Cardiac Events in Childhood Cancer Survivors Treated with Anthracyclines: The Value of Previous Myocardial Strain Measurement.

In echocardiographic surveillance of anthracycline-treated childhood cancer survivors (CCS), left ventricular ejection fraction (LVEF) has insufficient prognostic value for future cardiac events, whereas longitudinal strain may be more sensitive. We describe the long-term incidence of cardiac events in CCS after previous measurement of LVEF and myocardial strain. Echocardiography, including four-chamber view longitudinal strain (4CH-LS), of 116 anthracycline-treated CCS was obtained between 2005−2009 (index echocardiography). Follow-up was obtained at the late-effects clinic. Primary outcome was occurrence of cardiac events, defined as either symptomatic heart failure, life-threatening arrhythmias, LVEF < 40% or cardiac death, in CCS with normal versus abnormal index 4CH-LS. LVEF from subsequent echocardiograms was obtained to evaluate its natural course as a secondary outcome. After index echocardiography (median 13.1 years since childhood cancer diagnosis), our study added a median follow-up of 11.3 years (median last clinical contact 23.6 years since diagnosis). Only three CCS developed a cardiac event (6.2, 6.4 and 6.7 years after index echocardiography), resulting in a ten-year cumulative incidence of 2.7% (95%CI 0.9−8.2). All three CCS had a clearly reduced index 4CH-LS and relevant cardiovascular risk factors, whereas their index LVEFs were around the lower limit of normal. Index LVEF correlated with index 4CH-LS but mean long-term natural course of LVEF was comparable for CCS with abnormal versus normal index 4CH-LS. Absolute 10-year cumulative incidence of cardiac events in anthracycline-treated CCS during long-term follow-up was low. Sensitive echocardiographic measurements, such as 4CH-LS may be useful to tailor surveillance frequency in a selected group of CCS without cardiovascular disease.

Left ventricular dyssynchrony in long-term childhood cancer survivors treated with anthracyclines: a retrospective cross-sectional study.

The purpose of this study was to investigate left ventricular contraction patterns in asymptomatic Childhood cancer survivors (CCS) using two-dimensional speckle tracking echocardiography (2DSTE). Left ventricular longitudinal and circumferential myocardial parameters were assessed using 2DSTE, in asymptomatic CCS and age matched healthy controls. Time to peak (T2P) systolic strain was quantified. Dyssynchrony index (DI) was measured by calculating the standard deviation of T2P systolic strain of six segments in each view. Difference between T2P systolic longitudinal strain of septal and lateral wall was also assessed as a parameter for dyssynchrony. We included 115 CCS with a median age of 17.2 years (range 5.6-39.5) and a median follow up of 11.3 years (range 4.9-29.5) and 119 controls. Conventional echocardiographic parameters and global longitudinal strain were significantly decreased in CCS compared to controls (p < 0.01 and p = 0.02, respectively). Dyssynchrony index did not differ between CCS and controls. There was a clinically insignificant smaller absolute difference between T2P systolic longitudinal of septal and lateral wall in CCS compared to controls. We showed no difference in longitudinal or circumferential left ventricular dyssynchrony in CCS compared to controls using 2DSTE. Future research should focus on assessing dyssynchrony in more segments and a larger CCS population, using both 2D and 3DSTE.

Refining the 10-Year Prediction of Left Ventricular Systolic Dysfunction in Long-Term Survivors of Childhood Cancer.

