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ElLaboudy MA, Saber MM, Adly AA, Ismail EA, Ibrahim FA, Elalfy OM. Oxidative stress markers and tissue iron overload after 12-months vitamin E supplementation for children with transfusion-dependent β-thalassemia on different iron chelators: A randomized placebo-controlled trial. Clin Nutr 2025; 50:154-163. [PMID: 40424814 DOI: 10.1016/j.clnu.2025.05.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Revised: 05/01/2025] [Accepted: 05/09/2025] [Indexed: 05/29/2025]
Abstract
BACKGROUND Vitamin E is an anti-oxidant depleted in thalassemia as a result of iron overload. AIM We investigated the efficacy and safety of vitamin E as an adjuvant therapy to iron chelators in transfusion-dependent thalassemia patients in relation to tissue iron overload and examine its potential corrective value to oxidative stress markers including peroxiredoxin-2 (PRDX2). METHODS This randomized prospective study included 180 pediatric patients with transfusion-dependent β-thalassemia who were equally divided into three groups to either receive desferrioxamine (DFO), deferiprone (DFP) or deferasirox (DFX). Patients in each group were further randomized to receive vitamin E supplementation (400 mg daily) or matching placebo. Patients were followed-up for 12 months with assessment of oxidative stress markers (malondialdehyde [MDA], reduced glutathione, superoxide dismutase, glutathione peroxidase and PRDX2), serum ferritin (SF), liver iron content (LIC) and cardiac T2∗ by magnetic resonance imaging. The primary endpoint was the change between groups from baseline to 12 months as regards LIC. RESULTS After vitamin E therapy, transfusion index, SF and LIC were significantly decreased while hemoglobin and cardiac T2∗ were elevated compared with baseline levels or placebo group. MDA levels were decreased while the studied antioxidants were improved after vitamin E supplementation compared with baseline levels or placebo. DFX-treated patients had the highest hemoglobin level with the lowest SF, LIC and MDA levels compared with DFO or DFP subgroups. CONCLUSIONS Vitamin E is a safe adjuvant anti-oxidant therapy that potentiates the efficacy of DFX in reducing iron burden in transfusion-dependent β-thalassemia patients. This trial was registered under ClinicalTrials.gov Identifier no. NCT06509581.
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Affiliation(s)
- Mohamed A ElLaboudy
- Pediatrics Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Maha M Saber
- Complementary Medicine Department, National Research Center, Cairo, Egypt
| | - Amira A Adly
- Pediatrics Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
| | - Eman A Ismail
- Clinical Pathology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Fatma A Ibrahim
- Biochemistry Department, National Research Center, Cairo, Egypt
| | - Omar M Elalfy
- Complementary Medicine Department, National Research Center, Cairo, Egypt
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Meloni A, Saba L, Positano V, Taccori M, Pistoia L, De Marco E, Sanna PMG, Longo F, Giovangrossi P, Gerardi C, Barone A, Visceglie D, Barra V, Clemente A, Cau R. Left ventricular diastolic and systolic functions by cardiac magnetic resonance in beta-thalassemia major: correlation with clinical findings and cardiac complications. THE INTERNATIONAL JOURNAL OF CARDIOVASCULAR IMAGING 2025; 41:847-857. [PMID: 39928284 DOI: 10.1007/s10554-025-03352-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Accepted: 01/30/2025] [Indexed: 02/11/2025]
Abstract
This cross-sectional study explored the association of left ventricular (LV) fractional area change (FAC) with demographic characteristics, clinical data, cardiovascular magnetic resonance (CMR) findings, and cardiac complications (heart failure and arrythmias) in patients with beta-thalassemia major (β-TM). We included 292 β-TM patients (151 females, 36.72 ± 11.76 years) consecutively enrolled in the Extension-Myocardial Iron Overload in Thalassemia project and 20 healthy controls (8 females, 36.97 ± 3.54 years). CMR was used to assess FAC and derive LV systolic and diastolic indexes, to quantify myocardial iron overload (MIO) by the T2* technique and LV volumes and ejection fraction, and to detect late gadolinium enhancement (LGE). Healthy subjects and β-TM patients showed comparable LV systolic and diastolic indexes. In β-TM, the LV systolic index was significantly correlated with global heart T2* values, and patients with significant MIO (T2*<20ms) were more likely to have a reduced LV systolic index compared to those without MIO (odds ratio-OR = 3.13; p = 0.013). In multivariate analysis, global heart T2* values and positive LGE emerged as independent determinants of the LV systolic index. The number of segments with LGE inversely correlated with the LV systolic index (p = 0.003). Patients with a reduced LV systolic index were more likely to have cardiac diseases than those with a normal LV systolic index (OR = 5.34; p < 0.0001). No significant correlates were found for the LV diastolic index. In well-treated β-TM patients, MIO and LGE were the strongest determinants of the LV systolic index, and a reduced LV systolic index was associated with an increased risk of cardiac complications.
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Affiliation(s)
- Antonella Meloni
- Bioengineering Unit, Fondazione G. Monasterio CNR-Regione Toscana, Via Moruzzi, 1, Pisa, 56124, Italy.
| | - Luca Saba
- Dipartimento di Radiologia, Azienda Ospedaliero-Universitaria di Cagliari - Polo di Monserrato, Cagliari, Italy
| | - Vincenzo Positano
- Bioengineering Unit, Fondazione G. Monasterio CNR-Regione Toscana, Via Moruzzi, 1, Pisa, 56124, Italy
| | - Mauro Taccori
- Dipartimento di Radiologia, Azienda Ospedaliero-Universitaria di Cagliari - Polo di Monserrato, Cagliari, Italy
| | - Laura Pistoia
- U.O.C. Ricerca Clinica, Fondazione G. Monasterio CNR-Regione Toscana, Pisa, Italy
| | - Emanuela De Marco
- U.O. Oncoematologia Pediatrica, Azienda Ospedaliero Universitaria Pisana- Stabilimento S. Chiara, Pisa, Italy
| | | | - Filomena Longo
- Unità Operativa Day Hospital Della Talassemia e Delle Emoglobinopatie, Azienda Ospedaliero-Universitaria "S. Anna", Cona- Ferrara, Italy
| | - Piera Giovangrossi
- Servizio di Immunoematologia e Medicina Trasfusionale, Ospedale S. M. Goretti, Latina, Italy
| | - Calogera Gerardi
- Unità Operativa Semplice Dipartimentale di Talassemia, Presidio Ospedaliero "Giovanni Paolo II" - Distretto AG2 di Sciacca, Sciacca, AG, Italy
| | - Angelica Barone
- Unità Operativa di Pediatria e Oncoematologia Dipartimento Materno-Infantile, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
| | - Domenico Visceglie
- Servizio di Immunoematologia e Medicina Trasfusionale, Ospedale "Di Venere", Bari, Italy
| | - Valerio Barra
- Department of Radiology, Fondazione G. Monasterio CNR-Regione Toscana, Pisa, Italy
| | - Alberto Clemente
- Department of Radiology, Fondazione G. Monasterio CNR-Regione Toscana, Pisa, Italy
| | - Riccardo Cau
- Dipartimento di Radiologia, Azienda Ospedaliero-Universitaria di Cagliari - Polo di Monserrato, Cagliari, Italy
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Meloni A, Positano V, Ricchi P, Pepe A, Cau R. What is the importance of monitoring iron levels in different organs over time with magnetic resonance imaging in transfusion-dependent thalassemia patients? Expert Rev Hematol 2025; 18:291-299. [PMID: 40152085 DOI: 10.1080/17474086.2025.2486379] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2025] [Revised: 03/19/2025] [Accepted: 03/26/2025] [Indexed: 03/29/2025]
Abstract
INTRODUCTION Iron overload is the main pathophysiological driver of organ damage in transfusion-dependent thalassemia (TDT). Magnetic resonance imaging (MRI) provides detailed insights into the distribution and severity of iron accumulation in the different organs. AREAS COVERED This special report describes the impact of MRI on clinical and therapeutic management and short- and long-term outcomes in TDT patients. PubMed, Scopus, and Google Scholar databases were searched to identify the relevant studies published before November 2024. EXPERT OPINION Cardiac and hepatic MRI are now well-established modalities, integrated into the clinical practice. They have become essential for tailoring iron chelation therapies to the specific patient's needs and for monitoring treatment efficacy. The improved control of cardiac iron burden has translated into reduced morbidity and mortality. The MRI accessibility remains limited in resource-limited settings and progress in this field relies on educating and training centers to ensure accurate execution and interpretation. The clinicopathological significance, prognostic value, and reproducibility of pancreatic iron levels assessment have been established, charting a path toward its clinical use. There are limited data about renal, adrenal, and pituitary iron deposition, and more research is needed to fully establish the functional significance and to standardize and validate the MRI protocols.
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Affiliation(s)
- Antonella Meloni
- Bioengineering Unit, Fondazione G. Monasterio CNR-Regione Toscana, Pisa, Italy
| | - Vincenzo Positano
- Bioengineering Unit, Fondazione G. Monasterio CNR-Regione Toscana, Pisa, Italy
| | - Paolo Ricchi
- Unità Operativa Semplice Dipartimentale Malattie Rare del Globulo Rosso, Azienda Ospedaliera di Rilievo Nazionale "A. Cardarelli", Napoli, Italy
| | - Alessia Pepe
- Institute of Radiology, Department of Medicine, University of Padua, Padua, Italy
| | - Riccardo Cau
- Dipartimento di Radiologia, Azienda Ospedaliero-Universitaria di Cagliari - Polo di Monserrato, Monserrato, Italy
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Meloni A, Pistoia L, Spasiano A, Sorrentino F, Messina G, Santodirocco M, Borsellino Z, Cecinati V, Positano V, Restaino G, Schicchi N, Grassedonio E, Vallone A, Emdin M, Clemente A, Barison A. Prevalence and Correlates of Dilated and Non-Dilated Left Ventricular Cardiomyopathy in Transfusion-Dependent Thalassemia: Data from a National, Multicenter, Observational Registry. J Cardiovasc Dev Dis 2025; 12:103. [PMID: 40137101 PMCID: PMC11943376 DOI: 10.3390/jcdd12030103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2025] [Revised: 03/10/2025] [Accepted: 03/14/2025] [Indexed: 03/27/2025] Open
Abstract
We investigated the prevalence, clinical characteristics, and prognostic role of dilated cardiomyopathy (DCM) and non-dilated left ventricular cardiomyopathy (NDLVC) in patients with transfusion-dependent β-thalassemia (β-TDT). We retrospectively included 415 β-TDT patients who underwent cardiovascular magnetic resonance to quantify myocardial iron overload (MIO) and biventricular function parameters and to detect replacement myocardial fibrosis. Demographic and laboratory parameters were comparable among patients with no overt cardiomyopathy (NOCM; n = 294), DCM (n = 12), and NDLVC (n = 109), while cardiac size and systolic function were significantly different. Compared to NOCM patients, DCM and NDLVC patients had a higher prevalence of MIO and replacement myocardial fibrosis. During a mean follow-up of 57.03 ± 18.01 months, cardiac complications occurred in 32 (7.7%) patients: 15 heart failures, 15 supraventricular arrhythmias, and 2 pulmonary hypertensions. Compared to the NOCM group, both the NDLVC and the DCM groups were associated with a significantly increased risk of cardiac complications (hazard ratio = 4.26 and 8.81, respectively). In the multivariate analysis, the independent predictive factors were age, MIO, and the presence of DCM and NDLVC versus the NOCM phenotype. In β-TDT, the detection of NDLVC and DCM phenotypes may hold value in predicting cardiac outcomes.
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Affiliation(s)
- Antonella Meloni
- Bioengineering Unit, Fondazione G. Monasterio CNR-Regione Toscana, 56124 Pisa, Italy; (A.M.); (V.P.)
| | - Laura Pistoia
- Unità Operativa Semplice Dipartimentale Ricerca Clinica, Fondazione G. Monasterio CNR-Regione Toscana, 56124 Pisa, Italy;
| | - Anna Spasiano
- Unità Operativa Semplice Dipartimentale Malattie Rare del Globulo Rosso, Azienda Ospedaliera di Rilievo Nazionale “A. Cardarelli”, 80131 Napoli, Italy;
| | - Francesco Sorrentino
- Unità Operativa Semplice Dipartimentale Day Hospital Talassemici, Ospedale “Sant’Eugenio”, 00143 Roma, Italy;
| | - Giuseppe Messina
- Centro Microcitemie, Grande Ospedale Metropolitano “Bianchi-Melacrino-Morelli”, 89100 Reggio Calabria, Italy;
| | - Michele Santodirocco
- Centro Microcitemia—Day Hospital Thalassemia Poliambulatorio “Giovanni Paolo II”, Istituto di Ricovero e Cura a Carattere Scientifico Ospedale Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy;
| | - Zelia Borsellino
- Unità Operativa Complessa Ematologia con Talassemia, Azienda di Rilievo Nazionale ad Alta Specializzazione Civico “Benfratelli-Di Cristina”, 90134 Palermo, Italy;
| | - Valerio Cecinati
- Struttura Semplice di Microcitemia, Ospedale “SS. Annunziata”, 74123 Taranto, Italy;
| | - Vincenzo Positano
- Bioengineering Unit, Fondazione G. Monasterio CNR-Regione Toscana, 56124 Pisa, Italy; (A.M.); (V.P.)
| | - Gennaro Restaino
- Radiology Department, Responsible Research Hospital, 86100 Campobasso, Italy;
| | - Nicolò Schicchi
- Dipartimento di Radiologia, Azienda Ospedaliero-Universitaria Ospedali Riuniti “Umberto I-Lancisi-Salesi”, 60020 Ancona, Italy;
| | - Emanuele Grassedonio
- Sezione di Scienze Radiologiche—Dipartimento di Biopatologia e Biotecnologie Mediche, Policlinico “Paolo Giaccone”, 90127 Palermo, Italy;
| | - Antonino Vallone
- Reparto di Radiologia, Azienda Ospedaliera “Garibaldi” Presidio Ospedaliero Nesima, 95126 Catania, Italy;
| | - Michele Emdin
- Cardiology and Cardiovascular Medicine, Fondazione G. Monasterio CNR-Regione Toscana, 56124 Pisa, Italy;
- Institute of Life Sciences, Scuola Superiore Sant’Anna, 56124 Pisa, Italy
| | - Alberto Clemente
- Department of Radiology, Fondazione G. Monasterio CNR-Regione Toscana, 56124 Pisa, Italy;
| | - Andrea Barison
- Cardiology and Cardiovascular Medicine, Fondazione G. Monasterio CNR-Regione Toscana, 56124 Pisa, Italy;
- Institute of Life Sciences, Scuola Superiore Sant’Anna, 56124 Pisa, Italy
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Ru Q, Li Y, Zhang X, Chen L, Wu Y, Min J, Wang F. Iron homeostasis and ferroptosis in muscle diseases and disorders: mechanisms and therapeutic prospects. Bone Res 2025; 13:27. [PMID: 40000618 PMCID: PMC11861620 DOI: 10.1038/s41413-024-00398-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Revised: 11/23/2024] [Accepted: 12/16/2024] [Indexed: 02/27/2025] Open
Abstract
The muscular system plays a critical role in the human body by governing skeletal movement, cardiovascular function, and the activities of digestive organs. Additionally, muscle tissues serve an endocrine function by secreting myogenic cytokines, thereby regulating metabolism throughout the entire body. Maintaining muscle function requires iron homeostasis. Recent studies suggest that disruptions in iron metabolism and ferroptosis, a form of iron-dependent cell death, are essential contributors to the progression of a wide range of muscle diseases and disorders, including sarcopenia, cardiomyopathy, and amyotrophic lateral sclerosis. Thus, a comprehensive overview of the mechanisms regulating iron metabolism and ferroptosis in these conditions is crucial for identifying potential therapeutic targets and developing new strategies for disease treatment and/or prevention. This review aims to summarize recent advances in understanding the molecular mechanisms underlying ferroptosis in the context of muscle injury, as well as associated muscle diseases and disorders. Moreover, we discuss potential targets within the ferroptosis pathway and possible strategies for managing muscle disorders. Finally, we shed new light on current limitations and future prospects for therapeutic interventions targeting ferroptosis.
