Cardiac Function After Cardiotoxic Treatments for Childhood Cancer-Left Ventricular Longitudinal Strain in Screening.

Background: The majority of childhood cancer survivors (CCSs) have been exposed to cardiotoxic treatments and often present with modifiable cardiovascular risk factors. Our aim was to evaluate the value of left ventricular (LV) longitudinal strain for increasing the sensitivity of cardiac dysfunction detection among CCSs. Methods: We combined two national cohorts: neuroblastoma and other childhood cancer survivors treated with anthracyclines. The final data consisted of 90 long-term CCSs exposed to anthracyclines and/or high-dose chemotherapy with autologous stem cell rescue and followed up for > 5 years and their controls (n = 86). LV longitudinal strain was assessed with speckle tracking (Qlab) and LV ejection fraction (EF) by three-dimensional echocardiography (3DE). Results: Of the CCSs, 11% (10/90) had abnormal LV longitudinal strain (i.e., < -17.5%); of those, 70% (7/10) had normal 3DE LV EF. Multivariable linear model analysis demonstrated that follow-up time (p = 0.027), sex (p = 0.020), and BMI (p = 0.002) were significantly associated with LV longitudinal strain. Conversely, cardiac risk group, hypertension, age, cumulative anthracycline dose or exposure to chest radiation were not. Conclusion: LV longitudinal strain is a more sensitive method than LV EF for the detection of cardiac dysfunction among CCSs. Therefore, LV longitudinal strain should be added to the screening panel, especially for those with modifiable cardiovascular risk factors.

Velocity vector imaging shows normal cardiac systolic function in survivors of severe bronchopulmonary dysplasia at six to 16 years of age.

AIM: This study evaluated global myocardial function and associations between cardiac function and lung function in very low birth weight (VLBW) children, with and without severe radiographic bronchopulmonary dysplasia (BPD), at six to 14 years of age. METHODS: We studied 34 VLBW and 19 term-born controls, and the VLBW group was further divided into a BPD group with severe radiographic BPD and those without radiographic BPD in infancy. Detailed right and left ventricular myocardial functions were analysed by velocity vector imaging, and the left ventricular mass was calculated. The associations between cardiac function and lung function were assessed by impulse oscillometry. RESULTS: The right and left ventricular myocardial systolic functions and the left ventricular mass were similar in the three groups. Lung function was not associated with cardiac systolic function. Neonatal exposure to dexamethasone treatment was negatively associated with right ventricular function, as measured by the automated fractional area change, with an odds ratio of 7.9 and 95% confidence interval of 1.9-33.5 (p = 0.005). CONCLUSION: Lung function measurements were not associated with cardiac systolic function in preterm infants at six to 14 years of age. Neonatal exposure to dexamethasone, used for weaning from the ventilator, was negatively associated with right ventricular function.

Very low birthweight bronchopulmonary dysplasia survivors had similar cardiac outcomes to controls at six years to 14 years of age.

AIM: This study evaluated cardiac function and its associations with lung function and neonatal pulmonary morbidity in very low birthweight (VLBW) children, with and without severe radiographic bronchopulmonary dysplasia (radBPD), at school age. METHODS: We examined 18 VLBW children with radBPD, 17 VLBW children without radBPD and 18 healthy term-born children using conventional echocardiography, tissue Doppler imaging, speckle tracking echocardiography and real-time three-dimensional echocardiography at six years to 14 years of age. Lung function was studied by impulse oscillometry. Plasma N-terminal-proBNP concentrations were measured. RESULTS: Cardiac function and N-terminal-proBNP concentrations did not differ between the groups. No associations were found between cardiac function and neonatal dexamethasone, oxygen or ventilator therapies. In VLBW children, poorer reactance correlated with larger left ventricle (LV) end-systolic (Spearman's ρ = -0.45) and end-diastolic (ρ = -0.50) volumes and higher resistance correlated with higher LV dyssynchrony indexes, with ρ ranging from 0.37 to 0.48. Greater bronchodilation responses correlated with lower early diastolic myocardial relaxation velocities, with ρ ranging from 0.39 to 0.42. CONCLUSION: BPD survivors had normal cardiac function at the age of six years to 14 years. No associations were found between neonatal pulmonary morbidity and cardiac parameters. Poorer lung function correlated modestly with LV echocardiographic parameters in VLBW children.

