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• W2010658812 abstract "Objectives. To investigate effects of doxorubicin therapy on cardiac electrophysiology, with special emphasis on QT dispersion and late potentials, in lymphoma patients. Design. Prospective study. Setting. University hospital. Subjects. Twenty-eight adult non-Hodgkin’s lymphoma patients who received doxorubicin to a cumulative dose of 400–500 mg m–2. Main outcome measures. Standard 12-lead electrocardiogram (ECG) and signal-averaged ECG (SAECG) recordings were performed at baseline and after cumulative doxorubicin doses of 200, 400 and 500 mg m–2. Results. Heart rate-corrected QT interval (QTc) increased from 402 ± 4 to 416 ± 5 ms (P = 0.002) during the study period. QT dispersion (variability in QT interval duration amongst the different leads of the standard 12-lead ECG) increased from 24.1 ± 2.5 to 35.0 ± 2.8 ms (P = 0.041) and QTc dispersion increased from 26.5 ± 2.5 to 39.0 ± 3.5 ms (P = 0.039). Five patients (18%) developed QT dispersion exceeding 50 ms. In addition, two patients (7%) developed late potentials during doxorubicin therapy. The changes in QTc duration, QT dispersion and late potentials occurred independently of the impairment of left ventricular function. Conclusions. Prolongation of QTc, increased QT dispersion and development of late potentials are indicative of doxorubicin-induced abnormal ventricular depolarization and repolarization. QT dispersion and late potentials are both known to be associated with increased risk of serious ventricular dysrhythmias and sudden death in various cardiac diseases. Thus, follow-up of these parameters might also be useful in assessing the risk of late cardiovascular events in cancer patients treated with anthracyclines. Doxorubicin is one of the most widely used antineoplastic agents in the treatment of lymphomas. Its use is, however, limited by dose-related cumulative cardiotoxicity. Anthracycline therapy is also known to induce non-specific electrocardiographic changes, including decreased QRS voltages, ST-T wave changes, prolongation of QT interval and various dysrhythmias. The incidence of these changes depends on the frequency of ECG monitoring [1] and has been reported to be 11–29% [1-3]. The variability in QT interval duration amongst the different leads of the standard 12-lead ECG (QT dispersion) is considered to reflect local differences in the repolarization of the myocardium [4]. QT dispersion is increased in patients with long QT syndrome [4], after myocardial infarction [5, 6] and in patients with hypertrophic cardiomyopathy [7]. Increased QT dispersion has been associated with increased risk of ventricular tachydysrhythmias [4, 8]. There are no data of QT dispersion in patients undergoing anthracycline therapy. Ventricular late potentials are high-frequency, low-level signals that occur after normal ventricular depolarization. They can be visualized by high-resolution, signal-averaged ECG (SAECG) [9]. Late potentials correspond to delayed and fragmented ventricular activation arising typically in border zones between vital and fibrotic myocardial fibres. Late potentials have been observed after myocardial infarction [9] and in patients with congestive cardiomyopathy [10, 11], and they have been proven to be independent risk factors for severe dysrhythmias and sudden cardiac death in these patients [11, 12]. The occurrence of late potentials has not previously been studied in adult patients treated with anthracyclines. The aim of this prospective study was to investigate cardiac electrophysiology – with special emphasis on QT dispersion and late potentials – during doxorubicin therapy for lymphoma. Thirty consecutive adult patients ≤ 75 years of age with previously untreated non-Hodgkin’s lymphoma, who were scheduled to receive CHOP chemotherapy, were studied. The patients were regarded as eligible for study entry if they had not received prior anthracycline therapy or radiation therapy to the mediastinum. A history of heart failure was also considered as an exclusion criterion. Two patients died early during therapy and were not included in the evaluation. Thus the final study population consisted of 28 patients (17 men and 11 women) with a mean age of 53 (range 22–75) years. Six patients had a pre-existing cardiovascular disease (four patients had WHO class II hypertension, one patient had suffered from a prior myocardial infarction and one patient from recurrent episodes of atrial fibrillation). Approval for the study was obtained