Myocardial Iron Overload Research Articles

Cardiovascular magnetic resonance in β-thalassemia major: beyond T2.

Β-thalassemia major (TM) patients underwent regular transfusions to prevent complications of chronic anemia. However, these regular transfusions result in progressive iron accumulation in vital organs, including the heart. Myocardial iron overload can lead to cardiac dysfunction and ultimately to heart failure. Diagnosis of cardiac dysfunction in β-TM patients is usually made through clinical examination, electrocardiogram, and echocardiography. Cardiac magnetic resonance (CMR), through the measurement of T2* relaxation time, represents the diagnostic modality of choice for assessing myocardial iron overload and guiding the iron chelation therapy. Despite a tailored chelation therapy reducing myocardial iron overload, heart failure remains the leading cause of morbidity and mortality even in well-treated β-TM patients. Advances in CMR, including myocardial strain, parametric mapping (T1, T2, and extracellular volume), and late gadolinium enhancement (LGE) measurements, have expanded its role in the diagnosis, prognosis, and follow-up of these patients. This review seeks to offer a thorough overview of the potential uses of CMR in β-TM, extending beyond the established role of T2* measurement in guiding chelation therapy. It delves into the emerging applications of new CMR imaging biomarkers that could improve the overall management of β-TM patients.

Myocardial iron overload: the use of speckle-tracking echocardiography in patients with transfusion-dependent beta-thalassaemia

Myocardial iron overload: the use of speckle-tracking echocardiography in patients with transfusion-dependent beta-thalassaemia

Iron chelation therapy failed to improve cardiac dysfunction caused by mitochondrial injury in rats with iron overload cardiomyopathy a 7T Cardiac MR research in vivo

Abstract Purpose To assess the efficacy of iron chelation therapy in improving cardiac function in iron overload cardiomyopathy (IOC) rats by using Cardiac magnetic resonance feature-tracking (CMR-FT). Methods The IOC rat model was induced by intraperitoneal injection of iron dextran over 2 months. Subsequently, 7 rats with IOC were assigned as IOC group to receive continued intraperitoneal injections of saline for an additional 2 months, while another group of 5 rats received intraperitoneal injections of deferoxamine (DFO) for the same duration, forming the IOC+DFO group. Meanwhile, a control group consisting of 7 healthy rats received intraperitoneal injections of saline for the entire duration of 4 months. All rats underwent a 7T CMR scan to assess cardiac function, myocardial iron overload, and myocardial fibrosis via cine, T2 mapping, and late gadolinium enhancement (LGE) scanning, respectively. The cardiac function analysis included left ventricular ejection fraction (LVEF) and left ventricular global longitudinal strain (GLS) using cine images. Following CMR scans, all rats underwent open-chest blood collection to detect serum iron levels, and cardiac gross specimens were then subjected to pathological staining, including hematoxylin and eosin (HE) for cardiomyocytes injury, Prussian blue for iron deposition , and Masson staining for myocardial fibrosis. Furthermore, the ultrastructure of cardiomyocyte was examined using transmission electron microscopy (TEM). Results The T2 value, measured in the septum wall at the mid-layer of the LV, and LVEF, and GLS exhibited a significant decrease in the IOC or IOC+DFO group, compared to the control group, while there were no significant difference observed between the IOC and IOC+DFO group (Fig. 1A, B, C). Myocardial fibrosis was not detected in the LGE images in both IOC and IOC+DFO group. Compared to the control group (37.5±12.5μmol/L) , serum iron levels were significantly elevated in the IOC group (368.6±181.0μmol/L) and in chelation treatment group (106.1±32.2μmol/L). Histological examination with HE staining revealed a normal arrangement of myocardial cells in all rats, without cellular degeneration or necrosis. Prussian blue staining highlighted the presence of iron particles within the myocardial interstitium in the IOC and IOC+DFO groups. Masson staining demonstrated intact myocardial muscle bundles without any evidence of myocardial fibrosis. Transmission electron microscopy (TEM) revealed myocardial mitochondria injury, characterized by ruptured outer membranes, reduced cristae, and vacuolization. Conclusions Following iron chelation therapy, the excessive iron burden in the bloodstream was alleviated. However, myocardial iron overload persisted in IOC rats, with no significant improvement in cardiac function observed. This persistence may be attributed to mitochondrial injury. The findings underscore the importance of monitoring cardiac dysfunction in patients with iron overload.CMR parameters analysis in IOC rats

