E N Moore

Cesium chloride-induced long QT syndrome: demonstration of afterdepolarizations and triggered activity in vivo.

The identification of afterdepolarizations and their relationship to arrhythmias in vivo is not available. Experiments were undertaken to determine whether afterdepolarizations could be detected in monophasic action potentials (MAPs) recorded in vivo and whether they were related to arrhythmias in an intact canine preparation of the long QT syndrome. Isolated cardiac tissues from six dogs were studied to validate the technique. In simultaneous MAP and transmembrane recordings, afterdepolarizations induced with barium (early) or acetylstrophanthidin (delayed) were detected in MAPs when present in microelectrode recordings. MAPs were then recorded in situ in eight dogs with cesium chloride-induced long QT syndrome associated with ventricular arrhythmias. Afterdepolarizations were identified in each of the dogs and were similar to early afterdepolarizations identified in vitro; they occurred during phase 3 and were attenuated during overdrive pacing. The afterdepolarizations were closely related to arrhythmias: (1) afterdepolarizations always preceded ventricular arrhythmias, (2) the coupling intervals (CI) of the afterdepolarizations (AD) and the ventricular premature beats (VPB) were nearly identical (VPB CI = 1.06 AD CI -10.24; r2 = .87), (3) the take-off potentials of the ventricular premature beats were nearly identical to the amplitude of the afterdepolarizations (take-off potential = 0.98 afterdepolarization amplitude +0.46, r2 = .87), and (4) afterdepolarizations and ventricular arrhythmias resolved concurrently during overdrive pacing and with time. Thus, a new catheter technique has been validated and has been used to directly identify afterdepolarizations and triggered activity in vivo.

The limitations of epicardial mapping as a guide to the surgical therapy of ventricular tachycardia.

SUMMARYThe adequacy of intraoperative epicardial mapping as a guide to surgical procedures performed to terminate ventricular arrhythmias was investigated. Ligation of the anterior septal or left anterior descending coronary artery in 28 dogs produced ventricular arrhythmias that were studied 24-36 hours following occlusion. The sites of origin of 26 tachycardias were determined to be in the subendocardium by using extensive epicardial, endocardial and intramural mapping techniques and were verified by demonstrating unaltered activation sequences during pacing from these earliest sites.Epicardial breakthrough followed earliest directly recordable ven- tricular activity by as little as 7 msec. Without endocardial mapping many of these tachycardias would have been incorrectly identified as originating in the fascicles or epicardium. The sites of epicardial breakthrough were anatomically distant from the sites of origin by a markedly varying extent (5 mm to 6 cm). Two rhythms might be close in their sites of earliest epicardial appearance yet distant on the endocardium or vice versa.We conclude that epicardial mapping may not be sufficient to identify or predict the origins of many ventricular tachycardias and that the success of surgery to abolish these arrhythmias may be enhanced by preoperative and intraoperative endocardial mapping.

Reduced space constant in slowly conducting regions of chronically infarcted canine myocardium.

Experiments were performed to test the hypothesis that a reduction in the space constant contributes to slow conduction in the infarcted myocardium of dogs 5–8 days after coronary artery occlusion and reperfusion. Standard microelectrode techniques were used to measure action potential characteristics and conduction velocity parallel to fiber orientation in normal and infarcted ventricular epicardial strips superfused in a tissue bath. The space constants were determined by measuring the decay of the transmembrane steady state electrotonic potential with distance from a suction electrode current source. In eight normal epicardial preparations, conduction velocity ranged between 0.305 and 0.603 m/sec, and the space constant was between 0.712 and 1.202 mm. In 10 infarcted epicardial preparations, in regions of slow conduction (0.032–0.299 m/sec), the space constant was reduced to values between 0.281 and 0.917 mm. Action potential amplitude and maximum rate of depolarization were also reduced in infarcted myocardium. There was a direct relationship between conduction velocity and space constant and maximum rate of depolarization. In infarcted tissues, two types of slow conduction occurred. Slow conduction was uniform down to a velocity of approximately 0.181 m/sec, and a space constant of 0.523 mm. Below these values, conduction was discontinuous with prepotentials associated with the action potential upstroke. Indirect evidence from our studies suggests that a depression in action potential depolarization and an increase in effective axial resistance contribute approximately equally to uniform slow conduction in the infarcted myocardium.

