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Background Shocks near defibrillation threshold (nDFT) strength commonly extinguish all ventricular fibrillation (VF) wavefronts, but a train of rapid, well-organized postshock activations (PAs) typically appears before sinus rhythm ensues. If one of the PA waves undergoes partial propagation block (wavebreak), reentry may be induced, causing VF to reinitiate and the shock to fail. Objective The purpose of this study was to determine whether wavebreak leading to VF reinititation following nDFT shocks occurs preferentially at the right ventricular insertion (RVI), which previous studies have identified as a key site for wavebreak. Methods We used panoramic optical mapping to image the ventricular epicardium of 6 isolated swine hearts during nDFT defibrillation episodes. After each experiment, the hearts were fixed and their geometry scanned with magnetic resonance imaging (MRI). The MRI and mapping datasets were spatially coregistered. For failed shocks, we identified the site of the first wavebreak of a PA wave during VF reinitiation. Results We recorded 59 nDFT failures. In 31 of these, the first wavebreak event occurred within 1 cm of the RVI centerline, most commonly on the anterior side of the right ventricular insertion (aRVI) (23/31). The aRVI region occupies 16.8% ± 2.5% of the epicardial surface and would be expected to account for only 10 wavebreaks if they were uniformly distributed. By χ2 analysis, aRVI wavebreaks were significantly overrepresented. Conclusion The anterior RVI is a key site in promoting nDFT failure. Targeting this site to prevent wavebreak could convert defibrillation failure to success and improve defibrillation efficacy.

On March 1 and 2, 2018, the National Institutes of Health 2018 Progenitor Cell Translational Consortium (PCTC) and Cardiovascular Bioengineering Symposium (CVBE) was held at the University of Alabama at Birmingham. Convergence of life sciences and engineering to advance the understanding and treatment of heart failure was the theme of the meeting. Over 150 attendees were present for more than 40 scientists presenting their latest works on engineering human functional myocardium for disease modeling, drug development, and heart failure research. The scientists, engineers and physicians in the field of cardiovascular sciences, met and discussed on the most recent advances in their works and propose future strategies in overcoming the major roadblocks of cardiovascular bioengineering and therapy. Particular emphasis was given for manipulation and using of stem/progenitor cells, biomaterials, and methods to provide molecular, chemical and mechanical cues to cells in order to influence their identity and fate in vitro and in vivo. Collectively, these works are profoundly impacting and progressing toward deciphering the mechanisms and developing novel treatments for left ventricular dysfunction of failing hearts. Here we present some important perspectives that emerged from this meeting.

BACKGROUND: Cardiomyocytes that have been differentiated from CCND2-overexpressing human induced-pluripotent stem cells (hiPSC-CCND2(OE) CMs) can proliferate when transplanted into mouse hearts after myocardial infarction (MI). However, it is unknown whether remuscularization can replace the thin LV scar and if the large muscle graft can electrophysiologically synchronize to the recipient myocardium. Our objectives are to evaluate the structural and functional potential of hiPSC-CCND2(OE) CMs in replacing the LV thin scar. METHODS: NOD/SCID mice were treated with hiPSC-CCND2(OE) CMs (i.e., the CCND2(OE) group), hiPSC-CCND2(WT) CMs (the CCND2(WT) group), or an equal volume of PBS immediately after experimentally-induced myocardial infarction. The treatments were administered to one site in the infarcted zone (IZ), two sites in the border zone (BZ), and a fourth group of animals underwent Sham surgery. RESULTS: Six months later, engrafted cells occupied more than 50% of the scarred region in CCND2(OE) animals, and exceeded the number of engrafted cells in CCND2(WT) animals by ~8-fold. Engrafted cells were also more common in the IZ than in the BZ for both cell-treatment groups. Measurements of cardiac function, infarct size, wall thickness, and cardiomyocyte hypertrophy were significantly improved in CCND2(OE) animals compared to animals from the CCND2(WT) or PBS-treatment groups. Measurements in the CCND2(WT) and PBS groups were similar, and markers for cell cycle activation and proliferation were significantly higher in hiPSC-CCND2(OE) CMs than in hiPSC-CCND2(WT) CMs. Optical mapping of action potential propagation indicated that the engrafted hiPSC-CCND2(OE) CMs were electrically coupled to each other and to the cells of the native myocardium. No evidence of tumor formation was observed in any animals. CONCLUSIONS: Six months after the transplantation, CCND2-overexpressing hiPSC-CMs proliferated and replaced more than 50% of the myocardial scar tissue. The large graft hiPSC-CCND2(OE) CMs also electrically integrated with the host myocardium, which was accompanied by a significant improvement in LV function.

Background: Acute regional ischemia is a leading cause of death. Ectopic beats may initiate ventricular arrhythmias in the first hour after coronary occlusion; however, the origin of these beats remains poorly understood. Some studies suggest that abnormal mechanical stretch at the ischemic border zone may contribute to the initiation of ectopy. If mechanical stretch plays a major role in triggering ectopic beats, we therefore expect: I , left ventricular working (LVW) hearts will have higher frequency of post-occlusion ectopic activity than non-beating (NB) hearts; II , in LVW hearts, ectopic beats will arise from ventricular sites undergoing mechanical stretch. Methods and Results: Isolated pig hearts were assigned to NB or LVW groups (8 per group) and prepared for Langendorff or LVW perfusion, respectively. Contraction of NB hearts was suppressed with 10 μM blebbistatin. Acute regional ischemia was induced by LAD occlusion. Using a newly developed optical mapping system, electrical activity and mechanical deformation were simultaneously recorded from 0 to 60 minutes after LAD occlusion. Mechanical stretch (positive strain in 2 principal directions) was observed in the ischemic and border zones of LVW but not NB hearts (Figure, Panel A). There was no significant difference in the number of ectopic events in LVW hearts compared to NB hearts (58±35 vs. 32±36, p=0.17). Of the 45 ectopic events that originated from the LV mapping region in LVW hearts, Conclusion: Mechanical stretch does not play a major role in triggering ectopic beats in early acute regional ischemia in this model.

Mechanical stimulation can elicit electrical activation of the heart. This mechanosensitivity can start life-threatening arrhythmias (commotio cordis) or terminate them (precordial thump). Mechanosensitivity may also be involved in arrhythmogenesis in other settings. Stretch-activated ion channels (SACs) are thought to be important in mechanosensitivity and a number of agents that block them have been identified. Such agents could potentially be used as tools in experimental investigation of mechanosensitivity. However, studies using them in intact-heart preparations have yielded inconsistent results. In the present study, we used isolated, perfused hearts from 25–35 kg pigs and a computer-controlled device that repeatably delivered focal mechanical stimuli. The concentration-dependent ability of the SAC blocker gadolinium to suppress mechanical activation was assessed by the success rate of mechanical stimulation and by the delay between successful mechanical stimulation and electrical activation. In six hearts, perfusate was recirculated. In an additional six hearts, perfusate was not recirculated to prevent gadolinium from forming complexes with metabolic waste and possibly precipitating. Gadolinium did not suppress mechanically-induced activation. Although gadolinium has been shown to be an effective SAC blocker in isolated cells, using it to probe the role of mechanical stimulation in whole heart preparations should be done with great caution.

