Myocardial Iron Overload In Thalassemia Research Articles

Multiparametric Cardiac Magnetic Resonance Assessment in Sickle Beta Thalassemia.

Cardiac involvement in sickle beta thalassemia (Sβ-thal) patients has been poorly investigated. We aimed to evaluate cardiac function and myocardial iron overload by cardiovascular magnetic resonance (CMR) in patients with Sβ-thal. One-hundred and eleven Sβ-thal patients consecutively enrolled in the Myocardial Iron Overload in Thalassemia (MIOT) network were studied and compared with 46 sickle cell anemia (SCA) patients and with 111 gender- and age- matched healthy volunteers. Cine images were acquired to quantify biventricular function. Myocardial iron overload (MIO) was assessed by the T2* technique, while macroscopic myocardial fibrosis was evaluated by the late gadolinium enhancement (LGE) technique. In Sβ-thal and SCA patients, the morphological and functional CMR parameters were not significantly different, except for the left atrial area and left ventricular (LV) stroke volume, indexed by body surface area (p = 0.023 and p = 0.048, respectively), which were significantly higher in SCA patients. No significant differences between the two groups were found in terms of myocardial iron overload and macroscopic myocardial fibrosis. When compared to healthy subjects, Sβ-thal patients showed significantly higher bi-atrial and biventricular parameters, except for LV ejection fraction, which was significantly lower. The CMR analysis confirmed that Sβ-thal and SCA patients are phenotypically similar. Since Sβ-thal patients showed markedly different morphological and functional indices from healthy subjects, it would be useful to identify Sβ-thal/SCA-specific bi-atrial and biventricular reference values.

Phenotypic Clustering of Beta-Thalassemia Intermedia Patients Using Cardiovascular Magnetic Resonance.

We employed an unsupervised clustering method that integrated demographic, clinical, and cardiac magnetic resonance (CMR) data to identify distinct phenogroups (PGs) of patients with beta-thalassemia intermedia (β-TI). We considered 138 β-TI patients consecutively enrolled in the Myocardial Iron Overload in Thalassemia (MIOT) Network who underwent MR for the quantification of hepatic and cardiac iron overload (T2* technique), the assessment of biventricular size and function and atrial dimensions (cine images), and the detection of replacement myocardial fibrosis (late gadolinium enhancement technique). Three mutually exclusive phenogroups were identified based on unsupervised hierarchical clustering of principal components: PG1, women; PG2, patients with replacement myocardial fibrosis, increased biventricular volumes and masses, and lower left ventricular ejection fraction; and PG3, men without replacement myocardial fibrosis, but with increased biventricular volumes and masses and lower left ventricular ejection fraction. The hematochemical parameters and the hepatic and cardiac iron levels did not contribute to the PG definition. PG2 exhibited a significantly higher risk of future cardiovascular events (heart failure, arrhythmias, and pulmonary hypertension) than PG1 (hazard ratio-HR = 10.5; p = 0.027) and PG3 (HR = 9.0; p = 0.038). Clustering emerged as a useful tool for risk stratification in TI, enabling the identification of three phenogroups with distinct clinical and prognostic characteristics.

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.

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 ± 12.67years, 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* < 20ms). During a mean follow-up of 63.01 ± 24.95months, 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 > 31g/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.

Cardiac Magnetic Resonance Predicts Heart Failure Mortality in Patients with Thalassemia Major

Iron-induced Heart Failure (HF) still remains the main cause of mortality in patients with thalassemia major (TM), although the introduction of the T2* Cardiovascular Magnetic Resonance (CMR) for the non-invasive assessment of Myocardial Iron Overload (MIO) led to a significant increase in survival rate. However, the pathophysiology of heart failure in TM can be multifactorial. Thanks to its multiparametric potential, CMR represents a unique tool for characterization of myocardial involvement. It is the gold standard for the quantification of biventricular size and function by cine images and for the detection of replacement fibrosis by late gadolinium enhancement (LGE) technique. The aim of this multicenter study was to evaluate the prognostic value of multiparametric CMR in predicting death for HF. We considered 1398 white TM patients who performed a baseline CMR exam within the Myocardial Iron Overload in Thalassemia (MIOT) network. As per inclusion criteria, no patient had a history of HF. Mean age was 30.8±8.9 years and 725 (51.9%) patients were females. During a mean follow-up of 4.83±2.05 years, 49.1% of the patients changed at least once the chelation regimen (i.e.: either switched to a different type of chelator or underwent dose/frequency modification); these patients were more likely to have a global heart T2* value<20ms than patients who maintained the same regimen (33.2% vs 19.7%; P<0.0001) Twelve (1.0%) patients died from heart failure. Table 1 shows the results, presented as hazard ratio (HR) with 95% confidence intervals (CI), of the univariate Cox Regression analysis, performed to test the association between the considered prognostic variables and the outcome. No association was detected between age or gender and HF mortality. Significant MIO (global heart T2*<20 ms), ventricular dysfunction, ventricular dilation, and replacement myocardial fibrosis were identified as significant univariate prognosticators. Due to the low number of deaths for HF, it was not possible to perform a multivariate model. However, based on the presence of the four CMR predictors of HF death, patients were divided into three subgroups: four markers (7 patients; one HF death-14.3%), one to four markers (617 patients, 9 HF deaths-1.5%), and none of the four markers (488 patients; one HF death-0.2%). Patients having all four markers had a significantly higher risk of dying for HF than patients without markers (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). In our homogeneous white and well-treated Italian/Mediterranean population, we detected a low incidence of deaths for HF, since the T2* report guided the patient-specific adjustment of the chelation regimen. As expected, MIO was a significant predictor of HF death but also other CMR parameters, namely ventricular dilatation, ventricular dysfunction, and replacement myocardial fibrosis emerged as unfavorable prognosis determinant. Importantly, when the four CMR indices were evaluated in combination, they fine-tuned the prognostic stratification of TM patients. Hence, the findings of the present study promote the exploitation of the full potential of CMR, including LGE, for a better risk stratification of TM patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Chronic Hepatitis C Virus Infection Is Associated with an Increased Risk of Diabetes Mellitus in Thalassemia Major

