Liver steatosis in patients with transfusion-dependent thalassaemia.

We evaluated the prevalence and the clinical associations of liver steatosis (LS) in patients with transfusion-dependent thalassaemia (TDT). We considered 301 TDT patients (177 females, median age = 40.61 years) enrolled in the Extension-Myocardial Iron Overload in Thalassaemia Network, and 25 healthy subjects. Magnetic resonance imaging was used to quantify iron overload and hepatic fat fraction (FF) by T2* technique and cardiac function by cine images. The glucose metabolism was assessed by the oral glucose tolerance test (OGTT). Hepatic FF was significantly higher in TDT patients than in healthy subjects (median value: 1.48% vs. 0.55%; p = 0.013). In TDT, hepatic FF was not associated with age, gender, serum ferritin levels or liver function parameters, but showed a weak inverse correlation with high-density lipoprotein cholesterol. The 36.4% of TDT patients showed LS (FF >3.7%). Active hepatitis C virus (HCV) infection, increased body mass index and hepatic iron were independent determinants of LS. A hepatic FF >3.53% predicted the presence of an abnormal OGTT. Hepatic FF was not correlated with cardiac iron, biventricular volumes or ejection fractions, but was correlated with left ventricular mass index. In TDT, LS is a frequent finding, associated with iron overload, increased weight and HCV, and conveying an increased risk for the alterations of glucose metabolism.

Impact of genotype on multi-organ iron and complications in patients with non-transfusion-dependent ß-thalassemia intermedia.

We evaluated the impact of the genotype on clinical and hematochemical features, hepatic and cardiac iron levels, and endocrine, hepatic, and cardiovascular complications in non-transfusion-dependent (NTD) ß-thalassemia intermedia (TI) patients. Sixty patients (39.09 ± 11.11 years, 29 females) consecutively enrolled in the Myocardial Iron Overload in Thalassemia project underwent Magnetic Resonance Imaging to quantify iron overload, biventricular function parameters, and atrial areas and to detect replacement myocardial fibrosis. Three groups of patients were identified: homozygous ß+ (N = 18), heterozygous ß0ß+ (N = 22), and homozygous ß0 (N = 20). The groups were homogeneous for sex, age, splenectomy, hematochemical parameters, chelation therapy, and iron levels. The homozygous ß° genotype was associated with significantly higher biventricular end-diastolic and end-systolic volume indexes and bi-atrial area indexes. No difference was detected in biventricular ejection fractions or myocardial fibrosis. Extramedullary hematopoiesis and leg ulcers were significantly more frequent in the homozygous ß° group compared to the homozygous ß+ group. No association was detected between genotype and liver cirrhosis, hypogonadism, hypothyroidism, osteoporosis, heart failure, arrhythmias, and pulmonary hypertension. Heart remodelling related to a high cardiac output state cardiomyopathy, extramedullary hematopoiesis, and leg ulcers were more pronounced in patients with the homozygous ß° genotype compared to the other genotypes analyzed. The knowledge of the genotype can assist in the clinical management of NTD ß-TI patients.

Left atrial strain in patients with ß-thalassemia major: a cross-sectional CMR study.

