Author's Accepted Manuscript
The Electrocardiographic Predictors of Bradycardiainduced Torsades de Pointes in Patients with Acquired Atrioventricular Block Min Soo Cho MD, Gi-Byoung Nam MD, Ph.D., Yong-Guin Kim MD, Ki-Won Hwang MD, Yoo-ri Kim MD, HyungOh Choi MD, Sung-Hwan Kim MD, Kyoung-Suk Rhee MD, Ph.D., Nam-Joon Kim MD, June-Soo Kim MD, Ph.D., Jun Kim MD, Ph.D., KeeJoon Choi MD, Ph.D., You-Ho Kim MD, Ph.D.
PII: DOI: Reference:
S1547-5271(14)01315-0 http://dx.doi.org/10.1016/j.hrthm.2014.11.018 HRTHM6015
To appear in:
Heart Rhythm
www.elsevier.com/locate/buildenv
Cite this article as: Min Soo Cho MD, Gi-Byoung Nam MD, Ph.D., Yong-Guin Kim MD, Ki-Won Hwang MD, Yoo-ri Kim MD, HyungOh Choi MD, Sung-Hwan Kim MD, Kyoung-Suk Rhee MD, Ph.D., Nam-Joon Kim MD, June-Soo Kim MD, Ph.D., Jun Kim MD, Ph.D., Kee-Joon Choi MD, Ph.D., You-Ho Kim MD, Ph.D., The Electrocardiographic Predictors of Bradycardia-induced Torsades de Pointes in Patients with Acquired Atrioventricular Block, Heart Rhythm, http://dx.doi.org/10.1016/j. hrthm.2014.11.018 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
The Electrocardiographic Predictors of Bradycardia-induced Torsades de Pointes in Patients with Acquired Atrioventricular Block Running title: Cho et al.; ECG predictors of Torsades de Pointes
Min Soo Cho, MD,* Gi-Byoung Nam, MD, PhD,* Yong-Guin Kim, MD,* Ki-Won Hwang, MD,* Yoo-ri Kim, MD,* HyungOh Choi, MD,* Sung-Hwan Kim, MD,* Kyoung-Suk Rhee, MD, PhD† Nam-Joon Kim, MD,‡ June-Soo Kim, MD, PhD,‡ Jun Kim, MD, PhD,* Kee-Joon Choi, MD, PhD,* and You-Ho Kim, MD, PhD* *
Heart Institute, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea;
†
Department of Cardiology, Chon-Buk National University Hospital, Jeon-Ju, Korea;
‡
Department of Cardiology, Samsung Medical Center, University of Sungkyunkwan, College of
Medicine, Seoul, Korea.
Corresponding author: Gi-Byoung Nam, M.D., Heart Institute, Asan Medical Center University of Ulsan College of Medicine, 388–1 Poongnap-dong Songpa-gu, Seoul, 138–736 South Korea. Phone: 82–2–3010–3159; Fax: 82–2–487–5918; E-mail: [email protected] Word count: 4,988 Conflicts of interests: None Funding sources: This study was supported by grants from the Asan Institute for Life Science (2011– 232, 2012-232), Asan Medical Center Clinical Research Fund (2010–0469).
Abstract Background: Predictors of Torsades de Pointes (TdP) in bradyarrhythmia-induced acquired long QT syndrome (LQTS) are not well defined. Objective: This study looked for electrocardiographic TdP predictors in patients with acquired atrioventricular block (AVB) and QT prolongation. Methods: We analyzed 12-lead electrocardiograms(ECGs) from 20 patients (2.2%, 15 females, 65.9±15.6 years old) with TdP episodes out of 898 AVB patients in three tertiary hospitals. The ECG repolarization parameters in TdP patients were compared with those of 80 age- and sex-matched control AVB patients with no TdP episodes. Results: TdP was initiated by premature ventricular complexes (PVCs) with a long-short sequence of activation. The average cycle length of the long sequence was 1289.9±228.9ms, and was 2.3±0.6 times longer than the cycle length of the short sequence. TdP patients had a significantly longer mean QT interval (716.4±98.9 vs. 523.2±91.3ms, p=0.001), mean T peak-to-end interval (334.2±59.1 vs. 144.0±73.7ms, p=0.001) and a higher Tpe/QT ratio (0.49±0.09 vs. 0.27±0.11, p=0.001) compared with non-TdP controls. TdP patients showed a higher prevalence of notched T waves in which T 2 was at least 3mm taller than T1 (45.0% vs. 1.3%, p=0.001), triphasic T waves (30.0% vs. 1.3%, p=0.001), reversed asymmetry (20.0% vs. 0%, p=0.001), and T wave alternans (35.0% vs. 0%, p=0.001). An algorithm combining these morphological parameters was able to differentiate TdP patients from nonTdP patients with high sensitivity (85.0%) and specificity (97.5%). Conclusion: An algorithm combining specific T wave morphologies was useful to identify patients with AVB who are at risk of developing TdP.