Introduction. Hepatitis C virus (HCV) infection is associated with a number of important extrahepatic manifestations. The association between HCV infection and the occurrence of diabetes mellitus remains controversial. Aim. The aim of this multicentric study was to prospectively assess the relationship between HCV infection and diabetes mellitus in patients with thalassemia major (TM). Methods. We considered 1057 TM patients (539 females; 29.79±10.08 years) consecutively enrolled in the Myocardial Iron Overload in Thalassemia (MIOT). Every 18±3 months the patients performed a magnetic resonance imaging (MRI) scan for iron overload assessment by the T2* technique. The disturbances of glucose metabolism were assessed within three months from each MRI by means of oral glucose tolerance test (OGTT). Results. On the basis of the presence of HCV antibodies and RNA, a categorization in 4 groups was performed: negative patients (group 1a, N=460), patients who spontaneously cleared the virus in the first 6 months of infection (group 1b, N=242), patients who eradicated the virus after the treatment with antiviral therapy obtaining a sustained virological response (SVR) (group 2, N=102), and patients with chronic HCV infection (group 3, N=254). The absolute first MRI was the baseline for patients in groups 1a, 1b and 3 while for patients in group 2 the baseline was represented by the first MRI performed after the virus eradication. The follow-up date coincided with the date of the last available MRI. Mean age was significantly lower in group 1a than in all the other 3 groups and in both groups 1b and 3 than in group 2. Group 1a and 1b were considered as a unique group (group 1, no chronic HCV infection). A match 1:1 for age and sex with group 2 was performed. At the baseline ALT and AST levels were significantly increased in group 3 versus both groups 1 and 2 (P<0.0001 for all comparison) and GGT was significantly higher in group 3 than in group 2 (P=0.024). No significant difference was detected in iron overload indices. The OGTT was not performed in 5 patients without known diabetes and frequency of diabetes was comparable among the three groups. Mean follow-up time was 66.27±39.23 months. Among the 253 (84.1%) patients free of diabetes at the baseline MRI, 8 did not perform the OGTT at the follow-up. So, we considered 245 patients: 85 in group 1, 83 in group 2, and 77 in group 3. During the follow-up, diabetes mellitus was recorded in the 2.4%, 6.0% and 7.8% of patients in group 1, 2 and 3, respectively. The chronic HCV group showed a significantly higher risk of diabetes than group 1 (hazard-ratio-HR=5.33, 95%CI=1.06-26.93; P=0.043). The Figure shows the Kaplan-Meier curve. Conclusion. Chronic HCV infection is associated with a significant higher risk of diabetes mellitus in TM patients and, as a consequence, it should be analyzed as a systemic disease in which extrahepatic consequences increase the weight of its pathological burden. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