BACKGROUND: In childhood cancer survivors (CCS) at risk for heart failure, echocardiographic surveillance recommendations are currently based on anthracyclines and chest-directed radiotherapy dose. Whether the ejection fraction (EF) measured at an initial surveillance echocardiogram can refine these recommendations is unknown. OBJECTIVES: The purpose of this study was to assess the added predictive value of EF at >5 years after cancer diagnosis to anthracyclines and chest-directed radiotherapy dose in CCS, for the development of left ventricular dysfunction with an ejection fraction <40% (LVD40). METHODS: Echocardiographic surveillance was performed in 299 CCS from the Emma Children's Hospital in the Netherlands. Cox regression models were built including cardiotoxic cancer treatment exposures with and without EF to estimate the probability of LVD40 at 10-year follow-up. Calibration, discrimination, and reclassification were assessed. Results were externally validated in 218 CCS. RESULTS: Cumulative incidences of LVD40 at 10-year follow-up were 3.7% and 3.6% in the derivation and validation cohort, respectively. The addition of EF resulted in an integrated area under the curve increase from 0.74 to 0.87 in the derivation cohort and from 0.72 to 0.86 in the validation cohort (likelihood ratio p < 0.001). Reclassification of CCS without LVD40 improved significantly (noncase continuous net reclassification improvement 0.50; 95% confidence interval [CI]: 0.40 to 0.60). A predicted LVD40 probability ≤3%, representing 75% of the CCS, had a negative predictive value of 99% (95% CI: 98% to 100%) for LVD40 within 10 years. However, patients with midrange EF (40% to 49%) at initial screening had an incidence of LVD40 of 11% and a 7.81-fold (95% CI: 2.07- to 29.50-fold) increased risk of LV40 at follow-up. CONCLUSIONS: In CCS, an initial surveillance EF, in addition to anthracyclines and chest-directed radiotherapy dose, improves the 10-year prediction for LVD40. Through this strategy, both the identification of low-risk survivors in whom the surveillance frequency may be reduced and a group of survivors at increased risk of LVD40 could be identified.

Myocardial 2D Strain During Long-Term (>5 Years) Follow-Up of Childhood Survivors of Acute Lymphoblastic Leukemia Treated With Anthracyclines.

Anthracycline-induced cardiotoxicity can lead to clinical and subclinical heart failure. Decrease of global longitudinal strain is a predictor for heart failure. Early detection of subclinical cardiotoxicity is crucial for timely intervention and prevention of further progression. Cardiac function of 41 survivors of childhood acute lymphoblastic leukemia (ALL) was assessed. Values of cardiac troponin T, N-terminal-pro-brain natriuretic peptide, conventional and myocardial 2D strain echocardiography were measured before (T = 0), during (T = 1, cumulative dose of 120 mg/m2), shortly after (T = 2) and long after anthracycline treatment (T = 3, ≥5 years after anthracycline exposure). Cardiac function of survivors at the latest follow up was compared with 70 healthy age-matched controls. None of the survivors showed clinical signs of cardiac failure at T = 3. Strain values decreased during anthracycline treatment and an ongoing reduction was seen at the latest follow-up (T = 3) with preserved cardiac function (normal ejection fraction and shortening fraction). At T = 1, a relative reduction in longitudinal strain (≥10% compared with baseline) was observed in 38% of the survivors, which increased to 54% at T=3. ALL survivors showed significantly lower conventional and myocardial 2D strain values, especially strain rate, compared with healthy age-matched controls. At T = 3, we did not find any abnormal cardiac troponin T levels. Six percent of the survivors showed abnormal N-terminal-pro-brain natriuretic peptide levels. This prospective study showed an ongoing reduction of 2D myocardial strain and strain rate, with preserved left ventricular ejection fraction (≤10% decrease compared with baseline) in asymptomatic ALL survivors at late follow-up.

Biomarkers to diagnose ventricular dysfunction in childhood cancer survivors: a systematic review.

OBJECTIVE: To systematically review the literature and assess the diagnostic value of biomarkers in detection of late-onset left ventricular (LV) dysfunction in childhood cancer survivors (CCS) treated with anthracyclines. METHODS: We systematically searched the literature for studies that evaluated the use of biomarkers for detection of LV dysfunction in CCS treated with anthracyclines more than 1 year since childhood cancer diagnosis. LV dysfunction definitions were accepted as an ejection fraction <50% or <55% and/or a fractional shortening <28%, <29% or <30%. Contingency tables were created to assess diagnostic accuracies of biomarkers for diagnosing LV dysfunction. RESULTS: Of 1362 original studies screened, eight heterogeneous studies evaluating four different biomarkers in mostly asymptomatic CCS were included. In four studies, an abnormal N-terminal pro-B-type natriuretic peptide (NT-proBNP, cut-off range 63-125 ng/L) had low sensitivity (maximally 22%) and a specificity of up to 97% for detection of LV dysfunction. For troponin levels, in five studies one patient had an abnormal troponin value as well as LV dysfunction, while in total 127 patients had LV dysfunction without troponin elevations above cut-off values (lowest 0.01 ng/mL). Two studies that evaluated brain natriuretic peptide and nitric oxide were underpowered to draw conclusions. CONCLUSIONS: In individual studies, the diagnostic value of NT-proBNP for detection of LV dysfunction in CCS is limited. Troponins have no role in detecting late-onset LV dysfunction with cut-off values as low as 0.01 ng/mL. Further study on optimal NT-proBNP cut-off values for rule out or rule in of LV dysfunction is warranted.