Speckle tracking echocardiography detects decreased cardiac longitudinal function in anthracycline-exposed survivors of childhood cancer.

UNLABELLED: Longitudinal motion significantly contributes to the contraction of the ventricles. We studied the left (LV) and right ventricular (RV) longitudinal functions in 75 anthracycline-exposed, long-term childhood cancer survivors and 75 healthy controls with conventional echocardiography, tissue Doppler imaging (TDI), speckle tracking echocardiography (STE) of the mitral and tricuspid annular motion, and real-time three-dimensional echocardiography (RT-3DE). Cardiac magnetic resonance (CMR) imaging was performed on 61 of the survivors. The survivors had lower systolic myocardial velocities in the LV and lower diastolic velocities in both ventricles by TDI than did their healthy peers. The STE-based tissue motion annular displacement (TMAD) values describing the LV and RV systolic longitudinal function (MAD and TAD mid%, respectively) were also lower among the survivors (15.4 ± 2.4 vs. 16.1 ± 2.2 %, p = 0.049 and 22.5 ± 3.0 vs. 23.5 ± 3.0 %, p = 0.035). MAD and TAD mid in millimeters correlated with the respective ventricular volumes measured with RT-3DE or CMR. CONCLUSION: Childhood cancer survivors exposed to low to moderate anthracycline doses had decreased longitudinal systolic and diastolic functions (TDI or STE) compared with healthy controls. The STE-based TMAD is a fast and reproducible method to assess cardiac longitudinal function. What is Known? • High anthracycline doses cause LV dysfunction as evidenced by a decreased ejection fraction. What is new? • Low to moderate anthracycline doses also have a negative impact on the LV and RV longitudinal systolic and diastolic function. • TMAD is a new and fast method to assess the cardiac longitudinal function after anthracycline exposure.

Fate of fenestration in children treated with fontan operation.

OBJECTIVE: To review the operative history and clinical and catheterization data on patients treated with total cavopulmonary connection (TCPC) with baffle fenestration and to study whether it is possible to predict the fate of fenestration. BACKGROUND: A baffle fenestration may improve postoperative outcomes after Fontan operation but is later associated with cyanosis and thromboembolic risk. Fenestration may close spontaneously or it can be closed percutaneously in patients with favorable hemodynamics. METHODS: Patients were divided into three groups: those with spontaneous closure of fenestration (group S, n = 34) and those with patent fenestration and favorable (group F, n = 36) or unfavorable (group U, n = 20) response to fenestration test occlusion. Clinical records were reviewed for demographic and anatomical characteristics, previous surgeries, and catheterizations. RESULTS: Predominant ventricular morphology was right ventricle (RV)/left ventricle (LV)/undeterminate in 19/14/1 patients in group S, 14/22/0 in group F, and 14/6/0 in group U. No differences were detected between groups in pre-TCPC catheterization data. Type of baffle fenestration was window/tube in 20/14 in group S, 28/8 in group F, and 20/0 in group U. All tube fenestrations either closed spontaneously or could be closed percutaneously. Twenty-nine percent of patients with window-type fenestrations failed the test occlusion. CONCLUSIONS: Spontaneous closure and favorable result in test occlusion are more common in tube than in window fenestrations. Since most preoperative anatomic and hemodynamic factors were similar in all patient groups, we find it difficult to predict the fate of a window-type fenestration and the result of test occlusion. © 2015 Wiley Periodicals, Inc.

Cardiac biomarkers indicate a need for sensitive cardiac imaging among long-term childhood cancer survivors exposed to anthracyclines.