P1514: MULTI-PARAMETRIC CARDIAC MAGNETIC RESONANCE FOR RISK PREDICTION OF HEART FAILURE DEATH IN THALASSEMIA MAJOR

Background: Iron-induced heart failure (HF) is the main cause of mortality in patients with thalassemia major (TM). Cardiovascular Magnetic Resonance (CMR) plays a key role in the management of these patients, assessing myocardial iron overload (MIO), biventricular function, and myocardial fibrosis. Aims: We evaluated the prognostic value of CMR parameters in predicting death for HF. Methods: We followed prospectively 1681 white TM patients who performed a baseline CMR exam within the Myocardial Iron Overload in Thalassemia (MIOT) network. All prognostic variables associated with the outcome at the univariate Cox model were placed in the multivariate model and were ruled out if they did not significantly improve the adjustment. Results: At baseline the mean age was 31.11±9.01 years and 874 (52.0%) patients were females. During a mean follow-up of 4.76±2.07 years, 47.3% of the patients changed at least once the chelation regimen, that is switched to a different type of chelator or underwent dose/frequency modification. Sixteen (1.0%) patients died for heart failure. No association was detected between age or gender and HF mortality. Patients who died for HF had significantly lower baseline global heart T2* values (19.45±15.11 ms vs 29.52±12.02 ms, P=0.006) and significantly higher baseline MR liver iron concentration (LIC) values (19.17±15.95 mg/g dw vs 8.72±10.63 mg/g dw, P=0.005) than patients still alive or died for a different cause, but the presence of a pathologic MRI LIC (>3 mg/g dw) was not associated with an increased risk of HF mortality. Heart iron, ventricular dysfunction, and ventricular dilatation were significant univariate prognosticators. In the multivariate analysis the independent predictive factors were a global heart T2*<10 ms (compared to a global heart T2*≥20 ms) (hazard ratio-HR=5.38, 95%CI=1.79-16.22, P=0.003) and ventricular dilatation (HR=4.59, 95%CI=1.55-13.59, P=0.006). The Figure shows the Kaplan–Meier survival curves. The log-rank test revealed a significant difference in the curves for each predictor (severe MIO: P<0.0001 and ventricular dilatation: P<0.0001). Image:Summary/Conclusion: We detected few HF deaths thanks to a MR-guided patient-specific adjustment of the chelation therapy. Severe MIO and ventricular dilatation identified TM patients at high risk for heart failure death. So, a widespread program using CMR exploiting its multi-parametric potential can have considerable power for further opening the prognosis of TM patients.

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

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.

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

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). 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. 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.

Changes in CMR Parameters and Prediction of Cardiac Complications in Thalassemia Major: Fibrosis Tells Us More Than Iron

Introduction. Cardiovascular magnetic Resonance (CMR) has dramatically changed the clinical practice and improved the prognosis in thalassemia major (TM). This is the first study evaluating the predictive value of changes in CMR parameters (myocardial iron, function, and fibrosis) for cardiac complications in TM.Methods. We followed prospectively 709 TM patients (374 females; 29.77±8.53 years) consecutively enrolled in the Myocardial Iron Overload in Thalassemia (MIOT) Network who performed a baseline and a 1 st follow up CMR scan after 18 months. Myocardial iron overload (MIO) was measured by multislice multiecho T2* technique and atrial dimensions and biventricular function by cine images. Macroscopic myocardial fibrosis was detected by late gadolinium enhancement technique.Risk classes were defined based on the 4 patterns of MIO from worst to normal. For patients with baseline MIO (at least one segmental T2*<20 ms), improvement was defined as a transition to a better risk class, stabilization as no change in risk class, and worsening as a transition to a worse risk class. For patients without baseline MIO, the worsening was the transition to a worse risk class.The percentage change was used for continuous variables. For biventricular ejection fractions, improvement was a %change>10%, stabilization a %change between -10% and 10%, and worsening a %change<-10%. For biventricular volumes, LV mass index, and atrial areas, improvement was a % change<-10%, stabilization a % change between -10% and 10%, and worsening a % change>10%.Myocardial fibrosis was considered absent if not detected in any of the two CMRs and present if detected in at least one examination .Results. During a mean follow-up of 89.4±33.3 months, cardiac events were recorded in 50 (7.1%) patients: 24 (48%) episodes of heart failure, 24 (48%) arrhythmias (23 supraventricular and 1 hypokinetic), and 2 (4.0%) pulmonary hypertension. Mean time from the 1 st follow up CMR to the development of a cardiac complication was 75.31±35.35 months.In the univariate Cox regression analysis, cardiac iron cleareance and myocardial fibrosis were identified as univariate prognosticators (Table 1). In the multivariate analysis only myocardial fibrosis remained an independent predictor factor.Conclusion. The presence of myocardial fibrosis at the baseline CMR or developed within 18 months emerges as the strongest long-term predictor for cardiac complications in TM. Our data demonstrate the importance in using the contrast medium for CMR scans in thalassemia patients. [Display omitted] DisclosuresPepe: Bayer S.p.A.: Other: no profit support; Chiesi Farmaceutici S.p.A: Other: no profit support. Maggio: Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene Corp: Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Membership on an entity's Board of Directors or advisory committees.

