The prognostic value of the Tpeak-Tend interval in patients undergoing primary percutaneous coronary intervention for ST-segment elevation myocardial infarction☆
Article Outline
Abstract
Introduction
The Tpeak-Tend interval (TpTe) has been linked to increased arrhythmic risk. TpTe was investigated before and after primary percutaneous coronary intervention (pPCI) in patients with ST-segment elevation myocardial infarction (STEMI).
Method
Patients with first-time STEMI treated with pPCI were included (n = 101; mean age 62 years; range 39-89 years; 74% men). Digital electrocardiograms were taken pre- and post-PCI, respectively. Tpeak-Tend interval was measured in leads with limited ST-segment deviation. The primary end point was all-cause mortality during 22 ± 7 months (mean ± SD) of follow-up.
Results
Pre- and post-PCI TpTe were 104 milliseconds [98-109 milliseconds] and 106 milliseconds [99-112 milliseconds], respectively (mean [95% confidence interval], P = .59). A prolonged pre-PCI TpTe was associated with increased mortality (hazard ratio, 10.5 [1.7-20.4] for a cutoff value of 100 milliseconds). Uncorrected QT and heart rate–corrected QT intervals (Fridericia-corrected QT) were prolonged after PCI (QT: 401 vs 410 milliseconds, P = .022, and Fridericia-corrected QT: 430 vs 448 milliseconds, P < .0001).
Conclusion
In patients with STEMI undergoing pPCI, pre-PCI TpTe predicted subsequent all-cause mortality, and the QT interval was increased after the procedure.
Keywords: Tpeak-Tend interval, ST-segment elevation myocardial infarction, Percutaneous coronary intervention, QT interval, mortality
Introduction
Myocardial infarction (MI) is a major cause of morbidity and mortality. Electrophysiological characterization of arrhythmogenic substrates in the myocardium of post-MI patients has shown clinical promise for prediction of malignant arrhythmias. Among these variables and measurements are a prolonged QT interval, signal-averaged electrocardiogram (ECG), and T wave alternans, but they all have drawback of not being useful in the acute clinical setting because their prognostic value is first manifested when measured 6 to 8 weeks post-MI.1, 2, 3, 4, 5
The interval from the peak to the end of the T wave (Tpeak-Tend interval, or TpTe) has been proposed to represent repolarization dispersion in the heart. However, to what extent TpTe expresses transmural apicobasal, left-to-right ventricle, or anterior-posterior electrical gradients influence is not clear.6, 7 A prolonged TpTe has been associated with arrhythmic events in various clinical conditions,2,8, 9, 10, 11, 12, 13 but little is known about TpTe in the acute setting of transmural myocardial ischemia and reperfusion, for example, in patients with ST-segment elevation MI (STEMI) undergoing primary percutaneous coronary intervention (pPCI). The purpose of the present study was to evaluate TpTe immediately before and after pPCI in patients with STEMI and evaluate its prognostic value.
Methods
Study subjects
Patients were recruited from a single tertiary catheterization laboratory of a high PCI volume center (Gentofte University Hospital, Copenhagen, Denmark: 650 pPCI and 1200 elective PCI per year performed by 5 PCI operators). Patients were included if they had (1) relevant chest discomfort, (2) ECG changes fulfilling the criteria for STEMI, (3) pPCI, and (4) a significant stenosis or occlusion requiring placement of at least 1 intracoronary stent. After pPCI, patients received usual standard of care according to clinical guidelines, including treatment with clopidogrel for 12 months.
Patients were excluded if they had atrial fibrillation (n = 8), left bundle branch block (n = 7), prior MI (n = 34), lacked a timely ECG immediately before and after pPCI (pre- and post-pPCI; n = 25), or if the ECG was not interpretable (n = 28). A total of 203 were screened and 102 were excluded based on the above criteria, ending up with inclusion of 101 patients in the study.
