Multiparametric cardiac magnetic resonance in patients with thalassemia intermedia: new insights from the E-MIOT network.

PURPOSE: In a relatively large cohort of thalassemia intermedia (TI) patients, we systematically investigated myocardial iron overload (MIO), function, and replacement fibrosis using cardiac magnetic resonance (CMR), we assessed the clinical determinants of global heart T2* values, and we explored the association between multiparametric CMR findings and cardiac complications. MATERIALS AND METHODS: We considered 254 beta-TI patients (43.14 ± 13.69 years, 138 females) consecutively enrolled in the Extension-Myocardial Iron Overload in Thalassemia project. MIO was quantified by T2* technique and biventricular function and atrial areas by cine images. Macroscopic myocardial fibrosis was detected by late gadolinium enhancement technique. RESULTS: Compared to never/sporadically transfused patients, regularly transfused (RT)-TI patients exhibited significantly lower global heart T2* values, biventricular end-diastolic volume indexes, left ventricular mass index, and cardiac index. In RT-TI patients, age and serum ferritin levels were the strongest predictors of global heart T2* values. Independently from the transfusional state, cardiac T2* values were not associated with biventricular function. Of the 103 (40.6%) patients in whom the contrast medium was administrated, 27 (26.2%) had replacement myocardial fibrosis. Age, sex distribution, cardiac iron, and biventricular function parameters were comparable between patients without and without replacement myocardial fibrosis. Twenty-five (9.8%) patients had a history of cardiac complications (heart failure and arrhythmias). Increased age and replacement myocardial fibrosis emerged as significant risk markers for cardiac complications. CONCLUSIONS: In TI, regular transfusions are associated with less pronounced cardiac remodeling but increase the risk of MIO. Replacement myocardial fibrosis is a frequent finding associated with cardiac complications.

Longitudinal prospective comparison of pancreatic iron by magnetic resonance in thalassemia patients transfusion-dependent since early childhood treated with combination deferiprone-desferrioxamine vs deferiprone or deferasirox monotherapy.

BACKGROUND: In transfusion-dependent thalassemia patients who started regular transfusions in early childhood, we prospectively and longitudinally evaluated the efficacy on pancreatic iron of a combined deferiprone (DFP) + desferrioxamine (DFO) regimen versus either oral iron chelator as monotherapy over a follow-up of 18 months. MATERIALS AND METHODS: We selected patients consecutively enrolled in the Extension-Myocardial Iron Overload in Thalassemia network who received a combined regimen of DFO+DFP (No.=28) or DFP (No.=61) or deferasirox (DFX) (No.=159) monotherapy between the two magnetic resonance imaging scans. Pancreatic iron overload was quantified by the T2* technique. RESULTS: At baseline no patient in the combined treatment group had a normal global pancreas T2* (≥26 ms). At follow-up the percentage of patients who maintained a normal pancreas T2* was comparable between the DFP and DFX groups (57.1 vs 70%; p=0.517).Among the patients with pancreatic iron overload at baseline, global pancreatic T2* values were significantly lower in the combined DFO+DFP group than in the DFP or DFX groups. Since changes in global pancreas T2* values were negatively correlated with baseline pancreas T2* values, the percent changes in global pancreas T2* values, normalized for the baseline values, were considered. The percent changes in global pancreas T2* values were significantly higher in the combined DFO+DFP group than in either the DFP (p=0.036) or DFX (p=0.030) groups. DISCUSSION: In transfusion-dependent patients who started regular transfusions in early childhood, combined DFP+DFO was significantly more effective in reducing pancreatic iron than was either DFP or DFX.

The impact of HCV chronic positivity and clearance on extrahepatic morbidity in thalassemia major patients: an observational study from MIOT Network.

