| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Themed Issue Papers |
1 Bioengineering Institute and Engineering Science, University of Auckland, New Zealand2 Burdon Sanderson Cardiac Science Centre, Department of Physiology, Anatomy & Genetics, University of Oxford, UK3 Departments of Cardiology and Cardiothoracic Surgery, University College Hospital, London, UK4 Department of Computer Science, University of Sheffield, UK
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
(Received 31 October 2005;
accepted after revision 10 January 2006; first published online 1 February 2006)
Corresponding author P. Taggart: Departments of Cardiology and Cardiothoracic Surgery, University College Hospital, 16–18 Westmoreland Street, London W1G 8PH, UK. Email: peter.taggart{at}uclh.nhs.uk
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The spatial dispersion of action potential duration (APD) is known to play a major role in arrhythmogenesis (Han & Moe, 1964; Kuo et al. 1983; Sampson & Henriquez, 2001; Xie et al. 2001a). Several disease processes are commonly associated with increased spatial dispersion of repolarization, including coronary artery disease and ventricular hypertrophy (Janse & Wit, 1989). Recent attention has focused on the dynamic modulation of APD by an abrupt change in cycle length referred to as restitution (Boyett & Jewell, 1978). When the restitution curve relating APD to the preceding diastolic interval (DI) has a steep slope (i.e. greater than unity), successive changes in cycle length at a fast rate may induce oscillations in APD (Nolasco & Dahlen, 1968). It has been shown experimentally that steep APD restitution may facilitate wavebreak and fibrillation (Karma, 1994; Gilmour & Chialvo, 1999; Weiss et al. 1999), whereas reducing the slope may prevent or terminate fibrillation (Garfinkel et al. 2000). Whether restitution in the human heart is steep enough to sustain multiple wavebreak mechanisms of ventricular fibrillation (VF) has been questioned on the basis of the available data, which have been limited to a small number of single or paired site recordings (Franz et al. 1988; Morgan et al. 1992; Taggart et al. 2003).
In addition to the steepness of the APD restitution curve, spatial heterogeneity of restitution slopes is thought to be important (Laurita et al. 1996, 1998; Sampson & Henriquez, 2001; Xie et al. 2001a; Banville & Gray, 2002; Fenton et al. 2002) through several mechanisms, including the promotion of the coexistence of multiple spiral waves (Xie et al. 2001b), enhancment of oscillations of refractoriness (Watanabe et al. 2001) and creation of discordant alternans (Laurita et al. 1996; Pastore et al. 1999). Discordant alternans occurs when the steep portion of the restitution curves in adjacent regions cross, resulting in a reversal of voltage gradient on alternate beats. Calcium cycling and cellular calcium accumulation have been shown to modulate APD restitution and alternans, so regional heterogeneities of calcium dynamics are likely to be important (Goldhaber et al. 2005). However, the spatial dispersion of APD restitution in humans is at present unknown and usually assumes homogeneous restitution or a smooth apex-to-base gradient, as present in some animal models (Rosenbaum et al. 1991; Laurita et al. 1996). Our unpublished pilot observations in humans have suggested that restitution may be markedly heterogeneous, which underlines the need for global assessment of restitution properties in typical patient groups. Subsequent to these pilot studies, a recent modelling study has provided further theoretical evidence that heterogeneous restitution can form a potent arrhythmogenic substrate (Clayton & Taggart, 2005).
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
We studied 14 patients aged 52–85 years (mean 67; 11 males) undergoing routine cardiac surgical procedures. The study was approved by the local hospital ethics committee, and written informed consent was obtained from all patients prior to the study. The protocols comply with the Declaration of Helsinki. Individual patient details are given in Tables 1 and 2. Eight patients were undergoing graft procedures for coronary artery disease. Six patients were undergoing replacement surgery for aortic valve disease and had no haemodynamically significant coronary artery disease (defined as greater than 50% stenosis in any one major vessel). The patient groups were at low risk of ventricular tachycardia (VT)/VF (Sanders et al. 2005); none had a history of arrhythmia or syncopal episodes; left ventricular ejection fraction was normal in all patients; and only two subjects had previous myocardial infarction. Routine medication was continued until approximately 15 h prior to surgery.
