Synchronization of Early Afterdepolarizations and Arrhythmogenesis in Heterogeneous Cardiac Tissue Models

Early afterdepolarizations (EADs) are linked to both triggered arrhythmias and reentrant arrhythmias by causing premature ventricular complexes (PVCs), focal excitations, or heterogeneous tissue substrates for reentry formation. However, a critical number of cells that synchronously exhibit EADs are needed to result in arrhythmia triggers and substrates in tissue. In this study, we use mathematical modeling and computer simulations to investigate EAD synchronization and arrhythmia induction in tissue models with random cell-to-cell variations. Our major observations are as follows. Random cell-to-cell variations in action potential duration without EAD presence do not cause large dispersion of refractoriness in well-coupled tissue. In the presence of phase-2 EADs, the cells may synchronously exhibit the same number of EADs or no EADs with a very small dispersion of refractoriness, or synchronize regionally to result in large dispersion of refractoriness. In the presence of phase-3 EADs, regional synchronization leads to propagating EADs, forming PVCs in tissue. Interestingly, even though the uncoupled cells exhibit either no EAD or only a single EAD, when these cells are coupled to form a tissue, more than one PVC can occur. When the PVCs occur at different locations and time, multifocal arrhythmias are triggered, with the foci shifting in space and time in an irregular manner. The focal arrhythmias either spontaneously terminate or degenerate into reentrant arrhythmias due to heterogeneities and spatiotemporal chaotic dynamics of the foci.     

Calcium-Voltage Coupling in the Genesis of Early and Delayed Afterdepolarizations in Cardiac Myocytes

Early afterdepolarizations (EADs) and delayed afterdepolarizations (DADs) are voltage oscillations known to cause cardiac arrhythmias. EADs are mainly driven by voltage oscillations in the repolarizing phase of the action potential (AP), while DADs are driven by spontaneous calcium (Ca) release during diastole. Because voltage and Ca are bidirectionally coupled, they modulate each other’s behaviors, and new AP and Ca cycling dynamics can emerge from this coupling. In this study, we performed computer simulations using an AP model with detailed spatiotemporal Ca cycling incorporating stochastic openings of Ca channels and ryanodine receptors to investigate the effects of Ca-voltage coupling on EAD and DAD dynamics. Simulations were complemented by experiments in mouse ventricular myocytes. We show that: 1) alteration of the Ca transient due to increased ryanodine receptor leakiness and/or sarco/endoplasmic reticulum Ca ATPase activity can either promote or suppress EADs due to the complex effects of Ca on ionic current properties; 2) spontaneous Ca waves also exhibit complex effects on EADs, but cannot induce EADs of significant amplitude without the participation of I_Ca,L; 3) lengthening AP duration and the occurrence of EADs promote DADs by increasing intracellular Ca loading, and two mechanisms of DADs are identified, i.e., Ca-wave-dependent and Ca-wave-independent; and 4) Ca-voltage coupling promotes complex EAD patterns such as EAD alternans that are not observed for solely voltage-driven EADs. In conclusion, Ca-voltage coupling combined with the nonlinear dynamical behaviors of voltage and Ca cycling play a key role in generating complex EAD and DAD dynamics observed experimentally in cardiac myocytes, whose mechanisms are complex but analyzable.     

Mechanisms of Premature Ventricular Complexes Caused by QT Prolongation

QT prolongation, due to lengthening of the action potential duration in the ventricles, is a major risk factor of lethal ventricular arrhythmias. A widely known consequence of QT prolongation is the genesis of early afterdepolarizations (EADs), which are associated with arrhythmias through the generation of premature ventricular complexes (PVCs). However, the vast majority of the EADs observed experimentally in isolated ventricular myocytes are phase-2 EADs, and whether phase-2 EADs are mechanistically linked to PVCs in cardiac tissue remains an unanswered question. In this study, we investigate the genesis of PVCs using computer simulations with eight different ventricular action potential models of various species. Based on our results, we classify PVCs as arising from two distinct mechanisms: repolarization gradient (RG)-induced PVCs and phase-2 EAD-induced PVCs. The RG-induced PVCs are promoted by increasing RG and L-type calcium current and are insensitive to gap junction coupling. EADs are not required for this PVC mechanism. In a paced beat, a single or multiple PVCs can occur depending on the properties of the RG. In contrast, phase-2 EAD-induced PVCs occur only when the RG is small and are suppressed by increasing RG and more sensitive to gap junction coupling. Unlike with RG-induced PVCs, in each paced beat, only a single EAD-induced PVC can occur no matter how many EADs in an action potential. In the wide parameter ranges we explore, RG-induced PVCs can be observed in all models, but the EAD-induced PVCs can only be observed in five of the eight models. The links between these two distinct PVC mechanisms and arrhythmogenesis in animal experiments and clinical settings are discussed.     

