The Importance of Cardiac T2* Magnetic Resonance Imaging for Monitoring Cardiac Siderosis in Thalassemia Major Patients

Objective: Cardiac T2* magnetic resonance imaging (MRI) has recently attracted considerable attention as a non-invasive method for detecting iron overload in various organs in thalassemia major patients. This study aimed to identify the prevalence of cardiac siderosis in thalassemia major patients and evaluate cardiac T2* MRI for monitoring cardiac siderosis before and after patients receive iron chelation therapy and its relation to serum ferritin, left ventricular ejection fraction, and liver iron concentration. The information gathered would be used for the direct monitoring, detection, and treatment of complications early on. Methods: A total of 119 thalassemia major patients were recruited in the present study. The cardiac T2* MRI was compared to serum ferritin levels, liver iron concentration (LIC), and left ventricular ejection fraction. All patients were classified into four groups based on their cardiac siderosis as having normal, marginal, mild to moderate, or severe cardiac iron overload. At the follow-up at years one, three, and five, the cardiac T2* MRI, LIC, serum ferritin, and left ventricular ejection fraction (LVEF) were determined. Results: The prevalence of cardiac siderosis with cardiac T2* MRI ≤ 25 ms was 17.6% (n = 21). There was no correlation between cardiac T2* MRI and serum ferritin, liver iron concentration, and LVEF (p = 0.39, 0.54, and 0.09, respectively). During one year to five years’ follow-up periods, cardiac T2* MRI (ms) in patients with severe cardiac siderosis had significantly improved from 8.5 ± 1.49 at baseline to 33.9 ± 1.9 at five years (p < 0.0001). Patients with severe, mild-moderate, marginal, and no cardiac siderosis had median LIC (mg/g dw) of 23.9 ± 6.5, 21.6 ± 13.3, 25.3 ± 7.7, and 19.9 ± 5.5 at baseline, respectively. Conclusions: This study supports the use of cardiac T2* MRI to monitor cardiac iron overload in patients who have had multiple blood transfusions. Early diagnosis and treatment of patients at risk of cardiac siderosis is a reasonable method of reducing the substantial cardiac mortality burden associated with myocardial siderosis. Cardiac T2* MRI is the best test that can identify at-risk patients who can be managed with optimization of their chelation therapy.

Iron Overload in Transfusion-Dependent Indonesian Thalassemic Patients

Thalassemia is a genetic disease caused by disruption of globin chain synthesis leading to severe anemia and thus regular blood transfusion is necessary. However, there have been known transfusions-related consequences, including iron overload and multi-organ damage. The aims of this study were to evaluate liver and cardiac function in youth and adult transfusion-dependent Indonesian thalassemic patients and to assess its correlation with serum ferritin levels, as well as T2 ∗ magnetic resonance imaging (MRI). Transfusion-dependent thalassemic (TDT) outpatients (n = 66; mean age, 21.5 ± 7.2 years) were carried out for the complete assessment consisting of blood test including liver enzyme and serum ferritin, followed by electrocardiography (ECG) and echocardiography. Subjects were also divided by serum ferritin levels into three groups: < 2500 ng/mL, 2500–5000 ng/mL, and >5000 ng/mL. Additionally, subgroup analysis in patients with T2∗ MRI assessment was conducted. In terms of age of first blood transfusion, subjects with ferritin >5000 ng/mL were the youngest among others. The alanine aminotransferase (ALT) levels in group with serum ferritin >5000 ng/mL were significantly higher than those of the group with serum ferritin <2500 ng/mL. Additionally, youth and adult TDT patients whose serum ferritin >5000 ng/mL had significantly lower tricuspid annular plane systolic excursion (TAPSE) when compared with those who had serum ferritin <2500 ng/mL. Similarly, TAPSE in patients with moderate cardiac siderosis based on cardiac T2∗ MRI was significantly lower than those without cardiac siderosis. There was significant, but only moderate correlation between serum ferritin and cardiac T2∗ MRI. Based on these findings, it is important to routinely monitor iron accumulation-related complications, including liver and cardiac damage in youth and adult TDT patients.

