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―Original― Early Detection of Subclinical Anthracycline Cardiotoxicity on the Basis of QT Dispersion Yohko Uchikoba, Ryuji Fukazawa, Takashi Ohkubo, Miho Maeda and Shunichi Ogawa Department of Pediatrics, Graduate School of Medicine, Nippon Medical School Abstract Background: We examined whether dobutamine-stress QT dispersion (QTd) and heartrate corrected QT dispersion (QTcd) are useful for detecting subclinical anthracycline cardiotoxicity. Methods: The subjects were10 control subjects and 37 patients divided into 4 groups according to cumulative anthracycline dose: non-anthracycline group (group N), 7 patients; low anthracycline cumulative dose group (group L), 8 patients (<200 mg! m2); medium anthracycline cumulative dose group (group M), 16 patients (200 to <400 mg! m2); and high cumulative group (group H), 6 patients ("400 mg! m2). Standard 12-lead electrocardiograms were recorded. QTd and QTcd were measured and calculated at rest and after administration of dobutamine at 5 or 30 μg! kg! min. We also estimated cardiac function and cardiac reserve function at rest and after administration of dobutamine at a dose of 5 or 30 μg! kg! min. Results: At rest, QTd and QTcd were significantly greater in groups M and H. After administration of dobutamine at 30 μg! kg! min, QTd and QTcd were significantly greater in groups L, M, and H. There was good correlation between QTd and the cumulative anthracycline dose; the correlation formula was y=0.051x + 42.2 (r=0.81, p<0.001). The cumulative anthracycline dose of 152.9 mg! m2, calculated from the correlation formula, was the cut-off for detection of electrophysiological cardiac abnormalities. Cardiac performance data at rest and dobutamine stress by echocardiography and pulsed Doppler echocardiography are less sensitive for detecting cardiac abnormalities than are QTd and QTcd. Conclusions: Dobutamine-stress QTd and QTcd are useful for detecting anthracycline cardiotoxicity and subclinical cardiac abnormality at low cumulative anthracycline doses. We must be aware of the possibility of subclinical myocardial abnormalities in patients with a cumulative anthracycline dose of "150 mg! m2 . (J Nippon Med Sch 2010; 77: 234―243) Key words: anthracycline cardiotoxicity, QT dispersion, heart-rate corrected QT dispersion, dobutamine, malignancy Correspondence to Shunichi Ogawa, MD, Department of Pediatrics, Nippon Medical School, 1―1―5 Sendagi, Bunkyoku, Tokyo 113―8603, Japan E-mail: [email protected] Journal Website (http:! ! www.nms.ac.jp! jnms! ) 234 J Nippon Med Sch 2010; 77 (5) Anthracycline Cardiotoxicity durations on 12-lead standard electrocardiography (ECG), and is considered to reflect local differences in Introduction the repolarization of the myocardium. QT dispersion, Anthracyclines, doxorubicin, are such as daunorubicin highly effective and which reflects cardiac autonomic imbalance 13, antineoplastic increases in various cardiac diseases, such as heart agents in the treatment of solid tumors and failure6, cardiomyopathy7, ischemic heart disease8, hematological malignancies and form an important hypertension10, long-QT syndrome11,12, and after 9 component of many antineoplastic chemotherapeutic myocardial infarction . QT dispersion is useful for regimens. Unfortunately, because anthracycline have determining prognosis in these diseases. acute and chronic effects on the myocardium, their use is limited by their hypothesize that dobutamine-stress QT Acute dispersion (QTd) can be causes ventricular spatial heterogeneity of repolarization, electrocardiographic abnormalities, such as sinus which is a sign of anthracycline cardiotoxicity at tachycardia, ST depression, and arrhythmias, during lower cumulative doses in long-term survivors after administration or several hours to several days after early-stage treatment for childhood malignancies. administration. This study presents data to test this hypothesis. anthracycline cardiotoxicity. We cardiotoxicity However, most of the acute used to detect the cardiotoxic effects of anthracycline are transient and reversible 1. In contrast, chronic Patients and Methods anthracycline cardiotoxicity causes irreversible cardiomyopathies and congestive heart failure that can restrict