|
|
Following cannulation for cardiopulmonary bypass (but prior to its commencement), a sock containing 256 unipolar contact electrodes (interelectrode spacing approximately 10 mm) spanning the entire left and right ventricles was fitted over the epicardium. As previously described (Nash et al. 2001, 2003), unipolar epicardial electrograms were sampled at 1 kHz using a UnEmap system (Auckland UniServices Ltd, New Zealand), and conventional signal analysis techniques were used to obtain epicardial activation–recovery intervals (ARI) as a surrogate for APD (Haws & Lux, 1990). Bipolar ventricular pacing was established from two sock electrodes at twice diastolic threshold using a 2 ms pulse duration. A basic cycle length (BCL) of 600 ms was chosen when possible (9 patients), but in five patients a shorter basic cycle (between 450 and 550 ms) was necessary to ensure capture, owing to a faster intrinsic heart rate. The pacing sites were: coronary artery disease (CAD), 4 mid-left ventricle (LV), 2 mid-LV/right ventricle (RV) border, 1 mid-RV, 1 apex; and aortic valve disease (AVD), 4 mid-LV, 2 apex. Following each train of nine steady-state S1 stimuli at the BCL, a shorter interval S2 stimulus was interposed. The S1–S2 interval was decremented by 50 ms steps to 400 ms; then by 20 ms steps to 340 ms; and then by 5 ms intervals until loss of ventricular capture.
Estimating APD restitution using ARI
The ARI is an established (Haws & Lux, 1990) and now widely used surrogate for APD and APD restitution. In pilot studies (unpublished observations), we compared restitution curves obtained using monophasic action potential (MAP) and ARI recordings from the same epicardial site in humans, which confirmed the applicability of the technique in the setting of patients undergoing cardiac surgery. A recent study using non-contact mapping of the endocardium in humans (Yue et al. 2004) has shown that for complexes with upright T waves, a closer correlation was obtained between ARI and MAP duration (measured at 90% repolarization) when ARI was measured to the steepest downstroke of the T wave (‘alternative method’), rather than the standard (Wyatt) method of measuring the ARI to the steepest upstroke of the T wave (Haws & Lux, 1990). We compared ARIs and restitution curves computed using the standard method against the alternative method. The alternative method yielded ARI values that were longer by 74 ± 10 ms (mean ±S.D.), but exerted only minimal influence on the resulting restitution slopes and spatial distributions of restitution properties (data not shown). The standard (Wyatt) method of calculating ARI was used throughout the present study.
Restitution analysis
Only signals with good quality signal-to-noise ratios were accepted. From the 256 electrode sites, good quality electrograms suitable for analysis were obtained with an overall mean ±S.D. of 206 ± 45 signals per patient. Standard restitution curves for ARI versus DI were constructed for each individual electrode site using a least-squares fit to the mono-exponential function:
|
| (1) |
|
| (2) |
|
| (3) |
These quantities are related by:
|
| (4) |
Statistical analysis
The statistical model used for analysis throughout this paper was a linear mixed model. The fixed factors were a pathology group (CAD versus AVD), an apex–base group (apex versus base) and a left–right group (LV versus RV). All electrodes were designated as either apical or basal, and either LV or RV, according to their epicardial location. The interactions of pathology*apex–base, pathology*left–right and apex–base*left–right were included in the model only if the main effects were significant. The multiple electrode measurements made for each patient formed the random effect for the analysis. For situations where non-normal data prevented direct application of the linear mixed model, a non-parametric Mann–Whitney U test was used to test for significance of a group. The analysis was performed using the SPSS statistical package (SPSS 13.0 for Windows).
Computational model
We examined the implications of heterogeneous APD restitution for the initiation and stability of re-entrant arrhythmias using a simplified model of 2-D cardiac tissue. Action potential propagation was described by the monodomain equation:
|
| (5) |
|
t) of 0.1 ms, a space step (x) of 0.25 mm, and no-flux boundary conditions at each external edge. The specific membrane capacitance was set to 1 µF cm–2, and the diffusion coefficient set to 0.1 mm2 ms–1. We observed only small (< 1%) changes in conduction velocity for time steps of 0.8 and 0.12 ms, indicating that the numerical scheme was stable. We examined the initiation and stability of re-entry in several 150 x 150 mm 2-D tissue models, each with a circular region at the centre being assigned Steep2 restitution, and the surrounding tissue assigned Steep1 restitution. The circular region was varied in size by setting the radius to 12.5, 25 or 50 mm. We studied the initiation of re-entry by setting the tissue to a resting state, and pacing from the bottom edge. We studied the stability of re-entry by imposing an Archimedean spiral as the initial condition.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The overall mean ±S.E.M. steady-state ARI was 242 ± 6 ms across all patients. The maximum restitution slopes spanned a wide range. Figure 1A shows the distribution of slopes ranging from shallow to steep. The standard (Wyatt) and alternative methods of determining ARI yielded slope distributions with good overall correspondence (Fig. 1B). The mean ±S.E.M. maximum slope for all patients was 1.1 ± 0.02 (median 0.9, range 0.0–5.6), with 55% of electrodes having slopes below 1, 20% having slopes between 1 and 1.5, and 13% having slopes above 2. A slope that is steep over a greater length of the rising portion of the restitution curve is thought to be more proarrhythmic than a slope of comparable steepness, but that is steep over only a short length of the curve (Qu et al. 1999). We therefore evaluated the range of diastolic intervals over which slopes steeper than 1 remained steeper than 1. For the 45% of electrode sites with slopes steeper than 1, only 11% were maintained steeper than 1 over a DI range of at least 30 ms, and only 0.3% of sites over a DI range of at least 50 ms.
