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1.  Ability of ambulatory ECG-based T-wave alternans to modify risk assessment of cardiac events: a systematic review 
Exercise-based spectral T-wave alternans (TWA) has been proposed as a noninvasive tool-identifying patients at risk of sudden cardiac death (SCD) and cardiac mortality. Prior studies have indicated that ambulatory electrocardiogram (AECG)-based TWA is an important alternative platform to exercise for risk stratification of cardiac events. This study sought to review data regarding 24-hour AECG-based TWA and to discuss its potential role in risk stratification of fatal cardiac events across a series of patient risk profiles.
Prospective clinical studies of the predictive value of AECG-based TWA obtained with daily activity published between January 1990 and November 2014 were retrieved. Major endpoints included composite endpoint of SCD, cardiac mortality, and severe arrhythmic events.
Data were accumulated from 5 studies involving a total of 1,588 patients, including 317 positive and 1,271 negative TWA results. Compared with the negative group, positive group showed increased rates of SCD (hazard ratio [HR]: 7.49, 95% confidence interval [CI]: 2.65 to 21.15), cardiac mortality (HR: 4.75, 95% CI: 0.42 to 53.55), and composite endpoint (SCD, cardiac mortality, and severe arrhythmic events, HR: 5.94, 95% CI: 1.80 to 19.63). For the 4 studies evaluating TWA measured using the modified moving average method, the HR associated with a positive versus negative TWA result was 9.51 (95% CI: 4.99 to 18.11) for the composite endpoint.
The positive group of AECG-based TWA has a nearly six-fold risk of severe outcomes compared with the negative group. Therefore, AECG-based TWA provides an accurate means of predicting fatal cardiac events.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2261-14-198) contains supplementary material, which is available to authorized users.
PMCID: PMC4289555  PMID: 25528490
T-wave alternans; Ambulatory electrocardiogram; Sudden cardiac death; Cardiac event
2.  On the Estimation of T-Wave Alternans Using the Spectral Fast Fourier Transform Method 
Heart Rhythm  2011;9(3):449-456.
T-wave alternans (TWA), has been associated with increased vulnerability to ventricular tachyarrhythmias and sudden cardiac death (SCD). However, both random (white) noise and (patho)physiologic processes (i.e. premature ventricular contractions [PVCs], heart and respiration rates) may hamper TWA estimation and therefore, lessen its clinical utility for risk stratification.
To investigate the effect of random noise and certain (patho)physiologic processes on the estimation of TWA using the Fast Fourier Transform (FFT) method and to develop methods to overcome these potential sources of error.
We used a combination of human electrocardiogram data and computer simulations to assess the effects of a PVC, random and colored noise on the accuracy of TWA estimation.
We quantitatively demonstrate that replacing a “bad” beat with an odd/even median beat is a more accurate approach than replacing it with the overall average or the overall median beat. We also show that phase resetting may have a significant effect on alternans estimation and that estimation of alternans using frequencies greater than 0.4922 cycles/beat in a 128-point FFT provides the most accurate approach for estimating the alternans when phase resetting is likely to occur. Additionally, our data demonstrate that the number of indeterminate TWA tests due to high levels of noise can be reduced when the alternans voltage exceeds a new higher threshold. Also, the amplitude of random noise has a significant effect on alternans estimation and should be considered to adjust the alternans voltage threshold for noise levels greater than 1.8 μV. Finally, we quantitatively demonstrate that colored noise may lead to a false positive or a false negative result. We propose methods to estimate the effect of these (patho)physiologic processes on the alternans estimation in order to determine whether a TWA test is likely to be a true positive or a true negative.
This study introduces novel methods to overcome potential sources of error in the estimation of TWA. These methods may improve the utility of TWA either for ambulatory monitoring or for clinical risk stratification for ventricular arrhythmias and SCD.
PMCID: PMC3288719  PMID: 22001706
arrhythmias; alternans; phase resetting; random and colored noise
3.  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, namely, heart rate, autonomic nervous system activities, 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 circadian factors, mental stress, and sleep-state related disturbances in respiratory and cardiovascular function. Two major emerging concepts in clinical TWA testing are discussed, namely, 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.
PMCID: PMC2672309  PMID: 19251221
T-wave alternans; sudden cardiac death; cardiac arrest; ventricular fibrillation; ventricular tachycardia; risk stratification
4.  The Role of Microvolt T-Wave Alternans to Assess Arrhythmia Vulnerability Among Patients with Heart Failure and Systolic Dysfunction: Primary Results from the TWA SCD-HeFT Substudy 
Circulation  2008;118(20):2022-2028.
