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Background We compared cardiovascular magnetic resonance segmental native T1 against T2* values for the detection of myocardial iron overload (MIO) in thalassaemia major and we evaluated the clinical correlates of native T1 measurements. Methods We considered 146 patients (87 females, 38.7 ± 11.1 years) consecutively enrolled in the Extension-Myocardial Iron Overload in Thalassaemia Network. T1 and T2* values were obtained in the 16 left ventricular (LV) segments. LV function parameters were quantified by cine images. Post-contrast late gadolinium enhancement (LGE) and T1 images were acquired. Results 64.1% of segments had normal T2* and T1 values while 10.1% had pathologic T2* and T1 values. In 526 (23.0%) segments, there was a pathologic T1 and a normal T2* value while 65 (2.8%) segments had a pathologic T2* value but a normal T1 and an extracellular volume (ECV) ≥ 25% was detected in 16 of 19 segments where ECV was quantified. Global native T1 was independent from gender or LV function but decreased with increasing age. Patients with replacement myocardial fibrosis had significantly lower native global T1. Patients with cardiac complications had significantly lower native global T1. Conclusions The combined use of both segmental native T1 and T2* values could improve the sensitivity for detecting MIO. Native T1 is associated with cardiac complications in thalassaemia major.

Background In 2004 seven Italian centers reported survival data for patients with thalassemia major (TM) and showed that heart disease due to iron overload was the most common cause of death (Borgna et al Haematologica 2004). In the same years the accurate and noninvasive assessment of cardiac siderosis was made possible in Italy by the introduction of the T2* cardiovascular magnetic resonance (CMR). We aimed to evaluate if the deployment of T2* CMR had an impact on the mortality rate.

Background In thalassemia intermedia (TI) patients no observational study prospectively evaluated in the real life the efficacy of the desferrioxamine (DFO) therapy in removing or preventing myocardial iron overload. The efficacy endpoint of this study is represented by the changes in cardiac T2* values and left ventricular (LV) function parameters in non-transfusion dependent (NTD) TI patients after 18 months of desferrioxamine therapy.

Background Recently two novels indicators of left ventricular (LV) performance assessed by Cardiovascular Magnetic Resonance (CMR) have been introduced: the LV global function index (LVGFI) and the LV mass/volume ratio (LVMVR). The LVGFI combines LV stroke volume, end-systolic and end diastolic volumes, as well as LV mass, integrating structural as well as mechanical behaviour. Elevated LVMVR is indicative of concentric remodelling. A LVGFI 1 were shown to be associated with the occurrence of cardiovascular events in no-thalassemic populations. This retrospective cohort study aimed to systematically evaluate in a large historical cohort of thalassemia major (TM) in the CMR era whether the LVGFI and the LVMVR were associated with a higher risk of heart failure.

Results Three groups of patients were identified: 27 patients (13 females, mean age 40.12±10.31 years) treated with desferioxamine (DFO mean dosage 37.52±8.69 mg/kg/ die), 23 patients (14 females, mean age 34.73±10.67 years) treated with deferiprone (DFPdosage 71.70 ±14.46mg/kg/die) and 14 patients (9 females, mean age 36.63±10.92 years) treated with deferasirox (DFX mean dosage 27.75±5.04 mg/kg/die). Excellent/good levels of compliance were similar in the DFO (92.6%), DFP (100%) and DFX (100%) groups (P=0.345). The mean starting age of regular transfusion was 14.73 ±15.89 years. At baseline in DFO group two patients (7.4%) showed a global heart T2*

Background There are no prospective studies comparing the effectiveness of the three iron chelators commercially available in preventing or decreasing iron overload in the heart in pediatric thalassemia major (TM) patients. Our aim was to evaluate the changes in cardiac iron and function by quantitative magnetic resonance imaging (MRI) over a follow-up (FU) of 18 months in pediatric TM patients treated with one of the 3 available iron chelators in monotherapy or non-chelated. Methods Among the first 1611 TM patients enrolled in the MIOT (Myocardial Iron Overload in Thalassemia) network, we considered pediatric patients who had maintained the same chelation regimen between the two MRI scans. Myocardial iron overload (MIO) was quantified by a multislice multiecho T2* sequence. Biventricular function parameters were evaluated by cine images. Due to the low sample size, no inter-treatment comparisons were performed.

