Diverse phenotypes of outward currents in cells that have survived in the 5-day-infarcted heart

We have shown reduced density and altered kinetics in slowly activating K+ currents (I(Ks)) in epicardial border zone (EBZ) cells (IZs) of the 5-day-infarcted canine heart (Jiang M, Cabo, C, Yao J-A, Boyden PA, and Tseng G-N. Cardiovasc Res 48: 34-43, 2000). beta-Adrenergic stimulation with isoproterenol increases I(Ks) in normal cells (NZs). In this study, we used a voltage-clamp protocol with an external solution to isolate I(Ks) from contaminating currents to determine the effects of 1 muM isoproterenol on I(Ks) in IZs and NZs. Under our recording conditions, 10 microM azimilide-sensitive currents were stimulated with isoproterenol to compare responsiveness of I(Ks) to isoproterenol in the two cell groups. I(Ks) tail density was reduced 67% in IZs (group I, n = 26) compared with NZs (n = 24, P < 0.05). Isoproterenol-stimulated azimilide-sensitive tail currents were increased 1.72 +/- 0.2-fold in NZs and 2.2 +/- 0.3-fold in IZs (P > 0.05). In 33% of IZs (group II, n = 13), native currents showed no tail currents; however, isoproterenol-stimulated azimilide-sensitive currents were voltage dependent, fast activating, and large in amplitude compared with group I IZs, similar to "lone" KCNQ1 currents. Using short clamp pulses, we also found an increase in sustained currents sensitive to tetraethylammonium chloride (TEA) and no change in C-9356-sensitive currents in IZs with little or no transient outward current. In some IZs where I(Ks) is downregulated, the effect of isoproterenol on I(Ks) was similar to that on I(Ks) in NZs. In others, the existence of lone KCNQ1-type currents, which are sensitive to beta-adrenergic stimulation, is consistent with our findings of an increased KCNQ1-to-KCNE1 mRNA ratio (Jiang et al.). Accompanying altered I(Ks) in IZs are an enhanced TEA-sensitive current and a normal C-9356-sensitive current.     

Dynamic changes of cardiac conduction during rapid pacing

Slow conduction and unidirectional conduction block (UCB) are key mechanisms of reentry. Following abrupt changes in heart rate, dynamic changes of conduction velocity (CV) and structurally determined UCB may critically influence arrhythmogenesis. Using patterned cultures of neonatal rat ventricular myocytes grown on microelectrode arrays, we investigated the dynamics of CV in linear strands and the behavior of UCB in tissue expansions following an abrupt decrease in pacing cycle length (CL). Ionic mechanisms underlying rate-dependent conduction changes were investigated using the Pandit-Clark-Giles-Demir model. In linear strands, CV gradually decreased upon a reduction of CL from 500 ms to 230-300 ms. In contrast, at very short CLs (110-220 ms), CV first decreased before increasing again. The simulations suggested that the initial conduction slowing resulted from gradually increasing action potential duration (APD), decreasing diastolic intervals, and increasing postrepolarization refractoriness, which impaired Na(+) current (I(Na)) recovery. Only at very short CLs did APD subsequently shorten again due to increasing Na(+)/K(+) pump current secondary to intracellular Na(+) accumulation, which caused recovery of CV. Across tissue expansions, the degree of UCB gradually increased at CLs of 250-390 ms, whereas at CLs of 180-240 ms, it first increased and subsequently decreased. In the simulations, reduction of inward currents caused by increasing intracellular Na(+) and Ca(2+) concentrations contributed to UCB progression, which was reversed by increasing Na(+)/K(+) pump activity. In conclusion, CV and UCB follow intricate dynamics upon an abrupt decrease in CL that are determined by the interplay among I(Na) recovery, postrepolarization refractoriness, APD changes, ion accumulation, and Na(+)/K(+) pump function.     

