fronts or a "missed" activation, the related intervals would appear at the left (eg, at 10 ms) or at the right of the histogram (eg, at 300 ms, ie, far beyond the range of the abscissa) in C, and their respective values would not influence the mean value of the peak depicted by the black bars. See Reference 24 for the details of this procedure. CL indicates length of ventricular fibrillation intervals; n, number of observations.

Spatial Dispersion in VT Group Versus VF Group
Fig 3 shows VF intervals at multiple sites in 1 patient from each group. The mean VF interval in the patient from the VT group was 155.3±1.37 (SD) ms (Fig 3A), and in the patient with aborted sudden death, it was 131.9±8.34 (SD) ms (Fig 3B). Table 2 summarizes data from all 14 patients. Reliable ventricular signals were recorded at 195 sites in the VT group and at 207 sites in the VF group. The corresponding mean VF intervals were 136±5.5 and 129±3.4 ms in the two groups, respectively (n=7; Table 2). This difference was not statistically significant. However, these SEM values describe only the variability of the mean values of individual hearts in the two groups. They do not take into account the spatial differences within hearts (for further explanation, see the legend of Table 2). Fig 4 shows the coefficients of variation, indicating spatial dispersion in VF intervals, in the individual hearts. On average, these coefficients of variation were 1.55±0.40 in the VT group and 3.63±0.56 in the VF group (Table 2; Wilcoxon test; P<.01). The largest difference between VF intervals at two adjacent sites was 5.9±1.74 ms in the VT patients and 10.3±2.20 ms in the VF group (Table 2; Wilcoxon test; P<.05). The difference between the longest and shortest VF intervals in one and the same heart was 8.9±2.27 ms in the VT group and 17.4±2.66 ms in the VF group (Table 2; Wilcoxon test; P<.02). Thus, for each of the three parameters by which spatial dispersion of VF intervals was assessed, the value was associated with the index arrhythmia. The values were significantly larger in the VF group than in the VT group.

View larger version (52K): [in this window] [in a new window]   Figure 3. A, Ventricular fibrillation (VF) intervals at 30 sites in one patient from the ventricular tachycardia group (VT-patient). Interelectrode distance was 7 mm. Measurements were restricted to areas remote from the infarcted myocardium. The mean VF interval at all sites was 155.3 ms. The SD was 1.37 ms, and the coefficient of variation amounted to 0.88. B, VF intervals at 27 sites in one patient from the VF group (VF-patient). The mean VF interval at all sites was 131.9 ms. The SD was 8.34 ms, and the coefficient of variation amounted to 6.33.

View this table: [in this window] [in a new window]   Table 2. Recording Sites and VF Intervals in Patients From VT and VF Groups

View larger version (10K): [in this window] [in a new window]   Figure 4. Scatterplot showing spatial dispersion of ventricular fibrillation (VF) intervals expressed by coefficients of variation (SDx100/mean VF interval) in 7 patients from the ventricular tachycardia group (VT, ) and in 7 patients from the VF group (VF, ). Measurements were restricted to areas remote from the infarcted myocardium. The coefficients of variation were significantly larger in the VF group (Wilcoxon test; P<.01).

	Discussion

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The most frequent mechanism of sudden cardiac death in patients with ischemic heart disease is VF, frequently preceded by VT of variable duration.^{16 17 35 36 37} The importance of tachycardia cycle length as a major determinant of syncope during VT is supported by several studies.^{20 21 38} In our study, the mean VT cycle length during electrophysiological examination was not significantly shorter in the patients with aborted sudden death than in the VT patients. In patients with a previous myocardial infarction, the degree of left ventricular dysfunction appears to be a very important factor determining the risk of sudden cardiac death.^{39 40 41 42 43} In our study, however, there was no difference in ejection fraction between the two groups. The left ventricular ejection fraction was <0.40 in all but 1 patient in the VT group and in 5 of the 7 patients in the VF group. Furthermore, we found no difference in coronary anatomy between the two groups. These factors, therefore, cannot explain why VT or VF occurred after myocardial infarction in the two groups.

We realize that the patients in this study form a highly selected group. Not all survivors of cardiac arrest nor all patients who develop VT after infarction are eligible for surgery. Monomorphic sustained VT can be induced in only 41% of survivors of cardiac arrest,⁴⁴ whereas VT was inducible in all patients of the present study. Therefore, our findings may not apply to all patients who develop postinfarction VT or VF.

