Multislice Multiecho T2 Research Articles

Assessment of Tumor Cell Invasion and Radiotherapy Response in Experimental Glioma by Magnetic Resonance Elastography.

Gliomas are highly invasive brain neoplasms. MRI is the most important tool to diagnose and monitor glioma but has shortcomings. In particular, the assessment of tumor cell invasion is insufficient. This is a clinical dilemma, as recurrence can arise from MRI-occult glioma cell invasion. Tumor cell invasion, tumor growth and radiotherapy alter the brain parenchymal microstructure and thus are assessable by diffusion tensor imaging (DTI) and MR elastography (MRE). Experimental, animal model. Twenty-three male NMRI nude mice orthotopically implanted with S24 patient-derived glioma cells (experimental mice) and 9 NMRI nude mice stereotactically injected with 1 μL PBS (sham-injected mice). 2D and 3D T2-weighted rapid acquisition with refocused echoes (RARE), 2D echo planar imaging (EPI) DTI, 2D multi-slice multi-echo (MSME) T2 relaxometry, 3D MSME MRE at 900 Hz acquired at 9.4 T (675 mT/m gradient strength). Longitudinal 4-weekly imaging was performed for up to 4 months. Tumor volume was assessed in experimental mice (n = 10 treatment-control, n = 13 radiotherapy). The radiotherapy subgroup and 5 sham-injected mice underwent irradiation (3 × 6 Gy) 9 weeks post-implantation/sham injection. MRI-/MRE-parameters were assessed in the corpus callosum and tumor core/injection tract. Imaging data were correlated to light sheet microscopy (LSM) and histology. Paired and unpaired t-tests, a P-value ≤0.05 was considered significant. From week 4 to 8, a significant callosal stiffening (4.44 ± 0.22 vs. 5.31 ± 0.29 kPa) was detected correlating with LSM-proven tumor cell invasion. This was occult to all other imaging metrics. Histologically proven tissue destruction in the tumor core led to an increased T2 relaxation time (41.65 ± 0.34 vs. 44.83 ± 0.66 msec) and ADC (610.2 ± 12.27 vs. 711.2 ± 13.42 × 10-6 mm2/s) and a softening (5.51 ± 0.30 vs. 4.24 ± 0.29 kPa) from week 8 to 12. Radiotherapy slowed tumor progression. MRE is promising for the assessment of key glioma characteristics. NA TECHNICAL EFFICACY: Stage 2.

Can Automated 3-Dimensional Dixon-Based Methods Be Used in Patients With Liver Iron Overload?

Accurate quantification of liver iron concentration (LIC) can be achieved via magnetic resonance imaging (MRI). Maps of liver T2*/R2* are provided by commercially available, vendor-provided, 3-dimensional (3D) multiecho Dixon sequences and allow automated, inline postprocessing, which removes the need for manual curve fitting associated with conventional 2-dimensional (2D) gradient echo (GRE)-based postprocessing. The main goal of our study was to investigate the relationship among LIC estimates generated by 3D multiecho Dixon sequence to values generated by 2D GRE-based R2* relaxometry as the reference standard. A retrospective review of patients who had undergone MRI scans for estimation of LIC with conventional T2* relaxometry and 3D multiecho Dixon sequences was performed. A 1.5 T scanner was used to acquire the magnetic resonance studies. Acquisition of standard multislice multiecho T2*-based sequences was performed, and R2* values with corresponding LIC were estimated. The comparison between R2* and corresponding LIC estimates obtained by the 2 methods was analyzed via the correlation coefficients and Bland-Altman difference plots. This study included 104 patients (51 male and 53 female patients) with 158 MRI scans. The mean age of the patients at the time of scan was 15.2 (SD, 8.8) years. There was a very strong correlation between the 2 LIC estimation methods for LIC values up to 3.2 mg/g (LIC quantitative multiecho Dixon [qDixon; from region of interest R2*] vs LIC GRE [in-house]: r = 0.83, P < 0.01; LIC qDixon [from segmentation volume R2*] vs LIC GRE [in-house]: r = 0.92, P < 0.01); and very weak correlation between the 2 methods at liver iron levels >7 mg/g. Three-dimensional-based multiecho Dixon technique can accurately measure LIC up to 7 mg/g and has the potential to replace 2D GRE-based relaxometry methods.

Mitigating slice cross-talk in multi-slice multi-echo spin echo T2 mapping.