Sudden cardiac death remains a leading cause of mortality despite advances in medical treatment for the prevention of ischemic heart disease and heart failure. Recent studies showed a benefit of ICD implantation, but appropriate shocks for ventricular tachyarrhythmias were only noted in a minority of patients during 4-5 years of follow-up. Accordingly, better risk stratification is needed to optimize patient selection. In this regard microvolt T-wave alternans (TWA) has emerged as a potentially useful measure of arrhythmia vulnerability, but it has not been evaluated previously in a prospective randomized trial of ICD therapy.
Methods and Results
This investigation was a prospective substudy of the SCD-HeFT trial including 490 patients at 37 clinical sites. TWA tests were classified by blinded readers as + (37%), - (22%), or indeterminate (41%) by standard criteria. The composite primary endpoint was the first occurrence of any of the following events: sudden cardiac death, sustained ventricular tachycardia/fibrillation or appropriate ICD discharge. During a median follow-up of 30 months, there were no significant differences in event rates between TWA + or − patients (Hazard ratio 1.24, p=0.56, [CI 0.60, 2.59]), or TWA − and non − (+ and indeterminate) subjects (Hazard ratio 1.28, p=0.46, CI [0.65, 2.53]). Similar results were obtained including or excluding patients randomized to amiodarone in the analyses.
TWA testing did not predict arrhythmic events or mortality in SCD-HeFT, although a small reduction of events (20-25%) among TWA − patients cannot be excluded given the sample size of this study. Accordingly, these results suggest that TWA is not useful to help make clinical decisions regarding ICD therapy among patients with heart failure and left ventricular systolic dysfunction.
PMCID: PMC2777708  PMID: 18955671
Defibrillation; Electrocardiography; Heart Failure; T-wave alternans
5.  Body Surface Mapping of T-wave Alternans Depends on the Distribution of Myocardial Scarring 
T-Wave alternans (TWA) testing using 12-lead electrocardiogram/Frank leads is emerging as an important non-invasive biomarker to identify patients at high risk of Sudden Cardiac Death (SCD). Cardiac scarring is very common among cardiomyopathy patients; however, its influence on the body surface distribution of TWA has not yet been defined. Our objective was to perform a simulation study in order to determine whether cardiac scarring affects the distribution of TWA on thorax such that the standard leads fail to detect TWA in some of cardiomyopathy patients; thereby producing a false-negative test. Developing such a novel lead configuration could improve TWA quantification and potentially optimize electrocardiogram (ECG) lead configuration and risk stratification of SCD in cardiomyopathy patients. The simulation was performed in a 1500-node heart model using ECGSIM. TWA was mimicked by simulating action potential duration alternans in the ventricles. Cardiac scarring with different sizes were simulated by manipulating the apparent velocity, transmembrane potential and transition zone at varied locations along the left ventricular posterior wall. Our simulation study showed that the location of maximum TWA depends on the location and size of the myocardium scarring in patients with cardiomyopathy, which can give rise to false-negative TWA signal detection using standard clinical leads. The TWA amplitude generally increased with the increment of scar size (P<0.00001). We found one specific location (a non-standard lead) that consistently appeared as the top five maximum TWA leads and could be considered as an additional lead to improve the outcome of the TWA testing in cardiomyopathy patients.
PMCID: PMC4378024  PMID: 25834653
Body surface mapping; cardiomy-opathy; ECGSIM; sudden cardiac death; t-wave alternans testing
6.  Correlation between T-Wave Alternans and Cardiac Volume Status via Intrathoracic Impedance Measurements 
Case Reports in Cardiology  2012;2012:167562.
Introduction. The presence of T-wave alternans (TWA) has been shown to correlate with a higher risk for sudden cardiac death. The mechanism of TWA may be related to abnormalities in intracellular calcium handling, which is a mechanism in heart failure and associated arrhythmias as well. However, an association between TWA and cardiac volume status has not been demonstrated. Methods Used. We report the case of a 54-year-old man with a dilated cardiomyopathy who had a biventricular defibrillator system implanted with intrathoracic impedance measurement capability. We performed baseline TWA testing, which was normal and was associated with normal clinical status and normal intrathoracic impedance. We followed intrathoracic impedance measurements, and when the measurement suggested volume overload eight months later, we repeated the TWA test. TWA was grossly positive, and volume overload was corroborated with clinical heart failure. The patient was diuresed, and when clinical status and intrathoracic impedance returned to normal a month later, we repeated TWA, which was again negative. Conclusion. This case demonstrates a correlation between cardiac volume status, as measured by intrathoracic impedance measurements, and TWA status. This data suggests that conditions of volume overload such as heart failure could be causally related to increased TWA, perhaps by the common mechanism of altered intracellular calcium handling.
PMCID: PMC4008472  PMID: 24826235
7.  Identification of Gender-Related Normality Regions for T-Wave Alternans 
T-wave alternans (TWA), a harbinger of sudden cardiac death, associates to a broad variety of pathologies. In a previous study, we observed the presence of unstable and low-amplitude TWA also in healthy subjects, and considered it as “physiological TWA.” The possible existence of different TWA characteristics between males and female is investigated in the present work.
