T-Wave Alternans

Number: 0579

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses T-Wave Alternans.

1. Medical Necessity

   Aetna considers microvolt T-wave alternans (MTWA) diagnostic testing using the spectral analytic method medically necessary for the evaluation of persons at risk of sudden cardiac death who meet criteria for implantable cardioverter-defibrillator placement.  

2. Experimental and Investigational

   Microvolt T-wave alternans (MTWA) is considered experimental and investigational for the following indications (not an all-inclusive list) because the effectiveness of this approach for these indications has not been established:

   1. MTWA diagnostic testing using the spectral analytic method for all other indications not listed in Section I including the following (not an all-inclusive list):
      
      
      1. Diagnosis and risk assessment of acute coronary syndrome
      2. Diagnosis of reversible myocardial ischemia in individuals without structural heart disease
      3. Evaluation of non-pathological preterm infants
      4. Evaluation of children and adolescents with Eisenmenger syndrome
      5. Evaluation of malignant ventricular arrhythmias in Chagas disease
      6. Evaluation of the adequacy of medical therapy
      7. Guidance of anti-arrhythmic therapy
      8. Judgement of the severity of ischemic cardiomyopathy
      9. Prediction of major adverse cardiac events in ischemic heart failure
      10. Prediction of post-operative mortality in cardiac surgery
      11. Prognosis of myocardial function in newborns with hypoxic-ischemic encephalopathy
      12. Prognosis of pulmonary arterial hypertension
      13. Risk assessment of sudden cardiac death in children with chronic renal failure
      14. Risk stratification of cardiac events (e.g., sudden cardiac death) in members following repair of tetralogy of Fallot
      15. Risk stratification in Brugada syndrome
      16. Tracking changes in risk during cardiac disease progression;
          
          
   2. MTWA combined with electrophysiologic study for prediction of ventricular tachyarrhythmias in individuals with arrhythmogenic right ventricular cardiomyopathy.

3. Related Policies

   • CPB 0585 - Cardioverter-Defibrillators

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
CPT codes covered if selection criteria are met:
93025	Microvolt T-wave alternans for assessment of ventricular arrhythmias [not covered for the diagnosis and risk assessment of acute coronary syndrome and guiding anti-arrhythmic therapy]
Other CPT codes related to the CPB:
93000 - 93010	Electrocardiogram
93224	External electrocardiographic recording up to 48 hours by continuous rhythm recording and storage; includes recording, scanning analysis with report, review and interpretation by a physician or other qualified health care professional
93225	recording (includes connection, recording, and disconnection)
93226	scanning analyis with report
93278	Signal-averaged electrocardiography (SAECG), with or without ECG
93600 - 93662	Intracardiac electrophysiological procedures/studies
ICD-10 codes covered if selection criteria are met:
I42.0 - I42.2 I42.5 I42.8 - I42.9	Other and unspecified cardiomyopathies
I46.2 - I46.9	Cardiac arrest [not covered guiding anti-arrhythmic therapy]
I47.0 - I47.9	Paroxysmal tachycardia [not covered guiding anti-arrhythmic therapy]
I49.01	Ventricular fibrillation [not covered guiding anti-arrhythmic therapy]
I49.02	Ventricular flutter [not covered guiding anti-arrhythmic therapy]
I49.2	Junctional premature depolarization
I49.3	Ventricular premature depolarization
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
B57.0 - B57.5	Chagas' disease
I20.0 - I25.9	Ischemic Heart Disease [including Ischemic Heart Failure]
I25.110, I25.112, I25.700, I25.702, I25.710, I25.712, I25.720, I25.722, I25.730, I25.732, I25.750, I25.752, I25.760, I25.762, I25.790, I25.792	Atherosclerotic heart disease with unstable angina pectoris
I27.0	Primary pulmonary hypertension
I27.83	Eisenmenger's syndrome
I48.0 - I48.1, I49.1, I49.40 - I49.9	Other cardiac arrhythmias [other than tachycardia, ventricular fibrillation, ventricular flutter, and cardiac arrest] [Brugada syndrome]
N18.1 - N18.9	Chronic kidney disease (CKD) [not covered for risk assessment of sudden cardiac death in children]
P07.00 - P07.03	Extremely low birth weight newborn
P07.10 - P07.18	Other low birth weight newborn
P07.20 - P07.26	Extreme immaturity of newborn
P07.30 - P07.39	Preterm [premature] newborn [other]
P91.60 - P91.63	Hypoxic ischemic encephalopathy [HIE]
Q21.3	Tetralogy of Fallot [not covered for risk stratification of cardiac events e.g., sudden cardiac death]
R00.1	Bradycardia, unspecified
Z13.6	Encounter for screening for cardiovascular disorders
Z98.890	Other specified postprocedural states [prediction of post-operative mortality in cardiac surgery]

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Background

The term alternans applies to conditions characterized by the sudden appearance of a periodic beat-to-beat change in some aspect of cardiac electrical or mechanical behavior.  Many different examples of electrical alternans have been described clinically; a number of others have been reported in the laboratory. 

T-wave alternans has long been recognized as a marker of electrical instability in acute ischemia, where it may precede ventricular tachyarrhythmia.  Studies have shown that T wave (or ST-T) alternans can also precede non-ischemic ventricular tachyarrhythmias.  Considerable interest has recently been shown in the detection of microvolt T wave alternans as a noninvasive marker of the risk of ventricular tachyarrhythmia in patients with chronic heart disease.

Assessment of left ventricular ejection fraction (LVEF), Holter monitoring, and signal-averaged late potentials are the principal non-invasive means of determining the risk of ventricular arrhythmias after myocardial infarction (MI).  However, these measures of vulnerability to arrhythmias have been found to be less predictive of arrhythmic events than invasive electrophysiologic testing.

Microvolt T-wave alternans testing is performed by placing high-resolution electrodes, designed to reduce electrical interference, on a patient’s chest prior to a period of controlled exercise (CMS, 2005).  These electrodes detect tiny beat-to-beat changes, on the order of one-millionth of volt, in the electrocardiogram (EKG) T-wave.  Spectral analysis is used to calculate these minute voltage changes.  Spectral analysis is a sensitive mathematical method of measuring and comparing time and the electrocardiogram signals.  Software then analyzes these microvolt changes and produces a report to be interpreted by a physician.

T-wave alternans has primarily been used for defining the risk of ventricular arrhythmias in persons at risk for sudden cardiac death and determining which patients are most likely to benefit from implantable cardioverter-defibrillators.  Cambridge Heart, Inc. (Fort Lauderdale, FL) Cardiac Diagnostic System Model CH 2000, which measures T-wave alternans at rest and with exercise, was cleared by the Food and Drug Administration (FDA) based on an 510(k) application.

