Ventricular tachy-arrhythmias are the commonest cause of sudden cardiac death in patients
with ischemic heart disease.[1] It is estimated that up to 20% patients with acute
myocardial infarction suffer from these arrhythmias.[2] There is a growing need for
developing tools for risk assessment for sudden cardiac death (SCD) in this population.
Several ECG indices have been proposed for risk stratification and for prognostication
after myocardial infarction (MI).[3]–[5] These can divided broadly into those based
on repolarization, conduction or both, as reviewed recently.[3] Repolarization indices
include QT interval, QT dispersion, Tpeak-Tend interval, Tpeak-Tend/QT ratio, JTpeak/JT,
(Tpeak-Tend)/ JTpeak and Tpeak/JT ratios. Conduction indices include QRS duration
and QRS dispersion. Conduction-repolarization indices are exemplified by index of
Cardiac Electrophysiological Balance (iCEB: QT/QRS),[6] and QRS-T angle, amongst others.[7]–[9]
Of the repolarization markers, Tpeak-Tend interval, the difference between the peak
and the end of the T wave, and Tpeak-Tend/QT ratio, represent the dispersion of repolarization.[10]
A meta-analysis recently published by our group demonstrated its predictive value
in several cardiac conditions that included Brugada syndrome, heart failure and myocardial
infarction.[11] Other investigators have proposed dividing Tpeak-Tend by the QT interval.
This yields the Tpeak-Tend/QT ratio, which has a relatively constant normal range
between 0.17 and 0.23.[12] Theoretically, increases in this ratio represent a higher
dispersion of repolarization, which should promote ventricular arrhythmogenesis, however
its value for predictive arrhythmic or mortality risk after MI remains controversial.
Thus, three studies also did not demonstrate differences in this ratio between high
and low risk groups.[13]–[15] Therefore, we performed a systematic review and meta-analysis
to examine whether Tpeak-Tend interval and Tpeak-Tend/QT ratio can distinguish patients
with MI who are at high risk of arrhythmic or mortality events from those free from
these events.
A total of 42 and 95 entries were retrieved from Pubmed and Embase, respectively,
of which 10 studies met the inclusion criteria and were therefore included. A total
of 1967 MI patients were included in this meta-analysis. The patients had a mean age
of 68 and 78% were male with a mean follow-up period of 15 ± 12 months. We found that
Tpeak-Tend/QT ratios were significantly higher in high risk patients compared to the
low risk group (mean difference: 0.06, standard error 0.02, P < 0.01; I
2 = 88%; Figure 1). The Cochran's Q value was greater than the degrees of freedom
(58 vs. 7), indicating that the true effect size was different between studies. I
2 was 88%, which indicates the presence of substantial heterogeneity. Begg and Mazumdar
rank correlation analysis demonstrated that Kendall's Tau took a value of -0.1 with
P > 0.05, which suggests no significant publication bias. Egger's test demonstrated
no significant asymmetry (intercept 2.2, t-value 2.1; P > 0.05). To identify the source
of the heterogeneity, sensitivity analysis was performed by removing one study at
a time, but this did not significantly influence the mean difference. This suggests
that none of the studies was singly responsible for the heterogeneity observed. ORs/HRs
were available for five studies and are shown in Figure 2. In terms of risk quantification,
all five studies reported a positive association between increased Tpeak-Tend/QT and
increased risk of VT/VF or mortality (two studies used multivariate analysis and three
studies used univariate analysis). The pooled meta-analysis demonstrated that a higher
Tpeak-Tend/QT ratio is associated with approximately 3.16 times higher risk of these
endpoints (95% CI: 1.13 to 8.82; P < 0.05). The Cochran's Q value was greater than
the degrees of freedom (21 vs. 4), indicating the true effect size were different
among different studies. I
2 of 81% suggested substantial heterogeneity. Begg and Mazumdar rank correlation analysis
demonstrated that Kendall's Tau took a value of 0 with P > 0.05, which suggests no
significant publication bias. Egger's test demonstrated significant asymmetry (intercept
2.2, t-value 5.0; P < 0.05). To identify the source of the heterogeneity, sensitivity
analysis was performed by removing one study at a time, but this did not significantly
influence the mean difference. This suggests that none of the studies was singly responsible
for the heterogeneity observed.
Figure 1.
Flow diagram of the study selection process for studies investigating Tpeak-Tend interval
and Tpeak-Tend/QT ratio in myocardial infarction patients.
CI: confidence inervals; MD: Mean difference.
Figure 2.
