Interaction of Activation–Repolarization Coupling and Restitution Properties in HumansCLINICAL PERSPECTIVE
Background— Dynamic modulation of repolarization is important in arrhythmogenesis. An inverse relation exists in myocardium between activation time (AT) and action potential duration (APD). We hypothesized that resulting gradients of APD and diastolic interval (DI) interact with restitution properties and modulate the timing of repolarization.
Methods and Results— Activation-recovery intervals (ARI) were acquired from reconstructed noncontact unipolar electrograms from the left ventricular endocardium in 9 patients (7 male) with normal ventricles. At a basic paced cycle length (median, 450 ms), ARIs shortened along the path of activation, with a mandatory reciprocal increase of DIs. In the median patient, this range of DIs started at 230 ms at the site of earliest activation and increased to 279 ms at the site of latest activation at a basic cycle length of 450 ms. Four consecutive standard S1 to S2 restitution curves were performed. At sites with a longer ARI (and therefore shorter DI) close to the site of stimulation, premature stimulation produced more shortening of ARIs; therefore, the time course of restitution was steeper than at more distal sites. At normal heart rate, the decrease in ARIs along the conduction pathway compensated for later activation. Thus, dispersion in repolarization time (RT) is smaller than dispersion in ARI in a heart with a steep negative AT–ARI relationship. This protective effect is lost in hearts without such a relationship. In the patients with a steep AT–ARI relationship at basic cycle length, this relation is lost after premature stimulation and is a function of prematurity. Thus, dispersion in RT is larger after shortly coupled extra stimuli in patients with a steep AT–ARI relationship.
Conclusions— A complex interplay exists between activation–repolarization coupling and restitution properties, largely driven by ARI and DI gradients. This plays a significant role in the dynamics of repolarization in humans.
Received April 23, 2008; accepted January 7, 2009.
Studies in tissues,1,2 animal hearts,3,4 and humans4–7 have shown that as ventricular activation propagates, action potential duration (APD) or activation recovery intervals (ARIs) shorten progressively. The resulting inverse coupling between APD and activation time is thought to limit dispersion of repolarization. Both APD and activation time are strongly cycle-length dependent, and during premature activation, several dynamic processes are engaged, including APD and conduction velocity restitution.8,9 Activation–repolarization coupling generates a gradient of APD along the activation path. We hypothesized that this in turn may create a reciprocal gradient of the subsequent diastolic intervals and thereby interact with restitution. Restitution properties have been shown to modulate the timing of activation and repolarization in simulation studies9–14 and animal models15–18 and may be critically important in arrhythmogenesis.12,14,18–21 In humans, it is unclear at present how APD/activation time coupling and restitution properties interact, and how this affects the dynamic aspects of activation and repolarization at premature stimulation.
Editorial see p 100
Clinical Perspective see p 162
Reconstructed electrograms obtained by noncontact mapping of the human ventricular endocardium have been validated as an accurate representation of the electrogram obtained using contact electrodes.6 We recorded activation–recovery intervals (ARI) from the left ventricular endocardium in patients with normal ventricles during a standard restitution pacing protocol to examine the interaction between activation–repolarization coupling and restitution properties.
Nine patients (2 females and 7 males; aged 24 to 68 years; median, 59) who were undergoing radiofrequency ablation procedures for supraventricular arrhythmias were studied using noncontact mapping. Four patients had atrial fibrillation, 4 had supraventricular tachycardia, and 1 had fascicular tachycardia. Individual patient details are given in Supplemental Table I. The study was approved by the Guy’s and St Thomas Hospitals Ethics Committee, and written informed consent was obtained from all patients. Antiarrhythmic drugs were discontinued for 5 days before the study. All studies were performed in the left ventricle before the routine clinical procedure.
The noncontact mapping system (Ensite 3000, Endocardial Solutions Inc) consists of an array of 64 electrodes mounted on an inflatable 7.5-mL 9F balloon catheter together with a recording/graphics workstation. Its use for electroanatomical mapping of the left ventricular endocardium has been described.22 The mapping array was introduced into the left ventricle via the retrograde route through the aortic valve or via a transeptal puncture and across the mitral valve. The array was positioned in the middle of the chamber with the pigtail portion in or near the apex and deployed to obtain a stable position. An anatomy of the left ventricular chamber was obtained using a roving deflectable ablating catheter (Boston Scientific Slazer). The validity of the map was checked by examining the map of sinus rhythm propagation within the chamber. No patient was known to have ventricular scar or have disordered conduction attributable to bundle branch abnormality. The waveform data on the Ensite system was digitized and stored at 1200 Hz. Data can potentially be obtained from 3000 points around the chamber. We selected 64 points evenly distributed on the endocardial surface of the chamber from which data were analyzed. These points gave a good spatial distribution without an overwhelming amount of data.