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Affiliation(s)
- Qin Ru
- Institute of Intelligent Sport and Proactive Health, Department of Health and Physical Education, Jianghan University, Wuhan, China
| | - Yusheng Li
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Xi Zhang
- Institute of Intelligent Sport and Proactive Health, Department of Health and Physical Education, Jianghan University, Wuhan, China
| | - Lin Chen
- Institute of Intelligent Sport and Proactive Health, Department of Health and Physical Education, Jianghan University, Wuhan, China
| | - Yuxiang Wu
- Institute of Intelligent Sport and Proactive Health, Department of Health and Physical Education, Jianghan University, Wuhan, China.
| | - Junxia Min
- The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.
| | - Fudi Wang
- The Second Affiliated Hospital, School of Public Health, State Key Laboratory of Experimental Hematology, Zhejiang University School of Medicine, Hangzhou, China.
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Allegra S, Comità S, Roetto A, De Francia S. Sex and Gender Differences in Iron Chelation. Biomedicines 2024; 12:2885. [PMID: 39767791 PMCID: PMC11673655 DOI: 10.3390/biomedicines12122885] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Revised: 12/13/2024] [Accepted: 12/17/2024] [Indexed: 01/11/2025] Open
Abstract
BACKGROUND/OBJECTIVES In the absence of physiological mechanisms to excrete excessive iron, the administration of iron chelation therapy is necessary. Age and hormones have an impact on the absorption, distribution, metabolism, and excretion of the medications used to treat iron excess, resulting in notable sex- and gender-related variances. METHODS Here, we aimed to review the literature on sex and gender in iron overload assessment and treatment. RESULTS The development of iron chelators has shown to be a successful therapy for lowering the body's iron levels and averting the tissue damage and organ failure that follows. Numerous studies have described how individual factors can impact chelation treatment, potentially impact therapeutic response, and/or result in inadequate chelation or elevated toxicity; however, most of these data have not considered male and female patients as different groups, and particularly, the effect of hormonal variations in women have never been considered. CONCLUSIONS An effective iron chelation treatment should take into account sex and gender differences.
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Affiliation(s)
- Sarah Allegra
- Department of Clinical and Biological Sciences, University of Turin, San Luigi Gonzaga University Hospital, 10043 Orbassano, Italy; (S.C.); (A.R.); (S.D.F.)
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Premawardhena A, Wanasinghe S, Perera C, Wijethilaka MN, Rajakaruna R, Samarasinghe R, Williams S, Mettananda S. Deferoxamine, deferasirox, and deferiprone triple iron chelator combination therapy for transfusion-dependent β-thalassaemia with very high iron overload: a randomised clinical trial. THE LANCET REGIONAL HEALTH. SOUTHEAST ASIA 2024; 30:100495. [PMID: 39802421 PMCID: PMC11718414 DOI: 10.1016/j.lansea.2024.100495] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/21/2024] [Revised: 09/26/2024] [Accepted: 09/26/2024] [Indexed: 01/16/2025]
Abstract
Background Many patients with β-thalassaemia die prematurely due to iron overload. In this study, we aim to evaluate the efficacy and safety of the triple combination of deferoxamine, deferasirox and deferiprone on iron chelation in patients with transfusion-dependent β-thalassaemia with very high iron overload. Methods This open-label, randomised, controlled clinical trial was conducted at Colombo North Teaching Hospital, Sri Lanka. Transfusion-dependent β-thalassaemia patients with ferritin >3500 ng/mL were randomised 2:1 into intervention (deferoxamine, deferasirox and deferiprone) and control (deferoxamine and deferasirox) arms. Reduction in serum ferritin after six months was the primary outcome measure. Reduction in liver iron content, improvement in cardiac T2∗, and adverse effects were secondary outcome measures. Findings Twenty-three patients (intervention-15, control-8) were recruited. 92% and 62% in the intervention and control arms showed a reduction in ferritin, respectively. The mean reduction of ferritin was significantly higher in intervention (-1094 ± 907 ng/mL) compared to control (+82 ± 1588 ng/mL) arm (p = 0.042). There was no statistically significant difference in the liver iron content in two arms. In the intervention arm, 67% improved cardiac T2∗ (mean change +6.72 ± 9.63 ms) compared to 20% in the control arm (mean change -3.00 ± 8.24 ms). Five patients discontinued deferiprone due to arthralgia, which resolved completely after stopping the drug. Interpretation Triple combination therapy with deferoxamine, deferasirox and deferiprone is more efficacious in reducing iron burden measured by serum ferritin and showed a positive trend in reducing myocardial iron content in patients with transfusion-dependent β-thalassaemia with very high iron overload. Deferiprone has the disturbing side effect of reversible but severe arthropathy. Funding None.
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Affiliation(s)
- Anuja Premawardhena
- Colombo North Teaching Hospital, Ragama, 11010, Sri Lanka
- Department of Medicine, Faculty of Medicine, University of Kelaniya, Thalagolla Road, Ragama, 11010, Sri Lanka
| | - Sakuni Wanasinghe
- Department of Medicine, Faculty of Medicine, University of Kelaniya, Thalagolla Road, Ragama, 11010, Sri Lanka
| | - Chamodi Perera
- Department of Paediatrics, Faculty of Medicine, University of Kelaniya, Thalagolla Road, Ragama, 11010, Sri Lanka
| | | | - R.H.M.G. Rajakaruna
- Department of Radiology, Lady Ridgeway Children's Hospital, Colombo, 00700, Sri Lanka
| | | | - Senani Williams
- Department of Pathology, Faculty of Medicine, University of Kelaniya, Thalagolla Road, Ragama, 11010, Sri Lanka
| | - Sachith Mettananda
- Colombo North Teaching Hospital, Ragama, 11010, Sri Lanka
- Department of Paediatrics, Faculty of Medicine, University of Kelaniya, Thalagolla Road, Ragama, 11010, Sri Lanka
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Musallam KM, Barella S, Origa R, Ferrero GB, Lisi R, Pasanisi A, Longo F, Gianesin B, Forni GL. Differential effects of iron chelators on iron burden and long-term morbidity and mortality outcomes in a large cohort of transfusion-dependent β-thalassemia patients who remained on the same monotherapy over 10 years. Blood Cells Mol Dis 2024; 107:102859. [PMID: 38820707 DOI: 10.1016/j.bcmd.2024.102859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2024] [Revised: 05/23/2024] [Accepted: 05/28/2024] [Indexed: 06/02/2024]
Abstract
We conducted a retrospective cohort study on 663 transfusion-dependent β-thalassemia patients receiving the same iron chelation monotherapy with deferoxamine, deferiprone, or deferasirox for up to 10 years (median age 31.8 years, 49.9 % females). Patients on all three iron chelators had a steady and significant decline in serum ferritin over the 10 years (median deferoxamine: -170.7 ng/mL, P = 0.049, deferiprone: -236.7 ng/mL, P = 0.001; deferasirox: -323.7 ng/mL, P < 0.001) yet had no significant change in liver iron concentration or cardiac T2*; while noting that patients generally had low hepatic and cardiac iron levels at study start. Median absolute, relative, and normalized changes were generally comparable between the three iron chelators. Patients receiving deferasirox had the highest morbidity and mortality-free survival probability among the three chelators, although the difference was only statistically significant when compared with deferoxamine (P = 0.037). On multivariate Cox regression analysis, there was no significant association between iron chelator type and the composite outcome of morbidity or mortality. In a real-world setting, there is comparable long-term iron chelation effectiveness between the three available iron chelators for patients with mild-to-moderate iron overload.
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Affiliation(s)
- Khaled M Musallam
- Center for Research on Rare Blood Disorders (CR-RBD), Burjeel Medical City, Abu Dhabi, United Arab Emirates; Division of Hematology/Oncology, Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA
| | - Susanna Barella
- S.C. Centro delle Microcitemie e Anemie Rare, ASL Cagliari, Cagliari, Italy
| | - Raffaella Origa
- Università di Cagliari, S.C. Centro delle Microcitemie e Anemie Rare, ASL Cagliari, Cagliari, Italy
| | - Giovanni Battista Ferrero
- Hemoglobinopathies and Rare Anemia Reference Center, San Luigi Gonzaga University Hospital, Department of Biological and Clinical Sciences, University of Turin, Turin, Italy
| | - Roberto Lisi
- Thalassemia Unit, ARNAS Garibaldi, Catania, Italy
| | - Annamaria Pasanisi
- Centro della Microcitemia A.Quarta, Hematology Unit, A. Perrino Hospital, Brindisi, Italy
| | - Filomena Longo
- Day Hospital della Talassemia e delle Emoglobinopatie, Azienda Ospedaliero Universitaria S. Anna, Ferrara, Italy
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Salimi Z, Afsharinasab M, Rostami M, Eshaghi Milasi Y, Mousavi Ezmareh SF, Sakhaei F, Mohammad-Sadeghipour M, Rasooli Manesh SM, Asemi Z. Iron chelators: as therapeutic agents in diseases. Ann Med Surg (Lond) 2024; 86:2759-2776. [PMID: 38694398 PMCID: PMC11060230 DOI: 10.1097/ms9.0000000000001717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Accepted: 01/03/2024] [Indexed: 05/04/2024] Open
Abstract
The concentration of iron is tightly regulated, making it an essential element. Various cellular processes in the body rely on iron, such as oxygen sensing, oxygen transport, electron transfer, and DNA synthesis. Iron excess can be toxic because it participates in redox reactions that catalyze the production of reactive oxygen species and elevate oxidative stress. Iron chelators are chemically diverse; they can coordinate six ligands in an octagonal sequence. Because of the ability of chelators to trap essential metals, including iron, they may be involved in diseases caused by oxidative stress, such as infectious diseases, cardiovascular diseases, neurodegenerative diseases, and cancer. Iron-chelating agents, by tightly binding to iron, prohibit it from functioning as a catalyst in redox reactions and transfer iron and excrete it from the body. Thus, the use of iron chelators as therapeutic agents has received increasing attention. This review investigates the function of various iron chelators in treating iron overload in different clinical conditions.
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Affiliation(s)
- Zohreh Salimi
- Department of Clinical Biochemistry, Faculty of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan
| | - Mehdi Afsharinasab
- Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran
| | - Mehdi Rostami
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad
| | - Yaser Eshaghi Milasi
- Department of Clinical Biochemistry, Faculty of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan
| | - Seyedeh Fatemeh Mousavi Ezmareh
- Department of Clinical Biochemistry, Faculty of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan
| | - Fariba Sakhaei
- Department of Clinical Biochemistry, Faculty of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan
| | - Maryam Mohammad-Sadeghipour
- Department of Clinical Biochemistry, Afzalipoor Faculty of Medicine, Kerman University of Medical Sciences, Kerman
| | | | - Zatollah Asemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Islamic Republic of Iran
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10
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Meloni A, Pistoia L, Putti MC, Longo F, Corigliano E, Ricchi P, Rossi V, Casini T, Righi R, Renne S, Peritore G, Barbuto L, Positano V, Cademartiri F. Pancreatic iron in pediatric transfusion-dependent beta-thalassemia patients: A longitudinal MRI study. Pediatr Blood Cancer 2024; 71:e30923. [PMID: 38385860 DOI: 10.1002/pbc.30923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 02/02/2024] [Accepted: 02/08/2024] [Indexed: 02/23/2024]
Abstract
BACKGROUND In pediatric transfusion-dependent thalassemia (TDT) patients, we evaluated the prevalence, pattern, and clinical associations of pancreatic siderosis and the changes in pancreatic iron levels and their association with baseline and changes in total body iron balance. PROCEDURE We considered 86 pediatric TDT patients consecutively enrolled in the Extension-Myocardial Iron Overload in Thalassemia Network. Iron overload (IO) was quantified by R2* magnetic resonance imaging (MRI). RESULTS Sixty-three (73%) patients had pancreatic IO (R2* > 38 Hz). Global pancreas R2* values were significantly correlated with mean serum ferritin levels, MRI liver iron concentration (LIC) values, and global heart R2* values. Global pancreas R2* values were significantly higher in patients with altered versus normal glucose metabolism. Thirty-one patients also performed the follow-up MRI at 18 ± 3 months. Higher pancreatic R2* values were detected at the follow-up, but the difference versus the baseline MRI was not significant. The 20% of patients with baseline pancreatic IO showed no pancreatic IO at the follow-up. The 46% of patients without baseline pancreatic IO developed pancreatic siderosis. The changes in global pancreas R2* between the two MRIs were not correlated with baseline serum ferritin levels, baseline, final, and changes in MRI LIC values, or baseline pancreatic iron levels. CONCLUSIONS In children with TDT, pancreatic siderosis is a frequent finding associated with hepatic siderosis and represents a risk factor for myocardial siderosis and alterations of glucose metabolism. Iron removal from the pancreas is exceptionally challenging and independent from hepatic iron status.
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Affiliation(s)
- Antonella Meloni
- Bioengineering Unit, Fondazione G. Monasterio CNR-Regione Toscana, Pisa, Italy
- Department of Radiology, Fondazione G. Monasterio CNR-Regione Toscana, Pisa, Italy
| | - Laura Pistoia
- Department of Radiology, Fondazione G. Monasterio CNR-Regione Toscana, Pisa, Italy
- U.O.C. Ricerca Clinica, Fondazione G. Monasterio CNR-Regione Toscana, Pisa, Italy
| | - Maria Caterina Putti
- Dipartimento della Salute della Donna e del Bambino, Clinica di Emato-Oncologia Pediatrica, Azienda Ospedaliero-Università di Padova, Padua, Italy
| | - Filomena Longo
- Unità Operativa Day Hospital della Talassemia e delle Emoglobinopatie, Azienda Ospedaliero-Universitaria "S. Anna,", Cona, Ferrara, Italy
| | | | - Paolo Ricchi
- U.O.S.D. Malattie Rare del Globulo Rosso, Azienda Ospedaliera di Rilievo Nazionale "A. Cardarelli", Naples, Italy
| | | | - Tommaso Casini
- SOC Oncologia, Ematologia e Trapianto di Cellule Staminali Emopoietiche, Meyer Children's Hospital IRCCS, Florence, Italy
| | - Riccardo Righi
- Diagnostica per Immagini e Radiologia Interventistica, Ospedale del Delta, Lagosanto, Ferrara, Italy
| | - Stefania Renne
- Struttura Complessa di Cardioradiologia-UTIC, Presidio Ospedaliero "Giovanni Paolo II,", Lamezia Terme, Italy
| | - Giuseppe Peritore
- Unità Operativa Complessa di Radiologia, "ARNAS" Civico, Di Cristina Benfratelli, Palermo, Italy
| | - Luigi Barbuto
- U.O.C. Radiologia Generale e di Pronto Soccorso, Azienda Ospedaliera di Rilievo Nazionale "A. Cardarelli", Naples, Italy
| | - Vincenzo Positano
- Bioengineering Unit, Fondazione G. Monasterio CNR-Regione Toscana, Pisa, Italy
- Department of Radiology, Fondazione G. Monasterio CNR-Regione Toscana, Pisa, Italy
| | - Filippo Cademartiri
- Department of Radiology, Fondazione G. Monasterio CNR-Regione Toscana, Pisa, Italy
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11
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Corbacioglu S, Frangoul H, Locatelli F, Hobbs W, Walters M. Defining curative endpoints for transfusion-dependent β-thalassemia in the era of gene therapy and gene editing. Am J Hematol 2024; 99:422-429. [PMID: 38100154 DOI: 10.1002/ajh.27166] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Revised: 10/16/2023] [Accepted: 11/06/2023] [Indexed: 02/15/2024]
Abstract
β-thalassemia is a monogenic disease that results in varying degrees of anemia. In the most severe form, known as transfusion-dependent β-thalassemia (TDT), the clinical hallmarks are ineffective erythropoiesis and a requirement of regular, life-long red blood cell transfusions, with the development of secondary clinical complications such as iron overload, end-organ damage, and a risk of early mortality. With the exception of allogeneic hematopoietic cell transplantation, current treatments for TDT address disease symptoms and not the underlying cause of disease. Recently, a growing number of gene addition and gene editing-based treatments for patients with TDT with the potential to provide a one-time functional cure have entered clinical trials. A key challenge in the design and evaluation of these trials is selecting endpoints to evaluate if these novel genetic therapies have a curative versus an ameliorative effect. Here, we present an overview of the pathophysiology of TDT, review emerging gene addition or gene editing therapeutic approaches for TDT currently in clinical trials, and identify a series of endpoints that can quantify therapeutic effects, including a curative outcome.