ECG recordings and analyses
Just before arterial puncture, a digital 12-lead standard ECG (pre-pPCI ECG) was obtained, with the patient supine on the catheterization table using a MAC 5000 digital ECG apparatus (GE Healthcare, Milwaukee, WI). Immediately after the end of the procedure, the post-pPCI ECG was acquired.
The ECGs were transferred to a computer with Magellan Workstation (GE Healthcare) programmed to assign fiducial points corresponding to Q onset, R waves, and T wave peak and end. TpTe was evaluated in non–infarct-related leads, that is, leads with ST-segment deviations below 0.055 mV at the J-point in the pre-pPCI ECG, to avoid difficulties in assessing T wave markers. The preferred leads for measurement of TpTe were in descending order: V5, V4, V6, II, III, and I. This selection was based on previous experience with TpTe in a healthy population, where TpTe in these leads are almost identical, whereas difficult T wave morphology gives longer or shorter TpTe in V1-V2 and augmented leads.14 The RR interval, QT, QTcB (Bazett-corrected QT), and QTcF (Fridericia-corrected QT) were obtained from the Magellan workstation using the 12SL algorithm (GE Healthcare). In brief, the algorithm computed QT intervals based on a superlead on the basis of the 8 recorded leads (II, III, V1-V6) and measured QT as the first QRS deflection in any lead to last T wave–related deflection in any lead.15
Demographic and clinical data, follow-up, and end point
Demographic and clinical data were retrieved from the catheterization laboratory's electronic patient database. Symptom to balloon time (time to treatment) was defined as time from first symptom to first balloon inflation and was divided into quartiles for comparisons of TpTe. The infarct-related artery was classified as left anterior descending, or right coronary artery, or “other coronary arteries” (including the circumflex artery and other >2-mm diameter epicardial coronary arteries). Left ventricular ejection fraction (LVEF) was evaluated with echocardiography during the hospital stay. The primary end point was all-cause mortality. The patients were prospectively followed in the central Danish citizen registry for the primary end point.
Statistics
Descriptive statistics are presented as mean and SD or mean and 95% confidence interval (CI) for continuous variables. Categorical data are presented as percent or mean and range. Times are shown as median and range. A paired t test was used for comparisons between ECG variables pre-pPCI and post-pPCI. One-way or 2-way analysis of variance (ANOVA) was used where appropriate; to compare means between pre-pPCI or post-pPCI variables according to the infarct-related artery, LVEF, and quartiles of symptom to balloon time. A 2-sided P value less than .05 was considered significant. Receiver operator characteristic curves were computed for TpTe pre-pPCI and post-pPCI to assess cutoff points. Optimal cutoff point was defined as the cutoff yielding the maximal Youden index [Youden index = (sensitivity) + (specificity) − 1].16 Survival statistics was done by Kaplan-Meier plots with logrank test. Hazard ratio was calculated using Cox analysis. All statistics were done in SAS 9.1.3 (SAS Institute Inc, Cary, NC).
Results
Demographics and follow-up
Demographic, clinical, and angiographic data are summarized in Table 1. No patients were lost to follow-up. There were 10 deaths in the population, with a mean (SD) follow-up time of 683 (211) days.
