Clinical value of T-wave alternans assessment

Microvolt-level T-wave alternans (TWA) is a new arrhythmia risk marker to assess subtle changesin repolarization that has been introduced for arrhythmia risk stratification. Recent experimental studies havedemonstrated that it reflects a heartrate dependent increased spatial dispersion of repolarization associated withunidirectional conduction block, and reentry that may result in the occurrence of ventricular fibrillation.Clinical studies have convincingly demonstrated that TWA is closely related to arrhythmia induction in theelectrophysiology (EP) laboratory as well as to the occurrence of spontaneous ventriculartachyarrhythmias in patients undergoing EP study. Subsequent studies showed that TWA—assessednoninvasively—is predictive of future arrhythmic events in patients with implanted ICDs as well as forventricular tachyarrhythmias in patients with congestive heart failure without a prior history of arrhythmias.There is still controversy, however, about the predictive value of TWA in patients following acute myocardialinfarction (MI). Several studies which differ in patient selection, pharmacologic treatment of thepatients, and endpoint definitions, have reported conflicting results. Therefore, studies with a large number ofunselected patients after acute MI on optimal treatment according to contemporary therapeutic guidelines as wellas of patients with reduced left ventricular ejection fraction following MI are needed to define its role withregard to identifying patients who may benefit from primary preventive ICD therapy. Future research should alsofocus on evaluation of alternative methods to increase heart rate (i.e., pharmacological stimulation) inan attempt to reduce the proportion of incomplete tests in patients with insufficient increase in heart rateduring exercise testing.     

Cardiac repolarization instability during psychological stress in patients with ventricular arrhythmias

Introduction

Changes in the autonomic nervous system activity are a major trigger of life-threatening ventricular tachyarrhythmias (VTAs). Mental arithmetic, a condition administered in a laboratory setting, can provide insight into the autonomic nervous system activity effects on cardiac physiology. We examined the responses of cardiac repolarization to laboratory-induced psychological stressors in patients with implantable cardioverter-defibrillators (ICDs) with the objective of identifying the indices that differentiate patients with and without subsequent VTA in follow-up.

Methods

Continuous electrocardiographic signals were recorded using 3 standard bipolar (Holter) leads in 56 patients (age, 63.6 ± 11.9; female, 12%; left ventricular ejection fraction, 32.3 ± 11) with ICDs during mental arithmetic. The patients were separated into those with subsequent VTA during 3 to 4 years of follow-up (group 1: n = 9) and those without VTA (group 2: n = 47). Changes in repolarization (QT interval, mean T wave amplitude [Tamp], and T wave area) were analyzed during 5 minutes at baseline, stress, and recovery. The temporal instability of Tamp and T wave area was examined using the range (Δ) and variance (σ²) of beat-to-beat variations of the corresponding parameters.

Results

There were no significant differences in heart rate between the 2 groups at baseline (61 vs 63 beats per minute, P = .97), stress (64 vs 65 beats per minute, P = .40), and recovery (62 vs 61 beats per minute, P = .88). However, during mental stress and poststress recovery, ΔTamp was almost 2-fold greater in group 1 compared with group 2 (111 [57-203] vs 68 [44-94] μV, P = .04, respectively). Changes in QT intervals were also greater in group 1 compared with group 2 (P = .02).

Conclusion

Among patients with ICDs, changes of Tamp after psychological stress were greater in those with subsequent arrhythmic events. This might signal proarrhythmic repolarization response and help identify patients who would benefit the most from ICD implantation and proactive management.     

T-wave alternans for risk stratification and prevention of sudden cardiac death

Despite considerable progress in the management of ischemic heart disease, a substantial proportion of patients continue to experience life-threatening arrhythmic events. The Multicenter Automatic Defibrillator Implantation Trial 2 has recently shown the superiority of implantable cardioverter defibrillators (ICDs) over conventional strategies to prevent sudden death in patients with reduced ejection fraction, but at the expense of potentially unnecessary ICD implantation in a large percentage of patients. T-wave alternans (TWA), which reflects alternation of cellular repolarization, results in a substantial increase in dispersion of repolarization, a prerequisite for reentrant arrhythmias. Recent trials, cumulating close to 3000 patients, have established TWA analysis as a powerful tool for arrhythmia prevention. Based on the most recent estimates, at least one third of post-myocardial infarction patients are expected to be tested negative. With a negative predictive value greater than 90%, TWA might allow for targeting of patients most likely to benefit from ICD therapy. Accurate identification of high-risk patients by noninvasive TWA may allow for improved widespread screening for sudden death prevention in the general population.     