Dynamic remodeling of K+ and Ca2+ currents in cells that survived in the epicardial border zone of canine healed infarcted heart

Action potentials (APs) of the epicardial border zone (EBZ) cells from the day 5 infarcted heart continue to be altered by day 14 postocclusion, namely, they shortened. However, by 2 mo, EBZ APs appear "normal," yet conduction of wave fronts remains abnormal. We hypothesize that the changes in transmembrane APs are due to a change in the distribution of ion channels in either density or function. Thus we focused on the changes in Ca2+ and K+ currents in cells isolated from the 14-day (IZ14d) and 2-mo (IZ2m) EBZ and compared them with those occurring in cells from the same hearts but remote (Rem) from the EBZ. Whole cell voltage-clamp techniques were used to measure and compare Ca2+ and K+ currents in cells from the different groups. Ca2+ current densities remain reduced in cells of the 14-day and 2-mo infarcted heart and the kinetic changes previously identified in the 5-day heart begin to, but do not recover to, cells from noninfarcted epicardium (NZ) values. Importantly, I(Ca,L) in both the EBZ and Rem regions still show a slowed recovery from inactivation. Furthermore, during the remodeling process, there is an increased expression of T-type Ca2+ currents, but only regionally, and only within a specific time window postmyocardial infarction (MI). Regional heterogeneity in beta-adrenergic responsiveness of I(Ca,L) exists between EBZ and remote cells of the 14-day hearts, but this regional heterogeneity is gone in the healed infarcted heart. In IZ14d, the transient outward K+ current (Ito) begins to reemerge and is accompanied by an upregulated tetraethylammonium-sensitive outward current. By 2-mo postocclusion, Ito and sustained outward K+ current have completed the reverse remodeling process. During the healing process post-MI, canine epicardial cells downregulate the fast Ito but compensate by upregulating a K+ current that in normal cells is minimally functional. For recovering I(Ca,L) of the 14-day and 2-mo EBZ cells, voltage-dependent processes appear to be reset, such that I(Ca,L) "window" current occurs at hyperpolarized potentials. Thus dynamic changes in both Ca2+ and K+ currents contribute to the altered AP observed in 14-day fibers and may account for return of APs of 2 mo EBZ fibers.     

Modelling changes in transmural propagation and susceptibility to arrhythmia induced by volatile anaesthetics in ventricular tissue

Volatile anaesthetics such as halothane, isoflurane and sevoflurane inhibit membrane currents contributing to the ventricular action potential. Transmural variation in the extent of current blockade induces differential effects on action potential duration (APD) in the endocardium and epicardium which may be pro-arrhythmic. Biophysical modelling techniques were used to simulate the functional impact of anaesthetic-induced blockade of membrane currents on APD and effective refractory period (ERP) in rat endocardial and epicardial cell models. Additionally, the transmural conduction of excitation waves in 1-dimensional cell arrays, the tissue's vulnerability to arrhythmogenesis and dynamic behaviour of re-entrant excitation in 2-dimensional cell arrays were studied. Simulated anaesthetic exposure reduced APD and ERP in both epicardial and endocardial cell models. The reduction in APD was greater in endocardial than epicardial cells, reducing transmural APD dispersion consistent with experimental data. However, the transmural ERP dispersion was augmented. All three anaesthetics increased the width of the tissue's vulnerable window during which a premature stimulus could induce unidirectional conduction block but only halothane reduced the critical size of ventricular substrates necessary to initiate and sustain re-entrant excitation. All three anaesthetics accelerated the rate of re-entrant excitation waves, but only halothane prolonged the lifespan of re-entry. These data illustrate in silico, that modest changes in ion channel conductance abbreviate rat ventricular APD and ERP, reduce transmural APD dispersion, but augment transmural ERP dispersion. These changes collectively enhance the propensity for arrhythmia generation and provide a substrate for re-entry circuits with a longer half life than in control conditions.     

Structural Heterogeneity Modulates Effective Refractory Period: A Mechanism of Focal Arrhythmia Initiation

Reductions in electrotonic loading around regions of structural and electrophysiological heterogeneity may facilitate capture of focal triggered activity, initiating reentrant arrhythmias. How electrotonic loading, refractoriness and capture of focal ectopics depend upon the intricate nature of physiological structural anatomy, as well as pathological tissue remodelling, however, is not well understood. In this study, we performed computational bidomain simulations with anatomically-detailed models representing the rabbit left ventricle. We used these models to quantify the relationship between local structural anatomy and spatial heterogeneity in action potential (AP) characteristics, electrotonic currents and effective refractory periods (ERPs) under pacing and restitution protocols. Regions surrounding vessel cavities, in addition to tissue surfaces, had significantly lower peak downstream electrotonic currents than well coupled myocardium ( vs A/cm²), with faster maximum AP upstroke velocities ( vs mV/ms), although noticeably very similar APDs ( vs ms) and AP restitution properties. Despite similarities in APDs, ERPs in regions of low electrotonic load in the vicinity of surfaces, intramural vessel cavities and endocardial structures were up to ms shorter compared to neighbouring well-coupled tissue, leading to regions of sharp ERP gradients. Consequently, focal extra-stimuli timed within this window of ERP heterogeneity between neighbouring regions readily induced uni-directional block, inducing reentry. Most effective induction sites were within channels of low ERPs between large vessels and epicardium. Significant differences in ERP driven by reductions in electrotonic loading due to fine-scale physiological structural heterogeneity provides an important mechanism of capture of focal activity and reentry induction. Application to pathological ventricles, particularly myocardial infarction, will have important implications in anti-arrhythmia therapy.     