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Affiliation(s)
| | - Haydar Frangoul
- Sarah Cannon Research Institute and the Children's Hospital at TriStar Centennial, Nashville, Tennessee, USA
| | - Franco Locatelli
- IRCCS, Ospedale Pediatrico Bambino, Gesù Rome, Catholic University of the Sacred Heart, Rome, Italy
| | - William Hobbs
- Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA
| | - Mark Walters
- Department of Pediatrics, UCSF Benioff Children's Hospital Oakland, Oakland, California, USA
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12
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Musallam KM, Cappellini MD, Coates TD, Kuo KHM, Al-Samkari H, Sheth S, Viprakasit V, Taher AT. Αlpha-thalassemia: A practical overview. Blood Rev 2024; 64:101165. [PMID: 38182489 DOI: 10.1016/j.blre.2023.101165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 12/19/2023] [Accepted: 12/29/2023] [Indexed: 01/07/2024]
Abstract
α-Thalassemia is an inherited blood disorder characterized by decreased synthesis of α-globin chains that results in an imbalance of α and β globin and thus varying degrees of ineffective erythropoiesis, decreased red blood cell (RBC) survival, chronic hemolytic anemia, and subsequent comorbidities. Clinical presentation varies depending on the genotype, ranging from a silent or mild carrier state to severe, transfusion-dependent or lethal disease. Management of patients with α-thalassemia is primarily supportive, addressing either symptoms (eg, RBC transfusions for anemia), complications of the disease, or its transfusion-dependence (eg, chelation therapy for iron overload). Several novel therapies are also in development, including curative gene manipulation techniques and disease modifying agents that target ineffective erythropoiesis and chronic hemolytic anemia. This review of α-thalassemia and its various manifestations provides practical information for clinicians who practice beyond those regions where it is found with high frequency.
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Affiliation(s)
- Khaled M Musallam
- Center for Research on Rare Blood Disorders (CR-RBD), Burjeel Medical City, Abu Dhabi, United Arab Emirates
| | - M Domenica Cappellini
- Department of Clinical Sciences and Community, University of Milan, Ca' Granda Foundation IRCCS Maggiore Policlinico Hospital, Milan, Italy
| | - Thomas D Coates
- Hematology Section, Cancer and Blood Disease Institute, Children's Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA, USA
| | - Kevin H M Kuo
- Division of Hematology, Department of Medicine, University of Toronto, Toronto, ON, Canada
| | - Hanny Al-Samkari
- Center for Hematology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Sujit Sheth
- Division of Pediatric Hematology and Oncology, Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA
| | - Vip Viprakasit
- Department of Pediatrics & Thalassemia Center, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Ali T Taher
- Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon.
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13
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El-Beshlawy A, Dewedar H, Hindawi S, Alkindi S, Tantawy AA, Yassin MA, Taher AT. Management of transfusion-dependent β-thalassemia (TDT): Expert insights and practical overview from the Middle East. Blood Rev 2024; 63:101138. [PMID: 37867006 DOI: 10.1016/j.blre.2023.101138] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 10/04/2023] [Accepted: 10/05/2023] [Indexed: 10/24/2023]
Abstract
β-Thalassemia is one of the most common monogenetic diseases worldwide, with a particularly high prevalence in the Middle East region. As such, we have developed long-standing experience with disease management and devising solutions to address challenges attributed to resource limitations. The region has also participated in the majority of clinical trials and development programs of iron chelators and more novel ineffective erythropoiesis-targeted therapy. In this review, we provide a practical overview of management for patients with transfusion-dependent β-thalassemia, primarily driven by such experiences, with the aim of transferring knowledge to colleagues in other regions facing similar challenges.
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Affiliation(s)
- Amal El-Beshlawy
- Department of Pediatric Hematology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Hany Dewedar
- Thalassemia Center, Latifa Hospital, Dubai, United Arab Emirates
| | - Salwa Hindawi
- Department of Hematology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Salam Alkindi
- Department of Hematology, Sultan Qaboos University Hospital, Muscat, Oman
| | - Azza A Tantawy
- Department of Pediatrics, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Mohamed A Yassin
- Department of Hematology and Oncology, National Centre for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar
| | - Ali T Taher
- Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon.
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14
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Hamdy M, El-Beshlawy A, Veríssimo MPA, Kanter J, Inusa B, Williams S, Lee D, Temin NT, Fradette C, Tricta F, Ebeid FSE, Kwiatkowski JL, Elalfy MS. Deferiprone versus deferoxamine for transfusional iron overload in sickle cell disease and other anemias: Pediatric subgroup analysis of the randomized, open-label FIRST study. Pediatr Blood Cancer 2024; 71:e30711. [PMID: 37807937 DOI: 10.1002/pbc.30711] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 09/13/2023] [Accepted: 09/25/2023] [Indexed: 10/10/2023]
Abstract
BACKGROUND Children with sickle cell disease (SCD) who are chronically transfused often, require iron chelation therapy. There are limited data that allow for comparison of the efficacy and safety of the iron chelator deferiprone versus deferoxamine in children with SCD. METHODS This post hoc analysis of the phase 3b/4, randomized, open-label FIRST (Ferriprox in Patients with IRon Overload in Sickle Cell Disease Trial) study (NCT02041299) included patients 17 years and younger with SCD or other anemias receiving deferiprone or deferoxamine. RESULTS Overall, 142 patients were evaluated; mean ages were 10.5 and 11.7 years in the deferiprone and deferoxamine groups, respectively. At 12 months: mean change from baseline in liver iron concentration was -3.3 mg/g dry weight (dw) with deferiprone and -3.4 mg/g dw with deferoxamine (p = .8216); relative mean change (coefficient of variation %) in log cardiac T2* magnetic resonance imaging was 1.02 (21.8%) with deferiprone and 0.95 (19.5%) with deferoxamine (p = .0717); and the mean (standard error) change in serum ferritin levels was -133.0 (200.3) μg/L with deferiprone and -467.1 (244.1) μg/L with deferoxamine (p = .2924). The most common deferiprone-related adverse events (AEs) were upper abdominal pain (20.2%), vomiting (13.8%), pyrexia (9.6%), decreased neutrophil count (9.6%), increased alanine aminotransferase (ALT; 9.6%), and increased aspartate aminotransferase (AST; 9.6%). All cases of increased ALT, increased AST, and neutropenia resolved, most without intervention. CONCLUSIONS This post hoc analysis of pediatric patients from FIRST corroborated previous findings in adults that deferiprone is comparable to deferoxamine in reducing iron overload. No new safety concerns were observed. Deferiprone is an oral chelation option that could improve adherence and outcomes in children.
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Affiliation(s)
- Mona Hamdy
- Department of Pediatrics, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Amal El-Beshlawy
- Department of Pediatric Hematology, Pediatric Hospital of Cairo University, Cairo, Egypt
| | | | - Julie Kanter
- Division of Hematology and Oncology, Department of Medicine, University of Alabama, Birmingham, Alabama, USA
| | - Baba Inusa
- Paediatric Haematology, Evelina Children's Hospital, Guy's and St. Thomas NHS Foundation Trust, London, UK
| | - Suzan Williams
- Department of Haematology and Oncology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - David Lee
- Hematology/Immunology Program, Chiesi Canada Corporation, Toronto, Ontario, Canada
| | - Noemi Toiber Temin
- Hematology/Immunology Program, Chiesi Canada Corporation, Toronto, Ontario, Canada
| | - Caroline Fradette
- Hematology/Immunology Program, Chiesi Canada Corporation, Toronto, Ontario, Canada
| | - Fernando Tricta
- Hematology/Immunology Program, Chiesi Canada Corporation, Toronto, Ontario, Canada
| | - Fatma S E Ebeid
- Pediatric Hematology Oncology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Janet L Kwiatkowski
- Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
- Department of Pediatrics, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Mohsen S Elalfy
- Pediatric Hematology Oncology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
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15
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Meloni A, Pistoia L, Vassalle C, Spasiano A, Fotzi I, Bagnato S, Putti MC, Cossu A, Massei F, Giovangrossi P, Maffei S, Positano V, Cademartiri F. Low Vitamin D Levels Are Associated with Increased Cardiac Iron Uptake in Beta-Thalassemia Major. Diagnostics (Basel) 2023; 13:3656. [PMID: 38132240 PMCID: PMC10742632 DOI: 10.3390/diagnostics13243656] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Revised: 12/12/2023] [Accepted: 12/13/2023] [Indexed: 12/23/2023] Open
Abstract
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.
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Affiliation(s)
- Antonella Meloni
- Bioengineering Unit, Fondazione G. Monasterio CNR—Regione Toscana, 56124 Pisa, Italy; (A.M.); (V.P.)
- Department of Radiology, Fondazione G. Monasterio CNR—Regione Toscana, 56124 Pisa, Italy;
| | - Laura Pistoia
- Department of Radiology, Fondazione G. Monasterio CNR—Regione Toscana, 56124 Pisa, Italy;
- Unità Operativa Complessa Ricerca Clinica, Fondazione G. Monasterio CNR—Regione Toscana, 56124 Pisa, Italy
| | - Cristina Vassalle
- Medicina di Laboratorio, Fondazione G. Monasterio CNR—Regione Toscana, 56124 Pisa, Italy;
| | - Anna Spasiano
- Unità Operativa Semplice Dipartimentale Malattie Rare del Globulo Rosso, Azienda Ospedaliera di Rilievo Nazionale “A. Cardarelli”, 80131 Napoli, Italy;
| | - Ilaria Fotzi
- Oncologia, Ematologia e Trapianto di Cellule Staminali Emopoietiche, Meyer Children’s Hospital IRCCS, 50139 Firenze, Italy;
| | - Sergio Bagnato
- Ematologia Microcitemia, Ospedale San Giovanni di Dio—ASP Crotone, 88900 Crotone, Italy;
| | - Maria Caterina Putti
- Dipartimento della Salute della Donna e del Bambino, Clinica di Emato-Oncologia Pediatrica, Azienda Ospedaliero Università di Padova, 35128 Padova, Italy;
| | - Antonella Cossu
- Ambulatorio Trasfusionale—Servizio Immunoematologia e Medicina Trasfusionale Dipartimento dei Servizi, Presidio Ospedaliero “San Francesco”, 08100 Nuoro, Italy;
| | - Francesco Massei
- Unità Operativa Oncoematologia Pediatrica, Azienda Ospedaliero Universitaria Pisana—Stabilimento S. Chiara, 56126 Pisa, Italy;
| | - Piera Giovangrossi
- Servizio di Immunoematologia e Medicina Trasfusionale, Ospedale S. M. Goretti, 04100 Latina, Italy;
| | - Silvia Maffei
- Cardiovascular and Gynaecological Endocrinology Unit, Fondazione G. Monasterio CNR—Regione Toscana, 56124 Pisa, Italy;
| | - Vincenzo Positano
- Bioengineering Unit, Fondazione G. Monasterio CNR—Regione Toscana, 56124 Pisa, Italy; (A.M.); (V.P.)
- Department of Radiology, Fondazione G. Monasterio CNR—Regione Toscana, 56124 Pisa, Italy;
| | - Filippo Cademartiri
- Department of Radiology, Fondazione G. Monasterio CNR—Regione Toscana, 56124 Pisa, Italy;
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16
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Benz DC, Gräni C, Antiochos P, Heydari B, Gissler MC, Ge Y, Cuddy SAM, Dorbala S, Kwong RY. Cardiac magnetic resonance biomarkers as surrogate endpoints in cardiovascular trials for myocardial diseases. Eur Heart J 2023; 44:4738-4747. [PMID: 37700499 PMCID: PMC11032206 DOI: 10.1093/eurheartj/ehad510] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2022] [Revised: 07/05/2023] [Accepted: 07/25/2023] [Indexed: 09/14/2023] Open
Abstract
Cardiac magnetic resonance offers multiple facets in the diagnosis, risk stratification, and management of patients with myocardial diseases. Particularly, its feature to precisely monitor disease activity lends itself to quantify response to novel therapeutics. This review critically appraises the value of cardiac magnetic resonance imaging biomarkers as surrogate endpoints for prospective clinical trials. The primary focus is to comprehensively outline the value of established cardiac magnetic resonance parameters in myocardial diseases. These include heart failure, cardiac amyloidosis, iron overload cardiomyopathy, hypertrophic cardiomyopathy, cardio-oncology, and inflammatory cardiomyopathies like myocarditis and sarcoidosis.
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Affiliation(s)
- Dominik C Benz
- Noninvasive Cardiovascular Imaging Section, Cardiovascular Division, Department of Medicine and Department of Radiology, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115, USA
| | - Christoph Gräni
- Department of Cardiology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Panagiotis Antiochos
- Cardiology and Cardiac MR Centre, University Hospital Lausanne, Lausanne, Switzerland
| | - Bobak Heydari
- Cardiovascular Division, Department of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Mark Colin Gissler
- Department of Cardiology and Angiology, University Heart Center Freiburg-Bad Krozingen, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Yin Ge
- Terrence Donnelly Heart Center, St Michael’s Hospital, Toronto, Canada
| | - Sarah A M Cuddy
- Noninvasive Cardiovascular Imaging Section, Cardiovascular Division, Department of Medicine and Department of Radiology, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115, USA
| | - Sharmila Dorbala
- Noninvasive Cardiovascular Imaging Section, Cardiovascular Division, Department of Medicine and Department of Radiology, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115, USA
| | - Raymond Y Kwong
- Noninvasive Cardiovascular Imaging Section, Cardiovascular Division, Department of Medicine and Department of Radiology, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115, USA
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17
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Abstract
Thalassemias are among the most common hereditary diseases in the world because heterozygosity offers protection against malarial infection. Affected individuals have variable expression of alpha or beta chains that lead to their unbalanced utilization during hemoglobin formation, oxidative stress, and apoptosis of red cell precursors prior to maturation. Some individuals produce sufficient hemoglobin to survive but suffer the vascular stress imposed by chronic anemia and ineffective erythropoiesis. In other patients, mature red cell formation is insufficient, and chronic transfusions are required-suppressing anemia and ineffective erythropoiesis but at the expense of iron overload. The cardiovascular consequences of thalassemia have changed dramatically over the previous five decades because of evolving treatment practices. This review summarizes this evolution, focusing on complications and management pertinent to modern patient cohorts.
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Affiliation(s)
- John C Wood
- Division of Cardiology, Children's Hospital Los Angeles, Los Angeles, California, USA
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18
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Salem A, Desai P, Elgebaly A. Efficacy and Safety of Combined Deferiprone and Deferasirox in Iron-Overloaded Patients: A Systematic Review. Cureus 2023; 15:e48276. [PMID: 38058350 PMCID: PMC10695738 DOI: 10.7759/cureus.48276] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Accepted: 11/04/2023] [Indexed: 12/08/2023] Open
Abstract
Despite the established efficacy of iron chelation therapy in transfusion-induced iron-overloaded patients, there is no universal agreement regarding the choice of an optimal chelating regimen. Deferasirox (DFX) and deferiprone (DFP) are two oral iron chelators, and combination usage demonstrated effectiveness as an alternative to monotherapies in patients with a limited response to monotherapy. The present systematic review aimed to assess the evidence regarding the outcomes of combined DFP and DFX in iron-overloaded patients. An online search was conducted in PubMed, Scopus, Web of Science, and CENTRAL databases. Interventional and observational studies that assessed the outcomes of combined DFP and DFX in iron-overloaded patients were included. Eleven studies (12 reports) were considered in this meta-analysis. The studies included dual iron chelation strategies for a number of diagnoses. Single-arm studies (n =7) showed a reduction of serum ferritin, which reached the level of statistical significance in three studies. Likewise, most studies reported a numerical reduction in liver iron concentration (LIC) and increased cardiac MRI-T2* values after chelating therapy. Alternatively, comparative studies showed no significant difference in post-treatment serum ferritin between DFX plus DFP and DFX/DFP plus deferoxamine (DFO). The adherence to combination therapy was good to average in nearly 66.7-100% of the patients across four studies. One study reported a poor adherence rate. The combined regimen was generally tolerable, with no reported incidence of serious adverse events among the included studies. In conclusion, the DFP and DFX combination is a safe and feasible option for iron overload patients with a limited response to monotherapy.