BACKGROUND: No study has evaluated the effect of hepatitis C virus (HCV) infection on the wide spectrum of complications affecting patients with thalassemia. OBJECTIVES: This multicenter study prospectively assessed the relationship of HCV infection with diabetes mellitus and cardiovascular complications in patients with thalassemia major (TM). METHODS: We considered 1057 TM patients (539 females; 29.79±10.08 years) enrolled in the MIOT Network and categorized into 4 groups: negative patients (group 1a, N=460), patients who spontaneously cleared the virus within 6months (group 1b, N=242), patients who eradicated the virus after the treatment with antiviral therapy (group 2, N=102), and patients with chronic HCV infection (group 3, N=254). RESULTS: Group 1a and 1b were considered as a unique group (group 1). For both groups 1 and 3, a match 1:1 for age and sex with group 2 was performed. The effective study cohort consisted of 306 patients (three groups of 102 patients). During a mean follow-up of 67.93±39.20months, the group 3 experienced a significantly higher % increase/month in aspartate transaminase levels and left ventricular mass index than both groups 1 and 2. The changes in iron overload indexes were comparable among the three groups. Compared to group 1, the chronic HCV group showed a significantly higher risk of diabetes (hazard ratio-HR=5.33; p=0.043) and of cardiovascular diseases (HR=3.80; p=0.034). CONCLUSION: Chronic HCV infection is associated with a significant higher risk of diabetes mellitus and cardiovascular complications in TM patients and should be approached as a systemic disease in which extrahepatic complications increase the weight of its pathological burden.

Pancreatic fatty replacement as risk marker for altered glucose metabolism and cardiac iron and complications in thalassemia major.

OBJECTIVES: This multicenter study assessed the extent of pancreatic fatty replacement and its correlation with demographics, iron overload, glucose metabolism, and cardiac complications in a cohort of well-treated patients with thalassemia major (TM). METHODS: We considered 308 TM patients (median age: 39.79 years; 182 females) consecutively enrolled in the Extension-Myocardial Iron Overload in Thalassemia Network. Magnetic resonance imaging was used to quantify iron overload (IO) and pancreatic fat fraction (FF) by T2* technique, cardiac function by cine images, and to detect replacement myocardial fibrosis by late gadolinium enhancement technique. The glucose metabolism was assessed by the oral glucose tolerance test. RESULTS: Pancreatic FF was associated with age, body mass index, and history of hepatitis C virus infection. Patients with normal glucose metabolism showed a significantly lower pancreatic FF than patients with impaired fasting glucose (p = 0.030), impaired glucose tolerance (p < 0.0001), and diabetes (p < 0.0001). A normal pancreatic FF (< 6.6%) showed a negative predictive value of 100% for abnormal glucose metabolism. A pancreatic FF > 15.33% predicted the presence of abnormal glucose metabolism. Pancreas FF was inversely correlated with global pancreas and heart T2* values. A normal pancreatic FF showed a negative predictive value of 100% for cardiac iron. Pancreatic FF was significantly higher in patients with myocardial fibrosis (p = 0.002). All patients with cardiac complications had fatty replacement, and they showed a significantly higher pancreatic FF than complications-free patients (p = 0.002). CONCLUSION: Pancreatic FF is a risk marker not only for alterations of glucose metabolism, but also for cardiac iron and complications, further supporting the close link between pancreatic and cardiac disease. KEY POINTS: • In thalassemia major, pancreatic fatty replacement by MRI is a frequent clinical entity, predicted by a pancreas T2* < 20.81 ms and associated with a higher risk of alterations in glucose metabolism. • In thalassemia major, pancreatic fatty replacement is a strong risk marker for cardiac iron, replacement fibrosis, and complications, highlighting a deep connection between pancreatic and cardiac impairment.

Myocardial tissue characterization by segmental T2 mapping in thalassaemia major: detecting inflammation beyond iron.

