Continuous T-wave alternans monitoring to predict impending life-threatening cardiac arrhythmias during emergent coronary reperfusion therapy in patients with acute coronary syndrome

EP Europace, May 2011

T-wave alternans (TWA) can precede onset of ventricular tachyarrhythmia (VTA). We evaluated the usefulness of continuous TWA monitoring in ultra-short-term prediction of impending life-threatening VTA upon emergent reperfusion in acute coronary syndrome (ACS) patients.

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Continuous T-wave alternans monitoring to predict impending life-threatening cardiac arrhythmias during emergent coronary reperfusion therapy in patients with acute coronary syndrome

Europace Continuous T-wave alternans monitoring to predict impending life-threatening cardiac arrhythmias during emergent coronary reperfusion therapy in patients with acute coronary syndrome Nobuhiro Takasugi 0 Tomoki Kubota 0 Kazuhiko Nishigaki 0 Richard L. Verrier 1 Masanori Kawasaki 0 Mieko Takasugi 2 Hiroaki Ushikoshi 0 Arihiro Hattori 0 Shinsuke Ojio 3 Takuma Aoyama 0 Genzou Takemura 0 Shinya Minatoguchi 0 0 Regeneration & Advanced Medical Science, Gifu University Graduate School of Medicine , 1-1 Yanagido, Gifu 501-1194 , Japan 1 Harvard Medical School, Beth Israel Deaconess Medical Center, Harvard-Thorndike Electrophysiology Institute , 99 Brookline Avenue, RN-301, Boston, MA 02215 , USA 2 Department of Radiology, Matsunami General Hospital , 185-1 Dendai, Kasamatsu-cho, Gifu 501-6062 , Japan 3 Department of Cardiology, Gifu Municipal Hospital , 7-1 Kashima-cho, Gifu 500-8513 , Japan Aims T-wave alternans (TWA) can precede onset of ventricular tachyarrhythmia (VTA). We evaluated the usefulness of continuous TWA monitoring in ultra-short-term prediction of impending life-threatening VTA upon emergent reperfusion in acute coronary syndrome (ACS) patients. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methods Twenty consecutive ACS patients undergoing emergent reperfusion therapy were studied. Continuous ambulatory and results electrocardiograms (ECGs) (leads V1 and V5) were recorded during emergency room visit and therapy. Peak TWA was determined before and after reperfusion by the modified moving average method. Coronary balloon angioplasty/stenting was successfully performed in 19 patients and intracoronary vasodilator was administered in 1 patient with coronary spasm. Three (15.0%) patients developed VTA requiring cardioversion soon after reperfusion. Peak TWA before reperfusion was higher in patients with VTA than in those without (33.0 + 4.4 vs. 15.8 + 4.0 mV, P , 0.001). Two patients with arrhythmia exhibited an upsurge in TWA to 75 and 105 mV before onset of VTA. In the third patient, macroscopic TWA appeared in leads V1 - V4 in a 12-lead ECG prior to VTA upon pharmacological resolution of vasospasm, although the ambulatory ECG field of view could not detect the upsurge. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion Acute coronary syndrome patients at risk of developing VTA soon after reperfusion exhibit premonitory episodes of increased TWA. Thus, TWA monitoring may be useful for ultra-short-term prediction of life-threatening cardiac arrhythmia risk upon emergent reperfusion in ACS patients. Continuous 12-lead ECGs may be required to optimize detection of TWA, which is regionally specific. - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - Introduction In-hospital occurrence of ventricular tachyarrhythmia (VTA) characterizes a high-risk group of acute coronary syndrome (ACS) patients.1 Patients with ST-segment elevation myocardial infarction (STEMI) presenting for primary percutaneous coronary intervention experienced VTA during reperfusion therapy at a rate of .3%, 17% of whom died within 30 days.2 Aggressive electrolyte correction and attempts to reduce myocardial ischaemia and adrenergic activity with therapies such as beta-adrenoreceptor blockade, intra-aortic balloon pump use, and consideration of emergent coronary revascularization reduce the risk of lifethreatening cardiac arrhythmias during the acute phase of myocardial infarction.3 Accurate identification of ACS patients at risk of life-threatening VTA during the acute phase may prompt administration of antifibrillatory agents. Moreover, ready availability of an external defibrillator for predicted events may allow rapid response to the crisis. In patients with STEMI, the following factors are associated with a high risk of developing VTA during reperfusion therapy: preprocedural thrombolysis in myocardial infarction (TIMI) flow grade 0, inferior infarction, total