Utility of T-wave alternans in congestive heart failure.

ABSTRACT

The use of implantable cardioverter defibrillator (ICD) in heart failure patients decreases the arrhythmic mortality with the cost of increasing the number of patients to be treated, and microvolt T-wave alternans (MTWA) testing can be used as a good criteria to better select the candidate for such a therapy. This article examines generalities about the mechanism of alternans, definitions of positive, negative, and indeterminate MTWA tests, and factors that can modify these results. We review clinical studies that have found MTWA as a marker of ventricular arrhythmias in patients with heart failure, independent of etiology, ischemic or idiopathic. Microvolt T-wave alternans permits the selection of low risk patients who may not benefit of ICD implantation by standard criteria, due to high negative predictive values in most studies.

Keywords: T-wave alternans, heart failure

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Heart failure is one of the most important public-health problems, and the leading death causes of this syndrome are sudden cardiac arrhythmic death (SCD) along with pump failure. Therefore, the use of Internal cardiac defibrillator (ICD) as primary and secondary prevention of SCD in patients with low ejection fraction (EF) reduces significantly the mortality (1, 2). But, as it was expected, this action increases considerably the number of treat per one life saving in the primary prevention. That why a better selection of the candidate for ICD implantation is needed, mainly to reduce the side effects of an invasive approach, and, if possible, to decrease the costs of treat the heart failure patient. Considering all of the above, the microscopic T-wave alternans (MTWA) seems to be a good criterion for conducting risk stratification analysis.

Macroscopic alternans of the T-wave is a rare appearance, and it was linked to malignant ventricular arrhythmias (more frequent in the long QT syndrome (3), but also after administration of some drugs (4)). Subsequently, it was demonstrated that variation of magnitude and/or shape of T-wave in the microvolt domain involves the same arrhythmic risk as do macroscopic alternans. The exact mechanism of alternans is unknown. However, it can be determined by spatial and/or temporal differences in re-polarization of different regions of myocardium (5), generating unidirectional block and reentrant arrhythmias (6) or ventricular fibrillation (VF) (7).These differences are deter mined by alteration of Ca homeostasis in myocytes, metabolic disturbance in ischemia (depleted ATP reserve), and spatial differences in sensitivity of KATP channel activation (8).

The presence of alternans is relied on elevated heart rate (HR), and the methods of HR increase are stress test or atrial pacing. In some studies, the stress test method was shown to induce greater amplitude of alternans probably by increasing the sympathetic tone (9). Some authors found that only the MTWA during exercise is a predictor of arrhythmic events (10). Alternans is significant at rest or at elevated heart rate, but below 110 beats/min. The parameters has to be calculated using spectral methods measuring the beat-to-beat fluctuations of amplitude of 128 aligned beats at the same point of the T-wave relative to (IRS complex. These are the alternans voltage (Vast), which represents the square root of alternans power (difference between of power at alternation frequency - 0.5 cycles per beat, and the power at the noise frequency band -frequency between 0.44 and 0.49 cycle per beat) (11). Valt corresponds to the half difference between the even mean and odd mean voltages of the T-wave (11). Alternans ratio (k score) is a measure of statistical significance of alternation and represents the ratio between alternation power and the standard deviation of the noise. The alternans is positive, if Valt is greater than 1.9 [micro]V at a heart rate less than 110 beats/min for more than 1 min in any vector (X, Y, Z), or two precordial ECG leads; k score must be at least 3. The alternans is negative, if the criteria for positive test are not present at a heart rate lower than 105 beats per minute, and noise level is less than 1.8 [micro]V. The indeterminate test does not meet criteria for positive or negative (8,11); usually it is due to high noise level, high ectopy rate, or incapacity to reach the target heart rate. It seems to have prognostic significance similar to positive test (12), and in most recent studies, it is considered in the same group of non-negative or abnormal test.

Some additional factors can influence the significance of MTWA test. The presence of left bundle branch block is more often associated with abnormal MTWA tests (maybe due to advanced disease and increased arrhythmic risk), having similar sensitivity, but lower specificity for arrhythmic events (13). Concomitant medication can influence test results, as found by some authors, especially beta-blockers (14,15), possibly by reducing the adrenergic drive. Also, the rate of indeterminate tests are increased by inability to reach target heart rate (15).

Clinical studies in patients with heart failure are very promising, because it was revealed that T-wave alternans is a good predictor of ventricular arrhythmias.

The comparison with other risk predictors in heart failure revealed MTWA to be equal or superior to other risk stratifiers.