Resting ECG recordings from 142 control healthy subjects, 77 males and 65 females, were submitted to our adaptive match filter (AMF) based method for TWA detection and characterization in terms of duration, amplitude, and their product. The 99.5th percentile of these parameters distributions over the entire control population and over the male and female subgroups, were used to define thresholds which delimit a gender-independent and male- and female-related TWA normality regions, respectively, out of which abnormal TWA cases (TWA+) are expected to fall. Clinical usefulness of these regions was tested using a population of 151 coronary artery disease (CAD) patients, divided into 128 males and 23 females.
In our control-female population, TWA duration was significantly longer than in control-male population (65 ± 13 beat vs 52 ± 14 beat; P < 10−6). Our gender-related normality regions allowed identification of 36 (23.8%) TWA+ cases among the CAD patients, 17 more than those obtained from a gender-independent region. All these 17 patients were CAD males with over-threshold TWA duration.
TWA is a gender-related phenomenon. Definition of gender-related TWA normality regions improves identification of patients at increased TWA stability (i.e., prolonged TWA duration) and, thus, at increased risk of arrhythmic events.
PMCID: PMC3124337  PMID: 20946555
repolarization variability; sudden cardiac death; ECG signal processing
8.  Explaining the clinical manifestations of T wave alternans in patients at risk for sudden cardiac death 
The mechanisms underlying sudden cardiac death (SCD) are complex and diverse. Therefore, correct application of any marker to risk stratify patients for appropriate therapy requires knowledge regarding how the marker is reflective of a particular electro-anatomical substrate for arrhythmias. Non-invasive measurement of beat-to-beat alternation of the electrocardiographic T-wave, referred to as T-wave alternans (TWA), is an important marker of risk for sudden cardiac death (SCD). Is this relationship a mere association or is TWA mechanistically linked to SCD? Recent experimental evidence strongly supports a mechanistic relationship between TWA and SCD. This review will consider the underlying mechanisms of TWA derived from experimental studies, as they relate to clinical observations of TWA in humans, addressing the following questions derived from common clinical observations: 1) Where does TWA on the surface ECG come from? 2) Why is controlled heart rate elevation required to elicit TWA? 3) Why is TWA associated with risk for SCD? 4) Why is TWA associated with a broad range of ventricular arrhythmias? and 5) How do commonly used medications affect TWA?
PMCID: PMC2680220  PMID: 19168395
repolarization; electrophysiology; tachycardia; calcium
9.  T-Wave Alternans Patterns During Sleep in Healthy, Cardiac Disease and Sleep Apnea Patients 
Journal of electrocardiology  2010;44(2):126-130.
T-Wave Alternans (TWA) activity is known to be a function of heart rate and condition, as well as perhaps physiological state. A recently published non-parametric non-stationary TWA analysis method has been shown to reject nonstationary noise accurately using phase randomized surrogates and has been shown to estimate TWA accurately. This new method was evaluated on multiple databases over a range of heart rates and in healthy subjects, cardiac patients, and obstructive sleep apnea (OSA) patients. We hypothesized that TWA would be lower than previously reported when measured with our new technique and that higher levels of TWA would be observed in OSA patients when compared to normals.
Five databases were analyzed: 1) Healthy subjects from PhysioNet’s Normal Sinus Rhythm Database (NSRDB), 2) Arrhythmia patients from PhysioNet’s Chronic Heart Failure Database (CHFDB) and 3) PhysioNet’s Sudden Cardiac Death Database (SCDDB), 4) OSA patients from PhysioNet’s MIT-BIH Polysomnographic Database (SLPDB), and 5) a private Sleep Apnea Database (SADB) of 85 subjects. TWA magnitudes were calculated for 7 heart rate decades [intervals of 10 beats per minute (BPM) between 40 and 110 BPM] for each database. The Mann-Whitney U-test and the two-sample Kolmogorov-Smirnov test were applied to test for significant differences between data from each database in each heart rate decade interval.
In the healthy population TWA activity level tended to increase with heart rate. Moreover, there appeared to be an unexpected nadir in TWA activity around 60–70 BPM, and a small but significant rise in TWA above and below these heart rates. The rise in TWA at lower heart rates has not been previously reported to our knowledge. We also observed that TWA is unexpectedly lower in OSA patients and did not increase with heart rate.
Although the physiological mechanisms underlying our observations are unclear, there may be clinical implications for TWA testing, particularly at low heart rates, a previously overlooked aspect of TWA.
PMCID: PMC3062089  PMID: 21163493
10.  Prognostic utility of T-wave alternans in a real-world population of patients with left ventricular dysfunction: the PREVENT-SCD study 
Clinical Research in Cardiology  2011;101(2):89-99.