A decision memorandum from the Centers for Medicare and Medicaid Services (CMS, 2006) found that the quality of evidence is adequate to conclude that microvolt T-wave alternans testing using a spectral analysis algorithm can improve net health outcomes, and is reasonable and necessary for Medicare patients who are candidates for implantable cardioverter defibrillator (ICD) placement.  The decision memorandum explained that the reviewed literature contains a number of studies evaluating the use of microvolt T-wave alternans (MTWA) in a variety of population settings, including subjects with congestive heart failure (CHF), ischemic CHF, non-ischemic CHF, dilated cardiomyopathy, hypertrophic cardiomyopathy, post-MI, and in healthy subjects.  The decision memorandum noted that the material reviewed included not only small prospective studies with a homogenous patient population, but also large systematic reviews with heterogeneous patient populations.  Also included in the CMS analysis were studies that looked specifically at MTWA's role as a risk stratification tool in patient populations similar to those in pivotal clinical studies of implantable cardioverter-defibrillators.

The decision memorandum noted that most of the studies used in CMS’ assessment of MTWA included measures of diagnostic accuracy (e.g., sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) (CMS, 2006).  CMS found that, when reviewing these measures of accuracy, MTWA testing demonstrated superior findings related to sensitivity and NPV when compared to other diagnostic tests used to assess risk of ventricular tachyarrhythmias.

The CMS decision memorandum stated that “[a]cross a number of population settings, MTWA [microvolt T-wave alternans] consistently demonstrates superiority when compared to other diagnostic measures that assess risk of VTEs [ventricular tachyarrhythmic events].  Though some of the studies noted some limitations related to methodology as well as research design, these limitations were not enough to invalidate their findings” (CMS, 2006).

The CMS decision memorandum commented on a technology assessment of MTWA published by the BlueCross BlueShield Association (BCBSA) Technology Evaluation Center (TEC).  The TEC assessment concluded that that “[t]he available evidence on MTWA is insufficient to permit conclusions regarding the effect on health outcomes.”  Regarding use of MTWA in evaluating subjects eligible for placement of an implantable cardioverter defibrillator given current patient selection criteria, the TEC assessment stated that the available evidence is limited (BCBSA, 2005). 

The CMS decision memorandum explained that differences in the conclusions of the TEC assessment and CMS analysis are due, in part, to the unique characteristics of the Medicare-eligible population (i.e. elderly, and more likely to have multiple co-morbidities) (CMS, 2006).  The decision memorandum explained that sudden cardiac death has a higher potential to occur as a result of ventricular tachyarrhythmias in this population.  The decision memorandum explained that potential harms from adverse events are also more likely to occur within this population.  The CMS decision memorandum stated that “[b]ecause of these features of the Medicare population, the potential for benefit or harm from ICD placement varies from that of the BCBSA population at large, and plays a prominent role in our decision making.”  The decision memorandum also noted that indications for ICD placement also differ between the 2 organizations.  “Because of the higher potential for VTE occurrence in the Medicare population, and because CMS recognizes VTEs as an indication for ICD placement, CMS feels that the use of MTWA is reasonable and necessary to address problems related to VTE and its adverse consequences.”

The CMS decision memorandum concluded that MTWA is a useful risk stratification tool and can identify which heart patients are at negligible risk of sudden death, and who may therefore be able to avoid implantable cardioverter defibrillator placement and its attendant risks (CMS, 2006).

The CMS decision memorandum states that MTWA testing is only covered when the spectral analytic method is used (CMS, 2006) because the evidence only supports the use of this algorithm for the detection of MTWA.  The decision memorandum explained that, although algorithms other than spectral analysis have been used to measure MTWA (e.g., modified moving average), CMS identified no peer-reviewed published articles discussing these other algorithms.

It has also been suggested that MTWA testing may be useful in determining the types and doses of medications (e.g., angiotensin converting enzyme inhibitors, beta-blockers, aldosterone antagonists) used to treat underlying cardiac conditions (e.g., left ventricular dysfunction, patients with recent MI) and to suppress arrhythmias.  However, there are no prospective clinical studies of the use of MTWA testing in adjusting pharmacotherapy.

Verrier and Nieminen (2010) stated that over 100 studies enrolling a total of more than 12,000 patients support the predictivity of TWA testing for cardiovascular mortality and sudden cardiac death during both exercise and ambulatory electrocardiogram monitoring.  To date, the main intended application has been to aid decision-making for cardioverter-defibrillator implantation.  The prospect that TWA could be used to guide pharmacologic therapy has not received adequate attention.  These investigators reviewed the literature supporting the utility of TWA as a therapeutic marker of anti-arrhythmic effects and pro-arrhythmia for each of the major anti-arrhythmic drug classes.  Beta-adrenergic and sodium channel blocking agents are the most widely studied drug classes in clinical TWA investigations, which report reductions in TWA magnitude.  Patients with Brugada syndrome constitute a significant exception, because sodium channel blockade provokes the diagnostic electrocardiogram changes as well as macroscopic TWA.  Calcium channel blockers have undergone extensive research in several animal models, but, surprisingly, no clinical studies on TWA with this class of drugs have been performed.  Interestingly, TWA may help to detect the beneficial effects of non-antiarrhythmic agents such as the angiotensin II receptor blocker valsartan, which exert their protective effects through putative indirect actions on myocardial remodeling.  There is also suggestive evidence that the pro-arrhythmic effects associated with cardiovascular and non-cardiovascular agents may be disclosed by elevated levels of TWA.  Thus, the emerging collective evidence indicates the broad utility of TWA in estimating anti-arrhythmic and pro-arrhythmic effects of diverse agents across differing pathologies.  The authors concluded that quantitative analysis of TWA has considerable potential to guide pharmacologic therapy.

Gold et al (2008) noted that sudden cardiac death remains a leading cause of mortality despite advances in medical treatment for the prevention of ischemic heart disease and heart failure.  Recent studies showed a benefit of implantable cardioverter-defibrillator implantation, but appropriate shocks for ventricular tachyarrhythmias were noted only in a minority of patients during 4 to 5 years of follow-up.  Accordingly, better risk stratification is needed to optimize patient selection.  In this regard, MTWA has emerged as a potentially useful measure of arrhythmia vulnerability, but it has not been evaluated previously in a prospective, randomized trial of implantable cardioverter-defibrillator therapy.  This investigation was a prospective substudy of the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) that included 490 patients at 37 clinical sites.  Microvolt T-wave alternans tests were classified by blinded readers as positive (37 %), negative (22 %), or indeterminate (41 %) by standard criteria.  The composite primary end point was the first occurrence of any of the following events:

1. sudden cardiac death,
2. sustained ventricular tachycardia/fibrillation, or
3. appropriate implantable cardioverter-defibrillator discharge. 

During a median follow-up of 30 months, no significant differences in event rates were found between MTWA-positive or MTWA-negative patients (hazard ratio 1.24, 95 % confidence interval [CI]: 0.60 to 2.59, p = 0.56) or MTWA-negative and non-negative (positive and indeterminate) subjects (hazard ratio 1.28, 95 % CI: 0.65 to 2.53, p = 0.46).  Similar results were obtained with the inclusion or exclusion of patients randomized to amiodarone in the analyses.  The authors concluded that MTWA testing did not predict arrhythmic events or mortality in SCD-HeFT, although a small reduction in events (20 % to 25 %) among MTWA-negative patients can not be excluded given the sample size of this study.  Accordingly, these results suggested that MTWA is not useful as an aid in clinical decision making on implantable cardioverter-defibrillator therapy among patients with heart failure and left ventricular systolic dysfunction.