Speckle-tracking echocardiography as screening tool for myocardial fibrosis and Iron overload in transfusion-dependent beta-thalassemia

BackgroundTransfusion-dependent beta thalassemia (TDT) is a genetic disorder characterized by low haemoglobin levels, often leading to myocardial iron overload (MIO) and myocardial fibrosis (MF). Cardiac Magnetic Resonance (CMR) represents the gold standard for MIO and MF assessment, although its limited availability and high costs pose challenges. Left Ventricular Global Longitudinal Strain (LV GLS) measured by Speckle Tracking Echocardiography (STE) could offer a valuable alternative. MethodsA monocentric diagnostic accuracy study was conducted to compare the performance of LV GLS with CMR using T2* for evaluating MIO and late gadolinium enhancement (LGE) for detecting MF. Between January 2022 and January 2023, 44 consecutive patients with TDT were enrolled. For each participant was performed LV GLS with STE, including CMR with T2* technique and LGE sequences. ResultsCMR identified MIO in 8 patients (18 %) and MF in 5 (11 %). LV GLS STE was normal in patients without MIO (−20.6 ± 3.1 %) or MF (−20.6 ± 2.8 %), significantly differing from those with MIO (−18.2 ± 2.1 %, p = 0.043) and MF (−16.4 ± 1.7 %, p = 0.002). ROC analysis indicated an optimal LV GLS STE cutoff of −19.8 % for MIO (AUC = 0.76, 95 % CI: 0.59–0.93, p = 0.054) with an overall diagnostic accuracy of 64 % and an optimal cutoff of −18.3 % for MF (AUC = 0.93, 95 % CI: 0.85–1.00, p = 0.009) with an accuracy of 86 %. ConclusionsThe findings of this pilot study indicate that LV GLS with STE, may be a cost-effective screening tool for the early detection of MIO and MF in TDT patients.

Early detection of myocardial iron overload in patients with β-thalassemia major using cardiac magnetic resonance T1 mapping

BackgroundThe T2* technique, used for quantifying myocardial iron content (MIC), has limitations in detecting early myocardial iron overload (MIO). The in vivo mapping of the myocardial T1 relaxation time is a promising alternative for the early detection and management of MIO. Methods32 β-thalassemia major (βTM) patients aged 11.5 ± 4 years and 32 healthy controls were recruited and underwent thorough clinical and laboratory assessments. The mid-level septal iron overload was measured through T1 mapping using a modified Look-Locker inversion recovery sequence with a 3 (3 s) 3 (3 s) 5 scheme. Septum was divided at the mentioned level into 3 zones corresponding to segments 8 and 9 in the cardiac segmentation model. Results21.9 % of βTM had clinical cardiac morbidity. The cut-off of T1 mapping of hepatic and myocardium to differentiate between the patients and control groups was ≤466 and ≥ 923 ms respectively. The T1 technique was able to detect 4 patients with high MIC, two of them were not detected by the T2* technique. There was a statistically significant correlation between the average T1 values of the studied zones in patients with βTM and the liver iron content (LIC), the T1 values within segment 8 of the liver, age of patients, the age at first transfusion, age of splenectomy and serum ferritin value. ConclusionThe addition of the T1 mapping sequence to the conventional T2* technique was able to increase the efficacy of the MIC detection protocol by earlier detection of MIO. This would guide chelation therapy to decrease myocardial morbidity.