Electrotonic suppression of early afterdepolarizations in isolated rabbit Purkinje myocytes

Many studies suggest that early afterdepolarizations (EADs) arising from Purkinje fibers initiate triggered arrhythmias under pathological conditions. However, electrotonic interactions between Purkinje and ventricular myocytes may either facilitate or suppress EAD formation at the Purkinje-ventricular interface. To determine conditions that facilitated or suppressed EADs during Purkinje-ventricular interactions, we coupled single Purkinje myocytes and aggregates isolated from rabbit hearts to a passive model cell via an electronic circuit with junctional resistance (R(j)). The model cell had input resistance (R(m,v)) of 50 M Omega, capacitance of 39 pF, and a variable rest potential (V(rest,v)). EADs were induced in Purkinje myocytes during superfusion with 1 microM isoproterenol. Coupling at high R(j) to normally polarized V(rest,v) established a repolarizing coupling current during all phases of the Purkinje action potential. This coupling current preferentially suppressed EADs in single cells with mean membrane resistance (R(m,p)) of 297 M Omega, whereas EAD suppression in larger aggregates with mean R(m,p) of 80 M Omega required larger coupling currents. In contrast, coupling to elevated V(rest,v) established a depolarizing coupling current during late phase 2, phase 3, and phase 4 that facilitated EAD formation and induced spontaneous activity in single Purkinje myocytes and aggregates. These results have important implications for arrhythmogenesis in the infarcted heart when reduction of the ventricular mass due to scarring alters the R(m,p)-to-R(m,v) ratio and in the ischemic heart when injury currents are established during coupling between polarized Purkinje myocytes and depolarized ventricular myocytes.     

Dynamics of early afterdepolarization-mediated triggered activity in cardiac monolayers

Early afterdepolarizations (EADs) are voltage oscillations that occur during the repolarizing phase of the cardiac action potential and cause cardiac arrhythmias in a variety of clinical settings. EADs occur in the setting of reduced repolarization reserve and increased inward-over-outward currents, which intuitively explains the repolarization delay but does not mechanistically explain the time-dependent voltage oscillations that are characteristic of EADs. In a recent theoretical study, we identified a dual Hopf-homoclinic bifurcation as a dynamical mechanism that causes voltage oscillations during EADs, depending on the amplitude and kinetics of the L-type Ca(2+) channel (LTCC) current relative to the repolarizing K(+) currents. Here we demonstrate this mechanism experimentally. We show that cardiac monolayers exposed to the LTCC agonists BayK8644 and isoproterenol produce EAD bursts that are suppressed by the LTCC blocker nitrendipine but not by the Na(+) current blocker tetrodoxin, depletion of intracellular Ca(2+) stores with thapsigargin and caffeine, or buffering of intracellular Ca(2+) with BAPTA-AM. These EAD bursts exhibited a key dynamical signature of the dual Hopf-homoclinic bifurcation mechanism, namely, a gradual slowing in the frequency of oscillations before burst termination. A detailed cardiac action potential model reproduced the experimental observations, and identified intracellular Na(+) accumulation as the likely mechanism for terminating EAD bursts. Our findings in cardiac monolayers provide direct support for the Hopf-homoclinic bifurcation mechanism of EAD-mediated triggered activity, and raise the possibility that this mechanism may also contribute to EAD formation in clinical settings such as long QT syndromes, heart failure, and increased sympathetic output.     

