Myocardial Anisotropy Research Articles

Ultrasonic tissue characterization of the mouse myocardium: Successful in vivo cyclic variation measurements

Background Measurements of the systematic variation of backscattered ultrasonic energy from myocardium during the heart cycle (cyclic variation) have been successfully used to characterize a wide spectrum of cardiac pathologies in large animal models and human subjects. The purpose of this study was to evaluate the feasibility of extending cyclic variation measurements to the study of genetically manipulated mouse models of cardiac diseases as a method for developing further insights into the disease-altered properties of the myocardium and its characterization with ultrasound. Methods Parasternal long-axis images of the heart were obtained in 9 wild-type mice under light anesthesia using a commercial imaging system with a 15-MHz nominal center frequency linear array. Images of a tissue-mimicking phantom and the mouse hearts were obtained for a series of specific receiver gains for each of a series of specific dynamic range settings. Analyses of these data formed the basis for gray-scale image calibration. Cyclic variation measurements were obtained by determining the average gray-scale value for a region of interest placed in the midmyocardium of the posterior wall for each frame acquired during 4 cardiac cycles and converting these mean gray-scale values to backscatter values expressed in decibels using the determined calibration. Results are expressed in terms of the magnitude and time delay of cyclic variation. To evaluate repeatability of these measurements the same group of mice underwent the identical imaging protocol 2 weeks after the first study. Results The mean magnitude of cyclic variation was found to be 4.6 ± 0.2 dB with a corresponding normalized time delay of 1.02 ± 0.03 for data averaged over all dynamic range settings. There was no significant difference among results obtained with each of the dynamic range settings. A comparison of these results with those from data acquired 2 weeks after the initial study showed no significant difference. Conclusion This study represents the first reported measurement of cyclic variation in mice and demonstrates that reliable cyclic variation measurements can be obtained among individual animals and over different time points and, hence, forms the basis for subsequent investigations addressing specific cardiac pathologies and effects arising from myocardial anisotropy.

Radio frequency dual-spectra analysis of regional myocardial perfusion: Comparison with harmonic densitometric method

Our objective was to compare harmonic-to-fundamental frequency ratio peak (HFRp) analysis with conventional harmonic gray-scale densitometric analysis on the basis of ability to eliminate heterogeneity in ultrasound signals. Broadband radio frequency and harmonic data were obtained by using intermittent short-axis scans in 10 open-chest pigs before and during infusion of contrast microbubbles. HFRp and gray-scale intensity values were measured in 6 segments of left ventricular myocardium. In baseline images, the influence of anisotropy on HFRp values was significantly less than that in gray-scale intensities. In perfusion assessment with subtraction, contrast heterogeneity in HFRp values was significantly smaller than that in gray-scale intensities. The increase in HFRp values after subtraction was significantly greater than that in gray-scale intensities in lateral ( P < .001), posterior ( P < .0001), and inferior ( P < .01) myocardium. HFRp analysis can compensate for baseline myocardial anisotropy and regional contrast heterogeneity. With background subtraction, HFRp analysis allows better quantification of myocardial perfusion. (J Am Soc Echocardiogr 2002;15:1277-84.)

The effect of volume currents due to myocardial anisotropy on body surface potentials

Changes in anterior and posterior body surface potential maps (BSPMs) due to myocardial anisotropy were examined using a highly heterogeneous finite element model of an adult male subject constructed from segmented magnetic resonance images. A total of 23 different tissue types were identified in the whole torso. The myocardial fibre orientations in the human heart wall were mapped from the fibre orientations of a canine heart which are available in the literature using deformable mapping techniques. The current and potential distributions in the whole torso were computed using dipolar sources in the septum, apical area, left ventricular wall or right ventricular wall. For each dipole x, y, z orientations were studied. An adaptive finite element solver was used to compute currents and potential distributions in the whole torso with an element size of 0.78 × 0.78 × 3 mm in the myocardium and larger elements in other parts of the torso. For each dipole position two cases were studied. In one case the myocardium was isotropic and in the other it was anisotropic. It was found that BSPMs showed a very notable difference between the isotropic and the anisotropic myocardium for all dipole positions with the largest difference for the apical dipoles. The correlation coefficients for the BSPMs between the isotropic and anisotropic cases ranged from 0.83 for an apical dipole to 0.99 for an RV wall dipole. These results suggest that myocardial fibre anisotropy plays an important role in determining the body surface potentials.