Pacing was established from the right ventricular apex at a pulse width of 2 ms and stimulus strength of 2× diastolic threshold. After a 3-minute stabilization period, a standard restitution curve was constructed by interposing a test beat after each sequence of 9 basic beats (basic cycle length for median subject, 450 ms). The test beat coupling interval was decremented by 50 ms to 300 ms, and then by 10 ms to loss of capture. Four consecutive restitution curves were constructed for each subject under identical conditions at the same basic paced cycle length. For the analysis of restitution data, parameters were identified from each curve and mean values are presented. Illustrations present either the most typical example or a diagrammatic representation of averaged data.
Analysis of Data
Two methods are available for measuring ARIs: the traditional Wyatt method and an “alternative” method.23–27 Both have been the subject of theoretical scrutiny.28,29 We obtained similar overall results by both methods (though absolute values of ARI differed) and report here values obtained using the traditional method. Activation and repolarization times were identified by a computer algorithm based on the time derivative of the recorded signal (dV/dt). These points were individually verified by eye to ensure they had been placed appropriately. Electrograms in which the T waves were inadequately defined were excluded from the analysis.
The moments of activation (A) and repolarization (R) times are shown in Figure 1 for the test beat and 2 preceding basic beats. Activation time (AT) and repolarization time (RT) were measured from the stimulus time, defined as t=0. The activation to repolarization interval (ARI) for a beat is given by the time difference between AT and RT, such that the repolarization time RT=AT+ARI. Across the ventricle, the local times of activation and repolarization vary; dispersion of AT and dispersion of RT are defined as the time difference between earliest and latest times. Diastolic interval (DI) for the test beat was calculated as the difference between the measured activation interval A1A2 and the basic beat ARI measured from the preceding beat A0R0.
The local activation and repolarization times were combined with endocardial geometry data to produce animations comparing propagation of basic and premature beats as shown in supplementary data.
Continuous data that were approximately normally distributed are presented as mean±SD. To determine relationships between activation times and the basic beat ARIs, normal least-squares linear regression was performed for all basic beats recorded; coefficients reported in the Table are median values. The Student paired t test was used to determine statistical significance of differences in restitution properties between earliest- and latest-activating regions in the ventricle. A paired t test was also used to determine statistical significance of differences between various parameters for basic beats versus early beats.
Exponential models were applied to the recorded ARI restitution data, having the form:
The model parameters (ARImax, C0, C1) were selected and optimized to fit the data to minimize the square error between the model and experimentally recorded ARI values (a linear scale was used to determine error). Here, parameter C1 defines the value of DI below which restitution begins to have a significant effect on ARI, and C0 defines the curvature and maximum slope.
Statement of Responsibility
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
AT–ARI Relationship at the Basic Cycle Length
A total of 36 AT–ARI relationships for the basic paced cycle length were generated in the 9 patients; a typical example is shown in Figure 2A. An inverse relation was observed between local ARIs and activation times: electrode sites activating earliest had longer ARIs and electrode sites activating later had shorter ARIs. ARI values for all patients were 231±20 ms (mean±SD) at earliest activation sites versus 203±22 ms at the latest activation sites (P<0.001). Linear regression of ARI on AT resulted in a correlation that varied between patients (median correlation: slope, −0.41, R2=0.73). Linear regression coefficients for all patients are presented in Supplemental Table II.
ARI/Diastolic Interval at the Basic Cycle Length
At the basic cycle length, the progressive shortening of ARIs along the activation path resulted in a corresponding lengthening of the following DI as shown in Figure 2B (eg, patient 5: from 203 ms to 258 ms; range, 55 ms at a basic paced cycle length of 400 ms). Under a pacing protocol with constant cycle length a reciprocal relationship is mandatory because any variation in ARI must cause an equal and opposite variation in DI. Therefore, plots of local ARI versus DI had a linear regression coefficient of −1.
