Myocardial Iron Loading Research Articles

Burden of Cardiac Siderosis in a Thalassemia-Major Endemic Population: A Preliminary Report From Pakistan.

To describe the initial experience and demographics of T2* cardiac magnetic resonance-based myocardial-iron quantification of transfusion-dependent thalassemia-major (TM) patients from Pakistan and the correlation with serum ferritin. Eligible TM patients presenting between April 2014 and April 2015 to Aga Khan University Hospital, Pakistan, for T2*CMR were included. The severity of myocardial-iron deposition was defined as follows: normal T2*>20 ms, mild-moderate T2*10 to 20 ms, and severe T2*<10 ms. Cardiac symptoms were classified using the NYHA functional classification. Echocardiographic systolic and diastolic functions were performed. Continuous variables were presented as the median (minimum-maximum value). Correlation was measured using the Spearman rank correlation. Multivariate logistic regression was used to determine factors associated with the NYHA functional class. A total of 83 patients (49 male and 34 female) with TM, age 19 (5 to 45) years at presentation for T2*CMR, were reviewed. At presentation, 70% of the patients were classified as NYHA class II or worse. T2*<20 ms was observed in 62.6% of the patients, with 47% showing severe iron deposition (T2<10 ms). No correlation of T2*<20 ms (r=-0.157, P=0.302) and T2*<10 ms (r=-0.128, P=0.464) was observed with serum ferritin. On multivariate analysis, lower T2* values correlated with a worsening NYHA functional class. There is a high prevalence of severe myocardial iron load in Pakistani TM patients. Serum ferritin did not correlate with T2* values. Lower T2* was the only clinical factor associated with the NYHA functional class.

The Association between Serum Ferritin Level, Tissue Doppler Echocardiography, Cardiac T2* MRI, and Heart Rate Recovery in Patients with Beta Thalassemia Major.

It is generally well-understood that iron-mediated cardiomyopathy is the major complication that can arise from beta thalassemia major (TM). Therefore, early diagnosis, risk stratification, and the effective treatment of beta TM patients are clinically important to optimize long-term positive outcomes. This study included 57 beta TM patients with a mean age of 25 ± 7 years. We determined the serum ferritin level, echocardiography, heart rate recovery (HRR), and cardiac magnetic resonance (CMR) T2* in all patients. CMR T2* findings were categorized as normal myocardium (T2* > 20 ms), and myocardial involvement (T2* ≤ 20 ms). HRR values at 1-5 min (HRR1-5) were recorded; Subsequently. HRR was calculated by subtracting the heart rate at each time point from the heart rate at peak exercise. There was a significant negative correlation between the serum ferritin level and the cardiac T2* MRI findings (r = -0.34, p = 0.009). A similar result was found in the negative correlation between serum ferritin and all heart rate recovery values. There was a significant positive correlation between HRR1, HRR2, and HRR3 values, and CMR T2* (T2* heart rate recovery (HRR)1: r = 0.51, p < 0.001; T2* HRR2: r = 0.48, p < 0.001; T2* HRR3: r = 0.47, p < 0.001, respectively). The serum ferritin level and echocardiography can be used to predict the presence of myocardial iron load in beta TM patients. Therefore, HRR can be used to screen beta TM patients, and the clinical use of HRR can be a predictive marker for autonomic dysfunction in beta TM patients. Beta thalassemia major • Cardiac magnetic resonance T2* • Heart rate recovery • Iron overload • Serum ferritin level • Tissue Doppler imaging.

Benign Cardiac Effects of Hemoglobin H Disease

Background/Aims: Hemoglobin H (HbH) disease is associated with iron overload, but whether this results in serious cardiac or vascular sequelae is unresolved. Methods: We identified 39 adult subjects (age 42 ± 12 years, 13 men) with HbH disease who had undergone echocardiography, 27 of whom had also undergone cardiac and liver magnetic resonance assessment of iron loading using T2*-weighted imaging. Results: None of the subjects had a history of heart failure or arrhythmias. There were 13/39 subjects with a ferritin level within the sex-based normal range and only 4/39 had ferritin >1,000 ng/ml. Left ventricular (LV) and left atrial dilatation was common, but LV ejection fraction was normal (≥55%) in all subjects. Age was positively correlated with log ferritin in the 27 nontransfused subjects (r = 0.43) and was inversely correlated with the transmitral E wave and E/A ratio (r = -0.69 and r = -0.79, respectively), but no relation of log ferritin with E or E/A was evident. The peak tricuspid regurgitation velocity was normal in 24/29 subjects for whom this was obtained, and it was no more than mildly elevated in the other 5. None of the tested subjects had an abnormal cardiac T2* reading, but half had evidence of liver iron loading. Conclusion: No myocardial iron loading or serious cardiac or vascular sequelae were identified in this cohort with HbH disease.