Targeting the late component of the cardiac L-type Ca2+ current to suppress early afterdepolarizations

Early afterdepolarizations (EADs) associated with prolongation of the cardiac action potential (AP) can create heterogeneity of repolarization and premature extrasystoles, triggering focal and reentrant arrhythmias. Because the L-type Ca²⁺ current (I_Ca,L) plays a key role in both AP prolongation and EAD formation, L-type Ca²⁺ channels (LTCCs) represent a promising therapeutic target to normalize AP duration (APD) and suppress EADs and their arrhythmogenic consequences. We used the dynamic-clamp technique to systematically explore how the biophysical properties of LTCCs could be modified to normalize APD and suppress EADs without impairing excitation–contraction coupling. Isolated rabbit ventricular myocytes were first exposed to H₂O₂ or moderate hypokalemia to induce EADs, after which their endogenous I_Ca,L was replaced by a virtual I_Ca,L with tunable parameters, in dynamic-clamp mode. We probed the sensitivity of EADs to changes in the (a) amplitude of the noninactivating pedestal current; (b) slope of voltage-dependent activation; (c) slope of voltage-dependent inactivation; (d) time constant of voltage-dependent activation; and (e) time constant of voltage-dependent inactivation. We found that reducing the amplitude of the noninactivating pedestal component of I_Ca,L effectively suppressed both H₂O₂- and hypokalemia-induced EADs and restored APD. These results, together with our previous work, demonstrate the potential of this hybrid experimental–computational approach to guide drug discovery or gene therapy strategies by identifying and targeting selective properties of LTCC.     

Revisiting the ionic mechanisms of early afterdepolarizations in cardiomyocytes: predominant by Ca waves or Ca currents?

Early afterdepolarizations (EADs) have been implicated in severe cardiac arrhythmias and sudden cardiac deaths. However, the mechanism(s) for EAD genesis, especially regarding the relative contribution of Ca(2+) wave (CaW) vs. L-type Ca current (I(Ca,L)), still remains controversial. In the present study, we simultaneously recorded action potentials (APs) and intracellular Ca(2+) images in isolated rabbit ventricular myocytes and systematically compared the properties of EADs in the following two pharmacological models: 1) hydrogen peroxide (H(2)O(2); 200 μM); and 2) isoproterenol (100 nM) and BayK 8644 (50 nM) (Iso + BayK). We assessed the rate dependency of EADs, the temporal relationship between EADs and corresponding CaWs, the distribution of EADs over voltage, and the effects of blockers of I(Ca,L), Na/Ca exchangers, and ryanodine receptors. The most convincing evidence came from the AP-clamp experiment, in which the cell membrane clamp was switched from current clamp to voltage clamp using a normal AP waveform without EAD; CaWs disappeared in the H(2)O(2) model, but persisted in the Iso + BayK model. We postulate that, although CaWs and reactivation of I(Ca,L) may act synergistically in either case, reactivation of I(Ca,L) plays a predominant role in EAD genesis under oxidative stress (H(2)O(2) model), while spontaneous CaWs are a predominant cause for EADs under Ca(2+) overload condition (Iso + BayK model).     

Early afterdepolarizations in cardiac myocytes: mechanism and rate dependence.

A model of the cardiac ventricular action potential that accounts for dynamic changes in ionic concentrations was used to study the mechanism, characteristics, and rate dependence of early after depolarizations (EADs). A simulation approach to the study of the effects of pharmacological agents on cellular processes was introduced. The simulation results are qualitatively consistent with experimental observations and help resolve contradictory conclusions in the literature regarding the mechanism of EADs. Our results demonstrate that: 1) the L-type calcium current, ICa, is necessary as a depolarizing charge carrier during an EAD; 2) recovery and reactivation of ICa is the mechanism of EAD formation, independent of the intervention used to induce the EADs (cesium, Bay K 8644, or isoproterenol were used in our simulations, following similar published experimental protocols); 3) high [Ca2+]i is not required for EADs to develop and calcium release by the sarcoplasmic reticulum does not occur during the EAD; 4) although the primary mechanism of EAD formation is recovery of ICa, other plateau currents can modulate EAD formation by affecting the balance of currents during a conditional phase before the EAD take-off; and 5) EADs are present at drive cycle lengths longer than 1000 ms. Because of the very long activation time constant of the delayed rectifier potassium current, IK, the activation gate of IK does not deactivate completely between consecutive stimuli at fast rates (drive cycle length < 1000 ms). As a result, IK plays a key role in determining the rate dependence of EADs.     

