Evaluation of anthracycline-induced early left ventricular dysfunction in children with cancer: a comparative study with echocardiography and multigated radionuclide angiography

The study aimed to compare diastolic and systolic dysfunctions detected by echocardiography (ECHO) and multigated radionuclide angiography (MUGA) in patients with cancer in the first 3 months after anthracycline-comprising chemotherapy. Children with leukemia and solid tumors who had anthracycline-comprising chemotherapy were enrolled in the study. ECHO and MUGA were performed in all patients before the first chemotherapy course and in the first 3 month of completing anthracycline-comprising chemotherapy. Cumulative anthracycline doses per body surface were calculated. Left ventricular systolic and diastolic functions were measured by both techniques. Twenty-one patients with a median age of 6.9 ± 3.6 years were enrolled in the study. Mean cumulative anthracycline doses were equivalent to 276 ± 83 mg/m² doxorubicin. After anthracycline chemotherapy, cardiac dysfunction was detected in 14 and 48% of the patients by ECHO and MUGA, respectively. All dysfunctions detected by ECHO were systolic, whereas 29% of the patients had diastolic and 38% of the patients had systolic dysfunction in MUGA study. Although the study group is small, MUGA seems more sensitive in detecting anthracycline-induced systolic and diastolic cardiac dysfunctions compared to ECHO.     

A stress echocardiography study of cardiac function during progressive exercise in pediatric oncology patients treated with anthracyclines

BACKGROUND: Anthracycline-treated patients (AP) are at risk for cardiac dysfunction years after treatment. Cardiac function has not been evaluated during exercise in AP. The purpose of this study was to assess exercise tolerance, left ventricular (LV) function, and hemodynamics during progressive exercise. PROCEDURE: We studied 47 AP (cumulative dose: 36-504 mg/m(2)) who were in complete remission and 12 healthy controls (CON). AP were further grouped by cumulative dose (LOW or= 260 mg/m(2)) and resting echocardiographic function. All subjects performed 3-min incremental stages on a semi-recumbent cycle ergometer until volitional fatigue. Using echocardiography and Doppler, LV dimensions, posterior wall thickness (LVPWs), peak aortic velocity (PAoV), shortening fraction (SF), rate-corrected mean velocity of fiber shortening (MVCFc), wall stress at peak systole (sigmaPS), stroke volume index (SVI), and cardiac index (CI) were determined. Measurements were performed at rest, during each stage of exercise, and in recovery. RESULTS: AP did less work than CON (P < 0.050). CON and LOW had similar resting function, while HIGH had a lower SF and MVCFc (P < 0.050) and a higher sigmaPS (P < 0.001). Resting SVI and CI were also lower in HIGH. At peak exercise, MVCFc and sigmaPS remained different in HIGH, and both AP groups had a lower SF, SVI, and CI (P < 0.001). AP had an abnormal SVI response to exercise. AP showed a smaller initial increase in SVI that was not maintained throughout exercise. CONCLUSIONS: AP have reduced exercise tolerance. There also appears to be a dose-related effect on myocardial contractility and SVI. These findings may help to guide treatment.     

Longitudinal evaluation of anthracycline cardiotoxicity by signal-averaged electrocardiography in children with cancer

BACKGROUND: The aim of the present study was to investigate the detection of anthracycline cardiotoxicity by signal-averaged electrocardiography (SAE) in children with cancer. METHODS: There were 29 patients with a cumulative anthracycline (ATC) dose of 75-600 mg/m2. None of them had congestive heart failure. Patients underwent SAE just before (detection of chronic cardiotoxicity) and just after (detection of acute cardiotoxicity) ATC therapy. Echocardiography and Holter electrocardiography were performed at the same time. The rates of abnormal SAE, echocardiography, and electrocardiogram findings were calculated and compared for every 100 mg/m2 of ATC. RESULTS: The SAE showed a significantly higher detection rate for acute cardiotoxicity was at a cumulative ATC dose of less than 400 mg/m2 when compared with other methods (P < 0.05). The lowest dose at which acute cardiotoxicity was detected by SAE was 117.3 mg/m2. The detection of chronic cardiotoxicity by SAE was significantly higher at a cumulative ATC dose of 100-400 mg/m2 when compared with other methods (P < 0.05), and the lowest value showing toxicity was 373.3 mg/m2. The lowest ATC dose causing chronic cardiotoxicity was significantly lower in patients less than 2-years-old (120.0 +/- 28.3 mg/m2) than in the other age groups (P < 0.05). CONCLUSIONS: Acute and chronic ATC cardiotoxicity were detected by SAE at lower cumulative doses compared with other methods. The technique of SAE was a potentially useful method for detection of cardiotoxicity among those investigated and it provides useful information on subclinical cardiac dysfunction in patients receiving ATC therapy.     

