Use dependence of amiodarone during the sinus tachycardia of exercise in coronary artery disease.

The QRS duration at rest and during exercise was studied in 19 patients with coronary artery disease before and after oral amiodarone therapy to determine if this drug produces detectable rate-dependent conduction slowing during physiologic increases in heart rate. QRS duration did not change significantly during exercise in the absence of the drug. However, after amiodarone, QRS duration at rest increased from 99 to 114 ms (p less than 0.001), and increased further from 114 to 127 ms (p less than 0.001) during the 45 beats/min mean increase in heart rate produced by exercise. The magnitude of this effect was related to the resting QRS duration. After amiodarone therapy, the QRS increased during exercise by only 6% in 8 patients with QRS less than 110 ms, while in 12 patients with QRS greater than or equal to 110 ms, the QRS increased by 15% (p less than 0.05). Rate-dependent conduction slowing occurs during the sinus tachycardia of exercise in patients treated with amiodarone, presumbably due to use-dependent sodium channel blockade. This result is most pronounced in patients with abnormal ventricular conduction at rest.

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.

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.

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.

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.

Transmembrane voltage changes during unipolar stimulation of rabbit ventricle.

This study tested the prediction of bidomain models that unipolar stimulation of anisotropic myocardium produces transmembrane voltage changes (delta VmS) of opposite signs away from the electrode on perpendicular axes. Stimulation with a strength of 0.1 to 40 mA was applied from a point electrode on the left or right ventricle of isolated perfused rabbit hearts at 37 degrees C to 38 degrees C stained with the potentiometric dye di-4-ANEPPS. A laser scanner system recorded Vm-sensitive fluorescence at 63 spots in an 8 x 8-mm region around the electrode. Cathodal stimulation in the refractory period produced regions of -delta Vm 1 to 5 mm away from the electrode on an axis oriented parallel to the fast propagation axis to within 1.8 +/- 11 degrees (P > or = .7 for difference versus zero, n = 7). Recording spots in these regions underwent + delta Vm when anodal stimulation was used. At recording spots on the slow propagation axis, cathodal stimulation produced + delta Vm and anodal stimulation produced -delta Vm. During diastolic stimulation, early excitation occurred near the electrode for cathodal stimulation or on the fast propagation axis as fas as 2.8 +/- 1 mm away from the electrode for anodal stimulation. A "dog-bone" region of + delta Vm that included tissue near and away from the electrode on the slow propagation axis occurred when cathodal stimulation was given in diastole. Regions of + delta Vm occurred away from the electrode on the fast propagation axis when anodal stimulation was given in diastole. Thus, delta Vm differs in regions along and across myocardial fibers, indicating that delta Vm depends on anisotropic bidomain properties. Sites of early excitation are those where + delta Vm occurs, indicating that membrane channel excitation depends on the distribution of delta Vm.

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.

Characterization of shock-induced action potential extension during acute regional ischemia in rabbit hearts.

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. METHODS AND RESULTS: Before and after left anterior descending (LAD) coronary artery occlusion, APs were recorded on the anterior left ventricular epicardium with an epifluorescence measurement system. Hearts were paced with a train of 10 stimuli (S1) and then during the 10th AP were given a defibrillation shock (S2) from epicardial electrodes on either side of the recording region. Before LAD occlusion, duration of the 9th S1-induced AP measured at full repolarization was 171 +/- 11 msec (mean +/- SD). Within 15 minutes after LAD occlusion, the AP duration became shorter (P < 0.05) and more variable (137 +/- 47 msec), and APs with negligible plateaus were observed. Extension of the 10th AP by S2 was significant both before (mean extension of 59 to 65 msec for three S2 waveforms tested) and after LAD occlusion (mean extension of 35 to 41 msec). Unlike the results before LAD occlusion, AP extension after occlusion was independent of absolute shock timing expressed in msec. When timing was expressed as a fraction of individual AP durations, AP extension after occlusion increased with increases in shock timing. CONCLUSIONS: Shocks extend APs during ischemia; however, absolute time dependence of AP extension is not constant among cells that have different AP durations during ischemia. This may influence postshock repolarization synchrony when different AP durations exist in different parts of regionally ischemic hearts.

