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Variant 3 of the congenital long-QT syndrome (LQTS-3) is caused by mutations in the gene encoding the alpha subunit of the cardiac Na(+) channel. In the present study, we report a novel LQTS-3 mutation, E1295K (EK), and describe its functional consequences when expressed in HEK293 cells. The clinical phenotype of the proband indicated QT interval prolongation in the absence of T-wave morphological abnormalities and a steep QT/R-R relationship, consistent with an LQTS-3 lesion. However, biophysical analysis of mutant channels indicates that the EK mutation changes channel activity in a manner that is distinct from previously investigated LQTS-3 mutations. The EK mutation causes significant positive shifts in the half-maximal voltage (V(1/2)) of steady-state inactivation and activation (+5.2 and +3.4 mV, respectively). These gating changes shift the window of voltages over which Na(+) channels do not completely inactivate without altering the magnitude of these currents. The change in voltage dependence of window currents suggests that this alteration in the voltage dependence of Na(+) channel gating may cause marked changes in action potential duration because of the unique voltage-dependent rectifying properties of cardiac K(+) channels that underlie the plateau and terminal repolarization phases of the action potential. Na(+) channel window current is likely to have a greater effect on net membrane current at more positive potentials (EK channels) where total K(+) channel conductance is low than at more negative potentials (wild-type channels), where total K(+) channel conductance is high. These findings suggest a fundamentally distinct mechanism of arrhythmogenesis for congenital LQTS-3.

In cardiac tissue, during partial blockade of the membrane sodium channels, or at high frequencies of excitation, inexcitable obstacles with sharp edges may destabilize the propagation of electrical excitation waves, causing the formation of self-sustained vortices and turbulent cardiac electrical activity. The formation of such vortices, which visually resembles vortex shedding in hydrodynamic turbulent flows, was observed in sheep epicardial tissue using voltage-sensitive dyes in combination with video-imaging techniques. Vortex shedding is a potential mechanism leading to the spontaneous initiation of uncontrolled high-frequency excitation of the heart.

Background: Ventricular tachycardia may result from vortexlike reentrant excitation of the myocardium. Our general hypothesis is that in the structurally normal heart, these arrhythmias are the result of one or two nonstationary three-dimensional electrical scroll waves activating the heart muscle at very high frequencies., Methods and Results: We used a combination of high-resolution video imaging, electrocardiography, and image processing in the isolated rabbit heart, together with mathematical modeling. We characterized the dynamics of changes in transmembrane potential patterns on the epicardial surface of the ventricles using optical mapping. Image processing techniques were used to identify the surface manifestation of the reentrant organizing centers, and the location of these centers was used to determine the movement of the reentrant pathway. We also used numerical simulations incorporating Fitzhugh-Nagumo kinetics and realistic heart geometry to study how stationary and nonstationary scroll waves are manifest on the epicardial surface and in the simulated ECG. We present epicardial surface manifestations (reentrant spiral waves) and ECG patterns of nonstationary reentrant activity that are consistent with those generated by scroll waves established at the right and left ventricles. We identified the organizing centers of the reentrant circuits on the epicardial surface during polymorphic tachycardia, and these centers moved during the episodes. In addition, the arrhythmias that showed the greatest movement of the reentrant centers displayed the largest changes in QRS morphology. The numerical simulations showed that stationary scroll waves give rise to monomorphic ECG signals, but nonstationary meandering scroll waves give rise to undulating ECGs characteristic of torsade de pointes., Conclusions: Polymorphic ventricular tachycardia in the healthy, isolated rabbit heart is the result of either a single or paired ("figure-of-eight") nonstationary scroll waves. The extent of the scroll wave movement corresponds to the degree of polymorphism in the ECG. These results are consistent with our numerical simulations that showed monomorphic ECG patterns of activity for stationary scroll waves but polymorphic patterns for scroll waves that were nonstationary.

