Atrial defibrillation thresholds of electrode configurations available to an atrioventricular defibrillator.

INTRODUCTION: Little investigation has been conducted to assess the atrial defibrillation thresholds of electrode configurations using electrodes designed for internal ventricular defibrillation (right ventricle [RV], superior vena cava [SVC], and pulse generator housing [Can]) combined with coronary sinus (CS) electrodes. We hypothesized that a CS-->SVC+Can electrode configuration would have a lower atrial defibrillation threshold than a standard configuration for defibrillation, RV-->SVC+Can. We also tested the atrial defibrillation thresholds of five other configurations. METHODS AND RESULTS: In 12 closed chest sheep, we situated a two-coil (RV, SVC) defibrillation catheter, a left-pectoral subcutaneous Can, and a CS lead. Atrial fibrillation was burst induced and maintained with continuous infusion of intrapericardial acetyl-beta-methylcholine chloride. Using fixed-tilt biphasic shocks, we determined the atrial defibrillation thresholds of seven test configurations in random order according to a multiple-reversal protocol. The peak voltage and delivered energy atrial defibrillation thresholds of CS-->SVC+Can (168+/-67 V, 2.68+/-2.40 J) were significantly lower than those of RV-->SVC+Can (215+/-88 V, 4.46+/-3.40 J). The atrial defibrillation thresholds of the other test configurations were RV+CS-->SVC+Can: 146+/-59 V, 1.92+/-1.45 J; RV-->CS+SVC+Can: 191+/-89 V, 3.53+/-3.19 J; CS-->SVC: 188+/-98 V, 3.77+/-4.14 J; SVC-->CS+ Can: 265+/-145 V, 7.37+/-9.12 J; and SVC-->Can: 516+/-209 V, 24.5+/-15.0 J. CONCLUSIONS: The atrial defibrillation threshold of CS-->SVC+Can is significantly lower than that of RV-->SVC+Can. In addition, the low atrial defibrillation threshold of RV+CS-->SVC+Can merits further investigation. Based on corroboration of low atrial defibrillation thresholds of CS-based configurations in humans, physicians might consider using CS leads with atrioventricular defibrillators.

Role of wavelength adaptation in the initiation, maintenance, and pharmacologic suppression of reentry.

INTRODUCTION: The stability of reentry is thought to depend on a critical balance between the spatial extent of refractory tissue in a reentrant wave (i.e., wavelength lambda) and the reentrant path length. Because considerable evidence suggests that lambda changes continuously in space and time during abrupt rate changes associated with the onset of tachycardia, we hypothesized that beat-by-beat adaptation of A to the dimensions of the reentrant path plays a central role in the mechanism of initiation of reentry. METHODS AND RESULTS: To investigate the dynamic relationship between lambda and path length during initiation of reentry, optical mapping with voltage-sensitive dyes was used in a guinea pig model of reentrant ventricular tachycardia (VT). In this model, a computer-guided laser obstacle precisely controlled the position and dimensions of the reentrant path. Under control perfusion and after addition of 15 microM d-sotalol, lambda was monitored during steady-state pacing, premature stimulation, and the initiating beats leading to nonsustained and sustained VT. During control perfusion, reentrant VT was reproducibly induced in 8 of 8 hearts, whereas in the presence of d-sotalol, reentry could only be initiated in 1 of 8 hearts due primarily to the failure of lambda to adapt to the reentrant path length. During successful initiation of VT, a consistent sequence was observed. The sequence was characterized by antidromic and orthodromic propagation around both sides of the anatomic obstacle, followed by unidirectional block of the antidromic impulse and persistence of reentry only if the A of the orthodromic impulse adapted to the reentrant path (lambda < path length). d-Sotalol prevented initiation of VT by altering lambda adaptation of the orthodromic wave; however, it failed to terminate ongoing VT because reverse use-dependence developed after several beats of tachycardia. CONCLUSION: In an experimental model where lambda, path length, and cellular action potentials were monitored during initiation of reentry, we found that, in contrast to termination, the initiation of reentry and the transition from nonsustained to sustained VT is strongly dependent on beat-to-beat adaptation of lambda to the dimensions of the reentrant path.

Reduction of atrial defibrillation threshold with an interatrial septal electrode.

