Action Potential Duration Restitution Curve Research Articles

Regional differences in APD restitution can initiate wavebreak and re-entry in cardiac tissue: A computational study

BackgroundRegional differences in action potential duration (APD) restitution in the heart favour arrhythmias, but the mechanism is not well understood.MethodsWe simulated a 150 × 150 mm 2D sheet of cardiac ventricular tissue using a simplified computational model. We investigated wavebreak and re-entry initiated by an S1S2S3 stimulus protocol in tissue sheets with two regions, each with different APD restitution. The two regions had a different APD at short diastolic interval (DI), but similar APD at long DI. Simulations were performed twice; once with both regions having steep (slope > 1), and once with both regions having flat (slope < 1) APD restitution.ResultsWavebreak and re-entry were readily initiated using the S1S2S3 protocol in tissue sheets with two regions having different APD restitution properties. Initiation occurred irrespective of whether the APD restitution slopes were steep or flat. With steep APD restitution, the range of S2S3 intervals resulting in wavebreak increased from 1 ms with S1S2 of 250 ms, to 75 ms (S1S2 180 ms). With flat APD restitution, the range of S2S3 intervals resulting in wavebreak increased from 1 ms (S1S2 250 ms), to 21 ms (S1S2 340 ms) and then 11 ms (S1S2 400 ms).ConclusionRegional differences in APD restitution are an arrhythmogenic substrate that can be concealed at normal heart rates. A premature stimulus produces regional differences in repolarisation, and a further premature stimulus can then result in wavebreak and initiate re-entry. This mechanism for initiating re-entry is independent of the steepness of the APD restitution curve.

Head-tail interactions in numerical simulations of reentry in a ring of cardiac tissue

The relationships between action potential duration (APD) and conduction velocity (CV) to the previous diastolic interval (DI) are known as the APD and CV restitution relationships. There is considerable debate regarding the importance of these relationships in the development and stability of reentry. The purpose of this study was to increase the understanding of the ionic basis for restitution during reentry. APD and CV were studied numerically during one-dimensional reentry as ring length (L) was shortened. A three-state variable model (u, v, w) was used to analyze the effect of gating variables of the fast (v) and slow (w) currents on the spatial and temporal dynamics of transmembrane potential (u). Three parameter sets were used corresponding to three APD and CV restitution curves. Sustained spatial oscillations of APD and CV larger than the ring length were observed in two of the parameter sets (cytochalasin-D model [CYTO] and model 3 [M3]) before block occurred at L = 6 cm. The last model (diacetyl monoxime [DAM]) resulted in uniform APD and CV for all L until block occurred at L = 3 cm. Multivalued APD and CV restitution relationships due to "dephasing" of w and v with DI were observed in M3 and CYTO simulations. Overall, these dynamics could be explained by the wavelength-to-ring length ratio and the sensitivity of APD on the value of the gating variables w and v. Propagation stability is mostly controlled by APD sensitivity to w, but the APD restitution slope does not always reflect this sensitivity. The interaction of the dynamic history (i.e., memory) of the fast and slow currents and electrotonic effects resulted in multivalued restitution curves.

On the mechanisms for the conversion of ventricular fibrillation to tachycardia by perfusion with ruthenium red

We have recently demonstrated that during pacing-induced sustained ventricular fibrillation (VF), perfusion of the heart with either ruthenium red (RR) or Ru 360, blockers of the mitochondrial Ca 2+ uniporter, resulted in the reversible conversion of VF to ventricular tachycardia (VT). Here, we aimed at elucidating the electrophysiological mechanisms for the RR-induced conversion of VF to VT. The experiments were performed using Langendorff-perfused isolated rat hearts in which left ventricular pressure and left ventricular intracellular action potential were recorded. Perfusion with either RR or Ru 360 resulted in decreases in the action potential duration (APD), refractory period, and slope of APD restitution curves. These changes were antagonized by cotreatment with S(−)-Bay K8644. In addition, perfusion with verapamil produced the decreases in APD at 90% repolarization, refractory period and slope of APD restitution curves similar to the RR or Ru 360 perfusion. Such electrophysiological changes may be responsible for the reversible conversion of sustained VF to VT caused by perfusion with RR or Ru 360.

