Diminished basal phosphorylation level of phospholamban in the postinfarction remodeled rat ventricle: role of beta-adrenergic pathway, G(i) protein, phosphodiesterase, and phosphatases.

Three weeks after myocardial infarction (MI) in the rat, remodeled hypertrophy of noninfarcted myocardium is at its maximum and the heart is in a compensated stage with no evidence of heart failure. Our hemodynamic measurements at this stage showed a slight but insignificant decrease of +dP/dt but a significantly higher left ventricular end-diastolic pressure. To investigate the basis of the diastolic dysfunction, we explored possible defects in the beta-adrenergic receptor-G(s/i) protein-adenylyl cyclase-cAMP-protein kinase A-phosphatase pathway, as well as molecular or functional alterations of sarcoplasmic reticulum Ca(2+)-ATPase and phospholamban (PLB). We found no significant difference in both mRNA and protein levels of sarcoplasmic reticulum Ca(2+)-ATPase and PLB in post-MI left ventricle compared with control. However, the basal levels of both the protein kinase A-phosphorylated site (Ser16) of PLB (p16-PLB) and the calcium/calmodulin-dependent protein kinase-phosphorylated site (Thr17) of PLB (p17-PLB) were decreased by 76% and 51% in post-MI myocytes (P<0.05), respectively. No change was found in the beta-adrenoceptor density, G(salpha) protein level, or adenylyl cyclase activity. Inhibition of phosphodiesterase and G(i) protein by Ro-20-1724 and pertussis toxin, respectively, did not correct the decreased p16-PLB or p17-PLB levels. Stimulation of beta-adrenoceptor or adenylyl cyclase increased both p16-PLB and p17-PLB in post-MI myocytes to the same levels as in sham myocytes, suggesting that decreased p16-PLB and p17-PLB in post-MI myocytes is not due to a decrease in the generation of p16-PLB or p17-PLB. We found that type 1 phosphatase activity was increased by 32% (P<0.05) with no change in phosphatase 2A activity. Okadaic acid, a protein phosphatase inhibitor, significantly increased p16-PLB and p17-PLB levels in post-MI myocytes and partially corrected the prolonged relaxation of the [Ca(2+)](i) transient. In summary, prolonged relaxation of post-MI remodeled myocardium could be explained, in part, by altered basal levels of p16-PLB and p17-PLB caused by increased protein phosphatase 1 activity.

Electrocardiographic abnormalities in a murine model injected with IgG from mothers of children with congenital heart block.

BACKGROUND: It is a widely held view that congenital heart block (CHB) is caused by the transplacental transfer of maternal autoantibodies (anti-SSA/Ro and/or anti-SSB/La) into the fetal circulation. To test this hypothesis and to reproduce human CHB, an experimental mouse model (BALB/c) was developed by passive transfer of human autoantibodies into pregnant mice. METHODS AND RESULTS: Timed pregnant mice (n=54) were injected with a single intravenous bolus of purified IgG containing human anti-SSA/Ro and anti-SSB/La antibodies from mothers of children with CHB. To parallel the "window period" of susceptibility to CHB in humans, 3 groups of mice were used: 8, 11, and 16 days of gestation. Within each group, we tested 10, 25, 50, and 100 microg of IgG. At delivery, ECGs were recorded and analyzed for conduction abnormalities. Bradycardia and PR interval were significantly increased in 8-, 11-, and 16-day gestational groups when compared with controls (P<0.05). QRS duration was not significantly different between all groups. Antibody levels measured by ELISA in both mothers and their offspring confirmed the transplacental transfer of the human antibodies to the pups. CONCLUSIONS: The passive transfer model demonstrated bradycardia, first-degree but not complete atrioventricular block in pups. The greater percentage and degree of bradycardia and PR prolongation in the 11-day mouse group correlates with the "window period" of susceptibility observed in humans. The high incidence of bradycardia suggests possible sinoatrial node involvement. All together, these data provide relevant insights into the pathogenesis of CHB.

Effects of clofilium on ischemic subendocardial Purkinje fibers 1 day postinfarction.

