T-wave Alternans Levels Research Articles

T-Wave Alternans as a Therapeutic Marker for Antiarrhythmic Agents

Over the course of more than a century, visible T-wave alternans (TWA), defined as a beat-to-beat alternation in the morphology and amplitude of the ST segment or T wave, has been observed to occur in close association with life-threatening arrhythmias in patients with acute myocardial ischemia and infarction, heart failure, Prinzmetal's angina, and channelopathies, including Brugada and long QT syndromes. Over 100 studies enrolling a total of more than 12,000 patients support the predictivity of TWA testing for cardiovascular mortality and sudden cardiac death during both exercise and ambulatory electrocardiogram monitoring. To date, the main intended application has been to aid decision-making for cardioverter-defibrillator implantation. The prospect that TWA could be used to guide pharmacologic therapy has not received adequate attention. The literature supporting the utility of TWA as a therapeutic marker of antiarrhythmic effects and proarrhythmia is reviewed for each of the major antiarrhythmic drug classes. Beta-adrenergic and sodium channel blocking agents are the most widely studied drug classes in clinical TWA investigations, which report reductions in TWA magnitude. Patients with Brugada syndrome constitute a significant exception, because sodium channel blockade provokes the diagnostic electrocardiogram changes as well as macroscopic TWA. Calcium channel blockers have undergone extensive research in several animal models, but, surprisingly, no clinical studies on TWA with this class of drugs have been performed. Interestingly, TWA may help to detect the beneficial effects of nonantiarrhythmic agents such as the angiotensin II receptor blocker valsartan, which exert their protective effects through putative indirect actions on myocardial remodeling. There is also suggestive evidence that the proarrhythmic effects associated with cardiovascular and noncardiovascular agents may be disclosed by elevated levels of TWA. Thus, the emerging collective evidence indicates the broad utility of TWA in estimating antiarrhythmic and proarrhythmic effects of diverse agents across differing pathologies. We conclude that quantitative analysis of TWA has considerable potential to guide pharmacologic therapy.

Assessment of Physiological Amplitude, Duration, and Magnitude of ECG T‐Wave Alternans

An association between T-wave alternans (TWA) and malignant ventricular arrhythmias is generally recognized. Because relatively low levels of TWA have also been observed in healthy (H) subjects, the question arises as to whether these are ascribable to noise and artifacts, or can be given the relevance of a physiological phenomenon characterizing a preclinical condition. To answer this question, in the present study 20-minute not noisy, sinus ECG recordings, from 138 H-subjects and 148 coronary artery diseased (CAD) patients, were submitted to our adaptive match filter (AMF) procedure to identify and parameterize TWA in terms of duration (TWAD), amplitude (TWAA), and magnitude (TWAM, defined as the product of TWAD times TWAA). The 99.5th percentiles of mean values of TWAA, TWAD, and TWAM over 20-minute ECGs were used to define three threshold levels (THRD, THRA, and THRM), which allow discrimination of abnormal TWA levels. Nonstationary TWA was found in all our H-subjects and CAD-patients. TWAD, TWAA, and TWAM levels were classified as being physiological in 99% of H-subjects and 87% of CAD-patients. A linear correlation (r =-0.52, P < 0.001) was found between TWAA and RR interval in the H-population. Our results support the hypothesis of the existence of physiological TWA levels, which are to be considered in the effort to improve reliability of nonphysiological TWA levels discrimination.

Comparative analysis of methods for automatic detection and quantification of microvolt T-wave alternans

