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