BACKGROUND: The standard lead configuration for internal atrial defibrillation consists of a shock between electrodes in the right atrial appendage (RAA) and coronary sinus (CS). We tested the hypothesis that the atrial defibrillation threshold (ADFT) of this RAA-->CS configuration would be lowered with use of an additional electrode at the atrial septum (SP). METHODS AND RESULTS: Sustained atrial fibrillation was induced in 8 closed-chest sheep with burst pacing and continuous pericardial infusion of acetyl-ss-methylcholine. Defibrillation electrodes were situated in the RAA, CS, pulmonary artery (PA), low right atrium (LRA), and across the SP. ADFTs of RAA-->CS and 4 other lead configurations were determined in random order by use of a multiple-reversal protocol. Biphasic waveforms of 3/1-ms duration were used for all single and sequential shocks. The ADFT delivered energies for the single-shock configurations were 1.27+/-0.67 J for RAA-->CS and 0. 86+/-0.59 J for RAA+CS-->SP; the ADFTs for the sequential-shock configurations were 0.39+/-0.18 J for RAA-->SP/CS-->SP, 1.16+/-0.72 J for CS-->SP/RAA-->SP, and 0.68+/-0.46 J for RAA-->CS/LRA-->PA. Except for CS-->SP/RAA-->SP versus RAA-->CS and RAA-->CS/LRA-->PA versus RAA+CS-->SP, the ADFT delivered energies of all of the configurations were significantly different from each other (P:<0. 05). CONCLUSIONS: The ADFT of the standard RAA-->CS configuration is markedly reduced with an additional electrode at the atrial SP.

Mechanism linking T-wave alternans to the genesis of cardiac fibrillation.

BACKGROUND: Although T-wave alternans has been closely associated with vulnerability to ventricular arrhythmias, the cellular processes underlying T-wave alternans and their role, if any, in the mechanism of reentry remain unclear. METHODS AND RESULTS: -T-wave alternans on the surface ECG was elicited in 8 Langendorff-perfused guinea pig hearts during fixed-rate pacing while action potentials were recorded simultaneously from 128 epicardial sites with voltage-sensitive dyes. Alternans of the repolarization phase of the action potential was observed above a critical threshold heart rate (HR) (209+/-46 bpm) that was significantly lower (by 57+/-36 bpm) than the HR threshold for alternation of action potential depolarization. The magnitude (range, 2.7 to 47.0 mV) and HR threshold (range, 171 to 272 bpm) of repolarization alternans varied substantially between cells across the epicardial surface. T-wave alternans on the surface ECG was explained primarily by beat-to-beat alternation in the time course of cellular repolarization. Above a critical HR, membrane repolarization alternated with the opposite phase between neighboring cells (ie, discordant alternans), creating large spatial gradients of repolarization. In the presence of discordant alternans, a small acceleration of pacing cycle length produced a characteristic sequence of events: (1) unidirectional block of an impulse propagating against steep gradients of repolarization, (2) reentrant propagation, and (3) the initiation of ventricular fibrillation. CONCLUSIONS: Repolarization alternans at the level of the single cell accounts for T-wave alternans on the surface ECG. Discordant alternans produces spatial gradients of repolarization of sufficient magnitude to cause unidirectional block and reentrant ventricular fibrillation. These data establish a mechanism linking T-wave alternans of the ECG to the pathogenesis of sudden cardiac death.

Modulated dispersion explains changes in arrhythmia vulnerability during premature stimulation of the heart.

BACKGROUND: Previously, we have shown that a premature stimulus can significantly modulate spatial gradients of ventricular repolarization (ie, modulated dispersion), which result from heterogeneous electrophysiological properties between cells. The role modulated dispersion may play in determining electrical instability in the heart is unknown. METHODS AND RESULTS: To determine if premature stimulus-induced changes in repolarization are a mechanism that governs susceptibility to cardiac arrhythmias, optical action potentials were recorded simultaneously from 128 ventricular sites (1 cm2) in 8 Langendorff-perfused guinea pig hearts. After baseline pacing (S1), a single premature stimulus (S2) was introduced over a range of S1S2 coupling intervals. Arrhythmia vulnerability after each premature stimulus was determined by measurement of a modified ventricular fibrillation threshold (VFT) during the T wave of each S2 beat (ie, S2-VFT). As the S1S2 interval was shortened to an intermediate value, spatial gradients of repolarization and vulnerability to fibrillation decreased by 51+/-9% (mean+/-SEM) and 73+/-45%, respectively, compared with baseline levels. As the S1S2 interval was further shortened, repolarization gradients increased above baseline levels by 54+/-30%, which was paralleled by a corresponding increase (37+/-8%) in vulnerability. CONCLUSIONS: These data demonstrate that modulation of repolarization gradients by a single premature stimulus significantly influences vulnerability to ventricular fibrillation. This may represent a novel mechanism for the formation of arrhythmogenic substrates during premature stimulation of the heart.

