Evaluation of cardiac functions by tissue Doppler echocardiography method in long-term follow-up of pediatric Hodgkin lymphoma patients.
Marked advances have been observed in treatment of pediatric Hodgkin lymphoma disease in recent years in developing countries (1). However, side effects related to the medications and radiotherapy used for the primary disease constitute an important problem. Cardiomyopathy which develops with combined use of radiotherapy and anthracycline group medications is one of these problems. Combined use of these two therapies as well as each therapy method individually has potential cardiotoxic effect. Studies demonstrated cardiac side effects with a high rate in Hodgkin lymphoma patients who received only chemotherapy (2). Anthracyline group of medications included in the chemotherapeuticals used is an important negative factor for occurrence of this picture.
Even if Hodgkin lymphoma patients who survive for long-term appear complaint-free and problem-free, the actual rate of cardiac problems is higher than expected (3,4). This rate reaches a high level of 57% in some series and factors including total anthracycline dose (especially values higher than 250-300mg/[m.sup.2]), anthracycline treatment at an early or advanced age, female gender, radiation therapy, high dose treatments have been proposed to play an important role in the occurence of this problem (3,5). The most commonly used test to determine this cardiac complication is uninterventional two-dimension echocardiography which measures left ventricular ejection fraction and shortening fraction. There are studies reporting that tests including stress echocardiography with low or high dose dopamin, measurement of myocardial tension with echocardiography, evaluation of exercise electrocardiogram, measurement of blood atrial natriuretic hormon and cardiac MR give better results for evaluation of cardiac side effects which may develop in long-term compared to classical echocardiography (6-9). However, in spite of all these studies, there is still no appropriate test which can early determine cardiomyopathy which may develop in long-term (10). Tissue Doppler echocardiography is a new technique which measures the acceleration process of the movements of the cardiac wall muscles. The main advantage of this test is the fact that it is not affected by age, blood pressure and cardiac rate. Tissue Doppler echocardiography can prematurely determine cardiac pathologies which may lead to mortality (11,12). Studies reported that tissue Doppler echocardiography evaluated long-term side effects with various subvariables in patients with pediatric malignencies and determined the picture of cardiomyopathy earlier compared to traditional methods (12,23,24,26,27). In this study, it was aimed to investigate if tissue Doppler echocardiography was superior to traditional echocardiography in determining long-term cardiac side effects of chemotherapeuticals in pediatric Hodgkin lymphoma patients who had not received radiotherapy.
Material and Method
17 Hodgkin lymphoma patients (12 male and 5 female) who were diagnosed between 1994 and 2003 in Dr.Sami Ulus Children's Hospital, had not received radiotherapy, had discontinued their treatment at least for four years and followed up as disease-free patients and had traditional echocardiograms taken with regular intervals during treatment and 14 healthy individuals (8 male and 6 female) as the control group were included in this study. Echocardiographic investigation was done using Vivid Pro7 device and 3 MHz probe. Dimensions of the right ventricle and left ventricle, outlets, valve failures, stenoses were evaluated using M-mod, two dimension, colored Doppler, CW Doppler and pulse Doppler.
The process was conducted in association with electrocardiographic monitorization. Tissue Doppler investigation was performed using 3 MHz probe. Apical four chamber position was selected as the test position. To obtain clean, residue-free vision Doppler "gain" was considered. Fitler format of echocardiography device was used. Doppler signals were recorded at a rate of 100 mm/sec. Isovolumic relaxation time and isovolumic contraction time from the basal part of the left ventricle, myocardial rate during the systole, myocardial rate during the erly diastole, the rate during the late diastole, ejection time, isovolumic contraction acceleration and acceleration of the ventricle at the time of isovolumic contraction were measured.