Heterogeneous gap junction remodeling stabilizes reentrant circuits in the epicardial border zone of the healing canine infarct: a computational study

The ventricular tachycardias (VTs) that originate in the 5-day epicardial border zone (EBZ) of the healing canine infarcted heart are due to reentrant excitation. In cells surviving in the EBZ, both sarcolemmal ionic channels and gap junction conductance and distribution are remodeled. We previously showed that the heterogeneities in sodium current (I(Na)) and L-type calcium channel current (I(CaL)) of the center and outer pathway cells result in a homogenization of the refractory period that in turn stabilizes reentrant VTs for approximately 10 beats. To understand how heterogeneities in transverse gap junctional conductance remodeling reported experimentally contribute to the stability of these tachycardias, we studied the dynamics of reentering waves in two-dimensional computer models of the EBZ. First we used a computer model with homogeneous ionic channel properties [infarcted border zone cell model (IZ)]. These simulations show that, in the absence of heterogeneities in ionic channel properties, reentrant waves tend to drift to localized regions of uncoupling and stabilize there. Second, we used a computer model with a more realistic representation of the heterogeneous EBZ, including cellular models for both the center (IZ(c)) and outer (IZ(o)) pathway cells. These simulations show that neither a region of uniform uncoupling nor a step transition between two regions with different side-to-side (transverse) cell coupling stabilizes reentry in this substrate. However, an area of localized uncoupling did stabilize reentry in such a model. We propose that in addition to the heterogeneities in I(Na) and I(CaL) properties, heterogeneities in gap junctional conductance in the EBZ causing regions of localized uncoupling stabilize VT in the EBZ. Previous experimental in situ activation maps of the 5-day EBZ show that the lines of block form in regions of slow transverse propagation. This is consistent with our findings that areas of localized uncoupling stabilize reentry.     

Is there a correlation between ventricular fibrillation cycle length and electrophysiological and anatomic properties of the canine left ventricle?

We hypothesized that myocardial infarction-related alterations in ventricular fibrillation (VF) cycle length (VFCL) would correlate with changes in local cardiac electrophysiological and anatomic properties. An electrophysiological study was performed in normal, subacute, and chronic infarction mongrel dogs. VF was induced by programmed electrical stimulation and mean and minimum early and late VFCL was determined and correlated with local electrophysiological and anatomic properties. Effective refractory period (ERP), activation recovery time (ART), ERP/ART ratio, threshold, and ERP and ART dispersion were determined at 112 sites on the anterior left ventricle. Wave front progression was analyzed over a 2-s period. The extent of local tissue necrosis and of myocardial fiber disarray was also evaluated. The early mean VFCL was significantly longer in the subacute infarction (149 +/- 35 ms) and chronic infarction dogs (129 +/- 18 ms) compared with control dogs (102 +/- 15 ms; P < 0.0001 for both comparisons) as was the early minimum VFCL with similar trends seen during late VF. Complete epicardial reentrant circuits were significantly more common in normal dogs (4.3 +/- 2.4, 22.4% of cycles) than in subacute (0.75 +/- 0.96, 5.3% of cycles, P < 0.05 vs. normal) and chronic infarction dogs (1.3 +/- 1.3, 7.5% of cycles, P < 0.05 vs. normal). There was a poor correlation between the mean and minimum early and late VFCL and local electrophysiological and anatomic properties (R(2) < 0.2 for all comparisons) with a much better correlation between average mean and minimum VFCL (over the entire plaque) and global ERP and ART dispersion during early and late VF. In conclusion, VFCL in normal and infarcted myocardium shows a poor correlation with local ventricular electrophysiological and anatomic properties measured in sinus rhythm. However, there was a much better correlation between the average VFCL with global dispersion of repolarization. The lack of correlation between local VFCL and refractoriness and the infrequent occurrence of epicardial reentry suggests that intramural reentry may be the primary mechanism of VF in this model.     

