MItL to the following relationship: 11 3. 5. Dibbs et a)., AIDS Res. Hum. Retrovir. 10, 607 and 2BD1 A135533 02, DAMD grant 1 7 94-J-4431 (1994) Fig. 1 A, the frequency of lence in 3Ds only, then we will find no breakrotation of the rotor (f s = 7.5 Hz) was calculated
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 ,um for longitudinal propagation and 600 gm for I n a cable of electrically coupled cells, slow conduction and block often result from a decreased transmembrane inward current and/or uncoupling between cells. In each case, the "safety factor," defined as the ratio between the current available to excite cells downstream (the "source") and the current needed to excite those cells (the "sink"), determines whether there will be conduction or block. If there is conduction, the safety factor determines the velocity of propagation.1 The sink-to-source relation is contemplated by the concept of liminal length, which establishes that there is a minimal length of a one-dimensional fiber that needs to be excited simultaneously for propagation to proceed.1-3 However, in normal cardiac muscle, certain structural factors may lead to an "impedance mismatch" between the sink and the source, with a consequent alteration of the propagation process. Such factors have been well studied in a number of experimental Received February 25, 1994; accepted August 29, 1994 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 inc...
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.
Gap junction conductance and distribution is heterogeneous in different regions of reentrant circuits. Lateralization of Cx43 gap junctions in CCP of reentrant circuits is associated with normal transverse conductance between cell pairs. In contrast, absence of lateralization in OP is associated with reduced transverse conductance. Despite normal anisotropic ratio, conduction velocity in CCP region remains slower than normal. This suggests that the effects of Cx43 remodeling in the infarcted heart should be interpreted in conjunction with other types of remodeling occurring in the EBZ (i.e. sarcolemmal ion channels).
Background-Anisotropic reentrant excitation occurs in the remodeled substrate of the epicardial border zone (EBZ) of the 5-day infarcted canine heart. Reentry is stabilized because of the formation of functional lines of block. We hypothesized that regional differences of ionic currents in cells of the EBZ form these lines of block. Therefore, we first mapped reentrant circuits of sustained tachycardias, then dispersed cells (infarct zone cells, IZs) from the central common pathway of the circuit (IZc) as well as from the other side of the line of block (outer pathway, IZo) for study. Methods and Results-We mapped reentrant circuits in the EBZ of infarcted hearts during sustained ventricular tachycardias (Ͼ30 seconds, nϭ17 episodes, cycle lengthsϭ218Ϯ7.9 ms). I Na density was reduced in both IZc and IZo, and the kinetic properties of IZc I Na were markedly altered versus IZo. Structural remodeling of the sodium channel protein Na v 1.5 occurred in IZs, with cell surface localization differing from normal cells. Both IZc and IZo have similar but reduced I CaL , whereas IZc showed changes in Ca 2ϩ current kinetics with an acceleration of current decay. Computer simulations of the 2D EBZ showed that incorporating only differences between I Na in IZc and IZo prevented stability of the reentrant circuit. Incorporating only differences between I CaL in the IZc and IZo cells also prevented stability of the circuit. However, incorporating both I Na and I CaL current differences stabilized the simulated reentrant circuit, and lines of block formed between the 2 distinct regions. Conclusions-Despite differences in I Na and I CaL properties in cells of the center and outer pathways of a reentrant circuit, the resulting changes in effective refractory periods tend to stabilize reentry in this remodeled substrate.
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.
Abstract-Variant 3 of the congenital long-QT syndrome (LQTS-3) is caused by mutations in the gene encoding the ␣ subunit of the cardiac Na ϩ 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 (ϩ5.2 and ϩ3.4 mV, respectively). These gating changes shift the window of voltages over which Na ϩ 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 ϩ channel gating may cause marked changes in action potential duration because of the unique voltage-dependent rectifying properties of cardiac K ϩ channels that underlie the plateau and terminal repolarization phases of the action potential. Na ϩ channel window current is likely to have a greater effect on net membrane current at more positive potentials (EK channels) where total K ϩ channel conductance is low than at more negative potentials (wild-type channels), where total K ϩ channel conductance is high. These findings suggest a fundamentally distinct mechanism of arrhythmogenesis for congenital LQTS-3. (Circ Res. 2001;88:740-745.)
Transgenic mice have become important experimental models in the investigation of mechanisms causing cardiac arrhythmias because of the ability to create strains with alterations in repolarizing membrane currents. It is important to relate alterations in membrane currents in cells to their phenotypic expression on the electrocardiogram (ECG). The murine ECG, however, has unusual characteristics that make interpretation of the phenotypic expression of changes in ventricular repolarization uncertain. The major deflection representing the QRS (referred to as "a") is often followed by a secondary slower deflection ("b") and sometimes a subtle third deflection ("c"). To determine whether the second or third deflections or both represent ventricular repolarization, we recorded the ventricular monophasic action potential (MAP) in open-chest mice and correlated repolarization with the ECG. There was no significant correlation by linear regression, between action potential duration to 50% or 90% repolarization (APD(50) or APD(90)), respectively, of the MAP and either the interval from onset of Q to onset of b (Qb interval) or onset of c (Qc interval). Administration of 4-aminopyridine (4-AP) significantly prolonged APD(50) and APD(90) and the Qb interval, indicating that this deflection on the ECG represents part of ventricular repolarization. After 4-AP, the c wave disappeared, also suggesting that it represents a component of ventricular repolarization. Although it appears that both the b and c waves that follow the Q wave on the ECG represent ventricular repolarization, neither correlates exactly with APD(90) of the MAP. Therefore, an accurate measurement of complete repolarization of the murine ventricle cannot be obtained from the surface ECG.
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