A model analysis of aftereffects of high-intensity DC stimulationon action potential of ventricular muscle

The mechanism for aftereffects of high-intensity dc stimulation on ventricular muscle was studied by using Beeler-Reuter's action potential model. A leak conductance (G_pore maximal value from 40 to 80 μS for 1 cm² of membrane), which mimics reversible dielectric breakdown of the cell membrane by the shock, was incorporated into the model. To simulate resealing process, G_pore was assumed to decrease after the shock exponentially at a time constant (τ_pore) of 5-50 s. The simulation results are qualitatively consistent with the authors' experimental observations in guinea pig papillary muscle (Amer. J. Physiol., vol. 267, p. H248-58, 1994); they include prolonged depolarization, diastolic depolarization or oscillation of membrane potential leading to a single or multiple spontaneous excitation. The phase-independence and shock intensity-dependence can also be reproduced. Analysis of current components has revealed that: (1) a large inward leak current (l_leak) is responsible for the prolonged depolarization (2) time-dependent decay of outward current (I_X1) in combination with I_leak and slow inward current (I_s) results in diastolic depolarization or oscillation of membrane potential; (3) spontaneous excitation depends on an activation of I_s. These findings support the authors' hypothesis that strong shocks (>15 V/cm) will produce abnormal arrhythmogenic responses in ventricular muscle through a transient rupture of sarcolemmal membrane     

Functional reentry's influence on intracellular calcium in the LRd membrane equations

This paper examines relationships between transmembrane potential (Vm), [Ca2+]i dependent membrane ionic currents, and [Ca2+]i handling by the sarcoplasmic reticulum (SR) in a two-dimensional model of cardiac tissue. Luo-Rudy dynamic (LRd) membrane equations were used because they include detailed formulations for triggered SR Ca2+ release dependent on membrane Ca2+ influx (CICR) and for spontaneous SR Ca2+ release following calsequestrin buffer overload (SCR). Reentry's rapid rate (110-ms cycle length) elevated [Ca2+]i and limited CICR, which in turn promoted SCR that occurred at intervals of 320-350 ms, was preferential at sites located inside the functional center, and destabilized the reentrant activation sequence. Although adjustment of LRd parameters for SR Ca2+ modified SCR interval and peak [Ca2+]i in voltage clamp simulations with a command waveform representing Vm time course within the functional center, SCR persisted. Using the same command waveform, SCR also occurred with an alternate SR Ca2+ formulation that represented subcellular details underlying CICR. LRd parameter adjustments to promote CICR and limit SCR in subsequent reentry simulations failed to eliminate SCR completely, as they modulated SCR intervals in a manner consistent with the voltage clamp simulations. Taken together, our findings support a destabilizing influence of functional reentry on [Ca2+]i handling. However, [Ca2+]i instabilities did not always fractionate depolarization wavefronts during reentry. Fractionation depended, in part, upon CICR and SCR parameters in the LRd formulation for SR Ca2+ release.     

Voltage-dependent effects of Ca(2+)/calmodulin on Cl(-) channel in cardiac sarcoplasmic reticulum

A new kind of chloride channels in the cardiac sarcoplasmic reticulum, 116 pS Cl(-) channel (500 mM Cl(-) in the cis and 50 mM Cl(-) in the trans chamber solutions), which is activated by protein-kinase-A-dependent phosphorylation, has been determined to conduct adenine nucleotide as a transporter between cytosol and SR lumen. We investigated the voltage-dependent gating of this Cl(-) channel by recording single-channel activities using the planar lipid bilayer-vesicle fusion technique. The channel activities did not change at different membrane potentials (-100 mV to +50 mV) or different Ca(2+) concentrations (1 nM to 1 mM) in cis solution. In the presence of calmodulin (CaM) (0.1 microM /microg SR vesicles), however, Ca(2+) added to the cis solution at 0 mV inhibited channel openings in a Ca(2+) -concentration-dependent manner. These effects were prevented by the addition of CaM inhibitors. The blocking effects of CaM differed depending on the membrane potentials at negative potentials below -20 mV. With CaM and 3 microM Ca(2+), the values of opening probability were 0 at -80 mV, 0.2 at -40 mV, 0.3 at -20 mV, 0.71 at 0 mV and 0.92 at +20 mV. These results may indicate the membrane potential affects the action of Ca(2+) /CaM complex     

