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'''Editors-In-Chief:''' Richard L. Verrier, PhD, FACC, and Tuomo Nieminen, MD, PhD; '''Assistant Editors-in-Chief:''' Jose Roberto Pegler, MD, and Caio Tavares, MD.
'''Editors-In-Chief:''' Richard L. Verrier, PhD, FACC, FHRS, and Tuomo Nieminen, MD, PhD; '''Assistant Editors-in-Chief:''' Jose Roberto Pegler, MD, and Caio Tavares, MD.


==Overview==
==Overview==
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==Causes==
==Causes==


T-wave alternans heralds ventricular arrhythmias in these patient groups:  
The integrated physiology and cellular basis for the T-wave alternans phenomenon has been extensively discussed. <ref>Narayan SM. T-wave alternans and the susceptibility to ventricular arrhythmias. J Am Coll Cardiol 2006;47:269–81.</ref><ref>Cutler MJ, Rosenbaum DS. Explaining the clinical manifestations of T-wave alternans in patients at risk for sudden cardiac death. Heart Rhythm 2009;6:S22–8.</ref><ref>Verrier RL, Kumar K, Nearing BD. Basis for sudden cardiac death prediction by T-wave alternans from an integrative physiology perspective. Heart Rhythm 2009;6:416 –22.</ref><ref>Weiss JN, Nivala M, Garfinkel A, Qu Z. Alternans and arrhythmias:from cell to heart. Circ Res 2011;108:98 –112.</ref><ref>Clusin WT. Mechanisms of calcium transient and action potential alternans in cardiac cells and tissues. Am J Physiol Heart Circ Physiol 2008;294:H1–10.</ref><ref>Verrier RL, Klingenheben T, Malik M, El-Sherif N, Exner D, Hohnloser S, Ikeda T, Martinez JP, Narayan S, Nieminen T, Rosenbaum DS. Microvolt T-wave alternans: Physiologic basis, methods of measurement, and clinical utility. Consensus guideline by the International Society for Holter and Noninvasive Electrocardiology. J Am Coll Cardiol 2011; 44:1309-1324.</ref>
*[[Anger in patients with ICDs]] <ref>Kop WJ, Krantz DS, Nearing BD, et al: Effects of acute mental and exercise stress on T-wave alternans in patients with implantable cardioverter defibrillators and controls. Circulation 2004 109:1864-1869.</ref> <ref>Lampert R, Shusterman V, Burg M, et al: Anger-induced T-wave alternans predicts future ventricular arrhythmias in patients with implantable cardioverter-defibrillators. J Am Coll Cardiol 2009 53:774–778.</ref>
 
*[[Brugada syndrome]] <ref> Uchimura-Makita Y, Nakano Y, Tokuyama T, Fujiwara M, Watanabe Y, Sairaku A, Kawazoe H, Matsumura H, Oda N, Ikanaga H, Motoda C, Kajihara K, Oda N, Verrier RL, Kihara Y. Time-domain T-wave alternans is strongly associated with a history of ventricular fibrillation in patients with Brugada Syndrome. J Cardiovasc Electrophysiol 2014; 25:1021-1027. </ref>
==Clinical Utility==
*[[Congenital heart disease]] <ref> Alexander ME, Cecchin F, Huang KP, Berul CI. Microvolt T-wave alternans with exercise in pediatrics and congenital heart disease: limitations and predictive value. Pacing Clin Electrophysiol 2006;29: 733–41. </ref>
 