Electrophysiology studies in patients with dilated cardiomyopathies.

Dilated cardiomyopathy is a diverse group of heart diseases with variable arrhythmia substrates. The response to programmed stimulation is dependent on spontaneous arrhythmia presentation. In patients with dilated cardiomyopathy, the majority of sustained monomorphic VT is caused by a scar-related reentrant mechanism, similar to that of coronary artery disease. The arrhythmia is uniformly inducible and is often refractory to pharmacologic therapy. Sustained VT is associated with more extensive myocardial fibrosis and non-uniform anisotropy, involving both the endocardium and epicardium, compared to those without sustained reentry. The response to programmed stimulation is more variable in patients presenting with nonsustained arrhythmia, cardiac arrest or syncope. Inducibility of monomorphic VT is much lower compared to those with ischemic heart disease. Other non-reentrant mechanism, such as focal automaticity, can also be observed in patients with monomorphic VT, in the absence of myocardial scar or evidence of slow conduction. The utility of electrophysiology studies to determine prognosis and to guide therapy remains limited in this patient population. The clinical outcome does not correlate with arrhythmia inducibility, and suppression of induced arrhythmia does not predict a good prognosis. The diagnosis of sarcoidosis or Chagas' cardiomyopathy should be considered in patients with dilated cardiomyopathy of unknown etiology, particularly in those with marked regional wall motion abnormalities and inducible VT. Epicardial reentrant circuits may be more prevalent in these cardiomyopathies, especially in those with VT related to chronic Chagas' disease. Although bundle branch reentry VT is a common finding in patients with dilated cardiomyopathy, it can occur in cardiomyopathy of any type and may coexist with other myocardial reentrant VT. It often has a typical bundle branch block QRS pattern during VT and is associated with His-Purkinje conduction delay. Evidence of macroreentry involving the bundle branches can usually be demonstrated, and catheter ablation of the bundle branches provides an effective and specific treatment.

Transmural variation of myocardial attenuation and its potential effect on contrast-mediated estimates of regional myocardial perfusion

Promising technical developments suggest that it may be feasible to use contrast echocardiography to estimate regional myocardial perfusion. Although the optimal approach has not yet been determined, the use of a nonlinear (harmonic) response of the contrast agent is common to several recent advances. The purpose of this article is to delineate the relation between the anisotropic (angle-dependent) ultrasonic attenuation of the myocardium through which the sound wave has propagated and the regional, nonlinear response of the contrast agent. Apparent perfusion will be modulated by this regionally varying, path-dependent attenuation, which is determined by the local angle between the propagating sound wave and the myofiber orientation. We illustrate the potential magnitude of the effect of myocardial anisotropy for the apical 4-chamber view by examining propagation along the septum and the lateral wall. We present experimentally measured values of the attenuation of excised sheep myocardium, showing statistically significant differences in the attenuation in the mid wall compared with that in symmetrical zones to the left and right of the mid wall, reflecting the well-known myofiber orientations in these 3 regions. The nonlinear (harmonic) response of a contrast agent depends on the local pressure amplitude, which for a given mechanical index is determined by the attenuation accumulated along the path to the point where the regional perfusion is estimated. (J Am Soc Echocardiogr 2001;14:782-8.)

Anisotropic reentry in a perfused 2-dimensional layer of rabbit ventricular myocardium.

Anisotropy creates nonuniformity in electrical propagation and may contribute to the occurrence of unidirectional conduction block and reentry. We describe the characteristics of reentrant tachycardia in a 2D layer of anisotropic ventricular myocardium. A Langendorff-perfused epicardial sheet (1.0+/-0.4 mm, n=35) was created by freezing the intramural layers of the rabbit left ventricle. Epicardial activation maps were constructed by use of different high-resolution mapping arrays connected to a mapping system. In 5 experiments, monophasic action potentials were recorded. In the intact left ventricle, no arrhythmias except VF could be induced. After freezing, programmed electrical stimulation or rapid pacing led to the induction of sustained VT (cycle length 130+/-11 ms). VT was caused by reentry around a functional line of block oriented parallel to the epicardial fiber direction. Action potential recordings demonstrated that the central line of block was kept refractory by electrotonic currents generated by the depolarization waves propagating at either side of the line of block. At the pivot points of the line of block, the pronounced curvature of the turning wave and abrupt loading changes created an excitable gap of 30 ms in the reentrant pathway. In uniform anisotropic myocardium, reentry around a functional Z-shaped line of block may occur. The core of the circuit is kept refractory by electrotonic currents. The pronounced wave-front curvature and abrupt loading changes at the pivot points cause local conduction delay and create a small excitable gap.