from the local ethical committee and the patients provided written informed consent before the study. The CHOP chemotherapy was administered in standard doses (750 mg m–2 cyclophosphamide, 50 mg m–2 doxorubicin and 1.4 mg m–2 (maximum 2) vincristine were given intravenously on day 1, and prednisolone 100 mg was given orally on days 1–5). Doxorubicin was given as a 30 min infusion. The cycle was repeated every 3 weeks. Treatment response was routinely assessed with computerized tomography and, when necessary, with bone marrow biopsy after four and eight cycles. At least two additional cycles of CHOP were given after a complete remission was achieved, and thus the patients received a total of eight to 10 cycles. No radiotherapy was given during the study period. ECG and SAECG recordings were performed at baseline and after the cumulative doxorubicin doses of 200, 400 and 500 mg m–2. A computerized ECG system was used to record both standard 12-lead ECG and SAECG at rest (Hewlett-Packard M1700 A Xli; M1754 A SAECG software, Hewlett-Packard Company, McMinnville, OR, USA). ECG was recorded using a 50 mm s–1 paper speed. PR interval, QRS duration and heart rate-corrected QT interval were measured automatically by the recording system. SAECG was recorded according to a recent recommendation [13]. Signal-averaging was continued until a 0.3 µV noise level was reached. High-pass bidirectional filtering (40 Hz) was used, and a technician interactively confirmed the measurement points from the filtered QRS complex. The patient was considered to have abnormal late potentials if at least two of the following criteria were fulfilled: (i) QRS duration > 114 ms; (ii) root-mean-square voltage of the terminal 40 ms of the filtered QRS < 20 µV (RMS40); and (iii) the terminal vector magnitude complex < 40 µV for more than 38 ms (LAS) [13]. The QT intervals for QT dispersion calculations were measured in each of the 12-lead standard ECGs from two consecutive cycles. The QT intervals were measured from the onset of QRS complex to the end of the T wave by means of a tangential method. The QT dispersion was defined as the difference between the maximal and minimal QT values. Bazzett’s formula was used to obtain heart rate-corrected values for QT interval (QTc = QT/√RR interval) and QT dispersion. The measurements were performed manually by two independent observers blinded to clinical data and in random order within the course of therapy. The mean values of the two observers were used for statistical analysis. A QT dispersion > 50 ms was considered abnormal [14, 15]. The interobserver variability of QT dispersion measurements was evaluated by calculating the correlation coefficient, the mean absolute difference and the relative difference between the two observers. The relative difference was calculated as the mean absolute difference divided by the mean QT dispersion. In addition, a method described by Bland and Altman [16] was used to define the upper and lower limits of agreement between the two observers. Systolic left ventricular function (left ventricular ejection fraction, LVEF) was assessed with radionuclide ventriculography (RVG) using standard techniques [17, 18]. RVG was performed at baseline and after the cumulative doxorubicin doses of 200, 400 and 500 mg m–2. A decrease in LVEF of more than 10% and below 50% was considered as indicative of doxorubicin-induced systolic dysfunction. All calculations were performed with the SPSS/PC statistical program (version 7.5.1, SPSS Inc., Chicago, IL, USA). The differences for continuous variables were compared with multivariate analysis of variance ( manova). Paired, two-tailed t-tests were applied for post hoc analyses. The correlations between variables were studied using Pearson’s correlation test. P < 0.05 was considered to be statistically significant. The data are expressed as mean ± SE unless otherwise indicated. Twenty-eight of the initial patient population received at least eight courses of CHOP (cumulative doxorubicin dose ≥ 400 mg m–2) and were included in the analysis. Twenty-four patients received 10 cycles (cumulative doxorubicin dose, 500 mg m–2). The baseline LVEF of the patients was 58.0 ± 1.3%. It decreased to 52.5 ± 1.1 (P < 0.001 vs. baseline), 50.4 ± 1.0 (P < 0.001 vs. baseline) and 49.6 ± 1.7% (P < 0.001 vs. baseline) after the cumulative doxorubicin doses of 200, 400 and 500 mg m–2, respectively. Clinical heart failure developed in two patients (7%) at 1 month and 10 months after the last dose of doxorubicin (cumulative