Mechanism of Abnormal Sarcoplasmic Reticulum Calcium Release in Canine Left-Ventricular Myocytes Results in Cellular Alternans

Electrocardiographic alternans are known to predispose to increased susceptibility to life threatening arrhythmias and sudden cardiac death. While deficiencies in Ca²⁺ transport processes have been implicated in the genesis of cellular alternans, the underlying mechanisms have been elusive, and are the goal of this study. A novel reverse engineering approach that applies a simultaneous action potential (AP) and [Ca²⁺ ]i clamp of experimentally obtained data, to a previously described left-ventricular canine myocyte model, is employed to isolate the molecular and cellular mechanisms underlying cardiac alternans. The model-derived sarcoplasmic reticulum (SR) Ca²⁺ in control beats (102.1 plusmn 12.9 nM, n = 639 ), although larger, is not statistically significantly different as compared to beats corresponding to small [Ca²⁺ ]_i (99.3 plusmn 35.4 nM, n = 310, p = NS), but is significantly smaller as compared to beats corresponding to large [Ca²⁺ ]_i (122.6 plusmn 31.0 nM, n = 311, p<0.000001) during alternans. The model indicates that the increased SR Ca²⁺ in these beats triggers multiple ryanodine receptor (RyR) channel openings and delayed Ca²⁺ release that subsequently triggers an inward depolarizing current, a subthreshold early after depolarization, and AP prolongation. In conclusion, the results presented in this study support the idea that aberrant RyR openings on alternate beats are responsible for the [Ca²⁺ ]_i alternans-type oscillations, which, in turn, give rise to AP alternans.     

Three-Dimensional Simulation of the Ventricular Depolarization and Repolarization Processes and Body Surface Potentials: Nornal Heart and Bundle Branch Block

A three-dimensional computer model has been constructed to simulate the ventricular depolarization and repolarization processes in a human heart. The electrocardiogram (ECG), the vectorcardiogram(VCG), and the body surface potential map (BSPM) during the QRS-T period are obtained automatically under certain heart conditions such as bundle branch block and myocardial infarctions. The ventricles, together with bundle branches and the Purkinje fibers, are composed of approximately 50 000 cell units which are arranged in a cubic close-packed structure. A different action potential waveform was assigned to each unit. The heart model is mounted in a homogeneous human torso model. Electric dipoles, which are proportional to the spatial gradient of the action potential, are generated in all the cell units. These dipoles give rise to a potential distribution on the torso surface, which is calculated by means of the boundary element method. The resulting ECG's, VCG's, and BSPM's are within the expected range of clinical observations.     

A model study of electric field interactions between cardiacmyocytes

The transmission of excitation via electric field coupling was studied in a model comprising two myocytes abutted end-to-end and placed in an unbounded volume conductor. Each myocyte was modeled as a small cylinder of membrane (10 microns in diameter and 100 microns in length) capped at both ends. A Beeler-Reuter model modified for the Na+ current dynamics served to simulate the membrane ionic current. There was no resistive coupling between the myocytes and the intercellular junction consisted of closely apposed pre- and post-junctional membranes, separated by a uniform cleft distance. The membrane current crossing the prejunctional membrane during the action potential upstroke tends to flow out of the cleft, but it is partly prevented from doing so by the shunt resistance constituted by the cleft volume conductor. The prejunctional upstroke gives rise to a pulse of positive potential within the cleft which induces a small capacitive current across the post-junctional membrane to yield a small positive change in the intracellular potential in the post-junctional cell. The net result is an hyperpolarization of the post-junctional cleft membrane and a slight depolarization of the rest of the cell membrane since the extracellular potential outside of the cell is zero. The magnitude of this depolarization is quite small for a flat junctional membrane and it can be increased by membrane folding and interdigitation, so as to increase the junctional membrane area by a factor of 10 or more. Even then the post-junctional depolarization does not reach threshold when the extracellular potential around the post-junctional cell is effectively zero. Threshold depolarization occurs in the presence of a large decrease of post-junctional load, by increasing the junctional membrane capacitance and/or decreasing the volume of the post-junctional cell. Assuming that the normal resistive coupling between two cardiac myocytes is 1-4 M omega, our model study indicates that electric field coupling would then be about two orders of magnitude smaller. However, substantial enhancement of the efficacy of electric field transmission was observed in the case of cells with substantial junctional membrane folding.     