|
The mean ±S.E.M. maximum restitution slopes were slightly steeper over the LV (1.19 ± 0.03; median 0.98; range 0.0–5.6) compared to the RV (1.03 ± 0.02; median 0.83; range 0.0–5.03), as illustrated in Fig. 2A. The distribution of restitution slopes was non-normal (as shown in Fig. 1), so standard statistical tests could not be applied. However, a non-parametric test showed a significant difference in the restitution slope between the LV and RV (P < 0.001 non-parametric). Apex and base slopes were relatively similar in magnitude, i.e. apex 1.12 ± 0.02 (median 0.94; range 0.0–5.54) compared to the base 1.10 ± 0.03 (median 0.84; range 0.0–5.6; P < 0.01 non-parametric).
|
Restitution was shallower in the CAD group compared to the AVD group (Fig. 2B). The overall mean ±S.E.M. slopes were: CAD 1.0 ± 0.02 (median 0.83, range 0.0–4.88); and AVD 1.2 ± 0.03 (median 0.96, range 0.0–5.7; P < 0.001 non-parametric). The amplitude of the restitution curve was measured as the range of ARIs between that at the shortest non-refractory S1–S2 coupling interval, and the ARI at an S1–S2 interval of 400 ms (see Fig. 2C). Again consistent with flatter restitution in the CAD patients, the restitution amplitude was substantially lower in this patient group compared to the AVD patients (CAD 38 ± 5 ms; AVD 56 ± 6 ms; P < 0.05).
Spatial organization of restitution
The spatial distribution of the maximum restitution slope in the patients we studied was heterogeneous. The distribution was not random, but exhibited regional organization, resulting in multiple gradients over the epicardium between areas of steep slope and areas of shallower slope (Fig. 3). Figure 3A shows examples from four patients, illustrating the wide range of restitution slopes and the juxtaposition of large areas of steep slopes with areas of shallower slopes. These regions of different slope were separated by spatial gradients, which are illustrated in Fig. 3B with contours of equal slope. A similar pattern pertains with regard to the portion of the restitution curve over which a steep curve remains steep before flattening to approach its asymptote (see inset in Fig. 3B). This parameter (so-called ‘DI range’, quantifying the range of diastolic intervals over which the restitution slope is > 1), was also regionally organized with a similar spatial pattern to the associated maximum restitution slope distribution. This was expected, given the mathematical relationship between DI range and maximum slope as detailed in the Methods section (Equation (4)).
|
|
|
As a measure of ARI dispersion, the coefficient of variation (COV = standard deviation as a percentage of the mean) was found to be substantially greater at shorter DIs (Fig 6A). Similar results in animal models have been attributed to the shape of the restitution curve. To investigate this notion, ARIs following short diastolic intervals in the range of 0–100 ms were subdivided according to the steepness of their restitution curves. A positive correlation with a regression coefficient of 2.44 ± 0.56 (P < 0.001) was present between dispersion of repolarization (COV of ARI) and the steepness of the restitution slope (Fig. 6B).
|
The model geometry, APD and conduction velocity (CV) restitution for each model variant are shown in Fig. 7. In this study, we investigated the potential arrhythmogenic influence of a region of steep APD restitution (Steep2, relatively long APD at short DI) located within a region of shallower APD restitution (Steep1, relatively short APD at short DI). We found that we could readily initiate wavebreak and re-entry in this model with an S1–S2–S3 stimulus protocol (see Fig. 8) and with this combination of restitution properties. Using an S1–S2 interval of 200 ms, we were able to initiate wavebreak and re-entry for S2–S3 intervals of between 102 and 158 ms for a radius of 50 mm, and between 102 and 153 ms for a radius of 12.5 mm. Figure 8 shows an illustrative example for a radius of 50 mm, an S1–S2 interval of 200 ms, and an S2–S3 interval of 120 ms.