OBJECTIVES: The aim of this cross-sectional study was to investigate the association of left atrial (LA) strain parameters with demographics, clinical data, cardiovascular magnetic resonance (CMR) findings, and cardiac complications (heart failure and arrhythmias) in a cohort of patients with ß-thalassemia major (ß-TM). MATERIALS AND METHODS: We considered 264 ß-TM patients (133 females, 36.79 ± 11.95 years) consecutively enrolled in the Extension-Myocardial Iron Overload in Thalassemia (E-MIOT) project. Moreover, we included 35 sex- and age-matched healthy controls (14 females, mean age 37.36 ± 17.52 years). Reservoir, conduit, and booster LA functions were analysed by CMR feature tracking using dedicated software. RESULTS: Compared to the healthy control group, ß-TM patients demonstrated lower LA reservoir strain and booster strains, as well as LA reservoir and booster strain rates. However, no differences were found in LA conduit deformation parameters. In ß-TM patients, ageing, sex, and left ventricle (LV) volume indexes were independent determinants of LA strain parameters. The number of segments with late gadolinium enhancement (LGE) significantly correlated with all LA strain parameters, with the exception of the LA conduit rate. Patients with cardiac complications exhibited significantly impaired strain parameters compared to patients without cardiac complications. CONCLUSION: In patients with ß-TM, LA strain parameters were impaired compared to control subjects, and they exhibited a significant correlation with the number of LV segments with LGE. Furthermore, patients with cardiac complications had impaired left atrial strain parameters. Clinical relevance statement In patients with ß-thalassemia major, left atrial strain parameters were impaired compared to control subjects and emerged as a sensitive marker of cardiac complications, stronger than cardiac iron levels. KEY POINTS: • Compared to healthy subjects, ß-thalassemia major patients demonstrated significantly lower left atrial reservoir strain and booster strains, as well as left atrial reservoir and booster strain rates. • In ß-thalassemia major, ageing, sex, and left ventricular volume indexes were independent determinants of left atrial strain parameters, while left atrial strain parameters were not correlated with myocardial iron overload. • An independent association between reduced left atrial strain parameters and a history of cardiac complications was found in ß-thalassemia major patients.

Pancreatic iron in pediatric transfusion-dependent beta-thalassemia patients: A longitudinal MRI study.

BACKGROUND: In pediatric transfusion-dependent thalassemia (TDT) patients, we evaluated the prevalence, pattern, and clinical associations of pancreatic siderosis and the changes in pancreatic iron levels and their association with baseline and changes in total body iron balance. PROCEDURE: We considered 86 pediatric TDT patients consecutively enrolled in the Extension-Myocardial Iron Overload in Thalassemia Network. Iron overload (IO) was quantified by R2* magnetic resonance imaging (MRI). RESULTS: Sixty-three (73%) patients had pancreatic IO (R2* > 38 Hz). Global pancreas R2* values were significantly correlated with mean serum ferritin levels, MRI liver iron concentration (LIC) values, and global heart R2* values. Global pancreas R2* values were significantly higher in patients with altered versus normal glucose metabolism. Thirty-one patients also performed the follow-up MRI at 18 ± 3 months. Higher pancreatic R2* values were detected at the follow-up, but the difference versus the baseline MRI was not significant. The 20% of patients with baseline pancreatic IO showed no pancreatic IO at the follow-up. The 46% of patients without baseline pancreatic IO developed pancreatic siderosis. The changes in global pancreas R2* between the two MRIs were not correlated with baseline serum ferritin levels, baseline, final, and changes in MRI LIC values, or baseline pancreatic iron levels. CONCLUSIONS: In children with TDT, pancreatic siderosis is a frequent finding associated with hepatic siderosis and represents a risk factor for myocardial siderosis and alterations of glucose metabolism. Iron removal from the pancreas is exceptionally challenging and independent from hepatic iron status.

Liver T1 and T2 mapping in a large cohort of healthy subjects: normal ranges and correlation with age and sex.

OBJECTIVE: We established normal ranges for native T1 and T2 values in the human liver using a 1.5 T whole-body imager (General Electric) and we evaluated their variation across hepatic segments and their association with age and sex. MATERIALS AND METHODS: One-hundred healthy volunteers aged 20-70 years (50% females) underwent MRI. Modified Look-Locker inversion recovery and multi-echo fast-spin-echo sequences were used to measure hepatic native global and segmental T1 and T2 values, respectively. RESULTS: T1 and T2 values exhibited good intra- and inter-observer reproducibility (coefficient of variation < 5%). T1 value over segment 4 was significantly lower than the T1 values over segments 2 and 3 (p < 0.0001). No significant regional T2 variability was detected. Segmental and global T1 values were not associated with age or sex. Global T2 values were independent from age but were significantly lower in males than in females. The lower and upper limits of normal for global T1 values were, respectively, 442 ms and 705 ms. The normal range for global T2 values was 35 ms-54 ms in males and 39 ms-54 ms in females. DISCUSSION: Liver T1 and T2 mapping is feasible and reproducible and the provided normal ranges may help to establish diagnosis and progression of various liver diseases.

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.

Development of a Thalassemia International Prognostic Scoring System (TIPSS).

