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Invited Review Article

T-Wave Alternans as a Therapeutic Marker for Antiarrhythmic Agents

Verrier, Richard L PhD, FACC*; Nieminen, Tuomo MD, PhD*†

Author Information
Journal of Cardiovascular Pharmacology: June 2010 - Volume 55 - Issue 6 - p 544-554
doi: 10.1097/FJC.0b013e3181d6b781
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Abstract

INTRODUCTION

Sudden cardiac death remains a leading cause of mortality in the industrially developed world, claiming 310,000 lives annually in the United States alone. Reducing the sudden death toll necessitates identification of a reliable index that reflects fundamental electrophysiological properties underlying arrhythmogenesis in diverse forms of cardiac disease. Such a tool may constitute a therapeutic marker, namely, an electrophysiological property or phenomenon that is within the causal pathway of arrhythmogenesis and can be altered by pharmacologic therapy to decrease the occurrence of arrhythmia. By definition, a therapeutic marker encompasses one or more “vulnerable parameters,” or arrhythmia mechanism targets, as described in the Sicilian Gambit1 and in the review article by Rosen and Janse in this series.2 As discussed below, T-wave alternans (TWA), a beat-to-beat fluctuation in the morphology and amplitude of the ST segment or T wave, reflects temporal-spatial heterogeneity of repolarization, a process that underlies arrhythmogenesis.3,4 Furthermore, there is substantial evidence that TWA may be not only a marker of risk but also a trigger of arrhythmia because of the intense electrophysiological gradients that attend its development. This influence is particularly evident during discordant TWA,4-7 when cells in neighboring regions alternate out of phase, thereby exacerbating heterogeneity of repolarization and setting the stage for conduction block and re-entry.

The overall objective of this review is to discuss the evidence that TWA constitutes a clinically applicable marker of sudden death risk and a measure of antiarrhythmic drug efficacy as well as of proarrhythmic potential.

HISTORICAL PERSPECTIVE

The evidence linking TWA with arrhythmias spans more than a century, dating from the pioneering observations of Hering in 1908.8 Macroscopic levels of TWA have been detected under diverse clinical conditions in association with life-threatening arrhythmias, including acute myocardial ischemia and infarction, heart failure, Prinzmetal's angina, and channelopathies, including Brugada and long QT syndromes. Although TWA is a singular phenomenon, its morphology varies considerably as a function of the underlying pathology. In ambulatory patients with stable coronary artery disease, alternation is localized primarily in the first half of the T wave (Fig. 1).9-11 TWA is particularly prevalent in patients with congenital long QT syndrome, in which the T wave frequently alternates above and below the isoelectric line without concomitant ST-segment changes12 and heralds initiation of torsades de pointes.13 In patients with Brugada syndrome, the signature ST-T wave pattern is the locus of alternation.14 Collectively, these observations indicate that repolarization alternans is fundamentally linked to arrhythmogenesis but that the underlying pathophysiology differs, requiring that therapy be tailored to address the electrophysiological derangement or vulnerable parameter.

FIGURE 1
FIGURE 1:
Survival curves from the Finnish Cardiovascular Study (FINCAVAS), which enrolled more than 1000 consecutive patients referred for routine exercise testing.10 Inset is a high-resolution QRS-aligned template from a FINCAVAS patient illustrating T-wave alternans (TWA) as the separation between successive T waves.11 TWA was measured by the Modified Moving Average method. (Reprinted with permission from Oxford University Press and John Wiley & Sons, Inc.)