The predictive value of T-wave alternans (TWA) for lethal ventricular tachyarrhythmia in patients with left ventricular (LV) dysfunction is controversial. Also, long-term arrhythmia risk of patients ineligible for the TWA test is unknown.
This was a multicenter, prospective observational study of patients with LV ejection fraction ≤40% due to ischemic or non-ischemic cardiomyopathies, designed to evaluate the prognostic value of TWA for lethal ventricular tachyarrhythmia. The primary end point was a composite of sudden cardiac death, sustained rapid ventricular tachycardia (VT) or ventricular fibrillation (VF), and appropriate defibrillator therapy for rapid VT or VF.
Among 453 patients enrolled in the study, 280 (62%) were eligible for the TWA test. TWA was negative in 82 patients (29%), who accounted for 18% of the total population. The median of follow-up was 36 months. The 3-year event-free rate for the primary end point was significantly higher in TWA-negative patients (97.0%) than in TWA non-negative patients (89.5%, P = 0.037) and those ineligible for the TWA test (84.4%, P = 0.003). Multivariable analysis identified both non-negative TWA [hazard ratio (HR) 4.43; 95% confidence interval (CI) 1.02–19.2; P = 0.047) and ineligibility for the TWA test (HR 6.89; 95% CI 1.59–29.9; P = 0.010) to be independent predictors of the primary end point.
TWA showed high negative predictive ability for lethal ventricular tachyarrhythmia in patients with LV dysfunction, although the TWA-negative patients accounted for only 18% of the entire population. Those ineligible for the TWA test had the highest risk for lethal ventricular tachyarrhythmia.
Electronic supplementary material
The online version of this article (doi:10.1007/s00392-011-0368-2) contains supplementary material, which is available to authorized users.
PMCID: PMC3268016  PMID: 21960418
Sudden death; Ventricular arrhythmia; Cardiomyopathy; T-wave alternans
11.  Microvolt T-Wave Alternans 
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.
PMCID: PMC4111570  PMID: 21920259
ambulatory ECG monitoring; cardiovascular mortality; exercise testing; risk stratification; sudden cardiac death; T-wave alternans
12.  A Non-Parametric Surrogate-based Test of Significance for T-Wave Alternans Detection 
We present a non-parametric adaptive surrogate test that allows for the differentiation of statistically significant T-Wave Alternans (TWA) from alternating patterns that can be solely explained by the statistics of noise. The proposed test is based on estimating the distribution of noise induced alternating patterns in a beat sequence from a set of surrogate data derived from repeated reshuffling of the original beat sequence. Thus, in assessing the significance of the observed alternating patterns in the data no assumptions are made about the underlying noise distribution. In addition, since the distribution of noise-induced alternans magnitudes is calculated separately for each sequence of beats within the analysis window, the method is robust to data non-stationarities in both noise and TWA. The proposed surrogate method for rejecting noise was compared to the standard noise rejection methods used with the Spectral Method (SM) and the Modified Moving Average (MMA) techniques. Using a previously described realistic multi-lead model of TWA, and real physiological noise, we demonstrate the proposed approach reduces false TWA detections, while maintaining a lower missed TWA detection compared with all the other methods tested.
A simple averaging-based TWA estimation algorithm was coupled with the surrogate significance testing and was evaluated on three public databases; the Normal Sinus Rhythm Database (NRSDB), the Chronic Heart Failure Database (CHFDB) and the Sudden Cardiac Death Database (SCDDB). Differences in TWA amplitudes between each database were evaluated at matched heart rate (HR) intervals from 40 to 120 beats per minute (BPM). Using the two-sample Kolmogorov-Smirnov test, we found that significant differences in TWA levels exist between each patient group at all decades of heart rates. The most marked difference was generally found at higher heart rates, and the new technique resulted in a larger margin of separability between patient populations than when the SM or MMA were applied to the same data.
PMCID: PMC2991534  PMID: 20409986
ECG; Noise; Surrogate Analysis; T-Wave Alternans; TWA
13.  T Wave Alternans And Ventricular Tachyarrhythmia Risk Stratification: A Review 
Sudden cardiac death (SCD) is one of the leading causes of mortality in industrialized countries. Thus, identifying patients at high risk of SCD is an important goal. T wave alternans (TWA) is a new method for identifying patients with lethal ventricular tachyarrhythmias, and is dependent on heart rate. The maximal predictive accuracy is achieved at heart rates between 100 and 120 bpm, so that TWA is usually measured during exercise, phamacological stress, or atrial pacing. It has been shown that TWA has high sensitivity and negative predictive value for predicting SCD after myocardial infarction and is also useful for predicting SCD in patients with nonischemic cardiomyopathy. Although the implantable cardioverter defibrillator (ICD) is now the primary therapy for preventing SCD, it is difficult to identify those patients who are susceptible to lethal ventricular tachyarrhythmias for primary prevention. In the prediction of SCD, TWA can be used as a screening test of appropriate patients for further electrophysiological examination and therapy.
