|Year : 2014 | Volume
| Issue : 1 | Page : 25-28
Early detection of anthracycline-induced cardiotoxicity in long-term survivors of acute lymphoblastic leukemia treated with low cumulative dose
Giovanni Di Salvo1, Fabio D'Aiello1, Fortuna Del Gaizo1, Paolo Indolfi2, Fiorina Casale2, Maria Teresa di Tullio2, Diana Iarussi1, Raffaele Calabrò1, Maria Giovanna Russo1
1 Second University of Naples, Chair of Cardiology, Monaldi Hospital, Naples, Italy
2 Pediatric Oncology Service, Second University of Naples, Naples, Italy
|Date of Web Publication||12-May-2014|
Giovanni Di Salvo
Via Omodeo 45, Naples-80128
Source of Support: None, Conflict of Interest: None
We investigated the left ventricular (LV) function, using for the first time strain (S) and strain rate (SR) imaging, in long-term survivors affected by acute lymphoblastic leukemia treated with a low cumulative dose of anthracyclines, and in presence of a normal global LV systolic and diastolic function. A total of 21 were enrolled in the study. The mean cumulative dose of anthracylines was 180 mg/m 2 (range: 120-210 mg/m 2 ). As control group 21 age-sex matched healthy subjects were included. Radial S (17 ± 3% vs. 55 ± 6%, P < 0.0001) and SR (2.1 ± 0.3 vs. 3.0 ± 0.8 1\s, P < 0.0001), assessed on the midsegment of the posterior wall from the parasternal views were significantly reduced when compared with controls. Conversely, myocardial performance index was not able to discriminate between patients and controls. In this preliminary study, the myocardial deformation indices appear to be a more sensitive noninvasive technique for detecting subclinical LV dysfunction than other echocardiographic measurements.
Keywords: Anthracycline cardiomyopathy, SR imaging, ventricular function
|How to cite this article:|
Salvo GD, D'Aiello F, Gaizo FD, Indolfi P, Casale F, di Tullio MT, Iarussi D, Calabrò R, Russo MG. Early detection of anthracycline-induced cardiotoxicity in long-term survivors of acute lymphoblastic leukemia treated with low cumulative dose. J Cardiovasc Echography 2014;24:25-8
|How to cite this URL:|
Salvo GD, D'Aiello F, Gaizo FD, Indolfi P, Casale F, di Tullio MT, Iarussi D, Calabrò R, Russo MG. Early detection of anthracycline-induced cardiotoxicity in long-term survivors of acute lymphoblastic leukemia treated with low cumulative dose. J Cardiovasc Echography [serial online] 2014 [cited 2021 Oct 22];24:25-8. Available from: https://www.jcecho.org/text.asp?2014/24/1/25/132282
| Introduction|| |
Anthracyclines are the most frequent cause of iatrogenic congestive heart failure ranging from acute reversible minor to irreversible reduction in the left ventricular (LV) ejection fraction and death despite preventive measures. 
Serial surveillance for cardiotoxicity in patients receiving anthracyclines has most commonly centered on the assessment of LV systolic function by standard echocardiography. ,
The development of new quantitative echocardiographic techniques, such as ultrasonic strain (S) and strain rate (SR) imaging,  has enhanced our ability to noninvasively assess regional myocardial function.
We investigated the LV function, using Doppler derived S and SR imaging, in long-term survivors affected by acute lymphoblastic leukemia (ALL) treated with a low cumulative dose (≤210 mg/m 2 ) of anthracyclines, and in presence of a normal global LV systolic and diastolic function, as assessed by standard echocardiography.
| Materials and methods|| |
The study population was recruited between January 1983 and December 1990 at the Pediatric Oncology Service of Second University of Naples and studied at the Pediatric Cardiology outpatient clinic of the same University.
All patients were affected by ALL: Of the original 112 patients diagnosed in that period, 44 were excluded because died of disease, 30 declined the invitation to undergo Echocardiogram, and 16 were excluded for inadequate echocardiogram. The remaining 21 patients, who were in continuous remission, presented no cardiac symptoms, have been treated with a low cumulative dose of anthracyclines (≤210 mg/m 2 ), and had received the last dose at least 10 years previously, were considered eligible for the study.
