Liver enzyme monitoring in patients treated with troglitazone.

CONTEXT: Soon after initial marketing in March 1997, troglitazone, the first thiazolidinedione antidiabetic agent, was found to cause life-threatening acute liver failure. The drug was removed from the market in March 2000. OBJECTIVE: To evaluate the effect of US Food and Drug Administration (FDA) risk management efforts, including repeated labeling changes and "Dear Healthcare Professional" letters, on periodic liver enzyme monitoring of patients taking troglitazone. DESIGN, SETTING, AND PARTICIPANTS: Claims data from a large, multistate managed care organization were used to establish 4 cohorts of patients (N = 7603) with at least 90 days of health plan enrollment before first troglitazone prescription during 4 consecutive periods spanning April 1997 to September 1999 and representing 4 progressively stringent liver monitoring recommendations. MAIN OUTCOME MEASURES: Percentage of eligible troglitazone users in each cohort with baseline, monthly (for up to 6 months of continuous use), and complete (baseline and monthly) enzyme monitoring, based on computerized records of laboratory claims. RESULTS: Baseline testing increased from 15% before any FDA monitoring recommendations (cohort 1) to 44.6% following 4 separate FDA interventions (cohort 4; P<.001). In cohort 4, 33.4% of users had follow-up testing after 1 month of therapy, falling to 13% after 5 months of continuous use. In all cohorts, less than 5% received all recommended liver enzyme tests by the third month of continuous use. CONCLUSIONS: The FDA risk management efforts did not achieve meaningful or sustained improvement in liver enzyme testing. Evaluation of the impact of regulatory actions is needed before such actions can be regarded as effective or sufficient.

Contributions of the specialized conduction system to the activation sequence in the canine pulmonary conus.

This study was designed to characterize the relative contributions of the specialized conduction system and the myocardial architecture to the ventricular activation sequence. In animal experiments, the activation sequence within a 14 x 14-mm region on each surface of the pulmonary conus from isolated canine hearts was determined from electrograms recorded during ventricular drives applied at the periphery of the measurement region. Recordings were obtained simultaneously from electrode arrays mounted on the endocardium and epicardium. Activation sequences were determined before and after the right ventricular cavity was bathed with a dilute Lugol-normal Tyrode (LNT) solution that selectively inhibited excitation of Purkinje cells. Simulations of action potential propagation in three-dimensional models (14.4 mm long x 7.2 mm wide x 3.6 mm thick) that included the major features of the midwall architecture were performed to aid in the interpretation of the experimental findings. During endocardial pacing (7 animals, 43 total drives), LNT application markedly prolonged the endocardial (13.7 +/- 1.3 ms) and epicardial (5.7 +/- 1.0 ms) activation sequences. However, epicardial isochrone maps constructed with electrograms recorded before LNT application showed no signs of multiple breakthrough sites and, with the exception of overall timing, closely resembled isochrone maps constructed with electrograms recorded after LNT application. During epicardial pacing (9 animals, 55 total drives), LNT application prolonged the endocardial (3.7 +/- 0.6 ms) and epicardial (1.9 +/- 0.6 ms) activation sequences much less dramatically than during endocardial pacing, suggesting a primary contribution of myocardial architecture. However, in those instances where nonuniform anisotropy slowed epicardial expansion of the depolarization wavefront, the specialized conduction system contributed to the activation sequence to a greater extent.

Effects of premature beats on repolarization of postextrasystolic beats.