Subjects physical The subjects were 37 long-term survivors of activity. anthracycline The incidence cardiotoxicity of chronic depends on the childhood malignancies who underwent cumulative anthracycline dose administered. For anthracycline therapy from 1998 through 2003 at example, the incidence of congestive heart failure is our hospital (17 female and 20 male; present age 0.01% to 0.27% for cumulative anthracycline doses range, 3 years 7 months to 28 years 3 months), and < 550 mg !m , cumulative 10 volunteer healthy control subjects (control group; . Even at low age range, 17―28 years). Of the 37 patients, 24 had 2 and is > 30% for anthracycline doses >550 mg! m doses, anthracyclines myocardial damage can with 2 2,3 cause late subclinical fibrosis of the had acute lymphoblastic leukemia, 5 had had acute non-lymphoblastic leukemia, 2 had had Ewing specimens 4. sarcoma, 3 had had non-Hodgkin s lymphoma, 1 had Therefore, effective monitoring of the cardiotoxic had neuroblastoma, 1 had had Wilms tumor, and 1 effects of anthracycline requires early assessment of had both cardiac function and cardiac reserve function. cumulative anthracycline doses of the patients This form of assessment may involve an exercise ranged from 0 to 840 mg! m2 (Table 1). None of the test. patients had symptoms of congestive heart failure. myocardium, We as seen previously echocardiography in biopsy performed The to their cumulative anthracycline dose, based on our therapy, and detected cardiac dysfunction even in previous findings14. The groups were the non- children anthracycline received receiving low-dose bicycle histiocytosis. anthracycline who supine cell The patients were divided into 4 groups according patients a Langerhans for asymptomatic using exercise-stress had anthracycline (group N, 7 patients); the low therapy (175 mg! m2)5. For patients with a low cumulative anthracycline dose group (group L, <200 tolerance for physical exercise, such as infants and mg!m 2 ; small anthracycline dose group (group M, 200―<400 mg! children, monitoring of cardiac function 8 patients ) ; the middle cumulative requires an alternative exercise test, such as a drug- m2; induced exercise test. anthracycline dose group (group H, "400 mg! m2 ; 6 QT dispersion is defined as the difference between the maximum and minimum QT interval J Nippon Med Sch 2010; 77 (5) 16 patients); and the high cumulative patients) (Table 1). Informed consent was obtained for all subjects. 235 Y. Uchikoba, et al Ta bl e1 Pa t i e ntc ha r a c t e r i s t i c s Ca s e No Gr o up s e x ATCc umul a t i vedo s e ( mg/ m2) 1 2 3 4 5 6 7 8 9 1 0 1 1 1 2 1 3 1 4 1 5 1 6 1 7 1 8 1 9 2 0 N N N N N N N L L L L L L L L M M M M M M F M M M M M F M M F F M M M M F F F F 0 0 0 0 0 0 0 8 0( THP: 8 0 ) 1 0 0( THP: 1 0 0 ) 1 7 5( ADM: 7 5 , DXR: 1 0 0 ) 1 8 0( ADM: 1 8 0 ) 1 4 0( ADM: 1 4 0 ) 1 3 0( THP: 1 0 0 , ACR: 3 0 ) 1 0 0( THP: 1 0 0 ) 1 7 0( THP: 1 2 0 , MI T: 2 0 , ACR: 3 0 ) 2 0 0( ADM: 2 0 0 ) 2 2 0( THP: 2 2 0 ) 2 2 0( I DAR: 1 2 0 , THP: 2 0 ) 2 5 0( DNR: 5 0 , ADM: 2 0 0 ) 2 7 0( ADM: 2 7 0 ) 2 1 2 2 M M F F 3 0 0( ADM: 2 0 0 , DNR: 1 0 0 ) 3 0 0( ADM: 3 0 0 ) 2 3 2 4 2 5 2 6 2 7 M M M M M F F M M F 3 0 0( ADM: 2 0 0 , DNR: 1 0 0 ) 3 0 5( THP: 9 0 , MI T: 3 5 , ACR: 1 8 0 ) 3 3 0( DNR: 1 8 0 , ACR: 1 5 0 ) 3 3 0( DNR: 1 8 0 , ACR: 1 5 0 ) 3 6 0( ADM: 3 6 0 ) 2 8 2 9 3 0 3 1 3 2 3 3 3 4 3 5 3 6 3 7 M M M M H H H H H H F M M F M M F M M F 2 2 0( THP: 2 2 0 ) 2 3 2( THP: 1 0 0 , I DAR: 1 3 2 ) 3 0 0( ADM: 2 0 0 , DNR: 1 0 0 ) 3 7 5( THP: 3 7 5 ) 4 2 0( ADM: 4 2 0 ) 4 9 0( ADM: 5 0 , EPR: 4 4 0 ) 5 4 0( ADM: 3 6 0 , THP: 1 8 0 ) 6 0 0( DNR: 6 0 , THP: 3 6 0 , ACR: 1 8 0 ) 8 4 0( DNR: 1 4 0 , THP: 7 2 0 ) 4 6 0( ADM: 3 6 0 , THP: 1 0 0 ) a gea tt e s t di a gno s i s 8 y1 1 m 1 5 y9 m 1 2 y2 m 1 6 y8 m 1 4 y6 m 1 3 y2 m 1 1 y2 m 1 3 y2 m 8 y1 1 m 2 8 y3 m 1 7 y9 m 3 y7 m 1 2 y1 0 m 6 y9 m 1 8 y0 m 9 y5 m 1 1 y0 m 1 1 y0 m 7 y5 m 3 y8 m ALL ALL ALL ALL ALL ALL ALL ALL ALL ALL ALL LCH ALL ALL ALL NHL ALL ALL ALL Ewi ng s a r c o ma ALL Wi l ms t umo r ALL ANLL ALL ALL Ewi ng s a r c o ma ALL ALL ALL ANLL Ne ur o bl a s t o ma NHL ANLL ANLL NHL ANLL 7 y0 m 9 y5 m 8 y0 m 1 5 y1 1 m 1 8 y4 m 1 5 y5 m 8 y1 0 m 7 y0 m 1 5 y0 m 1 6 y9 m 1 3 y0 m 1 3 y3 m 9 y6 m 1 8 y4 m 1 8 y0 m 6 y8 m 1 