Exploring cardiac response to AC stimulation.
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Electric Stimulation↗
Biomedical subjects
S B Knisley
Publications and source records attributed to S B Knisley.
Quantifying spatial localization of optical mapping using Monte Carlo simulations.
Optical mapping techniques used to study spatial distributions of cardiac activity can be divided into two categories. 1) Broad-field excitation method, in which hearts stained with voltage or calcium sensitive dyes are illuminated with broad-field excitation light and fluorescence is collected by image or photodiode arrays. 2) Laser scanning method, in which illumination uses a scanning laser and fluorescence is collected with a photomultiplier tube. The spatial localization of the fluorescence signal for these two methods is unknown and may depend upon light absorption and scattering at both excitation and emission wavelengths. We measured the absorption coefficients (micro a), scattering coefficients (micro s), and scattering anisotropy coefficients (g) at representative excitation and emission wavelengths in rabbit heart tissue stained with di-4-ANEPPS or co-stained with both Rh237 and Oregon Green 488 BAPTA 1. Monte Carlo models were then used to simulate absorption and scattering of excitation light and fluorescence emission light for both broad-field and laser methods in three-dimensional tissue. Contributions of local emissions throughout the tissue to fluorescence collected from the tissue surface were determined for both methods. Our results show that spatial localization depends on the light absorption and scattering in tissue and on the optical mapping method that is used. A tissue region larger than the laser beam or collecting area of the array element contributes to the optical recordings.
Animals↗
Roles of line stimulation-induced virtual electrodes and action potential prolongation in arrhythmic propagation.
INTRODUCTION: Line stimulation across fibers generates a virtual electrode (VE) pattern that consists of adjacent +Vm and -Vm regions. In this study, we evaluated Vm at the break of line stimulation pulses to determine where arrhythmias arise and their propagation direction relative to +Vm and -Vm regions. METHODS AND RESULTS: We optically mapped the anterior left ventricular epicardium of isolated rabbit hearts (n = 9). Monophasic line stimuli were applied across fibers at various coupling intervals. In 18 of 24 break arrhythmias, i.e., arrhythmias in which propagation occurred after the break but < or = 30 msec postshock, excitation propagated from the border between +Vm and -Vm regions toward the -Vm region (P < 0.05) for either shock polarity, even though locations of positive and negative Vm changed with shock polarity. In 13 of 18 make arrhythmias, i.e., arrhythmias in which propagation occurred before the break, the excitation propagated from the center of the +Vm region toward the -Vm regions (P < 0.05). For late arrhythmias, i.e., arrhythmias in which propagation was found >30 msec postshock, propagation was reversed, i.e., toward the +Vm region (P < 0.01), which was where the positive VE produced action potential prolongation. CONCLUSION: The propagation of break, make, and late arrhythmias is spatially related to VEs. The different direction of propagation of late arrhythmias relative to the VEs is explained by the delayed recovery of Vm due to VE-induced action potential prolongation.
Action Potentials↗
Roles of line stimulation-induced virtual electrodes and action potential prolongation in arrhythmic propagation.
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Action Potentials↗
Evidence for roles of the activating function in electric stimulation.
The hypothesis that the activating function drives transmembrane voltage changes (delta Vm) has been tested in hearts. Optical delta Vm were measured during activating functions produced with nonuniform and uniform transparent electrodes. When a nonuniform electrode was used to produce [equation: see text], the signs of delta Vm and [equation: see text] matched. The extracellular voltage gradients, often assumed important, did not predict delta Vm. When a uniform electrode was used to eliminate [equation: see text], the signs of delta Vm matched the signs of [equation: see text] estimated from variations in heart width. Demonstration of the activating function as a determinant of stimulation may improve research and therapy that use electric stimulation.
Animals↗
Regional differences in arrhythmogenic aftereffects of high intensity DC stimulation in the ventricles.