Normal CMR Bi-Atrial and Biventricular Reference Values in Sickle Cell Disease Patients without Heart Damage

Background. Cardiac function indices in patients with hemoglobinopathies are different from those in healthy population, mainly due to chronic anemia. Normal reference values specific for SCD patients are not available by CMR.Aim. We aimed to define the normal cut-off value in SCD patients for bi-atrial and biventricular cardiac magnetic resonance (CMR) parameters.Methods. We considered forty-eight adult SCD patients with no known risk factors or cardiac disease, normal electrocardiogram, no macroscopic myocardial fibrosis, and all cardiac segments with T2*≥20 ms, consecutively enrolled in the MIOT network (Myocardial iron overload in thalassemia). SCD patients were compared with ninety-six healthy controls and 96 thalassemia major (TM) patients without cardiac damage, both matched for age and gender. Nine pediatric SCD patients were also analysed in comparison with 9 TM patients and 9 healthy subjects matched for age and gender. Cine images were acquired to quantify biventricular function parameters: LV and RV end-diastolic volume (EDV), end-systolic volume (ESV) and stroke volume (SV) were normalized for body surface area (EDVI, ESVI, SVI), as well as biventricular mass and atrial areas. Myocardial iron overload was assessed by segmental T2* technique. Late gadolinium enhancement (LGE) images were acquired for evaluation of macroscopic myocardial fibrosis.Results. In all three groups males showed higher biventricular volumes and mass indexes than females. SCD male patients had significantly higher LVEDVI (p<0.0001), LVESVI (p=0.010), LVSVI (p=0.003), cardiac index (p=0.002), LV and RV mass index (p=0.008 and p=0.001, respectively) and left and right atrial areas (p<0.001 and p=0.011) than healthy subjects. No significant differences were found in RVEDVI, EVESVI and biventricular EF. Compared to healthy volunteers, females with SCD showed a larger LVEDVI (p=0.020), LVSVI (p=0.039), RV mass index (p=0.002) and left atrial area (p=0.008).SCD and TM patients showed comparable values of bi-atrial and biventricular volumes and function. When compared to TM, SCD patients showed a larger LV (p<0.001) and RV mass index (p=0.001) in male group and a larger RV mass index (p=0.001) in female group. Table 1 shows the cut-offs for bi-atrial and biventricular MR parameters for adult SCD patients by gender.No significant differences in MR parameters were found among the pediatric groups.Conclusions. Normal reference ranges of bi-atrial and biventricular MR parameters for adult males and females SCD patients were established. The use of these reference values will prevent possible misdiagnosis of cardiomyopathy in patients with SCD. [Display omitted] DisclosuresPepe: Chiesi Farmaceutici S.p.A: Other: no profit support; Bayer S.p.A.: Other: no profit support. Quarta: Sanofi - Genzyme: Membership on an entity's Board of Directors or advisory committees, Other: collaboration relationships for Advisory boards, Webinar events, editorial projects; Speaker at conferences; Blue Bird Bio: Other: collaboration relationships for Advisory boards, Webinar events, editorial projects; Celgene: Other: collaboration relationships for Advisory boards, Webinar events, editorial projects; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: collaboration relationships for Advisory boards, Webinar events, editorial projects; Speaker at conferences; Takeda: Other: collaboration relationships for Advisory boards, Webinar events, editorial projects; speaker at conferences; Bristol Meyer Squibb: Membership on an entity's Board of Directors or advisory committees, Other: Speaker at conferences. Maggio: Bluebird Bio: Membership on an entity's Board of Directors or advisory committees; Celgene Corp: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.

Changes in CMR parameters and prediction of cardiac complications in thalassemia major: fibrosis tells us more than iron

Abstract Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): The MIOT project received “no-profit support” from industrial sponsorships (Chiesi Farmaceutici S.p.A. and ApoPharma Inc.). Background Cardiovascular magnetic Resonance (CMR) has dramatically changed the clinical practice and improved the prognosis in thalassemia major (TM). Aim This is the first study evaluating the predictive value of changes in CMR parameters (myocardial iron, function, and fibrosis) for cardiac complications in TM. Methods We followed prospectively 709 TM patients (374 females; 29.77 ± 8.53 years) consecutively enrolled in the Myocardial Iron Overload in Thalassemia (MIOT) Network who performed a baseline and a 1st follow up CMR scan after 18 months. Myocardial iron overload (MIO) was measured by multislice multiecho T2* technique and atrial dimensions and biventricular function by cine images. Macroscopic myocardial fibrosis was detected by late gadolinium enhancement technique. Risk classes were defined based on the 4 patterns of MIO from worst to normal. For patients with baseline MIO (at least one segmental T2*&amp;lt;20 ms), improvement was defined as a transition to a better risk class, stabilization as no change in risk class, and worsening as a transition to a worse risk class. For patients without baseline MIO, the worsening was the transition to a worse risk class. The percentage change was used for continuous variables. For biventricular ejection fractions, improvement was a %change &amp;gt; 10%, stabilization a %change between -10% and 10%, and worsening a %change&amp;lt;-10%. For biventricular volumes, LV mass index, and atrial areas, improvement was a % change&amp;lt;-10%, stabilization a % change between -10% and 10%, and worsening a % change &amp;gt; 10%. Myocardial fibrosis was considered absent if not detected in any of the two CMRs and present if detected in at least one examination. Results During a mean follow-up of 89.4 ± 33.3 months, cardiac events were recorded in 50 (7.1%) patients: 24 (48%) episodes of heart failure, 24 (48%) arrhythmias (23 supraventricular and 1 hypokinetic), and 2 (4.0%) pulmonary hypertension. Mean time from the 1st follow up CMR to the development of a cardiac complication was 75.31 ± 35.35 months. In the univariate Cox regression analysis, cardiac iron cleareance and myocardial fibrosis were identified as univariate prognosticators (Table 1). In the multivariate analysis only myocardial fibrosis remained an independent predictor factor. Conclusion The presence of myocardial fibrosis at the baseline CMR or developed within 18 months emerges as the strongest long-term predictor for cardiac complications in TM. Our data demonstrate the importance in using the contrast medium for CMR scans in thalassemia patients.