CONTEMPORARY T-WAVE ALTERNANS MEASUREMENT METHODOLOGY AND EVIDENCE OF PREDICTIVITY

Over the last two decades, evaluation of TWA has evolved from visual inspection of the electrocardiogram (ECG) to the use of computerized analytical methods for detection of nonvisible TWA in the microvolt range. The two analytical approaches that have received U.S. Food and Drug Administration clearance and are in contemporary clinical use are described in detail elsewhere. Briefly, the Spectral Method uses the Fast Fourier Transform to analyze the ECG across 128 consecutive J-T segments in the frequency domain (Cambridge Heart, Inc., Tewksbury, MA).15-18 The generated spectrum at 0.5 cycle/beat, i.e., occurring on every other beat, is defined as the alternans power. The test is usually conducted during bicycle or treadmill exercise. An alternans level greater than 1.9 μV is considered a positive test, whereas test results below this level are negative. The Modified Moving Average (MMA) method (GE Healthcare, Inc., Milwaukee, WI)19 is a time-domain technique developed to allow TWA analysis during routine exercise stress testing and ambulatory ECG monitoring. The MMA algorithm continuously streams odd and even beats into separate bins and creates median complexes for each bin.20 A high-resolution template of QRS-aligned superimposed complexes is generated for quantification of TWA as the maximum difference between the odd and even median complexes and for visual verification.

A sizeable body of evidence supports the predictivity of both techniques. Overall, as reviewed in recent meta-analyses of studies enrolling more than 9000 patients,17,18 TWA testing with the Spectral Method exhibits valuable predictive capacity. More specifically, a composite hazard ratio of TWA for prediction of ventricular tachyarrhythmic events in studies enrolling relatively few patients with implantable cardioverter-defibrillators (ICDs) was 13.6 (95% confidence interval [CI], 8.5-30.4). However, predictive accuracy in studies with high ICD use was lower at 1.6 (95% CI, 1.2-2.1), potentially because ICD firing may not be an adequate surrogate endpoint for sudden death.18

Experience with the MMA TWA test, which has been used both during exercise testing and ambulatory ECG monitoring, extends to more than 3000 patients with preserved as well as with depressed ejection fraction. Hazard ratios for sudden cardiac death have been reported at 7.4 (95% CI, 2.8-19.4) for MMA-based TWA measured during clinical exercise tests10,11 and as high as 22.6 (95% CI, 2.6-193.7) for TWA assessed with ambulatory ECG recording (Fig. 2).21

FIGURE 2
FIGURE 2:
Event-free curves for cardiac mortality using maximal voltage of time-domain T-wave alternans (TD-TWA) from 24-hour Holter electrocardiograms in ischemic (A) and nonischemic (B) study subgroups.21 TWA was analyzed by the Modified Moving Average method. (Reprinted with permission from Elsevier).

Collectively, the literature suggests that predictivity by two methods is comparable, consistent with the fact that they are measuring the same electrophysiological property, namely microvolt levels of TWA. However, as a result of differing methodologic approaches to averaging, the TWA values reported with the MMA algorithm are consistently larger by a factor of 4 to 10.

MECHANISTIC BASIS FOR T-WAVE ALTERNANS AS A MARKER OF VULNERABILITY TO VENTRICULAR FIBRILLATION

Heterogeneity of Repolarization

Both experimental4-6 and clinical evidence7 indicates that TWA appears to parallel changes in temporal-spatial heterogeneity of repolarization, which is a critical factor in arrhythmogenesis arising from different cardiac pathologies associated with sudden death, including ischemic heart disease, myocardial infarction, heart failure, and cardiomyopathies.22 The fundamental association between TWA and heterogeneity of repolarization is best established during discordant TWA, in which cells in neighboring regions alternate out of phase, thereby markedly enhancing heterogeneity of repolarization and establishing the preconditions for conduction block, re-entry, and life-threatening arrhythmias. The detailed electrophysiological and ionic mechanisms underlying TWA have been reviewed.23-34 The fundamental link between TWA and cardiac vulnerability is underscored by the finding that TWA magnitude exhibits a parallel time course with the spontaneous occurrence of ventricular fibrillation during myocardial ischemia and reperfusion (Fig. 3).35 Moreover, during myocardial ischemia, the alternation pattern is concentrated during the vulnerable phase of the cardiac cycle.