PMCID: PMC1513519  PMID: 16943959
T wave alternans; sudden cardiac death; ventricular tachyarrhythmia
14.  Ventricular arrhythmias in competitive athletes: risk stratification with T-wave alternans 
Heart International  2007;3(1):58.
Aim of our study is to evaluate the role of TWA to stratify the risk of sudden cardiac death in athletes (Ath) with complex ventricular arrhythmias (VA), and to document a possible correlation between TWA and electrophysiological testing (EES) results.
We studied 43 Ath with VA (31 M, mean age 34 ± 12 years). In all cases a cardiological evaluation was performed, including TWA and EES. The patients were evaluated during a follow-up of 25 ± 22 months. The end-point was the occurrence of sudden death or malignant ventricular tachyarrhythmias (VT).
TWA was negative in 28 Ath (65%), positive in 8 (19%) and indeterminate in 7 (16%). All subjects with negative TWA did not show induction of VT at EES, with significant correlation between negative TWA and negative EES (p<0.001). All Ath with positive TWA also had VT induced by a EES, but without significant correlation between positive TWA and positive EES. In 2 Ath with undetermined TWA (29%) VT were induced at EES. Our data did not show significant correlation between indeterminate TWA and positive or negative EES. However, logistic regression analysis showed significant correlation between abnormal TWA test (positive or indeterminate) and inducibility of VT at EES (p<0.001). During follow-up we observed a significant difference in end-point occurrence between Ath with negative or positive TWA and between Ath with negative or positive EES.
TWA confirm its role as a simple and non-invasive test, and it seems useful for prognostic stratification of Ath with VA.
PMCID: PMC3184678  PMID: 21977276
T-wave alternans; Sudden death; Ventricular arrhythmias; Sport activity
15.  T-wave Alternans, Air Pollution and Traffic in High-risk Subjects 
The American journal of cardiology  2009;104(5):665-670.
Particulate pollution has been linked to risk of cardiac death; possible mechanisms include pollution-related increases in cardiac electrical instability. T-wave alternans (TWA) is a marker of cardiac electrical instability measured as differences in the magnitude between adjacent T waves. In a repeated-measures study of 48 patients aged 43-75 years, we investigated associations of ambient and home indoor particulate pollution including black carbon (BC) and report of traffic exposure, with changes in half-hourly maximum TWA (TWA-MAX), measured by 24 hour Holter electrocardiogram monitoring. Each patient was observed up to 4 times within one year after percutaneous intervention for myocardial infarction, acute coronary syndrome without infarction, or stable coronary artery disease for a total of 5,830 half-hour observations. Diary data for each half-hour period defined whether the patient was home or not home, or in traffic. Increases in TWA-MAX were independently associated both with the previous 2-h mean ambient BC (2.1%; 95% C.I.: 0.9-3.3) and with being in traffic in the previous 2 hours (6.1%; 95% C.I.: 3.4-8.8). When subjects were home, indoor home BC effects were largest and most precise; when subjects were away from home, ambient central site BC effects were strongest. Increases in pollution increased the odds of TWA-MAX ≥ 75th percentile (OR 1.4; 95% CI: 1.2-1.6 for 1 μg/m3 increase in 6-h mean BC). In conclusion, following hospitalization for coronary artery disease, being in traffic, and short-term ambient or indoor BC exposures increase TWA, a marker of cardiac electrical instability.
PMCID: PMC3139397  PMID: 19699342
Air pollution; coronary disease; myocardial infarction; T-wave alternans; circadian rhythm
16.  Hormone Replacement Therapy Is Safe in Women Undergoing Coronary Artery Bypass Grafting 
In postmenopausal women, hormone replacement therapy (HRT) does not substantially reduce the incidence of cardiovascular disease and may produce a short-term increase in risk. Therefore, we investigated whether HRT increased risk in patients with severe coronary artery disease necessitating surgery.
We prospectively studied 4,782 patients undergoing coronary artery bypass grafting at 70 centers in 17 countries from November 1996 through June 2000. Patients were selected using a systematic sampling technique. Mortality, major morbidity, and transfusion requirements were compared among 3 groups: men (n = 3,840), women receiving HRT (n = 144), and women not receiving HRT (n = 798).