Potential errors in contrast-agent-mediated estimates of regional myocardial perfusion arising from myocardial anisotropy

Recently developed imaging modalities based on the nonlinear response of contrast agents are dependent upon the local acoustic pressure. Thus, regional variations of acoustic pressure arising from myocardial anisotropy can result in nonuniform ‘‘apparent perfusion’’ in the absence of a perfusion defect. Measurements of regional variation of myocardial attenuation in the septum and lateral walls of excised sheep hearts are reported. Studies were carried out on hearts obtained immediately after slaughter from 8 healthy adult sheep. These measurements of attenuation were carried out in orientations analogous to those encountered in the apical four-chamber view, which is the preferred view for clinical studies of myocardial perfusion using contrast-agent-enhanced echocardiography. The video signal analysis method introduced by the University of Wisconsin group was used to analyze data obtained with a commercially available (ATL) clinical scanner using a linear array (L 7-4) operating in fundamental mode. Tissue mimicking phantoms were imaged under identical conditions. Normalizing sample data by reference data from the phantoms yields quantitative estimates of slope of attenuation. Results of these experimental measurements document significant transmural variations in attenuation that could lead to apparent perfusion anomalies in contrast-agent-mediated estimates of regional myocardial perfusion. [Work supported by NIHHL40302.]

Effects of Electrode‐Myocardial Separation on Cardiac Stimulation in Conductive Solution

Effects of a conductive bath and electrode-myocardial separation on cardiac stimulation have not been elucidated. These factors may play a role in endocardial catheter stimulation or defibrillation. We studied effects of a bath and separation on transmembrane voltage changes during stimulation (deltaVm) and excitation thresholds in rabbit hearts, cultured rat cardiac cell monolayers, and cardiac bidomain computer models. Similar to previous epicardial measurements with no bath, a dogbone pattern of deltaVm during stimulation was found in bathed epicardium and right ventricular septal endocardium and in models of bathed anisotropic myocardium. Electrode-myocardial separation altered spatial distributions of deltaVm, moved reversals of the sign of deltaVm farther from the stimulation epicenter, and decreased aspect ratio of deltaVm (i.e., length/width of dogbone contours of deltaVm). The separation increased thresholds and reduced maximal deltaVm, while deltaVm at sites away from maxima increased or decreased. Anodal thresholds in models initially were larger than those in experiments and decreased when models were altered to include nonuniform cellular coupling. Existence of nonuniformity in monolayers was indicated by irregular excitation patterns. Electrode-myocardial separation alters spatial distributions of deltaVm, which may impact on arrhythmia induction by altering distributions of states of deltaVm-sensitive ion channels. The results also indicate that excitation thresholds may depend on tissue nonuniformities.

A bidomain model based BEM-FEM coupling formulation for anisotropic cardiac tissue.

A hybrid boundary element method (BEM)/finite element method (FEM) approach is proposed in order to properly consider the anisotropic properties of the cardiac muscle in the magneto- and electrocardiographic forward problem. Within the anisotropic myocardium a bidomain model based FEM formulation is applied. In the surrounding isotropic volume conductor the BEM is adopted. Coupling is enabled by requesting continuity of the electric potential and the normal of the current density across the boundary of the heart. Here, the BEM part is coupled as an equivalent finite element to the finite element stiffness matrix, thus preserving in part its sparse property. First, continuous convergence of the coupling scheme is shown for a spherical model comparing the computed results to an analytic reference solution. Then, the method is extended to the depolarization phase in a fibrous model of a dog ventricle. A precomputed activation sequence obtained using a fine mesh of the heart was downsampled and used to calculate body surface potentials and extracorporal magnetic fields considering the anisotropic bidomain conductivities. Results are compared to those obtained by neglecting in part or totally (oblique or uniform dipole layer model) anisotropic properties. The relatively large errors computed indicate that the cardiac muscle is one of the major torso inhomogeneities.

