Long-duration Ventricular Fibrillation Research Articles

Synchronizing systolic calcium release with azumolene in an experimental model.

Post-defibrillation myocardial contractile dysfunction adversely affects the survival of patients after cardiac arrest. Attenuation of diastolic calcium (Ca2+) overload by stabilization of the cardiac ryanodine receptor (RyR2) is found to reduce refibrillation after long-duration ventricular fibrillation (LDVF). In the present study, we explored the effects of RyR2 stabilization by azumolene on systolic Ca2+ release synchrony and myocardial contractility. After completion of baseline optical mapping, Langendorff-perfused rabbit hearts were subjected to global ischemia followed by reperfusion with azumolene or deionized distilled water (vehicle). Following reperfusion, LDVF was induced with burst pacing. In the first series of experiments (n = 16), epicardial Ca2+ transient was analyzed for Ca2+ transient amplitude alternans and dispersion of Ca2+ transient amplitude alternans index (CAAI). In the second series of experiments following the same protocol (n= 12), ventricular contractility was assessed by measuring the left ventricular pressure. Ischemic LDVF led to greater CAAI (0.06 ± 0.02 at baseline vs 0.12 ± 0.02 post-LDVF, P < .01) and magnitude of dispersion of CAAI (0.04 ± 0.01 vs 0.09 ± 0.01, P < .01) in control hearts. In azumolene-treated hearts, no significant changes in CAAI (0.05 ± 0.01 vs 0.05 ± 0.01, P = .84) and dispersion of CAAI (0.04 ± 0.01 vs 0.04 ± 0.01, P = .99) were noted following ischemic LDVF. Ischemic LDVF was associated with reduction in left ventricular developed pressure (100% vs 36.8% ± 6.1%, P=.002) and dP/dtmax (100% vs 45.3% ± 6.5%, P = .003) in control hearts, but these reductions were mitigated (left ventricular developed pressure: 100% vs 74.0% ± 8.1%, P = .052, dP/dtmax: 100% vs 80.8% ± 7.9%, P= .09) in azumolene-treated hearts. Treatment with azumolene is associated with improvement of systolic Ca2+ release synchrony and myocardial contractility following ischemic LDVF.

Effects of azumolene on arrhythmia substrate in a model of recurrent long-duration ventricular fibrillation

BackgroundProarrhythmic risk of conventional anti-arrhythmic agents is linked to unintended modulation of membrane voltage dynamics. We have demonstrated that the anti-fibrillatory effect of azumolene is mediated via stabilization of the hyperphosphorylated ryanodine receptor (RyR2), leading to attenuation of diastolic calcium leak. However, the concomitant effects on membrane voltage dynamics have not been evaluated yet. MethodsAfter baseline optical mapping, Langendorff-perfused rabbit hearts treated with azumolene, or vehicle, were subjected to global ischemia-reperfusion (I/R) followed by two episodes of long-duration ventricular fibrillation (LDVF). Simultaneous dual epicardial calcium transient (CaT) and voltage dynamics were studied optically. ResultsPre-treatment with azumolene was associated with higher CaT amplitude alternans ratios (0.94 ± 0.02 vs. 0.78 ± 0.03 in control hearts, at 6 Hz; p = 0.005; and action potential amplitude alternans ratio (0.95 ± 0.02 vs. 0.78 ± 0.04 at 6.0 Hz; p = 0.02), and reduction of action potential duration (APD80) dispersion (9.0 ± 4.8 msec vs. 19.3 ± 6.6 msec at 6.0 Hz p = 0.02) and optical action potential upstroke rise time (26.3 ± 2.6 msec in control vs. 13.8 ± 0.6 msec at 6.0 Hz, p = 0.02) after LDVF. No change in action potential duration (APD) was noted with azumolene treatment. ConclusionIn a model of ischemic recurrent LDVF, treatment with azumolene led to reduction of cardiac alternans, i.e., calcium and voltage alternans. Unlike conventional anti-arrhythmic agents, reduction of action potential upstroke rise time and preservation of action potential duration following azumolene treatment may reduce the proarrhythmia risk.

