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Beta-Blockers and Microvolt T-Wave Alternans. Introduction: Results of microvolt T-wave alternans (MTWA) studies vary and may be influenced by whether beta-blocker therapy was withheld prior to MTWA assessment. We conducted a meta-analysis of the predictive value of MTWA screening for ventricular arrhythmic events in primary prevention patients with left ventricular dysfunction and examined whether results differed depending upon whether beta-blocker use was withheld prior to MTWA testing. Methods and Results: Prospective studies that evaluated whether MTWA predicted ventricular arrhythmic events published between January 1980 and September 2008 were identified. Summary estimates for the predictive value of MTWA were derived with random-effects models. Nine studies involving 3,939 patients were identified. Overall, an abnormal MTWA (positive and indeterminate) test was associated with an almost 2-fold increased risk for arrhythmic events (pooled RR = 1.95, 95% CI: 1.29‐2.96; P = 0.002). However, significant heterogeneity across studies was observed (P = 0.024). In the 4 studies in which betablocker therapy was not withheld prior to MTWA assessment, an abnormal MTWA test was associated with a 5-fold increased risk for arrhythmic events (pooled RR = 5.39, 95% CI: 2.68‐10.84; P < 0.001) and was robust to sensitivity analyses. In contrast, the association was much weaker in those studies where the use of beta-blocker therapy was withheld prior to MTWA testing (pooled RR = 1.40, 95% CI: 1.06‐1.84; P = 0.02). Conclusions: In primary prevention patients with left ventricular dysfunction, the predictive power of MTWA varied widely, based on whether beta-blocker therapy was withheld prior to its assessment. This observation may explain the inconsistent results of MTWA studies in this population. (J Cardiovasc

Background T-wave alternans (TWA), a marker of electrical instability, can be modulated by cardiac resynchronization therapy (CRT). The relationship between TWA and heart failure response to CRT has not been clearly defined. Methods and results In 40-patients (age 65±11 years, left ventricular ejection-fraction [LVEF] 23±7%), TWA was evaluated prospectively at median of 2 months (baseline) and 8 months (follow-up) post-CRT implant. TWA-magnitude (Valt >0μV, k≥3), its duration (d), and burden (Valt ·d) were quantified in moving 128-beat segments during incremental atrial (AAI, native-TWA) and atrio-biventricular (DDD-CRT) pacing. The immediate and long-term effect of CRT on TWA was examined. Clinical response to CRT was defined as an increase in LVEF of ≥5%. Native-TWA was clinically significant (Valt ≥1.9μV, k≥3) in 68% of subjects at baseline. Compared to native-TWA at baseline, DDD-CRT pacing at baseline and follow-up reduced the number of positive TWA segments, peak-magnitude, longest-duration and peak-burden of TWA (44±5 to 33±5 to 28±4%, p = 0.02 and 0.002; 5.9±0.8 to 4.1±0.7 to 3.8±0.7μV, p = 0.01 and 0.01; 97±9 to 76±8 to 67±8sec, p = 0.004 and

Background Better risk stratification of patients receiving an implantable cardioverter-defibrillator (ICD) for primary prevention of sudden cardiac death (SCD) is needed. Although microvolt T-wave alternans (MTWA) and electrophysiologic study (EPS) are independent markers for SCD, the Alternans Before Cardioverter Defibrillator (ABCD) trial found the combination to be more predictive than either test alone. Objective The purpose of this study was to test the hypothesis that EPS and MTWA measure different elements of the arrhythmogenic substrate and, therefore, predict distinct arrhythmia outcomes. Methods The ABCD trial enrolled 566 patients with ischemic cardiomyopathy, left ventricular ejection fraction (LVEF) ≤0.40, and nonsustained ventricular tachycardia. All patients underwent both MTWA test and EPS. The performance of MTWA and EPS in predicting stable ventricular tachyarrhythmic events (S-VTEs) versus unstable ventricular tachyarrhythmic events (U-VTEs), defined as either polymorphic ventricular tachycardia or ventricular fibrillation, was analyzed using Kaplan-Meier event rates and the log rank test. Results MTWA and EPS were abnormal in 71% and 39% of patients, respectively. There were 28 S-VTEs and 10 U-VTEs. MTWA was predictive of U-VTEs (event rate 2.7% in abnormals vs 0% in normals, P = .04), whereas EPS was not (1.5% vs 3.2%, P = .55). In contrast, EPS predicted S-VTEs (9.7% vs 2.2%, P P = .57). Whereas the extent of left ventricular contractile dysfunction alone (LVEF ≤0.30 vs LVEF 0.31–0.40) did not predict events, MTWA predicted events better than did EPS in subjects with LVEF ≤0.30. In contrast, EPS predicted events better than did MTWA test in subjects with LVEF >0.30. Conclusion The study data suggest that EPS and MTWA identify distinct arrhythmogenic substrates and, when used in combination, may better predict the complex electroanatomic substrates that underlie the risk for SCD.

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

Introduction The role of implantable cardioverter-defibrillator (ICD) placement in the primary prevention of sudden cardiac death (SCD) in all consecutive patients with left ventricular ejection fraction (LVEF) ≤ 35% is still a matter of hot debate due to the fact that the population of these patients is highly heterogeneous in terms of the SCD risk. Nevertheless, reduced LVEF is still the only established criterion during qualification of patients for ICD implantation in the primary prevention of SCD, therefore identification of persons with particularly high risk among patients with LVEF ≤35% is currently of lesser importance. More important seems to be the selection of individuals with relatively low risk of SCD in whom ICD implantation can be safely postponed. The aim of the study was to determine whether well-known, non-invasive parameters, such as microvolt T-wave alternans (MTWA), baroreflex sensitivity (BRS) and short-term heart rate variability (HRV), can be helpful in the identification of low-arrhythmic risk patients with ischemic left ventricular systolic dysfunction. Methods In 141 patients with coronary artery disease and LVEF ≤ 35%, MTWA testing, as well as BRS and short-term HRV parameters, were analysed. During 34 ± 13 months of follow-up 37 patients had arrhythmic episode (EVENT): SCD, non-fatal sustained ventricular arrhythmia (ventricular tachycardia [VT] or ventricular fibrillation [VF]), or adequate high-voltage ICD intervention (shock) due to a rapid ventricular arrhythmia ≥200/min. LVEF, non-negative MTWA (MTWA_non-neg), BRS and low frequency power in normalized units (LFnu) turned out to be associated with the incidence of EVENT in univariate Cox analysis. The cut-off values for BRS and LFnu that most accurately distinguished between patients with and without EVENT were 3 ms/mmHg and 23, respectively. The only variable that provided 100% negative predictive value (NPV) for EVENT was negative MTWA result (MTWA_neg), but solely for initial 12 months of the follow-up; the NPVs for other potential predictors of the EVENT were lower. The cut-off values for BRS and LFnu that provide 100% NPV for EVENT during 12 and 24 months were higher: 6.0 ms/mmHg and 73 respectively, but the gain in the NPV occurred at an expense of the number of identified patients. However, the number of identified non-risk patients turned out to be higher when the predictive model included MTWA_neg and the lower cut-off values for ANS parameters: 100% NPV for 12 and 24 months of follow-up was obtained for combination MTWA_neg and BRS ≥ 3 ms/mmHg, for combination MTWA_neg and LFnu ≥ 23 100% NPV was obtained for 12 months. Conclusion Well-known, non-invasive parameters, such as MTWA, BRS and short-term HRV indices may be helpful in the identification of individuals with a relatively low risk of malignant ventricular arrhythmias among patients with ischemic left ventricular systolic dysfunction; in such persons, implantation of ICD could be safely postponed.

Background Sudden cardiac death (SCD) can be the first manifestation of cardiovascular disease. Development of screening methods for higher/lower risk is critical. Methods The Cardiovascular Health Study is a population-based study of risk factors for coronary heart disease and stroke those 65 years or older. Forty-nine (of 1649) with usable Holters and in normal sinus rhythm had SCD during follow-up and were matched with 2 controls, alive at the time of death of the case and not experiencing SCD on follow-up. Univariate and multivariate conditional logistic regression determined the association of Holter-based information and SCD. Results In univariate models, the upper half of ventricular premature contraction (VPC) counts, abnormal heart rate turbulence, decreased normalized low-frequency power, increased T-wave alternans (TWA), and decreased the short-term fractal scaling exponent (DFA 1 ) were associated with SCD, but time domain heart rate variability was not. In multivariate models, the upper half of VPC counts (odds ratio [OR], 6.6) and having TWA of 37 μ V or greater on channel 2 (OR, 4.8) were independently associated with SCD. Also, the upper half of VPC counts (OR, 6.9) and having a DFA 1 of less than 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 with 2.6 for having either. Also, having both higher VPCs and lower DFA 1 was associated with an OR of 9.6 for SCD compared with 3.1 for having either. Conclusions Results support a potential role for 24-hour Holter recordings to identify older adults at increased or lower risk of SCD.

