José Jalife

Stable Microreentrant Sources as a Mechanism of Atrial Fibrillation in the Isolated Sheep Heart

BACKGROUND Atrial fibrillation (AF) has traditionally been described as aperiodic or random. Yet, ongoing sources of high-frequency periodic activity have recently been suggested to underlie AF in the sheep heart. Our objective was to use a combination of optical and bipolar electrode recordings to identify sites of periodic activity during AF and elucidate their mechanism. METHODS AND RESULTS AF was induced by rapid pacing in the presence of 0.1 to 0.5 micromol/L acetylcholine in 7 Langendorff-perfused sheep hearts. We used simultaneous optical mapping of the right and left atria (RA and LA) and frequency sampling of optical and bipolar electrode recordings (including a roving electrode) to identify sites having the highest dominant frequency (DF). Rotors were identified from optical recordings, and their rotation period, core area, and perimeter were measured. In all, 35 AF episodes were analyzed. Mean LA and RA DFs were 14.7+/-3.8 and 10.3+/-2.1 Hz, respectively. Spatiotemporal periodicity was seen in the LA during all episodes. In 5 of 7 experiments, a single site having periodic activity at the highest DF was localized. The highest DF was most often (80%) localized to the posterior LA, near or at the pulmonary vein ostium. Rotors (n=14) were localized on the LA. The mean core perimeter and area were 10.4+/-2.8 mm and 3.8+/-2.8 mm(2), respectively. CONCLUSIONS Frequency sampling allows rapid identification of discrete sites of high-frequency periodic activity during AF. Stable microreentrant sources are the most likely underlying mechanism of AF in this model.

Spatiotemporal Periodicity During Atrial Fibrillation in the Isolated Sheep Heart

BACKGROUND The activation patterns that underlie the irregular electrical activity during atrial fibrillation (AF) have traditionally been described as disorganized or random. Recent studies, based predominantly on statistical methods, have provided evidence that AF is spatially organized. The objective of this study was to demonstrate the presence of spatial and temporal periodicity during AF. METHODS AND RESULTS We used a combination of high-resolution video imaging, ECG recordings, and spectral analysis to identify sequential wave fronts with temporal periodicity and similar spatial patterns of propagation during 20 episodes of AF in 6 Langendorff-perfused sheep hearts. Spectral analysis of AF demonstrated multiple narrow-band peaks with a single dominant peak in all cases (mean, 9.4+/-2.6 Hz; cycle length, 112+/-26 ms). Evidence of spatiotemporal periodicity was found in 12 of 20 optical recordings of the right atrium (RA) and in all (n=19) recordings of the left atrium (LA). The cycle length of spatiotemporal periodic waves correlated with the dominant frequency of their respective optical pseudo-ECGs (LA: R2=0.99, slope=0.94 [95% CI, 0.88 to 0.99]; RA: R2=0.97, slope=0.92 [95% CI, 0.80 to 1.03]). The dominant frequency of the LA pseudo-ECG alone correlated with the global bipolar atrial EG (R2=0.76, slope=0.75 [95% CI, 0.52 to 0.99]). In specific examples, sources of periodic activity were seen as rotors in the epicardial sheet or as periodic breakthroughs that most likely represented transmural pectinate muscle reentry. However, in the majority of cases, periodic waves were seen to enter the mapping area from the edge of the field of view. CONCLUSIONS Reentry in anatomically or functionally determined circuits forms the basis of spatiotemporal periodic activity during AF. The cycle length of sources in the LA determines the dominant peak in the frequency spectra in this experimental model of AF.

Wave-front curvature as a cause of slow conduction and block in isolated cardiac muscle.

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.