Regional differences of the aftereffects of high intensity DC stimulation were investigated in isolated rabbit hearts stained with a voltage-sensitive dye (di-4-ANEPPS). Optical action potential signals were recorded from the epicardial surface of the right and left ventricular free wall (RVep, LVep) and from the right endocardial surface of the interventricular septum (IVS). Ten-millisecond monophasic DC stimulation (S2, 20-120 V) was applied to the signal recording spots during the early plateau phase of the action potential induced by basic stimuli (S1, 2.5 Hz). There was a linear relationship between S2 voltage and the S2 field intensity (FI). S2 caused postshock additional depolarization, giving rise to a prolongation of the shocked action potential. With S2 > or = 40 V (FI > or = approximately 20 V/cm), terminal repolarization of action potential was inhibited, and subsequent postshock S1 action potentials for 1-5 minutes were characterized by a decrease in the maximum diastolic potential and a decrease in the amplitude and a slowing of their upstroke phase. The higher the S2 voltage, the larger the aftereffects. The changes in postshock action potential configuration in RVep were significantly greater than those observed in LVep and IVS when compared at the same levels of S2 intensity. In RVep, 12 of 20 shocks of 120 V resulted in a prolonged refractoriness to S1 (> 1 s), and the arrest was often followed by oscillation of membrane potential. Ventricular tachycardia or fibrillation ensued from the oscillation in five cases. No such long arrest or serious arrhythmias were elicited in LVep and IVS. These results suggest that RVep is more susceptible than LVep and IVS for arrhythmogenic aftereffects of high intensity DC stimulation.
Animals↗
Effects of electrode-myocardial separation on cardiac stimulation in conductive solution.
INTRODUCTION: 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. METHODS AND RESULTS: 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. CONCLUSION: 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.
Animals↗
Ratiometry of transmembrane voltage-sensitive fluorescent dye emission in hearts.
Transmembrane voltage-sensitive fluorescence measurements are limited by baseline drift that can obscure changes in resting membrane potential and by motion artifacts that can obscure repolarization. Voltage-dependent shift of emission wavelengths may allow reduction of drift and motion artifacts by emission ratiometry. We have tested this for action potentials and potassium-induced changes in resting membrane potential in rabbit hearts stained with di-4-ANEPPS [Pyridinium, 4-(2-(6-(dibutylamino)-2-naphthalenyl) ethenyl)-1-(3-sulfopropyl)-, hydroxide, inner salt] using laser excitation (488 nm) and a two-photomultiplier tube system or spectrofluorometer (resolution of 500-1,000 Hz and <1 mm). Green and red emissions produced upright and inverted action potentials, respectively. Ratios of green emission to red emission followed action potential contours and exhibited larger fractional changes than either emission alone (P < 0.001). The largest changes and signal-to-noise ratio (signal/noise) were obtained with numerator wavelengths of 525-550 nm and denominator wavelengths of 650-700 nm. Ratiometry lessened drift 56-66% (P < 0.015) and indicated decreases in resting membrane potential. Ratiometry lessened motion artifacts and increased magnitudes of deflections representing phase-zero depolarizations relative to total deflections by 123-188% in intact hearts (P < 0.02). Durations of action potentials at different pacing rates, temperatures, and potassium concentrations were independent of whether they were measured ratiometrically or with microelectrodes (P > or = 0.65). The ratiometric calibration slope was 0.017/100 mV and decreased with time. Thus emission ratiometry lessens the effects of motion and drift and indicates resting membrane potential changes and repolarization.
Animals↗
Roles of electric field and fiber structure in cardiac electric stimulation.
This study investigated roles of the variation of extracellular voltage gradient (VG) over space and cardiac fibers in production of transmembrane voltage changes (DeltaV(m)) during shocks. Eleven isolated rabbit hearts were arterially perfused with solution containing V(m)-sensitive fluorescent dye (di-4-ANEPPS). The epicardium received shocks from symmetrical or asymmetrical electrodes to produce nominally uniform or nonuniform VGs. Extracellular electric field and DeltaV(m) produced by shocks in the absolute refractory period were measured with electrodes and a laser scanner and were simulated with a bidomain computer model that incorporated the anterior left ventricular epicardial fiber field. Measurements and simulations showed that fibers distorted extracellular voltages and influenced the DeltaV(m). For both uniform and nonuniform shocks, DeltaV(m) depended primarily on second spatial derivatives of extracellular voltages, whereas the VGs played a smaller role. Thus, 1) fiber structure influences the extracellular electric field and the distribution of DeltaV(m); 2) the DeltaV(m) depend on second spatial derivatives of extracellular voltage.
Animals↗
Optical transmembrane potential recordings during intracardiac defibrillation-strength shocks.