Effect of flunarizine on defibrillation outcomes and early refibrillation in a canine model of prolonged ventricular fibrillation

New Findings What is the central question of this study? Can successful electrical shock in combination with a delayed after‐depolarization (DAD) blocker suppress early refibrillation episodes following long duration ventricular fibrillation (LDVF)? What is the main finding and its importance? Flunarizine significantly reduced the activation of LDVF and early ventricular fibrillation (VF) recurrence following LDVF, suggesting that DADs potentially contribute to refibrillation in prolonged VF. Thus, DAD inhibition can be used as an adjunctive therapy for electrical defibrillation to treat prolonged VF and suppress refibrillation following LDVF. This study attempts to detect changes in the defibrillation threshold (DFT) at different stages of ventricular fibrillation (VF) (short duration VF, SDVF; long duration VF, LDVF) and during early refibrillation following successful defibrillation of LDVF by giving flunarizine, a blocker of delayed after‐depolarizations (DADs). Twelve beagles were divided into two groups (the control group, n = 6; and the flunarizine group, n = 6). Two 64‐electrode basket catheters were deployed into the left and the right ventricles for global endocardium mapping. The DFTs of SDVF and LDVF were determined at 20 s and 7 min, respectively, after VF induction in each group. Any refibrillation episodes were recorded within 15 min after the first successful defibrillation of LDVF. In the flunarizine group, the SDVF‐DFT values before and after the drug were not significantly different. The 7 min LDVF‐DFTs were markedly reduced by 26% (P < 0.05, the control group) and 38% (P < 0.01, the flunarizine group) compared to the 20 s SDVF‐DFTs within each group. The difference between SDVF‐DFT and LDVF‐DFT after flunarizine was larger than that in the control group (213 ± 65 vs. 120 ± 84 V, P < 0.05). The number of refibrillation episodes per animal (1.3 ± 1.0) following successful defibrillation of LDVF after flunarizine was 48% of that in controls (2.7 ± 2.0, P < 0.05). The effect of flunarizine on SDVF‐DFT and LDVF‐DFT indicates that the role of DADs in the defibrillation mechanism may differ as VF continues. Flunarizine significantly reduced early VF recurrence following LDVF, suggesting that DADs potentially contribute to refibrillation in a canine model of prolonged VF.

Essential role of ryanodine receptor 2 phosphorylation in the effect of azumolene on ventricular arrhythmia vulnerability in a rabbit heart model.

Following long-duration ventricular fibrillation (LDVF), reinitiation of ventricular fibrillation (VF) poses a major challenge during resuscitation. Ryanodine receptor 2 (RyR2) becomes dysfunctional followingVF. The relationship between LDVF, RyR2 modulation, and ventricular refibrillation, as well as the role of RyR2 phosphorylation, remains unknown. Langendorff-perfused rabbit hearts were subjected to global ischemia and treated with azumolene (or vehicle alone in controls) upon reperfusion. After electrical induction of an initial LDVF episode, each heart was further stimulated electrically to assess reinducibility of VF. Myocardial calcium dynamics were assessed by optical mapping. RyR2 phosphorylation in left ventricular tissue extracts was analyzed by Western blot analysis. Fewer episodes of refibrillation (lasting ≥ 10 seconds) were induced in azumolene-treated hearts than in controls (P = 0.01); however, this reduction in refibrillation was abrogated in the presence of the protein kinase A inhibitor H89. Spontaneous calcium elevation was significantly lower in azumolene-treated hearts than in control hearts ( P = 0.002) and in hearts pretreated with H89 before azumolene ( P = 0.01). RyR2 phosphorylation at Ser2808 was higher in hearts subjected to LDVF than in non-VF hearts ( P = 0.029), while no significant difference was found at Ser2814. Pretreatment with H89 led to significantly less RyR2 phosphorylation at Ser2808 ( P = 0.04) after LDVF, while pretreatment with KN93 or azumolene alone showed no effects on RyR2 phosphorylation. Ventricular refibrillation following LDVF was reduced by azumolene, which also improves calcium dynamics. RyR2 phosphorylation at Ser2808 is a prerequisite for the beneficial effects of azumolene.

