Cardiac iron overload in thalassemic patients: An endomyocardial biopsy study

Secondary heart failure induced by organ siderosis is the main cause of death in patients affected by thalassemia major. At present it cannot be predicted whether heart siderosis is correlated with iron overload and little is known about the real cardiac histological pattern of post transfusional hemochromatosis in patients with thalassemia major and intermedia. The study aim was to evaluate cardiac iron overload by non invasive and invasive techniques. Fifteen thalassemic patients were investigated and endomyocardial biopsy performed in ten revealed different grades of endomyocardial iron overload with histochemical positivity. Non invasive techniques are not able to furnish an exact picture of the cardiac hemochromatosis. There was a significant correlation between serum ferritin and myocardial iron grade.Patients with elevated ferritin levels and poor compliance to chelating therapy are at high risk of severe heart hemochromatosis. It was seen that endomyocardial biopsy is a useful tool in studying myocardial iron.     

Pulmonary hypertension in non-transfusion-dependent thalassemia: Correlation with clinical parameters,liver iron concentration,and non-transferrin-bound iron

Abstract

Background

Pulmonary hypertension is a major cardiac complication in non-transfusion-dependent thalassemia (NTDT). Several clinical and laboratory parameters, including iron overload, have been shown to have a positive correlation with the incidence of pulmonary hypertension. Non-transferrin-bound iron (NTBI) is a form of free-plasma iron that is a good indicator of iron overload.

Objectives

The aim of this study was to determine the prevalence of pulmonary hypertension in patients with NTDT and to investigate its correlation with the clinical parameters, liver iron concentration (LIC) and NTBI.

Methods

Patients with NTDT were evaluated using echocardiography, and magnetic resonance imaging for cardiac T2* and LIC. Pulmonary hypertension was de?ned as peak tricuspid regurgitation velocity ≥2.9 m/s measured using trans-thoracic echocardiography. Clinical parameters and the status of iron overload as determined by LIC, serum ferritin, and NTBI level were evaluated for their association with pulmonary hypertension.

Results

Of 76 NTDT patients, mean age 23.7 ± 8.5 years, seven patients (9.2%) had pulmonary hypertension. Previous splenectomy (71.4 vs. 24.6%, P-value 0.019), higher cumulative red blood cell (RBC) transfusions (received ≥10 RBC transfusions 85.7 vs. 33.3%, P-value 0.011), higher nucleated RBCs (353 ± 287 vs. 63 ± 160/100 white blood cells, P-value <0.001), and a high NTBI level (5.7 ± 3.0 vs. 3.3 ± 2.8 µmol/l, P-value 0.034) were associated with pulmonary hypertension. There was no significant correlation between LIC or serum ferritin and pulmonary hypertension.

Conclusion

Pulmonary hypertension in NTDT is common, and is associated with splenectomy and its related factors. NTBI level shows a significant correlation with pulmonary hypertension.     

Amlodipine Reduces Cardiac Iron Overload in Patients with Thalassemia Major: A Pilot Trial

Background

Iron chelation therapy in patients with thalassemia major may not prevent iron overload in all organs, especially those in which iron enters cells through specific calcium channels. We designed a controlled pilot study to assess the potential of the calcium channel blocker amlodipine in strengthening the efficacy of iron chelation.

Methods

Fifteen patients with thalassemia major undergoing chelation therapy were randomized to receive amlodipine added to standard treatment in a 1:2 allocation for 12 months. T2* values for assessment of iron overload in the liver and heart using magnetic resonance imaging were obtained at baseline and at 6 and 12 months.

Results

In the amlodipine-treated group, heart T2* increased significantly in comparison to baseline at 6 and 12 months (21.7 ± 7.2 ms to 28.2 ± 7.9 ms and 28.3 ± 8.0 ms, with P = .007 and .03, respectively), while no differences were observed in the control group (25.1 ± 8.8 ms to 24.7 ± 7.8 ms and 26.2 ± 11.4 ms; P = .99 and 0.95, respectively); significant differences between groups were observed at 6 months (28.2 ± 7.9 ms vs 24.7 ± 7.8 ms in the control group, P = .03). A significant reduction in ferritin levels also was observed in the treated group at 12 months.

Conclusions

The use of amlodipine in conjunction with standard chelation therapy may suggest a new strategy in preventing and treating iron overload in patients with thalassemia major, especially in organs where iron absorption depends on active uptake by calcium channels like the heart.     