BACKGROUND: A short-long-short sequence of cycle lengths predisposes to reentrant tachyarrhythmias. There is limited information about the effects of premature ventricular contractions (PVCs) on repolarization of postextrasystolic depolarizations (PEDs). Such information would contribute to understanding the mechanism for facilitating reentry with short-long-short cycle lengths. METHODS AND RESULTS: We introduced PVCs, over a range of coupling intervals and during a range of basic drive cycle lengths (BCLs), and determined PED repolarization. Our results from whole-animal experiments, isolated cell studies, and computer simulations are reported. In the whole-animal experiments, PED refractory periods (RPs) were longer than RPBCL. The greatest difference between RPPED and RPBCL (delta RPmax) occurred after short coupling interval PVCs and was 4.3 +/- 0.8, 4.2 +/- 0.8, and 2.1 +/- 0.5 ms (mean +/- SEM) during drives with short, intermediate, and long BCLs, respectively. The diastolic interval preceding the PED (DIPED) was inversely related to the coupling interval between the basic drive beat and the PVC and directly related to RPPED. PED action potential durations (APDs) of isolated canine myocytes were 9.8 +/- 4.9 ms (mean +/- SEM) longer than APD BCL (n = 19). The DiFrancesco-Noble membrane equations were used in simulations of action potential propagation in a one-dimensional cable, with stimulation protocols duplicating those in the animal experiments. PVCs prolonged APDPED, and APDPED was prolonged more during short than during long BCL drives. There was a direct relation between DIPED and APDPED. Analysis of the membrane currents over the time course of the PVCs and PEDs suggested that the ionic basis for PED repolarization prolongation was the interaction of Ito and Ik. Hyperpolarizing constant-current injections introduced immediately after the spike of isolated myocyte action potentials caused APD prolongation. This observation is consistent with the Ito and Ik interaction causing PED repolarization prolongation. CONCLUSIONS: PED repolarization prolongation could provide sites for unidirectional block to propagation of PVCs after PEDs and could facilitate initiation of reentrant tachyarrhythmias after short-long-short sequences of cycle lengths.

Effects of activation sequence on the spatial distribution of repolarization properties.

The electrotonic effects of activation spread on the spatial distribution of repolarization properties were studied in animal experiments and with computer simulations. Refractory periods (RPs) were measured at 36 sites within a 1.0 cm2 region of the epicardial surface of the canine pulmonary conus during 37 drives in 11 experiments. In each experiment three or four sites along the perimeter of the region bounding the RP test sites were driven. Activation propagated uniformly during some and nonuniformly during other drives in the same animals. In general, RPs were distributed uniformly when activation spread uniformly and nonuniformly when activation spread nonuniformly. The authors observed RP differences as large as 16 ms between sites with 2 mm separation during drive from some epicardial sites in these normal canine hearts. Indices of nonuniformity of activation and of relative RP values were used to quantify the relation between nonuniformity of activation spread and the spatial distribution of the RP. There was a significant negative correlation between nonuniformity of activation and RP indices during the 19 drives in which activation spread nonuniformly. This indicated that RPs were relatively long at sites where activation spread decelerated and relatively short at sites where activation spread accelerated. When nonuniform activation spread was simulated by introducing high-resistance barriers in a model with fixed anisotropic conductivities, there were marked spatial variations in action potential duration. The spatial variations in action potential duration were negatively correlated to acceleration and deceleration of activation spread. The major new finding of this study is that the spatial distributions of RPs are markedly affected by activation spread. Since both characteristics of activation sequence and nonuniformity of RP distributions have roles in reentrant arrhythmias, the findings suggest that some sites of origin of premature activity may be more arrhythmogenic than others. The findings may also explain why ventricular tachycardia can sometimes be initiated from one but not from other sites in patients undergoing electrophysiologic testing.

Computer simulations of three-dimensional propagation in ventricular myocardium. Effects of intramural fiber rotation and inhomogeneous conductivity on epicardial activation.