Forest plot demonstrating the mean differences for between Tpeak-Tend/QT ratios obtained
in event-positive and event-negative groups.
CI: confidence inervals; OR: odds ratio.
Our study is the only meta-analysis that evaluates the role of Tpeak-Tend/QT ratio
for prognostication in 1967 patients with prior MI. The main findings are: (1) Tpeak-
Tend/QT ratio is higher by 0.06 in patients who suffered from malignant ventricular
arrhythmias and/or death compared to those who were free from these events; (2) a
higher Tpeak-Tend/QT ratio with a mean cut-off of 0.26 are associated with 3.16-fold
increase in the risk of ventricular arrhythmias and/or death, respectively. Tpeak-Tend
is the interval between the peak and the end of the T-wave on the ECG, which is a
reflection of the dispersion of repolarization.[10] As this interval varies with heart
rate,[12] dividing it by the QT interval yields the Tpeak-Tend/QT ratio, which has
a relatively constant normal range between 0.17 and 0.23.[12] Theoretically, higher
values of both indices reflect increased dispersion of repolarization, which is expected
to increase arrhythmogenicity.[16] Pre-clinical experiments conducted in coronary-perfused,
canine wedge preparations showed that the end of action potential (AP) repolarization
at the epicardium coincided with the Tpeak and end of AP repolarization at the M-cell
coincided with Tend.[17] In other words, Tpeak- Tend can be used as a surrogate marker
of transmural dispersion of repolarization (TDR). Increases in TDR are pro-arrhythmic
owing to the increased likelihood of developing unidirectional conduction block and
therefore to re-entry. Increased TDR is also thought to underlie phase 2 reentry in
Brugada syndrome.[16] Tpeak-Tend is lead-dependent as the dispersion of repolarization
varies with cardiac regions.[18] This interval can be determined generally using two
methods, the tangent method and the tail method. This is important because one study
reported that Tpeak-Tend interval, when determined using the tangent method, was not
significantly between high risk and low risk groups.[13] However, using the tail method,
Tpeak-Tend interval was significantly prolonged in high risk MI patients compared
to the low risk cohort.[13]
Recently, our group conducted a comprehensive systematic review with meta-analysis
into the value of Tpeak-Tend interval in predicting arrhythmic and mortality outcomes
in different clinical conditions.[11] However, it did not examine the relationship
between Tpeak-Tend/QT ratio and adverse outcomes. Therefore, the present study goes
on to investigate the mean differences in Tpeak-Tend/QT ratio in a cohort of myocardial
infarction patients. The central hypothesis is that higher Tpeak-Tend/QT ratios increase
arrhythmic risk due to an exacerbation of the transmural or global dispersion of repolarization,
and that measures that reduce this exacerbation would reduce arrhythmic risk.[3] The
results of this meta-analysis clearly show that prolongations do indeed distinguish
high risk patients from patients who did not suffer from adverse cardiac events. It
should be noted that three studies reported no value of this ratio in risk stratification.[13]–[15]
There are several reasons why this might have been the case. Firstly, in normal hearts,
a degree of transmural repolarization heterogeneity ensures the normal unidirectional
conduction of the cardiac impulse through the heart. Normally the endocardium depolarizes
first and repolarizes last whereas the epicardium depolarizes last and repolarizes
first. Disturbances in this activation and recovery sequence could potentially lead
to arrhythmogenesis.[19] Decreases in transmural dispersion of repolarization, reflected
by shorter Tpeak-Tend intervals, may also be pro-arrhythmic. Indeed, this notion is
supported by a study published by Porthan and colleagues demonstrating that a reduction
in this interval was associated with a higher likelihood of ventricular arrhythmic
events in the general population.[20] Other studies found no significant difference
in Tpeak-Tend intervals[15] or in Tpeak-Tend/QT ratios[13]–[15] between high and low
risk groups. These findings suggest that increased transmural dispersion of repolarization
is only one mechanism through which arrhythmogenesis takes place. Other electrophysiological
abnormalities, such as reduced conduction velocity and increased dispersion of conduction
are also important, as suggested previously.[11]
In conclusion, this meta-analysis shows that Tpeak-Tend/QT ratio is a significant
predictor of ventricular tachy-arrhythmias and/or death in myocardial infarction.
Our study adds to growing body of evidence supporting utility of repolarization abnormalities
seen on a standard electrocardiogram for prognostication and risk stratification in
patients with prior myocardial infarction. These indices are should be utilized in
clinical practice to aid risk stratification.