Microvolt T-wave alternans (TWA), consisting of every-other-beat changes in ECG T-wave morphology, is an index of susceptibility to malignant ventricular arrhythmias, requiring automatic techniques to be identified. Five of these, namely, fast-Fourier-transform spectral method (FFTSM), complex-demodulation method (CDM), modified-moving-average method (MMAM), Laplacian-likelihood-ratio method (LLRM) and adaptive-match-filter method (AMFM), were applied here to simulated and sample clinical data. The aim was to compare individual methods ability to properly identify stationary and time-varying TWA, avoiding false-positive detections. The MMAM provided false-positive TWA when applied to simulated ECGs affected by amplitude variability, but TWA. Stationary TWA was properly quantified by the MMAM and, occasionally, underestimated by all other methods. The AMFM properly identified time-varying TWA. By contrast, the FFTSM detected not-stationary TWA as stationary, the MMAM introduced a time-delay in the estimated TWA-amplitude signal, while the CDM and LLRM were reliable only in the presence of slow-varying TWA. Altogether, the AMFM accomplished the best compromise between the needs to avoid false-positive TWA and to detect and characterize true-positive TWA. Results of our simulation approach were useful to explain different TWA levels measured by each competing methods applied to sample Holter ECGs from healthy subjects and coronary artery disease patients.

Enhanced Predictive Power of Quantitative TWA during Routine Exercise Testing in the Finnish Cardiovascular Study

We examined whether quantification of T-wave alternans (TWA) enhances this parameter's capacity to evaluate the risk for total and cardiovascular mortality and sudden cardiac death (SCD). The Finnish Cardiovascular Study (FINCAVAS) enrolled consecutive patients (n = 2,119; 1,342 men and 777 women) with a clinically indicated exercise test with bicycle ergometer. TWA (time domain-modified moving average method) was analyzed from precordial leads, and the results were grouped in increments of 10 microV. Hazard ratios (HR) for total and cardiovascular mortality and SCD were estimated for preexercise, routine exercise, and postexercise stages. Cox regression analysis was performed. During follow-up of 47.1 +/- 12.9 months (mean +/- standard deviation [SD]), 126 patients died: 62 were cardiovascular deaths, and 33 of these deaths were sudden. During preexercise, TWA >or= 20 microV predicted the risk for total and cardiovascular mortality (maximum HR >4.4 at 60 microV, P < 0.02 for both). During exercise, HRs of total and cardiovascular mortality were significant when TWA measured >or=50 microV, with 90 microV TWA yielding maximum HRs for total and cardiovascular death of 3.1 (P = 0.03) and 6.4 (P = 0.002), respectively. During postexercise, TWA >or=60 microV indicated risk for total and cardiovascular mortality, with maximum HR of 3.4 at 70 microV (P = 0.01) for cardiovascular mortality. SCD was strongly predicted by TWA levels >or=60 microV during exercise, with maximum HR of 4.6 at 60 microV (P = 0.002), but was not predicted during pre- or postexercise. Quantification of TWA enhances its capacity for determination of the risk for total and cardiovascular mortality and SCD in low-risk populations. Its prognostic power is superior during exercise compared to preexercise or postexercise.

Basis for sudden cardiac death prediction by T-wave alternans from an integrative physiology perspective

Detection of microvolt levels of T-wave alternans (TWA) has been shown to be useful in identifying individuals at heightened risk for sudden cardiac death. The mechanistic bases for TWA are complex, at the cellular level involving multiple mechanisms, particularly instabilities in membrane voltage (i.e., steep action potential duration restitution slope) and disruptions in intracellular calcium cycling dynamics. The integrative factors influencing TWA at the systemic level are also multifold. We focus on three main variables: heart rate, autonomic nervous system activity, and myocardial ischemia. Clinically, there is growing interest in extending TWA testing to include ambulatory ECG monitoring as well as exercise. The former modality permits assessment of the influence of diverse provocative stimuli of daily life, including physical activity, circadian factors, mental stress, and sleep-state related disturbances in respiratory and cardiovascular function. Two major emerging concepts in clinical TWA testing are discussed: quantitative analysis of TWA level to complement the current binary classification scheme, and risk stratification of patients with preserved left ventricular function, the population with the largest absolute number of sudden cardiac deaths.