The role of action potential duration restitution in vulnerability to reentry in a mathematical model of canine ventricle

The mechanism of initiation of ventricular fibrillation (VF) in normal and diseased heart is poorly understood. It has been shown that VF starts with a simple reentry, or ventricular tachycardia (VT), which then degenerates into the multiple meandering wavelets that characterize VF. Although a steeply-sloped action potential duration restitution (APDR) curve promotes the transition of VT to VF, its role in the initiation of reentry is less clear. We performed a comprehensive study using a detailed anatomic model of the canine heart to investigate the role of APDR in initiating reentry by a single extrastimulus (S2). In normal heart, S2 beats failed to initiate reentry with either steep or flat APDR. However, when diseased heart was simulated by adding an ischemic region (modeled by lowered excitability due to increased extracellular potassium), reentry was more easily induced by an S2 when APDR slope was steep (left figure). Flattening APDR reduced the “vulnerability window,” defined as the set of S2 intervals for which reentry was induced (right figure, black bars), from 60msec to 30msec. (White bars indicate that a propagated beat was initiated by S2 without reentry, gray bars indicate that the S2 beat failed to propagate). Flattening APDR may therefore be a promising therapy for preventing both initiation of reentry and the subsequent transition from VT to VF.

An Intimate Relationship

We last offered our ideas on the role of reverse EC coupling in the initiation of arrhythmias in 2001.1 At that time we emphasized that spurious Ca2+ release or oscillations in Ca2+ levels could serve as possible triggers for arrhythmias. Since then much has been done to confirm this role for intracellular Ca2+. At that time we did not discuss the role of Ca2+ cycling in the maintenance or conversion of stable tachycardias to VF. However, in consideration of the new data on the role of APD restitution in the initiation of VF (increase in wavebreaks; eg, see Garfinkel et al2), we turn our attention now to the role Ca2+ cycling in the myocyte and its impact on APD restitution relations in the isolated rabbit ventricular cell.3 Goldhaber et al consider the role of Ca2+ using different types of APD restitution protocols to emphasize the dynamic nature of intracellular Ca2+ changes and its subsequent impact on the myocyte APD. In their study APD alternans is coupled to Ca2+ cycling, which in itself is not new since others have observed that APD alternans demonstrates a hystersis and is inhibited with BAPTA-AM buffering.4 Some have suggested that repolarization alternans is more closely associated …

Action Potential Duration Restitution and Alternans in Rabbit Ventricular Myocytes

Action potential duration (APD) restitution properties and repolarization alternans are thought to be important arrhythmogenic factors. We investigated the role of intracellular calcium (Ca2+i) cycling in regulating APD restitution slope and repolarization (APD) alternans in patch-clamped rabbit ventricular myocytes at 34 to 36 degrees C, using the perforated or ruptured patch clamp techniques with Fura-2-AM to record Ca2+i. When APD restitution was measured by either the standard extrastimulus (S1S2) method or the dynamic rapid pacing method, the maximum APD restitution slope exceeded 1 by both methods, but was more shallow with the dynamic method. These differences were associated with greater Ca2+i accumulation during dynamic pacing. The onset of APD alternans occurred at diastolic intervals at which the APD restitution slope was significantly <1 and was abolished by suppressing sarcoplasmic reticulum (SR) Ca2+i cycling with thapsigargin and ryanodine, or buffering the global Ca2+i transient with BAPTA-AM or BAPTA. Thapsigargin and ryanodine flattened APD restitution slope to <1 when measured by the dynamic method, but not by the S1S2 method. BAPTA-AM or BAPTA failed to flatten APD restitution slope to <1 by either method. In conclusion, APD alternans requires intact Ca2+i cycling and is not reliably predicted by APD restitution slope when Ca2+i cycling is suppressed. Ca2+i cycling may contribute to differences between APD restitution curves measured by S1S2 versus dynamic pacing protocols by inducing short-term memory effects related to pacing-dependent Ca2+i accumulation.