*[[Congestive heart failure]]<ref>Stein PK, Sanghavi D, Domitrovich PP, et al. Ambulatory ECG-based T-wave alternans predicts sudden cardiac death in high-risk post-MI patients with left ventricular dysfunction in the EPHESUS study. J Cardiovasc Electrophysiol 2008 19:1037–1042.</ref> <ref>Klingenheben T, Zabel M, D’Agostino RB, Cohen RJ, Hohnloser SH. Predictive value of T-wave alternans for arrhythmic events in patients with congestive heart failure [letter]. Lancet 2000;356:651–2.</ref>
T-wave alternans predicts arrhythmia, sudden cardiac death, or cardiovascular or total mortality in these patient groups:
*[[Coronary artery disease]]<ref>Shusterman V, Goldberg A, London B. Upsurge in T-wave alternans and nonalternating repolarization instability precedes spontaneous initiation of ventricular tachyarrhythmias in humans. Circulation 2006;113:2880–7.</ref> <ref> Rashba EJ, Osman AF, MacMurdy K, et al. Influence of QRS duration on the prognostic value of T wave alternans. J Cardiovasc Electrophysiol 2002;13:770 –5.</ref>  
*[[Congenital heart disease]]<ref> Alexander ME, Cecchin F, Huang KP, Berul CI. Microvolt T-wave alternans with exercise in pediatrics and congenital heart disease: limitations and predictive value. Pacing Clin Electrophysiol 2006;29: 733–41. </ref>
*[[Congestive heart failure]]<ref>Stein PK, Sanghavi D, Domitrovich PP, et al. Ambulatory ECG-based T-wave alternans predicts sudden cardiac death in high-risk post-MI patients with left ventricular dysfunction in the EPHESUS study. J Cardiovasc Electrophysiol 2008 19:1037–1042.</ref><ref>Klingenheben T, Zabel M, D’Agostino RB, Cohen RJ, Hohnloser SH. Predictive value of T-wave alternans for arrhythmic events in patients with congestive heart failure [letter]. Lancet 2000;356:651–2.</ref>
*[[Dilated cardiomyopathy]] <ref>Hohnloser SH, Klingenheben T, Bloomfield D, Dabbous O, Cohen RJ. Usefulness of microvolt T-wave alternans for prediction of ventricular tachyarrhythmic events in patients with dilated cardiomyopathy: results from a prospective observational study. J Am Coll Cardiol 2003;41:2220–4.</ref>
*[[Dilated cardiomyopathy]] <ref>Hohnloser SH, Klingenheben T, Bloomfield D, Dabbous O, Cohen RJ. Usefulness of microvolt T-wave alternans for prediction of ventricular tachyarrhythmic events in patients with dilated cardiomyopathy: results from a prospective observational study. J Am Coll Cardiol 2003;41:2220–4.</ref>
*[[Diabetes]] <ref>Ren L-N, Fang XH, Ren LD, Gong J, Wang Yq, Qi G-x,et al. Ambulatory ECG-based T-wave alternans and heart rate turbulence can predict cardiac mortality in patients with myocardial infarction with or without diabetes mellitus. Cardiovasc Diabetol2012;11:104–11. </ref>
*[[Diabetes]] <ref>Ren L-N, Fang XH, Ren LD, Gong J, Wang Yq, Qi G-x,et al. Ambulatory ECG-based T-wave alternans and heart rate turbulence can predict cardiac mortality in patients with myocardial infarction with or without diabetes mellitus. Cardiovasc Diabetol2012;11:104–11. </ref>
*[[Epileptic seizure]] <ref>Strzelczyk A, Adjei P, Scott CA, et al. Postictal increase in T-wave alternans after generalized tonic–clonic seizures. Epilepsia 2011 52:2112-2117.</ref> <ref>Schomer AC, Nearing BD, Schachter SC, Verrier RL. Vagus nerve stimulation reduces cardiac electrical instability assessed by quantitative T-wave alternans analysis in patients with drug-resistant focal epilepsy. Epilepsia 2014; 55:1996–2002.</ref>
*[[Ischemic and nonischemic cardiomyopathy]]<ref>Sakaki K, Ikeda T, Miwa Y, et al. Time-domain T-wave alternans measured from Holter electrocardiograms predicts cardiac mortality in patients with left ventricular dysfunction: a prospective study. Heart Rhythm 2009 6:332–337.</ref><ref>Chow T, Kereiakes DJ, Bartone C, et al. Prognostic utility of microvolt T-wave alternans in risk stratification of patients with ischemic cardiomyopathy. J Am Coll Cardiol 2006;47:1820–7.</ref><ref>Salerno-Uriarte JA, De Ferrari GM, Klersy C, et al. Prognostic value of T-wave alternans in patients with heart failure due to nonischemic cardiomyopathy: results of the ALPHA study. J Am Coll Cardiol 2007;50:1896 –904.</ref><ref>Chow T, Saghir S, Bartone C, et al. Usefulness of microvolt T-wave alternans in predicting outcome in patients with ischemic cardiomyopathy with and without defibrillators. Am J Cardiol 2007;100:598–604.</ref><ref>Chow T, Kereiakes DJ, Bartone C, et al. Microvolt T-wave alternans identifies patients with ischemic cardiomyopathy who benefit from implantable cardioverter-defibrillator therapy. J Am Coll Cardiol 2007;49:50–8.</ref><ref>Chan PS, Kereiakes DJ, Bartone C, Chow T. Usefulness of microvolt T-wave alternans to predict outcomes in patients with ischemic cardiomyopathy beyond one year. Am J Cardiol 2008;102:280–4.</ref> <ref>Morin DP, Zacks ES, Mauer AC, et al. Effect of bundle branch block on microvolt T-wave alternans and electrophysiologic testing in patients with ischemic cardiomyopathy. Heart Rhythm 2007;4:904–12.</ref>
*[[ICD shocks]] <ref>Lampert R, Soufer R, McPherson CA, et al. Implantable cardioverter-defibrillator shocks increase T-wave alternans. J Cardiovasc Electrophysiol 2007 18:512-517.</ref>
*[[Left ventricular dysfunction]]<ref>Bloomfield DM, Bigger JT, Steinman RC, et al. Microvolt T-wave alternans and the risk of death or sustained ventricular arrhythmias in patients with left ventricular dysfunction. J Am Coll Cardiol 2006;47:456–63.</ref><ref>Cantillon DJ, Stein KM, Markowitz SM, et al. Predictive value of microvolt T-wave alternans in patients with left ventricular dysfunction. J Am Coll Cardiol 2007;50:166 –73.</ref><ref>Gorodeski EZ, Cantillon DJ, Goel SS, et al. Microvolt T-wave alternans, peak oxygen consumption, and outcome in patients with severely impaired left ventricular systolic function. J Heart Lung Transplant 2009;28:689 –96.</ref><ref>Stein PK, Sanghavi D, Domitrovich PP, Mackey RA, Deedwania P. Ambulatory ECG-based T-wave alternans predicts sudden cardiac death in high-risk post-MI patients with left ventricular dysfunction in the EPHESUS study. J Cardiovasc Electrophysiol 2008;19:1037–42.</ref><ref>Sakaki K, Ikeda T, Miwa Y, et al. Time-domain T-wave alternans measured from Holter electrocardiograms predicts cardiac mortality in patients with left ventricular dysfunction: a prospective study. Heart Rhythm 2009 6:332–337.</ref>
*[[Ischemic and nonischemic cardiomyopathy]] <ref>Sakaki K, Ikeda T, Miwa Y, et al. Time-domain T-wave alternans measured from Holter electrocardiograms predicts cardiac mortality in patients with left ventricular dysfunction: a prospective study. Heart Rhythm 2009 6:332–337.</ref> <ref>Chow T, Kereiakes DJ, Bartone C, et al. Prognostic utility of microvolt T-wave alternans in risk stratification of patients with ischemic cardiomyopathy. J Am Coll Cardiol 2006;47:1820 –7. </ref> <ref>Salerno-Uriarte JA, De Ferrari GM, Klersy C, et al. Prognostic value of T-wave alternans in patients with heart failure due to nonischemic cardiomyopathy: results of the ALPHA study. J Am Coll Cardiol 2007;50:1896 –904.</ref> <ref>Chow T, Saghir S, Bartone C, et al. Usefulness of microvolt T-wave alternans in predicting outcome in patients with ischemic cardiomyopathy with and without defibrillators. Am J Cardiol 2007;100:598–604.</ref> <ref> Chow T, Kereiakes DJ, Bartone C, et al. Microvolt T-wave alternans identifies patients with ischemic cardiomyopathy who benefit from implantable cardioverter-defibrillator therapy. J Am Coll Cardiol 2007;49:50–8.</ref><ref>Chan PS, Kereiakes DJ, Bartone C, Chow T. Usefulness of microvolt T-wave alternans to predict outcomes in patients with ischemic cardiomyopathy beyond one year. Am J Cardiol 2008;102:280–4.</ref> <ref>Morin DP, Zacks ES, Mauer AC, et al. Effect of bundle branch block on microvolt T-wave alternans and electrophysiologic testing in patients with ischemic cardiomyopathy. Heart Rhythm 2007;4:904–12.</ref>
*[[Long QT syndrome]]<ref>Schwartz PJ, Malliani A. Electrical alternation of the T-wave: clinical and experimental evidence of its relationship with the sympathetic nervous system and with the long Q-T syndrome. Am Heart J. 1975;89:45–50.</ref><ref>Cruz Filho FE, Maia IG, Fagundes ML, et al. Electrical behavior of T-wave polarity alternans in patients with congenital long QT syndrome. J Am Coll Cardiol. Jul 2000;36(1):167-73.</ref>
*[[Left ventricular dysfunction]] <ref>Bloomfield DM, Bigger JT, Steinman RC, et al. Microvolt T-wave alternans and the risk of death or sustained ventricular arrhythmias in patients with left ventricular dysfunction. J Am Coll Cardiol 2006;47:456–63.</ref> <ref> Cantillon DJ, Stein KM, Markowitz SM, et al. Predictive value of microvolt T-wave alternans in patients with left ventricular dysfunction. J Am Coll Cardiol 2007;50:166 –73. </ref><ref>Gorodeski EZ, Cantillon DJ, Goel SS, et al. Microvolt T-wave alternans, peak oxygen consumption, and outcome in patients with severely impaired left ventricular systolic function. J Heart Lung Transplant 2009;28:689 –96.</ref> <ref>Stein PK, Sanghavi D, Domitrovich PP, Mackey RA, Deedwania P. Ambulatory ECG-based T-wave alternans predicts sudden cardiac death in high-risk post-MI patients with left ventricular dysfunction in the EPHESUS study. J Cardiovasc Electrophysiol 2008;19:1037– 42.</ref><ref>Sakaki K, Ikeda T, Miwa Y, et al. Time-domain T-wave alternans measured from Holter electrocardiograms predicts cardiac mortality in patients with left ventricular dysfunction: a prospective study. Heart Rhythm 2009 6:332–337.</ref>\
