© 2015, Wiley Periodicals, Inc. DOI: 10.1111/echo.12988
Echocardiography
Assessment of Myocardial Function in Children before and after Autologous Peripheral Blood Stem Cell Transplantation Hala ElMarsafawy, M.D.,* Mohamed Matter, M.D.,* Mohamed Sarhan, M.D.,† Rasha El-Ashry, M.D.,† and Youssef Al-Tonbary, M.D.† *Cardiology Unit, Mansoura University Children Hospital, Mansoura, Egypt; and †Hematology/Oncology/ BMT Unit, Mansoura University Children Hospital, Mansoura, Egypt
Background: Increased interest is focused on the long-term adverse effects of bone marrow transplantation. Subclinical cardiac involvement appears common in adults, but only a few reports have examined pediatric patients. Materials and Methods: A prospective case–control study of 19 children with normal cardiac function undergoing autologous hematopoietic stem cell transplantation (HSCT) was performed. Tissue Doppler imaging (TDI) and echocardiographic measurements were obtained according to the guidelines of the American Society of Echocardiography before and 3 months after HSCT. Results: Lateral mitral annulus before HSCT showed significant reduced mitral systolic annular velocity (P < 0.0001), early diastolic annular velocity (P < 0.0001), late diastolic annular velocity (P = 0.02) and prolonged isovolumetric relaxation time (IRT) (P < 0.0001) compared with control. Significant reduced mitral systolic annular velocity (P < 0.0001), early diastolic annular velocity (P = 0.0005) and Em/Am ratio (P = 0.004), with higher late diastolic annular velocity (P = 0.02) and prolonged isovolumetric contraction time (ICT) (P = 0.003) and IRT (P = 0.002) after HSCT, were observed. Investigation of lateral tricuspid annulus showed nearly similar results as the lateral mitral annulus. LV and RV Tei indices were higher before HSCT compared with control and remained high after HSCT. Conclusion: TDI detected subtle abnormalities in systolic and diastolic functions before and after HSCT, which suggests that a conditioning regimen may affect cardiac function. (Echocardiography 2016;33:82–89) Key words: myocardial function, autologous stem cell transplantation, tissue doppler imaging Autologous hematopoietic stem cell transplantation (HSCT) preceded by myeloablative high-dose conditioning chemotherapy is a recognized treatment for hematological malignancies, amyloidosis and treatment-resistant autoimmune disorders.1 An increasing number of survivors after bone marrow transplantation (BMT) prompted more interest on the long-term adverse effects of BMT. Mechanisms of potential impairment of myocardial function in the transplant setting include the well-known cardiotoxic effects of high-dose cyclophosphamide (CY) and total body irradiation (TBI). Subclinical cardiac involvement is common in adults after BMT, but the reported incidence of cardiac morbidity varies from zero to 43%.2,3 Few previous reports of cardiac function after BMT have examined pediatric patients.4-6 The identification of patients with subclinical cardiac dysfunction, before the development of pulmonary edema, may permit Address for correspondence and reprint requests: Hala ElMarsafawy, M.D., Pediatric Cardiology Unit, Mansoura University Children Hospital, Mansoura, Egypt. Fax: +2050226 2307; E-mail: [email protected]
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judicious restriction of parenteral fluids and prompt the introduction of cardiac therapy.7 Tissue Doppler imaging (TDI) is a relatively new echocardiographic technique that provides quantitative information about myocardial motion with high temporal and spatial resolution independent of preload and after load.8 The myocardial performance index, or Tei index, is a powerful index that evaluates systolic and diastolic functions simultaneously.9 This investigation determined whether TDI is useful for the detection of functional myocardial impairment in survivors of childhood malignancy treated by autologous stem cell peripheral blood transplantation with normal resting ventricular function by conventional methods. Patients and Methods: This study was a prospective case–control study performed between September 2009 and December 2011. Written informed consent was obtained from the parents, and the Institutional Review Board of Mansoura University Children’s Hospital approved the study. Nineteen
Myocardial Function in Stem Cell Transplantation