BACKGROUND: The prolongation of the action potential after defibrillation-strength shocks is believed to be a critical component of defibrillation. The response of the transmembrane potential to the shock may affect this prolongation. We studied the effects of an intracardiac shock on the transmembrane potential and action potential duration at multiple sites on the epicardium using a voltage-sensitive dye and optical mapping system. METHODS AND RESULTS: A laser scanner recorded optical action potentials with voltage-sensitive dye at 63 spots on both the left and right ventricles of six isolated, perfused rabbit hearts. Hearts were paced with epicardial point stimulation followed by the delivery of a 2 A and 20 ms rectangular waveform shock during the relative refractory period. The shock was given between right atrial and right ventricular electrodes. Of 621 total spots analyzed, 241 spots hyperpolarized and 76 spots depolarized with a right ventricular anode, whereas 159 spots hyperpolarized and 145 spots depolarized with a right ventricular cathode (P < 0.05). Both hyperpolarized and depolarized spots exhibited prolonged action potential duration, although prolongation was greater with depolarizing responses (16.7 +/- 9 ms vs. 13.3 +/- 13.4 ms, p<0.001). Hyperpolarized and depolarized spots were not randomly distributed, but clustered into regions. The size of the hyperpolarized regions was larger than the depolarized regions with RV anodal stimulation (27 +/- 20 spots/hyperpolarized region vs. 8.5 +/- 9 spots/depolarized region, p < 0.03) but not with RV cathodal stimulation. With reversal of electrode polarity, spots hyperpolarized near the shocking electrodes frequently did not reverse polarization but remained hyperpolarized. CONCLUSIONS: Distinct regions of either polarization occur during intracardiac defibrillation-strength shocks. Although hyperpolarizing membrane responses were observed more often than depolarizing responses, depolarizing membrane polarization resulted in greater action potential prolongation. The absence of sign change in polarization in some regions with shocks of opposite polarities suggests that nonlinear intrinsic membrane properties are operative during strong electrical stimulation.
Action Potentials↗
Review of mechanisms by which electrical stimulation alters the transmembrane potential.
Electrical stimuli pace, cardiovert, or defibrillate the heart by changing transmembrane potential (deltaVm). Recent simulation studies provide insights into mechanisms by which stimuli establish deltaVm. This review attempts a nonmathematical description of these mechanisms. We start with the cable model in which the intracellular core conductor is bounded by a highly resistive and capacitive membrane that separates the intracellular and extracellular spaces. Intracellular and extracellular resistances are assumed to vary linearly with position. Although this model predicts anodal extracellular stimuli hyperpolarize adjacent tissue and cathodal extracellular stimuli depolarize that tissue, it fails to reproduce regions of opposite deltaVm distant from the electrodes. We then consider the sawtooth model in which microscopic discontinuities in intracellular resistance represent gap junctions. While model studies with such discontinuities demonstrate large deltaVm at cell ends, experimental validation of such deltaVm remains elusive. Extending the analysis to the two- and three-dimensional syncytium, we also consider the bidomain model in which intracellular, extracellular, and interstitial currents are explicitly characterized. Differences in resistance to these currents gives rise to virtual electrodes, which are experimentally observed regions of large deltaVm that arise distant from the stimulating electrode. Distant deltaVm regions are also evident when macroscopic discontinuities in intracellular resistance are introduced into the bidomain model. Such discontinuities are associated with clefts or scars that give rise to "secondary sources." Albeit the cable model offers remarkable insight the bidomain model and the concept of secondary sources provide a more complete understanding of membrane excitation, especially when combined into a unifying activating function.
Action Potentials↗
Spatial changes in the transmembrane potential during extracellular electric stimulation.
The purpose of this study was to determine the spatial changes in the transmembrane potential caused by extracellular electric field stimulation. The transmembrane potential was recorded in 10 guinea pig papillary muscles in a tissue bath using a double-barrel microelectrode. After 20 S1 stimuli, a 10-ms square wave S2 shock field with a 30-ms S1-S2 coupling interval was given via patch shock electrodes 1 cm on either side of the tissue during the action potential plateau. Two shock strengths (2.1+/-0.2 and 6.5+/-0.6 V/cm) were tested with both shock polarities. The recording site was moved across the tissue along fibers with either 200 micrometer (macroscopic group [n=5], 12 consecutive recording sites over a 2. 2-mm tissue length in each muscle) or 20 micrometer (microscopic group [n=5], 21 consecutive recording sites over a 0.4-mm tissue length in each muscle) between adjacent recording sites. In the macroscopic group, the portion of the tissue toward the anode was hyperpolarized, whereas the portion toward the cathode was depolarized, with 1 zero-potential crossing from hyperpolarization to depolarization present near the center of the tissue. In the microscopic group, only 1 zero-potential crossing was observed in the center region of the tissue, whereas, away from the center, only hyperpolarization was observed toward the anode and depolarization toward the cathode. Although these results are consistent with predictions from field stimulation of continuous representations of myocardial structure, ie, the bidomain and cable equation models, they are not consistent with the prediction of depolarization-hyperpolarization oscillation from representations based on cellular-level resistive discontinuities associated with gap junctions, ie, the sawtooth model.