Antifibrillatory and Proarrhythmic Effects of d,l-Sotalol Mediated by the Action Potential Duration Restitution Kinetics

Background and Objectives：The action potential duration (APD) restitution kinetics has been known to play a crucial role in the initiation and maintenance of ventricular tachycardia (VT)/fibrillation (VF). We hypothesized that “the anti-arrhythmic and proarrhythmic effects of d,l-sotalol are mediated by changing the APD restitution (APDR) kinetics”. Materials and Methods：The purposes of this study were: 1) to assess the effects of d,lsotalol on the APDR kinetics, and 2) to correlate the anti-arrhythmic and proarrhythmic action using the APDR kinetics. We recorded the transmembrane potentials (TMPs), using the microelectrode technique, in seven isolated perfused swine right ventricles, at the baseline, and with 1, 5, 10 and 20 mg/L of d,l-sotalol, with a washout period of 1 hour. The ventricular effective refractory periods (VERP), APD at 90% repolarization (APD90), spontaneous defibrillation rate and VF inducibility were measured at each concentration. We plotted APDR curves of S1-S2 pacing against VF, and calculated the maximal slopes (Smax) of the APDR. Results： Sotalol (10 mg/L) prolonged the APD90 (p<0.001) by reducing the Smax of the APDR (by S1-S2 pacing, p<0.01; during VF, p<0.05). Accordingly, 41.7% of the VT/VF was terminated spontaneously, and VT/VF inducibility reduced from 91.1% at the baseline to 25% with 10 mg/L sotalol. A higher dose of sotalol (20 mg/L) increased the Smax, despite continuous prolongation of the VERP and APD90, resulting in the increase in the VT/VF inducibility (36.4%). Conclusion：Sotalol produces its anti-fibrillatory effect by APD prolongation in parallel with a flattening of the Smax at therapeutic doses. However, a higher concentration of sotalol increased the Smax and VF inducibility in isolated swine ventricular tissue. (Korean Circulation J 2005;35:282-289)

Rate-dependent propagation of cardiac action potentials in a one-dimensional fiber

Action potential duration (APD) restitution, which relates APD to the preceding diastolic interval (DI), is a useful tool for predicting the onset of abnormal cardiac rhythms. However, it is known that different pacing protocols lead to different APD restitution curves (RCs). This phenomenon, known as APD rate dependence, is a consequence of memory in the tissue. In addition to APD restitution, conduction velocity restitution also plays an important role in the spatiotemporal dynamics of cardiac tissue. We present results concerning rate-dependent restitution in the velocity of propagating action potentials in a one-dimensional fiber. Our numerical simulations show that, independent of the amount of memory in the tissue, the wave-back velocity exhibits pronounced rate dependence and the wave-front velocity does not. Moreover, the discrepancy between wave-back velocity RCs is most significant for a small DI. We provide an analytical explanation of these results, using a system of coupled maps to relate the wave-front and wave-back velocities. Our calculations show that rate-dependent wave-back velocity can be present even if neither APD nor wave-front velocity exhibits rate dependence.

Spatial Dispersion of Action Potential Duration Restitution Kinetics Is Associated with Induction of Ventricular Tachycardia/Fibrillation in Humans

Action potential duration restitution (APDR) plays a role in initiation and maintenance of ventricular tachycardia (VT)/ventricular fibrillation (VF). We hypothesized that the steeply sloped APDR and its spatial heterogeneity contribute to VT/VF inducibility in patients with ventricular arrhythmia. After programmed ventricular stimulation (PVS) for evaluation of clinically documented VT, patients (n = 20, 15 male, age 52.5 +/- 9.5 years) were divided into two groups: inducible sustained VT/VF (IVT, n = 10) and noninducible VT/VF (NVT, n = 10). Data were compared with the corresponding results obtained from normal controls (C, n = 10). Right ventricular (RV) monophasic action potential duration at 90% repolarization (APD90) and ventricular effective refractory period (VERP) in the right ventricular apex (RVA) and right ventricular outflow tract (RVOT) were determined. APDR was acquired by scanning diastole with premature ventricular beats during a pacing cycle length of 600 msec (S1-S2) in all patients and by rapid pacing at the cycle lengths that induced APD alternans in three patients. Maximal slopes (Smax) of the APDR curves and DeltaAPD90 (APD90 at S2 400 ms - APD90 at the shortest S2) were measured. VERP and APD90 at each RV site did not differ among the three groups. Smax obtained by S1-S2 (1.6 +/- 0.6) did not differ from Smax obtained by rapid pacing (1.2 +/- 0.7), with a significant correlation noted between these values (r = 0.92, P < 0.01). The IVT group had a higher spatial dispersion of Smax (Smax at RVOT - Smax at RVA) compared to the C group (P < 0.05), with no difference between the NVT group and the IVT or C groups. The IVT group had a higher spatial dispersion of DeltaAPD90 compared to the NVT and C groups (P < 0.01, respectively). Smax at the RVOT (2.7 +/- 1.9) was steeper than that at the RVA (1.9 +/- 1.2, P < 0.05). Inducibility of sustained VT/VF was greater at the RVOT (83.3%) than at the RVA (50.0%, P < 0.05). In patients with ventricular arrhythmia, VT/VF is highly inducible under conditions of greater spatial dispersion of ventricular refractoriness and APDR.