Myocardial iron overload assessed by magnetic resonance imaging (MRI)T2* in multi-transfused patients with thalassemia and acquired anemias

Background

Cardiac complications secondary to iron overload remain a significant matter in patients with transfusion dependent anemias.

Patients and methods

To evaluate cardiac siderosis, Magnetic resonance imaging T2* (MRI T2*) was performed in 3 cohorts of transfusion dependent patients: 99 with thalassemia major (TM), 20 with thalassemia intermedia (TI), and 10 with acquired anemias (AA). Serum ferritin was measured and all patients underwent echocardiographic evaluation.

Results

In TM patients cardiac T2* pathologic values (below 20 ms) were found in 37 patients. Serum ferritin was negatively associated with age (r = −0.32, p = 0.001) and weakly with T2* values (r = −0.19, p = 0.057). A positive correlation was found between T2* and LVEF (r = 0.27, p = 0.006). Out of 37 patients with T2* < 20 ms, 18 (48%) had serum ferritin values < 1000 ng/ml. In TI cohort, 3 patients had cardiac T2* pathologic values. In AA cohort, pathologic T2* values were found in 2 patients, who received 234 and 199 PRBC units, respectively, and were both on chelation therapy (in one patient ferritin value was 399 ng/ml). T2* values were negatively associated, but not significantly, with the number of PRBC transfused (r = −0.53, p = 0.07).

Conclusion

In our experience, 37% of TM patients had a myocardial iron overload assessed by MRI T2*; this value is higher than in TI patients. Serum ferritin measurement was a poor predictor of myocardial siderosis. In patients with AA, more than 200 PRBC units transfused were required to induce cardiac hemosiderosis, in spite of chelation therapy and, in one patient, of normal ferritin values.     

Heart failure in beta-thalassemia syndromes: a decade of progress

The thalassemias are common monogenic disorders of hemoglobin synthesis. beta-thalassemias are the most important among the thalassemia syndromes and have become a worldwide clinical problem due to an increasing immigrant population. In beta-thalassemia major, regular blood transfusions are necessary early in life. Beta-thalassemia intermedia refers to a less severe phenotype, whereas beta-thalassemia/hemoglobin E disease encompasses a broad phenotypic spectrum. Blood transfusions and increased gastrointestinal iron absorption result in iron overload and tissue damage. Among patients with beta-thalassemia major, biventricular, dilated cardiomyopathy remains the leading cause of mortality. In some patients, a restrictive type of left ventricular cardiomyopathy or pulmonary hypertension is noted. The clinical course, although variable and occasionally fulminant, is more benign in recent than in older series. Myocarditis has been described as a cause of left-sided heart failure in younger patients. Pulmonary arterial hypertension is the principal cause of heart failure in beta-thalassemia intermedia. Chelation therapy has improved prognosis in beta-thalassemia major both by reducing the incidence of heart failure and by reversing cardiomyopathy. Estimation of the patient's cardiac risk is mainly based on clinical criteria and serial echocardiography. A new cardiovascular magnetic resonance technique will probably fulfill the need for more precise risk stratification in beta-thalassemia syndromes. By increasing the proportion of patients on optimal chelation, survival in beta-thalassemia major may further improve. Recent advances in gene therapy are expected to result in the long-awaited cure of this disease.     

Tissue Doppler echocardiography reliably reflects severity of iron overload in pediatric patients with beta thalassemia.

AIMS: Tissue Doppler imaging has been recently used to evaluate ventricular function in patients with beta thalassemia. In clinical practice, serum ferritin is commonly used to assess the severity of iron overload. The aim of this study was to determine which Doppler findings correlated with serum ferritin. METHODS AND RESULTS: Thirty-one pediatric patients with transfusion-dependent beta thalassemia with normal LVFS were evaluated. Seven patients with serum ferritin <2500 ng/ mL, 13 patients with serum ferritin 2500-5000 ng/mL, and 11 patients with serum ferritin >5000 ng/mL were studied. Diastolic dysfunction was absent in all patients with serum ferritin <2500 ng/mL, and was present in all patients with serum ferritin >5000 ng/mL. Deceleration time (DT) has a significant correlation with serum ferritin (r = -0.59, p < 0.0001). Difference of pulmonary vein atrial reversal flow and mitral valve A wave duration (PVAR - MVA) and early ventricular filling velocity to early diastolic myocardial velocity ratio (E/Em) significantly correlated with serum ferritin (r = 0.49, p = 0.006; r = 0.56, p = 0.001, respectively). CONCLUSION: Decreased DT, increased PVAR-MVA duration, and increased E/Em ratio reliably reflected severe iron overload in pediatric patients with beta thalassemia. Systolic and diastolic LV function is preserved in patients who have serum ferritin <2500 ng/mL.     