After treatment was ended, median follow up time was found to be 108 (54-174) months. Patients with previous cardiac problems were excluded from the study whether symptomatic or asymptomatic. Staging was done according to Ann-Arbor staging system. Five of the patients who were diagnosed as Hodgkin lymphoma were treated with adriablastine, belomycine, vinblastine, dacabazine, six were treated with cyclophosphamide, oncovin, procarbazine and prednisolone and six were treated with successive adriablastine, bleomycine, vinblastin, dacarbazine-cyclophosphmide, vincristin, procarbazine and prednisolone. Six cycles of cyclophosphamide, oncovin, procarbazine and prednisolone or adriablastine, bleomycine, vinblastin and dacarbasine were given to the patients in the early stage (stage 1-2). 12 cycles of successive therapy with adriablastine, bleomycine, vinblasatin, dacarbazine-cyclophosphamide, vincristin, procarbazine and prednisolone were given to the patients in the advanced stage (stage 3-4). Total doses of anthracycline and alkalinizing agents given to the patients with a diagnosis of Hodgkin lymphoma were calculated. No patient received radiotherapy. Clinical information about the patients are summarized in table 1.
Approval from the Hospital Local Ethics Committee and informed consent from all patients or relatives of the patients were obtained for this study (05.07.2007/number: 5639).
Analysis of the data was done using SPSS (Statistical Package for Social Science) for Windows 11.5 package program. Shapiro Wilk test was used to examine if the distribution of continious variables was close to normal. Descriptive statistical values were shown as mean [+ or -] standard deviation or median (range between quarters) for continious variables and as number of cases and (%) for numerical variables. Student's t test was used to determine if there was a statistically significant difference between the groups in terms of mean values and Mann Whitney U test was used to evaluate the statistical significance in terms of median values. Nominal variables were examined by Fisher's exact qui-square test. A p value of <0.05 was considered to be statistically significant.
A total of 31 individuals were included in this study. 17 of them had Hodgkin lymphoma and 14 constituted the control group. Men age of the patients with Hodgkin lymphoma was 180.1 [+ or -] 48.6 months; the mean age of the control group was 184.3 [+ or -] 28.9 months (p = 0.766). 12 of the patients with Hodgkin lymphoma were male and 5 were female. 8 of the healthy group were male and 6 were female (p = 0.477). When the two groups were comapred in terms of ejection fraction and shortening fraction by traditional echocardiography technique, no statisticlly significant difference was observed (p = 0.302 and p = 0.860, respectively). When the two groups were compared in terms of tissue Doppler echocardiography measurements, left ventricular isovolumic contraction time (LVBICT) in the Hodgkin lymphoma group (150.12 [+ or -] 44.72 ms) was found to be lower than the control group (118.57 [+ or -] 39.86 ms). The statistical difference between these two groups was found to be at the borderline (p = 0.049). Left ventricular isovolumic acceleration time (LVBIVA) was found to be lower in the Hodgkin lymphoma group (2.73 [+ or -]0.69 m/[s.sup.2]) compared to the control group (3.45 [+ or -] 1.05 m/[s.sup.2]). Statistical significant difference was found between the values of these two groups (p = 0.038). Myocardial performance index (MPI) was found to be 1.06 (0.63) in the Hodgkin lymphoma group and 0.77 (0.33) in the control group. A statistically significant difference was found between these values (p = 0.029). Marked relation between myocardial performance index and total doses of medicine was observed. Evaluation of the variables is summarized in Table 2.
In patients using anthracycline group of medicines, cardiotoxicity which develops both in short-term (during the first year of treatment) and in long-term follow up up to 20 years after treatment (chronic period) is well known. Free radicals which are released as a result of anthracycline treatment and apoptosis picture in myocytes which develops by stimulation of superoxides are thought to lead to this clinical pathology. While this effect may be independent of dose, it may increase in parallel to increased total doses of chemotherapeuticals (13). On the other hand, cardiotoxicity cases are reported in patients who use usual doses of alkalinizing agents, although cardiomyopathy is known to develop especially in patients with bone marrow transplant following treatment with high doses of alkalinizing agents (14). Stimulation of cell apopytosis in the heart by cyclophosphamide, reduction of serum carnitine level as a result of treatment and abnormalities in serum lipid levels are thought to be involved in the development cardiotoxicity (13,15,16). The majority of carciovascular problems developing in cancer patients who had used anthracycline group of drugs may be asymptomatic for a long period. In patients treated with alkalinizing agents and anthracyclines, monitoring of cardiomyopathy is done by traditional echocardiography technique measuring ejection fraction and shortening fraction. These investigations are done to evaluate systolic functions. However, diastolic functions are assumed to be disrupted firstly in patients who develop cardiomyopathy (5). Therefore, not only systolic, but also diastolic functions should be evaluated for early diagnosis and evaluation of cardiomyopathy in these patients. Tissue Doppler echocardiography technique is thought to be a more efficient technique compared to traditional echocardiography technique, since it gives information about both systolic and diastolic functions (4).