Interaction of the ARI/Diastolic Interval Regression Slope With ARI Restitution
On the ventricular endocardium there existed a gradient of increasing diastolic intervals along the activation path. To examine the interaction between this DI–ARI relationship and ARI restitution we used a standard restitution pacing protocol. For each test beat, as performed in Figure 2B, local ARIs were plotted against their preceding DI and a linear regression line was drawn. Figure 3 shows the combined results at each test coupling interval throughout a restitution protocol (1 example shown). The right hand side of Figure 3 shows the basic cycle length, having long DIs (range, 229 to 276 ms), and as with Figure 2B the regression line has a slope of −1. As the test beat coupling interval shortened, DI decreased and the restitution slope acted to reduce ARIs. Electrode sites having shorter DIs exhibited a larger reduction in ARI compared to electrode sites having longer DIs. This resulted in the progressive flattening of the regression lines as test beat coupling interval shortened. Values for the individual regression slopes in this example are given in Supplemental Table III.
From the relationships described in Figure 2A and 2B, the earliest activating sites exhibited the longest basic cycle length ARIs and shortest DIs, with the opposite scenario for latest-activating sites. To compare the time course of restitution of early versus late-activated sites, we plotted mean ARI and DI values for the electrode sites with the 8 shortest and 8 longest DIs selected at the basic cycle length and followed their response to premature test pulses through a standard restitution protocol. Figure 4 shows results from 1 example patient (No. 1). Exponential curves fitted to the 2 data sets obtained showed that electrode sites at which the basic cycle length ARI was longer had greater amplitude (66±26 versus 52±23 ms, P<0.005) and followed a steeper time course of restitution. Results for all patients are given in Supplemental Table IV.
AT increased at short test pulse intervals. An animation included in the supplemental data provides a demonstration of the difference between activation in a basic beat and a closely coupled test beat. The increase in AT between the RV stimulus site and early activated LV sites where DI was short was much greater than between early activated LV sites and later activated LV sites where DI was longer (Figure 5A). As activation propagated, these local activation delays summated to generate a cumulative delay along the propagation pathway, as shown in Figure 5B. Thus, the majority of the increase in activation time at the short coupling intervals occurred between the pacing site in the right ventricle and the earliest activated site in the left ventricle with a relatively small further increase during propagation over the left ventricular endocardium. The effects seen for each patient were consistent; at the basic cycle length, the time from stimulus site in the RV to the earliest activating electrode site in the LV for all patients was 60±15 ms. The time for propagation from the earliest activated LV sites to latest activated LV sites was 54±13 ms. At short coupling intervals the time from RV stimulus to the earliest activating LV electrode site increased by 28±9 ms, whereas the time for propagation across the LV increased by 7±5 ms. Individual values are shown in Supplemental Table V.
Interaction of AT–ARI Coupling With ARI and AT Restitution
An example of activation and repolarization times for all electrodes during 2 consecutive basic beats is shown in Figure 6A. The time to the first recorded activation represents latency from the S1 stimulus (53 ms), and activation was then dispersed over the following 65 ms. Repolarization started at the site of activation. The convergence of the lines labeled A1 and R1 highlights the progressive shortening of ARIs along the course of propagation in keeping with the negative correlation between ARI and activation time shown in Figure 2A. This created reciprocal lengthening of the following diastolic intervals, indicated by the divergence of lines R1 and A2.
Figure 6B is a similar representation for a basic beat followed by a closely coupled test beat. Activation of the test beat (A2) is slightly slower than for the basic beat (71 versus 65 ms); the line Y is drawn parallel to A1 as a visual aid to the slower activation of A2. Values for all patients are provided in Supplemental Table V. Despite the increasing gradient of DI along the propagation path, there is no increasing gradient of ARI.
Dispersion of AT and Repolarization
For the basic beat, the mean value for dispersion of repolarization was 53±19 ms (coefficient of variation, 0.18±0.06). To quantify numerically the relationships illustrated in Figure 6, basic beat dispersion of repolarization for each patient (Table) was plotted against their AT–ARI regression slope (from Supplemental Table II). There was found to be a strong correlation (R2=0.87, as shown in Figure 7A). Therefore, the weaker the AT–ARI correlation, the greater the dispersion of repolarization.