Table 1. Patient demographics, clinical, and angiographic data (n = 101)
| Age (y), mean (range) | 62 (39-89) |
| Sex, % male | 74 |
| BMI (kg/m2), mean (SD) | 27.2 (5.5) |
| Systolic blood pressure (mm Hg), mean (SD) | 137 (26) |
| Diastolic blood pressure (mm Hg), mean (SD) | 83 (15) |
| LVEF (%), mean (SD) | 39 (12) |
| Medical history at admission (%) | |
 Antihypertensive treatment | 28 |
| Diabetes | 5 |
| Treatment for hypercholesterolemia | 12 |
| Angina Pectoris | 15 |
| Positive family history for IHD | 37 |
| Smoking (%) | |
| Active | 51 |
| Ceased | 28 |
| Never | 21 |
| Infarct-related artery (%) | |
| LAD | 43 |
| RCA | 41 |
| Other | 16 |
| Stents | |
| No. of stents, mean (range) | 1.3 (1-4) |
| Bare metal stent (%) | 37 |
| Drug eluting stent (%) | 63 |
| Lesions | |
| % Occlusion, mean (SD) | 96 (7.1) |
| No. of lesions, mean (range) | 1.3 (1-5) |
| Symptom to balloon time (min), median (range) | 183 (30-725) |
TpTe and survival
The pre-pPCI TpTe was prolonged in patients that died during follow-up. However, the post-pPCI TpTe was similar between surviving and deceased patients (Table 2). Using the Youden index, the optimal cutoff point was determined to be 100 milliseconds for the pre-pPCI TpTe, with a sensitivity and specificity of 0.90 and 0.55, respectively. A pre-pPCI TpTe greater than 100 milliseconds had a positive and negative predictive value of 0.18 and 0.98, respectively. The corresponding Kaplan-Meier plot for this cutoff point is shown in Fig. 1 (logrank test for comparison of survival curves, P = .005). Hazard ratio for a prolonged TpTe was 10.5 (CI, 1.7-20.4).
Table 2. Mean (SD) values for TpTe intervals for survivors (n = 91) and nonsurvivors (n = 10) in patients with STEMI undergoing pPCI
| Survivors (n = 91) | Nonsurvivors (n = 10) | |
|---|---|---|
| Pre-pPCI TpTe (ms) | 102 (27) | 122 (37) |
| Post-pPCI TpTe (ms) | 106 (30) | 101 (32) |
| ΔPost-Pre TpTe (ms) | 5 (34) | −21 (55) |
Fig. 1.
Kaplan-Meier survival curves for patients with or without TpTe greater than 100 milliseconds. Black line: TpTe less than 100 milliseconds, gray line: TpTe greater than 100 milliseconds. Black dots indicates censored individuals.
TpTe, infarct-related artery, LVEF, and symptom to balloon time
Table 3 presents the ECG changes observed between pre- and post-pPCI in TpTe, RR interval, and QT intervals, respectively. There was no difference in TpTe before and after pPCI (Table 3). There was no difference in TpTe duration or mortality between the different chosen leads (ANOVA P = .54 and P = .64, respectively). Tpeak-Tend interval pre- and post-pPCI were independent of the infarct-related artery (ANOVA P = .33 and 0.59, respectively), LVEF (ANOVA P = .77 and 0.55, see Fig. 2), and the symptom to balloon time (ANOVA P = .77 and P = .38, respectively).
Table 3. ECG variables immediately before and after pPCI for STEMI (n = 101)
| Variable | Unit | pre-pPCI, mean (CI) | post-pPCI, mean (CI) | Δpost-pre, mean (CI) | P |
|---|---|---|---|---|---|
| TpTe interval | ms | 104 (98-109) | 106 (99-112) | 2 (−5 to 9) | .59 |
| RR interval | ms | 827 (790-865) | 776 (745-807) | −51 (−83 to −19) | .0023 |
| QT interval | ms | 401 (392-410) | 410 (402-417) | 9 (1-16) | .022 |
| QTcB | ms | 446 (438-453) | 469 (461-477) | 23 (17-30) | .0001 |
| QTcF | ms | 430 (423-436) | 448 (441-455) | 18 (12-24) | .0001 |
Fig. 2.
Tpeak-Tend interval by 5% increments in LVEF. Black bars: pre-pPCI TpTe, gray bars: post-pPCI TpTe. Error bars indicate 95% CIs of means.
Discussion
The main findings of this study of patients with STEMI undergoing pPCI were: (1) the pre-pPCI TpTe predict all-cause mortality; (2) TpTe was not associated with infarct-related artery, LVEF, or symptom to balloon time; and (3) QT interval was prolonged after pPCI.