To investigate whether a T2 inter-slice variation could occur when a multi-slice multi-echo spin echo (MESE) sequence is used for image acquisition and to propose an enhanced method for reconstructing T2 maps that can effectively address and correct these variations. Bloch simulations were performed accounting for the direct saturation effect to evaluate magnetization changes in multi-slice 2D MESE sequence. Experimental phantom scans were performed to validate these simulations. An improved version of the dictionary-based reconstruction approach was proposed, enabling the creation of a multi-slice dictionary of echo modulation curves (EMC). The corresponding method has been assayed considering inter-slice T2 variation with phantoms and in lower leg. Experimental and numerical study illustrate that direct saturation leads to a bias of EMCs. This bias during the T2 maps reconstructions using original single-slice EMC-dictionary method led to inter-slice T2 variation of 2.03% in average coefficient of variation (CV) in agarose phantoms, and up to 2.8% in vivo (for TR = 2 s, slice gap = 0%). A reduction of CV was observed when increasing the gap up to 100% (0.36% in phantoms, and up to 1.5% in vivo) or increasing TR up to 4 s (0.76% in phantoms, and up to 1.9% in vivo). Matching the multi-slice experimental data with multi-slice dictionaries provided a reduced CV of 0.54% in phantoms and up to 2.3% in vivo. T2 values quantified from multi-slice MESE images using single-slice dictionaries are biased. A dedicated multi-slice EMC method providing the appropriate dictionaries can reduce the inter-slice T2 variation.

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

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

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

The aim of this multicenter study was to prospectively assess the predictive value of multiparametric cardiac magnetic resonance (CMR) for cardiovascular complications in sickle cell disease (SCD) patients. Among all patients with hemoglobinopathies consecutively enrolled in the Myocardial Iron Overload in Thalassemia (MIOT) Network, we selected 102 SCD patients (34.38 ± 12.67years, 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.

Spatial Gradients of Quantitative MRI as Biomarkers for Early Detection of Osteoarthritis: Data From Human Explants and the Osteoarthritis Initiative.

Healthy articular cartilage presents structural gradients defined by distinct zonal patterns through the thickness, which may be disrupted in the pathogenesis of several disorders. Analysis of textural patterns using quantitative MRI data may identify structural gradients of healthy or degenerating tissue that correlate with early osteoarthritis (OA). To quantify spatial gradients and patterns in MRI data, and to probe new candidate biomarkers for early severity of OA. Retrospective study. Fourteen volunteers receiving total knee replacement surgery (eight males/two females/four unknown, average age ± standard deviation: 68.1 ± 9.6 years) and 10 patients from the OA Initiative (OAI) with radiographic OA onset (two males/eight females, average age ± standard deviation: 57.7 ± 9.4 years; initial Kellgren-Lawrence [KL] grade: 0; final KL grade: 3 over the 10-year study). 3.0-T and 14.1-T, biomechanics-based displacement-encoded imaging, fast spin echo, multi-slice multi-echo T2 mapping. We studied structure and strain in cartilage explants from volunteers receiving total knee replacement, or structure in cartilage of OAI patients with progressive OA. We calculated spatial gradients of quantitative MRI measures (eg, T2) normal to the cartilage surface to enhance zonal variations. We compared gradient values against histologically OA severity, conventional relaxometry, and/or KL grades. Multiparametric linear regression for evaluation of the relationship between residuals of the mixed effects models and histologically determined OA severity scoring, with a significance threshold at α=0.05. Gradients of individual relaxometry and biomechanics measures significantly correlated with OA severity, outperforming conventional relaxometry and strain metrics. In human explants, analysis of spatial gradients provided the strongest relationship to OA severity (R2 =0.627). Spatial gradients of T2 from OAI data identified variations in radiographic (KL Grade 2) OA severity in single subjects, while conventional T2 alone did not. Spatial gradients of quantitative MRI data may improve the predictive power of noninvasive imaging for early-stage degeneration. 1 TECHNICAL EFFICACY: Stage 1.

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.

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.

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.

