Maintenance Of Ventricular Fibrillation Research Articles

Influence of channel subunit composition on L-type Ca2+ current kinetics and cardiac wave stability

Previous studies have demonstrated that the slope of the function relating the action potential duration (APD) and the diastolic interval, known as the APD restitution curve, plays an important role in the initiation and maintenance of ventricular fibrillation. Since the APD restitution slope critically depends on the kinetics of the L-type Ca(2+) current, we hypothesized that manipulation of the subunit composition of these channels may represent a powerful strategy to control cardiac arrhythmias. We studied the kinetic properties of the human L-type Ca(2+) channel (Ca(v)1.2) coexpressed with the alpha(2)delta-subunit alone (alpha(1C) + alpha(2)delta) or in combination with beta(2a), beta(2b), or beta(3) subunits (alpha(1C) + alpha(2)delta + beta), using Ca(2+) as the charge carrier. We then incorporated the kinetic properties observed experimentally into the L-type Ca(2+) current mathematical model of the cardiac action potential to demonstrate that the APD restitution slope can be selectively controlled by altering the subunit composition of the Ca(2+) channel. Assuming that beta(2b) most closely resembles the native cardiac L-type Ca(2+) current, the absence of beta, as well as the coexpression of beta(2a), was found to flatten restitution slope and stabilize spiral waves. These results imply that subunit modification of L-type Ca(2+) channels can potentially be used as an antifibrillatory strategy.

Remodelling of action potential and intracellular calcium cycling dynamics during subacute myocardial infarction promotes ventricular arrhythmias in Langendorff‐perfused rabbit hearts

We hypothesize that remodelling of action potential and intracellular calcium (Ca(i)) dynamics in the peri-infarct zone contributes to ventricular arrhythmogenesis in the postmyocardial infarction setting. To test this hypothesis, we performed simultaneous optical mapping of Ca(i) and membrane potential (V(m)) in the left ventricle in 15 rabbit hearts with myocardial infarction for 1 week. Ventricular premature beats frequently originated from the peri-infarct zone, and 37% showed elevation of Ca(i) prior to V(m) depolarization, suggesting reverse excitation-contraction coupling as their aetiology. During electrically induced ventricular fibrillation, the highest dominant frequency was in the peri-infarct zone in 61 of 70 episodes. The site of highest dominant frequency had steeper action potential duration restitution and was more susceptible to pacing-induced Ca(i) alternans than sites remote from infarct. Wavebreaks during ventricular fibrillation tended to occur at sites of persistently elevated Ca(i). Infusion of propranolol flattened action potential duration restitution, reduced wavebreaks and converted ventricular fibrillation to ventricular tachycardia. We conclude that in the subacute phase of myocardial infarction, the peri-infarct zone exhibits regions with steep action potential duration restitution slope and unstable Ca(i) dynamics. These changes may promote ventricular extrasystoles and increase the incidence of wavebreaks during ventricular fibrillation. Whereas increased tissue heterogeneity after subacute myocardial infarction creates a highly arrhythmogenic substrate, dynamic action potential and Ca(i) cycling remodelling also contribute to the initiation and maintenance of ventricular fibrillation in this setting.

Arrhythmogenesis in the heart: Multiscale modeling of the effects of defibrillation shocks and the role of electrophysiological heterogeneity.

The mechanisms of initiation of ventricular arrhythmias as well as those behind the complex spatiotemporal wave dynamics and its filament organization during ventricular fibrillation (VF) are the topic of intense research and debate. Mechanistic inquiry into the various mechanisms that lead to arrhythmia initiation and VF maintenance is hampered by the inability of current experimental techniques to resolve, with sufficient accuracy, electrical behavior confined to the depth of the ventricles. The objective of this article is to demonstrate that realistic 3D simulations of electrical activity in the heart are capable of bringing a new level of understanding of the mechanisms that underlie arrhythmia initiation and subsequent organization. The article does this by presenting the results of two multiscale simulation studies of ventricular electrical behavior. The first study aims to uncover the mechanisms responsible for rendering the ventricles vulnerable to electric shocks during a specific interval of time, the vulnerable window. The second study focuses on elucidating the role of electrophysiological heterogeneity, and specifically, differences in action potential duration in various ventricular structures, in VF organization. Both studies share common multiscale modeling approaches and analysis, including characterization of scroll-wave filament dynamics.