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Affiliation(s)
- Ahmed Salem
- Department of Pharmacology and Therapeutics, Levien Cancer Institute, Atrium Health, Charlotte, USA
| | - Payal Desai
- Department of Hematologic Malignancies and Blood Disorders, Levine Cancer Institute, Charlotte, USA
- Department of Internal Medicine, Wake Forest School of Medicine, Charlotte, USA
| | - Ahmed Elgebaly
- Department of Medical Informatics, University of East London, London, GBR
- Department of Internal Medicine, Al-Azhar University, Cairo, EGY
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19
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Ullah H, Salih N, Tavaratsyan A, Sandesara M, Syed S, Us Saher N, Fleihan T. Secondary Hemochromatosis Leading to Acute Coronary Syndrome in a Thalassemic Patient. Cureus 2023; 15:e48226. [PMID: 38050510 PMCID: PMC10693904 DOI: 10.7759/cureus.48226] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/03/2023] [Indexed: 12/06/2023] Open
Abstract
Thalassemia, a congenital hemoglobinopathy, is characterized by impaired erythropoiesis and peripheral hemolysis, leading to anemia. Thalassemia major, in particular, necessitates regular blood transfusions, resulting in iron accumulation in the body. Iron overload primarily affects the heart and can induce cardiac disorder, including defects in the pump and conduction system, which is one of the leading causes of mortality among thalassemics. The existing literature has revealed limited support for the occurrence of acute coronary syndrome (ACS) due to hemochromatosis. However, it does show that elevated troponin levels can be observed even in cases not associated with ACS. Here, we offer a rare case study of acute coronary syndrome in a patient with thalassemia major who also had elevated ferritin levels and abnormal troponin I values. The difficulty of cardiac problems in thalassemia major is highlighted by this case, as well as the necessity for more clinical attention and study to better comprehend and handle such instances.
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Affiliation(s)
- Hidayat Ullah
- General Practice, Hayatabad Medical Complex Peshawar, Peshawar, PAK
| | - Noman Salih
- Internal Medicine, Hayatabad Medical Complex Peshawar, Peshawar, PAK
| | - Ani Tavaratsyan
- Cardiology, Yerevan State Medical University (YSMU), Yerevan, ARM
| | | | - Sarah Syed
- Medicine, Combined Military Hospital (CMH) Lahore Medical College and Institute of Dentistry, Lahore, PAK
| | - Najam Us Saher
- Internal Medicine, Hayatabad Medical Complex Peshawar, Peshawar, PAK
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20
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Wang X, Zhou Y, Min J, Wang F. Zooming in and out of ferroptosis in human disease. Front Med 2023; 17:173-206. [PMID: 37121959 DOI: 10.1007/s11684-023-0992-z] [Citation(s) in RCA: 46] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Accepted: 02/12/2023] [Indexed: 05/02/2023]
Abstract
Ferroptosis is defined as an iron-dependent regulated form of cell death driven by lipid peroxidation. In the past decade, it has been implicated in the pathogenesis of various diseases that together involve almost every organ of the body, including various cancers, neurodegenerative diseases, cardiovascular diseases, lung diseases, liver diseases, kidney diseases, endocrine metabolic diseases, iron-overload-related diseases, orthopedic diseases and autoimmune diseases. Understanding the underlying molecular mechanisms of ferroptosis and its regulatory pathways could provide additional strategies for the management of these disease conditions. Indeed, there are an expanding number of studies suggesting that ferroptosis serves as a bona-fide target for the prevention and treatment of these diseases in relevant pre-clinical models. In this review, we summarize the progress in the research into ferroptosis and its regulatory mechanisms in human disease, while providing evidence in support of ferroptosis as a target for the treatment of these diseases. We also discuss our perspectives on the future directions in the targeting of ferroptosis in human disease.
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Affiliation(s)
- Xue Wang
- The Second Affiliated Hospital, The First Affiliated Hospital, Institute of Translational Medicine, School of Public Health, State Key Laboratory of Experimental Hematology, Zhejiang University School of Medicine, Hangzhou, 310058, China
- The First Affiliated Hospital, Basic Medical Sciences, School of Public Health, Hengyang Medical School, University of South China, Hengyang, 421001, China
| | - Ye Zhou
- Department of Endocrinology and Metabolism, Ningbo First Hospital, Ningbo, 315000, China
| | - Junxia Min
- The Second Affiliated Hospital, The First Affiliated Hospital, Institute of Translational Medicine, School of Public Health, State Key Laboratory of Experimental Hematology, Zhejiang University School of Medicine, Hangzhou, 310058, China.
| | - Fudi Wang
- The Second Affiliated Hospital, The First Affiliated Hospital, Institute of Translational Medicine, School of Public Health, State Key Laboratory of Experimental Hematology, Zhejiang University School of Medicine, Hangzhou, 310058, China.
- The First Affiliated Hospital, Basic Medical Sciences, School of Public Health, Hengyang Medical School, University of South China, Hengyang, 421001, China.
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Geneen LJ, Dorée C, Estcourt LJ. Interventions for improving adherence to iron chelation therapy in people with sickle cell disease or thalassaemia. Cochrane Database Syst Rev 2023; 3:CD012349. [PMID: 36877640 PMCID: PMC9987409 DOI: 10.1002/14651858.cd012349.pub3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/07/2023]
Abstract
BACKGROUND Regularly transfused people with sickle cell disease (SCD) and people with thalassaemia are at risk of iron overload. Iron overload can lead to iron toxicity in vulnerable organs such as the heart, liver and endocrine glands, which can be prevented and treated with iron-chelating agents. The intensive demands and uncomfortable side effects of therapy can have a negative impact on daily activities and wellbeing, which may affect adherence. OBJECTIVES To identify and assess the effectiveness of different types of interventions (psychological and psychosocial, educational, medication interventions, or multi-component interventions) and interventions specific to different age groups, to improve adherence to iron chelation therapy compared to another listed intervention, or standard care in people with SCD or thalassaemia. SEARCH METHODS We searched CENTRAL (Cochrane Library), MEDLINE, PubMed, Embase, CINAHL, PsycINFO, ProQuest Dissertations & Global Theses, Web of Science & Social Sciences Conference Proceedings Indexes and ongoing trial databases (13 December 2021). We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register (1 August 2022). SELECTION CRITERIA For trials comparing medications or medication changes, only randomised controlled trials (RCTs) were eligible for inclusion. For studies including psychological and psychosocial interventions, educational interventions, or multi-component interventions, non-randomised studies of interventions (NRSIs), controlled before-after studies, and interrupted time series studies with adherence as a primary outcome were also eligible for inclusion. DATA COLLECTION AND ANALYSIS For this update, two authors independently assessed trial eligibility and risk of bias, and extracted data. We assessed the certainty of the evidence using GRADE. MAIN RESULTS We included 19 RCTs and one NRSI published between 1997 and 2021. One trial assessed medication management, one assessed an education intervention (NRSI) and 18 RCTs were of medication interventions. Medications assessed were subcutaneous deferoxamine, and two oral chelating agents, deferiprone and deferasirox. We rated the certainty of evidence as very low to low across all outcomes identified in this review. Four trials measured quality of life (QoL) with validated instruments, but provided no analysable data and reported no difference in QoL. We identified nine comparisons of interest. 1. Deferiprone versus deferoxamine We are uncertain whether or not deferiprone affects adherence to iron chelation therapy (four RCTs, unpooled, very low-certainty evidence), all-cause mortality (risk ratio (RR) 0.47, 95% confidence interval (CI) 0.18 to 1.21; 3 RCTs, 376 participants; very low-certainty evidence), or serious adverse events (SAEs) (RR 1.43, 95% CI 0.83 to 2.46; 1 RCT, 228 participants; very low-certainty evidence). Adherence was reported as "good", "high" or "excellent" by all seven trials, though the data could not be analysed formally: adherence ranged from 69% to 95% (deferiprone, mean 86.6%), and 71% to 93% (deferoxamine, mean 78.8%), based on five trials (474 participants) only. 2. Deferasirox versus deferoxamine We are uncertain whether or not deferasirox affects adherence to iron chelation therapy (three RCTs, unpooled, very low-certainty evidence), although medication adherence was high in all trials. We are uncertain whether or not there is any difference between the drug therapies in serious adverse events (SAEs) (SCD or thalassaemia) or all-cause mortality (thalassaemia). 3. Deferiprone versus deferasirox We are uncertain if there is a difference between oral deferiprone and deferasirox based on a single trial in children (average age 9 to 10 years) with any hereditary haemoglobinopathy in adherence, SAEs and all-cause mortality. 4. Deferasirox film-coated tablet (FCT) versus deferasirox dispersible tablet (DT) One RCT compared deferasirox in different tablet forms. There may be a preference for FCTs, shown through a trend for greater adherence (RR 1.10, 95% CI 0.99 to 1.22; 1 RCT, 88 participants), although medication adherence was high in both groups (FCT 92.9%; DT 85.3%). We are uncertain if there is a benefit in chelation-related AEs with FCTs. We are uncertain if there is a difference in the incidence of SAEs, all-cause mortality or sustained adherence. 5. Deferiprone and deferoxamine combined versus deferiprone alone We are uncertain if there is a difference in adherence, though reporting was usually narrative as triallists report it was "excellent" in both groups (three RCTs, unpooled). We are uncertain if there is a difference in the incidence of SAEs and all-cause mortality. 6. Deferiprone and deferoxamine combined versus deferoxamine alone We are uncertain if there is a difference in adherence (four RCTs), SAEs (none reported in the trial period) and all-cause mortality (no deaths reported in the trial period). There was high adherence in all trials. 7. Deferiprone and deferoxamine combined versus deferiprone and deferasirox combined There may be a difference in favour of deferiprone and deferasirox (combined) in rates of adherence (RR 0.84, 95% CI 0.72 to 0.99) (one RCT), although it was high (> 80%) in both groups. We are uncertain if there is a difference in SAEs, and no deaths were reported in the trial, so we cannot draw conclusions based on these data (one RCT). 8. Medication management versus standard care We are uncertain if there is a difference in QoL (one RCT), and we could not assess adherence due to a lack of reporting in the control group. 9. Education versus standard care One quasi-experimental (NRSI) study could not be analysed due to the severe baseline confounding. AUTHORS' CONCLUSIONS The medication comparisons included in this review had higher than average adherence rates not accounted for by differences in medication administration or side effects, though often follow-up was not good (high dropout over longer trials), with adherence based on a per protocol analysis. Participants may have been selected based on higher adherence to trial medications at baseline. Also, within the clinical trial context, there is increased attention and involvement of clinicians, thus high adherence rates may be an artefact of trial participation. Real-world, pragmatic trials in community and clinic settings are needed that examine both confirmed or unconfirmed adherence strategies that may increase adherence to iron chelation therapy. Due to lack of evidence this review cannot comment on intervention strategies for different age groups.
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Affiliation(s)
- Louise J Geneen
- Systematic Review Initiative, NHS Blood and Transplant, Oxford, UK
| | - Carolyn Dorée
- Systematic Review Initiative, NHS Blood and Transplant, Oxford, UK
| | - Lise J Estcourt
- Haematology/Transfusion Medicine, NHS Blood and Transplant, Oxford, UK
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22
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Zhang J, Song Y, Li Y, Lin HB, Fang X. Iron homeostasis in the heart: Molecular mechanisms and pharmacological implications. J Mol Cell Cardiol 2023; 174:15-24. [PMID: 36375319 DOI: 10.1016/j.yjmcc.2022.11.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2022] [Revised: 11/01/2022] [Accepted: 11/02/2022] [Indexed: 11/13/2022]
Abstract
Iron is necessary for the life of practically all living things, yet it may also harm people toxically. Accordingly, humans and other mammals have evolved an effective and tightly regulatory system to maintain iron homeostasis in healthy tissues, including the heart. Iron deficiency is common in patients with heart failure, and is associated with worse prognosis in this population; while the prevalence of iron overload-related cardiovascular disorders is also increasing. Therefore, enhancing the therapy of patients with cardiovascular disorders requires a thorough understanding of iron homeostasis. Here, we give readers an overview of the fundamental mechanisms governing systemic iron homeostasis as well as the most recent knowledge about the intake, storage, use, and export of iron from the heart. Genetic mouse models used for investigation of iron metabolism in various in vivo scenarios are summarized and highlighted. We also go through different clinical conditions and therapeutic approaches that target cardiac iron dyshomeostasis. Finally, we conclude the review by outlining the present knowledge gaps and important open questions in this field in order to guide future research on cardiac iron metabolism.
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Affiliation(s)
- Jiawei Zhang
- Department of Nutrition and Toxicology, School of Public Health, Hangzhou Normal University, Hangzhou, China
| | - Yijing Song
- Department of Nutrition and Toxicology, School of Public Health, Hangzhou Normal University, Hangzhou, China
| | - You Li
- Department of Nutrition and Toxicology, School of Public Health, Hangzhou Normal University, Hangzhou, China
| | - Han-Bin Lin
- Zhongshan Institute for Drug Discovery, SIMM, CAS, Zhongshan, China; Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Xuexian Fang
- Department of Nutrition and Toxicology, School of Public Health, Hangzhou Normal University, Hangzhou, China; Key Laboratory of Elemene Class Anti-cancer Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, China.
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23
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Fang X, Ardehali H, Min J, Wang F. The molecular and metabolic landscape of iron and ferroptosis in cardiovascular disease. Nat Rev Cardiol 2023; 20:7-23. [PMID: 35788564 PMCID: PMC9252571 DOI: 10.1038/s41569-022-00735-4] [Citation(s) in RCA: 553] [Impact Index Per Article: 276.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/30/2022] [Indexed: 02/08/2023]
Abstract
The maintenance of iron homeostasis is essential for proper cardiac function. A growing body of evidence suggests that iron imbalance is the common denominator in many subtypes of cardiovascular disease. In the past 10 years, ferroptosis, an iron-dependent form of regulated cell death, has become increasingly recognized as an important process that mediates the pathogenesis and progression of numerous cardiovascular diseases, including atherosclerosis, drug-induced heart failure, myocardial ischaemia-reperfusion injury, sepsis-induced cardiomyopathy, arrhythmia and diabetic cardiomyopathy. Therefore, a thorough understanding of the mechanisms involved in the regulation of iron metabolism and ferroptosis in cardiomyocytes might lead to improvements in disease management. In this Review, we summarize the relationship between the metabolic and molecular pathways of iron signalling and ferroptosis in the context of cardiovascular disease. We also discuss the potential targets of ferroptosis in the treatment of cardiovascular disease and describe the current limitations and future directions of these novel treatment targets.
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Affiliation(s)
- Xuexian Fang
- grid.410595.c0000 0001 2230 9154Department of Nutrition and Toxicology, School of Public Health, State Key Laboratory of Experimental Hematology, Hangzhou Normal University, Hangzhou, China ,grid.13402.340000 0004 1759 700XThe Fourth Affiliated Hospital, The First Affiliated Hospital, Institute of Translational Medicine, School of Public Health, Cancer Center, State Key Laboratory of Experimental Hematology, Zhejiang University School of Medicine, Hangzhou, China ,grid.412017.10000 0001 0266 8918The First Affiliated Hospital, The Second Affiliated Hospital, Basic Medical Sciences, School of Public Health, Hengyang Medical School, University of South China, Hengyang, China
| | - Hossein Ardehali
- grid.16753.360000 0001 2299 3507Feinberg Cardiovascular and Renal Research Institute, Northwestern University, Chicago, IL USA
| | - Junxia Min
- The Fourth Affiliated Hospital, The First Affiliated Hospital, Institute of Translational Medicine, School of Public Health, Cancer Center, State Key Laboratory of Experimental Hematology, Zhejiang University School of Medicine, Hangzhou, China.
| | - Fudi Wang
- The Fourth Affiliated Hospital, The First Affiliated Hospital, Institute of Translational Medicine, School of Public Health, Cancer Center, State Key Laboratory of Experimental Hematology, Zhejiang University School of Medicine, Hangzhou, China. .,The First Affiliated Hospital, The Second Affiliated Hospital, Basic Medical Sciences, School of Public Health, Hengyang Medical School, University of South China, Hengyang, China.