Prediction of Cardiac Complications in SCD

Introduction: Cardiac magnetic resonance (CMR) is the non-invasive gold standard for the quantification of biventricular functional parameters and for myocardial tissue characterization. The aim of this study was to prospectively assess the predictive value of CMR parameters for cardiovascular complications in sickle cell disease (SCD) patients. Methods: We considered 102 white SCD patients (34.38±12.67 years, 53 females) consecutively enrolled in the Myocardial Iron Overload in Thalassemia (MIOT) network. Myocardial iron overload (MIO) was measured by the multislice multiecho T2* technique. Atrial dimensions and biventricular function parameters were quantified by cine images. Results: At baseline CMR only two patients had MIO (global heart T2*&lt;20 ms). During a mean follow-up was of 63.29±24.41 months, 10 cardiac events (9.8%) were registered: 3 pulmonary hypertension, 1 pulmonary embolism, 1 peripheral vascular disease, 1 transient ischemic attack, 2 supraventricular arrhythmias, 1 heart failure, and 1 death after acute chest syndrome. CMR predictors of cardiovascular events at univariate analysis were left ventricular ejection fraction and right ventricular mass index (see Table). Both variables remained independent predictors at multivariate analysis (see Table). Conclusions: 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 also CMR could be added as screening tool for identifying SCD patients at high risk for pulmonary and systemic vasculopathy and death. Table Disclosures Pepe: Chiesi Farmaceutici S.p.A., ApoPharma Inc., and Bayer: Other: No profit support.

4326Reduction of cardiac outcomes in thalassemia major thanks to a ten-year national Italian networking

Abstract Introduction The MIOT (Myocardial Iron Overload in Thalassemia) Network was a network of thalassemia and CMR centers built in 2006 in order to assure homogeneous and standardized cardiac iron overload assessment for a significant number of patients. Purpose We describe the impact of this ten-year Network on cardiac iron, complications and deaths in patients with thalassemia major (TM). Methods 1746 TM patients (911 F; age 31.17±9.09 yrs) were enrolled in the MIOT Network. Myocardial iron overload (MIO) was quantified by the multislice multiecho T2* technique. Biventricular function was quantified by cine images. Results 1392 TM patients performed an end-of-study CMR. At the last CMR significantly higher global heart T2* values (35.44±10.69 ms vs 29.16±12.02 ms; P&lt;0.0001) and a significant lower number of patients with global heart T2*&lt;20 ms (26.3% vs 12.0%; P&lt;0.0001) were detected. Four patterns of MIO were identified: no MIO (all segments with T2*≥20 ms), heterogeneous MIO and global heart T2*≥20 ms, heterogeneous MIO and global heart T2*&lt;20 ms, and homogeneous MIO (all T2*&lt;20 ms). At the last CMR a significant higher frequency of patients with no MIO and a significant lower frequency for the other three patterns indicating MIO were found (Figure 1). In patients with global heart T2*&lt;20 ms a significant increase in left ventricular ejection fraction (EF) (difference: 3.2±8.5%, P&lt;0.0001) as well as in right ventricular EF (difference: 1.2±8.9%, P=0.002) were detected. Based on CMR results the 75% of the patients changed the chelation therapy. At the last CMR the percentage of patients with an excellent/good compliance was significantly higher (94.8% vs 92.2%%; P&lt;0.0001). The complete history of cardiac complications-CC (heart failure, arrhythmias, pulmonary hypertension, myocardial infarction, angina, myo/pericarditis, peripheral vascular disease) was present for 1062 patients. Out of the 1001 patients with resolved CC or without CC before the enrolment in the project, the 6.6% had a CC before the enrolment in the project. During the study, the frequency of CC was 4.4%, significantly lower (P=0.023). In particular, the frequency of heart failure (HF) was significantly lower (3.5% vs 0.8%, P&lt;0.0001). Forty-six patients died during the study. HF continues to be the leading cause of death (30.4% of all causes), but there was a consistent decline in HF mortality rate, that was 60.2% in an Italian study dated 2004. No patients died for arrhythmias while cancer was the second leading cause of death. Conclusion Over a period of 10 years, the continuous monitoring of cardiac iron levels and a tailored chelation therapy allowed a reduction of MIO in the 70% of patients, with consequent improvement of cardiac function and reduction of cardiac complications and mortality from MIO-related HF. So, a national networking was effective in improving the care and reducing cardiac outcomes of TM patients.