Panoramic Optical Mapping Reveals Continuous Epicardial Reentry during Ventricular Fibrillation in the Isolated Swine Heart

During ventricular fibrillation (VF), activation waves are fragmented and the heart cannot contract synchronously. It has been proposed that VF waves emanate from stable sources (“mother rotors”). Previously, we used new optical mapping technology to image VF wavefronts from nearly the entire epicardial surface of six isolated swine hearts. We found that VF was not driven by epicardial rotors, but could not exclude the presence of stable rotors hidden within the ventricular walls. Here, we use graph theoretic analysis to show that, in all 17 VF episodes we analyzed, it was always possible to trace sequences of wavefronts through series of fragmentation and collision events from the beginning to the end of the episode. The set of wavefronts that were so related (the dominant component) consisted of 92% ± 1% of epicardial wavefronts. Because each such wavefront sequence constitutes a continuous activation front, this finding shows that complete reentrant pathways were always present on the epicardial surface and therefore, that wavefront infusion from nonepicardial sources was not strictly necessary for VF maintenance. These data suggest that VF in this model is not driven by localized sources; thus, new anti-VF treatments designed to target such sources may be less effective than global interventions.

Ventricular Fibrillation

Ventricular fibrillation (VF) is the leading cause of sudden cardiac death. This brief review addresses issues relevant to the dynamics of the rotors responsible for functional reentry and VF. It also makes an attempt to summarize present-day knowledge of the manner in which the dynamic interplay between inward and outward transmembrane currents and the heterogeneous cardiac structure establish a substrate for the initiation and maintenance of rotors and VF. The fragmentary nature of our current understanding of ionic VF mechanisms does not even allow an approach toward a "Theory of VF". Yet some hope is provided by recently obtained insight into the roles played in VF by some of the sarcolemmal ion channels that control the excitation-recovery process. For example, strong evidence supports the idea that the interplay between the rapid-inward sodium current and the inward-rectifier potassium current controls rotor formation, as well as rotor stability and frequency. Solid evidence also exists for an involvement of L-type calcium current in the control of rotor frequency and in determining VF-to-ventricular tachycardia conversion. Less clear, however, is whether or not time dependent outward currents through voltage-gated potassium channels affect the fibrillatory process. Hopefully, taking advantage of currently available approaches of structural, molecular and cellular biology, together with computational and imaging techniques, will afford us the opportunity to further advance knowledge on VF mechanisms.

Human Ventricular Fibrillation

A major controversy in cardiac electrophysiology is whether ventricular fibrillation (VF) is maintained by wandering wavelets or mother rotors. On the basis of a computer model of atrial fibrillation by Moe1 developed in 1962, fibrillation was hypothesized to be maintained by multiple small, wandering wavelets, in which the activation pattern is constantly changing. According to the wandering wavelet hypothesis, fibrillation is maintained by constantly changing reentrant circuits formed by some of the wandering wavelets. Because this random reentry can occur anywhere within the cardiac muscle, this hypothesis suggests that all parts of the ventricular myocardium are equally important for the maintenance of VF. Article p 536 The mother rotor hypothesis was put forward for the maintenance of atrial fibrillation first by Lewis2 and later by Gurvich.3 Recently, this hypothesis has been applied to VF by Jalife’s group.4 This group reported that in isolated guinea pig hearts and in isolated right ventricular slabs of sheep, a long-lived, stationary, stable reentrant circuit that they called a “mother rotor” was present.5,6 The mother rotor gave rise to daughter wavefronts that propagated into the remainder of the myocardium. As opposed to the mother rotor, these daughter wavefronts did not have regular, repeating activation sequences. Instead, activation of the daughter wavefronts was less organized, with changing activation sequences, conduction block, and fractionation. It was these unstable daughter wavefronts that gave rise to the disorganized pattern in the ECG. The region containing the mother rotor had a shorter refractory period than the remainder of the myocardium. Jalife’s group postulated that the reason activation was less organized in the regions outside of the mother rotor was that the longer refractory periods in these regions did not allow them to keep up with the mother rotor, whose cycle length was shorter than their …

P5-26: A novel approach to study the ionic mechanism of action potential duration restitution and its memory effect

The adaptation of action potential duration (APD) during fast pacing and rate changes plays a critical role in the development of ventricular fibrillation (VF). APD restitution slope has been used to explain the initiation and maintenance of VF via alternans. However, different pacing protocols result in different APD restitution curves, a phenomenon known as APD memory. The ionic mechanism of APD rate dependency (APD restitution and its memory effect), as well as the contribution of gating variables and ion concentrations to APD rate dependency, are still not clear.