Myocardial performance index (MPI) which is also known as Tei index, since it was firstly determined by Tei (17) is a measure obtained by dividing the sum of isovolumic contraction and relaxation times to ejection time. Myocardial performance index is a simple, reproducible test independent of heart rate and blood pressure which are compatible with systolic and diastolic dysfunction of the myocardium (6). Myocardial performance index is thought to be a measure which can be used to demonstrate the effect of congenital cardiac diseases, heart failure, coronary heart disease, valvular diseases, pulmonary hypertension and drug-dependent cardiotoxicity on the heart at an early time (18). In a study performed by Santin et al. (19), MPI index was found to be significantly reduced in patients who received chemotherapy and radiotherapy compared to the control group, but no difference was found between the patients who only received chemotherapy and the control group. In contrary to these findings, MPI value was found to be significantly lower in the patient groups who received treatment protocols including both anthracycline and alkalinizing agents without radiotherapy compared to the control group in our study. In a previous study performed by Ocal et al (20) in our hospital in 35 pediatric patients with a diagnosis of pediatric malign disease, MPI index was shown to be significantly lower in patients who received anthracycline compared to the control group. However, there was no association between this lower value and the total dose of the chemotherapeutical drug. In a study performed by Larussi et al. (21) in patients with a diagnosis of pediatric Hodgkin lymphoma, left ventricular isovolumic shortening time (ICT) and MPI was found to be lower in patients who received chemotherapy compared to the control group in accordance with our study. There was no association between these lower values and anthracycline dose and radiotherapy. In addition, in the study performed by Karakurt et al. (22) in patients with pediatric malignancy who received treatment protocols including anthracycline group of drugs and who did not receive mediastinal radiotherapy, MPI values were found to be statistically significantly lower compared to the healthy group and these lower values were found to be significantly parallel to the total anthracycline doses. Increased severity of cardiomyopathy is expected with increased dose of anthracycline or other cardiotoxic drugs. The fact that no statistically significant relation was found between total drug dose and cardiomyopathy in our study may be due to the low number of subjects. In a study performed by Yildirim et al. (23) in pediatric patients who received treatment with a diagnosis of lymphoma and solid tumor, it was suggested that left ventricular flow MPI value was a better indicator for determining cardiomyopahty compared to left ventricular wall MPI value.
Isovolumic acceleration (IVA) value calculated using peak value of the rate measured at the time of isovolumic contraction and the time passed from the basal to the peak is a measure which provides evaluation of systolic functions without being affected by hemodynamic changes (24). In our study, although ejection fraction value in the group who received treatment and shortening fraction values in both groups were not significantly different, left ventricular isovolumic acceleration (LVBIVA) value was found to be significantly higher compared to the control group. This measure may be one of the first heralds of systolic dysfunction which occurs after diastolic dysfunction. There are studies reporting that ventricular isovolumic contraction and relaxation acceleration time values are good measures demonstrating systolic functions early without being affected by preload and afterload (25). In a study performed by Dorup et al. (5) in patients with pediatric Wilms tumor and acute lymphoblastic leucemia, diastolic early acceleration abnormalities were specifically found in subjects with a shortening fraction below 25%. In patients whose total anthracycline dose was 250 mg/[m.sup.2], lengthening of ventricular relaxation time and shortening in acceleration time were observed and these findings were emphasized to indicate that diastolic dysfunction occurred before systolic dysfunction. In a study performed by Baysal et al (26) in 20 subjects with pediatric tumor, left ventricular isovolumic contraction time and left ventricular isovolumic relaxation time values were found to be longer in patients who received anthracycline treatment compared to the control group. Similarly, in a study performed by Ocal et al. (20), a significant difference in MPI value as well as lengthening of left ventricular isovolumic contraction time was demonstrated in cancer patients receiving chemotherapy. In our study group, only left ventricular isovolumic contraction time was found to be lenghtened at the borderline of significance. This difference may be caused by the relatively low number of patients who received anthracycline treatment and by the fact that a part of the patients of Baysal et al (26) received radiotherapy.