PB2391 MYOCARDIAL CONTRACTILE FRACTION BY MAGNETIC RESONANCE AND RISK OF CARDIAC COMPLICATIONS IN THALASSEMIA MAJOR

Background:The analysis of cine cardiovascular magnetic resonance (CMR) images allows the quantification of the myocardial contraction fraction (MCF), a volumetric analog of myocardial deforming, that is calculated by dividing left ventricular (LV) stroke volume by LV myocardial volume.Aims:We verified the association of this new marker with myocardial iron overload and cardiac events (heart failure, arrhythmias and pulmonary hypertension) in thalassemia major (TM) patients.Methods:We considered 1492 TM patients (771 females, 31.06 ± 8.95 yrs) enrolled in the MIOT network. Myocardial iron overload (MIO) was quantified by the multislice multiecho T2∗ technique and biventricular morphological and functional parameters by cine sequences.Results:MCF values were significantly lower in males (0.94 ± 0.22 vs 1.01 ± 0.22; P &lt; 0.0001) and decreased with increasing age (R = −0.129 P &lt; 0.0001).Patients with MIO (global heart T2∗ &lt; 20 ms; N = 400) showed significant lower MCF values than patients without MIO (0.91 ± 0.20 vs 1.00 ± 0.22; P &lt; 0.0001).The patient population was randomly divided in two groups of equal size (N = 746).In the first group 99 patients had at least one cardiac complication and at receiver‐operating characteristic (ROC) curve analysis a MCF ≤ 0.87 was the best predictor of cardiac complications (area under the curve 0.659, 95% CI 0.64 to 0.69; sensitivity 60%, specificity 67%).In order to validate the result, the obtained value was tested in the remaining 746 patients (group 2). One hundred and thirty‐five patients had a cardiac complication and patients with a MCF ≤ 0.87 were more likely to have cardiac complications (odds ratio – OR = 2.73, 95%CI = 1.86‐4.01; P &lt; 0.0001), also adjusting for cardiac iron (see Figure).Summary/Conclusion:Contractile function is reduced in patients with MIO. A MCF ≤0.87 can help to identify patients with a significant higher risk of adverse cardiovascular events, independently by the presence of MIO.image

PS1295 IRON IN THE HUMAN HEARTS: DISTRIBUTION AND ASSOCIATION WITH R2∗ VALUES BY CMR

Background:T2∗ (or R2∗ = 1000/T2∗) cardiac magnetic resonance (CMR) allows the non‐invasive and reproducible measurement of myocardial iron and has been established as fundamental to the best practice management of iron loaded patients to improve morbidity and mortality.Aims:In the present study we calibrated cardiac R2∗ values against myocardial tissue ‐measured iron concentration by using a segmental approach and we assessed the distribution and regional variations in iron distribution.Methods:Five hearts of patients with thalassemia were donated after death (N = 4) or cardiac transplantation (N = 1) to the CoreLab of the MIOT (Myocardial Iron Overload in Thalassemia) Network. A multislice multiecho T2∗ approach was adopted. After CMR, used as guidance, the heart was cut in three short‐axis slice and each slice was cut into different equiangular segments accordingly with AHA segmentation and differentiated into endocardial and epicardial layer, the same ones in which the T2∗ was assessed. Tissue iron concentration in the segments was measured with an atomic absorption spectrometer.Results:55 samples were used since it was possible to analyze all the 16 samples only from two hearts due to medical‐forensic reasons. The mean iron concentration in all samples was 4.71 ± 4.67 mg/g dw. Segmental iron levels ranged from 0.24 to 13.78 mg/g dw. Mean iron concentration was significantly higher in the epicardial than in the endocardial layer (5.99 ± 6.01 mg/g dw vs 4.84 ± 4.87 mg/g dw; P = 0.042).The coefficient of variability (CoV) of iron for myocardial segments ranged from 8.08% to 24.54%, with a mean value for all patients of 13.49 ± 6.93%. Four different main circumferential regions (anterior, septal, inferior and lateral) were defined. A circumferential heterogeneity was noted, with more iron observed in the anterior region, followed by the inferior region. The heterogeneity in circumferential iron concentration expressed as percentage deviation of the regions from the global value is shown in the Figure 1A.A strong linear correlation (R‐square = 0.956) was found by plotting ln(R2∗‐ROI) and ln[Fe] with a slope s = 0.654 (95% confidence intervals‐CI = 0.616–0.693) and intercept i = 4.216 (95% CI = 4.150–4.281) (Figure 1B). The linear relation was converted to the calibration curve: [Fe] = 0.001591 X (R2∗)1.529.Summary/Conclusion:Our data suggests an heterogeneous pattern of cardiac iron distribution with higher epicardial layer involvement. Heart R2∗ provided a robust calibration against chemically assayed cardiac iron, further validating the current clinical practice of monitoring cardiac iron in vivo by CMR.image

