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ScienceDirect Journal of Electrocardiology 49 (2016) 214 – 215 www.jecgonline.com
Repolarization variability — Friend or foe? The duration of ventricular repolarization (VR), whether measured experimentally as action potential duration (APD) or in humans as the QT interval, is dependent on the preceding diastolic interval, a phenomenon known as restitution. A salient feature of restitution is hysteresis, which means that not only the preceding diastolic interval but several hundred preceding intervals influence the VR duration in any cardiac cycle, a phenomenon also referred to as ultra-rapid cardiac memory [1]. The physiological advantage of hysteresis is optimization of systolic ejection time and diastolic filling time, coronary perfusion, and electrical stabilization. Since the 1990s there has been a parallel development of different methods of assessing electrical – and especially VR – variability and its relation to vulnerability to ventricular arrhythmias in various conditions of congenital and acquired cardiac disease [2–6]. These methods are different and can be summarized as follows: (1) TWA, power spectral analysis of T-wave alternans on the microV level during atrial pacing close to 100 beats per minute (and subsequently during exercise testing) [2], (2) QTVI, the variance and mean of QT and RR intervals at rest and not taking into account the order in which these intervals were recorded [3], (3) TSV, T-wave spectral variance at rest based on 2-dimensional Fourier transform of consecutive T waves focusing on a 200 ms time window centered around T peak [4], and (4) STV, short-term variability of the APD [5] or QT interval measured from consecutive cardiac cycles at rest [6]. The figure illustrates in its upper part the relation between the earliest and latest end of repolarization and Tpeak (maximum repolarization gradient) and Tend on the ECG according to porcine and canine experiments (Fig. 1). The lower part of the figure shows approximations of the segments of the cardiac cycle used for beat-to-beat VR variability analysis in the different methods referred to. Several later studies (not mentioned here due to limited space) have shown that prognostic information concerning subsequent cardiac events can be gained from these measures of VR variability. In this issue of the Journal Drs. Arini and Valverde have applied a modified version of the TSV method to 12-lead ECGs from 38 patients with myocardial infarction under healing (within 7 days) and also at presumably healed myocardial infarction (after 60 days), and compared with ECGs from 49 healthy controls, all available on the so called Physio-Bank [7]. They observed that the T-wave spectral variance was considerably higher in ECGs from patients vs. control subjects, especially during the earlier phase. http://dx.doi.org/10.1016/j.jelectrocard.2016.01.006 0022-0736/© 2016 Elsevier Inc. All rights reserved.
Furthermore, they found that the preferential lead was V4 for anterior and aVF for inferior infarcts. They also used QTVI for comparison, for which they should be commended. They found similar results with the exception that the TSV but not the QTVI results were modulated over time, if this represents an asset for any of the two methods that can be argued. Does less abnormal TSV after 60 days represent a return to more normal repolarization and less risk for arrhythmia? We don't know. Is QTVI better than TSV for separating hearts with vs. without structural abnormalities (here healed infarcts) that might pose a risk for future arrhythmias? We don't know. This seems to be the first study comparing these two methods for assessing VR variability. Previously, however, both QTVI and STV-QT analyzed from right ventricular implantable cardioverter defibrillator electrograms were found predictive of sudden cardiac death or fast ventricular tachycardia or fibrillation during on average 2 years follow-up [8]. Furthermore, in 41 LQTS – patients type 1 and type 2 – the short-term variability of many VR measures was increased by a factor 2 compared to 41 healthy age and sex matched controls; for the QT interval the QTVI analysis gave a similar result [9]. It is certainly reassuring when different measures of VR variability agree, like in the present study from Drs. Arini and Valverde, despite the temporal and spatial complexity of VR. While the propensity for arrhythmias is mainly linked to VR abnormalities in congenital and acquired LQTS, it is different for myocardial infarction. In the acute phase of a myocardial infarction in humans and pigs, there is a temporal association between the propensity for primary ventricular fibrillation and large VR abnormalities (but minor depolarization changes) during both occlusion and reperfusion. In the chronic phase, conduction abnormalities, such as areas of slow conduction in the vicinity (border zone) of the infarct scar, set up the stage for monomorphic reentrant tachycardia, which might degenerate into ventricular fibrillation, and finally asystole. Without doubt, conduction and VR abnormalities together play important roles in the arrhythmogenesis in ischemic heart disease. Drs. Arini and Valverde have in this issue of the Journal brought VR variability into the limelight. Also in healthy individuals there are, however, both heart rate and VR variability. Therefore, some crucial issues are: when and how VR variability turns into instability, if it is possible to identify patients at risk for life-threatening ventricular arrhythmias, and
Repolarization variability — Friend or foe?
