Abstract
Hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment for many refractory malignancies, bone marrow failure syndromes and primary immune deficiencies in children. Cardiomyopathy and heart failure are well described late complications of HSCT. By the time they manifest clinically, a significant and irreversible damage to the myocardium has occurred with resultant substantial morbidity and mortality. This study aims to evaluate subclinical cardiac affection by using conventional echocardiography, two-dimensional (2D) speckle tracking and three-dimensional (3D) Echo among patients before and after Hematopoietic Stem Cell Transplantation. A prospective case control study was conducted from 2022 to 2023 on 25 patients who underwent bone marrow transplantation and 25 controls. Demographic, clinical data were collected. Echocardiography was performed, including LV functional assessment using conventional echocardiography, 2D speckle tracking, and 3D echocardiography. The mean age of the patients was 9.8 years. Neuroblastoma was the most common indication for transplantation, accounting for 44% of cases, while only 4% of patients underwent transplantation for thalassemia. Significant changes were observed in fractional shortening (FS), global longitudinal strain (GLS), segmental myocardial strain parameters, and 3D ejection fraction (3D EF) before and after transplantation. FS showed a significant correlation with the cumulative dose of cyclophosphamide, while GLS average was significantly associated with disease duration, cumulative doses of cyclophosphamide, and doxorubicin. Additionally, 3D EF demonstrated significant correlations with these factors. GLS average, lateral longitudinal strain at the base, and 3D EF differed significantly between autologous and allogeneic transplant recipients. This study demonstrates significant changes in cardiac function following HSCT, with alterations in fractional shortening, global and segmental myocardial strain, and 3D ejection fraction. 3D echocardiography proved effective in detecting these changes.
Keywords: LV strain, 3D echocardiography, Hematopoietic stem cell transplantation
Subject terms: Cardiology, Oncology
Introduction
Hematopoietic stem cell transplantation (HSCT) is a curative treatment for refractory malignancies, bone marrow failure syndromes, and primary immune deficiencies in children1. However, cardiomyopathy and heart failure are recognized late complications, often associated with irreversible myocardial damage, significant morbidity, and mortality2. Chemotherapy and radiation used in HSCT can cause cardiotoxicity, leading to complications such as pericardial effusion, cardiac dysfunction, and pulmonary hypertension, with long-term cardiac disease being a major cause of morbidity and mortality among survivors3.
Major risk factors include pre-HSCT anthracycline or chest radiation exposure, high-dose cyclophosphamide, graft-versus-host disease (GvHD), and tyrosine kinase inhibitors (TKIs), among others4. Anthracycline-related cardiotoxicity is linked to increased reactive oxygen species, mitochondrial damage, and impaired DNA repair mechanisms5,6. Cyclophosphamide doses > 100 mg/kg and chest radiotherapy ≥ 30 Gy significantly increase the risk of cardiac dysfunction7,8.
Routine cardiac evaluation pre-HSCT and longitudinal follow-ups are recommended to detect cardiotoxicity early9. Conventional echocardiographic measures like ejection fraction (EF) are commonly used, myocardial strain imaging offers earlier detection of myocardial stress or injury10. Given its reproducibility and precision, 3D echocardiography is vital for serial imaging in patients undergoing chemotherapy11. This study evaluates the role of 2D speckle tracking and 3D echocardiography in detecting subclinical cardiac dysfunction before and after HSCT, which may impact prognosis and quality of life.
Methods
Study design
The study is prospective case control study carried out at pediatric bone marrow transplantation units in Mansoura University Children Hospital (MUCH) and Oncology Center Mansoura University (OCMU) during the years 2022–2023.
Sample size
The study’s sample size was calculated using G*power version 3.1.9.7. The configured sample consisted of 25 participants for the patients’ group and for the control group, at a 5% level of significance and 85% power of the study.
Patient’s selection
All patients pre and post HSCT including either benign conditions like thalassemia and aplastic anemia or malignant diseases including leukemia, lymphoma and neuroblastoma were included. Patients with congenital heart diseases confirmed by echocardiography and Pre transplant patients proven to have cardiac affection before HSCT were excluded from the study.
Data included in the study
Thorough History including age, sex, diagnosis, duration of illness and chemotherapeutics given (type, dose, and duration). Additionally anthropometric measurements and vital signs of all patients were included.
Investigations
Echocardiography: was performed by experienced clinicians prior to hematopoietic stem cell transplantation (HSCT) and again during follow-up at least three months after HSCT for the patient group. Post-transplant echocardiography was exclusively conducted for patients, using the EPIQ CVx Release 5.0 (Philips Medical Systems, Bothell, WA, USA, 2018) equipped with an X5-1 matrix array transducer (5–1 MHz).
