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Background The coexistence of cardiac hypertrophy (H) and ischemia (I) can create a particularly arrhythmogenic substrate. Most studies investigate the effects of global I on H. However, global I is not a good surrogate model of the clinical situation. Objective The purpose of this study was to investigate the electrophysiological effects of regional I superimposed on H using optical mapping of membrane voltage. Methods We investigated the guinea pig model of left ventricular H (LVH) induced by suprarenal banding of abdominal aorta. Twelve hearts with or without LVH were mounted in a Langendorff preparation, and regional I was induced by 20 minutes of ligation of the left anterior descending artery. Results Left ventricle epicardial action potential duration (APD) was significantly prolonged in the LVH group compared with controls. I significantly shortened APD in the I risk zone in both groups, but the percentages of APD shortening (28% vs. 40%) and the magnitudes of shortening (57 ± 18 vs. 105 ± 32 ms) were greater in the LVH group. The greater dispersion of repolarization (DR) across the border of the I zone resulted in arcs of functional conduction block and circulating wave fronts. Tachycardia-dependent APD alternans developed more often in the LVH group, and the area of alternans versus the area of the I zone was significantly larger. Ventricular tachyarrhythmias (VTs) developed in all 12 hearts with LVH including six non-self-terminating VTs, compared with four control hearts with self-terminating VT. Conclusion Regional I superimposed on LVH resulted in greater DR at the border between the I and non-I zones as well as in a greater tendency to develop APD alternans. Both arrhythmogenic mechanisms correlated with an increased incidence of VT.

Introduction: The occurrence of significant spatial dispersion of repolarization in vivo as it relates to the mechanism of arrhythmia formation in the long QT syndrome (LQTS) continues to be questioned. Methods and Results: We investigated a guinea pig model of LQT3 using anthopleurin-A (AP-A) to study the contribution of rate-dependent spatial dispersion of repolarization in the intact heart to the arrhythmogenicity of LQTS. Optical action potentials were measured using potentiometric fluorescent dye di-4ANEPPS in Langendorff-perfused hearts with induced AV block. AP-A exacerbated the normal uniform epicardial apex-base action potential duration (APD) gradient, resulting in rate-dependent increased APD dispersion and nonuniform APD gradient. Spontaneous focal premature beats induced functional conduction block along boundaries where large nonuniform APD gradient occurred setting the stage for circulating wavefronts and ventricular tachyarrhythmia (VT). Endocardial ablation abolished spontaneous VT, but nonuniform epicardial APD gradient persisted and could be challenged by a stimulated premature stimulus to induce VT. Conclusion: The study shows that in LQT3, spatial variations in steady-state properties result in zones of nonuniform APD gradients. These provide a substrate for functional conduction block and reentrant excitation when challenged by subendocardial “early afterdepolarization-triggered” premature beats. The study emphasizes the key importance of spatial dispersion of repolarization, whether located in epicardial or intramyocardial layers, in arrhythmia formation in LQTS. (J Cardiovasc Electrophysiol, Vol. 15, pp. 323-331, March 2004)

Azimilide and Dofetilide Atrial Flutter Efficacy.Introduction: Azimilide dihydrochloride blocks both the rapid (IKr) and slow (IKs) components of the delayed rectified K+ current; dofetilide blocks only IKr. Their efficacies were assessed on atrial flutter reentrant circuits in dogs with surgically induced right atrial enlargement. Methods and Results: Multiple biopsies of the tricuspid valve and banding of the pulmonary artery in male mongrel dogs made them susceptible, about 3 weeks postoperatively, to stimulation-induced sustained (5 min or longer) atrial flutter. Azimilide 3 mg/kg administered intravenously (IV) terminated flutter in 8 of 8 dogs, but a slower, nonsustained arrhythmia could be reinduced in 5. In these 5 dogs, azimilide 10 mg/kg terminated flutter and prevented reinduction. This dose increased effective refractory period significantly more in the slow conduction zone (25%) than in the normal zone (17%) and increased flutter cycle length (37%). Termination followed progressive conduction delay in the slow zone of the reentrant circuit. Dofetilide 1 μg/kg IV terminated flutter in 6 of 6 dogs, but the arrhythmia could be reinduced. At 3 μg/kg, flutter terminated in all dogs and could not be reinduced. Dofetilide also increased the effective refractory period significantly more in the slow zone (17%) than in the normal zone (12%) and increased cycle length (33%), leading to interruption of the arrhythmia circuit. Conclusion: In the canine right atrial enlargement model of circus movement atrial flutter, both azimilide 10 mg/kg IV and dofetilide 3 μg/kg IV were 100% effective in terminating flutter and preventing reinduction. Efficacy relied on a similar mechanism of differentially prolonged refractoriness in the slow conduction component of the reentrant circuit where drug-induced termination occurred.