Dynamical effects of diffusive cell coupling on cardiac excitation and propagation: a simulation study.

Cell coupling is considered to be important for cardiac action potential propagation and arrhythmogenesis. We carried out computer simulations to investigate the effects of stimulation strength and cell-to-cell coupling on action potential duration (APD) restitution, APD alternans, and stability of reentry in models of isolated cell, one-dimensional cable, and two-dimensional tissue. Phase I formulation of the Luo and Rudy action potential model was used. We found that stronger stimulation resulted in a shallower APD restitution curve and onset of APD alternans at a faster pacing rate. Reducing diffusive coupling between cells prolonged APD. Weaker diffusive currents along the direction of propagation steepened APD restitution and caused APD alternans to occur at a slower pacing rate in tissue. Diffusive current due to curvature changed APD but had little effect on APD restitution slope and onset of instability. Heterogeneous cell coupling caused APD inhomogeneities in space. Reduction in coupling strength either uniformly or randomly had little effect on the rotation period and stability of a reentry, but random cell decoupling slowed the rotation period and, thus, stabilized the reentry, preventing it from breaking up into multiple waves. Therefore, in addition to its effects on action potential conduction velocity, diffusive cell coupling also affects APD in a rate-dependent manner, causes electrophysiological heterogeneities, and thus modulates the dynamics of cardiac excitation. These effects are brought about by the modulation of ionic current activation and inactivation.

Restitution dynamics during pacing and arrhythmias in isolated pig hearts.

The dependence of action potential duration (APD) on the preceding diastolic interval (DI), i.e., restitution, has been purported to predict the development of alternans and reentrant arrhythmias. However, restitution depends on the history of activation (i.e., memory), and its relevance to arrhythmia induction and maintenance is unknown. Using a dual-camera video imaging system, we recorded action potentials from thousands of sites on the surface of the isolated pig heart. A steady-state pacing (SSP) protocol was performed to generate the SSP APD restitution curve. During SSP, the minimum DI and APD were 57 +/- 6 ms and 107 +/- 6 ms, respectively. The restitution slope was >1 for DIs <85 +/- 5 ms; however, alternans were not observed. Abrupt decreases in cycle length (CL) resulted in a rapid (<5 beats) decrease in APD followed by a slower decrease to "steady state." DI, APD pairs for the initial beats following these rate changes were significantly above the SSP restitution curve. DI, APD pairs measured during sustained ventricular fibrillation clustered significantly below the SSP restitution curve, at significantly shorter APDs (57 +/- 4 ms) and DIs (49 +/- 6 ms) than could be achieved during SSP. In addition, abrupt increases in CL following SSP resulted in APDs significantly shorter than those predicted from the SSP restitution curve. Our results indicate that the responses of APD and DI to sudden rate changes and during arrhythmias are not predicted by the SSP restitution relationship. Acute dynamics act to damp out the proarrhythmic oscillations predicted from the SSP restitution curve.

Effect of beta-adrenergic blockade on dynamic electrical restitution in vivo.