In our study, no difference was observed between the patients who received only anthracycline and the patients who received anthracycline and alkalinizing agent or the patients who did not receive anthracycline treatment and received only alkalinizing agent in terms of cardiotoxicity. This result may be caused by the low number of patients. Consequently, long-term follow up is necessary not only in patients who received anthracycline treatment, but also in patients who received alkalinizing agent in terms of cardiomyopahty. MPI measurement by tissue Doppler echocardiography technique which evaluates diastolic functions adequately may be a beneficial method to determine cardiomyopathy at an early time which may develop in these patients. There are limited number of studies in the literature about the clinical significance of left ventricular isovolumic contraction time which was found to be different at the borderline of significance (p = 0.049) compared to the control group and left ventricular isovolumic acceleration time which was found to be statistically significantly different compared to the control group (p = 0.038) in our study. The significant difference in terms of acceleration time in our study is remarkable. Therefore, evaluation together with MPI may be significant in terms of demonstrating cardiac affection. To obtain more adequate data about this subject large-scale prospective studies in which serial examinations will be performed by tissue Doppler echocardiography from the time of diagnosis are needed. Limitation of the study:
The main limitation of our study is the small number of patients. In addition, absence of tissue Doppler records before and during treatment is another defect. Such defects can be prevented by planned, large-scale, prospective studies.
Conflict of interest: None declared.
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Ceyhun Bozkurt, Utku Arman Orun *, Ayse Ulya Ertem, Burhan Ocal *, Gurses Sahin, Nazmiye Yuksek **, Sonay Incesoy Ozdemir, Filiz Senocak *
Dr Sami Ulus Children's Hospital, Pediatric Oncology Clinic, Ankara, Turkey
* Dr Sami Ulus Children's Hospital, Pediatric Cardiology Clinic, Ankara, Turkey
** Zonguldak Karaelmas Medical Faculty, Pediatric Oncology Clinic, Zonguldak, Turkey
Address for Correspondence: Ceyhun Bozkurt MD, Dr Sami Ulus Children's Hospital, Pediatric Oncology Clinic, Ankara, Turkey
E-mail: email@example.com Received: 01.05.2011 Accepted: 03.03.2011
Turkish Archives of Pediatrics, published by Galenos Publishing.
Table 1. Clinical properties of the patients Age at the Gender Subgroup Stage Total dose of time of alkalinizing diagnosis agent (m2) months) 101 E LY II CTX: 6000 mg, PRO: 9000 mg 36 E KH II CTX: 6000 mg PRO: 9000 mg 92 E NS II CTX: 3000 mg, PRO: 4500 mg 84 E KH II 36 E NS III CTX: 3000 mg, PRO: 4500 mg 87 E KH III CTX: 3000 mg, PRO: 4500 mg 113 K LZ II CTX: 6000 mg, PRO: 9000 mg 151 K NS II CTX: 6000 mg, PRO: 9000 mg 106 K KH II CTX: 6000 mg, PRO: 9000 mg 65 E NS