Does manual T-wave window adjustment affect microvolt T-wave alternans results in patients with structural heart disease?

INTRODUCTION: Microvolt T-wave alternans (MTWA) analysis can identify patients at low risk of sudden cardiac death who might not benefit from an implantable cardioverter-defibrillator (ICD). Current spectral methodology for performing MTWA analysis may "miss" part of the T-wave in patients with QT prolongation. The value of T-wave window adjustment in patients with structural heart disease has not been studied. METHODS: We assembled MTWA data from 5 prior prospective studies including 170 patients with reduced left ventricular ejection fraction, adjusted the T-wave window to include the entire T-wave, and reanalyzed MTWA. RESULTS: Of 170 patients, 43% required T-wave window adjustment. Only 3 of 170 patients (1.8%) had a clinically significant change in MTWA results. CONCLUSIONS: In 98.2% of patients, T-wave window adjustment did not improve the accuracy of MTWA analysis. Spectral MTWA as currently implemented remains effective for identifying patients with structural heart disease unlikely to benefit from ICD therapy.

Microvolt T-wave alternans amplifies spatial dispersion of repolarization in human subjects with ischemic cardiomyopathy.

INTRODUCTION: In experimental models, spatial dispersion of repolarization (DOR) due to discordant cellular alternans predisposes to ventricular fibrillation. To test the hypothesis that microvolt T-wave alternans (MTWA) in humans causes spatial DOR, we measured Tpeak-Tend interval (Tpe) and Tpe/QT ratio, electrocardiographic indices of spatial DOR. METHODS: Mean Tpe and Tpe/QT were compared in ischemic cardiomyopathy patients with positive and negative MTWA studies. RESULTS: MTWA was positive in 12 and negative in 24 patients. Tpe and Tpe/QT were higher in MTWA+ subjects compared to MTWA- subjects during exercise (64.5±6.8 vs. 54.9±8.7ms, p=0.001 and 0.218±0.03 vs. 0.177±0.02, p=0.001) but not at rest. CONCLUSION: Ischemic cardiomyopathy patients have increased Tpe and Tpe/QT when MTWA is induced during exercise, suggesting that MTWA causes increased spatial DOR in humans. Future studies are needed to determine if Tpe and Tpe/QT during exercise might predict increased risk of SCD alone or in combination with measurement of MTWA.

ß-blockers protect against dispersion of repolarization during exercise in congenital long-QT syndrome type 1.

INTRODUCTION: ß-Blocker therapy reduces syncope and sudden death in long-QT syndrome type 1 (LQT1), but the mechanism of protection is incompletely understood. This study tested the hypothesis that ß-blockade reduces QT prolongation and dispersion of repolarization, measured as the T peak-to-end interval (T(pe) ), during exercise and recovery in LQT1 patients. METHODS AND RESULTS: QT and T(pe) were measured in 10 LQT1 patients (33 ± 13 years) and 35 normal subjects (32 ± 12 years) during exercise tests on and off ß-blockade. In LQT1 patients, ß-blockade reduced QT (391 ± 25 milliseconds vs 375 ± 26 milliseconds, P = 0.04 during exercise; 419 ± 41 milliseconds vs 391 ± 39 milliseconds, P = 0.02 during recovery) and markedly reduced T(pe) (91 ± 26 milliseconds vs 67 ± 19 milliseconds, P = 0.03 during exercise; 103 ± 26 milliseconds vs 78 ± 11 milliseconds, P = 0.02 during recovery). In contrast, in normal subjects, ß-blockade had no effect on QT (320 ± 17 milliseconds vs 317 ± 16 milliseconds, P = 0.29 during exercise; 317 ± 13 milliseconds vs 315 ± 14 milliseconds, P = 0.15 during recovery) and mildly reduced T(pe) (69 ± 13 milliseconds vs 61 ± 11 milliseconds, P = 0.01 during exercise; 77 ± 19 milliseconds vs. 68 ± 14 milliseconds, P < 0.001 during recovery). CONCLUSION: In LQT1 patients, ß-blockers reduced QT and T(pe) during exercise and recovery, supporting the theory that ß-blocker therapy protects LQT1 patients by reducing dispersion of repolarization during exercise and recovery.

The ABCD (Alternans Before Cardioverter Defibrillator) Trial: strategies using T-wave alternans to improve efficiency of sudden cardiac death prevention.

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 < or =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).

I(Kr) channel blockade to unmask occult congenital long QT syndrome.

BACKGROUND: Patients with genetic evidence of long QT syndromes type 1 and 2 (LQT1, associated with impaired outward potassium current I(Ks); and LQT2, associated with impaired outward potassium current I(Kr)) may have normal baseline QT intervals (phenotype/genotype discordance) and elude clinical detection. Beta-adrenergic stimulation may unmask occult LQT1, but no maneuver has consistently unmasked the LQT2 phenotype. OBJECTIVE: The purpose of this study was to test the repolarization reserve hypothesis (multiple challenges to repolarization are required to produce an abnormal phenotype), using subjects with LQT1 and LQT2 mutations but normal QT interval. We hypothesized that I(Kr) channel blockade would prolong the QT interval excessively in subjects with LQTS compared with controls and that I(Kr) channel blockade could unmask the abnormal LQTS phenotype in subjects with LQTS versus controls, as measured by the T peak-to-end interval (Tpe), a sensitive measure of abnormal repolarization. METHODS: Subjects with known LQT1 (n = 5) and LQT2 (n = 6) mutations but baseline QTc < or = 450 ms and age- and gender-matched controls (n = 22) received intravenous erythromycin (an I(Kr) blocker). RR, QRS, QT, and Tpe intervals were measured at baseline and after drug infusion. RESULTS: Erythromycin caused only modest QT prolongation in all groups. In contrast, Tpe was specifically prolonged by I(Kr) channel blockade in LQT2 subjects but not in LQT1 subjects or controls. CONCLUSION: Short-acting I(Kr) channel blockade, together with the sensitive repolarization measure Tpe, can unmask abnormal repolarization in LQT2. Our finding of abnormal repolarization in LQT2 subjects exposed to I(Kr) channel blockade supports the repolarization reserve hypothesis.

Use of autonomic maneuvers to probe phenotype/genotype discordance in congenital long QT syndrome.

Patients with congenital long QT syndrome due to potassium channel mutations (LQT1 and LQT2) may elude diagnosis due to normal electrocardiographic findings at rest, yet remain at risk of sudden death during bradycardia or sympathetic stimulation. To test the hypothesis that autonomic maneuvers can unmask long QT syndrome in genetically abnormal subjects with a normal phenotype (QTc < or =450 ms), we exposed 13 controls (33 +/- 9 years; 5 men), 5 patients with LQT1 (32 +/- 12 years; 3 men), and 5 patients with LQT2 (30 +/- 11 years; 5 men) to phenylephrine bolus, exercise, and epinephrine infusion. The QT interval was measured at baseline and after each intervention. A substantial overlap was found in QTc among the groups at baseline and after phenylephrine. In contrast, QTc was significantly and consistently longer in subjects with LQT1 compared with controls during and after exercise (492 +/- 40 vs 407 +/- 14 ms, p <0.0001, at peak exercise; 498 +/- 30 vs 399 +/- 20 ms, p <0.0001, at 1 minute into recovery) or epinephrine (623 +/- 51 vs 499 +/- 51 ms, p <0.001, at peak epinephrine; 604 +/- 36 vs 507 +/- 54 ms, p <0.01, at 1 minute into recovery) but not in subjects with LQT2. In conclusion, sympathetic stimulation can reveal the LQT1 phenotype even in subjects with normal baseline electrocardiographic findings.