Takanori Ikeda

Microvolt T-wave alternans physiological basis, methods of measurement, and clinical utility--consensus guideline by International Society for Holter and Noninvasive Electrocardiology.

This consensus guideline was prepared on behalf of the International Society for Holter and Noninvasive Electrocardiology and is cosponsored by the Japanese Circulation Society, the Computers in Cardiology Working Group on e-Cardiology of the European Society of Cardiology, and the European Cardiac Arrhythmia Society. It discusses the electrocardiographic phenomenon of T-wave alternans (TWA) (i.e., a beat-to-beat alternation in the morphology and amplitude of the ST-segment or T-wave). This statement focuses on its physiological basis and measurement technologies and its clinical utility in stratifying risk for life-threatening ventricular arrhythmias. Signal processing techniques including the frequency-domain Spectral Method and the time-domain Modified Moving Average method have demonstrated the utility of TWA in arrhythmia risk stratification in prospective studies in >12,000 patients. The majority of exercise-based studies using both methods have reported high relative risks for cardiovascular mortality and for sudden cardiac death in patients with preserved as well as depressed left ventricular ejection fraction. Studies with ambulatory electrocardiogram-based TWA analysis with Modified Moving Average method have yielded significant predictive capacity. However, negative studies with the Spectral Method have also appeared, including 2 interventional studies in patients with implantable defibrillators. Meta-analyses have been performed to gain insights into this issue. Frontiers of TWA research include use in arrhythmia risk stratification of individuals with preserved ejection fraction, improvements in predictivity with quantitative analysis, and utility in guiding medical as well as device-based therapy. Overall, although TWA appears to be a useful marker of risk for arrhythmic and cardiovascular death, there is as yet no definitive evidence that it can guide therapy.

Assessment of Noninvasive Markers in Identifying Patients at Risk in the Brugada Syndrome: Insight Into Risk Stratification

OBJECTIVES The aim of this study was to compare the use of various noninvasive markers for detecting risk of life-threatening arrhythmic events in patients with Brugada syndrome. BACKGROUND The role of conduction disturbance in arrhythmogenesis of the syndrome is controversial, whereas it is well established that repolarization abnormalities are responsible for arrhythmias. The value of noninvasive markers reflecting conduction or repolarization abnormalities in identifying patients at risk for significant arrhythmias has not been shown. METHODS We assessed late potentials (LP) using signal-averaged electrocardiography (ECG), microvolt T-wave alternans (TWA), and corrected QT-interval dispersion (QTD) in 44 consecutive patients who had ECGs showing a pattern of right bundle branch block and ST-segment elevation in leads V1 to V3 but structurally normal hearts. The patients were compared with 30 normal individuals. RESULTS Eleven patients were excluded from data analysis because of an absence of ECG manifestations of Brugada syndrome at the time of the tests. A history of life-threatening events defined as syncope and aborted sudden death was present in 19 of 33 patients (58%); in 15 of the 19 patients, stimulation induced ventricular fibrillation or polymorphic ventricular tachycardia. The LP were present in 24 of 33 patients (73%); TWA were present in 5 of 31 patients (16%); and a QTD >50 ms was present in 9 of 33 patients (27%). The incidence of LP in Brugada patients was significantly (p < 0.0001) higher than in the controls, whereas incidences of TWA and QTD were not significantly different. Multivariate logistic regression analysis revealed that the presence of LP had the most significant correlation to the occurrence of life-threatening events (p = 0.006). CONCLUSIONS Late potentials are a noninvasive risk stratifier in patients with Brugada syndrome. These results may support the idea that conduction disturbance per se is arrhythmogenic.

