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

doi:10.1016/j.hrthm.2008.12.011

Heart Rhythm

Volume 6, Issue 3, March 2009, Pages 332-337

https://doi.org/10.1016/j.hrthm.2008.12.011 Get rights and content

Background

Time-domain T-wave alternans (TWA) is useful for identifying patients at risk for serious events after myocardial infarction.

Objective

The purpose of this study was to prospectively evaluate the utility of time-domain TWA measured from Holter ECGs in predicting cardiac mortality in patients with left ventricular (LV) dysfunction.

Methods

Two hundred ninety-five consecutive patients with LV dysfunction were enrolled in the study. Patients were divided into two groups: the ischemic group (n = 195) and the nonischemic group (n = 100). Time-domain TWA was assessed using the modified moving average method from routine 24-hour Holter ECGs recorded during daily activity. The maximal time-domain TWA voltage at heart rate ≤120 bpm in either lead V₅ or V₁ was derived and its value defined as positive when the voltage was ≥65 μV. The primary end-point was defined as cardiac mortality.

Results

Mean maximal time-domain TWA voltage was 54 ± 16 μV. During follow-up of 390 ± 212 days, 27 patients (17 in the ischemic group and 10 in the nonischemic group) died of cardiac causes. Fifty-three patients (18%) were time-domain TWA positive and 242 (82%) were time-domain TWA negative. Univariate Cox proportional hazards analyses revealed that older age, New York Heart Association functional class III or IV, diabetes, renal dysfunction, nonsustained ventricular tachycardia, and time-domain TWA were associated with cardiac mortality. In multivariate analysis, time-domain TWA had the most significant value (hazard ratio = 17.1, P <.0001). This index also was significant in both subgroups (ischemic group: hazard ratio = 19.0, P <.0001; nonischemic group: hazard ratio = 12.3, P = .002).

Conclusion

Time-domain TWA measured from 24-hour Holter ECGs predicts cardiac mortality in patients with ischemic and nonischemic LV dysfunction.

Introduction

Extensive clinical evidence supports the usefulness of microvolt T-wave alternans (TWA), which is measured by spectral analysis, as an index in risk stratification for sudden cardiac death or mortality.1, 2, 3, 4, 5, 6, 7, 8, 9 This evidence encompasses several cardiac disorders, such as myocardial infarction, ischemic cardiomyopathy, and congestive heart failure. A “spectral TWA” test involves exercise or atrial pacing, which elevates and fixes heart rate for a sustained period and requires specialized electrodes. Therefore, not all patients can undergo a spectral TWA test, for example, patients taking medications such as beta-blockers and digoxin, and those with physical limitations.

Time-domain T-wave alternans (TWA) recently has been introduced and is a promising approach for identifying patients at risk for serious events.10, 11 At present it is feasible to measure time-domain TWA from 24-hour Holter ECGs recorded during daily activity. Clinical usefulness of this technique has been reported in a population after myocardial infarction12, 13 and in a population undergoing a clinically indicated exercise test.¹⁴ However, its value for risk stratification is unknown in patients with left ventricular (LV) dysfunction.

In the present study, we evaluated the utility of time-domain TWA measured from routine 24-hour Holter ECGs obtained with daily activity in predicting cardiac mortality in patients with LV dysfunction of both ischemic and nonischemic etiologies.

Section snippets

Study population

This prospective study included 312 consecutive patients (223 men and 89 women; mean age 66 ± 16 years) with LV systolic dysfunction (left ventricular ejection fraction [LVEF] <40%) and dilated left ventricle (left ventricular diastolic dimension [LVDD] ≥55 mm), undergoing 24-hour Holter ECG at Kyorin University Hospital between March 2006 and April 2008. LVEF and LVDD were measured by echocardiography, radionuclide angiography, or magnetic resonance imaging. Patients were eligible for the

Patient characteristics

Patient characteristics are listed in Table 1. Forty-one patients (14%) were in New York Heart Association (NYHA) functional class III or IV. Mean LVEF was 34 ± 6%, and mean LVDD was 58 ± 3 mm. Hypertension was defined as systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg. Hyperlipidemia was defined as serum cholesterol level ≥220 mg/dL or use of dyslipidemic therapy. Diabetes mellitus was defined as a morning fasting glucose ≥126 mg/dL, HbA_1C ≥6.5%, or use of hypoglycemic

Discussion

This prospective study is the first to demonstrate the utility of time-domain TWA measured from routine 24-hour Holter ECG with daily activity in patients with LV dysfunction. The results reveal that a positive time-domain TWA outcome is a significant predictor for cardiac mortality in both ischemic and nonischemic patients with LV dysfunction.