Angiotensin-converting enzyme inhibition produces electrophysiologic but not antiarrhythmic effects in the intact heart.

Although angiotensin-converting enzyme (ACE) inhibitors are known to influence favorably the structural remodeling of the heart after myocardial infarction, the mechanisms by which ACE inhibitors improve survival are not well understood. The hypothesis that ACE inhibitors may possess antiarrhythmic activity has been studied in various isolated tissue preparations. However, the electrophysiologic effects of ACE inhibitors in the intact heart are not well understood. The effect of the ACE inhibitor enalaprilat on intact heart electrophysiology was studied by using multisite optical action-potential recordings with voltage-sensitive dyes. Action potentials were recorded simultaneously from 128 left ventricular epicardial sites in 15 Langendorff perfused hearts subjected to an endocardial cryoablation procedure, which was used to restrict propagation to a thin viable rim of epicardium. Action-potential duration (APD) was significantly prolonged in 67% of preparations perfused with 5 mg/L enalaprilat. Higher concentration of enalaprilat (50 mg/L) prolonged APD in all preparations tested. This APD-prolonging effect persisted over a broad range of stimulus rates, indicating the absence of reverse use-dependent properties. Enalaprilat did not modify conduction velocity, nor did it affect spatial dispersion of repolarization times. In addition, enalaprilat had no effect on ventricular fibrillation threshold and failed to suppress the initiation of ventricular tachycardia using an anatomically defined reentrant circuit. These findings indicate that in the intact heart, enalaprilat does indeed have electrophysiologic effects that cause APD prolongation, particularly at high drug concentrations. However, this effect was not of sufficient magnitude in the guinea pig to suppress the initiation of ventricular fibrillation or reentrant ventricular tachycardia.

Hypoxia and hypothermia enhance spatial heterogeneities of repolarization in guinea pig hearts: analysis of spatial autocorrelation of optically recorded action potential durations.

INTRODUCTION: Regional dispersions of repolarization (DOR) are arrhythmogenic perturbations that are closely associated with reentry. However, the characteristics of DOR have not been well defined or adequately analyzed because previous algorithms did not take into account spatial heterogeneities of action potential durations (APDs). Earlier simulations proposed that pathologic conditions enhance DOR by decreasing electrical coupling between cells, thereby unmasking differences in cellular repolarization between neighboring cells. Optical mapping indicated that gradients of APD and DOR are associated with fiber structure and are largely independent of activation. We developed an approach to quantitatively characterize APD gradients and DOR to determine how they are influenced by tissue anisotropy and cell coupling during diverse arrhythmogenic insults such as hypoxia and hypothermia. METHODS AND RESULTS: Voltage-sensitive dyes were used to map APs from 124 sites on the epicardium of Langendorff-perfused guinea pig hearts during (1) cycles of hypoxia and reoxygenation and (2) after 30 minutes of hypothermia (32 degrees to 25 degrees C). We introduce an approach to quantitate DOR by analyzing two-dimensional spatial autocorrelation of APDs along directions perpendicular and parallel to the longitudinal axis of epicardial fibers. A spatial correlation length L was derived as a statistical measure of DOR. It corresponds to the distance over which APDs had comparable values, where L is inversely related to DOR. Hypoxia (30 min) caused a negligible decrease in longitudinal thetaL (from 0.530 +/- 0.138 to 0.478 +/- 0.052 m/sec) and transverse thetaT (from 0.225 +/- 0.034 to 0.204 +/- 0.021 m/sec) conduction velocities and did not alter thetaL/thetaT or activation patterns. In paced hearts (cycle length [CL] = 300 msec), hypoxia decreased APDs (123 +/- 18.2 to 46 +/- 0.6 msec; P < 0.001) within 10 to 15 minutes and enhanced DOR, as indicated by reductions of L from 1.8 +/- 0.9 to 1.1 +/- 0.5 mm (P < 0.005). Hypothermia caused marked reductions of thetaL (0.53 +/- 0.138 to 0.298 +/- 0.104 m/sec) and thetaT (0.225 +/- 0.034 to 0.138 +/- 0.027 m/sec), increased APDs (128 +/- 4.4 to 148 +/- 14.5 msec), and reduced L from 2.0 +/- 0.3 to 1.3 +/- 0.6 mm (P < 0.05). L decreased with increased time of hypoxia and recovered upon reoxygenation. Hypoxia and hypothermia reduced L measured along the longitudinal (L(L)) and transverse (L(T)) axes of cardiac fibers while the ratio of L(L)/L(T) remained constant. CONCLUSION: Conventional indexes of DOR (i.e., APD "range" or "standard deviation," evaluated with extracellular electrodes) did not convey the spatial inhomogeneities of repolarization revealed by L. Spatial autocorrelation analysis provides a statistically significant measurement of DOR, which can take into account intrinsic heterogeneities of APDs and fiber orientation. The data show that hypoxia and hypothermia produce reductions of L, even though they have different effects on mean APD and conduction velocity. The preservation of a constant L(L)/L(T) ratio during hypoxia and hypothermia, despite large reductions in L, is consistent with a mechanism in which reduced cell-to-cell coupling unmasks intrinsic dispersions of APD and reduces L(L) and L(T) by the same factor. Thus, the spatial autocorrelation of APDs provides a sensitive index of DOR under normal and arrhythmogenic conditions. It incorporates the anisotropic nature of the myocardium and therefore is preferable to conventional indexes of DOR.