dose, 500 mg m–2). Five patients had high QRS voltages, suggesting left ventricular hypertrophy at baseline. All other patients had normal 12-lead ECGs. QTc increased from 402 ± 4 to 416 ± 5 ms (P = 0.002) ( Fig. 1) after the cumulative doxorubicin dose of 500 mg m–2. QTc prolongation did not correlate with the decrease in LVEF (r = –0.085, P = 0.577). The change in QTc in relation to the cumulative doxorubicin dose. The values are mean ± SE. **P < 0.01 versus baseline. QT dispersion increased significantly from 24.1 ± 2.5 to 35.0 ± 2.8 ms (P = 0.041) and QTc dispersion increased from 26.5 ± 2.5 to 39.0 ± 3.5 ms (P = 0.039) during doxorubicin therapy ( Fig. 2). None of the patients presented with increased QT dispersion at baseline. However, five patients (18%) developed QT dispersion exceeding 50 (range 50–80) ms at the end of the study. The increase in QT dispersion did not correlate with the decrease in LVEF (r = –0.23 P = 0.291). The changes in QT dispersion (a) and QTc dispersion (b) in relation to the cumulative doxorubicin dose. The values are mean ± SE. *P < 0.05 versus baseline. There was a significant correlation between the QT dispersion measurement by the two observers (r = 0.672, P < 0.001). The interobserver variability, expressed as the mean absolute difference, was 1.9 ± 1.6 ms, corresponding to a relative difference of 6.8 ± 6.0%. By Bland–Altman analysis the upper and lower limits of agreement between the two observations were 25.9 and –22.1 ms, respectively. The mean values of SAECG measures at baseline (filtered QRS duration, 100 ± 2 ms; LAS, 29 ± 2 ms; and RMS40, 38 ± 4 µV) and after the cumulative doxorubicin dose of 500 mg m–2 (filtered QRS duration, 100 ± 2 ms; LAS, 31 ± 1 ms; and RMS40, 39 ± 4 µV) showed no significant changes. However, two patients (7%) developed late potentials after the cumulative doxorubicin dose of 200 mg m–2 (LAS = 39 ms, RMS40 = 19 µV and LAS = 41 ms, RMS40 = 19 µV, respectively). One of the patients with late potentials also presented with increased QT dispersion after doxorubicin therapy. Anthracycline therapy is known to be associated with impairment of systolic and diastolic left ventricular function and, in some patients, with clinical heart failure. An interesting and novel finding in our study was that doxorubicin therapy resulted in increased QT dispersion. This indicates that doxorubicin-induced cardiotoxicity does not only affect the mechanical function of the heart, but also results in inhomogeneity of ventricular repolarization. QT dispersion refers to spatial heterogeneity in myocardial repolarization. Increased QT dispersion has been observed in patients after myocardial infarction [6, 8], in patients with the long QT syndrome [15] and in patients with hypertrophic cardiomyopathy [7]. Most importantly, increased QT dispersion has been shown to be associated with cardiac electrical instability and increased risk of serious ventricular dysrhythmias [4, 8]. Further, QTc dispersion has been shown to be a strong and independent risk factor for cardiac mortality in elderly people [19] and in patients with newly diagnosed type 2 diabetes [20]. QT dispersion in healthy subjects is usually < 50 ms [14, 15]; in patients with uncomplicated myocardial infarction it is in the range of 60–80 ms; and in postinfarction patients with ventricular tachycardia it has been reported to be 95–120 ms [8, 21]. In this study, QT dispersion increased significantly during doxorubicin therapy. In addition, although all patients had normal QT dispersion at baseline, five (18%) developed abnormal QT dispersion during the study. Comparisons with earlier studies cannot be made because QT dispersion has not previously been investigated in patients receiving doxorubicin therapy. It is also of interest that the increasing QT dispersion was independent of the decrease in LVEF. This suggests that the increase in QT dispersion indicates, not change in cardiac mechanical function, but electrical instability and possibly also susceptibility to dysrhythmias in patients who have undergone anthracycline therapy. Naturally, this needs confirmation from larger studies with longer follow-up. In line with previous studies [22-25], we found a significant prolongation of QTc interval after doxorubicin therapy. The prolongation of QTc interval was related to cumulative doxorubicin dose. However, we did not find any correlation between QTc prolongation and the decrease in LVEF, which is in accordance with the results by Ferrari et al. [24]. On the contrary, in a