Key words: Atrioventricular block; Bradycardia; Torsades de Pointes; T waves; Long QT syndrome
1
List of abbreviations
TdP - Torsades de Pointes AVB - atrioventricular block LQTS - long QT syndrome Tpe - T peak to end interval ECG - electrocardiography VPC - ventricular premature complex TWA - T wave alternansIntroduction
The occurrence of QT prolongation and Torsades de Pointes (TdP) is a serious complication of an atrioventricular block (AVB). The prevention of TdP in the acquired QT prolongation is clinically important because of its potential to degenerate into ventricular fibrillation and sudden cardiac death.1 In this regard, the ability to identify patients at high risk of developing TdP would be clinically useful as preventive measures (temporary pacemaker or intravenous magnesium) could be applied more urgently. However, the predictors of TdP in bradyarrhythmia-induced acquired long QT syndrome (LQTS) are not well defined. Previous studies suggested that the QTc interval, the T peak to end interval (Tpe), or combination of LQT-2 like morphology with these intervals are predictors of TdP.2, 3 These predictors are based on the measurement of ECG intervals which are dependent on the individual observers and the methods used for measurement, which may lead to poor reproducibility.4 The morphologic change of T wave would be more intuitive, but was not sufficiently sensitive to use independently in the previous studies.3, 5 To find out the more easily recognizable predictors with sufficient sensitivity and specificity, we focused on the dynamicity of the T wave around TdP episode and hypothesized that there were more specific change of T wave morphology around the TdP occurrence.6 This retrospective case-control study attempted to find TdP predictors by focusing on T wave morphology close to the TdP episode, and proposes a simple electrocardiography (ECG) algorithm with easy applicability in clinical situations. 2
Methods
Patients We retrospectively reviewed medical records of 898 patients who were admitted and received permanent pacemaker therapy due to AVB at the Asan Medical Center (470 patients), the Chonbuk National University Hospital (122 patients) and the Samsung Medical Center (306 patients) from 1990 to 2010. Of these patients, 29 (3.2% [n=29/898]) patients had documented TdP during bradyarrhythmia. TdP was defined as polymorphic ventricular tachycardia (faster than 120 beats/min and at least three consecutive QRS complexes originating from the ventricles) with a twisting morphology and variable QRS complex amplitudes (Figure 1). Nine patients were excluded from the study: four patients with drug-induced QT prolongation (two patients had taken levofloxacin, one amiodarone, one haloperidol), one patient with hypomagenesemia, two patients with documented TdP only during pacing rhythm, and two patients with no available baseline ECGs. Therefore, the study group consisted of 20 patients whose TdP was caused solely by AVB-related bradyarrhythmia (Supplemental figure 1). For all these patients, more than 10 beats of TdP had been documented during ECG monitoring or telemetry. The control group patients (n=80) were randomly selected at a 1:4 ratio from age- and sex-matched patients with AVB without any evidence of TdP using random number generator in SPSS (version 18.0; SPSS Inc, Chicago, Illinois).This retrospective study was approved by the Institutional Review Board. The board exempted this study from the requirement for informed consents.