6 y8 m dur a t i o npo s t ATCt he r a py 5 y7 mo s 6 y7 mo s 5 y6 mo s 4 y7 mo s 4 y8 mo s 7 y2 mo s 6 y2 mo s 5 y1 1 mo s 5 y7 mo s 1 0 y2 mo s 1 3 y0 mo s 1 y6 mo s 8 y1 1 mo s 3 y9 mo s 4 y8 mo s 2 y8 mo s 2 y4 mo s 4 y3 mo s 3 y6 mo s 1 y4 mo s 4 y2 mo s 5 y6 mo s 4 y6 mo s 4 y9 mo s 1 2 y7 mo s 1 1 y1 0 mo s 3 y8 mo s 3 y2 mo s 3 y6 mo s 3 y5 mo s 9 y1 mo s 8 y4 mo s 4 y2 mo s 9 y2 mo s 4 y6 mo s 2 y3 mo s 8 y1 0 mo s M:ma l e ,F:f e ma l e ,ATC:a nt hr a c yc l i ne ,ALL:a c ut el ympho bl a s t i cl e uke mi a ,ANLL:a c ut e no nl ympho bl a s t i c ,LCH:La nge r ha ns c e l l hi s t i o c yt o s i s ,NHL:no nHo dgi ki n’ sl ympho ma .ADM:do xo r ubi c i n,DNR: l e uke mi a TPH: pi r a r ubi c i n, MI T: mi t o xa nt r o ne , ACR: a c l a r ubi c i n da uno r ubi c i n, I DAR: i da r ubi c i n, stopped under the following conditions: if the subject Dobutamine Stress Protocol experienced intolerable chest pain, palpitations, Dobutamine was infused at an initial rate of 5 μg! headache, nausea, or other symptoms; if the systolic kg! min for 3 minutes, and the infusion rate was blood pressure rose to >200 mmHg; if frequent increased by 5 μg! kg! min every 3 minutes to a episodes of ventricular arrhythmia were observed; maximum of 30 μg! kg! min. Infants and small or if sustained ventricular tachycardia was observed. children were sedated during the dobutamine stress Throughout test. Administration of dobutamine was prematurely monitoring was performed. Heart rate and blood 236 this protocol, continuous ECG J Nippon Med Sch 2010; 77 (5) Anthracycline Cardiotoxicity pressure were recorded at baseline and after each echocardiogram was recorded in the standard left stage of dobutamine infusion, and the double ventricular (LV) short axis view at the level of the product (DP: defined as heart rate multiplied by chordae tendineae, with the M-mode cursor angled systolic pressure) was calculated as an index of through the center of the LV cavity. We measured stress volume. the LV end-systolic and end-diastolic dimensions (LVDs and LVDd), and the end-systolic and end- ECG and QT Analysis diastolic posterior wall thickness (PWTs, PWTd). We Standard 12-lead ECGs were recorded at a paper calculated the following indices: 1) LV ejection speed of 25 mm! s for each study subject in the fraction (EF)=(LVDd3 LVDs3)! LVDd3, as an index supine position with Cardio Multi FDX-4520 (Fukuda of cardiac performance; 2) end-systolic wall stress Denshi, Tokyo, Japan). Subjects were required to lie (ESS)=P LVDs 1.35! 4 PWTs (1 + PWTs! 15 supine for 5 minutes for stabilization before ECGs LVDs) , where P is the LV end-systolic pressure were recorded. All ECGs were sampled at 250 Hz calculated from the measured upper limb systolic with simultaneous 12-lead recordings, and digitized blood pressure (P=0.66 systolic blood pressure + 16 data were saved to a floppy disk for automated 13.5 ), as an index of LV after-load; 3) percentage LV analysis. For each ECG, QT intervals in each lead posterior wall thickening (%PWT)=100 were manual PWTd)! PWTd, as an index of the rate of change of modification of the computerized recognition of the LV wall thickness. Pulsed Doppler echocardiograms T-wave offset. The T-wave offset was detected as were obtained in the left parasternal 4-chamber the intersect of the T-P isoelectric baseline with the view. The sample volumes were placed on the mitral least-squares-fit line around the target to the T-wave valve annulus, and the angle between the Doppler downslope. The heart-rate corrected QT (QTc) was beam and the presumed mitral flow vectors was calculated using the Bazett formula: QTc=QT! "RR kept as small as possible. We measured the interval. The QT intervals were measured from the maximum early filling peak velocity (E) and the QRS complex to the end of the T wave. If a U wave atrial contraction peak velocity (A) from the LV was present, the T wave offset was defined as the transmitral flow wave recordings, and calculated E! nadir between the T and U waves. If the T wave A as an index of diastolic function. automatically calculated without offset could not be identified, the lead was excluded The investigators who interpreted (PWTs the QT from analysis. The QTd, which is defined as the dispersion, M-mode