PF786 REDUCTION OF CARDIAC OUTCOMES IN THALASSEMIA MAJOR THANKS TO A TEN‐YEAR NATIONAL ITALIAN NETWORKING

Background:The MIOT (Myocardial Iron Overload in Thalassemia) Network was a network of thalassemia and CMR centers built in 2006 in order to assure homogeneous and standardized cardiac iron overload assessment for a significant number of patients.Aims:We describe the impact of this ten‐year Network on cardiac iron, complications and deaths in patients with thalassemia major (TM).Methods:1746 TM patients (911 females; mean age 31.17 ± 9.09 yrs) were enrolled in the MIOT Network. Myocardial iron overload (MIO) was quantified by the multislice multiecho T2∗ technique. Biventricular function was quantified by cine images.Results:1392 TM patients performed an end‐of‐study CMR. At the last CMR significantly higher global heart T2∗ values (35.44 ± 10.69 ms vs 29.16 ± 12.02 ms; P &lt; 0.0001) and a significant lower number of patients with global heart T2∗&lt;20 ms (26.3% vs 12.0%; P &lt; 0.0001) were detected. Four patterns of MIO were identified: no MIO (all segments with T2∗≥20 ms), heterogeneous MIO and global heart T2∗≥20 ms, heterogeneous MIO and global heart T2∗&lt;20 ms, and homogeneous MIO (all T2∗&lt;20 ms). Figure 1 shows the frequency of the 4 patterns at both scans. At the last CMR a significant higher frequency of patients with no MIO and a significant lower frequency for the other three patterns indicating MIO were detected.In patients with global heart T2∗&lt;20 ms a significant increase in left ventricular ejection fraction (EF) (difference: 3.2 ± 8.5 %, P &lt; 0.0001) as well as in right ventricular EF (difference: 1.2 ± 8.9 %, P = 0.002) were detected.Based on CMR results the 75% of the patients changed the chelation therapy. At the last CMR the percentage of patients with an excellent/good compliance was significantly higher (94.8% vs 92.2%%; P &lt; 0.0001).The complete history of cardiac complications‐CC (heart failure, arrhythmias, pulmonary hypertension, myocardial infarction, angina, myo/pericarditis, peripheral vascular disease) was present for 1062 patients. Out of the 1001 patients with resolved CC or without CC before the enrolment in the project, the 6.6% had a CC before the enrolment in the project. During the study, the frequency of CC was 4.4 %, significantly lower (P = 0.023). In particular, the frequency of heart failure (HF) was significantly lower (3.5% vs 0.8%, P &lt; 0.0001).Forty‐six patients died during the study. HF continues to be the leading cause of death (30.4% of all causes), but there was a consistent decline in HF mortality rate, that was 60.2% in an Italian study dated 2004. No patients died for arrhythmias while cancer was the second leading cause of death.Summary/Conclusion:Over a period of 10 years, the continuous monitoring of cardiac iron levels and a tailored chelation therapy allowed a reduction of MIO in the 70% of patients, with consequent improvement of cardiac function and reduction of cardiac complications and mortality from MIO‐related HF. So, a national networking was effective in improving the care and reducing cardiac outcomes of TM patients.image

Genotypic Groups As Risk Factor for Cardiac MR Abnormalities and Complications in Thalassemia Major