We have investigated the role of wave-front curvature on propagation by following the wave front that was diffracted through a narrow isthmus created in a two-dimensional ionic model (Luo-Rudy) of ventricular muscle and in a thin (0.5-mm) sheet of sheep ventricular epicardial muscle. The electrical activity in the experimental preparations was imaged by using a high-resolution video camera that monitored the changes in fluorescence of the potentiometric dye di-4-ANEPPS on the surface of the tissue. Isthmuses were created both parallel and perpendicular to the fiber orientation. In both numerical and biological experiments, when a planar wave front reached the isthmus, it was diffracted to an elliptical wave front whose pronounced curvature was very similar to that of a wave front initiated by point stimulation. In addition, the velocity of propagation was reduced in relation to that of the original planar wave. Furthermore, as shown by the numerical results, wave-front curvature changed as a function of the distance from the isthmus. Such changes in local curvature were accompanied by corresponding changes in velocity of propagation. In the model, the critical isthmus width was 200 microns for longitudinal propagation and 600 microns for transverse propagation of a single planar wave initiated proximal to the isthmus. In the experiments, propagation depended on the width of the isthmus for a fixed stimulation frequency. Propagation through an isthmus of fixed width was rate dependent both along and across fibers. Thus, the critical isthmus width for propagation was estimated in both directions for different frequencies of stimulation. In the longitudinal direction, for cycle lengths between 200 and 500 milliseconds, the critical width was < 1 mm; for 150 milliseconds, it was estimated to be between 1.3 and 2 mm; and for the maximum frequency of stimulation (117 +/- 15 milliseconds), it was > 2.5 mm. In the transverse direction, critical width was between 1.78 and 2.32 mm for a basic cycle length of 200 milliseconds. It increased to values between 2.46 and 3.53 mm for a basic cycle length of 150 milliseconds. The overall results demonstrate that the curvature of the wave front plays an important role in propagation in two-dimensional cardiac muscle and that changes in curvature may cause slow conduction or block.

Objective: Diacetyl monoxime (DAM), a nucleophilic agent with "phosphatase-like" activity, has been found to effectively and reversibly block cardiac muscle contraction, while the cells remain capable of generating transmembrane action potentials. The aim of this study was to characterise the effects of DAM on the electrical properties of cardiac muscle., Methods: Sheep epicardial muscle, guinea pig papillary muscle, and guinea pig ventricular myocytes were studied using conventional microelectrode techniques as well as single electrode current and voltage clamp techniques., Results: DAM (5-20 mM) decreased action potential duration at 50% and 90% repolarisation levels (APD50, APD90) and refractory period in a dose dependent manner without causing significant changes in action potential amplitude, maximum upstroke velocity, or resting membrane potential. DAM induced a slight decrease in action potential conduction velocity in both the longitudinal and transverse directions, but on average the conduction velocity recorded in the presence of the drug was not significantly different from control. The time course of the APD restitution curve was not significantly changed but the frequency dependent APD variations were reduced. The ionic bases for these changes were studied in guinea pig ventricular myocytes. As with the results obtained in tissue preparations, DAM 15 mM decreased APD50 and APD90 by 35% and 29%, respectively. Under voltage clamp conditions, DAM led to a 35% reduction of ICa. The delayed rectifier IK current and the inward rectifier background current were also partially depressed by DAM but to a lesser extent. All of these effects were reversible upon washout., Conclusions: Aside from its well known effect as an electromechanical uncoupler, DAM causes a small, reversible, and non-selective reduction of several membrane conductances. Provided such effects are taken into consideration, DAM is a valuable tool in electrophysiological studies.

The identification of local activation events in bipolar cardiac electrograms, the first step of isochronal map construction, is a time-consuming and difficult process. Owing to the variability among bipolar activation complexes and the lack of practical knowledge concerning the relationship of the bipolar waveform to action potential characteristics, a set of empirical rules to guide the assignment of local activation times have been adopted. A computer program, called AP, has been designed, which implements these rules in the form of a syntactic analyser. Canine epicardial recordings were used to evaluate AP by comparing local activation times, assigned by AP, with times assigned independently by three investigators. The Hermes-Cox model for detector evaluation and a bootstrap statistical method were used in conjunction with ROC analysis to evaluate the ability of AP to detect events. Analysis of discrepancies among investigator-assigned times showed that the reliabilities of AP event detection and AP-assigned times were comparable to those of the investigators. The methods used in system design and evaluation are applicable to a broad range of problems in the detection and localisation of waveform components.

This modeling study seeks to explain the experimentally detected delay between the application of an electric field and the recorded response of the transmembrane potential. In this experiment, conditions were deliberately set so that the field should excite all cells at once and so that no delay should be caused by a propagating wave front. The explanation of the observed delay may lie in the intrinsic properties of the membrane. To test this hypothesis, the strength latency curves were determined for three cases: (1) for a membrane patch model, in which the membrane is uniformly polarized and its intrinsic properties can be studied; (2) for the cardiac strand directly excited by the electric field; and (3) for the cardiac strand excited by a propagating wave front. The models of the membrane patch and the directly excited strand yield excitation delays that are comparable to those observed experimentally in magnitude and in the overall shape of the strength latency curves. The delays resulting from propagation are, in general, dependent on the position along the strand, although for some positions the strength latency curves for propagation are similar to those obtained from the directly activated strand and from the patch model. Therefore, the delay in excitation does not necessarily imply the presence of propagating wave fronts and can be attributed to intrinsic membrane kinetics.