Effect of myocardial anisotropy on the torso current flow patterns, potentials and magnetic fields*

The effects of myocardial anisotropy on the torso current flow patterns, voltage and the magnetic field were examined using an anatomically realistic torso model of an adult male subject. A finite element model of the torso was built with 19 major tissue types identified. The myocardial fibre orientation in the heart wall was included with a voxel resolution of 0.078×0.078×0.3 cm. The fibre orientations from the canine heart which are available in the literature were mapped to our adult male subject's human heart using deformable mapping techniques. The current and potential distribution in the whole torso were computed using an idealized dipolar source of ±1.0 V in the middle of the septum of the heart wall as a boundary condition. An adaptive finite element solver was used. Two cases were studied. In one case the myocardium was isotropic and in the other it was anisotropic. It was found that the current density distribution shows a very noticeable difference between the isotropic and anisotropic myocardium. The resultant magnetic field in front of the torso was computed using the Biot-Savart law. It was found that the magnetic field profile was slightly affected by the myocardial anisotropy. The potential on the torso surface also shows noticeable changes due to the myocardial anisotropy.

Cyclic variation of integrated backscatter: Dependence of time delay on the echocardiographic view used and the myocardial segment analyzed

To determine the influence of myocardial anisotropy in ultrasonic tissue characterization, we measured the time delay (and magnitude) of the cyclic variation of myocardial integrated backscatter from specific segments visualized in the 4 standard transthoracic echocardiographic views. The cyclic variation data in 10 myocardial regions were obtained from analyses of 2-dimensional integrated backscatter images from 23 healthy subjects. Resultant values (mean ± SD) for the time delay were as follows: parasternal long-axis view: 1.08 ± 0.17 (septum) and 1.00 ± 0.14 (posterior wall); parasternal short-axis view: 1.03 ± 0.16 (anterior septum), 1.03 ± 0.14 (posterior wall), 2.22 ± 0.71 (lateral wall), and 1.65 ± 0.66 (posterior septum); apical 4-chamber view: 1.08 ± 0.31 (septum) and 2.20 ± 0.79 (lateral wall); and apical 2-chamber view: 1.68 ± 0.62 (inferior wall) and 2.04 ± 0.72 (anterior wall). Hence, results of this study indicate that myocardial ultrasonic characterization that uses the cyclic variation is influenced by the echocardiographic view and the specific segment of the left ventricle.

Alterations in ultrasonic backscatter during intra-aortic balloon counterpulsation support in patients with acute myocardial infarction

Alterations of ultrasonic backscatter parameters have been evident in humans with myocardial infarction or ischemia. The backscatter variability could be restored in ischemic or stunned myocardium after reperfusion. The aims of this study were to determinate changes in regional myocardial ultrasonic backscatter during intra-aortic balloon counterpulsation (IABP) support in patients with acute myocardial infarction (AMI), and to evaluate whether backscatter imaging could be a functional guide of IABP support. A total of 9 patients with AMI were investigated during IABP support with a two-dimensional (2-D) ultrasonic backscatter imaging approach for parasternal short-axis view. Coronary angiography was performed in 6 of the 9 patients. A total of 21 vessel territories were studied in different modes of IABP support: 1:1, 1:2 and standby. Restoration of cyclic variation of backscatter after IABP support was demonstrated in 10 vessel territories. Failure of restoration of cyclic variation of backscatter after IABP support was noted in 6 vessel territories with severe coronary lesions (total or nearly total occlusion) or scar tissue. No changes of the ultrasonic backscatter were found in nonischemic vessel territories with patent coronary arteries or TIMI III coronary flow. In addition, the wall motion score did not change significantly with different IABP support. These results suggest that IABP could restore the cyclic variation of backscatter in ischemic myocardium. Myocardial anisotropy may play an influential role in the alterations of ultrasonic backscatter. We propose that ultrasonic backscatter could be a noninvasively functional guide of IABP use in patients with AMI.