The characteristics of reentrant circuits during short duration ventricular fibrillation (SDVF; 20 s in duration) and the role of Ca++and rapid-activating delayed rectifier potassium currents during long duration ventricular fibrillation (LDVF; up to 10 min in duration) were investigated using verapamil and sotalol. Activation mapping of the LV epicardium with a 21 × 24 electrode plaque was performed in 12 open-chest pigs. Pigs were given either verapamil (0.136 mg/kg) or sotalol (1.5 mg/kg) and verapamil. Reentry patterns were quantified for SDVF, and, for LDVF, activation patterns were compared with our previously reported control LDVF data. Verapamil significantly increased conduction velocity around the reentrant core by 10% and reduced the reentrant cycle length by 15%, with a net reduction in reentry incidence of 70%. Sotolol had an opposite effect of decreasing the conduction velocity around the core by 6% but increasing the reentrant cycle length by 13%, with a net reduction of reentry incidence of 50%. After 200 s of VF, verapamil significantly slowed wavefront conduction velocity and activation rate compared with control data. Verapamil decreased the incidence of reentry in SDVF by accelerating conduction velocity to increase the likelihood of conduction block, possibly through increased sympathetic tone. The drug slowed activation rate and conduction velocity after 200 s of VF, suggesting that L-type Ca++channels remain active and may be important in the maintenance of LDVF. Sotalol in addition to verapamil caused no additional antiarrhythmic effect.

asystole, identified as a flatline in all ECG leads, is a nonshockable rhythm that is associated with high mortality. Patients with coronary artery disease who suffer a sudden occlusion may progress to asystole through a sequence of events initiated at the onset of the occlusion: local ischemia, ventricular tachycardia (VT), ventricular fibrillation (VF), global ischemia, and asystole. Defibrillation has the highest efficacy when applied during VF, well before asystole. Prognosis is dim for patients suffering from out-of-hospital cardiac arrest (OHCA) who are found in asystole. An analysis of the Swedish OHCA registry has shown that patients who were found in a nonshockable rhythm had an average one-month survival rate of 1.3% (8). Several retrospective studies have analyzed the incidence of lethal arrhythmias in OHCA and found that the incidence of arrest with VT/VF as the first recorded rhythm has steadily declined while the incidence of non-VF arrest, including asystole, has markedly increased (10, 13). The decline in VF arrest could be the result of reduced incidence of VT/VF as the cause of OHCA, likely because of increased use of implantable cardioverter defibrillators and β-blockers. Interestingly, the incidence of asystole as the first recorded rhythm increased substantially from 1992-2002 in Milwaukee, WI, with the increase offsetting the decline in VT/VF arrests. Overall, the total incidence of OHCA remained constant over the period of that study (13). Observed increases in non-VF OHCA in the United States and Europe have lead to speculation that VF in OHCA is quickly deteriorating into another rhythm, primarily asystole (10). There is further speculation that β-blockers could be the culprit in the accelerated deterioration of VF to asystole (10). In this issue of the American Journal of Physiology-Heart and Circulatory Physiology, Garg and colleagues (6a) present the results of investigations into factors that influence electrical function's degeneration to asystole during global ischemia. They hypothesized that both rapid heart rate and β-adrenergic stimulation would accelerate electrical failure. They studied isolated rabbit hearts in which contraction had been pharmacologically arrested. The hearts were paced at cycle lengths of either 300 or 200 ms and either were or were not exposed to 30 nM of the β-adrenergic agonist isoproterenol. Global no-flow ischemia was initiated, and the resulting progression of electrical failure was monitored with optical mapping. They found that a rapid heart rate and β-adrenergic activation synergistically accelerated the development of regional loss of excitability, which was tightly correlated with the onset of VF and, ultimately, the complete loss of excitability (asystole). Although measured during global ischemia, the activation rate data of Garg et al. may provide new insight into clinical observations that elevated basal heart rate is associated with increased cardiovascular risk factors (2, 5, 12), including sudden myocardial infarction (7) and VF (1). These data support clinical efforts to maintain lower heart rates in patients with coronary artery disease. It is reasonable to hypothesize that acute local ischemia within the context of high heart rate and increased β-adrenergic activity would be correlated with increased risk of VF and possibly a fast progression to asystole. Thus, during a coronary event, reduced basal heart rate may lengthen the time to asystole, thereby increasing the likelihood of observing a shockable rhythm in OHCA. β-Blockers may further lengthen the time to asystole; however, this point could be debated (10). In previous animal studies, slowing of sinus rate and blocking β-adrenergic activity delayed the time to onset of VF during ischemic events, presumably by preserving myocardial energy status (21). Studies by Vaillant and colleagues (21) measured the time to VF after acute myocardial ischemia in pigs. From the onset of ischemia, the time to VF was prolonged when a pacemaker current (IKf) inhibitor (ivabradine) was administered to reduce heart rate. When a β-blocker (propranolol) was administered, time to VF was also prolonged, but not nearly as much as that with IKf inhibition. The isoproterenol results of Garg et al. corroborate these earlier findings. Phosphocreatine-to-ATP ratios measured by Vaillant et al. (21) at the onset of VF were also higher during IKf inhibition, indicating improved preservation of myocardial energy stores. In the clinic, heart rate reduction in patients with angina pectoris increases the time to ST-segment depression and prolongs the onset of angina symptoms (15, 20). These beneficial effects are attributed to improved myocardial energy status, including reductions in myocardial oxygen consumption and improved coronary perfusion secondary to a longer diastolic interval (2). Garg and colleagues provide several thought-provoking interpretations of their optical mapping data. During ischemia, diminished excitability, conduction block, and asystole are typically attributed to elevated extracellular potassium that depolarizes resting membrane potential, thereby inactivating sodium channels (3, 18). However, Garg and colleagues argue against this mechanism by suggesting that the enhanced electrical depression that they observed was caused by increased calcium loading, not the accumulation of extracellular potassium. They further suggest that the initiation of VF in their experiments was not due to early or delayed afterdepolarizations, which are usually attributed to altered intracellular calcium homeostasis (16) and are typically invoked to explain arrhythmogenesis during β-adrenergic stimulation in nonischemic myocardium (11). Instead, they explain that the development of a spatially heterogeneous mosaic pattern of electrical depression was the mechanism of VF. Such a pattern would be expected to promote unidirectional block and reentry. As the authors speculate, the Purkinje network could play an important role in initiating the observed VF. Rabbits, the species used in this study, are similar to dogs and humans in that the Purkinje network is primarily subendocardial, making it nearly impossible to definitively associate epicardially mapped activation fronts with endocardial Purkinje activations. However, a number of studies (4, 9) have indicated that the Purkinje network is active during long duration VF, in which the heart is globally ischemic and is likely important in maintaining VF activation through a variety of focal and reentrant mechanisms. Similar mechanisms could very well be at play in the initiation of VF during global ischemia. A benefit of optical mapping in the studies of Garg et al. was that action potential duration heterogeneity could be analyzed. This revealed differences in the time course of action potential duration shortening between the right and left ventricles, with faster shortening occurring in the left ventricle for three out of four combinations of heart rate and isoproterenol administration. This result implies a shortening of reentrant path length as well as increased dispersion of repolarization, both of which are important VF mechanisms. An important limitation of the optical mapping studies was the requirement of electromechanical uncoupling to reduce motion artifact in the optical action potentials. Interpretation of data when cross-bridge cycling is inhibited must be done cautiously because actomyosin ATPases comprise 75% of total myocardial energy consumption (23). The remaining energy consumption is attributed to the Ca2+ ATPases (15%) and the Na+/K+ ATPase (9%) (17). It is likely that ATP use during both nonischemic and ischemic conditions in the studies of Garg et al. was only 24% of what it might be in an in vivo working heart. As such, it is likely that the time course of electrical events could be significantly shorter in vivo. This limitation is especially important if energy preservation is a mechanism by which lower heart rate and absence of β-adrenergic stimulation protect against the onset of VF. Inhibition of actomyosin ATPases has a large effect on physiological processes that are modulated by the balance of energy production and use, such as during increases in cardiac work and during ischemia (22). It is also worth noting that in their experiments, Garg et al. paced globally ischemia hearts at normal heart rates until VF spontaneously occurred. While this is a reasonable way to assess the effects of activation rate on the degeneration of electrical function, it does not parallel the typical progression of OHCA, which is thought to begin as an event of acute local ischemia and progress as stated in the introductory paragraph. Future optical mapping studies of local ischemia in fully contracting hearts could provide deeper insight into the initiation of VF and the progression of electrical failure. In light of clinical data that indicates increased incidence of asystole as the first recorded rhythm in OHCA (13), there is a clear need to understand the physiological mechanisms of asystole. Garg and colleagues have provided important new insights showing that rapid heart rate and β-adrenergic stimulation accelerate heterogeneous electrical depression and quicken the pace to asystole. Many questions remain, several of which are related to the role of β-adrenergic activity. When is the best time to administer exogeneous epinephrine during cardiac arrest (6, 19)? Do β-blockers prolong the maintenance of adequate levels of metabolic reserve during ischemia to maintain VF while also reducing defibrillation threshold? Could β-blockers alter mechanisms that maintain VF during ischemia and shorten the time to asystole (10) or increase defibrillation threshold (14)? Answers to these questions, and many others, will likely have significant impact on improving therapy for OHCA.