Enhanced modified moving average analysis of T-wave alternans using a curve matching method: a simulation study

T-wave alternans (TWA) are beat-to-beat amplitude oscillations in the T-waves of electrocardiograms (ECGs). Numerous clinical studies have demonstrated the link between these oscillations and ventricular arrhythmias. Several methods have been developed in recent years to detect and quantify this important feature. Most methods estimate the amplitude differences between pairs of consecutive T-waves. One such method is known as modified moving average (MMA) analysis. The TWA magnitude is obtained by means of the maximum absolute difference of even and odd heartbeat series averages computed at T-waves or ST-T complexes. This method performs well for different levels of TWA, noise, and phase shifts, but it is sensitive to the alignment of the T-waves. In this paper we propose a preprocessing stage for the MMA method to ensure an optimal alignment of such averages. The alignment is performed by means of a continuous time warping technique. Our assessment study demonstrates the improved performance of the proposed algorithm.

Clinical significance of microvolt T-wave alternans

Several studies have recently proven that primary preventive therapy of sudden arrhythmogenic death is possible in selected patients with congestive heart failure, particularly in the setting of ischemic cardiomyopathy [1, 2]. However, a number needed to treat between 11 and 17 to save one life over three years in these studies indicates that a more accurate identification of high risk patients is desirable in order to avoid unnecessary implants of cardioverter/defibrillators (ICD). Since currently available risk stratification methods have limited predictive accuracy, development of new techniques is important in order to non-invasively assess arrhythmogenic risk in patients prone to sudden death. Microvolt level T-wave alternans (mTWA) has recently been proposed to assess abnormalities in ventricular repolarization favoring the occurrence of reentrant arrhythmias [3, 4]. In 1994, a first clinical study by Rosenbaum and coworkers [5] convincingly demonstrated that mTWA is closely related to arrhythmia induction in the electrophysiology (EP) laboratory as well as to the occurrence of spontaneous ventricular tachyarrhythmias during follow-up [5]. More recently, a number of clinical studies has examined its clinical applicability [4-7]. The present review summarizes currently available clinical data on TWA with a particular focus on risk stratifying patients with congestive heart failure and myocardial infarction.

Combined prognostic value of peak O 2 uptake and microvolt level T-wave alternans in patients with idiopathic dilated cardiomyopathy

Background Despite the great improvement in clinical management of patients with idiopathic dilated cardiomyopathy (DCM), sudden cardiac death (SCD) and death due to worsening heart failure (HF) remain a challenging problem. The assessment of oxygen consumption (peakVO 2) has been recognized as an independent marker of mortality. Nevertheless peakVO 2 is not helpful in the risk stratification of SCD. Given this limitation, the association with another non-invasive test able to predict SCD such as microvolt level T-wave alternans (MTWA) would be useful. Objectives To determine the combined predictive value of peakVO 2 and MTWA in patients with DCM. Methods Seventy consecutive DCM patients were prospectively investigated. PeakVO 2 and MTWA were determined during bicycle exercise testing. Primary composite study end-point was defined as major cardiac events (MCE): total cardiac death or documented sustained VT/VF (including appropriate ICD shock). Secondary end-point was defined as arrhythmic events (AE): SCD or documented sustained VT/VF. Results Thirty-nine patients (55%) had a peakVO 2 < 10 ml/kg/min, while 40 patients (57%) showed an abnormal MTWA test. During an average follow-up of 19.2 ± 10.7 months, 11 MCE of which 6 AE have been documented. Among patients with abnormal MTWA and peakVO 2 < 10 ml/kg/min 8 MCE of which 5 AE occurred while among patients with normal MTWA and peakVO 2 ≥ 10 ml/kg/min no event occurred. From multivariate analysis, the combined prognostic value of MTWA and peakVO 2 achieved statistical significance for MCE ( p = 0.03, HR 0.28, 95% CI 0.12–0.95) and for AE ( p = 0.05, HR 0.39, 95% CI 0.18–0.99) while MTWA alone was a significant predictor of AE ( p = 0.04, HR 0.32, 95% CI 0.14–0.93). Conclusions Our results suggest that only the association of MTWA and peakVO 2, but not the two single tests, is a significant prognostic marker of both MCE and AE in DCM patients. However, MTWA alone confirms its predictive power as arrhythmic risk stratifier in this population.

