Date Published: February 21, 2018
Publisher: Public Library of Science
Author(s): Camilla Torlasco, Elena Cassinerio, Alberto Roghi, Andrea Faini, Marco Capecchi, Amna Abdel-Gadir, Cristina Giannattasio, Gianfranco Parati, James C. Moon, Maria D. Cappellini, Patrizia Pedrotti, Wolfgang Rudolf Bauer.
Iron overload-related heart failure is the principal cause of death in transfusion dependent patients, including those with Thalassemia Major. Linking cardiac siderosis measured by T2* to therapy improves outcomes. T1 mapping can also measure iron; preliminary data suggests it may have higher sensitivity for iron, particularly for early overload (the conventional cut-point for no iron by T2* is 20ms, but this is believed insensitive). We compared T1 mapping to T2* in cardiac iron overload.
In a prospectively large single centre study of 138 Thalassemia Major patients and 32 healthy controls, we compared T1 mapping to dark blood and bright blood T2* acquired at 1.5T. Linear regression analysis was used to assess the association of T2* and T1. A “moving window” approach was taken to understand the strength of the association at different levels of iron overload.
The relationship between T2* (here dark blood) and T1 is described by a log-log linear regression, which can be split in three different slopes: 1) T2* low, <20ms, r2 = 0.92; 2) T2* = 20-30ms, r2 = 0.48; 3) T2*>30ms, weak relationship. All subjects with T2*<20ms had low T1; among those with T2*>20ms, 38% had low T1 with most of the subjects in the T2* range 20-30ms having a low T1.
In established cardiac iron overload, T1 and T2* are concordant. However, in the 20-30ms T2* range, T1 mapping appears to detect iron. These data support previous suggestions that T1 detects missed iron in 1 out of 3 subjects with normal T2*, and that T1 mapping is complementary to T2*. The clinical significance of a low T1 with normal T2* should be further investigated.
Iron overload-related heart failure is the principal cause of death in transfused Thalassemia Major (TM) and other iron overload patients. [1,2] Iron toxicity is dose dependent so a strategy of chelation therapy titration against measured iron dose [3,4] before the onset of left ventricle (LV) impairment improves outcomes.  The presence of iron in tissues determines microscopic magnetic field inhomogeneity and thus changes the magnetic properties of water, T1, T2 and T2*. This has been validated against tissue in animal and human models. [6,7,8] To date, T2* has been the most used technique to non-invasively assess cardiac iron load. T2* would be normal above 40ms ([Fe] = 0.50mg/g dw; ex-vivo calibration)  but in practice, a threshold of 20ms ([Fe] = 1.1mg/g dw, 2x normal) is used to avoid false positives. A higher threshold would reduce accuracy, because T2* at low iron levels has sensitivity to non-iron influences (susceptibility artefact). This is reflected by the exponential T2* standard deviation (SD) relationship with increasing T2*, meaning an increased inter-operator variability for T2*>20ms.  These technical limitations persist in spite of the development of a dark blood T2* sequence (DBT2*), which has been demonstrated to be more reproducible and accurate than the older bright blood T2* (BBT2*).  With DBT2*, a double inversion recovery pulse is used to null the signal from blood and the multi-echo T2* images are acquired in late diastole, when cardiac motion is negligible.  Also, T2* used to require post processing, but a new free-breathing T2* mapping using respiratory motion corrected averaging has recently been developed. [13,14]
All participants provided written informed consent for the study, approved by IRCCS Fondazione Policlinico CA’ Granda Ethics Committee. The study was conducted accordingly to the 1975 Helsinki Declaration.
All subjects underwent CMR without complications. Two patients and no HVs were excluded due to artefact in more than one sequence: DBT2* n = 3 (2%); BBT2* n = 4 (3%) and T1 n = 1 (<1%). Table 1 illustrates patients’ and HV’s characteristics. Raw data available at S1 File. This paper provides novel information on a different ability of T1 and T2* in detecting cardiac iron overload. The internationally accepted cut-point for iron load assessment by T2* of 20ms is known to be conservative–prioritising specificity over sensitivity. In our study T1 mapping trebles the number of patients diagnosed with cardiac iron overload, while T2* missed 2 out of every 3 patients with such an abnormality (Fig 3). The T1 vs T2* curve-fit relationship suggests that the actual T2* cut-point for normality (if T2* were a precise method at low iron levels) would be around 30ms. The value of 20ms was originally set because T2* becomes increasingly influenced by susceptibility artefact as iron levels fall resulting in increasingly poor reproducibility. The availability of a second test, T1 mapping, now further emphasises such a known limitation of T2* and brings new options into the clinical application of cardiac MRI. Source: http://doi.org/10.1371/journal.pone.0192890