Combined assessment of T-wave alternans and late potentials used to predict arrhythmic events after myocardial infarction ☆: A prospective study

OBJECTIVES The aim of the present study was to determine whether the combination of two markers that reflect depolarization and repolarization abnormalities can predict future arrhythmic events after acute myocardial infarction (MI). BACKGROUND Although various noninvasive markers have been used to predict arrhythmic events after MI, the positive predictive value of the markers remains low. METHODS We prospectively assessed T-wave alternans (TWA) and late potentials (LP) by signal-averaged electrocardiogram (ECG) and ejection fraction (EF) in 102 patients with successful determination results after acute MI. The TWA was analyzed using the power-spectral method during supine bicycle exercise testing. No antiarrhythmic drugs were used during the follow-up period. The study end point was the documentation of ventricular arrhythmias. RESULTS The TWA was present in 50 patients (49%), LP present in 21 patients (21%), and an EF <40% in 28 patients (27%). During a follow-up period of 13 +/- 6 months, symptomatic, sustained ventricular tachycardia or ventricular fibrillation occurred in 15 patients (15%). The event rates were significantly higher in patients with TWA, LP, or an abnormal EF. The sensitivity and the negative predictive value of TWA in predicting arrhythmic events were very high (93% and 98%, respectively), whereas its positive predictive value (28%) was lower than those for LP and EF. The highest positive predictive value (50%) was obtained when TWA and LP were combined. CONCLUSIONS The combined assessment of TWA and LP was associated with a high positive predictive value for an arrhythmic event after acute MI. Therefore, it could be a useful index to identify patients at high risk of arrhythmic events.

The Full Stomach Test as a Novel Diagnostic Technique for Identifying Patients at Risk of Brugada Syndrome

Introduction: Autonomic modulation, particularly high vagal tone, plays an important role in the occurrence of ventricular tachyarrhythmias in the Brugada syndrome. Food intake modulates vagal activity. We assessed the usefulness of a novel diagnostic technique, the “full stomach test,” for identifying a high‐risk group in patients with a Brugada‐type electrocardiogram (ECG).

Circadian variation of late potentials in idiopathic ventricular fibrillation associated with J waves: Insights into alternative pathophysiology and risk stratification

BACKGROUND The presence of J waves on ECGs is related to idiopathic ventricular fibrillation (VF). OBJECTIVE The purpose of this study was to investigate the pathophysiology of J waves by assessing risk markers that reflect electrophysiologic abnormalities. METHODS The study enrolled 22 idiopathic VF patients (17 men and 5 women; mean age 36 +/- 13 years). Patients were divided into two groups according to the presence or absence of J waves. The following risk stratifiers were assessed: late potentials (LPs; depolarization abnormality marker) for 24 hours using a newly developed signal-averaging system, and T-wave alternans and QT dispersion (repolarization abnormality markers). Frequency-domain heart rate variability (HRV), which reflects autonomic modulation, also was assessed. The results were compared to those of 30 control subjects with J waves and 30 with no J wave, matched for age and gender to the idiopathic VF patients. RESULTS J waves were present in 7 (32%) idiopathic VF patients. The incidence of LP in the idiopathic VF J-wave group was higher than in the idiopathic VF non-J-wave group (86% vs 27%, P = .02). In contrast, repolarization abnormality markers did not differ between the two groups. In the idiopathic VF J-wave group, dynamic changes in LP parameters (fQRS, RMS(40), LAS(40)) were observed and were pronounced at nighttime; this was not the case in the idiopathic VF non-J-wave group and the control J-wave group. High-frequency components (vagal tone index) on frequency-domain HRV analysis were associated with J waves in idiopathic VF patients (P < .05). CONCLUSION Idiopathic VF patients with J waves had a high incidence of LP showing circadian variation with night ascendancy. J waves may be more closely associated with depolarization abnormality and autonomic modulation than with repolarization abnormality.