Scirica (2010) stated that although there are many established tools for diagnosis, prognosis, and clinical decision making for acute coronary syndrome, understanding the advantages and limitations of each tool according the clinical scenario is essential.  Several emerging tools, such as novel biomarkers (e.g., high-sensitivity troponin and growth differential factor-15), electroencephalogrphic (ECG) techniques (e.g., heart rate turbulence or TWA), and imaging modalities (computed tomography angiography and cardiac magnetic resonance) may potentially improve clinical care; however, they must be fully evaluated and validated in different scenarios and patient cohorts before they are incorporated into clinical practice.

On behalf of the International Society for Holter and Noninvasive Electrocardiology (and co-sponsored by the Japanese Circulation Society, the Computers in Cardiology Working Group on e-Cardiology of the European Society of Cardiology, and the European Cardiac Arrhythmia Society), Verrier et al (2011) prepared a consensus guideline on the electrocardiographic phenomenon of TWA.  This statement focused on its physiological basis and measurement technologies and its clinical utility in stratifying risk for life-threatening ventricular arrhythmias.  Signal processing techniques including the frequency-domain spectral method and the time-domain modified moving average method have demonstrated the utility of TWA in arrhythmia risk stratification in prospective studies in  more than 12,000 patients.  The majority of exercise-based studies using both methods have reported high relative risks for cardiovascular mortality and for sudden cardiac death in patients with preserved as well as depressed LVEF.  Studies with ambulatory electrocardiogram-based TWA analysis with modified moving average method have yielded significant predictive capacity.  However, negative studies with the spectral method have also appeared, including 2 interventional studies in patients with implantable defibrillators.  Meta-analyses have been performed to gain insights into this issue.  Frontiers of TWA research include use in arrhythmia risk stratification of individuals with preserved ejection fraction, improvements in predictivity with quantitative analysis, and utility in guiding medical as well as device-based therapy.  The authors concluded that although TWA appears to be a useful marker of risk for arrhythmic and cardiovascular death, there is as yet no definitive evidence from interventional trials that it can guide therapy. 

In a meta-analysis, Chen et al (2013) systematically reviewed current literature to determine the ability of MTWA to predict the outcome severity following ischemic cardiomyopathy (ICM).  Major endpoints include composite endpoint of cardiac mortality and severe arrhythmic events in primary prevention of patients with ICM, as well as all-cause mortality (cardiac death, and/or non-cardiac death).  A total of 7 trials were included by using MTWA for risk stratification of cardiac events in 3,385 patients with ICM. All patients were distributed into two groups according to the results of MTWA tests: non-negative group included positive and indeterminate, and negative group. Compared with the negative group, non-negative group showed increased rates of cardiac mortality or severe arrhythmic events (RR = 1.65, 95 % CI: 1.32 to 2.071), sudden cardiac death (SCD) (RR = 2.04 95 % CI: 1.11 to 3.75), and all-cause mortality (RR = 2.11, 95 % CI: 1.60 to 2.79).  The funnel plot revealed that there might be bias within current publications.  The fail-safe number of composite endpoint and all-cause mortality was 14.42 and 18.93, respectively (when p = 0.01).  The fail-safe number of SCD was 1.07 (when p = 0.05), which may be caused by the small case number of included studies and some patients with ICD included.  The authors concluded that the non-negative group of MTWA had a nearly double risk of severe outcomes compared with the negative group.  Therefore, MTWA represents a potential useful tool for judging the severity of ICM.

Quan and associates (2014) stated that exercise-based spectral TWA has been proposed as a non-invasive tool for identifying patients at risk of SCD and cardiac mortality.  Prior studies have indicated that ambulatory electrocardiogram (AECG)-based TWA is an important alternative platform to exercise for risk stratification of cardiac events.  These investigators reviewed data regarding 24-hour AECG-based TWA and discussed its potential role in risk stratification of fatal cardiac events across a series of patient risk profiles.  Prospective clinical studies of the predictive value of AECG-based TWA obtained with daily activity published between January 1990 and November 2014 were retrieved.  Major end-points included composite end-point of SCD, cardiac mortality, and severe arrhythmic events.  Data were accumulated from 5 studies involving a total of 1,588 patients, including 317 positive and 1,271 negative TWA results.  Compared with the negative group, positive group showed increased rates of SCD (hazard ratio [HR]: 7.49, 95 % CI: 2.65 to 21.15), cardiac mortality (HR: 4.75, 95 % CI: 0.42 to 53.55), and composite end-point (SCD, cardiac mortality, and severe arrhythmic events, HR: 5.94, 95 % CI: 1.80 to 19.63).  For the 4 studies evaluating TWA measured using the modified moving average method, the HR associated with a positive versus negative TWA result was 9.51 (95 % CI: 4.99 to 18.11) for the composite end-point.  The authors concluded that the positive group of AECG-based TWA has a nearly 6-fold risk of severe outcomes compared with the negative group.  Therefore, AECG-based TWA provided an accurate means of predicting fatal cardiac events.

Goldberger and colleagues (2014) performed a meta-analysis to estimate the performance of 12 commonly reported risk stratification tests as predictors of arrhythmic events in patients with non-ischemic dilated cardiomyopathy.  A total of 45 studies enrolling 6,088 patients evaluating the association between arrhythmic events and predictive tests (baroreflex sensitivity, heart rate turbulence, heart rate variability, left ventricular end-diastolic dimension, LVEF, electrophysiology study, non-sustained ventricular tachycardia, left bundle branch block, signal-averaged electrocardiogram, fragmented QRS, QRS-T angle, and TWA) were included.  Raw event rates were extracted, and meta-analysis was performed using mixed effects methodology.  They also used the trim-and-fill method to estimate the influence of missing studies on the results.  Patients were 52.8 ± 14.5 years of age, and 77 % were male; LVEF was 30.6 ± 11.4 %.  Test sensitivities ranged from 28.8 % to 91.0 %, specificities from 36.2 % to 87.1 %, and odds ratios (OR) from 1.5 to 6.7.  Odds ratio was highest for fragmented QRS and TWA (OR: 6.73 and 4.66, 95 % CI: 3.85 to 11.76 and 2.55 to 8.53, respectively) and lowest for QRS duration (OR: 1.51, 95 % CI: 1.13 to 2.01).  None of the autonomic tests (heart rate variability, heart rate turbulence, baroreflex sensitivity) was significant predictors of arrhythmic outcomes.  Accounting for publication bias reduced the OR for the various predictors but did not eliminate the predictive association.  The authors concluded that techniques incorporating functional parameters, depolarization abnormalities, repolarization abnormalities, and arrhythmic markers provided only modest risk stratification for SCD in patients with non-ischemic dilated cardiomyopathy.  It is likely that combinations of tests will be needed to optimize risk stratification in this population.

An UpToDate review on “T wave (repolarization) alternans: Clinical aspects” (Narayan, 2015) states that “Major society guidelines -- The major limitation to implementation of TWA protocols is that specific guidance is not available on how to use TWA in clinical practice.  In addition, the optimum measurement conditions and criteria for detecting TWA remain controversial.  We agree with the 2008 American Heart Association/American College of Cardiology/Heart Rhythm Society (AHA/ACC/HRS) scientific statement on noninvasive risk stratification, which concluded that a moderate amount of data suggest that TWA may be useful for risk stratification for SCD, but that further information will be needed to determine the clinical applicability of this test”.