One day after ligation of the canine anterior descending coronary artery, clofilium, a long-acting class III antiarrhythmic agent, was studied for its effects on normal and ischemic Purkinje fibers. In normal Tyrode's solution (4 mM potassium, 2.7 mM calcium) clofilium (10(-7) to 10(-5) M) increased action potential duration. Although only 2 of 10 normal Purkinje fibers developed early after depolarizations and early afterdepolarization-initiated triggered activity, 10 of 11 ischemic Purkinje fibers developed these features. Consequently, action potentials in ischemic fibers were prolonged to durations greater than 10 s. The triggered activity in the ischemic Purkinje fibers produced repetitive activity in adjacent normal ventricular muscle. In vivo, 3 days after ligation, the administration of 3 to 10 mg/kg clofilium induced grouped beating. Action potentials recorded subsequently from these same hearts in vitro showed early afterdepolarizations, triggered activity and a similar grouping of responses. Therefore, clofilium differentially produced early afterdepolarizations in ischemic Purkinje fibers. This is a mechanism by which clofilium could be arrhythmogenic in an ischemic heart.

Quinidine-induced long QTU interval and torsade de pointes: role of bradycardia-dependent early afterdepolarizations.

Right ventricular endocardial monophasic action potential recordings were obtained in a patient with a qunidine-induced long QTU interval and polymorphic ventricular tachycardia of the torsade de pointes type. The recording showed a deflection on phase 3 repolarization characteristic of early afterdepolarization. The early afterdepolarization was synchronous with the U wave in surface electrocardiographic leads and there was a strong correlation between the amplitude of both waves. A strong correlation was also present between the cardiac cycle length and the U wave amplitude with larger amplitudes after longer cycles. Ventricular ectopic beats occurred only after long cycle lengths and seemed to arise close to the peak of the U wave and early afterdepolarization. However, there was no correlation between the amplitude of the U wave or early afterdepolarization and the occurrence of ectopic beats. Rapid ventricular pacing resulted in suppression of the ectopic rhythm associated with suppression of both the U wave and the early afterdepolarization. This case provides the first evidence to suggest that a quinidine-induced long QTU interval and torsade de pointes may be related to bradycardia-dependent early afterdepolarizations, although other factors may be involved in triggering the arrhythmia.

Reentrant ventricular arrhythmias in the late myocardial infarction period. 12. Spontaneous versus induced reentry and intramural versus epicardial circuits.

One to 5 days after one-stage ligation of the left anterior descending coronary artery in dogs, reentrant excitation can be induced by programmed premature stimulation in the surviving electrophysiologically abnormal, thin epicardial layer overlying the infarct. In experiments in four dogs, reentrant excitation occurred "spontaneously" during a regular sinus or atrial rhythm. A tachycardia-dependent Wenckebach conduction sequence in a potentially reentrant pathway was the initiating mechanism for spontaneous reentrant tachycardias and was the basis for both manifest and concealed reentrant extrasystolic rhythms. In all dogs showing spontaneous reentry, reentrant excitation could also be induced by premature stimulation at cycle lengths much shorter than those associated with spontaneous reentry, and induced reentrant circuits were always different from those during spontaneous reentry. In two dogs, the reentrant circuit was located intramurally in close proximity to a patchy septal infarction. The study illustrates that irrespective of the anatomic localization of reentrant circuits (epicardial or intramural), their dimension (large or small) or their mechanism of initiation (programmed premature stimulation or "spontaneous"), reentrant excitation always occurred in a figure 8 configuration (or a modification thereof). The figure 8 model, rather than the ring model or the leading circle model, may be the common model of reentry in the mammalian heart.

Reentrant ventricular arrhythmias in the late myocardial infarction period. II. Burst pacing versus multiple premature stimulation in the induction of reentry.