Introduction. Beta thalassemia major (β-TM) displays a great deal of genotypic heterogeneity, not fully investigated in terms of cause-effect. This prospective and multicentre study aimed to detect if different genotypic groups could predict the development of cardiovascular magnetic resonance (CMR) abnormalities and cardiac complications (CC).Methods. We considered 708 β-TM patients (373 females, 30.05±9.47 years), consecutively enrolled in Myocardial Iron Overload in Thalassemia (MIOT) network. Data were collected from birth to the first CMR imaging scan. Myocardial iron overload was assessed by the multislice multiecho T2* technique. Biventricular function parameters were quantified by cine images. Late gadolinium enhancement (LGE) images were acquired to detect myocardial fibrosis.Results. On the basis of the type of gene mutation, three groups of patients were identified: homozygotes β+ (N=158), compound heterozygotes β+ / β° (N=298) and homozygotes β° (N=252). Table 1 shows the effect of genotype group on the development of different cardiac outcomes. Compared to the milder genotype group homozygotes β+, the other two groups showed a significantly higher risk of myocardial iron overload (MIO) and left ventricular dysfunction. We recorded 90 (13.0 %) cardiac events: 46 heart failures (HF), 38 arrhythmias (33 supraventricular, 3 ventricular and 2 hypoinetic) and 6 pulmonary hypertensions (PH). No prospective association was detected between genotype group and HF and PH. The homozygous β° group showed a significantly higher risk of arrhythmias than the homozygous β+ group and at the limit of significance than the compound heterozygotes. Globally, homozygotes β° showed a significantly higher risk of CC than homozygotes β+.Conclusion. Different genotypic groups predict the development of MIO, left ventricular dysfunction, arrhythmias and CC in β-TM patients. These data support the knowledge of the different genotypic groups in the clinical management of β-TM patients. [Display omitted] DisclosuresPepe:Chiesi Farmaceutici S.p.A., ApoPharma Inc., and Bayer: Other: No profit support.

Impact of a Ten-Year National Italian Networking on Cardiac Complications in Patients with Thalassemia Major

▪Introduction. The MIOT (Myocardial Iron Overload in Thalassemia) Network was a national Italian network constituted by thalassemia and magnetic resonance imaging (MRI) centers built in 2006. The main aim was to assure available, accessible homogeneous and standardized T2* MRI cardiac and liver iron overload assessments for a significant number of patients with emoglobinopathies. Moreover, the creation of a solid clinical-instrumental web based database allowed data exchange between centers and constituted a means of monitoring health care processes and outcomes. We describe the impact of this ten-year Network on cardiac complications in patients with thalassemia major (TM).Methods. Among the 2497 emoglobinopathies patients consecutively enrolled in the MIOT Network we considered the 1401 TM patients who performed an end-of-study MRI. Per protocol the MRI follow up was scheduled every 18±3 months. Myocardial iron overload (MIO) was quantified by the multislice multiecho T2* technique. Biventricular function was quantified by cine images.Results. At the last MRI significantly higher global heart T2* values (35.5±10.7 ms vs 29.2±12.0 ms; P<0.0001) and a significant lower number of patients with global heart T2*<20 ms (26.3% vs 12.0%; P<0.0001) were detected. Four patterns of MIO were identified: no MIO (all segments with T2*≥20 ms), heterogeneous MIO and global heart T2*≥20 ms, heterogeneous MIO and global heart T2*<20 ms, and homogeneous MIO (all segments with T2*<20 ms). Figure 1 shows the frequency of the 4 patterns at both scans. At the last MRI a significant higher frequency of patients with no MIO and a significant lower frequency for the other three patterns indicating MIO were detected. An improvement in MIO, that is a transition to a better risk class, was detected in the 68.4% of patients showing MIO at the baseline (at least one pathologic segment).In patients with significant baseline MIO (global heart T2*<20 ms) a significant increase in left ventricular ejection fraction (EF) (mean difference: 3.2±8.5 %, P<0.0001) as well as in right ventricular EF (mean difference: 1.2±8.9 %, P=0.002) were detected with a concordant improvement of MIO status.Based on MRI results the 75% of the patients changed the chelation therapy. At the last MRI the percentage of patients with an excellent/good compliance was significantly higher (94.7% vs 92.7%%; P=0.034).The 13.1% of the patients had a cardiac complication (heart failure, arrhythmias, pulmonary hypertension, myocardial infarction, angina, myo/pericarditis, and peripheral vascular disease) before the enrolment in the project. During the study, the frequency of cardiac complications was 7.9 %, significantly lower (P<0.0001). In particular, the frequency of heart failure was significantly lower (5.9% vs 1.7%, P<0.0001).Conclusion. Over a period of 10 years, the continuous monitoring of cardiac iron levels and a tailored chelation therapy allowed a reduction of MIO in the 70% of patients and a consequent improvement of cardiac function and reduction of heart failure. So, a national networking as the MIOT project was effective in improving the care and reducing cardiac outcomes of TM patients. [Display omitted] DisclosuresPepe:Chiesi Farmaceutici S.p.A., ApoPharma Inc., and Bayer: Other: No profit support.