Risk Stratification of Sudden Cardiac Death following Repair of Tetralogy of Fallot

Cheung et al (2002) stated that sustained MTWA is a marker of increased risk for malignant ventricular arrhythmia (VA).  There is a significant risk of arrhythmia and sudden death after repair of congenital heart disease.  These researchers determined the prevalence and characteristics of TWA after repair of tetralogy of Fallot (TOF). T-wave alternans was evaluated during bicycle exercise in 49 subjects who had consecutively undergone transatrial-transpulmonary repair.  Median values for age, age at repair, and follow-up duration were 14.9 years (11.5 to 20.8), 1.6 years (0.2 to 4.9), and 11.6 years (9.4 to 17.2), respectively.  All patients were in New York Heart Association (NYHA) functional class I and were asymptomatic.  Median QRS duration was 120 msec (80 to 150).  Sustained TWA was detected in 7 (23 %) of 31 subjects with adequate tests.  In these 7 subjects, median onset heart rate (HR) was 120 (98 to 155).  Median HR threshold as a percentage of predicted maximum HR (220 – age) was 58 % (48 to 77). Sustained TWA prevalence was not significantly different compared with normal subjects (7/31 versus 9/83; p = 0.1).  Onset HR in the TOF group was significantly lower [mean (SD) of 122 (20) versus 139 (12), p < 0.05].  In the TOF group with sustained TWA, the TWA occurred in 4 of 7 at less than 60 % predicted maximum HR versus 1 of 9 normal subjects (p < 0.05); 3 of 7 had onset HR less than 120 versus 0 of 9 normal subjects (p < 0.03).  There was no significant difference in age, gender, transannular patch use, restrictive right ventricular physiology, QRS duration, QTc, QT/QRS dispersion, or non-sustained ventricular tachycardia in subjects with or those without sustained TWA.  The authors concluded that the onset HR for sustained TWA was significantly lower after repair of TOF.  They stated that further study is needed to examine if this represents an increased risk for arrhythmia in this patient group.

Bartczak et al (2015) noted that indications for SCD primary prevention are unknown in patients with repaired ToF.  The role of MTWA in SCD risk stratification was documented.  However, the prevalence of spectral MTWA and its association with VA in adults after ToF repair were not elucidated.  In this study, MTWA, ECG, ambulatory ECG monitoring, echocardiography, and spiro-ergometry were evaluated in 102 adults after ToF repair.  Microvolt T-wave alternans results were classified as normal: negative(-), abnormal: positive(+), and indeterminate(ind).  Owing to similar prognostic significance, MTWA(+) and MTWA(ind) due to patient factors were combined into non-negative group: MTWA(abnormal).  Microvolt T-wave alternans(abnormal) was more frequent in the studied group as compared with controls (p = 0.0005).  The MTWA(abnormal) group had greater right ventricular end-diastolic diameter (p = 0.005), higher incidence of pulmonary regurgitation (p = 0.015), lower peak oxygen consumption (p = 0.01), and higher VE/VCO2 slope (p = 0.04) in comparison with MTWA(normal).  Univariate logistic regression proved pulmonary regurgitation (OR = 3.57, 95 % CI: 1.27 to 10.04), VA (OR = 3.26, 95 % CI: 1.06 to 10.05), right ventricular end-diastolic enlargement (OR = 1.11, 95 % CI: 1.03 to 1.2), increase in VE/VCO2 slope (OR = 1.08, 95 % CI: 1.01 to 1.17), and decrease in peak oxygen uptake (OR = 0.91, 95 % CI: 0.83 to 0.99) to increase MTWA(abnormal) prevalence.  The authors concluded that in adults after ToF repair, abnormal MTWA occurred more often than in controls.  Probability of abnormal MTWA did not rise with prevalence of malignant VA; however, presence of abnormal MTWA was associated with VA risk factors: pulmonary regurgitation, right ventricular enlargement, and consequent heart failure.  They stated that the role of MTWA in selecting patients late after ToF repair at risk of SCD needs further observation.

Furthermore, UpToDate reviews on “Pathophysiology, clinical features, and diagnosis of tetralogy of Fallot” (Doyle and Kavanaugh-McHugh, 2015) and “Management and outcome of tetralogy of Fallot” (Doyle et al, 2015) do not mention the use of MTWA as a diagnostic/management tool.

Prognosis of Pulmonary Arterial Hypertension

Danilowicz-Szymanowicz et al (2016) stated that MTWA is a well-examined parameter for the risk stratification of SCD in patients with left ventricular dysfunction (LVD). However, the role of MTWA in pulmonary arterial hypertension (PAH) remains obscure.  These researchers analyzed the profile of MTWA among PAH patients in comparison with LVD patients and healthy volunteers.  The prospectively study included 22 patients with PAH (mean pulmonary artery pressure greater than or equal to 25 mm Hg and pulmonary capillary wedge pressure less than or equal to 15 mm Hg during right heart catheterization; mean age of 40 ± 17 years); 24 with LVD [LVEF less than or equal to 35 %; mean age of 40 ± 11 years]; and 28 healthy volunteers (mean age of 41 ± 8 years).  Patients with persistent atrial arrhythmia were excluded.  The MTWA (spectral method) categories were positive, negative, or indeterminate (MTWA_pos, MTWA_neg, or MTWA_ind, respectively).  MTWA_pos and MTWA_ind were qualified as abnormal (MTWA_abn).  Statistical analyses (Mann-Whitney U, chi-square with Yates's correction, Fisher's exact test) were performed.  Patients with PAH had higher LVEF than LVD patients (61 ± 7 % versus 27 ± 7 %; p < 0.05); MTWA_abn was observed more frequently in the PAH and LVD groups than in the healthy volunteers.  Patients with PAH were characterized by a considerable percentage of MTWA_pos and MTWA_abn (59 % and 73 %, respectively), but this did not differ from LVD patients.  The authors concluded that patients with PAH are characterized by a high rate of MTWA abnormalities similar to LVD patients, despite the relevant differences in LVEF.  Moreover, they stated that further research is needed to elucidate the clinical significance and prognostic value of this data, particularly in the context of SCD underlying mechanisms in PAH patients.

Evaluation of the Adequacy of Medical Therapy/Guidance of ICD implantation/Tracking Changes in Risk during Cardiac Disease Progression

Verrier and Sroubek (2016) addressed current questions regarding use of TWA to stratify risk for SCD.  Both of the currently available commercial methodologies, namely, the frequency-domain spectral method and the time-domain modified moving average (MMA) method, are supported by guideline statements, cleared by the FDA, and covered by the CMS.  Similar numbers of patients have been enrolled in predictive studies; OR generated by the 2 methods are similar including in a head-to-head study.  However, in 2 prospective studies, prediction by TWA with the spectral method was negative, likely due to withdrawal of beta-blockade before the test with later resumption, while all studies with MMA have achieved prediction when the commercial software was used appropriately.  The authors noted that questions currently undergoing investigation include TWA's potential to

1. guide ICD implantation,
2. track changes in risk during cardiac disease progression, and
3. evaluate the adequacy of medical therapy.