echocardiograms, and pulse difference between the maximum and minimum QT Doppler echocardiograms were blinded to intervals, was derived for each recording. The heart- clinical data. the rate corrected QTd (QTcd) was calculated with the Bazett formula. Statistical Analysis Differences among the groups were analyzed at Echocardiography and Pulsed Doppler Echocardiography each stage with one-way analysis of variance (Scheffe s method). Differences with a probability After 5 minutes of rest, systolic and diastolic blood pressures were measured in the upper limb by value of p<0.05 were considered statistically significant. means of a manual sphygmomanometer with a 5-, 9-, or 14-cm cuff. Echocardiography and pulsed Doppler Results echocardiography were performed with a HewlettPackard SONOS-2500 (Hewlett-Packard, Palo Alto, CA, USA) with a 5- or 3.5-MHz transducer. Clinical Data of the Patients and Control Subjects Phonocardiograms, indirect carotid pulse tracing, There were no significant differences in the levels and ECGs were simultaneously recorded at a paper of hemoglobin or electrolytes between any of the speed groups (Table 2). of 50 mm! s. J Nippon Med Sch 2010; 77 (5) The 2-dimensional 237 Y. Uchikoba, et al "200 mg! m2. When the cut-off value for normal Ta bl e2 He mbl o bi na nde l e c t r o l yt e s + 2 + Na K+ Ca ( mEq/ L) ( mEq/ L) ( mg/ dL) Hb ( g/ dL) c o nt r o l N L M H 1 3 . 5 ±0 . 8 1 2 . 6 ±0 . 6 1 1 . 9 ±0 . 9 1 2 . 6 ±0 . 8 1 2 . 1 ±0 . 7 1 4 1 . 4 ±4 . 3 1 3 9 . 8 ±3 . 6 1 4 0 . 2 ±2 . 9 1 4 2 . 3 ±4 . 9 1 4 0 . 6 ±5 . 2 4 . 3 ±0 . 3 4 . 2 ±0 . 2 4 . 5 ±0 . 3 4 . 2 ±0 . 2 4 . 1 ±0 . 2 9 . 4 ±0 . 2 9 . 6 ±0 . 3 9 . 4 ±0 . 2 9 . 7 ±0 . 4 9 . 5 ±0 . 2 QTd was set at <50 milliseconds17,18, 68.8% (11 of 16) of the patients in group M and 83.3% (5 of 6) of patients in group H had an abnormal QTd. After administration of dobutamine at 5 μg! kg! min, the results were the same as those at rest. After administration of dobutamine at 30 μg! kg! min, QTd and QTcd were significantly greater in patients Hb: he mo gl o bi n from group L (56.5 6.4, 81.3 4.8, 79.6 8.4), group M (61.2 8.5), or group H (64.3 7.7, 83.0 10.5) than in the other 2 groups or in healthy control Hemodynamic Changes before and after subjects (p<0.05) (Table 4). With a QTd cut-off value of <50 milliseconds, 5 of the 8 patients (62.5%) in Dobutamine Stress or group L, 15 of the 16 patients (93.8%) in group M, dobutamine and all 6 patients in group H had an abnormal QTd. administration, and all subjects were a given the full On the other hand, there were no significant dobutamine dose of 30 μg! kg! min. In each group, differences in QTd or QTcd between group N and the heart rate and systolic blood pressure increased the control subjects at rest or after administration of significantly from those at rest to those after dobutamine at 5 or 30 μg! kg! min. No subjects arrhythmias administration showed in of any response dobutamine symptoms to at 30 μg!kg!min. There were no significant differences between any Correlation between Cumulative Anthracycline of the groups at rest or after administration of Dose and QTd at Rest and after Dobutamine dobutamine at 30 μg! kg! min. In all groups, DP was Stress at 30 μg! kg! min. greater after administration of dobutamine at 30 μg! We tested the correlation between cumulative kg! min than at rest or after low-dose dobutamine anthracycline dose and QTd after dobutamine stress administration. In all groups, the mean DP increased at 30 μg! kg! min, and found a good correlation using significantly up to 20,000, which is thought to be a the following correlation formula: y=0.051x + 42.2 practical exercise volume after administration of (r=0.81, p<0.001) (Fig. 1). This correlation suggests dobutamine at 30 μg! kg! min (Table 3). that QTd was worse at the highest cumulative anthracycline dose. The cut-off value for detection of QTd, QTcd Values at Rest, and after Low- and abnormal cardiac reserve function was at a 2 cumulative anthracycline dose of 152.9 mg! m , which High-dose Dobutamine Stress We could not identify the T wave offset in 4 was calculated using the correlation formula patients at high-dose dobutamine stress, which between QTd and cumulative anthracycline dose. included leads I and aVL in 2 patients from