Electrocardiography The last 12 lead ECG before TdP occurrence was used for analysis. ECGs taken before TdP events were available for all TdP patients and the median interval between the ECG recordings and the TdP occurrences was 3 hours (interquartile range [IQR] 0.5–12 hours). ECGs were recorded at a gain of 10 mm/mV and paper speed of 25 mm/second. QT intervals were measured from the onset of the QRS complex to the end of T wave, which was defined as the point of its merger with the isoelectric line. 3
The QTc interval was calculated using Bazett’s formula (QTc=QT/square root of RR). The peak-toend (Tpe) interval was measured from the summit of the T wave to the end of the QT interval (Figure2). In case of notched T waves, the Tpe interval was measured from the summit of the first T wave. In addition, the Tpe/QT ratio was calculated from the QT and Tpe measurements.7 Both QT and Tpe intervals were measured in the leads with longest value. Whenever possible, these intervals were determined as a mean value derived from three consecutive cardiac cycles. However, in the cases with extremely slow heart rate and no available rhythm strips of the leads with longest intervals, only one or two cardiac cycles were used for measurement. Two cardiologists (MSC, GBN) independently measured these intervals. The intra- and inter-observer variabilities of QT interval measurement demonstrated an intraclass correlation coefficient of 0.97 (95% CI 0.96–0.98) and 0.95 (95% CI 0.930.97), respectively, and for Tpe interval measurement, 0.97 (95% CI 0.96–0.98) and 0.97 (95% CI 0.95-0.98), respectively. The differences between the two observers were resolved by consensus or opinion of a third author. For T wave morphology analysis, a normal T wave was defined as a single deflection having a smooth, rounded and positively directed morphology in all leads except aVR and V 1, with amplitudes not exceeding 0.5 mV in any limb lead or 1.5mV in any precordial lead.8 The following abnormal T wave patterns were identified: 1) T wave reversed asymmetry; 2) inverted T waves; 3) biphasic T waves; 4) notched T waves; and 5) T wave alternans (TWA). (Figure 2) The term reversed asymmetry was applied when the slope of the ascending limb was steeper than that of the descending limb (which is opposite to the normal, physiological asymmetric T wave). This reversed asymmetry means a long duration from the peak to the end of the T wave, or the Tpe interval, which can indicate a larger dispersion of ventricular repolarization. An inverted T wave pattern was defined when most of the leads showed only negative components. A biphasic T wave was defined as a T wave with two deflections, either positive/negative or negative/positive. A notched T wave was defined when the T wave had three deflections and two distinct peaks (T1, T2). In notched T waves, the term T1 < T2 was defined when the peak of T2 was taller than T1, and the term T1 < < T2, when the peak of T2 was taller than T1 by > 3 mm. When the nadir of the negative deflection of the notched T wave (between T1 and 4
T2) was below the isoelectric line, it was called a triphasic T wave. TWA was defined as macroscopic beat-to-beat alterations of the T wave amplitude >0.3 mV in the absence of significantly different (> 80 ms) RR intervals (Figure 3). Two cardiologists (MSC, GBN) independently analyzed the T wave morphology in the 12-lead ECGs. The intra- and inter-observer agreement was excellent with kappa value of 0.97 and 0.94, respectively. Physiologic U wave, which was completely separated from the T wave by an isoelectric line, was not included in our T wave analysis.9
Statistical analysis All statistical analyses were performed using SPSS (version 18.0; SPSS Inc, Chicago, Illinois) and MedCalc (version 11.6; MedCalc software, Mariakerke, Belgium). Summary statistics are presented as frequencies, percentages and means ± SD values. For continuous variables, the analysis of the differences between the group means was assessed using an unpaired Student's t-test and the MannWhitney U test. Chi-square tests and Fisher’s exact test were used to compare the frequencies of categorical variables. Receiver-operating characteristics (ROC) analysis was used to determine the optimal cut-off values of the continuous variables for TdP prediction. Pairwise comparisons between ROC curves were made using the method of Delong. All P values are 2-sided, and a value of P < 0.05 was considered significant.
Results
Baseline characteristics The baseline characteristics of the two groups are summarized in Table 1. The majority of the patients were female (75.0% [n=15/20]) and the mean age was 65.9±15.6 years. The number of syncopal episodes before hospital admission was significantly higher in the TdP group than in the control group (70.0% [n=14/20] vs. 30.0% [n=24/80], p=0.001). Four patients in the TdP group presented with progressively increasing dyspnea on exertion, two patients with non-specific dizziness, and two patients with asymptomatic AVB. The number of symptomatic patients and the duration of 5
symptoms were not significantly different between the two groups. There were no significant differences between the two groups in the history of medications, the degree of AVB, or prevalence of other arrhythmias (atrial fibrillation, sick sinus syndrome). There were no significant differences in echocardiography data.