Background: Time‐domain microvolt T‐wave alternans (TWA) has been described as a noninvasive marker of sudden cardiac death in adults. The incidence of TWA in pediatric populations has not been defined well. The aim of the study was to determine peculiarities of TWA in children. Methods: We examined 68 healthy patients—newborns (20) and children in age group of 7–17 years (48)—and 85 pediatric patients: ventricular premature beats—65; dilated cardiomyopathy (DCMP)—2; long QT syndrome (LQTS)—10; Brugada syndrome (BrS)—5, catecholaminergic ventricular tachycardia (CVT)—3. All underwent Holter monitoring (HM) with definition of the peak value of TWA by modified moving average method. Results: In healthy newborns, TWA was 32 ± 8 (12–55) μV (HR 123–156 bmp). In healthy children (7–17 years) it was 30 ± 11 (10–l 55) μV, (HR 64–132 bmp) without any differences between boys and girls. In all group of patients, TWA were significantly higher (P < 0.05) than in healthy. Circadian peak of TWA was found (90%) in a second part of day and at sleep (8%). Among them 60% (LQTS, BrS, and DCPM) had TWA > 55 μV. Conclusion: Time‐domain TWA during HM in children was independent of age, gender, and heart rate. In 94% healthy children, values of TWA do not exceed 55 μV but 20–50% children with cardiac pathology had TWA more than 55 μV. Night circadian type of TWA in diseases with risk of life‐threatening arrhythmias associated with TWA was more than 55 μV. Ann Noninvasive Electrocardiol 2010;15(2):138–144

Enhanced modified moving average method (EMMAM) and correlation method (CM) for microvolt TWA identification are compared by aid of simulated ECG tracings (cases of absence of TWA and presence of stationary or time-varying TWA) and ECG recordings from healthy subjects (H-group) and patients who survived an acute myocardial infarction (AMI-group). The two competing methods were found to be equivalent when analyzing clean ECGs affected by stationary TWA. Non-stationary TWA is correctly tracked by the CM, whereas it is identified as stationary by the EMMAM. Moreover, the EMMAM suffers for its tendency to identify as TWA noise and other kinds of repolarization variability. Such limitation is most likely the cause of its false-positive TWA production. Finally, only the CM incorporates a local threshold criterion in the TWA detection algorithm which allows better discrimination between H and AMI groups, who are well known to be at increased risk to develop TWA.

T-wave alternans (TWA) is a proarrhythmic repolarization instability that is common in congestive heart failure (CHF). Although transgenic mice are commonly used to study the mechanisms of arrhythmogenesis in CHF, little is known about the dynamics of TWA in these species. We hypothesized that TWA is present in a TNF-α model of CHF and can be further promoted by adrenergic stimulation. We studied 16 TNF-α mice and 12 FVB controls using 1) in vivo intracardiac electrophysiological testing and 2) ambulatory telemetry during 30 min before and after an intraperitoneal injection of isoproterenol. TWA was examined using both linear and nonlinear filtering applied in the time domain. In addition, changes in the mean amplitude of the T wave and area under the T wave were computed. During intracardiac electrophysiological testing, none of the animals had TWA or inducible arrhythmias before the injection of isoproterenol. After the injection, sustained TWA and inducible ventricular tachyarrhythmias were observed in TNF-α mice but not in FVB mice. In ambulatory telemetry, before the isoproterenol injection, the cardiac cycle length (CL) was longer in TNF-α mice than in FVB mice (98 ± 9 and 88 ± 3 ms, P = 0.04). After the injection of isoproterenol, the CL became 8% and 6% shorter in TNF-α and FVB mice ( P < 10−4); however, the 2% difference between the groups in the magnitude of CL changes was not significant. In TNF-α mice, the magnitude of TWA was 1.5–2 times greater than in FVB mice both before and after the isoproterenol injection. The magnitude of TWA increased significantly after the isoproterenol injection compared with the baseline in TNF-α mice ( P = 0.003) but not in FVB mice. The mean amplitude of the T wave and area under the T wave increased 60% and 80% in FVB mice ( P = 0.006 and 0.009) but not in TNF-α mice. In conclusion, TWA is present in a TNF-α model of CHF and can be further promoted by adrenergic stimulation, along with the enhanced susceptibility for ventricular arrhythmias.

Purpose of review Several invasive and noninvasive tests for risk stratification of sudden cardiac death (SCD) have been studied. Tests such as microwave T wave alternans (repolarization abnormality) and signal-averaged ECG (depolarization abnormality) have high negative predictive values but low positive predictive values in patients with heart disease. The presence of a fragmented QRS (fQRS) complex on a routine 12-lead ECG is another marker of depolarization abnormality. The purpose of this review is to discuss the potential utility of tests to detect depolarization abnormalities of the heart for the risk stratification of mortality and SCD with main emphasis on fQRS. Recent findings fQRS is associated with increased mortality and arrhythmic events in patients with coronary artery disease. fQRS has also been defined as a marker of arrhythmogenic right ventricular cardiomyopathy and Brugada syndrome. In Brugada syndrome, the presence of fQRS predicts episodes of ventricular fibrillation during follow-up. Summary fQRS may be of value in determining the risk for SCD and guiding selection for device therapy in patients with structural heart disease and Brugada syndrome. It is possible that the predictive value of fQRS for SCD can be enhanced further by combining a marker of repolarization abnormality such as microwave T wave alternans.

[EN] This paper presents T-wave alternans (TWA) detection, applying the Wavelet Transform (WT) to electrocardiographic (ECG) synthetic signals. The TWA is generated with or without the sinusoidal addition of the wave with the required electrical level from 0.01 to 1 mV. The TWA is measured using the difference between the amplitudes of the augmented T-waves and the normal ones. (C) 2009 Elsevier Ltd. All rights reserved

Action potential duration alternans (APDA) can vary regionally in magnitude and phase. The influence of APDA heterogeneity on T-wave alternans (TWA) has not been defined.Our objectives were: (1) to determine how APDA affects the magnitude and spatial distribution of TWA, and (2) to optimize electrocardiographic (ECG) lead configuration accordingly to improve TWA detection.Global, regional, and discordant APDA were simulated in a 257-node heart model. Using a forward solution, body surface potentials were derived at 300 points on the thorax and TWA was computed at each point. In 22 patients with cardiomyopathy (left ventricular ejection fraction 28% +/- 6%), TWA was measured from a 114-electrode body surface map using the spectral method during atrial pacing at 110 beats/min.An increase in global APDA from 4 to 12 ms resulted in an increase in maximum TWA from 10 to 30 microV. TWA magnitude varied with the size and location of the alternating myocardium, but was largest with discordant APDA compared with regional or global APDA. Irrespective of the location or phase of APDA, TWA was largest over the precordium and correlated with T-wave amplitude in the simulation (R(2) = 0.56 +/- 0.24, P.01) and clinical study (R(2) = 0.45 +/- 0.23, P.02). A novel lead configuration (12 precordial leads + limb leads) significantly improved maximum TWA detection compared with the conventional 12-lead ECG+ Frank lead configuration.TWA magnitude is dependent on the interaction of concordant and discordant alternating sources within the heart. Maximum TWA consistently localizes to the precordium and a novel lead configuration using 12 precordial leads improves TWA quantification.

T-wave alternans (TWA) is a cardiac phenomenon associated with the mechanisms leading to sudden cardiac death. Several methods exist to automatically detect and estimate TWA in the ECG on a single-lead basis, and their main drawback is their poor sensitivity to low-amplitude TWA. In this paper, we propose a multilead analysis scheme to improve the detection and estimation of TWA. It combines principal component analysis with a single-lead method based on the generalized likelihood ratio test. The proposed scheme is evaluated and compared to a single-lead scheme by means of a simulation study, in which different types of simulated and physiological noise are considered under realistic conditions. Simulation results show that the multilead scheme can detect TWA with an SNR 30 dB lower and allows the estimation of TWA with an SNR 25 dB lower than the single-lead scheme. The two analysis schemes are also applied to stress test ECG records. Results show that the multilead scheme provides a higher detection power and that TWA detections obtained with this scheme are significantly different in healthy volunteers and ischemic patients, whereas they are not with the single-lead scheme.