Conventional echocardiography 2D and M mode were done for LV assessment using apical long parasternal view and short axis view. LV end diastolic, end systolic diameters and posterior wall thickness were measured. Conventional LV systolic function was evaluated by assessment of ejection fraction (EF) % and fractional shortening (FS) %. EF was calculated using the Simpson’s biplane method, while FS was calculated using M-mode echocardiography based on measurements of left ventricular dimensions during diastole and systole.
2D speckle tracking to assess LV deformation function was assessed using transducer X5. The global longitudinal systolic strain was assessed through full volume acquisition recorded in five consecutive cardiac cycles while patient is holding breath. Three apical views, (apical four chamber, three chamber and two chamber views) were used for evaluation of longitudinal strain.
3D echocardiography
The Heart Model Acquisition (HM ACQ) mode was utilized to obtain full-volume 3D datasets from an LV-focused four-chamber view. All 3D volumes were digitally recorded and analyzed using the dedicated automated quantification software, *Dynamic Heart Model A.I.*, designed specifically for LV assessment. This software enables comprehensive volumetric and functional analysis of the left ventricle, leveraging 3D speckle tracking technology to provide a detailed evaluation of LV function throughout the cardiac cycle.
With automated border detection, the software generates key 3D echocardiographic parameters, including end-diastolic volume (EDV), indexed end-diastolic volume (EDVi), end-systolic volume (ESV), ejection fraction (EF), and stroke volume (SV). Figure 1 illustrates an example of 3D echocardiography in a case after HSCT .
Fig. 1.
Advanced echocardiographic evaluation includes 2D speckle tracking and 3D echocardiography. Panel A demonstrates 2D speckle tracking of the 4-chamber, 3-chamber, and 2-chamber views, with automated global longitudinal strain (GLS) calculation and a Bull’s eye plot, showing a reduced GLS average of – 13.2%. Panel B highlights 3D echocardiography with automated calculation of 3D-derived ejection fraction (EF), revealing a value of 49.4%.
Statistical methods
Statistical analysis was conducted using the Statistical Package for Social Sciences (SPSS), version 21 (IBM/SPSS Inc., Chicago, IL). Descriptive statistics were used to summarize continuous data, with mean ± standard deviation (SD) reported for normally distributed variables and median and range for non-normally distributed data. For analytical and inferential statistics, an independent samples t-test was utilized to compare parametric continuous data between two independent groups, while a paired samples t-test was applied to evaluate differences in parametric continuous data within two dependent groups. Pearson correlation was performed to assess relationships between two quantitative variables, with correlation coefficients (r) interpreted as follows: positive values indicated a direct correlation, negative values indicated an inverse correlation, and the strength of correlation was classified as weak (r < 0.29), moderate (0.30 ≤ r ≤ 0.49), or strong (r ≥ 0.50). The significance level for rejecting the null hypothesis was set at 0.05, with P-values interpreted as follows: P ≥ 0.05 was considered not statistically significant, P < 0.05 was considered statistically significant, and P < 0.01 was considered highly significant.
Results
The demographic and disease-related data of the study cohort are presented in Table 1. The mean age of patients was 9.8 ± 4.3 years, with a male predominance (60%). Neuroblastoma was the most common indication for hematopoietic stem cell transplantation (HSCT), followed by Hodgkin lymphoma (36%), acute myeloid leukemia (AML), and thalassemia (4%). The mean duration of disease before HSCT was 24.76 ± 9.82 months, and 80% of patients underwent autologous HSCT. GvHD prophylaxis was administered to 20% of patients, with acute GvHD reported in only one patient (4%), while no cases of chronic GvHD were observed.
Table 1.
Demographics and disease related data.
| Variables | Case (N = 25) |
Control (N = 25) |
P Value | |
|---|---|---|---|---|
| Age (years) | 9.8 ± 4.3 | 9.8 ± 4.2 | 1* | |
| Gender, n (%) | 0.39** | |||
| Males | 15 (60%) | 12 (48%) | ||
| Females | 10 (40%) | 13 (52%) | ||
| Weight (Kg) | 34.16 ± 17.6 | 33.5 ± 17 | 0.95* | |
| Primary disease | N | (%) | ||
| AML | 4 | 16 | ||
| Hodgkin lymphoma | 9 | 36 | ||
| Neuroblastoma | 11 | 44 | ||
| Thalassemia | 1 | 4 | ||
| Mean duration of disease before BMT (months) | 24.76 ± 9.82 | |||
| Conditioning regimen | N | (%) | ||
| BEAM | 9 | 36 | ||
| Bu-Alk | 11 | 44 | ||
| Bu-Cy | 5 | 20 | ||
| Type transplant | ||||
| Auto | 20 | 80 | ||
| Allo | 5 | 20 | ||
| GvHD prophylaxis | ||||
| No | 20 | 80 | ||
| Yes | 5 | 20 | ||
| Acute GvHD | ||||
| No | 24 | 96 | ||
| Yes | 1 | 4 | ||
| Chronic GvHD | ||||
| No | 25 | 100 | ||
| Yes | 0 | 0 | ||
*Independent sample t-test.