NDRG1 regulates iron metabolism and inhibits pathological cardiac hypertrophy

BackgroundCardiac pathological hypertrophy, a pathological physiological alteration in many cardiovascular diseases, can progress to heart failure. The cellular biology underlying myocardial hypertrophy remains to be fully elucidated. While NDRG1 has been reported to participate in cellular proliferation, differentiation, and cellular stress responses, its role in cardiac diseases remains unexplored. Here, we investigated the role of NDRG1 in pathological hypertrophy. MethodCardiomyocyte-specific-NDRG1 knockout (KO) transgenic mice and NDRG1-AAV9 were used in mice. Angiotensin II (AngII) stimulation were applied to induce hypertrophy. Histological, molecular, and RNA-sequencing analyses were performed, and ferroptosis markers and iron levels were studied. We used co-IP and application of iron chelator to further studied the mechanisms of NDRG1 in cardiac hypertrophy. ResultsWe found that NDRG1 expression is decreased in pathological hypertrophy induced by AngII stimulation. Conditional knockout of NDRG1 in mouse cardiomyocytes led to progressive cardiac hypertrophy and heart failure. Cardiomyocyte-specific overexpression of NDRG1 via AAV9 significantly reversed AngII-induced ventricular hypertrophy and fibrosis. Mechanistically, NDRG1-deficient cardiomyocytes exhibited iron overload and increased ferroptosis, accompanied by elevated levels of reactive oxygen species (ROS) and lipid peroxidation. Subsequently, we confirmed the involvement of NDRG1 in regulating ferroptosis and iron metabolism in myocardial cells. Finally, we identified an interaction between NDRG1 and transferrin in cells. The iron chelator Dp44mT effectively reduced myocardial iron overload and ventricular remodeling induced by NDRG1 deficiency. ConclusionThese findings highlight NDRG1's critical role in iron metabolism and ferroptosis in cardiomyocytes, suggesting that NDRG1 or iron metabolism may serve as therapeutic targets for cardiac hypertrophy.

Quantification of Cardiac Iron Overload at 3 T MRI in a Rabbit Model Utilizing ME-GRE T2* Sequence.

Myocardial iron overload can lead to myocardial dysfunction, muscle cell injury, and end-stage heart failure. The enhanced signal-to-noise ratio and technical advancements have made 3 T magnetic resonance imaging (MRI) more accessible in clinical settings. However, 3 T assessments for early diagnosis of myocardial iron overload are scarce. To evaluate the feasibility of myocardial iron quantification using 3 T MRI in a rabbit model of iron overload. Animal model. Overall, 40 male New Zealand white rabbits were categorized into control (N = 8; no treatment) and experimental (N = 32; weekly 200 mg/kg iron dextran injections) groups. 3 T MRI with multi-echo gradient echo (ME-GRE) T2* sequence. Each week, two experimental rabbits were randomly selected for blood collection to determine serum iron (SI) levels; their tissue was harvested to assess myocardial and hepatic iron deposition. Spearman's rank correlation tests were used to evaluate the correlations among R2*, cardiac iron concentration (CIC), liver iron concentration (LIC), total amount of iron injected, and SI levels. P ≤ 0.05 was considered statistically significant. The myocardial T2* value in the experimental group was significantly lower than that of the control group. An excellent correlation was observed between R2* values and CIC (r = 0.854). CIC moderately correlated with LIC (r = 0.712) and the total amount of iron injected (r = 0.698). A strong correlation was observed between the total amount of iron injected and LIC (r = 0.866). SI levels poorly correlated with the total amount of iron injected (r = 0.205, P = 0.277) and LIC (r = 0.170, P = 0.370) but fairly correlated with CIC (r = 0.415, P = 0.022). A 3 T MRI with an ME-GRE sequence may serve as a noninvasive method for evaluating cardiac iron content. N/A TECHNICAL EFFICACY: Stage 1.

Global and regional cardiac magnetic resonance feature tracking left ventricular strain analysis in assessing early myocardial disease in β thalassemia major patients

BackgroundCardiac magnetic resonance imaging (CMR) is the modality of choice for quantification of myocardial iron overload in β-thalassemia major patients using the T2* sequence. CMR feature tracking (FT) is a recent magnetic resonance imaging tool that gives an idea about myocardial fibers deformation; thus, it can detect early impairment in myocardial function even before the reduction in ejection fraction.MethodsThis study aims to assess the ability of left ventricular CMR-FT in the early detection of systolic dysfunction in β thalassemia major patients and to correlate it with the degree of myocardial iron overload measured by CMR T2*. This prospective study enrolled 57 β thalassemia major patients who received long-term blood transfusion and 20 healthy controls. CMR was used to evaluate left ventricular volumes, ejection fraction, and the amount of myocardial T2*. A two-dimensional left ventricular FT analysis was performed. Both global and segmental left ventricular strain values were obtained.ResultsThe mean global circumferential strain (GCS) and global radial strain (GRS) values were significantly lower in patients compared to control (P = 0.002 and P = 0.006, respectively). No correlation was found between T2* values and ejection fraction; however, there was a significant correlation between T2* values and GCS and GRS (P = 0.012 and P = 0.025, respectively) in thalassemia patients. Regional strain revealed significantly lower values of GCS and GRS in basal regions compared to apical ones (P = 0.000).ConclusionsOur study revealed that CMR-FT can play a role in the early detection of systolic impairment in thalassemia patients.