consecutive patients (14 males and 5 females) with a mean age of 10.73 2.90 years (range 3–14 years) and normal cardiac function (LVFS >30%) who were undergoing peripheral hematopoietic stem cell (CD34+) harvest and planned high-dose conditioning chemotherapy with autologous peripheral blood stem cell transplantation were investigated. The underlying diseases were Hodgkin’s lymphoma in 10 patients, NonHodgkin’s lymphoma in 5 patients and acute myeloid leukemia in 4 patients. Three patients only showed a history of cumulative noncardiotoxic doses of anthracycline (140, 122, and 217 mg/m2). All patients underwent echocardiography studies before their admission for HSCT and at least 3 months after HSCT. The echocardiographic findings of patients were compared to 20 age-matched normal controls. The control subjects were children who visited the cardiac outpatient clinic with heart murmur, (nonspecific) chest pain, palpitation, or syncope with echocardiographic findings that showed definitive normal cardiac structure and functions. Hematopoietic Stem Cell Transplantation Protocol: All patients underwent mobilization of stem cells using granulocyte-colony stimulating factor (G-CSF) at a dose of 10 lg/kg per day subcutaneously for 4–5 days. All patients underwent leukopheresis after G-CSF administration to harvest peripheral blood hematopoietic progenitor cells. Stem cell separation was initiated using a blood product separator machine (COBE, Spectra, Lakewood, CO, USA) when the WBC count was >40 000/mm3. The bag containing progenitor cells was cryopreserved until transplantation, and samples were taken for mononuclear cell and CD34+ cell calculation. Myeloablative highdose conditioning chemotherapy using etoposide (1600 mg/m2 IV infusion over 6 hours), cyclophosphamide (6000 mg/m2 IV infusion over 6 hours), carboplatin (1100 mg/m2 IV infusion over 4 hours), dexamethasone (40 mg/m2 per day for 5 days), and uromitexan were administered to avoid hemorrhagic cystitis after cyclophosphamide administration. Stem cell infusion was provided through a central line 36 hours after the start of the conditioning regimen with a minimum injection of 100 million nucleated cells per kilogram. Each patient was monitored for symptoms and signs of chemotherapy toxicity, hemodynamic instability, organ dysfunction, and hematopoietic reconstruction as evidence of successful engraftment. None of our patients developed hemodynamic instability that necessitated inotropic support. G-CSF (10 lg/kg per day) was administered subcutaneously from day 4 and
continued for 2 days after engraftment, which is defined as a total leukocytic count >1000/lL, an absolute neutrophil count >500/lL and a platelet count >20 000/lL (without transfusion). Echocardiographic Measurements: Echocardiographic measurements were performed using a SONOS-5500 (Hewlett Packard, Andover, MA,USA) with an 8-MHz probe incorporating color flow, pulsed-wave, continuouswave Doppler, and pulsed-wave TDI. Images were recorded on videotapes. Conventional echocardiographic measurements were obtained according to the guidelines of the American Society of Echocardiography.10,11 Twodimensional M-mode measurements were obtained from a parasternal short-axis view according to the guidelines for M-mode echocardiography of the American Society of Echocardiography.11 Aortic diameter (AO) at the level of the valvular annulus, left ventricular cavity dimensions at end-diastole (LVIDd) and left ventricular cavity dimensions at end-systole (LVIDs), left atrial size, and right ventricular cavity dimension at end-diastole (RVDd), and left ventricular posterior wall thickness at end-systole (LVPWs) and at end-diastole (LVPWd) were assessed. Fractional shortening was calculated as (FS %) = (LVIDd – LVIDs)/LVIDd X 100. LV mass index was derived using the Devereux formula.10 At least three consecutive beats in sinus rhythm were recorded, and average values were obtained. A mitral inflow velocity pattern (E-wave, A-wave and E/A ratio) and tricuspid inflow velocity pattern (E-wave, A-wave and E/A ratio) were recorded from an apical four-chamber view using a pulsed-wave Doppler sample volume positioned at the tips of the mitral leaflets and tricuspid leaflets, respectively. All measurements for diastolic indices were obtained in three consecutive cardiac cycles at end expiration and averaged.12 Pulsed-Wave TDI Study: Pulsed-wave TDI was performed using a special software package on a SONOS-5500 echo machine. Pulsed-wave TDI was performed by adjusting the spectral pulsed Doppler signal filters to obtain a Nyquist limit of 15–20 cm/sec and using the minimal optimal gain. High-framerate (>150 frames/sec) images were acquired in the tissue Doppler mode. The pulsed Doppler sample volume was placed at the lateral margin of the mitral annulus, lateral tricuspid annulus, and mid-interventricular septum in the apical 4chamber view with subjects in the left lateral decubitus position during shallow respiration or end-expiratory apnea. Care was taken to obtain an ultrasound beam parallel to the direction of 83
ElMarsafawy, et al.
