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.
T-wave alternans; sudden cardiac death; cardiac arrest; ventricular fibrillation; ventricular tachycardia; risk stratification
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.
Obesity; Heart Rate; Autonomic Nervous System
This paper presents a software package for quantitative evaluation of heart rate variability (HRV), heart rate turbulence (HRT), and T-wave alternans (TWA) from ECG recordings. The software has been developed for the purpose of scientific research rather than clinical diagnosis.
The software is written in Matlab Mathematical Language. Procedures for evaluation of HRV, HRT and TWA were implemented. HRV analysis was carried out by applying statistical and spectral parametric and nonparametric methods. HRT parameters were derived using the Schmidt algorithm. TWA analysis was performed both in spectral and in time domain by applying Poincare mapping. A flexibility of choosing from a number of classical modelling approaches and their modifications was foreseen and implemented. The software underwent preliminary verification tests both on ECGs from the Physionet online ECG signal repository and recordings taken at the Department of Electrocardiology of the Medical University Hospital in Lodz.
The result of the research is a program enabling simultaneous analysis of a number of parameters computed from ECG recordings with the use of the indicated analysis methods. The program offers options to preview the intermediate results and to alter the preprocessing steps.
By offering the possibility to cross-validate the results of analyses obtained by several methods and to preview the intermediate analysis steps, the program can serve as a helpful aid for clinicians in comprehensive research studies. The software tool can also be utilized in training programs for students and medical personnel.
ECG; HRV; HRT; TWA; computed ECG analysis
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%.
Autonomic function; Myocardial infarction; Risk stratification; Sudden 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?
repolarization; electrophysiology; tachycardia; calcium
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.
T wave alternans; sudden cardiac death; ventricular tachyarrhythmia
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.
Heart rate turbulence (HRT) is the baroreflex-mediated short-term oscillation of cardiac cycle lengths after spontaneous ventricular premature complexes. HRT is composed of a brief heart rate acceleration followed by a gradual heart rate deceleration. In high risk patients after myocardial infarction (MI) HRT is blunted or diminished. Since its first description in 1999 HRT emerged as one of the most potent risk factors after MI. Predictive power of HRT has been studied in more than 10,000 post-infarction patients. This review is intended to provide an overview of HRT as risk-predictor after MI.
autonomic function; heart rate turbulence; myocardial infarction; risk stratification; sudden death
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.
Air pollution; coronary disease; myocardial infarction; T-wave alternans; circadian rhythm
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.
arrhythmias; alternans; phase resetting; random and colored noise
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.
T-wave alternans; Continuous wavelet transform; Rank-sum test; Quantitive estimation
Background: Epidemiological studies have assessed T-wave alternans (TWA) as a possible mechanism of cardiac arrhythmias related to air pollution in high-risk subjects and have reported associations with increased TWA magnitude.
Objective: In this controlled human exposure study, we assessed the impact of exposure to concentrated ambient particulate matter (CAP) and ozone (O3) on T-wave alternans in resting volunteers without preexisting cardiovascular disease.
Methods: Seventeen participants without preexisting cardiovascular disease were randomized to filtered air (FA), CAP (150 μg/m3), O3 (120 ppb), or combined CAP + O3 exposures for 2 hr. Continuous electrocardiograms (ECGs) were recorded at rest and T-wave alternans (TWA) was computed by modified moving average analysis with QRS alignment for the artifact-free intervals of 20 beats along the V2 and V5 leads. Exposure-induced changes in the highest TWA magnitude (TWAMax) were estimated for the first and last 5 min of each exposure (TWAMax_Early and TWAMax_Late respectively). ΔTWAMax (Late–Early) were compared among exposure groups using analysis of variance.
Results: Mean ± SD values for ΔTWAMax were –2.1 ± 0.4, –2.7 ± 1.1, –1.9 ± 1.5, and –1.2 ± 1.5 in FA, CAP, O3, and CAP + O3 exposure groups, respectively. No significant differences were observed between pollutant exposures and FA.
Conclusion: In our study of 17 volunteers who had no preexisting cardiovascular disease, we did not observe significant changes in T-wave alternans after 2-hr exposures to CAP, O3, or combined CAP + O3. This finding, however, does not preclude the possibility of pollution-related effects on TWA at elevated heart rates, such as during exercise, or the possibility of delayed responses.
air pollution; arrhythmia; controlled exposure; ozone; particulate matter; T-wave alternans
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.
repolarization; ontogeny; alternans; neonate; arrhythmia; adolescent
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.
Sudden death; risk stratification; ambulatory ECG monitoring; heart rate variability; heart rate turbulence; T-wave alternans; arrhythmias; population-dwelling elderly
To determine whether risk stratification tests can predict serious arrhythmic events after acute myocardial infarction (AMI) in patients with reduced left ventricular ejection fraction (LVEF ≤ 0.40).