Left and right atrioventricular coupling index in patients with beta-thalassemia major.

The aim of this cross-sectional study was to investigate the relationship of left atrioventricular coupling index (LACI) and right atrioventricular coupling index (RACI) with demographics, clinical data, cardiovascular magnetic resonance findings, and cardiac complications (heart failure, arrhythmias, and pulmonary hypertension) in a cohort of patients with beta-thalassemia major (β-TM). We evaluated 292 β-TM patients (151 females, 36.72 ± 11.76years) consecutively enrolled in the Extension-Myocardial Iron Overload in Thalassemia (E-MIOT) project. Moreover, we assessed 32 sex- and age-matched healthy controls (12 females, mean age 40.78 ± 14.35years). LACI was determined by calculating the ratio of the left atrium end-diastolic volume to the left ventricle end-diastolic volume, while RACI was defined by calculating the ratio of the right atrium end-diastolic volume to the right ventricle end-diastolic volume. Compared to healthy control, β-TM demonstrated increased LACI (22.99 ± 13.58% vs. 16.05 ± 5.28%; p < 0.0001) and RACI (27.84 ± 10.30% vs. 17.06 ± 5.03%; p < 0.0001). Aging, diabetes, splenectomy, and the presence of late gadolinium enhancement (LGE) showed a significant positive association with both LACI and RACI. In stepwise regression analysis, the presence of LGE was found to be an independent predictor of both impaired LACI and RACI (β coefficient = 0.244, p < 0.0001 and β coefficient = 0.218, p = 0.003; respectively). LACI and RACI were not correlated with myocardial iron overload. Patients with cardiac complications had significantly higher LACI and RACI than patients without cardiac complications. In patients with β-TM, LACI and RACI were significantly associated with the presence of LV LGE. In addition, patients with cardiac complications had impaired LACI and RACI.

Global longitudinal strain by cardiac magnetic resonance is associated with cardiac iron and complications in beta-thalassemia major patients

BackgroundThe aim of this cross-sectional study was to investigate the association of left ventricular (LV) strain parameters with demographics, clinical data, cardiovascular magnetic resonance (CMR) findings, and cardiac complications (heart failure and arrhythmias) in patients with β-thalassemia major (β-TM). MethodWe considered 266 β-TM patients (134 females, 37.08 ± 11.60 years) consecutively enrolled in the Extension-Myocardial Iron Overload in Thalassemia (E-MIOT) project and 80 healthy controls (50 females, mean age 39.77 ± 11.29 years). The CMR protocol included cine images for the assessment of global longitudinal strain (GLS), global circumferential strain (GCS), and global radial strain (GRS) using feature tracking (FT) and for the quantification of LV function parameters, the T2* technique for the assessment of myocardial iron overload, and late gadolinium enhancement (LGE) technique. ResultsIn comparison to the healthy control group, β-TM patients showed impaired GLS, GCS, and GRS values.Among β-TM patients, sex was identified as the sole independent determinant of all LV strain parameters. All LV strain parameters displayed a significant correlation with LV end-diastolic volume index, end-systolic volume index, mass index, and ejection fraction, and with the number of segments exhibiting LGE. Only GLS exhibited a significant correlation with global heart T2* values and the number of segments with T2* < 20 ms. Patients with cardiac complications exhibited significantly impaired GLS compared to those without cardiac complications. ConclusionIn patients with β-TM, GLS, GCS, and GRS were impaired in comparison with control subjects. Among LV strain parameters, only GLS demonstrated a significant association with cardiac iron levels and complications.