Refractoriness of the sheep superior vena cava myocardial sleeve

The cardiomyocytes in the superior vena cava (SVC) myocardial sleeve have distinct action potentials and ionic current profiles, but the refractoriness of these cells has not been reported. Using standard intracellular microelectrode techniques, we demonstrated in sheep that the effective refractory period (ERP) of the cardiomyocytes in the SVC (114.7 +/- 6.5 ms) is shorter than that in the inferior vena cava (IVC) (166.7 +/- 6.2 ms), right atrial free wall (RAFW) (201.0 +/- 6.0 ms) and right atrial appendage (RAA) (203.1 +/- 5.8 ms) (P < 0.05). The right atrial cardiomyocyte ERP was heterogeneously shortened by acetylcholine, a muscarinic type 2 receptor (M(2)R) agonist. After perfusion with 15 microM acetylcholine, the shortest ERP occurred in the SVC (the ERP in the SVC, IVC, RAFW and RAA was 53.6 +/- 2.7, 98.9 +/- 2.2, 121.8 +/- 6.0 and 109.7 +/- 5.1 ms, respectively; P < 0.05). Carbachol (1 microM), another M(2)R agonist, produced a similar effect as acetylcholine. Furthermore, we used methoctramine, a M(2)R blocker, 4-DAMP, a muscarinic type 3 receptor (M(3)R) blocker, and tropicamide, a muscarinic type 4 receptor (M(4)R) blocker to inhibit the acetylcholine-induced ERP shortening of SVC cardiomyocytes, and found that the 50% inhibitory concentration for methoctramine, 4-DAMP and tropicamide was 5.91, 45.72 and 80.34 nM, respectively. Therefore, we conclude that the sheep SVC myocardial sleeve is a unique electrophysiological region of the right atrium with the shortest ERP both under physiological condition and under cholinergic agonist stimulation. M(2)R might play a major role in the response of the SVC myocardial sleeve to parasympathetic nerve tone. The association between the distinct refractoriness in SVC and atrial fibrillation originating from the region deserves further investigation.     

Modeling ventricular repolarization: effects of transmural and apex-to-base heterogeneities in action potential durations

Heterogeneities in the densities of membrane ionic currents of myocytes cause regional variations in action potential duration (APD) at various intramural depths and along the apico-basal and circumferential directions in the left ventricle. This work extends our previous study of cartesian slabs to ventricular walls shaped as an ellipsoidal volume and including both transmural and apex-to-base APD heterogeneities. Our 3D simulation study investigates the combined effect on repolarization sequences and APD distributions of: (a) the intrinsic APD heterogeneity across the wall and along the apex-to-base direction, and (b) the electrotonic currents that modulate the APDs when myocytes are embedded in a ventricular wall with fiber rotation and orthotropic anisotropy. Our findings show that: (i) the transmural and apex-to-base heterogeneities have only a weak influence on the repolarization patterns on myocardial layers parallel to the epicardium; (ii) the patterns of APD distribution on the epicardial surface are mostly affected by the apex-to-base heterogeneities and do not reveal the APD transmural heterogeneity; (iii) the transmural heterogeneity is clearly discernible in both repolarization and APD patterns only on transmural sections; (iv) the apex-to-base heterogeneity is clearly discernible only in APD patterns on layers parallel to the epicardium. Thus, in our orthotropic ellipsoidal wall, the complex 3D electrotonic modulation of APDs does not fully mix the effects of the transmural and apex-to-base heterogeneity. The intrinsic spatial heterogeneity of the APDs is unmasked in the modulated APD patterns only in the appropriate transmural or intramural sections. These findings are independent of the stimulus location (epicardial, endocardial) and of Purkinje involvement.     