Effects of combination of sotalol and verapamil on initiation, maintenance, and termination of ventricular fibrillation in swine hearts.

Sotalol and verapamil alone reduce reentry incidence during ventricular fibrillation (VF). We tested whether the combination of these two drugs had a synergistic effect on initiation, maintenance, and termination of VF. Six open-chest pigs received intravenous sotalol (1.5mg/kg) followed by verapamil (0.136mg/kg). VF threshold (VFT) was determined by a burst pacing protocol. Two 20seconds episodes of VF were recorded from a 21×24 unipolar electrode plaque on the lateral posterior left ventricular epicardium before and after each drug. VF activation patterns were quantified. The duration of long duration VF (LDVF) maintenance was compared to our previously published data. Sotalol alone and combined with verapamil significantly increased the VFT from 12.3±4.1 to 20.3±7.1 and 26.7±8.6mA compared with baseline (P<.05). Sotalol decreased the number of wavefronts by 20%, VF activation rate by 17% and conduction velocity 11%, while the addition of verapamil neutralized these effects. Addition of verapamil to sotalol further decreased the fractionation incidence from 14% to 29% and multiplicity from 24% to 31% compared with baseline. The combination of the two drugs increased the VF cycle length, decreased synchronicity, increased regularity index and shortened the duration of LDVF maintenance compared with our previous data of verapamil alone or no drug. Synchronicity index was lower and regularity index was higher in animals in which VF spontaneously terminated earlier than 10minutes than in animals in which VF terminated longer than 10minutes. The combination of sotalol and verapamil increased VFT but accelerated LDVF termination.

Endocardial Activation Drives Activation Patterns During Long-Duration Ventricular Fibrillation and Defibrillation.

Understanding the mechanisms that drive ventricular fibrillation is essential for developing improved defibrillation techniques to terminate ventricular fibrillation (VF). Distinct organization patterns of chaotic, regular, and synchronized activity were previously demonstrated in VF that persisted over 1 to 2 minutes (long-duration VF [LDVF]). We hypothesized that activity on the endocardium may be driving these activation patterns in LDVF and that unsuccessful defibrillation shocks may alter activation patterns. The study was performed using a 64-electrode basket catheter on the left ventricle endocardium and 54 6-electrode plunge needles inserted into the left ventricles of 6 dogs. VF was induced electrically, and after short-duration VF (10 seconds) and LDVF (7 minutes), shocks of increasing strengths were delivered every 10 seconds until VF was terminated. Endocardial activation patterns were classified as chaotic (varying cycle lengths and nonsynchronous activations), regular (highly repeatable cycle lengths), and synchronized (activation that spreads rapidly over the endocardium with diastolic periods between activations). The results showed that the chaotic pattern was predominant in early VF, but the regular pattern emerges as VF progressed. The synchronized pattern only emerged occasionally during late VF. Failed defibrillation shocks changed chaotic and regular activation patterns to synchronized patterns in LDVF but not in short-duration VF. The regular and synchronized patterns of activation were driven by rapid activations on the endocardial surface that blocked and broke up transmurally, leading to an endocardial to epicardial activation rate gradient as LDVF progressed.

Global Bi-ventricular endocardial distribution of activation rate during long duration ventricular fibrillation in normal and heart failure canines

BackgroundThe objective of this study was to detect differences in the distribution of the left and right ventricle (LV & RV) activation rate (AR) during short-duration ventricular fibrillation (SDVF, <1 min) and long-duration ventricular fibrillation VF (LDVF, >1 min) in normal and heart failure (HF) canine hearts.MethodsVentricular fibrillation (VF) was electrically induced in six healthy dogs (control group) and six dogs with right ventricular pacing-induced congestive HF (HF group). Two 64-electrode basket catheters deployed in the LV and RV were used for global endocardium electrical mapping. The AR of VF was estimated by fast Fourier transform analysis from each electrode.ResultsIn the control group, the LV was activated faster than the RV in the first 20 s, after which there was no detectable difference in the AR between them. When analyzing the distribution of the AR within the bi-ventricles at 3 min of LDVF, the posterior LV was activated fastest, while the anterior was slowest. In the HF group, a detectable AR gradient existed between the two ventricles within 3 min of VF, with the LV activating more quickly than the RV. When analyzing the distribution of the AR within the bi-ventricles at 3 min of LDVF, the septum of the LV was activated fastest, while the anterior was activated slowest.ConclusionsA global bi-ventricular endocardial AR gradient existed within the first 20 s of VF but disappeared in the LDVF in healthy hearts. However, the AR gradient was always observed in both SDVF and LDVF in HF hearts. The findings of this study suggest that LDVF in HF hearts can be maintained differently from normal hearts, which accordingly should lead to the development of different management strategies for LDVF resuscitation.

