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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.To develop a deep-learning method for unsupervised classification of LIC from magnitude T2* multiecho MR images.Retrospective.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.A5 T, T2* multiecho magnitude images.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.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.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.The proposed HippoNet-Ensemble network can perform unsupervised LIC staging and achieves good prognostic performance.4 TECHNICAL EFFICACY: Stage 2.

The thalassaemia syndromes (TS) show different phenotype severity. Developing a reliable, practical and global tool to determine disease severity and tailor treatment would be of great value. Overall, 7910 patients were analysed with the aim of constructing a complication risk score (CoRS) to evaluate the probability of developing one or more complications. Nine independent variables were included in the investigation as predictors. Logistic regression models were used for Group A [transfusion-dependent thalassaemia (TDT)], Group B [transfused non-TDT (NTDT)] and Group C (non-transfused NTDT). Statistically significant predictors included age (years), haemoglobin levels, hepatic transaminases [alanine aminotransferase (ALT) and aspartate aminotransferase] and left-ventricular ejection fraction (LVEF) for Group A; age (years), age at first chelation (months), ALT and LVEF for Group B; and age (years), mean serum ferritin (SF) levels and LVEF for Group C. The area under the receiver operating characteristic curve was 84·5%, 82·1% and 80·0% for Groups A, Group B and Group C respectively, suggesting the models had good discrimination. Finally, the CoRS for each group was categorised into four risk classes (low, intermediate, high, and very high) using the centiles of its distribution. In conclusion, we have developed a CoRS for TS that can assist physicians in prospectively tailoring patients’ treatment.

This study analysed the impact of liver steatosis (LS) on the parameters of iron overload in 110 patients with non-transfusion dependent thalassaemia (NTDT). LS was diagnosed by ultrasound. Liver iron concentration (LIC) measurements were available for 64 patients who underwent a magnetic resonance imaging (MRI) scan. LS was frequent (35·5%) and was significantly more prevalent in males than in females (49·0% vs. 24·6%, P = 0·008). Patients with LS had significant higher levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), ALT/AST ratio and ferritin than those without, but LIC values were comparable. An ALT/AST ratio0·89 predicted the presence of LS with a sensitivity of 0·872 and a specificity of 0·901 (P 0·0001). Ferritin levels correlated with LIC values (R = 0·558, P 0·0001) but the correlation was stronger in patients without LS (R = 0·656, P 0·0001) than in patients with LS (R = 0·426, P = 0·05). LS is a frequent issue in NTDT patients and should be suspected in the presence of an ALT/AST ratio0·89. Recently, serum ferritin thresholds that predict clinically relevant LIC for guiding iron chelation therapy when MRI is unavailable have been determined. Our data show that LS may cause increase in ferritin levels and may be responsible for anticipating/exceeding chelation treatment in NTDT patients in the absence of LIC evaluation.

Purpose To define reference values of cardiac volumes, dimensions, and new morpho-functional parameters normalized for age, gender, and body surface area by cine-bSSFP (balanced steady-state free-precession) magnetic resonance (MR). Materials and Methods We enrolled 308 healthy subjects subdivided by gender and by six age classes: class I, >15–20 years; class II, >20–30 years; class III, >30–40 years; class IV, >40–50 years; class V, >50–60 years; and class VI >60 years. Dimensional, volumetric and morpho-functional parameters of the left (LV) and right (RV) ventricles were measured using cine-bSSFP MRI at 1.5T. Results The LV and RV end-diastolic volume indexes (EDVi) were inversely related to age (P < 0.0001 r = –0.34 and P < 0.0001 r = –0.37, respectively). In addition, the LV mass index decreased with age (P = 0.0004, r = –0.21). The LV longitudinal shortening was not significantly different among groups: ≥15% in all populations (95% confidence interval [CI]: 16–31). The sphericity index measured in end-diastole was higher in females than in males (P < 0.03): the upper limit was 40% for males and 42% for females. The normality cutoff of LV global function index was ≥33% in males and ≥35% in females. The end-diastolic volume (EDV) of RV and LV was balanced (RV/LV ratio 0.85–1.15) without differences in the population. The LV EDV/mass was 1.0–1.8 in males and 1.0–2.1 in females. Conclusion This study provides potential age- and gender-specific reference. Evidence level 2 J. Magn. Reson. Imaging 2016.

