Abstract: Eighteen pediatric oncology or bone marrow transplant (BMT) survivors who had liver iron content of >12 mg/g dry weight also underwent Cardiac MR (CMR) to quantify cardiac iron content. Despite high transfused packed red blood cell volumes (median 383 ml/kg) patients all had cardiac T2* relaxation times in normal ranges (T2* relaxation time mean 35.1 msec ± 7.1 [normal >20 msec]).

Introduction: Cardiovascular late effects are a leading cause of mortality and morbidity in childhood cancer and Bone Marrow Transplant (BMT) survivors.¹ In patients with chronic transfusion-dependent conditions, such as beta thalassemia major, high levels of iron deposition in the liver may be accompanied by iron loading into the heart,² which is a major cause of mortality.³ Iron overload cardiomyopathy is characterized as a restrictive physiology with early diastolic dysfunction, or poor relaxation, that may ultimately progress to end-stage dilated cardiomyopathy. Chronic iron overload can also lead to arrhythmias and may increase myocardial ischemia reperfusion injury due to increased formation of reactive oxygen species.⁴ It is not yet known whether high transfused packed red blood cell volumes in cancer and BMT patients leads to cardiac iron deposition, and whether iron-induced cardiac injury contributes to the observed cardiovascular late effects over time.

Results: Phoenix Children’s Hospital Institutional Review Board approved this retrospective chart review. From 2013-2020, 83 childhood cancer and BMT survivors at Phoenix Children’s Hospital with elevated serum ferritin levels underwent Magnetic Resonance (MR) imaging of the liver to evaluate liver iron content. The mean liver iron concentration was 9.53 ± 5.76 mg/g liver dry weight (normal range 0.8-1.8 mg/g). Per institutional protocol, 18 patients (21.7%) who had liver iron content of > 12mg/g (mean 16.0 ± 7.36 mg/g) also underwent Cardiac MRI (CMR) to determine cardiac iron content. Among patients who underwent CMR, median transfused blood volume was 393 ml/kg [95% Confidence Interval (CI) 170-780 ml/kg]. Patient demographics are presented in Table 1.

All patients underwent at least one echocardiogram to evaluate heart function which showed normal ventricular ejection fractions [mean 65.1 ± Standard Deviation (SD) 3.53%] and shortening fractions (mean 35.4 ± 3.67%). All patients had myocardial iron content within normal ranges (T2* relaxation time mean 35.1 msec ± 7.1 [normal >20 msec], mean ± SD iron content 0.63± 0.2 mg/g dry weight, range 0.5-1.1). There was no association of cardiac iron content with transfused blood volume, anthracycline dose (mg/m²) or liver iron content (Pearson Correlation Coefficients 0.27, 0.29 and 0.89 respectively).

Discussion: Childhood cancer and BMT patients often receive multiple packed red blood cell transfusions to treat symptomatic anemia. In patients with iron overload from multiple packed red blood cell transfusions, the non-transferrin bound iron enters cardiomyocytes through the L-type calcium channels calcium channels and causes slowing of the calcium current inactivation, which is thought to contribute to contribute to the cardiac effects of impaired diastolic function and ultimately systolic dysfunction. Restrictive physiology and diastolic dysfunction can be seen with lower concentrations of iron, progressing to systolic dysfunction and dilated cardiomyopathy over time with higher concentrations or iron.⁵ There is also evidence that iron overload may worsen cardiac atherosclerosis.⁶ In contrast, the mechanism for cardiac damage due to anthracyclines and radiation are posited to create reactive oxygen species generation and free radical damage.⁷

In this study, 11 of 18 patients (61.1%) with high levels of liver iron had at least 1 other risk factor for the development of future cardiac dysfunction (either anthracycline exposure, radiation to the chest or total body irradiation or both). Larger studies are needed to determine whether oncology patients with high levels of iron deposition in their liver are also at risk for clinically significant cardiac iron loading, and what risk factors may exist for elevated myocardial iron content. Although the cardiac iron content in this study was low, in combination with other cardiotoxic therapies, the presence of myocardial iron deposition may contribute to dysfunction over time.