AIMS: We measured myocardial T2 values by a segmental approach in thalassaemia major (TM) patients, comparing such values against T2* values for the detection of myocardial iron overload (MIO), evaluating their potential in detecting subclinical inflammation, and correlating with clinical status. METHODS AND RESULTS: One-hundred and sixty-six patients (102 females, 38.29 ± 11.49years) enrolled in the Extension-Myocardial Iron Overload in Thalassemia Network underwent magnetic resonance imaging for the assessment of hepatic, pancreatic, and cardiac iron overload (T2* technique), of biventricular function (cine images), and of replacement myocardial fibrosis [late gadolinium enhancement (LGE)]. T2 and T2* values were quantified in all 16 myocardial segments, and the global value was the mean of all segments. Global heart T2 values were significantly higher in TM than in a cohort of 80 healthy subjects. T2 and T2* values were significantly correlated. Out of the 25 patients with a decreased global heart T2* value, 11 (44.0%) had reduced T2 values. No patient with a normal T2* value had a decreased T2 value.Eleven (6.6%) patients had a decreased global heart T2 value, 74 (44.6%) a normal global heart T2 value, and 81 (48.8%) an increased global heart T2 value. Biventricular function was comparable amongst the three groups, whilst LGE was significantly more frequent in patients with reduced vs. increased global heart T2 value. Compared with the other two groups, patients with reduced T2 values had significantly higher hepatic and pancreatic iron deposition. CONCLUSION: In TM, T2 mapping does not offer any advantage in terms of sensitivity for MIO assessment but detects subclinical myocardial inflammation.

Left Ventricle Detection from Cardiac Magnetic Resonance Relaxometry Images Using Visual Transformer.

Left Ventricle (LV) detection from Cardiac Magnetic Resonance (CMR) imaging is a fundamental step, preliminary to myocardium segmentation and characterization. This paper focuses on the application of a Visual Transformer (ViT), a novel neural network architecture, to automatically detect LV from CMR relaxometry sequences. We implemented an object detector based on the ViT model to identify LV from CMR multi-echo T2* sequences. We evaluated performances differentiated by slice location according to the American Heart Association model using 5-fold cross-validation and on an independent dataset of CMR T2*, T2, and T1 acquisitions. To the best of our knowledge, this is the first attempt to localize LV from relaxometry sequences and the first application of ViT for LV detection. We collected an Intersection over Union (IoU) index of 0.68 and a Correct Identification Rate (CIR) of blood pool centroid of 0.99, comparable with other state-of-the-art methods. IoU and CIR values were significantly lower in apical slices. No significant differences in performances were assessed on independent T2* dataset (IoU = 0.68, p = 0.405; CIR = 0.94, p = 0.066). Performances were significantly worse on the T2 and T1 independent datasets (T2: IoU = 0.62, CIR = 0.95; T1: IoU = 0.67, CIR = 0.98), but still encouraging considering the different types of acquisition. This study confirms the feasibility of the application of ViT architectures in LV detection and defines a benchmark for relaxometry imaging.

Multi-Parametric Cardiac Magnetic Resonance for Prediction of Heart Failure Death in Thalassemia Major.

We assessed the prognostic value of multiparametric cardiovascular magnetic resonance (CMR) in predicting death from heart failure (HF) in thalassemia major (TM). We considered 1398 white TM patients (30.8 ± 8.9 years, 725 women) without a history of HF at baseline CMR, which was performed within the Myocardial Iron Overload in Thalassemia (MIOT) network. Iron overload was quantified by using the T2* technique, and biventricular function was determined with cine images. Late gadolinium enhancement (LGE) images were acquired to detect replacement myocardial fibrosis. During a mean follow-up of 4.83 ± 2.05 years, 49.1% of the patients changed the chelation regimen at least once; these patients were more likely to have significant myocardial iron overload (MIO) than patients who maintained the same regimen. Twelve (1.0%) patients died from HF. Significant MIO, ventricular dysfunction, ventricular dilation, and replacement myocardial fibrosis were identified as significant univariate prognosticators. Based on the presence of the four CMR predictors of HF death, patients were divided into three subgroups. Patients having all four markers had a significantly higher risk of dying for HF than patients without markers (hazard ratio (HR) = 89.93; 95%CI = 5.62-1439.46; p = 0.001) or with one to three CMR markers (HR = 12.69; 95%CI = 1.60-100.36; p = 0.016). Our findings promote the exploitation of the multiparametric potential of CMR, including LGE, for better risk stratification for TM patients.

Bone status and HCV infection in thalassemia major patients.

