Effect of Traditional Heart Failure Risk Factors on Myocardial Dysfunction in Adult Survivors of Childhood Cancer

Childhood cancer treatments, including anthracycline chemotherapy and chest-directed radiotherapy (CDR), are associated with increased risk of late cardiac events (1). However, heart failure (HF) represents end-stage disease with limited potential to change disease trajectory. Our objective was to quantify the relative impact of conventional HF risk factors (HFRFs) on cardiac dysfunction in childhood cancer survivors, in the expectation of guiding clinicians toward appropriate early intervention for these modifiable risk factors.

Participants were recruited from St Jude Children’s Research Hospital for the St Jude Lifetime cohort study (SJLIFE). Patients ≥18 years of age and ≥10 years from diagnosis were included if anthracycline and/or CDR were used for childhood cancer treatment. Based on established associations with incident HF in general population (2); hypertension (systolic blood pressure (BP) >140 mm Hg or diastolic BP >90 mm Hg), insulin resistance (homoeostatic model assessment for insulin resistance (HOMA-IR) > 2.86), obesity (body mass index [BMI] > 30 mg/m²) and smoking status (self-reported current, former or never) were selected as risk factors. Thresholds used for designating abnormal echocardiograms were 3D-EF<53%, global longitudinal strain (GLS) >2 standard deviations from age/sex-based population norms (3), and diastolic dysfunction determined using ASE 2016 criteria(4). HFRFs were evaluated using Bayesian model averaging to automatically select final logistic regression model for testing. All variables underwent univariable analysis, and variables with p≥0.1 were included in multivariable analysis; variables known to be associated with abnormal cardiac function (sex, anthracycline cumulative dose, chest-directed radiotherapy, time since diagnosis, age at diagnosis) were included in separate models for each echocardiography 1outcome. Effect sizes were estimated using the semi-partial omega-square method to measure the adjusted effect as proportion of total variation in the dependent variable. For effect size calculations, indexed left atrial volume (LAVi) was used as a surrogate marker for diastolic dysfunction.

The selected group comprised 1807 participants (48% female; median age 32 years, range 18–66; median interval from diagnosis 23 years, range 10–48; 58% treated with anthracyclines, 17% treated with CDR and 25% with both. On echocardiographic assessment, 14% had 3D-LVEF<53%, 32% had abnormal GLS values and 32% had diastolic dysfunction. Hypertension was associated with abnormal 3D-LVEF (OR 1.82 95%CI 1.25–2.63, p=0.002) and diastolic dysfunction (OR 1.40, 95%CI 1.0.2–1.93], p=0.04). Insulin resistance was associated with abnormal GLS (OR 1.72, 95%CI 1.30–2.27, p<0.001) and diastolic dysfunction (OR 1.43, 95%CI 1.07–1.91, p=0.01). Obesity was associated with abnormal GLS (OR 1.59, 95%CI 1.19–2.13, p=0.002) and diastolic dysfunction (OR 1.92, 95%CI 1.43–2.59, p<0.001). Smoking status was not significantly associated with any echocardiographic abnormality.

Standardized coefficients were estimated to compare the effect size (ES) of the impact of HFRFs with traditional factors (Figure 1). In this aging population, treatment-related risk factors had significant impact on myocardial dysfunction. For example cumulative anthracycline dose significantly affected 3D-LVEF (1.51 × 10⁻² p<0.001) and current age significantly affected GLS (ES 0.20 × 10⁻², p=0.05). In comparison, effect sizes of selected HFRFs were on same order of magnitude or higher. Hypertension significantly affected 3D-LVEF (ES 0.55 X10⁻², p=0.01). Insulin resistance (ES 1.09 × 10⁻², p<0.001), and obesity (ES 9.80 X10⁻², p<0.001) were significantly associated with abnormal GLS. Insulin resistance was associated with abnormal LAVi (ES 0.58 × 10⁻², p=0.04).

Figure 1:

Effect sizes of impact of treatment-related risk factors and conventional HFRFs on A) Systolic function (GLS) and B) diastolic function (LAVi). Anthracycline refers to cumulative anthracycline dose. BMI – Body mass index; CD-RT – Chest Directed Radiotherapy; CTR-RF – Cancer-Therapeutic-Related Risk Factor; GLS – Global Longitudinal Strain; HFRF – Heart Failure Risk Factor; HOMA-IR – Homeostatic Model Assessment Insulin Resistance; HTN – Hypertension.

These results extends prior findings of our group (5) and add new information on the relative impact of traditional HFRFs on subclinical echocardiographic markers of myocardial dysfunction, confirming the clinical relevance of HFRFs in this population and identifying targets for intervention. Effect sizes of several HFRFs were equal or higher than for traditional factors, including cumulative anthracycline dose. Childhood cancer survivors may represent a population that merits more aggressive HFRF management compared with the general population.