|
|
Heterogeneous APD restitution may also play a role in the stability of arrhythmias, as well as their initiation (an illustrative example is shown in Fig. 9). Both Steep1 and Steep2 variants of our model had steep (slope > 1) APD restitution, and the Steep1 variant was associated with unstable re-entry, consistent with the restitution hypothesis (Fig. 9A). However, although the Steep2 variant possessed steep APD restitution at very short DI, the DI range for steep slopes was substantially smaller than the Steep1 variant. Thus, during re-entry, curvature effects prevented these values of DI from being achieved, and so re-entry was stable despite the steep APD restitution (Fig. 9B).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Methodological considerations
The cellular properties of the ventricular wall are heterogeneous (Antzelevitch et al. 1991). Our measurements were made on the epicardial surface, so we have no information from endocardium or mid-myocardium. Steep APD restitution results in a greater variation in APD and so in refractoriness over a given range of diastolic intervals. Depressed conduction results in a broader conduction velocity restitution curve and so in a wider range of conduction velocities over a given range of diastolic intervals. Therefore, APD restitution alters the sensitivity of the wave back, whilst conduction velocity restitution alters the sensitivity of the wave front to small changes in diastolic interval (Qu et al. 2000). Hence, an integral part of the interpretation of APD restitution is conduction velocity restitution. However, the interelectrode distance on the sock was approximately 10 mm, so in view of this relatively low spatial resolution, conduction velocity restitution was not quantified in this study.
The variation in pacing site between patients may have contributed to the interpatient variability owing to tissue anisotropy, since the latter has been shown to influence repolarization (Gotoh et al. 1997; Furukawa et al. 2000). However, this would not have altered the overall findings of spatial heterogeneity within individual hearts. Comparison of hearts for which the pacing sites were similar did not reveal any topographical similarities between hearts (data not shown).
At some electrode sites, we observed ARI restitution data that exhibited a non-monotonic (e.g. triphasic) relationship at short DIs, as reported in some studies (Franz et al. 1988; Morgan et al. 1992). However, this was seen infrequently in our data, occurring for less than 2% of the 2885 restitution recording sites across all 14 patients. This was despite spanning the range of DIs over which this pattern has been observed (i.e. between approximately 50 and 100 ms) and changing the S1–S2 pacing interval by small (5 ms) decrements over this range. Reasons for this discrepancy in restitution shape are not clear, but may relate to endocardial-to-epicardial differences. In a previous study of APD restitution on the endocardium using single site recordings, the curves were more angulated and did not always follow a mono-exponential time course (Taggart et al. 2003). For these curves, we used piecewise linear regression to measure the maximum slope. In the present study, the curves were smooth, and we used a mono-exponential fit, which has the advantage of being in line with the majority of other published reports. We found that the mono-exponential function provided an accurate fit to the vast majority of our data, with small root-mean-squared errors and no consistent pattern to the errors between the recorded data and fitted restitution curves.
APD restitution slopes
Previous estimates of the restitution slope in humans have relied on studies reporting a limited number of single or paired site recordings (e.g. Franz et al. 1988; Morgan et al. 1992; Taggart et al. 2003; Pak et al. 2004). Our data using multi-electrode recording over the complete left and right ventricular epicardium provides a global map of APD restitution for low risk cardiac patients. A striking feature was the spatial heterogeneity of slope in all patients, with multiple gradients between numerous adjacent regions with widely disparate slopes. This is consistent with the non-uniformity seen in some animal models, such as a single apex-to-base gradient in the guinea-pig (Pastore et al. 1999). However, the apex-to-base restitution gradient in guinea-pig hearts is characteristically smooth and contrasts with the multiple gradients we observed. Thus no heart could be described as having either steep or flat restitution, since regions of each were present in all hearts studied.
In the present studies, a relatively high proportion (45%) of electrode sites had restitution slopes > 1. There was no obvious relationship between steepness and pathology (such as infarction) in any individual patient. Overall, slopes were steeper than those recently reported by Yue et al. (2005) on human endocardium using non-contact mapping in patients undergoing electrophysiological procedures for supraventricular arrhythmias. In their study, mean restitution slopes of 0.93 ± 0.49 in left ventricle and 0.65 ± 0.26 in right ventricle were observed. In our previous studies using single site monophasic action potential recordings from right ventricular endocardium (Taggart et al. 2003), we observed mean restitution slopes of 1.05 ± 0.09 and 0.71 ± 0.05 at cycle lengths of 600 and 400 ms, respectively. In another study by Pak et al. (2004) using monophasic action potential recordings in patients at high risk of ventricular arrhythmia, restitution slopes from the right ventricular endocardium were considerably steeper (2.7 ± 1.9 and 1.9 ± 1.2 at the RV outflow tract and RV apex, respectively). The reason for the steeper slopes we observed compared to those of Yue et al. (2005) and and compared to our own previous observations is not clear. Possible explanations include endocardial versus epicardial differences, differences intrinsic to the patient populations, different basic cycle lengths, and the methodology employed for calculating the slope (a mono-exponential fit was used in the present study, whereas piecewise linear regression was used in our previous study and that of Yue et al. 2005). A recent study by Koller et al. (2005) showed that the steep portion of the dynamic restitution curve was shifted to the right in patients with structural heart disease, and that alternans occurred over a wider range of diastolic intervals compared to control subjects. This suggests the importance of restitution parameters other than slope per se in mechanisms underlying arrhythmogenesis.