Methods and results
A total of 5869 consecutive patients were screened in 10 European centres, and 312 patients (age 65 ± 11 years) with a mean LVEF of 31 ± 6% were included in the study. Heart rate variability/turbulence, ambient arrhythmias, signal-averaged electrocardiogram (SAECG), T-wave alternans, and programmed electrical stimulation (PES) were performed 6 weeks after AMI. The primary endpoint was ECG-documented ventricular fibrillation or symptomatic sustained ventricular tachycardia (VT). To document these arrhythmic events, the patients received an implantable ECG loop-recorder. There were 25 primary endpoints (8.0%) during the follow-up of 2 years. The strongest predictors of primary endpoint were measures of heart rate variability, e.g. hazard ratio (HR) for reduced very-low frequency component (<5.7 ln ms2) adjusted for clinical variables was 7.0 (95% CI: 2.4–20.3, P < 0.001). Induction of sustained monomorphic VT during PES (adjusted HR = 4.8, 95% CI, 1.7–13.4, P = 0.003) also predicted the primary endpoint.
Fatal or near-fatal arrhythmias can be predicted by many risk stratification methods, especially by heart rate variability, in patients with reduced LVEF after AMI.
Sudden cardiac death; Heart rate; Variability; Implantable cardioverter-defibrillator
The aim of this study was to explore the correlation between sinus heart rate turbulence (HRT) and short-term prognosis in patients with unstable angina (UA). Seventy-five patients with UA received Holter monitoring for 24 h, within 48 h of hospitalization to obtain parameters of HRT, including turbulence onset (TO) and turbulence slope (TS), as well as parameters of heart rate variability (HRV), including standard deviation of all NN intervals (SDNN) and average R-R interval. The left ventricular ejection fraction (LVEF) was measured with an ultrasound cardiogram. Patients were divided into a stable group and a refractory group based on the prognosis during a 7- to 21-day hospital stay. The correlation between the prognosis and each risk factor was analyzed. Of the 75 patients with UA, the pathogenetic condition was stable in 50 patients (stable group) and cardiac events occurred in 25 patients (refractory group). Univariate analysis indicated that the risk factors of short-term poor prognosis of UA include TS ≤2.5 msec/R-R, age ≥70 years, LVEF <40% and SDNN <70 msec. Logistic multivariate regression analysis revealed that only TS ≤2.5 msec/R-R and LVEF <40% were independent risk factors of short-term poor prognosis. Our study revealed that weakening or disappearance of HRT is an independent predictor of short-term poor prognosis in patients with UA.
unstable angina; predictor; sinus heart rate turbulence
Heart rate turbulence (HRT) has been shown to be vagally-mediated with a strong correlation to baroreflex indices. However, the relationship between HRT and peripheral sympathetic nerve activity (SNA) following a premature ventricular contraction (PVC) remains unclear.
We sought to evaluate the relationship between HRT and the changes in peripheral SNA following PVCs.
We recorded post-ganglionic muscle SNA during ECG monitoring in 8 patients with spontaneous PVCs. Fifty-two PVCs were observed and analyzed for turbulence onset (TO) and slope (TS). SNA was quantified during 1) the dominant burst following the PVC (Dominant-Burst Area), and 2) the 10 seconds following the dominant burst (Post-Burst SNA).
The mean TO was 0.1±4.6% and the mean TS was 6.1±6.6. The Dominant-Burst Area negatively correlated with TO (-0.50, p=0.0002). The Post-Burst SNA showed a significant positive correlation with TO (r=0.44, p=0.001) and a negative correlation with TS (r=-0.42, p=0.002). These correlations remained significant after controlling for either the PVC coupling interval or the left ventricular ejection fraction.
Our findings highlight the relationship between perturbations in HRT and pathology in the sympathetic limb of the autonomic nervous system. Future studies are needed to evaluate the prognostic role of baroreflex control of sympathetic activity in patients with structural heart disease.
heart rate turbulence; sympathetic nervous system; baroreflex; premature ventricular contraction
Heart rhythm turbulence (HRT) is a novel tool for evaluation of cardiovascular mortality. Liver cirrhosis is associated with hemodynamic and myocardial disturbances termed cirrhotic cardiomyopathy. In the stable stage of liver cirrhosis, systolic and myocardial dysfunction is correlated with brain natriuretic peptide (BNP).
The aim was to evaluate HRT and its correlation with NT-proBNP, echocardiographic and biochemical parameters in patients with decompensation of liver cirrhosis.
The study included 18 patients with decompensated liver cirrhosis and 18 healthy volunteers. Participants underwent echocardiography and 24-hour ECG monitoring. Serum NT-proBNP and other biochemical parameters were measured. Turbulence onset (TO) and turbulence slope (TS) were used to indicate HRT.