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.

Aims The first seconds of ventricular fibrillation (VF) are well organized and can consist of just one to two rotating waves (rotors). New rotors are spawned when local propagation block causes wave fragmentation. We hypothesized that this process, which leads to fully developed VF, begins at a consistent anatomic site. Methods and results We initiated VF with a stimulus timed to the local T-wave in 10 isolated pig hearts. Hearts were stained with a voltage-sensitive dye and four video cameras recorded electrical propagation panoramically across the epicardium. In each VF episode, we identified the position of the first wavebreak event that produced new rotor(s) that persisted for at least one cycle. The first such wavebreak occurred along the anterior right ventricular insertion (ARVI) in 26 of 32 VF episodes. In these episodes, wavebreak sites were 6 ± 4 mm from the midline of the ARVI. In the remaining 6 episodes, wavebreak sites were 24 ± 5 mm from the midline on either the LV or RV. During rapid pacing, conduction speed was locally depressed at the ARVI when waves crossed parallel to the midline. Action potential duration (APD) was slightly longer (2.2 ± 2.1 ms) at the ARVI compared with other sites ( P < 0.01). Temporal APD alternans were small and not unique to the break site, suggesting that dynamic APD properties were not the cause of wavebreak. Conclusion The ARVI is the dominant site for wavebreak at the onset of VF in normal myocardium. This may be due to the anatomic complexity of the region.

INTRODUCTION 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. METHODS Six open-chest pigs received intravenous sotalol (1.5 mg/kg) followed by verapamil (0.136 mg/kg). VF threshold (VFT) was determined by a burst pacing protocol. Two 20 seconds 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. RESULTS Sotalol alone and combined with verapamil significantly increased the VFT from 12.3 ± 4.1 to 20.3 ± 7.1 and 26.7 ± 8.6 mA compared with baseline (P

Quantifying the regional frequency variation in ventricular fibrillation (VF) may lead to focal strategies in treating human VF. We hypothesized that during human VF there are quantifiable regional frequency variations in the ventricles and they relate to underlying fixed myocardial substrate. In eight myopathic human hearts, we studied 35 VF episodes. The electrograms during VF were acquired simultaneously from the epicardium and endocardium using 2 electrode arrays each consisting of 112 electrodes. Regional characterization was performed using a ratio parameter derived from the dominant frequency analysis of the electrograms. The findings were related to the anatomical substrate using bipolar voltage maps. The results of the analysis indicate that LV had a larger dominant frequency (DF) span than RV (p = 0.0111) while there was no significant difference (p = 0.1488) in the DF span between LV freewall (FW) and septum (SE). Correlation of areas of abnormal myocardium with the dominant frequency feature matched only in 50% of the cases indicating that ion channel heterogeneity and time-varying physiological factors may play an important role in maintaining VF.

Our objective was to establish a novel model for the study of ventricular fibrillation (VF) in humans. We adopted the established techniques of optical mapping to human ventricles for the first time to determine whether human VF is the result of wave breaks and singularity point formation and is maintained by high-frequency rotors and fibrillatory conduction. We describe the technique of acquiring optical signals in human hearts during VF, their characteristics, and the feasibility of possible analyses that could be performed to elucidate mechanisms of human VF. We used explanted hearts from five cardiomyopathic patients who underwent transplantation. The hearts were Langendorff perfused with Tyrode solution (95% O2-5% CO2), and the potentiometric dye di-4-ANEPPS was injected as a bolus into the coronary circulation. Fluorescence was excited at 531 ± 20 nm with a 150-W halogen light source; the emission signal was long-pass filtered at 610 nm and recorded with a mapping camera. Fractional change of fluorescence varied between 2% and 12%. Average signal-to-noise ratio was 40 dB. The mean velocity of VF wave fronts was 0.25 ± 0.04 m/s. Submillimetric spatial resolution (0.65–0.85 mm), activation mapping, and transformation of the data to phase-based analysis revealed reentrant, colliding, and fractionating wave fronts in human VF. On many occasions the VF wave fronts were as large as the entire vertical length (8 cm) of the mapping field, suggesting that there are a limited number of wave fronts on the human heart during VF. Phase transformation of the optical signals allowed the first demonstration ever of phase singularity point, wave breaks, and rotor formation in human VF. This method provides opportunities for potential analyses toward elucidation of the mechanisms of VF and defibrillation in humans.