*[[Myocardial ischemia and infarction]]<ref> Verrier RL, Nearing BD, LaRovere MT, Pinna GD, Mittleman MA, Bigger JT, Schwartz PJ for the ATRAMI Investigators. Ambulatory ECG-based tracking of T-wave alternans in post-myocardial infarction patients to assess risk of cardiac arrest or arrhythmic death. J Cardiovasc Electrophysiol 2003; 14:705-711.</ref><ref>Hoshida K, Miwa Y, Miyakoshi M, et al. Simultaneous assessment of T-wave alternans and heart rate turbulence on Holter electrocardiograms as predictors for serious cardiac events in patients after myocardial infarction. Circ J 2013 77:432-438.</ref><ref>Hou Y, Fang PH, Wu Y, et al. Prediction of sudden cardiac death in patients after acute myocardial infarction using T-wave alternans: a prospective study. J Electrocardiol 2012 45:60–65</ref><ref>Sulimov V, Okisheva E, Tsaregorodtsev D. Non-invasive risk stratification for sudden cardiac death by heart rate turbulence and microvolt T wave alternans in patients after myocardial infarction. Europace 2012 14:1786-1792.</ref><ref>Exner DV, Kavanagh KM, Slawnych MP, et al. Noninvasive risk assessment early after a myocardial infarction the REFINE study. J Am Coll Cardiol 2007 Dec 11; 50:2275-84.</ref><ref>Slawnych MP, Nieminen T, Kahonen M, et al. Post-exercise assessment of cardiac repolarization alternans in patients with coronary artery disease using the modified moving average method. J Am Coll Cardiol 2009 Mar 31; 53:1130-7.</ref><ref>Arisha MM, Girerd N, Chauveau S, Bresson D, Scridon A, Bonnefoy E, et al. In-hospital heart rate turbulence and microvolt T-wave alternans abnormalities for prediction of early life-threatening ventricular arrhythmia after acute myocardial infarction. Ann Noninvasive Electrocardiol 2013;18:530–7.</ref><ref>Ikeda T, Sakata T, Takami M, et al. Combined assessment of T-wave alternans and late potentials used to predict arrhythmic events after myocardial infarction. A prospective study. J Am Coll Cardiol 2000;35:722–30. </ref> <ref> Ikeda T, Saito H, Tanno K, et al. T-wave alternans as a predictor for sudden cardiac death after myocardial infarction. Am J Cardiol 2002;89:79–82.</ref><ref>Ikeda T, Yoshino H, Sugi K, et al. Predictive value of microvolt T-wave alternans for sudden cardiac death in patients with preserved cardiac function after acute myocardial infarction: results of a collaborative cohort study. J Am Coll Cardiol 2006;48:2268 –74.</ref>
*[[Long QT syndrome]]<ref>Schwartz PJ, Malliani A. Electrical alternation of the T-wave: clinical and experimental evidence of its relationship with the sympathetic nervous system and with the long Q-T syndrome. Am Heart J. 1975;89:45–50.</ref> <ref>Cruz Filho FE, Maia IG, Fagundes ML, et al. Electrical behavior of T-wave polarity alternans in patients with congenital long QT syndrome. J Am Coll Cardiol. Jul 2000;36(1):167-73.</ref>
*[[Non-STEMI acute coronary syndrome]]<ref>Nieminen T, Scirica BM, Pegler JRM, Tavares C, Pagotto VPF, Kanas AF, Sobrado MF, Nearing BD, Umez-Eronini AA, Morrow DA, Belardinelli L, Verrier RL. Relation of T-wave alternans to mortality and nonsustained ventricular tachycardia in patients with non-ST segment elevation acute coronary syndrome from the MERLIN-TIMI 36 trial of ranolazine versus placebo. Am J Cardiol 2014; 114:17-23.</ref>
*[[Myocardial ischemia and infarction]] <ref> Verrier RL, Nearing BD, LaRovere MT, Pinna GD, Mittleman MA, Bigger JT, Schwartz PJ for the ATRAMI Investigators. Ambulatory ECG-based tracking of T-wave alternans in post-myocardial infarction patients to assess risk of cardiac arrest or arrhythmic death. J Cardiovasc Electrophysiol 2003; 14:705-711. </ref> <ref>Hoshida K, Miwa Y, Miyakoshi M, et al. Simultaneous assessment of T-wave alternans and heart rate turbulence on Holter electrocardiograms as predictors for serious cardiac events in patients after myocardial infarction. Circ J 2013 77:432-438.</ref> <ref>Hou Y, Fang PH, Wu Y, et al. Prediction of sudden cardiac death in patients after acute myocardial infarction using T-wave alternans: a prospective study. J Electrocardiol 2012 45:60–65</ref> <ref>Sulimov V, Okisheva E, Tsaregorodtsev D. Non-invasive risk stratification for sudden cardiac death by heart rate turbulence and microvolt T wave alternans in patients after myocardial infarction. Europace 2012 14:1786-1792.</ref> <ref>Exner DV, Kavanagh KM, Slawnych MP, et al. Noninvasive risk assessment early after a myocardial infarction the REFINE study. J Am Coll Cardiol 2007 Dec 11; 50:2275-84.</ref> <ref>Slawnych MP, Nieminen T, Kahonen M, et al. Post-exercise assessment of cardiac repolarization alternans in patients with coronary artery disease using the modified moving average method. J Am Coll Cardiol 2009 Mar 31; 53:1130-7. </ref> <ref>Arisha MM, Girerd N, Chauveau S, Bresson D, Scridon A, Bonnefoy E, et al. In-hospital heart rate turbulence and microvolt T-wave alternans abnormalities for prediction of early life-threatening ventricular arrhythmia after acute myocardial infarction. Ann Noninvasive Electrocardiol 2013;18:530–7. </ref> <ref>Ikeda T, Sakata T, Takami M, et al. Combined assessment of T-wave alternans and late potentials used to predict arrhythmic events after myocardial infarction. A prospective study. J Am Coll Cardiol 2000;35:722–30. </ref> <ref> Ikeda T, Saito H, Tanno K, et al. T-wave alternans as a predictor for sudden cardiac death after myocardial infarction. Am J Cardiol 2002;89:79–82.</ref> <ref>Ikeda T, Yoshino H, Sugi K, et al. Predictive value of microvolt T-wave alternans for sudden cardiac death in patients with preserved cardiac function after acute myocardial infarction: results of a collaborative cohort study. J Am Coll Cardiol 2006;48:2268 –74.</ref>
*[[Patients with ICDs during anger]]<ref>Lampert R, Shusterman V, Burg M, et al: Anger-induced T-wave alternans predicts future ventricular arrhythmias in patients with implantable cardioverter-defibrillators. J Am Coll Cardiol 2009 53:774–778.</ref> See also: <ref>Kop WJ, Krantz DS, Nearing BD, et al: Effects of acute mental and exercise stress on T-wave alternans in patients with implantable cardioverter defibrillators and controls. Circulation 2004 109:1864-1869.</ref>  
*[[Non-STEMI acute coronary syndrome]] <ref>Nieminen T, Scirica BM, Pegler JRM, Tavares C, Pagotto VPF, Kanas AF, Sobrado MF, Nearing BD, Umez-Eronini AA, Morrow DA, Belardinelli L, Verrier RL. Relation of T-wave alternans to mortality and nonsustained ventricular tachycardia in patients with non-ST segment elevation acute coronary syndrome from the MERLIN-TIMI 36 trial of ranolazine versus placebo.  Am J Cardiol 2014; 114:17-23.</ref>
*[[Patients with acute coronary syndrome during percutaneous coronary intervention]]<ref>Takasugi N, Kubota T, Nishigaki K, et al. Continuous T-wave alternans monitoring to predict impending life-threatening cardiac arrhythmias during emergent coronary reperfusion therapy in patients with acute coronary syndrome.  Europace 2011 13:708-715.</ref>
*[[Percutaneous coronary intervention in patients with acurte coronary syndrome and with lethal arrhythmia]] <ref>Takasugi N, Kubota T, Nishigaki K, et al. Continuous T-wave alternans monitoring to predict impending life-threatening cardiac arrhythmias during emergent coronary reperfusion therapy in patients with acute coronary syndrome.  Europace 2011 13:708-715.</ref>
*[[Patients with STEMI during percutaneous coronary intervention]]<ref>Verrier RL, Nearing BD, Ghanem RN, Olson RE, Garberich RF, Katsiyiannis WT, Gornick CC, Tang CY, Henry TD. Elevated T-wave alternans predicts nonsustained ventricular tachycardia in association with percutaneous coronary intervention in ST-segment elevation myocardial infarction (STEMI) patients.  J Cardiovasc Electrophysiol 2013; 24:658-663.</ref>
*[[Percutaneous coronary intervention in patients with STEMI]] <ref>Verrier RL, Nearing BD, Ghanem RN, Olson RE, Garberich RF, Katsiyiannis WT, Gornick CC, Tang CY, Henry TD. Elevated T-wave alternans predicts nonsustained ventricular tachycardia in association with percutaneous coronary intervention in ST-segment elevation myocardial infarction (STEMI) patients.  J Cardiovasc Electrophysiol 2013; 24:658-663.</ref>
*[[Vasospastic angina]]<ref>Shimada H, Nishizaki M, Fujii H, et al. Ambulatory electrocardiogram-based T-wave alternans in patients with vasospastic angina during asymptomatic periods. Am J Cardiol 2012 110:1446-1451.</ref>
*[[Proarrhythmia]] <ref>Verrier RL, Nieminen T. T-wave alternans as a therapeutic marker for antiarrhythmic agents. J Cardiovasc Pharmacol 2010; 55(6):544-554.</ref> including Amiodarone,<ref>Bardaji A, Vidal F, Richart C. T wave alternans associated with amiodarone. J Electrocardiol. Apr 1993;26(2):155-7.</ref><ref>Hohnloser SH. Macroscopic T wave alternans as a harbinger of sudden death. J Cardiovasc Electrophysiol. 1999;10:625.</ref> <ref> Tomcsanyi J, Somloi M, Horvath L. Amiodarone-induced giant T wave alternans hastens proarrhythmic response. J Cardiovasc Electrophysiol. 2002;13:629.</ref> <ref> Wegener FT, Ehrlich JR, Hohnloser SH. Amiodarone-associated macroscopic T-wave alternans and torsade de pointes unmasking the inherited long QT syndrome. Europace. 2008;10:112–113.</ref> [[Antibiotics]],<ref>Kroll CR, Gettes LS. T wave alternans and torsades de pointes after the use of intravenous pentamidine. J Cardiovasc Electrophysiol. 2002;13:936-938.</ref> [[Cancer therapy agents]] <ref>Yamazaki K, Terada H, Satoh H, et al. Arrhythmogenic effects of arsenic trioxide in patients with acute promyelocytic leukemia and an electrophysiological study in isolated guinea pig papillary muscles. Circ J. 2006;70:1407–1414.</ref>
*[[Renal failure]] <ref>Secemsky EA, Verrier RL, Cooke G, et al: High prevalence of cardiac autonomic dysfunction and T-wave alternans in dialysis patients. Heart Rhythm 2011 8:592-598.</ref>
*[[Sleep apnea]] <ref>Takasugi N, Nishigaki K, Kubota T, Tsuchiya K, Natsuyama K, Takasugi M, et al.Sleep apnoea induces cardiac electrical instability assessed by T-wave alternans in patients with congestive heart failure. Eur J Heart Fail 2009;11:1063–70.</ref> <ref> Yamada S,Suzuki H,Kamioka M,Suzuki S,Kamiyama Y, Yoshihisa A, et al. Sleep-disordered breathing increases risk for fatal ventricular arrhythmias in patients with chronic heart failure. Circ J 2013;77:1466–73.</ref>
*[[Vasospastic angina]] <ref>Shimada H, Nishizaki M, Fujii H, et al. Ambulatory electrocardiogram-based T-wave alternans in patients with vasospastic angina during asymptomatic periods. Am J Cardiol 2012 110:1446-1451.</ref>