Cardiac function in paediatric patients with congenital adrenal hyperplasia due to 21 hydroxylase deficiency.

BACKGROUND: Hyperandrogenism and exogenous glucocorticoid excess may cause unfavourable changes in the cardiovascular risk profile of patients with congenital adrenal hyperplasia (CAH). OBJECTIVE: To evaluate the cardiac function in paediatric patients with CAH. PATIENTS AND METHODS: Twenty-seven paediatric patients with CAH, aged 8-16 years, were evaluated by physical examination, electrocardiogram (ECG), conventional echocardiography, tissue Doppler imaging and two-dimensional (2D) myocardial strain (rate) imaging. Results were compared to 27 age- and gender- matched healthy controls. RESULTS: No signs of left ventricular hypertrophy or dilatation were detected on echocardiography. ECG revealed a high prevalence (25.9%) of incomplete right bundle branch block. Left ventricular posterior wall thickness in diastole (LVPWd) was significantly lower in patients with CAH compared to controls (5.55 vs 6.53 mm; P = .009). The LVPWd Z-score was significantly lower in patients with CAH yet within the normal range (-1.12 vs -0.35; P = .002). Isovolumetric relaxation time was significantly lower in patients with CAH (49 vs 62 ms; P = .003). Global longitudinal, radial and circumferential strain was not significantly different compared to controls. Global radial strain rate was significantly higher compared to healthy controls (2.58 vs 2.06 1/s; P = .046). Global longitudinal strain was negatively correlated with 24-hour blood pressure parameters. CONCLUSION: Cardiac evaluation of paediatric patients with CAH showed no signs of left ventricular hypertrophy or ventricular dilatation. LVPWd was lower in patients with CAH than in controls but within the normal range. A shorter isovolumetric relaxation time in patients with CAH may be a sign of mild left ventricular diastolic dysfunction.

Is screening for abnormal ECG patterns justified in long-term follow-up of childhood cancer survivors treated with anthracyclines?

BACKGROUND: ECG and echocardiography are noninvasive screening tools to detect subclinical cardiotoxicity in childhood cancer survivors (CCSs). Our aims were as follows: (1) assess the prevalence of abnormal ECG patterns, (2) determine the agreement between abnormal ECG patterns and echocardiographic abnormalities; and (3) determine whether ECG screening for subclinical cardiotoxicity in CCSs is justified. PROCEDURE: We retrospectively studied ECG and echocardiography in asymptomatic CCSs more than 5 years after anthracycline treatment. Exclusion criteria were abnormal ECG and/or echocardiogram at the start of therapy, incomplete follow-up data, clinical heart failure, cardiac medication, and congenital heart disease. ECG abnormalities were classified using the Minnesota Code. Level of agreement between ECG and echocardiography was calculated with Cohen kappa. RESULTS: We included 340 survivors with a mean follow-up of 14.5 years (range 5-32). ECG was abnormal in 73 survivors (21.5%), with ventricular conduction disorders, sinus bradycardia, and high-amplitude R waves being most common. Prolonged QTc (>0.45 msec) was found in two survivors, both with a cumulative anthracycline dose of 300 mg/m2 or higher. Echocardiography showed abnormalities in 44 survivors (12.9%), mostly mild valvular abnormalities. The level of agreement between ECG and echocardiography was low (kappa 0.09). Male survivors more often had an abnormal ECG (corrected odds ratio: 3.00, 95% confidence interval: 1.68-5.37). CONCLUSIONS: Abnormal ECG patterns were present in 21% of asymptomatic long-term CCSs. Lack of agreement between abnormal ECG patterns and echocardiographic abnormalities may suggest that ECG is valuable in long-term follow-up of CCSs. However, it is not clear whether these abnormal ECG patterns will be clinically relevant.

Values of high sensitive troponin T in long-term survivors of childhood cancer treated with anthracyclines.