Poster: "ESCR 2014 / 415 / Prognostic CMR parameters for heart failure and arrhythmias in large cohort of well treated thalassemia major patients" by: "C. Tudisca1, A. Meloni2, E. Chiodi3, R. Rosso4, A. Carollo5, M. Midiri1, A. Pepe2; 1Palermo/IT, 2Pisa/IT, 3Ferrara/IT, 4Catania/IT, 5Trapani/IT"

Summary The age at which it is necessary to start Cardiovascular Magnetic Resonance (CMR) T2* screening in thalassaemia major (TM) is still uncertain. To clarify this point, we evaluated the prevalence of myocardial iron overload (MIO), function and fibrosis by CMR in TM patients younger than 10 years. We retrospectively selected 35 TM patients enrolled in the Myocardial Iron Overload in Thalassaemia network. MIO was measured by T2* multislice multiecho technique. Biventricular function parameters were evaluated by cine images. To detect myocardial fibrosis, late gadolinium enhancement images were acquired. Patients’ age ranged from 4 2t o 97 years. All scans were performed without sedation. Nine patients showed no MIO, 22 patients had heterogeneous MIO with a T2* global value ≥20 ms; two patients had heterogeneous MIO with a T2* global value

Results One-hundred and eighty-eight (74.6%) patients showed no MIO in any segment, 56 (22%) had an heterogeneous distribution (52 with global heart T2*≥20 ms), and 8 (0.3%) showed an homogeneous MIO. Left ventricular (LV) and right ventricular (RV) dilatations were present in 113 (45%) and in 49 (19%) patients, respectively. LV dysfunction was present in the 18.0% of the cases while RV dysfunction in the 3.63%. High LV mass indexes were present in 22 (8.7%) patients. Fifty-two/227 (22.9%) patients showed myocardial fibrosis. Myocardial fibrosis was associated to LV dysfunction (P = 0.001) and high mass indexes (P = 0.038). One-hundred and fourteen patients were non-transfusion dependent (transfusion requirements absent or sporadic) while 138 patients were transfusion-dependent (regular transfusions). The mean age at start of chronic transfusions was 11.8 ± 12.3 years. Table 1 shows the comparison between the two groups. Non-transfusion-dependent patients showed significantly higher global heart T2* values and MIO with a global heart T2* < 20 ms was detected in two of them (one requiring occasional blood transfusions and one non transfused). Biventricular end-diastolic volume index, stroke volume index, left ventricular (LV) mass index, and LV cardiac index were significantly higher in the non-transfusion dependent group.

Background CMR R2* is the gold standard for monitoring cardiac iron overload in patients with hemoglobinopathies. The R2* value is obtained by fitting the signal at different echo times (TEs) to an appropriate decay model. Patients with heavy cardiac iron burden (R2*>100 Hz) exhibit rapid signal, leading to a plateau in the later images. Two approaches have been used to address this. The first one (truncation model) consists in discarding the late “plateau” points and fitting the remaining ones with a single exponential model. The second approach is to fit the signal to an exponential decay plus a constant offset (Exp-C). We aimed to determine whether systematic differences were present between R2* values obtained with these two approaches. Methods Single-center cohorts were used to compare black blood and bright sequences separately and a multi-center cohort of mixed bright and black blood studies was used to compare robustness and generalizability of the comparison. The R2* value within a region of interest (ROI) drawn in mid-ventricular septum was assessed using each of the two methods in turn. Truncated exponential estimates were calculated with CMRTools that uses a region-based approach (R2*CMRTools). Exp-C estimates were calculated using a rapid pseudo-pixelwise (PPW) implementation written in MATLAB. The mean and the median (R2*PPW-mean and R2*PPW-median) from the R2* distribution were obtained. To distinguish whether differences in measured R2* values resulted from the underlying fitting model or from the use of a PPW rather than a region-based approach, we performed Exp-C fits to a single ROI (R2*PPW-ROI_based). Results Table 1 shows the results for the two methods. No differences could be distinguished based upon whether a white or black blood sequence was examined. The two fitting algorithms gave similar R2* values, with R-squared values exceeding 0.997 and CoV of 3-4%. Results using the PPW method yielded a small systematic bias that became apparent in patients with severe iron deposition. This disparity disappeared when Exp+C fitting was used on a single ROI suggesting that the use of pixelwise mapping was responsible for 3% bias. In the multicenter cohort the strong agreement between R2* values obtained with the two approaches was reconfirmed. Conclusions Cardiac R2* values are independent of the signal model used for its calculation over clinically relevant ranges; pixelwise fitting generate insignificantly greater R2* estimates at high iron concentrations. The overall variability between the techniques is exceeding small allowing clinicians to compare results with confidence.