Relevance of ventricular electrical dispersion to arrhythmogenesis in ischemic myocardium--a simulation study

A computer simulation method was used to study the possible role of electrical dispersion induced by regional ischemia in the mechanisms underlying cardiac arrhythmias. Ischemic cells were simulated by considering the three major component conditions of acute ischemia (elevated extracellular K+ concentration, acidosis and anoxia) at the level of ionic currents and ionic concentrations. An ischemic area was introduced into a homogeneous healthy tissue to create a localized inhomogeneity. The constructed models were solved using the operator splitting and adaptive time step methods. The numerical experiments showed that action potential durations (APDs) of ischemic cells did not change with beats of shorter or longer cycle length. The smaller percentage increase of slow component of the delayed rectifier K+ current, I(ks), and smaller outward Na+-Ca2+ exchange current were found to be the ionic mechanisms underlying the decreased rate dependence in ischemic cells. The results suggest that ischemia flattens the APD restitution curve; however, the dispersion of refractory period can be greatly increased by a premature beat in the constructed inhomogeneous sheet. This demonstrates that the dispersion of refractoriness rather than APD by a premature beat contributes to reentrant tachyarrhythmias in the locally ischemic tissue.     

Transmural action potential and ionic current remodeling in ventricles of failing canine hearts

Heart failure (HF) produces important alterations in currents underlying cardiac repolarization, but the transmural distribution of such changes is unknown. We therefore recorded action potentials and ionic currents in cells isolated from the endocardium, midmyocardium, and epicardium of the left ventricle from dogs with and without tachypacing-induced HF. HF greatly increased action potential duration (APD) but attenuated APD heterogeneity in the three regions. Early afterdepolarizations (EADs) were observed in all cell types of failing hearts but not in controls. Inward rectifier K(+) current (I(K1)) was homogeneously reduced by approximately 41% (at -60 mV) in the three cell types. Transient outward K(+) current (I(to1)) was decreased by 43-45% at +30 mV, and the slow component of the delayed rectifier K(+) current (I(Ks)) was significantly downregulated by 57%, 49%, and 58%, respectively, in epicardial, midmyocardial, and endocardial cells, whereas the rapid component of the delayed rectifier K(+) current was not altered. The results indicate that HF remodels electrophysiology in all layers of the left ventricle, and the downregulation of I(K1), I(to1), and I(Ks) increases APD and favors occurrence of EADs.     

The Na+/K+ pump is an important modulator of refractoriness and rotor dynamics in human atrial tissue

Pharmacological treatment of atrial fibrillation (AF) exhibits limited efficacy. Further developments require a comprehensive characterization of ionic modulators of electrophysiology in human atria. Our aim is to systematically investigate the relative importance of ionic properties in modulating excitability, refractoriness, and rotor dynamics in human atria before and after AF-related electrical remodeling (AFER). Computer simulations of single cell and tissue atrial electrophysiology were conducted using two human atrial action potential (AP) models. Changes in AP, refractory period (RP), conduction velocity (CV), and rotor dynamics caused by alterations in key properties of all atrial ionic currents were characterized before and after AFER. Results show that the investigated human atrial electrophysiological properties are primarily modulated by maximal value of Na(+)/K(+) pump current (G(NaK)) as well as conductances of inward rectifier potassium current (G(K1)) and fast inward sodium current (G(Na)). G(NaK) plays a fundamental role through both electrogenic and homeostatic modulation of AP duration (APD), APD restitution, RP, and reentrant dominant frequency (DF). G(K1) controls DF through modulation of AP, APD restitution, RP, and CV. G(Na) is key in determining DF through alteration of CV and RP, particularly in AFER. Changes in ionic currents have qualitatively similar effects in control and AFER, but effects are smaller in AFER. The systematic analysis conducted in this study unravels the important role of the Na(+)/K(+) pump current in determining human atrial electrophysiology.     

Effect of activation sequence on transmural patterns of repolarization and action potential duration in rabbit ventricular myocardium

Although transmural heterogeneity of action potential duration (APD) is established in single cells isolated from different tissue layers, the extent to which it produces transmural gradients of repolarization in electrotonically coupled ventricular myocardium remains controversial. The purpose of this study was to examine the relative contribution of intrinsic cellular gradients of APD and electrotonic influences to transmural repolarization in rabbit ventricular myocardium. Transmural optical mapping was performed in left ventricular wedge preparations from eight rabbits. Transmural patterns of activation, repolarization, and APD were recorded during endocardial and epicardial stimulation. Experimental results were compared with modeled data during variations in electrotonic coupling. A transmural gradient of APD was evident during endocardial stimulation, which reflected differences previously seen in isolated cells, with the longest APD at the endocardium and the shortest at the epicardium (endo: 165 ± 5 vs. epi: 147 ± 4 ms; P < 0.05). During epicardial stimulation, this gradient reversed (epi: 162 ± 4 vs. endo: 148 ± 6 ms; P < 0.05). In both activation sequences, transmural repolarization followed activation and APD shortened along the activation path such that significant transmural gradients of repolarization did not occur. This correlation between transmural activation time and APD was recapitulated in simulations and varied with changes in intercellular coupling, confirming that it is mediated by electrotonic current flow between cells. These data suggest that electrotonic influences are important in determining the transmural repolarization sequence in rabbit ventricular myocardium and that they are sufficient to overcome intrinsic differences in the electrophysiological properties of the cells across the ventricular wall.     