T-wave alternans: marker,mechanism, and methodology for predicting sudden cardiac death

Sudden cardiac death (SCD) is a leading cause of cardiovascular mortality. Therefore, identifying patients at highest risk for SCD is crucial. Conventional noninvasive markers of SCD are inadequate because of low positive predictive value. The presence of visible T-wave alternans (TWA) on electrocardiogram often predicts the occurrence of lethal ventricular arrhythmias. Signal processing methods have made it possible to detect microvolt-level and visually inapparent TWA on electrocardiogram. TWA is caused by underlying regional inhomogeneities of ventricular repolarization, which predispose patients to have ventricular arrhythmias. Microvolt TWA provoked either by atrial pacing, pharmacological stress, or exercise is a promising marker of arrhythmia vulnerability. Several large trials have shown TWA to be comparable or superior to other noninvasive markers and electrophysiologic study in the prediction of SCD. The patient populations in these trials include post myocardial infarction, both ischemic and nonischemic heart failure, and suspected arrhythmias. Prospective trials regarding benefits of implantation of cardioverter-defibrillator therapy based on TWA results are ongoing.     

Implantable cardioverter-defibrillator shocks increase T-wave alternans

Introduction: While implantable defibrillator shocks save lives, shock can lead to ventricular arrhythmias. However, the mechanism of shock-related proarrhythmia remains unclear. We evaluated the impact of ICD shock on repolarization instability, a factor associated with ventricular arrhythmogenesis.
Methods and Results: Sixty-five patients with ICDs underwent ambulatory ECG monitoring during defibrillation testing 3 months postimplant. TWA was analyzed continuously in the time domain during baseline, sedated, and post-shock states. RR, QRS, and QT intervals and catecholamines were also measured continuously. Adequate pre- and post-shock Holter data were recorded in 55 patients, 48 male, mean 64 ± 12 years, 50 with coronary disease, 48 with prior spontaneous or induced arrhythmia. TWA significantly increased after shock, from 9.6 ± 0.5 to 11.9 ± 0.6 μV, as did QRS duration, epinephrine, and norepinephrine levels, compared with sedated and baseline states. RR intervals decreased minimally. TWA changes with shock were not associated with RR or QRS duration changes, but were associated with changes in epinephrine.
Conclusions: ICD shock, even in the sedated state, increases repolarization instability as measured by TWA, an effect mediated in part by sympathetic stimulation. This association between shock and TWA may have important mechanistic and clinical implications for optimization of defibrillation therapy.     

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.     

Pathophysiological basis and clinical application of T-wave alternans

We review the contemporary understanding of the pathophysiology of repolarization alternans and present a perspective on the use of T-wave alternans (TWA) as a risk stratification marker of malignant ventricular arrhythmias. Several studies have demonstrated a high correlation of susceptibility to ventricular arrhythmias and sudden cardiac death with the existence of TWA. We describe a number of cellular and molecular alterations in the diseased heart that may provide a link between electrical and mechanical alternans and arrhythmia susceptibility. Repolarization alternans is likely the result of distinct and diverse cellular and molecular alterations that are associated with exaggerated regional repolarization heterogeneity, which renders the heart susceptible to malignant arrhythmias.     

T-wave alternans and the susceptibility to ventricular arrhythmias.

T-wave alternans (TWA) reflects beat-to-beat fluctuations in the electrocardiographic T-wave, and is associated with dispersion of repolarization and the mechanisms for sudden cardiac arrest (SCA). This review examines the bench-to-bedside literature that, over decades, has linked alternans of repolarization in cellular, whole-heart, and human studies with spatial dispersion of repolarization, alternans of cellular action potential, and fluctuations in ionic currents that may lead to ventricular arrhythmias. Collectively, these studies provide a foundation for the clinical use of TWA to reflect susceptibility to ventricular arrhythmias in several disease states. This review then provides a contemporary evidence-based framework for the use of TWA to enhance risk stratification for SCA, identifying populations for whom TWA is best established, those for whom further studies are required, and areas for additional investigation.     