In this group, mean age at diagnosis was 3.6 years (range 1-11 years) and the mean of follow-up interval from last dose of anthracycline was 15.7 years (range 11-20 years). The mean cumulative dose of anthracylines was 180 mg/m 2 (range 120-210 mg/m 2 ). All patients were recruited in Associatione Italiana Ematologia-Oncologia Pediatrica-ALL protocols. In detail, 1 patient was enrolled in 8201-protocol; 5 patients in 8202 protocol; 12 patients in 8702 protocol; and 3 patients in 8703 protocol.
The control group consisted of 21 healthy subjects, comparable for age and sex. All patients and controls gave written informed consent to participate in the study. The study protocol was approved by our institutional ethics committee.
Both the standard echocardiographic study and the color Doppler myocardial imaging (CDMI) data were digitally stored and all the measurements were performed off-line by 2 independent observers who were blind to the clinical status of the subjects.
Echocardiography measurements were taken with a System Seven (GE, Norway). LV measurements were taken from two-dimensional guided M-mode tracings.
The standard echocardiographic study has been performed following a standard methodology. 
The myocardial performance index (MPI), defined as the sum of isovolumic activity (isovolumic contraction time and isovolumic relaxation time) divided by ventricular ejection time, was measured following a previously described protocol. 
All CDMI data were acquired at a frame rate of 220 ± 15 frames/s (GE Vingmed System Seven; 3.5 MHz). Our methodology for CDMI study has been previously described. 
Peak systolic S and SR values were used for the analysis.
The normality Kolmogorov-Smirnov test was performed to determine whether continuous variables were normally distributed.
Data are presented as the mean value ± standard deviation (SD). A comparison between groups of continuous variables was performed by using the Student's t test, whereas skewed distributed variables were compared by using the rank Mann-Whitney U test. Categorical variables were compared by using the chi-square test.
A P value < 0.01 was used to reject the null hypotesis. All the analyses were performed using a commercially available package (SPSS, Rel 11.0 2002. Chicago: SPSS inc).
| Results|| |
[Table 1] summarizes the clinical characteristics of the two groups.
|Table 1: Clinical and standard echocardiographic characteristics of the studied sample |
Click here to view
The normal children did not significantly differ from patients in age, sex, heart rate, and blood pressure. Both groups had similar standard measurements of LV systolic and diastolic function (LV ejection fraction and mitral E/A ratios). The LV MPI in the study patients was not statistically different from that of normals [Table 1].
Longitudinal S and SR were similar to those measured in healthy subjects [Table 2].
|Table 2: Peak systolic longitudinal strain values (%) of the studied sample |
Click here to view
Radial S (17 ± 3% vs. 55 ± 6%, P < 0.0001) and SR (2.1 ± 0.3 vs. 3.0 ± 0.8 1\s, P < 0.0001), assessed on the midsegment of the posterior wall from the parasternal views were significantly reduced when compared to healthy subjects [Table 3]. One patient (5%) had both peak systolic radial S and SR < 2 SDs below the mean of normal subjects.
|Table 3: Peak systolic radial strain and strain rate values of the studied sample |
Click here to view
| Discussion|| |
Doppler derived S and SR indices unmask early systolic abnormalities in long-term survivors of ALL treated with low cumulative dose of anthracycline.
Radial myocardial deformation is involved in systolic dysfunction, while longitudinal myocardial deformation is normal.
This finding may seem surprising since in several cardiac disease (coronary artery diseases or valvular heart diseases) longitudinal dysfunction generally appears very early as the first stage of subclinical myocardial damage, ,, in contrast radial strain deteriorates later when ejection fraction starts to decrease.
Conversely, in our study we found an earlier involvement of the radial function. The possible explanation of this earlier radial functional deterioration may be related to the different mechanism leading to cardiac dysfunction in in long-term survivors of ALL treated with anthracycline.
Indeed, oxidative stress plays a major role in anthracycline-induced cardiomyopathy, stochastically involving myocites.  The longitudinally directed fibers compose only a small portion of the myocardial mass,  while myocardial fibers responsible of the radial function are quantitatively more represented,  and thus more exposed to oxidative damage.
On the contrary in coronary artery disease or valvular heart disease the subendocardial layer, responsible of longitudinal function, is the first to be involved.
Significant abnormalities of S and SR occurred in presence of normal standard echocardiogrphic Doppler measures of LV systolic or diastolic function. ,, These changes occurred at cumulative dosages as low as 100-210 mg/m 2 . In our sample, only four patients had a cumulative dosage between 200 and 210 mg/m 2 .