Initiation of sustained ventricular tachyarrhythmias in a canine model of chronic myocardial infarction: importance of the site of stimulation.

The importance of the site of stimulation to the initiation of sustained ventricular tachyarrhythmias was determined in 24 adult mongrel dogs. Studies were performed 3–30 days after two-stage occlusion of the mid- or distal left anterior descending coronary artery, modified by a reperfusion stage. Unipolar cathodal stimuli of twice-threshold intensity and 2 msec duration were introduced at five to 24 sites in each dog in the distribution of occluded and nonoccluded vessels. Strength-interval curves were constructed from 232 measurements at these sites and local properties of excitability and refractoriness were correlated with the ability to initiate arrhythmias. All dogs had sustained ventricular tachyarrhythmias inducible from at least one site. Intramyocardial sites with normal excitability and refractoriness within 2 cm of an area of infarction were most often successful (27 of 44, 61%) in the initiation of sustained arrhythmias. Less successful sites included normal left ventricular plunge electrode sites > 2 cm from an area of infarction (eight of 32, 25%) (p = 0.002), left ventricular plunge electrode sites within an area of infarction (20 of 103, 19%) (p < 0.001), normal right ventricular sites (five of 24, 21%) (p < 0.001), and endocardial catheter sites (six of 29, 21%), (p < 0.001). These findings suggest that local properties of excitability and refractoriness at the site of stimulation, as well as anatomic and geometric factors, may be critical in the initiation of sustained ventricular tachyarrhythmias using the technique of programmed electrical stimulation.

Vector mapping of myocardial activation.

A custom-made probe, consisting of four electrodes arranged so that two orthogonal bipolar electrograms could be recorded from a single site, was used to record epicardial activity during atrial and ventricular pacing in five normal and five anesthetized open-chest mongrel dogs with myocardial infarction. Unfiltered bipolar electrograms recorded with a 2 mm interelectrode distance averaged 36 +/- 15 mV in amplitude and 16 +/- 5 msec in duration in normal areas and 14 +/- 11 mV and 23 +/- 12 msec in infarcted areas (p less than .01 infarct vs normal). The bipolar electrograms were vector summed so that a vector loop could be generated at each site. The direction of epicardial impulse propagation as determined by multipoint isochronal activation mapping was compared with that indicated by maximum x,y deflection of the vector loop. At 203 sites (141 normal and 62 infarcted) there was a median error of only 13 degrees and an excellent correlation by linear regression (r2 = .95). In normal myocardium vector loops were straight (60%), open (21%), or hooked (19%). In infarcted myocardium, notched and irregular loops were occasionally seen. However, a clear maximum x,y deflection was still obtained from 98% of infarcted sites. During ventricular pacing in normal dogs, uniform epicardial conduction was observed for up to 4 cm longitudinal to fiber orientation but only 1 cm transverse to it. At selected sites longitudinal to fiber orientation conduction velocity was 0.618 m/sec, electrogram duration 12 msec, and vector amplitude 76 mV compared with 0.304 m/sec, 18 msec, and 38 mV during conduction transverse to fiber orientation (p less than .05 for all comparisons). Vector mapping of epicardial activation was performed during ventricular tachycardia induced by programmed stimulation in two of five 2-week-old canine myocardial infarcts. Aside from minor irregularities caused by impulse spread around areas of block, vector loops indicated when impulses were spreading away from the area of early epicardial activity and thus directed mapping to the region of earliest activation. We conclude that vector loops generated by summing orthogonal local bipolar electrograms accurately represent the direction of epicardial activation in both normal and infarcted myocardium. Such loops may prove useful in mapping tachycardias and in clarifying details about cardiac activation processes.