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.

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.

The objective of this study was to test the hypothesis that on the epicardium of the in vivo human heart, ventricular fibrillation (VF) consists of chaotic small wavefronts that constantly change paths.Despite the significance of VF to cardiovascular mortality, little is known about the wavefronts that constitute VF in humans.In 9 patients undergoing cardiac surgery, a single VF episode was induced by rapid pacing immediately after institution of cardiopulmonary bypass while recordings were made from 504 electrodes spaced 2 mm apart in a 20 cm(2) plaque held against the anterior left ventricle epicardium. A total of 26 segments of VF, each 2 s long, were analyzed. A computer algorithm identified individual wavefronts and classified them into groups that followed similar activation sequences.The mean activation rate was 5.8 +/- 1.8 (mean +/- SD) cycles/s. The wavefronts during each epoch were grouped into 9.4 +/- 7.1 different activation pathways, and 8.3 +/- 2.3 wavefronts followed each pathway. Individual wavefronts spread to activate an area of 5.1 +/- 3.0 cm(2) in the mapped region. The majority of the wavefronts propagated into the mapped region and/or propagated out of the mapped region into adjacent tissue, suggesting that the wavefronts were larger than 5.1 cm(2). Reentry was identified in only 16 of the 26 (62%) 2-s segments, always completed2 cycles, and lasted for 9.5 +/- 6.6% of these 16 epochs, which is 5.8% of the total duration of all the segments analyzed.VF wavefronts on the human epicardium are usually large, repeatedly follow distinct pathways, and only occasionally reenter. If these results for the left ventricular epicardium are representative of those for the entire ventricular mass, they do not support the hypothesis that human VF consists of small, constantly changing wavefronts, but rather suggest that there is significant organization of human VF.

We tested whether the interventions typically required for optical mapping affect activation patterns during ventricular fibrillation (VF). A 21 × 24 unipolar electrode array (1.5 mm spacing) was sutured to the left ventricular epicardium of 16 anesthetized pigs, and four episodes of electrically induced VF (30-s duration) were recorded. The hearts were then rapidly excised and connected to a Langendorff perfusion apparatus. Four of the hearts were controls, in which 24 additional VF episodes were then mapped. In the remaining 12 hearts, four VF episodes were mapped after isolation, four more episodes were mapped after exposure to the voltage-sensitive dye di-4-ANEPPS, and six more episodes were mapped after exposure to the electromechanical uncoupling agents diacetyl monoxime (DAM; 20 mmol/l, n = 6) or cytochalasin D (CytoD; 10 μmol/l, n = 6). VF episodes were separated by 4 min. VF activation patterns were quantified using custom pattern analysis algorithms. From comparisons with time-corrected control data, all interventions significantly changed VF patterns. Most changes were broadly consistent with slowing and regularization due to loss of excitability. Heart isolation had the largest effect on VF patterns, followed by CytoD, DAM, and dye.

It has been hypothesized that during ventricular fibrillation (VF), the fastest activating region, the dominant domain, contains a stable reentrant circuit called a mother rotor. This hypothesis postulates that the mother rotor spawns wavefronts that propagate to maintain VF elsewhere and implies that the ratio of wavefronts propagating off a region to those propagating onto it (propoff/propon) should be >1 for the dominant domain but P P

Background The 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 Results In‐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 P >0.05). From 2 to 10 minutes of LDVF , recordings exhibiting Purkinje activations were near the endocardium in dogs ( P 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 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 Conclusion These extracellular and intracellular findings about activation support the hypothesis that Purkinje activation propagates to stimulate WM during sinus rhythm, pacing, and LDVF .

Objective: Controlled reperfusion and secondary cardioplegia are used to minimize reperfusion injury. The mechanisms for their benefit are incompletely defined and may include attenuation of myocyte sodium uptake. Methods: Pigs had 1 hour of cardioplegic arrest followed by reperfusion with blood (control) or warm cardioplegic solution followed by blood (test). Reperfusion injury in the control and test groups was quantified by measuring changes of intramyocyte ion content with atomic absorption spectrometry and by analyzing electrophysiologic recovery from recordings of reperfusion arrhythmias. Results: Control animals had an increase in intramyocyte sodium content at 5 minutes after initiating reperfusion (+20.2 μmol/g dry weight, P < .04), whereas the test group had an insignificant decrease (–14.0 μmol/g dry weight, P = .33). The first rhythm after initiating reperfusion was more often ventricular fibrillation in the control group (100% vs 50%, P < .02), and the control group required more defibrillations to establish a nonfibrillating rhythm (4.5 ± 1.2 vs 1.1 ± 0.3, P < .03). Conclusions: Controlled reperfusion eliminated the increase in intramyocyte sodium that was observed in the control group at 5 minutes after cardioplegic arrest. This improvement in myocyte ion homeostasis during postcardioplegia reperfusion was associated with fewer reperfusion arrhythmias. These data support the hypothesis that attenuation of myocyte sodium gain during postischemic reperfusion is a mechanism by which controlled reperfusion and secondary cardioplegia are beneficial. (J Thorac Cardiovasc Surg 2000;119:1093-101)

d e t s v b b d e n g a r w r s d t p For more than a century, ventricular fibrillation (VF) has een considered a disorganized, uncoordinated tachyarhythmia. However, recent electrical and optical mapping tudies have demonstrated a certain level of organization uring VF in which some activation fronts are large and ctivate large portions of the ventricular myocardium. uestions about VF currently being investigated by maping studies include (1) how large are the activation fronts, 2) how repeatable are the activation sequences, (3) do onduction block and reentry occur more commonly in ome anatomic regions of the ventricles than others, and (4) hat are the mechanisms causing conduction block during F? The article by Choi et al in this issue of Heart Rhythm rovides new information about all of these questions using ptical mapping with the highest spatial and temporal samling yet reported. Because of the huge amount of data ollected by recording simultaneously from a large number f sites during VF, these authors developed computer algoithms for detecting different types of conduction block imilar to those developed by Rogers et al for analyzing ata obtained from electrical mapping of VF. Choi et al observed that activation fronts terminated requently during VF, with a mean number of wavefront erminations and or fractionations of 34/cm/s of VF. In pproximately half of these cases, the activation fronts terinated by decremental conduction in which the upstrokes f the action potentials became small before the front terinated. In one third of the cases, the activation fronts erminated by colliding with another activation front. In the emaining one sixth of cases, the activation fronts blocked at ites of discordant alternans. At these sites, block occurred t the node between two regions with alternans of the action otentials and in which the two regions were out of phase ith each other so that one region had a small action

It has been known for 85 years that ventricular fibrillation (VF) is a dynamic process. In a foundational study, Wiggers [(1)][1] used high-speed photography to show that VF progresses through a series of stages. Much more has been learned as cardiac mapping technology has progressed. In cardiac

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 …

Few techniques have been developed for deriving quantitative measures of activation patterns during ventricular fibrillation (VF). Such measures have many potential applications, for example, assessing the effects of time, drugs, or electrical interventions. We have developed a new framework for quantifying VF patterns as mapped from an array of approximately 500 unipolar electrodes. Individual activation wavefronts are isolated from one another using an algorithm that groups together adjacent active electrogram samples (dV/dt-0.5 V/sec). Contacts between wavefronts are detected: these include fractionations, in which a single wavefront breaks into multiple wavefronts, and collisions, in which multiple wavefronts coalesce to form a new wavefront. The timing and contact relationships between wavefronts are summarized as a directed graph. From this model of the VF episode, we derive several parameters: number of wavefronts, number of fractionations, number of collisions, mean wavefront size, mean area swept out, and mean duration. As an example of this analysis, we computed these parameters in six open-chest pigs at 5, 10, 15, and 20 sec after electrical induction of VF. The number of wavefronts and the number of collisions decreased, whereas the mean wavefront size and mean area swept out increased during this period. These results are consistent with previous studies showing a recovery of organization during the first minute of VF.