Of note, in our study MPI was not able to discriminate patients from controls. This finding is in agreement with previous report demonstrating that MPI is able to detect changes in global myocardial function in presence of a cumulative dose of antracycline ≥ 200 mg/m 2 . 
In this preliminary study, the myocardial deformation indices appear to be a more sensitive noninvasive technique for detecting subclinical LV dysfunction than other echocardiographic measurements.
This study was conducted using color Doppler derived S and SR. Thus, we are limited by angle dependency and we can only assess radial function at the level of the midsegment of the posterior wall. For the same reason, reliable CDMI data were obtained in all patients from the apical 4 chamber view, while relible data were obtained only from 80% of our patients in apical 2 chamber view. Conversely, color Doppler derived imaging is the only way to fully resolve SR which is less load dependent compared with S. 
| References|| |
|1.||Bu'Lock FA, Mott MG, Oakhill A, Martin RP. Left ventricular diastolic filling patterns associated with progressive anthracycline-induced myocardial damage: A prospective study. Ped Cardiol 1999;20:252-63. |
|2.||Lipshultz SE, Colan SD, Gelber RD, Perez-Atayde AR, Sallan SE, Sanders SP. Late cardiac effects of doxorubicin therapy for acute lymphoblastic leukemia in childhood. N Engl J Med 1991;324:808-15. |
|3.||Sutherland GR, Di Salvo G, Claus P, D'Hooge J, Bijnens B. Strain and strain rate imaging: A new clinical approach to quantifying regional myocardial function. J Am Soc Echocardiogr 2004;17:788-802. |
|4.||American Society of Echocardiography Committee on Standards. Recommendations for quantitation of the left ventricle by two-dimensional echocardiography. J Am Soc Echocardiogr 1989;2:358-67. |
|5.||Tei C, Ling LH, Hodge DO, Bailey KR, Oh JK, Rodeheffer RJ, et al. New index of combined systolic and diastolic myocardial performance: A simple and reproducible measure of cardiac function - a study in normals and dilated cardiomyopathy. J Cardiol 1995;26:357-66. |
|6.||Di Salvo G, Drago M, Pacileo G, Carrozza M, Santoro G, Cappelli Bigazzi M, et al. Comparison of strain rate imaging for quantitative evaluation of regional left and right ventricular function after surgical versus percutaneous closure of atrial septal defect. Am J Cardiol 2005;96:299-302. |
|7.||Di Salvo G, D'Aiello AF, Castaldi B, Fadel B, Limongelli G, D'Andrea A, et al. Early left ventricular abnormalities in children with heterozygous familial hypercholesterolemia. J Am Soc Echocardiogr 2012;25:1075-82. |
|8.||Di Salvo G, Rea A, Mormile A, Limongelli G, D'Andrea A, Pergola V, et al. 22. Usefulness of bidimensional strain imaging for predicting outcome in asymptomatic patients aged ≤ 16 years with isolated moderate to severe aortic regurgitation. Am J Cardiol 2012;110:1051-5. |
|9.||Eidem BW, Sapp BG, Suarez CR, Cetta F. Usefulness of the myocardial performance index for early detection of anthracycline-induced cardiotoxicity in children. Am J Cardiol 2001;87:1120-2. |
[Table 1], [Table 3]
|This article has been cited by|
||Promising genes and variants to reduce chemotherapy adverse effects in acute lymphoblastic leukemia
| ||Diego Alberto Bárcenas-López,Diana Karen Mendiola-Soto,Juan Carlos Núñez-Enríquez,Juan Manuel Mejía-Aranguré,Alfredo Hidalgo-Miranda,Silvia Jiménez-Morales |
| ||Translational Oncology. 2021; 14(1): 100978 |
|[Pubmed] | [DOI]|
||Timing of the negative effects of trastuzumab on cardiac mechanics after anthracycline chemotherapy
| ||Christian Cadeddu,Alessandra Piras,Mariele Dessì,Clelia Madeddu,Giovanni Mantovani,Mario Scartozzi,Andreas Hagendorff,Paolo Colonna,Giuseppe Mercuro |
| ||The International Journal of Cardiovascular Imaging. 2016; |
|[Pubmed] | [DOI]|