Three-dimensional membrane-based simulations of action potential propagation in ventricular myocardium were performed. Specifically, the effects of the intramural rotation of the fiber axes and inhomogeneous conductivity on the timing and pattern of epicardial activation were examined. Models were built, with approximately 400,000 microscopic elements arranged in rectangular parallelepipeds in each model. Simulations used the nonlinear Ebihara and Johnson membrane equations for the fast sodium current. Constructed models had histological features of ventricular myocardium. All models were anisotropic. In a subset of the models, an abrupt intramural rotation of the fiber axes was included. This feature was also combined with randomly distributed inhomogeneous conductivity and regions of high transverse resistance to represent nonuniform anisotropy in a further subset of the models. Epicardial stimuli were applied for each simulation. Three-dimensional activation patterns and epicardial isochron maps were constructed from the simulations. We noted that the rotation of fiber axes accelerated epicardial activation distant from the stimulus site. The inhomogeneous conductivity caused regional acceleration and deceleration of activation spread. We also noted features of epicardial activation that resulted from the fiber rotation, and the inhomogeneous conductivity corresponded to that observed in maps from experimental animals.

Effects of sudden changes in cycle length and pacing site on canine cardiac surface QRST isoarea maps.

The effects of changes in paced cycle length alone and changes in both paced cycle length and site of pacing on canine cardiac surface QRST isoarea maps were studied. The correlations between QRST isoarea maps acquired during right ventricular pacing at 900 ms and 700 ms averaged 0.97. The correlations between maps acquired during RV pacing at 900 ms and 500 ms averaged 0.94. The root mean square value of QRST areas progressively decreased as cycle length was decreased from 900 ms to 700 ms and then to 500 ms. This suggests that the pattern of distribution of repolarization properties remained the same and the magnitude of difference in repolarization properties decreased as cycle length was decreased. The correlation coefficients of QRST isoarea maps acquired during RV pacing at 900 ms and those acquired during left ventricular pacing at 700 ms and 500 ms averaged 0.74 +/- 0.01 and 0.68 +/- 0.03, respectively. These correlations were lower than those associated with a change in pacing cycle length alone. Root mean square differences in QRST areas recorded during changes in both pacing site and pacing cycle length were greater than the differences associated with change in cycle length alone. This suggests that changes in activation sequence altered repolarization properties more than they were altered by changes in cycle length alone. QRST isoarea maps have been proposed for assessing arrhythmia vulnerability. The results of this study provide a framework for interpreting QRST isoarea maps acquired during supraventricular tachycardias, premature ventricular complexes, and sustained ventricular tachycardias.

Modulation of collision-induced changes in canine heart repolarization by cycle length.

The possibility that cycle length modulates the electronic effect of activation sequence on repolarization was investigated in experiments using isolated canine cardiac Purkinje strands, in situ canine ventricular myocardium, and computer simulations. Action potential durations and refractory periods during one-way propagation were compared to those obtained during action potential collision. In both the computer simulations and the Purkinje strand experiments, collision decreased action potential duration more at long cycle lengths than at short cycle lengths. Comparably, collision of activation fronts in ventricular myocardium was associated with greater reductions in refractory period during pacing at long cycle lengths than at short cycle lengths. Theoretic considerations indicate that the magnitude of electrotonic effects of activation sequence on repolarization are directly related to action potential height and the square root of membrane resistance during repolarization and are inversely related to conduction velocity. In computer simulations and Purkinje strand experiments, changes in conduction velocity and action potential height elicited by decreasing cycle length could not fully account for the cycle length dependence of collision-induced changes in repolarization. Time-varying membrane resistance of a single cell was calculated in the simulations by briefly hyperpolarizing the membrane and determining the change in total ionic current. Membrane resistance during repolarization was less at short cycle lengths than at long cycle lengths. The results suggest the cycle length dependence of collision-induced changes in repolarization results largely from the effect of cycle length on membrane resistance during action potential repolarization, with changes in action potential height and conduction velocity playing a lesser role.

Determination of transmural location of onset of activation from cardiac surface electrograms.