A Study of Early Afterdepolarizations in a Model for Human Ventricular Tissue

Sudden cardiac death is often caused by cardiac arrhythmias. Recently, special attention has been given to a certain arrhythmogenic condition, the long-QT syndrome, which occurs as a result of genetic mutations or drug toxicity. The underlying mechanisms of arrhythmias, caused by the long-QT syndrome, are not fully understood. However, arrhythmias are often connected to special excitations of cardiac cells, called early afterdepolarizations (EADs), which are depolarizations during the repolarizing phase of the action potential. So far, EADs have been studied mainly in isolated cardiac cells. However, the question on how EADs at the single-cell level can result in fibrillation at the tissue level, especially in human cell models, has not been widely studied yet. In this paper, we study wave patterns that result from single-cell EAD dynamics in a mathematical model for human ventricular cardiac tissue. We induce EADs by modeling experimental conditions which have been shown to evoke EADs at a single-cell level: by an increase of L-type Ca currents and a decrease of the delayed rectifier potassium currents. We show that, at the tissue level and depending on these parameters, three types of abnormal wave patterns emerge. We classify them into two types of spiral fibrillation and one type of oscillatory dynamics. Moreover, we find that the emergent wave patterns can be driven by calcium or sodium currents and we find phase waves in the oscillatory excitation regime. From our simulations we predict that arrhythmias caused by EADs can occur during normal wave propagation and do not require tissue heterogeneities. Experimental verification of our results is possible for experiments at the cell-culture level, where EADs can be induced by an increase of the L-type calcium conductance and by the application of I blockers, and the properties of the emergent patterns can be studied by optical mapping of the voltage and calcium.     

High purity human-induced pluripotent stem cell-derived cardiomyocytes: electrophysiological properties of action potentials and ionic currents

Human-induced pluripotent stem cells (hiPSCs) can differentiate into functional cardiomyocytes; however, the electrophysiological properties of hiPSC-derived cardiomyocytes have yet to be fully characterized. We performed detailed electrophysiological characterization of highly pure hiPSC-derived cardiomyocytes. Action potentials (APs) were recorded from spontaneously beating cardiomyocytes using a perforated patch method and had atrial-, nodal-, and ventricular-like properties. Ventricular-like APs were more common and had maximum diastolic potentials close to those of human cardiac myocytes, AP durations were within the range of the normal human electrocardiographic QT interval, and APs showed expected sensitivity to multiple drugs (tetrodotoxin, nifedipine, and E4031). Early afterdepolarizations (EADs) were induced with E4031 and were bradycardia dependent, and EAD peak voltage varied inversely with the EAD take-off potential. Gating properties of seven ionic currents were studied including sodium (I(Na)), L-type calcium (I(Ca)), hyperpolarization-activated pacemaker (I(f)), transient outward potassium (I(to)), inward rectifier potassium (I(K1)), and the rapidly and slowly activating components of delayed rectifier potassium (I(Kr) and I(Ks), respectively) current. The high purity and large cell numbers also enabled automated patch-clamp analysis. We conclude that these hiPSC-derived cardiomyocytes have ionic currents and channel gating properties underlying their APs and EADs that are quantitatively similar to those reported for human cardiac myocytes. These hiPSC-derived cardiomyocytes have the added advantage that they can be used in high-throughput assays, and they have the potential to impact multiple areas of cardiovascular research and therapeutic applications.     

Circadian Rhythms of Early Afterdepolarizations and Ventricular Arrhythmias in a Cardiomyocyte Model