Cellular automata model of cardiac excitation waves

We present a new computer simulation technology suitable for rapid and quantitatively reliable simulation of propagating excitation waves in anisotropic myocardium. Our model utilizes a finite element or cellular automata (CA) approach in which the elements undergo transitions between a finite number of states (e.g., excited, refractory) according to specific rules. The transition parameter values for the CA elements at each location are computed using the characteristic relations governing propagation at the given point in the tissue, such as the anisotropy ratio and the dependence of the plane wave speed on diastolic interval. The model is well-suited for analysis of arrhythmogenesis and hypothetical therapeutic interventions. Once the effects of an antiarrhythmic drug or disease process on the characteristic relationships have been determined for different cardiac cell types, the electrical activity in tissue with the modified properties can be simulated by our model. In this article, we discuss the basic structure of the model and use it to demonstrate wavelet formation in myocardium with a fixed scar (infarct) in the presence of a sodium channel blocker. This mechanism may help explain the proarrhythmic effects of these agents.

High-density epicardial mapping during current injection and ventricular activation in rat hearts.

The purpose of this study is to report new methods for manufacturing precision electrode arrays for recording high-resolution potential distributions from epicardial surfaces of small-animal hearts. Electrode arrays of 64 leads (8 x 8) and 121 leads (11 x 11) were constructed with a tulle substrate to which insulated, fine silver wires (60-micrometer diameter) were attached by knots at mesh node intervals of 540 x 720 micrometers. Insulation was removed at the tips of the knots. Potential distributions and waveforms were recorded from saline solutions and rat heart epicardium during ventricular paced beats and during passive current injection in the diastolic interval. Electrical responses obtained from rat epicardium compared favorably with those observed in studies of larger-animal hearts, which used arrays having greater electrode spacing, and revealed the effects of myocardial anisotropy. Epicardial potentials measured early after stimulation in the region surrounding the pacing site were interpreted in terms of potentials generated by an equivalent quadrupolar source. We conclude that electrode arrays for epicardial mapping of small hearts can be constructed with sufficient ease and precision to allow detailed study of fiber structure and electrophysiology in these hearts in normal and pathological conditions.

Simulation of depolarization in a membrane-equations-based model of the anisotropic ventricle.

The results of a simulation study of the propagation of depolarization in inhomogeneous anisotropic (monodomain) myocardial tissue are presented. Simulations are based on modified Beeler-Reuter membrane equations, and performed on a block of anisotropic myocardium with rotating fiber geometry, measuring 1 cm x 1 cm x 0.3 cm, at various levels of spatial discretization (0.15 mm, 0.30 mm, 0.60 mm). At a discretization level of 0.6 mm the algorithm allowed the simulation in a realistically shaped model of the ventricle, including rotational anisotropy, as well. For this simulation results are justified by comparing results for the block at various levels of discretization, for which the surface to volume ratio has been adjusted. By placing the model ventricle in a realistically shaped (human) volume conductor model, realistic body surface potentials (QRST waveforms) are simulated.

Electrocardiographic imaging: Noninvasive characterization of intramural myocardial activation from inverse-reconstructed epicardial potentials and electrograms.

A recent study demonstrated the ability of electrocardiographic imaging (ECGI) to reconstruct, noninvasively, epicardial potentials, electrograms, and activation sequences (isochrones) generated by epicardial activation. The current study expands the earlier work to the three-dimensional myocardium and investigates the ability of ECGI to characterize intramural myocardial activation noninvasively and to relate it to the underlying fiber structure of the myocardium. This objective is motivated by the fact that cardiac excitation and arrhythmogenesis involve the three-dimensional ventricular wall and its anisotropic structure. Intramural activation was initiated by pacing a dog heart in a human torso tank. Body surface potentials (384 electrodes) were used to compute epicardial potentials noninvasively. Accuracy of reconstructed epicardial potentials was evaluated by direct comparison to measured ones (134 electrodes). Protocols included pacing from five intramural depths. Epicardial potentials showed characteristic patterns (1) early in activation, central negative region with two flanking maxima aligned with the orientation of fibers at the depth of pacing; (2) counterclockwise rotation of positive potentials with time for epicardial pacing, clockwise rotation for subendocardial pacing, and dual rotation for midmyocardial pacing; and (3) central positive region for endocardial pacing. Noninvasively reconstructed potentials closely approximated these patterns. Reconstructed epicardial electrograms and epicardial breakthrough times closely resembled measured ones, demonstrating progressively later epicardial activation with deeper pacing. ECGI can noninvasively estimate the depth of intramyocardial electrophysiological events and provides information on the spread of excitation in the three-dimensional anisotropic myocardium on a beat-by-beat basis.