215
Fig. 1. The figure illustrates in its upper part the relation between the earliest and latest end of repolarization and Tpeak and Tend on the ECG according to porcine and canine experiments. The lower part of the figure shows approximations of the segments of the cardiac cycle used for beat-to-beat ventricular repolarization variability analysis in the different methods referred to in the text.Modified from Vahedi F, “Vectorcardiographic evaluation of ventricular repolarization in healthy individuals and LQTS mutation carriers.” Thesis, University of Gothenburg 2013. ISBN 978-91-628-8733-9.
the clinical usefulness of the proposed methods in such a process. On this occasion it seems appropriate to bring to the readership's attention an article published in this Journal in 2009, where the title says it all: “The many faces of repolarization instability: which one is prognostic?” [10]. Lennart Bergfeldt MD, PhD Department of Molecular and Clinical Medicine/Cardiology Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden *Corresponding author: Department of Cardiology Sahlgrenska University Hospital, Blaa Straaket 3, 1st floor S-413 45 Gothenburg, Sweden E-mail addres: [email protected] References [1] Rosen MR, Bergfeldt L. Cardiac memory: the slippery slope twixt normalcy and pathology. Trends Cardiovasc Med 2015;25:687–96. [2] Rosenbaum DS, Jackson LE, Smith JM, Garan H, Ruskin JN, Cohen RJ. Electrical alternans and vulnerability to ventricular arrhythmias. N Engl J Med 1994;330:235–41.
[3] Berger RD, Kasper EK, Baughman KL, Marban E, Calkins H, Tomaselli GF. Beat-to-beat QT interval variability: novel evidence for repolarization lability in ischemic and nonischemic dilated cardiomyopathy. Circulation 1997;96:1557–65. [4] Steinbigler P, Haberl R, Nespithal K, Spiegl A, Schmücking I, Steinbeck G. T wave spectral variance: a new method to determine inhomogeneous repolarization by T wave beat-to-beat variability in patients prone to ventricular arrhythmias. J Electrocardiol 1998;30(Suppl):137–44. [5] Hondeghem LM, Carlsson L, Duker G. Instability and triangulation of the action potential predict serious proarrthythmia, but action potential duration prolongation is antiarrhythmic. Circulation 2001;103:2004–13. [6] Hinterseer M, Thomsen MB, Beckmann B-M, Pfeufer A, Schimpf R, Wichmann H-E, et al. Beat-to-beat variability of QT intervals is increased in patients with drug-induced long-QT syndrome: a case– control study. Eur Heart J 2008;29:185–90. [7] Arini PD, Valverde ER. Beat-to-beat electrocardiographic analysis of ventricular repolarization variability in patients after myocardial infarction. J Electrocardiol, to be completed. [8] Oosterhoff P, Tereshchenko LG, van der Heyden MA, Ghanem RN, Fetics BJ, Berger RD, et al. Short-term variability of repolarization predicts ventricular tachycardia and sudden cardiac death in patients with structural heart disease: a comparison with QT variability index. Heart Rhythm 2011;8:1584–90. [9] Diamant UB, Vahedi F, Winbo A, Rydberg A, Stattin EL, Jensen SM, et al. Electrophysiological phenotype in the LQTS mutations Y111C and R518X in the KCNQ1 gene. J Appl Physiol 2013;115:1423–32. [10] Shusterman V, Lampert R, London B. The many faces of repolarization instability: which one is prognostic? J Electrocardiol 2009;42:511–6.