Effects of cellular uncoupling on conduction in anisotropic canine ventricular myocardium.

Experiments were performed on canine superfused ventricular epicardial tissue slices to determine the effects of 1.0–2.0 mM heptanol, an uncoupling agent, on conduction longitudinal and transverse to myocardial fiber orientation. Conduction velocities were measured between proximal and distal pairs of epicardial electrodes oriented transverse and longitudinal to the direction of a conducted wavefront evoked by pacing at a basic cycle length of 2,000 msec from one margin of the tissue before and after the addition of heptanol. In a separate group of tissues, the dual bipolar orthogonal electrode was used to sequentially map epicardial activation at 40 to 45 sites in a 1 cm x 2 cm area before and 30 minutes after the introduction of heptanol. In a third group of tissues, transmembrane potentials were recorded with standard microelectrode techniques to determine the effects of heptanol on action potential characteristics. Heptanol did not significantly effect action potential amplitude or maximum rate of depolarization. After 1.0 mM heptanol, conduction velocity began to decrease in 1-2 minutes and reached a steady state in 15-20 minutes. Conduction velocity in the longitudinal direction decreased from a control value of 0.56±0.13 to 0.46±0.10 M/sec (±SD) at 30 minutes after heptanol (p = 0.005). In the transverse direction, it decreased from 0.24±0.09 to 0.17 ±0.05 M/sec (p = 0.002). The ratio of longitudinal to transverse conduction velocities increased from 2.54 1.00 to 2.94 0.82 (p = 0.042). Thus, heptanol preferentially slowed conduction in the transverse direction. Because heptanol did not greatly influence active membrane properties, we used cable equations to calculate the time course of the change in effective junctional resistivity, which rose from 133.2 &OHgr; · cm before heptanol to 312.2 &OHgr; · cm 30 minutes after heptanol administration. We conclude that heptanol slows conduction velocity by selectively increasing junctional resistivity. The preferential slowing of conduction in the transverse direction is most likely due to the fact that more junctional resistances are encountered per unit distance in the transverse than in the longitudinal direction.

Interaction of fiber orientation and direction of impulse propagation with anatomic barriers in anisotropic canine myocardium.

We developed a computer model of the interaction of impulse propagation with anatomic barriers in uniformly anisotropic tissue. Its predictions were confirmed experimentally by using an in vitro cut to create a 6 X 1-mm anatomic barrier in 12 canine epicardial strips. The model predicted that long, thin barriers located parallel to the direction of impulse propagation would have little effect in delaying conduction regardless of the arrangement of cardiac fibers. In this situation, the mean experimental ratio of postcut to control conduction times across the barrier was 1.05:1.00 in 10 tissues. When impulses were proceeding perpendicular to an anatomic barrier, significant distal conduction delay was predicted and found to occur only when the conduction from pacing to recording sites was initially longitudinal to fiber orientation (mean experimental ratio, 2.34:1.00 in five tissues) but not transverse to fiber orientation (ratio, 1.08:1.00 in five tissues). We conclude that the direction of initial impulse propagation and the orientation of myocardial fibers have large effects on the degree to which anatomic barriers delay activation in cardiac tissue. These findings may have implications for the participation of anatomic barriers in reentrant circuits.

The cellular electrophysiologic changes induced by high-energy electrical ablation in canine myocardium.