Organized Frequency Structure of Electrocardiogram During Long-Duration Ventricular Fibrillation Under Experimental Conditions

Organized Frequency Structure of Electrocardiogram During Long-Duration Ventricular Fibrillation Under Experimental Conditions

Mechanisms of Long-Duration Ventricular Fibrillation in Human Hearts and Experimental Validation in Canine Purkinje Fibers

ObjectivesThis study sought to determine the characteristics of human LDVF, particularly as it contrasts with short-duration VF (SDVF), and evaluate the role of Purkinje fibers in its maintenance. BackgroundThe electrophysiological mechanisms of long-duration ventricular fibrillation (LDVF) have not been studied in the human heart. MethodsVF was induced in 12 human Langendorff hearts, and the hearts were examined from initiation to LDVF (10 min). Endocardial, epicardial, and transmural plunge needle mapping were performed on the hearts. Simulated LDVF was studied in canine hearts to determine the potential role of Purkinje fiber automaticity. ResultsThe mean age at transplant was 48 ± 20 years, and the mean ejection fraction was <20%. The mean cycle length of local activation times on the endocardium was 252 ± 66 ms in SDVF and 441 ± 80 ms in LDVF (p = 0.0002). On the endocardium and the epicardium in LDVF, cycle length was 441 ± 80 ms and 590 ± 88 ms, respectively (p = 0.0002). No endocardial to epicardial activation frequency gradient was seen in SDVF. Simultaneous transmural needle activation was most common in SDVF, whereas endocardial to epicardial activation was most common in LDVF (47.7% and 38.8% of activations, respectively [p = 0.031]). Re-entry was less common in LDVF, and over time, wave break (i.e., nontransmural propagation of wave fronts) developed. Isochronal maps of the left ventricular endocardium in LDVF identified Purkinje potentials as preceding and predominating endocardial activations. In explanted canine heart preparations, rapid pacing led to spontaneous Purkinje fiber activity that was dependent on pacing rate and duration. ConclusionsLDVF in human hearts is characterized by focal endocardial activity with mid-myocardial wave break and not by re-entry. This arrhythmia is modulated by rapid activations in early VF that lead to spontaneous Purkinje fiber activity.

The Importance of Purkinje Activation in Long Duration Ventricular Fibrillation

BackgroundThe mechanisms that maintain long duration ventricular fibrillation (LDVF) are unclear. The difference in distribution of the Purkinje system in dogs and pigs was explored to determine if Purkinje activation propagates to stimulate working myocardium (WM) during LDVF and WM pacing.Methods and ResultsIn‐vivo extracellular recordings were made from 1044 intramural plunge and epicardial plaque electrodes in 6 pig and 6 dog hearts. Sinus activation propagated sequentially from the endocardium to the epicardium in dogs but not pigs. During epicardial pacing, activation propagated along the endocardium and traversed the LV wall almost parallel to the epicardium in dogs, but in pigs propagated away from the pacing site approximately perpendicular to the epicardium. After 1 minute of VF, activation rate near the endocardium was significantly faster than near the epicardium in dogs (P<0.01) but not pigs (P>0.05). From 2 to 10 minutes of LDVF, recordings exhibiting Purkinje activations were near the endocardium in dogs (P<0.01) but were scattered transmurally in pigs, and the WM activation rate in recordings in which Purkinje activations were present was significantly faster than the WM activation rate in recordings in which Purkinje activations were absent (P<0.01). In 10 isolated perfused dog hearts, the LV endocardium was exposed and 2 microelectrodes were inserted into Purkinje and adjacent myocardial cells. After 5 minutes of LDVF, mean Purkinje activation rate was significantly faster than mean WM activation rate (P<0.01).ConclusionThese extracellular and intracellular findings about activation support the hypothesis that Purkinje activation propagates to stimulate WM during sinus rhythm, pacing, and LDVF.