Multiparametric cardiac magnetic resonance assessmenti in sickle-beta-thalassemia

Abstract Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): The MIOT project receives “no-profit support” from industrial sponsorships (Chiesi Farmaceutici S.p.A., ApoPharma Inc.). Background. Sickle β-thalassemia (Sβ-thal) is a hereditary hemoglobinopathy resulting from the combined heterozygosity for sickle cell and β-thalassemia genes. Cardiac involvement in Sβ-thal patients has been poorly investigated. Aim. We aimed to evaluate myocardial iron overload and cardiac function by cardiovascular magnetic resonance (CMR) in patients with Sβ-thal. Methods. One hundred and eleven Sβ-thal patients consecutively enrolled in the Myocardial Iron Overload in Thalassemia (MIOT) network were studied and compared with 46 sickle cell disease (SCD) patients. Biatrial and biventricular function CMR parameters of Sβ-thal patients were compared with those of 111 healthy volunteers, matched by gender and age. Myocardial iron overload (MIO) was assessed by T2* technique. Cine images were acquired to quantify biventricular function. Macroscopic myocardial fibrosis was evaluated by late gadolinium enhancement (LGE) technique. Results. In Sβ-thal and SCD patients morphological and functional MR parameters were not significantly different, except for left atrial area and SVI (p = 0.023 and p = 0.048, respectively) that were significantly higher in SCD patients. No significant differences between the two groups were found in terms of myocardial iron overload and macroscopic myocardial fibrosis. When compared to healthy subjects, Sβ-thal patients showed significantly higher bi-atrial and biventricular parameters except for LVEF that was significantly lower (Fig.1). Conclusions. The CMR analysis confirmed that Sβ-thal and SCD patients are phenotypically similar. Since Sβ-thal patients showed markedly different morphological and functional indices from healthy subjects, it would be useful to identify Sβ-thal/SCD-specific bi-atrial and biventricular reference values.

Normal CMR bi-atrial and biventricular reference values in sickle cell disease patients without heart damage

Abstract Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): The MIOT project receives “no-profit support” from industrial sponsorships (Chiesi Farmaceutici S.p.A., ApoPharma Inc.). Background. Cardiac function indices in patients with hemoglobinopathies are different from those in healthy population, mainly due to chronic anemia. Normal reference values specific for SCD patients are not available by CMR. Aim. We aimed to define the normal cut-off value in SCD patients for bi-atrial and biventricular cardiac magnetic resonance (CMR) parameters. Methods. We considered forty-eight adult SCD patients with no known risk factors or cardiac disease, normal electrocardiogram, no macroscopic myocardial fibrosis, and all cardiac segments with T2*≥20 ms, consecutively enrolled in the MIOT network (Myocardial iron overload in thalassemia). SCD patients were compared with ninety-six healthy controls and 96 thalassemia major (TM) patients without cardiac damage, both matched for age and gender. Nine pediatric SCD patients were also analysed in comparison with 9 TM patients and 9 healthy subjects matched for age and gender. Cine images were acquired to quantify biventricular function parameters: LV and RV end-diastolic volume (EDV), end-systolic volume (ESV) and stroke volume (SV) were normalized for body surface area (EDVI, ESVI, SVI), as well as biventricular mass and atrial areas. Myocardial iron overload was assessed by segmental T2* technique. Late gadolinium enhancement (LGE) images were acquired for evaluation of macroscopic myocardial fibrosis. Results. In all three groups males showed higher biventricular volumes and mass indexes than females. SCD male patients had significantly higher LVEDVI (p &amp;lt; 0.0001), LVESVI (p = 0.010), LVSVI (p = 0.003), cardiac index (p = 0.002), LV and RV mass index (p = 0.008 and p = 0.001, respectively) and left and right atrial areas (p &amp;lt; 0.001 and p = 0.011) than healthy subjects. No significant differences were found in RVEDVI, EVESVI and biventricular EF. Compared to healthy volunteers, females with SCD showed a larger LVEDVI (p = 0.020), LVSVI (p = 0.039), RV mass index (p = 0.002) and left atrial area (p = 0.008). SCD and TM patients showed comparable values of bi-atrial and biventricular volumes and function. When compared to TM, SCD patients showed a larger LV (p &amp;lt; 0.001) and RV mass index (p = 0.001) in male group and a larger RV mass index (p = 0.001) in female group. Table 1 shows the cut-offs for bi-atrial and biventricular MR parameters for adult SCD patients by gender. No significant differences in MR parameters were found among the pediatric groups. Conclusions. Normal reference ranges of bi-atrial and biventricular MR parameters for adult males and females SCD patients were established. The use of these reference values will prevent possible misdiagnosis of cardiomyopathy in patients with SCD.