Role of passive electrical properties during action potential restitution in intact heart.

Action potential duration (APD) restitution is classically attributed to membrane ionic currents; however, the role of cell-to-cell coupling in restitution is poorly understood. To test the hypothesis that passive electrical properties of multicellular preparations influence restitution, spatial gradients of transmembrane voltage were measured with high spatial (0.83 mm), voltage (1 mV), and temporal (0.5 ms) resolutions using voltage-sensitive dye in Langendorff-perfused guinea pig ventricle. At short premature coupling intervals, APD failed to shorten in cells located near (< 3 mm) the site of pacing corresponding to the site of earliest repolarization, deviating from classical restitution. In contrast, APD shortened exponentially with increasing stimulus prematurity when pacing was remote from the identical recording site. The mechanism responsible for nonexponential restitution was investigated in a one-dimensional propagation model using the dynamic Luo-Rudy formulation of the ventricular cell and was found to be attributable to depolarizing axial current present in regions of steep repolarization gradients. Moreover, axial current loading attenuated spatial gradients of repolarization that were prominent in the absence of cell-to-cell coupling. These data demonstrate that 1) in contrast to restitution in isolated cells, restitution in multicellular tissue is influenced by axial current from neighboring cells, and 2) in normal myocardium, axial current between cells attenuates dispersion of repolarization during premature stimulation of the heart.

Unique properties of cardiac action potentials recorded with voltage-sensitive dyes.

INTRODUCTION: Optical mapping with voltage-sensitive dyes has made it possible to record cardiac action potentials with high spatial resolution that is unattainable by conventional techniques. Optically recorded signals possess distinct properties that differ importantly from electrograms recorded with extracellular electrodes or action potentials recorded with microelectrode techniques. Despite the growing application of optical mapping to cardiac electrophysiology, relatively little quantitative information is available regarding the characteristics of optical action potentials recorded from cardiac tissue. METHODS AND RESULTS: A high-resolution optical mapping system and microelectrode techniques were used to determine the characteristics of guinea pig ventricular action potentials recorded with the voltage-sensitive dye di-4-ANEPPS. The effects of optical magnification, tissue-light interaction, sampling rate, voltage resolution, spatial resolution, and cardiac motion on action potential signal characteristics were determined. The optical action potential signal represents the relative change in transmembrane potential arising from a volume of cells, where the area of a recording site is determined by optical magnification and detector area, and the depth of recording is determined by system optics and the visible light transmission characteristics of cardiac muscle. Using photographic lenses, the depth of tissue contributing to the signal is < 250 microns. The action potential plateau and final repolarization can be accurately reconstructed from data digitized at modest sampling rates (450 to 750 Hz), since the frequency content of optical action potentials is band-limited to approximately 150 Hz. However, faster sampling rates are needed to depict the subtle details of the action potential upstroke. In addition to temporal resolution, it is essential to achieve sufficient dynamic range and voltage resolution to accurately represent the time course of membrane potential change. Voltage resolution is inversely related to the square of spatial resolution, hence, there exists an inherent trade-off between increased spatial resolution and diminished voltage resolution. Cardiac motion, which can otherwise limit spatial resolution as well as signal fidelity, can be effectively reduced using mechanical stabilization of the heart without distorting action potential characteristics. CONCLUSIONS: Optical mapping with voltage-sensitive dyes provides high-fidelity multisite action potential recording with flexible spatial resolution. When recording cardiac action potentials with voltage-sensitive dyes, the interdependence of temporal, spatial, and voltage resolutions must be carefully considered.