Long-Duration Ventricular Fibrillation Exhibits 2 Distinct Organized States

Previous studies showed that endocardial activation during long-duration ventricular fibrillation (VF) exhibits organized activity. We identified and quantified the different types of organized activity. Two 64-electrode basket catheters were inserted, respectively, into the left ventricle and right ventricle of dogs to record endocardial activation from the endocardium during 7 minutes of VF (controls, n=6). The study was repeated with the K(ATP) channel opener pinacidil (n=6) and the calcium channel blocker flunarizine (n=6). After 2 minutes of VF without drugs, 2 highly organized left ventricular endocardial activation patterns were observed: (1) ventricular electric synchrony pattern, in which endocardial activation arose focally and either had a propagation sequence similar to sinus rhythm or arose near papillary muscles, and (2) stable pattern, in which activation was regular and repeatable, sometimes forming a stable re-entrant circuit around the left ventricular apex. Between 3 and 7 minutes of VF, the percent of time ventricular electric synchrony was present was control=25%, flunarizine=24% (P=0.44), and pinacidil=0.1% (P<0.001) and the percent of time stable pattern was present was control=71%, flunarizine=48% (P<0.001), and pinacidil=56% (P<0.001). The remainder of the time, nonstable re-entrant activation with little repeatability was present. After 3 minutes, VF exhibits 2 highly organized endocardial activation patterns 96% of the time, one potentially arising focally in the Purkinje system that was prevented with a K(ATP) channel opener but not a calcium channel blocker and the other potentially arising from a stable re-entrant circuit near the apical left ventricular endocardium.

Different types of long-duration ventricular fibrillation: Can they be identified by electrocardiography

We tested the hypothesis that after 2 minutes of ventricular fibrillation (VF), periods of highly organized activations occur on the endocardium, arising from an intramural mother rotor or triggered activity originating in the Purkinje fibers. In 6 anesthetized dogs, we recorded electrically induced VF from two-thirds of the endocardium with a 64-electrode basket catheter. In another 12 dogs, the study was repeated with the addition of the early afterdepolarization blocker pinacidil in 6 animals and the delayed afterdepolarization blocker flunarizine in the other 6 animals. We found that, in addition to periods of disorganized chaotic activation (type I pattern), at between 3 and 7 minutes of VF, 2 highly organized patterns were observed (type II pattern, regular activity and type III pattern, triggered activity). When present, these patterns were observed in all 64 electrodes simultaneously. Type II arises from the apex and may be an intramural mother rotor and type III arises focally in Purkinje fibers and may be caused by early afterdepolarizations. The optimal defibrillation strategy may be different for the 3 different VF patterns. Therefore, it is important to determine if these 3 patterns can be differentiated from the body surface electrocardiogram.

Defibrillation Threshold Varies During Different Stages of Ventricular Fibrillation in Canine Hearts

Recent studies have shown that short duration ventricular fibrillation (SDVF) and long duration ventricular fibrillation (LDVF) are maintained by different mechanisms. The objective of this study is to evaluate how the defibrillation threshold (DFT) varies over the duration of fibrillation since the mechanism of VF maintenance changes as VF progresses. Twelve canines were randomly divided into two groups (Group A and B, n=6 each). DFTs were measured three times in each group: SDVF (20s), LDVF (3min in Group A and 7min in Group B) and the first episode of refibrillation after successful defibrillation for LDVF. Two 64-electrode baskets used to globally map the endocardium were deployed into the left ventricle and right ventricle, respectively. LDVF-DFT in Group A was significantly higher than that of Group B (628±98V vs 313±81V, P<0.001). In Group B, the DFT of refibrillation was significantly increased compared with the LDVF-DFT (570±199V vs 313±81V, P=0.035) but did not differ from the DFT of refibrillation in Group A (570±199V vs 638±116V, P=0.39). Highly synchronised activation patterns on the left ventricular endocardium were observed between 3 and 7min of LDVF in Group B but not within 3min-LDVF in Group A or during refibrillation in each group. DFT varied during different stages of VF. The highly synchronised activation patterns exhibiting after 3min VF might contribute to the decreased LDVF-DFT.