baseline ST deviation, creatinine clearance, Killip class .I, baseline systolic blood pressure, body weight, and baseline heart rate .70 bpm.2 However, the risk factors have not been fully elucidated in patients with non-ST-segment elevation myocardial infarction (NSTEMI) or unstable angina (UA). In addition, electrophysiological markers directly related to arrhythmogenic substrate have not been evaluated during the acute phase of ACS for the prediction of imminent VTA. T-wave alternans (TWA), a beat-to-beat fluctuation in T-wave amplitude and morphology, is mechanistically linked to vulnerability to life-threatening arrhythmias.4 T-wave alternans is a wellestablished risk marker for long-term prediction of these arrhythmias.5,6 In addition, several studies have reported that an increase in TWA precedes the onset of VTA.7 ? 9 However, the usefulness of TWA in the short-term prediction of VTA has not been fully elucidated in prospective studies. The time-domain modified moving average (MMA) method10 is a suitable approach for TWA analysis during dynamically changing pathophysiological conditions such as acute myocardial ischaemia and reperfusion. Thus, we hypothesized that continuous TWA monitoring using the MMA method can predict VTA upon emergent coronary reperfusion in ACS patients. Methods Study patients This study included 20 consecutive patients diagnosed with ACS who were undergoing clinically indicated emergent reperfusion therapy. The patients were enrolled between September 2007 and January 2010. Exclusion criteria were the presence of cardiogenic shock (systolic blood pressure ,80 mmHg), atrial fibrillation, high-grade atrioventricular block, or pacemaker rhythm on arrival. Patients with pre-procedural TIMI flow grade 3 were excluded. This study was approved by the Ethics Committee of Gifu University Hospital and written informed consent was obtained from all patients. Definition of acute coronary syndrome Patients were classified as having UA, NSTEMI, or STEMI according to the presenting symptoms, electrocardiogram (ECG) and biomarker. Patients were diagnosed with UA if they had ischaemic chest pain within the previous 12 h and the presence of transient ST-segment change or T-wave abnormality (e.g., T-wave inversion) with negative biomarker [creatine kinase (CK)-MB ,25 IU/L]. Patients were diagnosed with NSTEMI if they had ischaemic chest pain within the previous 12 h and the presence of ST-segment depression or transient elevation of .0.1 mV in at least two contiguous leads with a typical rise and fall pattern in serial CK-MB measurement. ST-segment elevation myocardial infarction was defined as the presence of ischaemic chest pain (.30 min duration) within the previous 12 h and ECG changes with ST-segment elevation of .0.2 mV in at least two contiguous precordial leads or .0.1 mV in at least two contiguous limb leads and with a typical rise and fall pattern in serial CK-MB measurement. Emergent coronary reperfusion therapy On admission, all patients received 162 mg aspirin, 200 mg ticlopidine, and sublingual nitroglycerin or intravenous isosorbide dinitrate. In the catheterization laboratory, periprocedural intravenous heparin was given to maintain an activated clotting time .250 s. Intracoronary isosorbide dinitrate (2.0 ? 2.5 mg) was administered before diagnostic angiography. After identification of culprit lesion, intravascular ultrasound examination was performed. Thrombus aspiration was performed before intravascular ultrasound examination as necessary. Balloon angioplasty and/or stent implantation was performed in 19 patients with organic coronary stenosis. One patient who was classified with UA had no organic coronary stenosis but coronary vasospasm. In this patient, coronary angioplasty was not performed, but intracoronary isosorbide dinitrate and nicorandil were administered to achieve coronary reperfusion. Variables associated with acute coronary syndrome Patients were prospectively classified according to Killip class at the emergency room. On the basis of coronary angiographic findings, culprit vessel, pre-procedural TIMI flow grade, and presence of collateral vessel were determined. Creatine kinase and CK-MB at emergency room, and peak CK and CK-MB after admission were measured. Measurement of T-wave alternans by the time-domain modified moving average method All patients underwent two-channel (bipolar modified V1 and V5 leads) continuous electrocardiography (SEER Light Ambulatory Recorder, Software Version 1, GE Healthcare, Milwaukee, WI, USA) during emergency room visit. Careful skin preparation and high-resolution electrodes (Blue