Cellular Basis for Trigger and Maintenance of Ventricular Fibrillation in the Brugada Syndrome Model: High-Resolution Optical Mapping Study

We examined how repolarization and depolarization abnormalities contribute to the development of extrasystoles and subsequent ventricular fibrillation (VF) in a model of the Brugada syndrome. Repolarization and depolarization abnormalities have been considered to be mechanisms of the coved-type ST-segment elevation (Brugada-electrocardiogram [ECG]) and development of VF in the Brugada syndrome. We used high-resolution (256 x 256) optical mapping techniques to study arterially perfused canine right ventricular wedges (n = 20) in baseline and in the Brugada-ECG produced by administration of terfenadine (5 micromol/l), pinacidil (2 micromol/l), and pilsicainide (5 micromol/l). We recorded spontaneous episodes of phase 2 re-entrant (P2R)-extrasystoles and subsequent self-terminating polymorphic ventricular tachycardia (PVT) or VF under the Brugada-ECG condition and analyzed the epicardial conduction velocity and action potential duration (APD) restitutions in each condition. Forty-one episodes of spontaneous P2R-extrasystoles in the Brugada-ECG were successfully mapped in 9 of 10 preparations, and 33 of them were originated from the maximum gradient of repolarization (GR(max): 176 +/- 54 ms/mm) area in the epicardium, leading to PVT (n = 12) or VF (n = 5). The epicardial GR(max) was not different between PVT and VF. Wave-break during the first P2R-extrasystole produced multiple wavelets in all VF cases, whereas no wave-break or wave-break followed by wave collision and termination occurred in PVT cases. Moreover, conduction velocity restitution was shifted lower and APD restitution was more variable in VF cases than in PVT cases. Steep repolarization gradient in the epicardium but not endocardium develops P2R-extrasystoles in the Brugada-ECG condition, which might degenerate into VF by further depolarization and repolarization abnormalities.

Lifetimes of epicardial rotors in panoramic optical maps of fibrillating swine ventricles

During ventricular fibrillation (VF), electrical activation waves are fragmented, and the heart cannot contract in synchrony. It has been proposed that VF waves emanate from stable periodic sources (often called "mother rotors"). The objective of the present study was to determine if stable rotors are consistently present on the epicardial surface of hearts comparable in size to human hearts. Using new optical mapping technology, we imaged VF from nearly the entire ventricular surface of six isolated swine hearts. Using newly developed pattern analysis algorithms, we identified and tracked VF wave fronts and phase singularities (PS; the pivot point of a reentrant wave front). We introduce the notion of a compound rotor in which the rotor's central PS can change and describe an algorithm for automatically identifying such patterns. This prevents rotor lifetimes from being inappropriately abbreviated by wave front fragmentation and collision events near the PS. We found that stable epicardial rotors were not consistently present during VF: only 1 of 17 VF episodes contained a compound rotor that lasted for the entire mapped interval of 4 s. However, shorter-lived rotors were common; 12.2 (SD 3.3) compound rotors with lifetime >200 ms were visible on the epicardium at any given instant. We conclude that epicardial mother rotors do not drive VF in this experimental model; if mother rotors do exist, they are intramural or septal. This paucity of persistent rotors suggests that individual rotors will eventually terminate by themselves and therefore that the continual formation of new rotors is critical for VF maintenance.

Discovery of gradient pattern in dominant frequency maps during fibrillation: implication of rotor drift and epicardial conduction velocity changes