Pancreatic Iron and Bone Health in Thalassemia Major

Background. It has been shown that serum ferritin and heart iron content are good indicators of bone mineral density (BMD) in patients with beta thalassemia major (TM). In the present study we explored for the first time the relationship between pancreatic iron and BMD and bone markers in TM.Methods. We considered 135 TM patients (68 M, mean age 37.79±7.74 years) enrolled in the MIOT (Myocardial Iron Overload in Thalassemia) Network. BMDs of the lumbar vertebrae (L1-L4) and femoral neck were measured by dual X-ray absorptiometry (DEXA) and were expressed as T-scores. Pancreatic iron overload was quantified by the T2* Magnetic Resonance Imaging (MRI) technique. Blood samples were collected for the measurement of bone formation markers (procollagen 1 amino-terminal propeptide-P1NP, osteocalcin and bone-specific-BAP alkaline phosphatise), bone resorption marker (carboxy-terminal telopeptide of type I collagen-CTX), calcium, and vitamin D.Results. Pancreatic T2* values were significantly associated to lumbar T-scores (R=0.207, P=0.017) as well as to femoral T-scores (R=0.242, P=0.005). The correlations remained significant also in patients without diabetes. Pancreatic iron (global pancreas T2*<26 ms) was detected in 8 patients. Patients with pancreatic iron showed significant lower lumbar T-scores (-2.61±0.89 vs -1.60±0.89; P=0.031) as well as femoral T-scores (-2.12±1.17 vs -1.03±0.97; P=0.009) and 7 of them (87.6%) had lumbar and femoral T-scores indicating osteopathy (osteopenia or osteoporosis).As regards as the markers, pancreatic T2* values were negatively correlated to BAP (R=-0.196 P=0.031) and positively correlated to vitamin D (R=0.220, P=0.014).Conclusion. A significant correlation, although not strong, was detected between pancreatic iron overload and bone disease. From a different point of view, our results support the role of endocrinopathies in thalassemic osteopathy and underline the critical role of a multi-disciplinary intervention in preventing bone complications. DisclosuresPepe:Chiesi Farmaceutici and ApoPharma Inc.: Other: Alessia Pepe is the PI of the MIOT project, that receives no profit support from Chiesi Farmaceutici S.p.A. and ApoPharma Inc.

Pancreatic Iron Loading in Emoglobinopathies

Background.The MIOT (Myocardial Iron Overload in Thalassemia) project is a multicentric study aimed to validate the T2* Magnetic Resonance Imaging (MRI) technique as non invasive approach for the cardiac and hepatic iron overload assessment in patients with hemoglobinopathies and to correlate the T2* values with other clinical-instrumental parameters. More recently, the E-MIOT (Extension-MIOT) project has been approved, with the aim of adding the assessment of the pancreatic ironMethods. We report the baseline MRI findings at the end of the first year of recruitment in the E-MIOT study, outlying the differences among different emoglobinopathies.Results. First, we selected all transfusion-dependent (TD) patients: 7 with sickle-cell disease-SCD or thalasso-drepanocytosis (42.9% F, 32.47 ± 17.93 years), 16 with thalassemia intermedia-TI (56.3% F, 36.66 ± 13.72 years), and 232 with thalassemia major-TM (55.6% F, 36.95 ± 9.83 years). Sex, mean age, serum ferritin levels, MRI liver iron concentration (LIC) values, and global heart T2* values were comparable among the three groups of patients. Pancreatic T2* values were significantly lower in TM patients versus both SCD and TI patients (see Figure).Second, we focused our analysis on all TI patients, divided in two subgroups: transfusion dependent and no-TD. Global pancreas T2* values and the number of patients with pancreatic iron (T2*<26 ms) were comparable between the two groups (see Table).Conclusion. SCD and TI TD patients have lower pancreatic iron loading than chronically-transfused TM patients. Much of this disparity can be explained by the larger transfusional burdens and durations observed in TM patients (years of regular transfusions: 34.18 ± 10.75 in TM, 22.27 ± 18.53 in SCD and 28.33 ± 15.30 in TI, P=0.023). However, TI-TD and TI-noTD patients had comparable pancreatic T2* values. So, innate differences in iron handling and elimination among different diseases also could contribute to the differences in pancreatic iron loading. [Display omitted] DisclosuresPepe:Chiesi Farmaceutici and ApoPharma Inc.: Other: Alessia Pepe is the PI of the MIOT project, that receives no profit support from Chiesi Farmaceutici S.p.A. and ApoPharma Inc.