**Chi square test. BEAM: BCNU/carmustine, etoposide, cytarabine, and melphalan. Bu-Alk and Bu-Cy refer to chemotherapy regimens involving Busulfan combined with an alkylating agent or Cyclophosphamide, respectively. Categorical data expressed as numbers and percentages.
The chemotherapeutics administered before bone marrow transplantation (BMT) are summarized in Table 2. Doxorubicin was used in 18 patients, with a mean cumulative dose of 300 ± 93 mg/m2. Cyclophosphamide was administered to 15 patients prior to HSCT, with a mean cumulative dose of 5.5 ± 2.3 g/m2. Nine patients received both doxorubicin and cyclophosphamide. Only one patient, who had thalassemia, did not receive either of these medications.
Table 2.
Chemotherapeutics used before and during BMT.
| Variables | Study cases (N = 25) | |
|---|---|---|
| N | % | |
| Chemotherapeutics before BMT | ||
| Cyclophosphamide | 18 | 72 |
|
Doxorubicin Total cumulative dose (mg/m 2 ) |
15 300 ± 93* |
60 |
| Cyclophosphamide + Doxorubicin | 9 | 36 |
| Chemotherapeutics during BMT | ||
|
Cyclophosphamide Total cumulative dose (g/m 2 ) |
5 15.5 ± 2.3* |
20 |
| Busulfan | 16 | 64 |
| Melphalan | 20 | 80 |
| Carmustine | 9 | 36 |
N: number. Categorical data expressed as Number (%)continuous variables : mean ± standard deviation.
Table 3 summarizes the comparison of M-mode, 2D speckle tracking, and 3D echocardiographic parameters among the studied groups. Fractional shortening (FS) showed a statistically significant difference between the control group and patients both before and after HSCT, although the mean FS values remained within the normal range across all groups. Other M-mode parameters did not show significant differences. For 2D strain imaging, global and segmental strain parameters demonstrated statistically significant differences among the groups. Regarding 3D echocardiographic parameters, a significant difference was observed in EF between the groups and in stroke volume (SV) between the control group and post-transplant patients.
Table 3.
Conventional, speckle tracking and 3D echocardiography findings in patient and control groups.
| Variables | Control | Before transplant | After transplant | P* | P† |
|---|---|---|---|---|---|
| Conventional echo | |||||
| LVIDs (mm) | 2.5 ± 1.22 | 2.67 ± 0.80 | 2.64 ± 0.76 | 0.622 | 0.275 |
| LVIDd (mm) | 3.9 ± 0.89 | 3.84 ± 0.87 | 3.95 ± 0.81 | 0.59 | 0.065 |
| EF (%) | 67 ± 3 | 67.02 ± 3.30 | 67.03 ± 5.90 | 0.57 | 0.997 |
| FS (%) | 40 ± 4.8 | 36.99 ± 4.27 | 35.52 ± 3.92 | 0.04* | 0.029* |
| Speckle tracking (%) | |||||
| GLS Avg | − 19.8 ± 1.7 | − 18.98 ± 1.82 | − 17.34 ± 2.04 | 0.09 | < 0.001* |
| Septal LS apex | − 16.5 ± 1.8 | − 15.44 ± 2.01 | − 14.88 ± 1.58 | 0.06 | 0.015* |
| Septal LS mid | − 16.9 ± 1.3 | − 16.58 ± 1.72 | − 15.90 ± 1.73 | 0.33 | 0.005* |
| Septal LS base | − 21 ± 3.2 | − 20.33 ± 3.90 | − 19.70 ± 3.88 | 0.37 | 0.006* |
| Lateral LS apex | − 16.5 ± 1.5 | − 15.73 ± 1.46 | − 14.66 ± 1.52 | 0.07 | < 0.001* |
| Lateral LS mid | − 19.3 ± 2.6 | − 18 ± 3.47 | − 16.98 ± 3.02 | 0.18 | 0.004* |
| Lateral LS base | − 31 ± 4.7 | − 29.36 ± 5.16 | − 27.98 ± 5.40 | 0.25 | < 0.001* |
| 3D ECHO | |||||
| EDVI (ml) | 70.9 ± 18.5 | 70.09 ± 18.13 | 69.22 ± 23.57 | 0.87 | 0.767 |
| ESVI(ml) | 27.40 ± 11 | 26.60 ± 11.12 | 25.16 ± 9.82 | 0.80 | 0.115 |
| 3D EF (%) | 70.3 ± 4.6 | 67.62 ± 3.87 | 64.74 ± 6.57 | 0.04* | 0.005* |
| 3D SV (ml) | 59.9 ± 9 | 57.04 ± 9.71 | 53.34 ± 10.66 | 0.29 | 0.002* |
Significant values are in [bold].