Background Abnormal microvolt T-wave alternans (MTWA) and low peak oxygen consumption (VO 2 ) both predict poor outcome in heart failure. However, their independent predictive properties have not been assessed in large-scale cohorts. Methods This was an observational prospective cohort study of 303 consecutive patients referred for metabolic stress testing. All had an ejection fraction ≤ 40% and were considered candidates for transplantation. The exercise laboratory did not collect MTWA data from patients with implanted pacemakers or defibrillators. The primary end point was a composite of all-cause death or United Network for Organ Sharing status 1 transplantation. Results During a 2.8-year period, there were 34 deaths and 17 transplantations. Patients with abnormal MTWA had a higher event rate of 23% (31 of 136) vs 12% (20 of 167), with an unadjusted hazard ratio (HR) of 1.90 (95% confidence interval [CI], 1.90–3.33; p = 0.03). The association remained significant after adjustment for 3 clinical variables (HR, 1.89; 95% CI, 1.05–3.39; p = 0.03). After adding peak VO 2 to the model, the association was no longer significant (adjusted HR, 1.18; 95% CI, 0.64–2.17, p = 0.60). After accounting for peak VO 2 and 28 other confounders in a matched propensity analysis, MTWA was not predictive (propensity-matched HR, 0.79; 95% CI, 0.37–1.66; p = 0.53). Conclusions These results confirm the association of abnormal MTWA with poor outcome amongst patients with impaired left ventricular systolic function. However, this association is markedly attenuated after accounting for peak VO 2 .

Objectives:Implantable cardioverter defibrillators (ICDs) are an effective but expensive treatment for the prevention of sudden cardiac deaths in patients with severe left-ventricular dysfunction. Recent studies suggest that microvolt T-wave alternans (MTWA) predicts mortality and severe arrhythmic events in this population. However, the impact of MTWA on ICD cost-effectiveness is unknown.Methods:A Markov decision-analysis model evaluated three treatment strategies for primary prevention in patients with severe left-ventricular dysfunction: (i) medical therapy for all; (ii) ICD therapy for all; and (iii) selective ICD therapy based on non-negative (positive or indeterminate) MTWA test results. Incremental cost-effectiveness ratios (ICER) were calculated from the perspective of a third party payer using a 10-year time horizon. Sensitivity analyses examined the robustness of the estimates.Results:A treatment strategy involving ICD therapy in all patients was associated with an ICER of $121,800/quality-adjusted life-year (QALY) compared with medical therapy, whereas a treatment strategy involving the selective use of ICDs based on MTWA test results was associated with an ICER of $108,900/QALY compared with medical therapy. Sensitivity analyses suggest that, under most scenarios, the selective use of ICDs based on MTWA results does not decrease the ICER to below $100,000/QALY.Conclusion:MTWA only marginally improves the cost-effectiveness of ICDs for primary prevention in patients with severe left-ventricular dysfunction. There remains a need for improved means to effectively identify which patients will derive the greatest benefit from ICD implantation.

The public health challenge of preventing sudden cardiac death (SCD) is significant. Various risk factors for SCD have been well articulated from clinical trials and the importance of reduced left ventricular ejection fraction (LVEF) has been validated. However, significant challenges persist in identifying which patients are most vulnerable to SCD, particularly in the setting of preserved left ventricular systolic function. The current article outlines strategies to capture high-risk patients. This strategy includes the implementation of noninvasive risk stratification with microvolt T-wave alternans (MTWA) as well as utilizing health information technology (HIT) to identify patients at risk. The application of HIT in a clinic setting provides electronic decision support tools to document adherence to currently published cardiovascular practice guidelines. Electronic alerts facilitate measurement of LVEF as well as ensure that patients are receiving optimal pharmacologic therapy. A process of care is outlined for patients who are discharged post myocardial infarction and post congestive heart failure hospitalization. This coupled with educational information provided to families and primary care physicians is supportive of an overall process of care focused on SCD prevention. The current article outlines the role of implementing these strategies in a community practice setting to potentially reduce the burden of SCD.

Objectives Because risk stratification with electrophysiological study (EPS) improves efficiency but is invasive, we sought to determine whether noninvasive microvolt T-wave alternans (MTWA) testing could identify patients who benefit from implantable cardioverter-defibrillators (ICDs) as well as EPS. Background Prevention of sudden cardiac death on the basis of left ventricular ejection fraction (LVEF) alone is inefficient, because most ICDs never deliver therapy. Methods The ABCD (Alternans Before Cardioverter Defibrillator) trial is a multicenter prospective study that enrolled patients with ischemic cardiomyopathy (LVEF ≤0.40) and nonsustained ventricular tachycardia. All patients underwent MTWA and EPS. ICDs were mandated if either test was positive. Results Of 566 patients followed for a median of 1.9 years, 39 (7.5%) met the primary end point of appropriate ICD discharge or sudden death at 1 year. As hypothesized, primary analysis showed that MTWA achieved 1-year positive (9%) and negative (95%) predictive values that were comparable to EPS (11% and 95%, respectively). In addition, secondary analysis showed that at the pre-specified 1-year end point, event rates were significantly higher in patients with both a positive MTWA-directed strategy (hazard ratio: 2.1, p = 0.03) and a positive EPS-directed strategy (hazard ratio: 2.4, p = 0.007). Moreover, the event rate in patients with both negative MTWA test and EPS was lower than in those with 2 positive tests (2% vs. 12%; p = 0.017). Conclusions The ABCD study is the first trial to use MTWA to guide prophylactic ICD insertion. Risk stratification strategies using noninvasive MTWA versus invasive EPS are comparable at 1 year and complementary when applied in combination. Strategies employing MTWA, EPS, or both might identify subsets of patients least likely to benefit from ICD insertion. (Study to Compare TWA Test and EPS Test for Predicting Patients at Risk for Life-Threatening Heart Rhythms [ABCD Study]; NCT00187291)

Sarcoidosis is a systemic granulomatous disorder whose prognosis worsens when the heart is involved, and early diagnosis is important. Endomyocardial biopsy is the most helpful diagnostic examination, but suffers from low sensitivity and low specificity. Microvolt T wave alternans (MVTWA) is utilized in noninvasive examinations to detect beat-to-beat changes in the shape of the T wave at the microvolt level. Such beat-to-beat T wave changes arise from beat-to-beat changes in the transmural gradient of action potential duration. We speculate that the granulomatous changes of cardiac sarcoidosis produce cell-to-cell uncoupling and augment the transmural gradients of action potential duration. To examine the clinical significance of MVTWA in the prediction of cardiac involvement in sarcoidosis patients, we obtained MVTWA in a total of 35 sarcoidosis patients with and without cardiac involvement. All patients underwent electrocardiography (ECG), ambulatory electrocardiography, chest radiography, transthoracic echocardiography, and MVTWA examination using a CH 2000 system. We diagnosed cardiac sarcoidosis in 7 patients according to the accepted diagnostic criteria. MVTWA was detected in 6 out of 7 cardiac sarcoidosis patients (85.7%) as opposed to in 2 out of 28 patients without cardiac involvement (7.1%). The difference between the two groups was statistically significant (P < 0.001). The sensitivity and specificity of MVTWA in cardiac sarcoidosis detection were 85.7% and 92.8%, respectively. The positive and negative predictive values were 75% and 96.3%, respectively, with an overall accuracy of 91.4%. Noninvasive examination of MVTWA using a CH 2000 is a useful diagnostic tool for detecting cardiac involvement in patients with sarcoidosis.

