T-wave Alternans Testing in Pacemaker Patients

Comparison of Pacing Modes and Long-Term Prognostic Relevance

Marc Dorenkamp, M.D.; Christoph Breitwieser, M.D.; Andreas J. Morguet, M.D.; Joachim Seegers, M.D.; Steffen Behrens, M.D.; Markus Zabel, M.D.


Pacing Clin Electrophysiol. 2011;34(9):1054-1062. 

In This Article


Main Findings

To the best of our knowledge, this is the first study to investigate the prognostic value of microvolt TWA in pacemaker patients with preserved or moderately impaired LV ejection fraction. Moreover, atrial and ventricular pacing modes have never been compared prognostically although it was presumed from the outset of TWA testing that unphysiologic RV pacing would yield unspecific results. The main finding of our study is that microvolt TWA has prognostic value in pacemaker patients with structural heart disease and preserved or moderately impaired LV function. Moreover, we demonstrated that while test results during atrial pacing are predictive of outcome, TWA testing using ventricular pacing has no predictive value.

Microvolt TWA and Risk Stratification

Microvolt TWA is best established for identifying susceptibility to SCD in high-risk patients with history of MI and reduced LV ejection fraction.[19] Several studies have suggested that TWA can improve the efficiency of ICD therapy in this patient population.[5–9] Especially the high negative predictive value of microvolt TWA may be used to support decision making regarding ICD placement. However, the issue is still under debate because recent studies failed to show that a nonnegative TWA test result is predictive of ICD-detected ventricular tachyarrhythmias.[20,21] Importantly, a nonnegative TWA test result did predict an increase in total mortality in one of the latter trials.[20] Although our own results are in line with the findings that link TWA to mortality, we cannot comment on arrhythmic events because if at all they occurred with an incidence too small to draw conclusions from.

Microvolt TWA testing is less validated in patients with preserved LV function; however, two recent clinical studies have suggested that TWA testing is able to predict SCD and total mortality in these patients despite a lower rate of events.[22] Ikeda et al. measured TWA 48 ± 66 days post-MI in 1,041 patients with an LV ejection fraction ≥40%.[10] Exhibiting a very low event rate of 1.8% during a follow-up of 32 ± 14 months, a positive microvolt TWA test was a significant predictor of SCD and life-threatening ventricular arrhythmias in this population. A study by Nieminen et al. applied microvolt TWA testing to a more general population of patients referred for clinically indicated exercise testing.[23] Most of the patients had a normal LV ejection fraction. Using the modified moving average TWA method, a positive TWA was both predictive of cardiovascular and of all-cause mortality during a follow-up of 44 ± 7 months.[23]

Overall, the role of TWA in patients with preserved LV systolic function is still less clear and so are the pathophysiological mechanisms leading to TWA in these patients.[3,22] In general, experimental research could demonstrate that repolarization alternans is associated with beat-by-beat cycling of calcium transients resulting in increased and dynamically changing dispersion of ventricular repolarization.[24,25] However, a closer link as to the exact mechanism in the human heart and its link to prognosis still has to be found. Prior studies did not find a correlation between TWA and the presence of cardiovascular risk factors or coronary artery disease, a finding that we could confirm.[23] It has been presumed that in a population with preserved LV function SCD is mainly caused by VF.[26] The presence of TWA during atrial pacing may therefore reflect the existence of an abnormal repolarization substrate leading to higher vulnerability of the myocardium to VF. This may add to or include less-evident arrhythmogenic substrates that may be present in preserved LV ejection fraction such as fibrosis, hypertrophy, or alteration of ion channels.[27–29]

Previous Studies on Microvolt TWA Using Pacemaker Stimulation

Assessment of microvolt TWA is usually performed during exercise testing. However, many patients are unable to reach an adequate increase of heart rate due to inability to exercise or chronotropic incompetence with or without a drug therapy. This results in the necessity for alternative techniques to measure microvolt TWA. One possible technique is pacing of the heart, as used in the electrophysiology laboratory in early TWA studies.[1,12] An earlier study demonstrated a high degree of concordance in the presence or absence of TWA during exercise stress testing and atrial pacing by means of temporary cardiac pacing upon invasive electrophysiologic study.[12] This finding has been confirmed more recently by Raatikainen et al.[13] The high concordance between exercise and atrial pacing protocols can be explained by the fact that during atrial pacing, ventricular depolarization and repolarization remains unchanged in the case of physiologic AV conduction to the ventricles. The only difference between the two situations, the presence of catecholamines and increased blood pressure upon exercise obviously did not impair the good correlation. If the patient is already treated with a pacemaker or ICD, it is evident that the programming features of the device may be utilized to increase heart rate and measure TWA.