No Association of Genetic Markers with Carotid Intimal Medial Thickness in β-Thalassemia Major Patients

Regular transfusion leads to cardiac siderosis resulting in cardiac complications that account for more than 71% of the total mortality in thalassemia patients. We aimed to study the variants of matrix metalloproteinase-9 (MMP9), matrix Gla protein (MGP), and estrogen receptor α(ERα), which might be contributing to atherosclerosis, leading to heart failure in thalassemia major. One hundred and five thalassemia patients on regular transfusion and iron chelation therapy were enrolled for the study. Carotid artery intimal medial thickness (CIMT) measurement was done to check for atherosclerosis. MMP9 (C1562T), MGP (T138C), and ERα gene (PvuII (rs2234693T > C) and XbaI (rs9340799A > G) polymorphism were analyzed using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. CIMT values were within the normal range (<0.90 mm) in all patients. There was no difference in mean CIMT values between males and females (0.56 ± 0.11 versus 0.56 ± 0.12, p = 0.928). There was no correlation of CIMT with age, body surface area, and body mass index as well as with serum ferritin levels. No statistically significant difference in frequency of MMP9, MGP, and ERα genotypes was seen in two dichotomized groups of CIMT (CIMT < 0.56 and CIMT ≥ 0.56). Variants of MMP9, MGP, and ERα have a reserved influence on cardiac disease pathogenesis, and the disease phenotype in thalassemia patients may be more strongly impacted by other factors.

Longitudinal Serum Ferritin Cut-Off Level for Cardiac Iron Overload Prediction in Transfusion-Dependent Thalassemia in a Resource Limited Country

Introduction: Although routine tissue iron monitoring using magnetic resonance imaging (MRI) has become a standard clinical management of both transfusion dependent and non-transfusion dependent thalassemias (TDT & NTDT) in several developed countries since this module can provide a better organ-directed iron measurement and related to clinical outcome including morbidity and mortality secondary to iron overload (IOL). However, accessibility of this monitoring remains limited in several developing countries including Thailand, where thalassemia and hemoglobinopathies are highly prevalent. Earlier in 2016, we have demonstrated that although not so perfectly crafted, a cross-sectional measurement of serum ferritin (SF) can be used for determination of IOL as a predictive marker; in NTDT, MRI for liver iron concentration (LIC) should be performed in those with SF >300 ug/L and for TDT, the SF cut off of >2,500 and >3,500 ug/L are useful to predict patients with severe LIC (>15 mgFe/g dw) and cardiac siderosis (T2*< 20 ms) (Ekwattanakit S. et.al., EHA 2016). In this study, we performed a further analysis to evaluate whether a serial measurement of SF and its trend can provide a better prediction. Objectives: To evaluate the clinical utility of serial SF trend compared with a cross-sectional SF cut-off for early detection of IOL in a real-life practice in thalassemic patients in order to select the most vulnerable patients for further MRI evaluation in a resource limited setting. Methods: In this prospective study, total 968 standard MRI for LIC and cardiac T2*were performed at Siriraj hospital during 2009-2014 and paired clinical data including serial SF measurements were collected from 301 thalassemia patients; NTDT (N=76; 109 LIC and 95 cardiac T2* results) and TDT (N=155; 478 LIC and 474 cardiac T2*). In addition, 71 patients were NTDT with regular blood transfusion later on in their life, mainly Hb E/β thalassemia (218 LIC and 210 cardiac T2*). These patients were evaluated for IOL using SF every 4-12 weeks during their follow up. Median follow up time was 96 months. Receiver operating characteristic (ROC) analysis was performed using different SF cut-off levels (1000, 1500 and 2000ug/L) and percentage of serial SF measurements that above each these cut-off levels (50 and 75%) during different durations before MRI (1, 2, or 3 years priori) for predicting liver IOL (LIC >5 in NTDT and severe liver siderosis; LIC > 15 mgFe/g dw) and cardiac IOL (T2*<20ms). Results: Baseline characteristics were shown in Table1. In NTDT, using ROC analysis, SF >1000 ug/L over 75% of serial measurements in 1-year period prior to MRI can predict LIC > 5 mgFe/g dw with the AUC of 0.59 with PPV 86.7% and NPV 51.1% and serial SF >1500 ug/l over 50% of measurement in a year prior predict LIC >15 mgFe/g dw (AUC of 0.72, PPV 75% and NPV 89.7%). Only 1 NTDT had cardiac IO. These newly identified criteria do not provide a more sensitive predictor of LIC results than our previous SF cut-off. In TDT population, the majority of patients were HbE/β thal (78%) and cardiac iron overload was detected mainly in patients older than 15 yrs (81/83; 97.6%). The best predictor for LIC>15 mgFe/g dw was SF >2000 ug/L over 75% of serial measurement durations in 3-year period (AUC 0.778, PPV 50.8%, NPV 95.5%). However this cut-off during 1 year priori also provided a similar prediction (AUC 0.769, PPV 51%, NPV 93.6%). This cut-off value also provided the best prediction for cardiac T2* < 20 ms in all age group (AUC 0.754, PPV 31.5%, NPV 97.4%) and a higher sensitivity and specificity when it was applied in patients >15 yrs of age (AUC 0.764, PPV 41.9%, NPV 96.3%). In NTDT with regular transfusion, all cardiac IOL (N=19) occurred after 15 years of age and again the same criteria was the good predictive cut-off for cardiac IO (AUC 0.788, PPV 19%, NPV 100%) and severe LIC >15 mgFe/g dw (AUC 0.728, PPV 52.8%, NPV 87.3%). Conclusions: In a resource limited setting for MRI evaluation, a serial measurement of SF and its values in thalassemic patients who received regular blood transfusion above the cut-off of 2000 ug/L over 75% of measurement in one year priori could be used as a predictive marker for selecting the most vulnerable TDT for MRI evaluation since this criteria is strongly associated with severe liver (LIC > 15 mgFe/g dw) and cardiac siderosis (T2* <20 ms). Moreover this criterion provides a more sensitive predictor than a single SF cut-off we proposed before. Disclosures Siritanaratkul: Novartis: Research Funding; Jansen-Cilag: Research Funding; Roche: Research Funding; Pfizer: Research Funding. Wood:Celgene: Consultancy; AMAG: Consultancy; Ionis Pharmaceuticals: Consultancy; Ionis Pharmaceuticals: Consultancy; World Care Clinical: Consultancy; Biomed Informatics: Consultancy; Vifor: Consultancy; Apopharma: Consultancy; Biomed Informatics: Consultancy; Vifor: Consultancy; Apopharma: Consultancy; World Care Clinical: Consultancy; AMAG: Consultancy; Celgene: Consultancy. Viprakasit:Agios: Consultancy; Mersanger: Consultancy; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene Corporation: Consultancy, Research Funding; Faculty of Medicine, Siriraj Hospital, Mahidol University: Employment; Shire: Research Funding.