An electronic device for triggering a stimulator during membraneresponsiveness determinations in cardiac tissues

A device is described that monitors the repolarization phase of a cardiac action potential and compares the membrane potential to a voltage selected by the investigator. When the voltages are the same, the device triggers a stimulator that injects the stimulus at the desired membrane potential. The device can stimulate tissue at any membrane potential during the repolarization phase of the action potential between 0 and -100 mV without regard to action potential duration. When it is precisely calibrated, its accuracy is within ±1.0 mV     

Multiscale modeling of calcium dynamics in ventricular myocytes with realistic transverse tubules

Spatial-temporal Ca(2+) dynamics due to Ca(2+) release, buffering, and reuptaking plays a central role in studying excitation-contraction (E-C) coupling in both normal and diseased cardiac myocytes. In this paper, we employ two numerical methods, namely, the meshless method and the finite element method, to model such Ca(2+) behaviors by solving a nonlinear system of reaction-diffusion partial differential equations at two scales. In particular, a subcellular model containing several realistic transverse tubules (or t-tubules) is investigated and assumed to reside at different locations relative to the cell membrane. To this end, the Ca(2+) concentration calculated from the whole-cell modeling is adopted as part of the boundary constraint in the subcellular model. The preliminary simulations show that Ca(2+) concentration changes in ventricular myocytes are mainly influenced by calcium release from t-tubules.     

An estimate of the dispersion of repolarization times based on a biophysical model of the ECG

Temporal heterogeneity of ventricular repolarization is a key quantity for the development of ventricular reentrant arrhythmia. In this paper, we introduce the V-index, a novel ECG-based estimator of the standard deviation of ventricular myocytes' repolarization times s(?). Differently from other ECG metrics of repolarization heterogeneity, the V-index was derived from the analysis of a biophysical model of the ECG, where repolarization is described by the dominant T-wave (DTW) paradigm. The model explains the shape of T-waves in each lead as a projection of a main waveform (the DTW) and its derivatives weighted by scalars, the lead factors. A mathematical formula is derived to link the heterogeneity of ventricular repolarization s(?) and the V-index. The formula was verified using synthetic 12-lead ECGs generated with a direct electrophysiological model for increasing values of s(?) (in the range 20-70 ms). A linear relationship between the V-index and s(?) was observed, V ≈ 0.675 s(?) + 1.8 ms (R(2) = 0.9992). Finally, 68 ECGs from the E-OTH-12-0068-010 database of the Telemetric and Holter ECG Warehouse were analyzed. The V-index coherently increased after sotalol administration, a drug known to have QT-prolonging potential (p < 0.001).     

Cancellation of ventricular activity in the ECG: evaluation of novel and existing methods

Due to the much higher amplitude of the electrical activity of the ventricles in the surface electrocardiogram (ECG), its cancellation is crucial for the analysis and characterization of atrial fibrillation. In this paper, two different methods are proposed for this cancellation. The first one is an average beat subtraction type of method. Two sets of templates are created: one set for the ventricular depolarization waves and one for the ventricular repolarization waves. Next, spatial optimization (rotation and amplitude scaling) is applied to the QRS templates. The second method is a single beat method that cancels the ventricular involvement in each cardiac cycle in an independent manner. The estimation and cancellation of the ventricular repolarization is based on the concept of dominant T and U waves. Subsequently, the atrial activities during the ventricular depolarization intervals are estimated by a weighted sum of sinusoids observed in the cleaned up segments. ECG signals generated by a biophysical model as well as clinical ECG signals are used to evaluate the performance of the proposed methods in comparison to two standard ABS-based methods.     