Previous tridimensional activation mapping showed that the development of functional conduction block at the onset of torsades de pointes was regionally heterogeneous; conduction block was frequently observed in the LV and the interventricular septum (IVS) but not in the RV, in the canine anthopleurin-A (AP-A) model of long QT syndrome (LQTS). This may be related to the distribution of myocytes with M celllike electrophysiological characteristics. To better understand the regional difference of arrhythmogenicity in LQTS, the authors investigated cycle length related modulation of ventricular repolarization among three different layers: the endocardium (End), mid-myocardium (Mid), and epicardium (Epi) of the LV and RV and at two different areas: the Epi and septum (Sep) in the IVS. The LQT3 model was produced by AP-A in dogs. Using constant pacing and single premature stimulation (S1S2), the ventricular repolarization pattern was analyzed from 256 unipolar electrograms. Activation-recovery intervals (ARIs) were used to estimate local repolarization. In seven experiments, AP-A increased regional ARI dispersion to 88.1 +/- 36.0 ms in the LV, to 72.9 +/- 35.7 ms in the IVS, and to 23.0 +/- 8.7 ms in the RV at the pacing cycle length (CL) of 1,000 ms. Development of the large ARI dispersion was due to greater ARI prolongation at the Mid site in the LV and at Sep site in the IVS. As the S1S2 interval was shortened, regional ARI dispersion decreased gradually, and finally, ARI dispersion showed a reversal gradient of repolarization between the Mid and Epi sites in the LV and between the Sep and Epi sites in the IVS. Two factors contributed to create the reversal gradient of repolarization: (1) a difference in restitution kinetics at the Mid site in the LV and at the Sep site in the IVS, characterized by a larger delta ARI and slower time constant (tau), and (2) a difference in diastolic intervals at each site resulting in different input to restitution at the same CL. However, the RV showed small alteration in the transmural dispersion of repolarization in the S1S2 protocol. S2 created heterogeneous functional conduction block in the LV and IVS but not in the RV. In the LQT3 model, the arrhythmogenicity of torsades de pointes is primarily due to dispersion of repolarization in the LV and IVS because of prominent distribution of M cells. The RV seems to participate passively in reentrant excitation during torsades de pointes.

OBJECTIVES The purpose of this study was to investigate the electrophysiologic mechanism(s) that underlie the transition of one or more short–long (S-L) cardiac sequences to ventricular tachyarrhythmias (VTs) in the long QT syndrome. BACKGROUND One or more S-L cardiac cycles, usually the result of a ventricular bigeminal rhythm, frequently precedes the onset of VT in patients with either normal or prolonged QT interval. Electrophysiologic mechanisms that underlie this relationship have not been fully explained. METHODS We investigated electrophysiologic changes associated with the transition of a S-L cardiac sequence to VT in the canine anthopleurin-A model, a surrogate of LQT3. Experiments were performed on 12 mongrel puppies after administration of anthopleurin-A. Correlation of tridimensional activation and repolarization patterns was obtained from up to 384 electrograms. Activation–recovery intervals were measured from unipolar electrograms and were considered to represent local repolarization. RESULTS We analyzed 24 different episodes of a S-L sequence that preceded VT obtained from 12 experiments. The VT followed one S-L sequence (five episodes), two to five S-L sequences (12 episodes) and more than five S-L sequences (seven episodes). The single premature ventricular beats coupled to the basic beats were consistently due to a subendocardial focal activity (SFA). There were two basic mechanisms for the development of VT after one or more S-L sequences: 1) in 10 examples of a S-L sequence due to a stable unifocal bigeminal rhythm, the occurrence of a second SFA, which arose consistently from a different site, infringed on the pattern of dispersion of repolarization (DR) of the first SFA to initiate reentrant excitation; 2) in the remaining 14 episodes of a S-L sequence, a slight lengthening (50 to 150 ms) in one or more preceding cycle lengths (CLs) resulted in alterations of the spatial pattern of DR at key sites to promote reentry. The lengthening of the preceding CL produced differentially a greater degree of prolongation of repolarization at midmyocardial and endocardial sites compared with epicardial sites with consequent increase of DR. The increased DR at key adjacent sites resulted in the development of de novo zones of functional conduction block and/or slowed conduction to create the necessary prerequisites for successful reentry. CONCLUSIONS The occurrence of VT after one or more S-L cardiac sequences was due to well defined electrophysiologic changes with predictable consequences that promoted reentrant excitation.

Background Time domain analysis (TD) of the signal-averaged electrocardiogram (SAECG) presents a higher incidence of false positives in inferior myocardial infarction (MI), whereas spectral turbulence analysis (STA) suffers from a higher incidence of false positives in anterior MI. We investigated the hypothesis that a combined TD and STA (TD+STA) analysis of the SAECG could improve its predictive accuracy for major arrhythmic events (MAE) after MI. Methods Signal-averaged electrocardiograms were prospectively recorded 10.1 ± 2.6 days after acute MI in 602 patients. Time domain analysis and STA were performed using standard parameters and criteria for abnormality. For the combined TD+STA model, stepwise discriminant analysis was utilized to optimize prediction of MAE. Receiver operating characteristic curves were utilized to optimize cutoff values for each SAECG parameter separately, and also for the combined TD+STA model. Results During a one-year follow-up period, 38 patients had MAE: 14 sustained ventricular tachycardia, 2 resuscitated ventricular fibrillation and 22 sudden cardiac deaths. The total predictive accuracy of combined TD+STA (89.9%) was significantly higher than TD (75.1%) or STA (77.6%). The negative predictive accuracy of all three analyses was high (98%). The positive predictive accuracy of TD (19.6%) or STA (18.3%) was quite low, and significantly improved to 35.8% by combined TD+STA analysis. The positive predictive accuracy of TD+STA improved to 51.2% in patients with left ventricular ejection fraction Conclusions Combined TD+STA analysis of the SAECG significantly improves its prognostic ability for MAE in post-MI patients compared with TD or STA analyzed separately.