PURPOSE: Hepatitis C virus (HCV) infection increases the risk for osteoporosis but this relationship has not been investigated among multi-transfused patients with thalassemia major (TM). We cross-sectionally explored the association of HCV infection with bone mineral density (BMD), vitamin D, and bone turnover biomarkers in TM. METHODS: We considered 130 TM patients (41.89 ± 5.49 years, 67 females) enrolled in the E-MIOT (Extension-Myocardial Iron Overload in Thalassemia) Network. BMD measurements taken at the lumbar spine, femoral neck and total hip were expressed as Z-scores, with a BMD Z-score ≤ -2.0 indicating low bone mass. RESULTS: Z-scores were not associated with gender, iron overload indices, vitamin D levels, and biochemical bone turnover markers, but decreased with aging and in presence of hypogonadism and were directly correlated with body mass index (BMI). The prevalence of low bone mass was 70.7 %. Three groups of patients were identified: 78 who never contracted the infection (group 0), 72 who cleared HCV (group 1), and 29 with chronic HCV infection (CHC) (group 2). All Z-scores progressively decreased according to HCV status from group 0 to group 2. Osteocalcin levels were significantly lower in groups 2 and 1 than in group 0. CHC patients were more likely to have low bone mass compared to HCV naive patients, after adjusting for age, BMI, hypogonadism, and pancreatic iron. CONCLUSION: In TM, CHC appears as one additive risk factor for low bone mass and osteocalcin may play a role in this association.

Left ventricular global function index is associated with myocardial iron overload and heart failure in thalassemia major patients.

PURPOSE: The left ventricular global function index (LVGFI) is a comprehensive marker of cardiac performance, integrating LV morphology with global function. We explored the cross-sectional association of LVGFI with myocardial iron overload (MIO), LV ejection fraction (LVEF), myocardial fibrosis, and heart failure (HF) in ß-thalassemia major (TM) patients. METHODS: We considered 1352 adult TM patients (708 females, 32.79 ± 7.16years) enrolled in the Myocardial Iron Overload in Thalassemia Network and 112 healthy subjects (50 females, 32.09 ± 6.08years). LVGFI and LVEF were assessed by cine images and MIO by multislice multiecho T2* technique. Replacement myocardial fibrosis was detected by late gadolinium enhancement technique. RESULTS: LVGFI and LVEF were significantly lower in patients with significant MIO (global heart T2*<20ms) than in patients without MIO and in healthy subjects but were comparable between TM patients without MIO and healthy subjects. In TM, LVGFI was significantly associated with LVEF (R = 0.733; p < 0.0001). Global heart T2* values were significantly associated with both LVGFI and LVEF, but the correlation with LVGFI was significantly stronger (p = 0.0001). Male sex, diabetes mellitus, significant MIO, and replacement myocardial fibrosis were the strongest predictors of LVGFI. Eighty-six patients had a history of HF and showed significantly lower global heart T2* values, LVEF, and LVGFI than HF-free patients. A LVGFI ≤ 44.9% predicted the presence of HF. The LVGFI showed a diagnostic performance superior to that of LVEF (area under the curve: 0.67 vs. 0.62; p = 0.039). CONCLUSION: In TM patients the LVGFI correlates with MIO and provides incremental diagnostic value for HF detection compared with LVEF.

Prognostic value of multiparametric cardiac magnetic resonance in sickle cell patients.