Time-domain T-wave alternans measured from Holter electrocardiograms predicts cardiac mortality in patients with left ventricular dysfunction: A prospective study

BACKGROUND Time-domain T-wave alternans (TWA) is useful for identifying patients at risk for serious events after myocardial infarction. OBJECTIVE The purpose of this study was to prospectively evaluate the utility of time-domain TWA measured from Holter ECGs in predicting cardiac mortality in patients with left ventricular (LV) dysfunction. METHODS Two hundred ninety-five consecutive patients with LV dysfunction were enrolled in the study. Patients were divided into two groups: the ischemic group (n = 195) and the nonischemic group (n = 100). Time-domain TWA was assessed using the modified moving average method from routine 24-hour Holter ECGs recorded during daily activity. The maximal time-domain TWA voltage at heart rate <or=120 bpm in either lead V(5) or V(1) was derived and its value defined as positive when the voltage was >or=65 microV. The primary end-point was defined as cardiac mortality. RESULTS Mean maximal time-domain TWA voltage was 54 +/- 16 microV. During follow-up of 390 +/- 212 days, 27 patients (17 in the ischemic group and 10 in the nonischemic group) died of cardiac causes. Fifty-three patients (18%) were time-domain TWA positive and 242 (82%) were time-domain TWA negative. Univariate Cox proportional hazards analyses revealed that older age, New York Heart Association functional class III or IV, diabetes, renal dysfunction, nonsustained ventricular tachycardia, and time-domain TWA were associated with cardiac mortality. In multivariate analysis, time-domain TWA had the most significant value (hazard ratio = 17.1, P <.0001). This index also was significant in both subgroups (ischemic group: hazard ratio = 19.0, P <.0001; nonischemic group: hazard ratio = 12.3, P = .002). CONCLUSION Time-domain TWA measured from 24-hour Holter ECGs predicts cardiac mortality in patients with ischemic and nonischemic LV dysfunction.

The Role of Fibroblasts in Complex Fractionated Electrograms During Persistent/Permanent Atrial Fibrillation Implications for Electrogram-Based Catheter Ablation

Rationale: Electrogram-based catheter ablation, targeting complex fractionated atrial electrograms (CFAEs), is empirically known to be effective in halting persistent/permanent atrial fibrillation (AF). However, the mechanisms underlying CFAEs and electrogram-based ablation remain unclear. Objective: Because atrial fibrosis is associated with persistent/permanent AF, we hypothesized that electrotonic interactions between atrial myocytes and fibroblasts play an important role in CFAE genesis and electrogram-based catheter ablation. Methods and Results: We used a human atrial tissue model in heart failure and simulated propagation and spiral wave reentry with and without regionally proliferated fibroblasts. Coupling of fibroblasts to atrial myocytes resulted in shorter action potential duration, slower conduction velocity, and lower excitability. Consequently, heterogeneous fibroblast proliferation in the myocardial sheet resulted in frequent spiral wave breakups, and the bipolar electrograms recorded at the fibroblast proliferation area exhibited CFAEs. The simulations demonstrated that ablation targeting such fibroblast-derived CFAEs terminated AF, resulting from the ablation site transiently pinning the spiral wave and then pushing it out of the fibroblast proliferation area. CFAEs could not be attributed to collagen accumulation alone. Conclusions: Fibroblast proliferation in atria might be responsible for the genesis of CFAEs during persistent/permanent AF. Our findings could contribute to better understanding of the mechanisms underlying CFAE-targeted AF ablation.

Widening of the Excitable Gap and Enlargement of the Core of Reentry During Atrial Fibrillation With a Pure Sodium Channel Blocker in Canine Atria