Background The long-QT syndrome (LQTS) is an electrophysiological (EP) entity characterized by prolongation of cardiac repolarization and the occurrence of polymorphic ventricular tachyarrhythmias (VTs), sometimes with a twisting QRS morphology, better known as torsade de pointes (TdP). In the present study, detailed analysis of ventricular tridimensional activation patterns during nonsustained TdP VT was performed to provide an EP mechanism of the periodic transition in QRS axis. Methods and Results The studies were conducted with the anthopleurin-A canine model of LQTS. Tridimensional isochronal maps of ventricular activation were constructed from 256 bipolar electrograms obtained from the use of 64 plunge needle electrodes. In 26 episodes of nonsustained TdP VT, detailed activation maps could be accurately constructed during QRS-axis transitions in surface ECGs. The initial beat of all VTs consistently arose as a subendocardial focal activity, whereas subsequent beats were due to reentrant excitation in the form of rotating scrolls. The VT ended when reentrant excitation was terminated. In 22 of 26 episodes, the transition in QRS axis coincided with the transient bifurcation of a predominantly single rotating scroll into two simultaneous scrolls involving both the right ventricle and left ventricle separately. The common mechanism for initiation or termination of bifurcation was the development of functional conduction block between the anterior or posterior right ventricle free wall and the ventricular septum. In 4 of 26 episodes, a fast polymorphic VT, with an apparent shift in QRS axis, was due to a predominantly single localized circuit that varied its location and orientation from beat to beat, with the majority of ventricular myocardium being activated in a centrifugal pattern. Conclusions The study provides for the first time an EP mechanism for the characteristic periodic transition of the QRS axis during TdP VT in the LQTS.

After myocardial infarction (MI), the noninfarcted myocardium undergoes significant hypertrophy as part of the post-MI structural remodeling. Electrophysiological changes associated with the hypertrophied remodeled myocardium may play a key role in arrhythmia generation in the post-MI heart. We investigated the cellular and ionic basis of arrhythmias in remodeled left ventricular (LV) myocardium 3 to 4 weeks after MI in the rat. We analyzed (1) the incidence of induced ventricular tachyarrhythmias (VTs) in the in vivo heart, (2) action potential characteristics and arrhythmia mechanisms in multicellular preparations and isolated remodeled LV myocytes, and (3) the density and kinetics of the L-type Ca 2+ current (I Ca-L ) and the fast and slow components of transient outward K + currents (I to-f and I to-s , respectively). The results were compared with those from sham-operated rats. In vivo, programmed stimulation induced sustained VT in 80% of post-MI rats but not in sham-operated rats. The capacitance of post-MI hypertrophied myocytes was significantly increased compared with myocytes from sham-operated rats. Post-MI myocytes had prolonged action potential duration (APD) with marked heterogeneity of the time course of repolarization. The prolongation of APD could be explained by the significant decrease of the density of both I to-f and I to-s . There was no change in the kinetics of both currents compared with control. Both the density and kinetics of I Ca-L were not significantly different in post-MI remodeled myocytes compared with control. The cellular studies showed that reentrant excitation secondary to dispersion of repolarization and triggered activity from both early and delayed afterdepolarizations are potential mechanisms for VT in the post-MI remodeled heart.

Background The electrophysiological mechanisms of spontaneous termination of sustained monomorphic ventricular tachycardia (SMVT), in the postinfarction heart, generally considered secondary to a reentrant mechanism, have not been fully investigated. Method and Results Epicardial activation maps of spontaneous termination of 20 different episodes of SMVT (lasting 30 seconds to 10 minutes) from 8 dogs, 4 to 5 days after one-stage ligation of the left anterior descending coronary artery, were analyzed with the use of 254 bipolar electrode recordings with high density (2.5 to 2.8 mm between bipolar electrodes) in the ischemic zone. All ventricular tachycardias (VTs) were due to circus movement reentry with a characteristic figure-8 configuration. Termination always occurred when the two circulating wave fronts blocked in the central common pathway (CCP). Two basic mechanisms of spontaneous termination were observed: (1) In 15 episodes, acceleration of conduction occurred in parts of the reentrant circuit and was associated with slowing of conduction and finally conduction block in the CCP. Acceleration of conduction occurred in the last few cycles of VT both at the outer border of the arcs of functional conduction block in the “normal” myocardial zone and at the pivot points to the entrance to the CCP. When acceleration of conduction was compensated on a beat-to-beat basis by an equal degree of slowing in the CCP, there was no discernible change in the cycle length of the VT in the ECG. In some episodes, the termination of the original reentrant circuit was followed by the development of a different, slower reentrant pathway that lasted for one or a few cycles prior to termination. (2) In 5 VT episodes, the activation wave front in the CCP abruptly broke across a stable arc of functional conduction block, resulting in premature activation of the CCP and conduction block. Conclusions Distinct electrophysiological changes always preceded spontaneous termination of stable SMVT. The electrophysiological basis for acceleration of conduction in parts of the reentrant circuit during the last few beats prior to termination and of the abrupt reactivation across a stable arc of block remains to be determined.

The aim of this prospective study was to compare the short-term reproducibility of the signal-averaged ECG (SAECG) with three analysis techniques, conventional time-domain analysis, spectral-temporal mapping (STM), and spectral-turbulence analysis (STA), in a large series of normal subjects and patients with acute myocardial infarction (AMI). Two consecutive SAECGs were recorded in 225 consecutive patients 10.2 ± 2.7 days after AMI and in 85 healthy volunteers. The visual, diagnostic, and quantitative reproducibility of the three techniques was compared. Time-domain analysis was the most reproducible method, having high R 2 correlations, statistically fewer inconsistent diagnostic recordings, and statistically smaller differences compared with other techniques. STM was the least reproducible, justifying caution in its current form. Although STA was significantly less reproducible than time-domain analysis, it was also significantly better than STM. Two STA parameters, spectral entropy and interslice correlation mean, showed good reproducibility, suggesting that modification of this analysis technique could be useful in risk stratification.