T-wave alternans and the susceptibility to ventricular arrhythmias

T-wave alternans (TWA) reflects beat-to-beat fluctuations in the electrocardiographic T-wave, and is associated with dispersion of repolarization and the mechanisms for sudden cardiac arrest (SCA). This review examines the bench-to-bedside literature that, over decades, has linked alternans of repolarization in cellular, whole-heart, and human studies with spatial dispersion of repolarization, alternans of cellular action potential, and fluctuations in ionic currents that may lead to ventricular arrhythmias. Collectively, these studies provide a foundation for the clinical use of TWA to reflect susceptibility to ventricular arrhythmias in several disease states. This review then provides a contemporary evidence-based framework for the use of TWA to enhance risk stratification for SCA, identifying populations for whom TWA is best established, those for whom further studies are required, and areas for additional investigation.     

Microvolt T-wave alternans identifies patients with ischemic cardiomyopathy who benefit from implantable cardioverter-defibrillator therapy.

OBJECTIVES: This study sought to assess whether implantable cardioverter-defibrillators (ICDs) have different mortality benefits among patients with ischemic cardiomyopathy who screen negative and non-negative (positive and indeterminate) for microvolt T-wave alternans (MTWA). BACKGROUND: Microvolt T-wave alternans has been proposed as an effective tool for risk stratification. However, no studies have examined whether ICD benefits differ by MTWA group. METHODS: We developed a prospective cohort of 768 patients with ischemic cardiomyopathy (left ventricular ejection fraction < or =35%) and no prior sustained ventricular arrhythmia, of which 392 (51%) received ICDs. The mean follow-up time was 27 +/- 12 months. Propensity scores for ICD implantation based on the variables most likely to influence defibrillator implantation were developed for each MTWA cohort. Multivariable Cox analyses that controlled for propensity score, demographics, and clinical variables evaluated the degree to which ICDs decreased mortality risk for each MTWA group. RESULTS: We identified 514 (67%) patients with a non-negative MTWA test result. After multivariable adjustment, ICDs were associated with lower all-cause mortality in MTWA-non-negative patients (hazard ratio [HR] 0.45, 95% confidence interval [CI] 0.27 to 0.76, p = 0.003) but not in MTWA-negative patients (HR 0.85, 95% CI 0.33 to 2.20, p = 0.73) (for interaction, p = 0.04), with the mortality benefit in MTWA-non-negative patients largely mediated through arrhythmic mortality reduction (HR 0.30, 95% CI 0.13 to 0.68, p = 0.004). The number needed to treat with an ICD for 2 years to save 1 life was 9 among MTWA-non-negative patients and 76 among MTWA-negative patients. CONCLUSIONS: In patients with ischemic cardiomyopathy and no prior history of ventricular arrhythmia, mortality reduction with ICD implantation differs by MTWA status, with implications for risk stratification and health policy.     

Comparison of T-wave alternans and QT interval dispersion to predict ventricular tachyarrhythmia in patients with dilated cardiomyopathy and without antiarrhythmic drugs: a prospective study.

Microvolt T-wave alternans (TWA) and QT interval dispersion (QTD), which reflect temporal and spatial repolarization abnormalities, respectively, have been proposed as useful indices to identify patients at risk for ventricular tachyarrhythmias (VTs). The purpose of this study was to clarify which repolarization abnormality marker is more useful in predicting arrhythmic events in patients with dilated cardiomyopathy (DCM). Forty-two consecutive nonischemic DCM patients underwent the assessment of TWA and QTD. Patients undergoing antiarrhythmic pharmacotherapy, except beta-blockers and those with irregular basic rhythms, were excluded from entry. Eight patients were also excluded because of indeterminate test results. Therefore, 34 DCM patients were prospectively assessed. The end point of the study was the documentation of VT defined as > or = 5 consecutive ectopic beats during the follow-up period. TWA and QTD (> or = 65 msec) were positive in 24 (80%) and 11 (37%) of 30 patients with available follow-up data, respectively. There was no relationship between TWA and QTD. During a follow-up of 13+/-11 months, VTs occurred in 13 patients (43%). In Cox regression analysis, TWA was a significant risk stratifier (p=0.02), whereas QTD was not. The sensitivity, specificity, and positive and negative predictive values of TWA in predicting VTs were 100%, 35%, 54%, and 100%, respectively. TWA could be a useful noninvasive index to identify patients at risk for VTs in the setting of DCM. This study may suggest that temporal repolarization abnormality is associated more with arrhythmogenesis than with spatial repolarization abnormality in DCM patients.     