Sensor L, Ambu A/S, Ballerup, Denmark) were used to minimize noise. T-wave alternans values were calculated by the time-domain MMA method using MARS Holter Analysis Workstation Software Version 7 (GE Healthcare, Milwaukee, WI, USA). The MMA method has been described in detail.10 In brief, a stream of beats is divided into odd and even bins and the morphology of the beats in each bin is averaged over a few beats successively to create a moving average complex. Average morphologies of both the odd and even beats are continuously updated by a weighting factor of one-eighth of the difference between the ongoing average and the new incoming beats. T-wave alternans is computed as the maximum difference in amplitude between the odd-beat and the even-beat average complexes from the J point to the end of the T wave for each 15 s beat stream. Additional algorithms minimize the effect of noise and artefacts. The MMA method remains synchronized with the alternation pattern, skipping over excessively noisy beats or premature ventricular contractions (PVCs). The option to scan the ECG with MMA technology may bring to the user?s attention clinically important surges in TWA that may be missed during routine review. T-wave alternans values at heart rates .120 bpm or those with noise levels .20 mV were excluded from the analysis. Peak TWA values both before and after reperfusion were determined in modified V1 and V5 ambulatory electrocardiogram (AECG) leads; of these two leads, the one with the higher TWA values was termed the ?higher lead?. Peak TWA before reperfusion was defined as peak TWA in the period between emergency room visit and first improvement in TIMI flow grade by invasive procedure (coronary balloon angioplasty/stenting or administration of intracoronary vasodilator). Peak TWA after reperfusion was defined as peak TWA in the period between first improvement in TIMI flow grade and VTA onset (in patients with VTA) or the end of therapy (in patients without VTA). Statistical analysis Statistical analyses were performed using Stat View version 5.0 (SAS Institute Inc., Cary, NC, USA). Values are presented as means + SD. The F-test was used to compare the variances of the two groups. Differences between groups were assessed using the unpaired Student?s t-test, or Welch?s t-test for continuous variables, and Fisher?s exact test for categorical variables. All significance tests were twosided. Results were considered statistically significant when the P-value was ,0.05. Results Patient characteristics Thrombolysis in myocardial infarction grade 3 flow was established during reperfusion therapy in all patients. Of the 20 patients, 3 (15.0%) developed ventricular fibrillation (VF, n ? 2) or sustained ventricular tachycardia (VT, n ? 1) requiring cardioversion soon after reperfusion. The clinical characteristics of the 17 patients without VTA and the 3 patients with VTA are summarized in Table 1. Univariate analysis showed that peak CK and CK-MB were significantly higher in patients with VTA than in those without VTA. However, there were no significant differences in the clinical characteristics on admission between the two groups. Peak T-wave alternans before and after reperfusion in patients with and without ventricular tachyarrhythmia Peak TWA before reperfusion was significantly higher in patients with VTA than in those without (33.0 + 4.4 vs. 14.9 + 5.4 mV, P , 0.001, in modified V5; 21.0 + 9.8 vs. 12.4 + 4.1 mV, P ? 0.01, in modified V1; 33.0 + 4.4 vs. 15.8 + 4.0 mV, P , 0.001, in the higher lead) (unpaired Student?s t-test) (Figure 1A). Two patients with VTA undergoing coronary balloon angioplasty/stenting exhibited an upsurge in TWA to 75 and 105 mV in AECG leads V1 and V5, respectively, before onset of VTA. In the third patient, macroscopic TWA appeared in leads V1 ? V4 of the 12-lead ECG prior to VTA upon pharmacological resolution of vasospasm, although the AECG field of view did not permit detection of the upsurge. There were no significant differences in peak TWA values after reperfusion between the two groups in the AECG leads (assessed by Welch?s t-test) (Figure 1B). A ) V (m 40 n isuo 30 fr rpee 20 froe 10 e bA 0 W T )B (Vm120 ion100 fsu 80 rpe 60 rre 40 e fta 20 A 0 W T 14.9?5.4 Results of continuous T-wave alternans monitoring in patients with ventricular tachyarrhythmia Continuous TWA monitoring trends of the modified V5 lead in the patient with NSTEMI who developed sustained VT are shown in Figure 2A and B. This patient had a history of anterior myocardial infarction. Urgent coronary angiography showed subtotal occlusion of the right coronary artery (pre-procedural TIMI flow grade, 1). There were three episodes of transient increases in TWA: to 36 mV before reperfusion therapy in the emergency room; to 80 mV at partial reperfusion (TIMI flow grade, 2); and to the maximum 105 mV in the 20 min preceding the onset of sustained VT in the modified V5 lead. T-wave alternans was also visible in the modified V1 lead at the time of maximum TWA in the modified V5 lead. A progressive increase in QRS-wave alternans occurred simultaneously with the upsurge in TWA, suggesting a component of depolarization effects in the repolarization changes (Figure 2C and D). The automated TWA output decreased, probably due to frequent PVCs, which may have interfered with TWA measurement, slightly before the onset of sustained VT. Similarly, continuous TWA monitoring of the modified V1 lead in a patient presenting with STEMI and right coronary artery occlusion showed several episodes of transient increases in TWA: a peak before reperfusion (32 mV) and a surge to maximum TWA (75 mV) at partial reperfusion in the 40 min preceding the onset of VF (Figure 3A). The automated TWA output decreased before the onset of VF, because complete atrioventricular block requiring temporary pacing, which interfered with TWA measurement, occurred upon partial reperfusion. Data obtained during pacing rhythm were excluded from the analysis. Continuous TWA monitoring of a patient presenting with UA and coronary artery spasm is shown in Figure 3B-i. In this patient, chest pain and marked ST-segment depression in almost all precordial leads suggested the presence of extended antero-lateral wall acute myocardial ischaemia (Figure 3B-ii) and were slightly improved after sublingual administration of nitroglycerin in the emergency room. At the time of diagnostic angiography, severe spasm of the right coronary artery was induced by mechanical stimulation by a catheter tip. The patient developed VF at 30 s after intracoronary injection of isosorbide dinitrate and nicorandil. Coronary balloon angioplasty/stenting was not performed. A few episodes of transient increases in TWA occurred in the modified V5 AECG lead before pharmacological resolution of vasospasm, although the AECG field of view did not permit optimal detection of upsurge in TWA, indicating a decrease in TWA in both modified V5 (Figure 3B-i) and V1 (data not shown) AECG leads, just prior to onset of VF. However, macroscopic TWA was present in leads V1 ? V4 in the simultaneously recorded 12-lead ECG along with newly emerged marked ST-segment depression in inferior leads from 90 s before the onset of VF, suggesting additional catheter-induced inferior wall ischaemia (Figure 3B-iii). Note that lead distribution of TWA may have shifted after the main ischaemic area changed from antero-lateral in the emergency room to inferior wall immediately before the VF onset. Discussion In the present study, we demonstrated that peak TWA before reperfusion is significantly higher in ACS patients who experience VTA upon emergent reperfusion than in those without VTA, and that patients with VTA show an upsurge in TWA during the procedure preceding the onset of VTA. These findings indicate that ACS patients at risk of developing VTA soon after reperfusion exhibit heightened TWA before the procedure and that TWA monitoring before reperfusion can predict the impending VTA. Moreover, the present study also suggests the need for the use of multi-lead ECGs to optimize detection of TWA, which appears regionally in the ischaemic area.11,12 This is the first study to elucidate the usefulness of continuous TWA monitoring with clinically available equipment in the ultra-short-term prediction of VTA upon emergent reperfusion in ACS patients. Dynamics of T-wave alternans during the acute phase of acute coronary syndrome The dynamics of TWA during the acute phase of ACS have not yet been elucidated. The present study showed that intermittent episodes of transient increases in TWA may occur before reperfusion. These results are not completely consistent with the finding reported by Shusterman and colleagues that a progressive increase in TWA precedes the onset of spontaneous VTA by as much as 30 min in patients with a history of VTA.7 However, ACS patients may have more unstable pathophysiological characteristics than those enrolled in their study. The dynamics of TWA before the onset of VTA may depend on the presence of provocative factors. T-wave alternans is exacerbated by acute myocardial ischaemia and reperfusion11,12 and by catecholamine excess.13 Acute coronary syndrome patients are exposed to all of these provocative factors during