Objectives. This study investigated prediction of arrhythmic events by the signal-averaged electrocardiogram (ECG) and programmed stimulation in patients with nonischemic dilated cardiomyopathy.Background. Risk stratification in patients with nonischemic dilated cardiomyopathy remains controversial.Methods. Eighty patients with nonischemic dilated cardiomyopathy and spontaneous nonsustained ventricular tachycardia underwent signal-averaged electrocardiography (both time-domain and spectral turbulence analysis) and programmed stimulation. All patients were followed up for a mean of 22 ± 26 months.Results. Sustained monomorphic ventricular tachycardia was induced in 10 patients (13%), who all received amiodarone. The remaining 70 patients were followed up without antiarrhythmic therapy. Of the 80 patients, 15% had abnormal findings on the time-domain signal-averaged ECG, and 39% had abnormal findings on spectral turbulence analysis. Time-domain signal-averaged electrocardiography had a better predictive accuracy for induced ventricular tachycardia than spectral turbulence analysis (88% vs. 66%, p < 0.01). During follow-up, there were 9 arrhythmic events (5 sudden deaths, 4 spontaneous ventricular tachycardia/fibrillation) and 10 nonsudden cardiac deaths. Cox regression analysis showed that no variables predicted arrhythmic events or total cardiac deaths. The 2-year actuarial survival free of arrhythmic events was similar in patients with or without abnormal findings on the signal-averaged ECG or induced ventricular tachycardia.Conclusions. In patients with nonischemic dilated cardiomyopathy, 1) there is a strong correlation between abnormal findings on the time-domain signal-averaged ECG and induced ventricular tachycardia, but both findings are uncommon; and 2) normal findings on the signal-averaged ECG, as well as failure to induce ventricular tachycardia, do not imply a benign outcome.

The value of time-domain and spectral turbulence analyses of the signal-averaged electrocardiogram (SAECG) for predicting induction of sustained monomorphic ventricular tachycardia (VT) was prospectively investigated in 70 patients with idiopathic dilated cardiomyopathy. Sustained VT was induced in 9 patients (13%). The prevalence of abnormal time-domain and spectral analyses was 16 and 37%, respectively. The total predictive accuracy of time-domain and spectral analyses for VT induction was 86 and 67%, respectively (p0.01). The predictive accuracy of time-domain and spectral analysis was similar in patients without an intraventricular conduction defect (94 and 84%, respectively). However, the predictive accuracy of time-domain was higher than that of spectral analysis in patients with an intraventricular conduction defect (65 vs 25%; p0.05). The poor concordance between spectral analysis and programmed stimulation results was mainly due to the high number of false-positive recordings in the presence of an intraventricular conduction defect (9 of 20 cases). With the use of stepwise discriminant function analysis, an abnormal time-domain SAECG was the only variable predicting the induction of sustained VT (p0.0003). In dilated cardiomyopathy, an abnormal time-domain SAECG and induced sustained VT are rare, both time-domain signal-averaged electrocardiography and spectral analysis have a high predictive accuracy for VT induction in patients without an intraventricular conduction defect, and spectral analysis does not improve VT prediction in those with a conduction defect.

The value of time-domain and frequency-domain (spectral turbulence) analyses of the signal-averaged electrocardiogram was investigated to predict induced sustained monomorphic ventricular tachycardia (VT). Two groups of patients with spontaneous nonsustained VT and left ventricular ejection fraction less than 50% were enrolled: 70 patients with idiopathic dilated cardiomyopathy (group 1) and 70 patients with ischemic heart disease (group 2). Sustained VT was induced in 9 cases (13%) in group 1 and 16 (23%) in group 2. The prevalence of abnormal time-domain and spectral turbulence analysis was 16 and 37%, respectively, in group 1 and 27 and 51%, respectively, in group 2 (NS). In group 1, the predictive accuracy of time-domain and spectral turbulence analysis for induced VT was 86 and 67%, respectively (P < .01). In group 2, the predictive accuracy of the two techniques for induced VT was, respectively, 79 and 66% (NS). In both groups, the predictive accuracy of time-domain analysis was higher than that of spectral turbulence analysis in patients with intraventricular conduction defect (IVCD): 65 versus 25%, respectively, in group 1 (P < .01), and 81 versus 44%, respectively, in group 2 (P < .05). However, the predictive accuracy of time-domain and spectral analyses was similar in patients without IVCD: 94 versus 84%, respectively, in group 1, and 77 versus 74%, respectively, in group 2. Thus, in patients with dilated cardiomyopathy, (1) the etiology does not affect the predictive accuracy of time and frequency domain and frequency-domain analyses have high predictive accuracy in patients without IVCD; and (3) spectral turbulence analysis does not improve VT prediction in patients with IVCD.

The predictive accuracy of time-domain (TD) late potential analysis of the signal-averaged electrocardiogram in postmyocardial infarction (MI) is limited by the high incidence of false positives in inferior MI. However, frequency-domain spectral turbulence (ST) analysis suffers from a high incidence of false positives, especially in anterior MI. A prospective study was conducted of 262 patients with acute MI to investigate the hypothesis that combined TD and ST analyses of the signal-averaged electrocardiogram could improve its predictive accuracy for serious arrhythmic events in the post-MI period. Abnormal TD criteria were RMS40 less than 25 μ V at 25 Hz plus RMS40 less than 16 μ V at 40 Hz, and abnormal ST criteria were a turbulence score of 3 or 4. Seventeen patients had arrhythmic events during 10.5 ± 2.4 months of follow-up evaluation (13 sudden cardiac death judged to be due to arrhythmia and 4 nonfatal sustained ventricular tachycardia). The total predictive accuracy of combined TD and ST (92%) was higher than TD (87%), whereas ST had the lowest total predictive accuracy of 78%. The negative predictive accuracy of all three analyses was high (96–97%). However, the positive predictive accuracy of TD (28%) was higher than ST (14%). Combined TD and ST significantly improved the positive predictive accuracy of the test to 35% in the total group and to 40% in patients with first anterior or inferior MI. The best results were obtained in patients with first anterior MI, where the positive predictive accuracy of combined analysis was 50%.