Purkinje-Muscle Reentry as a Mechanism of Polymorphic Ventricular Arrhythmias in a 3-Dimensional Model of the Ventricles

Multiple electrode mapping of the ventricles during complex tachyarrhythmias has revealed focal subendocardial activation whose mechanism remains unexplained. We hypothesized that reentry involving the Purkinje-muscle junctions (PMJs) may be a mechanism for such focal excitations. We have constructed an anatomically appropriate computerized 3-dimensional model of the mammalian ventricles that includes the Purkinje conduction system and 214 PMJs distributed throughout the endocardium. Isochronal maps during normal excitation, as well as during right or left bundle branch block, resembled experimental measurements and compared well with isochronal maps of propagation in the human heart. Activity observed at both sides of a PMJ in the model showed that propagation from Purkinje fibers to muscle was slower than in the opposite direction. Under these realistic and normal conditions, the evolution of reentrant activity involving muscle and the Purkinje network was simulated. The reentry pattern was independent of the initiation site. It evolved with drifting epicardial breakthroughs and transformed on the endocardium from focal activity to figure-of-8 reentry. In addition, the ECG amplitude undulated during the evolution, and decrease in the cycle period, apparent wavelength, and propagation velocity were observed. Finally, the reentry was terminated if the Purkinje system was disconnected from the muscle before it reached a relative steady state. The simulation results suggest the following: (1) Epicardial breakthroughs and endocardial focal activity may originate at the PMJs. (2) The ECG amplitude may decrease as the reentry stabilizes and the excitation wavelength decreases. (3) The Purkinje system may have a double role in the evolution of reentry: first, it is essential to the reentry at the initial stage; second, it may lead to the establishment of intramyocardial reentry, at which time the Purkinje system becomes irrelevant.

Characteristics of reflection as a mechanism of reentrant arrhythmias and its relationship to parasystole.

A model of “reflection” was developed in a sucrose gap preparation of Purkinje fibers. In this preparation, a driven impulse on the proximal side of a sucrose gap is electrotonically transmitted after a delay to the tissue distal to the gap. When the delay is long enough, electrotonic transmission in the reverse direction over the same blocked segment can reexcite the proximal segment. Frequency-dependent alterations of patterns of ectopic activity were qualitatively similar to those of a parasystolic model and to those described in previous in vivo demonstrations presumed to represent circus movement reentry. Moderate changes of frequency or in the degree of block were shown to convert a manifest bigeminal rhythm to a trigeminal or more complex rhythm with or without intervening periods of silence. Our observations suggest that reflection and parasystolic pacemaker activity are examples of a continuous spectrum of ectopic impulse generation.

Vortex shedding as a precursor of turbulent electrical activity in cardiac muscle

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.

Spiral waves in two-dimensional models of ventricular muscle: formation of a stationary core.

Previous experimental studies have clearly demonstrated the existence of drifting and stationary electrical spiral waves in cardiac muscle and their involvement in cardiac arrhythmias. Here we present results of a study of reentrant excitation in computer simulations based on a membrane model of the ventricular cell. We have explored in detail the parameter space of the model, using tools derived from previous numerical studies in excitation-dynamics models. We have found appropriate parametric conditions for sustained stable spiral wave dynamics (1 s of activity or approximately 10 rotations) in simulations of an anisotropic (ratio in velocity 4:1) cardiac sheet of 2 cm x 2 cm. Initially, we used a model that reproduced well the characteristics of planar electrical waves exhibited by thin sheets of sheep ventricular epicardial muscle during rapid pacing at a cycle length of 300 ms. Under these conditions, the refractory period was 147 ms; the action potential duration (APD) was 120 ms; the propagation velocity along fibers was 33 cm/s; and the wavelength along fibers was 4.85 cm. Using cross-field stimulation in this model, we obtained a stable self-sustaining spiral wave rotating around an unexcited core of 1.75 mm x 7 mm at a period of 115 ms, which reproduced well the experimental results. Thus the data demonstrate that stable spiral wave activity can occur in small cardiac sheets whose wavelength during planar wave excitation in the longitudinal direction is larger than the size of the sheet. Analysis of the mechanism of this observation demonstrates that, during rotating activity, the core exerts a strong electrotonic influence that effectively abbreviates APD (and thus wavelength) in its immediate surroundings and is responsible for the stabilization and perpetuation of the activity. We conclude that appropriate adjustments in the kinetics of the activation front (i.e., threshold for activation and upstroke velocity of the initiating beat) of currently available models of the cardiac cell allow accurate reproduction of experimentally observed self-sustaining spiral wave activity. As such, the results set the stage for an understanding of functional reentry in terms of ionic mechanisms.