Prediction of Outcome in Persons with Chagas Disease with Implantable Cardioverter Defibrillators

Barbosa and colleagues (2016) stated that Chagas disease (ChD) may lead to life-threatening heart disease, including malignant ventricular arrhythmias.  The use of ICDs has become the main therapeutic strategy for secondary prevention of SCD in ChD.  Microvolt T-wave alternans is a direct measure of ventricular repolarization instability and has emerged as a potentially useful way of determining arrhythmia vulnerability.  However, this methodology has not been evaluated in patients with ChD.  In a prospective study, these researchers evaluated the predictive value of MTWA testing for appropriate therapy or death in ChD patients with ICDs.  This study included consecutive patients who received ICD implantations in a Brazilian tertiary referral center.  A total of 72 patients were followed for a median time of 422 (range of 294 to 642) days; 33 patients had ChD.  The MTWA was non-negative (positive or indeterminate) in 27 (81.8 %) of ChD patients.  The combined primary outcome (appropriate ICD therapy or death) occurred in 29 patients (40.3 %); 17 out 33 ChD patients presented the primary outcome.  There was a statistically significant difference in event-free survival between ChD patients with negative and non-negative MTWA results (p = 0.02).  Non-negative MTWA tests nearly triple the risk of appropriate ICD therapy or death (HR = 2.7, 95 % CI: 1.7 to 4.4, p = 0.01) in patients with ChD and was the only variable associated with outcomes.  The sensitivity and the NPV was 100 % in ChD patients.  The authors concluded that MTWA may be useful in recognizing high-risk ICD patients who may require adjunctive therapies with anti-arrhythmic drugs or catheter ablation.

Risk Stratification in Brugada Syndrome

Adler and colleagues (2016) noted that risk stratification in Brugada syndrome remains a clinical challenge because the event rate is low but the presenting symptom is often cardiac arrest (CA).  These investigators reviewed the data on risk stratification.  A history of CA or malignant syncope is a strong predictor of spontaneous ventricular fibrillation (VF), whereas the prognostic value of a history of familial sudden death and the presence of a SCN5A mutation are less well defined.  On the EKG, the presence of spontaneous type I electrocardiogram increases the risk for VF in all studies, whereas the presence of fragmented QRS complexes and early repolarization correlates with increased risk in several studies.  The authors concluded that signal-averaged techniques using late potentials and MTWA showed some promising results in small studies that need to be confirmed.  The value of electrophysiological studies for predicting spontaneous VF remains controversial, and this included programmed stimulation protocols that avoid a third extra-stimuli or stimulation from the right ventricular outflow.  Risk prediction is particularly challenging in children and women.

Sakamoto and associates (2017) stated that the prognostic value of the seasonal variations of TWA and heart rate variability (HRV), and the seasonal distribution of VF in Brugada syndrome (Br-S) is unknown.  These researchers assessed the utility of seasonal variations in TWA and HRV for risk stratification in Br-S using a 24-h multi-channel Holter EKG (24-M-EKG).  They enrolled 81 patients with Br-S (grouped according to their history of VF, n = 12; syncope, n = 8; no symptoms, n = 61) who underwent 24-M-EKG in all 4 seasons.  Precordial electrodes were attached to the 3rd (3L-V2) and 4rth (4L-V2, 4L-V5) intercostal spaces.  These investigators determined the maximum TWA (max-TWA) values and calculated HRV during night and morning time periods for all seasons.  During a follow-up period of 5.8 ± 2.8 years, 11 patients experienced new VF episodes and there was a peak in new VF episodes in the summer.  The VF group had the greatest 3L-V2 max-TWA value during morning time in the summer among the 3 groups and showed higher 3L-V2 max-TWA value than in the other seasons.  The cut-off value for the 3L-V2 max-TWA during morning time in the summer was determined to be 42 µV using receiver operating characteristic (ROC) analysis (82 % sensitivity, 74 % specificity; p = 0.0006).  The authors concluded that multi-variate analysis revealed that a 3L-V2 max-TWA value of greater than or equal to 42 µV during morning time in the summer and previous VF episodes were predictors of future VF episodes.  They stated that the 3L-V2 max-TWA value during morning time in the summer may be a useful predictor of future VF episodes in Br-S.

Furthermore, an UpToDate review on “Brugada syndrome: Clinical presentation, diagnosis, and evaluation” (Wylie and Garlitski, 2017) does not mention T-wave alternans as a means of risk stratification.

Vitali et al (2021) stated that the 12-lead ECG plays a key role in the diagnosis of Brugada syndrome (BrS).  Since the spontaneous type 1 ECG pattern was first described, several other ECG signs have been linked to arrhythmic risk; however, results are conflicting.  In a systematic review, these researchers clarified the associations of these specific ECG signs with the risk of syncope, sudden death, or equivalents in patients with BrS.  The literature search identified 29 eligible articles comprising a total of 5,731 subjects.  The ECG findings associated with an incremental risk of syncope, sudden death, or equivalents (hazard ratio ranging from 1.1 to 39) were the following: localization of type 1 Brugada pattern (in V2 and peripheral leads), 1st-degree atrio-ventricular block (AVB), atrial fibrillation (AF), fragmented QRS, QRS duration of greater than 120 ms, R wave in lead aVR, S wave in L1 (greater than or equal to 40 ms, amplitude greater than or equal to 0.1 mV, area greater than or equal to 1 mm2), early re-polarization pattern in inferolateral leads, ST-segment depression, T-wave alternans, dispersion of re-polarization, and Tzou criteria.  The authors concluded that at least 12 features of standard ECG were associated with a higher risk of sudden death in BrS.  A multi-parametric risk assessment approach based on ECG parameters associated with clinical and genetic findings could help improve current risk stratification scores of patients with BrS and warrants further investigation.  Moreover, these researchers stated that this systematic review considered the overall data of the published series.  They didn't go into detail about specific issues regarding subgroups such as women and children, who have a very challenging risk profile.  Furthermore, many of the pathophysiological mechanisms proposed in these studies are hypothetical (i.e., not based on experimental data); thus, further rigorous studies are needed to confirm these hypotheses.

Evaluation of Children and Adolescents with Eisenmenger Syndrome

Karpuz and co-workers (2018) determined the values of MTWA in children and adolescents with Eisenmenger syndrome (ES) and controls.  A total of 13 patients (9 were diagnosed with PAH associated with ES due to ventricular septal defect and 4 with atrio-ventricular septal defect) were included in the study.  After analyzing the 24-hour ECG recordings, MTWA was considered using 3 leads (V5, V1, and aVF).  Right heart catheterization and 6-minute walk test (6MWD) were applied to the patients and pro-brain natriuretic peptide (BNP) levels were assessed; echocardiographic parameters were obtained from both the groups and the results were compared.  The MTWA value in lead V5 was 81.08 ± 10.73 µV in the patient group (63.50 ± 18.78 µV in the control group), in lead V1 was 75.00 ± 16.86 µV (73.94 ± 16.77 µV in the control group), and in lead aVF was 73.77 ± 17.81 µV (72.61 ± 16.21 µV in the control group).  Comparison of MTWA values between patients and controls revealed that only lead V5 values were statistically different in the ES group.  The 6MWD scores significantly correlated with lead V5.  Right atrial volume and right ventricular fractional area change were significantly correlated with lead V1.  The Tei index was significantly correlated with lead aVF.  The authors concluded that the MTWA lead V5 value was significantly higher in children with ES than in controls and was also correlated with decreased exercise tolerance.  Moreover, they stated that further studies are needed to determine the cut-off levels of MTWA as well as the possible predictive values for arrhythmia or cardiovascular mortality in pediatric patients.