This study was designed to assess the accuracy of a new noninvasive frequency analysis method for predicting patients with inducible sustained monomorphic ventricular tachycardia (VT) at electrophysiologic study and hence the risk of spontaneous ventricular tachyarrhythmias. Signal-averaged electrocardiograms from 3 orthogonal bipolar surface leads were evaluated using a microcomputer-based frequency analysis system that performs analysis of conventional time-domain late potentials as well as incorporating a new technique for spectral analysis of relatively short, overlapping signal segments spanning the whole QRS complex. The spectral analysis technique measured abnormalities anywhere in the entire QRS complex and did so without dependence on any arbitrarily defined frequency, duration or amplitude cutoffs. The hallmark of arrhythmogenic abnormality was hypothesized to be frequent and abrupt changes in the frequency signature of the QRS wave front velocity as it propagates throughout the ventricle around areas of abnormal conduction, resulting in a high degree of spectral turbulence. One-hundred forty-two subjects were studied, including 71 totally normal control subjects ("true negatives"), 33 with both late potentials by time-domain analysis and inducible sustained monomorphic VT ("true positives"), 28 with late potentials but no evidence of spontaneous or inducible sustained monomorphic VT ("false positives") and 10 with inducible sustained monomorphic VT but absence of time-domain late potentials ("false negatives"). The frequency analysis technique correctly classified 100% of the true negatives, 97% of the true positives, 86% of the late potentials false positives and 60% of the late potentials false negatives. The total predictive accuracy of frequency analysis for all groups was 94%, compared with 73% for time-domain late potential analysis. The results suggest that a high degree of spectral turbulence of the overall QRS signal during sinus rhythm may provide a more accurate marker for the anatomic-electrophysiologic substrate of reentrant tachyarrhythmias than detection of late potentials in the terminal QRS region by either time- or frequency-domain analysis. Spectral turbulence analysis is applicable to patients irrespective of the QRS duration and the presence or absence of bundle branch block.

The effects of exercise on the signal-averaged electrocardiogram (SAECG) were investigated in 52 patients with stable coronary artery disease. The SAECG was recorded before and immediately after the exercise test and analyzed at 25 to 250 Hz and 40 to 250 Hz. All patients had SAECG with noise level less than or equal 0.8 microV at 25 Hz and less than or equal to 0.6 microV at 40 Hz and with the difference in noise level between control SAECGs and SAECGs after exercise less than or equal to 0.2 to 0.3 microV. Twenty-eight patients developed ST changes consistent with transient subendocardial ischemia that persisted during the SAECG recording after exercise. There was no significant difference between control SAECGs and SAECGs after exercise in patients with or without a positive exercise test. The absence of significant change on the SAECG was not related to the presence or absence of prior myocardial infarction, site of infarction, development of exercise-induced ventricular arrhythmias or presence of an abnormal recording at baseline. These data suggest that exercise-induced electrophysiologic changes and ventricular arrhythmias may not be related to the anatomic-electrophysiologic substrate that underlies late potentials on the SAECG.

Objectives: This study was conducted to determine the optimal target heart rate (HR) for the use of exercise‐induced T‐wave alternans (TWA) as an index for risk of malignant ventricular tachyarrhythmias. Background: Rate‐dependent TWA is an index of vulnerability to ventricular tachyarrhythmias. However, false positive TWA was reported to occur in normal subjects at high HR. Methods: Two groups were evaluated: Group I: 50 patients with malignant ventricular tachyarrhythmias, who received an implantable cardioverter‐defibrillator (ICD); and Group II: 55 agematched normal subjects. In both Groups, TWA was evaluated during symptom‐limited bicycle exercise test. Results: Peak HR during exercise test was 103 ± 17 beats/min in Group I, versus 124 ± 18 beats/min in Group II (P < 0.001). In Group I, 4 patients were excluded from analysis, due to high noise level or frequent ectopy during exercise. Out of the remaining 46 patients, TWA was present in 28 patients (61%), and absent in 18 (39%). In group II, TWA was present in four subjects (7%), and absent in 51 (93%). HR at the onset of TWA was 91 ± 11/min in Group I, and 119 ± 12/min in Group II (P < 0.001). Receiver operated characteristics curves demonstrated that a HR of 115 beats/min was the cutoff with the best sensitivity and specificity for TWA (100 and 96%, respectively). None of the patients in Group I developed TWA at HR > 115 beats/min, while two out of four in Group II had TWA at HR > 115/minutes. However, 13 patients in Group I who had no TWA were unable to exercise to a peak HR > 115 beats/min, compared to nine subjects in Group II. Conclusions: A target HR of 115 beats/min was highly sensitive and specific for determination of exercise‐induced TWA as an index of risk of malignant ventricular tachyarrhythmias. However, a significant number of patients may not be able to achieve this target HR, resulting in an indeterminate test. The value of pharmacologic testing in this group should be assessed. A.N.E. 2001;6(2):123–128

Because time-domain (TD) analysis of the signal-averaged ECG (SAECG) has some limitations that limit its use, several frequency-domain analysis techniques were developed in an attempt to improve the diagnostic ability of the SAECG. However, it is not known how reliable these techniques are at detecting late potentials. This prospective study compares the short-term reproducibility of 4 analysis techniques: TD analysis, spectral temporal mapping (STM), spectral turbulence analysis (STA), and acceleration spectrum analysis (ASA), in a large series of normal patients and post-myocardial infarction (MI) patients. Two consecutive SAECGs were recorded in 634 patients that were divided into 3 groups: 117 remote MI patients undergoing programmed electrical stimulation for the inducibility of ventricular tachycardia (Group 1), 407 consecutive acute MI survivors (Group 2), and in 110 healthy volunteers (Group 3). The diagnostic reproducibility of the 4 techniques was evaluated by comparing rates of inconsistent results (1 normal and the other abnormal). The numeric reproducibility for each technique was assessed by comparing the normalized differences of each single SAECG parameter between the 2 recordings. Inconsistent results of diagnostic reproducibility were observed in 4.1%, 6.9%, 9.8%, and 18.0%, with TD, STA, ASA, and STM, respectively. Comparisons of these rates were significantly different (P < .05) except between STA and ASA (P = .07). The numeric reproducibility was highest for TD parameters, lowest for STM factors of normality, and intermediate for STA and ASA indices. TD analysis remains the most reproducible SAECG analysis technique, whereas STM showed the worst reproducibility, which limits its clinical applicability. STA and ASA provide an acceptable intermediate reproducibility, the former being slightly, although not significantly, more reproducible than the latter.