groups M The sensitivity and specificity for detection of and H, lead aVL in 1 patient from group M, and lead anthracycline cardiotoxicity based on our findings of V1 in 1 patient from group L. We examined whether abnormal QTd ("50 milliseconds) after high-dose sex affected QTd and found that QTd is not sex- dobutamine stress in patients with a cumulative dependent (male QTd: 44.5 anthracycline dose of >150 mg! m2 were 96.0% and 3.9, female QTd: 46.3 4.1). At rest, QTd and QTcd were significantly 83.3%, respectively. This finding shows that patients greater in groups M and H (group M: 51.3 receiving a cumulative dose of anthracycline of 3.6, group H: 52.1 4.1, 54.0 4.5, 52.8 3.4) than in the 150 mg! m2 or more display subclinical other 3 groups or in healthy control subjects (p< electrophysiological 0.05). This finding indicates that inhomogeneity of Thus, QTd is a reliable predictor of anthracycline ventricular repolarization occurred even at rest in cardiotoxicity patients who received an anthracycline dose of anthracyclines, 238 anthracycline in and patients cardiotoxicity. treated subclinical with myocardial J Nippon Med Sch 2010; 77 (5) Anthracycline Cardiotoxicity Ta bl e3 Ca r di o va s c ul a rhe mo dyna mi cc ha nge sbe f o r ea nda f t e rdo but a mi nes t r e s s gr o up HRr e s t HR DOB5 HR DOB3 0 s ysBP r e s t s ysBP DOB5 s ysBP DOB3 0 DPr e s t DPDOB5 DPDOB3 0 c o nt r o l7 1 . 6 ±1 2 . 27 5 . 3 ±1 6 . 31 2 1 . 7 ±2 0 . 81 0 9 . 1 ±1 2 . 31 2 3 . 8 ±1 1 . 21 6 6 . 3 ±1 9 . 47 , 7 8 4 ±6 8 49 , 4 3 6 ±1 , 6 7 92 0 , 8 9 2 ±1 , 1 2 6 N 6 5 . 0 ±1 1 . 26 7 . 1 ±1 0 . 21 2 1 . 3 ±9 . 1 1 0 7 . 1 ±6 . 7 1 2 4 . 3 ±1 0 . 41 6 6 . 2 ±1 4 . 07 , 6 0 8 ±8 3 2 9 , 5 6 3 ±9 5 6 2 1 , 4 5 4 ±9 6 9 L 7 3 . 1 ±1 6 . 67 2 . 0 ±1 2 . 31 2 0 . 4 ±2 8 . 91 0 7 . 2 ±1 2 . 01 2 2 . 5 ±1 2 . 31 6 3 . 2 ±1 7 . 17 , 8 0 3 ±7 6 6 9 , 4 5 7 ±8 8 7 2 1 , 7 9 8 ±9 4 5 M 7 3 . 4 ±1 1 . 17 2 . 6 ±1 2 . 61 2 5 . 2 ±1 9 . 81 0 0 . 9 ±1 2 . 61 2 5 . 4 ±1 4 . 71 5 0 . 5 ±1 8 . 88 , 0 2 1 ±8 9 69 , 1 3 8 ±1 , 2 3 62 2 , 1 0 5 ±1 , 2 0 3 H 6 8 . 8 ±9 . 9 8 3 . 5 ±3 6 . 41 3 7 . 0 ±1 5 . 41 0 0 . 5 ±1 0 . 51 2 3 . 0 ±5 . 3 1 5 4 . 0 ±1 8 . 67 , 9 9 6 ±9 1 31 0 , 1 6 6 ±2 , 0 7 62 1 , 3 2 6 ±1 , 0 2 6 HR: he a r tr a t e , DOB: do but a mi ne , s ysBP: s ys t o l i cbl o o dpr e s s ur e , DP: do ubl epr o duc t Ta bl e4 QTda ndQTc dva l ue sa tr e s t , a f t e rDOB5μg/ kg/ mi nut ea nd3 0μg/ kg/ mi nut es t r e s s c o nt r o l N L M H QTdr e s t ( ms e c ) QTdDOB5 ( ms e c ) QTdDOB3 0 ( ms e c ) QTc dr e s t ( ms e c ) QTc dDOB5 ( ms e c ) QTc dDOB3 0 ( ms e e c ) 3 7 . 1 ±9 . 0 3 8 . 7 ±3 . 6 3 9 . 1 ±4 . 6 * 5 1 . 3 ±4 . 5 * 5 2 . 1 ±4 . 1 4 1 . 1 ±7 . 8 3 9 . 2 ±4 . 6 4 1 . 1 ±4 . 2 * 5 1 . 7 ±5 . 3 * 5 2 . 2 ±6 . 8 4 2 . 6 ±7 . 9 4 1 . 2 ±4 . 6 * 5 6 . 5 ±4 . 8 * 6 1 . 2 ±6 . 4 * 6 4 . 3 ±7 . 7 4 4 . 1 ±1 0 . 9 4 4 . 7 ±7 . 8 4 3 . 1 ±6 . 0 * 5 2 . 8 ±3 . 6 * 5 4 . 0 ±3 . 4 4 6 . 8 ±1 3 . 1 4 7 . 2 ±5 . 6 4 8 . 3 ±7 . 1 * 5 6 . 6 ±6 . 5 * 5 7 . 3 ±8 . 4 5 7 . 8 ±9 . 8 5 8 . 3 ±7 . 9 * 7 9 . 6 ±8 . 4 * 8 1 . 3 ±8 . 5 * 8 3 . 0 ±1 0 . 5 QTd: QT di s pe r s i o n, QTc d: c o r r e c t e dQT di s pe r s i o n *p <0 . 0 5vs . o t he rgr o ups cardiotoxicity was a cumulative anthracycline dose of 526.3 mg! m2, which seems far less sensitive for detecting anthracycline cardiotoxicity. EF, ESS, E! A, and %PWT at Rest and after Low- and High-dose Dobutamine Stress We could perform cardiac performance tests for 7 of 10 control subjects, all patients of group N, 7 of 8 patients of group L, 14 of 16 patients of group M, and all patients of group H. At rest and after Fi g.1 Co r r e l a t i o n be t we e n c umul a t i ve a nt hr a c yc l i nedo s ea ndQT di s pe r s i o na f t e r kg/ mi n. do but a mi nes t r e s sa t3 0μg/ The Y a xi ss ho ws QT di s pe r s i o na f t e r do but a mi nes t r e s sa t3 0μg/ kg/ mi n, a ndt he hr a c yc l i ne Xa xi ss ho wst hec umul a t i vea nt do s e .The r ewa sago o dc o r r e l a t i o nbe t we e n t he s ei ndi c e s ,wi t hac o r r e l a t i o nf o r mul ao f 1 x+ 4 2 . 2( r =0 . 8 1 , p<0 . 0 0 1 ) . y=0 . 