Time-dependent transients in an ionically based mathematical model of the canine atrial action potential

Ionically based cardiac action potential (AP) models are based on equations with singular Jacobians and display time-dependent AP and ionic changes (transients), which may be due to this mathematical limitation. The present study evaluated transients during long-term simulated activity in a mathematical model of the canine atrial AP. Stimulus current assignment to a specific ionic species contributed to stability. Ionic concentrations were least disturbed with the K(+) stimulus current. All parameters stabilized within 6-7 h. Inward rectifier, Na(+)/Ca(2+) exchanger, L-type Ca(2+), and Na(+)-Cl(-) cotransporter currents made the greatest contributions to stabilization of intracellular [K(+)], [Na(+)], [Ca(2+)], and [Cl(-)], respectively. Time-dependent AP shortening was largely due to the outward shift of Na(+)/Ca(2+) exchange related to intracellular Na(+) (Na) accumulation. AP duration (APD) reached a steady state after approximately 40 min. AP transients also occurred in canine atrial preparations, with the APD decreasing by approximately 10 ms over 35 min, compared with approximately 27 ms in the model. We conclude that model APD and ionic transients stabilize with the appropriate stimulus current assignment and that the mathematical limitation of equation singularity does not preclude meaningful long-term simulations. The model agrees qualitatively with experimental observations, but quantitative discrepancies highlight limitations of long-term model simulations.     

Assessing redistribution of muscle innervation zones after spinal cord injuries

This study aimed to examine the redistribution of neuromuscular junctions or innervation zones (IZs) after spinal cord injuries (SCI). Fifteen able-bodied subjects and 15 subjects with SCI (American Spinal Injury Association Impairment Scale A to D), participated in the study. Surface electromyography (EMG) signals were collected from the biceps brachii muscle by a customized linear electrode array when subjects generated maximal isometric voluntary contractions. The Radon transform was applied to detect the IZ locations in the multiple channel surface EMG signals which were differentiated between consecutive channels. The distribution of IZs was compared between the SCI and control groups using the student-t test. Statistical analysis disclosed a significantly wider range of IZs in the SCI group compared with the control group (SCI: 3.83 ± 1.32 IED, control: 2.83 ± 0. 87 IED, IED: inter-electrode distance, p < 0.05). No remarkable shifts of the center of the distribution were observed between the two groups (SCI: 9.23 ± 2.35 IED, control: 8.53 ± 2.33 IED, p = 0.42). Changes of IZ distribution in the paralyzed muscles could be associated with the complex neuromuscular reorganization after the SCI.     

Effects of Na(+) channel and cell coupling abnormalities on vulnerability to reentry: a simulation study

The role of dynamic instabilities in the initiation of reentry in diseased (remodeled) hearts remains poorly explored. Using computer simulations, we studied the effects of altered Na(+) channel and cell coupling properties on the vulnerable window (VW) for reentry in simulated two-dimensional cardiac tissue with and without dynamic instabilities. We related the VW for reentry to effects on conduction velocity, action potential duration (APD), effective refractory period dispersion and restitution, and concordant and discordant APD alternans. We found the following: 1). reduced Na(+) current density and slowed recovery promoted postrepolarization refractoriness and enhanced concordant and discordant APD alternans, which increased the VW for reentry; 2). uniformly reduced cell coupling had little effect on cellular electrophysiological properties and the VW for reentry. However, randomly reduced cell coupling combined with decoupling promoted APD dispersion and alternans, which also increased the VW for reentry; 3). the combination of decreased Na(+) channel conductance, slowed Na(+) channel recovery, and cellular uncoupling synergistically increased the VW for reentry; and 4) the VW for reentry was greater when APD restitution slope was steep than when it was flat. In summary, altered Na(+) channel and cellular coupling properties increase vulnerability to reentrant arrhythmias. In remodeled hearts with altered Na(+) channel properties and cellular uncoupling, dynamic instabilities arising from electrical restitution exert important influences on the VW for reentry.     