Repeated assessment of microvolt level T-wave alternans in patients with acute myocardial infarction and reduced LVEF: Results from a long-term follow-up study

Background: Microvolt level T-wave alternans (MTWA) is increasingly used for arrhythmia risk stratification. Particularly, its high negative predictive value points to a potential use as a risk stratifier in pts with ischemic cardiomyopathy. The value of MTWA assessed early after acute myocardial infarction (MI), however, seems to be limited. There are no data about the long-term course of MTWA in post-MI pts with reduced left ventricular ejection fraction (LVEF).

Ambulatory ECG monitoring of T-Wave alternans for arrhythmia risk assessment

Experimental and clinical studies indicate a basic linkage between T-wave alternans (TWA) and susceptibility to malignant arrhythmias. In a variety of clinical populations with elevated risk of ventricular tachyarrhythmias, Fast Fourier Transform (FFT)-based assessment of TWA during fixed-rate atrial pacing or bicycle ergometry has shown predictive ability for arrhythmic events. However, after more than a decade since the introduction of TWA testing in human subjects, few studies have explored its utility in ambulatory ECG (AECG) recordings. This gap probably relates to major technical obstacles associated with monitoring of ambulatory subjects, including motion artifact and the requirement of data stationarity, which mandates fixing heart rate. To cicumvent these difficulties, we devised a time-domain method, “Modified Moving Average Beat Analysis” (MMA) to determine TWA level accurately in freely moving subjects. Recently, MMA analysis was employed to analyze ambulatory ECG (AECG) records of post-myocardial infarction patients who were were at low risk of arrhythmic death. An increased risk of arrhythmic death was predicted by TWA level above the 75 th percentile of controls ( p <.05). Thus, the predictive power of TWA obtained with MMA analysis from AECG records obtained appears promising.

Progressive increases in complexity of T-wave oscillations herald ischemia-induced ventricular fibrillation.

T-wave alternans (TWA), an ABAB oscillation, has been postulated as the initial pattern in a stepwise progression to higher-order oscillations, culminating in sudden arrhythmic death. The present study is the first to provide experimental evidence to support this intriguing concept. Epicardial and endocardial ECGs from 12 dogs were monitored during 8-minute left anterior descending coronary artery occlusion with right atrial pacing at 150 bpm. TWA magnitude was measured by modified moving average beat analysis, and the complexity of T-wave oscillations was assessed by complex demodulation. In 6 animals with subsequent ventricular fibrillation (VF), TWA achieved a threshold of 5.00+/-1.30 mV in epicardial ischemic-zone electrograms, which then exhibited a stepwise increase in T-wave oscillation complexity to quadrupling (ABCDABCD, 3 cases) or tripling (ABCABC, 2 cases) and to more complex forms (5 cases) preceding VF (6 cases). In dogs without VF, peak TWA levels did not increase from baseline, measuring a maximum of 0.35+/-0.10 mV (P=NS), or only 7% the value of those with VF, and T-wave multupling was not observed (0 of 6 versus 5 of 6, P<0.005). Discordant TWA episodes, with T waves alternating out of phase, were associated with increased T-wave complexity and fibrillation in 4 of 6 dogs with VF but in none of the 6 dogs without VF (P<0.025). TWA appears to be the first step in an orderly progression of T-wave complexity, episodes of discordant TWA, and VF. This demonstrated increase in T-wave complexity points to a fundamental mechanistic link underlying the ability of TWA to predict lethal arrhythmias.

T wave alternans and ventricular arrhythmias in arterial hypertension.

