Evidence for Three Distinct Classes of Phenotype Severity in Beta-Thalassaemia

Background: Classification of phenotype severity in patients with beta-thalassaemia has so far relied mainly on expert opinion using parameters of genotype, clinical features at diagnosis, and transfusion requirement. The aim of this study was to use a large dataset of patients with beta-thalassaemia and evaluate a classification system based on onset variables agreed on by an international expert group, including age at diagnosis, at first transfusion, and at first iron chelation. Methods: A retrospective dataset of 7910 patients with homozygous or compound heterozygous beta-thalassaemia was used and subjected to cluster and classification analysis starting with the onset variables. Result…

Different patterns of myocardial iron distribution by whole-heart T2* magnetic resonance as risk markers for heart complications in thalassemia major.

Background The multislice multiecho T2* cardiovascular magnetic resonance (CMR) technique allows to detect different patterns of myocardial iron overload (MIO). The aim of this cross-sectional study was to verify the association between cardiac complications (heart failure and arrhythmias), biventricular dysfunction and myocardial fibrosis with different patterns of MIO in thalassemia major (TM) patients. Methods We considered 812 TM patients enrolled in the Myocardial Iron Overload in Thalassemia (MIOT) Network. The T2* value in all the 16 cardiac segments was evaluated. Results We identified 4 groups of patients: 138 with homogeneous MIO (all segments with T2* < 20 ms), 97 with heterogene…

Preferential patterns of myocardial iron overload by multislice multiecho T2* CMR in thalassemia major patients.

T*(2) multislice multiecho cardiac MR allows quantification of the segmental distribution of myocardial iron overload. This study aimed to determine if there were preferential patterns of myocardial iron overload in thalassemia major. Five hundred twenty-three thalassemia major patients underwent cardiac MR. Three short-axis views of the left ventricle were acquired and analyzed using a 16-segment standardized model. The T*(2) value on each segment was calculated, as well as the global value. Four main circumferential regions (anterior, septal, inferior, and lateral) were defined. Significant segmental variability was found in the 229 patients with significant myocardial iron overload (glob…

Feasibility, reproducibility, and reliability for the T*2 iron evaluation at 3 T in comparison with 1.5 T

This study aimed to determine the feasibility, reproducibility, and reliability of the multiecho T * 2 Magnetic resonance imaging technique at 3 T for myocardial and liver iron burden quantification and the relationship between T * 2 values at 3 and 1.5 T. Thirty-eight transfusion-dependent patients and 20 healthy subjects were studied. Cardiac segmental and global T * 2 values were calculated after developing a correction map to compensate the artifactual T * 2 variations. The hepatic T * 2 value was determined over a region of interest. The intraoperator and interoperator reproducibility for T * 2 measurements at 3 T was good. A linear relationship was found between patients' R (1000/T * …

Pressure–volume relationship by pharmacological stress cardiovascular magnetic resonance

Abstract Background. The variation between rest and peak stress end-systolic pressure-volume relation (ΔESPVR) is an index of myocardial contractility, easily obtained during routine stress echocardiography and never tested during dipyridamole stress-cardiac magnetic resonance (CMR). We assessed the ΔESPVR index in patients with known/suspected coronary artery disease (CAD) who underwent dipyridamole stress-CMR.Methods. One-hundred consecutive patients (24 females, 63.76±10.17 years) were considered. ESPVR index was evaluated at rest and stress from raw measurement of systolic arterial pressure and end-systolic volume by biplane Simpson’s method. Results. The ΔESPVR index showed a good inte…

Myocardial fibrosis by delayed enhancement cardiovascular magnetic resonance and HCV infection in thalassemia major patients.

Abstract Abstract 4265 Introduction. Delayed enhancement (DE) cardiac magnetic resonance (CMR) technique with intravenous administration of gadolinium (Gd) chelates contrast agents is the only validated non-invasive approach for detecting myocardial fibrosis (Mahrholdt H et al, Eur Heart J 2005). This technique has been confirmed safe in patients with hemoglobinopathies (Meloni A et al, Haematologica 2009). In thalassemia major (TM), myocardial fibrosis has been detected using the DE technique and a positive correlation with anti-HCV antibodies has been described (Pepe A et al, Heart 2009). However, HCV-induced cardiomyopathy is still controversial (Matsumori A et al. J Card Fail 2006). The…