Animals↗
Optical mapping of cardiac electrical stimulation.
Optical mapping has been used to determine changes in transmembrane voltage during electrical stimulation pulses (deltaVm) and whether deltaVm depends on fiber orientation, as predicted from bidomain models. Fiber orientation in an approximately 1 cm2 mm mapped region on the rabbit left or right ventricular epicardium was estimated optically from the fast axis of action potential (AP) propagation. Hearts were paced outside of the region to produce APs. Unipolar stimulation (S2) was then applied early in the AP, when tissue was refractory, so that deltaVm was not obscured by a new AP. Anodal S2 produced negative deltaVm near a point S2 electrode and away from it in the direction perpendicular to the fibers. Anodal S2 produced reversal of the sign of deltaVm about 1 mm from the electrode in the direction parallel to the fibers, such that a positive deltaVm existed about 1-5 mm away from the electrode. Reversal of the sign of deltaVm in the direction parallel to the fibers also occurred with cathodal S2, which produced a negative deltaVm away from the electrode parallel to the fibers. The results indicate a "dogbone" pattern of deltaVm, as predicted from bidomain models that have resistance anisotropy ratios of trabecular muscles (ie, an intracellular ratio that does not equal the extracellular ratio). Thus, optical mapping can indicate fiber orientation and deltaVm, and the deltaVm during unipolar stimulation reverses sign on the axis parallel to the fibers, which differs from one-dimensional model predictions. The deltaVm agrees with multidimensional bidomain model predictions that have unequal resistance anisotropy.
Action Potentials↗
Transmembrane potentials during high voltage shocks in ischemic cardiac tissue.
Transmembrane, voltage sensitive fluorescent dye (TMF) recording techniques have shown that high voltage shocks (HVS), typically used in defibrillation, produce either hyper- or depolarization of the transmembrane potential (TMP) when delivered in the refractory period of an action potential (AP) in normal cardiac tissue (NT). Further, HVS produce an extension of the AP, which has been hypothesized as a potential mechanism for electrical defibrillation. We examined whether HVS modify TMP of ischemic tissue (IT) in a similar manner. In seven Langendorff rabbit hearts, recordings of APs were obtained in both NT and IT with TMF using di-4-ANEPPS, and diacetylmonoxime (23 microM) to avoid motion artifacts. Local ischemia was produced by occlusion of the LAD, HVS of either biphasic (5 + 5 ms) or (3 + 2 ms) or monophasic shapes (5 ms) were delivered at varying times (20%-90%) of the paced AP. Intracardiac ECG and TMF recordings of the TMP were each amplified, recorded, and digitized at a frequency of 1 kHz. The paced AP in IT was triangular in shape with no obvious phase 3 plateau, typically seen in NT. There was normally a reduced AP amplitude (expressed as fractional fluorescence) in IT (2.6% +/- 1.79%) compared to 3.8% +/- 0.66% in NT, and shortened AP duration (137 +/- 42 vs 171 +/- 11 ms). One hundred-Volt HVS delivered during the refractory period of paced AP in IT in five rabbits, elicited a depolarization response of the TMP with an amplitude up to three times greater than the paced AP. This is in contrast to NT where the 100-V HVS produced hyperpolarization in four hearts, and only a slight depolarization response in one heart. These results suggest that HVS, typically delivered by a defibrillation shock, modify TMPs in a significantly different manner for ischemic cells, which may influence success in defibrillation.
Action Potentials↗
On the mechanism of ventricular defibrillation.
The mechanism of ventricular defibrillation can be considered at many different levels. The highest level is considered at strength of the shock given through the defibrillation electrodes. At the next level, the mechanism of defibrillation can be examined in terms of the electrical field that the shock produces throughout the ventricles. Other levels include the effects this electric field has on the activation sequences and on the cellular action potentials that either initiate or inhibit the early sites of activation following the shock. Yet another level considers the mechanism by which the shock field initiates new action potentials or prolongs the action potential by changing the transmembrane potential during the shock. Finally, the subcellular level is considered, which involves the response of the individual ion channels to the shock. This review gives a brief overview of some salient features of defibrillation at each of these mechanistic levels.
Action Potentials↗
Line stimulation parallel to myofibers enhances regional uniformity of transmembrane voltage changes in rabbit hearts.