A prognostic scoring system that can differentiate ß-thalassemia patients based on mortality risk is lacking. We analysed data from 3145 ß-thalassemia patients followed through a retrospective cohort design for the outcome of death. An a priori list of prognostic variables was collected. ß Coefficients from a multivariate cox regression model were used from a development dataset (n = 2516) to construct a formula for a Thalassemia International Prognostic Scoring System (TIPSS) which was subsequently applied to a validation dataset (n = 629). The median duration of observation was 10.0 years. The TIPSS score formula was constructed as exp (1.4 × heart disease + 0.9 × liver disease + 0.9 × diabetes + 0.9 × sepsis + 0.6 × alanine aminotransferase ≥42 IU/L + 0.6 × hemoglobin ≤9 g/dL + 0.4 × serum ferritin ≥1850 ng/mL). TIPSS score thresholds of greatest differentiation were assigned as <2.0 (low-risk), 2.0 to <5.0 (intermediate-risk), and ≥5.0 (high-risk). The TIPSS score was a good predictor for the outcome of death in the validation dataset (AUC: 0.722, 95%CI: 0.641-0.804) and survival was significantly different between patients in the three risk categories (P < 0.001). Compared to low-risk patients, the hazard ratio for death was 2.778 (95%CI: 1.335-5.780) in patients with intermediate-risk and 6.431 (95%CI: 3.151-13.128) in patients with high-risk. This study provides a novel tool to support mortality risk categorization for patients with ß-thalassemia that could help management and research decisions.

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.

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.

Increased myocardial extracellular volume is associated with myocardial iron overload and heart failure in thalassemia major.

OBJECTIVES: Myocardial extracellular volume (ECV) by cardiovascular magnetic resonance (CMR) is a surrogate marker of diffuse fibrosis. We evaluated the association between ECV and demographics, CMR findings, and cardiac involvement in patients with thalassemia major (TM). METHODS: A total of 108 ß-TM patients (62 females, 40.16 ± 8.83 years), consecutively enrolled in the Extension-Myocardial Iron Overload in Thalassemia Network, and 16 healthy subjects (6 females, 37.12 ± 16.13 years) underwent CMR. The protocol included assessment of T2*, native T1, and T2 values in all 16 myocardial segments for myocardial iron overload (MIO) quantification, cine images for left ventricular (LV) function quantification, post-contrast T1 mapping for ECV calculation, and late gadolinium enhancement (LGE) technique for replacement myocardial fibrosis detection. RESULTS: Global ECV values were significantly higher in females than in males. Global ECV values were significantly higher in patients with significant MIO (global heart T2* < 20 ms) than in patients without significant MIO, and both groups exhibited higher global ECV values than healthy subjects. No association was detected between native T1 and ECV values, while patients with reduced global heart T2 values showed significantly higher global ECV values than patients with normal and increased global heart T2. Global ECV values were not correlated with LV function/size and were comparable between patients with and without LGE. Compared to patients without heart failure, patients with a history of heart failure (N = 10) showed significantly higher global heart ECV values. CONCLUSION: In TM, increased myocardial ECV, potentially reflecting diffuse interstitial fibrosis, is associated with MIO and heart failure. KEY POINTS: • CMR-derived myocardial extracellular volume is increased in thalassemia major patients, irrespective of the presence of late gadolinium enhancement. • In thalassemia major, myocardial iron overload contributes to the increase in myocardial ECV, which potentially reflects diffuse interstitial fibrosis and is significantly associated with a history of heart failure.

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.

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.

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.

Gender Differences and Cardiometabolic Risk: The Importance of the Risk Factors.

Metabolic syndrome (Mets) is a clinical condition characterized by a cluster of major risk factors for cardiovascular disease (CVD) and type 2 diabetes: proatherogenic dyslipidemia, elevated blood pressure, dysglycemia, and abdominal obesity. Each risk factor has an independent effect, but, when aggregated, they become synergistic, doubling the risk of developing cardiovascular diseases and causing a 1.5-fold increase in all-cause mortality. We will highlight gender differences in the epidemiology, etiology, pathophysiology, and clinical expression of the aforementioned Mets components. Moreover, we will discuss gender differences in new biochemical markers of metabolic syndrome and cardiovascular risk.