Dominant frequency (DF) maps for mapping epicardial activations of ventricular fibrillation (VF) have been studied mainly using fast Fourier transform (FFT). Small and discrete DF domains exhibited in these DF maps have undermined the hypothesis of mother rotor for VF maintenance. We applied continuous Fourier transform (CFT) to generate high-precision DF maps and studied characteristics of these high-precision DF maps. Optical epicardial activations were recorded in isolated rabbit hearts (n = 10). Continuous Fourier transform of 1-second segments was performed in VF (n = 188) and ventricular tachycardia (n = 189) at 0.1 Hz precisions. Banded gradient patterns of gradual change in DF values were observed in 136 of 188 VF segments, but not in ventricular tachycardia. These gradients were not observed when FFT was used. Gradients were observed along the conduction path of reentrant-like waves with decreasing DF values along the path. Spectra in the gradients did not exhibit bimodal spectra as is usually observed in traditional DF domain boundaries. Time-space plots revealed clear association between gradient pattern and epicardial conduction velocity changes. Prior simulation studies predicted a gradient in activation rate during rotor drift. This gradient pattern has been observed for the first time experimentally by only using CFT, but not FFT. High-precision DF videos indicated the existence of gradient movement from one spatial location to another, smoothly instead of randomly disappearing from one location and appearing in another. The discovery of associated pseudoconduction velocity changes, and gradient patterns might suggest that dominant rotor (mother rotor) drifting plays a maintenance role only detectable by CFT and not FFT.

Mechanisms for the maintenance of ventricular fibrillation: The nonuniform dispersion of refractoriness, restitution properties, or anatomic heterogeneities?

Mechanisms for the Maintenance of Ventricular Fibrillation. Introduction: The relative importance of nonuniform dispersion of refractoriness, steep restitution slopes, and anatomic heterogeneities in causing conduction block during ventricular fibrillation (VF) remains unknown. Methods and Results: In six open-chest pigs, ventricular refractoriness and restitution curves were estimated from activation recovery intervals (ARIs) calculated from 504 (21 x 24) unipolar electrode recordings 2 mm apart in a plaque sutured to the left ventricular (LV) free wall. A steady-state restitution protocol was performed twice at each of two pacing sites: the LV base and near the left anterior descending artery. VF was electrically induced four times and the incidence of conduction block at each electrode during the first 20 seconds was determined by an automated algorithm. The gradient of the ARI was calculated at each electrode to estimate the spatial dispersion of refractoriness. An exponential curve was fit to the restitution plots of ARIs versus the corresponding diastolic intervals (DIs) for all pacing cycle lengths at each electrode. The locations of epicardial blood vessels were noted after the study. Spatial patterns of conduction block were significantly correlated between the four VF episodes in the same animal (r = 0.66 ′ 0.07, P 2 msec/mm were present between many clusters and ∼90% of restitution slopes were >1. Instead, conduction block frequently appeared to cluster along epicardial vessels. Conclusion: Neither the dispersion of refractoriness nor action potential duration restitution determined during rapid pacing by itself is the major determinant of the location of conduction block during early VF in normal pigs. It may be that these factors interact synergistically with each other as well as with other factors, including anatomic heterogeneities such as those caused by blood vessels, which may be particularly important for the formation of conduction block and maintenance of VF.

Mechanisms for the Maintenance of Ventricular Fibrillation: The Nonuniform Dispersion of Refractoriness, Restitution Properties, or Anatomic Heterogeneities?

The relative importance of nonuniform dispersion of refractoriness, steep restitution slopes, and anatomic heterogeneities in causing conduction block during ventricular fibrillation (VF) remains unknown. In six open-chest pigs, ventricular refractoriness and restitution curves were estimated from activation recovery intervals (ARIs) calculated from 504 (21 x 24) unipolar electrode recordings 2 mm apart in a plaque sutured to the left ventricular (LV) free wall. A steady-state restitution protocol was performed twice at each of two pacing sites: the LV base and near the left anterior descending artery. VF was electrically induced four times and the incidence of conduction block at each electrode during the first 20 seconds was determined by an automated algorithm. The gradient of the ARI was calculated at each electrode to estimate the spatial dispersion of refractoriness. An exponential curve was fit to the restitution plots of ARIs versus the corresponding diastolic intervals (DIs) for all pacing cycle lengths at each electrode. The locations of epicardial blood vessels were noted after the study. Spatial patterns of conduction block were significantly correlated between the four VF episodes in the same animal (r = 0.66 +/- 0.07, P < 0.05). At the shortest pacing cycle length, the spatial distribution of ARIs, ARI gradients, and restitution slopes was not random but formed clusters of similar values. However, none of these variables was significantly correlated with the incidence of conduction block, even though ARI gradients >2 msec/mm were present between many clusters and approximately 90% of restitution slopes were >1. Instead, conduction block frequently appeared to cluster along epicardial vessels. Neither the dispersion of refractoriness nor action potential duration restitution determined during rapid pacing by itself is the major determinant of the location of conduction block during early VF in normal pigs. It may be that these factors interact synergistically with each other as well as with other factors, including anatomic heterogeneities such as those caused by blood vessels, which may be particularly important for the formation of conduction block and maintenance of VF.