Abstract —Tachycardia-dependent QT/T alternans occurs in patients with the congenital or idiopathic form of long-QT syndrome (LQTS) and may presage the onset of polymorphic ventricular tachyarrhythmias. To examine the electrophysiological basis of arrhythmogenicity of QT/T alternans in LQTS, the tridimensional repolarization pattern of QT/T alternans was studied in the anthopleurin-A model of LQTS, a surrogate for LQT3. In 11 anesthetized mongrel puppies, tridimensional repolarization and activation patterns were analyzed from 256 to 384 unipolar electrograms. Cardiac repolarization was evaluated as the activation-recovery interval (ARI) of local electrograms. To induce QT/T alternans, the pacing cycle length (CL) was abruptly shortened in steps of 50 ms from a basic drive of 1000 ms. ARIs were calculated at epicardial (Epi), midmyocardial (Mid), and endocardial (End) sites. ARI restitution at each site was assessed by using a single premature stimulation delivered after the basic drive. ARI alternans occurred at longer CLs at Mid sites compared with End and Epi sites, and the magnitude of alternans at Mid sites was greater. Two factors contributed to the modulation of ARI during QT/T alternans: (1) differences in restitution kinetics at Mid sites, characterized by larger ΔARI and a slower time constant (τ), and (2) differences in diastolic intervals resulting in different input to restitution at the same constant CL. These 2 factors could explain not only the onset of alternans at Mid sites at longer CLs but also the critical observation that ARI dispersion between Epi and Mid sites during alternans was greater than during the slower basic CL. Marked ARI alternans could be present in local electrograms without manifest alternation of the QT/T segment in the surface ECG. The latter was seen at critically short CLs associated with reversal of the gradient of ARI between Epi and Mid sites, with a consequent reversal of polarity of the intramyocardial QT wave in alternate cycles. The arrhythmogenicity of QT/T alternans was primarily due to the greater degree of spatial dispersion of repolarization during alternans than during slower rates not associated with alternans. This could result in functional conduction block and reentrant ventricular tachyarrhythmias during the fixed drive associated with alternans.

The actions of lidocaine were studied in 18 dogs, 4 days after ligation of the left anterior descending artery, by computerized mapping. Lidocaine only occasionally suppressed the induction of reentry. At fast heart rates, lidocaine actually facilitated the induction of reentry. The effects on conduction and refractoriness of normal and ischemic myocardium were measured using high-resolution techniques. Lidocaine promoted reentry by a rate-dependent increase in refractory gradient, resulting in additional block, and a selective decrease in conduction velocity in ischemic tissue, resulting in additional conduction delay. Lidocaine could prevent reentry through a rate-independent differential increase in refractory period gradient at the entrance to the common pathway of the circuit, causing block of the reentrant impulse. We conclude that the proarrhythmic effect of lidocaine is due to increased conduction delay and block while the antiarrhythmic effect is due to block of the reentrant impulse by prolonged refractoriness in the common pathway.

We have previously developed a canine in vivo model of the long QT syndrome (LQTS) using the neurotoxin anthopleurin A (AP-A), which acts by slowing sodium channel inactivation. The recent discovery of a genetic mutation in the cardiac sodium channel in some patients with the congenital LQTS, resulting in abnormal gating behavior similar to sodium channels exposed to AP-A, provides a strong endorsement of this animal model as a valid surrogate to the clinical syndrome of LQTS. In the present study, we conducted high-resolution tridimensional isochronal mapping of both activation and repolarization patterns in puppies exposed to AP-A that developed LQTS and polymorphic ventricular tachyarrhythmias (VTs). To map repolarization, we measured activation-recovery intervals (ARIs) using multiple unipolar extracellular electrograms. We demonstrated, for the first time in vivo, the existence of spatial dispersion of repolarization in the ventricular wall and differences in regional recovery in response to cycle-length changes that were markedly exaggerated after AP-A administration. Analysis of tridimensional activation patterns showed that the initial beat of polymorphic VT consistently arose as focal activity from a subendocardial site, whereas subsequent beats were due to successive subendocardial focal activity, reentrant excitation, or a combination of both mechanisms. Reentrant excitation was due to infringement of a focal activity on the spatial dispersion of repolarization, resulting in functional conduction block and circulating wave fronts. The polymorphic QRS configuration of VT in the LQTS was due to either changing the site of origin of focal activity, resulting in varying activation patterns, or varying orientations of circulating wave fronts.