Cardiovascular magnetic resonance frontiers: Tissue characterisation with mapping

The clinical use of cardiovascular magnetic resonance (CMR) imaging has expanded rapidly over the last decade. Its role in cardiac morphological and functional assessment is established, with perfusion and late gadolinium enhancement (LGE) imaging for scar increasingly used in day-to-day clinical decision making. LGE allows a virtual histological assessment of the myocardium, with the pattern of scar suggesting disease aetiology, and the extent of predicting risk. However, even combined, the full range of pathological processes occurring in the myocardium are not interrogated. Mapping is a new frontier where the intrinsic magnetic properties of heart muscle are measured to probe further. T1, T2 and T2* mapping measures the three fundamental tissue relaxation rate constants before contrast, and the extracellular volume (ECV) after contrast. These are displayed in colour, often providing an immediate appreciation of pathology. These parameters are differently sensitive to pathologies. Iron (cardiac siderosis, intramyocardial haemorrhage) makes T1, T2 and T2* fall. T2 also falls with fat infiltration (Fabry disease). T2 increases with oedema (acute infarction, takotsubo cardiomyopathy, myocarditis, rheumatological disease). Native T1 increases with fibrosis, oedema and amyloid. Some of these changes are large (e.g. iron, oedema, amyloid), others more modest (diffuse fibrosis). They can be used to detect early disease, distinguish aetiology and, in some circumstances, guide therapy. In this review, we discuss these processes, illustrating clinical application and future advances.

A randomized trial of amlodipine in addition to standard chelation therapy in patients with thalassemia major

Key Points In thalassemia patients with cardiac siderosis, amlodipine combined with iron chelation resulted in more effective reduction of cardiac iron. The combined treatment did not have any effect on serum ferritin and left ventricular ejection fraction.