Role of KATP channel in electrical depression and asystole during long-duration ventricular fibrillation in ex vivo canine heart.

Long-duration ventricular fibrillation (LDVF) in the globally ischemic heart is characterized by transmurally heterogeneous decline in ventricular fibrillation rate (VFR), emergence of inexcitable regions, and eventual global asystole. Rapid loss of both local and global excitability is detrimental to successful defibrillation and resuscitation during cardiac arrest. We sought to assess the role of the ATP-sensitive potassium current (I(KATP)) in the timing and spatial pattern of electrical depression during LDVF in a structurally normal canine heart. We analyzed endo-, mid-, and epicardial unipolar electrograms and epicardial optical recordings in the left ventricle of isolated canine hearts during 10 min of LDVF in the absence (control) and presence of an I(KATP) blocker glybenclamide (60 μM). In all myocardial layers, average VFR was the same or higher in glybenclamide-treated than in control hearts. The difference increased with time of LDVF and was overall significant in all layers (P < 0.05). However, glybenclamide did not significantly affect the transmural VFR gradient. In epicardial optical recordings, glybenclamide shortened diastolic intervals, prolonged action potential duration, and decreased the percentage of inexcitable area (all differences P < 0.001). During 10 min of LDVF, asystole occurred in 55.6% of control and none of glybenclamide-treated hearts (P < 0.05). In three hearts paced after the onset of asystole, there was no response to LV epicardial or atrial pacing. In structurally normal canine hearts, I(KATP) opening during LDVF is a major factor in the onset of local and global inexcitability, whereas it has a limited role in overall deceleration of VFR and the transmural VFR gradient.

Intramural optical mapping of Vm and Cai2+ during long-duration ventricular fibrillation in canine hearts

Intramural gradients of intracellular Ca(2+) (Ca(i)(2+)) Ca(i)(2+) handling, Ca(i)(2+) oscillations, and Ca(i)(2+) transient (CaT) alternans may be important in long-duration ventricular fibrillation (LDVF). However, previous studies of Ca(i)(2+) handling have been limited to recordings from the heart surface during short-duration ventricular fibrillation. To examine whether abnormalities of intramural Ca(i)(2+) handling contribute to LDVF, we measured membrane voltage (V(m)) and Ca(i)(2+) during pacing and LDVF in six perfused canine hearts using five eight-fiber optrodes. Measurements were grouped into epicardial, midwall, and endocardial layers. We found that during pacing at 350-ms cycle length, CaT duration was slightly longer (by ≃10%) in endocardial layers than in epicardial layers, whereas action potential duration (APD) exhibited no difference. Rapid pacing at 150-ms cycle length caused alternans in both APD (APD-ALT) and CaT amplitude (CaA-ALT) without significant transmural differences. For 93% of optrode recordings, CaA-ALT was transmurally concordant, whereas APD-ALT was either concordant (36%) or discordant (54%), suggesting that APD-ALT was not caused by CaA-ALT. During LDVF, V(m) and Ca(i)(2+) progressively desynchronized when not every action potential was followed by a CaT. Such desynchronization developed faster in the epicardium than in the other layers. In addition, CaT duration strongly increased (by ∼240% at 5 min of LDVF), whereas APD shortened (by ∼17%). CaT rises always followed V(m) upstrokes during pacing and LDVF. In conclusion, the fact that V(m) upstrokes always preceded CaTs indicates that spontaneous Ca(i)(2+) oscillations in the working myocardium were not likely the reason for LDVF maintenance. Strong V(m)-Ca(i)(2+) desynchronization and the occurrence of long CaTs during LDVF indicate severely impaired Ca(i)(2+) handling and may potentially contribute to LDVF maintenance.