Women actively receiving HRT, compared with women not receiving HRT or with men, were at no greater risk of developing the following fatal or non-fatal complications: death (2.8% vs 4.4% vs 2.8%, respectively; P = 0.05), myocardial infarction (6.3% vs 7.0% vs 7.7%; P = 0.67), central nervous system complication (2.1% vs 2.8% vs 2.9%; P = 0.85), or renal dysfunction (0.7% vs 5.3% vs 4.8%; P = 0.06). Incidence of postoperative congestive heart failure was significantly lower in men (7.7%) than in women receiving HRT (12.5%; P = 0.04) and in women without HRT (12.8%; P <0.0001). Fewer men (61%) needed red blood cell transfusion than did women receiving HRT (79%) and women without HRT (88%) (P < 0.0001 compared with both other groups). However, the need for fresh frozen plasma transfusions was significantly less in women receiving HRT (16%) than in women not receiving HRT (25%; P = 0.01). We conclude that HRT administration before coronary artery bypass grafting does not increase women's risk of any adverse outcome.
PMCID: PMC1351821  PMID: 16429894
Coronary artery bypass; estrogen replacement therapy; female; hormone replacement therapy; male; mortality rate; postoperative complications; sex factors; transfusion, blood; treatment outcome
17.  Improved Stratification of Autonomic Regulation for risk prediction in post-infarction patients with preserved left ventricular function (ISAR-Risk) 
European Heart Journal  2008;30(5):576-583.
To investigate the combination of heart rate turbulence (HRT) and deceleration capacity (DC) as risk predictors in post-infarction patients with left ventricular ejection fraction (LVEF) > 30%.
Methods and results
We enrolled 2343 consecutive survivors of acute myocardial infarction (MI) (<76 years) in sinus rhythm. HRT and DC were obtained from 24 h Holter recordings. Patients with both abnormal HRT (slope ≤ 2.5 ms/RR and onset ≥ 0%) and abnormal DC (≤4.5 ms) were considered suffering from severe autonomic failure (SAF) and prospectively classified as high risk. Primary and secondary endpoints were all-cause, cardiac, and sudden cardiac mortality within the first 5 years of follow-up. During follow-up, 181 patients died; 39 deaths occurred in 120 patients with LVEF ≤ 30%, and 142 in 2223 patients with LVEF>30% (cumulative 5-year mortality rates of 37.9% and 7.8%, respectively). Among patients with LVEF > 30%, SAF identified another high-risk group of 117 patients with 37 deaths (cumulative 5-year mortality rates of 38.6% and 6.1%, respectively). Merging both high-risk groups (i.e. LVEF ≤ 30% and/or SAF) doubled the sensitivity of mortality prediction compared with LVEF ≤ 30% alone (21.1% vs. 42.1%, P < 0.001) while preserving 5-year mortality rate (38.2%).
In post-MI patients with LVEF>30%, SAF identifies a high-risk group equivalent in size and mortality risk to patients with LVEF ≤ 30%.
PMCID: PMC2649285  PMID: 19109245
Autonomic function; Myocardial infarction; Risk stratification; Sudden death
18.  Anger-induced T-wave alternans predicts future ventricular arrhythmias in patients with implantable cardioverter-defibrillators 
To determine whether T-wave alternans (TWA) induced by anger in a laboratory setting predicts future ventricular arrhythmias (VT/VF) in patients with implantable cardioverter-defibrillators (ICDs).
Anger can precipitate spontaneous VT/VF, and induce TWA. Whether anger-induced TWA predicts future arrhythmias is unknown.
Sixty-two patients with ICDs underwent ambulatory ECG during a mental stress protocol, three months post-implant. TWA was analyzed using time-domain methods. After ≥ 1 year follow-up, ICD stored data was reviewed to determine incidence of ICD-terminated VT/VF.
Patients with ICD-terminated arrhythmias during follow-up (N=10) had higher TWA induced by anger, 13.2uV (iqr 9.3-16), compared to 9.3uV (7.5-11.5) (p<0.01). Patients in the highest quartile of anger-induced TWA (>11.9uV, N=15) were more likely to experience arrhythmias by one year than those in the lower quartiles, (33% versus 4%), and during extended follow-up (40% versus 9%, p<0.01 for both.) In multivariable regression controlling for ejection fraction, prior clinical arrhythmia, and wide QRS, anger-induced TWA remained a significant predictor of arrhythmia, with likelihood in the top quartile 10.8 times that of other patients (CI 1.6-113, p<0.05.)
Anger-induced TWA predicts future ventricular arrhythmias in patients with ICDs, suggesting that emotion-induced repolarization instability may be one mechanism linking stress and sudden death. Whether there is a clinical role for anger-induced TWA testing requires further study.
PMCID: PMC3979284  PMID: 19245968
tachyarrhythmias (ventricular); anger; implantable cardioverter-defibrillator
19.  A Novel Method for Determining the Phase of T-Wave Alternans: Diagnostic and Therapeutic Implications 
Circulation. Arrhythmia and electrophysiology  2013;6(4):10.1161/CIRCEP.113.000114.