Multicenter Validation of the Magnetic Resonance T2* Technique for Quantification of Pancreatic Iron

Introduction. The gradient echo multiecho T2* MRI technique is the most robust method for the non invasive, sensitive, and fast quantification of organ-specific iron overload. A crucial aspect is the transferability of the T2* technique among different MRI scanners, in order to expand the availability of high-quality monitoring of iron accumulation to a large population. The intra- and inter-operator reproducibility, inter-study reproducibility, and inter-scanner reproducibility of the T2* MRI method for measuring iron concentrations in the heart and liver have already been demonstrated. However, the transferability of the MRI multislice multiecho T2* technique for pancreatic iron overload assessment has not been evaluated. Thus, the aim of our study was to assess the transferability of this approach among ten MRI sites.Methods. All subjects underwent MRI using conventional clinical 1.5T scanners of three main vendors. Fifty healthy subjects, five for each site, including the reference centre, were scanned. Five patients with thalassemia were scanned locally at each site and were rescanned at the reference site in Pisa within 1 month.T2* image analysis was performed using custom-written, previously validated software (HIPPO MIOT®). T2* values over pancreatic head, body and tail were calculated and the global pancreatic T2* value was obtained as the mean. The lowest threshold of normal T2* value was 26 ms6.Results. On healthy subjects the global pancreas T2* values ranged from 28.93 to 48.89 ms (mean 37.88 ms, SD 5.08 ms). No significant difference was detected among the sites (P=0.334).Table 1 shows the global pancreas T2* values measured at the different MRI sites. The global pancreas T2* values ranged from 2.08 to 38.39 ms. There was not a significant difference between the T2* values measured in the MRI sites and the correspondent values observed in Pisa (12.02±10.20 ms vs 11.98±10.47 ms; P=0.808). All patients categorized as having pancreatic iron overload in the MRI sites, fell in the same category after the MRI executed in Pisa.There was a strong correlation between the global pancreas T2* values calculated from images obtained in Pisa and at the other MRI sites (R=0.978, P<0.0001).Figure 1 shows the global pancreas T2* values calculated from images obtained at the 9 MRI sites as a function of global pancreas T2* calculated from images obtained in Pisa. The line of best fit had a slope of 0.965 ± 0.021 and an intercept of 0.459 ± 0.328 ms. The R-squared value for the fit was 0.981. Neither constant bias (intercept did not significantly differs from zero) nor proportional bias (angular coefficient did not significantly differ from 1) affected the measurements.CoVs for all MRI sites are provided in Table 2; they ranged from 4.22 to 9.77%. The CoV for all the T2* values independently from the sites was 8.55%.The ICC considering all the T2* values, independently from the sites, was 0.995. The ICC for each MRI site is provided in Table 2 and it was always excellent.The comparison between Pisa and the other MRI sites by Bland-Altman analysis showed a mean absolute difference of -0.04 ± 1.47 ms for the global pancreas T2* values (Figure 2). No bias was present and no greater differences for higher T2* values were detected.The mean absolute difference in patients with pancreatic iron (N=39) was -0.15 ± 1.38 ms.Conclusion. The gradient-echo T2* MRI technique is an accurate and reproducible means for the calculation of pancreatic iron and may be transferred between MRI scanners in different centers from different manufacturers. [Display omitted] DisclosuresPepe:Chiesi Farmaceutici S.p.A., ApoPharma Inc., and Bayer: Other: No profit support.

Multicenter validation of the magnetic resonance T2* technique for quantification of pancreatic iron.

To assess the transferability of the magnetic resonance imaging (MRI) multislice multiecho T2* technique for pancreatic iron overload assessment. Multiecho T2* sequences were installed on ten 1.5-T MRI scanners of the three main vendors. Five healthy subjects (n= 50) were scanned at each site. Five patients with thalassemia (n= 45) were scanned locally at each site and were rescanned at the reference site within 1month. T2* images were analyzed using a previously validated software and the global pancreatic T2* value was calculated as the mean of T2* values over the head, body, and tail. T2* values of healthy subjects were above 26ms and showed inter-site homogeneity. The T2* values measured in the MRI sites were comparable to the correspondent values observed in the reference site (12.02 ± 10.20ms vs 11.98 ± 10.47ms; p = 0.808), and the correlation coefficient was 0.978 (p < 0.0001). Coefficients of variation (CoVs) ranged from 4.22 to 9.77%, and the CoV for all the T2* values independently from the sites was 8.55%. The intraclass correlation coefficient (ICC) for each MRI site was always excellent and the global ICC was 0.995, independently from the sites. The mean absolute difference in patients with pancreatic iron (n = 39) was -0.15 ± 1.38ms. The gradient-echo T2* MRI technique is an accurate and reproducible means for the quantification of pancreatic iron and may be transferred among MRI scanners by different vendors in several centers. • The gradient-echo T2* MRI technique is an accurate and reproducible means for the quantification of pancreatic iron. • The gradient-echo T2* MRI technique for the quantification of pancreatic iron may be transferred among MRI scanners by different vendors in several centers. • Pancreatic iron might serve as an early predictor of cardiac siderosis and is the strongest overall predictor of glucose dysregulation.