Prospective Comparison on Cardiac Iron and Liver Iron by MR In Thalassemia Major Patients Treated with Combination Deferipron–Desferrioxamine Versus Deferipron and Desferrioxamine In Monoterapy

Abstract Abstract 5164 Introduction: Using T2* MR a randomised placebo controlled study from Sardinia demonstrated combination therapy with deferiprone and desferrioxamine (DFP+DFO) significantly more effective than DFO in improving myocardial iron. One non-randomised study from Sardinia and one observational study from Greece seem to confirm for DFP+DFO therapy the most rapid clearance of cardiac iron. No data are available in literature about prospective comparisons on cardiac iron and function and liver iron in TM patients treated with DFP+DFO versus DFP and DFO in monotherapy. The aim of this multi-centre study was to assess prospectively in a large clinical setting the efficacy of the …

A complication risk score to evaluate clinical severity of thalassaemia syndromes

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 transaminas…

Development of a Severity Score System for Thalassemia Syndromes

Introduction Thalassemia Syndromes (TS) are a group of inherited haemoglobin disorders characterized by different phenotype severity falling among heterozygote state, no transfusion dependent thalassemia (NTDT) and transfusion dependent Thalassemia (TDT) (Graffeo et al, 2018; Taher &amp; Saliba, 2017). Several factors, independently by genotype and globin chain unbalance, modulate the severity of ineffective erythropoiesis (Rivella et al, 2015). Considering the complexity of this pathophysiology, one tool to evaluate patients on an individual basis is needed. The aim of this study was to develop a severity scoring system with a view to initiate timely interventions that would prevent any fu…

Cardiac and hepatic iron and ejection fraction in thalassemia major: Multicentre prospective comparison of combined Deferiprone and Deferoxamine therapy against Deferiprone or Deferoxamine Monotherapy

Background: Due to the limited data available in literature, the aim of this multi-centre study was to prospectively compare in thalassemia major (TM) patients the efficacy of combined deferiprone (DFP) and deferoxamine (DFO) regimen versus either DFP and DFO in monotherapy by cardiovascular magnetic resonance (CMR) over a follow up of 18 months. Methods: Among the first 1135 TM patients in the MIOT (Myocardial Iron Overload in Thalassemia) network, we evaluated those who had received either combined regimen (DFO + DFP, N=51) or DFP (N=39) and DFO (N=74) monotherapies between the two CMR scans. Iron overload was measured by T2* multiecho technique. Biventricular function parameters were qua…

Non-compact myocardium assessment by cardiac magnetic resonance: dependence on image analysis method

To compare image analysis methods for the assessment of left ventricle non-compaction from cardiac magnetic resonance (CMR) imaging. CMR images were analyzed in 20 patients and 10 normal subjects. A reference model of the MR signal was introduced and validated based on image data. Non-compact (NC) myocardium size and distribution were assessed by tracing a single, continuous contour delimiting trabeculated region (Jacquier) or by one-by-one selection of trabeculae (Grothoff). The global non-compact/compact (NC/C) ratio, the NC mass, and the segmental NC/C ratio were assessed. Results were compared with the reference model. A significant difference between Grothoff and Jacquier approaches in…

268Prognostic value of dipyridamole stress CMR in patients with known or suspected coronary artery disease: a long term follow-up study

Deferasirox, deferiprone and desferrioxamine treatment in thalassemia major patients: cardiac iron and function comparison determined by quantitative magnetic resonance imaging

Background Oral deferiprone was suggested to be more effective than subcutaneous desferrioxamine for removing heart iron. Oral once-daily chelator deferasirox has recently been made commercially available but its long-term efficacy on cardiac iron and function has not yet been established. Our study aimed to compare the effectiveness of deferasirox, deferiprone and desferrioxamine on myocardial and liver iron concentrations and bi-ventricular function in thalassemia major patients by means of quantitative magnetic resonance imaging. Design and Methods From the first 550 thalassemia subjects enrolled in the Myocardial Iron Overload in Thalassemia network, we retrospectively selected thalasse…

Autoimmune polyendocrine syndrome type 1: an Italian survey on 158 patients

Abstract Background Autoimmune Polyglandular Syndrome type 1 (APS-1) is a rare recessive inherited disease, caused by AutoImmune Regulator (AIRE) gene mutations and characterized by three major manifestations: chronic mucocutaneous candidiasis (CMC), chronic hypoparathyroidism (CH) and Addison’s disease (AD). Methods Autoimmune conditions and associated autoantibodies (Abs) were analyzed in 158 Italian patients (103 females and 55 males; F/M 1.9/1) at the onset and during a follow-up of 23.7 ± 15.1 years. AIRE mutations were determined. Results The prevalence of APS-1 was 2.6 cases/million (range 0.5–17 in different regions). At the onset 93% of patients presented with one or more component…