Methods of estimating depth of origin of ventricular activation from cardiac surface electrograms were evaluated in experiments on eight dogs. The ventricles were paced via multielectrode needle arrays placed transmurally in from four to six locations in the wall of the left ventricle. A multiplexed data-recording system was used to simultaneously record from 64 unipolar cardiac surface electrodes during pacing at each multielectrode needle site. The four indexes evaluated were the maximum and average gradients of activation isochrones around the site of earliest epicardial activation, the QRS area at the site of earliest epicardial activation, the interval between the QRS onset computed from all 64 epicardial surface electrograms, and the time of the minimum dV/dt in the electrogram displaying the earliest epicardial activation time (t(ee)-t(rmso) interval). Correlation coefficients between depth of stimulation and average and maximum gradients of isochrones, QRS area at the site of earliest epicardial activation, and t(ee)-t(rmso) interval were 0.985 or higher. These methods, particularly those involving gradients of isochrones, should be useful for evaluating electromaps of patients undergoing surgery for ablation of tachyarrhythmias.

Activation sequence at the onset of arrhythmias induced by localized myocardial warming and programmed premature stimulation in dogs.

The effect of localized shortening of ventricular repolarization on arrhythmia vulnerability was studied in 10 pentobarbital anesthetized dogs. An area of the anterior right ventricle was warmed by directing a light beam through a condenser lens assembly and a rectangular aperture. Arrhythmia vulnerability was assessed with low-amplitude programmed stimulation. Activation sequence maps were constructed from electrograms recorded simultaneously from 40 epicardial sites and 24 endocardial sites in and surrounding the warmed area. Recordings were taken during regular atrial and ventricular drives and during programmed stimulation in control periods and during myocardial warming. Spontaneous activity could not be induced with low-amplitude programmed stimulation during control periods in any dog. During myocardial warming arrhythmias were induced in every dog. Most induced arrhythmias had features consistent with local reentry. However, activation sequence at the onset of some arrhythmias strongly resembled that of superventricular activation and was consistent with reentry involving the His-Purkinje system. The findings provide evidence that a localized area with short ventricular repolarization is an abnormality sufficient to increase arrhythmia vulnerability and also that even in this relatively simple setting there can be multiple mechanisms for arrhythmias.

Relation of cardiac surface QRST distributions to ventricular fibrillation threshold in dogs.

The relation between ventricular fibrillation threshold (VFT) and cardiac surface QRST area distributions was studied in eight pentobarbital-anesthetized dogs. Unipolar epicardial electrograms were recorded from 64 sites evenly distributed on the right and left ventricles. Localized areas of short repolarization properties were produced by directing five intensities of light onto the surface of the anterior right ventricle through apertures of three sizes. VFT, measured at the center of the lesion, decreased during warming and had a high negative correlation to the change (warming-control) in QRST area (delta QRST1) in the electrogram recorded from the center of the lesion. This correlation was independent of lesion size. For the six experiments, the correlation coefficients for 400-, 800-, and 1,600-mm2 lesions averaged -0.95, -0.94, and -0.96, respectively. The correlation between VFT and delta QRST1 without regard to lesion size averaged -0.88. VFT also had a negative correlation to root mean square (RMS)delta QRST because of warming. RMS delta QRST was calculated from the change in QRST areas (warming-control) in all 64 electrograms. The correlation between VFT and RMS delta QRST was dependent on lesion size. For all experiments, the correlation between VFT and RMS delta QRST averaged -0.97, -0.93, and -0.93 for 400-, 800-, and 1,600-mm2 lesions, respectively. The correlation between VFT and RMS delta QRST without regard to lesion size, however, was considerably lower, -0.59. The results of this study provide the first direct evidence that VFT is correlated with cardiac surface QRST area distributions.

Effects of coronary occlusion on cardiac and body surface PQRST isoarea maps of dogs with abnormal activation simulating left bundle branch block.