Isochronal maps of ventricular activation were analyzed in dogs 1 to 5 days after infarction utilizing a 64 channel multiplexer. Only dogs in which circus movement reentry could not be induced by a single premature stimulus were analyzed. Reentrant rhythms could be successfully induced equally by multiple (double or triple) premature stimuli and by burst pacing. Successive premature stimuli as well as successive beats during burst pacing resulted in progressively longer arcs of functional conduction block or slower circulating wave fronts, or both, that succeeded in reexciting myocardial zones on the proximal side of the arc of block to initiate reentry. However, for manifest reentry to be induced by burst pacing, the paced run had to be terminated after the beat that resulted in a critical degree of conduction delay. Otherwise, reentrant activation could be confined (concealed) by the subsequent paced wave front, which could also arrive earlier to the reentrant circuit zone of slow conduction resulting in block and interruption of reentry. Termination of a paced run after this beat would not result in reentry. If the paced run was extended past this beat, a new sequence of ventricular activation patterns characterized by progressively longer arcs of block or slower conduction, or both, developed again. The number of beats in a paced run that could initiate reentry varied with the cycle length of pacing, as well as in different experiments, and was difficult to standardize. It is therefore concluded that random burst pacing as a technique for induction of reentrant rhythms should probably be abandoned in favor of multiple premature stimulation.

Enhancement of triggered activity in ischemic Purkinje fibers by ouabain: a mechanism of increased susceptibility to digitalis toxicity in myocardial infarction.

Enhanced susceptibility to toxic arrhythmias by digitalis administration has been reported in clinical and experimental myocardial infarction. To investigate the mechanism responsible for this phenomenon, the effects of superfusion with normal Tyrode's solution and superfusion with Tyrode's solution containing 4 X 10(-8)M of ouabain in ischemic Purkinje fibers were compared. Ischemic Purkinje fibers of small endocardial preparations from 1 day old myocardial infarcts in 18 dogs were used for the study. During control conditions, these endocardial preparations demonstrated delayed afterdepolarizations and triggered activity. Superfusion with normal Tyrode's solution resulted in a gradual increase in maximal diastolic potential and action potential amplitude, a decrease in delayed afterdepolarizations amplitude and slowing and termination of triggered activity. Superfusion for 90 minutes with Tyrode's solution containing ouabain resulted in: 1) an increase in the magnitude of delayed afterdepolarizations in preparations demonstrating subthreshold delayed afterdepolarizations, 2) sustainment of triggered activity in preparations showing nonsustained triggered activity, and 3) shortening of cycle lengths of the triggered activity in preparations demonstrating sustained triggered activity before superfusion with ouabain. These effects occurred despite the gradual increase in maximal diastolic potential and action potential amplitude. Superfusion of normal Purkinje fibers with Tyrode's solution containing 4 X 10(-8)M of ouabain for 90 minutes did not result in delayed afterdepolarizations or triggered activity. Thus, ouabain at a concentration that has no toxic effect on normal Purkinje fibers may enhance arrhythmias in ischemic Purkinje fibers by increasing the magnitude of delayed afterdepolarizations and enhancing triggered activity.

Circus movement atrial flutter in the canine sterile pericarditis model. Relation of characteristics of the surface electrocardiogram and conduction properties of the reentrant pathway.

OBJECTIVES: This study was designed to elucidate the basis for the electrocardiographic (ECG) appearance of atrial flutter in the canine sterile pericarditis model. BACKGROUND: During atrial flutter, the surface ECG may show typical F waves or isolated P waves of any polarity. METHODS: Electrocardiographic leads II, III and aVF and epicardial atrial activation maps constructed from 127 simultaneously recorded bipolar electrograms were compared in 20 dogs with sterile pericarditis and inducible atrial flutter. RESULTS: In 10 dogs with F wave atrial flutter, single loop reentry occurred around combined functional/anatomic obstacles that included one or both caval veins and a vertically oriented arc of functional conduction block. In 10 dogs with P wave atrial flutter, a merely functional (n = 4) or combined (n = 6) obstacle involving any atrial vessel and more vertically (n = 5) or more horizontally (n = 5) oriented arcs of block was present. The isoelectric interval between P waves corresponded to the conduction time within the slow zone of the reentrant circuit (96 +/- 27 vs. 100 +/- 24 ms, mean +/- SD). Slow conduction accounted for 65 +/- 8% of the cycle length in P wave atrial flutter, but for only 29 +/- 7% in F wave atrial flutter (p < 0.05). Slow conduction was usually associated with activation of fewer than five epicardial electrodes per 10-ms isochronal interval, reflecting only a small amount of atrial tissue. The polarity of P or F waves was determined by the direction of the major wave front activating the most electrodes per 10-ms isochronal interval, irrespective of whether the right or the left atrium was activated. CONCLUSIONS: The F waves result from reentrant activation at a relatively constant speed around a vertically oriented functional/anatomic obstacle involving one or both caval veins. The P waves occur when the circuit contains a marked area of slow conduction.