To assess the association of electrocardiographic repolarization and depolarization patterns to vulnerability to ventricular tachyarrhythmias.In the present case-control study, a 12-lead ECG, signal-averaged ECG (SAECG), T-wave and QRS morphology, and T-wave alternans (TWA) were analyzed in post-MI patients with and without documented sustained ventricular tachycardia (VT) or fibrillation (VF) (VT/VF group, n=40, Non-VT/VF group, n=37, respectively) and healthy subjects (n=41).The QRS complex duration, measured from standard ECG (128 +/- 32 ms vs. 102 +/- 21 ms, p0.001) or SAECG (125 +/- 25 ms vs. 99 +/- 20 ms, p0.001), was significantly longer in the VT/VF than Non-VT/VF group. Several T-wave morphology variables, e.g., the total cosine of the angle between the main vectors of T-wave and QRS loops (TCRT), were different in the VT/VF (-0.13 +/- 0.58) and Non-VT/VF group (-0.11 +/- 0.48) compared to the healthy controls (0.47 +/- 0.50, p0.001). However, there were no significant differences in any of the T-wave morphology variables including TWA between the two post-MI groups.Abnormalities in ventricular depolarization are more common among post-MI patients with prior VT/VF than in those without documented ventricular tachyarrhythmias. Abnormal T-wave morphology and TWA seem to reflect the heart disease rather than specifically vulnerability to VT/VF.

In this paper we investigate frequency aliasing in spectral method of measuring T wave alter-nans, which may lead a high false positive rate. Microvolt T wave alternans(TWA) has been evaluated as a means of predicting occurrence of ventricular tachyarrhythmia events and its association with the genesis of ventricular ar-rhythmias has been demonstrated. Nowadays, spectral method is one of the most widely used procedures for measurement of microvolt TWA. In our study, based on the sampling theory, the alternans frequency 0.5 cycles/beat, at which the power of the spectrum is used to calculated the Valt and K score (these two parameters indicate the TWA), is equal to the nyquist frequency. Thus this generates frequency aliasing which will make the power at the alternans frequency (P0.5) be two times of the real magnitude of the original spectrum amplitude. With the assump-tion that the noise spectrum follows the normal distribution, in spectral method of measuring T wave alternans, the measuring standard K score>3 to consider the T wave alternans sig-nificant is only with a p 6 can solve this problem and make the p value to p

Although the cardiovascular death rate has fallen in recent years, the proportion of cardiovascular deaths attributed to sudden cardiac death (SCD) is on the rise. SCD is usually caused by ventricular tachyarrhythmias resulting from complex electroanatomic changes that follow myocardial injury, most often associated with coronary artery disease. Ventricular tachyarrhythmia episodes and the factors responsible for triggering them are poorly understood, usually occur without warning or provocation, and result almost invariably in death. Therefore, efforts aimed at predicting and preventing SCD have emerged as the major paradigm for addressing this significant unresolved public health dilemma. Article p 2022 Two major randomized clinical trials demonstrated that implantable cardioverter defibrillators (ICDs) reduce mortality in patients selected for primary prevention of SCD on the basis of reduced left ventricular ejection fraction (LVEF) alone.1,2 However, recent studies have questioned whether LVEF used in isolation from other disease markers is sufficient to guide SCD prevention.3 Although ICDs are highly effective in aborting SCD from ventricular fibrillation, only ≈1 of 15 patients satisfying current guidelines for prophylactic ICDs on the basis of an LVEF 0.35). Also, we have yet to ascertain how to incorporate estimates of competitive risk from nonarrhythmic and noncardiac mortality into the decision to implant ICDs. Finally, current paradigms that focus on assessing risk at 1 time point do not account for dynamic time-varying modulation of SCD substrates that occur in response to intervening cardiac events. Because LVEF only measures contractile but not electrophysiological dysfunction, it does not provide any direct assessment of functional electrophysiological substrates responsible for triggering SCD episodes. Therefore, it should not be surprising that most patients with markedly impaired LVEF do not benefit from ICDs, while it …

Ventricular tachyarrhythmias are potentially lethal cardiac pathologies and the commonest cause of sudden cardiac death. Efforts to predict the onset of such events are based on feature extraction from the surface ECG. T-wave alternans (TWAs) are considered a marker of abnormal ventricular function that may be associated with ventricular tachycardia (VT) and ventricular fibrillation. A novel TWA detection algorithm utilizing the continuous wavelet transform is described in this paper. Simulated ECGs containing artificial TWA were used to test the algorithm that achieved a sensitivity of 91.40% and a specificity of 94.00%. The algorithm was subsequently used to analyze the ECGs of eight patients prior to the onset of VT. Of these, the algorithm indicated that five patients exhibited TWA prior to the onset of the tachyarrhythmic events, while the remaining three patients did not exhibit identifiable TWA. Healthy individuals were also studied in which one short TWA episode was detected by the algorithm. However, closer visual inspection of the data revealed this to be a likely false positive result.

Objectives The purpose of this trial was to determine whether microvolt T-wave alternans (MTWA) predicts ventricular tachyarrhythmic events (VTEs) in post-myocardial infarction patients with left ventricular ejection fraction (LVEF) ≤30%. Background Previous studies have established MTWA as a predictor for total and arrhythmic mortality, but its ability to identify prophylactic implantable cardioverter-defibrillator (ICD) recipients most likely to experience VTEs remains uncertain. Methods This prospective trial was conducted at 50 U.S. centers. Patients were eligible if they met MADIT-II (Multicenter Automatic Defibrillator Implantation Trial II) indications for device implant. All patients underwent MTWA testing followed by ICD implantation, with pre-specified programming to minimize the likelihood of therapies for non–life-threatening VTE. Minimum follow-up was 2 years with annual MTWA testing. Initially indeterminate MTWA tests were repeated. Results Analyses were conducted on 575 patients (84% male; average age ± SD = 65 ± 11 years; average LVEF ± SD = 0.24 ± 0.05). The final distribution of MTWA results were: MTWA positive in 293 (51%), MTWA negative in 214 (37%), and indeterminate in 68 patients (12%). Over an average follow-up of 2.1 ± 0.9 years, there were 70 VTEs. A VTE occurred in 48 of 361 (13%, 6.3%/year) MTWA non-negative and 22 of 214 (10%, 5.0%/year) MTWA negative patients. A non-negative MTWA test result was not associated with VTE (hazard ratio: 1.26; 95% confidence interval: 0.76 to 2.09; p = 0.37), although total mortality was significantly increased (hazard ratio: 2.04; 95% confidence interval: 1.10 to 3.78; p = 0.02). Conclusions In MADIT-II–indicated ICD-treated patients, the risk of VTE does not differ according to MTWA classification, despite differences in total mortality. (MASTER I–Microvolt T Wave Alternans Testing for Risk Stratification of Post MI Patients; NCT00305240 )

Objectives The purpose of this study was to determine whether abnormalities of calcium cycling explain ventricular action potential (AP) oscillations and cause electrocardiogram T-wave alternans (TWA). Background Mechanisms explaining why heart failure patients are at risk for malignant ventricular arrhythmias (ventricular tachycardia [VT]/ventricular fibrillation [VF]) are unclear. We studied whether oscillations in human ventricular AP explain TWA and predict VT/VF, and used computer modeling to suggest potential cellular mechanisms. Methods We studied 53 patients with left ventricular ejection fraction 28 ± 8% and 18 control subjects. Monophasic APs were recorded in the right ventricle (n = 62) and/or left ventricle (n = 9) at 109 beats/min. Results Alternans of AP amplitude, computed spectrally, had higher magnitude in study patients than in controls (p = 0.03), particularly in AP phase II (p = 0.02) rather than phase III (p = 0.10). The AP duration and activation restitution (n = 11 patients) were flat at 109 beats/min and did not explain TWA. In computer simulations, only reduced sarcoplasmic reticulum calcium uptake explained our results, causing calcium oscillations, AP amplitude alternans, and TWA that were all abolished by calcium clamping. On prospective follow-up for 949 ± 553 days, 17 patients had VT/VF. The AP amplitude alternans predicted VT/VF (p = 0.04), and was 78% concordant with simultaneous TWA (p = 0.003). Conclusions Patients with systolic dysfunction show ventricular AP amplitude alternans that prospectively predicted VT/VF. Alternans in AP amplitude, but not variations in AP duration or conduction, explained TWA at ≤109 beats/min. In computer models, these findings were best explained by reduced sarcoplasmic reticulum calcium uptake. Thus, in heart failure patients, in vivo AP alternans may reflect cellular calcium abnormalities and provide a mechanistic link with VT/VF.