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This review addresses current questions regarding use of T-wave alternans to stratify risk for sudden cardiac death. Both of the currently available commercial methodologies, namely, the frequency-domain spectral method and the time-domain modified moving average (MMA) method, are supported by guideline statements, cleared by the US FDA, and covered by the US Center for Medicare and Medicaid services. Similar numbers of patients have been enrolled in predictive studies; odds ratios generated by the two methods are similar including in a head-to-head study. However, in two prospective studies, prediction by TWA with the spectral method was negative, likely due to withdrawal of beta-blockade before the test with later resumption, while all studies with MMA have achieved prediction when the commercial software was used appropriately. Questions currently undergoing investigation include TWA's potential to guide ICD implantation, to track changes in risk during cardiac disease progression, and to evaluate the adequacy of medical therapy.
Autonomic regulation therapy suppresses quantitative T-wave alternans and improves baroreflex sensitivity in patients with heart failure enrolled in the ANTHEM-HF study
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Citation Excerpt :
Compared to baseline, HRT onset was not statistically different at either 6 months or 12 months in either the left-sided or right-sided stimulation groups or combined cohort (Figure 5). This is the first report that chronic ART reduces TWA in patients with advanced heart failure, an established marker of risk of lethal arrhythmias in patients with cardiac dysfunction.14,15 There was a corresponding reduction in VT incidence.
Autonomic regulation therapy (ART) with chronic vagus nerve stimulation improves ventricular function in patients with chronic heart failure, but its effects on quantitative T-wave alternans (TWA), ventricular tachycardia (VT), baroreflex sensitivity, and autonomic tone remained unknown.
Effects on TWA, a marker of risk of life-threatening arrhythmias; heart rate turbulence (HRT), an indicator of baroreflex sensitivity; heart rate variability; and VT incidence were studied in 25 patients with chronic symptomatic heart failure and reduced ejection fraction enrolled in the ANTHEM-HF study (NCT01823887).
Twenty-four-hour ambulatory electrocardiographic recordings made before ART system (Cyberonics, Inc., Houston, TX) implantation involving the left or right vagus nerve and after 6 and 12 months of chronic therapy (10-Hz frequency, 250-μs pulse width, maximum tolerable current amplitude after 10 weeks of titration) at low-intensity (<2 mA; n = 10, 40%) or high-intensity (≥2 mA; n = 15, 60%) stimulation levels were analyzed.
At 12 months, peak TWA levels were reduced by 29% from 71.0 ± 4.6 to 50.5 ± 1.8 μV (P < .0001). The number of patients with severely abnormal TWA (≥60 μV) was reduced by 76% from 17 to 4 (P < .0005), and the number of patients with nonsustained VT decreased by 73% from 11 to 3 (P < .025). HRT slope (P < .025), high frequency heart rate variability (HRV) (P = .05), and square root of the mean squared differences of successive normal-to-normal interval HRV (P = .013) increased. The mean heart rate derived from 24-hour Holter electrocardiograms decreased by 10% from 77 ± 2 to 69 ± 2 beats/min (P = .0002). HRT onset was unchanged.
Chronic ART in patients with symptomatic heart failure improves cardiac electrical stability, as reflected by reduced TWA levels and heart rate, suppresses VT, and increases baroreceptor sensitivity. These observations deserve study in a larger population.
Late gadolinium enhancement of cardiac magnetic resonance imaging indicates abnormalities of time-domain T-wave alternans in hypertrophic cardiomyopathy with ventricular tachycardia
2015, Heart Rhythm
The presence of myocardial scar detected by late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) imaging has been described as a good independent predictor of mortality in patients with hypertrophic cardiomyopathy (HCM). Time-domain T-wave alternans (TWA) is also a potential predictor of cardiac mortality in patients with left ventricular dysfunction.
The purpose of this study was to elucidate the relationship between LGE distribution and TWA in patients with HCM.