Residual Erythropoiesis Protects Against Cardiac Iron Loading in Transfusion Dependent Thalassaemia (TDT) By Lowering Labile Plasma Iron (LPI) through Transient Apotransferrin Generation

▪IntroductionMyocardial iron loading frequently complicates TDT but factors affecting the highly variable risk are not fully understood and current available predictors do not explain this variability. Chronic blood transfusion in TDT, by correcting anemia, is life saving but also aims to reduce ineffective erythropoiesis (IE) and its complications. Such transfusion will also decrease utilisation of transferrin (Tf) iron by the erythron and increase Tf saturation (TfSat) (Porter et al, Brit J Haematol 2014). Here we examine for the first time, how variable levels of residual erythropoiesis in TDT (marked by soluble transferrin receptors, sTfR), and the consequent presence of ApoTf, affect myocardial iron loading. We then examine how the difference between the transfusional iron loading rate (ILR) and Tf iron utilisation (calculated from sTfR levels) impact on myocardial iron loading. We finally test the hypotheses generated by these findings, using in vitro models of cellular uptake of NTBI and its redox active component LPI, the main conduits of myocardial iron uptake, in the presence and absence of ApoTf.MethodsA cohort of 73 TDT patients on deferasirox (DFX) had cardiac MRI and blood biomarkers measured at baseline and at 1.5 years later, over which time the ILR was calculated. Patients were divided into those with cardiac iron (24 cases, cardiac T2*<20ms, R2* >50s-1) and those without (59 controls, T2*>20ms, R2* <50s-1): biomarkers of iron metabolism and routine biochemical variables were compared in both groups with data shown for the 1.5 year measurements. 48h washout from DFX was ensured prior to blood sampling for which patients gave written informed consent. NTBI, LPI, sTfR, TfSat were performed as in Porter et al 2014, mouse HL-1 cardiomyocytes grown as in Claycomb et al, PNAS 1998, Ferric citrate (Fe-cit) prepared as in Evans et al, J Biol Inorg Chem 2008, and total cellular iron was assayed by ferrozine as in Riemer et al Anal Biochem 2004.Results and DiscussionTf iron utilisation and myocardial iron in TDT. Of all biomarkers analysed, sTfR was most significantly associated with heart iron (p<0.001) being >3x higher in controls than cases. NTBI, LPI, TfSat and ILR were not significantly different in cases and controls, but LIC and ferritin were higher in cases (p=0.003 and 0.002). With sTfR expressed as Tf iron utilisation rate (or erythroid Tf uptake rate, ETUR) after Beguin et al, Blood 1993 and compared to ILR, myocardial iron was present only when the net ILR (ILR-ETUR) exceeded 0.21 mg/kg/d (p<0.001). Above and below this threshold LIC, TfSat and NTBI were similar (9.7 vs 10.1 mg/g dry weight, 96 vs 98%, 3 vs 2.6µM, p=ns), while LPI was 3x higher (0.35 vs 0.1 µM p=0.01). Thus LPI was high only in patients where the net ILR exceeded 0.21 whereas LIC, TfSat, NTBI showed no difference between patients with and without myocardial siderosis, even when adjusted for the net ILR (Figure 1).Effect of ApoTf and Fe:cit ratio on NTBI uptake into cultured cardiomyocytes. ApoTf or TfSat <100% inhibited NTBI uptake into HL-1 cells as well as LPI but did not increase iron release from cells preloaded with iron. Fe-cit, the main NTBI species, is less visible as LPI than NTA iron.Increasing excess of cit:Fe increases the proportion of iron visible to the LPI assay,increases myocardial iron uptake and iron binding to Tf. Previous work (Evans et al J Biol Inorg Chem 2008) showed that Fe:cit ratio does not affect the NTBI assay, by contrast we show it affects the LPI assay. The ratio affects uptake and because uptake may be redox dependent (Oudit et al, Nat Med 2003), it is very likely that a redox facile NTBI, i.e. LPI, is the key species taken up by the heart, further supported by Fe:cit ratios <1:100 (more citrate) accounting for the majority of uptake (EC90=1.09µM, Figure 2)ConclusionTaken together these data suggest that the risk of myocardial siderosis in TDT is critically dependent on the degree of residual erythropoiesis and the net balance between the transfusional iron delivery (ILR) and the iron utilisation rate by the erythron (ETUR). Myocardial siderosis occurs when the net ILR-ETUR exceeds 0.21 mg/kg/day, the same threshold at which LPI is increased. The likely mechanism is that higher ILR-ETUR values decrease TfSat<100% hence allowing transiently formed ApoTf to decrease LPI. This mechanism is supported by the finding that as little as 1µM ApoTf inhibits NTBI uptake into cardiomyocytes in culture while also decreasing LPI. [Display omitted] [Display omitted] DisclosuresPorter:Celgene: Consultancy; Shire: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding.

Three Dimensional Speckle Tracking Echocardiography (3D-STE) for Early Detection of Subtle Myocardial Deformation Dysfunction in Thalassemic Patients