Cardiac Disease in Egyptian Thalassemia Major and Sickle Cell Disease Adolescents in relation to Vitamin D Status Using Echocardiogram &amp; Ultrafast Magnetic Resonance Imaging

Abstract Background Cardiovascular complications are well recognized in patients with β-thalassemia major (β-TM) and sickle cell disease (SCD). Vitamin D deficiency is prevalent in patients with transfusion-dependent thalassemia and there is an association between vitamin D deficiency and both left ventricular function and iron overload in thalassemia. However, the relationship between vitamin D and cardiac iron is not well studied in Egypt and the role of vitamin D in cardiac disease in SCD and β-TM needs to be assessed. Aim To assess vitamin D status in children and adolescents with SCD and β-TM in relation to cardiac complications using echocardiography and cardiac magnetic resonance (CMR) T2*. Methods Forty-one patients with SCD and 35 patients with β-TM without symptomatic cardiac disease were studied stressing on history of splenectomy and transfusion history. Markers of hemolysis, serum ferritin and vitamin D levels were measured. Liver iron concentration (LIC) was assessed by magnetic resonance imaging (MRI). Screening for cardiovascular abnormalities was performed by the non-invasive Doppler echocardiography and CMR was used to assess myocardial iron overload. Results Echocardiography showed that cardiac functions were significantly impaired in β-TM patients compared with SCD while the frequency of pulmonary hypertension risk (elevated TRV ≥2.5 m/sec) was consistent between both β-TM and SCD groups. Cardiac T2* (which reflects cardiac iron overload) was significantly lower while myocardial iron concentration (MIC) was significantly higher in β -TM patients compared with SCD group. Vitamin D levels were decreased in both SCD and β-TM patients than control levels; however, SCD patients had significantly lower vitamin D levels. Low vitamin D levels were significantly associated withincreased risk of pulmonary hypertension in the SCD group while In β-TM group, vitamin D levels were significantly lower in patients with cardiac disease and those with serum ferritin levels ≥ 2500 µg/L. A significant evidence of diastolic dysfunction was found in SCD and β-TM patients who had low serum vitamin D level &amp;lt; 20 ng/mL. Vitamin D levels were negatively correlated to serum ferritin and LIC while positively correlated to cardiac T2*. Conclusion Low vitamin D levels were associated with cardiopulmonary dysfunction in adolescents with SCD and β-TM. Vitamin D deficiency in those patients was linked to cardiac iron overload leading to iron induced cardiomyopathy. Proper chelation therapy is mandatory to improve cardiac disease, iron overload and consequently, vitamin D status in β-TM patients.

Multiparametric cardiac magnetic resonance in patients with thalassemia intermedia: new insights from the E-MIOT network.

In a relatively large cohort of thalassemia intermedia (TI) patients, we systematically investigated myocardial iron overload (MIO), function, and replacement fibrosis using cardiac magnetic resonance (CMR), we assessed the clinical determinants of global heart T2* values, and we explored the association between multiparametric CMR findings and cardiac complications. We considered 254 beta-TI patients (43.14 ± 13.69years, 138 females) consecutively enrolled in the Extension-Myocardial Iron Overload in Thalassemia project. MIO was quantified by T2* technique and biventricular function and atrial areas by cine images. Macroscopic myocardial fibrosis was detected by late gadolinium enhancement technique. Compared to never/sporadically transfused patients, regularly transfused (RT)-TI patients exhibited significantly lower global heart T2* values, biventricular end-diastolic volume indexes, left ventricular mass index, and cardiac index. In RT-TI patients, age and serum ferritin levels were the strongest predictors of global heart T2* values. Independently from the transfusional state, cardiac T2* values were not associated with biventricular function. Of the 103 (40.6%) patients in whom the contrast medium was administrated, 27 (26.2%) had replacement myocardial fibrosis. Age, sex distribution, cardiac iron, and biventricular function parameters were comparable between patients without and without replacement myocardial fibrosis. Twenty-five (9.8%) patients had a history of cardiac complications (heart failure and arrhythmias). Increased age and replacement myocardial fibrosis emerged as significant risk markers for cardiac complications. In TI, regular transfusions are associated with less pronounced cardiac remodeling but increase the risk of MIO. Replacement myocardial fibrosis is a frequent finding associated with cardiac complications.