A simultaneous multichannel monophasic action potential electrode array for in vivo epicardial repolarization mapping

While the recording of extracellular monophasic action potentials (MAPs) from single epicardial or endocardial sites has been performed for over a century, we are unaware of any previous successful attempt to record MAPs simultaneously from a large number of sites in vivo. We report here the design and validation of an array of MAP electrodes which records both depolarization and repolarization simultaneously at up to 16 epicardial sites in a square array on the heart in vivo. The array consists of 16 sintered Ag-AgCl electrodes mounted in a common housing with individual suspensions allowing each electrode to exert a controlled pressure on the epicardial surface. The electrodes are arranged in a square array, with each quadrant of four having an additional recessed sintered Ag-AgCl reference electrode at its center. A saline-soaked sponge establishes ionic contact between the reference electrodes and the tissue. The array was tested on six anesthetized open-chested pigs. Simultaneous diagnostic-quality MAP recordings were obtained from up to 13 out of 16 ventricular sites. Ventricular MAPs had amplitudes of 10-40 mV with uniform morphologies and stable baselines for up to 30 min. MAP duration at 90% repolarization was measured and shown to vary as expected with cycle length during sustained pacing. The relationship between MAP duration and effective refractory period was also confirmed. The ability of the array to detect local differences in repolarization was tested in two ways. Placement of the array straddling the atrioventricular (AV) junction yielded simultaneous atrial or ventricular recordings at corresponding sites during 1:1 and 2:1 AV conduction. Localized ischemia via constriction of a coronary artery branch resulted in shortening of the repolarization phase at the ischemic, but not the nonischemic, sites. In conclusion, these results indicate that the simultaneous multichannel MAP electrode array is a viable method for in vivo epicardial repolarization mapping. The array has the potential to be expanded to increase the number of sites and spatial resolution.     

The Simulation of Repolarization Events of the Cardiac Purkinje Fiber Action Potential

A mathematical model based on the formalism of the Hodgkin-Huxley equations was implemented on a microcomputer system and used to simulate the membrane action potential of cardiac Purkinje fibers. The complete model is a modification of the representation used by McAllister et al. [1], mainly with respect to the outward current components during the late plateau, the repolarization phase, and the slow repolarization phase of the action potential. A new formulation of the potassium conductance was used, involving two distinct types of ionic channels corresponding, respectively, to the experimentally observed inward-going and outward-going rectification properties of the Purkinje fiber membrane. A unified representation of the Purkinje fiber current components was thus obtained which provides a more satisfactory interpretation of experimental results than was possible with the original model of McAllister et al. [1]. The membrane channel for the potassium pacemaker current is characterized by a set of first-order activation?inactivation variables and a constant fully activated conductance. The other channel carries the potassium current involved in the late plateau and repolarization phase of the action potential.     

Dynamic analysis of ventricular repolarization duration from24-hour Holter recordings

Evaluation of the influence of the autonomic nervous system on the ventricular repolarization duration was carried out using beat-to-beat analysis of the time intervals between the peaks of the R and T waves (RTm). After pre-processing of digitized Holter ECG's, auto and cross spectrum analyses were applied to heart rate and repolarization duration variability signals. Coherence analysis was used to assess the existence of common spectral contributions. The heart rate variability signal was used as reference of the sympatho-vagal balance at the sinus node. It was found that, in normal individuals, the autonomic nervous system directly influences the ventricular repolarization duration and that this influence is qualitatively very similar to the one that modulates the heart rate. Pathological alteration of these parallel autonomic activities to the heart (on the sinus node and on the ventricle) might cause uncoupling between depolarization and repolarization     