FIGURE 3
FIGURE 3:
Simultaneous time course of spontaneous ventricular fibrillation (VF) and tachycardia (VT), T-wave alternans (TWA), and ST-segment depression during 10 minutes of left anterior descending coronary artery occlusion and reperfusion in 61 dogs monitored with a left ventricular electrocardiogram catheter.35 Two occlusion/release sequences were performed in each dog. TWA was measured by complex demodulation. The waxing and waning of TWA magnitude closely paralleled (r2 = 0.98, P < 0.06) the spontaneous occurrence of malignant ventricular arrhythmias during both occlusion and reperfusion. By contrast, the ST-segment changes were dissociated from arrhythmogenesis during the initial and later minutes of the occlusion and on reperfusion. TWA and ST-segment values are means; error bars represent standard error of mean. (Reprinted with permission from Oxford University Press).

Intracellular Calcium Cycling and Action Potential Duration Restitution

In terms of ionic mechanisms, the picture is complex, but it is evident from numerous experimental investigations that instabilities in calcium handling in the sarcoplasmic reticulum give rise to cellular alternation of Ca2+, action potential duration (APD) alternans, and beat-to-beat alternation during repolarization. Calcium channel blockers and agents that block calcium release from the sarcoplasmic reticulum such as ryanodine are capable of suppressing pacing- and ischemia-induced APD alternans in ventricular muscle fibers.36,37 Moreover, APD alternans is augmented by calcium channel agonist Bay K 8644, an effect presumably attributable to altered levels of calcium entering through the sarcolemmal calcium channel.37 Adenoviral overexpression of SERCA2a enhances calcium reuptake into sarcoplasmic reticulum, thereby reducing calcium alternans in isolated cardiomyocytes37 and APD alternans in Langendorff-perfused hearts.38 Clusin26 observed ischemia-induced alternation in calcium transients detected by fluorescent dyes that was temporally correlated with APD alternans and TWA. Intrapericardial delivery of the classic nitric oxide donor nitroglycerin effectively suppresses ischemia-induced ventricular fibrillation and TWA in parallel in intact porcines.39 In a follow-up study, Zhao and coworkers40 determined the mechanism to be an improvement in calcium handling and reduction in T-wave heterogeneity. In a study of patients with heart failure, Narayan and coworkers41 reported that alternans of action potential amplitude, attributed to abnormalities of calcium cycling, strongly predicted ventricular tachycardia and fibrillation during a 2.6-year follow up.

An intriguing, although controversial, framework for explaining the action of pharmacologic agents relates to the slope of APD restitution curve.25,29-34 According to this construct, dynamic instabilities in the form of TWA can result from changes in membrane voltage resulting from steep APD restitution (the relationship between APD and the preceding diastolic interval). Flattening the APD restitution curve pharmacologically or otherwise is expected to diminish the propensity for tachyarrhythmias by reducing the likelihood of progression from spatially concordant TWA to discordant TWA. This phenomenon, in which APD alternates out of phase in adjoining regions, is thought to be highly arrhythmogenic because it establishes steep, heterogeneous repolarization gradients and is conducive to re-entry and wavebreak. It is facilitated by changes in APD and conduction velocity restitution, premature beats, and functional and anatomically based gradients in APD. Among the most important clinically significant anatomic barriers is myocardial scar associated with ischemic heart disease and infarction. In patients with hypertrophic cardiomyopathy, abnormal myocardial fiber orientation and/or fibrosis may constitute potentially arrhythmogenic anatomic barriers, because a positive TWA test has been linked to the severity of histopathologic changes. According to the restitution construct, antiarrhythmic agents may have the potential to reduce arrhythmogenic discordant TWA by affecting myocardial substrate and/or by altering the relationship between the APD and diastolic interval as affected by heart rate and other factors.

Thus, pharmacologic agents may protect against arrhythmias by altering fundamental cellular mechanisms, mainly improving intracellular calcium handling and/or potentially altering APD restitution.