We developed a new method for fabricating plunge needle electrodes for use in cardiac mapping. The needles have 12 electrodes with 1-mm spacing, are 0.5 mm in diameter, and are fabricated from fiberglass reinforced epoxy. They are stiff enough to be easily inserted into beating hearts and durable enough to be reused many times. We found that these new needles elicit smaller, more quickly resolving injury potentials, and when inserted in a row with 2-mm spacing, disrupt ventricular fibrillation activation patterns less than traditional steel needles.

Received January 25, 2009; accepted October 6, 2009. Phase is a descriptor that tracks the progression of a defined region of myocardium through the action potential and has been demonstrated to be an effective parameter in analyzing spatiotemporal changes during fibrillation. In this review, the basic principles behind phase mapping are presented mainly in the context of ventricular fibrillation (VF), atrial fibrillation (AF), and fibrillation from experimental monolayer data. During fibrillation, the phase distribution changes over time, depending on activation patterns. Analyzing these phase patterns provides us insight into the fibrillatory dynamics and helps clarify the mechanisms of cardiac fibrillation and modulation by interventions. Winfree1 introduced the phase analysis to study cardiac fibrillation in the late eighties. This time-encoding technique deals with a scenario where the activation periods are the same over the surface being mapped. To deal with the scenario of varying activation period over the mapped surface (common in animal and human fibrillation models), Gray et al2,3⇓ introduced the state-space encoding concept from nonlinear dynamics. In analyzing spatiotemporal phase maps constructed from electric or optical mapping of the surface of heart during VF, points around which the phase progresses through a complete cycle from −π to +π are of great interest. At these points, the phase becomes indeterminate and the activation wave fronts hinge to these points and rotate around them in an organized fashion. These points in the phase map are called phase singularity (PS) points. Bray et al4 developed a procedure to locate PS points in a phase map. Nash et al5 used phase mapping to study the entire ventricular epicardium of human hearts with a sock containing 256 unipolar contact electrodes. The development of this phase mapping tool has led to better understanding of fibrillation dynamics as evidenced by the …

Endocardial mapping has suggested that Purkinje fibers may play a role in the maintenance of long-duration ventricular fibrillation (LDVF). To determine the influence of Purkinje fibers on LDVF, we chemically ablated the Purkinje system with Lugol solution and recorded endocardial and transmural activation during LDVF. Dog hearts were isolated and perfused, and the ventricular endocardium was exposed and treated with Lugol solution ( n = 6) or normal Tyrode solution as a control ( n = 6). The left anterior papillary muscle endocardium was mapped with a 504-electrode (21 × 24) plaque with electrodes spaced 1 mm apart. Transmural activation was recorded with a six-electrode plunge needle on each side of the plaque. Ventricular fibrillation (VF) was induced, and perfusion was halted. LDVF spontaneously terminated sooner in Lugol-ablated hearts than in control hearts (4.9 ± 1.5 vs. 9.2 ± 3.2 min, P = 0.01). After termination of VF, both the control and Lugol hearts were typically excitable, but only short episodes of VF could be reinduced. Endocardial activation rates were similar during the first 2 min of LDVF for Lugol-ablated and control hearts but were significantly slower in Lugol hearts by 3 min. In control hearts, the endocardium activated more rapidly than the epicardium after 4 min of LDVF with wave fronts propagating most often from the endocardium to epicardium. No difference in transmural activation rate or wave front direction was observed in Lugol hearts. Ablation of the subendocardium hastens VF spontaneous termination and alters VF activation sequences, suggesting that Purkinje fibers are important in the maintenance of LDVF.

Recent studies suggest that during ventricular fibrillation (VF) epicardial vessels may be a site of conduction block and the posterior papillary muscle (PPM) in the left ventricle (LV) may be the location of a "mother rotor." The goal of this study was to obtain evidence to support or refute these possibilities.Epicardial activation over the posterior LV and right ventricle (RV) was mapped during the first 20 s of electrically induced VF in six open-chest pigs with a 504 electrode plaque covering a 20 cm(2) area centered over the posterior descending artery (PDA).The locations of epicardial breakthrough as well as reentry clustered in time and space during VF. Spatially, reentry occurred significantly more frequently over the LV than the RV in all 48 episodes, and breakthrough clustered near the PPM (p0.001). Significant temporal clustering occurred in 79% of breakthrough episodes and 100% of reentry episodes. These temporal clusters occurred at different times so that there was significantly less breakthrough when reentry was present (p0.0001). Conduction block occurred significantly more frequently near the PDA than elsewhere.The PDA is a site of epicardial block which may contribute to VF maintenance. Epicardial breakthrough clusters near the PPM. Reentry also clusters in space but at a separate site. The fact that breakthrough and reentry cluster at different locations and at different times supports the possibility of a drifting filament at the PPM so that at times reentry is present on the surface but at other times the reentrant wavefront breaks through to the epicardium.

It has been proposed that VF waves emanate from stable localized sources, often called "mother rotors." However, evidence for the existence of these rotors is conflicting. Using a new panoramic optical mapping system that can image nearly the entire ventricular epicardium, we recently excluded epicardial mother rotors as the drivers of Wiggers' stage II VF in the isolated swine heart. Furthermore, we were unable to find evidence that VF requires sustained intramural sources. The present study was designed to test the following hypotheses: 1. VF is driven by a specific region, and 2. Rotors that are long-lived, though not necessarily permanent, are the primary generators of VF wavefronts. Using panoramic optical mapping, we mapped VF wavefronts from 6 isolated swine hearts. Wavefronts were tracked to characterize their activation pathways and to locate their originating sources. We found that the wavefronts that participate in epicardial reentry were not confined to a compact region; rather they activated the entire epicardial surface. New wavefronts feeding into the epicardial activation pattern were generated over the majority of the epicardium and almost all of them were associated with rotors or repetitive breakthrough patterns that lasted for less than 2 s. These findings indicate that epicardial wavefronts in this model are generated by many transitory epicardial sources distributed over the entire surface of the heart.