The aim of this multicenter study was to prospectively assess the predictive value of multiparametric cardiac magnetic resonance (CMR) for cardiovascular complications in sickle cell disease (SCD) patients. Among all patients with hemoglobinopathies consecutively enrolled in the Myocardial Iron Overload in Thalassemia (MIOT) Network, we selected 102 SCD patients (34.38 ± 12.67 years, 49 females). Myocardial iron overload (MIO) was measured by the multislice multiecho T2* technique. Atrial dimensions and biventricular function parameters were quantified by cine images. Late gadolinium enhancement (LGE) images were acquired to detect focal myocardial fibrosis. At baseline CMR, only two patients had significant MIO (global heart T2* < 20 ms). During a mean follow-up of 63.01 ± 24.95 months, 11 cardiovascular events (10.8%) were registered: 3 pulmonary hypertension, 2 supraventricular arrhythmias, 1 heart failure, 1 death for heart failure, 1 pulmonary embolism, 1 peripheral vascular disease, 1 transient ischemic attack, and 1 death after acute chest syndrome. In the multivariate analysis, the independent CMR predictors of cardiovascular events were left ventricular (LV) ejection fraction (hazard ratio-HR = 0.88; p = 0.025) and right ventricular (RV) mass index (HR = 1.09; p = 0.047). According to the receiver-operating characteristic curve analysis for adverse events, an LV ejection fraction < 58.9% and an RV mass index > 31 g/m2 were optimal cut-off values. Reduced left ventricular ejection fraction and increased right ventricular mass index showed a significant prognostic value in patients with SCD. Our data seem to suggest that CMR may be added as a screening tool for identifying SCD patients at high risk for cardiopulmonary and vascular diseases.

Deep Learning Staging of Liver Iron Content From Multiecho MR Images.

BACKGROUND: MRI represents the most established liver iron content (LIC) evaluation approach by estimation of liver T2* value, but it is dependent on the choice of the measurement region and the software used for image analysis. PURPOSE: To develop a deep-learning method for unsupervised classification of LIC from magnitude T2* multiecho MR images. STUDY TYPE: Retrospective. POPULATION/SUBJECTS: A total of 1069 thalassemia major patients enrolled in the core laboratory of the Myocardial Iron Overload in Thalassemia (MIOT) network, which were included in the training (80%) and test (20%) sets. Twenty patients from different MRI vendors included in the external test set. FIELD STRENGTH/SEQUENCE: A5 T, T2* multiecho magnitude images. ASSESSMENT: Four deep-learning convolutional neural networks (HippoNet-2D, HippoNet-3D, HippoNet-LSTM, and an ensemble network HippoNet-Ensemble) were used to achieve unsupervised staging of LIC using five classes (normal, borderline, middle, moderate, severe). The training set was employed to construct the deep-learning model. The performance of the LIC staging model was evaluated in the test set and in the external test set. The model's performances were assessed by evaluating the accuracy, sensitivity, and specificity with respect to the ground truth labels obtained by T2* measurements and by comparison with operator-induced variability originating from different region of interest (ROI) placements. STATISTICAL TESTS: The network's performances were evaluated by single-class accuracy, specificity, and sensitivity and compared by one-way repeated measures analysis of variance (ANOVA) and one-way ANOVA. RESULTS: HippoNet-Ensemble reached an accuracy significantly higher than the other networks, and a sensitivity and specificity higher than HippoNet-LSTM. Accuracy, sensitivity, and specificity values for the LIC stages were: normal: 0.96/0.93/0.97, borderline: 0.95/0.85/0.98, mild: 0.96/0.88/0.98, moderate: 0.95/0.89/0.97, severe: 0.97/0.95/0.98. Correctly staging of cases was in the range of 85%-95%, depending on the LIC class. Multiclass accuracy was 0.90 against 0.92 for the interobserver variability. DATA CONCLUSION: The proposed HippoNet-Ensemble network can perform unsupervised LIC staging and achieves good prognostic performance. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 2.

Quantitative T2* MRI for bone marrow iron overload: normal reference values and assessment in thalassemia major patients.