Heart Rate

Heart rate plays a role in TWA, largely because of its impact on intracellular calcium cycling.28 In patients with ischemic heart disease or heart failure, the capacity of the sarcoplasmic reticulum to reuptake calcium may be impaired, and TWA can be induced at lower heart rates.42 Thus, heart rate is not the sole determinant of TWA. Moreover, autonomic neurotransmitters and changes in myocardial substrate can lead to elevated levels of TWA during fixed-rate pacing.35,43 Pacing alone does not replicate the enhancement in TWA achieved by adrenergic stimulation or myocardial ischemia to a comparable heart rate.43 In patients with a history of cardiac arrest, beta-adrenergic stimulation with isoproterenol elicited a 2.8-fold greater (from 4.4 to 12.4 μV by spectral analysis) increase in TWA during electrophysiological study compared with pacing to the same heart rate.27,44

Continuum of Electrical Instability

Finally, a critical consideration is that TWA magnitude reflects the continuum of cardiac electrical instability. The higher the level of TWA, the more likely is the onset of ventricular tachyarrhythmia. In fact, both experimentally45 and clinically,46 life-threatening arrhythmias are preceded by a crescendo in the level of TWA. The concept of a continuum of instability underlies the opportunity to estimate risk by quantifying TWA11,47 to monitor the efficacy of pharmacologic therapy.

CALCIUM CHANNEL BLOCKADE

Experimental Evidence

A broad consensus from extensive experimental studies in large animal models across 30 years implicates beat-to-beat cycling of calcium as a basis for TWA and the associated development of ischemia-induced ventricular tachyarrhythmias. In several elegant experimental series, Hashimoto and colleagues48-51 reported that calcium channel blockade with verapamil, diltiazem, nifedipine, or nicardipine inhibited visible levels of TWA during myocardial ischemia in canines. This effect was not the result of the vasodilatory effects of these agents, because dipyridamole did not induce similar decreases in TWA magnitude.48,49 In studies in canines, Hashimoto and colleagues48,51 and Hirayama and coworkers52 found TWA to be well correlated with APD alternans, including its suppression by verapamil, diltiazem, or nifedipine. Hayakawa and coworkers53 and Nearing and colleagues54 reported that diltiazem reduced TWA magnitude in parallel with incidence of ischemia-induced ventricular tachyarrhythmias during atrial pacing, which was used to factor out potential effects of heart rate lowering (Fig. 4).

FIGURE 4
FIGURE 4:
Suppression by diltiazem (0.02 mg/kg per minute for 45 minutes) of T-wave alternans magnitude (upper panel) and ventricular tachyarrhythmias (P < 0.05) (lower panel) during 10-minute coronary artery occlusion in 10 dogs.54 Each line represents a single animal. Values are means ± standard error of mean. The marked blunting of ischemia-induced alternans was associated with a significant corresponding reduction in the incidence of ventricular fibrillation (VF) and tachycardia (VT) and number of ventricular premature beats (VPBs). One hour after drug administration, parallel partial recovery in T-wave alternans magnitude and arrhythmogenesis had occurred.

Clinical Studies

Despite extensive experimental evidence suggesting the capacity of calcium channel-blocking agents to suppress TWA, our medical literature searches have identified no clinical studies or reports regarding effects of this class of compounds on TWA. This is an important question in light of the fact that the nondihydropyridine calcium channel blockers verapamil and diltiazem have not been shown to reduce sudden cardiac death. A potential explanation is that the negative inotropic effect of these agents resulting from reduced calcium entry can be deleterious in patients with prior myocardial infarction and heart failure and may counteract cardioprotective actions on electrophysiological function. Specifically, the Multicenter Diltiazem Post-Infarction Trial Research Group55 observed a diltiazem-related reduction in cardiac death (hazard ratio, 0.77; 95% CI, 0.61-0.98) for patients with preserved ventricular function and a significant diltiazem-related increase in cardiac death (hazard ratio, 1.41; 95% CI, 1.01-1.96) for those with pulmonary congestion. The increase in cardiac death was similar for patients with left ventricular ejection fraction less than 40%. In terms of mechanisms, depression of contractility by calcium channel blockade can lead to systemic hypotension, thereby reducing coronary perfusion and predisposing to myocardial ischemia and arrhythmias. Thus, in clinical settings, nondihydropyridine calcium channel blockers may not reduce TWA. By contrast, beta-adrenergic blocking agents, which influence calcium handling through the cyclic nucleotide cascade, can improve cardiac mechanical function in patients with heart failure. These agents decrease TWA consonant with their reduction in sudden cardiac death.