Because the duration of repolarization also depends on the duration of activation, which varied between patients (33 to 69 ms), we normalized for this variation. We considered the decrease in dispersion of repolarization as a fraction of the preceding activation dispersion. From the linear relationships above, the fractional reduction in dispersion should be equal to the slope of the AT–ARI regression line (δARI/δAT). We scaled each patient’s activation dispersion down by a factor equal to the slope of the AT–ARI regression line. This gave a prediction of the repolarization dispersion that was closely related to the measured dispersion, as shown in Figure 7B (R2=0.86).
For the early beat, dispersion of activation was increased by a small amount compared to the basic beat, as shown in Figure 6B and Supplemental Table V. The relationship of decreasing ARI with AT was no longer present, indicated by the lines A2 and R2 being parallel, offering no reduction in the dispersion of repolarization. Therefore, the dispersion of repolarization was longer for the early beat than for the basic beat (in the example of Figure 6B: 84 versus 50 ms). Values for all patients are given in the Table.
In patients exhibiting a strong AT–ARI correlation at basic cycle length, the dispersion of RT is less than the dispersion of ARI. Across all patients dispersion of RT was 53±19 ms and dispersion of ARI was 53±10 ms at long coupling interval. As restitution engages, the AT–ARI relationship has been shown to diminish resulting in the loss of this protective mechanism. At short coupling intervals the dispersion of RT is considerably greater than the dispersion of ARI (across all patients: 75±19 versus 60±13 ms at shortest cycle length).
These studies using noncontact mapping in humans demonstrate a complex interaction between activation–repolarization coupling and restitution properties and provide insight into the effect of this interaction on the timing and dispersion of activation and repolarization. Specifically, we have shown that: (1) ARIs shortened progressively along the propagation path of activation creating a negative ARI gradient; (2) the ARI gradient generated a reciprocal gradient of increasing diastolic intervals for the following beat; (3) AT restitution delayed activation of test beats at short S1–S2 intervals, thereby further increasing the range of diastolic intervals before the test beat; and (4) the steepness of ARI restitution varied systematically along the path of propagation, being steeper at electrode sites with longer basic beat ARIs and shorter DI (ie, closer to the activation site, as shown in Figure 4).
The consequences of these effects were that at long coupling intervals when diastolic intervals fell on the restitution plateau, a negative AT–ARI correlation tended to reduce dispersion of repolarization; a strong correlation was present between the regression coefficient of the AT–ARI relationship and dispersion of repolarization (R2=0.87). As S1–S2 shortened, the situation changed when the diastolic intervals fell on the slope of ARI and AT restitution, then a complex interaction occurred between the AT–ARI relationship and ARI and AT restitution, resulting in an increased dispersion of repolarization at the shortest intervals. A diagrammatic representation of these effects is provided in Supplemental Figure III.
A negative correlation between activation time and either ARI or APD has previously been reported in experimental models1–4 and humans.4–7 The correlations of ARI with AT found in our study are consistent with values reported in these studies. A likely mechanism is local electrotonic current flow via gap junctions between cells which tends to equalize action potential durations. This coupled with the later repolarization of cells downstream and electrotonic current flow from cells downstream to cells upstream would facilitate the AT–ARI gradient.30–32 A further illustration in supplemental data, SF1, shows this relationship still in evidence where some local “short-circuiting” of activation through the Purkinje system may have occurred.
It can be seen in Figure 6A that repolarization of the basic beat commences at the earliest activated electrode sites where ARIs are longest. It has been a point of discussion as to whether repolarization propagates from the opposite direction to the activation sequence, or commences at the site of activation. In all our patients repolarization started at the site of activation, as can be seen in the animation in the supplemental data section. Similar concordant activation–repolarization sequences have been observed in pigs,3 canines,33 and humans.32,34 As pointed out by Yue et al,6 if an AT/repolarization slope is more negative than −1, repolarization should complete earliest at sites of latest activation, and if the slope were more positive than −1, the AT/repolarization sequence would be concordant. In our studies, the slopes were all more positive than −1.
AT–ARI Coupling and ARI Restitution
One study in humans showed a flattening of the AT–ARI regression slope at a medium and a short steady-state pacing cycle length suggesting a cycle length dependence.6 The effect of AT–ARI coupling that we observed was to generate a gradient of decreasing ARIs along the course of activation, which in turn created a reciprocal gradient of the following DI. Diastolic interval and steady state APD are major determinants of the time course of APD restitution,8,35 suggesting the possibility that AT–ARI coupling may generate a range of restitution profiles along the path of activation. In this study, we examined the effect of a restitution pacing protocol on the ARIs and corresponding DIs along the propagation pathway. The interactions are illustrated in the Supplemental Figure II.