Background Thalassemia intermedia (TI) patients were shown to have significantly higher cardiac output and cardiac volumes with respect to thalassemia major (TM) patients. So, to compare biventricular parameters in TI patients with established ranges from TM may be misleading. The aim of this study was to establish the ranges for normal biventricular volumes and ejection fraction (EF) and for left ventricular (LV) mass assessed by cardiovascular magnetic resonance (CMR) in TI.

Background Combination therapy with deferipron and desferrioxamine (DFP+DFO) seems more effective than DFP and DFO in monotherapy in removing myocardial iron. However, no data are available in literature about prospective comparisons on cardiac iron and function in TM patients treated with DFP+DFO versus DFP and DFO in monotherapy. Aim: The aim of this multi-centre study was to assess prospectively in a large clinical setting the efficacy of the DFP+DFO versus DFP and DFO in TM patients by quantitative MR. Methods

5293 Introduction. Cardiovascular Magnetic Resonance (CMR) has provided the opportunity to quantify right ventricular (RV) parameters with excellent reproducibility and accuracy. The role of the RV is gaining ground in thalassemia major (TM) patients and this population could experience different “normal” RV values due to chronic anemia and eventually pre-existing iron burdens. The aim of this study was to establish the ranges for normal RV volumes, mass and ejection fraction (EF) normalized to the influence of body surface area (BSA), age and sex from CMR in a large cohort of well-treated TM patients without myocardial iron overload. Methods. Among the 923 TM patients enrolled in the Myocardial Iron Overload (MIOT) network who underwent CMR for the assessment of cardiac iron overload, function and fibrosis, we selected 142 patients with no known risk factors or history of cardiac disease, normal electrocardiogram, no myocardial iron overload (all the cardiac segments with a normal T2* value) and no myocardial fibrosis. All patients had been regularly transfused and chelated since early childhood. Moreover, we studied 71 healthy subjects matched for age and sex. RV function parameters were quantitatively evaluated in a standard way by SSFP cine images using MASS® software. RV end-diastolic volume (EDV), end-systolic volume (ESV) and stroke volume (SV) were normalized by body surface area (EDVI, ESVI, SVI). Results. The table shows the comparison of the CMR parameters with differentiation for sex and age in TM patients and healthy subjects and the cut-off of normality defined as mean – 2 standard deviation (SD). TM patients showed significantly lower BSA than the controls (P Conclusion. In a large cohort of well-treated TM patients males showed significantly higher RV EF compared to controls. Due to the influence of BSA, sex and age, appropriate “normal” reference ranges normalized to these variables should be used to avoid misdiagnosis of cardiomyopathy in the clinical arena in TM patients. Disclosures: No relevant conflicts of interest to declare.

Cardiovascular Magnetic Resonance (CMR) allows an accurate and reproducible quantification of left ventricular (LV) parameters. In Thalassemia major (TM) patients have been reported different “normal” LV values due to chronic anemia and eventually pre-existing iron burdens. Moreover, in this population it is unknown the influence of sex and age on LV parameters and no ranges of normal have been reported using MASS® software. The aim of this study was to establish the ranges for normal LV volumes, mass and ejection fraction normalized to the influence of body surface area(BSA), age and sex from CMR in a large cohort of well-treated TM patients without myocardial iron overload.

Introduction In thalassemia patients heart failure remains the main cause of mortality. High cardiac output state due to chronic anaemia is a significant determinant of cardiomyopathy, in particular in thalassemia intermedia (TI) patients (a moderate form, not transfusion dependent). Hypoxia and volume overload are known stimuli for plasma N-terminal fragment of proBNP (NT-proBNP) raise. Nevertheless, NT-proBNP role in clinical management of thalassemia patients has not been fully investigated.

ss Open Acce Oral presentation Myocardial fibrosis by delayed enhancement cardiovascular magnetic resonance and HCV infection in thalassemia major patients Alessia Pepe1, Antonella Meloni1, Zelia Borsellino2, Maria Chiara Dell'Amico1, Vincenzo Positano1, Caterina Borgna-Pignatti3, Aurelio Maggio4, Gennaro Restaino5, Francesco Gagliardotto2, Paolo Cianciulli6, Luciano Prossomariti7, Aldo Filosa7, Michele Centra8, Domenico D'Ascola9, Antonella Quarta10, Angelo Peluso11, Antonello Pietrangelo12, Eliana Cracolici13, Massimo Lombardi*1 and Marcello Capra2

Introduction Cardiac complications are the main cause of morbidity and mortality in thalassemia major (TM). In particular, thalassemic cardiomyopathy include forms with right involvement difficult to detect by usual approach, whereas early diagnosis could permit early treatment and improvement in prognosis. Plasma N-terminal fragment of proBNP (NT-proBNP) concentration holds a known value in asymptomatic cardiac patients, too, but its usefulness in the management of TM has not been fully investigated.