These investigators stated that although the importance of MTWA values in predicting the development of arrhythmia were shown in other studies, the value of this negative correlation could not be demonstrated clearly because arrhythmia and sudden death did not occur in this study group (children and adolescents).  They stated that studies with longer follow-up periods investigating the risks of development of sudden death and arrhythmia are needed to obtain definite results.  The lack of normal values for MMA for ambulatory MTWA test in children was one drawback of the study.  Thus, a control group was used in this study.

Prognosis of Myocardial Function in Newborns with Hypoxic-Ischemic Encephalopathy

Karpuz and colleagues (2017) noted that this was the 1st study evaluating the predictive value of myocardial performance on arrhythmia and mortality via tissue-Doppler and MTWA in infants with hypoxic-ischemic encephalopathy (HIE) treated with therapeutic hypothermia-rewarming.  The study included 23 term newborns having criteria for HIE and 12 controls.  Tissue-Doppler imaging and MTWA were performed in the first 6 hours after birth in patients from both groups and after hypothermia-rewarming treatment on the 5th day.  The basal MTWA values were higher in patients in lead aVF (augmented vector foot [also known as lead VI]; p < 0.001) which also correlated with existing acidemia (r = 0.517; p = 0.012).  Basal MTWA and post‑treatment values of patients were compared in leads V1 (p < 0.001) and aVF (p < 0.001); a significant decrease was found on the 5th day.  Moreover, right ventricle diastolic diameter and estimated systolic pulmonary artery pressure of patients in the first 6 hours were higher (p = 0.03, p < 0.001, respectively).  Although, the ejection fraction of patients did not decrease, basal values of left and right ventricular systolic and diastolic functions were lower initially, and increased significantly after treatment.  The authors concluded that the global cardiac functions and myocardial performance of newborns with HIE might be improved with therapeutic hypothermia which can be determined by using MTWA and tissue-Doppler measurements.  Moreover, they stated that further studies are needed to evaluate whether these measurements are prognostic in determining the myocardial dysfunction and arrhythmias.

Evaluation of Malignant Ventricular Arrhythmias in Chagas Disease

Almeida and colleagues (2018) noted that sudden cardiac death (SCD) is the most frequent cause of death in patients with Chagas disease, responsible for 55 % to 65 % of deaths in chronic Chagas cardiomyopathy (CCC).  The most often involved electrophysiological mechanisms are ventricular tachycardia and ventricular fibrillation.  The ICD has a beneficial role in preventing SCD due to malignant ventricular arrhythmias, and, thus the correct identification of patients at risk is required.  The association of MTWA with the appearance of ventricular arrhythmias has been assessed in different heart diseases.  The role of MTWA is mostly unknown in patients with CCC.  In an observational, case-control study, these researchers evaluated the association between MTWA and the occurrence of malignant ventricular arrhythmias in patients with CCC.  This trial included patients with CCC and ICD, with history of malignant ventricular arrhythmias (case group), and patients with CCC and no history of those arrhythmias (control group).  The MTWA test results were classified as negative and non-negative (positive and indeterminate).  The significance level adopted was a = 0.05.  These investigators recruited 96 patients, 45 cases (46.8 %) and 51 controls (53.1 %).  The MTWA test was non-negative in 36/45 cases (80 %) and 15/51 controls (29.4 %) [OR = 9.60 (9 5% CI: 3.41 to 27.93)].  After adjustment for known confounding factors in a logistic regression model, the non-negative result continued to be associated with malignant ventricular arrhythmias [OR = 5.17 (95 % CI: 1.05 to 25.51)].  The authors concluded that this study evaluated the presence of MTWA in patients with CCC and previous history of malignant ventricular arrhythmias and in patients with no previous history of those arrhythmias.  The association between non-negativity of the MTWA test and the occurrence of malignant ventricular arrhythmias in CCC was evidenced.  These researchers stated that further assessment in a prospective study is needed to establish the causality and clinical application of the test in those patients.

The authors stated that this study had limitations related partially to its observational, case-control design.  The number of patients found for the case group was 45, not the 50 predicted in the sample calculation.  The case group, defined by a previous history of malignant arrhythmias and indication for ICD, had a greater number of patients with reduced LVEF, of beta-blocker users and of patients with more advanced age.  This was justified by the inclusion criterion in the group, because the patients with reduced LVEF would be more predisposed to develop ventricular arrhythmias.  In addition, according to the 2007 ordinance,19 patients with LVEF of less than 35 % had an indication for priority to undergo ICD implantation.  A logistic regression model was created to correct the disparity between the groups, maintaining the association between non-negative test and the occurrence of arrhythmias.  The model may, however, not have corrected all differences between patients.  Nevertheless, the large proportional difference of non-negativity between the case and control groups, corroborated by the magnitude of the association obtained on logistic regression, suggested that the phenomenon observed was real and significant.

Risk Assessment of Sudden Cardiac Death in Children with Chronic Renal Failure

Hallioglu and colleagues (2018) TWA is known to be useful in prediction of ischemia and SCD in high-risk populations and there are no studies in children with chronic renal failure (CRF).  Cardiac problems appeared to be responsible for an important part of death in children and young adults with CRF.  In a prospective study, these researchers evaluated Holter microvolts TWA measurements in children with CRF comparing to the control group.  This trial included 40 patients with CRF and 48 healthy controls.  The history, EKG and microvolt TWA values based on 24-hour ECG recordings of the patients were evaluated.  Analysis of microvolt TWA was considered on the basis of 3 leads (V5, V1 and AVF).  Compared with the controls, the mean systolic and diastolic blood pressure values and average heart rates were significantly higher in the children with CRF (p = 0.001 and p = 0.026, respectively).  Furthermore, the values of left ventricular internal dimensions at end diastole and end-diastolic volume were significantly higher in CRF group (p = 0.01 and p = 0.049, respectively) and couplet ventricular extra-systole was detected in 2 patients with CRF.  Consequently, all TWA values in 3 leads were increased in CRF group than the control group but the only increase in V5 lead was statistically significant (p = 0.028).  The authors concluded that the findings of this study has demonstrated that microvolt TWA values increased in pediatric patients with CRF.  These researchers stated that TWA might be used for early risk assessment in pediatric patients with CRF in the future.