T-wave alternans testing for ventricular arrhythmias

T-wave alterans (TWA) measures alternate-beat fluctuations in the ECG T-wave, and has been used to predict the risk for life-threatening ventricular arrhythmias in various clinical populations. This work reviews the traditional literature linking repolarization alternans in cellular and tissue-level studies, with clinical studies that TWA can successfully add to existing clinical risk factors in predicting ventricular arrhythmias. We conclude by providing an evidence-based framework integrating TWA with other risk factors to stratify risk for sudden cardiac arrest.     

Arrhythmogenesis of T wave alternans associated with surface QRS complex alternans and the role of ventricular prematurity: observations from a canine model of LQT3 syndrome

INTRODUCTION: T wave alternans (TWA) is characterized by cycle-to-cycle changes in the QT interval and/or T wave morphology. It is believed to amplify the underlying dispersion of ventricular repolarization. The aim of this study was to examine the mechanisms and arrhythmogenesis of TWA accompanied by QRS complex and/or blood pressure (BP) waveform alternans, using transmural ventricular electrogram recordings in an anthopleurin-A model of long QT syndrome. METHODS AND RESULTS: The cardiac cycle length was gradually shortened by interruption of vagal stimulation, and TWA was induced in six canine hearts. Transmural unipolar electrograms were recorded with plunge needle electrodes from endocardial (Endo), mid-myocardial (Mid), and epicardial (Epi) sites, along with the surface ECG and BP. The activation-recovery interval (ARI) was measured to estimate local refractoriness. During TWA, ARI alternans was greater at the Mid than the Epi/Endo sites, and it was associated with the development of marked spatial dispersion of ventricular repolarization. As TWA increased, ventricular activation of the cycles associated with shorter QT intervals displayed delayed conduction at the Mid sites as a result of a critically longer ARI of the preceding cycle and longer QT interval, while normal conduction was preserved at the Epi site. Delayed conduction at the Mid sites manifested as surface ECG QRS and BP waveform alternans, and spontaneous ventricular tachyarrhythmias developed in absence of ventricular prematurity. In other instances, in absence of delayed conduction during TWA, ventricular premature complexes infringed on a prominent spatial dispersion of ventricular repolarization of cycles with long QT intervals and initiated ventricular tachyarrhythmia. CONCLUSION: TWA accompanied by QRS alternans may signal a greater ventricular electrical instability, since it is associated with intramural delayed conduction, which can initiate ventricular tachyarrhythmia without ventricular premature complexes.     

Prediction of sudden cardiac death in patients after acute myocardial infarction using T-wave alternans: a prospective study

Background and PurposeWe assessed the value of T-wave alternans (TWA) in prediction of sudden cardiac death (SCD) in patients with acute myocardial infarction (AMI).MethodsConsecutive patients (N = 227) were enrolled and were monitored with 24-hour ambulatory electrocardiogram within 1 to 15 days after AMI. T-wave alternans was identified by a modified moving average (MMA) algorithm computer software. The primary end point was SCD or lethal ventricular arrhythmia. We analyzed the hazard ratios (HRs) using the previously determined 47 μV TWA cutpoint.ResultsDuring the 16 ± 7-month follow-up, 10 (4.4%) patients died suddenly. T-wave alternans (≥47 μV) predicted SCD (HR, 17.78 [95% confidence interval, 3.75-84.31]; P < .0001). Moreover, patients with 5 or more TWA episodes (≥47 μV) were at higher risk for SCD (HR, 20.75 [95% confidence interval, 5.77-74.57]; P < .0001).ConclusionsT-wave alternans (≥47 μV) monitored at 1 to 15 days after AMI-predicted heightened risk of SCD. Prediction is improved when the frequency of TWA episodes (≥47 μV) is analyzed.     