Azimilide and Atrial Flutter. Introduction: The effects of a Class III agent, azimilide di-hydrochloride, on atrial flutter circuits were studied in a functional model of single loop reentrant atrial flutter using dogs, 3 to 5 days after production of sterile pericarditis. Methods and Results: A computerized mapping system was used to construct activation maps from 138 to 222 epicardial sites in the right atrium. Doses of 3, 10, and 30 mg/kg IV azimilide dihydrochloride were analyzed in 8 dogs in which sustained atrial flutter lasting more than 30 minutes was induced by burst pacing. Atrial flutter was always due to a single loop circus movement reentry in the lower right atrium. At 3 mg/kg, azimilide dihydrochloride terminated atrial flutter in 2 dogs; however, atrial flutter was reinduced. At 10 mg/kg, atrial flutter was terminated in all 8 dogs but was reinduced in 4 dogs with slower rate. At 30 mg/kg, atrial flutter was terminated in the remaining 4 dogs and could not be reinduced. Atrial flutter cycle length always increased prior to termination. Isochronal activation maps showed that the increase in cycle length was due to additional conduction delays in the slow zone of the reentrant circuit. The site of termination was always located within the slow conduction zone situated in the lower right atrium between the line of functional conduction block and the AV ring. effective refractory periods (ERPs) were measured at selected sites in the slow zone and normal zone at twice diastolic threshold for the 10 mg/kg dose. Azimilide preferentially prolonged ERP in the slow zone (42.4 ± 20.l msec, mean ± SD) compared with (he normal zone (23.3 ± 15.4 msec, P < 0.0001). The increase in cycle length corresponded with the increase in ERP in the slow zone. Conclusions: In a functional model of circus movement atrial flutter, azimilide dihydrochloride terminates and prevents reinduction of atrial flutter by a preferential increase in refractoriness leading to further conduction delay and conduction block in the slow zone of the functional reentrant circuit.

Background The Cardiac Arrhythmia Suppression Trial has shown that flecainide was associated with an increased incidence of sudden cardiac death in postinfarction patients. The exact mechanism(s) of the proarrhythmic effects of flecainide remain unclear. We performed a detailed analysis of the electrophysiological and proarrhythmic effects of flecainide in a well-characterized model of reentrant arrhythmias in the subacute phase of myocardial infarction. Methods and Results Sixteen dogs were studied 4 days after ligation of the left anterior descending coronary artery. Isochronal mapping of ventricular activation showed that flecainide facilitated both the induction and sustenance of ventricular tachycardia, especially at shorter basic cycle lengths. Flecainide had negligible effect on the length of the arc of functional conduction block but markedly depressed conduction of the common reentrant wave front that was usually oriented parallel to fiber axis. Whole heart mapping was analyzed in combination with basic measurements of the effects of flecainide on conduction and refractory properties of both normal and ischemic myocardia using a high-resolution cross electrode consisting of four orthogonal arms, each comprised of 16 poles with an interelectrode spacing of 500 μm. The electrode was especially designed to study the effects of the drug on anisotropic conduction as determined by a linear regression of activation time and distance in each direction. Flecainide resulted preferentially in more marked rate-dependent depression of conduction in ischemic compared with normal myocardium. On the other hand, the effect of flecainide on refractoriness in both normal and ischemic myocardia was negligible. Conclusions Because flecainide caused no significant change in refractoriness in both normal and ischemic myocardia, there was no difference in the dimension of the potential reentrant pathway, that is, the continuous line of functional conduction block, around which the reentrant wave fronts circulate. Yet, flecainide resulted in significant rate-dependent slowing of conduction preferentially in ischemic myocardium. The additional slowing of conduction of the common reentrant wave front coupled with minimal changes in the length of the reentrant pathway allowed additional time for the wave front to reexcite normal myocardium on the proximal side of the arc of block. After flecainide, reentry could be induced in hearts in which reentry could not be induced during control. The same proarrhythmic mechanism explains the propensity of nonsustained figure-8 reentrant tachycardias to become sustained after flecainide.

The effects of transient myocardial ischemia on the signal-averaged electrocardiogram were investigated in 13 patients with coronary artery disease and spontaneous angina undergoing 3-channel ambulatory electrocardiography. Ischemia was seen as ST elevation in 2 patients or ST depression in 11; it was anterior in 5 patients, inferior in 4 and undefined in 4. Signal-averaged electrocardiograms with noise levels less than or equal to 1 microV were obtained from Holter tapes during 54 of 61 ischemic attacks recorded in the study group (88%), and compared with 54 tracings recorded within 60 minutes of the index attacks. Baseline tracings were normal in 8 patients (62%), showed a long QRS duration in 2 (15%), and both a long QRS duration and a late potential in the remaining 3 (23%). Comparison of recordings at baseline and during ischemic attacks revealed no significant changes in signal-averaged electrocardiographic parameters. Absence of significant differences was also noted when analysis was performed according to the type of ischemic attacks (associated with ST elevation [n = 14] or ST depression [n = 40]), their location (anterior [n = 21] or inferior [n = 23]), their duration (greater than 10 minutes [n = 29] or less than or equal to 10 minutes [n = 25]), and their magnitude (greater than 2 mm [n = 18] or less than or equal to 2 mm [n = 36]). It is concluded that spontaneous transient myocardial ischemia, independent of its type, location, duration and magnitude, does not generate a substrate for late potentials on the signal-averaged electrocardiogram.

The presence of late potentials on the body surface recording was correlated with ventricular activation maps of reentrant circuits in the postinfarction canine model of reentrant excitation. Late potentials were found to correlate with delayed myocardial activation. However, during a reentrant rhythm complete diastolic activity on the body surface could not be detected if the mass of electrically active cells was too small and/or if very slow conduction in part of the reentrant circuit generated low amplitude extracellular potentials. Myocardial zones responsible for late potentials during a basic rhythm (e.g., sinus rhythm) may not necessarily be part of the critical zone of slow conduction during reentrant activation. Dynamic changes in late potentials are not amenable to temporal signal averaging techniques but could be detected by a high resolution beat-to-beat recording. A thorough understanding of the electrophysiological limitations of late potentials in the signal-averaged ECG could result in better utilization of the technique in clinical practice as well as in the development of new approaches for the detection of the arrhythmogenic substrate.