Background: Among patients with beta-thalassemia early detection of transfusion-induced myocardial iron loading and its intervention with aggressive chelation therapy may delay or reverse heart failure. Three dimensional speckle tracking echocardiography (3D-STE) is a novel tool that may early detect myocardial affection in these patients.Methods: Thirty-two thalassemic patients with a mean age of 18.1± 7.03 years and 30 aged matched healthy control subjects have been included in the study. Patients have been recruited from pediatric hematology clinics in both Cairo University, Egypt (n=18) and Padova University, Italy (n=14). 3D-STE was performed to all patients and control subjects in addition to the myocardial relaxometry T2* by cardiac MRI.Results: The left ventricular ejection fraction (LVEF) derived from 3D echocardiography among the studied thalassemia patients was within normal range 62.5± 5.6%. Compared to the normal subjects, thalassemia patients had a statistical significant reduction of the left ventricular global longitudinal strain (-16.81± 0.93% vs -18.76 ± 1.12 %, p=0.001), the left ventricular global circumferential strain (-10.56 ± 0.61% vs -11.83 ± 0.71 %, p=0.001 ) and the left ventricular global area strain (-20.13 ±1.18% vs -22.48 ±,1.29 %, p=0.001). No statistical significant correlation was found between the severity of myocardial iron overload measured by T2* and the measured left ventricular global strain.Conclusion: In asymptomatic thalassemia patients with preserved left ventricular global systolic function 3D-STE derived strain can detect early subtle myocardial dysfunction. The observed subtle myocardial deformation dysfunction is not related to the extent of myocardial iron deposition. DisclosuresNo relevant conflicts of interest to declare.

Myocardial Iron Loading Assessment by Automatic Left Ventricle Segmentation with Morphological Operations and Geodesic Active Contour on T2* images.

Myocardial iron loading thalassemia patients could be identified using T2* magnetic resonance images (MRI). To quantitatively assess cardiac iron loading, we proposed an effective algorithm to segment aligned free induction decay sequential myocardium images based on morphological operations and geodesic active contour (GAC). Nine patients with thalassemia major were recruited (10 male and 16 female) to undergo a thoracic MRI scan in the short axis view. Free induction decay images were registered for T2* mapping. The GAC were utilized to segment aligned MR images with a robust initialization. Segmented myocardium regions were divided into sectors for a region-based quantification of cardiac iron loading. Our proposed automatic segmentation approach achieve a true positive rate at 84.6% and false positive rate at 53.8%. The area difference between manual and automatic segmentation was 25.5% after 1000 iterations. Results from T2* analysis indicated that regions with intensity lower than 20 ms were suffered from heavy iron loading in thalassemia major patients. The proposed method benefited from abundant edge information of the free induction decay sequential MRI. Experiment results demonstrated that the proposed method is feasible in myocardium segmentation and was clinically applicable to measure myocardium iron loading.

Serum Ferritin Levels Correlation With Heart and Liver MRI and LIC in Patients With Transfusion-Dependent Thalassemia.

Background:Iron-loaded cardiac complication is the essential cause of mortality in patients with thalassemia. Early detection and treatment of cardiac over-load can reduce mortality.Objectives:The current study aimed to evaluate the relationship between serum ferritin levels and T2* magnetic resonance imaging (MRI) of heart and liver and liver iron concentration (LIC) to diagnose iron over load in countries with limited access.Patients and Methods:In the current cross-sectional study, 85 Iranian patients with thalassemia with the mean age of 22.7 ± 7 years were randomly selected. All patients were on regular blood transfusion. Echocardiography of heart and liver T2* MRI, determination of serum ferritin levels, and LIC were performed in all subjects at the same time. The correlation of serum ferritin levels with T2*MRI of heart and liver, and LIC was assessed. P value < 0.05 was considered statistically significant.Results:Abnormal myocardial iron load (T2* MRI < 20 ms) was detected in 58% of the patients and among whom, 36% had severe myocardial iron load (T2* MRI < 10 ms). Median and interquartile range of serum ferritin levels were 1434 and 2702 respectively in patients with thalassemia. Serum ferritin levels showed a statistically significant positive correlation with LIC (rs = 0.718, P < 0.001) and significant negative correlation with T2* Heart (rs = -0.329, P = 0.002), and T2* Liver (rs = -0.698, P < 0.001). However, Ejection fraction was not significantly correlated with serum ferritin levels in the patients (P = 0.399).Conclusions:Serum ferritin levels can be used to diagnose iron over-load in patients with thalassemiaas an alternative method in areas where T2* MRI is not available.

Thalassemia major between liver and heart: Where we are now

The aim of the study was to assess the current state in terms of liver and heart iron overload as well as of liver and heart related morbidity and mortality in a large cohort of thalassemia patients. Myocardial iron loading was present in 28.9% patients, which was severe in 3.2%. Liver iron was normal in 9.3% and severe in 15%. The rate of cardiac deaths started to decrease between 2000 and 2003 and dropped significantly afterwards. The prescription of combination therapy soon after the hospital admission for decompensated heart failure was associated with a decrease in the short-term mortality. In 111 adult patients who underwent liver elastometry, 14 HCVRNA positive subjects and 2 HCVRNA negative, had stiffness values suggestive of cirrhosis. No cases of hepatocarcinoma were reported. Liver "iron free foci" occurred in a HCV negative patient and the occurrence of a malignant epithelioid hemangioendothelioma led to liver transplantation in another. The study suggests that a subset of patients continues to develop progressive hemosiderosis that may lead to cardiac disease and death. Beyond its key role in preventing myocardial iron overload, liver iron chelation is essential for hampering the onset of hepatic tumors, which may not be limited to hepatocarcinoma.

A 5-year follow-up in deferasirox treatment: improvement of cardiac and hepatic iron overload and amelioration in cardiac function in thalassemia major patients.