The possibility of detecting myocardial infarction in the presence of left bundle branch block by analysis of cardiac and body surface PQRST isoarea maps was studied in nine open-chest and six closed-chest dogs. Recordings were taken during supraventricular drive or right atrial plus right ventricular pacing in control periods and at intervals for up to 10 hr after left anterior descending coronary artery occlusion. Right ventricular pacing was used to simulate left bundle branch block. Myocardial infarction was documented with triphenyl tetrazolium staining. The PQRST areas during supraventricular drive and right atrial plus right ventricular pacing were highly correlated to each other both before and after coronary occlusion. The PQRST isoarea maps after coronary occlusion showed a strong pole overlying the ischemic area on the cardiac surface in open-chest animals and over the left anterior thorax in closed-chest animals. The PQRST pole was positive during the first 1 to 2 hr of occlusion and became negative after several hours. The findings demonstrate that localized abnormalities due to ischemia and infarction are manifest in body and cardiac surface PQRST isoarea maps of both supraventricular complexes and right ventricular paced complexes. The findings suggest that PQRST isoarea maps may aid in identification and localization of ischemic or infarcted myocardium in the setting of abnormal activation such as left bundle branch block.

Nonuniform epicardial activation and repolarization properties of in vivo canine pulmonary conus.

The relation between nonuniform epicardial activation and ventricular repolarization properties was studied in 14 pentobarbital anesthetized dogs and with a computer model. In 11 dogs, isochrone maps of epicardial activation sequence were constructed from electrograms recorded from the pulmonary conus with 64 electrodes on an 8 X 8 grid with 2-mm electrode separation. The heart was paced from multiple sites on the periphery of the array. Uniformity of epicardial activation was estimated from activation times at test sites and their eight neighboring sites. Acceleration shortened and deceleration prolonged refractory periods. The locations of acceleration and deceleration sites of activation differed during drives from various sites, and differences in uniformity of activation during pairs of drives were correlated to differences in refractory periods (r = 0.76, range 0.59-0.93). In three additional experiments, transmural activation sequence maps were constructed from electrograms recorded from needle-mounted electrodes placed upstream and downstream to epicardial activation delays. Activation proceeded from epicardium to endocardium upstream to the delays and from endocardium to epicardium downstream to the delays. A computer simulation of two-dimensional action potential propagation based on the Beeler-Reuter myocardial membrane model provided insights to the mechanism for the results of the animal experiments. The two-dimensional sheet modeled the transmural anisotropic histology of the canine pulmonary conus and corresponded to previous reports and histology of specimens from five experiments. Simulated activation patterns were similar to those found in the experimental animals. In addition, action potentials were electronically prolonged at sites of deceleration and shortened at sites of acceleration, results comparable to the animal experiments. Our findings demonstrate that the location of areas of nonuniform epicardial activation is dependent on drive site and that nonuniform activation electronically modulates repolarization properties. Therefore it seems likely that the site of origin of ectopic ventricular complexes, especially in ischemic myocardium where activation is nonuniform, could be an important determinant of whether ectopic activity initiates sustained tachyarrhythmias.

Effects of cardiac sympathetic nerve stimulation on regional coronary blood flow.

The purpose of this study was to examine the effects of cardiac sympathetic nerve stimulation on regional coronary blood flow following beta-blockade. In 17 anesthetized dogs treated with propranolol (2 mg/kg iv) regional myocardial perfusion was measured (microspheres) during control and during stimulation of the ventrolateral, ventromedial, or recurrent cardiac nerve (8-10 V, 4-ms pulses at 10 Hz for 30 s). Ventrolateral nerve stimulation produced 25.5 +/- 3.4 and 23.5 +/- 3.1% (mean +/- SE) decreases in coronary blood flow in the posterior and lateral quadrants of the left ventricle. These changes were significantly greater than the 8.5 +/- 2.9, 11.5 +/- 3.0, and 3.7 +/- 2.8% decreases in the anterior and septal left ventricle and right ventricle, respectively (P less than 0.01). Ventromedial nerve stimulation produced 18.6 +/- 2.8, 15.4 +/- 2.8, and 10.1 +/- 3.2% decreases in flow in the anterior, septal, and lateral left ventricle, respectively. These changes were significantly greater than the 5.3 +/- 3.8 and 9.9 +/- 3.6% decrease in the posterior left ventricle and right ventricle (P less than 0.01). Recurrent cardiac nerve stimulation produced 16.4 +/- 2.1, 15.6 +/- 2.2, and 13.6 +/- 2.5% decreases in flow in the anterior and septal left ventricle and right ventricle, respectively. These changes were significantly greater than the 5.2 +/- 3.2 and 5.4 +/- 3.0% changes in the posterior and lateral quadrants (P less than 0.01). Ventrolateral nerve stimulation resulted in a small but significant increase in the endocardial-to-epicardial blood flow ratio in the posterolateral left ventricle.(ABSTRACT TRUNCATED AT 250 WORDS)

Determination of activation and recovery sequences and local repolarization durations from distant electrocardiographic leads.