Accurate recognition of individuals at higher immediate risk of sudden cardiac death (SCD) is still an open question. The fortuitous nature of acute cardiovascular events just does not seem to fit the well-known model of ventricular tachycardia/fibrillation induction in a static arrhythmogenic substrate by a synchronous trigger. On the mechanism of SCD, a dynamical electrical instability would better explain the rarity of the simultaneous association of a correct trigger and an appropriate cardiac substrate. Several studies have been conducted trying to measure this cardiac electrical instability (or any valid surrogate) in an ECG beat stream. Among the current possible candidates we can number QT prolongation, QT dispersion, late potentials, T-wave alternans (TWA), and heart rate turbulence. This article reviews the particular role of TWA in the current cardiac risk stratification scenario. TWA findings are still heterogeneous, ranging from very good to nearly null prognostic performance depending on the clinical population observed and clinical protocol in use. To fill the current gaps in the TWA base of knowledge, practitioners, and researchers should better explore the technical features of the several technologies available for TWA evaluation and pay greater attention to the fact that TWA values are responsive to several factors other than medications. Information about the cellular and subcellular mechanisms of TWA is outside the scope of this article, but the reader is referred to some of the good papers available on this topic whenever this extra information could help the understanding of the concepts and facts covered herein.

The gain-of-function Scn5a+/DeltaKPQ mutation in the cardiac Na(+) channel causes human long QT type 3 syndrome (LQT3) associated with ventricular arrhythmogenesis. The K(ATP) channel-opener nicorandil (20muM) significantly reduced arrhythmic incidence in Langendorff-perfused Scn5a+/Delta hearts during programmed electrical stimulation; wild-types (WTs) showed a total absence of arrhythmogenicity. These observations precisely correlated with alterations in recently established criteria for re-entrant excitation reflected in: (1) shortened left-ventricular epicardial but not endocardial monophasic action potential durations at 90% repolarization (APD(90)) that (2) restored transmural repolarization gradients, DeltaAPD(90). Scn5a+/Delta hearts showed longer epicardial but not endocardial APD(90)s, giving shorter DeltaAPD(90)s than WT hearts. Nicorandil reduced epicardial APD(90) in both Scn5a+/Delta and WT hearts thereby increasing DeltaAPD(90). (3) Reduced epicardial critical intervals for re-excitation; Scn5a+/Delta hearts showed greater differences between APD(90) and ventricular effective refractory period than WT hearts that were reduced by nicorandil. (4) Reduced APD(90) alternans. Scn5a+/Delta hearts showed greater epicardial and endocardial alternans than WTs, which increased with pacing rate. Nicorandil reduced these in Scn5a+/Delta hearts to levels indistinguishable from untreated WTs. (5) Flattened restitution curves. Scn5a+/Delta hearts showed larger epicardial and endocardial critical diastolic intervals than WT hearts. Nicorandil decreased these in Scn5a+/Delta and WT hearts. The presence or absence of arrhythmogenesis in Scn5a+/Delta and WT hearts thus agreed with previously established criteria for re-entrant excitation, and alterations in these precisely correlated with the corresponding antiarrhythmic effects of nicorandil. Together these findings implicate spatial and temporal re-entrant mechanisms in arrhythmogenesis in LQT3 and their reversal by nicorandil.

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

Previous studies have demonstrated that microvolt T-wave alternans (MTWA) screening effectively risk-stratifies patients with ischemic cardiomyopathy. Whether the prognostic utility of MTWA diminishes over 3 years of follow-up remains unknown. In this study, a prospective cohort of 768 patients with ischemic cardiomyopathy (left ventricular ejection fraction35%) and no previous sustained ventricular arrhythmia was developed, of whom 514 (67%) screened MTWA nonnegative (positive and indeterminate). The mean follow-up period was 18 +/- 11 months. The primary end point was all-cause mortality and appropriate implantable cardioverter-defibrillator shocks. Stratified Cox regression analyses (by implantable cardioverter-defibrillator status) estimated the predictive power of MTWA within each year of follow-up and determined whether this diminished over time. There were 99 deaths (MTWA negative: 21 [8.3%]; MTWA nonnegative: 78 [15.2%]) and 33 appropriate implantable cardioverter-defibrillator shocks (MTWA negative: 3 [4.0%]; MTWA nonnegative: 30 [9.5%]). After multivariate adjustment, a nonnegative MTWA test result was associated with a greater than twofold increased risk for events in each of the 3 years of follow-up (year 1: stratified hazard ratio 2.19, 95% confidence interval 1.10 to 4.34, p = 0.03; year 2: stratified hazard ratio 3.36, 95% confidence interval 1.28 to 8.83, p = 0.01; year 3: stratified hazard ratio 2.06, 95% confidence interval 0.81 to 5.22, p = 0.13). There were no significant interactions between the time periods (year 1 vs year 2: p = 0.47; year 1 vs year 3: p = 0.92). In conclusion, MTWA reliably and consistently predicts mortality and arrhythmic risk throughout the first 2 to 3 years of follow-up. Although these findings need further validation, they suggest that rescreening with MTWA may not need to be performed more frequently than once every 2 years.

To develop a new method for non-invasive identification of patients prone to ventricular tachyarrhythmia and sudden cardiac death, an adaptive match-filter (AMF) was applied to detect and characterize T-wave alternans (TWA) in 200 coronary artery diseased (CAD) patients compared with 176 healthy (H) subjects. TWA was characterized in terms of duration (TWAD), amplitude (TWAA), and magnitude (TWAM, defined as the product of TWAD times TWAA). A criterion derived from these parameters, estimated over the H-population, allowed discrimination between a risk (TWA+) and a normality (NO TWA) zone in the TWAD-TWAA plane. To gain further ability to discriminate among different risk levels, the TWA+ zone was divided into four sub-zones respectively characterized by low duration and low amplitude (LDLA), low duration and high amplitude (LDHA), high duration and low amplitude (HDLA), and high duration and high amplitude (HDHA). With our methodology, 21 CAD-patients (10.5%) were identified as TWA+, 9 falling in the LDLA zone, 4 in the HDLA, 7 in the LDHA, and 1 in the HDHA. These results are in agreement with clinical expectations and pave the way to further clinical follow-up studies finalized to analyze pathophysiological implications and risk factors associated to each TWA+ zone.

T-wave alternans, characterized by a beat-to-beat change in T-wave morphology, amplitude, and/or polarity on the ECG, often heralds the development of lethal ventricular arrhythmias in patients with left ventricular hypertrophy (LVH). The aim of our study was to examine the ionic basis for a beat-to-beat change in ventricular repolarization in the setting of LVH. Transmembrane action potentials (APs) from epicardium and endocardium were recorded simultaneously, together with transmural ECG and contraction force, in arterially perfused rabbit left ventricular wedge preparation. APs and Ca2+-activated chloride current ( ICl,Ca) were recorded from left ventricular myocytes isolated from normal rabbits and those with renovascular LVH using the standard microelectrode and whole cell patch-clamping techniques, respectively. In the LVH rabbits, a significant beat-to-beat change in endocardial AP duration (APD) created beat-to-beat alteration in transmural voltage gradient that manifested as T-wave alternans on the ECG. Interestingly, contraction force alternated in an opposite phase (“out of phase”) with APD. In the single myocytes of LVH rabbits, a significant beat-to-beat change in APD was also observed in both left ventricular endocardial and epicardial myocytes at various pacing rates. APD alternans was suppressed by adding 1 μM ryanodine, 100 μM 4,4′-diisothiocyanostilbene-2,2′-disulfonic acid (DIDS), and 100 μM 4-acetamido-4′-isothiocyanostilbene-2,2′-disulfonic acid (SITS). The density of the Ca2+-activated chloride currents ( ICl,Ca) in left ventricular myocytes was significantly greater in the LVH rabbits than in the normal group. Our data indicate that abnormal intracellular Ca2+ fluctuation may exert a strong feedback on the membrane ICl,Ca, leading to a beat-to-beat change in the net repolarizing current that manifests as T-wave alternans on the ECG.