Background— The roles of Purkinje fibers (PFs) and focal wave fronts, if any, in the maintenance of ventricular fibrillation (VF) are unknown. If PFs are involved in VF maintenance, it should be possible to map wave fronts propagating from PFs into the working ventricular myocardium during VF. If wave fronts ever arise focally during VF, it should be possible to map them appearing de novo. Methods and Results— Six canine hearts were isolated, and the left main coronary artery was cannulated and perfused. The left ventricular cavity was exposed, which allowed direct endocardial mapping of the anterior papillary muscle insertion. Nonperfused VF was induced, and 6 segments of data, each 5 seconds long, were analyzed during 10 minutes of VF. During 36 segments of data that were analyzed, 1018 PF or focal wave fronts of activation were identified. In 534 wave fronts, activation was mapped propagating from working ventricular myocardium to PF. In 142 wave fronts, activation was mapped propagating from PF to working ventricular myocardium. In 342 wave fronts, activation was mapped arising focally. More than 1 of these 3 patterns could occur in the same wave front. Conclusions— PFs are highly active throughout the first 10 minutes of VF. In addition to retrograde propagation from the working ventricular myocardium to PFs, antegrade propagation occurs from PFs to working ventricular myocardium, which suggests PFs are important in VF maintenance. Prior plunge needle recordings in dogs indicate activation propagates from the endocardium toward the epicardium after 1 minute of VF, which suggests that focal sites on the endocardium may represent foci and not breakthrough. If so, in addition to reentry, abnormal automaticity or triggered activity may also occur during VF.

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, P0.05). 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 gradients2 msec/mm were present between many clusters and approximately 90% of restitution slopes were1. 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.

Background A single stationary mother rotor has been hypothesized to be responsible for maintenance of ventricular fibrillation (VF) in the guinea pig. Previous studies have pointed to the ventricular septum as a possible location for a mother rotor in the pig heart. Objectives The purpose of this study was to test the hypothesis that a mother rotor is located in the septum. Methods In seven open-chest pigs, we mapped the first 20 seconds of electrically induced VF simultaneously from the posterior left ventricle (LV) and right side of the septum with two electrical arrays. Each array contained 504 electrodes (21 × 24) spaced 2 mm apart in the LV and 1.5 mm apart in the septum. Results The percentage of VF wavefronts that formed reentrant circuits was significantly lower in the septum (1% ± 1% [mean ± SD]) than in the LV (2% ± 1%). The peak frequency during VF also was significantly smaller in the septum (8.6 Hz ± 3.0 Hz) than in the LV (10.4 Hz ± 3.4 Hz). The mean direction of spread of activation of VF wavefronts was away from the region where the posterior LV free wall intersects the posterior septum in both the LV and septum. Conclusions The lower incidence of reentry and lower peak frequency in the mapped region of the septum than in the LV indicate that a mother rotor is not present in swine on the RV side of the septum. The mean directions of the VF activation sequences in the LV and septum suggest that if a mother rotor is present during the first 20 seconds of VF, it exists where the posterior LV free wall joins the septum, the region where the posterior papillary muscle inserts.

Modeling of Biventricular ATP. Introduction: ICDs often are programmed with antitachycardia pacing (ATP) as the first response to ventricular tachycardia (VT). Many ICDs have an additional lead available for ventricular pacing. We hypothesized that using the additional lead for ATP would improve therapy by advancing the orthodromic wavefront, thereby reducing the size of the excitable gap and inducing block of all reentrant activity. Methods and Results: Monomorphic VT was initiated in a thin-walled model of rabbit ventricular myocardium that included an apical infarct and anatomically realistic dimensions. ATP with up to eight pulses was delivered at 90% of VT cycle length to one (conventional) or two (biventricular) stimulation areas. Stimulation areas were adjusted from 0.017 cm 2 to 0.169 cm 2 to modulate interactions between the antidromic and VT wavefronts, and between the orthodromic wavefront and the VT's refractory region. During conventional ATP, we found that larger stimulation areas terminated the VT in three pulses. Continued pacing after termination caused VT reinitiation in the reversed direction in some instances. With smaller stimulation areas, conventional ATP simply reset the circuit. During biventricular ATP, larger stimulation areas terminated VT in one pulse. There were no instances of reinitiation with reversal. However, with smaller stimulation areas, prolongation of refractoriness near the additional stimulation area facilitated induction of functional reentry with pathways modified by continued pacing. Conclusion: Our modeling suggests that biventricular ATP is superior to conventional ATP under conditions where the additional ventricular lead effectively advances the orthodromic wavefront. Failure to achieve this advancement poses a risk of VT acceleration.

It has been proposed that ventricular fibrillation (VF) is driven by sustained reentry. However, mapping studies have not detected such “mother rotors” in large mammalian hearts. We mapped VF from three 21×12 unipolar electrode arrays in 6 pigs. Two of the arrays were adjacent to each other on the left-ventricular epicardium. Electrode spacing was 2 mm. The third array consisted of 21 needles (0.5-mm diameter, 12 electrodes, 1-mm spacing) inserted in a row (2-mm spacing) between the epicardial arrays. A total of 88 5-second VF epochs were analyzed with automatic reentry detection algorithms. Although intramural reentry was sporadically present (29 total occurrences), it was always short-lived with a mean life span of 127±57 ms. However, in 3 of the 6 animals, sustained epicardial reentry (ie, reentry persisting for more than a few cycles) was consistently present, often lasting for several seconds. For each epoch, we computed indices characterizing (1) the relative duration of reentry on the two epicardial arrays ( R ), (2) the flow of wavefronts between epicardial arrays ( W ), and (3) the relative activation rates of the two epicardial arrays ( F ). R did not correlate with either W or F indicating that rotor-containing regions did not produce a net outflow of wavefronts and were not faster than neighboring regions. Thus, sustained epicardial, but not intramural, rotors were consistently present in some large animal hearts during VF. However, we found no evidence that these rotors were responsible for sustaining VF through the mechanisms outlined in the mother rotor hypothesis.

We present a new quantitative framework for analyzing epicardial activation patterns recorded by high-resolution mapping during ventricular fibrillation (VF). Individual activation wavefronts are isolated from one another using an algorithm that groups adjacent active electrogram samples (dV/dt

A new method was developed for quantifying the repeatability of activation wavefronts during VF. Individual wavefronts were isolated and partitioned into clusters of similar wavefronts using a correlation technique. Repeatability was quantified by the number and size of resulting clusters: a few large clusters indicated repeatability while many small clusters indicated disorganization. This analysis was performed on three example datasets: 15 beats of normal sinus rhythm, 1 sec of VF 5 sec after initiation, and 1 sec of VF 20 sec after initiation. In these examples, normal sinus rhythm was most repeatable and VF was more repeatable 20 s after initiation than 5 s after initiation.

Objectives This study was designed to characterize the organization of ventricular fibrillation (VF) on the endocardium of humans. Background Most 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. Methods Electrograms 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. Results The 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. Conclusions Ventricular 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.