ss Open Acce Poster presentation Cramer-Rao lower bounds for precision in T2* assessment for myocardial iron overload measurements by T2* multi-echo CMR Vincenzo Positano*1, Antonella Meloni1, Alessia Pepe1, Maria Filomena Santarelli1, Daniele De Marchi1, Luca Menichetti1, Chiara Dell'Amico1, Brunella Favilli1, Matteo Milanesi1, Gianluca Valeri2, Luigi Natale3, Cristina Tassi4, Tommaso Casini5, Luigi Landini1 and Massimo Lombardi1

Background Cardiovascular Magnetic Resonance (CMR) by late gadolinium enhancement (LGE) allows to detect myocardial fibrosis. Myocardial fibrosis was shown to be a relative common finding in large cohort of Italian thalassemia major (TM) patients mainly related to HCV infection, but specific studies involving only pediatric patients are not available. Our aim was to investigate the prevalence and clinical-instrumental correlates of myocardial fibrosis in pediatric TM patients.

Background Movement abnormalities in the left ventricle (LV) were shown to be not really frequent in thalassemia major (TM) patients but they were associated with age, myocardial iron overload, LV dilation and dysfunction, and myocardial fibrosis. No data are available about the prevalence and the correlates of right ventricular (RV) wall motion abnormalities. This study investigated the relationship between RV and LV motion abnormalities and between RV motion and function in a large cohort of well-treated TM patients. Methods CMR was performed in 1092 TM patients (537 male; 30.6 ± 8.5 years) enrolled in the Myocardial Iron Overload in Thalassemia (MIOT) Network. Cine images were acquired to evaluate wall motion and to quantify RV volumes and ejection fraction (EF). Results

Background: Due to the limited data available in literature, the aim of this multi-centre study was to prospectively compare in thalassemia major (TM) patients the efficacy of combined deferiprone (DFP) and deferoxamine (DFO) regimen versus either DFP and DFO in monotherapy by cardiovascular magnetic resonance (CMR) over a follow up of 18 months. Methods: Among the first 1135 TM patients in the MIOT (Myocardial Iron Overload in Thalassemia) network, we evaluated those who had received either combined regimen (DFO + DFP, N=51) or DFP (N=39) and DFO (N=74) monotherapies between the two CMR scans. Iron overload was measured by T2* multiecho technique. Biventricular function parameters were quantitatively evaluated by cine images. Results: The percentage of patients that maintained a normal global heart T2* value was comparable between DFP+DFO versus both monotherapy groups. Among the patients with myocardial iron overload at baseline, the changes in the global heart T2* and in biventricular function were not significantly different in DFP+DFO compared with the DFP group. The improvement in the global heart T2* was significantly higher in the DFP+DFO than the DFO group, without a difference in biventricular function. Among the patients with hepatic iron at baseline, the decrease in liver iron concentration values was significantly higher with combination therapy than with either monotherapy group. Conclusions: In TM patients at the dosages used in the real world, the combined DFP+DFO regimen was more effective in removing cardiac iron than DFO, and was superior in clearing hepatic iron than either DFO or DFP monotherapy. Combined therapy did not show an additional effect on heart function over DFP.

Background Chronically anemic patients develop compensatory ventricular dilation, even when maintained on chronic transfusion regimens. Our primary goal was to compare right and left ventricular dimensions and function assessed by Cardiovascular Magnetic Resonance (CMR) in pediatric, chronically-transfused sickle-cell disease (SCD) and thalassemia major (TM) patients who lacked cardiac iron. Moreover we explored systematic sex differences in ventricular dimensions in both populations. Methods We reviewed all CMRs identifying 261 studies suitable for analysis from 64 SCD patients (34 females and 30 males) and 49 TM patients (29 males and 20 females). All demographic and CMR parameters were inversely weighted by the number of exams. Analysis of covariance (ANCOVA) models were used to evaluate the impact of potential covariates (variables unbalanced between groups and associated with the outcome) on group differences in CMR parameters. Results In both populations, males had larger left ventricular (LV) and right ventricular (RV) dimensions than females, with a more marked effect observed in SCD patients. The percentage difference for the RV was larger than that one seen in normal subjects (from 8 to 14%). Table 1 shows the comparison of LV parameters between SCD and TM with the differentiation by sex. All LV volumes as well as the LV mass were significantly higher in SCD than in TM patients, also adjusting for the covariates. Table 2 shows the comparison of RV parameters between SCD and TM, by sex. Overall findings are similar to those from the LV. All RV volumes remained significantly higher in SCD also after ANCOVA adjustments, except RV ESVI. Conclusions Compared to TM patients, SCD patients showed significantly greater biventricular dilation and LV hypertrophy. This difference could not be explained by different hemoglobin levels, cardiac iron overload and systolic blood pressure. Our results represent important baseline findings that place changes introduced by iron overload as well as systemic and pulmonary vasculopathy in proper context.