0 5 dobutamine stress at 5 μg! kg! min, E! A and %PWT were significantly lower in group H than in the other 4 groups. After dobutamine stress at 30 μg! kg! min, groups M and H showed ESS, E! A, and %PWT values that were significantly different from those of the other 3 groups. Increases in ESS and decreases in %PWT were due to reduced endsystolic LV wall thickness (data not shown), and decreases in E!A indicated reduced diastolic abnormalities can develop in patients receiving a function. These results suggest that patients with a cumulative anthracycline dose of "150 mg! m2. On cumulative m2dose of "400 mg! m2 had subclinical the other hand, we found a good correlation decreases in LV muscle volume and subclinical between anthracycline dose and QTd at rest using increases in LV wall stiffness. On the other hand, the following correlation formula: y=0.04x + 28.9 (r= there were no significant differences in EF among 0.78, p<0.001). When the abnormal value was 50 the 5 groups at rest, after dobutamine stress at 5 milliseconds, the cut-off value for detection of μg! kg! min, or after dobutamine stress at 30 μg! kg! J Nippon Med Sch 2010; 77 (5) 239 Y. Uchikoba, et al Ta bl e5 1 EFa ndESSva l ue sa tr e s t , a f t e rDOB5μg/ kg/ mi nut ea nd3 0μg/ kg/ mi nut es t r e s s c o nt r o l N L M H EFr e s t EFDOB5 EFDOB3 0 ESSr e s t ESSDOB5 ESSDOB3 0 6 4 . 1 ±6 . 0 6 8 . 3 ±3 . 6 6 2 . 5 ±9 . 1 6 1 . 6 ±8 . 3 5 8 . 7 ±9 . 5 6 9 . 7 ±9 . 6 7 4 . 9 ±3 . 6 7 0 . 4 ±8 . 7 6 7 . 0 ±8 . 4 6 8 . 7 ±4 . 9 7 9 . 0 ±4 . 7 8 0 . 9 ±4 . 8 7 8 . 0 ±7 . 7 7 5 . 8 ±1 0 . 8 8 1 . 0 ±1 . 0 5 5 . 1 ±7 . 0 5 5 . 8 ±6 . 3 5 6 . 6 ±2 . 1 5 4 . 7 ±8 . 7 5 8 . 8 ±1 4 . 8 5 4 . 2 ±3 . 2 5 5 . 3 ±2 . 9 5 6 . 4 ±9 . 1 5 6 . 2 ±8 . 6 6 1 . 6 ±1 7 . 5 5 1 . 1 ±2 . 5 5 2 . 3 ±3 . 1 5 1 . 5 ±2 . 1 * 6 3 . 9 ±7 . 1 * 6 2 . 2 ±1 3 . 1 *p EF: e j e c t i o nf r a c t i o n, ESS: e nds ys t o l i cl e f tve nt r i c ul a rwa l ls t r e s s , <0 . 0 5vs . o t he rgr o ups Ta bl e5 2 E/ Aa nd%PWT va l ue sa tr e s t , a f t e rDOB5μg/ kg/ mi nut ea nd3 0μg/ kg/ mi nut es t r e s s c o nt r o l N L M H E/ Ar e s t E/ A DOB5 E/ A DOB3 0 %PWT r e s t %PWT DOB5 %PWT DOB3 0 2 . 0 ±0 . 1 2 . 1 ±0 . 2 2 . 1 ±0 . 1 2 . 0 ±0 . 2 * 1 . 7 ±0 . 2 2 . 2 ±0 . 1 2 . 3 ±0 . 1 2 . 3 ±0 . 2 2 . 1 ±0 . 3 * 1 . 8 ±0 . 2 1 . 5 ±0 . 1 1 . 4 ±0 . 1 1 . 6 ±0 . 2 * 1 . 2 ±0 . 1 * 1 . 0 ±0 . 1 9 6 . 2 ±1 . 6 9 4 . 8 ±4 . 3 9 1 . 2 ±4 . 6 9 1 . 7 ±3 . 2 * 6 8 . 9 ±6 . 1 1 1 5 . 3 ±5 . 6 1 1 8 . 6 ±7 . 6 1 0 9 . 1 ±9 . 5 1 1 2 . 4 ±6 . 1 * 9 2 . 4 ±1 1 . 2 1 3 2 . 7 ±5 . 7 1 3 4 . 8 ±4 . 9 1 3 5 . 8 ±2 6 . 3 * 9 6 . 2 ±3 . 8 * 9 2 . 2 ±5 . 5 E/ A:r a t i oo ft hema xi mum e a r l yf i l l i ngpe a kve l o c i t y( E)a ndt hea t r i a lc o nt r a c t i o npe a kve l o c i t y( A) ,%PWT: pe r c e nt a gel e f tve nt r i c ul a rpo s t e r i o rwa l lt hi c kne s s *p <0 . 0 5vs . o t he rgr o ups min. These findings suggest that even the highest 2 cardiomyopathy have been described. Most studies cumulative m doses in the patients did not reduce support the view that an increase in oxidative stress LV systolic function (Table 5-1, 5-2). These findings (evidenced by increases in free radicals and lipid using 2-dimensional echocardiography and pulse peroxidation and decreases in antioxidants and Doppler echocardiography are similar to the findings sulfhydryl groups) plays an important role in the we obtained in our previous study14. pathogenesis of anthracycline cardiomyopathy21,22. The unique sensitivity of the myocardium to Discussion anthracyclines may be due to the low levels of catalase Late cardiotoxic effects of anthracycline are an increasing problem for survivors of childhood cancer. and superoxide dismutase in cardiac 23 myocytes . The main features of cardiac biopsies from Anthracycline-induced congestive heart failure is a anthracycline-treated dose-dependent phenomenon. Reported incidences of vacuolization due to dilation of the sarcotubules and anthracycline-induced congestive heart failure range loss of myofibrils19,24. In patients who received a high from >5% (cumulative adriamycin dose, 501 to 550 dose 2 patients (455―500 mg!m 2 ) of are cytoplasmic daunomycin, cardiac mg! m ) to >30% (cumulative adriamycin dose, >601 biopsies exhibited degenerative, atrophic, and lytic mg! m2)19. In a long-term follow-up study, patients lesions in cardiac muscle cells, and interstitial edema who had no symptoms of cardiotoxicity at the time and fibrosis23. These histological