Automatic localisation of innervation zones: A simulation study of the external anal sphincter

Traumas of the innervation zone (IZ) of the external anal sphincter (EAS), e.g. during delivery, can promote the development of faecal incontinence. Recently developed probes allow high-resolution detection of EMG signals from the EAS. The analysis of pelvic floor muscles by surface EMG (in particular, the estimation of the location of the IZ) has potential applications in the diagnosis and investigation of the mechanisms of incontinence.An automatic method (based on matched filter approach) for the estimation of the IZ distribution of EAS from surface EMG is discussed and tested using an analytical model of generation of EMG signals from sphincter muscles. Simulations are performed varying length of the fibres, thickness of the mucosa, position of the motor units, and force level. Different distributions of IZs are simulated.The performance of the proposed method in the estimation of the IZ distribution is affected by surface MUAP amplitude (as the estimation made by visual inspection), by mucosa thickness (performance decreases when fibre length is higher) and by different MU distributions. However, in general the method is able to identify the position of two IZ locations and can measure asymmetry of the IZ distribution. This strengthens the potential applications of high density surface EMG in the prevention and investigation of incontinence.     

Auditory event-related potentials to the apparent auditory image motion

Auditory event-related potentials (ERP) were registered to the dichotically presented white noise stimuli (duration 1500 ms, band 150-1200 Hz). Abrupt or gradual change ofinteraural time difference in the middle of stimuli (750 ms after sound offset) was perceived as an apparent auditory image (AI) instant relocation or motion from the midline to one of the ears. In responses these stimuli two ERPs were observed: one to the sound onset, and second--to the onset of motion or AI relocation. ERPs to AI relocation differed from those to sound onset in longer components latencies (123 ms versus 105 ms for N 1,227 ms versus 190 ms for P2). In responses to AI motion component latencies were even longer (N1: 137 ms, P2: 240 ms); N1 amplitude was greater at sites contralateral to the AI motion direction.     

Thyroid hormone regulates mRNA expression and currents of ion channels in rat atrium

Atrial fibrillation is one of the common arrhythmias associated with hyperthyroidism. This study examined the effects of thyroid hormone (T3) on mRNA expression and currents of major ionic channels determining the action potential duration (APD) in the rat atrium using the RNase protection assay and the whole-cell patch-clamp technique, respectively. T3 increased the Kv1.5 mRNA expression and decreased the L-type calcium channel mRNA expression, while the Kv4.2 mRNA expression did not change. APD was shorter in hyperthyroid than in euthyroid myocytes. The ultrarapid delayed rectifier potassium currents were remarkably increased in hyperthyroid than in euthyroid myocytes, whereas the transient outward potassium currents were unchanged. L-type calcium currents were decreased in hyperthyroid than in euthyroid myocytes. T3 shifted the current-voltage relationship for calcium currents negatively. In conclusion, T3 increased the outward currents and decreased the inward currents. The resultant changes of ionic currents shortened APD, providing a substrate for atrial fibrillation.     

牵张所致心室不应性变化的频率依赖现象及其机制

本文旨在探讨牵张所致麻醉兔心室不应性变化的频率依赖现象及其机制。采用部分夹闭兔主动脉根部以增加左室后负荷的在体心脏模型 ,观察不同起搏周长时左室后负荷增加后心室有效不应期 (effectiverefractoryperi od ,ERP)的变化及链霉素对此的影响。结果显示 ,当起搏周长为 10 0 0和 5 0 0ms时 ,左室收缩期内压增加后的心室ERP较主动脉夹闭前略有缩短 ( 10 0 0ms,3± 2ms,1 5 % ;5 0 0ms,7± 3ms,4 0 % .P >0 0 5 ) ,而起搏周长 3 0 0和 2 0 0ms时则明显缩短 ( 3 0 0ms,2 1± 5ms ,17 0 % ;2 0 0ms,19± 3ms,18 8% P <0 0 1) ;( 2 )链霉素可有效消除基本驱动周长 3 0 0和 2 0 0ms时左心室后负荷增加对ERP的影响 (P >0 0 5 ,组内比较 )。结果提示 ,牵张所致心室ERP变化具有快频率依赖性 ,且链霉素通过抑制牵张激活性离子通道的活化而消除这种电生理效应