Multiplicative optical tomography of cardiac electrical activity.

Cardiac electrical activity can be mapped today through the response of voltage-sensitive dyes; but poor transparency of muscle tissue has enforced shallow-depth imaging. We present a three-dimensional (3D) reconstruction method for electrical activity deep inside the myocardial wall. Our approach is nonlinear and differs substantially from standard diffusive optical tomography. It does not require matrix inversion, data regularization or a priori information concerning the original object. Opposite sides of a slab-shaped preparation are scanned in parallel by detection and illumination points with a constant vector offset between illumination and detection axes (biaxial scanning). Scanning is performed in two perpendicular directions. In each direction, a pair of 2D images is obtained under offsets of opposite signs. These two pairs are the input for a multiplicative reconstruction algorithm, whose output is a 3D image. The overall procedure was successfully tested on computer-generated sources that include points, lines and hemispheres, patterned after actual electrophysiological excitations. The algorithm is computationally efficient and stable with respect to varying noise levels in the raw data.

Method for the three-dimensional localization of intramyocardial excitation centers using optical imaging.

This study explores the possibility of localizing the excitation centers of electrical waves inside the heart wall using voltage-sensitive dyes (fluorescent or absorptive). In the present study, we propose a method for the 3-D localization of excitation centers from pairs of 2-D images obtained in two modes of observation: reflection and transillumination. Such images can be obtained using high-speed charge-coupled device (CCD) cameras and photodiode arrays with time resolution up to 0.5 ms. To test the method, we simulate optical signals produced by point sources and propagating ellipsoidal waves in 1-cm-thick slabs of myocardial tissue. Solutions of the optical diffusion equation are constructed by employing the method of images with Robin boundary conditions. The coordinates of point sources as well as of the centers of expanding waves can be accurately determined using the proposed algorithm. The method can be extended to depth estimations of the outer boundaries of the expanding wave. The depth estimates are based on ratios of spatially integrated images. The method shows high tolerance to noise and can give accurate results even at relatively low signal-to-noise ratios. In conclusion, we propose a novel and efficient algorithm for the localization of excitation centers in 3-D cardiac tissue.

Fluorescence imaging of cardiac propagation: spectral properties and filtering of optical action potentials.

Fluorescence imaging using voltage-sensitive dyes is an important tool for studying electrical propagation in the heart. Yet, the low amplitude of the voltage-sensitive component in the fluorescence signal and high acquisition rates dictated by the rapid propagation of the excitation wave front make it difficult to achieve recordings with high signal-to-noise ratios. Although spatially and temporally filtering the acquired signals has become de facto one of the key elements of optical mapping, there is no consensus regarding their use. Here we characterize the spatiotemporal spectra of optically recorded action potentials and determine the distortion produced by conical filters of different sizes. On the basis of these findings, we formulate the criteria for rational selection of filter characteristics. We studied the evolution of the spatial spectra of the propagating wave front after epicardial point stimulation of the isolated, perfused right ventricular free wall of the pig heart stained with di-4-ANEPPS. We found that short-wavelength (<3 mm) spectral components represent primarily noise and surface features of the preparation (coronary vessels, fat, and connective tissue). The time domain of the optical action potential spectrum also lacks high-frequency components (>100 Hz). Both findings are consistent with the reported effect of intrinsic blurring caused by light scattering inside the myocardial wall. The absence of high-frequency spectral components allows the use of aggressive low-pass spatial and temporal filters without affecting the optical action potential morphology. We show examples where the signal-to-noise ratio increased up to 150 with <3% distortion. A generalization of our approach to the rational filter selection in various applications is discussed.

Alternating conduction in the ischaemic border zone as precursor of reentrant arrhythmias: a simulation study.

AIMS: Here, we investigate the mechanisms underlying the onset of conduction-related arrhythmias in a three-dimensional (3D) computational model of acute regional ischaemia. METHODS: Ischaemia was introduced by realistic gradients of potassium, pH, oxygen and electrical coupling in a 3D slab of ventricular tissue using the LRd model. We focused on a specific stage (10-15 min after occlusion) at which an intramural non-conductive ischaemic core (IC) surrounded by a border zone (BZ) has formed. RESULTS: At pacing frequencies greater than 4.5 Hz, we observed narrow areas (0.5 mm wide) of 2:1 conduction blocks at the periphery of the IC. As the pacing frequency increased, the area of block widened to 9 mm and gave rise to reentry at the periphery of the BZ. Alternating conduction blocks produced discordant action potential duration (APD) alternans throughout the slab and T-wave alternans in pseudo-ECG. Slowing the recovery of the calcium current broadened the range of pacing frequencies at which blocks were observed. Hyperkalaemia alone was sufficient to induce the alternating blocks. CONCLUSION: Computer modelling predicts that ischaemia-related arrhythmias are triggered by calcium-mediated alternating conduction blocks in the ischaemic border zone. Alternating conduction blocks lead to intramural reentry and APD alternans.