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Hanna M, Seddiek H, Aboulhoda BE, Morcos GNB, Akabawy AMA, Elbaset MA, Ibrahim AA, Khalifa MM, Khalifah IM, Fadel MS, Shoukry T. Synergistic cardioprotective effects of melatonin and deferoxamine through the improvement of ferritinophagy in doxorubicin-induced acute cardiotoxicity. Front Physiol 2022; 13:1050598. [PMID: 36531171 PMCID: PMC9748574 DOI: 10.3389/fphys.2022.1050598] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Accepted: 11/09/2022] [Indexed: 11/08/2023] Open
Abstract
Ferritinophagy is one of the most recent molecular mechanisms affecting cardiac function. In addition, it is one of the pathways by which doxorubicin, one of the anticancer drugs commonly used, negatively impacts the cardiac muscle, leading to cardiac function impairment. This side effect limits the use of doxorubicin. Iron chelators play an important role in hindering ferritinophagy. Antioxidants can also impact ferritinophagy by improving oxidative stress. In this study, it was assumed that the antioxidant function of melatonin could promote the action of deferoxamine, an iron chelator, at the level of ferritinophagy. A total of 42 male Wistar rats (150-200 g) were divided into seven groups (n = 6) which consisted of group I: control normal, group II: doxorubicin (Dox), group III: melatonin (Mel), group IV: deferoxamine (Des), group V: Mel + Dox, group VI: Des + Dox, and group VII: Mel + Des + Dox. Groups III, V and VII were orally pretreated with melatonin 20 mg/kg/day for 7 days. Groups IV, VI and VII were treated with deferoxamine at a 250 mg/kg/dose once on D4 before Dox was given. Doxorubicin was given at a 20 mg/kg ip single dose. On the 8th day, the rats were lightly anaesthetized for electrocardiography analysis and echocardiography. Serum samples were collected and then sacrificed for tissue sampling. The following biochemical assessments were carried out: PCR of NCOA4, IREB2, FTH1, SLC7A11, and GPX4; and ELISA for serum cTnI, serum transferrin, tissue GSH, and malondialdehyde. In addition, histopathological assessment of heart injury; immunostaining of caspase-3, Bax, and Bcl2; and physiological function assessment by ECG and ECHO were carried out. Doxorubicin-induced acute significant cardiac injury with increased ferritinophagy and apoptosis responded to single and combined prophylactic treatment, in which the combined treatment showed mostly the best results. In conclusion, using melatonin as an antioxidant with an iron chelator, deferoxamine, could hinder the hazardous cardiotoxic effect of doxorubicin. However, further studies are needed to detect the impact of higher doses of melatonin and deferoxamine with a prolonged treatment period.
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Affiliation(s)
- Mira Hanna
- Department of Human Physiology, Faculty of Medicine (Kasr Al-Ainy), Cairo University, Egypt
| | - Hanan Seddiek
- Department of Human Physiology, Faculty of Medicine (Kasr Al-Ainy), Cairo University, Egypt
| | - Basma Emad Aboulhoda
- Department of Anatomy and Embryology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - George N. B. Morcos
- Department of Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
- Department of Basic Medical Science, Faculty of Medicine, King Salman International University, South Sinai, Egypt
| | - Ahmed M. A. Akabawy
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Helwan University, Cairo, Egypt
| | - Marawan Abd Elbaset
- Department of Pharmacology, Medical Research and Clinical Studies Institute, National Research Centre, Cairo, Egypt
| | | | - Mohamed Mansour Khalifa
- Department of Human Physiology, Faculty of Medicine (Kasr Al-Ainy), Cairo University, Egypt
- Department of Human Physiology, College of Medicine, King Saud University, Kingdom of Saudi Arabia, Riyadh, Saudi Arabia
| | - Ibtesam Mahmoud Khalifah
- Department of Internal Medicine, Faculty of Medicine, Ain Shams University, Cairo, Egypt
- Department of Clinical Sciences, Faculty of Medicine, Fakeeh College for Medical Sciences, Riyadh, Saudi Arabia
| | - Mostafa Said Fadel
- Department of Basic Medical Science, Faculty of Medicine, King Salman International University, South Sinai, Egypt
| | - Tarek Shoukry
- Department of Human Physiology, Faculty of Medicine (Kasr Al-Ainy), Cairo University, Egypt
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25
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Rapezzi C, Aimo A, Barison A, Emdin M, Porcari A, Linhart A, Keren A, Merlo M, Sinagra G. Restrictive cardiomyopathy: definition and diagnosis. Eur Heart J 2022; 43:4679-4693. [PMID: 36269634 PMCID: PMC9712030 DOI: 10.1093/eurheartj/ehac543] [Citation(s) in RCA: 85] [Impact Index Per Article: 28.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 08/23/2022] [Accepted: 09/16/2022] [Indexed: 01/05/2023] Open
Abstract
Restrictive cardiomyopathy (RCM) is a heterogeneous group of diseases characterized by restrictive left ventricular pathophysiology, i.e. a rapid rise in ventricular pressure with only small increases in filling volume due to increased myocardial stiffness. More precisely, the defining feature of RCM is the coexistence of persistent restrictive pathophysiology, diastolic dysfunction, non-dilated ventricles, and atrial dilatation, regardless of ventricular wall thickness and systolic function. Beyond this shared haemodynamic hallmark, the phenotypic spectrum of RCM is wide. The disorders manifesting as RCM may be classified according to four main disease mechanisms: (i) interstitial fibrosis and intrinsic myocardial dysfunction, (ii) infiltration of extracellular spaces, (iii) accumulation of storage material within cardiomyocytes, or (iv) endomyocardial fibrosis. Many disorders do not show restrictive pathophysiology throughout their natural history, but only at an initial stage (with an evolution towards a hypokinetic and dilated phenotype) or at a terminal stage (often progressing from a hypertrophic phenotype). Furthermore, elements of both hypertrophic and restrictive phenotypes may coexist in some patients, making the classification challenge. Restrictive pathophysiology can be demonstrated by cardiac catheterization or Doppler echocardiography. The specific conditions may usually be diagnosed based on clinical data, 12-lead electrocardiogram, echocardiography, nuclear medicine, or cardiovascular magnetic resonance, but further investigations may be needed, up to endomyocardial biopsy and genetic evaluation. The spectrum of therapies is also wide and heterogeneous, but disease-modifying treatments are available only for cardiac amyloidosis and, partially, for iron overload cardiomyopathy.
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Affiliation(s)
- Claudio Rapezzi
- Corresponding author. Tel: +39 0532239882, Fax: +39 0532 293031,
| | - Alberto Aimo
- Health Science Interdisciplinary Center, Scuola Superiore Sant'Anna, piazza Martiri della Libertà 33, 56127 Pisa, Italy,Cardiology Division, Fondazione Toscana Gabriele Monasterio, via Moruzzi 1, 56124 Pisa, Italy
| | - Andrea Barison
- Health Science Interdisciplinary Center, Scuola Superiore Sant'Anna, piazza Martiri della Libertà 33, 56127 Pisa, Italy,Cardiology Division, Fondazione Toscana Gabriele Monasterio, via Moruzzi 1, 56124 Pisa, Italy
| | - Michele Emdin
- Health Science Interdisciplinary Center, Scuola Superiore Sant'Anna, piazza Martiri della Libertà 33, 56127 Pisa, Italy,Cardiology Division, Fondazione Toscana Gabriele Monasterio, via Moruzzi 1, 56124 Pisa, Italy
| | - Aldostefano Porcari
- Center for Diagnosis and Treatment of Cardiomyopathies, Cardiovascular Department, Azienda Sanitaria Universitaria Giuliano-Isontina (ASUGI), University of Trieste, European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart-ERN GUARD-Heart, Via Giacomo Puccini, 50, 34148 Trieste, Italy
| | - Ales Linhart
- General University Hospital and Charles University, Opletalova 38, 110 00 Staré Město, Czech Republic
| | - Andre Keren
- Cardiology Division, Hadassah Hebrew University Hospital, Sderot Churchill 8, Jerusalem, Israel,Heart Failure Center, Clalit Health Services, Bnei Brit St 22, Jerusalem, Israel
| | - Marco Merlo
- Center for Diagnosis and Treatment of Cardiomyopathies, Cardiovascular Department, Azienda Sanitaria Universitaria Giuliano-Isontina (ASUGI), University of Trieste, European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart-ERN GUARD-Heart, Via Giacomo Puccini, 50, 34148 Trieste, Italy
| | - Gianfranco Sinagra
- Center for Diagnosis and Treatment of Cardiomyopathies, Cardiovascular Department, Azienda Sanitaria Universitaria Giuliano-Isontina (ASUGI), University of Trieste, European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart-ERN GUARD-Heart, Via Giacomo Puccini, 50, 34148 Trieste, Italy
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Sriwichaiin S, Thiennimitr P, Thonusin C, Sarichai P, Buddhasiri S, Kumfu S, Nawara W, Kittichotirat W, Fucharoen S, Chattipakorn N, Chattipakorn SC. Deferiprone has less benefits on gut microbiota and metabolites in high iron-diet induced iron overload thalassemic mice than in iron overload wild-type mice: A preclinical study. Life Sci 2022; 307:120871. [PMID: 35952729 DOI: 10.1016/j.lfs.2022.120871] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Revised: 08/02/2022] [Accepted: 08/04/2022] [Indexed: 11/29/2022]
Abstract
AIMS This study aimed to investigate the changes in gut microbiota in iron-overload thalassemia and the roles of an iron chelator on gut dysbiosis/inflammation, and metabolites, including short-chain fatty acids (SCFAs) and trimethylamine N-oxide (TMAO). MAIN METHODS Adult male C57BL/6 mice both wild-type (WT: n = 15) and heterozygous β-thalassemia (BKO: n = 15) were fed on either a normal (ND: n = 5/group) or a high‑iron diet for four months (HFe: n = 10/group). HFe-treated WT and HFe-treated BKO groups were further subdivided into two subgroups and each subgroup given either vehicle (n = 5/subgroup) or deferiprone (n = 5/subgroup) during the last month. Gut microbiota profiles, gut barrier characteristics, levels of proinflammatory cytokines, and plasma SCFAs and TMAO were determined at the end of the study. KEY FINDINGS HFe-fed WT mice showed distinct gut microbiota profiles from those of ND-fed WT mice, whereas HFe-fed BKO mice showed slightly different gut microbiota profiles from ND-fed BKO. Gut inflammation and barrier disruption were found only in HFe-fed BKO mice, however, an increase in plasma TMAO levels and decreased levels of SCFAs were observed in both WT and BKO mice with HFe-feeding. Treatment with deferiprone, gut dysbiosis and disturbance of metabolites were attenuated in HFe-fed WT mice, but not in HFe-fed BKO mice. Increased Verrucomicrobia and Ruminococcaceae were associated with the beneficial effects of deferiprone. SIGNIFICANCE Iron-overload leads to gut dysbiosis/inflammation and disturbance of metabolites, and deferiprone alleviates those conditions more effectively in WT than in those that are thalassemic.
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Affiliation(s)
- Sirawit Sriwichaiin
- Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai 50200, Thailand; Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Parameth Thiennimitr
- Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai 50200, Thailand; Department of Microbiology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Chanisa Thonusin
- Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai 50200, Thailand; Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Phinitphong Sarichai
- Department of Microbiology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Songphon Buddhasiri
- Department of Microbiology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; Department of Veterinary Bioscience and Veterinary Public Health, Faculty of Veterinary Medicine, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Sirinart Kumfu
- Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai 50200, Thailand; Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Wichwara Nawara
- Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai 50200, Thailand; Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Weerayuth Kittichotirat
- Bioinformatics and Systems Biology Program, School of Bioresources and Technology and School of Information Technology, King Mongkut's University of Technology Thonburi, Bangkok 10150, Thailand; Systems Biology and Bioinformatics Research Group, Pilot Plant Development and Training Institute, King Mongkut's University of Technology Thonburi, Bangkok 10150, Thailand
| | - Suthat Fucharoen
- Thalassemia Research Center, Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom 73170, Thailand
| | - Nipon Chattipakorn
- Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai 50200, Thailand; Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Siriporn C Chattipakorn
- Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai 50200, Thailand; Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; Department of Oral Biology and Diagnostic Sciences, Faculty of Dentistry, Chiang Mai University, Chiang Mai 50200, Thailand.
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Locke M, Reddy PS, Badawy SM. Adherence to Iron Chelation Therapy among Adults with Thalassemia: A Systematic Review. Hemoglobin 2022; 46:201-213. [PMID: 35930250 PMCID: PMC9948767 DOI: 10.1080/03630269.2022.2072320] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Iron chelation therapy (ICT) is essential to prevent complications of iron overload in patients with transfusion-dependent thalassemia. However, the role that adherence to ICT plays in health-related outcomes is less well known. Our objectives were to identify adherence rates of ICT, and to assess methods of measurement, predictors of adherence, and adherence-related health outcomes in the literature published between 1980 and 2020. Of 543 articles, 43 met the inclusion criteria. Studies measured ICT adherence, predictors, and/or outcomes associated with adherence. Most studies were across multiple countries in Europe and North America (n = 8/43, 18.6%), recruited in clinics (n = 39/43, 90.7%), and focused on β-thalassemia (β-thal) (n = 25/43, 58.1%). Common methods of assessing ICT adherence included patient self-report (n = 24/43, 55.8%), pill count (n = 9/43, 20.9%), prescription refill history (n = 3/43, 7.0%), provider scoring (n = 3/43, 7.0%), and combinations of methods (n = 4/43, 9.3%). Studies reported adherence either in 'categories' with different levels of adherence (n = 24) or 'quantitatively' as a percentage of doses of medication taken out of those prescribed (n = 17). Adherence levels varied (median 91.7%, range 42.0-99.97%). Studies varied in sample size and methods of adherence assessment and reporting, which prohibited meta-analysis. Due to a lack of consensus on how adherence is defined, it is difficult to compare ICT adherence reporting. Further research is needed to establish guidelines for assessing adherence and identifying suboptimal adherence. Behavioral digital interventions have the potential to optimize ICT adherence and health outcomes.
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Affiliation(s)
- Margaret Locke
- Department of Internal Medicine, Zucker School of Medicine at Hofstra/Northwell Institute, Hempstead, NY, USA
| | - Paavani S. Reddy
- Department of Medical Education, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Sherif M. Badawy
- Division of Hematology, Oncology, and Stem Cell Transplant, Ann & Robert H. Lurie Children’s Hospital of Chicago, IL, USA,Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
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Iron Chelators in Treatment of Iron Overload. J Toxicol 2022; 2022:4911205. [PMID: 35571382 PMCID: PMC9098311 DOI: 10.1155/2022/4911205] [Citation(s) in RCA: 71] [Impact Index Per Article: 23.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 03/19/2022] [Accepted: 04/05/2022] [Indexed: 01/19/2023] Open
Abstract
Patients suffering from iron overload can experience serious complications. In such patients, various organs, such as endocrine glands and liver, can be damaged. Although iron is a crucial element for life, iron overload can be potentially toxic for human cells due to its role in generating free radicals. In the past few decades, there has been a major improvement in the survival of patients who suffer from iron overload due to the application of iron chelation therapy in clinical practice. In clinical use, deferoxamine, deferiprone, and deferasirox are the three United States Food and Drug Administration-approved iron chelators. Each of these iron chelators is well known for the treatment of iron overload in various clinical conditions. Based on several up-to-date studies, this study explained iron overload and its clinical symptoms, introduced each of the above-mentioned iron chelators, and evaluated their advantages and disadvantages with an emphasis on combination therapy, which in recent studies seems a promising approach. In numerous clinical conditions, due to the lack of accurate indicators, choosing a standard approach for iron chelation therapy can be difficult; therefore, further studies on the issue are still required. This study aimed to introduce each of these iron chelators, combination therapy, usage doses, specific clinical applications, and their advantages, toxicity, and side effects.