AIM: The role that plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) and cardiac troponins T (cTnT) and I (cTnI) play in supplementing imaging to screen for cardiac late effects remains controversial and the impact of high-sensitivity cTnT and troponin-specific autoantibodies (cTnAAbs) remains unexplored. We studied the role of cardiac biomarkers as indicators of the late effects of anthracyclines among childhood cancer survivors. METHODS: We measured NT-proBNP, cTnT, high-sensitivity cTnT, cTnI and cTnAAbs in 76 childhood cancer survivors at a median of 9 years after primary diagnosis. The survivors underwent conventional and real-time three-dimensional echocardiography and 62 underwent cardiac magnetic resonance imaging (MRI). RESULTS: Of the survivors, four (5.3%) without risk factors for cardiotoxicity were cTnAAb-positive with an impaired cardiac function in MRI. Another four (5.3%) had an abnormal NT-proBNP level associated with an abnormal cardiac function and risk factors for cardiotoxicity. None showed measurable cardiac troponins, determined by the three different methods, with even the high-sensitivity cTnT-levels remaining normal. CONCLUSION: Elevated plasma NT-proBNP or cTnAAbs indicated that childhood cancer survivors benefitted from being evaluated with modern imaging, despite normal function in conventional echocardiography. However, troponins did not seem to provide additional information on the late cardiotoxicity of anthracyclines.

Three-dimensional echocardiography and cardiac magnetic resonance imaging in the screening of long-term survivors of childhood cancer after cardiotoxic therapy.

The left ventricular (LV) volumes, ejection fraction (EF), and dyssynchrony indexes for the 16 and 12 cardiac segments (Tmsv16-SD and Tmsv12-SD, respectively) were analyzed among nonadult, anthracycline-exposed long-term survivors of childhood cancer and compared with those of healthy controls using conventional and real-time 3-dimensional echocardiography (RT-3DE) with cardiac magnetic resonance (CMR) imaging in a prospective, cross-sectional, single tertiary center setting. Seventy-one survivors and gender-, body surface area-, and age-matched healthy controls were studied by conventional echocardiography and RT-3DE. Fifty-eight of the 71 survivors underwent also CMR. The survivors were evaluated in 2 groups. Group I consisted of 63 exposed to anthracyclines and group II consisted of 8 also exposed to cardiac irradiation. By RT-3DE, the group I survivors had a lower LVEF (57% vs 60%, respectively, p = 0.003) and larger body surface area-indexed LV end-systolic volume (31 vs 28 ml/m(2), respectively, p = 0.001) than controls. The Tmsv16-SD was higher in group II than in I (1.93% vs 1.39%, respectively, p = 0.003). None of the survivors had an abnormal fractional shortening (<28%), but 10% had an LVEF <50% by RT-3DE. An LVEF <55% was detected in 45 of 58 (78%) of those imaged with CMR. In conclusion, RT-3DE seems to detect more abnormalities in cardiac function than conventional echocardiography following childhood cancer therapy. The LV dyssynchrony indexes derived from RT-3DE appear potentially useful in assessing the early signs of cardiotoxicity between anthracycline and cardiac irradiation exposed long-term survivors of childhood cancer.

Cardiac troponin I, cardiac troponin-specific autoantibodies and natriuretic peptides in children with hypoplastic left heart syndrome.

OBJECTIVES: To evaluate serum levels of cardiac troponin I (cTnI), autoantibodies against cardiac troponin (cTnAAbs) and natriuretic peptides during the treatment protocol in children with hypoplastic left heart syndrome (HLHS). METHODS: In a prospective study, we had 18 consecutive children with HLHS, for whom serum samples were analysed before the Norwood operation, before the bidirectional Glenn (BDG) operation, at the age of one year and before total cavo-pulmonary connection (TCPC). In addition, we performed a cross-sectional study in 22 children examined before TCPC. Controls comprised 34 healthy children. RESULTS: In the prospective study, troponin I was positive in eight children before the Norwood operation. At the next follow-up, six children were positive. Thereafter, in all samples, cTnI was negative. Serum levels of natriuretic peptides decreased during the treatment protocol but remained higher than in controls throughout the study. In the cross-sectional study, cTnI levels were negative, but levels of natriuretic peptides were higher than in controls. Levels of cTnI and natriuretic peptides showed no correlation with oxygen saturation or haemoglobin concentration. Autoantibodies against cardiac troponin appeared in one patient but not in the control children. CONCLUSIONS: Cardiac TnI release is common before Norwood and BDG operations; then during the treatment protocol for HLHS, cTnI release resolves and serum levels of natriuretic peptides decrease. This may reflect a reduction of volume overload of the right ventricle during the surgical programme.