Dihydropyridine calcium channel blocking agents, typified by amlodipine, have greater affinity for the L-type channels in vascular smooth muscle than in myocardium and may affect cardiovascular mortality not directly through calcium entry through myocardial cells but through “upstream” processes. Specifically, amlodipine's indirect cardioprotective effects may include reduction in the progression of atherosclerosis, decrease in coronary vascular resistance, and reduction in myocardial injury.56

BETA-ADRENERGIC BLOCKADE

Experimental Evidence

At the experimental level, Nakashima and colleagues57 reported that propranolol, nadolol, and alprenolol suppressed visible ischemia-induced TWA in parallel with arrhythmias in canines. Kovach and coworkers43 documented significant suppression by metoprolol of TWA magnitude during an anger-like state both before and during induction of myocardial ischemia in canines.

Clinical Studies

Several human studies have reported suppression of TWA magnitude and/or incidence in response to beta-adrenergic blockade. Klingenheben and colleagues58 found that infusions of metoprolol, a pure beta-blocker, or d,l-sotalol, a beta-blocker with Class III antiarrhythmic effects, diminished TWA in patients with documented or suspected malignant ventricular tachycardia during electrophysiological testing. The reduction in TWA was comparable with metoprolol (by 35%, from 7.9 to 4.9 μV by spectral analysis, n = 25) and d,l-sotalol (by 38%, from 8.6 to 4.4 μV, n = 29) groups (Fig. 5). The authors also concluded that patients' medications should not be withdrawn before TWA testing.

FIGURE 5
FIGURE 5:
Changes in T-wave alternans (TWA) amplitude after drug administration in patients with d,l-sotalol (dark bars) and metoprolol (gray bars).58 TWA was measured by the Spectral Method. (Reprinted with permission from Elsevier).

During electrophysiological testing, Rashba and colleagues59 infused the beta-blocker esmolol (n = 20) in patients with ischemic cardiomyopathy and inducible sustained ventricular tachycardia. Esmolol significantly diminished the absolute values of TWA and cut the number of TWA tests classified as positive by 50%.

Komiya and coworkers60 confirmed the influence of propranolol infusion on TWA in patients with prior ventricular tachycardia (n = 15) and supraventricular tachycardia (n = 20) also during electrophysiological study. The decrement in TWA magnitude by propranolol was greater among patients with a history of ventricular tachycardia than among those with a history of supraventricular tachycardia. Despite this effect, TWA remained larger in the ventricular tachycardia group than in the supraventricular tachycardia group during pacing at 110 beats/min.

Murata and colleagues61 reported improvement in several parameters of sympathetic nerve activity as well as in left ventricular ejection fraction in correlation with the decrease in positive TWA test results after a 3-month course of oral beta-adrenergic blockade. TWA testing during rest and exercise, (123)I-metaiodobenzylguanidine imaging, and echocardiography were performed at baseline and after beta-blocker therapy in 26 patients with nonischemic heart disease and positive TWA test results. The agents used were metoprolol (mean dose, 26 mg), carvedilol (11 mg), bisoprolol (5 mg), and atenolol (5 mg). Post-treatment, TWA tested with the Spectral Method during rest or exercise became negative in eight patients but remained positive although decreased in magnitude in the remaining 18 patients.

Zacks and colleagues62 evaluated 387 patients with coronary artery disease, ejection fraction less than 40%, and nonsustained ventricular tachycardia. They found that beta-blockade use (within 24 hours before testing) was not linked to electrophysiological study results or to the rate of abnormal TWA test results nor did the medication change arrhythmia-free 3-year survival. The authors concluded that oral beta-blocker therapy appears to have no effect on yield or predictive value of electrophysiological study or TWA. They recommended against withdrawing these agents before TWA testing.

SODIUM CHANNEL BLOCKADE

Experimental Evidence

Tachibana and colleagues63 reported induction of visible TWA (to 8.7 ± 3.4 mV, measured by subtraction analysis) and spontaneous ventricular fibrillation in all canines challenged by intracoronary administration of flecainide. TWA and arrhythmias were suppressed by blockade of the 4-aminopyridine sensitive current. Intracoronary disopyramide and lidocaine provoked visible TWA that was an order of magnitude smaller (0.9 ± 0.4 and 0.8 ± 0.2 mV, respectively, P < 0.05) with ventricular fibrillation in only one of 15 canines tested. Watanabe and colleagues64 observed that high levels of intracoronary flecainide but not intracoronary lidocaine or disopyramide provoked local activation sequence alternans that correlated with the occurrence of ventricular fibrillation in canines. Because of the high dose of flecainide delivered through the intracoronary route in these studies, relevance of these results to responses in humans with systemic dosing is questioned.