ECG characteristics at TdP initiation ECGs at TdP initiation were available for twelve patients as rhythm strips and for two patients as 12lead ECGs. All TdP episodes occurred at the end of the T wave of the last QRS complex following a long pause triggered by one or more ventricular premature complexes (VPCs). In these patients the mean of the longest pause was 1289.9±228.9 ms, which was on average 2.3±0.6 times longer than the intervals of the following short sequence. The classic ‘short–long–short sequence’ was seen in 8 out of 14 patients (Figure 1A).
ECG characteristics of TdP patients The morphologic characteristics and measured parameters of T waves in TdP patients and controls are summarized in Table 2. Mean baseline RR intervals were not significantly different between the two groups. The mean QT interval (716.4±98.9 vs. 523.2±91.3ms, p=0.001) and mean QTc interval (590.5±65.8 vs. 430.3±77.3ms, p=0.001) were significantly longer in the TdP group than that in the control group. In addition, the mean Tpe (334.2±59.1 vs. 144.0±73.7ms, p=0.001) and corrected Tpe (280.4±66.9 vs. 118.9±62.2ms, p=0.001) intervals were significantly longer in the TdP group. On a scatter plot of the distribution of QT and Tpe intervals for TdP patients and controls, there was little overlap between the two groups (Figure 4). Tpe/QT ratio was also higher in the TdP group (0.49±0.09 vs. 0.27±0.11, p=0.001) In the morphology analysis, reversed asymmetry (20.0% [n=4/20] vs. 0% [n=0/80], p=0.001) and TWA (35.0% [n=7/20] vs. 0% [n=0/80], p=0.001) were seen only in the TdP group. Of the patients with single-deflection T waves (TdP group, n=6; control group, n=72), the Tpe interval was significantly longer (347.2±51.8 vs. 137.3±65.7ms, p=0.001) and Tpe/QT ratio was significantly 6
higher (0.51±0.11 vs. 0.27±0.11, p=0.001) in patients with reversed asymmetry. Notched T waves were seen more frequently in TdP patients than in control group patients (70.0% [n=14/20] vs. 10.0% [n=8/80], p=0.001). The prevalences of T1 < T2 (55.0% [n=11/20] vs. 3.8% [n=3/80], p=0.001) and T1
The Electrocardiographic Predictors of Bradycardiainduced Torsades de Pointes in Patients with Acquired Atrioventricular Block Min Soo Cho MD, Gi-Byoung Nam MD, Ph.D., Yong-Guin Kim MD, Ki-Won Hwang MD, Yoo-ri Kim MD, HyungOh Choi MD, Sung-Hwan Kim MD, Kyoung-Suk Rhee MD, Ph.D., Nam-Joon Kim MD, June-Soo Kim MD, Ph.D., Jun Kim MD, Ph.D., KeeJoon Choi MD, Ph.D., You-Ho Kim MD, Ph.D.
PII: DOI: Reference:
S1547-5271(14)01315-0 http://dx.doi.org/10.1016/j.hrthm.2014.11.018 HRTHM6015
To appear in:
Heart Rhythm
www.elsevier.com/locate/buildenv
Cite this article as: Min Soo Cho MD, Gi-Byoung Nam MD, Ph.D., Yong-Guin Kim MD, Ki-Won Hwang MD, Yoo-ri Kim MD, HyungOh Choi MD, Sung-Hwan Kim MD, Kyoung-Suk Rhee MD, Ph.D., Nam-Joon Kim MD, June-Soo Kim MD, Ph.D., Jun Kim MD, Ph.D., Kee-Joon Choi MD, Ph.D., You-Ho Kim MD, Ph.D., The Electrocardiographic Predictors of Bradycardia-induced Torsades de Pointes in Patients with Acquired Atrioventricular Block, Heart Rhythm, http://dx.doi.org/10.1016/j. hrthm.2014.11.018 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
The Electrocardiographic Predictors of Bradycardia-induced Torsades de Pointes in Patients with Acquired Atrioventricular Block Running title: Cho et al.; ECG predictors of Torsades de Pointes
Min Soo Cho, MD,* Gi-Byoung Nam, MD, PhD,* Yong-Guin Kim, MD,* Ki-Won Hwang, MD,* Yoo-ri Kim, MD,* HyungOh Choi, MD,* Sung-Hwan Kim, MD,* Kyoung-Suk Rhee, MD, PhD† Nam-Joon Kim, MD,‡ June-Soo Kim, MD, PhD,‡ Jun Kim, MD, PhD,* Kee-Joon Choi, MD, PhD,* and You-Ho Kim, MD, PhD* *
Heart Institute, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea;
†
Department of Cardiology, Chon-Buk National University Hospital, Jeon-Ju, Korea;
‡
Department of Cardiology, Samsung Medical Center, University of Sungkyunkwan, College of
Medicine, Seoul, Korea.