BACKGROUND: Cardiac biomarkers can play an important role in the early detection of subclinical heart failure. Our aims are to 1) obtain values of high sensitive cardiac troponin T (hs-cTnT) in long-term survivors of childhood cancer and 2) investigate the potential role of hs-cTnT in the detection of subclinical late-onset cardiotoxicity. METHODS: Hs-cTnT and N-terminal-pro-brain natriuretic peptide (NT-pro-BNP) were measured in 64 survivors. Electrocardiography and echocardiography were performed to evaluate cardiac function. RESULTS: Mean follow-up period was 8.3 years (range of 4.5 to 34.1). All survivors were clinically asymptomatic and had no history of clinical heart failure during or immediately after anthracycline treatment. Electrocardiography (available in 59 of 64 survivors) showed no signs of myocardial injury related to ischemia or abnormal QTc. Echocardiography was performed in all survivors. Mean left ventricular shortening fraction (SF) was 34% (range of 28 to 43%); mean ejection fraction (EF) was 61% (range of 48 to 74%). Seven survivors had a mildly decreased EF between 48% and 55%. Normal hs-cTnT levels were found in all 64 survivors (range of 3 to 13 ng/L) and did not differ among different anthracycline dosage groups: ≤120, 120-300 and ≥300 mg/m(2). Yet, 5/64 survivors had elevated NT-pro-BNP levels (range of 7 to 25 pg/ml) with normal SF and ECG findings and only one mildly abnormal EF of 51%. CONCLUSIONS: Hs-cTnT concentrations are normal in long-term survivors of childhood cancer, even in the subpopulations with elevated NT-pro-BNP and/or a mildly decreased EF, indicating that it is not a sensitive marker for late onset subclinical anthracycline induced cardiotoxicity.

Myocardial 2D strain echocardiography and cardiac biomarkers in children during and shortly after anthracycline therapy for acute lymphoblastic leukaemia (ALL): a prospective study.

AIMS: The aim of this study was to investigate myocardial 2D strain echocardiography and cardiac biomarkers in the assessment of cardiac function in children with acute lymphoblastic leukaemia (ALL) during and shortly after treatment with anthracyclines. METHODS AND RESULTS: Cardiac function of 60 children with ALL was prospectively studied with measurements of cardiac troponin T (cTnT) and N-terminal-pro-brain natriuretic peptide (NT-pro-BNP) and conventional and myocardial 2D strain echocardiography before start (T = 0), after 3 months (T = 1), and after 1 year (T = 2), and were compared with 60 healthy age-matched controls. None of the patients showed clinical signs of cardiac failure or abnormal fractional shortening. Cardiac function decreased significantly during treatment and was significantly decreased compared with normal controls. Cardiac troponin T levels were abnormal in 11% of the patients at T = 1 and were significantly related to increased time to global peak systolic longitudinal strain at T = 2 (P = 0.003). N-terminal-pro-brain natriuretic peptide levels were abnormal in 13% of patients at T = 1 and in 20% at T = 2, absolute values increased throughout treatment in 59%. Predictors for abnormal NT-pro-BNP at T = 2 were abnormal NT-pro-BNP at T = 0 and T = 1, for abnormal myocardial 2D strain parameters at T = 2 cumulative anthracycline dose and z-score of the diastolic left ventricular internal diameter at baseline. CONCLUSION: Children with newly diagnosed ALL showed decline of systolic and diastolic function during treatment with anthracyclines using cardiac biomarkers and myocardial 2D strain echocardiography. N-terminal-pro-brain natriuretic peptide levels were not related to echocardiographic strain parameters and cTnT was not a predictor for abnormal strain at T = 2.Therefore, the combination of cardiac biomarkers and myocardial 2D strain echocardiography is important in the assessment of cardiac function of children with ALL treated with anthracyclines.

Abnormal NT-pro-BNP levels in asymptomatic long-term survivors of childhood cancer treated with anthracyclines.