冲击工艺对铝合金激光熔覆的影响

通过有效控制Nd:YAG 脉冲式激光器电流、脉冲宽度、频率、光斑直径、扫描速度、离焦量等有关工艺参数，对模拟腐蚀损伤的铝合金试样表面激光熔覆Al-Y(1.4%)合金，并对其中的一组试样进行机械冲击，充分时效后进行疲劳实验、疲劳断口分析及金相分析。研究结果表明，熔覆后机械冲击试样的疲劳寿命远远高于只熔覆不冲击试样的疲劳寿命，疲劳断口有明显的疲劳条带，熔覆层和基体结合得非常紧密，熔覆层内没有大的气孔和裂纹缺陷。     

Action Potential Collision in Heart Tissue-Computer Simulations and Tissue Expenrments

The electrical effects of action potential collision were studied using a computer simulation of one-dimensional action potential propagation and tissue experiments from isolated cardiac Purkinje strands and papillary muscles. The effects of collision, when compared to normal one-way propagation, included quantitative changes in all of the measured indexes of action potential upstroke and repolarization. These changes can be attributed to spatiotemporal changes in the net membrane current. Parameter sensitivity and analytic techniques identified five factors which determine the collision-induced decrease in action potential area: conduction velocity, action potential height, cable radius, specific intracellular resistivity, and the specific membrane resistance during action potential repolarization. The simulations demonstrated that collision effects were independent of inhomogeneity in action potential duration, the spatial extent of the collision effects was greater than the passive space constant, and certain simulated abnormal conditions (e. g., discontinuous propagation, ischemic tissue) increased the magnitude of the collision effects. The tissue experiments supported the simulations regarding the changes in action potential configuration directly at and on each side of the collision site. Elevated [K+]0 increased the changes in action potential duration in both tissue preparations. In papillary muscles, collision effects in the transverse direction were confined to a narrower region than collision effects in the longitudinal direction with no difference in the peak magnitude of the changes. Action potential collision is a common occurrence in the heart.     

Electrical coupling and impulse propagation in anatomically modeledventricular tissue

Computer simulations were used to study the role of resistive couplings on flat-wave action potential propagation through a thin sheet of ventricular tissue. Unlike simulations using continuous or periodic structures, this unique electrical model includes random size cells with random spaced longitudinal and lateral connections to simulate the physiologic structure of the tissue. The resolution of the electrical model is ten microns, thus providing a simulated view at the subcellular level. Flat-wave longitudinal propagation was evaluated with an electrical circuit of over 140,000 circuit elements, modeling a 0.25 mm by 5.0 mm sheet of tissue. An electrical circuit of over 84,000 circuit elements, modeling a 0.5 mm by 1.5 mm sheet was used to study flat-wave transverse propagation. Under normal cellular coupling conditions, at the macrostructure level, electrical conduction through the simulated sheets appeared continuous and directional differences in conduction velocity, action potential amplitude and V˙_max were observed. However, at the subcellular level (10 μm) unequal action potential delays were measured at the longitudinal and lateral gap junctions and irregular wave-shapes were observed in the propagating signal. Furthermore, when the modeled tissue was homogeneously uncoupled at the gap junctions conduction velocities decreased as the action potential delay between modeled cells increased. The variability in the measured action potential was most significant in areas with fewer lateral gap junctions, i.e., lateral gap junctions between fibers were separated by a distance of 100 μm or more     

Contributions of Purkinje-myocardial coupling to suppression and facilitation of early afterdepolarization-induced triggered activity