Cardiac magnetic resonance imaging in the evaluation of the late effects of anthracyclines among long-term survivors of childhood cancer.

OBJECTIVES: This study sought to examine the left ventricular (LV) and right ventricular (RV) function and signs of focal fibrosis among long-term survivors of childhood cancer with the use of cardiac magnetic resonance (CMR) imaging. BACKGROUND: Increased myocardial fibrosis has been detected in the endomyocardial biopsies of survivors. CMR has established its role in the assessment of both cardiac function and structure, and focal fibrosis of the myocardium is detectable with late gadolinium enhancement (LGE). METHODS: Sixty-two anthracycline-exposed long-term survivors of childhood cancer were studied at a mean age of 14.6 years. The LV and RV ejection fractions (EFs) and volumes were measured, and LGE was assessed using CMR. RESULTS: An abnormal LV function (EF <45%) was detected in 18% (11 of 62) of the survivors, and an abnormal RV function was detected in 27% (17 of 62) of the survivors. Subnormal (45% ≤ EF <55%) LV function were demonstrated in 61% (38 of 62) and subnormal RV function in 53% (33 of 62) of the survivors, respectively. Both the LV and RV end-systolic and LV end-diastolic volumes were increased compared with reference values. None of the study patients showed LGE. CONCLUSIONS: A considerable proportion of the long-term survivors of childhood cancer with anthracycline exposure demonstrate signs of cardiac dysfunction detectable by CMR, with the RV also being involved. Yet, myocardial fibrosis does not seem to be detectable at a median of 7.8 years after anthracycline therapy.

Cardiac troponin I in congenital heart defects with pressure or volume overload.

OBJECTIVE: To evaluate the prevalence of cardiac troponin I (cTnI) and autoantibodies to cTn in children with congenital heart defects with volume or pressure overload fulfilling the criteria for treatment, and in healthy children. DESIGN: The study groups comprised 78 children with volume overload caused by an atrial septal defect or a patent ductus arteriosus, and 60 children with pressure overload caused by coarctation of the aorta or stenosis of the aortic or the pulmonary valve, and 74 healthy controls. Serum levels of natriuretic peptides, cTnI, and autoantibodies to cTn were analyzed at baseline, prior to treatment and in 64 patients 6 months after treatment. RESULTS: At baseline, one child with volume overload, 12 children with pressure overload, and one healthy control had positive cTnI. Further analysis of the pressure overload subgroup revealed that the children with positive cTnI were younger than those with negative cTnI, and had higher levels of natriuretic peptides. The pressure gradient at the coarctation site or stenotic valve was higher in those with positive TnI. Six months after treatment, 63 of 64 children examined were cTnI negative. CONCLUSIONS: The cTnI release is more frequently associated with pressure than volume overload which resolves after treatment in most children.

Bilateral absence of the superior vena cava.

Bilateral absence of the superior vena cava (SVC) is a very rarely detected, mainly asymptomatic congenital vascular anomaly. Though usually innocent, this anomaly may complicate cardiothoracic surgery and certain procedures like central venous catheter insertion. This SVC anomaly is poorly known, and we assume that its incidence in the general population may be higher than detected. In this paper, we summarize current knowledge on this anomaly and its clinical implications. In addition, we present a neonatal case with bilateral absence of the SVC associated with a fetal cystic hygroma. Conclusion. Totally absent SVC can cause unexpected problems during cardiothoracic surgery. Suspicion of SVC absence should arise in basic echocardiography. Our paper suggests that, like other congenital anomalies, bilateral absent SVC may be associated with a fetal cyctic hygroma.

Serum Levels of Natriuretic Peptides in Children before and after Treatment for an Atrial Septal Defect, a Patent Ductus Arteriosus, and a Coarctation of the Aorta-A Prospective Study.

