Background: Transfusion-dependent-thalassemia (TDT) is the most severe clinical presentation of β-thalassemia. It is characterized by extremely diverse clinical manifestations, further complicated by the inclusion in TDT group of the patients with TI patients who started regular transfusion in adult age. Determination of factors causing such a diverse clinical presentation has clinical significance. Aims: Our study aimed to investigate if the presence of a β°/β° homozygous genotype was associated to increased iron overload and rate of complications. Methods: We considered 747 TDT patients enrolled in the Myocardial Iron Overload in Thalassemia (MIOT) project. Magnetic Resonance Imaging (MRI) was used to quantify iron overload (T2∗ technique), biventricular morphological and functional parameters (cine sequences), and the presence of myocardial fibrosis (late gadolinium enhancement-LGE technique). All complications were classified according to international guidelines. Results: Two groups of patients were identified: non homozygous β°/β° genotype (N = 493) and homozygous β°/ β° genotype (N = 254). No significant differences for sex was found between the groups while the homozygous β°/β° group was significantly older (30.8 ± 8.9 yrs vs 29.1 ± 9.4 yrs; P = 0.009) and showed a significant higher frequency of transfusions in the past 12 months (41.7 ± 11.8 vs 37.4 ± 11.2; P < 0.0001). Mean haemoglobin levels, serum ferritin levels, liver transaminases and MRI liver iron concentration (LIC) values were comparable between the groups. Patients with homozygous β°/β° genotype had a significant higher frequency of liver fibrosis, also adjusting for age (12.4% vs 3.2%; P = 0.015). The homozygous β°/β° group showed significantly lower global heart T2∗ values (26.6 ± 13.0 ms vs 30.1 ± 11.6 ms; P = 0.001) and a higher number of patients with a global heart T2∗ value<20 ms (33.1% vs 21.3%; P < 0.0001). Left ventricular (LV) stroke volume index was significantly lower in the homozygous β°/β° group, also adjusting for age and number of transfusions (52.1 ± 10.1 ml/m2 vs 54.4 ± 11.7 ml/m2; P = 0.001). No difference between groups was detected in terms of frequency of diabetes, osteoporosis, hypogonadism, and hypoparathyroidism while frequency of hypothyroidism was significantly higher in the homozygous β°/β° group, also adjusting for age (23.4% vs 13.5%, P = 0.004) Frequency of heart failure was comparable between groups while the frequency of arrhythmias was significantly higher in the homozygous β°/β° group (7.8% vs 1.9%; P = 0.001). Summary/Conclusion: Patients with β°/β° homozygous genotype had more cardiac iron and showed an higher frequency of liver fibrosis, hypothyroidism, and arrhythmias. These data support the knowledge of different phenotypic groups in the management of TDT patients.

Abstract Introduction The MIOT (Myocardial Iron Overload in Thalassemia) Network was a network of thalassemia and CMR centers built in 2006 in order to assure homogeneous and standardized cardiac iron overload assessment for a significant number of patients. Purpose We describe the impact of this ten-year Network on cardiac iron, complications and deaths in patients with thalassemia major (TM). Methods 1746 TM patients (911 F; age 31.17±9.09 yrs) were enrolled in the MIOT Network. Myocardial iron overload (MIO) was quantified by the multislice multiecho T2* technique. Biventricular function was quantified by cine images. Results 1392 TM patients performed an end-of-study CMR. At the last CMR significantly higher global heart T2* values (35.44±10.69 ms vs 29.16±12.02 ms; P<0.0001) and a significant lower number of patients with global heart T2*<20 ms (26.3% vs 12.0%; P<0.0001) were detected. Four patterns of MIO were identified: no MIO (all segments with T2*≥20 ms), heterogeneous MIO and global heart T2*≥20 ms, heterogeneous MIO and global heart T2*<20 ms, and homogeneous MIO (all T2*<20 ms). At the last CMR a significant higher frequency of patients with no MIO and a significant lower frequency for the other three patterns indicating MIO were found (Figure 1). In patients with global heart T2*<20 ms a significant increase in left ventricular ejection fraction (EF) (difference: 3.2±8.5%, P<0.0001) as well as in right ventricular EF (difference: 1.2±8.9%, P=0.002) were detected. Based on CMR results the 75% of the patients changed the chelation therapy. At the last CMR the percentage of patients with an excellent/good compliance was significantly higher (94.8% vs 92.2%%; P<0.0001). The complete history of cardiac complications-CC (heart failure, arrhythmias, pulmonary hypertension, myocardial infarction, angina, myo/pericarditis, peripheral vascular disease) was present for 1062 patients. Out of the 1001 patients with resolved CC or without CC before the enrolment in the project, the 6.6% had a CC before the enrolment in the project. During the study, the frequency of CC was 4.4%, significantly lower (P=0.023). In particular, the frequency of heart failure (HF) was significantly lower (3.5% vs 0.8%, P<0.0001). Forty-six patients died during the study. HF continues to be the leading cause of death (30.4% of all causes), but there was a consistent decline in HF mortality rate, that was 60.2% in an Italian study dated 2004. No patients died for arrhythmias while cancer was the second leading cause of death. Conclusion Over a period of 10 years, the continuous monitoring of cardiac iron levels and a tailored chelation therapy allowed a reduction of MIO in the 70% of patients, with consequent improvement of cardiac function and reduction of cardiac complications and mortality from MIO-related HF. So, a national networking was effective in improving the care and reducing cardiac outcomes of TM patients.

Introduction. T2* measurement of myocardial iron overload (MIO) is presently the gold standard for monitoring and tailoring the chelation in thalassemia patients. Native T1 mapping has been proposed also for the MIO quantification because it is known that iron can reduce native T1 values. No data are available in literature comparing T1 and T2* mapping using a segmental approach including the whole left ventricle. The goal of our study was to assess the relationship between T1 and T2* values using a segmental approach.