LVIDs: left ventricular internal dimension at end-systole, LVIDd: left ventricular internal dimension at end-diastole, EF: ejection fraction, FS: fractional shortening, SD: standard deviation, GLS: global longitudinal strain, LS: longitudinal strain, Avg: Average, LVEDV: left ventricular end-diastolic volume, LVESV: left ventricular end-systolic volume, 3D EF: three-dimensional ejection fraction, SV: three-dimensional stroke volume. Data are expressed as mean ± SD*Control group versus patient group before HSCT.†Patients before HSCT versus patients after HSCT. P*: independent sample t-test. P†: paired sample t-test.*significant p ≤ 0.05.
Correlation analysis (Table 4) revealed a strong negative correlation between disease duration, cumulative doses (CD) of cyclophosphamide and doxorubicin, and global longitudinal strain (GLS). Additionally, a moderate negative correlation was noted between disease duration, CD of cyclophosphamide, and 3D EF, while a strong negative correlation was observed between the CD of doxorubicin and 3D EF as shown in Fig. 2.
Table 4.
Correlation between disease duration, cumulative drug doses of cyclophosphamide and doxorubicin and post-transplant echocardiographic parameters.
| Variables | Disease duration | CD of cyclophosphamide | CD of doxorubicin | |||
|---|---|---|---|---|---|---|
| R | P value | R | P value | R | P value | |
| Conventional echo | ||||||
| LVIDs (mm) | 0.039 | 0.855 | 0.157 | 0.535 | 0.013 | 0.964 |
| LVIDd (mm) | 0.185 | 0.375 | 0.433 | 0.073 | 0.055 | 0.845 |
| EF (%) | 0.21 | 0.314 | – 0.565 | 0.015* | 0.203 | 0.467 |
| FS (%) | 0.02 | 0.994 | 0.265 | 0.288 | 0.506 | 0.054 |
| Speckle tracking | ||||||
| GLS Avg (%) | – 0.419 | 0.037* | – 0.654 | 0.003* | – 0.546 | 0.046* |
| Septal LS apex (%) | 0.446 | 0.096 | 0.188 | 0.452 | – 0.421 | 0.118 |
| Septal LS mid (%) | 0.421 | 0.118 | – 0.124 | 0.623 | – 0.351 | 0.20 |
| Septal LS base (%) | 0.351 | 0.20 | – 0.178 | 0.479 | – 0.198 | 0.478 |
| Lateral LS apex (%) | – 0.198 | 0.478 | – 0.284 | 0.523 | – 0.126 | 0.556 |
| Lateral LS mid (%) | 0.126 | 0.556 | 0.083 | 0.743 | – 0.452 | 0.091 |
| Lateral LS base (%) | 0.452 | 0.091 | – 0.397 | 0.103 | – 0.020 | 0.945 |
| 3D echo | ||||||
| EDVI (ml/m2) | 0.300 | 0.277 | 0.103 | 0.684 | 0.014 | 0.961 |
| ESVI (ml/m2) | 0.349 | 0.202 | 0.270 | 0.268 | 0.222 | 0.426 |
| 3D EF (%) | 0.447 | 0.045* | 0.407 | 0.044* | 0.654 | 0.048* |
| 3D SV (ml) | 0.247 | 0.243 | 0.211 | 0.401 | 0.044 | 0.878 |
Significant values are in [bold].
CD: cumulative dose, LVIDs: left ventricular internal dimension at end-systole, LVIDd: left ventricular internal dimension at end-diastole, EF: ejection fraction, FS: fractional shortening, GLS: global longitudinal strain, LVEDV left ventricular end-diastolic volume, 3D LVESV: left ventricular end-systolic volume, 3D EF: ejection fraction, SV: stroke volume, r: Pearson correlation, P: Probability.
Fig. 2.
Scatter diagram showing negative correlation between: (A) Duration of the disease and GLS post-transplant, (B) duration of the disease and 3D derived ejection fraction post-transplant, (C) total cumulative dose of cyclophosphamide and 3D derived ejection fraction post-transplant, (D) total cumulative dose of Doxorubicin and 3D derived ejection fraction post-transplant.