Background and Objectives. We evaluated and compared the influence of treatment for atrial septal defect (ASD), patent ductus arteriosus (PDA), and coarctation of the aorta (CoA) on serum levels of N-terminal proatriopeptide and N-terminal probrain natriuretic peptide. Correlations between peptide levels and echocardiographic measurements were calculated. Patients and Methods. Peptide levels were measured and echocardiography performed before and 6-12 months after treatment in 21 children with ASD, 25 with PDA, 15 with CoA, and 76 control children. Results. ANPN levels were higher than in controls at baseline in all patient groups, and NT-proBNP in patients with ASD and PDA. Both peptide levels were elevated 6 months after treatment and decreased thereafter. Peptide levels were higher in patients with volume than pressure overload. They correlated with echocardiographic measurements. At the 6-month follow-up, dimensions of the originally overloaded ventricle had normalized only in patients with PDA. Conclusions. After intervention, peptide levels decrease but normalization takes over 6 months. The type of correlation between peptide levels and echocardiography varies according to the loading condition. Measurement of peptide levels can be used for monitoring the course of a patient's heart disease.

During treatment protocol for univentricular heart serum levels of natriuretic peptides decrease.

OBJECTIVE: In children treated for univentricular heart (UVH), prospective evaluation of serum levels of N-terminal proatriopeptide (ANPN) and N-terminal pro-brain natriuretic peptide (NT-proBNP) was performed. METHODS: Serum samples were analysed in 19 children before the first operation, before the bi-directional Glenn (BDG) operation, at age 1 year and before total cavopulmonary connection (TCPC). In addition, we performed cross-sectional measurement of peptide levels in 32 children: 22 hypoplastic left ventricle (LV), 10 hypoplastic right ventricle (RV) before; and in 12 children: nine hypoplastic LV, three hypoplastic RV, 2 (range: 0.5-5.3) years after the TCPC operation. Controls comprised 12 children aged less than 6 months and 41 children aged from 6 months to 7 years. RESULTS: Between the first and second operations, peptide levels decreased. Before TCPC, further decreases had occurred. Throughout follow-up, peptide levels were higher than in controls. In the cross-sectional study, before TCPC, median ANPN concentration measured 0.37 (range: 0.18-1.00) nmol l(-1) (P=0.059, compared with controls) and NT-proBNP 155 (range: 13-718) ng l(-1) (P<0.001). After TCPC, median ANPN concentration measured 0.39 (range: 0.09-0.98) nmol l(-1) (P=ns) and NT-proBNP 201 (range: 76-1406) ng l(-1) (P<0.001). Before TCPC, levels of NT-proBNP were higher in patients with RV than with LV morphology. CONCLUSIONS: Natriuretic peptide levels decreased during treatment protocol for UVH, but NT-proBNP levels remained higher than in controls. These reflect reduction of volume overload of the single ventricle and can prove useful for haemodynamic monitoring.

Serum levels of natriuretic peptides in children with various types of loading conditions.

OBJECTIVES: To evaluate the influence of volume overload of the left (LV) and right ventricle (RV) and pressure overload of LV and restrictive physiology on levels of N-terminal proatriopeptide (ANPN) and N-terminal pro-brain natriuretic peptide (NT-proBNP). DESIGN: We studied 41 children with atrial septal defect (ASD), 35 with patent ductus arteriosus (PDA), 27 with coarctation of the aorta (CoA), 25 with restrictive physiology caused by Mulibrey nanism, and 64 control children. We measured serum concentrations of natriuretic peptides and evaluated ventricular size and function with echocardiography. RESULTS: In patients with ASD, PDA, and Mulibrey nanism, levels of both ANPN and NT-proBNP were higher than in controls but in children with CoA, only ANPN levels were higher. ANPN levels correlated with RV size in ASD and NT-proBNP levels with LV size in PDA. In patients with restriction, NT-proBNP levels correlated negatively with LV size. CONCLUSIONS: Correlation between echo measurements and levels of natriuretic peptides varied according to loading condition. Measurement of natriuretic peptide levels provides a supplemental method for non-invasive haemodynamic evaluation of children's heart disease.

Left ventricular hypertrophy persists after successful treatment for coarctation of the aorta.