Assessment of cardiac function by M-mode echocardiography in selenium-deficient phenylketonuric children

Selenium (Se) deficiency is associated with cardiac and skeletal muscle dysfunction. Twenty well children aged 2-16 years (10 male) attending the Phenylketonuria (PKU) Clinic at the Royal Children's Hospital, Brisbane, had low Se levels (mean 0.29 +/- 0.02 s.e.m. mumol/L; normal range 0.56-1.16 mumol/L). Their myocardial function was assessed at rest and after exercise provocation by M-mode echocardiography in order to exclude occult left ventricular dysfunction. At rest, fractional shortening (FS) was normal (mean 38.1 +/- 1.1 s.e.m. %, n = 20). After exercise, FS increased significantly (P less than 0.001) from 37.6 +/- 1.4% to 44.3 +/- 1.2%, n = 12). This was associated with a significant rise (P less than 0.001) in heart rate (HR) from 77.3 +/- 3.1 beats/min to 125.8 +/- 5.2 beats/min (n = 12). The normal resting FS and normal increase in FS and HR with exercise is evidence against significant cardiac impairment in this group of Se-deficient children.     

Echocardiographic surveillance for asymptomatic late-onset anthracycline cardiomyopathy in childhood cancer survivors

Background

The optimal frequency of echocardiographic surveillance in asymptomatic childhood cancer survivors exposed to anthracyclines has not been established. We evaluated the effectiveness of performing surveillance echocardiograms according to the Children's Oncology Group's (COG) Long‐Term Follow‐Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers in survivors ≥1 year from concluding therapy.

Methods

We reviewed all children treated at our institution with anthracycline chemotherapy from 1995 to 2003. We assessed the frequency of abnormal echocardiograms according to risk groups defined in the COG guidelines, and evaluated the risk factors for an abnormal echocardiogram using Cox proportional hazards modeling.

Results

At least one echocardiogram was completed by 469/603 (77.8%) eligible survivors. Mean diagnosis age was 7.7 (SD = 4.6) years. Mean cumulative doxorubicin‐equivalent dose was 205 mg/m² (SD = 115). Survivors completed 1,013 echocardiograms (median = 2, range = 1–10) beyond 1 year after concluding therapy. Seventy‐nine (16.8%) survivors had an abnormal echocardiogram at a median of 2.9 years (range 0.01–9.8) from 1 year after concluding therapy. Anthracycline dose >300 mg/m² (hazard ratio [HR] 3.00; 95% CI 1.51–5.98), age 1–4 years at treatment (HR 1.89; 95% CI 1.08–3.31) and radiation to a field involving the heart (HR 1.73; 95% CI 1.08–2.76) predicted an increased risk of an abnormal echocardiogram; however, even survivors in the lower COG risk groups demonstrated abnormalities.

Conclusion

Periodic echocardiographic surveillance in childhood cancer survivors can yield abnormalities that require further evaluation. Abnormalities may become evident as early as 1 year after the conclusion of therapy and can impact even those survivors considered to be at low risk. Pediatr Blood Cancer 2011; 57: 467–472. © 2011 Wiley‐Liss, Inc.     

Transition from fetal to neonatal life: Changes in cardiac function assessed by speckle-tracking echocardiography

Objective

Assessment of cardiac function by speckle-tracking (2D-S) echocardiography in the transitional period from fetal to neonatal life in a healthy population.