Primary HBB gene mutation severity and long-term outcomes in a global cohort of ß-thalassaemia.

In ß-thalassaemia, the severity of inherited ß-globin gene mutations determines the severity of the clinical phenotype at presentation and subsequent transfusion requirements. However, data on associated long-term outcomes remain limited. We analysed data from 2109 ß-thalassaemia patients with available genotypes in a global database. Genotype severity was grouped as ß0 /ß0 , ß0 /ß+ , ß+ /ß+ , ß0 /ß++ , ß+ /ß++ , and ß++ /ß++ . Patients were followed from birth until death or loss to follow-up. The median follow-up time was 34·1 years. Mortality and multiple morbidity outcomes were analyzed through five different stratification models of genotype severity groups. Interestingly, ß0 and ß+ mutations showed similar risk profiles. Upon adjustment for demographics and receipt of conventional therapy, patients with ß0 /ß0 , ß0 /ß+ , or ß+ /ß+ had a 2·104-increased risk of death [95% confidence interval (CI): 1·176-3·763, P = 0·011] and 2·956-increased odds of multiple morbidity (95% CI: 2·310-3·784, P < 0·001) compared to patients in lower genotype severity groups. Cumulative survival estimates by age 65 years were 36·8% for this subgroup compared with 90·2% for patients in lower genotype severity groups (P < 0·001). Our study identified mortality and morbidity risk estimates across various genotype severity groups in patients with ß-thalassaemia and suggests inclusion of both ß+ and ß0 mutations in strata of greatest severity.

Frequency, pattern, and associations of renal iron accumulation in sickle/ß-thalassemia patients.

We evaluated frequency, pattern, and associations of renal iron accumulation in sickle/ß-thalassemia. Thirty-three sickle/ß-thalassemia patients (36.5 ± 14.7 years; 13 females), 14 homozygous sickle cell disease (SCD) patients, and 71 thalassemia major (TM) patients, enrolled in the E-MIOT Network, underwent magnetic resonance imaging. Iron overload (IO) was quantified by the T2* technique. Sickle/ß-thalassemia patients had a significantly lower frequency of renal IO (T2* < 31 ms) than homozygous SCD patients (9.1% vs. 57.1%; P = 0.001), besides having similar hepatic, cardiac and pancreatic IO. Kidney T2* values were comparable between regularly transfused sickle/ß-thalassemia and TM patients but were significantly lower in regularly transfused homozygous SCD patients than in the other two groups. In sickle/ß-thalassemia patients, global renal T2* values were not associated with age, gender, splenectomy, and presence of regular transfusions or chelation. No correlation was detected between renal T2* values and serum ferritin levels or iron load in the other organs. Global renal T2* values were not associated with serum creatinine levels but showed a significant inverse correlation with serum lactate dehydrogenase (R = - 0.709; P < 0.0001) and indirect bilirubin (R = - 0.462; P = 0.012). Renal IO is not common in sickle/ß-thalassemia patients, with a prevalence significantly lower compared to that of homozygous SCD patients, but with a similar underlying mechanism due to the chronic hemolysis.

Relationship between pancreatic iron overload, glucose metabolism and cardiac complications in sickle cell disease: An Italian multicentre study.

OBJECTIVES: Evidence about the cross-talk between iron, glucose metabolism, and cardiac disease is increasing. We aimed to explore the link of pancreatic iron by Magnetic Resonance Imaging (MRI) with glucose metabolism and cardiac complications (CC) in sickle cell disease (SCD) patients. METHODS: We considered 70 SCD patients consecutively enrolled in the Extension-Myocardial Iron Overload in Thalassemia Network. Iron overload was quantified by R2* technique and biventricular function by cine images. Macroscopic myocardial fibrosis was evaluated by late gadolinium enhancement technique. Glucose metabolism was assessed by the oral glucose tolerance test. RESULTS: Patients with an altered glucose metabolism showed a significantly higher pancreas R2* than patients with normal glucose metabolism. Pancreatic siderosis emerged as a risk factor for the development of metabolic alterations (OddsRatio 8.25, 95%confidence intervals 1.51-45.1; p = .015). Global pancreas R2* values were directly correlated with mean serum ferritin levels and liver iron concentration. Global pancreas R2* was not significantly associated with global heart R2* and macroscopic myocardial fibrosis. Patients with history of CC showed a significantly higher global pancreas R2* than patients with no CC. CONCLUSIONS: Our findings support the evaluation of pancreatic R2* by MRI in SCD patients to prevent the development of metabolic and cardiac disorders.