Gender Differences in the Development of CMR Abnormalities and Cardiac Complications: A Multicentric Prospective Study in a Cohort of Sickle Cell Disease Patients

Introduction. No data are available in literature about the relationship between gender and the development of CMR abnormalities and/or cardiac complications in sickle cell disease (SCD). This prospective and multicentre study aimed to assess if there was an association between gender and risk of cardiac iron overload, heart dilation, hypertrophy, and dysfunction, and myocardial fibrosis, assessed by Cardiovascular Magnetic Resonance (CMR), and of cardio-vascular complications in sickle cell disease (SCD) patients.Methods. We considered 115 SCD patients (58 females, 34.79±13.26 years), consecutively enrolled in the Myocardial Iron Overload in Thalassemia (MIOT) Network. Myocardial iron overload was assessed by the multislice multiecho T2* technique. Biventricular function parameters and atrial areas were quantified by cine images. Late gadolinium enhancement (LGE) images were acquired to detect myocardial fibrosis.Results. Table 1 shows the comparison between sexes in the development of cardiac outcomes.Males and fameles showed a similar risk of accumulating cardiac iron, but both patients with cardiac iron were females.Compared to females, males showed a significant lower risk of developing biventricular hypertrophy (Kaplan-Meyer curve shown in Figure 1), although having a similar risk for biventricular dilation and dysfunction and for myocardial fibrosis. No patients with less than 34 years developed biventricular hypertrophy and age at the CMR was significantly higher in patients with hypertrophy versus patients without it (42.93±7.23 years versus 34.64±12.79 years; P=0.001).We recorded 12 (10.4%) cardiac events: 4 ischemic strokes, 5 arrhythmias (4 supraventricular and 1 ventricular), two pulmonary hypertensions and one pulmonary embolism. No prospective association was detected between gender and cardiac complications.Conclusion. In SCD male and female seem to show a comparable risk in developing cardiac complication, although compared to females, males showed a significant lower risk of developing biventricular hypertrophy. There are no specific guidelines for SCD patients and, as a consequence, the cardiovascular follow-up is conformed to that one of thalassemia patients (complete cardiac evaluation performed annually for both genders). Our data not support a different follow up time based on the gender. [Display omitted] DisclosuresPepe:Chiesi Farmaceutici and ApoPharma Inc.: Other: Alessia Pepe is the PI of the MIOT project, that receives no profit support from Chiesi Farmaceutici S.p.A. and ApoPharma Inc.

Common Link between Bone and Heart Health in Thalassemia Major

Background. A common link between bone and heart health has been detected in the general population. In the present study we evaluated the relationship between bone mineral density (BMD) and cardiac iron, cardiovascular complications, and cardiovascular risk factors in patients with thalassemia major (TM).Methods. We considered 135 TM patients (68 M, mean age 37.79±7.74 years) enrolled in the MIOT (Myocardial Iron Overload in Thalassemia) Network. BMDs of the lumbar vertebrae (L1-L4) and femoral neck were measured by dual X-ray absorptiometry (DEXA) and were expressed as T-scores. Myocardial iron overload (MIO) was quantified by the T2* Magnetic Resonance Imaging (MRI) technique. Blood samples were drawn for the analysis of N-terminal pro-brain natriuretic peptide (NT-proBNP), the gold standard biomarker in determining the diagnosis and prognosis of heart failure.Results. MIO (global heart t2*<20 ms) was detected in 20 (14.8%) patients. Patients with MIO showed significant lower femoral T-scores (-2.64±1.87 vs -1.96±0.99; P=0.045).Twelve patients showed cardiac complications (8 arrhythmias, 2 heart failure, 2 pulmonary hyperthension) and all of them had lumbar and femoral T-scores indicating osteopathy (osteopenia/osteoporosis). Patients with cardiac complications showed significant lower lumbar T-scores (-3.27±0.89 vs -2.43±1.29; P=0.031) and femoral T-scores (-2.96±2.02 vs -1.98±1.04; P=0.042).Patients with abnormal NTproBNP values (>157 ng/L) showed significantly lower femoral T-scores (-2.41±0.61 vs -1.79±1.16; P=0.048).Patients with diabetes (N=17) showed significant lower femoral T-scores (-2.45±0.79 vs -2.00±1.25; P=0.041).Conclusion. Lower femoral BMD was associated with MIO, cardiac complications, elevated NTproBNP values, and diabetes in patients with thalassemia major. So, our data support and interaction between bone and cardiovascular diseases in TM, suggesting that prevention and treatment strategies targeted for one of the two diseases may be beneficial for the other one. DisclosuresPepe:Chiesi Farmaceutici and ApoPharma Inc.: Other: Alessia Pepe is the PI of the MIOT project, that receives no profit support from Chiesi Farmaceutici S.p.A. and ApoPharma Inc.