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

We evaluated the impact of the genotype on clinical and hematochemical features, hepatic and cardiac iron levels, and endocrine, hepatic, and cardiovascular complications in non-transfusion-dependent (NTD) β-thalassemia intermedia (TI) patients. Sixty patients (39.09 ± 11.11years, 29 females) consecutively enrolled in the Myocardial Iron Overload in Thalassemia project underwent Magnetic Resonance Imaging to quantify iron overload, biventricular function parameters, and atrial areas and to detect replacement myocardial fibrosis. Three groups of patients were identified: homozygous β+ (N = 18), heterozygous β0β+ (N = 22), and homozygous β0 (N = 20). The groups were homogeneous for sex, age, splenectomy, hematochemical parameters, chelation therapy, and iron levels. The homozygous β° genotype was associated with significantly higher biventricular end-diastolic and end-systolic volume indexes and bi-atrial area indexes. No difference was detected in biventricular ejection fractions or myocardial fibrosis. Extramedullary hematopoiesis and leg ulcers were significantly more frequent in the homozygous β° group compared to the homozygous β+ group. No association was detected between genotype and liver cirrhosis, hypogonadism, hypothyroidism, osteoporosis, heart failure, arrhythmias, and pulmonary hypertension. Heart remodelling related to a high cardiac output state cardiomyopathy, extramedullary hematopoiesis, and leg ulcers were more pronounced in patients with the homozygous β° genotype compared to the other genotypes analyzed. The knowledge of the genotype can assist in the clinical management of NTD β-TI patients.

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.

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

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

Beta-Thalassemia Major and Myocardial Iron Overload: A Longitudinal Study with Magnetic Resonance Imaging.

Patients with β-thalassemia major depend on lifelong transfusion, resulting in tissue iron overload. This longitudinal retrospective observational study aims to assess myocardial and liver iron overload using magnetic resonance imaging (MRI) and investigate the lag between myocardial and liver iron unloading in β-thalassemia patients undergoing chelation therapy. Beta-thalassemia major patients with at least two MRI studies between 2016 and 2020 were enrolled. Myocardial and liver iron overload were defined as T2 ∗ less than 20 and 2.1, respectively. Outcomes included mortality, myocardial and liver T2 ∗ changes, and systolic dysfunction assessed by cardiac MRI. Fifty-five patients with a mean age of 24.62 ± 7.94 years, a mean follow-up duration of 24.3 ± 12.9 months, and a mean ferritin level of 1475.75 ± 771.12 ng/mL were enrolled. All of the abovementioned patients only took deferoxamine as the iron-chelating medication. Mortality occurred in three patients (5.5%) during follow-up. Liver T2 ∗ significantly increased (p value <0.05), while myocardial T2 ∗ showed a nonsignificant increase. Iron unloading of the myocardium was not significantly different from that of the liver and did not result in a significant lag (56% vs. 44%; p value = 0.419). Baseline myocardial T2 ∗ correlated with extramedullary hematopoiesis, weekly number of deferoxamine injections (p value <0.01), timing between the transfusions, and serum ferritin (p value <0.05). Liver T2 ∗ reduced during deferoxamine chelation therapy, while myocardial T2 ∗ remained unchanged. No significant lag was observed between myocardial and liver iron unloading. Further studies are required to elucidate these findings.

Low Vitamin D Levels Are Associated with Increased Cardiac Iron Uptake in Beta-Thalassemia Major.

We evaluated the association of vitamin D and parathormone (PTH) levels with cardiac iron and function in beta-thalassemia major (β-TM) patients. Two-hundred and seventy-eight TM patients (39.04 ± 8.58 years, 56.8% females) underwent magnetic resonance imaging for the assessment of iron overload (T2* technique), biventricular function parameters (cine images), and replacement myocardial fibrosis (late gadolinium enhancement technique). Vitamin D levels were deficient (<20 ng/dL) in 107 (38.5%) patients, insufficient (20-30 ng/dL) in 96 (34.5%) patients, and sufficient (≥30 ng/dL) in 75 (27.0%) patients. Deficient vitamin D patients had a significantly higher frequency of myocardial iron overload (MIO; global heart T2* < 20 ms) than patients with sufficient and insufficient vitamin D levels and a significantly higher left ventricular end-diastolic volume index and mass index than patients with sufficient vitamin D levels. PTH was not associated with cardiac iron, function, or fibrosis. In the multivariate regression analysis, vitamin D, serum ferritin, and pancreatic iron levels were the strongest predictors of global heart T2* values. In receiver operating characteristic curve analysis, a vitamin D level ≤ 17.3 ng/dL predicted MIO with a sensitivity of 81.5% and a specificity of 75.3% (p < 0.0001). In TM, the periodic and regular assessment of vitamin D levels can be beneficial for the prevention of cardiac iron accumulation and subsequent overt dysfunction.