Effects of rotational myocardial anisotropy in forward potential computations with equivalent heart dipoles.

Rotating fibers in the heart lead to a myocardium of inhomogeneous anisotropic conductivity. Besides affecting the activation isochrones, this anisotropy modifies the equivalent dipoles used in calculating extracardiac potentials, rendering them oblique rather than normal to the activation wavefront due to an added axial dipole component oriented along the fibers. Herein, however, consequences of the assumption usually made in forward potential calculations that the equivalent dipoles act in a myocardium that is homogeneous and isotropic are examined. A layered inner block representing the heart was placed inside an outer block representing an isotropic volume conductor. Fiber direction in the inner block rotated uniformly from layer to layer. Current dipoles of different orientations were placed in the inner block and the potentials calculated everywhere. Effects of the anisotropy of the inner block were gauged by computing an equivalent dipole that best fit the outer block surface potentials. For volume conductor conductivities close to that of the torso, the anisotropy diminished dipoles oriented along the fibers. Since the intraventricular blood masses in the heart also diminish such dipoles, these reductions of the axial component may explain the success of heart model simulations that ignore this component.

On measuring curvature and electrical diffusion coefficients in anisotropic myocardium: comments on "effects of bipolar point and line simulation in anisotropic rabbit epicardium: assessment of the critical radius of curvature for longitudinal block".

Notion of "curvature" and "propagation perpendicular to the activation front" inherited from electrophysiological theory of isotropic reaction-diffusion media do not apply directly to experimental data taken in uniformly anisotropic myocardium. They apply directly only after the concept of "curvature" is normalized and propagation is made to look perpendicular to activation fronts by rescaling distances to achieve isotropy. Without rescaling, the curvature-dependence of longitudinal propagation speed turns out counter-intuitively to measure transverse intercellular electrical coupling.

Comparison of body surface potential maps simulated with isotropic and anisotropic computer heart models

Simulated body surface potential maps (SBSPM) with isotropic and anisotropic heart models were compared to investigate the effect of myocardial anisotropy on body surface electrocardiograms at a whole heart level. Rotative fiber orientations of total 90° was incorporated into an isotropic heart model. The anisotropy of conduction velocity and intracellular electric conductivity was included in the simulation. SBSPM based on epicardial, intramural, and endocardial stimulation show high correlation with fiber orientations. On the other hand, the anisotropy cannot be distinguished from the SBSPM in the simulation of normal heart model.

Fractionated Electrograms From a Computer Model of Heterogeneously Uncoupled Anisotropic Ventricular Myocardium

The relation between heterogeneously coupled myocardium and fractionated electrograms is incompletely understood. The purpose of this study was to use a detailed computer model of nonuniformly anisotropic myocardium to test the hypothesis that spatial variation of morphology of electrograms recorded simultaneously from multiple sites increases with increasing heterogeneity of intercellular coupling. A sheet of elements with Beeler-Reuter ionic kinetics was coupled with cytoplasmic resistivity to model cells. Gap junctional resistance values were assigned by recursive randomization to produce a fractal pattern of heterogeneous coupling, simulating damage resulting from infarction. The correlation dimension of the pattern, D, measured heterogeneity of intercellular coupling. The peak-to-peak amplitude, duration, minimum derivative (steepest downslope), number of inflections, frequency of peak power, and bandwidth of unfiltered unipolar electrograms were calculated. Linear regressions indicate (P < .001) that the coefficient of variation of five electrogram metrics increases with increasing substrate heterogeneity and that the distance over which electrogram morphology decorrelates decreases with increasing heterogeneity of intercellular coupling. These findings confirm our hypothesis that the spatial variation of morphology of electrograms recorded simultaneously from multiple sites increases with increasing heterogeneity of intercellular coupling.