Is HCV Infection a Risk Factor for Cardiac Complications in TM?

Hepatitis C virus (HCV) infection is associated with a number of important extrahepatic manifestations. The aim of this multicentric study was to assess the relationship between HCV infection and some traditional cardiovascular risk factors (CRF) and its predictive value and cardiovascular complications (CC) in thalassemia major (TM) patients.We considered 827 TM patients (435 F) consecutively enrolled in the Myocardial Iron Overload in Thalassemia (MIOT) network.At the baseline assessment mean age of the patients, all free of CC, was 29.65±8.89 years and a categorization in 4 groups was performed: negative patients (group 0), patients who spontaneously cleared HCV (group 1), patients who eradicated the virus after treatment with antiviral therapy attaining a sustained virological response-SVR (group 2), and patients with chronic HCV infection (group 3). Patients in group 0 were significantly younger than patients in all the other three groups (P<0.0001) and had a significant lower frequency of diabetes than patients in group 3 (3.6% vs 11.0%; P=0.006).Patients were followed-up for 79.53±28.71 months and 84 cardiovascular events (42 arrhythmias, 29 heart failure, and 13 vascular diseases) were registered. Table 1 shows the results of the univariate Cox regression analysis. Patients with chronic HCV infection had a significant higher risk of developing CC than negative patients.In conclusion, HCV chronic infection is associated with a significant higher risk of CC in TM patients and, as a consequence, it should be analyzed as a systemic disease in which extrahepatic consequences increase the weight of its pathological burden. [Display omitted] DisclosuresPepe:Chiesi Farmaceutici and ApoPharma Inc.: Other: Alessia Pepe is the PI of the MIOT project, that receives no profit support from Chiesi Farmaceutici S.p.A. and ApoPharma Inc.

Myocardial Tissue Characterization By T2 Mapping in Thalassemia Major

Introduction.The presence of iron deposits results in a significant reduction in all magnetic resonance imaging (MRI) relaxation times (T1, T2 and T2*). In the clinical setting the T2* technique is the method of choice for cardiac iron quantification and it has revolutionized the management of patients with hemoglopinopathies. Purpose.To compare myocardial T2 against T2* in patients with thalassemia major (TM) for myocardial iron characterization. Methods.133 TM patients (79 females, 38.4±11.3 years) enrolled in the Extension Myocardial Iron Overload in Thalassemia (eMIOT) Network were considered. T2 and T2* images were acquired, respectively, with multi-echo fast-spin-echo and gradient-echo sequences. Global heart T2 and T2* values were obtained by averaging the values in all 16 myocardial segments. The normal T2 range was established as mean±2 standard deviations on data acquired on 80 healthy volunteers (males: 48-56 ms and females: 50-57 ms). The lower limit of normal for global heart T2*, established on the same healthy population, was 32 ms. Results.A significant correlation was detected between global heart T2 and T2* values (R=0.577; P&amp;lt;0.0001) (Figure). Out of the 113 (84.9%) patients with a normal global heart T2* value, none had a decreased global heart T2 value, while 58 (51.3%) had an increased T2 value. Out of the 20 patents with a decreased global heart T2* value, only 10 (50%) had also a reduced T2 value. Conversely, 9 (45.0%) had a normal global heart T2 value and one (4.5) showed an increased T2 value. The 59 patients with increased global heart T2 value were significantly older than the remaining patients (40.8±10.5 vs 36.4±11.6 years; P=0.019) Conclusion.All patients with decreased T2 value had also a decreased T2* value and in half of the patients iron load was undetected by T2, suggesting that T2 mapping does not offer any advantage in terms of sensitivity for MIO assessment. However, more than half of TM patients had an increased T2 value, thus may be caused by the presence of myocardial inflammation and/or edema. So, T2 mapping could reveal subclinical myocardial involvement in TM patients. Figure Disclosures Pistoia: Chiesi Farmaceutici S.p.A.:Other: speakers' honoraria.Meloni:Chiesi Farmaceutici S.p.A.:Other: speakers' honoraria.