ScienceDirect Journal of Electrocardiology 49 (2016) 214 – 215 www.jecgonline.com
Repolarization variability — Friend or foe? The duration of ventricular repolarization (VR), whether measured experimentally as action potential duration (APD) or in humans as the QT interval, is dependent on the preceding diastolic interval, a phenomenon known as restitution. A salient feature of restitution is hysteresis, which means that not only the preceding diastolic interval but several hundred preceding intervals influence the VR duration in any cardiac cycle, a phenomenon also referred to as ultra-rapid cardiac memory [1]. The physiological advantage of hysteresis is optimization of systolic ejection time and diastolic filling time, coronary perfusion, and electrical stabilization. Since the 1990s there has been a parallel development of different methods of assessing electrical – and especially VR – variability and its relation to vulnerability to ventricular arrhythmias in various conditions of congenital and acquired cardiac disease [2–6]. These methods are different and can be summarized as follows: (1) TWA, power spectral analysis of T-wave alternans on the microV level during atrial pacing close to 100 beats per minute (and subsequently during exercise testing) [2], (2) QTVI, the variance and mean of QT and RR intervals at rest and not taking into account the order in which these intervals were recorded [3], (3) TSV, T-wave spectral variance at rest based on 2-dimensional Fourier transform of consecutive T waves focusing on a 200 ms time window centered around T peak [4], and (4) STV, short-term variability of the APD [5] or QT interval measured from consecutive cardiac cycles at rest [6]. The figure illustrates in its upper part the relation between the earliest and latest end of repolarization and Tpeak (maximum repolarization gradient) and Tend on the ECG according to porcine and canine experiments (Fig. 1). The lower part of the figure shows approximations of the segments of the cardiac cycle used for beat-to-beat VR variability analysis in the different methods referred to. Several later studies (not mentioned here due to limited space) have shown that prognostic information concerning subsequent cardiac events can be gained from these measures of VR variability. In this issue of the Journal Drs. Arini and Valverde have applied a modified version of the TSV method to 12-lead ECGs from 38 patients with myocardial infarction under healing (within 7 days) and also at presumably healed myocardial infarction (after 60 days), and compared with ECGs from 49 healthy controls, all available on the so called Physio-Bank [7]. They observed that the T-wave spectral variance was considerably higher in ECGs from patients vs. control subjects, especially during the earlier phase. http://dx.doi.org/10.1016/j.jelectrocard.2016.01.006 0022-0736/© 2016 Elsevier Inc. All rights reserved.
Furthermore, they found that the preferential lead was V4 for anterior and aVF for inferior infarcts. They also used QTVI for comparison, for which they should be commended. They found similar results with the exception that the TSV but not the QTVI results were modulated over time, if this represents an asset for any of the two methods that can be argued. Does less abnormal TSV after 60 days represent a return to more normal repolarization and less risk for arrhythmia? We don't know. Is QTVI better than TSV for separating hearts with vs. without structural abnormalities (here healed infarcts) that might pose a risk for future arrhythmias? We don't know. This seems to be the first study comparing these two methods for assessing VR variability. Previously, however, both QTVI and STV-QT analyzed from right ventricular implantable cardioverter defibrillator electrograms were found predictive of sudden cardiac death or fast ventricular tachycardia or fibrillation during on average 2 years follow-up [8]. Furthermore, in 41 LQTS – patients type 1 and type 2 – the short-term variability of many VR measures was increased by a factor 2 compared to 41 healthy age and sex matched controls; for the QT interval the QTVI analysis gave a similar result [9]. It is certainly reassuring when different measures of VR variability agree, like in the present study from Drs. Arini and Valverde, despite the temporal and spatial complexity of VR. While the propensity for arrhythmias is mainly linked to VR abnormalities in congenital and acquired LQTS, it is different for myocardial infarction. In the acute phase of a myocardial infarction in humans and pigs, there is a temporal association between the propensity for primary ventricular fibrillation and large VR abnormalities (but minor depolarization changes) during both occlusion and reperfusion. In the chronic phase, conduction abnormalities, such as areas of slow conduction in the vicinity (border zone) of the infarct scar, set up the stage for monomorphic reentrant tachycardia, which might degenerate into ventricular fibrillation, and finally asystole. Without doubt, conduction and VR abnormalities together play important roles in the arrhythmogenesis in ischemic heart disease. Drs. Arini and Valverde have in this issue of the Journal brought VR variability into the limelight. Also in healthy individuals there are, however, both heart rate and VR variability. Therefore, some crucial issues are: when and how VR variability turns into instability, if it is possible to identify patients at risk for life-threatening ventricular arrhythmias, and
Repolarization variability — Friend or foe?