Pathophysiological mechanisms
The metabolic and electrochemical changes that occur in the heart during acute MI treated with reperfusion therapy are complex and include alterations of tissue oxygen levels, pH, and intercellular and intracellular electrochemical gradients.17, 18 Action potential duration (APD) in the ischemic zone briefly increases (lasting seconds to a few minutes), thereafter a shortening of the APD is seen. This is caused by reduction in transmembrane potential, action potential amplitude and upstroke velocity. These changes are not uniform, with steep dispersion of APD across the ischemic border zone.18, 19, 20 Cell-to-cell interactions are also compromised via closing and redistribution of gap junctions.17, 19, 21 During early reperfusion, APD remains shortened20 or may even shorten further22 before APD restitution begins. In brief, the overall dispersion between normal or less affected tissue compared with the infarcted tissue and ischemic border zone is increased in the infarcted heart, creating a substrate for arrhythmias.17 This dispersion has been suggested to be reflected in TpTe and increased TpTe is thought to be arrhythmogenic,8 although the value of corresponding results in experimental models has been disputed, for example, because of increased intercellular electrical coupling in human hearts that may minimize APD differences as compared with many animal models.18
Changes of QT intervals and TpTe during myocardial ischemia-reperfusion
In our study, both the RR interval and QT and corrected QT intervals changed after pPCI. As mentioned previously, the APD is more dispersed during myocardial ischemia-reperfusion, and Kenigsberg et al23 also found that QTc intervals increased during balloon inflation in patients undergoing elective PCI and remained increased postinflation.23 Moreover, Bonnemeier et al24 showed that the QTc interval was prolonged and reached a peak in the first hour after myocardial reperfusion, decreased during the following hours, and then remained relatively stable, albeit significantly increased. Thus, myocardial ischemia-reperfusion first induces a large increase of the QT interval that subsequently decreases but does not return to baseline values within the first 24 hours after reperfusion. In the present study, the TpTe did not change significantly immediately after reperfusion, whereas Bonnemeier et al24 found that TpTe decreased with time in the first 4 hours post-pPCI, to achieve a stable level hereafter. The magnitude of the T wave and hence the TpTe are dependent of the angle between the repolarization vector and the investigating lead.25 Because the evaluation of TpTe is performed in varying leads to avoid leads with ST elevation, there is a risk that the repolarization angle may influence the result. However, there was no difference in TpTe between the chosen leads, and mortality was similar between chosen leads, making it unlikely that lead selection has major effects.
Prolongation of TpTe and survival after pPCI
There are limited data on the reference range of TpTe in healthy individuals, but most studies have found values below 100 milliseconds in healthy populations.9, 10, 26, 27 In groups of patients with increased risk of arrhythmias, the TpTe was often more than 100 milliseconds.2, 10, 13, 28 Tpeak-Tend interval greater than 100 milliseconds could therefore be considered as prolonged, and in agreement with this contention, we found that only 1 of 10 fatalities during follow-up occurred in patients with TpTe less than 100 milliseconds. The high negative predictive value of TpTe seems to be comparable with values obtained with T wave alternans and signal-averaged ECG analyses. However, TpTe is much easier to determine for risk stratification in the acute phase of MI.1, 5
TpTe pre-pPCI versus post-pPCl
Tpeak-Tend interval pre-pPCI, but not post-pPCI, predicted patient survival in our study. One explanation may be that during myocardial ischemia, increased TpTe represented a temporary arrhythmogenic substrate in nonsurvivors that was resolved, in part, by reperfusion and that the interval subsequently shortened and became comparable with TpTe in survivors. With a later ischemic episode, the substrate may reappear, suggesting that the nonsurvivors are more sensitive to ischemic injury and more susceptible to arrhythmias. There was an increased mortality around the index MI, which, after the mortality, remained low until approximately 1-year post-MI, in which it increased in the group with TpTe greater than 100 milliseconds. The reason for this temporal course of mortality is unclear at present, but it is notable that the increased mortality after 12 months coincided with the discontinuation of clopidogrel.