Electrical loading by ventricular myocardium modulates conduction system repolarization near Purkinje-ventricular junctions (PVJs). We investigated how that loading suppresses and facilitates early afterdepolarizations (EADs) under conditions where there is a high degree of functional coupling between tissue types, which is consistent with the anatomic arrangement at the peripheral conduction system-myocardial interface. Experiments were completed in eight rabbit right ventricular (RV) free wall preparations. Free-running Purkinje strands were locally superfused, and action potentials were recorded from strands. RV free walls were bathed in normal solution. Surface electrograms were recorded near strand insertions into downstream free wall myocardium. Detailed histology was performed to assemble a computer model with interspersed Purkinje and ventricular myocytes weakly coupled throughout the region. Delays from Purkinje upstrokes to downstream peripheral conduction system and myocardial activation were comparable between experiments and simulations, supporting model node-to-node electrical coupling, i.e., the functional coupling. Purkinje action potential duration (APD) prolongation with localized isoproterenol in experiments and calcium current enhancement in simulations failed to establish EADs. With myocardial APD prolongation by delayed rectifier potassium current inhibition or L-type calcium current enhancement accompanying Purkinje APD prolongation in simulations, however, EAD-induced triggered activity developed. Collectively, our findings suggest competing contributions of the myocardial sink when there is a high degree of functional coupling between tissue types, with the transition from suppression to facilitation of EAD-induced triggered activity depending critically upon myocardial APD prolongation.     

Genomic organization of a voltage-gated Na+ channel in a hydrozoan jellyfish: insights into the evolution of voltage-gated Na+ channel genes

Voltage-gated Na+ channels are responsible for fast propagating action potentials. The structurally simplest animals known to contain rapid, transient, voltage-gated currents carried exclusively by Na+ ions are the Cnidaria. The Cnidaria are thought to be close to the origin of the metazoan radiation and thus are pivotal organisms for studying the evolution of the Na+ channel gene. Here we describe the genomic organization of the Na+ channel alpha subunit, PpSCN1, from the hydrozoan jellyfish, Polyorchis penicillatus. We show that most of the 20 intron sites in this diploblast are conserved in mammalian Na+ channel genes, with some even shared by Ca2+ channels. One of these conserved introns is spliced by a rare U 12-type spliceosome. Such conservation places the origin of the primary exon arrangement of Na+ channels and different intron splicing mechanisms to at least the common ancestors of diploblasts and triploblasts, approximately 600 million-1 billion years ago.     

A model study of propagation of early afterdepolarizations

Early afterdepolarizations (EAD's) are irregularities of the cardiac action potential that interrupt or retard repolarization. EAD's have been linked to the development of specific types of cardiac arrhythmias, however, the mechanism underlying the development of these arrhythmias remains unclear. The authors implemented a two-element kinetic model of the ventricular action potential to investigate a potentially arrhythmogenic form of triggered activity. By approximating EAD's by a sinusoidal driving force, the authors were able to study the effects of interelement coupling resistivity and sinusoidal frequency and amplitude on the triggering of action potentials. They demonstrated EAD's in a ventricular action potential model by altering the potassium and calcium channels to simulate experimental conditions under which EAD's occur. They also found that triggered activity depends critically on the frequency and amplitude of the driving force and also on the degree of cellular uncoupling between the elements. The authors' results suggest that triggered activity (due to EAD's) may be suppressed by drugs that improve coupling in unhealthy tissue, or ones that prevent EAD formation by inhibiting calcium channels     

A-96氧化铝陶瓷机电性能的改进

为了解决由氧化铝粉Na+含量较高导致的A-96氧化铝陶瓷产品性能较差的问题,在陶瓷的三元配方(Al2O3-MgO-SiO2)体系中加入了CaCO3。研究了Ca2+含量对A-96氧化铝陶瓷性能的影响。结果表明,Ca2+的引入抑制了陶瓷中Na+的迁移,从而明显改善了A-96氧化铝陶瓷的性能。在CaCO3质量分数为0.8%时,A-96氧化铝陶瓷基板的机电性能达到国标要求。当CaCO3质量分数为1.0%时,该陶瓷基板的机电性能最佳,体密度最大(3.72 g/cm3),但其颜色发黄,这可能是由于陶瓷中生成了黄色的钙长石。