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.

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.

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.

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.

Optical recordings of the effect of electrical stimulation on action potential repolarization and the induction of reentry in two-dimensional perfused rabbit epicardium.

BACKGROUND: Prolonged membrane depolarization induced by an electric shock in the heart may produce propagation block leading to repetitive beats. We studied prolonged depolarization and its role in repetitive beats in a thin epicardial layer of endocardially prefrozen arterially perfused rabbit heart. METHODS AND RESULTS: A laser scanner recorded optical action potentials at 63 sites within a 1-cm2 area on the left ventricle of hearts stained with potentiometric fluorescent dye. Pacing (S1) produced propagation across the myofibers; then, a 3-millisecond shock (S2) given in the S1 refractory period produced an electric field that decreased in strength with distance along the fibers. The S2 strengths at the center of the scanned region (C) were 2.1 +/- 0.2 or 5.6 +/- 0.3 V/cm (mean +/- SD, n = 4). Repetitive beats occurred in 50% of hearts when C was 2.1 V/cm and in 100% of hearts when C was 5.6 V/cm. With each occurrence of repetitive beats, prolonged depolarization of the shocked action potential occurred within 1 mm of the S2 electrode when C was 2.1 V/cm and within 3 mm when C was 5.6 V/cm. Transient block immediately after S2 occurred between tissue with prolonged depolarization (S2 strength, 6 to 9 V/cm) and tissue without prolonged depolarization (S2 strength, 1 to 3 V/cm). Propagation in the scanned region after S2 occurred first on the side of the block distal to the S2 electrode, propagated from the most recovered to the least recovered tissue, and then turned toward the S2 electrode. When C was 5.6 V/cm, reentry by retrograde propagation near the S2 electrode produced repetitive beats. The center of the reentrant circuit exhibited further transient block and small depolarizations associated with the circulating activation. CONCLUSIONS: Prolonged depolarization occurs where the S2 strength is more than 6 V/cm, block occurs between regions of prolonged depolarization and no prolonged depolarization, and reentry occurs around the block. Shock-induced prolonged depolarization can be proarrhythmic and may account for electrically induced arrhythmias.

Effective epicardial resistance of rabbit ventricles.

This 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.

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.

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 10 cm 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.

Interstitial potential during propagation in bathed ventricular muscle.

Theoretical simulations have suggested that interstitial potential (Vis) during action potential propagation affects measurements of the transmembrane action potential in bathed ventricular muscle. To evaluate the Vis experimentally, we obtained Vis and intracellular action potential (Vic) recordings at various depths in paced guinea pig papillary muscles bathed in oxygenated Tyrode's solution. The peak-to-peak amplitude and the maximum dV/dt (dV/dtmax) of the intrinsic downward deflection of the Vis recordings were determined. The transmembrane action potential (TM) was obtained by subtracting each Vis from the corresponding Vic recording, and measurements for the phase zero depolarization and action potential foot of the Vic were compared with the measurements for the TM. At penetration depths of approximately 54 microns, the amplitude and dV/dtmax of the Vis were 13 mV and -38 V/s. When the depth was increased to 200 microns, these parameters increased to 24 mV and -59 V/s (P less than 0.005), and when the depth was further increased to 390 microns, the parameters decreased to 16 mV and -38 V/s. Because of the Vis at the various depths, the Vic underestimated dV/dtmax of phase zero of the TM by 20-31%, which would reduce estimates of Na+ current obtained from dV/dt. Also, the Vic overestimated the time constant of the 2-8 mV foot of the action potential by 48-82%, which would reduce estimates of the "effective" membrane capacitance by 33-45%. These influences of the Vis on measurements may affect results of quantitative studies of the ventricular action potential.

Virtual electrode effects in myocardial fibers.