High-energy electrical ablation is a new experimental approach to control arrhythmias. In this study, the cellular electrophysiologic effects of high-energy shocks (5 to 40 J) delivered in vitro to 14 epicardial tissues from 11 dogs were studied in an attempt to understand the nature and extent of injury as well as potential arrhythmogenic mechanisms. In addition, this preparation was used to test the importance of cathode-anode configuration, current density, and fiber orientation in the induction of tissue injury in vitro. Electrophysiologic abnormalities were noted up to 10 mm from the electrode wall, and their extent was determined in part by current density and the cathode-anode orientation. A decrease in resting membrane potential, action potential amplitude, and dV/dT occurred in all tissues after high-energy shocks, which was worst nearest the cathode and of graded severity at increasing distances from the cathode. The most severe effects were noted with high current densities and in tissues located between the cathode and anode. In addition, impaired impulse conduction and abnormal repolarization were documented. Histologic study demonstrated contraction band necrosis immediately after delivery of high-energy shocks. The extent and distribution of the contraction bands was in part dependent on the energy delivered and the cathode-anode configuration. These findings suggest potential mechanisms for arrhythmogenesis and altered regional hemodynamic abnormalities that occur in vivo.

The effects of procainamide on conduction in anisotropic canine ventricular myocardium.

Although conduction velocity in cardiac tissue is dependent on fiber orientation, the influence of commonly used antiarrhythmic agents on conduction longitudinal and transverse to such fibers is unknown. We evaluated the effects of procainamide on conduction velocity and intracellular potentials in vitro during conduction longitudinal and transverse to fiber orientation in epicardial strips obtained from areas of uniform fiber orientation from 15 adult mongrel dogs. Ventricular epicardial strips demonstrated marked anisotropy. At a pacing cycle length of 1000 msec, mean conduction velocity longitudinal to fiber orientation averaged 0.602 +/- 0.051 m/sec and mean conduction velocity transverse to fiber orientation was 0.186 +/- 0.024 m/sec, resulting in a ratio of longitudinal to transverse conduction velocities of (theta L/T) 3.27 +/- 0.38. After the addition of procainamide, conduction velocity decreased to 0.532 +/- 0.062 m/sec longitudinal to fiber orientation and to 0.174 +/- 0.023 m/sec transverse to fiber orientation resulting in a decrease of theta L/T to 3.09 +/- 0.37 (p less than .05 vs control). Before the addition of procainamide, when pacing at progressively shorter cycle lengths, conduction velocity longitudinal to fiber orientation was relatively unchanged, whereas conduction velocity transverse to fiber orientation decreased resulting in an increase in theta L/T. After the addition of procainamide, conduction velocity at shorter pacing cycle lengths decreased both longitudinal and transverse to fiber orientation demonstrating the well-known use-dependent effect of procainamide. However, in contrast to control conditions, conduction velocity longitudinal to fiber orientation was slowed by a greater extent than the conduction transverse to fiber orientation, resulting in an even greater decrease in theta L/T. To investigate the effect of differences in drug binding during propagation in different directions, we examined conduction velocity during alternations in pacing direction and compared it with velocity during steady-state pacing. At a pacing cycle length of 1000 msec, no difference was observed between the initial conduction velocity after changing pacing directions and the steady-state conduction velocity. At pacing cycle lengths shorter than 1000 msec, when changing from transverse to longitudinal conduction, there was an initial drop in normalized conduction velocity that was present on the first beat of longitudinal conduction; however, with continued pacing in a longitudinal direction there was a further decrease in conduction velocity.(ABSTRACT TRUNCATED AT 400 WORDS)

The effects of coronary artery disease on the ventricular fibrillation threshold in man.

The ventricular fibrillation threshold (VFT) was measured in 28 patients at the time of cardiac surgery. The VFT was measured with a 100 Hz train of 24 rectangular pulses positioned across the ST segment and T wave. Current was applied to the epicardial surface of either ventricle with a bipolar electrode probe. In six patients, the normal right VFT was 24.3 ± 5.2 mA, and in 10 patients the normal left VFT was 33.6 ± 9.5 mA (p < 0.05). In 12 patients with > 75% obstruction of the left anterior descending coronary artery, the left VFT was 18.6 ± 6.9 mA. This value was significantly less than the left VFT in patients without coronary artery disease (p < 0.001). This study shows that the VFT can be measured in man and that coronary artery disease reduces this parameter.