Evaluation of Non-Pathological Preterm Infants

Marcanton and colleagues (2020) noted that sudden infant death syndrome is more frequent in pre-term infants (PTI) than term infants and may be due to cardiac repolarization instability, which may manifest as TWA on the ECG.  These researchers analyzed TWA in non-pathological PTI and discussed an issue on its physiological interpretation.  This trial included 10 non-pathological PTI (gestational age ranging from 29 3(,7) to 34 2(,7) weeks; birth weight ranging from 0.84 to 2.10 kg) from whom ECG recordings were obtained.  TWA was identified through the heart-rate adapting match filter method and characterized in terms of mean amplitude values (TWAA).  TWA correlation with several other clinical and ECG features, among which gestational age-birth weight ratio, RR interval, heart-rate variability, and QT interval, were also performed.  TWA was variable among infants (TWAA = 26 ± 11 µV).  Significant correlations were found between TWAA versus birth weight (ρ = -0.72, p = 0.02), TWAA versus gestational age-birth weight ratio (ρ = 0.76, p = 0.02) and TWAA versus heart-rate variability (ρ = -0.71, p = 0.02).  The authors concluded that the findings of this preliminary retrospective study suggested that non-pathological PTI showed TWA of few 10s of µV, the interpretation of which was still an open issue but could indicate a condition of cardiac risk possibly related to the low development status of the infant.  Moreover, these researchers stated that further investigations are needed to solve this issue.  The main drawbacks of this study wee its retrospective design and small sample size (n = 10).

Prediction of Post-Operative Mortality in Cardiac Surgery

Koo and colleagues (2019) stated that MTWA is known to be associated with arrhythmia or sudden cardiac death in high-risk patients.  These investigators examined the relationship between MTWA and post-operative mortality in 330 cardiac surgery patients.  Electrocardiogram, official national data and electric chart were analyzed to provide in-hospital and mid-term outcome.  MTWA at the end of surgery was significantly associated with in-hospital mortality in both uni-variate analysis (OR = 27.378, 95 % CI: 5.616 to 133.466, p < 0.001) and multi-variate analysis (OR = 59.225, 95 % CI: 6.061 to 578.748, p < 0.001).  Cox proportional hazards model revealed MTWA at the end of surgery was independently associated with mid-term mortality (HR = 4.337, 95 % CI: 1.594 to 11.795).  The area under the curve (AUC) of the model evaluating MTWA at the end of surgery was 0.764 (95 % CI: 0.715 to 0.809) and it increased to 0.929 (95 % CI: 0.896 to 0.954) when combined with the EuroSCORE II.  The authors concluded that MTWA positive at the end of surgery had a 60-fold increase in in-hospital mortality and a 4-fold increase in mid-term mortality.  Moreover, MTWA at the end of surgery could predict in-hospital mortality and this predictability was more robust when combined with the EuroSCORE II.  Moreover, these researchers stated that additional studies on the robustness of MTWA as predictive marker in a larger cohort are needed.

The authors stated that this study had several drawbacks.  First, although MTWA showed strong relationship with post-operative mortality, it did not suggest what to do for the patients with positive MTWA.  Positive MTWA in these cases was just a marker of very sick patients who were in circulatory shock.  Second, the method used in this study has not been fully tested.  Although these researchers validated the performance of their implementation using Physionet data, it was not compared with commercialized device such as the HeartWave system.  However, because these investigators opened it on the public repository, details of their implementation of calculating MTWA and the parameters such as the moving steps, time for averaging, and the threshold value of TWA ratio could be optimized in future studies using their implementation.  Third, the cause and effect relationship between MTWA and in-hospital death was uncertain.  Moreover, the causes of mortality in cardiac surgery patients could not only be cardiogenic ones, but also many others such as bleeding or infection.  This may explain the low sensitivity of MTWA test in this study.  Nevertheless, a MTWA test may give clinicians useful information since MTWA test showed high specificity in this study.  Combined with other parameters, MTWA test could be a practical risk prediction system in cardiac surgical patients.  Fourth, the findings of this study did not suggest any early intervention to decrease post-operative mortality when the patients showed positive MTWA at the end of surgery.  Most patients with MTWA positive in this study did not show ventricular arrhythmia.  Thus, myocardial ischemia and excessive adrenergic stimulation may be important pathophysiology in these patients.  If then, resting the myocardium might be helpful in these MTWA positive patients such as avoiding use of inotropes, and venting the left ventricle during ECMO.  However, this topic was beyond the scope of this study and further study may be needed.  Finally, these investigators enrolled a total of 330 patients, which may still be too low to evaluate mortality effectively.  There is a concern of relatively small sample size due to over-fitted model.  More than 50 % of patients who underwent cardiovascular surgery during study period were excluded due to technical problems such as device malfunction.

Diagnosis of Reversible Myocardial Ischemia in Patients Without Structural Cardiac Disease

Puljevic and colleagues (2019) noted that MTWA testing is a beat-to-beat fluctuation in the amplitude of T wave.  These investigators examined if MTWA could be a new non-invasive tool for detecting reversible ischemia in patients with suspected coronary artery disease (CAD) without structural heart disease; if MTWA could detect ischemia earlier and with greater test accuracy compared with exercise electrocardiogram (ECG) ST-segment testing, and if threshold value of MTWA and heart rate at which the alternans is estimated could be different compared to standard values.  A total of 101 patients with suspected stable coronary disease, but without structural heart disease, were included.  Echocardiography, exercise ECG test, MTWA with classical and modified threshold alternans values, and coronary angiography were performed.  Approximately 33.3 % patients had a false-positive (FP) result on exercise ECG test.  The sensitivity of exercise ECG ST-segment test in the detection of CAD was 97.8 %, and the specificity was 42.5 % (diagnostic odds ratio [DOR] 33.89).  In a group of angiographically positive patients, standard MTWA accurately identified 60 % of patients, while 40 % had a false-negative (FN) result.  Approximately 91.8 % patients with negative angiography result were accurately identified with 8.2 % FPs).  The sensitivity of MTWA was 59.61 % and specificity 91.83 %.  Best ratio of sensitivity and specificity (86.53 % and 95.91 %, DOR 151.06) had modified criteria for positive MTWA (MTWA greater than 1.5 µV at heart rate of 115 to 125/min).  The authors concluded that the findings of this study showed that MTWA could be the new non-invasive tool for the detection of reversible ischemia in patients with suspected CAD without structural heart disease.  Furthermore, MTWA can detect ischemia earlier and with greater accuracy compared with exercise ECG testing.

The authors stated that this study had several drawbacks.  The study was conducted on a relatively small number of patients.  However, since these researchers demonstrated a high statistical significance, they believed that the data for the total population and the male subgroup were clearly confirmed.  Taking into consideration that the number of female respondents was relatively small, especially in the group with a positive coronary angiography, actual value of T‐wave alternans in the female population should be tested at a much larger sample.  In addition, these investigators mentioned that MTWA was calculated during bicycle ergometry to avoid artifacts while ST‐segment was calculated during treadmill testing.  Criteria of positive alternans with the best balance of sensitivity and specificity with respect to the amplitude of alternans and the target heart rate were set for prediction of sudden death in patients with structural heart disease.  In their research, the best balance of sensitivity and specificity for diagnosis of reversible ischemia was with lower MTWA threshold and with higher heart rate.  Thus, the research could be seen as a pilot study and encouragement for large multi-center study with a view to a definitive confirmation of criteria and values of MTWA for the diagnosis of reversible ischemia in patients without structural heart disease and helpful diagnostic test for patients who could not achieve necessary heart rate, patients with left bundle branch block or pacemaker, and rule out unnecessary invasive testing.