abnormalities could of complete remission of cancer after adriamycin strongly affect myocardial action potentials and cell- therapy to-cell conduction, and lead to inhomogeneity of had an unusually high incidence of cardiovascular complications typical of adriamycin 20 ventricular depolarization and repolarization. cardiomyopathy over the subsequent 4 to 20 years . Previously, we reported that anthracycline-treated Thus, it is important to find ways to avoid or patients minimize the cardiotoxic side effects of anthracycline depolarization, in the treatment of cancer. Several effects of anthracycline which may play critical roles in the pathogenesis of anthracycline 240 exhibited as abnormal revealed by ventricular signal-averaged 25 electrocardiography . However, there have been no other reports of abnormalities of ventricular repolarization in anthracycline-treated patients. QT J Nippon Med Sch 2010; 77 (5) Anthracycline Cardiotoxicity dispersion is defined as the difference between the kg! min, patients with a very low cumulative maximum and minimum QT interval durations on a anthracycline dose (anthracycline dose "80 mg! m2 ) 12-lead standard ECG and is considered to reflect had significantly greater QTd and QTcd than did local differences in repolarization of the myocardium. control subjects or patients who had not received an In the present study, at rest, when the cut-off value anthracycline. 17,18 for normal QTd was set at <50 milliseconds With the cut-off value of >50 , the milliseconds, an abnormal QTd was found in 62.5% QTd was abnormal in 68.8% of the patients with a of patients with a cumulative anthracycline dose of cumulative anthracycline dose of "200 mg! m and 80 to <200 mg! m2, 93.8% of in cumulative anthracycline dose of 200 to <400 mg! m2 , 2 83.3% of the patients with a cumulative anthracycline dose of "400 mg! m2. An abnormal and 100% of patients with a a cumulative "400 mg!m . 2 of with increase in QT dispersion could be caused by anthracycline inhomogeneity of ventricular repolarization. The evaluated QTc was prolonged at rest by more than 450 muscle performance under dobutamine stress using milliseconds in only 5 of the present cases. The QTc 2-dimensional echocardiography and pulsed Doppler may be less sensitive as an index of anthracycline echocardiography. The values for ESS, E! A, and cardiotoxicity at rest than are the QTd data. On the %PWT that we obtained were consistent with our other hand, in the present study, 2-dimensional previous findings25, yet were much less sensitive echocardiography showed that only patients with a than were the QTd and QTcd data that we obtained cumulative anthracycline dose of "400 mg! m2 had a in the present study. Because these indices are significantly reduced LV cardiac muscle volume at calculated from changes in LV wall motion on 25 dose patients cardiotoxicity by examining We also cardiac rest, which is consistent with our previous findings . echocardiograms, detectable changes in wall motion It appears likely that decreased numbers of cardiac must require much higher cumulative doses than myocytes and increased interstitial edema and the electrophysiological changes detected on the fibrosis leads not only to reduced ventricular cardiac basis of QT dispersion. Data from 2-dimensional volume but also to abnormal microelectrical findings. echocardiography Our a echocardiography is more difficult to evaluate than "200 mg!m , are data from 12-lead ECG. Moreover, whereas electrical findings at rest indicates cardiotoxic effects sedation may be needed for infants and small (morphological changes in ventricular myocardium) children when they undergo echocardiography, that require intervention. there is no need for sedation to perform 12-lead findings cumulative show that anthracycline for patients dose of with 2 and pulsed Doppler Dobutamine is a synthetic catecholamine α1, β1 ECG. Thus, in terms of ease of use, QTd and QTcd and β2 with mimetic activity. Dobutamine has have clear advantages over ESS, E! A, and %PWT inotropic effects at low doses (5―10 μg! kg! min) and as indices for detecting anthracycline cardiotoxicity causes increased heart rate, blood pressure, and that manifests as abnormal cardiac reserve function. coronary vasodilation at high doses (>20 μg! kg! min). In the present study, there was little difference oxygen between QTd and QTcd. Some earlier studies have consumption in the myocardium and increase the found no evidence that QT dispersion requires the inhomogeneity of ventricular myocytes at moderate same type of heart rate correction as the duration of doses (>10 μg! kg! min) . These findings suggest that the QT interval27,28. Also, clear criteria have recently the inhomogeneity of ventricular repolarization can been established for detecting abnormal QTd based be increased in cardiac myocytes exposed to on anthracyclines. evaluated precise value for detecting abnormal QTcd has been myocardial reserve function as an indicator of established. Moreover, assessing QTd is much easier cardiotoxicity, by performing electrophysiological than assessing QTcd. Thus, QTd has an advantage and morphological evaluations under dobutamine- over QTcd as an index for detecting abnormal induced stress. After dobutamine stress at 30 μg! ventricular inhomogeneity. Thease changes lead to increased 26 In this study, J Nippon Med Sch 2010; 77 (5) we electrophysiological findings 17,18, whereas no 241 Y. Uchikoba, et al In the present study, we also assessed the analysis. correlation between cumulative anthracycline dose The Bazett formula is commnly used to correct and QTd after dobutamine stress at 30 μg! kg! min. the QT interval for heart rate. Recently, the We found a good correlation between those 2 Fridericia formula has been considered better for variables when using the correlation formula: y= correcting the QT interval when the heart rate is 0.051x + 42.2 (r=0.81, p<0.001) (Fig. 1). With this high. We would have liked to use the Fridericia formula, cumulative formula in the present study, especially for high we determined that a 2 anthracycline dose of 152.9 mg! m was the cut-off for heart rates during dobutamine stress, however, the detecting abnormal cardiac reserve function. Based Cardio Mulyi FDX-4520 is not formatted for the on these results, the sensitivity and specificity for Friderica formula. Hence, in this study the QT detecting anthracycline cardiotoxicity as indicated interval was corrected with the Bazett formula. by abnormal QTd after high-dose dobutamine stress In the present study, we did not obtain control ("50 milliseconds) in patients with a cumulative data from children because we decided that the anthracycline dose of >150 mg! m2 were 96.0% and dobutamine stress test was too invasive and that 83.3%, respectively. This finding suggests that the healthy children should not be subjected to such a physicians cumulative stress test. Also, we could not obtain age-matched anthracycline dose of >150 mg! m should consider data. However, there were no significant differences the possibility of decreased cardiac reserve function. between the control group and any of the 3 patient QTd appears to be a useful index for detecting groups in the basic findings of heart rate and blood cumulative anthracycline cardiotoxicity. pressure, which strongly affect electrophysiological of patients with a 2 Previously, we reported that anthracycline-treated patients exhibit abnormal ventricular depolarization, data. Therefore, we felt that the index of age could be ignored in this study. as revealed by signal-averaged ECG (SAE). However, Conclusions the microvolt electrophysiological changes detected with SAE dependent require on measurement of several method QTd criteria and is a age. that are Because convenient and 29 Dobutamine-stress QT dispersion is a useful method for detectinglate anthracycline independent of age and sex , it is, therefore, a much cardiotoxicity, especially for patients who cannot better method than SAE for detecting anthracycline tolerate physical exercise. On the basis of these cardiotoxicity. findings we believe that the physicians of patients Finally, we did not evaluate the reproducibility of with a cumulative anthracycline dose of >150 mg! m2 QTd in this study. Many papers have reported that should be aware of the possibility of subclinical the reproducibility of QT dispersion is significantly anthracycline cardiotoxicity. poorer than the reproducibility of the QT interval itself. 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