==T-wave alternans has also been observed in these conditions==
T-wave alternans is associated with ventricular arrhythmias in these patient groups:


Alcoholic cardiomyopathy
*[[Brugada syndrome]]<ref> Uchimura-Makita Y, Nakano Y, Tokuyama T, Fujiwara M, Watanabe Y, Sairaku A, Kawazoe H, Matsumura H, Oda N, Ikanaga H, Motoda C, Kajihara K, Oda N, Verrier RL, Kihara Y. Time-domain T-wave alternans is strongly associated with a history of ventricular fibrillation in patients with Brugada Syndrome. J Cardiovasc Electrophysiol 2014; 25:1021-1027.</ref>
*[[Coronary artery disease]]<ref>Shusterman V, Goldberg A, London B. Upsurge in T-wave alternans and nonalternating repolarization instability precedes spontaneous initiation of ventricular tachyarrhythmias in humans. Circulation 2006;113:2880–7.</ref> <ref> Rashba EJ, Osman AF, MacMurdy K, et al. Influence of QRS duration on the prognostic value of T wave alternans. J Cardiovasc Electrophysiol 2002;13:770 –5.</ref>
*[[Medical therapy/Proarrhythmia]]<ref>Verrier RL, Nieminen T. T-wave alternans as a therapeutic marker for antiarrhythmic agents. J Cardiovasc Pharmacol 2010; 55(6):544-554.</ref> including Amiodarone,<ref>Bardaji A, Vidal F, Richart C. T wave alternans associated with amiodarone. J Electrocardiol. Apr 1993;26(2):155-7.</ref><ref>Hohnloser SH. Macroscopic T wave alternans as a harbinger of sudden death. J Cardiovasc Electrophysiol. 1999;10:625.</ref><ref> Tomcsanyi J, Somloi M, Horvath L. Amiodarone-induced giant T wave alternans hastens proarrhythmic response. J Cardiovasc Electrophysiol. 2002;13:629.</ref><ref> Wegener FT, Ehrlich JR, Hohnloser SH. Amiodarone-associated macroscopic T-wave alternans and torsade de pointes unmasking the inherited long QT syndrome. Europace. 2008;10:112–113.</ref> [[Antibiotics]],<ref>Kroll CR, Gettes LS. T wave alternans and torsades de pointes after the use of intravenous pentamidine. J Cardiovasc Electrophysiol. 2002;13:936-938.</ref> [[Cancer therapy agents]]<ref>Yamazaki K, Terada H, Satoh H, et al. Arrhythmogenic effects of arsenic trioxide in patients with acute promyelocytic leukemia and an electrophysiological study in isolated guinea pig papillary muscles. Circ J. 2006;70:1407–1414.</ref>
*[[Sleep apnea]]<ref>Takasugi N, Nishigaki K, Kubota T, Tsuchiya K, Natsuyama K, Takasugi M, et al.Sleep apnoea induces cardiac electrical instability assessed by T-wave alternans in patients with congestive heart failure. Eur J Heart Fail 2009;11:1063–70.</ref><ref>Yamada S,Suzuki H,Kamioka M,Suzuki S,Kamiyama Y, Yoshihisa A, et al. Sleep-disordered breathing increases risk for fatal ventricular arrhythmias in patients with chronic heart failure. Circ J 2013;77:1466–73.</ref>