Optical action potential upstroke morphology reveals near-surface transmural propagation direction.

The analysis of surface-activation patterns and measurements of conduction velocity in ventricular myocardium is complicated by the fact that the electrical wavefront has a complex 3D shape and can approach the heart surface at various angles. Recent theoretical studies suggest that the optical upstroke is sensitive to the subsurface orientation of the wavefront. Our goal here was to (1) establish the quantitative relationship between optical upstroke morphology and subsurface wavefront orientation using computer modeling and (2) test theoretical predictions experimentally in isolated coronary-perfused swine right ventricular preparations. We show in numerical simulations that by suitable placement of linear epicardial stimulating electrodes, the angle phi of wavefronts with respect to the heart surface can be controlled. Using this method, we developed theoretical predictions of the optical upstroke shape dependence on phi. We determined that the level VF* at which the rate of rise of the optical upstroke reaches the maximum linearly depends on phi. A similar relationship was found in simulations with epicardial point stimulation. The optical mapping data were in good agreement with theory. Plane waves propagating parallel to myocardial fibers produced upstrokes with VF*<0.5, consistent with theoretical predictions for phi>0. Similarly, we obtained good agreement with theory for plane waves propagating in a direction perpendicular to fibers (VF*>0.5 when phi<0). Finally, during epicardial point stimulation, we discovered characteristic saddle-shaped VF* maps that were in excellent agreement with theoretically predicted changes in phi during wavefront expansion. Our findings should allow for improved interpretation of the results of optical mapping of intact heart preparations.

Intermittent self-organization of scroll wave turbulence in three-dimensional excitable media.

We study the asymptotic behavior of scroll wave turbulence in large three-dimensional excitable media modeled by FitzHugh-Nagumo equations. The focus is on the type of turbulence caused by negative tension of scroll wave filaments, which is considered to be one of the mechanisms of cardiac fibrillation. We discovered that the initial increase in turbulence complexity can be followed by intermittent self-organization, when complex filament tangles are replaced by a small number of relatively stable triple filament strands. The intermittency is the result of a competition between the destabilizing effect of negative tension and mutual attraction of filaments with similar orientation.

Synthesis of voltage-sensitive fluorescence signals from three-dimensional myocardial activation patterns.

Voltage-sensitive fluorescent dyes are commonly used to measure cardiac electrical activity. Recent studies indicate, however, that optical action potentials (OAPs) recorded from the myocardial surface originate from a widely distributed volume beneath the surface and may contain useful information regarding intramural activation. The first step toward obtaining this information is to predict OAPs from known patterns of three-dimensional (3-D) electrical activity. To achieve this goal, we developed a two-stage model in which the output of a 3-D ionic model of electrical excitation serves as the input to an optical model of light scattering and absorption inside heart tissue. The two-stage model permits unique optical signatures to be obtained for given 3-D patterns of electrical activity for direct comparison with experimental data, thus yielding information about intramural electrical activity. To illustrate applications of the model, we simulated surface fluorescence signals produced by 3-D electrical activity during epicardial and endocardial pacing. We discovered that OAP upstroke morphology was highly sensitive to the transmural component of wave front velocity and could be used to predict wave front orientation with respect to the surface. These findings demonstrate the potential of the model for obtaining useful 3-D information about intramural propagation.

Frequency-dependent breakdown of wave propagation into fibrillatory conduction across the pectinate muscle network in the isolated sheep right atrium.

Atrial fibrillation (AF) may result from stationary reentry in the left atrium (LA), with fibrillatory conduction toward the right atrium (RA). We hypothesize that periodic input to the RA at an exceedingly high frequency results in disorganized wave propagation, compatible with fibrillatory conduction. Simultaneous endocardial and epicardial optical mapping (di-4-ANEPPS) was performed in isolated, coronary-perfused sheep RA. Rhythmic pacing of Bachmann's bundle allowed well-controlled and realistic conditions for LA-driven RA. Pacing at increasingly higher frequencies (2.0 to 6.0 Hz) led to increasing delays in activation distal to major branching sites of the crista terminalis and pectinate bundles, culminating in spatially distributed intermittent blockade at or above approximately 6.5 Hz. At this "breakdown frequency," the direction of RA propagation became completely variable from beat to beat and thus transformed into fibrillatory conduction. Such frequency-dependent changes were independent of action potential duration. Rather, the spatial boundaries between proximal and distal frequencies correlated well with branch sites of the pectinate musculature. Thus, there exists a breakdown frequency in the sheep RA below which activity is periodic throughout the atrium and above which it is fibrillation-like. The data are consistent with the ideas that during AF, high-frequency activation initiated in the LA undergoes fibrillatory conduction toward the RA, and that sink-to-source effect at branch points of the crista terminalis and pectinate muscles is important in determining the complexity of the arrhythmia.