Overall, the restitution slope was steeper in the left ventricle compared to the right ventricle, as has been reported by others in a guinea-pig model (Laurita et al. 1996) and recently in humans (Yue et al. 2005). The slope was flatter in patients with CAD compared to those with AVD. Several mechanisms may be contributory. Acute ischaemia has been shown to flatten APD restitution in animal (Dilly & Lab, 1988) and human hearts (Taggart et al. 1996). In our studies, there was no evidence of ischaemia on the standard ECG, on the routine monitors or on the epicardial electrograms. None of the patients were known to have angina at rest or fluctuating ECG ST segment changes. Nevertheless, the possibility of an effect of ischaemia on restitution, particularly in patients with CAD with critical stenoses, cannot be excluded. Medication with ß-blockers or calcium antagonists taken by the CAD patients could have contributed significantly to this result, since both drugs flatten restitution (Weiss et al. 1999; Taggart et al. 2003). ß-Blockers may also be expected to reduce ARI dispersion.
Modelling studies suggest that, as well as the steepness of the restitution curve, the range of diastolic intervals over which the curve remains steep is important (Qu et al. 1999). A slope that is steep over a larger portion of the curve is more profibrillatory than one that is steep over only a short section of the curve (Qu et al. 1999). In our studies, the range of diastolic intervals over which a curve with a slope steeper than 1 remains steeper than 1 was also regionally distributed (Fig. 3).
Why the regionality?
The reason for the striking pattern of spatial heterogeneity of restitution slope seen in this human study is not clear. There was no obvious anatomical orientation, and the topographical pattern was different between patients. Acute ischaemia flattens the APD restitution curve (Dilly & Lab, 1988; Taggart et al. 1996), but is unlikely to have played more than a minor role for reasons mentioned above, and also because similar characteristics were observed for the AVD patients, for whom no haemodynamically significant coronary artery narrowing was present. Cooling prolongs APD and steepens APD restitution (Bjornstad et al. 1993); therefore, local variations in epicardial temperature could have influenced our results. However, we consider this also to be an unlikely explanation for the regionality of APD and restitution slope we observed, since we have previously shown that just prior to bypass the epicardial temperature drop was less than 1°C and was uniform (Taggart et al. 1988).
Differences in restitution properties in the RV have been reported between patients with RV disease and ischaemic heart disease (Morgan et al. 1992). Since spatial variation in restitution kinetics is thought to be governed by regional differences in ion channel density, one possible explanation for the heterogeneity on the global scale that we observed may be the result of remodelling. A possible mechanism, albeit speculative, is the effect of altered myocardial stress–strain relations acting through mechano-electric feedback, whereby changes in mechanical stretch alter the local electrophysiology (Lab, 2004; Nash & Panfilov, 2004). Ischaemia is well known to alter local ventricular wall motion and thus regional stretch. Hypertrophy in patients with AVD is also known to alter local stretch forces. Mechano-electric feedback in response to altered stretch may influence ion channel behaviour and in the longer term ion channel density (Meghji et al. 1997). The widely varying location of the ischaemic territory and the differing patterns of hypertrophy in these patients provide a likely basis for the interpatient variability of restitution slopes seen in our data.
Implications
Steepness of the restitution slope. Experimental and modelling studies have demonstrated that steeply sloped APD restitution creates electrical instability and is profibrillatory (Nolasco & Dahlen, 1968; Karma, 1994; Gilmour & Chialvo, 1999; Weiss et al. 1999; Garfinkel et al. 2000). The original restitution hypothesis predicts that a restitution slope steeper than 1 may result in wavebreak, whereas at slopes below 1 wavebreak does not occur.
Modelling initiation and stability of re-entry in tissue with heterogeneous restitution. Computational models are a valuable tool for exploring the properties and behaviour of cardiac tissue. We have used a much-simplified computational model of action potential propagation to investigate the arrhythmogenic potential of heterogeneous restitution. In a detailed and systematic study (Clayton & Taggart, 2005), we have shown that the interaction of a premature beat (S2) with heterogeneous restitution acts to produce regional differences in recovery, which block an additional premature beat (S3), resulting in wavebreak and re-entry. These observations are in agreement with experimental studies (Laurita et al. 1996, 1998), which showed that a premature stimulus could produce regional differences in recovery. An important feature of this finding is that wavebreak and re-entry can be produced by this mechanism for tissue with both steep (slope > 1) and shallow (slope < 1) APD restitution (Clayton & Taggart, 2005). As well as influencing the initiation of re-entry, we have also shown that heterogeneous restitution can influence the stability of re-entry. Our preliminary results presented in Fig. 9 suggest that the location of the tip of the re-entrant wave plays an important role, with other factors, including the size of the heterogeneity and the meander pattern of the tip, contributing to the stability. More detailed studies are needed to understand how these components interact, because stability may also be moderated by propagation of action potentials far from the tip of a re-entrant wave (Fenton et al. 2002). However, our overall finding, that heterogeneity is important for stability, is in agreement with those of others who have simulated the behaviour of re-entry in heterogeneous atrial tissue (Vigmond et al. 2004; Zou et al. 2005).