The slope of the action potential duration (APD) restitution curve may be a significant determinant of the propensity to develop ventricular fibrillation, with steeper slopes associated with a more arrhythmogenic substrate. We hypothesized that one mechanism by which beta-blockers reduce sudden cardiac death is by flattening the APD restitution curve. Therefore, we investigated whether infusion of esmolol modulates the APD restitution curve in vivo. In 10 Yorkshire pigs, dynamic APD restitution curves were determined from measurements of APD at 90% repolarization with a monophasic action potential catheter positioned against the right ventricular septum during right ventricular apical pacing in the basal state and during infusion of esmolol. APD restitution curves were fitted to the three-parameter (a, b, c) exponential equation, APD = a.[1 - e((-b.DI))] + c, where DI is the diastolic interval. Esmolol decreased the maximal APD slope, 0.68 +/- 0.14 vs. 0.94 +/- 0.24 (baseline), P = 0.002, and flattened the APD restitution curve at shorter DIs, 75 and 100 ms (P < 0.05). To compare the slopes of the APD restitution curves at similar steady states, slopes were also computed at points of intersection between the restitution curve and the lines representing pacing at a fixed cycle length (CL) of 200, 225, 250, 275, and 300 ms using the relationship CL = APD + DI. Esmolol decreased APD restitution slopes at CLs 200-275 ms (P < 0.05). Esmolol flattens the cardiac APD restitution curve in vivo, particularly at shorter CLs and DIs. This may represent a novel mechanism by which beta-blockers prevent sudden cardiac death.

Suppression of alternans and conduction blocks despite steep APD restitution: electrotonic, memory, and conduction velocity restitution effects.

We examine the utility of the action potential (AP) duration (APD) restitution curve slope in predicting the onset of electrical alternans when electrotonic and memory effects are considered. We develop and use two ionic cell models without memory that have the same restitution curve with slope >1 but different AP shapes and, therefore, different electrotonic effects. We also study a third cell model that incorporates short-term memory of previous cycle lengths, so that it has a family of S1-S2 restitution curves as well as a dynamic restitution curve with slope >1. Our results indicate that both electrotonic and memory effects can suppress alternans, even when the APD restitution curve is steep. In the absence of memory, electrotonic currents related to the shape of the AP, as well as conduction velocity restitution, can affect how alternans develops in tissue and, in some cases, can prevent its induction entirely, even when isolated cells exhibit alternans. When short-term memory is included, alternans may not occur in isolated cells, despite a steep APD restitution curve, and may or may not occur in tissue, depending on conduction velocity restitution. We show for the first time that electrotonic and memory effects can prevent conduction blocks and stabilize reentrant waves in two and three dimensions. Thus we find that the slope of the APD restitution curve alone does not always well predict the onset of alternans and that incorporating electrotonic and memory effects may provide a more useful alternans criterion.

Catheter ablation of ventricular fibrillation in rabbit ventricles treated with beta-blockers.

A therapeutic implication of the focal-source hypothesis of ventricular fibrillation (VF) is that VF can be terminated by focal ablation. We hypothesize that beta-adrenergic receptor blockade converts multiple-wavelet VF to focal-source VF and that this focal source is located near the papillary muscle (PM). We used optical mapping techniques to study the effects of propranolol (0.3 mg/L) on VF dynamics in Langendorff-perfused rabbit hearts. The left ventricular (LV) anterior wall was mapped and optical action potential duration restitution (APDR) was determined at 25 epicardial sites. We performed ablation during VF of the left anterior PM in hearts with (N=6) or without (N=6) cytochalasin infusion, the LV lateral epicardium (Epi group, N=3), and the LV endocardium (Endo group, N=3). The PM was also ablated in 3 hearts without propranolol (control group). Propranolol converted multiple-wavelet VF to slow VF with reentry localized to the PM. Propranolol decreased the maximal slope of the APDR curve (P<0.001) as well as its spatial heterogeneity (P<0.01) and conduction velocity (P=0.01) while increasing the VF cycle length (P<0.001). PM ablation terminated VF during propropranolol infusion with (6 of 6, 100%) or without (4 of 6, 67%) cytochalasin D and significantly reduced inducibility. VF did not terminate in the Epi, Endo, and control groups (P<0.001). Propranolol flattens the APDR curve and reduces conduction velocity, converting multiple-wavelet VF into VF with a focal source anchored to the PM. Ablation of this focal source may terminate VF.

Effects of cytochalasin D on electrical restitution and the dynamics of ventricular fibrillation in isolated rabbit heart.