Lidocaine enhanced conduction delay and alternans of the ST-T complex in acutely ischemic and infarcted canines.65 By contrast, bepridil, which inhibits both the fast sodium channel and the slow calcium channel in cardiac muscle and increases coronary blood flow, prevented the increase in conduction delay and suppressed TWA.

Clinical Studies

The first prospective trial on the effects of this class of antiarrhythmic drugs on TWA was published by Kavesh and coworkers,66 who reported their experience in 24 patients with inducible sustained ventricular tachycardia. Procainamide infusion decreased TWA magnitude by 43% to 65% during electrophysiological study, but no outcomes were reported.

There has been increased interest in late INa blockade as an antiarrhythmic modality.67 Experimentally, the prototypical late INa blocking agent ranolazine decreased ventricular vulnerability and TWA in a large animal model.68,69 Clinically, it suppressed ventricular tachyarrhythmias in the MERLIN TIMI 36 trial.70 Recently, Murdock and coworkers71 reported parallel suppression of ventricular tachycardia and TWA in a patient with cardiomyopathy (Fig. 6).

FIGURE 6
FIGURE 6:
Significant microvolt T-wave alternans (TWA), determined by the Spectral Method, was present at 110 beats/min just before ranolazine was restarted (A). TWA was not significant after ranolazine (B).71 (Reprinted with permission from John Wiley & Sons, Inc.).

Pharmacologic Testing to Disclose Brugada Syndrome

Brugada syndrome predisposes individuals with structurally normal hearts to ventricular arrhythmias and sudden cardiac death secondary to an autosomal-dominant ion channel disorder. Distinct ST-segment elevation in the right precordial leads (V1 to V3) and incomplete or complete right bundle branch block characterize the ECG of patients with Brugada syndrome and confirm this diagnosis. Visible TWA may also appear spontaneously.72,73 Exercise or atrial pacing mask TWA in patients with this syndrome,72 indicating the poor suitability of these platforms for TWA-based risk assessment. Provocative testing with pilsicainide, a Class Ic drug, can be used to disclose TWA along with the diagnostic Brugada ECG.74,75 Morita and colleagues74 administered pilsicainide either orally or intravenously to 65 patients with Brugada syndrome during electrophysiological study to evaluate the occurrence of TWA and ventricular arrhythmia. At baseline, no TWA was visually detected. Macroscopic TWA occurred in six of 10 patients with pilsicainide-induced sustained polymorphic ventricular tachycardia or ventricular fibrillation but in only one of 55 without arrhythmia. Tada and colleagues75 investigated the association between spontaneous ventricular fibrillation and TWA. None of the patients exhibited TWA before the drug, but intravenous pilsicainide provoked visible TWA in 17 (22.1%) of 77 patients with Brugada syndrome. Patients with TWA had a significantly higher incidence of spontaneous ventricular fibrillation (52.9% versus 8.3%) and syncope (58.8% versus 26.7%) than their counterparts without TWA.

MULTICHANNEL BLOCKADE

Experimental and clinical information regarding the effects of agents with multichannel actions, particularly the potent antiarrhythmic agent amiodarone, on TWA is surprisingly limited given their clinical importance.