Deferasirox (DFX) is an oral iron chelator with established efficacy and safety. We evaluated by T2* cardiovascular magnetic resonance (CMR) the efficacy of DFX in preventing and removing cardiac and liver iron load and cardiac volume changes, along 5years in adult thalassemia major (TM) patients. Twenty-three TM patients (9 males/14 women, mean age 36 ± 4years) were included in this study. Repeated CMR was performed to assess myocardial and liver iron load(baseline t0, after 2.5 years t1, after 5 years t2). Myocardial T2* values changed progressively and increased significantly between t0 and t2 (t0: 27.15 ± 9.58 vs t2: 36.64 ± 6.68, p = 0.0001). At baseline evaluation, a cardiac T2* value <20ms was detected in six patients (26%): they showed an improvement of cardiac T2* values between t0 and t1, with normal T2* levels reached in all patients at t2. In the overall population, a significant reduction of both end-diastolic and end-systolic left ventricular volumes (EDV, ESV) were detected between t0 and t2 (EDV, t0: 132 ± 31ml vs t2: 124 ± 22ml, p = 0.033; ESV, t0: 48 ± 14ml vs t2: 41 ± 10ml, p = 0.0007). A significant reduction in liver iron concentration (LIC) was detected at t1 (5.36 ± 3.58mg/g dw at baseline vs 3.35 ± 2.68mg/g dw at t1, p = 0.004). In patients with cardiac iron overload at baseline (n.6), mean cardiac T2* values doubled at t2, and mean LIC value is reduced of 29%. After 5years of treatment, DFX continually and significantly reduced myocardial and liver iron overload, and it prevented further iron deposition.

Does myocardial iron load determine the severity of heart insufficiency?

Reduced exercise capacity, fatigue and breathlessness are the most common symptoms in heart failure (HF) patients [ [1] McMurray J.J. Adamopoulos S. Anker S.D. et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur. J. Heart Fail. 2012; 14: 803-869 Crossref PubMed Scopus (68) Google Scholar ]. The mechanism responsible for the development of these symptoms is not fully understood, however the most important factors involved are: decreased peripheral circulatory perfusion with reduced oxygen delivery and impaired peripheral muscle strength and oxygen utilization due to iron deficiency [ 2 Jankowska E.A. von Haehling S. Anker S.D. Macdougall I.C. Ponikowski P. Iron deficiency and heart failure: diagnostic dilemmas and therapeutic perspectives. Eur. Heart J. 2013; 34: 816-829 Crossref PubMed Scopus (252) Google Scholar , 3 von Haehling S. Steinbeck L. Doehner W. Springer J. Anker S.D. Muscle wasting in heart failure: An overview. Int. J. Biochem. Cell Biol. 2013; 45: 2257-2265 Crossref PubMed Scopus (35) Google Scholar , 4 Ventura-Clapier R. Exercise training, energy metabolism, and heart failure. Appl. Physiol. Nutr. Metab. 2009; 34: 336-339 Crossref PubMed Scopus (32) Google Scholar ]. Iron as a component of many enzymes (including oxidative and respiratory chains) participating in crucial biological events, in muscles, plays a key role in oxygen uptake, transport, and storage, as well as oxidative metabolism, catalysis and energy production [ 5 Palus S. von Haehling S. Springer J. Muscle wasting: an overview of recent developments in basic research. Int. J. Cardiol. 2014; 176: 640-644 Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar , 6 Ingwall J.S. Energy metabolism in heart failure and remodelling. Cardiovasc. Res. 2009; 81: 412-419 Crossref PubMed Scopus (339) Google Scholar ]. Targeting these abnormalities by the correction of iron deficiency (with or without anemia) with intravenous iron brings a functional benefit to such patients [ 7 Anker S.D. Colet J.C. Filippatos G. et al. Rationale and design of Ferinject assessment in patients with IRon deficiency and chronic Heart Failure (FAIR-HF) study: a randomized, placebo-controlled study of intravenous iron supplementation in patients with and without anaemia. Eur. J. Heart Fail. 2009; 11: 1084-1091 Crossref PubMed Scopus (86) Google Scholar , 8 Ponikowski P. van Veldhuisen D.J. Comin-Colet J. et al. Beneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiencydagger. Eur. Heart J. 2014; 36: 657-668 Crossref PubMed Scopus (656) Google Scholar ]. Role of quantitative myocardial-iron in hemodialysis-dependent end-stage renal disease subjectsInternational Journal of CardiologyVol. 256PreviewFirst of all, I'd like to thank Leszek et al. for putting light on such a promising topic on myocardial-iron load and severity of heart insufficiency [1]. Full-Text PDF

A 5-Years Follow-up in Deferasirox Treatment: Improvement of Cardiac and Hepatic Iron Overload and Amelioration in Cardiac Function in Thalassemia Major Patients