Mean HR (87/min vs. 75/min), TO (−0.385% vs. −0.92%), NT-proBNP (304.85 pg/ml vs. 83.2 pg/ml), LAd (42.5 mm vs. 34.5 mm), RVdd (29.5 mm vs. 25 mm), SPAP (36.5 mmHg vs. 22.5 mmHg) were significantly (p<0.05) higher in patients with liver cirrhosis. Patients with normal TO and TS had better stage in Child-Pugh classification (P=0.04) than patients with abnormal values. Significant negative correlation was found between creatinine and TO, and between mean HR and TS, and significant positive correlation was found between LAd and TS. LV diastolic dysfunction was noted in a majority of cirrhotic patients (n=16).
Patients with decompensated cirrhosis had elevated levels of NT-proBNP and LV diastolic dysfunction. TO values in cirrhotic patients differed significantly from the control group. These findings can indicate risk of symptomatic heart failure development and may be a marker of cirrhotic cardiomyopathy. HRT parameters seem not to be appropriate death predicators.
liver cirrhosis; heart rhythm turbulence; NT-proBNP
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.
Sudden death; Ventricular arrhythmia; Cardiomyopathy; T-wave alternans
We examined whether heart rate turbulence (HRT) adds to traditional risk factors for cardiac mortality in older adults at low, intermediate and high risk.
Methods and Results
N=1298, age ≥65 years, with 24-hour Holter recordings were studied. HRT, which quantifies heart rate response to ventricular premature contractions, was categorized as: both turbulence onset (TO) and turbulence slope (TS) normal; TO abnormal; TS abnormal; or both abnormal. Independent risks for cardiac mortality associated with HRT or, for comparison, elevated C-reactive protein (CRP) (>3.0 mg/L), were calculated using Cox regression analysis adjusted for traditional cardiovascular disease risk factors and stratified by the presence of no, isolated subclinical (i.e., intermediate risk) or clinical CVD. Having both TS and TO abnormal compared to both normal was associated with cardiac mortality in the low risk group [HR 7.9, 95% CI 2.8–22.5, (p<0.001)]. In the high and intermediate risk groups, abnormal TS and TO ([HR 2.2, 95% CI 1.5–4.0, p=0.016] and [HR 2.7, 95% CI 1.2–5.9, p=0.012]), respectively, were also significantly associated with cardiac mortality. In contrast, elevated CRP was associated with increased cardiac mortality risk only in low risk individuals [HR 2.5, 95% CI 1.3–5.1, p=0.009]. In the low risk group, the c-statistic was 0.706 for the base model, 0.725 for the base model with CRP, and 0.767 for the base model with HRT.
Abnormal HRT independently adds to risk stratification of low, intermediate and high risk individuals but appears to add especially to the stratification of those considered at low risk.
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.
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.
Defibrillation; Electrocardiography; Heart Failure; 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.
repolarization variability; sudden cardiac death; ECG signal processing
A critical need exists for reliable warning markers of in-hospital life-threatening arrhythmias. We employed a new quantitative method to track interlead heterogeneity of depolarization and repolarization to detect premonitory changes prior to ventricular tachycardia (VT) in hospitalized patients with acute decompensated heart failure.
Methods and Results
Ambulatory ECGs (leads V1, V5, and aVF) recorded before initiation of drug therapy from patients enrolled in the Prospective Randomized Evaluation of Cardiac Ectopy with Dobutamine or Nesiritide Therapy (PRECEDENT) trial were analyzed. R-wave and T-wave heterogeneity (RWH, TWH) were assessed by second central moment analysis and T-wave alternans (TWA) by Modified Moving Average analysis. Patients (N=44) studied included those (N = 22) with episodes of VT (≥4 beats at heart rates >100 beats/min) following ≥120 minutes of stable sinus rhythm and age- and sex-matched patients (N=22) without VT. TWA increased from 18.6±2.1μV (baseline, mean ± SEM) to 27.9±4.6μV in lead V5 at 15–30 minutes prior to VT (p<0.05) and remained elevated until the arrhythmia occurred. TWA results in V1 and aVF were similar. RWH and TWH were elevated from 164.1±33.1μV and 134.5±20.6μV (baseline) to 299.8±54.5μV and 239.2±37.0μV at 30–45 minutes prior to VT (p<0.05), respectively, preceding the crescendo in TWA by 15 minutes. Matched patients without VT did not display elevated RWH (185.5±29.4μV) or TWH (157.1±27.2μV) during the 24–hour period.
This is the first clinical demonstration of the potential utility of tracking depolarization and repolarization heterogeneity to detect crescendos in electrical instability that could forewarn of impending nonsustained ventricular tachycardia.
Clinical Trial Registration
T-wave alternans; heterogeneity; depolarization; repolarization; tachycardia
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.
Microvolt T-wave alternans; Implantable cardioverter defibrillator; Risk stratification; Ischemic cardiomyopathy; Dilated cardiomyopathy