Experiments using an isolated heart, perfused by a support dog were done to compare estimates of activation times, recovery times and activation recovery intervals from cardiac surface electrograms to estimates from distant electrocardiographic leads and to known features concerning normal activation and recovery sequences. The isolated heart was suspended in a tank with 600 electrodes located at sites 0.5 cm to 7.5 cm from the surface of the heart. In some experiments up to 330 electrodes, spaced 2.5 mm to 5 mm apart on a nylon matrix, were placed on the cardiac surface. Recordings were made during atrial and ventricular drives at cycle lengths of 400 msec to 700 msec. The minimum QRS and maximum T derivatives and the interval between them were taken as the estimates of activation times, recovery times and activation recovery intervals respectively. Maps of activation sequence, and the distribution of activation recovery intervals were constructed from cardiac surface data and from data recorded at various distances from the heart. Regions of earliest and latest activation and recovery times, range between the earliest and latest activation and recovery times and the average activation recovery interval could be determined from data recorded at distances from the heart comparable to the distance between the cardiac and thoracic surfaces. The results indicate that electrocardiographic signals, recorded with regionally sensitive distant leads, contain considerable detail concerning local activation and recovery sequences and the distribution of repolarization properties. This information should be useful in the evaluation of patients and in guiding drug therapy.

Effects of activation sequence on ventricular refractory periods of ischemic canine myocardium.

Refractory periods were measured in pentobarbital-anesthetized dogs during control periods and one to one and a half hours after distal left anterior descending coronary artery occlusion. The refractory period test site was on the anterior surface of the left ventricle in the distribution of the artery to be occluded. Measurements were made during drive of the refractory period test site, drive of a distant site on the pulmonary conus and during fusion drive in which drive of the test site was delayed with respect to drive of the pulmonary conus. Refractory periods were longer during test site drive than during pulmonary conus or fusion drives in both the control periods and following coronary occlusion. However, the effects of driving mode on refractory periods were greater following coronary occlusion than in the control periods. The findings are likely secondary to different magnitudes of change in electrotonic interactions associated with changes in activation sequence in ischemic and nonischemic myocardium. The greater dependence of repolarization properties in ischemic than nonischemic tissue suggests that inhomogeneity of these properties could be modified considerably by the site of origin of ectopic ventricular complexes.

Effects of age, sex, and body habitus on QRS and ST-T potential maps of 1100 normal subjects.

Body surface potential maps provide more detailed regional cardiac electrophysiologic information than the standard electrocardiogram. We performed a large-scale study of a normal population to form a comparison base for evaluation of the clinical utility of this technique. We analyzed body surface maps from 1113 normal subjects from 10 to 80 years old to detail map features as a function of age, sex, and body habitus. Maps were analyzed by visual inspection and by a spatial and temporal data reduction technique that allows statistical comparison of map features. On average, both QRS and ST-T potentials decreased with increasing age. Potential pattern distributions remained constant from 10 to 40 years. Beyond age 40, larger numbers of maps from normal subjects showed depolarization patterns consistent with delayed activation of the left anterior fasicle, despite normal 12-lead electrocardiograms. Only minor QRS potential amplitude and distribution differences were noted when male and female subjects were compared within groups of similar age and body habitus. Male subjects consistently showed greater average T potential amplitudes. Slender body habitus was associated with a more horizontal "zero" potential line. In female subjects over age 40 there were more extensive low-level negative potentials recorded over the precordium during the ST segment than in men. This study defines the range of normal body surface potential maps in a large clinically normal population and provides a basis for qualitative and statistical comparison with map features of patients with disease.