Sudden cardiac arrest is a malfunction of the heart’s electrical system, typically caused by ventricular arrhythmias, that can lead to sudden cardiac death (SCD) within minutes. Epidemiological studies have shown that SCD and ventricular arrhythmias are more likely to occur in the morning than in the evening, and laboratory studies indicate that these daily rhythms in adverse cardiovascular events are at least partially under the control of the endogenous circadian timekeeping system. However, the biophysical mechanisms linking molecular circadian clocks to cardiac arrhythmogenesis are not fully understood. Recent experiments have shown that L-type calcium channels exhibit circadian rhythms in both expression and function in guinea pig ventricular cardiomyocytes. We developed an electrophysiological model of these cells to simulate the effect of circadian variation in L-type calcium conductance. In our simulations, we found that there is a circadian pattern in the occurrence of early afterdepolarizations (EADs), which are abnormal depolarizations during the repolarization phase of a cardiac action potential that can trigger fatal ventricular arrhythmias. Specifically, the model produces EADs in the morning, but not at other times of day. We show that the model exhibits a codimension-2 Takens-Bogdanov bifurcation that serves as an organizing center for different types of EAD dynamics. We also simulated a two-dimensional spatial version of this model across a circadian cycle. We found that there is a circadian pattern in the breakup of spiral waves, which represents ventricular fibrillation in cardiac tissue. Specifically, the model produces spiral wave breakup in the morning, but not in the evening. Our computational study is the first, to our knowledge, to propose a link between circadian rhythms and EAD formation and suggests that the efficacy of drugs targeting EAD-mediated arrhythmias may depend on the time of day that they are administered.     

Irregularly Appearing Early Afterdepolarizations in Cardiac Myocytes: Random Fluctuations or Dynamical Chaos?

Irregularly occurring early afterdepolarizations (EADs) in cardiac myocytes are traditionally hypothesized to be caused by random ion channel fluctuations. In this study, we combined 1), patch-clamp experiments in which action potentials were recorded at different pacing cycle lengths from isolated rabbit ventricular myocytes under several experimental conditions inducing EADs, including oxidative stress with hydrogen peroxide, calcium overload with BayK8644, and ionic stress with hypokalemia; 2), computer simulations using a physiologically detailed rabbit ventricular action potential model, in which repolarization reserve was reduced to generate EADs and random ion channel or path cycle length fluctuations were implemented; and 3), iterated maps with or without noise. By comparing experimental, modeling, and bifurcation analyses, we present evidence that noise-induced transitions between bistable states (i.e., between an action potential with and without an EAD) is not sufficient to account for the large variation in action potential duration fluctuations observed in experimental studies. We conclude that the irregular dynamics of EADs is intrinsically chaotic, with random fluctuations playing a nonessential, auxiliary role potentiating the complex dynamics.     

Single "early" action potential cause by Ni2+ ions in true pacemaker cells of the sinoatrial ring of the dace heart

Single "early" action potentials (AP) or "early" postdepolarization (EAD) were recorded in multicellular stripes working in the regimen of true pacemaker cells located in the basis of the sinoatrial valve of the dace (Leuciscus rutilus) heart after Ni2+ (0.3 mM) were added to superfused solution on the 15 th min. The standard microelectrode technique was used. The appearance of single EAD was preceded by increase of AP spike duration almost 1.5-fold due to increase of the duration of a final repolarization phase and of diastolic depolarization. EADs appeared at different levels of repolarization from -20 to -60 mV. EAD's amplitude was lower than the AP proper. The effect is reversible. Nifedipine (2 microM) decreased by 20% the AP duration to 50% repolarization in the cells of atrial type. In case the stripes were primarily subjected to nifedipine effect and then even after a long procedure of washout, the Ni2+ (0.3 mM) did not cause EADs. The hypothesis has been tested of what is the main reason of single EAD appearance in pacemaker cells under the effect of Ni2+; it is either blocking Ca release from the cell by Ni2+, or reactivation of L-type Ca-channels' conductivity. The analysis of the data obtained leads to the conclusion that 30-50% Na-Ca-exchangers block is the basic reason of single EAD appearance in pacemaker cells.     

小鼠主动脉狭窄后不同时期心室肌细胞后除极和触发活动的变化

目的：探讨小鼠主动脉狭窄后不同时期心室肌细胞后除极和触发活动的变化及可能的机制。方法：复制小鼠主动脉狭窄模型后,取小鼠心脏,采用玻璃微电极技术,记录左心室乳头肌动作电位早后除极（EAD）、迟后除极（DAD）和触发活动情况,以及灌流低钾或异丙肾上腺素溶液后,所诱发后除极触发活动的变化。结果：①与同时期对照组比较,小鼠乳头肌动作电位APD90模型组2周和5周组保持不变,9周和13周明显延长。②在记录的30min时间内,模型组9周和13周动物出现EAD和DAD,而对照组以及模型组2周和5周动物未出现EAD和DAD。③低钾或异丙肾上腺素诱发EAD和DAD的发生率,模型组显著高于同期对照组,并且模型组动物的发生率随着时间进行性增加。结论：小鼠主动脉狭窄后,心肌细胞EAD、DAD以及触发活动逐渐增多,心肌细胞的电不稳定性逐渐增加。     