the acute phase, especially during emergent reperfusion therapy. In addition, some ACS patients present with brief coronary artery occlusion and spontaneous reperfusion prior to treatment. Therefore, ACS patients may not always show a sustained increase in TWA after ACS onset. A transient increase in TWA during the acute phase of ACS is expected to appear upon sudden reduction of coronary blood flow or reperfusion, for example, after sublingual administration of nitroglycerin in the emergency room, after intracoronary injection of contrast media or nitroglycerin, during intracoronary balloon inflation and after deflation, and at subsequent excess release of catecholamine. From the perspective of prophylactic measures, the evaluation of TWA before emergent reperfusion therapy, especially noting peak TWA during emergency room stay, may be important in the prediction of impending VTA and delivering appropriate antiarrhythmic therapy. It is recommended to start monitoring TWA before the administration of coronary dilator in the emergency room to avoid missing a transient increase at partial coronary reperfusion since the disappearance of TWA following reperfusion may be rapid.12 It is difficult to measure TWA accurately just before VTA onset in some cases because arrhythmias that occur during acute ischaemia and reperfusion or before the onset of VTA, such as frequent extrasystoles, non-sustained VT, or transient atrio-ventricular block, may interfere with TWA measurement and underestimate the arrhythmia risk. Regional specificity of T-wave alternans Two patients with VTA undergoing coronary angioplasty/stenting exhibited an upsurge in TWA to 75 and 105 mV in modified V1 or V5 AECG leads before onset of VTA. In the third patient, macroscopic TWA appeared in leads V1 ? V4 in the simultaneously recorded 12-lead ECG prior to VTA during antero-lateral and additional catheter-induced inferior wall ischaemia, although the AECG field of view could not detect the upsurge immediately before VTA. In this patient, a transient increase in TWA had been detected in the modified V5 AECG lead during antero-lateral wall ischaemia before reperfusion therapy. T-wave alternans is expected to appear in the ischaemic area11,12 and the precordial leads overlying the ischaemic zone are superior to the limb or Frank leads in the assessment of TWA during both the coronary occlusion and the reperfusion phases from the body surface.11 These findings suggest that the use of multi-lead ECGs including 12-lead continuous ECGs for patient monitoring from emergency room admission through the procedure may be required to avoid underestimating TWA, which is regionally specific. Continuous T-wave alternans monitoring using the time-domain modified moving average method We employed the time-domain MMA method in the present study to enable continuous TWA monitoring during the acute phase of ACS. This method reports quantifiable TWA values for each 15 s of data10 and thus is suitable for TWA analysis during dynamically changing pathophysiological conditions such as ACS. Because of the power of recursive averaging, it is inherently capable of rejecting noise14 and has filters to remove baseline wander and respiratory artefact. In addition, potential artefacts may be reviewed by inspecting the template of superimposed ECG beats. This novel approach has been demonstrated to be equivalent in risk assessment to the conventional spectral method in long-term prediction of cardiac death.15 Continuous ECG recordings are often interrupted by motion artefacts. Nevertheless, TWA testing can be performed with high signal-to-noise ratio in ACS patients at rest in the supine position. Limitations First, the sample size was small. Sample imbalance between the groups arose because of the rare occurrence (15%) of VTA events. Therefore, multivariate analysis to elucidate the independent relationship between the increase in TWA and VTA risk could not be performed. Second, TWA monitoring could not be performed in patients with persistent atrial fibrillation or highgrade atrio-ventricular block, which frequently occur during the acute phase of ACS. Third, it is possible that some episodes of heightened TWA were not detected as only two-channel AECG recordings were obtained.11,12 Fourth, this study included all types of ACS (UA, NSTEMI, and STEMI). Thus pre-procedural TIMI flow grade and preceding ischaemic interval varied from case to case and may have affected the results. Fifth, TWA that appeared immediately before VF in the third patient with coronary spasm was assessed only by subjective visual inspection due to failure