Effects of premature depolarization on refractoriness of ischemic canine myocardium.

In 25 pentobarbital anesthetized dogs we measured refractory periods (RPs) of regularly driven complexes and premature ventricular depolarizations (PVDs) with a range of coupling intervals or of regularly driven complexes and the complex following the PVD, i.e. the postextrasystolic depolarization (PED). Measurements were made during control periods and during occlusion of a branch of the left anterior descending coronary artery. The difference in control and occlusion RPs was less following some PVDs with short coupling intervals than following other PVDs with longer coupling intervals. Variations in the coupling interval of PVDs had less effect on RPs of the PVDs in ischemic than in nonischemic tissue. RPs of PEDs were prolonged with respect to RPs of regularly driven complexes in both ischemic and nonischemic tissue, but the prolongation in ischemic tissue was significantly greater than that in nonischemic tissue, 8 +/- 4 msec and 2 +/- 2 msec respectively, p less than .001. The difference in effect of PVDs on RPs of ischemic and nonischemic tissue results in greater disparity of refractoriness between ischemic and nonischemic tissue following some long coupling interval PVDs than following some PVDs with shorter coupling intervals. In addition the greater prolongation of RPs of PEDs in ischemic than in nonischemic tissue can result in increased disparity in RPs than the disparity between ischemic and nonischemic tissue present during regular drive.

Relation of canine atrial activation sequence to anatomic landmarks.

Activation sequence in the atria was investigated in 35 dogs. The atria were studied as four regions, and activation sequence in one region was determined in each experiment. In each region 60 electrograms were recorded simultaneously from bipolar electrodes. The maximal first derivative of the electrograms was taken as activation time. Dried atrial specimens, which permitted identification of pectinate muscles, crista terminalis, and the axis of fiber direction, were prepared. Nonuniform activation was demonstrated with more rapid conduction over the long axis of fiber direction and in Bachmann's bundle, crista terminalis, and pectinate muscles. These regions of rapid conduction were the same during sinus rhythm and ectopic and retrograde activation. Findings confirm the presence of paths with relatively rapid conduction in the atria and demonstrate that these are related to gross anatomic features. Findings also demonstrate that the paths are accessible to activation from multiple sites rather than insulated conduction paths with limited sites for entry and exit of activation.

Effects of sympathetic stimulation on refractory periods of ischemic canine ventricular myocardium.

We studied the difference in effect of sympathetic stimulation on refractory periods of ischemic and non ischemic myocardium in eight dogs, and the effect of sympathetic stimulation on dispersion of refractory periods in ischemic myocardium in seven additional dogs. In the first group of dogs, refractory periods of ischemic sites averaged 164 +/- 2.2 msec (M +/- SEM) and those at non ischemic sites averaged 193 +/- 1.8 msec. Sympathetic stimulation shortened refractory periods at non ischemic sites to an average of 183 +/- 2.0 msec and prolonged refractory periods at ischemic sites to an average of 171 +/- 2.2 msec. As a result of the different effects of sympathetic stimulation on refractory periods of ischemic and non ischemic myocardium, refractory periods between ischemic and non ischemic areas were more uniform during sympathetic stimulation than during coronary occlusion alone. In the second group of dogs in which the effects of sympathetic stimulation on dispersion of refractory periods were studied, pooled variances in refractory periods were calculated. There was no statistically significant difference in the pooled variance of refractory periods during control periods and during sympathetic stimulation alone. Coronary occlusion alone significantly increased the variance in refractory periods, but there was no statistically significant difference in the variance of refractory periods during coronary occlusion alone and during coronary occlusion and sympathetic stimulation. Our findings suggest that at some times during the course of myocardial infarction the effects of high sympathetic tone may be partially protective with respect to arrhythmias by reducing inequalities of recovery between ischemic and non ischemic tissue.