Factors associated with abnormal T-wave axis and increased QRS-T angle in type 2 diabetes

Frontal plane T-wave axis and QRS-T angle are novel electrocardiographic ventricular repolarization parameters that have been scarcely evaluated in type 2 diabetes. The aim was to investigate the factors associated with these parameters of abnormal ventricular repolarization in a cross-sectional analysis of 594 patients with type 2 diabetes. Clinical, laboratory, 2D-echocardiographic, ambulatory blood pressure (BP) monitoring, aortic pulse wave velocity (PWV) and carotid ultrasonographic data were obtained. Digital 12-lead ECG was recorded, and frontal plane T-wave axis and QRS-T angle were automatically measured. T-wave axis was considered abnormal if >75° or <15° and QRS-T angle if ≥73° in men and ≥67° in woman. Associations were assessed by bivariate tests and multivariate logistic regressions. One hundred and four (20.9 %) patients had abnormal T-wave axis, and 84 (14 %) had increased QRS-T angle. Patients with abnormal ventricular repolarization were older and had greater prevalence of micro- and macrovascular diabetic complications than patients with normal repolarization. They had higher office and ambulatory BPs, greater prevalence of the non-dipping pattern, and greater left ventricular mass, aortic PWV and carotid intima-media thickness. On multivariate analysis, abnormal ventricular repolarization parameters were independently associated with left ventricular hypertrophy, non-dipping pattern, higher ambulatory systolic BPs, glycated hemoglobin and common carotid intima-media thickness, and with the presence of coronary artery disease. In conclusion, abnormal frontal plane T-wave axis and QRS-T angle are independently associated with several markers of pre-clinical atherosclerotic disease; whether these associations represent additional cardiovascular risk in type 2 diabetes shall be confirmed in prospective studies.     

Determinant of microvolt-level T-wave alternans in patients with dilated cardiomyopathy.

OBJECTIVES: The aim of this study was to clarify the clinical significance and the determinant of microvolt-level T-wave alternans (TWA) in patients with dilated cardiomyopathy (DCM). BACKGROUND: The prevention of sudden death in patients with DCM remains the therapeutic target. T-wave alternans has been proposed as a powerful tool for identification of patients at high risk for ventricular arrhythmias and sudden death in coronary artery disease. METHODS: In 58 DCM patients, TWA was measured during bicycle exercise testing using a CH 2000 system (Cambridge Heart, Bedford, Massachusetts). The New York Heart Association class, signal-averaged electrocardiogram, QT dispersion, left ventricular end-diastolic diameter (LVDd) and percent fractional shortening detected by echocardiogram and the grade of the ventricular arrhythmia were obtained in all patients. RESULTS: T-wave alternans was positive in 23 patients (TWA+ group), negative in 25 (TWA- group) and indeterminate in 10. Univariate analysis showed that the percentage of patients with ventricular tachycardia (VT) and the LVDd in the TWA+ group was significantly higher than those in the TWA- group (61% vs. 8%, p < 0.001 and 65 +/- 11 mm vs. 58 +/- 8 mm, p < 0.05, respectively). The sensitivity, specificity and predictive accuracy of TWA for VT were 88%, 72% and 77%, respectively. Multivariate analysis showed that the presence of VT was a major independent determinant of TWA in patients with DCM (p = 0.003). CONCLUSIONS: T-wave alternans was closely related to VT in patients with DCM. T-wave alternans is a useful noninvasive test for identifying high risk patients with DCM who have VT.     

T-wave alternans in microwave frequency as a new indicator of disordered ventricular repolarization: pathophysiology, methodology, clinical results

Primary prevention of sudden cardiac death is hampered by the inability to accurately identify high risk patients. Various noninvasive methods such as determination of left ventricular function or heart rate variability as well as invasive electrophysiologic testing are currently used for risk stratification. Noninvasive measurement of microvolt T wave alternans (TWA) is a promising new method to assess repolarization abnormalities; in experimental studies, TWA was associated with an increased incidence of ventricular tachyarrhythmias. Since the occurrence of TWA is heart rate-dependent, it is measured either during atrial pacing or during exercise stress testing. The first clinical validation of the method was performed in patients undergoing invasive EP testing to assess prediction of inducibility of ventricular tachyarrhythmias. A first prospective validation of the noninvasive method was performed in patients surviving out-of-hospital cardiac arrest fitted with an ICD. Further studies have shown a good concordance between invasive and noninvasive TWA determination. The occurrence of TWA in this population was of predictive value with respect to arrhythmia recurrence. Recently published data confirm the value of TWA assessment with respect to identification of patients with congestive heart failure at high risk of malignant ventricular tachyarrhythmias. The use of this method in post myocardial infarction risk stratification is currently under prospective evaluation.     