Limitations of the modelling. In the modelling part of this study, we chose to use a greatly simplified model of cardiac tissue. The model had an APD of around 145 ms at long DI. Although this is around 100 ms shorter than the APDs observed in the experimental part of this study, the key idea behind the modelling study is that regional differences in APD restitution are arrhythmogenic, and we have shown elsewhere that this mechanism is independent both of APD and of APD restitution slope (Clayton & Taggart, 2005). In our model, we imposed sharp boundaries between regions with different APD restitution. In real tissue, boundaries arising from regional differences in ion channel expression or remodelling are likely to be smooth, and further studies are needed to examine how smooth boundaries could affect the initiation and stability of re-entry. In addition, we used a simplified model of membrane excitability, our simulations were limited to a 2-D tissue sheet, and we neglected the effects of tissue contraction.
Although these simplifications do limit the extent to which the findings of the modelling study can be applied to the human heart, this approach was valuable because it enabled us to study how a single mechanism (heterogeneous APD restitution) influences the initiation and stability of re-entry in isolation. The present study therefore illustrates the value of combining a carefully chosen computational model with experiment. The experiments showed that APD restitution properties in the human heart are spatially heterogeneous. The computer modelling studies showed that the juxtaposition of restitution curves with different slopes facilitated wavebreak and degeneration of VT to VF irrespective of whether the steepness of the slopes was greater than 1 or less than 1. Thus, although recent interest in the arrhythmogenic potential of APD restitution has focused on whether the slope is greater or less than 1 (a slope of greater than 1 being considered profibrillatory, and less than 1 tending to stabilize re-entrant rotors), the combined modelling and observational data suggest that spatial heterogeneity may be of equal importance to the APD restitution slope. Whilst providing observational data on human heart electrophysiology, our experiments on their own do not elucidate the mechanisms of arrhythmogenesis. Moreover, the computer modelling in the absence of the clinical profile would have limited value. However, their combination provides a step forwards in our understanding of arrhythmogenesis in human hearts.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Antzelevitch C, Sicouri S, Litovsky SH, Lukas A, Krishnan SC, Di Diego JM, Gintant GA & Liu DW (1991). Heterogeneity within the ventricular wall. Electrophysiology and pharmacology of epicardial, endocardial, and M cells. Circ Res 69, 1427–1449.
Banville I & Gray RA (2002). Effect of action potential duration and conduction velocity restitution and their spatial dispersion on alternans and the stability of arrhythmias. J Cardiovasc Electrophysiol 13, 1141–1149.[CrossRef][Medline]
Bjornstad H, Tande PM, Lathrop DA & Refsum H (1993). Effects of temperature on cycle length dependent changes and restitution of action potential duration in guinea pig ventricular muscle. Cardiovasc Res 27, 946–950.[Medline]
Boyett MR & Jewell BR (1978). A study of the factors responsible for rate-dependent shortening of the action potential in mammalian ventricular muscle. J Physiol 285, 359–380.
Clayton RH & Holden AV (2002). A method to quantify the dynamics and complexity of re-entry in computational models of ventricular fibrillation. Physics Med Biol 47, 225–238.[CrossRef][Medline]
Clayton RH & Taggart P (2005). Regional differences in APD restitution can initiate wavebreak and re-entry in cardiac tissue: a computational study. Biomed Eng Online 4, 54.[CrossRef][Medline]
Dilly SG & Lab MJ (1988). Electrophysiological alternans and restitution during acute regional ischaemia in myocardium of anaesthetized pig. J Physiol 402, 315–333.
Fenton FH, Cherry EM, Hastings HM & Evans SJ (2002). Multiple mechanisms of spiral wave breakup in a model of cardiac electrical activity. Chaos 12, 852–892.[CrossRef][Medline]
Fenton F & Karma A (1998). Vortex dynamics in three-dimensional continuous myocardium with fibre rotation: filament instability and fibrillation. Chaos 8, 20–47.[CrossRef][Medline]
Franz MR, Swerdlow CD, Liem LB & Schaefer J (1988). Cycle length dependence of human action potential duration in vivo. Effects of single extrastimuli, sudden sustained rate acceleration and deceleration, and different steady-state frequencies. J Clin Invest 82, 972–979.[Medline]
Furukawa Y, Miyazaki T, Miyoshi S, Moritani K & Ogawa S (2000). Anisotropic conduction prolongs ventricular repolarization and increases its spatial gradient in the intact canine heart. Jpn Circ J 64, 287–294.[Medline]
Garfinkel A, Kim YH, Voroshilovsky O, Qu Z, Kil JR, Lee MH, Karagueuzian HS, Weiss JN & Chen PS (2000). Preventing ventricular fibrillation by flattening cardiac restitution. Proc Natl Acad Sci U S A 97, 6061–6066.