An increased TpTe has previously been shown to be associated with an increase in arrhythmic events under various conditions2, 13, 29, 30 including in patients with coronary artery disease and post-MI.10, 11, 31 Some of these studies, however, used a retrospective case-control design, whereas we used a prospective design that allowed for a firmer conclusion that a prolonged TpTe does indeed carry prognostic information. Bonnemeier et al24 found that the TpTe assessed from Holter recordings was hour-by-hour significantly higher in patients with major arrhythmic events in the first 24 hours post-PCI. On the other hand, other studies did not confirm the association between TpTe and adverse outcome.28, 32 Zabel et al28 investigated TpTe in 280 MI survivors and found no significant difference in TpTe in those with arrhythmia or death in the follow-up period. Several factors may explain this discrepancy with the results in our study. First, the study of Zabel et al was from 1998, with only 12% of patients receiving pPCI, and the investigators only evaluated TpTe post-pPCI, where we also found no prognostic power of the parameter. Second, we only examined patients with first-time MI, whereas Zabel et al looked at MI survivors regardless of earlier MI. Finally, Zabel et al used TpTe measurements that were averaged over either all leads or the precordial leads, whereas we used alternating single leads (depending on ST-segment deviation).
Effects of infarct-related artery, LVEF, and symptom to balloon time
The TpTe does not vary according to infarct-related artery when examined in leads with limited ST-segment deviation. In our study, there was no association between a decreased LVEF and the TpTe. This finding seems to be in agreement with results from patients undergoing elective PCI, where reduced LVEF was not associated with significant changes of TpTe.24 Thus, TpTe does not seem to be a surrogate of decreased left ventricular function. The symptom to balloon time is a well-defined prognostic factor in patients with STEMI undergoing pPCI,33, 34 and the current study, to the best of our knowledge, is the first to evaluate effects of symptom to balloon time on TpTe. There was, however, no difference in TpTe between the quartiles of symptom to balloon time, indicating that the duration of myocardial ischemia does not influence the magnitude of TpTe increase.
Limitations
Because of the limited number of events during follow-up, we were not able to perform Cox regression models with inclusion of all study parameters. No attempt was made to analyze causes of death because of the small number of events. This was a single-center study, and the findings should be confirmed in larger multicenter trials.
Conclusion
In conclusion, TpTe pre-pPCI predicted all-cause mortality in patients with STEMI undergoing pPCI. TpTe and the QT interval were increased after pPCI, whereas TpTe seems to be independent of infarct-related artery, LVEF, and symptom to balloon time. Pre-pPCI may be a new marker of increased risk in patients with STEMI undergoing pPCI, and the clinical value of this parameter should be further evaluated.
References
- Noninvasive risk assessment early after a myocardial infarction: The REFINE Study. J Am Coll Cardiol. 2007;50:2275
- Changes and predictive value of dispersion of repolarization parameters for appropriate therapy in patients with biventricular implantable cardioverter-defibrillators. Heart Rhythm. 2007;4:1274
- . Role of risk stratification after myocardial infarction. Curr Treat Options Cardiovasc Med. 2009;11:10
- . Risk stratification and prognostic factors in the post-myocardial infarction patient. Am J Cardiol. 2008;102:13G
- Prediction of fatal or near-fatal cardiac arrhythmia events in patients with depressed left ventricular function after an acute myocardial infarction. Eur Heart J. 2009;30:689
- Transmural repolarisation in the left ventricle in humans during normoxia and ischaemia. Cardiovasc Res. 2001;50:454
- . Is there a significant transmural gradient in repolarization time in the intact heart? Repolarization gradients in the intact heart. Circ Arrhythmia Electrophysiol. 2009;2:89