Effects of early afterdepolarizations on reentry in cardiac tissue: a simulation study

Early afterdepolarizations (EADs) are classically generated at slow heart rates when repolarization reserve is reduced by genetic diseases or drugs. However, EADs may also occur at rapid heart rates if repolarization reserve is sufficiently reduced. In this setting, spontaneous diastolic sarcoplasmic reticulum (SR) Ca release can facilitate cellular EAD formation by augmenting inward currents during the action potential plateau, allowing reactivation of the window L-type Ca current to reverse repolarization. Here, we investigated the effects of spontaneous SR Ca release-induced EADs on reentrant wave propagation in simulated one-, two-, and three-dimensional homogeneous cardiac tissue using a version of the Luo-Rudy dynamic ventricular action potential model modified to increase the likelihood of these EADs. We found: 1) during reentry, nonuniformity in spontaneous SR Ca release related to subtle differences in excitation history throughout the tissue created adjacent regions with and without EADs. This allowed EADs to initiate new wavefronts propagating into repolarized tissue; 2) EAD-generated wavefronts could propagate in either the original or opposite direction, as a single new wave or two new waves, depending on the refractoriness of tissue bordering the EAD region; 3) by suddenly prolonging local refractoriness, EADs caused rapid rotor displacement, shifting the electrical axis; and 4) rapid rotor displacement promoted self-termination by collision with tissue borders, but persistent EADs could regenerate single or multiple focal excitations that reinitiated reentry. These findings may explain many features of Torsades des pointes, such as perpetuation by focal excitations, rapidly changing electrical axis, frequent self-termination, and occasional degeneration to fibrillation.     

The role of stochastic and modal gating of cardiac L-type Ca2+ channels on early after-depolarizations

Certain signaling events that promote L-type Ca2+ channel (LCC) phosphorylation, such as beta-adrenergic stimulation or an increased expression of Ca(2+)/calmodulin-dependent protein kinase II, promote mode 2 gating of LCCs. Experimental data suggest the hypothesis that these events increase the likelihood of early after-depolarizations (EADs). We test this hypothesis using an ionic model of the canine ventricular myocyte incorporating stochastic gating of LCCs and ryanodine-sensitive calcium release channels. The model is extended to describe myocyte responses to the beta-adrenergic agonist isoproterenol. Results demonstrate that in the presence of isoproterenol the random opening of a small number of LCCs gating in mode 2 during the plateau phase of the action potential (AP) can trigger EADs. EADs occur randomly, where the likelihood of these events increases as a function of the fraction of LCCs gating in mode 2. Fluctuations of the L-type Ca2+ current during the AP plateau lead to variability in AP duration. Consequently, prolonged APs are occasionally observed and exhibit an increased likelihood of EAD formation. These results suggest a novel stochastic mechanism, whereby phosphorylation-induced changes in LCC gating properties contribute to EAD generation.     

Contribution of L-type Ca2+ channels to early afterdepolarizations induced by I Kr and I Ks channel suppression in guinea pig ventricular myocytes

Early afterdepolarizations (EADs) induced by suppression of cardiac delayed rectifier I (Kr) and/or I (Ks) channels cause fatal ventricular tachyarrhythmias. In guinea pig ventricular myocytes, partial block of one of the channels with complete block of the other reproducibly induced EADs. Complete block of both I (Kr) and I (Ks) channels depolarized the take-off potential and reduced the amplitude of EADs, which in some cases were not clearly separated from the preceding action potentials. A selective L-type Ca(2+) (I (Ca,L)) channel blocker, nifedipine, effectively suppressed EADs at submicromolar concentrations. As examined with the action potential-clamp method, I (Ca,L) channels mediated inward currents with a spike and dome shape during action potentials. I (Ca,L) currents decayed mainly due to inactivation in phase 2 and deactivation in phase 3 repolarization. When EADs were induced by complete block of I (Kr) channels with partial block of I (Ks) channels, repolarization of the action potential prior to EAD take-off failed to increase I (K1) currents and thus failed to completely deactivate I (Ca,L) channels, which reactivated and mediated inward currents during EADs. When both I (Kr) and I (Ks) channels were completely blocked, I (Ca,L) channels were not deactivated and mediated sustained inward currents until the end of EADs. Under this condition, the recovery and reactivation of I (Ca,L) channels were absent before EADs. Therefore, an essential mechanism underlying EADs caused by suppression of the delayed rectifiers is the failure to completely deactivate I (Ca,L) channels.     