Background: The impact of altered ventricular activation, including biventricular (BV) pacing, on T-wave alternans (TWA) and arrhythmic substrates is unclear. We studied how differing ventricular activation sequence alters TWA; the interval from peak-to-end of the T-wave (TpTe) and T-wave amplitude during right (RV), left (LV), and biventricular (BV) pacing; and right atrial (RA) pacing in patients with preexisting conduction delay. Methods and Results: We measured TWA during RA, RV, LV, and BV pacing in 33 patients receiving cardiac-resynchronization-therapy-defibrillators. TWA magnitude (Valt) was lower during BV than RV (P < 0.01), RA (P < 0.01), or LV pacing. As a result, BV-TWA was more often negative than RV-TWA (P < 0.01), LV-TWA, and RA-TWA, particularly when discordant between pacing modes (P < 0.01). Overall, 83% of TWA recordings were abnormal (25% indeterminate), and 17% negative. BV pacing reduced T-wave amplitude (P < 0.05) and TpTe (P < 0.005) compared to RV pacing and LV pacing (P < 0.05; P < 0.005 respectively). Notably, TWA magnitude varied linearly with T-wave amplitude for all pacing modes (P < 0.001). Over 410 ± 252 days' follow-up, RV-TWA predicted the combined endpoint of death and ICD therapy with 86% negative predictive value (P < 0.05). BV-TWA, RA-TWA, and other repolarization indices were not predictive. Conclusions: BV pacing attenuates TWA in tandem with reduced T-wave magnitude. In these patients with baseline QRS prolongation, RV-TWA predicted events more effectively than BV-TWA and RA-TWA. Further studies are required to understand how altered ventricular activation influences repolarization dynamics and arrhythmic tendency.

Background Brugada syndrome (BrS) is characterized by repolarization abnormality with ST-segment elevation in the right ventricular outflow tract (RVOT). Objective Although action potential (AP) heterogeneity is associated with induction of ventricular arrhythmias (VA) in BrS, clinical evidence and its experimental correlations are still absent and are the focus of this study. Methods We evaluated repolarization heterogeneity in 15 patients with BrS using body surface mapping and in 8 pairs of isolated canine RVOT and right ventricular anteroinferior (RVAI) preparations having drug-induced BrS using optical mapping. Results Patients had large J-ST-segment elevation and long QT interval in the RVOT at baseline. Administration of pilsicainide (1 mg/kg) exaggerated J-ST-segment elevation, caused simultaneous long and short QT intervals in the RVOT, and induced polymorphic ventricular tachycardia (VT) and T wave alternans (TWA). Dispersion of QT within the RVOT after pilsicainide was greater in patients that had syncope or ventricular fibrillation than those that did not. Ventricular arrhythmias originated from the RVOT along with local electrocardiogram changes and TWA. Repolarization heterogeneity was much less in areas outside the RVOT. Inducing BrS increased AP heterogeneity (with and without spike-and-dome) within the RVOT epicardium. Phase 2 reentry and TWA originated from the epicardium in 88% and 50% of RVOT preparations, respectively. In contrast, the RVOT endocardium and RVAI had little AP heterogeneity, with neither reentry nor TWA. Conclusion The instability and heterogeneity of repolarization within the epicardium of the RVOT seem to be associated with arrhythmogenesis in both patients and in the in vitro tissue models of BrS.

T-wave alternans (TWA) increases acutely prior to ventricular tachycardia (VT) or fibrillation (VF) in animal studies, suggesting that it may provide a warning for VT/VF in implantable cardioverter defibrillator (ICD) patients. Clinically, measurement of surface ECG TWA requires preprocessing the input signal to reduce noise and/or analyzing more sinus beats than are recorded in ICDs as pre-onset, stored intracardiac electrograms (EGMs) before VT/VF. Our objective was to measure TWA from the few sinus EGMs stored in ICDs before spontaneous VT/VF in humans.The purpose of this study was to evaluate the technical feasibility of measuring TWA from pre-onset ICD EGMs and to measure EGM TWA before spontaneous VT/VF in humans.We developed a method to measure EGM TWA as a simple average (AVE) of peak-to-peak alternans. Using simulation, we determined the effect of ICD signal processing on EGM TWA for durations comparable to those in pre-onset EGMs. We then applied this method to pre-onset ICD EGMs that preceded 101 episodes of sustained VT/VF in 10 patients. In 6 of these patients, EGM recordings in atrial pacing and sinus rhythm provided control data.In simulation, the AVE method discriminated input TWA differencesor = 15 microV. In patients, EGM TWA was 78 +/- 62 microV prior to VT/VF vs. 13 +/- 10 microV in control recordings (p.0001). Eighty percent of pre-onset measurements exceeded 30 microV, while 95% of control measurements were less than 30 microV.A simple averaging method can measure TWA preceding VT/VF in stored ICD EGMs. Pilot data indicate that high-amplitude EGM TWA usually precedes spontaneous VT/VF and is infrequent in control recordings. They provide a rationale for developing ICD technology to measure EGM TWA continuously, both to warn patients and to initiate pacing algorithms to prevent VT/VF.

BACKGROUND Temporal QT interval variability is associated with sudden cardiac death. The purpose of this study was to evaluate temporal QT interval variability in Brugada syndrome (BS). METHODS We measured QT and RR intervals in precordial leads (V(1)-V(6)) based on 12-beat resting ECG recordings from 16 BS patients (B group) with spontaneous ST elevation in right precordial leads (V(1)-V(2)) and from 10 patients with normal hearts (C group). We measured the response in B group before and after administration of pilsicainide (1 mg/kg). The standard deviation (QT-SD, RR-SD) of the time domain and total frequency power (QT-TP, RR-TP) were calculated for all precordial leads, and the latter was to analyze the frequency domain. RESULTS The right precordial leads in BS exhibited an additional and prominent ST elevation (coved-type) after pilsicainide administration. Both QT-SD and QT-TP values were significantly more increased in B, than in C (5.1 +/- 1.2 vs 3.6 +/- 0.2 and 23.4 +/- 2.9 vs 12.3 +/- 1.7 msec(2), P < 0.01, respectively) and after pilsicainide administration in B. (5.1 +/- 0.4 vs 3.9 +/- 0.3, 25.8 +/- 3.4 vs 16.3 +/- 2.6 msec(2), P < 0.01, respectively) However, QT-SD and QT-TP did not significantly change in any of other leads (V(3)-V(6)) and RR-SD and RR-TP were similar for both groups, as well as after intravenous pilsicainide administration in B. CONCLUSIONS The temporal QT interval variability was identified in BS. Moreover, sodium channel blocker induced temporal fluctuation in QT interval and it may possibly provide a substrate for ventricular arrhythmia in BS patients.

A 67-year-old male with dilated cardiomyopathy and chronic renal failure who received chronic hemodialysis for 9 years admitted with pulmonary edema. Three days after admission, electrocardiogram showed transient prolongation of QT interval which was followed by macroscopic T wave alternans (TWA) and ventricular fibrillation (VF). Temporary pacing from right ventricular apex suppressed TWA and VF effectively. Combined cardiac resynchronization therapy and implantable cardioverter defibrillator device was implanted for the secondary prevention of VF. Both prolongation of QT interval and TWA disappeared for 10 days after therapy and no arrhythmic event occurred since then.

Despite recent advances in the prevention and treatment of cardiovascular disease, sudden cardiac death (SCD) still accounts for ≈50% of all cardiovascular deaths in developed countries, thus accounting for a significant proportion of annual death worldwide.1 Reduction of the incidence of SCD depends on identification of those at most risk. In the present review we will concentrate on the challenges of risk stratification for SCD in chronic heart failure (CHF). We evaluate the utility of microvolt T-wave alternans (MTWA) as a tool for predicting SCD and consider whether MTWA is currently a valid means of selecting which patients should, or should not, receive an implantable cardioverter-defibrillator (ICD). Until recently, attempts to prevent SCD relied on pharmacological therapy. β-Blockers,2 angiotensin-converting enzyme inhibitors,3 angiotensin receptor blockers4 and aldosterone antagonists5 modestly reduce the risk of SCD in patients with CHF and after myocardial infarction (MI), whereas antiarrhythmic therapy has largely failed.6 Despite such treatments, these patients remained at high risk until the advent of the ICD. Although ICDs have further reduced the risk of SCD, they are expensive and can be associated with significant morbidity; therefore, precisely targeting their use is crucial. Implantation of ICDs for secondary prevention is clear. Prior sustained ventricular arrhythmia confers high risk and the benefit/risk balance is clearly favorable.7 Also, the secondary prevention population is relatively small and readily identified, thus the financial costs are not insurmountable. Primary prevention ICD therapy is an entirely different scenario. Large, randomized controlled trials have shown a mortality benefit with ICDs in patients with a low left ventricular ejection fraction (LVEF) and a history of MI or CHF.6,8 However, 2 major concerns have restricted implementation of this strategy. First, although analyses have estimated an acceptable cost-effectiveness profile,9 the immediate cost of implanting devices …