Cardiac arrest
T-wave alternans has also been observed in these conditions


Cardiopulmonary resuscitation
*[[Alcoholic cardiomyopathy]]<ref>Ricketts HH, Denison EK, Haywood LJ. Unusual T-wave abnormality. Repolarization alternans associated with hypomagnesemia, acute alcoholism, and cardiomyopathy. JAMA 1969; 207:365-6.</ref><ref>Luomanmaki K, Heikkila J, Hartikainen M. T-wave alternans associated with heart failure and hypomagnesemia in alcoholic cardiomyopathy. Eur J Cardiol 1975;3:167-70.</ref><ref>Reddy CV, Kiok JP, Khan RG, El-Sherif N. Repolarization alternans associated with alcoholism and hypomagnesemia. Am J Cardiol 1984;53:390-1.</ref>
*[[Epileptic seizure]]<ref>Strzelczyk A, Adjei P, Scott CA, et al. Postictal increase in T-wave alternans after generalized tonic–clonic seizures. Epilepsia 2011 52:2112-2117.</ref><ref>Schomer AC, Nearing BD, Schachter SC, Verrier RL. Vagus nerve stimulation reduces cardiac electrical instability assessed by quantitative T-wave alternans analysis in patients with drug-resistant focal epilepsy.  Epilepsia 2014; 55:1996–2002.</ref>
*[[Hypocalcemia]]<ref>Navarro-Lopez F, Cinca J, Sanz G, Periz A, Magrina J, Betriu A. Isolated T wave alternans. Am Heart J 1978;95:369-74.</ref> <ref>Iwazu Y, Muto S, Ikeuchi S, Yanagiba S, Miyata Y, Asano Y, Kusano E. Reversible hypocalcemic heart failure with T wave alternans and increased QTc dispersion in a patient with chronic renal failure after parathyroidectomy. Clin Nephrol 2006;65:65-70.</ref>
*[[Hypokalemia]]<ref>Ishikawa K, Tateno M. Alternans of the repolarization wave in a case of hypochloremic alkalosis with hypopotassemia. J Electrocardiol 1976;9:75-9.</ref>
*[[Hypomagnesemia]]<ref>Ricketts HH, Denison EK, Haywood LJ. Unusual T-wave abnormality. Repolarization alternans associated with hypomagnesemia, acute alcoholism, and cardiomyopathy. JAMA 1969; 207:365-6.</ref><ref>Luomanmaki K, Heikkila J, Hartikainen M. T-wave alternans associated with heart failure and hypomagnesemia in alcoholic cardiomyopathy. Eur J Cardiol 1975;3:167-70.</ref><ref>Reddy CV, Kiok JP, Khan RG, El-Sherif N. Repolarization alternans associated with alcoholism and hypomagnesemia. Am J Cardiol 1984;53:390-1.</ref>
*[[ICD shocks]]<ref>Lampert R, Soufer R, McPherson CA, et al. Implantable cardioverter-defibrillator shocks increase T-wave alternans. J Cardiovasc Electrophysiol 2007 18:512-517.</ref>
*[[Myocardial scar]]<ref>Mewton N, Strauss DG, Rizzi P, Verrier RL, Liu CY, Tereshchenko LG, Nearing BD, Volpe GJ, Marchlinski FE, Moxley J, Killian T, Wu KC, Spooner P, Lima JAC. Screening for cardiac magnetic resonance scar features by 12-lead ECG in patients with preserved ejection fraction. Ann Noninvasiv Electrocardiol, 2015, in press.</ref>
*[[Pulmonary embolism]]<ref>Tighe DA, Chung EK, Park CH. Electric alternans associated with acute pulmonary embolism. Am Heart J 1994;128:188-90.</ref> <ref>Nichols KB, Littmann L. Electrical alternans as a manifestation of pulmonary embolism. Am J Emerg Med 2011;29:1236.e5-7.</ref>
*[[Quinidine]]<ref>Luca C. Right ventricular monophasic action potential during quinidine induces marked T and U waves abnormalities. Acta Cardiol 1977;32:305-11.</ref>
*[[Renal failure]]<ref>Secemsky EA, Verrier RL, Cooke G, et al: High prevalence of cardiac autonomic dysfunction and T-wave alternans in dialysis patients. Heart Rhythm 2011 8:592-598.</ref>


Electrolyte imbalance
Hypertrophic cardiomyopathy
Hypocalcemia
Hypokalemia
Hypomagnesemia
Pulmonary embolism
Quinidine


==Antiarrhythmic Interventions Reduce TWA Level Allowing TWA to Serve as a Therapeutic Target==
==Antiarrhythmic Interventions Reduce TWA Level Allowing TWA to Serve as a Therapeutic Target==
*[[Antiarrhythmic agents]]<ref>Verrier RL, Nieminen T. T-wave alternans as a therapeutic marker for antiarrhythmic agents. J Cardiovasc Pharmacol 2010; 55(6):544-554</ref>
*[[Antiarrhythmic agents]]<ref>Verrier RL, Nieminen T. T-wave alternans as a therapeutic marker for antiarrhythmic agents. J Cardiovasc Pharmacol 2010; 55(6):544-554</ref>
*[[Vagus nerve]] stimulation in patients with epilepsy <ref> Schomer AC, Nearing BD, Schachter SC, Verrier RL. Vagus nerve stimulation reduces cardiac electrical instability assessed by quantitative T-wave alternans analysis in patients with drug-resistant focal epilepsy.  Epilepsia 2014; 55:1996–2002. </ref>
*[[Vagus nerve]] stimulation in patients with epilepsy<ref>Schomer AC, Nearing BD, Schachter SC, Verrier RL. Vagus nerve stimulation reduces cardiac electrical instability assessed by quantitative T-wave alternans analysis in patients with drug-resistant focal epilepsy.  Epilepsia 2014; 55:1996–2002. </ref>
*[[Spinal cord]] stimulation in patients with ischemic cardiomyopathy <ref>Ferrero P, Castagno D, Massa R, et al. Spinal cord stimulation affects T-wave alternans in patients with ischaemic cardiomyopathy: a pilot study. Europace 2008;10:506–8. </ref>
*[[Spinal cord]] stimulation in patients with ischemic cardiomyopathy<ref>Ferrero P, Castagno D, Massa R, et al. Spinal cord stimulation affects T-wave alternans in patients with ischaemic cardiomyopathy: a pilot study. Europace 2008;10:506–8.</ref>
*[[Beta-adrenergic receptor blockade]] <ref> Klingenheben T, Gronefeld G, Li YG, Hohnloser SH. Effect of metoprolol and d,l-sotalol on microvolt-level T-wave alternans. Results of a prospective, double-blind, randomized study. J Am Coll Cardiol 2001; 38:2013-9. </ref> <ref>Rashba EJ, Cooklin M, Macmurdy K, et al. Effects of selective autonomic blockade on T-wave alternans in humans. Circulation. 2002;105:837–842. </ref> <ref> Komiya N, Seto S, Nakao K, et al. The influence of beta-adrenergic agonists and antagonists on T-wave alternans in patients with and without ventricular tachyarrhythmia. Pacing Clin Electrophysiol. 2005;28:680–684.</ref> <ref> Murata M, Harada M, Shimizu A, et al. Effect of long-term beta-blocker therapy on microvolt-level T-wave alternans in association with the improvement of the cardiac sympathetic nervous system and systolic function in patients with non-ischemic heart disease. Circ J. 2003;67:821–825. </ref><ref> Zacks ES, Morin DP, Ageno S, et al. Effect of oral beta-blocker therapy on microvolt T-wave alternans and electrophysiology testing in patients with ischemic cardiomyopathy. Am Heart J. 2007;153:392–397.</ref><ref>Chan PS, Gold MR, Nallamothu BK. Do beta-blockers impact microvolt T-wave alternans testing in patients at risk for ventricular arrhythmias? A meta-analysis. J Cardiovasc Electrophysiol 2010;21:1009–14.</ref>
*[[Beta-adrenergic receptor blockade]]<ref>Klingenheben T, Gronefeld G, Li YG, Hohnloser SH. Effect of metoprolol and d,l-sotalol on microvolt-level T-wave alternans. Results of a prospective, double-blind, randomized study. J Am Coll Cardiol 2001; 38:2013-9.</ref><ref>Rashba EJ, Cooklin M, Macmurdy K, et al. Effects of selective autonomic blockade on T-wave alternans in humans. Circulation. 2002;105:837–842.</ref><ref>Komiya N, Seto S, Nakao K, et al. The influence of beta-adrenergic agonists and antagonists on T-wave alternans in patients with and without ventricular tachyarrhythmia. Pacing Clin Electrophysiol. 2005;28:680–684.</ref><ref>Murata M, Harada M, Shimizu A, et al. Effect of long-term beta-blocker therapy on microvolt-level T-wave alternans in association with the improvement of the cardiac sympathetic nervous system and systolic function in patients with non-ischemic heart disease. Circ J. 2003;67:821–825. </ref><ref> Zacks ES, Morin DP, Ageno S, et al. Effect of oral beta-blocker therapy on microvolt T-wave alternans and electrophysiology testing in patients with ischemic cardiomyopathy. Am Heart J. 2007;153:392–397.</ref><ref>Chan PS, Gold MR, Nallamothu BK. Do beta-blockers impact microvolt T-wave alternans testing in patients at risk for ventricular arrhythmias? A meta-analysis. J Cardiovasc Electrophysiol 2010;21:1009–14.</ref>
*[[Sodium channel]] blockade <ref> Kavesh NG, Shorofsky SR, Sarang SE, Gold MR. The effect of procainamide on T wave alternans. J Cardiovasc Electrophysiol 1999 May; 10:649-54. </ref> <ref>Murdock DK, Kaliebe J, Overton N. Ranolazine-induced suppression of ventricular tachycardia in a patient with nonischemic cardiomyopathy: a case report. PACE. 2008;31:765–768.</ref>
*[[Sodium channel]] blockade<ref>Kavesh NG, Shorofsky SR, Sarang SE, Gold MR. The effect of procainamide on T wave alternans. J Cardiovasc Electrophysiol 1999 May; 10:649-54.</ref><ref>Murdock DK, Kaliebe J, Overton N. Ranolazine-induced suppression of ventricular tachycardia in a patient with nonischemic cardiomyopathy: a case report. PACE. 2008;31:765–768.</ref>
*[[Angiotensin II receptor]] blockade <ref> Kubo S, Yoshida A, Kitamura H, Yokoyama M. Acute effects of angiotensin II receptor blocker on ventricular repolarization alternans in chronic heart failure. Kobe J Med Sci 2008 Feb 8; 53:365-74. </ref>
*[[Angiotensin II receptor]] blockade<ref>Kubo S, Yoshida A, Kitamura H, Yokoyama M. Acute effects of angiotensin II receptor blocker on ventricular repolarization alternans in chronic heart failure. Kobe J Med Sci 2008 Feb 8; 53:365-74.</ref>
*[[Calcium channel blockade]] in patients with vasospastic angina <ref>Shimada H, Nishizaki M, Fujii H, et al. Ambulatory electrocardiogram-based T-wave alternans in patients with vasospastic angina during asymptomatic periods. Am J Cardiol 2012 110:1446-1451.</ref>
*[[Calcium channel blockade]] in patients with vasospastic angina<ref>Shimada H, Nishizaki M, Fujii H, et al. Ambulatory electrocardiogram-based T-wave alternans in patients with vasospastic angina during asymptomatic periods. Am J Cardiol 2012 110:1446-1451.</ref>
*[[Cardiac exercise rehabilitation]] <ref>Kentta T, Tulppo MP, Nearing BD, Karjalainen JJ, Hautala AJ, Kiviniemi AM, Huikuri HV, Verrier RL.  Effects of exercise rehabilitation on cardiac electrical instability assessed by T-wave alternans during ambulatory electrocardiogram monitoring in coronary artery disease patients without and with diabetes mellitus. Am J Cardiol 2014; 114:832-837.</ref>
*[[Cardiac exercise rehabilitation]]<ref>Kentta T, Tulppo MP, Nearing BD, Karjalainen JJ, Hautala AJ, Kiviniemi AM, Huikuri HV, Verrier RL.  Effects of exercise rehabilitation on cardiac electrical instability assessed by T-wave alternans during ambulatory electrocardiogram monitoring in coronary artery disease patients without and with diabetes mellitus. Am J Cardiol 2014; 114:832-837.</ref>
*[[Amiodarone]]<ref>Groh WJ, Shinn TS, Engelstein EE, et al. Amiodarone reduces the prevalence of T wave alternans in a population with ventricular tachyarrhythmias. J Cardiovasc Electrophysiol. 1999;10:1335–1339.</ref>
*[[Amiodarone]]<ref>Groh WJ, Shinn TS, Engelstein EE, et al. Amiodarone reduces the prevalence of T wave alternans in a population with ventricular tachyarrhythmias. J Cardiovasc Electrophysiol. 1999;10:1335–1339.</ref>