Cytochalasin D in Rabbit Ventricle. Cytochalasin D (cyto-D) has been used as an excitation-contraction uncoupler during optical mapping studies. However, its effects on action potential duration restitution (APDR) and dynamics during ventricular fibrillation (VF) are unclear. Langendorff-perfused rabbit hearts (N = 6) were immersed in a tissue chamber. Transmembrane potential was recorded using glass microelectrodes. APD measured to 90% repolarization (APD90) was used to construct the APDR curve. During regular pacing at 300-msec cycle length, increasing concentrations of cyto-D resulted in progressively prolonged APD90 (131 +/- 26 msec, 171 +/- 14 msec, and 177 +/- 14 msec) and steepened maximum slope of the APDR curve (1.1 +/- 0.2, 1.3 +/- 0.2, and 1.6 +/- 0.4 for control, 5 micromoles, and 10 micromoles, respectively; P < 0.01). Resting membrane potential, AP amplitude, and maximum dV/dt did not change. Cyto-D lengthened VF cycle length and APD90, and steepened the maximum slope of the APDR curve. However, cyto-D did not significantly change the diastolic interval. The dominant frequency of pseudoelectrocardiogram progressively decreased with increasing concentrations of cyto-D (15.2 +/- 0.6 Hz, 11.1 +/- 2.4 Hz, and 9.8 +/- 3.2 Hz for control, 5 micromoles, and 10 micromoles, respectively; P < 0.01). Sustained (>1 min) VF was repeatedly inducible at baseline and with 5 or 10 micromoles of cyto-D. Continuous perfusion of cyto-D at 5 or 10 micromoles prolonged APD90, steepened APDR slope, and reduced dominant frequency in rabbit ventricles. Cyto-D at these concentrations allowed induction of sustained VF.

Spiral wave stability in cardiac tissue with biphasic restitution

Human ventricular tissue as well as several animal ventricular preparations show a biphasic shape of the action potential duration restitution curve, with a local maximum at low diastolic intervals. We study numerically how the location and properties of this nonmonotonicity affect the stability of spiral waves. We find that, depending on the slopes of the ascending and of the descending parts of the restitution curve, we can have either stable rotation of the spiral wave or spiral breakup. We identify two types of spiral breakup: one due to a steep positive slope and another due to a steep negative slope in the restitution curve. We discuss the differences in their manifestation and possible implications. We also find that increasing the slope of the descending part of the restitution curve increases the meandering of the spiral wave, due to the repeated occurrence of conduction blocks near the spiral wave tip.

Effect of action potential duration and conduction velocity restitution and their spatial dispersion on alternans and the stability of arrhythmias.

The slope of the action potential duration (APD) restitution curve has been used to explain wavebreaks during arrhythmia initiation and maintenance. This hypothesis remains incomplete to fully describe the experimental data. Other factors contributing to wavebreaks must be studied to further understand arrhythmia dynamics. Control APDs were measured from isolated rabbit hearts using a monophasic action potential probe. APD and conduction velocity (CV) restitution were quantified over the heart surface for two drugs, diacetyl monoxime (DAM) and cytochalasin D (CytoD), using a dual camera video imaging system. For all pacing intervals: (1) control APDs were shorter than for CytoD but longer than for DAM; and (2) CV was greater for CytoD compared with DAM. APD dispersion increased as pacing interval decreased for both drugs. For DAM, increased dispersion was due to a difference in APD restitution between the right and left ventricle. For CytoD, increased dispersion was due to discordant alternans, with no significant spatial variation in restitution. Fibrillation was sustained only in the control hearts; with DAM, stable reentry was sustained with shorter APD and cycle length compared with CytoD for which only nonsustained unstable reentry occurred. Alternans and arrhythmia dynamics are affected by the spatial dispersion of APD restitution as well as CV restitution, not simply the slope of APD restitution. Therefore, a direct link of the APD restitution slope to alternans and arrhythmia dynamics in rabbit heart does not exist. Designing antiarrhythmic drugs to alter only the restitution slope may not be appropriate.

Resetting and annihilation of reentrant activity in a model of a one-dimensional loop of ventricular tissue.