Isotropic three-dimensional T2 mapping of knee cartilage: Development and validation.

1) To implement a higher-resolution isotropic 3D T2 mapping technique that uses sequential T2 -prepared segmented gradient-recalled echo (Iso3DGRE) images for knee cartilage evaluation, and 2) to validate it both in vitro and in vivo in healthy volunteers and patients with knee osteoarthritis. The Iso3DGRE sequence with an isotropic 0.6 mm spatial resolution was developed on a clinical 3T MR scanner. Numerical simulations were performed to optimize the pulse sequence parameters. A phantom study was performed to validate the T2 estimation accuracy. The repeatability of the sequence was assessed in healthy volunteers (n = 7). T2 values were compared with those from a clinical standard 2D multislice multiecho (MSME) T2 mapping sequence in knees of healthy volunteers (n = 13) and in patients with knee osteoarthritis (OA, n = 5). The numerical simulations resulted in 100 excitations per segment and an optimal radiofrequency (RF) excitation angle of 15°. The phantom study demonstrated a good correlation of the technique with the reference standard (slope 0.9 ± 0.05, intercept 0.2 ± 1.7 msec, R2 ≥ 0.99). Repeated measurements of cartilage T2 values in healthy volunteers showed a coefficient of variation of 5.6%. Both Iso3DGRE and MSME techniques found significantly higher cartilage T2 values (P < 0.03) in OA patients. Iso3DGRE precision was equal to that of the MSME T2 mapping in healthy volunteers, and significantly higher in OA (P = 0.01). This study successfully demonstrated that high-resolution isotropic 3D T2 mapping for knee cartilage characterization is feasible, accurate, repeatable, and precise. The technique allows for multiplanar reformatting and thus T2 quantification in any plane of interest. 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:362-371.

Gender Differences in the Development of CMR Abnormalities and Cardiac Complications: A Multicentric Prospective Study in a Large Cohort of Thalassemia Major Patients

Introduction. We aimed to prospectively assess if the male gender was associated with an higher risk of progressive cardiac iron accumulation, development of biventricular dysfunction and myocardial fibrosis assessed by CMR, and development of cardiac complications including heart failure (HF), arrhythmias and pulmonary hypertension (PH).Methods. We considered 1711 TM patients (899 females, 31.09±9.08 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 was quantified by cine images. Late gadolinium enhancement (LGE) images were acquired to detect myocardial fibrosis.Results. Although having a similar risk of accumulating iron, males showed a significant higher risk of developing cardiac dysfunction, heart failure, arrhythmias and cardiac complications globally considered (Table 1). Figure 1 shows the Kaplan-Meier curves for the outcomes for which the male sex was a significant prognosticator. Until 20-30 years of follow-up the two lines (male and female sex) were almost overlapping while after they clearly diverged. So, patients were divided in two groups based on the follow-up duration. A significant gender-specific difference in the frequency of ventricular dysfunction and cardiac complications appeared for patients followed for at least 20 years. So, two subgroups of patients were identified: patients followed for less than 20 years and patients followed for more than 20 years. In the first subgroup males and females had a comparable risk of developing cardiac iron overload, ventricular dysfunction and cardiac complications. Conversely, if a follow-up longer than 20 years was considered, males exhibited a significant higher risk of having ventricular dysfunction, heart failure, arrhythmias, and cardiac complications.Conclusion. Females seem to tolerate iron toxicity better, possibly as an effect of reduced sensitivity to chronic oxidative stress. According to the International Guidelines, TM patients should perform a complete cardiac evaluation every year. Our study suggested that in females older than 20 years the follow-up may be performed every 24 months, thus reducing health care costs. [Display omitted] [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.. De Franceschi:F. Hoffmann-La Roche Ltd, Basel, Switzerland: Research Funding.