Table 5 compares echocardiographic parameters between autologous and allogeneic HSCT groups. A statistically significant difference was identified in average GLS, lateral longitudinal strain (LS) at the basal segment, and 3D EF, with these parameters differing significantly between the two types of graft.
Table 5.
Comparison of echocardiographic parameters and type of transplant:
| Variables | Allograft (N = 5) |
Autograft (N = 20) |
P Value |
|---|---|---|---|
| Conventional ECHO | |||
| LVIDs (mm) | 2.5 ± 0.52 | 2.6 ± 0.82 | 0.238 |
| LVIDd (mm) | 3.9 ± 0.55 | 3.9 ± 0.87 | 0.407 |
| EF (%) | 68 ± 4 | 66 ± 6.3 | 0.347 |
| FS (%) | 36.8 ± 3.6 | 35.2 ± 4 | 0.291 |
| 2D speckle | |||
| GLS Avg (%) | – 14.7 ± 2 | – 19.3 ± 1.9 | 0.034* |
| Septal LS apex (%) | -14.1 ± 1.07 | -15 ± 1.6 | 0.521 |
| Septal LS mid (%) | -15.8 ± 2.2 | -15.9 ± 1.6 | 0.341 |
| Septal LS base (%) | -21.4 ± 2.8 | -19.2 ± 4 | 0.161 |
| Lateral LS apex (%) | -14.5 ± 1.3 | -14.6 ± 1.5 | 0.238 |
| Lateral LS mid (%) | -15.5 ± 2.3 | -17.3 ± 3.1 | 0.111 |
| Lateral LS base (%) | -26 ± 3.4 | -31 ± 5.5 | 0.026* |
| 3D ECHO | |||
| 3D EDV (ml/m2) | 55.9 ± 17.5 | 72.5 ± 24 | 0.278 |
| 3D ESV (ml/ m2) | 31.8 ± 10 | 23.4 ± 9.2 | 0.111 |
| 3D EF (%) | 51.9 ± 4 | 64.8 ± 7 | 0.031* |
| 3D SV (ml) | 47 ± 6.3 | 54 ± 11.2 | 0.095 |
Significant values are in [bold].
LVIDs: left ventricular internal dimension at end-systole, LVIDd: left ventricular internal dimension at end-diastole,, EF: ejection fraction, FS: fractional shortening, GLS: global longitudinal strain, LS: longitudinal strain, 3D LVEDV: three-dimensional left ventricular end-diastolic volume, 3D LVESV: three-dimensional left ventricular end-systolic volume, 3D EF: three-dimensional ejection fraction, 3D SV: three-dimensional stroke volume.
Paired sample t test used.
Discussion
In the present study, conventional, 2D, and 3D echocardiography were utilized to evaluate cardiac function, revealing significant differences between patient groups before and after hematopoietic stem cell transplantation (HSCT) in fractional shortening (FS), global longitudinal strain (GLS), regional longitudinal strain, 3D stroke volume (3D SV), and 3D EF.
Conventional echocardiography
Conventional echocardiography is a non-invasive, cost-effective, and widely available technique traditionally reliant on 2D-LVEF to assess systolic function. However, the limitations of 2D-LVEF have been well documented, leading expert consensus panels to recommend advanced techniques such as 3D and speckle-tracking echocardiography12. Oncology experts emphasize the importance of modern echocardiographic methods to evaluate structural and functional changes in HSCT survivors9. In the current cohort, conventional echocardiography showed a statistically significant difference between the control group and both patient groups before and after transplantation. In contrast, Piranfar et al. found a significant decrease in left ventricular end diastolic diameter (LVEDD) and left ventricular end systolic diameter (LVESD) by 4.8% and 3.3%, respectively, and a 7% increase in EF following BMT13. The discrepancy may be attributed to differing methodologies, as Piranfar et al. relied on tissue Doppler and conventional echocardiography, whereas this study employed 2D speckle tracking and 3D echocardiography.
2D strain imaging
This study found significant changes in GLS and all segmental regional strain parameters (e.g., septal LS apex, mid, and base; lateral LS apex, mid, and base) before and after HSCT. A meta-analysis by Oikonomou et al. confirmed the utility of GLS as an early detection tool for cardiotoxicity associated with oncological treatments, though it noted the need for larger, multicenter prospective studies due to statistical heterogeneity in published research14. Watanabe et al.15 also demonstrated that GLS decreased significantly after allogeneic HSCT, whereas EF remained unchanged, underscoring GLS as a more sensitive cardiac function parameter. Furthermore, Massey et al.16 reported significantly reduced 3D LVEF and GLS in allo-HSCT survivors compared to controls. Myrdal et al.17 found that while most survivors had normal mean LVEF, one-third exhibited systolic dysfunction despite the absence of overt symptoms. Gripp et al.18 highlighted a 14% reduction in strain (absolute value − 16.6) as an early marker of anthracycline-induced cardiotoxicity.