Corresponding author: Gi-Byoung Nam, M.D., Heart Institute, Asan Medical Center University of Ulsan College of Medicine, 388–1 Poongnap-dong Songpa-gu, Seoul, 138–736 South Korea. Phone: 82–2–3010–3159; Fax: 82–2–487–5918; E-mail: [email protected] Word count: 4,988 Conflicts of interests: None Funding sources: This study was supported by grants from the Asan Institute for Life Science (2011– 232, 2012-232), Asan Medical Center Clinical Research Fund (2010–0469).
Abstract Background: Predictors of Torsades de Pointes (TdP) in bradyarrhythmia-induced acquired long QT syndrome (LQTS) are not well defined. Objective: This study looked for electrocardiographic TdP predictors in patients with acquired atrioventricular block (AVB) and QT prolongation. Methods: We analyzed 12-lead electrocardiograms(ECGs) from 20 patients (2.2%, 15 females, 65.9±15.6 years old) with TdP episodes out of 898 AVB patients in three tertiary hospitals. The ECG repolarization parameters in TdP patients were compared with those of 80 age- and sex-matched control AVB patients with no TdP episodes. Results: TdP was initiated by premature ventricular complexes (PVCs) with a long-short sequence of activation. The average cycle length of the long sequence was 1289.9±228.9ms, and was 2.3±0.6 times longer than the cycle length of the short sequence. TdP patients had a significantly longer mean QT interval (716.4±98.9 vs. 523.2±91.3ms, p=0.001), mean T peak-to-end interval (334.2±59.1 vs. 144.0±73.7ms, p=0.001) and a higher Tpe/QT ratio (0.49±0.09 vs. 0.27±0.11, p=0.001) compared with non-TdP controls. TdP patients showed a higher prevalence of notched T waves in which T 2 was at least 3mm taller than T1 (45.0% vs. 1.3%, p=0.001), triphasic T waves (30.0% vs. 1.3%, p=0.001), reversed asymmetry (20.0% vs. 0%, p=0.001), and T wave alternans (35.0% vs. 0%, p=0.001). An algorithm combining these morphological parameters was able to differentiate TdP patients from nonTdP patients with high sensitivity (85.0%) and specificity (97.5%). Conclusion: An algorithm combining specific T wave morphologies was useful to identify patients with AVB who are at risk of developing TdP.
Key words: Atrioventricular block; Bradycardia; Torsades de Pointes; T waves; Long QT syndrome
1
List of abbreviations
TdP - Torsades de Pointes AVB - atrioventricular block LQTS - long QT syndrome Tpe - T peak to end interval ECG - electrocardiography VPC - ventricular premature complex TWA - T wave alternansIntroduction
The occurrence of QT prolongation and Torsades de Pointes (TdP) is a serious complication of an atrioventricular block (AVB). The prevention of TdP in the acquired QT prolongation is clinically important because of its potential to degenerate into ventricular fibrillation and sudden cardiac death.1 In this regard, the ability to identify patients at high risk of developing TdP would be clinically useful as preventive measures (temporary pacemaker or intravenous magnesium) could be applied more urgently. However, the predictors of TdP in bradyarrhythmia-induced acquired long QT syndrome (LQTS) are not well defined. Previous studies suggested that the QTc interval, the T peak to end interval (Tpe), or combination of LQT-2 like morphology with these intervals are predictors of TdP.2, 3 These predictors are based on the measurement of ECG intervals which are dependent on the individual observers and the methods used for measurement, which may lead to poor reproducibility.4 The morphologic change of T wave would be more intuitive, but was not sufficiently sensitive to use independently in the previous studies.3, 5 To find out the more easily recognizable predictors with sufficient sensitivity and specificity, we focused on the dynamicity of the T wave around TdP episode and hypothesized that there were more specific change of T wave morphology around the TdP occurrence.6 This retrospective case-control study attempted to find TdP predictors by focusing on T wave morphology close to the TdP episode, and proposes a simple electrocardiography (ECG) algorithm with easy applicability in clinical situations. 2
Methods
Patients We retrospectively reviewed medical records of 898 patients who were admitted and received permanent pacemaker therapy due to AVB at the Asan Medical Center (470 patients), the Chonbuk National University Hospital (122 patients) and the Samsung Medical Center (306 patients) from 1990 to 2010. Of these patients, 29 (3.2% [n=29/898]) patients had documented TdP during bradyarrhythmia. TdP was defined as polymorphic ventricular tachycardia (faster than 120 beats/min and at least three consecutive QRS complexes originating from the ventricles) with a twisting morphology and variable QRS complex amplitudes (Figure 1). Nine patients were excluded from the study: four patients with drug-induced QT prolongation (two patients had taken levofloxacin, one amiodarone, one haloperidol), one patient with hypomagenesemia, two patients with documented TdP only during pacing rhythm, and two patients with no available baseline ECGs. Therefore, the study group consisted of 20 patients whose TdP was caused solely by AVB-related bradyarrhythmia (Supplemental figure 1). For all these patients, more than 10 beats of TdP had been documented during ECG monitoring or telemetry. The control group patients (n=80) were randomly selected at a 1:4 ratio from age- and sex-matched patients with AVB without any evidence of TdP using random number generator in SPSS (version 18.0; SPSS Inc, Chicago, Illinois).This retrospective study was approved by the Institutional Review Board. The board exempted this study from the requirement for informed consents.