PURPOSE: We evaluated the feasibility and reproducibility of bone marrow T2* values and established the lower limit of normal in a cohort of healthy subjects. We investigated the clinical correlates of bone marrow T2* values in patients with thalassemia major (TM). MATERIAL AND METHODS: Thirty healthy subjects and 274 consecutive TM patients (38.96 ± 8.49 years, 151 females) underwent MRI at 1.5T. An axial slice in the upper abdomen was acquired by a T2* gradient-echo multiecho sequence and the T2* value was calculated in a circular region of interest defined in the visible body of the first or second lumbar vertebra. In patients, also liver and heart T2* values were assessed. RESULTS: In healthy subjects bone marrow T2* values were independent of age and gender. The lower limit of normal for bone marrow T2* was 13 ms. In both healthy subjects and 30 randomly selected patients, the coefficient of variation for inter-operator-reproducibility was < 10%. TM patients exhibited significantly lower bone marrow T2* values than healthy subjects (7.47 ± 5.18 ms vs. 17.08 ± 1.89 ms; p < 0.0001). A pathological bone marrow T2* was detected in 82.8% of TM patients. In TM, the female sex was associated with reduced bone marrow T2* values. Bone marrow T2* values were inversely correlated with mean serum ferritin levels (R = -0.431; P < 0.0001) and hepatic iron load (R = - 0.215; P < 0.0001). A serum ferritin level > 536 ng/ml predicted the presence of a pathological bone marrow T2*. A positive correlation was found between bone marrow and heart T2* values (R = 0.143; P = 0.018). A normal bone marrow T2* showed a negative predictive value of 100% for cardiac iron. CONCLUSION: Bone marrow T2* measurements can be easily obtained using the same sequences acquired for liver iron quantification and may bring new insights into the pathophysiology of iron deposition; hence, they should be incorporated into clinical practice.

Gender Differences in Knowledge and Perception of Cardiovascular Disease among Italian Thalassemia Major Patients.

We evaluated gender differences in knowledge and perception of cardiovascular disease (CVD) among Italian thalassemia major (TM) patients. An anonymous questionnaire was completed by 139 ß-TM patients (87 (62.7%) females, 40.90 ± 8.03 years). Compared to females, males showed a significantly higher frequency of CVDs, and they less frequently selected tumors in general as the greatest health problem for people of the same age and gender (48.1% vs. 66.7%; p = 0.031) and as the greatest danger to their future health (26.9% vs. 43.7%; p = 0.048). CVDs were designated as the greatest danger to their future health by a significantly higher percentage of males than females (53.8% vs. 36.8%; p = 0.048). Both males and females showed a good knowledge of cardiovascular risk factors and preventive measures for CVDs. No gender differences were detected in the subjective well-being and the perceived cardiovascular risk. The perceived risk was not influenced by age, presence of cardiovascular risk factors, or disease, but no patient with a low perceived CVD risk had myocardial iron overload. Our findings highlight the need to implement future educational programs aimed at increasing the awareness of CVD as the greatest health issue, especially among the female TM population, and at informing TM patients of the different actors, besides iron, that play a role in the development of cardiovascular complications.

Link between Genotype and Multi-Organ Iron and Complications in Children with Transfusion-Dependent Thalassemia.

We evaluated the impact of the genotype on hepatic, pancreatic and myocardial iron content, and on hepatic, cardiac and endocrine complications in children with transfusion-dependent ß-thalassemia (ß-TDT). We considered 68 ß-TDT patients (11.98 ± 3.67 years, 51.5% females) consecutively enrolled in the Extension-Myocardial Iron Overload in Thalassemia network. Iron overload was quantified by T2* technique and biventricular function by cine images. Replacement myocardial fibrosis was evaluated by late gadolinium enhancement technique. Three groups of patients were identified: homozygous ß+ (N = 19), compound heterozygous ß0ß+ (N = 24), and homozygous ß0 (N = 25). The homozygous ß0 group showed significantly lower global heart and pancreas T2* values than the homozygous ß+ group. Compared to patients with homozygous ß+ genotype, ß0ß+ as well as ß0ß0 patients were more likely to have pancreatic iron overload (odds ratio = 6.53 and 10.08, respectively). No difference was detected in biventricular function parameters and frequency of replacement fibrosis. No patient had cirrhosis/fibrosis, diabetes or heart failure, and the frequency of endocrinopathies was comparable among the groups. In pediatric ß-TDT patients, there is an association between genotype and cardiac and pancreatic iron overload. The knowledge of patients' genotype can be valuable in predicting some patients' phenotypic features and in helping the clinical management of ß-TDT patients.

Uncertain crisis time affects psychosocial dimensions in beta-thalassemia patients during Covid-19 pandemic: A cross-sectional study.