Advanced 3D echocardiography
To the best of our knowledge, this is the first study to use advanced 3D echocardiography to evaluate cardiac function post-HSCT. The findings suggest that 3D echocardiography is a valuable predictive tool for assessing cardiac function and cardiovascular risk in HSCT survivors, evidenced by significant differences in 3D SV and 3D EF before and after transplantation, while conventional echocardiographic parameters showed no significant differences for most measures.
Mechanisms of cardiac dysfunction in HSCT
Cardiotoxic chemotherapeutics, such as anthracyclines and antimetabolites, can cause permanent myocardial injury, leading to cardiac dysfunction. Anthracyclines, commonly used for hematologic malignancies (e.g., Hodgkin and non-Hodgkin lymphoma, acute lymphoblastic leukemia), are known to induce dose-dependent and progressive cardiac dysfunction, manifesting as decreased LVEF and symptomatic heart failure in up to 5% of patients18–20. This study demonstrated significant negative correlations between the duration of disease prior to transplantation, cumulative doses of cyclophosphamide and doxorubicin, and GLS average. Additionally, a significant negative correlation was observed between the total cumulative dose of cyclophosphamide and EF as assessed by conventional echocardiography. Similar findings have been reported in prior studies, with one showing that 12 out of 811 recipients (1.5%) who received ≥ 100 mg/kg of cyclophosphamide developed fatal heart failure22. Cyclophosphamide metabolites cause oxidative stress and endothelial capillary damage, leading to myocyte injury20,22. Mori et al. noted that cyclophosphamide-induced early cardiotoxicity primarily affects LV diastolic function rather than systolic function, contributing to acute hemodynamic instability following conditioning chemotherapy24.
Regarding doxorubicin, significant negative correlations were observed between its cumulative dose and both GLS average and 3D EF. In line with these results, Elbl et al. reported that high-dose doxorubicin administration prior to HSCT was associated with decreased EF post-transplant, with a significant relationship between EF changes and doxorubicin use25. Similarly, data from the European Group for Blood and Bone Marrow Transplantation identified total body irradiation (TBI) and pre-transplant doxorubicin as significant risk factors for reduced EF in pediatric patients within five years post-HSCT26.
Comparison between transplant types
This study found no significant differences in post-transplant echocardiographic parameters between autologous and allogeneic HSCT, except for a statistically higher GLS and lateral LS at the base in the autologous group. Consistent with this, Vasbinder et al. found no differences in short-term cardiovascular events between transplant types but noted a higher incidence of long-term cardiovascular events in allogeneic recipients compared to autologous recipients27.
Limitation of the study
The present study has several limitations. First, it is an observational study with a relatively small sample size, which may reduce its statistical power; however, the case-control design helps to partially address this limitation. Second, the study’s short-term nature restricts the evaluation of long-term outcomes, as it does not include extended post-HSCT follow-up or serial monitoring of echocardiographic parameters. Additionally, the assessment of right ventricular function and pulmonary artery pressure was not included, which could have provided further insights into cardiac function.
Conclusion
Significant changes were observed in fractional shortening (FS), global longitudinal strain (GLS), regional longitudinal strain, 3D stroke volume (3D SV), and 3D ejection fraction (3D EF) before and after hematopoietic stem cell transplantation (HSCT). These results highlight the utility of 3D echocardiography as a predictive tool for evaluating cardiovascular risk in HSCT survivors, as it identified notable alterations in 3D SV and 3D EF post-transplant, whereas most conventional echocardiographic parameters showed no significant changes. Differences in cardiac parameters between autologous and allogeneic transplants highlight the need for individualized cardiac monitoring based on transplant type.
Recommendations and future direction
3D echocardiography has demonstrated superior accuracy compared to conventional echocardiography in assessing left ventricular parameters, establishing it as a recommended tool for evaluating cardiac function in patients undergoing bone marrow transplantation. Its capability to detect significant changes in cardiac function underscores its predictive value in this patient population. However, to enhance the reliability of these findings, future studies with larger sample sizes are essential. Additionally, incorporating assessments of right ventricular function and right ventricular pressure would provide a more comprehensive evaluation of cardiac health in this group.