Dispersion of Refractoriness
We found that the amount of dispersion in VF intervals measured in noninfarcted myocardium remote from the infarct area, expressed as the coefficient of variation, the difference between the longest and shortest VF intervals in the same heart, or the largest difference between adjacent sites, was associated with the index arrhythmia. All values were significantly larger in the VF group than in the VT group. Noninfarcted myocardium is important because this part of the infarcted heart will be subjected to hypertrophy, which may cause inhomogeneous electrophysiological alterations. In a clinical study,⁴⁵ inhomogeneity in left ventricular refractory periods was the same in patients with normal hearts and those with prior myocardial infarction and VT. But in contrast to our study, refractory periods were determined successively and at limited sites.

Little is known about the differences in myocardial refractoriness between survivors of cardiac arrest and patients with recurrent sustained VT after myocardial infarction. The significance of nonuniformity of refractory periods in the genesis of tachyarrhythmias has been emphasized in several experimental studies.^{24 26 46 47 48} Inhomogeneity of refractory periods decreases the fibrillation threshold in the canine ventricle under various experimental conditions.^{49 50} This suggests that disparity of refractoriness facilitates VF, presumably by an increasing opportunity for reentry of an impulse from a region with a shorter refractory period into a region with a longer refractory period. However, VF threshold is measured with very strong stimuli.^{49 50 51} A decrease in VF threshold associated with increased dispersion in refractoriness does not prove that the same amount of dispersion in refractoriness would also be arrhythmogenic when the premature stimulus has a physiological intensity instead of the very high value during measurement of the VF threshold. Measurement of refractory periods with premature stimulation constitutes a time-consuming procedure, because the measurement disturbs the variable under study.^{24 52 53} As an alternative, averaged local fibrillation intervals have been used as an index of local refractoriness in atrium and ventricle.^{23 24 25 26 27 28} These intervals correlate well with refractory periods in atria and ventricles of pigs, dogs, and humans during normal activation.^{23 24 25 26} This method therefore allows simultaneous assessment of refractory periods at multiple sites.²⁴ It has to be stressed, however, that the process of fibrillation requires a minimum period of at least 1 minute before steady-state values are reached. During the first seconds of the fibrillation process, the fibrillation cycle length has been reported to be as long as 120 ms in the canine ventricle, with a concomitant large excitable gap.⁵⁴ Under these circumstances, local fibrillation intervals are probably meaningless as an index of local refractory periods. Very soon, the fibrillation cycle length shortens to a steady-state value (about 80 ms in the canine ventricle^{24 55} ). Thus, in open-chest studies in ventricles, this technique can be applied only during cardiopulmonary bypass.

An excitable gap has been demonstrated during atrial fibrillation in dogs,⁵⁶ and leading circle excitation need not be the only mode of reentrant activation, especially during VF in larger species. Several studies^{57 58 59} have shown spiral or scroll waves during reentrant arrhythmias in isolated cardiac muscle. The presence of an excitable gap is not incompatible with the relation between mean local VF intervals and local refractory periods. As long as an excitable gap has a roughly similar probability (and duration) during the period of measurement of VF intervals, the local mean VF interval may equal the minimum local refractory period plus a constant.

Limitations
Epicardial areas remote from the infarcted myocardium were selected visually and by cineangiography. Myocardial biopsies have not been taken from these sites, and thus, there is no guarantee that the measurements were restricted to normal myocardium. However, in a preliminary set of observations on other patients not included in this study, we made observations with the grid of electrodes both on normal and infarcted myocardium. In that series, we also observed larger dispersion in VF intervals in patients with VF as index arrhythmia than in patients with VT as index arrhythmia. We also observed that measurements at sites in the infarcted area yielded histograms with SEM values considerably larger than 2.5 ms (compare with Fig 2C). Under these circumstances, VF intervals can probably no longer be regarded as an index of refractory periods.⁶⁰ The absence of sites with such wide histograms in the two groups of patients described in this study is, apart from visual inspection during surgery and cineangiography, another warrant that our measurements were indeed restricted to noninfarcted myocardium.

Conclusions
Our study shows larger dispersion in VF intervals and therefore suggests larger dispersion of refractory periods in noninfarcted ventricular myocardium of patients with VF than in patients with VT after myocardial infarction. Although the significance of other factors as dimensions and architecture of infarcts may not be neglected, electrophysiological properties of noninfarcted myocardium may be an additional factor for deterioration of VT into VF.

	Acknowledgments

 
The authors thank Dr Ruben Coronel for critical reading of this manuscript.

Received August 30, 1994; revision received November 29, 1994; accepted December 3, 1994.

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