BACKGROUND: Anthracycline-induced cardiotoxicity can cause serious health problems for an increasing number of survivors of childhood malignancies. The aims of this study were to document plasma concentrations of cardiac troponin T (cTnT) and NT-pro-brain natriuretic peptide (NT-pro-BNP) in a large group of asymptomatic long-term survivors of childhood cancer treated with anthracyclines, and to study the relation of the abnormal biomarker levels with different risk factors for anthracycline-induced cardiotoxicity and conventional echocardiographic parameters. PROCEDURES: One hundred twenty-two asymptomatic survivors of childhood cancer underwent a detailed echocardiography. Blood samples were taken to determine the levels of NT-pro-BNP and cTnT. RESULTS: None of the survivors had abnormal cTnT levels. Thirteen percent of the survivors (n = 16) had abnormal NT-pro-BNP levels. Abnormal NT-pro-BNP levels were significantly related to cumulative anthracycline dosage (P < 0.003). Eleven of 31 survivors (35%) treated with cumulative anthracycline dose of 300 mg/m(2) or more, had abnormal NT-pro-BNP levels which were significantly related to end-diastolic left ventricular internal diameter (LVIDd) indexed for body surface area (BSA) (P < 0.01). CONCLUSION: Cardiac TnT does not contribute to the early detection of late onset anthracycline-induced cardiotoxicity. Abnormal levels of NT-pro-BNP were detected in 13% of 122 asymptomatic, long-term survivors of childhood cancer. Follow-up of these survivors is essential to answer the question whether NT-pro-BNP is an early marker for late onset anthracycline-induced cardiotoxicity.

Interobserver, intraobserver and intrapatient reliability scores of myocardial strain imaging with 2-d echocardiography in patients treated with anthracyclines.

Myocardial strain imaging with 2-D echocardiography is a relatively new noninvasive method to assess myocardial deformation. To determine the interobserver, intraobserver and intrapatient reliability scores, we evaluated myocardial strain measurements of 10 asymptomatic survivors of childhood cancer. Ten patients were selected randomly out of a follow-up cohort of childhood cancer survivors. All 10 patients underwent a transthoracic echocardiographic examination. Two-dimensional gray scale images were made in parasternal apical four-chamber, apical two-chamber, midcavity short-axis and basal short-axis views. Offline analysis was performed using software for echocardiographic quantification (Echopac 6.1.0, GE Medical Systems, Horten, Norway). All echocardiographic studies were analyzed offline by three observers, separately (A.M., G.W., M.P.). A custom-made software package was designed for averaging the strain curves of three consecutive cardiac cycles. Values of peak systolic strain, time-to-peak strain and time-to-end systole of the different segments of the left ventricle were used for statistical analysis. Interobserver, intraobserver and intrapatient reliability were expressed as intraclass correlation coefficients (ICCs). Interobserver ICCs of peak strain, time to peak strain and time to aortic valve closure (AVC) were generally good to very good in all views and segments, except for in the two-chamber view. Intraobserver ICCs were rated as very good for almost all segments, except for the longitudinal peak strain values of the two-chamber view. Intrapatient ICCs were generally good for the two-chamber, four-chamber and midcavity short-axis views, but fair to moderate for the segments of the basal short-axis view (SaxMV). We recommend use of the four-chamber view for longitudinal peak strain values, and the basal and midcavity short-axis views for radial and circumferential peak strain values. Furthermore, we strongly recommend using the average of three cardiac cycles for peak strain values in clinical studies.

Bis(tributyltin)oxide (TBTO) decreases the food allergic response against peanut and ovalbumin in Brown Norway rats.

Other factors than the allergen itself may be of importance in the development of food allergy. This report describes the influence of the immunosuppressive compound bis(tributyltin)oxide (TBTO), present in the food chain, on the development of food allergy to peanut or ovalbumin in Brown Norway (BN) rats. To study these effects BN rats were sensitized to either 1 or 10mg peanut or ovalbumin by daily oral gavage and the TBTO-groups were fed a diet containing 80 mg TBTO per kg diet. Co-exposure to TBTO not only resulted in decreased general immunologic parameters such as weights of mesenteric lymph nodes and Peyer's patches, lymphocyte proliferation rates in splenocytes, but also on allergic parameters. In the peanut allergen-model TBTO decreased allergen-specific Th2 cytokine production by spleen cells, number of eosinophilic and basophilic granulocytes in the blood and production of mast cell protease II after oral food challenge. In the ovalbumin allergen-model TBTO decreased the number of eosinophilic and basophilic granulocytes, allergen-specific IgE and production of mast cell protease II after oral food challenge. The data imply that in the process of risk assessment of food allergy attention should be given to immunomodulating compounds present in the diet.