Evolution of activation patterns during long-duration ventricular fibrillation in pigs

Quantitative analysis has demonstrated five temporal stages of activation during the first 10 min of ventricular fibrillation (VF) in dogs. To determine whether these stages exist in another species, we applied the same analysis to the first 10 min of VF recorded in vivo from two 504-electrode arrays, one each on left anterior and posterior ventricular epicardium in six anesthetized pigs. The following descriptors were continuously quantified: 1) number of wavefronts, 2) wavefront fractionations, 3) wavefront collisions, 4) repeatability, 5) multiplicity index, 6) wavefront conduction velocity, 7) activation rate, 8) mean area activated by the wavefronts, 9) negative peak rate of voltage change, 10) incidence of breakthrough/foci, 11) incidence of block, and 12) incidence of reentry. Cluster analysis of these descriptors divided VF into four stages (stages i-iv). The values of most descriptors increased during stage i (1-22 s after VF induction), changed quickly to values indicating greater organization during stage ii (23-39 s), decreased steadily during stage iii (40-187 s), and remained relatively unchanged during stage iv (188-600 s). The epicardium still activated during stage iv instead of becoming silent as in dogs. In conclusion, during the first 10 min, VF activation can be divided into four stages in pigs instead of five stages as in dogs. Following a 16-s period during the first minute of VF when activation became more organized, all parameters exhibited progressive decreased organization. Further studies are warranted to determine whether these changes, particularly the increased organization of stage ii, have clinical consequences, such as alteration in defibrillation efficacy.

Abstract 9: Role of Hyperkalemia in the Transmural Activation Rate Gradient and Asystole During Long-Duration Ventricular Fibrillation (LDVF) in Isolated Canine Heart

During LDVF in globally ischemic hearts, a transmurally heterogeneous decrease in VF rate (VFR) occurs culminating in asystole. While hyperkalemia is considered to be a major modulator of excitability during ischemia, the magnitude of extracellular potassium ([K + ] o ) accumulation during LDVF and its role in the transmural VFR gradient and asystole remain unknown. Twelve isolated, blood perfused canine hearts underwent 20 min of global ischemia and VF; and an additional 4 hearts were subjected to VF during normoxic perfusion with varying [K + ] o (2 - 15 mM). Plunge needle electrodes with electrical and K + sensors were used for left ventricular endocardial (ENDO) and epicardial (EPI) measurements of VFR and [K + ] o . Cluster analysis revealed a dichotomy in the timing of asystole (Figure A, Inset): 6/12 hearts experienced asystole at 7.2 ± 1.0 min of ischemia (EARLY ASYS), while the remaining 6/12 hearts were still in VF at 20 min of ischemia (LATE ASYS). EARLY ASYS showed significantly faster K + accumulation in ENDO and EPI than LATE ASYS; neither group developed a gradient in [K + ] o (Figure A). Nevertheless, a prominent ENDO-EPI VFR gradient developed during LDVF in both groups (not shown). Compared to normoxic VF, LDVF exhibited a marked decrease in VFR as a function of [K + ] o . In addition, there was a significant difference in K + sensitivity of VFR between ENDO and EPI which was not observed during normoxic VF (Figure B). We conclude that during LDVF enhanced K + leak predicts early asystole, but the level of [K + ] o per se cannot explain VFR decline either in EPI or ENDO. Thus, hyperkalemia is not the main determinant of electrical depression and asystole during LDVF.

The Effects of Acute Amiodarone on Short- and Long-duration Ventricular Defibrillation Threshold in Canines