Single Lesion Lowers ADFT.Introduction: This study investigated a hybrid approach to reduce the atrial defibrillation threshold (ADFT) by determining the effect of a single linear radiofrequency ablation (RFA) lesion on both the ADFT and activation patterns during atrial fibrillation (AF). Methods and Results: In 18 open chest sheep (45 to 57 kg), coil defibrillation electrodes were placed in a superior vena cava/right ventricular configuration. AF was induced by burst pacing and maintained with acetyl β-methylcholine (2 to 42 μL/min). ADFTs were obtained before and after a linear RFA lesion was created in the left atrium (LAL; n = 6), right atrium (RAL; n = 6), or neither atrium as a control (n = 6). In animals receiving an LAL, a 504-unipolar-electrode plaque was sutured to the LA. For animals receiving an RAL, two 504-electrode plaques were placed, one each on the LA and RA. From each plaque, activations were recorded before and after ADFT shocks, and organizational characteristics of activations were analyzed using algorithms that track individual wavefronts. In sham-treated controls, the ADFT did not change. In contrast, LAL reduced ADFT energy 29%, from 4.5 ± 2.3 J to 3.2 ± 2.0 J (P < 0.05). RAL reduced ADFT energy 25%, from 2.0 ± 0.9 J to 1.5 ± 0.7 J (P < 0.05). AF activation was substantially more organized after RFA than before RFA for both the RAL- and LAL-treated animals. Conclusion: A single RFA lesion in either the RA or LA reduces the ADFT in this sheep model. This decrease is associated with an increase in fibrillatory organization.

Background —Little is known about the effects of heart failure (HF) on the defibrillation threshold (DFT) and the characteristics of activation during ventricular fibrillation (VF). Methods and Results —HF was induced by rapid right ventricular (RV) pacing for at least 3 weeks in 6 dogs. Another 6 dogs served as controls. Catheter defibrillation electrodes were placed in the RV apex, the superior vena cava, and the great cardiac vein (CV). An active can coupled to the superior vena cava electrode served as the return for the RV and CV electrodes. DFTs were determined before and during HF for a shock through the RV electrode with and without a smaller auxiliary shock through the CV electrode. VF activation patterns were recorded in HF and control animals from 21×24 unipolar electrodes spaced 2 mm apart on the ventricular epicardium. Using these recordings, we computed a number of quantitative VF descriptors. DFT was unchanged in the control dogs. DFT energy was increased 79% and 180% (with and without auxiliary shock, respectively) in HF compared with control dogs. During but not before HF, DFT energy was significantly lowered (21%) by addition of the auxiliary shock. The VF descriptors revealed marked VF differences between HF and control dogs. The differences suggest decreased excitability and an increased refractory period during HF. Most, but not all, descriptors indicate that VF was less complex during HF, suggesting that VF complexity is multifactorial and cannot be expressed by a scalar quantity. Conclusions —HF increases the DFT. This is partially reversed by an auxiliary shock. HF markedly changes VF activation patterns.

Pacing During Ventricular Fibrillation.Introduction: Recent studies showed that pacing atrial and ventricular fibrillation (VF) is possible. The studies presented here determined which parameters influence the efficacy of a pacing train to capture fibrillating ventricular myocardium. Electrode type, current strength, order of pacing trains, polarity, and VF morphology preceding the pacing trains were investigated. Methods and Results: A 504-electrode recording plaque sutured to the right ventricle of pig hearts was used to record the activations of VF and those resulting from the pacing stimulation. Capture of VF by pacing was determined by observing an animated display of the first temporal derivative of the electrograms. A series of electrodes in a line captured the heart more frequently during VF than did a point electrode. Increasing the current strength to 10× diastolic pacing threshold increased the incidence of capture, but increasing this strength further did not. The second or third train of 40 stimuli had greater capture rates than did the first train during the same VF episode. Anodal and cathodal unipolar, and bipolar stimulation were equally efficacious in capturing VF. VF activation during the 1-second interval preceding pacing was more organized for pacing trains that captured than those that did not. The highest incidence of capture, 46% to 61% of pacing trains, occurred with a line of electrodes at 10× diastolic pacing threshold delivered by the second or third train. Conclusion: The probability of a pacing train capturing fibrillating myocardium can be influenced by the pacing protocol parameters.

Background —Shocks of identical strength and timing sometimes induce ventricular fibrillation (VFI) and other times do not (NoVFI). To investigate this probabilistic behavior, a shock strength near the upper limit of vulnerability, ULV 50 , was delivered to yield equal numbers of VFI and NoVFI episodes. Methods and Results —In 6 pigs, a 504-electrode sock was pulled over the ventricles. ULV 50 was determined by scanning the T wave. S 1 pacing was from the right ventricular apex. Ten S 2 shocks of approximate ULV 50 strength were delivered at the same S 1 -S 2 coupling interval. Intercycle interval (ICI) and wave front conduction time (WCT) were determined for the first 5 postshock cycles. ICI and the WCT of cycle 1 were not different for VFI versus NoVFI episodes ( P =0.3). Beginning at cycle 2, ICI was shorter and WCT was longer for VFI than NoVFI episodes ( P Conclusions —The first cycle after shocks of the same strength (ULV 50 ) delivered at the same time has the same activation pattern regardless of shock outcome. During successive cycles, however, a progressive decrease in ICI and increase in WCT occur during VFI but not NoVFI episodes. These findings suggest shock outcome is (1) deterministic but exquisitely sensitive to differences in electrophysiological state at the time of the shock that are too small to detect or (2) probabilistic and not determined until after the first postshock cycle.

Until 20 years ago, it was thought that atrial and ventricular fibrillation were highly disorganized, with tens or hundreds of tiny wandering wavelets simultaneously present and following ever-changing pathways.1 In this model, the disorganization is due to intrinsic heterogeneity of refractory periods that causes transitory islets of refractoriness about which wavelets circulate. However, about two decades ago, a new view emerged. This model was based on the theoretical2 3 4 5 and experimental6 finding that the heart could support electrical waves that rotate about a functional, rather than anatomical, obstacle. These so-called rotors were thought to be the primary “organizing centers” for fibrillation, and refractory period heterogeneity was a secondary factor, possibly modulating and masking the activity of rotors, but not driving the rhythm.7 Indeed, electrical and optical mapping have demonstrated a considerable organization during ventricular fibrillation (VF).8 9 10 11 12 13 These studies indicate that activation fronts are frequently large during fibrillation and follow pathways that are centimeters in length. In addition, many of these activation fronts follow similar pathways. Surprisingly, however, after the first few seconds of VF, rotors are rarely observed. In several recent mapping studies, only 2% to 8% of activation fronts were identified as parts of reentrant circuits. …