Introduction. During the last 10 years the cardiac deaths in adult thalassemia major (TM) patients are significantly reduced because of the availability of new oral iron chelators and the introduction of T2* cardiovascular magnetic resonance (CMR), which allows to evaluate the cardiac iron load. Deferasirox (DFX) is an oral iron chelator with established efficacy and safety. Based on myocardial T2* values, the risk of cardiac heart failure can be estimated prompting to intensify chelation therapy, if necessary. We would evaluate by T2* CMR the efficacy of DFX in preventing and removing cardiac and hepatic iron load and cardiac volume changes, along 5 years in adult TM patients.Methods. Twenty-three TM patients (9 males/14 women, mean age 36 ± 4 yrs) were included in this study. They repeated CMR to assess myocardial and liver iron load. Cardiac and hepatic iron load was assessed measuring myocardial T2* at 3 different time-points: basal value (t0), after a period of 2.5 years ± 6 months (t1) and after a period of five years (t2). During the follow-up period two patients became pregnant and they stopped chelation therapy with deferasirox for the duration of the pregnancy: they restarted oral iron chelation therapy with DFX after the delivery without any adverse event. Six patients underwent treatment with interferon and ribavirin to treat their hepatitis C: the dose of DFX was modulated based on increased iron intake during the treatment period.Results. Overall, the mean iron intake was 0.34±0.10 mg/Kg/day and the pre-transfusional mean hemoglobin (Hb) was 9.7±0.5 g/dl. The median ferritin value was 575 ng/ml (range 252-2530 ng/ml). The mean dosage of deferasirox at the beginning of the observation period was 24.4 ± 5.3 mg/kg/day; the mean dose of DFX along the 5-years follow-up was 25.3 ± 1.2 mg/kg/day. An initial reduction of mean ferritin levels was observed in the first 2.5 years of observation reaching a statistical significance only after 5 years (1055±563 ng/ml at baseline vs 960±568 ng/ml at t1 vs 751±627 ng/ml at t2, p=0.009 between t1 and t2). Myocardial T2* values changed progressively and increased significantly between t0 and t2 (t0: 27.15 ± 9.58 vs t2: 36.64 ± 6.68, p=0.0001). At baseline evaluation, a cardiac T2* value < 20 ms was detected in 6 patients (26 %): they showed an improvement of cardiac T2* values between t0 and t1, with normal T2* levels reached in all patients at t2. In the overall population a significant reduction of both end-diastolic and end-systolic left ventricular volumes (EDV, ESV) were detected between t0 and t2 (EDV, t0: 132±31 ml vs t2: 124±22 ml, p=0.033; ESV, t0: 48±14 ml vs t2: 41±10 ml, p=0.0007) (Table 1). A significant reduction in Liver Iron Concentration (LIC) was detected at t1 (5.36±3.58 mg/g dw at baseline vs 3.35±2.68 mg/g dw at t1, p=0.004). In patients with cardiac iron overload at baseline (n.6), mean cardiac T2* values doubled at t2 and mean LIC value is reduced of 29 %.Conclusions. Wecan conclude that DFX, at a personalized dose, progressively and significantly reduces myocardial and liver iron overload and it prevented the iron deposition along 5-years of continuous treatment.Table 1Left ventricular ejection fraction and cardiac volumes during the period of follow-up.Overall patientsPatients with baseline T2* 10–20 mst0t2P-valuet0t2P-valueLVEF(%, mean ± SD)64 ± 666 ± 6ns61 ± 763 ± 6NsEDV(ml, mean ± SD)(nv: 52-141 ml)132 ± 31124 ± 220,033139 ± 33121 ± 220.03ESV(ml, mean ± SD)(nv: 13-51 ml)48 ± 1441 ± 100,000754 ± 1444 ± 100.02 LVEFLeft Ventricular Ejection Fraction; EDV: End-Diastolic left ventricular Volume; nv: normal value; ESV End-Systolic left ventricular Volume; SD: Standard Deviation; ns: not significative. DisclosuresCappellini:Novartis, Shire, Cellgene, Sanofi: Advisory board Other.

Relative Trends in Myocardial T2* Versus Myocardial Iron Concentration As Representations of Myocardial Iron Chelation Efficacy in Patients with β Thalassemia Major Treated with Deferasirox for up to 3 Years