OBJECTIVES: To evaluate cardiac size and function in patients with coarctation of the aorta (CoA) before and after treatment. DESIGN: Ventricular size and function were examined by 2- and 3-dimensional echocardiography, and concentrations of natriuretic peptides measured in 15 paediatric patients before repair, and one, 6, and 12 months thereafter. Controls comprised 15 children. RESULTS: Before repair, mitral inflow velocities and left ventricular (LV) size and wall thickness were higher in patients. Thicknesses of interventricular septum and LV posterior wall decreased after repair but increased to initial level one year thereafter. The LV end-diastolic diameter remained larger than in controls despite successful repair. The size of right ventricle increased and levels of natriuretic peptides decreased during follow-up. Levels of natriuretic peptides correlated with the smallest diameter of CoA segment and diastolic indices of LV function. CONCLUSION: LV hypertrophy persists and LV size remains larger than in controls after successful repair even in normotensive patients with normal growth of CoA segment. This may be due to remodelling of ventricles and the aorta caused by CoA.

Hemodynamic improvement is faster after percutaneous ASD closure than after surgery.

OBJECTIVES: Hemodynamic effects of surgical and percutaneous closure of atrial septal defect (ASD) were evaluated. BACKGROUND: ASD causes volume overload of right ventricle (RV) and is associated with distortion and dysfunction of left ventricle (LV). The amount and timing of hemodynamic changes after ASD closure are not well known. METHODS: The study group consisted of 7 children treated surgically and 17 treated in the catheterization laboratory. In the control group, there were 51 healthy children. RV size and LV end-diastolic and systolic dimensions, volumes, and function were examined by two- and three- dimensional echocardiography and serum concentrations of natriuretic peptides measured prior to ASD closure, and 1, 6, and 12 months thereafter. RESULTS: In all children with ASD, during the 1-year follow-up, the z score of RV end-diastolic diameter decreased from a median 5.00 SD to 2.25 SD (P < 0.001). Dilatation of RV did not resolve entirely during 1-year follow-up in either treatment group. End-diastolic LV diameter increased from -1.50 to -0.50 SD (P < 0.001). LV size increased slower in the surgical subgroup but reached control levels in both groups. Concentrations of natriuretic peptides increased during the first month after ASD closure and normalized thereafter in patients treated percutaneously but remained higher than in controls in patients treated surgically. CONCLUSIONS: During 1-year follow-up after ASD closure, RV size decreases but does not normalize in all patients. The size of the LV normalizes after ASD closure but the increase in LV size is slower in patients treated surgically. Serum levels of ANPN and proBNP are elevated prior to ASD closure but decrease thereafter to control levels in patients treated with the percutaneous technique but not in those treated surgically.

The influence of percutaneous closure of patent ductus arteriosus on left ventricular size and function: a prospective study using two- and three-dimensional echocardiography and measurements of serum natriuretic peptides.

OBJECTIVES: We aimed to evaluate the effect of percutaneous closure of patent ductus arteriosus (PDA) on left ventricular (LV) hemodynamics. BACKGROUND: Today, most PDAs are closed percutaneously. Little is known, however, about hemodynamic changes after the procedure. METHODS: Of 37 children (ages 0.6 to 10.6 years) taken to the catheterization laboratory for percutaneous PDA closure, the PDA was closed in 33. Left ventricular diastolic and systolic dimensions, volumes, and function were examined by two-dimensional (2D) and three-dimensional (3D) echocardiography and serum concentrations of natriuretic peptides measured before PDA closure, on the following day, and 6 months thereafter. Control subjects comprised 36 healthy children of comparable ages. RESULTS: At baseline, LV diastolic diameter measured >+2 SD in 5 of 33 patients. In 3D echocardiography, a median LV diastolic volume measured 54.0 ml/m2 in the control subjects and 58.4 ml/m2 (p < 0.05) in the PDA group before closure and 57.2 ml/m2 (p = NS) 6 months after closure. A median N-terminal brain natriuretic peptide (pro-BNP) concentration measured 72 ng/l in the control group and 141 ng/l in the PDA group before closure (p = 0.001) and 78.5 ng/l (p = NS) 6 months after closure. Patients differed from control subjects in indices of LV systolic and diastolic function at baseline. By the end of follow-up, all these differences had disappeared. Even in the subgroup of patients with normal-sized LV at baseline, the LV diastolic volume decreased significantly during follow-up. CONCLUSIONS: Changes in LV volume and function caused by PDA disappear by 6 months after percutaneous closure. Even the children with normal-sized LV benefit from the procedure.