Role of Repolarization Restitution in the Development of Coarse and Fine Atrial Fibrillation in the Isolated Canine Right Atria

Although the role of action potential duration restitution (APD-R) in the initiation and maintenance of ventricular fibrillation (VF) has been the subject of numerous investigations, its role in the generation of atrial fibrillation (AF) is less well studied. The cellular and ionic basis for coarse versus fine AF is not well delineated. We measured APD-R during acetylcholine-mediated AF as well as during pacing (standard and dynamic protocols) in crista teriminalis, pectinate muscle, superior vena cava, and appendage of isolated canine arterially perfused right atria (n = 15). Transmembrane action potential (TAP), pseudo-ECG, and isometric tension development were simultaneously recorded. Acetylcholine flattened APD-R measured by both standard and dynamic protocols, but promoted induction of AF. AF was initially coarse, converting to fine within 3-15 minutes of AF. Coarse, but not fine AF was associated with dramatic fluctuations in tension development, reflecting wide variations in intracellular calcium activity ([Ca(2+)](i)). During coarse AF, APD-R data displayed a cloud-like distribution pattern, with a wide range of maximum APD-R slope (from 1.21 to 0.35). A maximum APD-R slope >1 was observed only in crista terminalis (3/10). The APD-R relationship was relatively linear and flat during fine AF. Reduction of [Ca(2+)](i) was associated with fine AF whereas augmentation of [Ca(2+)](i) with coarse AF. Our data indicate that while APD-R may have a limited role in the maintenance of coarse AF, it is unlikely to contribute to the maintenance of fine AF and that [Ca(2+)](i) dynamics determine the degree to which AF is coarse or fine.

Change of Electrical Restitution Kinetics and Ventricular Fibrillation Threshold during Direct Autonomic Stimulation in Canine Heart

Background and Objectives：It is known that ventricular fibrillation (VF) can be enhanced by sympathetic activity and antagonized by vagal activity, and that the kinetics of electrical restitution is a key determinant of VF induction or maintenance. However, little is known about the effects of autonomic stimulation on electrical restitution. Therefore, we studied the effect of sympathetic (SS) and vagus nerve stimulation (VS) on the electrical restitution and VF induction. Materials and Methods：A monophasic action potential (MAP) was simultaneously recorded from the endocardium and epicardium of the left ventricle in 12 open chest canine hearts. The restitution kinetics were studied using a single ventricular extra-stimuli (S2), following a 15 beat drive train (300 ms), down to the effective refractory period (ERP). S2-MAPD was plotted against the preceding diastolic intervals, fitted to exponential curves and the maximum restitution slope (Smax) measured. The VF threshold (VFT) was determined as the minimum current that would induce VF with rapid pacing (50×50 ms). Parameters were studied at the baseline (control) and separately during VS and SS. Results：SS increased the Smax of the endocardium (1.14±0.37 vs. 0.80±0.25, p<0.001), but not that of the epicardium, and also increased the transmural dispersion of Smax and decreased the VFT (1.8±1.3 mA vs. 3.4±1.6 mA, p<0.05), even without significant shortening of the ERP, but VS had the opposite effects. There was a significant correlation between the endocardial Smax, transmural dispersion of the Smax and the VFT, respectively (r=-0.64, p<0.001 and r=-0.531, p=0.003). Conclusion：The role of the autonomic nervous system in ventricular arrhythmogenesis is by means of electrical restitution kinetics modulation. (Korean Circulation J 2005;35:539-546)

Wavebreak formation during ventricular fibrillation in the isolated, regionally ischemic pig heart.