Resetting and annihilation of reentrant activity by a single stimulus pulse (S1) or a pair (S1-S2) of coupled pulses are studied in a model of one-dimensional loop of cardiac tissue using a Beeler-Reuter-type ionic model. Different modes of reentry termination are described. The classical mode of termination by unidirectional block, in which a stimulus produces only a retrograde front that collides with the activation front of the reentry, can be obtained for both S1 and S1-S2 applied over a small vulnerable window. We demonstrate that another scenario of termination-that we term collision block-can also be induced by the S1-S2 protocol. This scenario is obtained over a much wider range of S1-S2 coupling intervals than the one leading to a unidirectional block. In the collision block, S1 produces a retrograde front, colliding with the activation front of the pre-existing reentry, and an antegrade front propagating in the same direction as the initial reentry. Then, S2 also produces an antegrade and a retrograde front. However, the propagation of these fronts in the spatial profile of repolarization left by S1 leads to a termination of the reentrant activity. More complex behaviors also occur in which the antegrade fronts produced by S1 and S2 both persist for several turns, displaying a growing alternation in action potential duration ("alternans amplification") that may lead to the termination of the reentrant activity. The hypothesis that both collision block and alternans amplification depend on the interaction between the action potential duration restitution curve and the recovery curve of conduction velocity is supported by the fact that the dynamical behaviors were reproduced using an integro-delay equation based on these two properties. We thus describe two new mechanisms (collision block and alternans amplification) whereby electrical stimulation can terminate reentrant activity. (c) 2002 American Institute of Physics.

Restitution curves and the stability of reentry in three-dimensional simulations of cardiac tissue

Recent studies have shown that cardiac antiarrhythmic drugs may actually increase mortality in certain instances. Due to the failure of the premise that an increased refractory period alone is sufficient to provide protection, it has been posited that the slope of the action potential duration (APD) restitution curve is a critical factor in the deterioration of tachycardia into fibrillation suggesting another avenue to explore in developing new antiarrhythmic drugs. This paper examines the relationship between APD restitution curves and the breakdown of stable reentry into fibrillation in a three dimensional model of a slab of cardiac tissue. The Luo–Rudy I model was used to describe the ionic current. Three different methods were used to measure the restitution curve: the standard protocol, the dynamic protocol and that measured directly, the natural restitution curve. The effects of altering conductances and time constants controlling the individual ionic currents on restitution and breakdown were determined. Manouevres which decreased action potential duration decreased the slope of the restitution curve. Consequently, reducing the slope of the restitution curve led to scroll waves which were more stable, taking longer time to break up. The restitution curves as measured by each of the different methods differed from each other as did restitution curves computed from two-dimensional sheets of tissue. Restitution curves produced by the standard and dynamic protocols defined an envelope in which the natural restitution curve was found to lie. From single cell experiments one could not determine whether the activity would break up by examining the peak slope of the restitution curve or the region of the slope above one, although the latter tended to correlate better with the simulated activity. This result suggests that the medium plays an important role in determining what behaviour gets expressed. Finally, the best route for preventing the breakdown of tachycardia into fibrillation would be to increase the kinetics of the slow inward current since it decreases the APD the least.

Sildenafil-nitric oxide donor combination promotes ventricular tachyarrhythmias in the swine right ventricle.

We tested the hypothesis that sildenafil, singly or in combination with nitric oxide (NO) donors, promotes ventricular tachycardia (VT) and ventricular fibrillation (VF). Vulnerability to VT/VF was tested by rapid pacing in eight isolated normal swine right ventricles (RV). The endocardial activation was optically mapped, and the dynamic action potential duration (APD) restitution curves were constructed with metal microelectrodes. At baseline, no VT/VF could be induced. Sildenafil (0.2 microg/ml) or NO donor singly or in combination did not alter VT/VF vulnerability. However, when 2 microg/ml sildenafil was combined with NO donors, the incidence of VT and VF rose significantly (P < 0.01). VT with a single periodic wavefront was induced in five of eight RVs, and VF with multiple wavefronts was induced in all eight RVs. The sildenafil-NO donor pro-VT/VF combination significantly increased the maximum slope of the APD restitution curve and the amplitude of the APD alternans. The pro-VT/VF effects of sildenafil were reversible after drug-free Tyrode solution perfusion. We conclude that a sildenafil (2 microg/ml) and NO donor combination increases VT/VF vulnerability in the normal RV by a mechanism compatible with the restitution hypothesis.