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Kittipoom T, Tantiworawit A, Punnachet T, Hantrakun N, Piriyakhuntorn P, Rattanathammethee T, Hantrakool S, Chai-Adisaksopha C, Rattarittamrong E, Norasetthada L, Fanhchaksai K, Charoenkwan P. The Long-Term Efficacy of Deferiprone in Thalassemia Patients With Iron Overload: Real-World Data from the Registry Database. Hemoglobin 2022; 46:75-80. [PMID: 35982534 DOI: 10.1080/03630269.2022.2072326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Deferiprone (DFP) is an oral iron-chelating agent that is widely used in thalassemia patients with iron overload. This study aimed to investigate the long-term efficacy of DFP monotherapy on serum ferritin (SF) and adverse events. All thalassemia patients aged 15 years or older who received DFP monotherapy were identified from the thalassemia registry database between November 2008 and October 2019. After treatment, patients who achieved a target SF level, defined as <1000.0 ng/mL in transfusion-dependent thalassemia (TDT) and <800.0 ng/mL in non-TDT (NTDT) for two consecutive visits, were categorized as the achievable group. We used multivariate analysis to identify factors that contribute to differences between groups. One hundred and five patients were enrolled in the study with a median age of 28 (19-41) years and median initial SF level of 1399.0 (1141.0-2169.0) ng/mL. Of these, 61.0% carried Hb E (HBB: c.79G>A)/β-thalassemia (β-thal) and 60.0% were TDT patients. The median DFP dose was 63 (47-73) mg/kg/d and the median follow-up duration of treatment was 36 (20-54) months. A total of 58 (55.24%) patients were in the achievable group. The initial SF level <1350.0 ng/mL was significantly associated with achieving a targeted SF level (p = 0.002). Ten adverse events resulted in withholding DFP. The most common was gastrointestinal irritation in four patients and three patients with agranulocytosis. In conclusion, DFP is an effective iron chelator in thalassemia patients. Slightly more than half the patients (55.0%) achieved a target SF level. Lower SF levels at the beginning were an important factor.
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Affiliation(s)
- Teerajed Kittipoom
- Department of Internal Medicine, Division of Hematology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Adisak Tantiworawit
- Department of Internal Medicine, Division of Hematology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Teerachat Punnachet
- Department of Internal Medicine, Division of Hematology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Nonthakorn Hantrakun
- Department of Internal Medicine, Division of Hematology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Pokpong Piriyakhuntorn
- Department of Internal Medicine, Division of Hematology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Thanawat Rattanathammethee
- Department of Internal Medicine, Division of Hematology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Sasinee Hantrakool
- Department of Internal Medicine, Division of Hematology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Chatree Chai-Adisaksopha
- Department of Internal Medicine, Division of Hematology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Ekarat Rattarittamrong
- Department of Internal Medicine, Division of Hematology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Lalita Norasetthada
- Department of Internal Medicine, Division of Hematology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Kanda Fanhchaksai
- Department of Pediatrics, Division of Hematology and Oncology, Chiang Mai University, Chiang Mai, Thailand
| | - Pimlak Charoenkwan
- Department of Pediatrics, Division of Hematology and Oncology, Chiang Mai University, Chiang Mai, Thailand
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30
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Borella E, Oosterholt S, Magni P, Pasqua OD. Characterisation of individual ferritin response in patients receiving chelation therapy. Br J Clin Pharmacol 2022; 88:3683-3694. [PMID: 35199367 PMCID: PMC9544664 DOI: 10.1111/bcp.15290] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Revised: 12/21/2021] [Accepted: 01/07/2022] [Indexed: 11/26/2022] Open
Abstract
Aims To develop a drug–disease model describing iron overload and its effect on ferritin response in patients affected by transfusion‐dependent haemoglobinopathies and investigate the contribution of interindividual differences in demographic and clinical factors on chelation therapy with deferiprone or deferasirox. Methods Individual and mean serum ferritin data were retrieved from 13 published studies in patients affected by haemoglobinopathies receiving deferiprone or deferasirox. A nonlinear mixed effects modelling approach was used to characterise iron homeostasis and serum ferritin production taking into account annual blood consumption, baseline demographic and clinical characteristics. The effect of chelation therapy was parameterised as an increase in the iron elimination rate. Internal and external validation procedures were used to assess model performance across different study populations. Results An indirect response model was identified, including baseline ferritin concentrations and annual blood consumption as covariates. The effect of chelation on iron elimination rate was characterised by a linear function, with different slopes for each drug (0.0109 [90% CI: 0.0079–0.0131] vs. 0.0013 [90% CI: 0.0008–0.0018] L/mg mo). In addition to drug‐specific differences in the magnitude of the ferritin response, simulation scenarios indicate that ferritin elimination rates depend on ferritin concentrations at baseline. Conclusion Modelling of serum ferritin following chronic blood transfusion enabled the evaluation of drug‐induced changes in iron elimination rate and ferritin production. The use of a semi‐mechanistic parameterisation allowed us to disentangle disease‐specific factors from drug‐specific properties. Despite comparable chelation mechanisms, deferiprone appears to have a significantly larger effect on the iron elimination rate than deferasirox.
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Affiliation(s)
- Elisa Borella
- Department of Industrial Engineering and Informatics, Università degli Studi di Pavia, Pavia, Italy
| | - Sean Oosterholt
- Clinical Pharmacology & Therapeutics Group, University College London, London, United Kingdom
| | - Paolo Magni
- Department of Industrial Engineering and Informatics, Università degli Studi di Pavia, Pavia, Italy
| | - Oscar Della Pasqua
- Clinical Pharmacology & Therapeutics Group, University College London, London, United Kingdom.,Clinical Pharmacology Modelling & Simulation, GlaxoSmithKline, Brentford, United Kingdom
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Kwiatkowski JL, Hamdy M, El-Beshlawy A, Ebeid FSE, Badr M, Alshehri A, Kanter J, Inusa B, Adly AAM, Williams S, Kilinc Y, Lee D, Tricta F, Elalfy MS. Deferiprone vs deferoxamine for transfusional iron overload in SCD and other anemias: a randomized, open-label noninferiority study. Blood Adv 2022; 6:1243-1254. [PMID: 34847228 PMCID: PMC8864642 DOI: 10.1182/bloodadvances.2021004938] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 10/14/2021] [Indexed: 11/26/2022] Open
Abstract
Many people with sickle cell disease (SCD) or other anemias require chronic blood transfusions, which often causes iron overload that requires chelation therapy. The iron chelator deferiprone is frequently used in individuals with thalassemia syndromes, but data in patients with SCD are limited. This open-label study assessed the efficacy and safety of deferiprone in patients with SCD or other anemias receiving chronic transfusion therapy. A total of 228 patients (mean age: 16.9 [range, 3-59] years; 46.9% female) were randomized to receive either oral deferiprone (n = 152) or subcutaneous deferoxamine (n = 76). The primary endpoint was change from baseline at 12 months in liver iron concentration (LIC), assessed by R2* magnetic resonance imaging (MRI). The least squares mean (standard error) change in LIC was -4.04 (0.48) mg/g dry weight for deferiprone vs -4.45 (0.57) mg/g dry weight for deferoxamine, with noninferiority of deferiprone to deferoxamine demonstrated by analysis of covariance (least squares mean difference 0.40 [0.56]; 96.01% confidence interval, -0.76 to 1.57). Noninferiority of deferiprone was also shown for both cardiac T2* MRI and serum ferritin. Rates of overall adverse events (AEs), treatment-related AEs, serious AEs, and AEs leading to withdrawal did not differ significantly between the groups. AEs related to deferiprone treatment included abdominal pain (17.1% of patients), vomiting (14.5%), pyrexia (9.2%), increased alanine transferase (9.2%) and aspartate transferase levels (9.2%), neutropenia (2.6%), and agranulocytosis (0.7%). The efficacy and safety profiles of deferiprone were acceptable and consistent with those seen in patients with transfusion-dependent thalassemia. This trial study was registered at www://clinicaltrials.gov as #NCT02041299.
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Affiliation(s)
- Janet L. Kwiatkowski
- Division of Hematology, The Children's Hospital of Philadelphia, and the Department of Pediatrics, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA
| | - Mona Hamdy
- Department of Pediatrics, School of Medicine, Cairo University, Cairo, Egypt
| | - Amal El-Beshlawy
- Department of Pediatric Hematology, Pediatric Hospital of Cairo University, Cairo, Egypt
| | - Fatma S. E. Ebeid
- Pediatric Hematology Oncology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Mohammed Badr
- Department of Pediatrics, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | | | - Julie Kanter
- Division of Hematology and Oncology, Department of Medicine, University of Alabama, Birmingham, AL
| | - Baba Inusa
- Paediatric Haematology, Evelina Children's Hospital, Guy’s and St. Thomas NHS Foundation Trust, London, United Kingdom
| | - Amira A. M. Adly
- Pediatric Hematology Oncology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Suzan Williams
- Department of Haematology and Oncology, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
| | - Yurdanur Kilinc
- Department of Pediatric Hematology, Faculty of Medicine, Cukurova University, Adana, Turkey; and
| | - David Lee
- Hematology/Immunology Program, Chiesi Rare Disease, Toronto, ON, Canada
| | - Fernando Tricta
- Hematology/Immunology Program, Chiesi Rare Disease, Toronto, ON, Canada
| | - Mohsen S. Elalfy
- Pediatric Hematology Oncology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
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Spasiano A, Meloni A, Costantini S, Quaia E, Cademartiri F, Cinque P, Pepe A, Ricchi P. Setting for "Normal" Serum Ferritin Levels in Patients with Transfusion-Dependent Thalassemia: Our Current Strategy. J Clin Med 2021; 10:5985. [PMID: 34945281 PMCID: PMC8708030 DOI: 10.3390/jcm10245985] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 11/27/2021] [Accepted: 12/17/2021] [Indexed: 11/16/2022] Open
Abstract
This cross-sectional study aimed to establish the association between serum ferritin levels and organ iron overload (IO) and overall morbidity in transfusion-dependent thalassemia (TDT) patients. One hundred and three TDT patients (40.03 ± 9.15 years; 57.3% females) with serum ferritin < 2500 ng/mL were included. IO was assessed by T2* magnetic resonance imaging. Three groups were identified based on mean serum ferritin levels: <500 ng/mL (group 0; N = 32), 500-1000 ng/mL (group 1; N = 43), and 1000-2500 ng/mL (group 2; N = 28). All demographic and biochemical parameters were comparable among the three groups, with the exception of the triglycerides being significantly lower in group 0 than in group 2. No difference was found in the frequency of hepatic, endocrine, and cardiac complications. Hepatic IO was significantly less frequent in group 0 versus both groups 1 and 2. No patient with a serum ferritin level < 500 ng/mL had significant myocardial IO and alterations in the main hematological parameters. No difference in the distribution of the different chelation regimens was found. Serum ferritin < 500 ng/mL appears to be achievable and safe for several TDT patients. This target is associated with the absence of significant cardiac iron and significantly lower hepatic IO and triglycerides that are well-demonstrated markers for cardiac and liver complications.
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Affiliation(s)
- Anna Spasiano
- Unità Operativa Semplice Dipartimentale Malattie Rare del Globulo Rosso, Azienda Ospedaliera di Rilievo Nazionale “A. Cardarelli”, 80131 Napoli, Italy; (A.S.); (S.C.); (P.C.)
| | - Antonella Meloni
- Cardiovascular and Neuroradiological Multimodality Unit, Fondazione G. Monasterio CNR-Regione Toscana, 56124 Pisa, Italy; (A.M.); (F.C.)
- U.O.C. Bioingegneria e Ingegneria Clinica, Fondazione G. Monasterio CNR-Regione Toscana, 56124 Pisa, Italy
| | - Silvia Costantini
- Unità Operativa Semplice Dipartimentale Malattie Rare del Globulo Rosso, Azienda Ospedaliera di Rilievo Nazionale “A. Cardarelli”, 80131 Napoli, Italy; (A.S.); (S.C.); (P.C.)
| | - Emilio Quaia
- Institute of Radiology, Department of Medicine, University of Padua, 35122 Padua, Italy; (E.Q.); (A.P.)
| | - Filippo Cademartiri
- Cardiovascular and Neuroradiological Multimodality Unit, Fondazione G. Monasterio CNR-Regione Toscana, 56124 Pisa, Italy; (A.M.); (F.C.)
| | - Patrizia Cinque
- Unità Operativa Semplice Dipartimentale Malattie Rare del Globulo Rosso, Azienda Ospedaliera di Rilievo Nazionale “A. Cardarelli”, 80131 Napoli, Italy; (A.S.); (S.C.); (P.C.)
| | - Alessia Pepe
- Institute of Radiology, Department of Medicine, University of Padua, 35122 Padua, Italy; (E.Q.); (A.P.)
| | - Paolo Ricchi
- Unità Operativa Semplice Dipartimentale Malattie Rare del Globulo Rosso, Azienda Ospedaliera di Rilievo Nazionale “A. Cardarelli”, 80131 Napoli, Italy; (A.S.); (S.C.); (P.C.)
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Westwood MA, Pennell DJ. Reducing mortality by myocardial T2* cardiovascular magnetic resonance at national level. Eur Heart J 2021; 43:2493-2495. [PMID: 34907427 DOI: 10.1093/eurheartj/ehab814] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
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Wantanajittikul K, Saiviroonporn P, Saekho S, Krittayaphong R, Viprakasit V. An automated liver segmentation in liver iron concentration map using fuzzy c-means clustering combined with anatomical landmark data. BMC Med Imaging 2021; 21:138. [PMID: 34583631 PMCID: PMC8477544 DOI: 10.1186/s12880-021-00669-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Accepted: 09/15/2021] [Indexed: 11/14/2022] Open
Abstract
Background To estimate median liver iron concentration (LIC) calculated from magnetic resonance imaging, excluded vessels of the liver parenchyma region were defined manually. Previous works proposed the automated method for excluding vessels from the liver region. However, only user-defined liver region remained a manual process. Therefore, this work aimed to develop an automated liver region segmentation technique to automate the whole process of median LIC calculation. Methods 553 MR examinations from 471 thalassemia major patients were used in this study. LIC maps (in mg/g dry weight) were calculated and used as the input of segmentation procedures. Anatomical landmark data were detected and used to restrict ROI. After that, the liver region was segmented using fuzzy c-means clustering and reduced segmentation errors by morphological processes. According to the clinical application, erosion with a suitable size of the structuring element was applied to reduce the segmented liver region to avoid uncertainty around the edge of the liver. The segmentation results were evaluated by comparing with manual segmentation performed by a board-certified radiologist. Results The proposed method was able to produce a good grade output in approximately 81% of all data. Approximately 11% of all data required an easy modification step. The rest of the output, approximately 8%, was an unsuccessful grade and required manual intervention by a user. For the evaluation matrices, percent dice similarity coefficient (%DSC) was in the range 86–92, percent Jaccard index (%JC) was 78–86, and Hausdorff distance (H) was 14–28 mm, respectively. In this study, percent false positive (%FP) and percent false negative (%FN) were applied to evaluate under- and over-segmentation that other evaluation matrices could not handle. The average of operation times could be reduced from 10 s per case using traditional method, to 1.5 s per case using our proposed method. Conclusion The experimental results showed that the proposed method provided an effective automated liver segmentation technique, which can be applied clinically for automated median LIC calculation in thalassemia major patients.