Both fixed and dynamic heterogeneities were implicated in the mechanism of wavebreak (WB) generation during ventricular fibrillation (VF). However, their relative roles remain unclear. We hypothesized that during ischemic VF, the WBs are produced primarily because of a fixed heterogeneity; namely, the gradient of refractoriness across the ischemic border zone (BZ). Ischemia was induced in 15 isolated blood-perfused hearts by occluding the left anterior descending coronary artery. Simultaneous video imaging (approximately 32x32 mm2) of Di-4-ANEPPS fluorescence in the ischemic zone (IZ), the BZ, and the nonischemic zone (NIZ) was performed. Dominant-frequency maps were constructed to assess gradients of refractoriness during VF. We used singularity points analysis to quantify the incidence of WBs per square centimeter per second. During preischemic VF, the distribution of WBs was relatively uniform. Ischemia caused an increase of WBs in the BZ (from 6.2+/-2.8 to 10.8+/-4.0) and a decrease of WBs in the IZ (from 5.8+/-2.8 to 2.8+/-1.4), without a significant change in NIZ (from 6.4+/-2.3 to 4.1+/-1.7). This finding is fully consistent with the dominant-frequency distribution during ischemic VF: the average dominant frequency was significantly slower in IZ than in NIZ (7.8+/-0.7 versus 10.1+/-1.0 Hz), suggesting a large gradient in refractory periods across the BZ. We concluded that acute regional ischemia plays a dual role in the maintenance of VF, decreasing the incidence of WB in the IZ while increasing it in the BZ. This suggests a predominant role of fixed heterogeneities in the formation of WB during VF in acute regional ischemia.

Two types of ventricular fibrillation in isolated rabbit hearts: importance of excitability and action potential duration restitution.

The combined effects of excitability and action potential duration (APD) restitution on wavefront dynamics remain unclear. We used optical mapping techniques to study Langendorff-perfused rabbit hearts. In protocol IA (n=10), D600 at increasing concentrations was infused during ventricular fibrillation (VF). With concentration increased to 0.5 mg/L, fast VF (dominant frequency, 19.1+/-1.8 Hz) was consistently converted to ventricular tachycardia (VT). However, increasing D600 further to 2.5 or 5.0 mg/L converted VT to slow VF (11.9+/-2.3 Hz, P=0.0011). In an additional 4 hearts (protocol IB), tetrodotoxin converted a preexisting VT to slow VF (11.0+/-1.4 Hz). Optical maps show wandering wavelets in fast VF, organized reentry in VT, and spatiotemporal periodicity in slow VF. In protocol II, we determined APD and conduction time(-1) (CT(-1)) restitutions during D600 infusion. CT(-1) was used as an estimate of excitability. At 0.1 mg/L, APD and CT(-1) restitutions were steep and flat, respectively. APD restitution became flattened when D600 increased to 0.5 mg/L, converting fast VF to VT. Further increasing D600 to 2.5 or 5.0 mg/L steepened CT(-1) restitution and widened the range of S(1) pacing cycle lengths over which CT(-1) decreased, converting VT to slow VF. Two types of VF exist in isolated rabbit hearts. Fast (type I) VF is associated with a steep APD restitution, a flat CT(-1) restitution, and wandering wavelets. Slow (type II) VF is associated with a flat APD restitution, a steep CT(-1) restitution, and spatiotemporal periodicity. Both excitability and APD restitution are important in VF maintenance.

Minimal principle for rotor filaments.

Three-dimensional rotors, or scroll waves, provide essential insight into the activity of excitable media. They also are a suspected cause in the formation and maintenance of ventricular fibrillation, whose lethality is well known. It is therefore of considerable interest to find out what configurations can be adopted by such pathologies. A scroll's behavior is embodied in its organizing center or filament, a largely quiescent tube about which the scroll rotates. Predicting filament shape has normally required computer-intensive simulations of the whole scroll in time. We have found a fast and robust principle that yields the prediction for stationary filaments on a purely geometrical basis, blind to the reaction parameters of the medium. The procedure is to calculate the filament shape as a minimal path. We work in singly diffusive media whose diffusivity tensor--and no other feature--varies spatially. Mathematical and numerical evidence is presented for the proposition that a stable filament is a geodesic in a three-dimensional space whose metric is given by the inverse diffusivity tensor of the medium. Away from the boundaries, a stable filament is unaffected by the reaction parameters. The algorithmic aspects of this work are subsidiary to our main purpose of drawing attention to the universal and unexpectedly exact fit of an elementary geodesic principle within reaction-diffusion theories.

Action potential duration restitution and ventricular fibrillation due to rapid focal excitation.