Myocardial fibrosis by delayed enhancement cardiovascular magnetic resonance and HCV infection in thalassemia major patients

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

Multislice multiecho T2* cardiac magnetic resonance for the detection of heterogeneous myocardial iron distribution in thalassaemia patients

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 segme…

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

In β-thalassaemia, the severity of inherited β-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 β-thalassaemia patients with available genotypes in a global database. Genotype severity was grouped as β0 /β0 , β0 /β+ , β+ /β+ , β0 /β++ , β+ /β++ , and β++ /β++ . 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, β0 and β+ mu…

Single region of interest versus multislice T2* MRI approach for the quantification of hepatic iron overload.

Purpose To evaluate the effectiveness of the single ROI approach for the detection of hepatic iron burden in thalassemia major (TM) patients in respect to a whole liver measurement. Materials and Methods Five transverse hepatic slices were acquired by a T2* gradient-echo sequence in 101 TM patients and 20 healthy subjects. The T2* value was calculated in a single region of interest (ROI) defined in the medium-hepatic slice. Moreover, the T2* value was extracted on each of the eight ROIs defined in the functionally independent segments. The mean hepatic T2* value was calculated. Results For patients, the mean T2* values over segments VII and VIII were significantly lower. This pattern was su…

1177 The additive prognostic value of end-systolic pressure-volume relation by CMR in patients with with known or suspected coronary artery disease

Abstract Background The variation between rest and peak stress end-systolic pressure-volume relation is an afterload-independent index of left ventricular contractility. This index is easily obtained during routine stress echocardiography but can be derived also during a stress cardiovascular magnetic resonance (CMR) exam, that is the gold standard for the quantification of biventricular volumes. Purpose The aim of this study was to assess for the first time the prognostic value ofdelta rest-stress ESPVR (DESPVR) by dipyridamole stress-CMR in patients with known or suspected coronary artery disease (CAD). Methods One hundred and sixty-six consecutive patients (37 females, main age 61.96 ± 1…

Survival and causes of death in 2,033 patients with non-transfusion-dependent β-thalassemia

P5285Pressure-volume relationship by cardiovascular magnetic resonance: feasibility and clinical implications

Abstract Background The variation between rest and peak stress end-systolic pressure-volume relation (ESPVR; the Suga index) is easily obtained during routine stress echocardiography and has been established as a reasonably load-independent index of myocardial contractile performance that provides prognostic information above and beyond regional wall motion. Purpose This is the first study assessing the delta rest-stress ESPVR (DESPVR) by stress Cardiovascular Magnetic Resonance (CMR). Methods Eighty-five consecutive patients (19 females, main age 62.99±9.26 years) who underwent dipyridamole stress-CMR in a high volume CMR Laboratory were considered. The ESPVR was evaluated at rest and peak…

A T2* MRI Prospective Survey on Heart and Liver Iron In Thalassemia Major Patients Treated with Deferasirox Versus Deferiprone and Desferrioxamine In Monotherapy.

Abstract Abstract 4267 Introduction: Most deaths in thalassemia major (TM) result from cardiac complications due to iron overload. In thalassaemia available three iron chelation regimes in monotherapy may achieve different changes in cardiac iron and function and liver iron. No data are available in literature about prospective comparisons on cardiac iron and function and liver iron in TM patients treated with deferasirox (DFX) versus deferiprone (DFP) and desferrioxamine (DFO) in monotherapy. Magnetic Resonance (MR) is the unique non invasive suitable technique to evaluated quantitatively this issue. The aim of this multi-centre study was to assess prospectively in the clinical practice th…

Prevalence and prognostic impact of nonischemic late gadolinium enhancement in stress cardiac magnetic resonance

Aim To assess the prevalence and prognostic significance of NI-LGE in patients undergoing stress-CMR. Methods Stress-CMR with either dipyridamole or adenosine was performed in 283 patients (228 men, 81%) including perfusion imaging, wall motion evaluation and LGE. Follow-up was completed in all enrolled patients (median time: 1850 days; interquartile range: 1225-2705 days). Composite endpoint included cardiac death, ventricular tachycardia, myocardial infarction, stroke, hospitalization for cardiac cause and coronary revascularization performed beyond 90 days from stress-CMR scans. Results One hundred and twelve patients (40%) had negative LGE (no-LGE), 140 patients (49%) I-LGE and 31 patie…

The prognostic role of CMR using global planimetric criteria in patients with excessive left ventricular trabeculation.