Relation of T-wave alternans to regional left ventricular dysfunction and eccentric hypertrophy secondary to coronary heart disease

Left ventricular (LV) hypertrophy and structural disease are associated with exaggerated repolarization dispersion and risk for cardiac arrest. We hypothesized that T-wave alternans (TWA) from the electrocardiogram, reflecting proarrhythmic repolarization dispersion, would increase with extent of eccentric LV hypertrophy and vary spatially with the distribution of myocardial scar. We studied 28 patients with coronary disease, systolic dysfunction, and nonsustained ventricular tachycardia. On echocardiography, 21 patients had wall motion abnormalities and 20 had LV hypertrophy (mass index > or =100 g/m(2)). TWA magnitude (voltage of alternation), which was computed spectrally during ventricular stimulation, varied linearly with LV mass index (p = 0.003). Spatially, positive TWA (magnitude > or =1.9 microV) in orthogonal electrocardiographic axes overlaid scar or wall motion abnormalities in corresponding echocardiographic segments (p <0.05 in x and y axes). After a follow-up of 35 +/- 13 months, positive TWA predicted the combined end point of death or sustained ventricular arrhythmias in all patients (p = 0.025), with a trend for those with echocardiographic LV hypertrophy (p = 0.058). In conclusion, in patients with systolic dysfunction due to coronary artery disease, TWA may indicate arrhythmic contributions from regional myocardial scar and eccentric LV hypertrophy.     

Changes in autonomic activity and ventricular repolarization

An increase in sympathetic activity, manifested by shortening of RR intervals (RR1) and changes in RRi variability, precedes and possibly triggers ventricular tachyarrhythmias (VTAs) by altering repolarization. We examined the effects of autonomic activity on the projection of repolarization as detected by body surface potential maps (BSPMs). We recorded 32 lead/192-point BSPMs during passive head-up tilt, tilt + infusion of isoproterenol, rapid atrial pacing, and atrial pacing + infusion of isoproterenol. Changes in QT; recovery time; activation-recovery interval (ARi); T-wave amplitude; and QT, QRST, and ST integrals and their dispersion were analyzed. Autonomic effects on sinus node were inferred from the Fourier transform-derived low and high frequency powers of RRi variability. Patients were divided into those with (SHD) and without structural heart disease (NSHD). Heart rate increased, whereas QT interval and ARi declined with tilt in both groups. RRi variability indices of sympathetic activity increased in NSHD but did not change in SHD. T-wave amplitudes declined in NSHD but did not change in SHD, suggesting altered responsiveness of ventricular repolarization to autonomic stimulation. Tilt and rapid atrial pacing during infusion of isoproterenol resulted in a paradoxical increase in T-wave amplitudes in some patients, similar to that observed before the onset of spontaneous arrhythmias. We conclude that altering autonomic activity by head-up tilt and/or infusion of sympathomimetic agents results in significant changes in the body surface projection of cardiac repolarization, which differ in patients with SHD from those without SHD. Similar paradoxical changes in the T-wave amplitude have been observed before the onset of spontaneous VTA, suggesting that abnormal response of repolarization to autonomic stimulation predisposes to arrhythmogenesis.     

Cardiac repolarization instability during normal postnatal development

Long QT syndrome is a disease characterized by abnormal lengthening of the QT interval and by sudden cardiac death. It is a disease of development, with the incidence of a sudden event increasing during childhood. Repolarization instability during postnatal development could make the substrate susceptible to a fatal arrhythmia. Dynamic changes in repolarization that occur on a beat-to-beat basis, known as alternans, are a hallmark of electrical instability. T-wave alternans (TWA) in the electrocardiogram correlates with arrhythmia risk and long-term survival in adults. We determined TWA properties longitudinally in vivo in 7 propofol-sedated New Zealand white rabbits using transesophageal pacing weekly from 2 to 10 weeks of age. Furthermore, TWA induction after the onset of rapid pacing was characterized in vitro in 6 infant (2 weeks) and 6 adolescent (7 weeks) isolated, arterially perfused rabbit hearts. In vivo, TWA amplitude was maximum at 2 weeks and declined with age. Isoproterenol increased TWA at 8 weeks (adolescence). In vitro, large-amplitude TWA was induced with rapid pacing in both infant and adolescents but decreased to low, steady-state levels in infants. We conclude that TWA properties are age dependent in rabbit. Significant TWA is induced in rabbit at the onset of rapid pacing.