Stephen B. Knisley

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.

Correlation Among Fibrillation, Defibrillation, and Cardiac Pacing

An electrical stimulus must create an electric field of approximately 1 V/cm in the extracellular space to stimulate myocardium during diastole. To initiate fibrillation by premature stimulation during the vulnerable period or to defibrillate, an extracellular electric field of approximately 6 V/cm is required, a value approximately six times greater than that necessary for diastolic pacing. Yet, the current strength of the pulse given to the stimulating electrode to initiate fibrillation or to defibrillate is much greater than six times the diastolic pacing threshold. The ventricular fibrillation threshold is typically 40 times greater than the diastolic pacing threshold expressed in terms of current. The defibrillation threshold in terms of current is typically thousands of times greater than the diastolic pacing threshold. The reason that these thresholds vary so much more in terms of stimulus current than in terms of extracellular potential gradient is that each of the three thresholds requires creation of the required potential gradient at different distances from the stimulating electrode. Pacing requires a potential gradient of approximately 1 V/cm only in a small liminal volume of tissue immediately adjacent to the electrode. Initiation of ventricular fibrillation by premature stimulation during the vulnerable period requires a potential gradient of approximately 6 V/cm about 1 cm away from the stimulating electrode to allow sufficient space for the central common pathway of a figure‐eight reentrant circuit to form. Since the potential gradient falls off rapidly with distance from the stimulating electrode, a stimulating current about 40 times greater than the diastolic pacing threshold is required to generate an electric field of 6 V/cm approximately 1 cm away from the stimulating electrode. Defibrillation requires an electric field of approximately 6 V/cm throughout all or almost all of the ventricular myocardium. Since some portions of the ventricles can be more than 10cm away from the defibrillation electrodes, a shock of several amps is required to create this field, a current thousands of times greater than the pacing threshold.

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.

ON THE MECHANISM OF VENTRICULAR DEFIBRILLATION

The mechanism of ventricular defibrillation can be considered at many different levels. The highest level is considered the 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.

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 intentisy (FI). S2 caused postshock additional depolarization. giving rise to a prolongation of the shocked action potential. With S2≥ 40 V (FI ≥≃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.

Characterization of Shock-Induced Action Potential Extension During Acute Regional Ischemia in Rabbit Hearts

Shock Effects During Ischemia. Introduction: Defibrillation shocks produce extension of the myocardial action potential repolarization time (AP extension) in nonischemic myocardium. AP extension may synchronize repolarization in the heart because the extension increases when shock timing is increased. We tested whether AP extension occurs and whether it increases when shock timing is increased in regionally ischemic isolated perfused rabbit hearts stained with the transmembrane voltage sensitive fluorescent dye, di‐4‐ANEPPS and given diacetyl monoxime to eliminate motion artifacts.

Effective epicardial resistance of rabbit ventricles

AbstractThis study evaluated effective resistances on the ventricular surfaces of arterially-perfused rabbit hearts. Effective resistances were determined with a four-electrode array that was parallel or perpendicular to epicardial fibers. Resistance along or across epicardial fibers was determined by applying current to the epicardium with two parallel line electrodes and measuring potentials in the region between the electrodes. Computer simulations were performed to gain insight into the distribution of current in the ventricular wall. The effective resistances were not different along versus across fibers. Simulations showed that transmural rotation of fibers causes current to be distributed differently when the electrode is oriented perpendicular versus parallel to epicardial fibers. When the array is oriented so that epicardial current is across fibers, the fraction of current that flows transmurally and along the deeper fibers increases while the fraction of current that flows epicardially decreases. This introduces isotropy of the effective resistance. Thus, in contrast to isolated cardiac fibers, the ventricular epicardium exhibits isotropic effective resistance due to transmural rotation of fibers. The rotation and isotropic resistance may be important for cardiac electrical behavior and effects of electrical current in the ventricles.

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 μM) 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.

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.

Intelligent Multichannel Stimulator for the Study of Cardiac Arrhythmias

AbstractAn intelligent multichannel stimulator (IMS) has been designed and built for use in a cardiac research environment. The device is capable of measuring and responding to cardiac electrophysiological phenomena in real time with carefully timed and placed electrical stimuli. The system consists of 16 channels of sense/stimulation electronics controlled by a digital signal processor (DSP) data acquisition card and a host computer and can be expanded to include more channels. The DSP allows for powerful and flexible algorithms to be implemented for real-time interaction with the cardiac tissue. Although a number of possible uses can be conceived for such a device, the initial motivation was to improve upon attempts to terminate fibrillation by pacing. The IMS was tested in an open-chest animal model, both in sinus rhythm and during fibrillation. It was shown to be an effective research tool by demonstrating the ability to measure and respond to cardiac activations in real time using complex numerical algorithms and appropriately timed stimuli.