A unified functional/anatomic substrate for circus movement atrial flutter: activation and refractory patterns in the canine right atrial enlargement model.

OBJECTIVES: This study was designed to test the concept of a functional/anatomic interaction in a canine model of reentry based on right atrial enlargement and to elucidate the electrophysiologic basis for functional conduction block. BACKGROUND: The monotonic feature of atrial flutter suggests a uniform substrate for the arrhythmia. Atrial flutter in the sterile pericarditis model is due to single-loop circus movement around a functional or a functional/anatomic obstacle near the atrioventricular (AV) ring. Sustained circus movement requires a critical interaction of a functional arc of block, a natural obstacle, the AV ring and a zone of slow conduction. The location of the inferior vena cava predisposes the lower right atrium to single-loop reentry. METHODS: In 11 dogs with right atrial enlargement, 127 bipolar epicardial electrograms were obtained during atrial flutter. For correlation of activation and refractory maps, the effective refractory period under each electrode was determined using the extrastimulus technique. RESULTS: Atrial flutter was due to single-loop reentry around functional arcs of block near the AV ring (n = 2) or around functional/anatomic obstacles (n = 8) involving the inferior vena cava. A slow zone was located between the arc and the AV ring and between the inferior vena cava and AV ring, respectively. During initiation, the arc joined the AV ring, forcing activation to proceed around the free end of the arc before breaking through the arc near the AV ring. Arrhythmia termination required the arc of block to rejoin the AV ring. Inducibility of sustained atrial flutter was associated with a marked spatial dispersion of refractoriness. The configuration of the functional arc of block was critically dependent on the spatial pattern of refractoriness. CONCLUSIONS: Atrial flutter requires a similar functional or functional/anatomic substrate independent of the underlying etiology. The spatial distribution of refractoriness in enlarged canine atria provides an adequate substrate for the development of functional conduction block.

Risk stratification for arrhythmic events in patients with nonischemic dilated cardiomyopathy and nonsustained ventricular tachycardia: role of programmed ventricular stimulation and the signal-averaged electrocardiogram.

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.

Appraisal of a Low Noise Electrocardiogram.

Two low noise electrocardiographic systems were designed to record low amplitude His-Purkinje potentials in the PR segment and delayed depolarization potentials in the ST-T segment from the body surface on a beat to beat basis. In one system, a bipolar electrode was utilized and the noise level was optimally reduced to 2 to 2.5 microV by a combination of noise reduction techniques. In the second system, better noise reduction (1 to 1.5 microV) was achieved by utilizing spatial averaging from 16 pairs of electrodes and a specially designed volume conductor electrode. The low noise electrocardiogram using the volume conductor electrode identified the His-Purkinje potential (up to 6 microV in amplitude) in 43% of patients compared with 71% recorded in the signal-averaged electrograms from the same patients. However, in contrast to the signal-averaged electrogram, only the low noise electrocardiogram could identify the His-Purkinje potential when moment to moment dynamic changes of the temporal relation of the P wave and QRS complex occurred. On the other hand, the low noise electrocardiogram recorded low amplitude, late diastolic potentials in the ST-T segment of postinfarction patients who showed a propensity to develop ventricular tachyarrhythmias. The diastolic potentials either: 1) remained constant in successive sinus beats, 2) varied in configuration, amplitude and timing in successive sinus beats, or 3) were only recorded in the diastolic interval preceding possible "reentrant" ventricular beats. The present study proves the feasibility of recording low amplitude His-Purkinje potentials and late diastolic potentials on the body surface on a beat to beat basis utilizing low noise electrocardiographic systems. Recording of late diastolic potentials on a beat to beat basis has the exciting potential of directly identifying malignant "reentrant" versus benign "focal" ventricular rhythms. However, the clinical relevance of these potentials remains to be established.