The changes in transmembrane potential during a stimulation pulse in the heart are not known. We have used transmembrane potential sensitive dye fluorescence to measure changes in transmembrane potential along fibers in an anisotropic arterially perfused rabbit epicardial layer. Cathodal or anodal extracellular point stimulation produced changes in transmembrane potential within 60 microns of the electrode that were positive or negative, respectively. The changes in transmembrane potential did not simply decrease to zero with increasing distance, as would occur with a theoretical fiber space constant, but instead became reversed beyond approximately 1 mm from the electrode consistent with a virtual electrode effect. Even stimulation from a line of terminals perpendicular to the fibers produced negative changes in transmembrane potential for cathodal stimulation with the largest negative changes during a 50-ms pulse at 3-4 mm from the electrode terminals. Negative changes as large as the amplitude of the action potential rising phase occurred during a 50-ms pulse for 20-volt cathodal stimulation. Switching to anodal stimulation reversed the directions of changes in transmembrane potential at most recording spots, however for stimulation during the refractory period negative changes in transmembrane potential were significantly larger than positive changes in transmembrane potential. Anodal stimulation during diastole with 3-ms pulses produced excitation in the region of depolarization that accelerated when the stimulation strength was increased to > 3 times the anodal threshold strength. Thus, virtual electrode effects of unipolar stimulation occur in myocardial fibers, and for sufficiently strong stimuli the virtual electrode effects may influence electrical behavior of the myocardium.

Prolongation and shortening of action potentials by electrical shocks in frog ventricular muscle.

Effects of electrical shocks on myocardium are important for defibrillation. We measured effects of shocks (5 ms, 1-40 V/cm) in isolated frog ventricular strips. We recorded contraction strength and intracellular action potential (AP) with a shock-voltage cancellation technique to allow recordings immediately after shocks. Shocks of > or = 5 V/cm produced a dose- and latency-dependent prolongation of the AP ongoing during the shock. Stronger shocks of 28-40 V/cm decreased the duration, maximum diastolic potential, amplitude, and maximum rate of rise of the phase zero depolarization of paced APs that began after the shock. The contraction strength increased 43 and 59% during the 10 s after the stronger shocks. The transmembrane potential was shifted toward 0 mV immediately after the stronger shocks. We concluded that weak or strong shocks prolong the AP ongoing during the shock, whereas sufficiently strong shocks also shorten APs that begin after the shock. AP prolongation and shortening may be important for defibrillation and acceleration of tachycardia after failed cardioversion shocks.

Effect of field stimulation on cellular repolarization in rabbit myocardium. Implications for reentry induction.

We have investigated the effects of electric field stimulation on membrane repolarization in rabbit papillary muscles and assessed the consequences of these effects for the dispersion of intracellular potentials and the production of a propagation wave front or unidirectional block in relatively refractory tissue. The stimuli studied had electric field strength of 0.25-14 V/cm, duration of 2 msec, and field orientation along or across the myocardial fibers. The field strengths to excite the muscles in diastole were 0.68 or 1.23 V/cm for stimuli oriented along or across the fibers, respectively (p less than 0.01, along versus across). A 2.5-V/cm stimulus given near the end of the action potential (AP) produced either no response or, after increasing the stimulus delay only 2-3 msec, a full response with almost no AP durations that were intermediate. For stimulation along and across the fibers, respectively, given at 70% of the AP duration, a 4-V/cm stimulus produced AP prolongation (measured at 90% repolarization) of 20% and 4% (p less than 0.05), an 8-V/cm stimulus produced AP prolongation of 36% and 20% (p less than 0.05), and a 14-V/cm stimulus produced AP prolongation of 36% and 30% (p = NS). For either orientation, AP prolongation by stimuli of 8 V/cm or 14 V/cm increased gradually as the stimulus delay was increased. The different effects in relatively refractory tissue of stimuli of 2.5 V/cm compared with 8 V/cm can explain the propagation wave front and block that occur with electrically induced functional reentry in the heart.(ABSTRACT TRUNCATED AT 250 WORDS)