The focal source hypothesis of ventricular fibrillation (VF) posits that rapid activation from a focal source, rather than action potential duration (APD) restitution properties, is responsible for the maintenance of VF. We injected aconitine (100 microg) into normal isolated perfused swine right ventricles (RVs) stained with 4-[beta-[2-(di-n-butylamino)-6-naphthyl]vinyl]pyridinium (di-4-ANEPPS) for optical mapping studies. Within 97 +/- 163 s, aconitine induced ventricular tachycardia (VT) with a mean cycle length 268 +/- 37 ms, which accelerated before converting to VF. Drugs that flatten the APD restitution slope, including diacetyl monoxime (10-20 mM, n = 6), bretylium (10-20 microg/ml, n = 3), and verapamil (2-4 microg/ml, n = 3), reversibly converted VF to VT in all cases. In two RVs, VF persisted despite of the excision of the aconitine site. Simulations in two-dimensional cardiac tissue showed that once VF was initiated, it remained sustained even after the "aconitine" site was eliminated. In this model of focal source VF, the VT-to-VF transition occurred due to a wave break outside the aconitine site, and drugs that flattened the APD restitution slope converted VF to VT despite continuous activation from aconitine site.

Endocardial wave front organization during ventricular fibrillation in humans

ObjectivesThis study was designed to characterize the organization of ventricular fibrillation (VF) on the endocardium of humans. BackgroundMost proposed mechanisms for the maintenance of VF postulate the propagation of a number of activation wave fronts that reenter to maintain the arrhythmia. We tested the hypothesis that, in patients undergoing internal cardioverter-defibrillator implantation, VF consists primarily of a few large wave fronts on the endocardium. MethodsElectrograms were recorded from a 36-electrode catheter in the left ventricle of 16 patients during VF. Activation times were chosen for a 2-s epoch for each fibrillation episode, and a two-dimensional Kolmogorov-Smirnov test was performed to determine if activation occurred randomly along the catheter over that time interval. The maximum cross-correlation was found for all possible pairs of electrodes on the catheter, and these values were plotted relative to the distance between the two electrodes. An exponential curve was then fit to the data, and a length constant was determined. Activation times were grouped into wave fronts along the catheter, and the lengths of the wave fronts were estimated. ResultsThe Kolmogorov-Smirnov test showed that activation was not random along the catheter in any of the patients studied. The correlation length determined was 9 ± 2 cm. The number of wave fronts recorded by the catheter was 9.2 ± 2.9 wave fronts/s. The length of the pathway of each wave front along the catheter was 6.5 ± 4.5 cm. ConclusionsVentricular fibrillation is well organized on the endocardial surface of humans, consisting primarily of a few large wave fronts on the order of 6 to 9 cm.

Frequency analysis of ventricular fibrillation in Swine ventricles.

It has been suggested from frequency analysis that cardiac fibrillation is driven by stable intramural reentry, with wavebreak occurring due to failure of 1:1 propagation. We tested this hypothesis with a combined experimental and theoretical approach. Optical mapping was performed on epicardial, endocardial, and transmural cut surfaces of fibrillating swine ventricles. Wavelets were characterized, the frequency content of optical signals analyzed, and space-time plots (STPs) constructed to detect Wenckebach-like conduction. The findings were compared with simulations in 2D and 3D cardiac tissue using the Luo-Rudy action potential model. The incidence of reentry in the cut transmural surface (11.8% in right ventricle, 14.3% in left ventricle) was similar to that on the endocardial surface (13.1%, P=NS) but greater than on the epicardial surface (7.7%, P<0.01). Frequency spectra of optically recorded membrane voltage were organized into spatial domains with the same dominant frequency, but these domains were nonstationary. In STPs, pseudo-2:1 conduction block was caused by double potentials arising when reentry occurred on the recording site rather than true Wenckebach conduction. The latter was observed in 11 of 166 STPs but did not occur at borders of high-to-low frequency domains. In simulations, similar findings were obtained when action potential duration (APD) restitution slope was steep. Stationary dominant frequency domains with Wenckebach conduction patterns were observed only in the presence of shallow APD restitution slope and marked nonuniform tissue heterogeneity. In conclusion, stable intramural reentry as the engine of fibrillation was not observed. Our findings support the idea that dynamic wavebreak plays a fundamental role in the generation and maintenance of ventricular fibrillation.