Mechanism of arrhythmogenicity of the short-long cardiac sequence that precedes ventricular tachyarrhythmias in the long QT syndrome.

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.

Reduction of ischemia-induced electrophysiologic abnormalities by glucose-insulin infusion.

OBJECTIVES: This study was designed to determine the effects of glucose-insulin infusion on ischemia-induced changes in extracellular potassium ([K+]o) accumulation and the associated electrophysiologic abnormalities in the canine heart. BACKGROUND: Although glucose-insulin-potassium infusion has been shown to limit myocardial injury in acute ischemia, its effect on ischemia-induced electrophysiologic alterations has not been investigated. METHODS: Recordings of [K+]o and local electrograms from the normal, border and ischemic zones were obtained during serial (10-min) left anterior descending coronary artery occlusions in the control state and after infusion of glucose-insulin (eight dogs), glucose alone (six dogs) or insulin alone (eight dogs). RESULTS: Glucose-insulin infusion caused significant reduction in the rise of [K+]o during the entire period of ischemia in both ischemic and border zones associated with significant improvement in the degree of intramyocardial conduction delay. At 10 min of ischemia, [K+]o was reduced from a mean control level of 15.9 +/- 3.7 to 10.1 +/- 4.3 mmol/liter (p < 0.005) in the ischemic zone and from 6.8 +/- 1.9 to 5.5 +/- 1.1 mmol/liter (p < 0.05) in the border zone. The electrogram duration was shortened from a mean control value of 102 +/- 13 to 78 +/- 12 ms in the ischemic zone and from 79.2 +/- 7.8 to 58.1 +/- 6.6 ms in the border zone (p < 0.005). Glucose alone caused significant reduction in [K+]o during the initial 6 min of ischemia, only in the ischemic zone. Conversely, insulin caused no changes in [K+]o accumulation during ischemia. Neither glucose nor insulin alone had any effect on ischemia-induced intramyocardial conduction delay. CONCLUSIONS: The present study demonstrated that the combination of glucose and insulin is essential for the salutary effect of reducing [K+]o accumulation during ischemia and improving the associated intramyocardial conduction delay. It could be postulated that glucose in the presence of insulin increases the glycolytic flux, thereby providing adequate adenosine triphosphate for suppressing the cardiac adenosine triphosphate-sensitive potassium ion channels. The latter are, at least partially, responsible for the [K+]o rise in the early phase of ischemia. This study highlights the antiarrhythmic potential of interventions that modulate the metabolic consequences of ischemia.

Definition of the best prediction criteria of the time domain signal-averaged electrocardiogram for serious arrhythmic events in the postinfarction period. The Cardiac Arrhythmia Suppression Trial/Signal-Averaged Electrocardiogram (CAST/SAECG) Substudy Investigators.

OBJECTIVES: The goal of this study was to establish guidelines for the prognostic use of the time domain signal-averaged electrocardiogram (ECG) after myocardial infarction. BACKGROUND: Previous studies of the prognostic use of the signal-averaged ECG in postinfarction patients had one or more of the following limitations: a small study group, empiric definition of an abnormal recording and possible bias in the selection of high risk groups or classification of arrhythmic events, or both. To correct for these limitations, a substudy was conducted in conjunction with the Cardiac Arrhythmia Suppression Trial (CAST). METHODS: Ten centers recruited 1,211 patients with acute myocardial infarction without application of the ejection fraction or Holter criteria restrictions of the main CAST protocol. Several clinical variables, ventricular arrhythmias on the Holter recording, ejection fraction and six signal-averaged ECG variables were analyzed. Patients with bundle branch block were excluded from the analysis, and the remaining 1,158 were followed for up to 1 year after infarction. The classification of arrhythmic events was reviewed independently by the CAST Events Committee. RESULTS: During an average (+/- SD) follow-up of 10.3 +/- 3.2 months, 45 patients had a serious arrhythmic event (nonfatal ventricular tachycardia or sudden cardiac arrhythmic death). A Cox regression analysis with only the six signal-averaged ECG variables indicated that the filtered QRS duration at 40 Hz > or = 120 ms (QRSD-40 Hz) at a cutpoint > or = 120 ms was the most predictive criterion of arrhythmic events. In a regression analysis that included all clinical, Holter and ejection fraction variables, a QRSD-40 Hz > or = 120 ms was the most significant predictor (p < 0.0001). The positive, negative and total predictive accuracy and odds ratio for QRSD-40 Hz > or = 120 ms were 17%, 98%, 88% and 8.4, respectively, and improved to 32%, 97%, 94% and 16.7, respectively, after combination with ejection fraction < or = 40% and complex ventricular arrhythmias on the Holter recording. CONCLUSIONS: The signal-averaged ECG predicts serious arrhythmic events in the first year after infarction better than do clinical, ejection fraction and ventricular arrhythmia variables, and QRSD-40 Hz > or = 120 ms provides the best predictive criterion in this clinical setting.