Gilmour RF Jr & Chialvo DR (1999). Electrical restitution, critical mass, and the riddle of fibrillation. J Cardiovasc Electrophysiol 10, 1087–1089.[Medline]
Goldhaber JI, Xie LH, Duong T, Motter C, Khuu K & Weiss JN (2005). Action potential duration restitution and alternans in rabbit ventricular myocytes: the key role of intracellular calcium cycling. Circ Res 96, 459–466.
Gotoh M, Uchida T, Fan W, Fishbein MC, Karagueuzian HS & Chen PS (1997). Anisotropic repolarization in ventricular tissue. Am J Physiol 272, H107–H113.
Han J & Moe GK (1964). Nonuniform recovery of excitability in ventricular muscle. Circ Res 14, 44–60.
Haws CW & Lux RL (1990). Correlation between in vivo transmembrane action potential durations and activation-recovery intervals from electrograms. Effects of interventions that alter repolarization time. Circulation 81, 281–288.
Janse MJ & Wit AL (1989). Electrophysiological mechanisms of ventricular arrhythmias resulting from myocardial ischemia and infarction. Physiol Rev 69, 1049–1169.
Karma A (1994). Electrical alternans and spiral wave breakup in cardiac tissue. Chaos 4, 461–472.[CrossRef][Medline]
Koller ML, Maier SK, Gelzer AR, Bauer WR, Meesmann M & Gilmour RF Jr (2005). Altered dynamics of action potential restitution and alternans in humans with structural heart disease. Circulation 112, 1542–1548.
Kuo CS, Munakata K, Reddy CP & Surawicz B (1983). Characteristics and possible mechanism of ventricular arrhythmia dependent on the dispersion of action potential durations. Circulation 67, 1356–1367.
Lab MJ (2004). Mechanoelectric feedback/transduction: prevalence and pathophysiology. In Cardiac Electrophysiology: from Cell to Bedside, ed. Zipes DP & Jalife J, pp. 242. Saunders, Philadelphia.
Laurita KR, Girouard SD, Akar FG & Rosenbaum DS (1998). Modulated dispersion explains changes in arrhythmia vulnerability during premature stimulation of the heart. Circulation 98, 2774–2780.
Laurita KR, Girouard SD & Rosenbaum DS (1996). Modulation of ventricular repolarization by a premature stimulus. Role of epicardial dispersion of repolarization kinetics demonstrated by optical mapping of the intact guinea pig heart. Circ Res 79, 493–503.
Meghji P, Nazir SA, Dick DJ, Bailey ME, Johnson KJ & Lab MJ (1997). Regional workload induced changes in electrophysiology and immediate early gene expression in intact in situ porcine heart. J Mol Cell Cardiol 29, 3147–3155.[CrossRef][Medline]
Morgan JM, Cunningham D & Rowland E (1992). Dispersion of monophasic action potential duration: demonstrable in humans after premature ventricular extrastimulation but not in steady state. J Am Coll Cardiol 19, 1244–1253.[Abstract]
Nash MP, Bradley CP & Paterson DJ (2003). Imaging electrocardiographic dispersion of depolarization and repolarization during ischemia: simultaneous body surface and epicardial mapping. Circulation 107, 2257–2263.
Nash MP & Panfilov AV (2004). Electromechanical model of excitable tissue to study reentrant cardiac arrhythmias. Prog Biophys Mol Biol 85, 501–522.[CrossRef][Medline]
Nash MP, Thornton JM, Sears CE, Varghese A, O'Neill M & Paterson DJ (2001). Ventricular activation during sympathetic imbalance and its computational reconstruction. J Appl Physiol 90, 287–298.
Nolasco JB & Dahlen RW (1968). A graphic method for the study of alternation in cardiac action potentials. J Appl Physiol 25, 191–196.
Pak HN, Hong SJ, Hwang GS, Lee HS, Park SW, Ahn JC, Moo Ro Y & Kim YH (2004). Spatial dispersion of action potential duration restitution kinetics is associated with induction of ventricular tachycardia/fibrillation in humans. J Cardiovasc Electrophysiol 15, 1357–1363.[CrossRef][Medline]
Pastore JM, Girouard SD, Laurita KR, Akar FG & Rosenbaum DS (1999). Mechanism linking T-wave alternans to the genesis of cardiac fibrillation. Circulation 99, 1385–1394.
Qu Z, Garfinkel A, Chen PS & Weiss JN (2000). Mechanisms of discordant alternans and induction of reentry in simulated cardiac tissue. Circulation 102, 1664–1670.