In vivo characterization of the transitional bronchioles by aerosol-derived airway morphometry.

Effective airway dimensions (EADs) were determined in vivo by aerosol-derived airway morphometry as a function of volumetric lung depth (VLD) to identify and characterize, noninvasively, the caliber of the transitional bronchiole region of the human lung and to compare the EADs by age, gender, and disease. By logarithmically plotting EAD vs. VLD, two distinct regions of the lung emerged that were identified by characteristic line slopes. The intersection of proximal and distal segments was defined as VLD(trans) and associated EAD(trans). In our normal subjects (n = 20), VLD(trans) [345 +/- 83 (SD) ml] correlated significantly with anatomic dead space (224 +/- 34 ml) and end of phase II of single-breath nitrogen washout (360 +/- 53 ml). The corresponding EAD(trans) was 0.42 +/- 0. 07 mm, in agreement with other ex vivo measurements of the transitional bronchioles. VLD(trans) was smaller (216 +/- 64 ml) and EAD(trans) was larger (0.83 +/- 0.04 mm) in our patients with chronic obstructive pulmonary disease (n = 13). VLD(trans) increased with age for children (age 8-18 yr; P = 0.006, n = 26) and with total lung capacity for age 8-81 yr (P < 0.001, n = 61). This study extends the usefulness of aerosol-derived airway morphometry to in vivo measurements of the transitional bronchioles.     

So Little Source, So Much Sink: Requirements for Afterdepolarizations to Propagate in Tissue

How early (EADs) and delayed afterdepolarizations (DADs) overcome electrotonic source-sink mismatches in tissue to trigger premature ventricular complexes remains incompletely understood. To study this question, we used a rabbit ventricular action potential model to simulate tissues in which a central area of contiguous myocytes susceptible to EADs or DADs was surrounded by unsusceptible tissue. In 1D tissue with normal longitudinal conduction velocity (0.55 m/s), the numbers of contiguous susceptible myocytes required for an EAD and a barely suprathreshold DAD to trigger a propagating action potential were 70 and 80, respectively. In 2D tissue, these numbers increased to 6940 and 7854, and in 3D tissue to 696,910 and 817,280. These numbers were significantly decreased by reduced gap junction conductance, simulated fibrosis, reduced repolarization reserve and heart failure electrical remodeling. In conclusion, the source-sink mismatch in well-coupled cardiac tissue powerfully protects the heart from arrhythmias due to sporadic afterdepolarizations. Structural and electrophysiological remodeling decrease these numbers significantly but still require synchronization mechanisms for EADs and DADs to overcome the robust protective effects of source-sink mismatch.     

Single and multiple early afterdepolarization caused by nickel in rat atrial muscle

We examined the possible role of the Na-Ca exchange (NCX) in the arrhythmogenesis in rat atrial preparations applying microelectrode technique. In control Tyrode solution preparations isolated from the sinoatrial area contracted with frequency of 48+/-4 min(-1) (group I) or 84+/-7 min(-1) (group II). In preparation beating with low frequency partial inhibition of NCX by administration of Ni2+ (0.3 mmol/l) to the bath solution caused single early afterdepolarization (EAD) on the 15th min. During the following five minutes they were transformed into multiple EADs from 4 to 47 (action potentials) with general duration of 1-12 s. The effects were reversible. Ni2+ (0.3 mmol/l) in the preparations beating with higher rate (group II) did not cause multiple EADs, but after higher Ni2+ concentration (0.5 mmol/l) single EAD was observed more often. It was concluded that Ca2+ overload due to partial block of the NCX can contribute to the development of atrial tachyarrhythmias.