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J Am Coll Cardiol, 2001; 38:2013-2019 © 2001 by the American College of Cardiology Foundation |
a Department of Medicine, Division of Cardiology, J.W. Goethe University, Frankfurt, Germany
Manuscript received January 23, 2001; revised manuscript received August 21, 2001, accepted August 29, 2001.
* Reprint requests and correspondence: Dr. Stefan H. Hohnloser, Department of Medicine, Division of Cardiology, J. W. Goethe University, Theodor-Stern-Kai 7, D-60590 Frankfurt, Germany
Hohnloser{at}em.uni-frankfurt.de
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Abstract |
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The study evaluated the effects of metoprolol, a pure beta-blocker, and d,l-sotalol, a beta-blocker with additional class III antiarrhythmic effects, on microvolt-level T-wave alternans (TWA).
BACKGROUND
Assessment of TWA is increasingly used for purposes of risk stratification in patients prone to sudden death. There are only sparse data regarding the effects of beta-blockers and antiarrhythmic drugs on TWA.
METHODS
Patients with a history of documented or suspected malignant ventricular tachyarrhythmias were eligible. All patients underwent invasive electrophysiologic (EP) testing including programmed ventricular stimulation and determination of TWA at increasing heart rates using atrial pacing. Reproducibility of TWA at two consecutive drug-free baseline measurements was tested in a random patient subset. Following baseline measurements, all patients were randomized either to double-blind intravenous infusion of sotalol (1.0 mg/kg) or metoprolol (0.1 mg/kg). Results of TWA assessment at baseline and after drug exposure were compared.
RESULTS
Fifty-four consecutive patients were studied. In 12 patients, repetitive baseline measurement of TWA revealed stable alternans voltage (Valt) values (9.1 ± 5.8 µV vs. 8.5 ± 5.7 µV, p = NS). After drug administration, Valt decreased by 35% with metoprolol (7.9 ± 6.0 µV to 4.9 ± 4.2 µV; p < 0.001) and by 38% with sotalol (8.6 ± 6.8 µV to 4.4 ± 2.3 µV; p = 0.001). In eight patients with positive TWA at baseline, repeated measurement revealed negative test results.
CONCLUSIONS
In patients prone to sudden cardiac death, there is a reduction in TWA amplitude following the administration of antiadrenergic drugs. This result indicates that TWA is responsive to the pharmacologic milieu and suggests that, to assess a patient’s risk of spontaneous ventricular arrhythmia, the patient should be tested while maintaining the pharmacologic regimen under which the risk of arrhythmia is being assessed. This applies particularly for beta-blocker therapy.
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The influence of the autonomic nervous system on TWA is incompletely understood. Whereas previous investigations provided evidence for a role of the sympathetic limb in eliciting TWA (7), recent observations by Kaufman et al. (8) suggest that sympathetic activation is not mandatory for the occurrence of arrhythmogenic TWA. Similarly, only sparse data exist on the modulating effects of antiarrhythmic drugs on TWA (9,10). From a clinical perspective, however, these issues are of particular importance because most patients at risk for serious ventricular arrhythmias are treated with antiadrenergic drugs and many are receiving antiarrhythmic drugs, which prolong ventricular repolarization. Accordingly, the present prospective study was designed to evaluate specifically the effects of metoprolol, a pure beta-blocker, and sotalol, a beta-blocker with additional class III antiarrhythmic effects (11), on microvolt-level TWA in patients prone to sudden cardiac death.
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Methods |
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Study protocol.
Electrophysiologic study
Previously administered antiarrhythmic drugs and beta-blockers were withheld for at least 5 half-lives prior to electrophysiologic (EP) study. Three multipolar electrode catheters were positioned via the right or left femoral vein in the high right atrium, the right ventricular apex and the His bundle region. Programmed ventricular stimulation was performed according to a standardized protocol at two different sites (right ventricular [RV] apex; RV outflow tract) at basic cycle lengths of 600, 500 and 430 ms using one to three extrastimuli. The results of the EP study were defined as positive if sustained monomorphic VT or ventricular fibrillation (VF) was repeatedly induced. According to these results, patients were assigned to two different randomization strata (Fig. 1).