Background:Microvolt T-wave alternans (MTWA) has been associated with malignant ventricular arrhythmias in patients (pts) with structural heart disease. MTWA has been shown to be a strong heart rate-dependent arrhythmia marker. However, in clinical practice some pts in which MTWA should be assessed are unable to perform physical exercise to increase heart rate due to various reasons. Methods:In this study, we investigated the feasibility of noninvasive MTWA measurement by using intravenous atropine to increase heart rate and compared the results to MTWA measurement by right atrial (RA) pacing during electrophysiologic (EP) study in 27 consecutive pts (53 ± 14 years; nine women). Determining the arrhythmia event-rate, a follow-up of 18 months was performed in all pts. Results:Using atropine, five pts (18%) did not reach the target heart rate (105 bpm). In the remaining group of pts, concordant results for MTWA assessment could be found in 21 pts (96%). Comparing MTWA positive tests there were slightly higher amplitudes using right atrial (RA) pacing than atropine (7.0 ± 2.3μV vs 6.3 ± 2.2μV, P = 0.03; r = 0.97). During follow-up all pts with a positive MTWA test had documented ventricular arrhythmias. There were no arrhythmic events in the MTWA negative group. Conclusion:Whenever target heart rate for MTWA evaluation is obtained by intravenous atropine, the results are comparable to RA pacing. In using atropine there has been observed no pharmacologically influenced increase of MTWA voltage leading to false positive MTWA results. Therefore the use of atropine can be recommended as a safe, non-invasive, and reliable method for MTWA assessment.

A number of mutations have been linked to diseases for which the underlying mechanisms are poorly understood. An example is Timothy Syndrome (TS), a multisystem disorder that includes severe cardiac arrhythmias. Here we employ theoretical simulations to examine the effects of a TS mutation in the L-type Ca2+ channel on cardiac dynamics over multiple scales, from a gene mutation to protein, cell, tissue, and finally the ECG, to connect a defective Ca2+ channel to arrhythmia susceptibility. Our results indicate that 1) the TS mutation disrupts the rate-dependent dynamics in a single cardiac cell and promotes the development of alternans; 2) in coupled tissue, concordant alternans is observed at slower heart rates in mutant tissue than in normal tissue and, once initiated, rapidly degenerates into discordant alternans and conduction block; and 3) the ECG computed from mutant-simulated tissue exhibits prolonged QT intervals at physiological rates and with small increases in pacing rate, T-wave alternans, and alternating T-wave inversion. At the cellular level, enhanced Ca2+ influx due to the TS mutation causes electrical instabilities. In tissue, the interplay between faulty Ca2+ influx and steep action potential duration restitution causes arrhythmogenic discordant alternans. The prolongation of action potentials causes spatial dispersion of the Na+ channel excitability, leading to inhomogeneous conduction velocity and large action potential spatial gradients. Our model simulations are consistent with the ECG patterns from TS patients, which suggest that the TS mutation is sufficient to cause the clinical phenotype and allows for the revelation of the complex interactions of currents underlying it.

ObjectivesOur aim was to study the relationship between T-wave alternans (TWA) and rate-response (restitution) of repolarization in subjects with and without ventricular systolic dysfunction.BackgroundT-wave alternans is a promising predictor of sudden death, yet the mechanisms linking it with human ventricular arrhythmias are unclear. From theoretic considerations, we hypothesized that abnormal TWA is linked with steep restitution of action potential duration (APD) and that both predict arrhythmic outcome.MethodsWe studied 53 subjects with left ventricular ejection fraction (LVEF) ≤40% and 18 control subjects. At electrophysiologic study, we recorded APD at 90% repolarization (APD90) in the right (n = 62) or left (n = 9) ventricle during pacing while measuring TWA from the body surface.ResultsAs expected, TWA (at 1; 58% vs. 67%). T-wave alternans and simultaneous APD alternans always occurred at diastolic intervals where APD restitution was not steep (p < 0.001), and there was no relationship between maximum restitution slope and TWA magnitude. Over 829 ± 473 days, TWA (p = 0.02), but not restitution slope >1, predicted ventricular arrhythmias in subjects with LVEF ≤40%.ConclusionsThe mechanism by which TWA predicts arrhythmic mortality does not reflect the maximum slope of ventricular APD restitution. Better understanding of the mechanisms underlying TWA may enable improved prediction and prevention of ventricular arrhythmias.

T-wave alternans, a powerful marker for the risk of sudden cardiac death is directly related to alternans of the cellular action potential. When action potential alternans is first initiated, it occurs with identical phase in all cells of a particular region of the heart. However, above a critical heart rate threshold, action potential alternans switches phase in some cells but not in others, such that some cells undergo a prolongation of action potential duration (APD), whereas neighbouring cells undergo APD shortening on the same beat (i.e. discordant alternans). Discordant alternans is linked to a mechanism of arrhythmogenesis because when ventricular action potentials from neighbouring cells are alternating out of phase, repolarization gradients are amplified, producing conduction block and re-entrant excitation. In this review, we discuss potential mechanisms which may underlie discordant alternans in the heart, including (i) conduction velocity restitution, (ii) spatial heterogeneities of calcium cycling and the sarcolemmal ionic currents which govern repolarization, and (iii) intercellular uncoupling.

Objectives The aim of this study was to assess the prognostic value of T-wave alternans (TWA) in New York Heart Association (NYHA) functional class II/III patients with nonischemic cardiomyopathy and left ventricular ejection fraction (LVEF) ≤40%. Background There is a strong need to identify reliable risk stratifiers among heart failure candidates for implantable cardioverter-defibrillator (ICD) prophylaxis. T-wave alternans may identify low-risk subjects among post-myocardial infarction patients with depressed LVEF, but its predictive role in nonischemic cardiomyopathy is unclear. Methods Four hundred forty-six patients were enrolled and followed up for 18 to 24 months. The primary end point was the combination of cardiac death + life-threatening arrhythmias; secondary end points were total mortality and the combination of arrhythmic death + life-threatening arrhythmias. Results Patients with abnormal TWA (65%) compared with normal TWA (35%) tests were older (60 ± 13 years vs. 57 ± 12 years), were more frequently in NYHA functional class III (22% vs. 19%), and had a modestly lower LVEF (29 ± 7% vs. 31 ± 7%). Primary end point rates in patients with abnormal and normal TWA tests were 6.5% (95% confidence interval [CI] 4.5% to 9.4%) and 1.6% (95% CI 0.6% to 4.4%), respectively. Unadjusted and adjusted hazard ratios were 4.0 (95% CI 1.4% to 11.4%; p = 0.002) and 3.2 (95% CI 1.1% to 9.2%; p = 0.013), respectively. Hazard ratios for total mortality and for arrhythmic death + life-threatening arrhythmias were 4.6 (p = 0.002) and 5.5 (p = 0.004), respectively; 18-month negative predictive values for the 3 end points ranged between 97.3% and 98.6%. Conclusions Among NYHA functional class II/III nonischemic cardiomyopathy patients, an abnormal TWA test is associated with a 4-fold higher risk of cardiac death and life-threatening arrhythmias. Patients with normal TWA tests have a very good prognosis and are likely to benefit little from ICD therapy.

Background:Abnormal microvolt T-wave alternans (TWA) predicts the risk of ventricular arrhythmias and sudden cardiac death. Although type 2 diabetes is associated with an increased risk of these events, there is a dearth of available data on microvolt TWA measurements in type 2 diabetic populations. Methods:We studied 59 consecutive type 2 diabetic outpatients without manifest cardiovascular disease (CVD) and 35 non-diabetic controls who were matched for age, sex, and blood pressure values. Microvolt TWA analysis was performed non-invasively using the CH-2000 system during a sub-maximal exercise with the patient sitting on a bicycle ergometer. Results:The frequency of abnormal TWA was significantly higher in diabetic patients than in controls (25.4 vs 5.7%; P < 0.01). Among diabetic patients, those with abnormal TWA (n = 15) had remarkably higher hemoglobin A1c (HbA1c) (8.1 ± 0.9 vs 7.1 ± 0.8%, P < 0.001) and slightly smaller time-domain heart rate variability parameters (i.e., RMSSD, root mean square of difference of successive R-R intervals) than those with normal TWA (n = 44). Gender, age, body mass index, lipids, blood pressure values, cigarette smoking, diabetes duration, microvascular complication status, QTc interval, and current use of medications did not significantly differ between the groups. In multivariate regression logistic analysis, HbA1c (OR 13.6, 95% CI 2.0–89.1; P = 0.0076) predicted abnormal TWA independent of RMSSD values and other potential confounders. Conclusions:Our findings suggest that abnormal TWA is a very common condition (∼25%) among people with type 2 diabetes without manifest CVD and is closely correlated to glycemic control.