Treatment of Congenital Hypotransferrinemia Patients with Human Apotransferrin Resolves Anemia and Reduces Iron Accumulation

Introduction Congenital hypotransferrinemia is a very rare inherited and life-threatening disorder (MIM#209300) characterized by systemic iron overload and anemia. The deficiency of serum transferrin leads to inadequate iron supply to erythroid bone marrow, resulting in microcytic hypochromic anemia. This triggers hepcidin downregulation, causing increased iron absorption and production of non-transferrin bound iron (NTBI), leading to iron overload in various organs and tissues. Currently, there is no targeted therapy for this disease. Method In an open-label phase II/III study, four children (age 0-7 years) and one adult (20 years) with congenital hypotransferrinaemia were treated with purified plasma-fractionated human apotransferrin for nearly 10 years. All patients received an initial intravenous dose of 75 mg/kg every 8 weeks for 6 months, followed by 75 mg/kg every 4 weeks for additional 6 months, and in the subsequent years apotransferrin was administered every 4 weeks but the dose was adjusted to 75-150 mg/kg based on clinical judgement of physician according to patient condition. Prior to the start of the study two patients already received replacement therapy, i.e., human apotransferrin or plasma. Serum transferrin and serum iron were determined before every infusion. Primary objective was to investigate the effect of apotransferrin treatment on anemia and iron overload. Hemoglobin, hematocrit, and erythrocytes as markers of anemia were measured every 8 weeks. Iron overload was monitored by measuring serum ferritin every 8 weeks and yearly iron quantification in liver and heart through MRI. Labile Plasma Iron (LPI) was measured before and after infusion (starting after 2 years of treatment). The need for additional treatment for anemia or iron overload was defined as a secondary outcome. Safety and clinical tolerance were evaluated by adverse event surveillance and laboratory measurements. Results Baseline serum transferrin levels were significantly below the normal range in all patients (&amp;lt;10-189 mg/L; normal range: 1800-3500 mg/L). Treatment with human apotransferrin increased serum transferrin and serum iron levels in all patients. Fifteen minutes after the first infusion, transferrin levels ranged from 1340-2415 mg/L, but declined to values just above baseline before the next infusion (dosing interval 8 weeks). During the study period serum transferrin concentrations were affected by dose adjustments; however, trough levels of transferrin remained below the normal range throughout the study (range 200-800 mg/L). Despite subnormal trough levels, apotransferrin infusion led to rapid increase of hemoglobin (Figure 1), hematocrit, and erythrocyte levels up to normal values. The two patients who were already treated before the study, showed normal levels at baseline that were maintained. In all patients hematologic parameters remained stable throughout the study. Ferritin levels were elevated at baseline and decreased to normal ranges in 1.2 to 7.3 years, with a maximum decrease ranging from 82% to 97% of baseline. MRI examinations revealed liver iron overload at baseline which normalized in all patients after apotransferrin treatment, in most cases after 3 to 4 years (Figure 2). No myocardial iron overload was observed at baseline and during the follow-up. Pre-infusion LPI was found in all five patients, however in three patients the values were undetectable on most occasions. Immediately after infusion with apotransferrin, in none of the patients LPI was present anymore. Throughout the study no additional use of plasma/blood products or iron chelators was needed. Apotransferrin infusions were well tolerated. No serious adverse events were reported. No loss of clinical response to treatment was detected over time. Conclusion Treatment with human apotransferrin in patients with congenital hypotransferrinemia demonstrated good long-term clinical efficacy. Apotransferrin infusions increased hematopoiesis, reduced iron overload in organs, and eliminated the need for additional medication. The therapy was well-tolerated and showed good clinical safety. Human apotransferrin holds promise as the mainstay treatment option for congenital hypotransferrinemia.