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Affiliation(s)
- Kittichai Wantanajittikul
- Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand
| | - Pairash Saiviroonporn
- Division of Diagnostic Radiology, Department of Radiology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand.
| | - Suwit Saekho
- Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand
| | - Rungroj Krittayaphong
- Division of Cardiology, Department of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Vip Viprakasit
- Haematology/Oncology Division, Department of Pediatrics and Thalassemia Center, Siriraj Hospital, Mahidol University, Bangkok, Thailand
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Karami H, Khalilzadeh Arjmandi H, Salehifar E, Darvishi-Khezri H, Dabirian M, Kosaryan M, Aliasgharian A, Akbarzadeh R, Naeimayi Aali R, Nasirzadeh A. A double-blind, controlled, crossover trial of amlodipine on iron overload status in transfusion dependent β-thalassemia patients. Int J Clin Pract 2021; 75:e14337. [PMID: 33969592 DOI: 10.1111/ijcp.14337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Accepted: 05/04/2021] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND AND AIM This study examined whether administration of amlodipine could improve myocardial iron loading status in patients with transfusion dependent β-thalassemia (TDT), through a placebo-controlled, crossover study. METHODS Amlodipine (5 mg, daily) or placebo were prescribed to all patients (n = 19) for 6 months, and after a 2-week washout period, patients were crossed over to the other group. The efficacy of amlodipine on iron loading was assessed by measuring myocardial T2*-weighted magnetic resonance imaging (MRI T2*, millisecond [ms]) and serum ferritin (ng/mL). RESULTS Seventeen patients completed the study. The mean ± standard deviation [SD] of myocardial MRI T2* at baseline was 9.83 ± 2.67 ms Myocardial MRI T2* value rose to 11.44 ± 4.14 ms post amlodipine treatment in all patients. After placebo, myocardial MRI T2* value reached 10.29 ± 4.01 ms After controlling the baseline measures, Hedges's g for ferritin and myocardial MRI T2* outcomes were estimated 3.84 (95% confidence interval [CI] 2.68 to 4.97) and -1.80 (95% CI -2.58 to -0.10), respectively. CONCLUSION Amlodipine might improve myocardial MRI T2* and serum ferritin level compared to placebo. However, larger clinical studies are needed to confirm the results.
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Affiliation(s)
- Hossein Karami
- Thalassemia Research Center (TRC), Hemoglobinopathy Institute, Mazandaran University of Medical Sciences, Sari, Iran
| | - Hadiseh Khalilzadeh Arjmandi
- Student Research Committee, Phamaceutical Science Research Center, Hemoglobinopathy Institute, Mazandaran University of Medical Sciences, Sari, Iran
| | - Ebrahim Salehifar
- Phamaceutical Science Research Center, Hemoglobinopathy Institute, Mazandaran University of Medical Sciences, Sari, Iran
| | - Hadi Darvishi-Khezri
- Thalassemia Research Center (TRC), Hemoglobinopathy Institute, Mazandaran University of Medical Sciences, Sari, Iran
| | - Mojdeh Dabirian
- Department of Cardiology, Cardiovascular Research Center, Mazandaran University of Medical Sciences, Sari, Iran
| | - Mehrnoush Kosaryan
- Thalassemia Research Center (TRC), Hemoglobinopathy Institute, Mazandaran University of Medical Sciences, Sari, Iran
| | - Aily Aliasgharian
- Medical Microbiology, Thalassemia Research Center (TRC), Hemoglobinopathy Institute, Mazandaran University of Medical Sciences, Sari, Iran
| | - Rosetta Akbarzadeh
- Thalassemia Research Center (TRC), Hemoglobinopathy Institute, Mazandaran University of Medical Sciences, Sari, Iran
| | | | - Amirreza Nasirzadeh
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
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Grech L, Borg K, Borg J. Novel therapies in β-thalassaemia. Br J Clin Pharmacol 2021; 88:2509-2524. [PMID: 34004015 DOI: 10.1111/bcp.14918] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 04/30/2021] [Accepted: 05/08/2021] [Indexed: 01/19/2023] Open
Abstract
Beta-thalassaemia is one of the most significant haemoglobinopathies worldwide resulting in the synthesis of little or no β-globin chains. Without treatment, β-thalassaemia major is lethal within the first decade of life due to the complex pathophysiology, which leads to wide clinical manifestations. Current clinical management for these patients depends on repeated transfusions followed by iron-chelating therapy. Several novel approaches to correct the resulting α/β-globin chain imbalance, treat ineffective erythropoiesis and improve iron overload are currently being developed. Up to now, the only curative treatment for β-thalassemia is haematopoietic stem-cell transplantation, but this is a risky and costly procedure. Gene therapy, gene editing and base editing are emerging as a powerful approach to treat this disease. In β-thalassaemia, gene therapy involves the insertion of a vector containing the normal β-globin or γ-globin gene into haematopoietic stem cells to permanently produce normal red blood cells. Gene editing and base editing involves the use of zinc finger nucleases, transcription activator-like nucleases and clustered regularly interspaced short palindromic repeats/Cas9 to either correct the causative mutation or else insert a single nucleotide variant that will increase foetal haemoglobin. In this review, we will examine the current management strategies used to treat β-thalassaemia and focus on the novel therapies targeting ineffective erythropoiesis, improving iron overload and correction of the globin chain imbalance.
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Affiliation(s)
- Laura Grech
- Centre for Molecular Medicine and Biobanking, University of Malta, Malta
| | - Karen Borg
- Department of Public Health Medicine, Ministry for Health, Malta
| | - Joseph Borg
- Centre for Molecular Medicine and Biobanking, University of Malta, Malta.,Applied Biomedical Science, Faculty of Health Sciences, University of Malta, Malta
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Elliott P, Cowie MR, Franke J, Ziegler A, Antoniades C, Bax J, Bucciarelli-Ducci C, Flachskampf FA, Hamm C, Jensen MT, Katus H, Maisel A, McDonagh T, Mittmann C, Muntendam P, Nagel E, Rosano G, Twerenbold R, Zannad F. Development, validation, and implementation of biomarker testing in cardiovascular medicine state-of-the-art: proceedings of the European Society of Cardiology-Cardiovascular Round Table. Cardiovasc Res 2021; 117:1248-1256. [PMID: 32960964 DOI: 10.1093/cvr/cvaa272] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 09/01/2020] [Accepted: 09/08/2020] [Indexed: 01/09/2023] Open
Abstract
Many biomarkers that could be used to assess ejection fraction, heart failure, or myocardial infarction fail to translate into clinical practice because they lack essential performance characteristics or fail to meet regulatory standards for approval. Despite their potential, new technologies have added to the complexities of successful translation into clinical practice. Biomarker discovery and implementation require a standardized approach that includes: identification of a clinical need; identification of a valid surrogate biomarker; stepwise assay refinement, demonstration of superiority over current standard-of-care; development and understanding of a clinical pathway; and demonstration of real-world performance. Successful biomarkers should improve efficacy or safety of treatment, while being practical at a realistic cost. Everyone involved in cardiovascular healthcare, including researchers, clinicians, and industry partners, are important stakeholders in facilitating the development and implementation of biomarkers. This article provides suggestions for a development pathway for new biomarkers, discusses regulatory issues and challenges, and suggestions for accelerating the pathway to improve patient outcomes. Real-life examples of successful biomarkers-high-sensitivity cardiac troponin, T2* cardiovascular magnetic resonance imaging, and echocardiography-are used to illustrate the value of a standardized development pathway in the translation of concepts into routine clinical practice.
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Affiliation(s)
- Perry Elliott
- Cardiovascular Medicine, University College London, Gower Street, WC1E 6BT London, UK
| | - Martin R Cowie
- Cardiology (Health Services Research), National Heart and Lung Institute, Imperial College London, Dovehouse Street, SW3 6LY London, UK
| | - Jennifer Franke
- Therapeutic Area, CardioMetabolism Respiratory Medicine, Boehringer-Ingelheim, Binger Straße 173, 55216 Ingelheim am Rhein, Germany
| | - André Ziegler
- Global Clinical Leader CVD, Roche Diagnostics International Ltd, RPD Medical & Scientific Affairs - Bldg 05 / 10th floor / Room 1.34 - Forrenstrasse 2 - CH 6343, Rotkreuz, Switzerland
| | - Charalambos Antoniades
- Cardiovascular Medicine, Oxford University, Headley Way, Headington - OX3 9DU, Oxford, UK
| | - Jeroen Bax
- Non-Invasive Imaging and Echocardiography Lab, Leiden University Medical Centre, Albinusdreef 2 - 2333 ZA, Leiden, Netherlands
| | - Chiara Bucciarelli-Ducci
- Cardiology/Non-Invasive Imaging, Bristol Heart Institute, Bristol National Institute of Health Research (NIHR) Biomedical Research Centre, Clinical Research and Imaging Centre (CRIC) Bristol, University Hospitals Bristol NHS Trust and University of Bristol, Malborough St, Bristol, BS2 8HW, UK
| | - Frank A Flachskampf
- Cardiology/Cardiac Imaging, Department of Medical Sciences, Uppsala University, Ingang 40, Plan 5 - S-751 85, Uppsala, Sweden
- Clinical Physiology and Cardiology, Akademiska sjukhuset, Ingang 40, Plan 5 - S-751 85, Uppsala, Sweden
| | - Christian Hamm
- Internal Medicine and Cardiology, Campus Kerckhoff, University of Giessen, Klinikstr. 33 - D-35392, Germany
| | - Magnus T Jensen
- Department of Cardiology, Copenhagen University Hospital, Amager-Hvidovre, Sankt Jakobs Gade 18, 4. Tv - 2100 Hvidovre, Denmark
| | - Hugo Katus
- Department of Internal Medicine III (Cardiology, Angiology, Pneumology), University of Heidelberg, Im Neuenheimer Feld 410 - D-69120, Heidelberg, Germany
| | - Alan Maisel
- Division of Cardiology, University of California-San Diego, 190 Del Mar Shores, #35; Solana Beach, CA 92075, USA
| | - Theresa McDonagh
- Clinical Lead for Heart Failure, King's College Hospital, Denmark Hill - SE5 9RS London, UK
| | - Clemens Mittmann
- Department of Diabetes and Cardiovascular Diseases, BfArM, Kurt-Georg-Kiesinger-Allee 3, 53175 Bonn, Germany
| | | | - Eike Nagel
- Institute for Experimental and Translational Cardiovascular Imaging, DZHK (German Centre for Cardiovascular Research) Centre for Cardiovascular Imaging, Partner Site RheinMain, University Hospital, Goethe University, Haus 1, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany
| | - Giuseppe Rosano
- Department of Medical Sciences, IRCCS San Raffaele, Via Ardeatina 306-354, 00179 Roma, Italy
- Cardiology, St George's Hospital, University of London, Blackshaw Road, Tooting, SW17 0QT London, UK
| | - Raphael Twerenbold
- Department of Cardiology, University Hospital Basel, Petersgraben 4 - 4031, Basel, Switzerland
| | - Faiez Zannad
- Université de Lorraine, Inserm CIC 1433, CHRU Nancy, FCRIN INI-CRCT, 4, rue du Morvan 54500 Vandoeuvre les Nancy, France
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Elfaituri MK, Ghozy S, Ebied A, Morra ME, Hassan OG, Alhusseiny A, Abbas AS, Sherif NA, Fernandes JL, Huy NT. Amlodipine as adjuvant therapy to current chelating agents for reducing iron overload in thalassaemia major: a systematic review, meta-analysis and simulation of future studies. Vox Sang 2021; 116:887-897. [PMID: 33634883 DOI: 10.1111/vox.13083] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 11/19/2020] [Accepted: 01/12/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND OBJECTIVES Iron overload in thalassaemia is a crucial prognostic factor and a major cause of death due to heart failure or arrhythmia. Therefore, previous research has recommended amlodipine as an auxiliary treatment to current chelating agents for reducing iron overload in thalassaemia patients. MATERIALS AND METHODS A systematic review and meta-analysis of the results of three randomized clinical trials evaluating the use of amlodipine in thalassaemia patients through 12 databases were carried out. RESULTS Our final cohort included 130 patients. Insignificant difference in decreasing liver iron concentrations was found between amlodipine and control groups {weighted mean difference = -0·2, [95% confidence interval = (-0·55-0·15), P = 0·26]}. As regards serum ferritin, our analysis also showed no significant difference in serum ferritin between amlodipine and control groups {weighted mean difference [95% confidence interval = -0·16 (-0·51-0·19), P = 0·36]}. Similarly, there was insignificant difference in cardiac T2* between amlodipine and control groups {weighted mean difference [95% confidence interval = 0·34 (-0·01-0·69), P = 0·06]}. CONCLUSIONS Despite the growing evidence supporting the role of amlodipine in reducing iron overload in thalassaemia patients, our meta-analysis did not find that evidence collectively significant. The results of our simulation suggest that when more data are available, a meta-analysis with more randomized clinical trials could provide more conclusive insights.
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Affiliation(s)
| | - Sherief Ghozy
- Online Research Club, Nagasaki, Japan.,Faculty of Medicine, Mansoura University, Mansoura, Egypt.,Neurosurgery Department, El Sheikh Zayed Specialized Hospital, Giza, Egypt
| | - Amr Ebied
- Online Research Club, Nagasaki, Japan.,Egyptian National Blood Transfusion Services, Alexandria, Egypt
| | - Mostafa Ebraheem Morra
- Online Research Club, Nagasaki, Japan.,Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | - Osama Gamal Hassan
- Online Research Club, Nagasaki, Japan.,Faculty of Medicine, South Valley University, Qena, Egypt
| | - Ahmed Alhusseiny
- Online Research Club, Nagasaki, Japan.,Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Alzhraa Salah Abbas
- Online Research Club, Nagasaki, Japan.,Faculty of Medicine, Minia University, Minia, Egypt
| | - Nourin Ali Sherif
- Online Research Club, Nagasaki, Japan.,Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | | | - Nguyen Tien Huy
- Institute of Research and Development, Duy Tan University, Da Nang, Vietnam.,School of Tropical Medicine and Global Health, Nagasaki University, Nagasaki, Japan
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Affiliation(s)
- Ali T Taher
- From the Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon (A.T.T.); the International Network of Hematology, London (K.M.M.); and the Department of Clinical Sciences and Community, University of Milan, Ca' Granda Foundation IRCCS Maggiore Policlinico Hospital, Milan (M.D.C.)
| | - Khaled M Musallam
- From the Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon (A.T.T.); the International Network of Hematology, London (K.M.M.); and the Department of Clinical Sciences and Community, University of Milan, Ca' Granda Foundation IRCCS Maggiore Policlinico Hospital, Milan (M.D.C.)
| | - M Domenica Cappellini
- From the Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon (A.T.T.); the International Network of Hematology, London (K.M.M.); and the Department of Clinical Sciences and Community, University of Milan, Ca' Granda Foundation IRCCS Maggiore Policlinico Hospital, Milan (M.D.C.)
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Nashat M, Khedr L, Khairat E, Elsheikh E. Evaluation of right and left ventricular function using speckle-tracking echocardiography in thalassemic patients. Ann Pediatr Cardiol 2021; 14:476-484. [PMID: 35527770 PMCID: PMC9075552 DOI: 10.4103/apc.apc_162_19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Revised: 06/13/2021] [Accepted: 08/16/2021] [Indexed: 11/04/2022] Open
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Pinto VM, Forni GL. Management of Iron Overload in Beta-Thalassemia Patients: Clinical Practice Update Based on Case Series. Int J Mol Sci 2020; 21:E8771. [PMID: 33233561 PMCID: PMC7699680 DOI: 10.3390/ijms21228771] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 11/14/2020] [Accepted: 11/18/2020] [Indexed: 12/29/2022] Open
Abstract
Thalassemia syndromes are characterized by the inability to produce normal hemoglobin. Ineffective erythropoiesis and red cell transfusions are sources of excess iron that the human organism is unable to remove. Iron that is not saturated by transferrin is a toxic agent that, in transfusion-dependent patients, leads to death from iron-induced cardiomyopathy in the second decade of life. The availability of effective iron chelators, advances in the understanding of the mechanism of iron toxicity and overloading, and the availability of noninvasive methods to monitor iron loading and unloading in the liver, heart, and pancreas have all significantly increased the survival of patients with thalassemia. Prolonged exposure to iron toxicity is involved in the development of endocrinopathy, osteoporosis, cirrhosis, renal failure, and malignant transformation. Now that survival has been dramatically improved, the challenge of iron chelation therapy is to prevent complications. The time has come to consider that the primary goal of chelation therapy is to avoid 24-h exposure to toxic iron and maintain body iron levels within the normal range, avoiding possible chelation-related damage. It is very important to minimize irreversible organ damage to prevent malignant transformation before complications set in and make patients ineligible for current and future curative therapies. In this clinical case-based review, we highlight particular aspects of the management of iron overload in patients with beta-thalassemia syndromes, focusing on our own experience in treating such patients. We review the pathophysiology of iron overload and the different ways to assess, quantify, and monitor it. We also discuss chelation strategies that can be used with currently available chelators, balancing the need to keep non-transferrin-bound iron levels to a minimum (zero) 24 h a day, 7 days a week and the risk of over-chelation.