Background—This study aimed to assess the effects of pilsicainide, a pure sodium channel blocker, on electrophysiological action and wavefront dynamics during atrial fibrillation (AF). Methods and Results—In a newly developed model of isolated, perfused, and superfused canine atria (n=12), the right and left endocardia were mapped simultaneously by use of a computerized mapping system. AF was induced with 1 to 5 &mgr;mol/L acetylcholine. The antifibrillatory actions of pilsicainide on AF cycle length (AFCL), refractory period (RP), conduction velocity (CV), excitable gap (EG), and the core of the mother rotor were studied. The RP was defined as the shortest coupling interval that could capture the fibrillating atrium. The EG was estimated as the difference between the AFCL and RP. At baseline, multiple wavefronts were observed. After 2.5 &mgr;g/mL infusion of pilsicainide, all preparations showed irregular activity, and AF was terminated in 2 preparations. The AFCL and RP were prolonged, and CV was decreased significantly. The EG was widened (147%;P <0.01), and the core perimeter was increased (100%;P <0.01). Increasing the dosage either terminated AF (6 preparations) or converted to organized activity (ie, atypical atrial flutter) (4 preparations). On the maps, all “unorganized” AFs were terminated with the excitation of the core of the mother rotor by an outside wavefront, whereas in preparations with atrial flutter, pilsicainide did not terminate its activity. Conclusions—Widening of the EG by pilsicainide facilitates the excitation of the core of the mother rotor, leading to the termination of AF. In some experiments, pilsicainide converts AF to persistent atrial flutter.

Induction of meandering functional reentrant wave front in isolated human atrial tissues

BACKGROUND The purpose of this study was to test the hypothesis that a single meandering functional reentrant wave front can result in rapid and irregular electrogram activity in human atrial tissues. METHODS AND RESULTS The study used the explanted hearts of five human cardiac transplant recipients. Three right and two left atrial tissue samples, 3.4+/-0.3 mm thick, were excised and trimmed to 3.5x3.0 cm. The isolated atrium was placed endocardial surface down in a chamber with a 477 bipolar recording electrode array built into the bottom of the tissue bath. The interelectrode distance was 1.6 mm. The tissue was constantly superfused with 36.5 degrees C oxygenated Tyrodes solution at a rate of 10 mL/min. After eight baseline stimuli (S1) delivered at 400- or 600-ms cycle length from the edge of the tissue, a single premature stimulus (S2) was given at the center of the tissue to induce reentry. A total of nine episodes of reentry were induced with S1-S2 coupling intervals of 232+/-29 ms (range, 190 to 290 ms) and an S2 strength of 10+/-3 mA (range, 5 to 15 mA). In all samples, a single meandering reentrant wave front was induced, causing irregular and rapid bipolar electrogram activity. These wave fronts had a mean cycle length of 229+/-45 ms (160 to 290 ms) and persisted for 1.1+/-0.3 seconds (0.6 seconds to 2.5 seconds), or 5.2+/-1.4 (3 to 9) cycles, before spontaneous termination. CONCLUSIONS A single meandering functional reentrant wave front can be induced in human atrial tissues and produce rapid and irregular electrical activity.

Differences in the Mode of Lethality Produced through Intravenous and Oral Administration of Organophosphorus Insecticides in Rats

This study was undertaken to investigate the possibility that mechanisms other than cholinesterase (ChE) inhibition account for the acute toxicity of organophosphorus insecticide. Both the P = O type insecticide (direct ChE inhibitors: chlorfenvinphos and dichlorvos) and the P = S type insecticide (indirect ChE inhibitors: diazinon and fenthion) were employed. Rats treated with lethal doses of intravenous and oral P = O type insecticides and oral P = S type insecticides exhibited typical signs of anti-ChE poisoning along with marked inhibition of brain and erythrocyte ChE activity. In contrast, rats given lethal doses of intravenous P = S type insecticides exhibited tonic convulsions and opisthotonos, with only slight inhibition of ChE activities. When P = O type insecticides were intravenously administered to anesthetized and conscious rats, animals exhibited typical anti-ChE poisoning signs in cardiorespiration: hypertension and apnea which were antagonized by atropine. After administration of lethal doses of P = O type insecticides, breathing disappeared before the cessation of heart beats. Rats receiving lethal doses of intravenous P = S type insecticides did not show hypertension, but exhibited transient cessation of breathing and heart beats. Breathing was observed after the disappearance of heart beats. The electroencephalogram (EEG) was characterized by spike and wave complexes. The EEG and cardiorespiratory changes were not antagonized by atropine. It was concluded that lethality following intravenous P = S type insecticides may be independent of ChE inhibition.