The aim of this study was to evaluate, in a large cohort of chronically transfused patients, whether the presence of extramedullary hematopoiesis (EMH) accounts for the typical patterns of cardiac iron distribution and/or cardiac function parameters. We retrospectively selected 1,266 thalassemia major patients who had undergone regular transfusions (611 men and 655 women; mean age: 31.3 ± 8.9 years, range: 4.2-66.6 years) and were consecutively enrolled within the Myocardial Iron Overload in Thalassemia network. The presence of EMH was evaluated based on steady-state free precession sequences; cardiac and liver iron overloads were quantified using a multiecho T2* approach; cardiac function parameters and pulmonary diameter were quantified using the steady-state free precession sequences; and myocardial fibrosis was evaluated using the late gadolinium enhancement technique. EMH was detected in 167 (13.2%) patients. The EMH+ patients had significantly lower cardiac iron overload than that of the EMH- patients (P = 0.003). The patterns of cardiac iron distribution were significantly different in the EMH+ and EMH- patients (P

Chronically transfused sickle cell disease (SCD) patients have lower risk of myocardial iron overload (MIO) than comparably transfused thalassemia major (TM) patients. However, cardioprotection is incomplete. We present the clinical characteristics of six patients who have prospectively developed MIO, to identify potential risk factors for cardiac iron accumulation. From 2002 to 2011, cardiac, hepatic, and pancreatic iron overload were assessed by R2 and R2 * magnetic resonance imaging techniques in 201 chronic transfused SCD patients as part of their clinical care. At the time, they developed MIO, five of six patients had been on chronic transfusion for more than 11 years; only one was on exchange transfusion. The time to MIO was correlated with reticulocyte and hemoglobin S percentages. All patients had qualitatively poor chelation compliance ( 4600 ng/ml and liver iron concentration >22 mg/g. Pancreatic R2 * was >100 Hz in every patient studied (5/6). Cardiac iron rose proportionally to pancreas R2 *, with all patients having pancreas R2 *>100 Hz when cardiac iron was present. MIO had a threshold relationship with liver iron that was higher than observed in TM patients. In conclusion, MIO occurs in a small percentage of chronically transfused SCD patients and is only associated with exceptionally poor control of total body iron stores. Duration of chronic transfusion is clearly important but other factors, such as levels of effective erythropoiesis, appear to contribute to cardiac risk. Pancreas R2 * can serve as a valuable screening tool for cardiac iron in SCD patients.

Purpose To evaluate the efficiency of a novel transit time (Δt) estimation method from cardiovascular magnetic resonance flow curves. Materials and Methods Flow curves were estimated from phase contrast images of 30 patients. Our method (TT-GD: transit time group delay) operates in the frequency domain and models the ascending aortic waveform as an input passing through a discrete-component “filter,” producing the observed descending aortic waveform. The GD of the filter represents the average time delay (Δt) across individual frequency bands of the input. This method was compared with two previously described time-domain methods: TT-point using the half-maximum of the curves and TT-wave using cross-correlation. High temporal resolution flow images were studied at multiple downsampling rates to study the impact of differences in temporal resolution. Results Mean Δts obtained with the three methods were comparable. The TT-GD method was the most robust to reduced temporal resolution. While the TT-GD and the TT-wave produced comparable results for velocity and flow waveforms, the TT-point resulted in significant shorter Δts when calculated from velocity waveforms (difference: 1.8 ± 2.7 msec; coefficient of variability: 8.7%). The TT-GD method was the most reproducible, with an intraobserver variability of 3.4% and an interobserver variability of 3.7%. Conclusion Compared to the traditional TT-point and TT-wave methods, the TT-GD approach was more robust to the choice of temporal resolution, waveform type, and observer. J. Magn. Reson. Imaging 2014;39:550–558. © 2013 Wiley Periodicals, Inc.

Purpose To determine whether systematic differences were present between myocardial R2* values obtained with two different decay models: truncation and exponential + constant (Exp-C). Methods Single-center cohorts were used to compare black and bright blood sequences separately, and a multicenter cohort of mixed bright and black blood studies was used to assess the generalizability. Truncated exponential estimates were calculated with CMRtools, which uses a single region of interest (ROI) method. Exp-C estimates were calculated using a pixelwise approach. Results No differences could be distinguished based upon whether a white or black blood sequence was examined. The two fitting algorithms yielded similar R2* values, with R-squared values exceeding 0.997 and a coefficient of variation of 3% to 4%. Results using the pixelwise method yielded a small systematic bias (∼3%) 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 the bias. In the multicenter cohort, the strong agreement between the two fitting approaches was reconfirmed. Conclusion Cardiac R2* values are independent of the signal model used for its calculation over clinically relevant ranges. Clinicians can compare results among centers using these disparate approaches with confidence. Magn Reson Med 72:485–491, 2014. © 2013 Wiley Periodicals, Inc.