Improved diagnostic value of combined time and frequency domain analysis of the signal-averaged electrocardiogram after myocardial infarction.

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 <40%. 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.

Events in the cardiac arrhythmia suppression trial: baseline predictors of mortality in placebo-treated patients.

Patients randomized to placebo in the encainide and flecainide arms of the Cardiac Arrhythmia Suppression Trial (CAST) have been found to have a relatively low 1-year mortality rate of 3.9% in comparison with previous studies of patients in the postmyocardial infarction period. To determine the comparability of CAST with previous studies, baseline variables were examined in the 743 patients randomized to placebo in the flecainide and encainide arms of CAST. Twenty-three baseline characteristics were correlated with major outcome events: arrhythmic death (16 events), total mortality (26 events) and congestive heart failure (51 events). On multivariate analysis the risk of new or worsening congestive heart failure was significantly associated with diuretic use, diabetes, high New York Heart Association functional class, age, prolonged QRS duration and low ejection fraction. The risk of arrhythmic death or resuscitated cardiac arrest was significantly associated with an index Q wave myocardial infarction, history of heart failure, use of digitalis, diabetes and prolonged QRS duration. Total mortality or resuscitated cardiac arrest was significantly associated with an index Q wave myocardial infarction, diabetes, ST segment depression, high functional class, prolonged QRS duration and low ejection fraction. The variables at baseline associated with mortality from all causes or arrhythmic death or resuscitated cardiac arrest and heart failure in the CAST placebo-treated patients are similar to those identified in previous postmyocardial infarction studies. Thus, the observation of increased mortality in CAST associated with the administration of encainide and flecainide for suppression of ventricular premature depolarizations is probably applicable to any comparably defined group of patients in the postmyocardial infarction period.

Standards for analysis of ventricular late potentials using high-resolution or signal-averaged electrocardiography: a statement by a task force committee of the European Society of Cardiology, the American Heart Association, and the American College of Cardiology.

Sufficient data are available to recommend the use of the high-resolution or signal-averaged electrocardiogram in patients recovering from myocardial infarction without bundle branch block to help determine their risk for developing sustained ventricular tachyarrhythmias. However, no data are available about the extent to which pharmacological or nonpharmacological interventions in patients with late potentials have an impact on the incidence of sudden cardiac death. Therefore, controlled, prospective studies are required before this issue can be resolved. As refinements in techniques evolve, it is anticipated that the clinical value of high-resolution or signal-averaged electrocardiography will continue to increase.

A comparison of T-wave alternans, signal averaged electrocardiography and programmed ventricular stimulation for arrhythmia risk stratification.