The sign of transmembrane voltage (Vm) change (delta Vm) in the heart during unipolar point stimulation is nonuniform, which introduces dispersion of states of Vm-dependent ion channels that depends on fiber orientation. We hypothesized that line stimulation parallel to cardiac fibers increases regional uniformity of the delta Vm sign. To test this, we evaluated electrode current distribution and delta Vm produced by unipolar line stimulation in isolated rabbit hearts. The Vm-sensitive fluorescent dye, di-4-ANEPPS, and a laser scanner provided delta Vm measurements at 63 spots in an 8 x 8-mm epicardial region. Line stimulation was tested at specific angles with respect to the fiber direction. Current peaks occurred at electrode ends. For electrodes parallel to fibers (0 degree), epicardium in regions beyond the ends exhibited a nonuniform delta Vm sign, whereas epicardium between the ends exhibited a uniform delta Vm sign that was essentially negative (hyperpolarized) during anodal pulses and positive (depolarized) during cathodal pulses. The delta Vm sign between the ends became less uniform when the stimulation angle was increased relative to the long axis of the fibers. At 90 degrees, the delta Vm sign between the ends was nonuniform and was frequently opposite, near versus away from the electrode. Spatial distributions of delta Vm during line stimulation were qualitatively predictable from anisotropic effects of point stimulation provided that combined effects of points along the electrode and points with higher current near ends were considered. For biphasic line stimulation, delta Vm during the second phase was weakly correlated with the temporal sum of effects of phases given individually, indicating limited ability of summation to predict delta Vm. Thus, uniformity of the delta Vm sign during stimulation is enhanced in the region between the ends of a line electrode parallel to fibers. This may lessen arrhythmogenic dispersion of Vm-dependent ion channel states in the region.
Action Potentials↗
Asymmetrical electrically induced injury of rabbit ventricular myocytes.
Strong defibrillation-type electric field stimulation may injure myocytes when transmembrane potentials during the pulse exceed the threshold for membrane permeabilization. The location of injury may depend on intrinsic transmembrane potential or influx of calcium by "electro-osmosis" during the stimulation pulse in addition to the transmembrane potential changes induced by the pulse. We have studied injury by examining contracture and changes in transmembrane potential-sensitive dye fluorescence induced by electric field stimulation (St) with a duration of 20 ms and strength of 16-400 V/cm in isolated rabbit ventricular myocytes. St of 100-150 V/cm produced injury in myocytes oriented parallel to the St field frequently without injuring myocytes oriented perpendicular to the field. Injury required calcium in the solution and was asymmetric, occurring first at the myocyte and facing the St anode in 100% of injured myocytes in normal Tyrode's solution. Injury depended significantly on whether the product of the electric field strength and myocyte length exceeded a threshold of 1.1 V (P < 0.05). Asymmetric injury at the end facing the anode was still present in 96% of injured myocytes for stimulation after depolarization by an action potential or 20 mM or 125 mM potassium, suggesting that intrinsic transmembrane potential is not responsible for asymmetry. In 125 mM potassium, eliminating calcium from the bathing solution during the St pulse and introducing calcium after the pulse decreased the fraction of injured myocytes in which injury occurred at the end facing the anode to 62%, suggesting that calcium influx by "electro-osmosis" at the myocyte end facing the anode contributes to asymmetry. Asymmetric injury at the end facing the anode was still present in 100% of injured myocytes after adding 1 mM tetraethylammonium chloride, indicating that asymmetry is not sensitive to the potassium channel blockade. For stimulation pulses stronger than 50 V/cm given after depolarization by an action potential, transmembrane potentials at both myocyte ends decayed after the initial deflection indicating that permeabilization occurred at both ends. In conclusion, injury depends on myocyte orientation and is asymmetric occurring first at the myocyte end facing the anode. Asymmetric injury is not explained by asymmetric permeabilization, is independent of the intrinsic transmembrane potential and may result from "electro-osmosis" during the stimulation pulse.
Animals↗
Effects of bipolar point and line stimulation in anisotropic rabbit epicardium: assessment of the critical radius of curvature for longitudinal block.
Excitation front shape and velocity were studied in anisotropic perfused rabbit epicardium stained with potentiometric fluorescent dye. In the combined results from all experiments, convex excitation fronts produced by stimulation with a single electrode propagated longitudinally 13.3% slower than flat excitation fronts produced by stimulation with a line of electrodes. For transverse propagation, the two stimulation methods produced similar flat excitation fronts and velocities. The critical excitation front radius of curvature for longitudinal block (Rcr), calculated from excitable media theory, was 92 microns in control hearts. In hearts exposed to diacetyl monoxime (20 mmol/L), which decreases inward sodium current, Rcr was 175 microns. The slower longitudinal propagation velocity of convex fronts versus flat fronts and the theoretically predicted critical radius of curvature may be important for propagation and block of ectopic depolarizations in the heart.
Action Potentials↗