Summary The relationship between diabetes mellitus (DM) and cardiac complications has never been systematically studied in thalassaemia major (TM). We evaluated a large retrospective historical cohort of TM to determine whether DM is associated with a higher risk of heart complications. We compared 86 TM patients affected by DM with 709 TM patients without DM consecutively included in the Myocardial Iron Overload in Thalassaemia database where clinical/instrumental data are recorded from birth to the first cardiovascular magnetic resonance (CMR) exam. All of the cardiac events considered were developed after the DM diagnosis. In DM patients versus non-DM patients we found a significantly higher frequency of cardiac complications (46·5% vs. 16·9%, P

Purpose Realizing the challenges and opportunities of effective transverse relaxation rate (R2*) mapping at high and ultrahigh fields, this work examines magnetic field strength (B0) dependence and segmental artifact distribution of myocardial R2* at 1.5, 3.0, and 7.0 T. Methods Healthy subjects were considered. Three short-axis views of the left ventricle were examined. R2* was calculated for 16 standard myocardial segments. Global and mid-septum R2* were determined. For each segment, an artifactual factor was estimated as the deviation of segmental from global R2* value. Results The global artifactual factor was significantly enlarged at 7.0 T versus 1.5 T (P = 0.010) but not versus 3.0 T. At 7.0 T, the most severe susceptibility artifacts were detected in the inferior lateral wall. The mid-septum showed minor artifactual factors at 7.0 T, similar to those at 1.5 and 3.0 T. Mean R2* increased linearly with the field strength, with larger changes for global heart R2* values. Conclusion At 7.0 T, segmental heart R2* analysis is challenging due to macroscopic susceptibility artifacts induced by the heart–lung interface and the posterior vein. Myocardial R2* depends linearly on the magnetic field strength. The increased R2* sensitivity at 7.0 T might offer means for susceptibility-weighted and oxygenation level-dependent MR imaging of the myocardium. Magn Reson Med 71:2224–2230, 2014. © 2013 Wiley Periodicals, Inc.

Multiecho gradient-echo T*2 magnetic resonance imaging is a well-established technique for iron overload assessment but there are few reports concerning the pancreas. The aim of this work was to assess the feasibility and reproducibility of the magnetic resonance imaging for measuring pancreatic regional and global T*2 values, to establish the lower limit of normal in a large cohort of healthy subjects and to correlate the measured values with age and gender. One hundred and twenty healthy subjects (61 males, 51±17 years) underwent magnetic resonance imaging (1.5T) using a multiecho gradient-echo T*2 sequence. T*2 measurements were performed in pancreatic head, body, and tail. The global value was calculated as the mean. Measurement of pancreatic T*2 values was feasible in all subjects. For the T*2 global value the coefficient of variation for intraoperator and interoperator reproducibility were 7.7% and 13%, respectively. The global T*2 values ranged from 24 to 52 ms with the lower limit of normal of 26 ms. There were no significant differences among the regional pancreatic T*2 values. No significant correlation was found between T*2 and patient age or gender. In conclusion, pancreatic T*2 measurements appear to be feasible, reproducible, nontime-consuming and reliable. Gender- and age-related differences concerning pancreatic T*2 were not found.

Female patients with thalassemia and other hemoglobinopathies enjoy a longer survival when compared to males. We report data from the literature and from our own studies on gender differences in survival of thalassemia patients, and also examine this phenomenon in animals and in the general population. Some of the more widely accepted hypotheses that try to explain the differences in longevity between males and females are reviewed. The oxidative stress hypothesis is commonly accepted by the researchers on ageing, although further support for it is needed. In conclusion, it appears that male and female patients with transfusion-dependent thalassemia major are at the same risk of accumulating iron, but females survive longer and develop less cardiac disease because they tolerate iron toxicity better, possibly as an effect of increased tolerance to chronic oxidative stress.