215
Fig. 1. The figure illustrates in its upper part the relation between the earliest and latest end of repolarization and Tpeak and Tend on the ECG according to porcine and canine experiments. The lower part of the figure shows approximations of the segments of the cardiac cycle used for beat-to-beat ventricular repolarization variability analysis in the different methods referred to in the text.Modified from Vahedi F, “Vectorcardiographic evaluation of ventricular repolarization in healthy individuals and LQTS mutation carriers.” Thesis, University of Gothenburg 2013. ISBN 978-91-628-8733-9.
the clinical usefulness of the proposed methods in such a process. On this occasion it seems appropriate to bring to the readership's attention an article published in this Journal in 2009, where the title says it all: “The many faces of repolarization instability: which one is prognostic?” [10]. Lennart Bergfeldt MD, PhD Department of Molecular and Clinical Medicine/Cardiology Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden *Corresponding author: Department of Cardiology Sahlgrenska University Hospital, Blaa Straaket 3, 1st floor S-413 45 Gothenburg, Sweden E-mail addres: [email protected] References [1] Rosen MR, Bergfeldt L. Cardiac memory: the slippery slope twixt normalcy and pathology. Trends Cardiovasc Med 2015;25:687–96. [2] Rosenbaum DS, Jackson LE, Smith JM, Garan H, Ruskin JN, Cohen RJ. Electrical alternans and vulnerability to ventricular arrhythmias. N Engl J Med 1994;330:235–41.
[3] Berger RD, Kasper EK, Baughman KL, Marban E, Calkins H, Tomaselli GF. Beat-to-beat QT interval variability: novel evidence for repolarization lability in ischemic and nonischemic dilated cardiomyopathy. Circulation 1997;96:1557–65. [4] Steinbigler P, Haberl R, Nespithal K, Spiegl A, Schmücking I, Steinbeck G. T wave spectral variance: a new method to determine inhomogeneous repolarization by T wave beat-to-beat variability in patients prone to ventricular arrhythmias. J Electrocardiol 1998;30(Suppl):137–44. [5] Hondeghem LM, Carlsson L, Duker G. Instability and triangulation of the action potential predict serious proarrthythmia, but action potential duration prolongation is antiarrhythmic. Circulation 2001;103:2004–13. [6] Hinterseer M, Thomsen MB, Beckmann B-M, Pfeufer A, Schimpf R, Wichmann H-E, et al. Beat-to-beat variability of QT intervals is increased in patients with drug-induced long-QT syndrome: a case– control study. Eur Heart J 2008;29:185–90. [7] Arini PD, Valverde ER. Beat-to-beat electrocardiographic analysis of ventricular repolarization variability in patients after myocardial infarction. J Electrocardiol, to be completed. [8] Oosterhoff P, Tereshchenko LG, van der Heyden MA, Ghanem RN, Fetics BJ, Berger RD, et al. Short-term variability of repolarization predicts ventricular tachycardia and sudden cardiac death in patients with structural heart disease: a comparison with QT variability index. Heart Rhythm 2011;8:1584–90. [9] Diamant UB, Vahedi F, Winbo A, Rydberg A, Stattin EL, Jensen SM, et al. Electrophysiological phenotype in the LQTS mutations Y111C and R518X in the KCNQ1 gene. J Appl Physiol 2013;115:1423–32. [10] Shusterman V, Lampert R, London B. The many faces of repolarization instability: which one is prognostic? J Electrocardiol 2009;42:511–6.