Objectives: Although cardiovascular magnetic resonance (CMR) is widely used in the assessment of left ventricular non-compaction (LVNC), there are no universally accepted diagnostic criteria and limited data regarding their prognostic value. We assessed the long-term prognostic role of the planimetric global Grothoff’s criteria and of the CMR findings in predicting adverse cardiovascular events (CE). Methods: We prospectively enrolled 78 patients (46.7 ± 18.7 years, 33.3% females) with documented positive Jenni’s echocardiographic criteria for LVNC. Cine images were used to quantify function parameters and to assess for the presence of all four quantitative Grothoff’s criteria (global Groth…

Iron in the human hearts: distribution and association with R2* values by CMR

Risk of mortality from anemia and iron overload in nontransfusion-dependent β-thalassemia

Improvement of heart iron with preserved patterns of iron store by CMR-guided chelation therapy

[Formula: see text] multislice multiecho cardiac magnetic resonance (CMR) allows quantification of the segmental distribution of myocardial iron overload (MIO). We evaluated whether a preferential pattern MIO was preserved between two CMR scans in regularly chelated thalassaemia major (TM) patients.We evaluated prospectively 259 TM patients enrolled in the MIO in Thalassaemia (MIOT) network with a CMR follow-up (FU) study at 18 ± 3 months and significant MIO at baseline. The [Formula: see text] in the 16 segments and the global value were calculated. Four main circumferential regions (anterior, septal, inferior and lateral) were defined. We identified two groups: severe (n = 80, global [For…

The Prognostic Role of Hypertrabeculation By Cardiac Magnetic Resonance in Thalassemia Intermedia Patients

Abstract Background. Differentiation of left ventricle non-compaction (LVNC) from hypertrabeculated LV due to a negative heart remodeling in thalassemia intermedia (TI) can depends on the selected CMR criterion. The recently proposed Piga's criterion (NC/C ratio threshold of &gt;2.5, Am J Haem 2012) seems to have a low specificity to identify the true LVNC in TI. Anyway, the Piga's criterion could well detect easy a negative heart remodeling in TI patients. Purpose: To assess prospectively whether the Piga's criterion has a prognostic role for adverse cardiovascular outcomes in TI patients. Methods. We studied prospectively by CMR 168 TI patients (81 males, mean age 38.32 ±11.61 years) cons…

Influence of myocardial fibrosis and blood oxygenation on heart T2* values in thalassemia patients

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 Myoca…

The planimetric Grothoff's criteria by cardiac magnetic resonance can improve the specificity of left ventricular non-compaction diagnosis in thalassemia intermedia

We differentiated the left ventricle non-compaction (LVNC) from hypertrabeculated myocardium due to a negative remodeling in thalassemia intermedia (TI) patients applying linear and planimetric criteria and comparing the cardiovascular magnetic resonance (CMR) findings. CMR images were analyzed in 181 TI patients enrolled in the Myocardial Iron Overload in Thalassemia Network and 27 patients with proved LVNC diagnosis. The CMR diagnostic criteria applied in TI patients were: a modified linear CMR Petersen’s criterion based on a more restrictive ratio of diastolic NC/C &gt; 2.5 at segmental level and the combination of planimetric Grothoff’s criteria (percentage of trabeculated LV myocardial…

Three Distinct Groups of Phenotype Severity in Beta-Thalassemia

Background Thalassemia Syndromes (TS) are commonly classified as transfusion-dependent-thalassemia (TDT) or non-transfusion-dependent thalassemia (NTDT) at diagnosis on the basis of requirement for lifelong regular transfusion therapy for survival. However, data from observational studies and expert opinion suggest that these categories may reflect a wide spectrum rather than a dichotomy, and may actually be interchangeable at many parts of the disease journey. Thus, an evaluation of alternate clusters to classify TS patients remains of merit. Aims The aim of this study was to cluster TS patients on the basis of possible clinical indicators of phenotype severity (IPhS) using suitable algori…