Methods

Ultrasound assessment of cardiac function of 30 healthy fetuses at the gestational age of 28 weeks, and follow-up after birth using 2-D strain derived novel parameters such as longitudinal strain (S), strain rate (SR), tissue velocities, MPI- and E/E′-index, E/A- and E′/A′-rate of both right (RV) and left ventricles (LV) and interventricular septum (IVS) and comparison to conventionally measured cardiac stroke volume (SV), cardiac output (CO) and ejection fraction (EF).

Results

Ultrasound 2D-S performance and analysis were technically feasible and reproducible in all 30 fetuses and in the neonatal period. In fetuses, tissue velocities and SR measurements were homogenous for all regions of interest in both ventricles, and strain increased from apex to base and was significantly higher in the RV compared to LV. All calculated indices were almost identical for RV and LV.After birth, strain and strain rate exhibited significantly lower values, and systolic tissue velocities were higher in comparison to fetal values in both chambers and in all regions of interest.

Conclusion

Speckle-tracking echocardiography is a feasible and reproducible technique in analyzing both fetal and newborn cardiac functions. Therefore, it might be useful in clinical routine examinations and give new insights in transitional physiology.     

Evaluation of left ventricular function in long-term survivors of childhood Hodgkin disease

BACKGROUND: Data on the presence of myocardial abnormalities in long-term Hodgkin disease survivors are contradictory. The purpose of this study was to determine if myocardial performance index (MPI) was capable of discovering cardiac abnormalities. PROCEDURE: Echocardiographic evaluation was performed in 31 survivors of Hodgkin disease (mean age 17.0 years), who received doxorubicin as part of chemotherapeutic treatment (median dose 164.8 +/- 42.5 mg/m(2)). Control group comprised 22 healthy subjects (mean age 16.7 years). RESULTS: Peak A velocity was increased (P = 0.004) and peak E/A velocity ratio was lower (P = 0.002) in patients compared to controls. Mean isovolumetric contraction time was longer in patients than in controls (P = 0.0001). Ejection time was significantly shorter in patients than in the controls (P = 0.001). Consequently, the MPI was significantly greater in the patients than in the controls (P = 0.0001). Abnormal MPI was found in 25/31 patients (83%). CONCLUSIONS: The Doppler-derived index of combined systolic and diastolic myocardial performance demonstrates the presence of subtle cardiac abnormalities in the majority of Hodgkin disease survivors.     

Cardiac function in survivors of acute lymphoblastic leukaemia and Hodgkin's lymphoma

Aim: The study objective was to assess plasma N‐terminal–pro‐brain natriuretic peptide (BNP) levels and to evaluate left ventricular mass as well as left ventricular systolic and diastolic functions in 44 children who had undergone treatment for acute lymphoblastic leukaemia and Hodgkin's lymphoma, with regard to gender, age at disease onset, time that had passed since therapy completion, cumulative dose of antracyclines and mediastinal radiotherapy applied. Methods: The median levels of pro‐BNP were found to be higher in the whole study group as compared with the control (55.9 ± 53.1 ng/mL vs. 38.5 ± 47.7 ng/mL, P= 0.059). The pro‐BNP values >80.0 ng/mL (standard deviation score (SDS)) were noted in 11/44 patients, including those exceeding 115.0 ng/mL (2 SDS) – in 6/44 patients. Results: No correlation was observed of pro‐BNP levels with the accumulated dose of antracyclines (r=?0.42, P= 0.79) or mediastinal radiotherapy (r= 0.197, P= 0.2). However, negative correlation was found between pro‐BNP and the time that had passed since therapy completion (r=?0.378, P= 0.009). In echocardiography, shortening and ejection fractions remained normal, whereas the indexed stroke volume was below 40 mL/m² in 16/44 patients. The E/A index below 1.5 was found in 6/44 cases. The left ventricular systolic mass remained within the normal range. Negative correlation was noted between isovolumetric diastolic time and pro‐BNP level. Conclusions: Increased levels of pro‐BNP after anti‐cancer treatment with the involvement of cardiotoxic substances may indicate the first symptoms of myocardial dysfunction, despite the lack of major echocardiographic disorders.     