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====Prognostic Value of the Spectral Method====
====Prognostic Value of the Spectral Method====
Over 8000 subjects have been enrolled in Spectral Method studies that predicted outcomes, including the ALPHA study <ref>Salerno-Uriarte JA, De Ferrari GM, Klersy C, Pedretti RF, Tritto M, Sallusti L, Libero L, Pettinati G, Molon G, Curnis A, Occhetta E, Morandi F, Ferrero P, Accardi F; ALPHA Study Group Investigators. Prognostic value of T-wave alternans in patients with heart failure due to nonischemic cardiomyopathy: results of the ALPHA Study. J Am Coll Cardiol. 2007 Nov 6;50(19):1896-904. Epub 2007 Oct 22.</ref> and the ABCD study.<ref> Costantini O, Hohnloser SH, Kirk MM, et al. The ABCD (Alternans Before Cardioverter Defibrillator) trial: strategies using T-wave alternans to improve efficiency of sudden cardiac death prevention. J Am Coll Cardiol 2009;53:471–9 </ref>  An additional 3145 (28% of total) subjects were enrolled in Spectral Method studies that did not predict outcomes, including the SCD-HeFT TWA substudy,<ref>Gold MR, Ip JH, Costantini O, et al. Role of microvolt T-wave alternans in assessment of arrhythmia vulnerability among patients with heart failure and systolic dysfunction: Primary results from the T-wave Alternans Sudden Cardiac Death in Heart Failure Trial substudy. Circulation 2008;118:2022–8.</ref> the MASTER study,<ref>Chow T, Kereiakes DJ, Onufer J, et al. Does microvolt T-wave alternans testing predict ventricular tachyarrhythmias in patients with ischemic cardiomyopathy and prophylactic defibrillators? The MASTER (Microvolt T-wave Alternans Testing for Risk Stratification of Post-Myocardial Infarction Patients) trial. J Am Coll Cardiol 2008; 52:1607–15.</ref> and the CARISMA study. <ref>Huikuri HV, Raatikainen MJ, Moerch-Joergensen R, et al. Prediction of fatal or near-fatal cardiac arrhythmia events in patients with depressed left ventricular function after an acute myocardial infarction. Eur Heart J 2009;30:689–98.</ref>  Withdrawal of beta-blockade to allow patients to attain the 105-110 beats/min target heart rate with its later resumption after the test has been implicated in failure of these studies.<ref>Chan PS, Gold MR, Nallamothu BK. Do beta-blockers impact microvolt T-wave alternans testing in patients at risk for ventricular arrhythmias? A meta-analysis. J Cardiovasc Electrophysiol 2010;21: 1009–14.</ref>
Over 8000 subjects have been enrolled in Spectral Method studies that predicted outcomes, including the ALPHA study <ref>Salerno-Uriarte JA, De Ferrari GM, Klersy C, Pedretti RF, Tritto M, Sallusti L, Libero L, Pettinati G, Molon G, Curnis A, Occhetta E, Morandi F, Ferrero P, Accardi F; ALPHA Study Group Investigators. Prognostic value of T-wave alternans in patients with heart failure due to nonischemic cardiomyopathy: results of the ALPHA Study. J Am Coll Cardiol. 2007 Nov 6;50(19):1896-904. Epub 2007 Oct 22.</ref> and the ABCD study.<ref> Costantini O, Hohnloser SH, Kirk MM, et al. The ABCD (Alternans Before Cardioverter Defibrillator) trial: strategies using T-wave alternans to improve efficiency of sudden cardiac death prevention. J Am Coll Cardiol 2009;53:471–9 </ref>  An additional 3145 (28% of total) subjects were enrolled in Spectral Method studies that did not predict outcomes, including the SCD-HeFT TWA substudy,<ref>Gold MR, Ip JH, Costantini O, et al. Role of microvolt T-wave alternans in assessment of arrhythmia vulnerability among patients with heart failure and systolic dysfunction: Primary results from the T-wave Alternans Sudden Cardiac Death in Heart Failure Trial substudy. Circulation 2008;118:2022–8.</ref> the MASTER study,<ref>Chow T, Kereiakes DJ, Onufer J, et al. Does microvolt T-wave alternans testing predict ventricular tachyarrhythmias in patients with ischemic cardiomyopathy and prophylactic defibrillators? The MASTER (Microvolt T-wave Alternans Testing for Risk Stratification of Post-Myocardial Infarction Patients) trial. J Am Coll Cardiol 2008; 52:1607–15.</ref> and the CARISMA study. <ref>Huikuri HV, Raatikainen MJ, Moerch-Joergensen R, et al. Prediction of fatal or near-fatal cardiac arrhythmia events in patients with depressed left ventricular function after an acute myocardial infarction. Eur Heart J 2009;30:689–98.</ref>  Withdrawal of beta-blockade to allow patients to attain the 105-110 beats/min target heart rate with its resumption after the test have been implicated in failure of these studies.<ref>Chan PS, Gold MR, Nallamothu BK. Do beta-blockers impact microvolt T-wave alternans testing in patients at risk for ventricular arrhythmias? A meta-analysis. J Cardiovasc Electrophysiol 2010;21: 1009–14.</ref>