Patients with a positive microvolt-level T wave alternans (TWA) are characterized by an increased risk of ventricular tachyarrhythmias. Arterial hypertension leads to an increase of sudden cardiac death risk, particularly if left ventricular hypertrophy is present. The aim of this study was to investigate the value of TWA in patients with arterial hypertension. Fifty-one consecutive patients were included in the study. TWA analysis was performed with patients sitting on a bicycle ergometer and exercising with a gradual increase of workload to maintain a heart rate of at least 105/min. After recording 254 consecutive low-noise-level heartbeats, the exercise test was stopped. The ECG signals were digitally processed by a spectral analysis method. The magnitude of TWA was measured at a frequency of 0.5 cycle per beat. A TWA was defined as positive if the ratio between TWA and noise level was >3.0 and the amplitude of the TWA was >1.8 microV. Eight of the 51 patients (16%) showed a positive TWA. If left ventricular hypertrophy was present, the prevalence of TWA was higher (33.3% versus 8.3%; P:<0.05). Sensitivity concerning a previous arrhythmic event was 73%, and specificity was 100%. The alternans ratio was significantly higher in patients with a previous event (39.3+/-62.3 versus 2.4+/-4.6; P:<0.001), as was the cumulative alternans voltage (4.7+/-4.1 versus 1.6+/-1.9 microV; P:<0.001). In 16 patients invasively investigated by an electrophysiological study, a significant correlation between inducibility of tachyarrhythmias and a positive TWA result was found (Spearman R:=0.36, P:=0.01). We conclude that the arrhythmic risk of patients with arterial hypertension is markedly increased if microvolt-level TWA is present. The prevalence of TWA is higher in patients with left ventricular hypertrophy.

Predictive value of T-wave alternans for arrhythmic events in patients with congestive heart failure

Measurement of microvolt level T-wave alternans in the surface electrocardiogram is a novel way to assess the risk of ventricular arrhythmias. Seven tests of arrhythmic risk, including T-wave alternans, were undertaken in 107 consecutive patients with congestive heart failure and no history of sustained ventricular arrhythmias; the patients were followed up for arrhythmic events during the next 18 months. Of the patients with events, 11 had positive and two indeterminate T-wave alternans results; there were no arrhythmic events among patients with negative T-wave alternans results. Of the seven tests, only T-wave alternans was a significant (p=0.0036) and independent predictor of arrhythmic events.

Modulation of Electrical Microvolt Level T-Wave Alternans and Left Ventricular Late Potentials Evaluated by Heart Rate Variability Indices, QT Dispersion, and Plasma Catecholamine Levels

Objective: The purpose of this study was to investigate how the modulation of electrical microvolt level T-wave alternans (Twa) relates to left ventricular late potentials as evaluated by heart rate variability (HRV), QT dispersion, and plasma catecholamine levels. Background: The Twa and left ventricular late potentials are promising noninvasive powerful markers for risk prediction in patients with ischemic heart disease (IHD) and/or cardiomyopathy. However, their relation to autonomic activity is unclear. Methods: In 56 patients with stable IHD-measured Twa at rest and during controlled bicycle ergometer testing, we simultaneously recorded recent noninvasive electrocardiographic approaches, such as HRV, QT dispersion, and left ventricular late potentials. Plasma norepinephrine (NE) and epinephrine (E) were also measured. Results: (1) There were no significant differences in clinical findings, NE, and E levels between positive (group A) and negative (group B) Twa. Left ventricular late potentials, LF (low frequency spectra), as well as HF (high frequency spectra) in group A were significantly lower than in group B, but LF/HF did not differ significantly between the two groups. There was a significant inverse correlation between Twa microvoltage and LF/HF that was higher during exercise (r = -0.51, P = 0.006) than at rest (r = -0.34, P < 0.01). (2) There were no significant differences in clinical findings between positive (group C) and negative (group D) left ventricular late potentials. Plasma NE in group C was significantly higher than in group D (1060 ± 429 pg/mL vs 395 ± 219, P < 0.05). Furthermore, LF/HF in group C was significantly lower than in group D (0.96 ± 0.27 vs 1.1 ± 0.11, P < 0.05). There were no significant correlations between left ventricular late potential parameters and QT or QTc dispersion. Conclusions: The Twa microvoltage in patients with stable IHD exhibits similar physiologic conditions as in patients with lower HRV indices. The presence of left ventricular late potentials might be affected by sympathetic nerve modulation.