Qu Z, Weiss JN & Garfinkel A (1999). Cardiac electrical restitution properties and stability of reentrant spiral waves: a simulation study. Am J Physiol 276, H269–H283.
Rosenbaum DS, Kaplan DT, Kanai A, Jackson L, Garan H, Cohen RJ & Salama G (1991). Repolarization inhomogeneities in ventricular myocardium change dynamically with abrupt cycle length shortening. Circulation 84, 1333–1345.
Sampson KJ & Henriquez CS (2001). Simulation and prediction of functional block in the presence of structural and ionic heterogeneity. Am J Physiol Heart Circ Physiol 281, H2597–H2603.
Sanders GD, Hlatky MA & Owens DK (2005). Cost-effectiveness of implantable cardioverter-defibrillators. N Engl J Med 353, 1471–1480.
Taggart P, Sutton PM, Boyett MR, Lab M & Swanton H (1996). Human ventricular action potential duration during short and long cycles. Rapid modulation by ischemia. Circulation 94, 2526–2534.
Taggart P, Sutton P, Chalabi Z, Boyett MR, Simon R, Elliott D & Gill JS (2003). Effect of adrenergic stimulation on action potential duration restitution in humans. Circulation 107, 285–289.
Taggart P, Sutton PM, Treasure T, Lab M, O'Brien W, Runnalls M, Swanton RH & Emanuel RW (1988). Monophasic action potentials at discontinuation of cardiopulmonary bypass: evidence for contraction-excitation feedback in man. Circulation 77, 1266–1275.
Tan LB (1996). SWORD trial of d-sotalol. Lancet 348, 827–828.[Medline]
Vigmond E, Tsoi V, Kuo S, Arevalo H, Kneller J, Nattel S & Trayanova N (2004). The effect of vagally induced dispersion of action potential duration on atrial arrhythmogenesis. Heart Rhythm 1, 334–344.
Watanabe MA, Fenton FH, Evans SJ, Hastings HM & Karma A (2001). Mechanisms for discordant alternans. J Cardiovasc Electrophysiol 12, 196–206.[CrossRef][Medline]
Weiss JN, Garfinkel A, Karagueuzian HS, Qu Z & Chen PS (1999). Chaos and the transition to ventricular fibrillation: a new approach to antiarrhythmic drug evaluation. Circulation 99, 2819–2826.
Xie F, Qu Z, Garfinkel A & Weiss JN (2001a). Electrophysiological heterogeneity and stability of reentry in simulated cardiac tissue. Am J Physiol Heart Circ Physiol 280, H535–H545.
Xie F, Qu Z, Weiss JN & Garfinkel A (2001b). Coexistence of multiple spiral waves with independent frequencies in a heterogeneous excitable medium. Phys Rev E Stat Nonlin Soft Matter Phys 63, 031905.[Medline]
Yue AM, Franz MR, Roberts PR & Morgan JM (2005). Global endocardial electrical restitution in human right and left ventricles determined by noncontact mapping. J Am Coll Cardiol 46, 1067–1075.
Yue AM, Paisey JR, Robinson S, Betts TR, Roberts PR & Morgan JM (2004). Determination of human ventricular repolarization by noncontact mapping: validation with monophasic action potential recordings. Circulation 110, 1343–1350.
Zou R, Kneller J, Leon LJ & Nattel S (2005). Substrate size as a determinant of fibrillatory activity maintenance in a mathematical model of canine atrium. Am J Physiol Heart Circ Physiol 289, H1002–H1012.
|
Acknowledgements |
|---|
This article has been cited by other articles:
|
|
 |
|
  C. L. del Rio, T. A. Dawson, B. D. Clymer, D. J. Paterson, and G. E. Billman Effects of acute vagal nerve stimulation on the early passive electrical changes induced by myocardial ischaemia in dogs: heart rate-mediated attenuation Exp Physiol, August 1, 2008; 93(8): 931 - 944. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. M. Narayan and M. R. Franz Reply J. Am. Coll. Cardiol., April 29, 2008; 51(17): 1722 - 1723. [Full Text] [PDF]
|
|
|
|
|
|
M. Hayashi, S. Takatsuki, P. Maison-Blanche, A. Messali, A. Haggui, P. Milliez, A. Leenhardt, and F. Extramiana Ventricular Repolarization Restitution Properties in Patients Exhibiting Type 1 Brugada Electrocardiogram With and Without Inducible Ventricular Fibrillation J. Am. Coll. Cardiol., March 25, 2008; 51(12): 1162 - 1168. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P.-S. Chen and S. G. Priori The Brugada Syndrome J. Am. Coll. Cardiol., March 25, 2008; 51(12): 1176 - 1180. [Full Text] [PDF]
|
|
|
|
 |
|