Psychosocial variables are key factors influencing the delicate equilibrium of chronic patients during crisis time. In this study, we explored distress, anxiety, depression, loneliness, coping strategies, and changes in life habits in 43 beta-thalassemia patients and 86 controls during Covid-19 pandemic. Patients showed higher anxiety levels and a predominant transcendent coping profile compared to controls. Patients significantly differed from controls in outdoor habits. Social isolation and habits changes in uncertain life-threaten situations as Covid-19 pandemic are particularly detrimental in fragile beta-thalassemia patients. Structured support interventions are needed to promote well-being in the Covid-19 era.

National networking in rare diseases and reduction of cardiac burden in thalassemia major.

AIMS: A tailored chelation therapy guided by magnetic resonance imaging (MRI) is a strategy to improve the prognosis in iron-loaded patients, in many cases still hampered by limited MRI availability. In order to address this issue, the Myocardial Iron Overload in Thalassemia (MIOT) network was established in Italy and we aimed to describe the impact of 10-year activity of this network on cardiac burden in thalassemia major (TM). METHODS AND RESULTS: Within the MIOT network, 1746 TM patients (911 females; mean age 31.2 ± 9.1 years) were consecutively enrolled and prospectively followed by 70 thalassemia and 10 MRI centres. Patients were scanned using a multiparametric approach for assessing myocardial iron overload (MIO), biventricular function, and myocardial fibrosis. At the last MRI scan, a significant increase in global heart T2* values and a significantly higher frequency of patients with no MIO (all segmental T2* ≥20 ms) were detected, with a concordant improvement in biventricular function, particularly in patients with baseline global heart T2* <20 ms. Forty-seven percentage of patients changed the chelation regimen based on MRI. The frequency of heart failure (HF) significantly decreased after baseline MRI from 3.5 to 0.8% (P < 0.0001). Forty-six patients died during the study, and HF accounted for 34.8% of deaths. CONCLUSION: Over 10 years, continuous monitoring of cardiac iron and a tailored chelation therapy allowed MIO reduction, with consequent improvement of cardiac function and reduction of cardiac complications and mortality from MIO-related HF. A national networking for rare diseases therefore proved effective in improving the care and reducing cardiac outcomes of TM patients.

The Link of Pancreatic Iron with Glucose Metabolism and Cardiac Iron in Thalassemia Intermedia: A Large, Multicenter Observational Study.

In thalassemia major, pancreatic iron was demonstrated as a powerful predictor not only for the alterations of glucose metabolism but also for cardiac iron, fibrosis, and complications, supporting a profound link between pancreatic iron and heart disease. We determined for the first time the prevalence of pancreatic iron overload (IO) in thalassemia intermedia (TI) and systematically explored the link between pancreas T2* values and glucose metabolism and cardiac outcomes. We considered 221 beta-TI patients (53.2% females, 42.95 ± 13.74 years) consecutively enrolled in the Extension-Myocardial Iron Overload in Thalassemia project. Magnetic Resonance Imaging was used to quantify IO (T2* technique) and biventricular function and to detect replacement myocardial fibrosis. The glucose metabolism was assessed by the oral glucose tolerance test (OGTT). Pancreatic IO was more frequent in regularly transfused (N = 145) than in nontransfused patients (67.6% vs. 31.6%; p < 0.0001). In the regular transfused group, splenectomy and hepatitis C virus infection were both associated with high pancreatic siderosis. Patients with normal glucose metabolism showed significantly higher global pancreas T2* values than patients with altered OGTT. A pancreas T2* < 17.9 ms predicted an abnormal OGTT. A normal pancreas T2* value showed a 100% negative predictive value for cardiac iron. Pancreas T2* values were not associated to biventricular function, replacement myocardial fibrosis, or cardiac complications. Our findings suggest that in the presence of pancreatic IO, it would be prudent to initiate or intensify iron chelation therapy to prospectively prevent both disturbances of glucose metabolism and cardiac iron accumulation.

Biventricular Reference Values by Body Surface Area, Age, and Gender in a Large Cohort of Well-Treated Thalassemia Major Patients Without Heart Damage Using a Multiparametric CMR Approach.