QT interval dispersion (QTD) is another marker of repolarization abnormalities, but it was not significantly associated with ventricular tachycardia (VT) or ventricular fibrillation (VF) as do MTWA in nonischemic dilated cardiomyopathy patients in a prospective study by Sakabe and colleagues (16). The MTWA was positive in 24 patients (80%) and QTD in 11 patients (37%) of 30 patients followed up. During the follow-up period of 13 [+ or -] 11 month VT (defined as at least 5 consecutive beats at [greater than or equal to] 120 beats/min) was present in 13 patients, including 7 patients with sustained ([greater than or equal to] 30s) VT and 2--with VF. The positive and predictive negative values for MTWA were 54% and 100%, respectively. Electrophysiological study (EPS) is one of the most powerful predictors of arrhythmic event, but it is an invasive and costly approach, and positive T-wave alternans can predict the induction of ventricular arrhythmias in programmed ventricular stimulation with a sensitivity of 81%, specificity of 84%, and a relative risk of 5.2 (17). The MTWA can replace EPS in guiding ICD implantation in patients with heart failure (EF [less than or equal to] 40%) and non-sustained VT, both tests have similar positive and negative predictive values (18). The tests are synergistic, the combination (EPS+and MTWA+) having highest event rate, and lowest event rate in the case of both negative; discordanttests have intermediary predictive rate of arrhythmic events. At 2 years, the positive predictive value of MTWA felt suggested the need to reevaluate the patient before the completion of this period, perhaps at 12-15 months as the authors suggest (18). In a recent study (19), more than 500 patients older than 18 years, with EF [less than or equal to] 40%, who had no history of ventricular arrhythmias were studied. The patients with atrial fibrillation, NYHA class IV symptoms, unable to sustain exercise, or unstable coronary disease were excluded. The MTWA was performed by exercise; patients were continuing their medications, including beta-blocker. The testwas classified as abnormal (positive or indeterminate) or negative using standard criteria. Primary end--points were all cause mortality and nonfatal sustained ventricular arrhythmias. The mean age was 56 years, the mean ejection fraction 25%, (IRS duration>120 msec was found in 28% of patients and 71% were men. The statistical significant differences between abnormal and normal MTWA group were age (older), sex (higher percentage), hypertension (higher percentage), drugs at enrolment (lower percentage for beta-blocker and antilipidemic and higher for digoxin therapy for abnormal group). The etiology of heart failure was well-balanced, ischemic heart being responsible for one-half. Microvolt T-wave alternans test done at baseline was abnormal in 66% of patients, and the two-year event rate was 15% and 2.5% in abnormal and normal groups, respectively (HR 6.5, 95% CI 2.4 to 18.1, p<0.001). T-wave alternans remained a strong predictor when was forced into a multivariate Cox model with LVEF (the event rate of patients with EF [less than or equal to] 0.30 and normal MTWA test was lower than in patients with abnormal test and EF 0.31-0.40). The attitude to not implanting ICD in patients with normal MTWA test and EF less than 0.40 seems reasonable. To assess the mortality benefit with ICD implantation in ischemic heart disease function of MTWA status Chow et al evaluate 768 consecutive patients with low ejection fraction ([less than or equal to] 35%), sinus rhythm and no history of arrhythmic event (20). Beta-blocker and calcium channel blockers were stopped more than 24 h before TWA test. Primary end-points was all cause mortality and secondary end points were cause-specific mortality, appropriate ICD shock discharge for VT/VF. The MTWA test was abnormal (positive or indeterminate) in 514 patients (67%) and negative in 254 (33%). The ICDs were implanted in 317 (62%) patients with non-negative test and in 75 (30%) patients with negative result. These differences were due to higher rates of positive EPS, abnormal Holter studies and prolonged (>120 msec) (IRS duration, the main determinants of ICD implantation (93% of all ICDs implanted). In the follow-up period of 27 [+ or -] 12 months, ICDs implantation reduced all cause and arrhythmic mortality in MTWA non-negative patients, but not in MTWA negative patients. The ICD therapy had no influence of non-arrhythmic mortality in all patients. The ICD and no-ICD patients were exposed to similar baseline combined rates of mortality and arrhythmic events.

In 137 patients with idiopathic dilated cardiomyopathy, Hohnloser et al. found MTWA and baroreflex sensitivity to be univariate independent predictors of ventricular arrhythmic events (sudden death, cardiac arrest due to VF, and hemodynamically unstable VT/VF stored on ICD electrogram) (21). Noteworthy in dilated cardiomyopathy the onset of heart rate of alternans had prognostic value ([less than or equal to] 100 beats/min) (22).

Interestingly the MTWA measured at 110 beats/min can be reduced in patients with biventricular stimulation (DDD-BiV), as opposed to atrial only or DOD right ventricular stimulation (23).

One of the most important limitations is the inability to use MTWA in atrial fibrillation patients. The studies did not define the interval for retesting, and it is possible that patients with negative result owe the abnormal test after some period.

The T-wave alternans test emerges as a good predictor of ventricular malignant arrhythmias permitting the selection of low risk heart failure patients (independent of etiology: ischemic or idiopathic), who may not benefit of ICD implantation by standard criteria, due to high negative predictive values in most studies.

References

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Alexandru Deutsch, * Bulent Gorenek

Department of Cardiology, Caritas Hospital, Carol Davila University, Bucharest, Romania

* Clinic of Cardiology, Faculty of Medicine, Osmangazi University, Eskisehir, Turkey