Oita International Electrocardiology Symposium 2000 “Electrophysiology and Management of Lethal Arrhythmias in the New Millennium: From Genes to Bedside”

μ-Volt level T-wave alternans (μ V-TWA), which is provocated by constant high heart rate, has recently been exposed to attension as an index of the lethal ventricular arrhythmia. Alternans of action potential after abrupt cycle length shortening was abolished by caffeine and, therefore, was attributed to intracellular Ca cycling by sarcoplasmic reticulum (SR) . We examined whether the alternans of action potential induced by constant high heart rate could also attributed to alternans of intracellular Ca.Monophasic action potential (MAP) alternans was induced in dog beating heart by constant high heart rate. MAP alternans tended to appear with shorter the CL and lower the body temperature. Caffeine decrease MAP alternans in the dose dependent manner. It was concluded that u V-TWA induced by constant high heart rate could be attributed to intracellular Ca cycling by sarcoplasmic reticulum.

Exercise recordings for the detection of T wave alternans: Promises and pitfalls

Despite significant advances in the treatment of sudden cardiac death, many individuals still go untreated because routine clinical tests do not identify them to be at risk. Recently, a study to identify individuals at risk has shown that the presence of T wave alternans (TWA), a fluctuation in T wave morphology occurring on an every-other-beat basis, is an accurate predictor of subsequent ventricular tachyarrhythmic events. T wave alternans as low as a few microvolts was found to be significant in predicting risk. Since TWA is often detectable only at elevated heart rates, the study used atrial pacing to increase the heart rate to approximately 100 beats/min. To make TWA measurement more broadly applicable, the authors have developed a methodology that uses noninvasive physiologic stress to raise the heart rate. A particular challenge was the measurement of TWA during exercise, since the levels of noise during exercise can far exceed the levels of TWA. However, by using special multisegment Hi-Res electrodes (Cambridge Heart, Bedford, MA), noise reduction software, and a spectral method of alternans analysis, the authors have been able to reduce noise and reliably measure microvolt-level alternans. This study presents an overview of the methodology for recording and analyzing microvolt-level TWA during ergometer exercise.

1027-40 How to Detect ECG T-Wave Alternans in Patients at Risk for Sudden Cardiac Death

We have shown previously that subtle and visually inapparent T wave alternans (TWA) is a marker of susceptibility to sudden cardiac death (SCD). Since the characteristics of TWA in patients with SCD are poorly understood. the optimal technique for detecting TWA remains controversial. To resolve this problem, high-fidelity orthogonal ECGs were recorded during atrial pacing (100 bpml from 35 patients undergoing EP testing. TWA measured by fast Fourier transform (FFT) and complex demodulation (CD) techniques were compared in two groups of patients; 1. High Risk Group (n = 15); Inducible sustained monomorphic VT at EP testing or SCD during 20 month follow up, and 2. Low Risk Group (n = 20); Negative EP test and no SCD during 20 month follow up. With FFT. beat-to-beat T wave amplitude oscillations occurring at the alternans frequency are measured relative to spectral noise. With CD, beat-to-beat T wave amplitude oscillations were modeled as a sinusoid whose amplitude is assumed to be a measure of TWA without regard to noise levels. The magnitude of TWA measured by FFT and CD correlated well (r 2 = 0.97) when TWA levels were relatively high (&gt;5 μ V). However, the detection of very low level (1 μ V – 5 μ V), but prognostically important TWA differed considerably between the two techniques. Using a cutoff TWA level of 2 μ V to define TWA positivity, FFT predicted high risk for SCD with a sensitivity of 70% and specificity of 80%, whereas CD had a sensitivity of 90% and specificity of only 5%. Computer simulations performed with an idealized alternans wave form demonstrated that the poor specificity of CD was due to an inability of CD to selectively discriminate TWA from noise. When the phase of TWA was reset on random beats (to simulate ectopic beats), TWA was measured more accurately by CD than FFT. However, phase resetting was found in only 2.7% of ECG complexes analyzed from patients and its presence did not substantially obscure the detection of TWA by FFT compared to CD. Very low level TWA is a prognostically significant marker for SCD and is more accurately measured using the FFT technique. The enhanced specificity of FFT compared to CD results from the capability of FFT to discriminate low level TWA from noise.