the annular motion and regional area of interest (ROI). The systolic velocity (Sm), early diastolic myocardial velocity (Em), late diastolic myocardial velocity (Am) at the time of atrial contraction, and the ratio of Em/Am were recorded simultaneously with electrocardiography at these locations and stored on videotape for subsequent analysis (Fig. 1). Regional isovolumetric contraction time (ICT) was measured from the onset of the QRS on a simultaneous electrocardiogram to the beginning of the Sm-wave, whereas regional isovolumetric relaxation time (IRT) was measured from the end of the Sm-wave to beginning of the following Em-wave. The intervals (a) between the end of the late diastolic annular velocity (Am) and the onset of the early diastolic annular velocity (Em) were equal to the sum of the isovolumetric contraction time (ICT), isovolumetric relaxation time (IRT), and ejection time (ET) using the TDI method at lateral mitral annulus. The ET (b) was measured as the duration of the systolic annular velocity (Sm) (Fig. 1). The sum of the ICT and IRT was obtained by subtracting (b) from (a). The LV Tei index was calculated as (a–b)/b. The IRT was measured from the pulsed-wave TDI recordings as the time interval from the end of the systolic annular velocity (Sm) to the onset of the early diastolic annular velocity, and the ICT was obtained by subtracting the IRT from (a–b). The RV Tei index was measured using the same method from the TDI time interval recording at the lateral tricuspid annulus. All parameters were
measured during end expiration, and three consecutive cardiac cycles were measured and averaged for each measurement.13 TDI recordings were adequately obtained in all patients. Statistical Analysis: Data were analyzed using the Statistical Package for Social Science program (SPSS version 15.0 for Windows; Chicago, IL, USA). Variables were compared between groups using a 2-tailed t-test. Data are presented as means SD. A P value
Echocardiography
Assessment of Myocardial Function in Children before and after Autologous Peripheral Blood Stem Cell Transplantation Hala ElMarsafawy, M.D.,* Mohamed Matter, M.D.,* Mohamed Sarhan, M.D.,† Rasha El-Ashry, M.D.,† and Youssef Al-Tonbary, M.D.† *Cardiology Unit, Mansoura University Children Hospital, Mansoura, Egypt; and †Hematology/Oncology/ BMT Unit, Mansoura University Children Hospital, Mansoura, Egypt
Background: Increased interest is focused on the long-term adverse effects of bone marrow transplantation. Subclinical cardiac involvement appears common in adults, but only a few reports have examined pediatric patients. Materials and Methods: A prospective case–control study of 19 children with normal cardiac function undergoing autologous hematopoietic stem cell transplantation (HSCT) was performed. Tissue Doppler imaging (TDI) and echocardiographic measurements were obtained according to the guidelines of the American Society of Echocardiography before and 3 months after HSCT. Results: Lateral mitral annulus before HSCT showed significant reduced mitral systolic annular velocity (P < 0.0001), early diastolic annular velocity (P < 0.0001), late diastolic annular velocity (P = 0.02) and prolonged isovolumetric relaxation time (IRT) (P < 0.0001) compared with control. Significant reduced mitral systolic annular velocity (P < 0.0001), early diastolic annular velocity (P = 0.0005) and Em/Am ratio (P = 0.004), with higher late diastolic annular velocity (P = 0.02) and prolonged isovolumetric contraction time (ICT) (P = 0.003) and IRT (P = 0.002) after HSCT, were observed. Investigation of lateral tricuspid annulus showed nearly similar results as the lateral mitral annulus. LV and RV Tei indices were higher before HSCT compared with control and remained high after HSCT. Conclusion: TDI detected subtle abnormalities in systolic and diastolic functions before and after HSCT, which suggests that a conditioning regimen may affect cardiac function. (Echocardiography 2016;33:82–89) Key words: myocardial function, autologous stem cell transplantation, tissue doppler imaging Autologous hematopoietic stem cell transplantation (HSCT) preceded by myeloablative high-dose conditioning chemotherapy is a recognized treatment for hematological malignancies, amyloidosis and treatment-resistant autoimmune disorders.1 An increasing number of survivors after bone marrow transplantation (BMT) prompted more interest on the long-term adverse effects