- . Tpeak-Tend interval as an index of transmural dispersion of repolarization. Eur J Clin Invest. 2001;31:555
- . Comparative reproducibility of QT, QT peak, and T peak-T end intervals and dispersion in normal subjects, patients with myocardial infarction, and patients with hypertrophic cardiomyopathy. Pacing Clin Electrophysiol. 1998;21:2376
- Transmural dispersion of repolarization and ventricular tachyarrhythmias. J Electrocardiol. 2004;37:191
- The terminal portion of the T wave: a new electrocardiographic marker of risk of ventricular arrhythmias. Pacing Clin Electrophysiol. 2000;23:1957
- . Cellular basis for the normal T Wave and the electrocardiographic manifestations of the long-QT syndrome. Circulation. 1998;98:1928
- Tpeak-Tend and Tpeak-Tend dispersion as risk factors for ventricular tachycardia/ventricular fibrillation in patients with the brugada syndrome. J Am Coll Cardiol. 2006;47:1828
- Reference values of ECG repolarization variables in a healthy population. J Electrocardiol. 2009;[in review]
- . Precision of QT interval measurement by advanced electrocardiographic equipment. Pacing Clin Electrophysiol. 2006;29:1277
- . Youden index and optimal cut-point estimated from observations affected by a lower limit of detection. Biom J. 2008;50:419
- . Mechanisms of sudden cardiac death. J Clin Invest. 2005;115:2305
- . Dispersion of ventricular repolarization and refractory period. Cardiovasc Res. 2001;50:10
- . Regulation of ion channels and arrhythmias in the ischemic heart. J Electrocardiol. 2007;40:S37
- . Cardiac ionic currents and acute ischemia: from channels to arrhythmias. Physiol Rev. 1999;79:917
- . Functional, structural, and dynamic basis of electrical heterogeneity in healthy and diseased cardiac muscle: implications for arrhythmogenesis and anti-arrhythmic drug therapy. Pharmacol Ther. 1999;84:207
- . Reperfusion arrhythmias in isolated perfused pig hearts. Inhomogeneities in extracellular potassium, ST and TQ potentials, and transmembrane action potentials. Circ Res. 1992;71:1131
- . Prolongation of the QTc interval is seen uniformly during early transmural ischemia. J Am Coll Cardiol. 2007;49:1299
- . Course and prognostic implications of QT interval and QT interval variability after primary coronary angioplasty in acute myocardial infarction. J Am Coll Cardiol. 2001;37:440
- . QT dispersion as an attribute of T-loop morphology. Circulation. 1999;99:1458
- . Computer quantitation of Q-T and terminal T wave (aT-eT) intervals during exercise: methodology and results in normal men. Am J Cardiol. 1981;47:1168
- Sex-dependent electrocardiographic pattern of cardiac repolarization. Am Heart J. 2000;140:430
- . Assessment of QT dispersion for prediction of mortality or arrhythmic events after myocardial infarction: results of a prospective, long-term follow-up study. Circulation. 1998;97:2543
- T wave peak-to-end interval and QT dispersion in acquired long QT syndrome: a new index for arrhythmogenicity. Clin Sci (Lond). 2003;105:671
- Baseline values and sotalol-induced changes of ventricular repolarization duration, heterogeneity, and instability in patients with a history of drug-induced Torsades de Pointes. J Clin Pharmacol. 2009;49:6
- Postmyocardial infarction patients susceptible to ventricular tachycardia show increased T wave dispersion independent of delayed ventricular conduction. J Cardiovasc Electrophysiol. 2001;12:1115
- T-peak to T-end (TpTe) interval in long QT syndrome. J Electrocardiol. 2008;41:603
- Symptom-onset-to-balloon time and mortality in patients with acute myocardial infarction treated by primary angioplasty. J Am Coll Cardiol. 2003;42:991
- Relationship of symptom-onset-to-balloon time and door-to-balloon time with mortality in patients undergoing angioplasty for acute myocardial infarction. JAMA. 2000;283:2941
☆ The study was supported by the Danish Heart Foundation, John and Tove Girotti's Foundation, Danish National Research Foundation, King Christian X' Foundation and Lægernes Forsikringsforening.
PII: S0022-0736(09)00254-4
doi:10.1016/j.jelectrocard.2009.06.009
© 2009 Elsevier Inc. All rights reserved.