Dynamics of rotating vortices in the Beeler-Reuter model of cardiac tissue

Abstract Cardiac muscle is a highly nonlinear active medium which may undergo rotating vortices of electrical activity. We have studied vortex dynamics using a detailed mathematical model of cardiac muscle based on the Beeler-Reuter equations. Specifically, we have investigated the dependence of vortex dynamics on parameters of the excitable cardiac cell membrane in a homogeneous isotropic medium. The results demonstrate that there is a transition from the vortex with circular core that is typical of most excitable media, including the Belousov-Zhabotinsky reaction, to a vortex with linear core that has been observed in heart muscle during so-called reentrant arrhythmias. The transition is not direct but goes through the well-known sequence of nonstationary quasiperiodic rotating vortices. In the parameter space there are domains of different types of vortex dynamics. Such domains include regions where: (1) vortices can not be generated, (2) vortices occur readily, and (3) vortices arise but have a short lifetime. The results provide testable predictions about dynamics associated with initiation, maintenance and termination of cardiac arrhythmias.

Gap junctional channels in adult mammalian sinus nodal cells. Immunolocalization and electrophysiology.

The subcellular mechanism of cell-to-cell communication in the natural pacemaker region of the mammalian heart was studied using electrophysiological and immunofluorescence techniques in isolated pairs of rabbit sinus nodal cells. By measuring whole-cell currents using a double patch-clamp approach, it was demonstrated that communication in the sinus node is mediated through gap junctional channels similar to those in other types of adult cardiac cell pairs. Macroscopic sinus nodal junctional resistance had a mean value of 387.9 +/- 97.1 M omega (mean +/- SEM, n = 10) and was greatly increased by superfusion with alkanols. Single-channel junctional conductance could be resolved in three cell pairs. Given their high membrane resistance (1.16 +/- 0.32 G omega, n = 12), the electrical coupling provided by as few as three gap junctional channels between nodal cells will allow for pacemaker synchronization. Further evidence for the presence of the channels was obtained from immunofluorescent double-labeling of desmin and the gap junction protein (connexin43) in sinus nodal tissue as well as in cultured sinus nodal cells. Using antisera against residues 243-257 of the connexin43 protein, a specific staining at the site of cell-to-cell apposition was demonstrated. These data provide direct evidence in favor of electronic coupling as the means for achieving pacemaker synchronization in the rabbit sinus node.

Nonlinear dynamics of rate-dependent activation in models of single cardiac cells.

Recent studies in isolated cardiac tissue preparations have demonstrated the applicability of a one-dimensional difference equation model describing the global behavior of a driven nonpacemaker cell to the understanding of rate-dependent cardiac excitation. As a first approximation to providing an ionic basis to complex excitation patterns in cardiac cells, we have compared the predictions of the one-dimensional model with those of numerical simulations using a modified high-dimensional ionic model of the space-clamped myocyte. Stimulus-response ratios were recorded at various stimulus magnitudes, durations, and frequencies. Iteration of the difference equation model reproduced all important features of the ionic model results, including a wide spectrum of stimulus-response locking patterns, period doubling, and irregular (chaotic) dynamics. In addition, in the parameter plane, both models predict that the bifurcation structure of the cardiac cell must change as a function of stimulus duration, because stimulus duration modifies the type of supernormal excitability present at short diastolic interval. We conclude that, to a large extent, the bifurcation structure of the ionic model under repetitive stimulation can be understood by two functions: excitability and action potential duration. The characteristics of these functions depend on the stimulus duration.