===Modified Moving Average (MMA) Method===
===Modified Moving Average (MMA) Method===
Line 97: Line 93:
Watch the video "TWA Analysis in Ambulatory ECG recording - Tutorial" to learn how to analyze TWA using the Modified Moving Average (MMA) Method. Click
Watch the video "TWA Analysis in Ambulatory ECG recording - Tutorial" to learn how to analyze TWA using the Modified Moving Average (MMA) Method. Click


[[
[[Media:Excel_Model_for_TWA_analysis.xls|here‎]]
 
Media:Excel_Model_for_TWA_analysis.xls|here‎]]


to obtain the excel file with the formulas mentioned in the video. For more details, see the following from [http://www.gehealthcare.com/euen/cardiology/docs/T-Wave_Alternans.pdf GE Healthcare, Inc.]
to obtain the excel file with the formulas mentioned in the video. For more details, see the following from [http://www.gehealthcare.com/euen/cardiology/docs/T-Wave_Alternans.pdf GE Healthcare, Inc.]
Line 107: Line 101:
====Interpreting Results of Modified Moving Average Method====
====Interpreting Results of Modified Moving Average Method====


Higher TWA values indicate greater risk for sudden cardiac death and cardiovascular and total mortality along a continuum.<ref>Minkkinen M, Kahonen M, Viik J, et al. Enhanced predictive power of quantitative TWA during routine exercise testing in the Finnish Cardiovascular Study. J Cardiovasc Electrophysiol 2009;20:408 –15.</ref> TWA <20µV indicates no increased risk, while TWA ≥47µV and ≥60µV are associated with abnormal and severely abnormal risk, respectively.<ref>Verrier RL, Klingenheben T, Malik M, El-Sherif N, Exner D, Hohnloser S, Ikeda T, Martinez JP, Narayan S, Nieminen T, Rosenbaum DS. Microvolt T-wave alternans: Physiologic basis, methods of measurement, and clinical utility. Consensus guideline by the International Society for Holter and Noninvasive Electrocardiology. J Am Coll Cardiol 2011; 44:1309-1324.</ref>  Quantification allows physicians to track disease progression as well as patients' response to medications and to cardiac rehabilitation.  Fewer than 3% of tests are indeterminate.
Higher TWA values indicate greater risk for sudden cardiac death and cardiovascular and total mortality along a continuum.<ref>Minkkinen M, Kahonen M, Viik J, et al. Enhanced predictive power of quantitative TWA during routine exercise testing in the Finnish Cardiovascular Study. J Cardiovasc Electrophysiol 2009;20:408 –15.</ref> TWA <20µV indicates no increased risk, while TWA ≥47µV and ≥60µV are associated with abnormal and severely abnormal risk, respectively.<ref>Verrier RL, Klingenheben T, Malik M, El-Sherif N, Exner D, Hohnloser S, Ikeda T, Martinez JP, Narayan S, Nieminen T, Rosenbaum DS. Microvolt T-wave alternans: Physiologic basis, methods of measurement, and clinical utility. Consensus guideline by the International Society for Holter and Noninvasive Electrocardiology. J Am Coll Cardiol 2011; 44:1309-1324.</ref>  Quantification allows physicians to track disease progression as well as patients' response to medications and to cardiac rehabilitation.  Fewer than 3% of MMA-based TWA tests are indeterminate.


====Prognostic Value of Modified Moving Average Method====
====Prognostic Value of Modified Moving Average Method====

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Editors-In-Chief: Richard L. Verrier, PhD, FACC, FHRS, and Tuomo Nieminen, MD, PhD; Assistant Editors-in-Chief: Jose Roberto Pegler, MD, and Caio Tavares, MD.

Overview

T-wave alternans is a beat-to-beat alternation in the repolarization cycle of the heartbeat. It can be observed in the electrocardiogram (ECG) as a difference in the amplitude and morphology of the ST-segment and/or the T wave among successive odd and even beats in an ABAB pattern (Figure).

T Wave Alternans

(Reprinted with permission from John Wiley & Sons, Inc., from [1]) This patient's peak TWA level was 124 microvolts, indicating severely abnormal risk. He died 12 months later of cardiovascular causes.

Interest is focused on this phenomenon because of its utility in identifying individuals with elevated risk for lethal heart rhythm disturbances and sudden cardiac death, the leading cause of death in the industrially developed world. In the video, the ABAB pattern of TWA heralds the onset of ventricular fibrillation during myocardial ischemia. The arrhythmia was successfully terminated by defibrillation countershock.

{{#ev:youtube|ZSJB3sB5Oi0}}

History of T Wave Alternans

Hering, in 1908, was the first to observe and describe visible macroscopic TWA and its association with increased susceptibility to ventricular tachyarrhythmias.[2] The advent of digital signal processing techniques allowed identification and measurement of nonvisible levels of TWA.

Causes

The integrated physiology and cellular basis for the T-wave alternans phenomenon has been extensively discussed. [3][4][5][6][7][8]

Clinical Utility

T-wave alternans predicts arrhythmia, sudden cardiac death, or cardiovascular or total mortality in these patient groups:

T-wave alternans is associated with ventricular arrhythmias in these patient groups:

T-wave alternans has also been observed in these conditions


Antiarrhythmic Interventions Reduce TWA Level Allowing TWA to Serve as a Therapeutic Target

Differentiating Electrical Alternans from other Disorders

The electrical form of alternans should be differentiated from mechanical alternans, which exhibits alternation of the strength of the pulse as is observed in pulsus alternans. Electrical and mechanical alternans may coexist.

Microvolt TWA and Test Methods

In the 1980’s, Drs. Richard J. Cohen, Joseph M. Smith, David S. Rosenbaum, and colleagues at Massachusetts Institute of Technology and Massachusetts General Hospital [88] [89] and Drs. Richard L. Verrier and Bruce D. Nearing at Georgetown University School of Medicine and later at Beth Israel Deaconess Medical Center, Harvard Medical School, [90] [91] applied signal processing techniques to detect visually indiscernible levels of TWA and established that at a microvolt level, TWA discloses risk for lethal cardiac arrhythmias and sudden cardiac death.

Two techniques for TWA analysis currently cleared by the United States Food and Drug Administration for risk stratification for arrhythmic death are the Spectral Method, which emanated from Dr. Cohen’s laboratory and was commercialized by Cambridge Heart, Inc. and Cambridge Cardiac Technologies; and the Modified Moving Average method, which resulted from Drs. Verrier and Nearing’s collaboration and is commercialized by GE Healthcare, Inc. and in Europe by Getemed AG.

Spectral Method (SM)

The Fast Fourier Transform is employed to analyze 128 consecutive beats from the J-point to the end of the T wave and produces a power spectrum at 0.5 cycle/beat (on every other beat), which is defined as the alternans power. Since the Spectral Method requires a graded heart-rate increase to a target heart rate, it is usually performed during bicycle ergometry or treadmill exercise. Specialized electrodes are required for noise reduction.