OBJECTIVES: The goal of this study was to compare T-wave alternans (TWA), signal-averaged electrocardiography (SAECG) and programmed ventricular stimulation (EPS) for arrhythmia risk stratification in patients undergoing electrophysiology study. BACKGROUND: Accurate identification of patients at increased risk for sustained ventricular arrhythmias is critical to prevent sudden cardiac death. T-wave alternans is a heart rate dependent measure of repolarization that correlates with arrhythmia vulnerability in animal and human studies. Signal-averaged electrocardiography and EPS are more established tests used for risk stratification. METHODS: This was a prospective, multicenter trial of 313 patients in sinus rhythm who were undergoing electrophysiologic study. T-wave alternans, assessed with bicycle ergometry, and SAECG were measured before EPS. The primary end point was sudden cardiac death, sustained ventricular tachycardia, ventricular fibrillation or appropriate implantable defibrillator (ICD) therapy, and the secondary end point was any of these arrhythmias or all-cause mortality. RESULTS: Kaplan-Meier survival analysis of the primary end point showed that TWA predicted events with a relative risk of 10.9, EPS had a relative risk of 7.1 and SAECG had a relative risk of 4.5. The relative risks for the secondary end point were 13.9, 4.7 and 3.3, respectively (p < 0.05). Multivariate analysis of 11 clinical parameters identified only TWA and EPS as independent predictors of events. In the prespecified subgroup with known or suspected ventricular arrhythmias, TWA predicted primary end points with a relative risk of 6.1 and secondary end points with a relative risk of 8.0. CONCLUSIONS: T-wave alternans is a strong independent predictor of spontaneous ventricular arrhythmias or death. It performed as well as programmed stimulation and better than SAECG in risk stratifying patients for life-threatening arrhythmias.

The differential response of normal and ischaemic Purkinje fibres to clofilium, d-sotalol and bretylium.

To determine whether ischaemic tissue is more sensitive than normal tissue to class III anti-arrhythmic agents, we studied the effects of the class III agents clofilium, d-sotalol and bretylium on normal and ischaemic Purkinje fibres one day after ligation of canine left anterior descending coronary artery. In ischaemic Purkinje fibres superfused with normal Tyrode's solution (4mM K+, 2.7mM Ca+2) clofilium produced early afterdepolarisations at 10(-7)M and 10(-6)M, d-sotalol at 10(-5)M to 10(-3)M, and bretylium at 10(-3)M. The early afterdepolarisation response of ischaemic tissue, which in some cases prolonged action potential duration to beyond 10 s, was significantly different from the simple prolongation of action potential duration seen in normal Purkinje fibres at the same concentrations. Clofilium and d-sotalol differentially produced early afterdepolarisations at or very near "anti-arrhythmic" doses. Therefore, class III anti-arrhythmics produced early afterdepolarisations differentially in ischaemic tissue at concentrations which did not produce early afterdepolarisations in normal tissue.

Pharmacological evaluation of early afterdepolarisations induced by sea anemone toxin (ATXII) in dog heart.

STUDY OBJECTIVE: ATXII is a polypeptide toxin isolated from the sea anemone, Anemonia sulcata, known to delay sodium inactivation markedly and to induce early afterdepolarisations. The aim was to investigate the mechanism of its action. DESIGN AND MATERIALS: The mechanism of ATXII induced early afterdepolarisations was investigated in vitro in canine endocardial preparations using standard microelectrode techniques. MEASUREMENTS AND MAIN RESULTS: ATXII (2 x 10(-7) M) induced cycle length dependent prolongation of plateau, more marked in Purkinje than in muscle fibres, and early afterdepolarisations in Purkinje fibres only. The calcium channel antagonists verapamil (10(-6) M, 10(-5) M) and cobalt (2-4 mM), and drugs that block calcium release from the sarcoplasmic reticulum, ryanodine (10(-6) M, 10(-5) M) and caffeine (10 mM), did not antagonise the ATXII effects. However, tetrodotoxin (5 x 10(-6) M) and lignocaine (4 x 10(-5) M) shortened the action potential and suppressed early afterdepolarisations. The effects of lignocaine were seen at concentrations that did not significantly affect Vmax. CONCLUSIONS: ATXII induced early after depolarisations are due to the effects of ATXII on Na+ entry, probably via a slowly inactivated Na+ channel population. Calcium entry through the sarcolemmal Ca2+ channels and cyclic Ca2+ release from the sarcoplasmic reticulum are not required for the genesis of early afterdepolarisations in this model.