II 114 K KH III CTX: 3000 mg, PRO: 4500 mg 48 E KH II 96 K KH II CTX: 6000 mg, PRO: 9000 mg 42 E LZ II CTX: 1000 mg, PRO: 1500 mg 126 E LZ II 58 E KH II 84 E KH III CTX: 3000 mg, PRO: 4500 mg Age at the Total dose of Time passed time of anthracycline after the diagnosis (m2) end of months) treatment (months) 101 -- 150 36 -- 132 92 ADM: 450 mg, 60 BLEO: 180 U 84 ADM: 300 mg, 108 BLEO: 120 U 36 ADM: 450 mg, 60 BLEO: 180 U 87 ADM: 450 mg 66 BLEO: 180 U 113 126 -- 151 87 106 132 65 ADM: 3000 mg 108 BLEO: 1200 U 114 ADM: 450 mg, 54 BLEO: 180 U 48 ADM: 300 mg, 63 BLEO: 120 U 96 84 42 ADM: 300 mg, 144 BLEO: 120 U 126 ADM: 300 mg, 115 BLEO: 120 U 58 ADM: 300 mg, 66 BLEO:120 U 84 ADM: 450 mg 55 BLEO: 180 U Abbreviations: ADM: Adriablastine, BLEO: Bleomycine, CTX: Cyclophosphamide, M: Male, MC: Mixed cell, F: Female, LD: Lymphocyte Deficient, LR: Lymphocyte Rich, mg: Miligram, NS: Nodular Sclerosing, PRO: Procarbazine, U: Unit Table 2. Evaluation of the clinical and demographical properties of the groups Variables Patient group (s=17) Control group (s=14) p Age 180.1 [+ or -] 48.6 184.3 [+ or -] 28.9 0.766 (a) Gender M/F 12/5 8/6 0.477 (b) LVBS 0.09 [+ or -] 0.02 0.09 [+ or -] 0.02 0.951 (a) LVBE 0.20 [+ or -] 0.03 0.22 [+ or -] 0.04 0.177 (a) LVBA 0.08 (0.02) 0.08 (0.03) 0.570 (b) LVBICT 150.12 [+ or -] 44.72 118.57 [+ or -] 39.86 0.049 (a) LVBSS 208.00 [+ or -] 37.67 231.50 [+ or -] 33.81 0.081 (a) LVBES 120.76 [+ or -] 20.16 111.50 [+ or -] 18.27 0.195 (a) LVBAS 61.59 [+ or -] 17.22 61.57 [+ or -] 11.37 0.998 (a) LVBIRT 70.18 [+ or -] 12.75 68.64 [+ or -] 19.70 0.804 (a) LVBIVA 2.73 [+ or -] 0.69 3.45 [+ or -] 1.05 0.038 (a) LVBSA 0.96 [+ or -] 0.39 0.91 [+ or -] 0.30 0.659 (a) LVBEA 3.85 [+ or -] 0.80 3.87 [+ or -] 1.00 0.941 (a) LVBAA 2.10 (1.68) 2.65 (2.40) 0.279 (b) EF 70.77 [+ or -] 7.86 68.06 [+ or -] 6.11 0.302 (a) FS 39.00 (11.50) 36.00 (7.50) 0.860 (b) TEI 1.06 (0.63) 0.77 (0.33) 0.029 (b) Abbreviations: a: Student's t test, b: Fisher's exact qui-square test, c: Mann Whitney U test., EF:Ejection Fraction (%),, FS: Shortening Fraction, LVBA: Left Ventricular Basal Amplitude A (m/s), LVBAA: Left Ventricular Acceleration A (m/s2 (%),LVBAS: Left Ventricular Basal Time A (ms), LVBE: Left Ventricular Basal amplitude E (m/s), LVBEA: Left Ventricular Acceleration E (m/s2), LVBES: Left Ventricular Basal time E (ms), LVBICT: Left Ventricular Isovolumic Contraciton Time (ms), LVBIRT: Left Ventricular Isovolumic Relaxation Time (ms), LVBIVA: Left Ventricular Isovolumic Acceleration Time (m/s2), LVBS: Left Ventricular Basal Amplitude S (m/s), LVBSA: Left Ventriular Acceleration S (m/s2), LVBSS: Left ventricular Basal Time S (ms), TEI: Tei index
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|Title Annotation:||Original Article|
|Author:||Bozkurt, Ceyhun; Orun, Utku Arman; Ertem, Ayse Ulya; Ocal, Burhan; Sahin, Gurses; Yuksek, Nazmiye; O|
|Publication:||Turkish Pediatrics Archive|
|Date:||Sep 1, 2011|
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