Some studies have shown that the defibrillation threshold (DFT) differs between short-duration ventricular fibrillation (SDVF, <1 minute) and long-duration ventricular fibrillation (LDVF > 1 minute). The goal of this study is to evaluate the effects of acute intravenous amiodarone on SDVF-DFT and LDVF-DFT and its possible mechanism as well. Twelve open-chest dogs were randomly divided into 2 groups (control group, normal saline, 10 mL·kg·h maintenance, n = 6; amiodarone group, loading dose 10 mg/kg over 10 minutes, maintenance dose 5 mg·kg·h, n = 6). VF was electrically induced and recorded with a 12 × 12 unipolar electrode plaque (2-mm spacing) sutured on the left ventricular epicardium and a plunge needle (6 unipolar electrode) inserted in the left ventricular apex. The DFTs of SDVF and LDVF were determined 20 seconds and 3 minutes after VF induction, respectively. Restitution was estimated from activation recovery intervals during pacing from the plaque and plunge needle electrodes. The activation rate was estimated by Fast Fourier Transform analysis of VF at same electrodes. The VF cycle length was defined as the reciprocal of the activation rate. The epicardial and transmural dispersion of the maximal slope of the restitution curve and VF cycle length of SDVF and LDVF were calculated, respectively. : In controls, LDVF-DFT was higher than SDVF-DFT (645 ± 61 vs. 520 ± 63 V, P < 0.01). Amiodarone did not significantly alter SDVF-DFTs (496 ± 49 vs. 552 ± 69 V, P > 0.05) but decreased LDVF-DFT by 31% (P < 0.01). Compared with control, amiodarone significantly reduced the maximum slope of the restitution curve (1.12 ± 0.35 vs. 0.81 ± 0.25, P = 0.03) and its epicardial dispersion (0.32 ± 0.07 vs. 0.24 ± 0.04,coefficient of variation, P = 0.017). Amiodarone significantly increased the SDVF-CL (92 ± 8 vs. 99 ± 10 milliseconds, P < 0.01) and epicardial dispersion 0.14 ± 0.06 vs. 0.18 ± 0.05, P < 0.01. Amiodarone did not change the LDVF-CL (228 ± 12 vs. 226 ± 10 milliseconds, P > 0.05) or epicardial dispersion (0.17 ± 0.03 vs. 0.15 ± 0.02, P > 0.05) compared with control. However, the drug significantly decreased the transmural dispersion of LDVF-CL (68 ± 28 vs. 39 ± 14 milliseconds, P < 0.01) without changing the transmural dispersion of SDVF-CL (29 ± 22 vs. 32 ± 30 milliseconds, P > 0.05). Acute amiodarone significantly decreased the LDVF-DFT. The decreased transmural dispersion of LDVF-CL by amiodarone might contribute to the decreased LDVF-DFT.

Periods of Highly Synchronous, Non‐Reentrant Endocardial Activation Cycles Occur During Long‐Duration Ventricular Fibrillation

Periods of Highly Organized Activation During VF. Little is known about long-duration ventricular fibrillation (LDVF), lasting 1-10 minutes when resuscitation is still possible. To determine global left ventricle (LV) endocardial activation during LDVF, 6 canines (9.5 ± 0.8 kg) received a 64-electrode basket catheter in the LV, a right ventricular (RV) catheter, and a 12-lead electrocardiogram (ECG). Activation sequences of 15 successive cycles after initiation and after 1, 2, 3, 5, 7, and 10 minutes of LDVF were determined. Early during VF, LV endocardial activation was complex and present throughout most (78.0 ± 9.7%) of each cycle consistent with reentry. After 3-7 minutes of LDVF in 5 animals, endocardial activation became highly synchronized and present for only a small percentage of each cycle (18.2 ± 7.7%), indicating that LV endocardial reentry was no longer present. During this synchronization, activations arose focally in Purkinje fibers and spread as large wavefronts to excite the Purkinje system followed by the subendocardial working myocardium. During this synchronization, the ECG continued to appear irregular, consistent with VF, and LV cycle length (183 ± 29 ms) was significantly different than RV cycle length (144 ± 14 ms) and significantly different than the LV cycle length when synchronization was not present (130 ± 11 ms). After 3-7 minutes of LDVF, a highly organized, synchronous, focal LV endocardial activation pattern frequently occurs that is not consistent with reentry but is consistent with triggered activity or abnormal automaticity in Purkinje fibers. The ECG continues to appear irregular during this period, partially because of differences in LV and RV cycle lengths.

Mechanisms of Fibrillation: Neurogenic or Myogenic? Reentrant or Focal? Multiple or Single?: Still Puzzling After 160 Years of Inquiry

Mechanisms of Fibrillation: Neurogenic or Myogenic? Reentrant or Focal? Multiple or Single?: Still Puzzling After 160 Years of Inquiry