T-wave alternans (TWA) has been implicated in the pathogenesis of ventricular arrhythmias and sudden cardiac death (SCD). However, in order to effectively estimate and suppress TWA, the phase of TWA must be accurately determined.
Methods and Results
We developed a method that computes the beat-by-beat integral of the T-wave morphology, over time points within the T-wave with positive alternans. Then, we estimated the signed derivative of the T-wave integral sequence which allows the classification of each beat to a binary phase index. In animal studies, we found that this method was able to accurately identify the T-wave phase in artificially induced alternans (p<0.0001). The coherence of the phase increased consistently after acute ischemia induction in all body-surface and intracardiac leads (p<0.0001). Also, we developed a phase resetting detection algorithm that enhances the diagnostic utility of TWA. We further established an algorithm that employs the phase of TWA in order to deliver appropriate polarity pacing pulses (all interventions compared to baseline, p<0.0001 for alternans voltage; p<0.0001 for Kscore), to suppress TWA. Finally, we demonstrated that using the phase of TWA we can suppress spontaneous TWA during acute ischemia; 77.6% for alternans voltage (p<0.0001) and 92.5% for Kscore (p<0.0001).
We developed a method to quantify the temporal variability of the TWA phase. This method is expected to enhance the utility of TWA in predicting ventricular arrhythmias and SCD and raises the possibility of using upstream therapies to abort a ventricular tachyarrhythmia prior to its onset.
PMCID: PMC3845209  PMID: 23884196
alternans; arrhythmia (heart rhythm disorders); pacing; implantable cardioverter-defibrillator
20.  Is T-Wave Alternans Testing Feasible in Candidates for Prophylactic Implantable Defibrillators? 
Netherlands Heart Journal  2010;19(1):6-9.
Previous studies have demonstrated that microvolt T-wave alternans (TWA) screening in patients with ischaemic and dilated cardiomyopathy is effective in identifying patients at high or low risk of sudden cardiac death. It remains unclear which percentage of potential recipients of an implantable cardioverter defibrillator (ICD) are able to perform TWA testing using an exercise protocol which is, at this moment, the golden standard. In this study, we evaluated the feasibility of TWA in the risk stratification of potential ICD recipients with ischaemic or dilated cardiomyopathy.
Methods and Results
Medical charts of 165 primary prevention ICD recipients were reviewed to decide if patients were able to perform a TWA exercise test or not. Reasons to waiver a test were: atrial fibrillation or flutter, pacemaker dependency, recent (cardiovascular) surgery (<1 month) and inability to exercise. Of the potential ICD recipients 35% had one or more of these contraindications and were therefore not suitable for testing.
In several studies, TWA is a promising risk stratifier for predicting sudden cardiac death; however, in our population, 35% of the potential ICD candidates could not be tested. In order to fulfil its promise as a predictor for SCD, an alternative means to measure TWA needs to be evaluated.
PMCID: PMC3077831  PMID: 22020855
Microvolt T-wave alternans; Implantable cardioverter defibrillator; Risk stratification; Ischemic cardiomyopathy; Dilated cardiomyopathy
21.  Cardiac Repolarization Instability During Normal Postnatal Development 
Journal of electrocardiology  2008;41(6):474-479.
Long QT Syndrome (LQTS) is a disease characterized by abnormal lengthening of the QT interval and by sudden cardiac death. LQTS 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 ECG correlates with arrhythmia risk and long-term survival in adults. We determined TWA properties longitudinally in vivo in seven propofol-sedated NZW rabbits using transesophageal pacing weekly from 2 to 10 weeks of age. Also, TWA induction following the onset of rapid pacing was characterized in vitro in six infant (2 week) and six adolescent (7 week) 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.
PMCID: PMC2600796  PMID: 18804789
repolarization; ontogeny; alternans; neonate; arrhythmia; adolescent
22.  The PhysioNet / Computers in Cardiology Challenge 2008: T-Wave Alternans 
Computers in cardiology  2008;2008:505-508.
The 9th annual PhysioNet/Computers in Cardiology challenge invited participants to measure T-wave alternans (TWA) in a set of 100 two-minute electrocardiograms that included subjects with a variety of risk factors for sudden cardiac death (including ventricular tachyarrhythmias, transient myocardial ischemia, and acute myocardial infarctions), healthy controls, and synthetic ECGs with calibrated amounts of artificial TWA. The participants’ TWA estimates were used to develop a ranking of the 100 test cases in order of TWA content, and the Kendall rank correlation coefficient between this reference ranking and each individual participant’s ranking of the 100 cases was calculated as a score (between −1 and 1; actual scores were between 0.11 and 0.92). The challenge yielded insights into the strengths and weaknesses of classic and novel TWA analyses, open-source implementations of a variety of methods, and a set of freely available ECGs with reference rankings of TWA content.