▪Background: Heart failure due to iron-induced cardiomyopathy is rare yet remains one of the leading causes of death in patients with β thalassemia. Using myocardial T2* (mT2*) cardiovascular magnetic resonance (CMR) to estimate myocardial iron burden has improved the management of cardiac siderosis. Myocardial T2* >20 ms is considered normal and as iron accumulates, mT2* reduces, with values <10 ms associated with an increased risk of heart failure. As reported by Carpenter et al (2011), a calibration for CMR R2* against atomic emission spectroscopy-measured myocardial iron concentration (MIC), showing a curvilinear relationship between R2* and MIC, actual MIC can now also be assessed and affords an additional efficacy measure for patients undergoing iron chelation therapy. In a previous post-hoc analysis of the 3-year EPIC (Evaluation of Patients’ Iron Chelation with Exjade®) cardiac substudy, the long-term effects of deferasirox on mT2* and MIC were reported. Here, we report relative trends between mT2* and MIC as a representation of myocardial chelation efficacy by determining how far the patient has progressed from baseline toward reaching normal levels, in order to further understand the interpretation of these two parameters.Methods: Patients aged ≥10 years with mT2* >5 to <20 ms by CMR, left ventricular ejection fraction ≥56%, serum ferritin >2500 ng/mL, MR (R2) liver iron concentration >10 mg Fe/g dry weight (dw) and ≥50 lifetime transfused blood units were included in the study. Cardiac iron removal was analyzed over 3 years in patients with mT2* at baseline and each considered time point. Post-hoc calculation of MIC from mT2* values was conducted using the formula described by Carpenter et al as follows: [Fe] = 45.0 x (mT2*)−1.22 where [Fe] is measured in milligrams per gram dw and mT2* is measured in milliseconds. Data are presented descriptively as the percentage of the progression of the patients toward achieving normalization of mT2* (>20 ms) or MIC (>1.16 mg Fe/g dw as derived from the formula based on normal mT2*) by mT2* at baseline: >5 to <10 ms, 10 to <15 ms and 15 to <20 ms.Results: Data were analyzed at Month 12 (n=67: baseline mT2* >5 to <10 ms, n=24; 10 to <15 ms, n=19; 15 to <20 ms, n=24), Month 24 (n=66: baseline mT2* >5 to <10 ms, n=24; 10 to <15 ms, n=18; 15 to <20 ms, n=24) and Month 36 (n=63: baseline mT2* >5 to <10 ms, n=22; 10 to <15 ms, n=18; 15 to <20 ms, n=23). As previously reported (Pennell et al. 2012), geometric mean mT2* in the overall population significantly increased from 12.0 ms at baseline to 13.9 ms at Month 12, 15.6 ms at Month 24 and 17.1 ms at Month 36. In parallel, mean MIC significantly decreased from 2.43 mg Fe/g dw at baseline to 2.10 mg Fe/g dw at Month 12, 1.94 mg Fe/g dw at Month 24 and 1.80 mg Fe/g dw at Month 36. The median percentage progression of patients towards normalizing mT2* and MIC by baseline mT2* category are presented in the Figure. In patients with severe myocardial iron overload at baseline, the percentage toward normalization in mT2* in the first, second and third year was less than the percentage towards normalization in MIC. This difference was less pronounced, but still evident, in patients with mild-to-moderate myocardial iron overload. [Display omitted] Discussion: The calibration of the relationship between CMR measurements and MIC by Carpenter et al allows an additional assessment to mT2* to determine chelator efficacy in terms of the actual concentration of iron in the myocardium. Here we show that, particularly in patients with severe myocardial iron overload, when analyzing the progression towards normalization, improvement in MIC is proportionally greater than that seen with mT2*. It could be interpreted that a small improvement (ie 1 ms) in mT2* when baseline values are >5 to <10 ms is not equivalent in terms of myocardial iron removal to a small improvement in patients with less severe myocardial iron overload at baseline; a consequence of the reciprocal relationship between mT2* and MIC. Therefore, analysis of mT2* only may underestimate the efficacy of iron chelation with respect to the myocardium in patients with severe myocardial iron loading (mT2* <10 ms) and thus MIC may better reflect response to chelation therapy. It would therefore be valuable if MIC were calculated and reported in parallel with mT2* when assessing and monitoring patients on iron chelation therapy across a range of baseline mT2* values. DisclosuresPorter:Novartis: Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria; Celgene: Consultancy; Cerus: Membership on an entity’s Board of Directors or advisory committees; Alnylam: Membership on an entity’s Board of Directors or advisory committees. Taher:Novartis: Honoraria, Research Funding. Aydinok:Novartis: Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. El-Ali:Novartis: Employment. Barbier:Novartis: Employment. Cappellini:Novartis: Honoraria, Speakers Bureau; Genzyme: Honoraria.

The Role of Magnetic Resonance Imaging in the Evaluation of Thalassemic Syndromes: Current Practice and Future Perspectives

Iron can be deposited in all internal organs, leading to different types of functional abnormalities. However, myocardial iron overload that contributes to heart failure remains one of the main causes of death in thalassemia major. Using magnetic resonance imaging, tissue iron is detected indirectly by the effects on relaxation times of ferritin and hemosiderin iron interacting with hydrogen nuclei. The presence of iron in the human body results in marked alterations of tissue relaxation times. Currently, cardiovascular magnetic resonance using T2* is routinely used in many countries to identify patients with myocardial iron loading and guide chelation therapy, specifically tailored to the heart. Myocardial T2* is the only clinically validated non-invasive measure of myocardial iron loading and is superior to surrogates such as serum ferritin, liver iron, ventricular ejection fraction and tissue Doppler parameters. Finally, the substantial amelioration of patients’ survival, allows the detection of other organs’ abnormalities due to iron overload, apart from the heart, missed in the past. Recent studies revealed that iron deposition has a different pattern in various parenchymal organs, which is independent from serum ferritin and follows an individual way after chelation treatment application. This new upcoming reality orders a closer monitoring of all organs of the body in order to detect preclinical lesions and early apply adequate treatment.

Left ventricular torsional mechanics and myocardial iron load in beta-thalassaemia major: a potential role of titin degradation.

BackgroundIron may damage sarcomeric proteins through oxidative stress. We explored the left ventricular (LV) torsional mechanics in patients with beta-thalassaemia major and its relationship to myocardial iron load. Using HL-1 cell and B6D2F1 mouse models, we further determined the impact of iron load on proteolysis of the giant sarcomeric protein titin.Methods and resultsIn 44 thalassaemia patients aged 25 ± 7 years and 38 healthy subjects, LV torsion and twisting velocities were determined at rest using speckle tracking echocardiography. Changes in LV torsional parameters during submaximal exercise testing were further assessed in 32 patients and 17 controls. Compared with controls, patients had significantly reduced LV apical rotation, torsion, systolic twisting velocity, and diastolic untwisting velocity. T2* cardiac magnetic resonance findings correlated with resting diastolic untwisting velocity. The increments from baseline and resultant LV torsion and systolic and diastolic untwisting velocities during exercise were significantly lower in patients than controls. Significant correlations existed between LV systolic torsion and diastolic untwisting velocities in patients and controls, both at rest and during exercise. In HL-1 cells and ventricular myocardium of B6D2F1 mice overloaded with iron, the titin-stained pattern of sarcomeric structure became disrupted. Gel electrophoresis of iron-overloaded mouse myocardial tissue further showed significant decrease in the amount of titin isoforms and increase in titin degradation products.ConclusionsResting and dynamic LV torsional mechanics is impaired in patients with beta-thalassaemia major. Cell and animal models suggest a potential role of titin degradation in iron overload-induced alteration of LV torsional mechanics.