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Measurement of TWA voltage. The TWA recordings were interpreted by one of the investigators (T. K.) who was unaware of the patient’s history, the drug administered, inducibility, or the sequence of TWA recordings. The magnitude of TWA voltage (Valt) in individual patients was measured as follows: TWA spectra were printed (Fig. 2) and the two recordings of each patient compared as to the quality of the recordings at different corresponding heart rates. The Valt was measured at the highest common heart rate by picking the highest amplitude from the TWA trend summary of baseline and on-drug recordings. Because TWA amplitude is usually most pronounced in the precordial leads V2 through V4, these leads were selected for Valt determination.
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Randomized intervention. After completion of baseline measurements, patients were randomized in a double-blind fashion to either metoprolol or d,l-sotalol treatment. Randomization was performed in two separate strata according to inducibility at EP testing (Fig. 1). Study drug was administered intravenously over 5 min at a dose of 1 mg/kg sotalol or a dose of 0.1 mg/kg metoprolol. On-drug TWA measurement was started 10 min after the end of drug infusion. Resting heart rate and ventricular effective refractory period (ERP) were also determined for comparison with baseline values.
Statistical analysis. Differences within and between (interaction) the two treatment groups with regard to the changes in heart rate, ERP, and TWA amplitude were performed using the two-way repeated measures analysis of variance (Statistical Package for Social Sciences [SPSS], version 7.0). Mean values and standard deviations are given. A p value <0.05 was defined as statistically significant.
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Results |
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Effects of metoprolol and d,l-sotalol on TWA.. Of the 54 patients, 25 received metoprolol and 29 d,l-sotalol. Both drugs resulted in a comparable decrease in resting heart rate (metoprolol: 79 ± 12 beats/min to 67 ± 10 beats/min; sotalol: 75 ± 12 beats/min to 60 ± 9 beats/min; p < 0.01 for both comparisons). Ventricular ERP increased significantly from 244 ± 26 ms to 276 ± 36 ms (p < 0.001) in patients treated with sotalol and from 237 ± 25 ms to 257 ± 31 ms (p = 0.002) in patients receiving metoprolol. These changes in heart rate and ERP were comparable within the two treatment groups (p = 0.67 and p = 0.31, respectively).
In 8 of 48 patients with positive baseline TWA, the TWA turned negative after drug administration; five patients had received metoprolol, and three had received sotalol. Baseline Valt was lower in these eight patients as compared to those who remained TWA positive after beta-blockers (4.1 ± 1.4 µV vs. 9.2 ± 6.7 µV; p = 0.026). Administration of beta-blockers in these patients reduced Valt below 2 µV. Four of these patients (50%) had inducible VT/VF compared to 23 of 40 (56%) patients in whom TWA remained positive after drug administration (p = 0.71). All six patients with a negative TWA at baseline remained negative after drug administration.
A significant decrease in Valt occurred after drug administration in the entire patient population (8.4 ± 6.4 µV to 4.7 ± 3.3 µV; p < 0.001) as well as in the subgroup of patients with CAD (8.2 ± 6.8 µV to 4.5 ± 3.5 µV; p < 0.001). The decrease in Valt was comparable in patients receiving metoprolol (7.9 ± 6.0 µV vs. 4.9 ± 4.2 µV; p < 0.001) and in those treated with sotalol (8.6 ± 6.8 µV vs. 4.4 ± 2.3 µV; p = 0.001). A representative example of drug-induced reduction in Valt is shown in Figure 3. The heart rate at which TWA became detectable was similar at baseline and on-drug assessment in both study groups (metoprolol 94 ± 8 beats/min vs. 95 ± 7 beats/min; p = 0.86; sotalol: 99 ± 10 beats/min vs. 98 ± 12 beats/min; p = 0.83). The observed changes in Valt and onset heart rate were comparable within the two treatment groups (p = 0.905 and p = 0.602, respectively).