Based on current guidelines, most electrophysiologists today are implanting cardioverter-defibrillators (ICDs) using a low left ventricular ejection fraction alone as the sole stratifier for the risk of sudden cardiac death. However, left ventricular ejection fraction is a better marker of total mortality than sudden death. As a result, this strategy is flawed because it exposes many patients to the risk and cost of ICD therapy without its benefits. Primary prevention trials based on this strategy show that the rate of appropriate ICD shocks is only 5% to 10% per year. We believe that the effectiveness of ICD therapy can be improved by the use, in addition to ejection fraction, of one or more of the noninvasive tests, which are reviewed in this article. Such tests are more adequate to evaluate the arrhythmogenic substrate of the patient than the left ventricular ejection fraction alone. Whether any of these tests can help us identify the patients at the lowest risk of sudden death, who could safely avoid ICD implant, remains to be determined.

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

Microvolt T-wave alternans (MTWA) was proposed as an effective tool to identify high-risk patients with ischemic cardiomyopathy. However, previous studies suggested that the prognostic utility of MTWA may be limited to only patients with normal QRS duration. It therefore was assessed whether MTWA and QRS duration120 ms independently predict mortality in patients with ischemic cardiomyopathy and whether the prognostic utility of MTWA differs by QRS duration. A total of 768 consecutive patients with ischemic cardiomyopathy (left ventricular ejection fractionor =35%) and no history of ventricular arrhythmia were enrolled, of whom 514 (67%) screened MTWA non-negative (positive or indeterminate) and 223 (29%) had a QRS120 ms on resting electrocardiogram. After multivariable adjustment, a non-negative MTWA test result was associated with a significantly higher risk for all-cause mortality in patients without an implantable cardioverter-defibrillator (ICD) (hazard ratio [HR] 2.27, 95% confidence interval [CI] 1.22 to 4.24, p = 0.01) and for all-cause mortality and appropriate ICD shocks in patients with an ICD (HR 2.42, 95% CI 1.07 to 5.41, p = 0.04). In contrast, a QRS120 ms was not associated with all-cause mortality and ICD shocks in patients without (HR 0.96, 95% CI 0.52 to 1.75, p = 0.88) or with an ICD (HR 1.25, 95% CI 0.76 to 2.08, p = 0.40). No significant interaction was found between MTWA and QRS120 ms (non-ICD p = 0.19, ICD p = 0.73). In conclusion, MTWA, but not QRS duration, predicted mortality outcomes in patients with ischemic cardiomyopathy. Moreover, the prognostic utility of MTWA did not appear to differ by QRS duration.

ObjectivesThe purpose of this study was to prospectively evaluate the utility of microvolt T-wave alternans (TWA) in predicting arrhythmia-free survival and total mortality in patients with left ventricular (LV) dysfunction.BackgroundMicrovolt TWA has been proposed as a useful tool in identifying patients unlikely to benefit from prophylaxis with implantable cardioverter-defibrillator (ICD) prophylaxis.MethodsWe evaluated 286 patients with an LV ejection fraction ≤35% who underwent TWA and electrophysiologic testing (EPS) owing to nonsustained ventricular tachycardia and/or syncope. Positive and indeterminate TWA results were grouped as non-negative. The primary end point was arrhythmia-free survival; the secondary end point was all-cause mortality.ResultsPatients were followed for a mean of 38 ± 11 months. There was no significant difference between the TWA-negative (n = 90; 31%) and non-negative (n = 196; 69%) groups with respect to ICD implant rates (54% vs. 64%, respectively; p = 0.95) or etiology of cardiomyopathy (ischemic: 73% vs. 76%; p = 0.71). The Kaplan-Meier curves demonstrated improved arrhythmia-free survival in TWA-negative patients (81% vs. 66% at 2 years; p < 0.001), including in both ischemic (79% vs. 64% at 2 years; p = 0.004) and nonischemic (88% vs. 71% at 2 years; p = 0.015) subgroups. Total mortality was lower in the TWA-negative group (10% vs. 18% at 2 years; p = 0.04). The negative predictive value of TWA for (2-year) total mortality was 90%, and 83% for EPS.ConclusionMicrovolt TWA predicts arrhythmia-free survival among patients with LV dysfunction. However, the event rate in the TWA-negative group suggests that TWA may not be capable of identifying a sufficiently low-risk subset in this population to obviate the need for ICD implantation.

T-wave alternans (TWA) and electrophysiology study (EPS) are used for risk stratification for sudden death.The purpose of the study was to determine the effect of bundle branch block or intraventricular conduction delay on TWA and EPS.386 patients with coronary artery disease, nonsustained ventricular tachycardia, and left ventricular ejection fractionor =40% underwent TWA and EPS, and were followed for 40 +/- 19 months.Patients with wide QRS were more likely than narrow QRS patients to have nonnegative TWA (77% vs 63%, P.01) or positive EPS (60% vs 48%, P = .03). Nonnegative TWA predicted the combined endpoint of ventricular tachyarrhythmia or death in narrow QRS (HR = 1.64, P = .04) but not wide QRS patients (HR = 1.04, P = .91). Similarly, positive EPS predicted the combined endpoint in narrow QRS (HR = 2.28, P.001) but not wide QRS patients (HR = 0.94, P = .84). In multivariate analysis, QRS width and TWA, as well as QRS width and EPS, were independent predictors of events. There was no TWA- or EPS-based difference in arrhythmia-free survival within any specific wide QRS morphology.TWA and EPS are more often abnormal in patients with a wide QRS than in those with a narrow QRS. In patients with narrow QRS, both TWA and EPS stratify patients according to their risk of ventricular tachyarrhythmia or death. However, among patients with a wide QRS, regardless of specific QRS morphology, the risk is high and comparable regardless of TWA or EPS results. Therefore, the only truly low-risk group consists of those patients with negative test results and a narrow QRS.

PURPOSE OF REVIEW Accurate identification of patients at risk for ventricular arrhythmias is critical to prevent sudden cardiac death. The perioperative period is usually regarded as one of risk for potential triggering conditions. This review focuses on the anaesthesiologic risk of inherited arrhythmias whose aetiology is a mutation in genes encoding cardiac ion channels in the absence of structural heart abnormalities. RECENT FINDINGS Genetic analysis identifies the genes whose expressions generate ion channel and regulating or anchoring subunits; electrophysiology can study the role of each ion current during cardiac fibrillation and develop many tests for risk. There is, however, a great heterogeneity of clinical phenotype and many histological studies detecting structural heart alterations despite negative noninvasive evaluations. SUMMARY For some ion channel diseases, a therapy has been established; for others, the therapy and risk stratification are still matters of concern, and it is necessary to evaluate the new tools and tests available. For the highly lethal complication of these 'channellopathies', anaesthesia should proceed with caution in the light of the characteristics of each arrhythmia to prevent complications.

Aims As a part of the Finnish Cardiovascular Study, we tested the hypothesis that T-wave alternans (TWA) predicts mortality in a general population of patients referred for a clinical exercise test. Methods and results A total of 1037 consecutive patients (mean age+SD of 58+13 years, 673 men and 364 women) with a clinically indicated exercise test and with technically successful electrocardiographic (ECG) data during a bicycle ergometer test were included in the study. Digital ECGs were recorded and TWA was analysed continuously with the time-domain modified moving average method. The maximum TWA value at heart rate (HR) ,125 b.p.m. was derived and its capacity to stratify risk for all-cause death, cardiovascular death, and sudden cardiac death (SCD) was tested. During a follow-up of 44+7 months (mean+SD), 59 patients died; 34 were due to cardiovascular causes and 20 were due to SCD. In multivariate analysis after adjustment for age, sex, use of b-blockers, functional class, maximal HR during exercise, previous myocardial infarction, and other common coronary risk factors, the relative risk of TWA � 65 mV for SCD was 7.4 (95% CI, 2.8–19.4; P , 0.001), for cardiovascular mortality 6.0 (95% CI, 2.8–12.8; P , 0.001), and for all-cause mortality 3.3 (95% CI, 1.8–6.3; P ¼ 0.001). Conclusion Time-domain TWA analysis powerfully predicts mortality in a general population undergoing a clinical exercise test.

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