Microvolt T-wave Alternans Combined with Electrophysiologic Study for Prediction of Ventricular Tachyarrhythmias in Patients With Arrhythmogenic Right Ventricular Cardiomyopathy

Xue and colleagues (2019) stated that the long-term predicted value of MTWA for ventricular tachyarrhythmia in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) remains unclear.  These researchers examined the characteristics of MTWA and its prognostic value when combined with an electrophysiologic study (EPS) in patients with ARVC.  All patients underwent non-invasive MTWA examination with modified moving average (MMA) analysis and an EPS.  A positive event was defined as the 1st occurrence of SCD, documented sustained VT, VF, or the administration of appropriate ICD therapy including shock or anti-tachycardia pacing.  A total of 35 patients with ARVC (age of 38.6 ± 11.0 years; 28 men) with preserved LV function were recruited.  The maximal TWA value (MaxValt) was 17.0 (11.0 to 27.0) μV.  Sustained VT was induced in 22 patients by the EPS.  During a median follow-up of 99.9 ± 7.7 months, 15 patients had positive clinical events.  When inducible VT was combined with the MaxValt, the AUC improved from 0.739 to 0.797.  The ROC curve showed that a MaxValt of 23.5 μV was the optimal cut-off value to identify positive events.  The multi-variate Cox regression model for survival showed that MTWA (MaxValt, [HR, 1.06; 95 % CI: 1.01 to 1.11; p = 0.01) and inducible VT (HR, 5.98; 95 % CI: 1.33 to 26.8; p = 0.01) independently predicted positive events in patients with ARVC.  The authors concluded that MTWA assessment with MMA analysis complemented by an EPS might provide improved prognostic ability in patients with ARVC with preserved LV function during long-term follow-up.

The authors stated that this study had 2 main drawbacks.  Despite a follow-up period as long as 8 years, this study was limited by a small sample size (n = 35) affiliated with a single center; ICD implantation was limited in the recruited patients.  Furthermore, these investigators used an update factor of 1/32 when analyzing TWA, which was less sensitive than the recommended update factor of 1/8.  As a result, the TWA values obtained were substantially lower than expected, and the capacity to predict VT might also be reduced.

Evaluation of Non-Pathological Preterm Infants

Marcantoni and colleagues (2020) noted that sudden infant death syndrome (SIDS) is more frequent in preterm infants (PTI) than term infants and may be due to cardiac repolarization instability, which may manifest as TWA on the ECG.  In a retrospective stud, these researchers analyzed TWA in non-pathological PTI and opened an issue on its physiological interpretation.  Subjects consisted of 10 non-pathological PTI (gestational age ranging from 293/7  to 342/7 weeks (mean of 311/7 ± 13/7 weeks; birth weight ranging from 0.84 to 2.10 kg) from whom ECG recordings were obtained ("Preterm infant cardio-respiratory signals database" by Physionet).  TWA was identified through the heart rate adapting match filter method and characterized in terms of mean amplitude values (TWAA).  TWA correlation with several other clinical and ECG features, among which gestational age-birth weight ratio, RR interval, HRV, and QT interval, was also performed.  TWA was variable among infants (TWAA = 26 ± 11 µV).  Significant correlations were found between TWAA versus birth weight (ρ = -0.72, p = 0.02), TWAA versus gestational age-birth weight ratio (ρ = 0.76, p = 0.02) and TWAA versus HRV (ρ = -0.71, p = 0.02).  The authors concluded that these preliminary findings suggested that non-pathological PTI showed TWA of few tens of µV, the interpretation of which was still an open issue but could indicate a condition of cardiac risk possibly related to the low development status of the infant.  These researchers stated that further investigations are needed to solve this issue.

Prediction of Major Adverse Cardiac Events in Ischemic Heart Failure

Kaufmann and colleagues (2020) stated that major adverse cardiovascular events (MACE) constitutes the main cause of morbidity and mortality in ischemic heart failure (HF) patients.  The prognostic value of the autonomic nervous system (ANS) parameters and MTWA in this issue has not been identified to-date.  These researchers examined the usefulness of the afore-mentioned parameters in the prediction of MACE in HF patients with left ventricular systolic dysfunction of ischemic origin.  Baroreflex sensitivity (BRS), HRV, MTWA and other well-known clinical parameters were analyzed in 188 ischemic HF outpatients with LVEF of less than or equal to 50 %.  During 34 (14 to 71) months of follow-up, 56 (30 %) endpoints were noted.  Univariate Cox analyses revealed BRS (but not HRV), MTWA, age, NYHA III, LVEF, ICD presence, use of diuretics and anti-arrhythmic drugs, diabetes, and kidney insufficiency were defined as significant predictors of MACE.  Pre-specified cut-off values for MACE occurrence for the afore-mentioned continuous parameters (age, LVEF, and BRS) were: greater than or equal to 72 years, less than or equal to 33 %, and less than or equal to 3 ms/mmHg, respectively.  In a multi-variate Cox analysis only BRS (hazard ratio 2.97, 95 % CI: 1.35 to 6.36, p < 0.006), and LVEF (hazard ratio 1.98, 95 % CI: 0.61 to 4.52, p < 0.038) maintained statistical significance in the prediction of MACE.  The authors concluded that BRS and LVEF are independent of other well-known clinical parameters (e.g., age, NYHA functional class, ICD presence, impaired renal function, use of diuretics and anti-arrhythmic drugs, and diabetes), in the prediction of MACE in patients with left ventricular systolic dysfunction of ischemic origin and LVEF up to 50 %; BRS of less than or equal to 3 ms/mmHg and LVEF of less than or equal to 33 % identified individuals with the highest probability of MACE during the follow-up period.

Cardiac Arrhythmias

Kulkarni et al (2021) noted that life-threatening ventricular arrhythmias and SCD are often preceded by cardiac alternans, a beat-to-beat oscillation in the T-wave morphology or duration.  However, given the spatiotemporal and structural complexity of the human heart, designing algorithms to effectively suppress alternans and prevent fatal rhythms is challenging.  Recently, an anti-arrhythmic constant diastolic interval pacing protocol was proposed and shown to be effective in suppressing alternans in 0-, 1-, and 2-dimensional in-silico studies as well as in ex-vivo whole heart experiments.  These researchers provided a systematic review of the electrophysiological conditions and mechanisms that enable constant diastolic interval pacing to be an effective anti-arrhythmic pacing strategy.  They also demonstrated a successful translation of the constant diastolic interval pacing protocol into an ECG-based real-time control system capable of modulating beat-to-beat cardiac electrical activity and preventing alternans.  Furthermore, these investigators presented evidence of the clinical use of real-time alternans suppression in reducing arrhythmia susceptibility in-vivo.  The authors provided a comprehensive overview of this promising pacing technique, which could potentially be translated into a clinically viable device that could radically improve the quality of life (QOL) of patients experiencing abnormal cardiac rhythms.

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References