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Discussion |
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Sympathetic nervous system and TWA. There are conflicting reports in the literature on the role of the sympathetic nervous system in triggering TWA. One of the first observations related to this issue was reported in 1975 by Schwartz and Malliani (7), who described the case of a nine-year-old girl with the idiopathic long QT syndrome who repeatedly showed macroscopic TWA during episodes of sympathetic excitation. In the same report, experimental findings in vagotomized cats were described. In these animals, TWA could be elicited during stimulation of the left stellate ganglion. Subsequently, several similar observations in patients afflicted with the long QT syndrome were reported (15). These experimental findings along with the clinical observations led to the hypothesis that increases in sympathetic activity may play a critical role in triggering TWA as a precursor of malignant ventricular tachyarrhythmias.
In a recent and careful study in patients referred for EP testing, Kaufman et al. (8) measured TWA at identical pacing cycle lengths with and without isoproterenol in 14 patients. Five patients with a history of sudden cardiac death were noninducible at EP testing; in two of these, TWA increased significantly during adrenergic stimulation. In another two patients, beta-adrenergic stimulation induced TWA that was not already present at baseline (8). The investigators concluded from their observations that there is only a modest contribution of adrenergic tone to the occurrence of microvolt TWA in most patients.
In contrast to the report of Kaufman et al. (8), all patients enrolled in the present study had a history of documented or suspected malignant ventricular arrhythmia. Administration of antiadrenergic drugs resulted in a significant decrease in TWA amplitude in all patients. Of note, however, only a few patients became TWA-negative after infusion of beta-blockers. From these observations, therefore, it appears tempting to speculate that, at least in some patients prone to sudden cardiac death, sympathetic activation plays a role in triggering the occurrence of discordant alternans in diseased regions of the myocardium. This hypothesis accords with findings demonstrating regional differences in sympathetic activation in patients after myocardial infarction (16,17).
The findings of the present prospective randomized study are further supported by preliminary observations reported on modulation of TWA by autonomic influences (18). The effects of selective sympathetic (esmolol, n = 17) or parasympathetic (atropine, n = 17) blockade on TWA were examined in 34 patients with inducible sustained VT. The Valt decreased with both sympathetic and parasympathetic blockade, but this decrease was more impressive with beta-blockade. Specifically, Valt, measured in the vector magnitude lead, decreased from 2.2 ± 1.9 µV to 1.3 ± 1.9 µV (p < 0.05) with esmolol, resulting in a decrease of TWA sensitivity for prediction of EP results, from 71% to 35% (p = 0.08) (18). In contrast to our study, however, the baseline Valt was 2.2 µV, which is just above the predefined positivity level of 1.9 µV. In the present study, baseline Valt, measured in the precordial leads, which tends to have a greater magnitude, averaged 8.4 µV, and TWA sensitivity decreased only from 88% to 72% (p = 0.06) with beta-blockers.
Finally, the well-appreciated benefits of beta-blocker therapy in preventing sudden arrhythmogenic death support the notion of a modulating effect of antiadrenergic therapy on triggers for ventricular tachyarrhythmias such as TWA (19).
Prolongation of ventricular repolarization by antiarrhythmic drugs and TWA. Despite the fact that assessment of microvolt-level TWA is increasingly used for risk stratification (2–5,20), to the best of our knowledge only one prospective study deals with the effects of antiarrhythmic drugs on TWA in patients with structural heart disease (10). Kavesh et al. (10) evaluated the effects of procainamide on TWA in 24 patients with inducible sustained VT at baseline and after acute drug loading. The magnitude of TWA amplitude decreased from 0.6 ± 0.8 µV to 0.3 ± 0.4 µV during sinus rhythm, from 2.0 ± 1.6 µV to 0.7 ± 0.7 µV during pacing at 100 beats/min, and from 3.0 ± 2.0 µV to 1.7 ± 1.8 µV during pacing at 120 beats/min (p < 0.001). This resulted in a decrease in the sensitivity of TWA for induction of sustained VT from 87% to 60% at a heart rate of 120 beats/min (10). It is again important to note that the mean TWA amplitude reported in that trial was markedly lower than that measured in the present study.
The only study dealing with the effects of class III antiarrhythmic drugs on TWA is a retrospective analysis evaluating the prevalence of TWA in relationship to amiodarone usage in patients with implantable cardioverter-defibrillators (ICDs) (9). In that study, Groh et al. (9) reported that a positive TWA was found only in 1 of 9 ICD patients (11%) treated with amiodarone as compared with 14 of 22 (64%) patients without antiarrhythmic drug therapy. During follow-up, the presence of TWA predicted future appropriate ICD therapy for ventricular tachyarrhythmias (9).