PMCID: PMC2749698  PMID: 19779602
23.  Association of Holter-Based Measures Including T-wave Alternans with Risk of Sudden Cardiac Death in the Community-Dwelling Elderly: The Cardiovascular Health Study 
Journal of electrocardiology  2010;43(3):251-259.
Sudden cardiac death (SCD) can be the first manifestation of cardiovascular disease. Development of screening methods for higher / lower risk is critical.
The Cardiovascular Healthy Study (CHS) is a population-based study of risk factors for coronary heart disease and stroke those ≥65 years. N=49 (of 1649) with usable Holters and in normal sinus rhythm, suffered SCD during follow up and were matched with 2 controls, alive at the time of death of the case and not suffering SCD on follow up. Univariate and multivariate conditional logistic regression determined the association of Holter-based information and SCD.
In univariate models, the upper half of VPC counts, abnormal heart rate turbulence, decreased normalized low frequency power, increased T-wave alternans (TWA) and decreased DFA1 (short-term fractal scaling exponent) were associated with SCD, but time domain HRV was not. In multivariate models, the upper half of VPC counts (OR=6.6) and having TWA ≥37µV on Ch2 (OR=4.8) were independently associated with SCD. Also, the upper half of VPC counts (OR=6.9) and having DFA1 <1.05 (OR=5.0) were independently associated with SCD. When additive effects were explored: having both higher VPCs and higher TWA was associated with an OR of 8.2 for SCD compared to 2.6 for having either. Also, having both higher VPCs and lower DFA1 was associated with an OR of 9.6 for SCD compared to 3.1 for having either.
Results support a potential role for 24-hour Holter recordings to identify older adults at increased or lower risk of SCD.
PMCID: PMC2856790  PMID: 20096853
Sudden death; risk stratification; ambulatory ECG monitoring; heart rate variability; heart rate turbulence; T-wave alternans; arrhythmias; population-dwelling elderly
24.  Cardiac Autonomic Function Evaluated by the Heart Rate Turbulence Method was not Changed in Obese Patients without Co-morbidities 
Journal of Korean Medical Science  2007;22(4):629-632.
Obese subjects are more prone to sudden deaths and arrhythmias than non-obese subjects. Heart rate turbulence (HRT) impairment reflects cardiac autonomic dysfunction, in particular impaired baroreflex sensitivity and reduced parasympathetic activity. Our aim was to evaluate the cardiac autonomic function in obesity by the HRT method. Ninety obese subjects and 112 healthy subjects were included in the study. Twenty-four hours ambulatory electrocardiograms were recorded and Holter recordings were analyzed. HRT parameters, turbulence onset (TO) and turbulence slope (TS), were calculated with HRT View Version 0.60-0.1 software program. HRT were calculated in 43 obese and 43 control subjects who had at least one ventricular premature beat in their Holter recordings. We excluded 47 obese patients and 69 control subjects who showed no ventricular premature beats in their Holter recordings from the statistical analysis. There were no significant differences in TO and TS between obese and control subjects (TO obese: -1.6±2.2%, TO control: -2.1±2.6%, p>0.05; TS obese: 8.2±5.2, TS control: 10.1±6.7, p>0.05, respectively). HRT parameters seem to be normal in obese patients without comorbidities.
PMCID: PMC2693810  PMID: 17728500
Obesity; Heart Rate; Autonomic Nervous System
25.  A combined algorithm for T-wave alternans qualitative detection and quantitative measurement 
T-wave alternans (TWA) provides a noninvasive and clinically useful marker for the risk of sudden cardiac death (SCD). Current most widely used TWA detection algorithms work in two different domains: time and frequency. The disadvantage of the spectral analytical techniques is that they treat the alternans signal as a stationary wave with a constant amplitude and a phase. They cannot detect non-stationary characteristics of the signal. The temporal domain methods are sensitive to the alignment of the T-waves. In this study, we sought to develop a robust combined algorithm (CA) to assess T-wave alternans, which can qualitatively detect and quantitatively measure TWA in time domain.
The T wave sequences were extracted and the total energy of each T wave within the specified time-frequency region was calculated. The rank-sum test was applied to the ranked energy sequences of T waves to detect TWA qualitatively. The ECG containing TWA was quantitatively analyzed with correlation method.
Simulation test result proved a mean sensitivity of 91.2% in detecting TWA, and for the SNR not less than 30 dB, the accuracy rate of detection achieved 100%. The clinical data experiment showed that the results from this method vs. spectral method had the correlation coefficients of 0.96.
A novel TWA analysis algorithm utilizing the wavelet transform and correlation technique is presented in this paper. TWAs are not only correctly detected qualitatively in frequency domain by energy value of T waves, but the alternans frequency and amplitude in temporal domain are measured quantitatively.
PMCID: PMC3554460  PMID: 23311454
T-wave alternans; Continuous wavelet transform; Rank-sum test; Quantitive estimation

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