Heterogeneity In Regional Myocardial T2* Improvement After Deferiprone Therapy,
Authors: Chih Sharon , Ross Heather J , Nguyen Elsie T , Ward Richard 
Published: October 2019

Abstract
Abstract 3176
Myocardial siderosis is a major cause of death in Thalassemia Major (TM). Intensification of iron chelation therapy (ICT) can reverse cardiac toxicity and improve survival. Cardiac magnetic resonance (CMR) imaging with T2* analysis of a single region of interest (ROI) within the mid septum has been shown to be representative of overall myocardial iron concentration. Histological studies, however, demonstrate heterogeneity in myocardial iron. To date, dynamics of cardiac iron removal by ICT has not been well studied. Deferiprone (DFP) is an effective oral myocardial iron chelator. This study aims to examine patterns of myocardial iron removal by DFP using a 4 segmental CMR T2* approach. All patients receiving DFP for myocardial iron overload at Toronto General Hospital, up until March 2011 were evaluated retrospectively. CMR was performed on a 1.5 Tesla scanner (Siemans, Germany) before and after DFP treatment using a gradient-multi-echo sequence and cardiac gating. 4 to 5 short-axis slices were acquired at 8 echo times (TE) in a single end-expiratory breath hold. T2* analysis was performed using CMR 42 software (Circle software, Calgary, Canada). A basal- and mid-ventricular short axis slice was chosen for analysis. CMR were analyzed by a single observer who remained blinded to the timing of the scans in relation to therapy. CMR were performed on 19 TM patients (37% (n=7) males, mean age 31 years) at an average of 83 days before and 205 days after the commencement of DFP. The average daily dose of DFP was 87mg/kg. 42% (n=8) of patients were on DFP alone and 58% (n=11) were on combination therapy with Deferoxamine (n=10) or Deferasirox (n=1). There was significant variation in myocardial T2* across the 4 regions assessed both before (P<0.001) and after (P=0.001) treatment. Prior to treatment, T2* values were lowest in the mid anteroseptum and highest in the basal inferoseptum (P<0.050) (Figure 1). Following treatment with DFP, T2* values improved significantly across all myocardial regions (P<0.030 for all). The overall median increase in T2* value was 1.6 ms (IQR: −0.2 to 4.5 ms). In the patient subgroup with severe iron overload (baseline T2* ≤10ms; n=11), the improvement in T2* varied across all 4 myocardial regions and showed a trend towards statistical significance (P=0.091). The greatest improvement was observed in the basal inferoseptum (median T2* change 4.8 ms; IQR: 0.0 to 7.2 ms) and the least improvement in the mid anteroseptum (median T2* change 1.1 ms; IQR 0.3 to 4.3 ms) (Figure 2). In this patient subgroup, trends towards significance were also demonstrated for greater improvement in median T2* in the basal (4.5 ms; IQR: 0.6 to 5.9 ms) versus mid septum (2.0 ms; IQR: −0.1 to 5.4 ms, P=0.075) and in the inferoseptum (3.9 ms; IQR: 0.0 to 6.3 ms) versus the anteroseptum (3.1 ms; IQR: 0.4 to 4.4 ms, P=0.084). The data indicate variable regional response to DFP chelation therapy that trended towards statistical significance in patients with severe myocardial iron overload (T2* ≤10 ms). The greatest increase in T2* values was observed in the myocardial region with the highest baseline T2* (basal inferoseptum) while the smallest improvement was seen in the region with the lowest baseline T2* (mid anteroseptum). This suggests that effective chelation may be more challenging in areas with more severe iron deposition. However, there was a non-significant trend to greater increase in T2* across all myocardial regions after treatment in patients with an overall baseline T2* ≤10 ms, versus T2* >10ms. Regional variability in T2* change following DFP therapy has not been previously investigated. Further studies using a multi-segmental T2* analysis approach may improve understanding of the dynamics of iron removal and provide new avenues for optimizing iron chelating regimens to maximize iron removal and improve patient-outcomes.
Figure 1. Median T2* measurements before (clear bar) and after (shaded bar) DFP treatment in each myocardial region (n=19). P<0.001 before treatment and P=0.001 after treatment by Friedman's test. *P<0.050 compared with basal inferoseptum and mid anteroseptum before treatment, †P<0.050 compared with basal inferoseptum after treatment by Dunn's multiple comparisons test. Error bars indicate interquartile ranges. Figure 1. Median T2* measurements before (clear bar) and after (shaded bar) DFP treatment in each myocardial region (n=19). P<0.001 before treatment and P=0.001 after treatment by Friedman's test. *P<0.050 compared with basal inferoseptum and mid anteroseptum before treatment, †P<0.050 compared with basal inferoseptum after treatment by Dunn's multiple comparisons test. Error bars indicate interquartile ranges.
Figure 2. Median change in T2* measurements after DFP for patients with an overall baseline T2* ≤10 ms (n=11). P=0.091 by Friedman's test. Error bars indicate interquartile ranges. Figure 2. Median change in T2* measurements after DFP for patients with an overall baseline T2* ≤10 ms (n=11). P=0.091 by Friedman's test. Error bars indicate interquartile ranges.

Disclosures:
Off Label Use: Deferiprone is an unlicensed drug in Canada and USA. It is an oral iron chelator.