CMR and TWA analyses using Holter monitoring were performed in 42 patients with HCM. The average transmural extent of LGE was scored as 1–4 in each segment, and the sum of the LGE scores (total LGE score) was calculated for each patient. The correlation between the maximal time-domain TWA voltage and LGE findings was analyzed, and the differences in time-domain TWA voltage, total LGE score, and cardiac function assessed by CMR imaging in the presence or absence of ventricular tachycardia (VT) were also compared.
The total LGE score was significantly and positively correlated with the maximal time-domain TWA voltage (r = 0.59; P < .001). Furthermore, the total LGE score and maximal time-domain TWA voltage were significantly greater in patients who had episodes of VT (n = 21) than in those without VT (23 ± 7 vs 10 ± 8; P < .001 and 87 ± 26 μV vs 62 ± 12 μV; P < .001, respectively). However, the left ventricular ejection fraction did not statistically differ between patients with VT and those without VT (56% ± 14% vs 61% ± 7%; P = .102).
The magnitude of the localized LGE was significantly correlated with abnormalities in ventricular repolarization as assessed by TWA and QT dispersion.
Early repolarization and positive T-wave alternans as risk markers for life-threatening arrhythmias in patients with vasospastic angina
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Several arrhythmogenic markers have been suggested as predictors for risk of life-threatening arrhythmias during symptom-free periods in vasospastic angina (VSA), but no definite conclusion has been drawn.
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We studied 116 consecutive patients with chest pain who underwent an acetylcholine provocation test for VSA diagnosis. Patients were divided into two groups with positive (VSA group; 66 cases) and negative (control group; 50 cases) provocation test results. The presence of ER on electrocardiogram and the modified moving average analysis of TWA during symptom-free periods were explored.
The incidences of ER and p-TWA were higher in the VSA than in the control group (P = 0.001 and P = 0.006, respectively). Multivariate analysis revealed that ER and p-TWA were independent predictors of VSA (odds ratio, 5.65 and 4.94; 95% confidence interval: 1.11–28.9 and 1.22–19.9, respectively). The incidence of coexisting baseline ER and p-TWA was significantly higher in VSA patients with life-threatening arrhythmic events (3/3 vs. 6/38; P < 0.001) than in those without.
VSA patients with arrhythmic events showed a high incidence of ER and p-TWA during symptom-free periods. Therefore, baseline ER and p-TWA may help to identify VSA patients at high risk for life-threatening arrhythmias.
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Reducing the toll of sudden cardiac death (SCD) remains a major challenge in cardiology, as it is the leading cause of adult mortality in the industrially developed world, claiming 310,000 lives annually in the United States alone. The main contemporary noninvasive index of cardiovascular risk, left ventricular ejection fraction (LVEF), has not proved adequately reliable, as the majority of individuals who die suddenly have relatively preserved cardiac mechanical function. Monitoring of T-wave alternans (TWA), a beat-to-beat fluctuation in ST-segment or T-wave morphology, is an attractive approach to risk stratification on both scientific and clinical grounds, as this ECG phenomenon has been shown using the FDA-cleared Spectral and Modified Moving Average methods to assess risk for cardiovascular mortality including SCD in studies enrolling >12,000 individuals with depressed or preserved LVEF. The evidence supporting TWA as a therapeutic target is reviewed.

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: This study was supported in part by a Grant-in-Aid (18300157) for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, by a grant from the Fukuda Memorial Foundation for Medical Research to Dr. Ikeda, and by a grant from Kyorin University School of Medicine to Dr. Ikeda.

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

Background

Objective

Methods

Results

Conclusion

Introduction

Section snippets

Study population

Patient characteristics

Discussion

Am J Cardiol

Lancet

J Am Coll Cardiol

J Am Coll Cardiol

J Am Coll Cardiol

J Am Coll Cardiol

J Am Coll Cardiol

J Am Coll Cardiol

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