of BMT. Mechanisms of potential impairment of myocardial function in the transplant setting include the well-known cardiotoxic effects of high-dose cyclophosphamide (CY) and total body irradiation (TBI). Subclinical cardiac involvement is common in adults after BMT, but the reported incidence of cardiac morbidity varies from zero to 43%.2,3 Few previous reports of cardiac function after BMT have examined pediatric patients.4-6 The identification of patients with subclinical cardiac dysfunction, before the development of pulmonary edema, may permit Address for correspondence and reprint requests: Hala ElMarsafawy, M.D., Pediatric Cardiology Unit, Mansoura University Children Hospital, Mansoura, Egypt. Fax: +2050226 2307; E-mail: [email protected]
82
judicious restriction of parenteral fluids and prompt the introduction of cardiac therapy.7 Tissue Doppler imaging (TDI) is a relatively new echocardiographic technique that provides quantitative information about myocardial motion with high temporal and spatial resolution independent of preload and after load.8 The myocardial performance index, or Tei index, is a powerful index that evaluates systolic and diastolic functions simultaneously.9 This investigation determined whether TDI is useful for the detection of functional myocardial impairment in survivors of childhood malignancy treated by autologous stem cell peripheral blood transplantation with normal resting ventricular function by conventional methods. Patients and Methods: This study was a prospective case–control study performed between September 2009 and December 2011. Written informed consent was obtained from the parents, and the Institutional Review Board of Mansoura University Children’s Hospital approved the study. Nineteen
Myocardial Function in Stem Cell Transplantation
consecutive patients (14 males and 5 females) with a mean age of 10.73 2.90 years (range 3–14 years) and normal cardiac function (LVFS >30%) who were undergoing peripheral hematopoietic stem cell (CD34+) harvest and planned high-dose conditioning chemotherapy with autologous peripheral blood stem cell transplantation were investigated. The underlying diseases were Hodgkin’s lymphoma in 10 patients, NonHodgkin’s lymphoma in 5 patients and acute myeloid leukemia in 4 patients. Three patients only showed a history of cumulative noncardiotoxic doses of anthracycline (140, 122, and 217 mg/m2). All patients underwent echocardiography studies before their admission for HSCT and at least 3 months after HSCT. The echocardiographic findings of patients were compared to 20 age-matched normal controls. The control subjects were children who visited the cardiac outpatient clinic with heart murmur, (nonspecific) chest pain, palpitation, or syncope with echocardiographic findings that showed definitive normal cardiac structure and functions. Hematopoietic Stem Cell Transplantation Protocol: All patients underwent mobilization of stem cells using granulocyte-colony stimulating factor (G-CSF) at a dose of 10 lg/kg per day subcutaneously for 4–5 days. All patients underwent leukopheresis after G-CSF administration to harvest peripheral blood hematopoietic progenitor cells. Stem cell separation was initiated using a blood product separator machine (COBE, Spectra, Lakewood, CO, USA) when the WBC count was >40 000/mm3. The bag containing progenitor cells was cryopreserved until transplantation, and samples were taken for mononuclear cell and CD34+ cell calculation. Myeloablative highdose conditioning chemotherapy using etoposide (1600 mg/m2 IV infusion over 6 hours), cyclophosphamide (6000 mg/m2 IV infusion over 6 hours), carboplatin (1100 mg/m2 IV infusion over 4 hours), dexamethasone (40 mg/m2 per day for 5 days), and uromitexan were administered to avoid hemorrhagic cystitis after cyclophosphamide administration. Stem cell infusion was provided through a central line 36 hours after the start of the conditioning regimen with a minimum injection of 100 million nucleated cells per kilogram. Each patient was monitored for symptoms and signs of chemotherapy toxicity, hemodynamic instability, organ dysfunction, and hematopoietic reconstruction as evidence of successful engraftment. None of our patients developed hemodynamic instability that necessitated inotropic support. G-CSF (10 lg/kg per day) was administered subcutaneously from day 4 and
