Background-More than 50% of >270 000 childhood cancer survivors in the United States have been treated with anthracyclines and are therefore at risk of developing cardiotoxicity. Cardiac magnetic resonance (CMR) has demonstrated utility to detect diffuse interstitial fibrosis and changes in regional myocardial function. We hypothesized that CMR would identify occult cardiotoxicity characterized by structural and functional myocardial abnormalities in a cohort of asymptomatic pediatric cancer survivors with normal global systolic function. Methods and Results-Forty-six long-term childhood cancer survivors with a cumulative anthracycline dose ≥200 mg/m 2 and normal systolic function were studied 2.5 to 26.9 years after anthracycline exposure. Subjects underwent transthoracic echocardiography, CMR with routine cine acquisition, tissue characterization, and left ventricular strain analysis using a modified 16-segment model. Extracellular volume was measured in 27 subjects, all of whom were late gadolinium enhancement negative. End-systolic fiber stress was elevated in 45 of 46 subjects. Low average circumferential strain magnitude (ε cc ) −14.9±1.4; P<0.001, longitudinal strain magnitude (ε ll ) −13.5±1.9; P<0.001, and regional peak circumferential strain were seen in multiple myocardial segments, despite normal global systolic function by transthoracic echocardiography and CMR. The mean T1 values of the myocardium were significantly lower than that of control subjects at 20 minutes (458±69 versus 487±44 milliseconds; P=0.01). Higher mean extracellular volume was observed in female subjects (0.34 versus 0.22; P=0.01). The purpose of this study was to use CMR T1 mapping techniques and measures of myocardial strain by tagged cine MRI to detect interstitial disease and changes in regional myocardial function in childhood cancer survivors. We tested the hypothesis that individuals with a history of high-dose anthracycline therapy may have occult cardiotoxicity, manifested by a decrease in circumferential ε cc and longitudinal ε ll strain magnitude and changes in myocardial T1 and ECV, despite normal standard measures of global left ventricular (LV) systolic function. Conclusions-Asymptomatic Methods Study PopulationEligible subjects with a cumulative anthracycline dose ≥200 mg/m 2 and normal LV systolic function defined as TTE-based shortening fraction ≥29% were identified and prospectively enrolled through a registry of pediatric cancer survivors treated with anthracyclines between 1985 and January 2011. Inclusion criteria for this study are shown in Figure 1. Subjects with high-dose radiation exposure to the chest (>3000 cGy) were excluded from the study to minimize the known synergistic effect of therapeutic radiation on cardiotoxicity. 5,21This study was approved by the Institutional Review Board at the Connecticut Children's Medical Center. The medical records of all enrolled subjects were reviewed to identify known risk factors associated with cardiotoxicity. Conversions to isotoxic equivalents of anthracycline a...

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Background: Subacute cardiotoxicity, consisting of acute myocyte damage and associated left ventricular dysfunction, occurs early during anthracycline therapy. We investigated the impact of myocardial dysfunction, defined herein by a shortening fraction (SF) < 29 % at any time during or after anthracycline therapy, on late onset cardiomyopathy and all-cause mortality, among childhood cancer survivors exposed to anthracyclines. In addition, we sought to identify subpopulations of subjects at highest risk for cardiomyopathy and death from all causes. Methods: Five hundred thirty-one childhood cancer survivors exposed to anthracyclines were enrolled and studied on average 10 (1.4-27.3) years following their initial exposure. The medical records were reviewed to identify known risk factors associated with cardiotoxicity, including cumulative anthracycline dose, length of post-therapy interval, administration of other cardiotoxic medications (vinca alkaloids), previous heart disease, radiation dose to the heart, history of bone marrow transplantation, age at treatment, gender, systolic dysfunction, and history of congestive heart failure during anthracycline therapy. Results: Ninety subjects (16.9 %) developed SF < 29 % and 71 patients (13.4 %) died on average 10 years after initial exposure (range 1.4-27.3 years). Total cumulative dose (OR 3.27, 95 % CI 1.94, 5.49, p < 0.001) and bone marrow transplantation (OR 2.57, 95 % CI 1.24, 5.30, p = 0.01) were found to be statistically significant risk factors for development of myocardial dysfunction. There was a 3-fold increase in the odds of having a SF < 29 % at any point during or following cancer therapy if a subject underwent bone marrow transplantation or had a total cumulative dose anthracycline therapy ≥ 240 mg/m 2 . The all-cause mortality ratio was almost seven-fold higher (95 % CI, 2.40-fold to 17.81-fold higher) if a subject developed systolic dysfunction, defined by a previous SF < 29 % anytime during or after anthracycline therapy. Nine deaths (12.7 %) were attributed to cardiovascular disease. The risk of dying as a result of cardiac disease also was significantly higher in individuals who had a SF < 29 % at any time during or after therapy. Conclusions: This study demonstrates an almost seven-fold increase in all cause mortality in pediatric cancer survivors with a history of anthracycline induced myocardial dysfunction defined as SF < 29 %.

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