Relation of Myocardial Systolic Mechanics to Serum Ferritin Level as a Prognosticator in Thalassemia Patients Undergoing Repeated Transfusion

Myocardial iron overload leading to congestive heart failure (HF) or arrhythmias is a recognized complication in thalassemia patients undergoing chronic blood transfusion. The relationship between myocardial iron load, subclinical systolic dysfunction, and clinical events remains less well known. We studied a total of 77 subjects, comprising 37 thalassemia patients (mean age: 24.2 ± 5.5 years) with a history of repeated blood transfusions, in addition to 40 age- and gender-matched controls (mean age: 24 ± 4.5 years). Serum ferritin levels were checked in all subjects, as well as semiautomated quantification of left ventricular (LV) longitudinal, circumferential, and radial deformations assessed by two-dimensional (2D) speckle tracking analysis. Compared with the control group, thalassemia patients showed significantly larger LV mass index and lower myocardial deformations (P < 0.05), but left ventricular ejection fraction (LVEF) did not differ significantly (P = 0.233). There was a significant linear correlation between serum ferritin level and longitudinal (r = 0.44, P = 0.0078) and radial strain (r = -0.46, P = 0.0051), with optimal cutoff provided to be -15.48%, -21.31%, and 26.67% for longitudinal, circumferential, and radial strain in predicting clinical events, respectively. During a median of 802.5 days follow-up, 11 clinical composites (HF incidence, ventricular tachyarrhythmia, and death) occurred (N = 9 subjects); subjects with composites had significantly reduced longitudinal and radial strain compared to those without (both P < 0.05). After adjusting for age, sex, serum ferritin level, and LV mass index, a worsening of longitudinal strain remained as an independent predictor of clinical events and death (HR: 6.05, P = 0.033). Subclinical systolic dysfunction appears more likely in thalassemia subjects with a history of repeated blood transfusions, which further correlated with serum ferritin levels. In addition, worsening LV myocardial deformation parameters may play an independent role in predicting clinical outcomes beyond traditional measures in this population.

Quantitative assessment of iron load in myocardial overload rabbit model: preliminary study of MRI T_2"* map

Objective To preliminarily investigate the feasibility of MRI-T2* map in evaluating myocardial iron load of myocardial iron overload rabbit models.Methods Eleven rabbits were included in this study and divided into two groups,myocardial iron overload group (n =10) and the control group (n =1).Iron dextrin (dose of 50 mg/kg) was injected in muscles of thigh once a week,totally 12 weeks.Serum iron test and MRI examination were performed before iron injection,and 1 week to 12 weeks after iron injection.MRI scan protocol included short axial T2* map of the left ventricle and cross-section T2* map of the liver.T2* and R2* of the heart and the liver were measured.One rabbit was killed after MRI examination at pre-iron injection,1 week to 8 weeks,11 weeks and 12 weeks after iron injection,respectively.Heart and liver were avulsed to undergo in vitro MRI scan and then paraffin embedded for pathological slices.MRI scan protocol and measurements of the heart and the liver samples were the same to that of in vivo ones.Pearson correlation was used to calculate the relationships between the parameters.Results Myocardial T2* [(32.5 ± 8.3 ms)] and R2* values [(38.4 ± 7.9) Hz] had significant correlation with injecting iron content(1 033.2 ± 673.4 mg),the Pearson coefficients were-0.799 (P =0.001) and 0.770 (P =0.002),respectively.Myocardial T2 had no significant correlation with liver T2* values (r =0.556,P =0.070).T2* values of heart and liver in vivo [(32.5 ± 8.3) ms and (8.8 ± 5.4) ms],respectively had strong correlation with those in vitro [(19.4 ± 6.5) ms and (9.8 ± 5.0) ms],respectively (r =0.757,P =0.007 and r=0.861,P=0.001).T2* and R2* values of the heart and the liver in vivo and in vitro had no significant correlations with serum iron (P ＞ 0.05).On Prussian blue staining slices,blue particles of myocardium,sinus hepaticus and hepatocyte increased with injecting iron content.Conclusions It is feasible for MRI-T2* map to evaluate the myocardial iron load noninvasively.It may provide reliable information for detecting myocardial iron overload in patients with iron overload at an early stage. Key words: Magnetic resonance imaging; Myocardium; Animal experiment

History of myocardial iron loading is a strong risk factor for diabetes mellitus and hypogonadism in adults with β thalassemia major