Electrocardiography The last 12 lead ECG before TdP occurrence was used for analysis. ECGs taken before TdP events were available for all TdP patients and the median interval between the ECG recordings and the TdP occurrences was 3 hours (interquartile range [IQR] 0.5–12 hours). ECGs were recorded at a gain of 10 mm/mV and paper speed of 25 mm/second. QT intervals were measured from the onset of the QRS complex to the end of T wave, which was defined as the point of its merger with the isoelectric line. 3
The QTc interval was calculated using Bazett’s formula (QTc=QT/square root of RR). The peak-toend (Tpe) interval was measured from the summit of the T wave to the end of the QT interval (Figure2). In case of notched T waves, the Tpe interval was measured from the summit of the first T wave. In addition, the Tpe/QT ratio was calculated from the QT and Tpe measurements.7 Both QT and Tpe intervals were measured in the leads with longest value. Whenever possible, these intervals were determined as a mean value derived from three consecutive cardiac cycles. However, in the cases with extremely slow heart rate and no available rhythm strips of the leads with longest intervals, only one or two cardiac cycles were used for measurement. Two cardiologists (MSC, GBN) independently measured these intervals. The intra- and inter-observer variabilities of QT interval measurement demonstrated an intraclass correlation coefficient of 0.97 (95% CI 0.96–0.98) and 0.95 (95% CI 0.930.97), respectively, and for Tpe interval measurement, 0.97 (95% CI 0.96–0.98) and 0.97 (95% CI 0.95-0.98), respectively. The differences between the two observers were resolved by consensus or opinion of a third author. For T wave morphology analysis, a normal T wave was defined as a single deflection having a smooth, rounded and positively directed morphology in all leads except aVR and V 1, with amplitudes not exceeding 0.5 mV in any limb lead or 1.5mV in any precordial lead.8 The following abnormal T wave patterns were identified: 1) T wave reversed asymmetry; 2) inverted T waves; 3) biphasic T waves; 4) notched T waves; and 5) T wave alternans (TWA). (Figure 2) The term reversed asymmetry was applied when the slope of the ascending limb was steeper than that of the descending limb (which is opposite to the normal, physiological asymmetric T wave). This reversed asymmetry means a long duration from the peak to the end of the T wave, or the Tpe interval, which can indicate a larger dispersion of ventricular repolarization. An inverted T wave pattern was defined when most of the leads showed only negative components. A biphasic T wave was defined as a T wave with two deflections, either positive/negative or negative/positive. A notched T wave was defined when the T wave had three deflections and two distinct peaks (T1, T2). In notched T waves, the term T1 < T2 was defined when the peak of T2 was taller than T1, and the term T1 < < T2, when the peak of T2 was taller than T1 by > 3 mm. When the nadir of the negative deflection of the notched T wave (between T1 and 4
T2) was below the isoelectric line, it was called a triphasic T wave. TWA was defined as macroscopic beat-to-beat alterations of the T wave amplitude >0.3 mV in the absence of significantly different (> 80 ms) RR intervals (Figure 3). Two cardiologists (MSC, GBN) independently analyzed the T wave morphology in the 12-lead ECGs. The intra- and inter-observer agreement was excellent with kappa value of 0.97 and 0.94, respectively. Physiologic U wave, which was completely separated from the T wave by an isoelectric line, was not included in our T wave analysis.9
Statistical analysis All statistical analyses were performed using SPSS (version 18.0; SPSS Inc, Chicago, Illinois) and MedCalc (version 11.6; MedCalc software, Mariakerke, Belgium). Summary statistics are presented as frequencies, percentages and means ± SD values. For continuous variables, the analysis of the differences between the group means was assessed using an unpaired Student's t-test and the MannWhitney U test. Chi-square tests and Fisher’s exact test were used to compare the frequencies of categorical variables. Receiver-operating characteristics (ROC) analysis was used to determine the optimal cut-off values of the continuous variables for TdP prediction. Pairwise comparisons between ROC curves were made using the method of Delong. All P values are 2-sided, and a value of P < 0.05 was considered significant.