Clinical Studies

Sakabe and colleagues76 analyzed whether TWA is capable of predicting recurrence of ventricular arrhythmias in patients receiving empirically guided pharmacologic therapy for sustained ventricular tachycardia or fibrillation. They prospectively evaluated 49 patients with ischemic or nonischemic dilated cardiomyopathy and a history of sustained ventricular tachycardia or ventricular fibrillation. Amiodarone, prescribed for 28 (57%) patients, was the most common antiarrhythmic medication; additional medications included beta-blockade in 17 (35%) and angiotensin-converting enzyme inhibition in all 49 patients. TWA was measured only once, after 2 to 4 weeks with antiarrhythmics, and was positive in 61% of cases. During the follow up of 13 ± 11 months, the investigators found that TWA (negative/positive), but not left ventricular ejection fraction, significantly predicted the recurrence of tachycardia and suggested the utility of TWA for evaluating the efficacy of antiarrhythmic drugs (Fig. 7). Thus, use of antiarrhythmic therapy did not disrupt TWA's predictive capacity.

FIGURE 7
FIGURE 7:
Kaplan-Meier event-free curves for ventricular tachyarrhythmias according to T-wave alternans (TWA) (A) and left ventricular ejection fraction (LVEF) (B).76 TWA-positive patients had more frequent event recurrences (P = 0.02), whereas LVEF did not (P = 0.68). (Reprinted with permission from John Wiley & Sons, Inc.).

Groh and colleagues77 reported that amiodarone was associated with decreased prevalence of TWA in patients with ICDs with ischemic or nonischemic cardiomyopathy and a history of ventricular tachycardia. A positive TWA test result was found in only one of nine patients (11%) treated with amiodarone as compared with 14 of 22 (64%) patients without the drug. Importantly, TWA status served as a predictor of appropriate ICD therapy over the follow up of 0.9 ± 0.2 years.

Proarrhythmia

There are recurring case reports of macroscopic levels of TWA in association with relatively uncommon instances of proarrhythmia after amiodarone administration.78-80 In one instance, visible TWA and arrhythmias provoked by amiodarone unmasked the inherited long QT syndrome (Fig. 8).80

FIGURE 8
FIGURE 8:
Case report of macroscopic T-wave alternans (TWA) heralding torsades de pointes induced by intravenous amiodarone in a 62-year-old male patient with new-onset atrial fibrillation and a rapid ventricular response. (A) Baseline electrocardiogram; (B) prominent QT prolongation and macroscopic TWA appeared after restoration of sinus rhythm after 48 hours of drug exposure; and (C) onset of torsades de pointes tachycardia that degenerated into ventricular fibrillation. The patient was resuscitated and QT interval normalized after amiodarone was discontinued. Genetic testing revealed a mutation at the KCNE2 gene, indicating congenital long QT syndrome Type VI, although the patient had no history of QT prolongation or ventricular tachyarrhythmias.80 (Reprinted with permission from Oxford University Press).

Houltz and coworkers81 explored predictors of torsades de pointes in patients who received almokalant, another Class III agent, to revert atrial fibrillation or flutter. They reported the occurrence of torsades de pointes in six of 100 patients, three of whom had also exhibited visible TWA before drug infusion. Only 16 of the remaining 94 patients (17%) exhibited TWA without torsades de pointes.

NONANTIARRHYTHMIC DRUGS USED IN PATIENTS AT RISK FOR SUDDEN CARDIAC DEATH

As is discussed by Das and Zipes in this series,82 a number of agents that are effective in reducing total mortality and sudden cardiac death do not act directly as antiarrhythmic agents. Rather, they act on “upstream” events and processes such as reducing ischemia and fibrosis, thereby improving the electrical stability of the myocardial substrate in patients with atherosclerosis, hypertension, ischemic heart disease, or heart failure. These agents include angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, statins, and aldosterone antagonists. They have the additional advantage of limited proarrhythmic potential because they do not act directly on cardiac ion channels, which can slow conduction, predisposing to re-entrant tachycardias, or prolong the long QT interval, conducing to torsades de pointes.

Recently, Kubo and colleagues83 provided the first investigation to address the basic concept that TWA may be useful to gauge the antifibrillatory potential of “upstream” agents known to protect against sudden cardiac death.84 They examined the potential of the angiotensin II receptor antagonist valsartan, administered orally, to affect TWA. Sixteen of the 50 patients enrolled initially tested positive for TWA and were treated with valsartan (80 mg/day) for 3 days. TWA markedly decreased from 6.1 ± 3.8 μV to 2.5 ± 1.9 μV (by spectral analysis) without accompanying changes in blood pressure, resting heart rate, or echocardiographic parameters.

