Abstract

Heart is the target lethal organ for iron accumulation in thalassemia major. Currently, magnetic resonance imaging (MRI) is the only non-invasive method with the potential to assess myocardial iron. MRI T2* has proven to be a fast, simple, robust and clinically useful tool for the assessment of cardiac iron load. In chelated patients, myocardial iron is usually inversely related to compliance with chelation while there is no meaningful correlation with liver iron and serum ferritin concentration measured at the time of T2* assessment. However, in a subset of patients, myocardial iron overload occurs despite an history of good compliance with chelation therapy, suggesting the possible role of genetic factors. Several gene polymorhisms including apolipoprotein epsylon and HLA haplotypes have been described as protective or predisposing factors for cardiac iron dysfunction. Wu et al. (2006) analyzed polymorphisms of two endogenous antioxidant enzymes, glutathione S-transferase M1 (GSTM1) and glutathione S-transferase T1 (GSTT1). They found that the GSTM1 null (deleted) genotype was associated with a decreased signal intensity ratio on MRI, suggesting that genetic variations of the GSTM1 enzyme are associated with cardiac iron deposition. The aim of the current study was to evaluate if the GSTM1 null genotype is a predisposing factor for myocardial iron overload in thalassemia major patients on chelation treatment with desferrioxamine with low body iron load as assessed by serum ferritin levels. Allelic distribution of wild and null GSTM1 genotype was assessed in 24 patients with thalassemia major in whom the severe myocardial iron overload (T2* <10 msec) was unexpected based on low body iron load (mean of lifelong serum ferritin determinations 1360 ± 268 ng/ml), and in 26 thalassemia patients in whom the myocardial iron overload was expected based on high body iron load (mean of lifelong serum ferritin determinations 4724 ± 1530 ng/ml). Twenty-six healthy subjects were analyzed as controls. We found that the GSTM1 null genotype was more frequent in thalassemia patients with unexpected myocardial iron load (p=0.02) than in patients with expected myocardial iron load (Table 1). The presence of the GSTM1 null genotype can therefore explain in part the development of severe myocardial iron overload in thalassemia major patients who have been adequately chelated since their first years of life. Based on the inhibition of the cardiac ryanodine receptor calcium channels by members of the glutathione transferase structural family, and given the little difference in permeability among divalent cations in those channels, we hypothesized that the deletion of GSTM1 is associated with increased entry of iron into the myocites, in patients with thalassemia major. Further studies are needed to understand the mechanisms that underlie the association between GSTM1 gene polymorphisms and predisposition to myocardial iron overload.

Table 1.

Allelic distribution of wild and null GSTM1 genotype in beta thalassemia patients with expected and unexpected heart iron overload, and in 26 healthy controls

GSTM1 wildGSTM1 wildGSTM1 nullGSTM1 null
n%n%
χ2 test : A vs C p>0.05; A vs B p=0.02; B vs C p=0.04 
A. Thalassemic patients with expected heart iron overload 17 65.4 34.6 
B. Thalassemic patients with unexpected heart iron overload 33.3 16 61.5 
C. Healthy controls 16 61.5 10 38.4 
GSTM1 wildGSTM1 wildGSTM1 nullGSTM1 null
n%n%
χ2 test : A vs C p>0.05; A vs B p=0.02; B vs C p=0.04 
A. Thalassemic patients with expected heart iron overload 17 65.4 34.6 
B. Thalassemic patients with unexpected heart iron overload 33.3 16 61.5 
C. Healthy controls 16 61.5 10 38.4 

Author notes

Disclosure: No relevant conflicts of interest to declare.