Total Body Irradiation (TBI) Increases Cardio-Metabolic Risk and Induces Carotid Vascular Stiffness in Survivors After Hematopoietic Cell Transplant (HCT) for Childhood Hematologic Malignancies.

Cardiovascular disease, hypertension and diabetes all contribute to the increased risk of late non-relapse mortality after HCT and lead to diminished life expectancy compared to the general population. An association between TBI exposure and cardio-metabolic (C-M) risk factors in adult HCT survivors has been described but this association has not been well characterized in children.

Measures of insulin resistance (euglycemic hyperinsulinemic clamp adjusted for lean body mass [Mlbm], low Mlbm represents insulin resistance), fasting glucose, insulin, lipids, anthropometry, blood pressure (BP), and carotid artery compliance and distensibility (lower values represent arterial stiffness) were determined in 106 children and young adults (current age 26.6 yr, 60.4% male) who had received HCT for hematologic malignancy during childhood (mean age at HCT 9.9 yr) and 72 healthy sibling controls (current age 23.7 yr, 51.4% male). Subjects were compared in 3 radiation exposure groups, all received myeloablative preparative regimens; 79 received allogeneic HCT and 27 received autologous HCT. Diagnoses included AML (n=50), ALL (n=30), myelodysplastic syndrome, n=8, Hodgkin's (n=10) and non-Hodgkin's lymphoma (n=8). Sixty two (58.5%) received TBI, 20 (18.9%) received cranial radiation (CRT) prior to TBI (TBI+CRT), and 24 (22.6%) received no TBI or cranial radiation (noXRT) before or during HCT. Linear regression models were used to evaluate risk factors between groups after adjusting for age, gender, pubertal stage, body mass index (BMI), and carotid lumen diameter (stiffness measures only).

Metabolic syndrome (MS) (ATP III criteria for adults, modified criteria for children) was present in 15 (15.6%) HCT survivors and 4 (5.6%) controls (OR 2.3, 95% CI 0.7-7.7, p=0.16). Two or more components of the MS were present in 39 (37.1%) survivors and 10 (14.5%) controls (OR, 2.7, 95% CI 1.2-5.9, p=0.015). Compared to siblings, there were no differences between groups for glucose, BMI, waist circumference, percent body fat, or BP. However, HCT survivors who had TBI or TBI+CRT all had significantly higher cholesterol, LDL cholesterol, triglycerides and insulin. Those who received TBI+CRT had significantly lower HDL cholesterol and were also more insulin resistant (Table). However, for the noXRT group there were no differences in any of the C-M risk factors compared to controls. Carotid artery distensibility was decreased in survivors who received TBI compared to controls with even greater negative impact in those who received TBI+CRT. There was not a significant difference in distensibility in the noXRT group compared to controls. Only the TBI+CRT group had lower compliance compared to controls.

Even at a relatively young age, and independent of obesity, HCT survivors of childhood hematologic malignancies have increased C-M risk factors present as well as adverse vascular changes, which are associated with exposure to TBI +/- CRT. These abnormalities may ultimately contribute to a higher risk of early cardiovascular morbidity and mortality thus early screening and management of modifiable C-M risk factors should be considered in HCT survivors.

No relevant conflicts of interest to declare.