Abbreviations
- 2D
Two-dimensional
- 3DE
Three-dimensional echocardiography
- AML
Acute Myeloid Leukemia
- BMT
Bone marrow transplantation
- EF
Ejection fraction
- GLS
Global longitudinal strain
- GvHD
Graft versus host disease
- HSCT
Hematopoietic stem cell transplantation
- LV
Left ventricle
- SV
Stoke volume
- TKIs
Tyrosine kinase inhibitors
Author contributions
A.H. and M.Y. conceived, conducted experiments, revised the echocardiographic data, analyzed the data, and participated in writing the protocol and manuscript. A.D. and M.H. approved and revised the data. All authors were involved in writing the paper and had final approval of the submitted version.
Funding
This work was not supported by a specific grant.
Data availability
The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.
Competing interests
The authors declare no competing interests.
Ethics approval and consent to participate
This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by Mansoura Faculty of Medicine Institutional Research Board (MD.21.11.558.R1). Informed consent was obtained for all caregivers of the included children.
Consent to participate
Written informed consent was obtained from all caregivers of the included children in the study.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
References
- 1.Rotz, S. J. et al. Treatment exposures stratify need for echocardiographic screening in asymptomatic long-term survivors of hematopoietic stem cell transplantation. Cardiol. Young29(3), 338–343. 10.1017/s104795111800238x (2019). [DOI] [PubMed] [Google Scholar]
- 2.Majhail, N. S. et al. Oct., Prevalence of hematopoietic cell transplant survivors in the United States. Biol. Blood Marrow Transplant.19(10), 1498–1501. 10.1016/j.bbmt.2013.07.020 (2013). [DOI] [PMC free article] [PubMed]
- 3.Dandoy, C. E., Hirsch, R., Chima, R., Davies, S. M. & Jodele, S. Pulmonary hypertension after hematopoietic stem cell transplantation. Biol. Blood Marrow Transplant.19(11), 1546–1556. 10.1016/j.bbmt.2013.07.017 (2013). [DOI] [PubMed] [Google Scholar]
- 4.Armenian, S. H. et al. Prediction of cardiovascular disease among hematopoietic cell transplantation survivors. Blood Adv.2, 1756–1764. 10.1182/bloodadvances.2018019117 (2018). [DOI] [PMC free article] [PubMed]
- 5.Curigliano, G. et al. Management of cardiac disease in cancer patients throughout oncological treatment: ESMO consensus recommendations. Ann. Oncol. Off. J. Eur. Soc. Med. Oncol.31(2), 171–190. 10.1016/j.annonc.2019.10.023 (2020). [DOI] [PMC free article] [PubMed]
- 6.Ohmoto, A. & Fuji, S. Cardiac complications associated with hematopoietic stem-cell transplantation. Bone Marrow Transplant.56(11), 2637–2643. 10.1038/s41409-021-01427-2 (2021). [DOI] [PubMed] [Google Scholar]
- 7.Armenian, S. H. et al. Incidence and predictors of congestive heart failure after autologous hematopoietic cell transplantation. Blood118(23), 6023–6029. 10.1182/blood-2011-06-358226 (2011). [DOI] [PMC free article] [PubMed]
- 8.Shanholtz, C. Acute life-threatening toxicity of cancer treatment. Crit. Care Clin.17(3), 483–502. 10.1016/s0749-0704(05)70196-2 (2001). [DOI] [PubMed]
- 9.Armenian, S. H. National institutes of health hematopoietic cell transplantation late effects initiative: the cardiovascular disease and associated risk factors working group report. Biol. Blood Marrow Transplant23(2), 201–210. 10.1016/j.bbmt.2016.08.019 (2017). [DOI] [PMC free article] [PubMed]
- 10.Thavendiranathan, P. et al. Reproducibility of echocardiographic techniques for sequential assessment of left ventricular ejection fraction and volumes. J. Am. Coll. Cardiol.61(1), 77–84. 10.1016/j.jacc.2012.09.035 (2013). [DOI] [PubMed] [Google Scholar]
- 11.Jenkins, C., Bricknell, K., Chan, J., Hanekom, L. & Marwick, T. H. Comparison of two- and three-dimensional echocardiography with sequential magnetic resonance imaging for evaluating left ventricular volume and ejection fraction over time in patients with healed myocardial infarction. Am. J. Cardiol.99(3), 300–306. 10.1016/j.amjcard.2006.08.026 (2007). [DOI] [PubMed] [Google Scholar]