At long coupling intervals, the DI was long such that the following ARI fell on the restitution plateau. The DI gradient then exerted little or no effect on the subsequent ARI. As the S1–S2 coupling interval shortened, the situation was different as DIs shortened and the restitution slope was engaged. It has been shown experimentally that the steepness of the APD restitution curve is partly dependent on the steady state APD whereby a longer basic beat APD is associated with steeper restitution.35 Therefore, the gradient of ARIs generated during activation may be expected to result in a steeper restitution time course closer to the activation site where ARIs are longer. An alternative explanation might be that at either a very short basic cycle length, or in short-coupled premature beats, the amount of IKs current is probably so large that it permits very fast repolarization leading to short APDs. However, this also prevents the late-activated myocytes from shortening further because of electrotonic interaction. These myocytes already have short APDs because of the large IKs conductance. This phenomenon was observed in our study: the earliest activated sites (having longer ARIs) followed a different time course of restitution compared to the latest activated sites (having shorter ARIs; Figure 3). Consequently, as the test beat coupling interval was reduced, the longer ARIs shortened more than the shorter ARIs (Figure 4). Therefore, for a very premature beat, the ARIs ceased to systematically decrease along the path of activation propagation. From Figure 6B, it is apparent that local variation in ARI still exists across the ventricle at short coupling intervals, however this variation of ARI was virtually independent of DI, thus the protective mechanism acting to reduce dispersion of repolarization has been lost.
The situation here is in many ways analogous to the guinea pig heart model in which heterogeneous restitution was generated by regional differences in intrinsic cellular ionic currents.16 In this model, the restitution curve with the longer basic beat APD had a faster time course of restitution (ie, a steeper curve) compared with the site where the basic beat APD was shorter. As the test beat coupling interval shortened, the longer APDs shortened more than the shorter APDs, resulting in an alteration of the APD gradient between the 2 regions. Inspection of Figure 2 in the study by Laurita et al16 shows a striking similarity to the ARI changes we observed (Figures 3 and 4⇑). We cannot exclude the possibility that regional differences in ionic currents contributed to our results. However, we would consider such an effect to be minor because to the best of our knowledge no systematic ionic gradients of the type present in guinea pig have been demonstrated in humans; in addition, different anatomic pathways of activation produced an overall similar pattern of AT–ARI coupling.
We were not able to demonstrate a reversal of the ARI gradient at the shortest coupling intervals similar to the APD gradient reversal observed in the guinea pig model by Laurita et al.16 This may be because of model-dependent differences, and in particular the inability in our study to acquire data at very short diastolic intervals. This was partly because the minimum diastolic interval attainable increases with increasing distance from the pacing site, resulting in some degree of attenuation of the restitution profiles at the more distal sites, as shown in Figure 4. In this regard, it should be emphasized that the restitution profiles in the present study are not intended as representations of local restitution curves but as representations of the restitution profile encountered by the propagating wavefront.
AT–ARI Coupling and Activation Time Restitution
Activation time restitution operated over a relatively narrow range of DIs, in keeping with the conduction velocity restitution curves reported by Yue et al.36 The critical coupling intervals below which ARIs/APDs start to shorten and conduction velocity starts to decrease are not necessarily the same; Supplemental Figure III illustrates the separate effects. As shown in Figure 5A, the 7 shortest DIs were attained near the activation site compared to late activated sites attributable to the time occupied by the spread of activation. Thus the impact of conduction velocity restitution on AT is greater closer to the activation site; AT restitution resulted in only a small (but significant) increase in activation time between early and late-activated sites.
On the basis of these results, we would speculate that factors that increase ARI and AT restitution would be expected to increase the dispersion of repolarization at a short coupling interval.