Background Aortic pulse wave velocity (PWV) is considered as the “gold standard” measurement of arterial stiffness and is commonly calculated as the ratio between the distance separating two locations along the artery and the transit time (Δt) needed for the pressure or velocity wave to cover this distance. PWV is increasingly assessed by means of cardiovascular magnetic resonance (CMR). Our goal was evaluate the efficiency of a novel method for Δt estimation, based on the principle of group delay (TT-GD method).

Excellent/good levels of compliance were similar in the 3 groups (DFX 99%, DFP 95%; DFO 96%, P =0 .6). There were no significant differences in all 3 groups to maintain the patients without significant myocardial iron overload (global heart T2*≥20 ms) (DFX 98%; DFP 100%; DFO 98%; P=1.0). The percentage of patients that maintained a normal LVEF (>57%) was significantly lower in DFX (77%) versus DFP (100%) (P=0.018), it was no significantly different in DFX and DFO group (82%) (P=0.59). Among the patients with myocardial iron overload at baseline in all 3 groups, there was a significant improvement in the global heart T2* value and in the number of segment with a normal T2* value; only in the DFP group there was a significant improvement in the right global systolic function (+ 6.8% P =0.016). The improvement in the global heart T2* was significantly lower in the DFX versus the DFP group (P=0.0026), but it was not significantly different in the DFX versus the DFO group (mean difference global heart T2* 3.5±4.7 ms versus 8.8±8.6 ms and versus 3.7±5.5 ms, respectively; P=0.90) (Figure 1). The changes in the global systolic biventricular function were not significantly different among groups. Conclusions

Background Magnetic resonance (MR) tagging analyzed by dedicated tracking algorithms allows very precise measurements of myocardial motion and characterization of regional myocardial function. No extensive data are available in literature. Our aim was to quantitatively assess for the regional myocardial contractility in thalassemia major (TM) patients and to correlate it with heart iron overload and global biventricular function. Methods

while one showed cardiac iron (global heart T2*=12.3 ms). Due mainly to technical reasons, biventricular function was assesses at both baseline and FU MRIs in 22 patients. At baseline 6 patients showed a reduced left ventricular ejection fraction (LVEF) and 4 of them recovered at the FU. All patients had a baseline global heart T2*>20 ms (one with 2 segmental T2* values

ss Open Acce Poster presentation MRI assessment of correlation between cardiac biventricular function, myocardial iron overload and pancreatic iron overload in a large cohort of thalassemia major patients Gennaro Restaino*1, Antonella Meloni2,3, Vincenzo Positano2, Massimiliano Missere1, Caterina Borgna Pignatti4, Aurelio Maggio5, Marcello Capra6, Antongiulio Luciani7, Gianluca Valeri8, Giuseppina Sallustio1 and Alessia Pepe2

Background The relationship between diabetes mellitus (DM) and cardiac complications has never been systematically studied in thalassemia major (TM). The aim of this crosssectional study was to evaluate in a large historical cohort of TM in the cardiovascular magnetic resonance (CMR) era if DM was associated with an higher prevalence and risk of heart complications, also regardless to the presence of myocardial iron overload (MIO). Methods We compared 86 TM patients affected by DM with 709 TM patients without DM enrolled in the Myocardial Iron Overload in Thalassemia (MIOT) network at their first CMR. The MIOT network involves 68 thalassemia centers and 8 CMR sites where the exams are performed using standardized and validated procedures and all centers are linked to a web-based database to collect and share patients’ history, clinical and diagnostic data. Cardiac iron was evaluated by T2* multiecho multislice technique. Biventricular function parameters were quantitatively evaluated by cine images. Myocardial fibrosis was evaluated by late gadolinium enhacement CMR technique. Heart failure (HF) was diagnosed by CMR in presence of a left ventricular (LV) and/or right ventricular (RV) ejection fraction (EF) lower than 4 standard deviations from the mean value normalized by sex and age. Moreover HF was identified by patients’ history, diagnosed by clinicians based on symptoms, signs and echocardiographic findings. All considered cardiac events were developed after the DM diagnosis. Results In DM patients versus no-DM patients we found a significantly higher prevalence of cardiac complications (HF, arrhythmias and pulmonary hypertension) (46.5% vs 16.9%, P