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Number 10-15: T2* CMR to Tailor Chelation Therapy in Thalassemia Major
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Number 10-15: T2* CMR to Tailor Chelation Therapy in Thalassemia Major
                                                     INVITED  CASE

Case from: Alessia Pepe, Vincenzo Positano, Massimo Lombardi
Magnetic Resonance Imaging Unit, Fondazione G Monasterio, CNR Regione Toscana, Pisa, Italy

History: A 35 year old male with beta-thalassemia major, regularly transfused since the age of 30 months, started chelation treatment with subcutaneous desferrioxamine at the age of 4 years. He is currently asymptomatic. Due to his age and the history of poor compliance with the chelation therapy during childhood, he was referred to our unit for quantitative evaluation of myocardial and liver iron load and assessment of biventricular function. The last echocardiogram 6 months prior to the current CMR showed normal LV size and ejection fraction.




Movie 1

CMR I: Standard SSFP cines images (Movie 1) showed a dilated LV (EDVi = 113 ml/m2) with global systolic dysfunction (EF 49%, indicative of a moderate impairment considering the chronic anaemic status of the patient). The RV was borderline in terms of size and ejection fraction. Of note, references ranges for LV function in thalassaemia major patients are different to the usual reference ranges, related to the chronic anaemia.



Movie 2


Cardiac and liver T2* iron load measurements I:

The iron, when present in an intracellular location in the form of haemosiderin, forms focal clusters of magnetic inhomogeneity. The presence of these clusters results in a dramatic reduction in the protons' transverse relaxation time T2*. T2* imaging is accomplished using a breath-hold multiple echo gradient pulse sequence to acquire a series of images with increasing echo times (Movie 2). The mean signal intensity within the region of interest is determined for each image in the series and is then plotted as a function of echo times (Figure 1). T2* values are then calculated by fitting the mean signal intensity data to a decay curve. The higher the slope of the decay curve, the lower the T2* value is, indicating higher iron burden.




Figure 1


In our institution we use the following reference tables for determining iron loading burden (Table 1)



In our patient, heart T2* images to assess iron loading were analyzed using the HIPPO MIOT® software (Movie 2). The bull's eye plot maps into a 2D representation the 3D distribution of the T2* values over the left ventricle. Each ring of the bull's eye corresponds to a short axis slice. The apical slice corresponds to  the internal ring, the basal slices to the external ring. Radial segmentation of the Bull's eye follows the American Heart Association guidelines (6 segments for basal and middle slices, four segments for apical slice).

In this case, there was homogeneous and significant myocardial iron loading as demonstrated by the cardiac T2* measurements with  values < 20 ms in all segments. Global heart T2* showed severe overall myocardial iron loading with a T2* value of 8ms (Figure 1, depicting the decay curve  of the patient related to the heart signal in the mid ventricular septum).

There was also severe liver iron loading as measured by the T2* value of 1.3 ms. Management: Based on the initial CMR findings, the patient was started on an intensive combined chelation treatment with oral deferiprone plus subcutaneous desferrioxamine. 
The patient was referred for a second follow-up CMR 12 months later.



Figure 2


Cardiac and liver T2* iron load measurements II: Heart T2* measurements on the follow-up CMR scan (Figure 2) 12 months later showed a significant reduction of myocardial iron overload. There was still a persistent and homogeneous myocardial iron burden with all cardiac LV segments having T2* values < 20 ms. However, the global heart T2* measurement was 13ms, confirming moderate overall myocardial iron loading, which was improved since the initial evaluation 12 months earlier.
Liver T2* measurements were also significantly improved, with a value of 16 ms on follow-up examination, confirming the near absence of liver iron loading 12 months after the start of the intensive chelation therapy.
CMR II: Standard SSFP cines images on follow up CMR examination 12 months after the initation of the combined chelation therapy showed the persistance of a dilated LV (EDVi =  124 ml/m2). There was however an improvement in the global LV systolic function with an LVEF calculated at 54%, indicating only a mild LV impairment considering the chronic anaemic status of the patient.

Based on the findings of the second CMR study, the patient continued the combination therapy, but at lower doses.



Figure 3


Cardiac and  liver T2* iron load measurements III: Heart T2* measurements on the follow-up CMR scan (Figure 3) 24 months after the initiation of the combined therapy showed a dramatic reduction of the cardiac iron burden, with the absence of myocardial iron loading.  All LV segments showed T2* values > 20 ms, and the global heart T2* measurement was 30 ms (Figure 2).
Similarly, there was no liver iron burden.



Movie 3


CMR III:  Standard SSFP cine images on follow-up CMR examination 24-months after the initiation of the intensive chelation regimen, demonstrated a significant improvement in LV systolic function with an LVEF of 60% (Movie 3).






                                                                   Table 2


Figure 4 compares the normalized decay curve of the patient in the three follow up CMR examinations. The slowing of the signal decay with the increase of the T2* value is well visible.
Table 2
sums up the improvement of the various CMR parameters as iron is removed with the chelation regimen over time.

Given the favorable outcome, the patient has now stopped the combined chelation therapy and is currently continuing iron chelation with oral deferiprone only.

Perspective: T2* CMR represents a unique technique for non invasive, reproducible and serial quantification of myocardial and liver iron burden [1-2]. Serum ferritin levels and liver iron cannot reliably predict myocardial siderosis [3]. CMR allows the detection of pre-clinical cardiomyopathy and enables individually tailored chelation regimes to reduce the likelihood of developing decompensated cardiac failure with its attendant poor prognosis [4].


1) Pepe A, Positano V, Santarelli F, Sorrentino F, Cracolici E, De Marchi D, Maggio A, Midiri M, Landini L, Lombardi M. Multislice multiecho T2* cardiovascular magnetic resonance for detection of the heterogeneous distribution of myocardial iron overload. J Magn Reson Imaging. 2006 May;23(5):662-8.

2) Ramazzotti A, Pepe A, Positano V, Rossi G, De Marchi D, Brizi MG, Midiri M, Valeri G, Sallustio G, Luciani A, Caruso V, Centra M, Cianciulli P, De Sanctis V, Maggio A, Lombardi M. Multicenter validation of the magnetic resonance T2* technique for segmental and global quantification of myocardial iron. J Magn Reson Imaging. 2009 Jun 25;30(1):62-8.

3) Noetzli LJ, Carson SM, Nord AS, Coates TD, Wood JC. Longitudinal analysis of heart and liver iron in thalassemia major. Blood. 2008 Oct 1;112(7):2973-8.

4) Modell B, Khan M, Darlison M, Westwood MA, Ingram D, Pennell DJ. Improved survival of thalassaemia major in the UK and relation to T2* cardiovascular magnetic resonance. J Cardiovasc Magn Reson. 2008;10(1):42.

5) Wood JC, Enriquez C, Ghugre N, Tyzka JM, Carson S, Nelson MD et al. MRI R2 and R2* mapping accurately estimates hepatic iron concentration in transfusion-dependent thalassemia and sickle cell disease patients. Blood. 2005 Aug;106:1460-5.


COTW Handling Editor: Monica Deac


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