The applicability of atrial pacing may be limited by the occurrence of rate-dependent AV block during the TWA test. In this respect, ventricular pacing offers the potential advantage of eliciting TWA in patients with atrial fibrillation and impaired AV nodal conduction. A small number of clinical studies have attempted to assess microvolt TWA during ventricular pacing. Shalaby et al. reported 80% concordant test results between short-term atrial and ventricular pacing.[14] In agreement with our own results, the same study found higher noise levels during ventricular pacing, probably due to an altered and amplified T-wave. It is important to keep in mind that the current cut-off values for amplitude and noise detection were originally developed for exercise-induced increase in sinus rate. Shalaby et al. suggested that these criteria might not apply for the altered T-wave configuration during ventricular pacing.[14] In three further studies, microvolt TWA characteristics during ventricular pacing were assessed in patients receiving ICD and/or cardiac resynchronization therapy.[15,30,31] Pacing modes included RV, LV, and biventricular stimulation as well as simultaneous atrial and ventricular stimulation. The concordance of TWA test results between different pacing modes varied substantially among those three studies. Ehrlich et al. found a high level of concordance between microvolt TWA test results obtained during various pacing modalities. Specifically, test results during RV pacing were concordant in 83% of patients when compared with right atrial pacing (κ= 0.66, n = 30).[31] The exact level of concordance was also reported by Anh et al. in a study involving 33 patients, although no kappa values were determined.[30] In contrast, Kraaier et al. found relatively low concordance rates between different protocols.[15] The level of concordance in their recently published study varied between 57% (κ= 0.06, n = 30) and 70% (κ= 0.35, n = 30). In line with the latter results, we found a concordance rate of 62% (κ= 0.22) between right atrial and RV pacing. Although our patient number is small, all of the previous studies involved only a small number of patients and the mean LV ejection fraction in all the above-mentioned studies was markedly lower than in our study (≤40%). Importantly, none of the previous studies provided information on follow-up of their patients.

Because of cardiac repolarization memory effects, the results of TWA measurements during chronic (bi-) ventricular pacing might not be extrapolated to conditions of no or only sporadic ventricular pacing. In our study, patients requiring frequent RV pacing were excluded and TWA testing was performed within 2–4 days after pacemaker implantation. Thus, confounding memory effects on cardiac repolarization were avoided.[32]

Our results indicate that the assessment of microvolt TWA during RV pacing is technically feasible, but that prognostic information is lost. This confirms the earlier notion in TWA testing that RV paced TWA measurements yield unspecific results. We do not expect but cannot rule out that a reassessment of TWA criteria could potentially recover prognostically relevant information during ventricular pacing.[33–36]

Clinical Implications

The problem of identifying patients at increased risk for SCD is that there is a reciprocal relationship between the risk in different patient subsets and the size of the subset. The size of the population at low risk is much higher than the sizes of populations at high risk.[37] The patients in our population do not meet current indications for ICD implantation. Although their SCD risk is higher than in individuals without structural heart disease, arrhythmic event rates are low and a potential SCD risk stratifier has to show a high positive predictive value. Our data suggest that microvolt TWA may help to stratify SCD risk in patients with structural heart disease and preserved LV function. However, future work is needed to improve the predictive value in this population by incorporating microvolt TWA into a risk scoring system with other validated clinical features.[10,38] More aggressive preventive strategies can then be targeted to high-risk individuals.[23]

Study Limitations

Our study has some limitations. We only had data on all-cause mortality and did not have information on cardiovascular mortality. Information on the mode of death may have provided insights into the arrhythmic risk of our population. However, all-cause mortality is an objective and unbiased outcome measure whereas the use of cardiovascular mortality has been criticized as inherently inaccurate.[39] It has to be pointed out that only a relatively small study population was examined. Larger studies are needed to define the predictive role of microvolt TWA in patients with structural heart disease and preserved LV function. The high incidence of indeterminate TWA test results may have compromised the value of ventricular pacing-induced TWA. Because of the small study size no final judgment can be provided on the lack of ventricular pacing-induced microvolt TWA utility. Finally, as this was the first study of its kind (hypothesis generating), no sample size calculation was performed.


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