- 12.Armstrong, G. T. et al. Comprehensive echocardiographic detection of treatment-related cardiac dysfunction in adult survivors of childhood cancer: results from the St. Jude lifetime cohort study. J. Am. Coll. Cardiol.65(23), 2511–2522. 10.1016/j.jacc.2015.04.013 (2015). [DOI] [PMC free article] [PubMed]
- 13.Piranfar, M. A. et al. Bone marrow transplantation May augment cardiac systolic function in patients with a reduced left ventricular ejection fraction. J. Cardiovasc. Dis. Res.3(4), 310–314. 10.4103/0975-3583.102713 (2012). [DOI] [PMC free article] [PubMed]
- 14.Oikonomou, E. K. et al. Assessment of prognostic value of left ventricular global longitudinal strain for early prediction of chemotherapy-induced cardiotoxicity. JAMA Cardiol.4(10), 1007–1007. 10.1001/jamacardio.2019.2952 (2019). [DOI] [PMC free article] [PubMed]
- 15.Watanabe, M. et al. Global longitudinal strain is superior to ejection fraction for long-term follow‐up after allogeneic hematopoietic stem cell transplantation. eJHaem4(1), 192–198. 10.1002/jha2.586 (2023). [DOI] [PMC free article] [PubMed]
- 16.Massey, R. J. et al. Left ventricular systolic function in long-term survivors of allogeneic hematopoietic stem cell transplantation. JACC. CardioOncology2(3), 460–471. 10.1016/j.jaccao.2020.06.011 (2020). [DOI] [PMC free article] [PubMed]
- 17.Myrdal, O. H. et al. Determinants of cardiorespiratory fitness in very long-term survivors of allogeneic hematopoietic stem cell transplantation: a national cohort study. Supportive Care Cancer29(4), 1959–1967. 10.1007/s00520-020-05644-1 (2021). [DOI] [PMC free article] [PubMed]
- 18.Gripp, E. A. et al. Global longitudinal strain accuracy for cardiotoxicity prediction in a cohort of breast Cancer patients during anthracycline and/or trastuzumab treatment. Arq. Bras. Cardiol.10.5935/abc.20180021 (2018). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Yeh, E. T. H. & Bickford, C. L. Cardiovascular complications of cancer therapy. J. Am. Coll. Cardiol.53(24), 2231–2247 10.1016/j.jacc.2009.02.050 (2009). [DOI] [PubMed]
- 20.Martin, P. J. et al. First- and second-line systemic treatment of acute graft-versus-host disease: recommendations of the American society of blood and marrow transplantation. Biol. Blood Marrow Transplant. J. Am. Soc. Blood Marrow Transplant.18(8), 1150–1163. 10.1016/j.bbmt.2012.04.005 (2012). [DOI] [PMC free article] [PubMed]
- 21.Dhesi, S. et al. Cyclophosphamide-induced cardiomyopathy: a case report, review, and recommendations for management. J. Investig. Med. High Impact Case Rep.1(1), 2324709613480346–2324709613480346. 10.1177/2324709613480346 (2013). [DOI] [PMC free article] [PubMed]
- 22.Ishida, S. et al. The clinical features of fatal cyclophosphamide-induced cardiotoxicity in a conditioning regimen for allogeneic hematopoietic stem cell transplantation (allo-HSCT). Ann. Hematol.95(7), 1145–1150. 10.1007/s00277-016-2654-6 (2016). [DOI] [PubMed] [Google Scholar]
- 23.Nieto, Y. et al. Cardiac toxicity following high-dose cyclophosphamide, cisplatin, and BCNU (STAMP-I) for breast cancer. Biol. Blood Marrow Transplant.6(2), 198–203. 10.1016/s1083-8791(00)70043-7 (2000). [DOI] [PubMed] [Google Scholar]
- 24.Mori, T. et al. Left ventricular diastolic dysfunction induced by cyclophosphamide in blood stem cell transplantation. Jpn. Heart J.43(3), 249–261. 10.1536/jhj.43.249 (2002). [DOI] [PubMed] [Google Scholar]
- 25.Elbahlawan, L. et al. Pulmonary complications in children following hematopoietic cell transplantation: a case report and review of the diagnostic approach. Front. Oncol.11, 772411–772411. 10.3389/fonc.2021.772411 (2021). [DOI] [PMC free article] [PubMed]
- 26.Uderzo, C. et al. Risk factors and severe outcome in thrombotic microangiopathy after allogeneic hematopoietic stem cell transplantation. Transplantation82(5), 638–644. 10.1097/01.tp.0000230373.82376.46 (2006). [DOI] [PubMed]
- 27.Vasbinder, A. et al. Cardiovascular events after hematopoietic stem cell transplant. JACC: CardioOncol.5(6), 821–832. 10.1016/j.jaccao.2023.07.007 (2023). [DOI] [PMC free article] [PubMed]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.