Clinical utility of circulating TWEAK and CD163 as biomarkers of iron-induced cardiac decompensation in transfusion dependent thalassemia major

Background and aimTumor necrosis factor-like weak inducer of apoptosis (TWEAK) affects most of the cells involved in cardiac fibrosis like inflammatory cells, cardiomyocytes and fibroblasts. CD163, the receptor of TWEAK on the surface of type 2 macrophages, is shed into plasma upon macrophages activation. This work aimed to evaluate serum TWEAK and its decoy receptor CD163 as probable biomarkers to monitor myocardial iron overload (MIO) in transfusion dependent thalassemia major (TDTM) patients and to predict iron-induced cardiac decompensation (IICD). MethodsA total of 140 TDTM patients were enrolled. Patients were categorized into two groups; group I (n = 70) diagnosed with IICD while group II (n = 70) had no evidence of IICD. sTWEAK and sCD163 were quantitated utilizing Enzyme-linked-immunosorbent- assay. ResultssTWEAK was evidently lower in group I than group II (medians, 412 and 1052 pg/mL respectively). sCD163 was higher in group I than group II (medians, 615.5 and 323.5 ng/mL respectively). sTWEAK positively correlated with cardiac MRI-T2 mapping and ventricular ejection fractions and negatively correlated with B-Natriuretic peptide and cardiac troponin. An inverse relationship between TWEAK and CD163 was documented throughout the study. sTWEAK, sCD163 and TWEAK/CD163 ratio proved to be significant predictors of IICD in TDTM patients. TWEAK/CD163 ratio < 1.04 discriminated IICD in TDTM patients with 100 % clinical sensitivity and specificity. ConclusionCirculating TWEAK and CD163 appears to be promising biomarkers for monitoring MIO and predicting IICD in TDTM patients.

Left Ventricular Global Longitudinal Strain (LV GLS) assessed by Echocardiography predicts myocardial fibrosis and iron overload in transfusion dependent beta-thalassemia patients

Abstract Background Cardiac involvement represents the leading cause of death in transfusion dependent beta-thalassemia (TDT) patients. It is mainly related to cardiac iron overload and myocardial fibrosis, causing progressive damage and a deterioration of systolic and diastolic function. Moreover, myocardial fibrosis may not be directly related with the degree of cardiac iron deposition and it is associated with a higher risk of cardiovascular complications. To date, Cardiac Magnetic Resonance (CMR) is the gold standard for the evaluation of iron overload with T2* sequences and for the detection of myocardial fibrosis with late gadolinium enhancement (LGE). However, CMR is not always feasible. Left Ventricular Global Longitudinal Strain (LV GLS) with Speckle Tracking Echocardiography (STE) is a non-invasive imaging tool, which may play a key role in the early recognition of subclinical myocardial damage and dysfunction (figure 1). Purpose The aim of this study was the evaluation of the role of LV GLS with STE in the characterization of myocardial involvement in a population of TDT patients. Methods An observational, cross-sectional, monocentric study was conducted enrolling 44 patients with TDT from the outpatient clinic of hematology located in our teritary hospital from January 2022 to December 2022. Each patient underwent a thorough clinical evaluation, laboratory testing, transthoracic echocardiogram (TTE) with LV GLS-STE by a trained cardiologist and contrast enhanced CMR with T2* technique and LGE sequences. A T2* value &amp;lt; 20 msec was set to define the presence of iron overload. Results The mean age of patients was 39± 9 years with a slight prevalence of female sex (53% vs 47% respectively). Atherosclerotic cardiovascular risk factors were rarely present, the most common was arterial hypertension in about 12% of patients. The TTE pointed out a left ventricular ejection fraction within the normal range (mean value of 59 ± 5%). As regards LV GLS, the mean value was -21.1 ± 3.0%. Cardiac iron overload was observed in 18% of patients, while about 15% of patients had cardiac fibrosis. A clinical and statistically significant difference was observed between LV GLS values in patients with cardiac iron overload as compared to patients without (-18.2 ± 2.1% vs -20.6 ± 3.1%; p value=0.043). A clinical and statistically significant difference was documented, also, between LV GLS values in patient with cardiac fibrosis as compared to patient without LGE (-16.4 ± 1.7% vs -20.6 ± 2.8%; p value=0.002). As regards cardiac fibrosis, a LV GLS cut-off value of -18,3% was found by the analysis of ROC curve with an AUC of 0.931 (95% CI: 0.846-1.000) (figure 2). Conclusions In a small population of TDT patients we observed that LV GLS with STE may be a promising tool able to help clinicians in the early identification of cardiac iron overload and fibrosis, providing useful information for diagnostic workup and therapeutic approach.