Anthracyline Induced Cardiotoxicity - translational insights

Introduction
Lymphoma survivors are at high risk of treatment related cardio-vascular morbidity and mortality. Anthracycline chemotherapy is one of the major causative factors but accurate methods of identifying patients at risk are lacking. Cardiac magnetic resonance imaging (CMR) can detect subtle changes in myocardial tissue and has the potential to identify subclinical damage at an earlier reversible stage. This study explored whether a combination of novel imaging and existing circulating biomarkers may be more powerful than clinical assessment to risk stratify lymphoma patients for monitoring and intervention.
Methods
30 patients receiving 1st line anthracycline based chemotherapy for lymphoma (doxorubicin) or breast cancer (epirubicin) were recruited December 2012 to May 2013. Patients underwent contrast enhanced CMR (1.5T Philips®) with 0.15mmol/kg gadolinium before, during, after and 1 year following treatment to assess cardiac function, strain and tissue characterisation using T1 and T2 mapping. Pre and post contrast Tl values and haematocrit were used to estimate myocardial extracellular volume (ECV), a surrogate for fibrosis and T2 mapping was used to estimate myocardial oedema. Blood was taken for circulating biomarkers at corresponding time points.
Results
17 patients (57%) experienced significant decline in LVEF over 18 months. Paradoxically an inverse relationship was observed between baseline fibrosis, measured by ECV, and subsequent decline in LVEF suggesting that patients with ‘healthier hearts’ at baseline may be at greatest risk. ECV increased over time in patients with significant LVEF decline but T2 mapping remained unchanged. Greater dyssynchrony (strain rate) at baseline was associated with significant LVEF decline. Longitudinal strain worsened during and after treatment but these changes occurred simultaneously with, and did not precede LVEF decline. Principle component analysis (PCA) combining baseline ECV, strain rate, anthracycline dose, peak trop I and peak MMP9 decline showed distinct clustering of patients.
Conclusions
The ECV findings in this study generated a new hypothesis that fibrosis due to damage from processes such as ageing and ischaemia may slow entry of anthracyclines into myocardial cells, thus limiting exposure. Contrary to current dogma “healthier hearts” may therefore be at greatest risk and the commonly employed clinical assessments (pre-existing cardiovascular risk factors and baseline LVEF) inadequate to identify high risk patients. ECV increased over time in patients with LVEF decline but no significant oedema was seen suggesting that collagen deposition occurs with little overt inflammation. Combining key imaging and circulating biomarkers using a PCA model may be useful in risk stratifying patients for monitoring and intervention but longer follow up is required before any strong conclusions can be drawn.