Exercise capacity in apparently healthy survivors of cancer

Aims

To evaluate cardiopulmonary exercise tolerance in a large cohort of apparently healthy paediatric cancer survivors in order to determine their participation in sporting activities.

Methods

A total of 84 young (<21 years) asymptomatic childhood cancer survivors, who had been exposed to anthracyclines (mean dose 212 mg/m²) and/or chest irradiation (median dose 2000 cGy), with normal left ventricular systolic function at rest (fractional shortening >29%), and 79 healthy controls were studied. Exercise testing was performed on a treadmill ergometer. Gas exchange analysis and derived variables were measured on a breath‐by‐breath basis. Pulmonary functional evaluation was performed before exercise. Echocardiographic evaluation at rest was performed within one month before the exercise test.

Results

There were no differences in exercise responses between patients and controls. In boys <13 years, mean VO₂ max was slightly but significantly lower than in controls. This finding was thought to be a result of decreased physical fitness as all the other exercise parameters were similar to those in the controls.

Conclusions

Results show that apparently healthy survivors of paediatric cancer can take part in dynamic sporting activities if they exhibit a normal response to cardiopulmonary exercise testing, while those that exhibit a reduced VO₂ max should be re‐evaluated after an aerobic training programme, and should undergo tailored dynamic physical activity if the VO₂ max does not normalise.     

Exercise echocardiography reveals subclinical cardiac dysfunction in young adult survivors of childhood acute lymphoblastic leukemia

OBJECTIVE: Anthracyclines (AC) have contributed significantly to increased survival rate in acute lymphoblastic leukemia (ALL), although the use of these drugs is limited due to cardiotoxicity. The aim was to evaluate heart muscle function in asymptomatic adult survivors of ALL treated in early childhood in relation to the combined effects of AC and other potential cardiotoxic factors. PROCEDURE: Twenty-three young adult ALL survivors who had all received treatment with median 120 (120-400) mg AC/m(2) before the onset of puberty were examined median 21 years after remission and compared with 12 healthy controls. Basal echocardiography including two-dimensional (2D) M-mode and Doppler examination was performed, followed by a maximal exercise stress test and stress echocardiography immediately after stress test and after 5 min recovery. RESULTS: We found significant differences in systolic function between patients and controls at maximal exercise despite absence of reported symptoms from the patients. The most marked difference was in ejection fraction at stress 59.5% (32.6-81.1) and 77.3% (66.2-85.3), respectively (P < 0.00006). Ten out of 23 patients reduced their ejection fraction at stress compared with at rest; this was not found in any of the controls. Cardiovascular risk factors such as GH deficiency and a high proportion of trunk fat did not have an impact on cardiac function. CONCLUSIONS: With very long follow up in a homogenous cohort of ALL survivors, we found subclinical cardiac dysfunction with exercise stress echocardiography even after low doses of AC.     

Exercise test in pediatric renal transplant recipients and its relationship with their cardiac function

Pediatric kidney transplant recipients are at increased risk of CVD. Exercise test is a good method to evaluate exercise capacity, cardiorespiratory fitness, and risk of potential CVDs. The aim of this study was to assess the exercise capacity in this population and determine its relationship with their cardiac function using conventional and tissue Doppler echocardiography. Exercise test, conventional and tissue Doppler echocardiography were performed on 44 kidney transplant children (age ranging 11–20, 59% male) with acceptable renal function, and the results were compared with their normal healthy counterparts. Our transplant patients achieved significantly lower maximal heart rate, maximal heart rate ratio, total energy expenditure during the exercise, and maximal O₂ consumption (Max VO₂) than the normal group (p < 0.05). No correlation was found between hemoglobin (Hb) level, dialysis duration, kidney function, and the exercise test parameters. Kidney transplant patients had preserved systolic despite diminished diastolic cardiac function compared to the normal children. Our pediatric renal transplant recipients had severely impaired diastolic dysfunction and significantly reduced MaxVO₂ compared with their healthy counterparts. No correlation was found between MaxVO₂ and measured indices of systolic and diastolic cardiac function.