BACKGROUND: Cardiac MRI plays a critical role in the management of thalassemic patients. No accurate biventricular reference values are available. PURPOSE: To establish the ranges for normal left ventricular (LV) and right ventricular (RV) volumes and ejection fraction (EF) and LV mass normalized to body surface area (BSA), age, and gender in a large cohort of well-treated beta-thalassemia major (ß-TM) patients without heart damage using a multiparametric MRI. STUDY TYPE: Retrospective/cohort study. POPULATION: In all, 251 ß-TM patients with no known risk factors or cardiac disease, normal electrocardiogram, no macroscopic myocardial fibrosis, and all cardiac segments with T2 * ≥20 msec, and 246 healthy subjects. FIELD STRENGTH/SEQUENCE: 1.5T/cine steady-state free precession (SSFP), gradient-echo T2 *, late gadolinium enhancement (LGE) images. ASSESSMENT: Biventricular end-diastolic volume, end-systolic volume, stroke volume, and LV mass were normalized to BSA (EDVI, ESVI, SVI). STATISTICAL TESTS: Comparisons between the two groups was performed with two-samples t-test or Wilcoxon's signed rank test. For more than two groups, one-way analysis of variance (ANOVA) or a Kruskal-Wallis test were applied. RESULTS: Compared to controls, males with ß-TM showed significantlt higher LVEDVI in all the age groups, while for the other volumes the difference was significant only within one or more age groups. In females the volumes were comparable between ß-TM patients and healthy subjects in all the age groups. In the male ß-TM population we found a significant effect of age on LVEDVI (P = 0.017), LVESVI (P = 0.001), RVESVI (P = 0.029), and RVEF (P = 0.031), while for females none of the biventricular parameters were significantly different among the age groups (LVEDVI: P = 0.614; LVESVI: P = 0.449; LVSVI: P = 0.186; LV mass index: P = 0.071; LVEF: P = 0.059; RVEDVI: P = 0.374; RVESVI: P = 0.180; RVSVI: P = 0.206; RVEF: P = 0.057). In ß-TM patients all biventricular volume indexes as well as the LV mass index were significantly larger in males than in females (P < 0.0001 in all cases). The LV and the RV EF were comparable between the sexes (P = 0.568 and P = 0.268, respectively). DATA CONCLUSION: Appropriate "normal" reference ranges normalized to BSA, sex, and age are recommended to avoid misdiagnosis of cardiomyopathy in ß-TM patients. LEVEL OF EVIDENCE: 4 TECHNICAL EFFICACY STAGE: 2.

Genotypic groups as risk factors for cardiac magnetic resonance abnormalities and complications in thalassemia major: a large, multicentre study.

BACKGROUND: The causes and effects of genotypic heterogeneity in beta-thalassemia major (ß-TM) have not been fully investigated. The aim of this multicentre study was to determine whether different genotype groups could predict the development of cardiovascular magnetic resonance abnormalities and cardiac complications. MATERIALS AND METHODS: We considered 708 ß-TM patients (373 females, age 30.05±9.47 years) consecutively enrolled in the Myocardial Iron Overload in Thalassemia (MIOT) network. Data were collected from birth to the first cardiac magnetic resonance scan. Myocardial iron overload was assessed using a T2* technique. Biventricular function was quantified by cine images. Macroscopic myocardial fibrosis was evaluated by a late gadolinium enhancement technique. RESULTS: Three groups of patients were identified: ß+ homozygotes (n=158), ß+/ß° heterozygotes (n=298) and ß° homozygotes (n=252). Compared to ß+ homozygotes, the other two groups showed a significantly higher risk of myocardial iron overload and left ventricular dysfunction. We recorded 90 (13.0%) cardiac events: 46 episodes of heart failures, 38 arrhythmias (33 supraventricular, 3 ventricular and 2 hypokinetic) and 6 cases of pulmonary hypertensions. ß° homozygotes showed a significantly higher risk than ß+ homozygotes of arrhythmias and cardiac complications considered globally. DISCUSSION: Different genotype groups predicted the development of myocardial iron overload, left ventricular dysfunction, arrhythmias and cardiac complications in ß-TM patients. These data support the importance of genotype knowledge in the management of ß-TM patients.