Electrograms recorded by the noncontact method we used have been validated as providing a highly accurate representation of the local electrogram recorded using contact electrodes.6 The validation for the use of noncontact mapping for repolarization study has been found to be less strong than the correlation reported elsewhere for activation.6,27 However, this has provided sufficient resolution for studies examining the construction of restitution curves36 and the AT–ARI relationship.6 The traditional method (Wyatt) of measuring ARIs from these waveforms, although having strong experimental and theoretical validation,23–25,28,29 has been suggested to underestimate the ARI for electrograms with positive T waves.3,26,27 In our study, the ARIs observed at the point of refractoriness in some cases reached as short as 140 ms, which concurred with the ARIs reported by Ramdat Misier et al37 using VF intervals as a surrogate measure of refractoriness in patients with VT/VF. An “alternative” method has been used by some workers whereby the repolarization moment of the ARI is measured as dv/dt min of the T wave rather than dv/dt max, as in the traditional method. However, because the global distribution of T wave morphology has been shown to remain constant with only small changes limited to border zones6 over cycle lengths from steady state to refractoriness, any difference between the 2 methods should remain consistent over the range of perturbations we used. We obtained qualitatively similar results by both methods and report here results using the traditional method.
The timing of activation, repolarization, and dispersion of repolarization are important in the initiation and maintenance of reentrant ventricular arrhythmias.38–40 The dynamic interplay that we have demonstrated between AT–ARI coupling and restitution properties suggests that their effects on both activation and repolarization are closely linked and may play an important role in arrhythmogenesis. Our results also suggest that strong AT–ARI coupling may be protective at the basic cycle length by limiting dispersion of repolarization, but that the situation may be much more complex at short coupling intervals attributable to interaction with restitution. Several studies have defined APD and conduction velocity restitution conditions that facilitate wavebreak and, in particular, the protective effect of flattening APD restitution.9,12,19 Our results suggest that any variation in the slope of APD restitution, for example by autonomic effects41 or drugs, may also modulate the time course of repolarization and dispersion of repolarization by interaction with AT-APD coupling. Our results are more likely to apply to conduction initiated by an ectopic focus rather than normal anterograde activation of the ventricle via the Purkinje system, because ARI dispersion depends heavily on a gradient of AT and the latter is greater during unifocally-initiated propagation though ventricular muscle. The dynamic interplay that we report here may be a fundamental property of wave propagation and therefore integral to the behavior of restitution properties in humans.
Our studies were confined to the left ventricular endocardium and therefore do not provide information on transmural gradients or other regions of the heart. In the interpretations offered we have not taken account of regional differences in intrinsic electrophysiological properties. In the protocol, we used the basic beat and the premature test beat were initiated from the same pacing site. A premature beat arising from a location different from the basic beat would be expected to modify the direction of the gradients we observed. In addition, many other factors are likely to play an interactive role with the parameters we have studied, including gap junctions,42 anisotropy,43 and other time-dependent mechanisms such as myocardial memory.18,44
We have shown that AT–ARI relationship generates gradients of ARI and DI along the propagation pathway resulting in systematic variation in the restitution profile encountered by a propagating wavefront. This may be a fundamental property of human myocardium of importance in arrhythmogenesis.
Sources of Funding
Drs Gray and Critchley were supported by the Wellcome Trust via a Programme Grant (to H.D.C.).
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Several dynamic processes modulate the timing of ventricular repolarization and are therefore of likely importance in determining the substrate for ventricular arrhythmias, including ventricular fibrillation. It has been shown, for example, that as activation propagates, action potential duration shortens progressively along the activation path, thereby modulating the spatial dispersion of repolarization. The nonlinear response of action potential duration and conduction velocity to abrupt changes in cycle length (referred to as restitution) also modulates the spatiotemporal pattern of repolarization. Using activation-recovery intervals as a surrogate for action potential duration in humans, we demonstrate a complex interaction between these 2 dynamic processes. Our results suggest that strong activation time–activation-recovery interval coupling may be protective at the basic cycle length by limiting dispersion of repolarization, but that the situation becomes more complex at short coupling intervals because of with restitution. Several studies have defined action potential duration and conduction velocity restitution conditions that facilitate wavebreak and promote ventricular fibrillation and, in particular, a potentially protective effect by altering restitution properties. Our results suggest that any variation in restitution, for example by autonomic effects or drugs, may modulate the time course of repolarization and dispersion of repolarization as a consequence of interaction with activation time–action potential duration coupling. The dynamic interplay that we report here may be a fundamental property of wave propagation and therefore integral to the behavior of restitution properties in humans.
The online-only Data Supplement can be found at http://circep.ahajournals.org/cgi/content/full/CIRCEP.108.785352/DC1.