continued for 2 days after engraftment, which is defined as a total leukocytic count >1000/lL, an absolute neutrophil count >500/lL and a platelet count >20 000/lL (without transfusion). Echocardiographic Measurements: Echocardiographic measurements were performed using a SONOS-5500 (Hewlett Packard, Andover, MA,USA) with an 8-MHz probe incorporating color flow, pulsed-wave, continuouswave Doppler, and pulsed-wave TDI. Images were recorded on videotapes. Conventional echocardiographic measurements were obtained according to the guidelines of the American Society of Echocardiography.10,11 Twodimensional M-mode measurements were obtained from a parasternal short-axis view according to the guidelines for M-mode echocardiography of the American Society of Echocardiography.11 Aortic diameter (AO) at the level of the valvular annulus, left ventricular cavity dimensions at end-diastole (LVIDd) and left ventricular cavity dimensions at end-systole (LVIDs), left atrial size, and right ventricular cavity dimension at end-diastole (RVDd), and left ventricular posterior wall thickness at end-systole (LVPWs) and at end-diastole (LVPWd) were assessed. Fractional shortening was calculated as (FS %) = (LVIDd – LVIDs)/LVIDd X 100. LV mass index was derived using the Devereux formula.10 At least three consecutive beats in sinus rhythm were recorded, and average values were obtained. A mitral inflow velocity pattern (E-wave, A-wave and E/A ratio) and tricuspid inflow velocity pattern (E-wave, A-wave and E/A ratio) were recorded from an apical four-chamber view using a pulsed-wave Doppler sample volume positioned at the tips of the mitral leaflets and tricuspid leaflets, respectively. All measurements for diastolic indices were obtained in three consecutive cardiac cycles at end expiration and averaged.12 Pulsed-Wave TDI Study: Pulsed-wave TDI was performed using a special software package on a SONOS-5500 echo machine. Pulsed-wave TDI was performed by adjusting the spectral pulsed Doppler signal filters to obtain a Nyquist limit of 15–20 cm/sec and using the minimal optimal gain. High-framerate (>150 frames/sec) images were acquired in the tissue Doppler mode. The pulsed Doppler sample volume was placed at the lateral margin of the mitral annulus, lateral tricuspid annulus, and mid-interventricular septum in the apical 4chamber view with subjects in the left lateral decubitus position during shallow respiration or end-expiratory apnea. Care was taken to obtain an ultrasound beam parallel to the direction of 83
ElMarsafawy, et al.
the annular motion and regional area of interest (ROI). The systolic velocity (Sm), early diastolic myocardial velocity (Em), late diastolic myocardial velocity (Am) at the time of atrial contraction, and the ratio of Em/Am were recorded simultaneously with electrocardiography at these locations and stored on videotape for subsequent analysis (Fig. 1). Regional isovolumetric contraction time (ICT) was measured from the onset of the QRS on a simultaneous electrocardiogram to the beginning of the Sm-wave, whereas regional isovolumetric relaxation time (IRT) was measured from the end of the Sm-wave to beginning of the following Em-wave. The intervals (a) between the end of the late diastolic annular velocity (Am) and the onset of the early diastolic annular velocity (Em) were equal to the sum of the isovolumetric contraction time (ICT), isovolumetric relaxation time (IRT), and ejection time (ET) using the TDI method at lateral mitral annulus. The ET (b) was measured as the duration of the systolic annular velocity (Sm) (Fig. 1). The sum of the ICT and IRT was obtained by subtracting (b) from (a). The LV Tei index was calculated as (a–b)/b. The IRT was measured from the pulsed-wave TDI recordings as the time interval from the end of the systolic annular velocity (Sm) to the onset of the early diastolic annular velocity, and the ICT was obtained by subtracting the IRT from (a–b). The RV Tei index was measured using the same method from the TDI time interval recording at the lateral tricuspid annulus. All parameters were
measured during end expiration, and three consecutive cardiac cycles were measured and averaged for each measurement.13 TDI recordings were adequately obtained in all patients. Statistical Analysis: Data were analyzed using the Statistical Package for Social Science program (SPSS version 15.0 for Windows; Chicago, IL, USA). Variables were compared between groups using a 2-tailed t-test. Data are presented as means SD. A P value