Serial recordings of the signal-averaged ECG and the 24-hour ambulatory ECG were obtained from 156 patients with acute myocardial infarction up to 5 days (phase 1), 6 to 30 days (phase 2), and 31 to 60 days (phase 3) after the infarction. Left ventricular ejection fraction by radionuclide ventriculography was also determined in phase 2. The signal-averaged ECG was abnormal during one or more of the three phases in 51 patients (31%). In 35 of these patients (69%) the recording changed category between normal and abnormal with the highest prevalence of abnormal recording occurring during phase 2. Eight patients had ventricular tachycardia/ventricular fibrillation in the first 48 hours after myocardial infarction. The signal-averaged ECG was abnormal in only one of these patients. Twelve patients had late arrhythmic events during the first year of follow-up (four sudden deaths and eight instances of documented ventricular tachycardia or ventricular fibrillation). Nine of the 12 patients had an abnormal signal-averaged ECG in phase 2 and four of these nine had a normal recording in phase 1. Five patients had a transient abnormal signal-averaged ECG in phase 1, whereas six patients had an abnormal recording only in phase 3. None of these 11 patients had an arrhythmic event. Stepwise logistic regression showed that an abnormal signal-averaged ECG in phase 2 has the most significant relation to late arrhythmic events. Both an abnormal signal-averaged ECG and a left ventricular ejection fraction less than 40%, but not complex ventricular arrhythmias, were independent significant risk factors for late arrhythmic events.(ABSTRACT TRUNCATED AT 250 WORDS)

A prospective assessment of several clinical variables, left ventricular function indexes, Holter recording characteristics and signal-averaged electrocardiogram (ECG) for their value in predicting the inducibility of sustained ventricular tachyarrhythmias was carried out in a consecutive series of 105 patients with nonsustained ventricular tachycardia (VT). The patients were divided into 3 groups based on the results of programmed electrical stimulation: group 1, 22 patients with induced sustained monomorphic VT; group 2, 14 patients with induced ventricular fibrillation (VF) and group 3, 69 patients with no induced sustained VT/VF. Left ventricular ejection fraction less than 0.40, history of syncope/presyncope and abnormal signal-averaged ECG were significantly more common in group 1 than in group 3. No significant difference was found between groups 2 and 3. The sensitivity, specificity and predictive accuracy of the signal-averaged ECG for the induction of sustained monomorphic VT were 64, 89 and 84%, respectively. Using stepwise discriminant function analysis, the signal-averaged ECG was found to be the single most accurate screening test to predict the inducibility of sustained VT in patients with nonsustained VT and its value was independent of the etiology of heart disease and the length of spontaneous runs. Because of the very high specificity and negative predictive accuracy, patients with normal signal-averaged ECGs may not require invasive evaluation.

The incidence and time course of complex ventricular arrhythmias and of the abnormal signal averaged electrocardiogram were studied prospectively in 90 patients in the first two months after acute myocardial infarction. Serial recordings of both 24 hour ambulatory and signal averaged electrocardiograms were obtained 0-5 days (phase 1), 6-30 days (phase 2), and 31-60 days (phase 3) after infarction. A total of 264 ambulatory electrocardiograms and 264 signal averaged electrocardiograms were available for analysis. Complex ventricular arrhythmias were seen in 31%, 17%, and 38% of patients during phases 1, 2, and 3 respectively, and abnormal signal averaged electrocardiogram in 13%, 24%, and 16%. The incidence of complex ventricular arrhythmias was not significantly different in patients with or without an abnormal signal averaged electrocardiogram in the entire study period nor in any of the three phases after infarction. During phase 2 when abnormal signal averaged electrocardiograms were most common complex ventricular arrhythmias were least common. This lack of correlation suggests that the abnormal signal averaged electrocardiogram and complex ventricular arrhythmias after infarction have different electrophysiological bases.

Normal values for the signal-averaged electrocardiogram (SAECG) at 11 different high-pass filter settings were obtained from 100 normal subjects (group I). The filtered QRS duration and the duration of low amplitude signals less than 40 microV, but not the root mean square voltage of the last 40 ms (RMS40), showed normal distribution. A normal distribution for RMS40 could be obtained by transforming each value to its natural logarithm. The normal values were used in a systematic approach to optimize the accuracy of the SAECG to predict the results of programmed stimulation in 80 patients with spontaneous nonsustained ventricular tachycardia (VT). Fifty-two patients with no inducible VT (group II) and 28 patients with inducible sustained monomorphic VT (group III) were investigated. The 3 SAECG parameters at each high-pass filter in groups II and III were categorized as normal or abnormal and were evaluated singly or in combinations of 2 or 3. There was no combination that provided a sensitivity greater than 82% that could also be obtained by single determinations of low amplitude signals less than 40 microV at 25 to 40 Hz or RMS40 at 40 Hz. On the other hand, there were 267 different combinations that provided a maximal specificity of 98%. The best total predictive accuracy of a single parameter was 85%, provided by RMS40 at 40 or 60 Hz. The total predictive accuracy could be improved to 89% by 1 of 32 different combinations. The top combinations were mostly in triplets and included SAECG parameters recorded at different high-pass filter settings. The only 2 paired combinations with the best total predictive accuracy were RMS40 at 20 or 25 Hz paired with RMS40 at 40 Hz. Frequencies at both ends of the analyzed high-pass filter settings (less than 20 Hz and greater than 60 Hz) were not represented in the top predictive combinations. The SAECG parameters analyzed at 40 Hz were most frequently represented in the top predictive combinations, suggesting that the SAECG may have the best predictive accuracy at this filter setting. In summary, the combination of SAECG parameters analyzed at different filter settings can enhance the accuracy of the technique as a screening test for the results of programmed stimulation in patients with spontaneous nonsustained VT.