Results
Baseline characteristics The baseline characteristics of the two groups are summarized in Table 1. The majority of the patients were female (75.0% [n=15/20]) and the mean age was 65.9±15.6 years. The number of syncopal episodes before hospital admission was significantly higher in the TdP group than in the control group (70.0% [n=14/20] vs. 30.0% [n=24/80], p=0.001). Four patients in the TdP group presented with progressively increasing dyspnea on exertion, two patients with non-specific dizziness, and two patients with asymptomatic AVB. The number of symptomatic patients and the duration of 5
symptoms were not significantly different between the two groups. There were no significant differences between the two groups in the history of medications, the degree of AVB, or prevalence of other arrhythmias (atrial fibrillation, sick sinus syndrome). There were no significant differences in echocardiography data.
ECG characteristics at TdP initiation ECGs at TdP initiation were available for twelve patients as rhythm strips and for two patients as 12lead ECGs. All TdP episodes occurred at the end of the T wave of the last QRS complex following a long pause triggered by one or more ventricular premature complexes (VPCs). In these patients the mean of the longest pause was 1289.9±228.9 ms, which was on average 2.3±0.6 times longer than the intervals of the following short sequence. The classic ‘short–long–short sequence’ was seen in 8 out of 14 patients (Figure 1A).
ECG characteristics of TdP patients The morphologic characteristics and measured parameters of T waves in TdP patients and controls are summarized in Table 2. Mean baseline RR intervals were not significantly different between the two groups. The mean QT interval (716.4±98.9 vs. 523.2±91.3ms, p=0.001) and mean QTc interval (590.5±65.8 vs. 430.3±77.3ms, p=0.001) were significantly longer in the TdP group than that in the control group. In addition, the mean Tpe (334.2±59.1 vs. 144.0±73.7ms, p=0.001) and corrected Tpe (280.4±66.9 vs. 118.9±62.2ms, p=0.001) intervals were significantly longer in the TdP group. On a scatter plot of the distribution of QT and Tpe intervals for TdP patients and controls, there was little overlap between the two groups (Figure 4). Tpe/QT ratio was also higher in the TdP group (0.49±0.09 vs. 0.27±0.11, p=0.001) In the morphology analysis, reversed asymmetry (20.0% [n=4/20] vs. 0% [n=0/80], p=0.001) and TWA (35.0% [n=7/20] vs. 0% [n=0/80], p=0.001) were seen only in the TdP group. Of the patients with single-deflection T waves (TdP group, n=6; control group, n=72), the Tpe interval was significantly longer (347.2±51.8 vs. 137.3±65.7ms, p=0.001) and Tpe/QT ratio was significantly 6
higher (0.51±0.11 vs. 0.27±0.11, p=0.001) in patients with reversed asymmetry. Notched T waves were seen more frequently in TdP patients than in control group patients (70.0% [n=14/20] vs. 10.0% [n=8/80], p=0.001). The prevalences of T1 < T2 (55.0% [n=11/20] vs. 3.8% [n=3/80], p=0.001) and T1