retrospective study in paediatric patients [23], the prolongation of QTc correlated with the decrease in fractional shortening. However, in that study QTc prolongation was observed only in patients with cumulative doxorubicin dose of > 400 mg m–2, and the decrease in fractional shortening was associated with a QTc prolongation > 460 ms. In our study, only one patient developed a QTc prolongation > 460 ms. In this study, late potentials developed in two (7%) patients during doxorubicin therapy. The effects of anthracycline therapy on late potentials are poorly known. There are only two previous studies of the effects of doxorubicin therapy on depolarization examined with SAECG. In addition, both these studies have been performed in children [3, 26]. In the study of Tamminga et al. [26], 15% of children with cancer had late potentials during or after chemotherapy. However, in contrast to our study, none of the patients developed late potentials during anthracycline therapy. In another study, late potentials were found in 13% of patients who had been treated with doxorubicin at cumulative doses of 225–550 mg m–2[3]. In our study, as well as in these two studies [3, 26], no correlations were found between late potentials, cumulative doxorubicin dose and development of left ventricular dysfunction. Whilst increased QT dispersion represents abnormal ventricular repolarization, late potentials indicate abnormality in ventricular depolarization. They arise from zones of delayed activation in myocardium, where viable tissue alternates with fibrous or necrotic tissue. Late potentials have been found after myocardial infarction [9], in congestive cardiomyopathy [10, 11], in hypertrophic cardiomyopathy [27], after myocarditis [28], and even in hypertension [28]. The presence of late potentials represents a substrate for re-entry ventricular tachycardias. Indeed, late potentials have been proven to be independent risk factors of severe dysrhythmias and sudden cardiac deaths after myocardial infarction and cardiomyopathies [11, 12]. Up to 16–26% of patients with positive late potentials develop severe arrhythmic events [28]. QT dispersion and late potentials have been shown to be of importance in patients with a variety of cardiac disease. Particularly, they have been found to be indicators of increased risk of arrhythmic death. With more efficient therapeutic modalities the long-term prognosis of many cancer patients has improved. As a consequence, factors not directly related to the cancer, such as cardiac dysfunction and dysrhythmias, become of prognostic importance. Indeed, the increased risk of sudden arrhythmic deaths in long-term survivors of childhood cancer has been well documented [29, 30]. In this setting, analysis of QT dispersion and late potentials may be useful in identifying patients who are at increased risk for arrhythmic events. However, it must be born in mind that the prognostic significance of increased QT/QTc dispersion in patients treated with doxorubicin, as well as in general, has not been evaluated in large prospective studies. Thus, so far one must be cautious when applying QT/QTc dispersion in clinical practice. The measurement of QT dispersion is subject to a number of limitations. The end of repolarization may be difficult to define because of flattening of the T wave or presence of a U wave. In addition, there is a considerable interobserver variability in the assessment of QT dispersion. The interobserver relative error has been shown to be about 30% in healthy subjects [8, 14]. However, when the QT dispersion increases, the interobserver errors usually become smaller. In our study, the correlation between the two independent observers was rather high and the interobserver variability was in accordance with previous studies. In summary, our study shows that doxorubicin therapy causes significant changes in myocardial depolarization and repolarization. These abnormalities in the homogeneity of depolarization and repolarization, reflected by the occurrence of late potentials and increased QT dispersion, may be useful in identifying patients who are at risk of potentially fatal arrhythmic events. Long-term follow-up is needed to validate the clinical significance of these findings. Received 19 August 1998; accepted 16 October 1998." @default.
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• W2010658812 title "QT dispersion and late potentials during doxorubicin therapy for non-Hodgkin's lymphoma" @default.
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