Modulation of ventricular repolarization by a premature stimulus. Role of epicardial dispersion of repolarization kinetics demonstrated by optical mapping of the intact guinea pig heart.

Recent evidence suggests that ion channels governing the response of action potential duration (APD) to a premature stimulus (ie, APD restitution) are heterogeneously dispersed throughout the heart. However, because of limitations of conventional electrophysiological recording techniques, the effects of restitution in single cells on ventricular repolarization at the level of the intact heart are poorly understood. Using high-resolution optical mapping with voltage-sensitive dyes, we measured APD restitution kinetics at 128 simultaneous sites on the epicardial surface (1 cm2) of intact guinea pig hearts (n = 15). During steady state baseline pacing, APD gradients that produced a spatial dispersion of repolarization were observed. Mean APD was shortened monotonically from 186 +/- 19 ms during baseline pacing (S1-S1 cycle length, 393 +/- 19 ms) to 120 +/- 4 ms as single premature stimuli were introduced at progressively shorter coupling intervals (shortest S1-S2, 190 +/- 15 ms). In contrast, premature stimuli caused biphasic modulation of APD dispersion (defined as the variance of APD measured throughout the mapping field). Over a broad range of increasingly premature coupling intervals, APD dispersion decreased from 70 +/- 29 ms2 to a minimum of 10 +/- 7 ms2 at a critical S1-S2 interval (216 +/- 18 ms), and then, at shorter premature coupling intervals, APD dispersion increased sharply to 66 +/- 25 ms2. Modulation of APD dispersion by premature stimuli was attributed to coupling interval-dependent changes in the magnitude and direction of ventricular APD gradients, which, in turn, were explained by systematic heterogeneities of APD restitution across the epicardial surface. There was a characteristic pattern in the spatial distribution of cellular restitution such that faster restitution kinetics were closely associated with longer baseline APD. This relationship explained the reversal of APD between single cells, inversion of APD gradients across the heart, and ECG T-wave inversion during closely coupled premature stimulation. Therefore, because of the heterogeneous distribution of cellular restitution kinetics across the epicardial surface, a single premature stimulus profoundly altered the pattern and synchronization of ventricular repolarization in the intact ventricle. This response has important mechanistic implications in the initiation of arrhythmias that are dependent on dispersion of repolarization.

Optical mapping in a new guinea pig model of ventricular tachycardia reveals mechanisms for multiple wavelengths in a single reentrant circuit.

BACKGROUND: Although the relationship between cardiac wavelength (lambda) and path length importantly determines the stability of reentrant arrhythmias, the physiological determinants of lambda are poorly understood. To investigate the cellular mechanisms that control lambda during reentry, we developed an experimental system for continuously monitoring lambda within a reentrant circuit with the use of voltage-sensitive dyes and a new guinea pig model of ventricular tachycardia (VT). METHODS AND RESULTS: Action potentials were recorded simultaneously from 128 ventricular sites in Langendorff-perfused hearts (n = 15) in which propagation was confined to a two-dimensional rim of epicardium by an endocardial cryoablating procedure. The reentrant path was precisely controlled by creating an epicardial obstacle (2 x 10 mm) with an argon laser. To control for fiber orientation and rate-dependent membrane properties, lambda during reentry was compared with lambda during plane wave propagation transverse and longitudinal to cardiac fibers at a stimulus cycle length (CL) comparable to the VT CL. Reentrant VT (CL = 97.0 +/- 6.2 ms) was reproducibly induced by programmed stimulation in 93% of preparations. lambda varied considerably within the reentrant circuit (range, 10.6 to 22.5 mm), because of heterogeneities of conduction rather than action potential duration. lambda was significantly shorter during reentrant propagation (ie, with pivoting) parallel to fibers (10.6 +/- 4.2 mm) compared with plane wave propagation (ie, without pivoting) parallel to fibers (32.8 +/- 6.5 mm, P < .02), indicating that wave-front pivoting was primarily responsible for shortening of lambda during reentry. The mechanism of lambda shortening was conduction slowing from increased current load experienced by the pivoting wave front. CONCLUSIONS: We provide direct experimental evidence that multiple wavelengths are present even within a relatively simple reentrant circuit. Abrupt changes in loading during wave-front pivoting, rather than membrane ionic properties or fiber structure, were a major determinant of lambda and, therefore, may play an important role in the stability of reentry.