In our study, the decrease in TWA amplitude observed after sotalol administration was comparable to that following metoprolol infusion. This suggests that the effect of sotalol on ventricular repolarization is less important in terms of modulating TWA, at least during short-term administration.
Clinical implications. The observations from this prospective study have a number of important implications for the clinical use of TWA determination for risk stratification in patients with structural heart disease. First, there is a good intraindividual reproducibility of TWA assessment in the absence of beta-blockers or antiarrhythmic drugs. Second, in agreement with previous studies (2–5,13), there is a patient-specific heart rate threshold at which microvolt TWA becomes detectable. In patients with significant organic heart disease, this threshold is about 90 to 110 beats/min. Third, in patients at high risk for ventricular tachyarrhythmias, such as the ones enrolled in our study, TWA is usually measurable even in the presence of antiadrenergic medication. This prospective study, in conjunction with the earlier studies cited above (8–10), indicates that TWA is responsive to the pharmacologic milieu. In particular, we find here that beta-blockers tend to reduce TWA; beta-blockers are also known to reduce risk of spontaneous ventricular arrhythmia. Because cardioactive drugs may alter TWA and may also modulate susceptibility to spontaneous ventricular arrhythmias, it would seem to make most sense to perform TWA testing for purposes of risk stratification while maintaining the ongoing pharmacologic milieu of the patient. When the pharmacologic milieu of the patient is altered, TWA testing should be repeated to determine whether TWA status is altered.
A specific issue arises in this regard with respect to beta-blockers. T-wave alternans testing is most commonly performed noninvasively during stress testing. One effect of beta-blocker therapy is to limit the peak heart rate that may be achieved by a patient during exercise stress. Initially, a stress TWA test was interpreted to be negative if the criteria for positivity were not met and significant TWA was documented not to be present for at least 1 min at a heart rate of at least 105 beats/min (e.g., see Gold et al. [3]). Patients on beta-blockers frequently cannot attain a heart rate of 105 beats/min for this period of time and, thus, if not meeting the criteria for positivity, would be classified as indeterminate. For this reason, beta-blockers would be withheld for 24 h prior to TWA testing (3). The present study demonstrates that testing patients on beta-blockers is feasible, with only a few patients turning TWA-negative after the drug.
In a recent study of heart-failure patients without prior history of ventricular arrhythmias (5) we prospectively determined not to withhold beta-blockers; accordingly, we prospectively modified the criteria for negativity to also include patients who did not meet the criteria for positivity, who had a maximal stress test achieving a maximum heart rate of at least 80 beats/min, and who had no significant alternans for at least 1 min at a heart rate within 5 beats/min of their maximum rate. None of the patients classified as negative by this criterion subsequently sustained a ventricular tachyarrhythmic event. These results also suggest that beta-blockers may reduce arrhythmic risk both via a direct myocardial effect and also by blocking an arrhythmogenic increase in heart rate.
Study limitations. The present study must be interpreted in the face of certain limitations. Because of obvious logistic reasons, we used only acute drug administration to assess changes in TWA. This, of course, does not necessarily imply that the same or similar changes can be observed during prolonged administration of beta-blockers or sotalol. A second potential limitation is the fact that we did not examine the effects of class I antiarrhythmic drugs. However, the use of this class of substances in patients with structural heart disease and serious ventricular arrhythmias has markedly decreased as the result of numerous prospective studies, including the Cardiac Arrhythmia Suppression Trial (21–23).
Conclusions. In patients with a history of documented or suspected ventricular tachyarrhythmias, there is a reduction in TWA amplitude following the administration of antiadrenergic drugs such as metoprolol and d,l-sotalol. This indicates that TWA is modulated—at least in some patients—by sympathetic activity. The fact that TWA is responsive to the pharmacologic milieu—as is the risk of spontaneous ventricular arrhythmias—suggests that for purposes of risk stratification TWA ought to be determined without alteration of the patient’s ongoing pharmacologic regimen.
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