Endocrinopathies are common complications of transfusional hemosiderosis among patients with β thalassemia major (TM). Previous studies had shown associations between some endocrinopathies and iron overload of the myocardium, liver and/or endocrine organs as assessed by MRI techniques. This retrospective analysis of 92 patients with TM (median age 36yr) from a tertiary adult thalassemia unit in UK aimed to determine independent risk factors associated with endocrinopathies among these patients. Unlike previous studies, longitudinal data on routine measurements of iron load [worst myocardial and liver T2* values since 1999, worst LIC by MRI-R2 since 2008 and average 10-yr serum ferritin (SF)] up to April 2010 together with demographic features and age of initiating chelation were analyzed for associations with endocrinopathies. The most common endocrinopathies in this cohort were hypogonadism (67%) and diabetes mellitus (DM) (41%), and these were independently associated with myocardial T2* <20ms (P<0.001 and P=0.008, respectively) and increased age (P=0.002 and P=0.016, respectively). DM and hypogonadism were independently associated with average SF >1250μg/L (P=0.003) and >2000μg/L (P=0.047), respectively. DM was also associated with initial detection of abnormal myocardial T2* at an older age (30yr vs. 24yr, P=0.039). An abnormal myocardial T2* may therefore portend the development of DM and hypogonadism in patients with TM.

T2* Imaging of the Heart

This review describes and discusses the rationale, technique, applications, and impact of cardiovascular magnetic resonance (CMR) T2* imaging, principally in the assessment of iron loading within the heart, and highlights how this robust imaging strategy has transformed disease outcome.Until recently, no simple noninvasive measurement was available to reliably indicate severe cardiac iron loading before the development of overt cardiac dysfunction or heart failure. Consequently, the majority of patients with transfusion-dependent anemias, such as β-thalassemia major, died prematurely of cardiovascular complications of severe iron overload.The magnetic properties of particulate iron disrupt magnetic field homogeneity in the CMR environment and consequently influence the CMR parameter T2*, which describes signal decay relating to both field inhomogeneity and loss of spin coherence. There is a direct relationship between T2* and myocardial iron concentration, enabling this to be used to identify and quantify myocardial iron load. Single breath-hold gradient-echo sequences in which a single midventricular short-axis myocardial slice is acquired at multiple echo times enables a myocardial T2* value to be measured from the rate of exponential decay. The application of T2* CMR to assessing cardiac iron loading is rapid, reproducible, extensively validated, and now widely performed. Data have highlighted the profound predictive power of this imaging technique and moreover its ability to inform management strategies such that, over a relatively short duration, outcome has been dramatically improved, and the disease course in β-thalassemia major transformed.

Spatial Repolarization Heterogeneity Detected by Magnetocardiography Correlates with Cardiac Iron Overload and Adverse Cardiac Events in Beta-Thalassemia Major

BackgroundPatients with transfusion-dependent beta-thalassemia major (TM) are at risk for myocardial iron overload and cardiac complications. Spatial repolarization heterogeneity is known to be elevated in patients with certain cardiac diseases, but little is known in TM patients. The purpose of this study was to evaluate spatial repolarization heterogeneity in patients with TM, and to investigate the relationships between spatial repolarization heterogeneity, cardiac iron load, and adverse cardiac events.Methods and ResultsFifty patients with TM and 55 control subjects received 64-channel magnetocardiography (MCG) to determine spatial repolarization heterogeneity, which was evaluated by a smoothness index of QTc (SI-QTc), a standard deviation of QTc (SD-QTc), and a QTc dispersion. Left ventricular function and myocardial T2* values were assessed by cardiac magnetic resonance. Patients with TM had significantly greater SI-QTc, SD-QTc, and QTc dispersion compared to the control subjects (all p values<0.001). Spatial repolarization heterogeneity was even more pronounced in patients with significant iron overload (T2*<20 ms, n = 20) compared to those with normal T2* (all p values<0.001). Loge cardiac T2* correlated with SI-QTc (r = −0.609, p<0.001), SD-QTc (r = −0.572, p<0.001), and QTc dispersion (r = −0.622, p<0.001), while all these indices had no relationship with measurements of the left ventricular geometry or function. At the time of study, 10 patients had either heart failure or arrhythmia. All 3 indices of repolarization heterogeneity were related to the presence of adverse cardiac events, with areas under the receiver operating characteristic curves (ranged between 0.79 and 0.86), similar to that of cardiac T2*.ConclusionsMultichannel MCG demonstrated that patients with TM had increased spatial repolarization heterogeneity, which is related to myocardial iron load and adverse cardiac events.

Emerging roles for cardiovascular magnetic resonance

Cardiovascular magnetic resonance (CMR) is a noninvasive imaging tool with high spatial resolution in the absence of ionising radiation. CMR imaging is routine in the functional assessment of coronary lesions and is widely held as the gold standard in myocardial viability imaging. Its unique tissue characterisation capabilities have revolutionised the assessment of the cardiomyopathies and it is the investigation of choice for cardiovascular surveillance imaging. To date its greatest success has been in the management of thalassaemia major, where the ability to detect myocardial iron loading has significantly improved patient survival. In the near future, CMR fibrosis imaging may serve as a risk stratification tool for the cardiomyopathies; and the ability to assess interstitial fibrosis may advance this role into other disease processes. Novel methods of tissue characterisation and emerging technical advances present new avenues for this modality, securing its place as the noninvasive imaging tool of the future.