Interpreting Results of Spectral Method

If the TWA level calculated by the Spectral Method exceeds 1.9µV, then the test is considered positive.[92] These patients should be referred to a cardiac electrophysiologist for further evaluation. Results below 1.9µV are interpreted as negative. Several prospective studies have demonstrated that a negative TWA test result with the Spectral Method confirms a low level of risk for an arrhythmic episode, since the test displays a negative predictive value ≥97% [93] [94] indicating that a negative test correctly identifies ≥97% of patients with diminished risk of developing a lethal cardiac arrhythmia or sudden cardiac death during the next year to two years. Test results may be indeterminate for technical reasons (noise from muscle, respiration, or movement artifact) or because of patient factors (inability to reach a target heart rate of 105-110 beats/min, excessive ectopy, or nonsustained TWA). Indeterminate test results due to patient factors indicate a level of the risk that is equivalent to a positive test result[95] and these patients should be immediately retested.

Prognostic Value of the Spectral Method

Over 8000 subjects have been enrolled in Spectral Method studies that predicted outcomes, including the ALPHA study [96] and the ABCD study.[97] An additional 3145 (28% of total) subjects were enrolled in Spectral Method studies that did not predict outcomes, including the SCD-HeFT TWA substudy,[98] the MASTER study,[99] and the CARISMA study. [100] Withdrawal of beta-blockade to allow patients to attain the 105-110 beats/min target heart rate with its resumption after the test have been implicated in failure of these studies.[101]

Modified Moving Average (MMA) Method

This approach employs the noise-rejection principle of recursive averaging.[102] It was designed to allow TWA measurement during routine, symptom limited exercise stress testing and ambulatory ECG monitoring, as it circumvents the requirement to stabilize heart rate. It uses standard electrodes at precordial sites. Chronic medications are maintained. Thus, TWA testing with the MMA method can be performed in the flow of clinical evaluation. Specifically, the algorithm continuously streams odd and even beats into separate bins and creates median complexes for each bin. The complexes are then superimposed and the peak difference between the odd and even median complexes at any point from the J point to the end of the T wave is the TWA level; this determination is updated every 10 to 15 seconds. The influence of new incoming beats is controlled by an adjustable update factor; the sensitive 1/8 update factor is recommended. Artifacts due to respiration and motion are reduced by software. High-resolution templates of superimposed beats display the alternation pattern and permit visual overreading to verify the automated TWA measurement.

Watch the video "TWA Analysis in Ambulatory ECG recording - Tutorial" to learn how to analyze TWA using the Modified Moving Average (MMA) Method. Click

here‎

to obtain the excel file with the formulas mentioned in the video. For more details, see the following from GE Healthcare, Inc.

{{#ev:youtube|-oC3GLoFXFo}}

Interpreting Results of Modified Moving Average Method

Higher TWA values indicate greater risk for sudden cardiac death and cardiovascular and total mortality along a continuum.[103] TWA <20µV indicates no increased risk, while TWA ≥47µV and ≥60µV are associated with abnormal and severely abnormal risk, respectively.[104] Quantification allows physicians to track disease progression as well as patients' response to medications and to cardiac rehabilitation. Fewer than 3% of MMA-based TWA tests are indeterminate.

Prognostic Value of Modified Moving Average Method

The MMA method has been endorsed by the International Society for Holter and Noninvasive Electrocardiology.

Over 5000 patients have been enrolled in MMA studies. The largest investigation of TWA by any method is the Finnish Cardiovascular Study (FINCAVAS), which enrolled >3500 generally low-risk patients who were referred for routine, symptom-limited exercise testing.[105] Approximately 1500 patients were studied during ambulatory ECG monitoring.[106] All MMA-based TWA studies have predicted outcomes. A trial of MTWA-guided ICD implantation by the MMA method, REFINE-ICD (NCT00673842), is underway.[107]

Comparison of Spectral and Modified Moving Average Methods

The MTWA consensus guideline, authored by 11 international experts in both methods, compared the methods and their utility in risk assessment [108] and established that hazard ratios for sudden cardiac death and cardiovascular mortality in all prospective studies were similar. A head-to-head prospective comparison of the Spectral and MMA methods in >300 post-myocardial infarction patients revealed similar hazard ratios, kappa statistics, and areas under the receiver-operator characteristic curve.[109]

The U.S. FDA has determined that both the Spectral and MMA methods achieve 1-microvolt resolution.

TWA values reported by MMA are typically 4- to 10-fold higher than Spectral Method test results. This difference is mainly attributable to the fact that the Spectral Method reports the average TWA level across the entire JT segment for 128 beats, whereas the MMA method reports the peak TWA value for each 15 seconds at any point within the JT interval.

Clinical Significance

MTWA testing has been recommended for arrhythmia risk assessment by the American College of Cardiology, American Heart Association and European Society of Cardiology [110] and by CMS in National Coverage Analysis for Implantable Cardioverter Defibrillators (CAG-00157N).

One proposed application of TWA testing has been to identify patients who would not benefit from implantation of an ICD,which rescues patients from a lethal arrhythmia. The current guidelines for ICD implantation state that the main parameter to be analyzed is left ventricular ejection fraction, a parameter that does not directly reveal information about the electrical substrate of the heart.

A second proposed application of TWA testing is in guiding medical therapy, since many agents that have been shown to reduce incidence of arrhythmias, sudden cardiac death, or cardiovascular mortality also diminish TWA magnitude. Thus, drug-induced changes in TWA magnitude may provide an indication of therapeutic efficacy on an individual patient basis.

Frontiers of TWA testing include risk stratification among patients with preserved ejection fraction, the patient group with the highest number of sudden cardiac deaths, and combined use with other noninvasive risk markers.

Reimbursement for T-Wave Alternans Testing

The 2006 decision summary from the U.S. Center for Medicare and Medicaid Services regarding reimbursement for T-wave alternans testing (CAG-00293N) states: “CMS has determined that there is sufficient evidence to conclude that Microvolt T-wave Alternans (MTWA) diagnostic testing is reasonable and necessary for the evaluation of patients at risk of sudden cardiac death, only when the spectral analytic method is used, and CMS is issuing the following national coverage determination (NCD) for this indication. Microvolt T-wave Alternans (MTWA) diagnostic testing is covered for the evaluation of patients at risk of sudden cardiac death, only when the spectral analytic method is used.”

A 2015 CMS decision memo regarding the MMA method for MTWA analysis (CAG-00293R2) states: “The Centers for Medicare & Medicaid Services has decided that no National Coverage Determination (NCD) is appropriate at this time for microvolt T-wave alternans (MTWA) testing using the modified moving average (MMA) method for the evaluation of patients at risk for sudden cardiac death (SCD). National non-coverage will be removed. Medicare coverage of MTWA using the MMA method will be determined by the local contractors.”

Both methods use CPT code 93025.

References

  1. ↑ Minkkinen et al, “Enhanced predictive power of quantitative TWA during routine exercise testing in the Finnish Cardiovascular Study,” published in J Cardiovasc Electrophysiol 2009; 20: 408-415.
  2. ↑ Hering HE. Das Wesen des Herzalternans. Muenchener Med Wochenschr 1908; 4:1417-1421.
  3. ↑ Narayan SM. T-wave alternans and the susceptibility to ventricular arrhythmias. J Am Coll Cardiol 2006;47:269–81.
  4. ↑ Cutler MJ, Rosenbaum DS. Explaining the clinical manifestations of T-wave alternans in patients at risk for sudden cardiac death. Heart Rhythm 2009;6:S22–8.
  5. ↑ Verrier RL, Kumar K, Nearing BD. Basis for sudden cardiac death prediction by T-wave alternans from an integrative physiology perspective. Heart Rhythm 2009;6:416 –22.
  6. ↑ Weiss JN, Nivala M, Garfinkel A, Qu Z. Alternans and arrhythmias:from cell to heart. Circ Res 2011;108:98 –112.
  7. ↑ Clusin WT. Mechanisms of calcium transient and action potential alternans in cardiac cells and tissues. Am J Physiol Heart Circ Physiol 2008;294:H1–10.
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