Abstract —Functional reentry has been hypothesized to be an underlying mechanism of ventricular fibrillation (VF); however, its contribution to activation patterns during fully developed VF is unclear. We applied new quantitative pattern analysis techniques to mapping data acquired from a 21×24 unipolar electrode array (2-mm spacing) located on the ventricular epicardium of 7 open-chest, unsupported pigs. Data epochs 4 seconds long beginning 1, 10, 20, 30, and 40 seconds after electrical induction were analyzed. Reentrant circuits were automatically identified and quantified. We found that 2.3% of activation pathways could unambiguously be classified as reentrant. From scaling analysis, an additional 28% of the pathways may also have been reentrant. Reentry was short-lived with 1.5±1.5 (mean±SD) complete cycles per circuit. The fraction of reentrant pathways, number of cycles per circuit, cycle duration, and area and perimeter of the cores all increased significantly as VF progressed. Core drift speed decreased significantly. Neither the orientation of the cores nor the direction of drift was well predicted by the epicardial fiber orientation ( r 2 =0.108 and 0.138, respectively, by linear regression). Reentrant circuits were clustered in regions of the epicardium. We conclude the following: (1) Epicardial reentry is relatively uncommon and short-lived during VF, suggesting either that sustained reentry is transmural or that mechanisms governing sustained reentry are relatively unimportant to the dynamics of VF. (2) Reentrant circuits become more common, larger, and longer-lived as VF progresses, which may explain a recently observed increase in VF organization during the first minute of VF. (3) The conditions necessary to induce and sustain reentry are distributed nonuniformly.

In high-resolution cardiac mapping, signals are simultaneously recorded from hundreds of electrodes in contact with the myocardium and then analyzed to reveal the underlying activation pattern. Activation mapping has a long history in both experimental and clinical cardiac electrophysiology and has also been used to study other organ systems. Much of the current emphasis in mapping technology is on data analysis-ways to extract useful information from the voluminous data stream-rather than on the acquisition of the data. Hence, in this article, the authors review the traditional method for analyzing and interpreting mapping data, isochronal mapping, and then report on additional techniques that have recently emerged. The authors focus on techniques applicable to quantifying the dynamics of complex tachyarrhythmias such as ventricular fibrillation (VF) and atrial fibrillation (AF).

Forearm glucose uptake and lactate balance across the forearm were determined in normal subjects during 100-gm. oral glucose tolerance tests (GTT) before and after a lowcarbohydrate diet; in addition, β-hydroxybutyrate and acetoacetateresponses were measured following carbohydrate restriction. After a low-carbohydrate diet, glucose tolerance was significantly impaired (dietary diabetes) and the rise in seruminsulin levels was frequently, but not invariably, delayed. Forearm glucose utilization, however, was not significantly decreased at any phase of the GTT or during the GTT as a whole. With a normal diet, lactate levels rose immediately after glucose loading, reaching peak concentrations at sixty minutes and falling progressively thereafter; this rise was associated with lactate utilization by the forearm and the subsequent fall in plasma concentrations with lactate release. In contrast, following carbohydrate restriction lactate concentrations were initially reduced by glucose administration, this reduction taking place despite continuing lactate release from the forearm. These results suggest that after glucose loading the shape of the lactate response curve is not determined primarily by changes in peripheral lactate balance. Marked elevation in basal FFA, β-hydroxybutyrate, and acetoacetate levels accompanied carbohydrate restriction. FFA and β-hydroxybutyrate concentrations were immediately decreased and acetoacetate levels initially increased by glucose loading, the latter declining only during the second hour of the GTT; throughout the test, acetoacetate was taken up by the forearm while β-hydroxybutyrate was released. Basal FFA and β-hydroxybutyrate concentrations were not correlated with the degree of glucose intolerance induced in the volunteers. The results show that the impairment of glucose tolerance following carbohydrate restriction is not the result of decreased peripheral glucose utilization. It is suggested that the major cause of dietary diabetes is a delay in the hepatic uptake of the glucose load and that this is primarily the. result of low hepatic glucokinase activity rather than delayed insulin secretion.

Coronary collateral development was examined in 34 pigs after gradual occlusion of the left circumflex coronary artery (LCX) with an Ameroid constrictor. Collateral development was assessed by measurements of myocardial blood flow and regional myocardial function at rest and during exercise over a 16-wk period after placement of the constrictor. Coronary collateral development was adequate to prevent severe infarction and restore blood flow to the collateral-dependent LCX region within 3-7 wk. Infarction averaged 5.0 +/- 1.3% of the LCX region. Blood flows at rest were 1.05 +/- 0.14 and 1.13 +/- 0.15 ml.min-1.g-1 in the subendocardium of the collateral and control regions, respectively, 7 wk postoperatively. Concurrently, collateral vessel development supported normal myocardial function at rest as determined by systolic wall thickening in the LCX region. However, collateral development was limited, since blood flows during moderate and severe exercise were reduced in the LCX region compared with control and left anterior descending and right coronary regions. Blood flow ratios (collateral/control flow) during severe exercise 3 wk postoperatively were 0.23 +/- 0.03 and 0.57 +/- 0.05 in the subendocardium and subepicardium and were constant throughout the 16-wk period throughout the study. Myocardial function of the collateral region also was reduced during exercise and a 30-min recovery period. We suggest that this limited coronary collateral circulation, which develops in response to gradual coronary occlusion in swine, serves as a model for the human collateral circulation for the study of protocols to alter growth and development of coronary collateral vessels.

In order to investigate spatial variations in ventricular fibrillation (VF), activation rates during VF in pigs were estimated on a grid of 504 epicardial sites using the maximum entropy (ME) method. ME spectral estimates were obtained from unipolar electrograms recorded with a 21/spl times/24 array of epicardial electrodes (1 mm spacing) during electrically induced VF. The frequency associated with the most power in each ME spectrum was denoted the peak frequency (PFreq). The authors compared ME estimates of mean activation interval (1/PFreq) to mean activation intervals (MAI) obtained by picking the local minimum dV/dt. The Class III drug artilide was used to extend the range of activation rate. A significant positive correlation was found between 1/PFreq and MAI. ME estimates of 1/PFreq did not correlate better with MAI than previous estimates obtained using the Fast Fourier Transform. The spatial distribution of activation rate varied dynamically during the first 12 seconds of VF.

A technique for quantitatively describing spatiotemporal myocardial activation dynamics in the frequency domain was developed and compared to results from the time domain. Peak frequencies (PFreq) from the FFT power spectrum were extracted from unipolar electrograms collected from 504 epicardial recording sites (1 mm separation) during multiple runs of electrically-induced ventricular fibrillation (VF) in open-chest pigs. To confirm that PFreq provides a reasonable metric of mean activation interval (MAI) during VF, the authors constructed spatial plots of PFreq over the mapped region and compared PFreq to the MAI at nine points equally-spaced over the mapped region during 2 s segments (n=20) of mapping data taken 1, 5, and 10 s after VF induction. To obtain data over a range of physiologically-relevant MAIs, a potent class III drug was used to decrease PFreq during VF. Regression analyses for all data revealed a statistically significant positive correlation between PFreq and MAI (R/sup 2/=0.828, p