of TWA detection in two-channel AECG recordings. Finally, the present study did not extend to the post-reperfusion in-hospital stay. Thus, it could not be determined whether continuous TWA monitoring can also predict VTA following the procedure. This information would be valuable because procedural failure is associated with a significantly higher risk of this event.2 Future perspective It will be worthwhile to evaluate whether prophylactic administration of beta-adrenoreceptor blockade,16 calcium channel blockade,17 or amiodarone,18 which have been shown to decrease TWA, prevents the progression of TWA and occurrence of VTA in ACS patients exhibiting high-amplitude TWA before emergent coronary reperfusion. Ultra-short-term prediction of VTA using TWA monitoring may be useful not only in the catheterization laboratory but also in the monitoring of critically ill patients at risk for lethal cardiac arrhythmias in the intensive care unit. Conclusion Acute coronary syndrome patients at risk of developing VTA upon emergent reperfusion already exhibit episodes of transient increases in TWA before the procedure and present with an upsurge in TWA preceding the onset of VTA. Thus, continuous TWA monitoring may be useful for the ultra-short-term prediction of VTA occurring soon after reperfusion in ACS patients. The use of 12-lead continuous ECGs is expected to optimize detection of TWA, which is regionally specific, appearing in the ischaemic zone.11,12 Acknowledgements We are grateful to members of Advanced Critical Care Center of Gifu University Hospital, Toshiaki Takeyama, Takahide Nawa, Chiharu Yokoyama, Takatomo Watanabe, and Tomonori Kawaguchi, for their collection of data. Funding We received no financial support for this study. Conflict of interest: Verrier is the co-inventor of the MMA method for T-wave alternans analysis with patent assigned to Beth Israel Deaconess Medical Center and licensed by GE Healthcare. 1. Al-Khatib SM , Granger CB , Huang Y , Lee KL , Califf RM , Simoons ML et al. Sustained ventricular arrhythmias among patients with acute coronary syndromes with no ST-segment elevation: incidence, predictors, and outcomes . Circulation 2002 ; 106 : 309 - 12 . 2. Mehta RH , Starr AZ , Lopes RD , Hochman JS , Widimsky P , Pieper KS et al. APEX AMI Investigators: incidence of and outcomes associated with ventricular tachycardia or fibrillation in patients undergoing primary percutaneous coronary intervention . JAMA 2009 ; 301 : 1779 - 89 . 3. Antman EM , Anbe DT , Armstrong PW , Bates ER , Green LA , Hand M et al. 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Mart? ?nez JP , Olmos S , Wagner G , Laguna P . Characterization of repolarization alternans during ischemia: time-course and spatial analysis . IEEE Trans Biomed Eng 2006 ; 53 : 701 - 11 . 13. Lampert R , Shusterman V , Burg MM , Lee FA , Earley C , Goldberg A et al. Effects of psychologic stress on repolarization and relationship to autonomic and hemodynamic factors . J Cardiovasc Electrophysiol 2005 ; 16 : 372 - 7 . 14. Martinez JP , Olmos S. Methodological principles of T wave alternans analysis: a unified framework . IEEE Trans Biomed Eng 2005 ; 52 : 599 - 613 . 15. Exner DV , Kavanagh KM , Slawnych MP , Mitchell LB , Ramadan D , Aggarwal SG et al. Noninvasive risk assessment early after a myocardial infarction the REFINE study . J Am Coll Cardiol 2007 ; 50 : 2275 - 84 . 16. Klingenheben T , Gr o?nefeld G , Li YG , Hohnloser SH . Effect of metoprolol and d,l-sotalol on microvolt-level T-wave alternans. Results of a prospective, doubleblind, randomized study . J Am Coll Cardiol 2001 ; 38 : 2013 - 9 . 17. Nearing BD , Hutter JJ , Verrier RL . Potent antifibrillatory effect of combined blockade of calcium channels and 5-HT2 receptors with nexopamil during myocardial ischemia and reperfusion in dogs: comparison to diltiazem . J Cardiovasc Pharmacol 1996 ; 27 : 777 - 87 . 18. Groh WJ , Shinn TS , Engelstein EE , Zipes DP . Amiodarone reduces the prevalence of T wave alternans in a population with ventricular tachyarrhythmias . J Cardiovasc Electrophysiol 1999 ; 10 : 1335 - 9 .


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Takasugi, Nobuhiro, Kubota, Tomoki, Nishigaki, Kazuhiko, Verrier, Richard L., Kawasaki, Masanori, Takasugi, Mieko, Ushikoshi, Hiroaki, Hattori, Arihiro, Ojio, Shinsuke, Aoyama, Takuma, Takemura, Genzou, Minatoguchi, Shinya. Continuous T-wave alternans monitoring to predict impending life-threatening cardiac arrhythmias during emergent coronary reperfusion therapy in patients with acute coronary syndrome, EP Europace, 2011, 708-715, DOI: 10.1093/europace/euq512