The present study investigated myocardial T2* heterogeneity in thalassaemia major (TM) patients by cardiac magnetic resonance (CMR), to determine whether is related to inhomogeneous iron overload distribution. A total of 230 TM patients consecutively referred to our laboratory were studied retrospectively. Three short-axis views (basal, medium and apical) of the left ventricle (LV) were obtained by multislice multiecho T2* CMR. T2* segmental distribution was mapped on a 16-segment LV model. The level of heterogeneity of the T2* segmental distribution, evaluated by the coefficient of variation (CoV), was compared with that of a surrogate data set, to determine whether the inhomogeneous segmental distribution of T2* could be generated by susceptibility artefacts. Susceptibility artefacts offer an explanation for the T2* heterogeneity observed in patients without iron overload. In subjects with global T2* below the lower limit of the normal, T2* heterogeneity increased abruptly which could not be explained by artefactual effects. Some segmental T2* values were below and others above the limit of normal threshold (20 ms) in 104 (45%) TM patients. Among these patients, 74% showed a normal T2* global value. In conclusion, a true heterogeneity in the iron overload distribution may be present in TM patients. Heterogeneity seemingly appears in the borderline myocardial iron and stabilizes at moderate to severe iron burden. Copyright © 2009 John Wiley & Sons, Ltd.

Purpose To assess the transferability of the magnetic resonance imaging (MRI) multislice multiecho T2* technique for global and segmental measurement of iron overload in thalassemia patients. Materials and Methods Multiecho T2* sequences were installed on six MRI scanners. Five healthy subjects (n = 30) were scanned at each site; five thalassemia major (TM) patients were scanned at the reference site and were rescanned locally (n = 25) within 1 month. T2* images were analyzed using previously validated software. Results T2* values of healthy subjects showed intersite homogeneity. On TM patients, for global heart T2* values the correlation coefficient was 0.97, coefficients of variation (CoVs) ranged from 0.04–0.12, and intraclass coefficients (ICCs) ranged from 0.94–0.99. The mean CoV and ICC for segmental T2* distribution were 0.198 and 88, respectively. Conclusion The multislice multiecho T2* technique is transferable among scanners with good reproducibility. J. Magn. Reson. Imaging 2009;30:62–68. © 2009 Wiley-Liss, Inc.

Purpose To determine whether T2* measurements quantifying myocardial iron overload in thalassemia patients are influenced by myocardial fibrosis and blood oxygenation. Materials and Methods Multislice multiecho T2* was performed in 94 thalassemia patients in order to quantify myocardial iron overload. The left ventricle was automatically segmented into a 16-segment standardized heart model, and the T2* value on each segment as well as the global T2* were calculated. Delayed enhanced cardiovascular magnetic resonance (DE-CMR) images were obtained to detect myocardial fibrosis. The blood oxygenation was assessed by the noninvasive measurement of partial pressure of oxygen (pO2). Results Myocardial fibrosis was detected in 31 patients (33%). The global T2* value in patients with fibrosis was comparable with that of patients without fibrosis (P = 0.88) and T2* values in segments with fibrosis were comparable with those in segments without fibrosis (P = 0.83). The global T2* value was not correlated with the pO2 (Spearman's coefficient of correlation = 0.99). Conclusion Myocardial fibrosis and blood oxygenation did not significantly affect the T2* values. These data further support the use of heart T2* as equivalent of heart iron in the clinical arena. J. Magn. Reson. Imaging 2009;29:832–837. © 2009 Wiley-Liss, Inc.

Purpose To evaluate the feasibility of assessing coronary vasodilation following exogenous nitrates, using magnetic resonance angiography (MRA). The assessment of coronary response to exogenous nitrovasodilators may have a diagnostic and prognostic impact in patients with coronary artery disease. To date, stress imaging of coronary artery vasomotion has been confined to the catheterization laboratory. MRA is emerging as a noninvasive tool for coronary artery imaging. Materials and Methods Coronary MRA was performed in 20 healthy volunteers (12 males, age = 33 ± 8). We used spiral spoiled gradient echo (SSGE) sequences for imaging of coronary artery lumen. After the baseline short-axis view of the coronary artery was obtained, sublingual nitroglycerin (NTG) (0.3 mg) was administered. In all subjects, short-axis views of the coronary artery were acquired repetitively (8–10 times) from 1 up to 10 minutes after NTG administration. Measurements were obtained by two independent investigators. Results Interpretable short-axis view of left anterior descending artery (LAD) was obtained in 15 subjects (75%); in the remaining five subjects the right coronary artery (RCA) was examined. The interobserver variability was 15%, and the intraobserver variability 4%. The NTG-induced maximal vasodilation was 43 ± 22%. The vasodilator response over time after NTG was maximal on average at 279 ± 112 seconds, but with substantial heterogeneity. Conclusion Entity and time course of nitrate-induced coronary vasodilation in the left anterior descending and/or RCA can be assessed using MRA with high feasibility and reproducibility. Coronary MRA has potential for dynamic imaging of coronary vasomotion. J. Magn. Reson. Imaging 2004;20:390–394. © 2004 Wiley-Liss, Inc.