Myocardial T2 values at 1.5 T by a segmental approach with healthy aging and gender.

OBJECTIVES: Our aims were to obtain myocardial regional and global T2 values as a reference for normality for the first time using a GE scanner and to assess their association with physiological variables. METHODS: One hundred healthy volunteers aged 20-70 years (50% females) underwent cardiovascular magnetic resonance. Basal, mid-ventricular, and apical short-axis slices of the left ventricle were acquired by a multi-echo fast-spin-echo (MEFSE) sequence. Image analysis was performed with a commercially available software package. The T2 value was assessed in all 16 myocardial segments and the global value was the mean. RESULTS: The global T2 value averaged across all subjects was 52.2 ± 2.5 ms (range: 47.0-59.9 ms). Inter-study, intra-observer, and inter-observer reproducibility was good (coefficient of variation < 5%). 3.6% of the segments was excluded because of artifacts and/or partial-volume effects. Segmental T2 values differed significantly (p < 0.0001), with the lowest value in the basal anterolateral segment (50.0 ± 3.5 ms) and the highest in the apical lateral segment (54.9 ± 5.1 ms). Mean T2 was significantly lower in the basal slice compared to both mid-ventricular and apical slices and in the mid-ventricular slice than in the apical slice. Aging was associated with increased segmental and global T2 values. Females showed higher T2 values than males. T2 values were not correlated to heart rate. A significant inverse correlation was detected between global T2 values and mean wall thickness. CONCLUSIONS: The optimized MEFSE sequence allows for robust and reproducible quantification of segmental T2 values. Gender- and age-specific segmental reference values must be defined for distinguishing healthy and diseased myocardium. KEY POINTS: • In healthy subjects, T2 values differ among myocardial segments and are influenced by age and gender. • Normal T2 values in the myocardium, usable as a benchmark by other GE sites, were established.

Global longitudinal strain for detection of cardiac iron overload in patients with thalassemia: a meta-analysis of observational studies with individual-level participant data.

BACKGROUND: Although cardiac magnetic resonance (CMR) is the most reliable tool for assessment of CIO in patients with thalassemia, it is not always readily available. Recent studies have explored the potential of GLS as an alternative for diagnosis of CIO. We aimed to investigate the efficacy of global longitudinal strain (GLS) for detection of cardiac iron level (CIO). METHODS: We searched SCOPUS, MEDLINE, and Embase to identify the studies which used GLS for assessment of CIO. We searched for individual participant data (IPD) in eligible studies to perform ROC curve analysis. CMR with a T2* cut-off value of 20 ms was considered as the gold standard. A meta-analysis was performed and the risk of bias was assessed using the JBI Checklist. RESULTS: A total of 14 studies with 789 thalassemia patients (310 and 430 with and without CIO respectively and 49 with undetermined condition) were considered eligible for meta-analysis. IPDs of 405 participants were available. GLS was significantly lower in patients with CIO (-17.5 ± 2.7%) compared to those without CIO (-19.9 ± 2.3%; WMD = 1.6%, 95% CI = [0.76-2.4], p = 0.001, I2 = 77.1%) and to normal population (-20.61 ± 2.26%; WMD = 2.2%, 95% CI = [0.91-3.5], p = 0.001, I2 = 83.9%). A GLS < -19.5% could predict CIO with 92.8% sensitivity and 34.63% specificity (AUC = 0.659, 95% CI = [0.6-0.72], p-value < 0.0001). A GLS value < -6% has 100% positive predictive and ≥ -24.5% has 100% negative predictive values for detection of CIO. CONCLUSIONS: According to our study, GLS is a strong predictor of CIO and when CMR is not available, it may be a useful screening method for identification of CIO in thalassemia patients.

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.