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Affiliation(s)
- Valeria Maria Pinto
- Centro della Microcitemia e delle Anemie Congenite Ente Ospedaliero Ospedali Galliera, Via Volta 6, 16128 Genoa, Italy;
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Combined chelation with high-dose deferiprone and deferoxamine to improve survival and restore cardiac function effectively in patients with transfusion-dependent thalassemia presenting severe cardiac complications. Ann Hematol 2020; 99:2289-2294. [DOI: 10.1007/s00277-020-04196-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2020] [Accepted: 07/20/2020] [Indexed: 01/19/2023]
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Cardiac T2* MR in patients with thalassemia major: a 10-year long-term follow-up. Ann Hematol 2020; 99:2009-2017. [PMID: 32556452 DOI: 10.1007/s00277-020-04117-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2020] [Accepted: 06/01/2020] [Indexed: 02/07/2023]
Abstract
The consequence of regular blood transfusion in patients with thalassemia major (TM) is iron overload. Herein, we report the long-term impact of chelation on liver iron concentration (LIC) and cardiac T2* MR in patients with TM. This is a retrospective cohort study over 10 years of adolescents and adults with TM aged at least 10 years who had their first cardiac T2* MR between September 2006 and February 2007. One-year chelation therapy was considered the unit of analysis. A total of 99 patients were included in this study with a median age of 18 years. The median cardiac T2* MR and LIC at baseline were 19 ms and 11.6 mg/g dw, respectively. During follow-up, 18 patients died and six underwent successful bone marrow transplantation. Factors associated with decreased survival were older age (HR 1.12, p = 0.014) and high risk cardiac T2* (HR 8.04, p = 0.004). The median cardiac T2* and LIC significantly improved over the 10-year follow-up period (p = 0.000011 and 0.00072, respectively). In conclusion, this long-term "real-life" study confirms that low cardiac T2* adversely impacts the overall survival in patients with TM. Higher baseline LIC predicts a larger reduction in LIC, and lower baseline cardiac T2* predicts a larger improvement in T2*.
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Maggio A, Kattamis A, Felisi M, Reggiardo G, El-Beshlawy A, Bejaoui M, Sherief L, Christou S, Cosmi C, Della Pasqua O, Del Vecchio GC, Filosa A, Cuccia L, Hassab H, Kreka M, Origa R, Putti MC, Spino M, Telfer P, Tempesta B, Vitrano A, Tsang YC, Zaka A, Tricta F, Bonifazi D, Ceci A. Evaluation of the efficacy and safety of deferiprone compared with deferasirox in paediatric patients with transfusion-dependent haemoglobinopathies (DEEP-2): a multicentre, randomised, open-label, non-inferiority, phase 3 trial. LANCET HAEMATOLOGY 2020; 7:e469-e478. [PMID: 32470438 DOI: 10.1016/s2352-3026(20)30100-9] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Revised: 03/19/2020] [Accepted: 03/19/2020] [Indexed: 02/08/2023]
Abstract
BACKGROUND Transfusion-dependent haemoglobinopathies require lifelong iron chelation therapy with one of the three iron chelators (deferiprone, deferasirox, or deferoxamine). Deferasirox and deferiprone are the only two oral chelators used in adult patients with transfusion-dependent haemoglobinopathies. To our knowledge, there are no randomised clinical trials comparing deferiprone, a less expensive iron chelator, with deferasirox in paediatric patients. We aimed to show the non-inferiority of deferiprone versus deferasirox. METHODS DEEP-2 was a phase 3, multicentre, randomised trial in paediatric patients (aged 1 month to 18 years) with transfusion-dependent haemoglobinopathies. The study was done in 21 research hospitals and universities in Italy, Egypt, Greece, Albania, Cyprus, Tunisia, and the UK. Participants were receiving at least 150 mL/kg per year of red blood cells for the past 2 years at the time of enrolment, and were receiving deferoxamine (<100 mg/kg per day) or deferasirox (<40 mg/kg per day; deferasirox is not registered for use in children aged <2 years so only deferoxamine was being used in these patients). Any previous chelation treatment was permitted with a 7-day washout period. Patients were randomly assigned 1:1 to receive orally administered daily deferiprone (75-100 mg/kg per day) or daily deferasirox (20-40 mg/kg per day) administered as dispersible tablets, both with dose adjustment for 12 months, stratified by age (<10 years and ≥10 years) and balanced by country. The primary efficacy endpoint was based on predefined success criteria for changes in serum ferritin concentration (all patients) and cardiac MRI T2-star (T2*; patients aged >10 years) to show non-inferiority of deferiprone versus deferasirox in the per-protocol population, defined as all randomly assigned patients who received the study drugs and had available data for both variables at baseline and after 1 year of treatment, without major protocol violations. Non-inferiority was based on the two-sided 95% CI of the difference in the proportion of patients with treatment success between the two groups and was shown if the lower limit of the two-sided 95% CI was greater than -12·5%. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with EudraCT, 2012-000353-31, and ClinicalTrials.gov, NCT01825512. FINDINGS 435 patients were enrolled between March 17, 2014, and June 16, 2016, 393 of whom were randomly assigned to a treatment group (194 to the deferiprone group; 199 to the deferasirox group). 352 (90%) of 390 patients had β-thalassaemia major, 27 (7%) had sickle cell disease, five (1%) had thalassodrepanocytosis, and six (2%) had other haemoglobinopathies. Median follow-up was 379 days (IQR 294-392) for deferiprone and 381 days (350-392) for deferasirox. Non-inferiority of deferiprone versus deferasirox was established (treatment success in 69 [55·2%] of 125 patients assigned deferiprone with primary composite efficacy endpoint data available at baseline and 1 year vs 80 [54·8%] of 146 assigned deferasirox, difference 0·4%; 95% CI -11·9 to 12·6). No significant difference between the groups was shown in the occurrence of serious and drug-related adverse events. Three (2%) cases of reversible agranulocytosis occurred in the 193 patients in the safety analysis in the deferiprone group and two (1%) cases of reversible renal and urinary disorders (one case of each) occurred in the 197 patients in the deferasirox group. Compliance was similar between treatment groups: 183 (95%) of 193 patients in the deferiprone group versus 192 (97%) of 197 patients in the deferisirox group. INTERPRETATION In paediatric patients with transfusion-dependent haemoglobinopathies, deferiprone was effective and safe in inducing control of iron overload during 12 months of treatment. Considering the need for availability of more chelation treatments in paediatric populations, deferiprone offers a valuable treatment option for this age group. FUNDING EU Seventh Framework Programme.
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Affiliation(s)
- Aurelio Maggio
- Department of Hematology and Rare Diseases, V Cervello, Azienda Ospedaliera Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy.
| | - Antonis Kattamis
- First Department of Pediatrics, National and Kapodistriam University of Athens, Athens, Greece
| | - Mariagrazia Felisi
- Consorzio per Valutazioni Biologiche e Farmacologiche, Bari-Pavia, Italy
| | | | | | - Mohamed Bejaoui
- Pediatrics and Bone Marrow Transplantation Centre, Tunis, Tunisia
| | - Laila Sherief
- Pediatrics Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | | | - Carlo Cosmi
- Clinica Pediatrica, Azienda Ospedaliero Universitaria (AOU) Sassari, Sassari, Italy
| | - Oscar Della Pasqua
- Clinical Pharmacology and Therapeutics Group, University College London, London, UK
| | | | - Aldo Filosa
- UOSD Malattie rare del globulo rosso, AORN A Cardarelli, Napoli, Italy
| | - Liana Cuccia
- UOC Ematologia con Talassemia, Dipartimento di Medicina, AO Civico Di Cristina-Benfratelli, Palermo, Italy
| | - Hoda Hassab
- Department of Pediatrics and Clinical Research Center, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Manika Kreka
- Pediatrics Department, University Hospital Center Mother Teresa, Tirana, Albania
| | - Raffaella Origa
- DH Talassemia, Ospedale Pediatrico Microcitemico A CAO, AO G Brotzu, Cagliari, Italy
| | - Maria Caterina Putti
- Department of Women's and Child's Health (DSDB), University Hospital, Padova, Italy
| | | | - Paul Telfer
- Centre for Genomics and Child Health, Blizard Institute, Queen Mary University of London, London, UK
| | - Bianca Tempesta
- Consorzio per Valutazioni Biologiche e Farmacologiche, Bari-Pavia, Italy
| | - Angela Vitrano
- Department of Hematology and Rare Diseases, V Cervello, Azienda Ospedaliera Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy
| | | | - Ariana Zaka
- Center of Thalassemia, Hospital Ihsan Cabej, Lushnje, Albania
| | | | - Donato Bonifazi
- Consorzio per Valutazioni Biologiche e Farmacologiche, Bari-Pavia, Italy
| | - Adriana Ceci
- Fondazione per la Ricerca Farmacologica Gianni Benzi Onlus, Valenzano, Italy
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Bewersdorf JP, Taher AT, Zeidan AM. No child with a transfusion-dependent haemoglobinopathy left unchelated: are we there yet? LANCET HAEMATOLOGY 2020; 7:e429-e430. [PMID: 32470430 DOI: 10.1016/s2352-3026(20)30114-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/04/2020] [Accepted: 04/06/2020] [Indexed: 10/24/2022]
Affiliation(s)
- Jan Philipp Bewersdorf
- Section of Hematology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520-8028, USA
| | - Ali T Taher
- Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Amer M Zeidan
- Section of Hematology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520-8028, USA.
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Bou-Fakhredin R, Tabbikha R, Daadaa H, Taher AT. Emerging therapies in β-thalassemia: toward a new era in management. Expert Opin Emerg Drugs 2020; 25:113-122. [DOI: 10.1080/14728214.2020.1752180] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- Rayan Bou-Fakhredin
- Division of Hematology and Oncology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Rami Tabbikha
- Division of Hematology and Oncology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Hisham Daadaa
- Division of Hematology and Oncology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Ali T. Taher
- Division of Hematology and Oncology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon
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Sobhani S, Rahmani F, Rahmani M, Askari M, Kompani F. Serum ferritin levels and irregular use of iron chelators predict liver iron load in patients with major beta thalassemia: a cross-sectional study. Croat Med J 2020. [PMID: 31686454 PMCID: PMC6852133 DOI: 10.3325/cmj.2019.60.405] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Aim To determine whether serum ferritin, liver transaminases, and regularity and type of iron chelation protocol can be used to predict liver iron load as assessed by T2* magnetic resonance imaging (MRI) in patients with beta thalassemia major (TM). Methods This cross-sectional study, conducted from March 1, 2014 to March 1, 2015, involved 90 patients with beta TM on regular packed red blood cell transfusion. Liver and cardiac iron load were evaluated with T2* MRI. Compliance with iron-chelating agents, deferoxamine or deferasirox, and regularity of their use, as well as serum ferritin and liver transaminase levels were assessed. Results Patients with high serum ferritin were 2.068 times (95% confidence interval 1.26-3.37) more likely to have higher liver or cardiac iron load. High serum aspartate aminotransferases and irregular use of iron chelating agents, but not their type, predicted higher cardiac iron load. In a multiple regression model, serum ferritin level was the only significant predictor of liver and myocardial iron load. Conclusions Higher serum ferritin strongly predicted the severity of cardiac and liver iron load. Irregular use of chelator drugs was associated with a higher risk of cardiac and liver iron load, regardless of the type of chelating agent.
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Affiliation(s)
| | | | | | | | - Farzad Kompani
- Farzad Kompani, Department of Pediatrics, Tehran University of Medical Sciences, Children's Medical Center, Keshavarz Blvd, Tehran 14194, Iran,
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Sripetchwandee J, Khamseekaew J, Svasti S, Srichairatanakool S, Fucharoen S, Chattipakorn N, Chattipakorn SC. Deferiprone and efonidipine mitigated iron-overload induced neurotoxicity in wild-type and thalassemic mice. Life Sci 2019; 239:116878. [PMID: 31669736 DOI: 10.1016/j.lfs.2019.116878] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Revised: 09/10/2019] [Accepted: 09/13/2019] [Indexed: 01/23/2023]
Abstract
AIMS We previously demonstrated that iron-overload in non-thalassemic rats induced neurotoxicity and cognitive decline. However, the effect of iron-overload on the brain of thalassemic condition has never been investigated. An iron chelator (deferiprone) provides neuroprotective effects against metal toxicity. Furthermore, a T-type calcium channels blocker (efonidipine) effectively attenuates cardiac dysfunction in thalassemic mice with iron-overload. However, the effects of both drugs on brain of iron-overload thalassemia has not been determined. We hypothesize that iron-overload induces neurotoxicity in Thalassemic and wild-type mice, and not only deferiprone, but also efonidipine, provides neuroprotection against iron-overload condition. MAIN METHODS Mice from both wild-type (WT) and β-thalassemic type (HT) groups were assigned to be fed with a standard-diet or high-iron diet containing 0.2% ferrocene/kg of diet (HFe) for 4 months consecutively. After three months of HFe, 75-mg/kg/d deferiprone or 4-mg/kg/d efonidipine were administered to the HFe-fed WT and HT mice for 1 month. KEY FINDINGS HFe consumption caused an equal impact on circulating iron-overload, oxidative stress, and inflammation in WT and HT mice. Brain iron-overload and iron-mediated neurotoxicity, such as oxidative stress, inflammation, glial activation, mitochondrial dysfunction, and Alzheimer's like pathologies, were observed to an equal degree in HFe fed WT and HT mice. These pathological conditions were mitigated by both deferiprone and efonidipine. SIGNIFICANCE These findings indicate that iron-overload itself caused neurotoxicity, and T-type calcium channels may play a role in this condition.
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Affiliation(s)
- Jirapas Sripetchwandee
- Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand; Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Juthamas Khamseekaew
- Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Saovaros Svasti
- Thalassemia Research Center, Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom, 73170, Thailand
| | | | - Suthat Fucharoen
- Thalassemia Research Center, Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom, 73170, Thailand
| | - Nipon Chattipakorn
- Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand; Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Siriporn C Chattipakorn
- Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand; Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand; Department of Oral Biology and Diagnostic Sciences, Faculty of Dentistry, Chiang Mai University, Chiang Mai, 50200, Thailand.
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Cilsal E. Immobile Tricuspid Valve: Incidental Finding in a Case of Terminal Cardiomyopathy Due to Thalassemia Major. Arq Bras Cardiol 2019; 113:438-443. [PMID: 31621785 PMCID: PMC6882387 DOI: 10.5935/abc.20190195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Accepted: 12/05/2018] [Indexed: 11/20/2022] Open
Affiliation(s)
- Erman Cilsal
- Adana City Education and Research Hospital, Adana - Turkey
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Sharma S, Leaf DE. Iron Chelation as a Potential Therapeutic Strategy for AKI Prevention. J Am Soc Nephrol 2019; 30:2060-2071. [PMID: 31554656 DOI: 10.1681/asn.2019060595] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AKI remains a major public health concern. Despite years of investigation, no intervention has been demonstrated to reliably prevent AKI in humans. Thus, development of novel therapeutic targets is urgently needed. An important role of iron in the pathophysiology of AKI has been recognized for over three decades. When present in excess and in nonphysiologic labile forms, iron is toxic to the kidneys and multiple other organs, whereas iron chelation is protective across a broad spectrum of insults. In humans, small studies have investigated iron chelation as a novel therapeutic strategy for prevention of AKI and extrarenal acute organ injury, and have demonstrated encouraging initial results. In this review, we examine the existing data on iron chelation for AKI prevention in both animal models and human studies. We discuss practical considerations for future clinical trials of AKI prevention using iron chelators, including selection of the ideal clinical setting, patient population, iron chelating agent, and dosing regimen. Finally, we compare the key differences among the currently available iron chelators, including pharmacokinetics, routes of administration, and adverse effects.
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Affiliation(s)
- Shreyak Sharma
- Division of Renal Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - David E Leaf
- Division of Renal Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
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