T-wave alternans in detection of proarrhythmia with noncardiac medications

Experimental studies85-87 and clinical observations78-81,88,89 provide convincing evidence that agents that markedly prolong the QT interval have the potential for inducing macroscopic levels of TWA that may presage the occurrence of torsades de pointes. In vitro23 and in vivo90,91 investigations demonstrate that extending the QT interval sets the stage for increased spatial heterogeneity of repolarization across the ventricular wall. It is therefore not surprising that TWA is often reported in association with QT prolongation induced by pharmacologic interventions.

Notably, in a clinical case series, Yamazaki and colleagues88 observed spatial heterogeneity of repolarization, prolonged QTc, and visible TWA in ECGs of patients receiving chemotherapy with arsenic trioxide to treat promyelocytic leukemia but which causes nonsustained monomorphic ventricular tachycardia. In a case report, the antimicrobial agent pentamidine was reported to provoke macroscopic TWA in association with torsades de pointes.89

In a preclinical safety study, Matsunaga and coworkers85 found that the antifungal agent D0870, which at high doses across 6-month exposures induced sudden death in canines, also produced torsades de pointes in seven of 10 canines and visible TWA in all 10 animals. Fossa and colleagues used APD alternans in preclinical drug screening of HERG-blocking agents,86 antidepressants, and antibacterial agents.87

Thus, the broad utility of TWA in detecting potential for proarrhythmia appears to be relevant not only to cardiac but also to noncardiac drugs.

CONCLUSIONS

TWA's capacity to predict sudden cardiac death rests on sound electrophysiological bases, because this phenomenon reflects the degree of heterogeneity of repolarization and the magnitude of perturbations in intracellular calcium handling, key mechanistic factors that are fundamentally linked to triggers of arrhythmia in diverse diseases. Accordingly, TWA fulfills the essential requirements of being a therapeutic marker, because it is within the causal pathway of arrhythmogenesis. Instabilities in calcium handling within the sarcoplasmic reticulum have been demonstrated to be at the root of TWA based on experiments with calcium channel blockade36,39,48-54 and adenoviral overexpression of SERCA2a.37,38 The evidence cited in this review, which indicates the broad utility of TWA in estimating antiarrhythmic and proarrhythmic effects of diverse agents across differing pathologies, supports the pivotal role of this phenomenon in arrhythmogenesis and potential to guide medical therapy.

TWA also shows promise in detecting proarrhythmia by noncardiovascular as well as cardiovascular agents. To date, the main parameter used to evaluate risk for adverse reactions to pharmacologic agents has been QT prolongation, which is assumed to provide an indication of drug-induced unevenness of repolarization and propensity for arrhythmogenesis. One consideration is that the length of the QT interval is subject to measurement errors, including determination of the precise end of the T wave and uncertainties regarding the optimum heart rate correction formula. A further concern is that QT-interval prolongation, unless excessive, has not been demonstrated to track proarrhythmia or its absence accurately.92,93 Because TWA is closely correlated to heterogeneity of repolarization4-7 and is amenable to analysis from ambulatory recordings,9,21 its potential role in evaluating drug safety deserves further exploration.

A critical aspect of TWA is that it exhibits a continuum of electrical instability and therefore is amenable to quantification,11,47 rather than being restricted to binary, all or nothing, classification. Measuring TWA magnitude during exercise and ambulatory ECG recordings may allow use of this therapeutic marker not only to evaluate the efficacy of therapy but also to determine risk of proarrhythmia. That patients should be tested while on discharge medications is an important corollary of the finding that medications affect TWA test results as well as outcomes. This viewpoint is supported by the recent meta-analysis by Chan and coworkers,94 demonstrating that withdrawing beta-blockade therapy weakens the predictivity of TWA testing. Finally, the recent availability of TWA testing based on ambulatory ECG records is an important pragmatic advance, because this platform is routinely used in drug evaluation trials as well as in medical practice.

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Keywords:

T-wave alternans; sudden cardiac death; therapeutic marker; antiarrhythmic effects; proarrhythmia

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