Early detection of cardiac dysfunction in thalassemic patients by radionuclide angiography and heart rate variability analysis

BACKGROUND: Cardiac dysfunction remains the major cause of death in beta-thalassemia. Aim of this study was to assess early myocardial damage in thalassemic patients with no symptoms or echocardiographic evidence of dysfunction at routine monitoring. METHODS: Twenty patients (seven females; median 25 yr [first quartile 22,third quartile 28]) with beta-thalassemia underwent radionuclide angiography (RNA) at rest and during low-dose dobutamine infusion (5-10 gamma/kg/min). Right and left ventricular ejection fractions (EF) were determined by first-pass method and gated equilibrium acquisition, respectively. Twenty-four-hour Holter monitoring with time-domain heart rate variability (HRV) assessment and echocardiographic follow-up (21 months [5,27]) were performed. RESULTS: Eleven patients showed regional wall motion abnormalities at RNA; left ventricular EF, HR and diastolic measurements significantly increased after dobutamine infusion. Patients with abnormal RNA right ventricular EF (n = 8, <0.45) showed lower echocardiographic left ventricular EF at the enrollment (0.54 [0.50,0.61] vs. 0.62 [0.56,0.67], P = 0.02) than those with a normal right ventricular EF. Patients with reduced standard deviation of the averages of RR intervals in all 5-minute periods of entire recording (SDANN) (n = 6, <100 ms), a measure of HRV, had lower echocardiographic left ventricular EF (0.53 [0.49,0.62] vs. 0.62 [0.56,0.66], P = 0.03) and lower fractional shortening (0.28 [0.25,0.32] vs. 0.36 [0.30,0.39], P = 0.003) at the enrollment than those with normal SDANN. No significant association was found between RNA and HRV measurements and follow-up left ventricular function. CONCLUSIONS: Right ventricular dysfunction and abnormal HRV may represent the early features of cardiac disease in thalassemic patients with no evidence of ventricular dysfunction at routine evaluation.     

Iron overload thalassemic cardiomyopathy: Iron status assessment and mechanisms of mechanical and electrical disturbance due to iron toxicity

Patients with thalassemia major have inevitably suffered from complications of the disease, due to iron overload. Among such complications, cardiomyopathy is the leading cause of morbidity and mortality (63.6% to 71%). The major causes of death in this group of patients are congestive heart failure and fatal cardiac tachyarrhythmias leading to sudden cardiac death. The free radical-mediated pathway is the principal mechanism of iron toxicity. The consequent series of events caused by iron overload lead to catastrophic cardiac effects. The authors review the electrophysiological and molecular mechanisms, pathophysiology and correlated clinical insight of heart failure and arrhythmias in iron overload thalassemic cardiomyopathy.     

Low Serum Ferritin Levels are Misleading for Detecting Cardiac Iron Overload and Increase the Risk of Cardiomyopathy in Thalassemia Patients. The Importance of Cardiac Iron Overload Monitoring Using Magnetic Resonance Imaging T2 and T2*

The incidence of cardiomyopathy was monitored in a 6-year follow-up study involving 56 transfused thalassemia patients treated with deferoxamine (DFO), deferiprone (L1) or their combination. During this period, five female patients on regular subcutaneous or intravenous DFO presented with cardiac complications. Three patients suffered congestive heart failure and the other two arrhythmias. Four of the five patients maintained serum ferritin levels of about 1 mg/L or below and the fifth about 1.5 mg/L for several years prior to the cardiomyopathy. Cardiac magnetic resonance imaging (MRI) T2* and T2 was performed in four patients after the cardiomyopathy, identifying the presence of moderate-to-heavy siderosis. The treatment of the five patients has since changed, involving mainly the use of L1. Low serum ferritin levels appear to be misleading for detecting cardiac iron overload and this may increase the risk of cardiomyopathy. The MRI T2 and T2* relaxation time measurements are a more accurate method of detecting cardiac iron overload. Chelation therapy using L1 or appropriate L1/DFO combinations can reduce cardiac iron overload and the mortality rate in thalassemia patients.     

Assessment of liver and cardiac iron overload using MRI in patients with chronic anemias in Latin American countries: results from ASIMILA study*

ABSTRACT

Objectives: A multicenter, noninterventional, observational study was conducted in the Latin American countries including Argentina, Brazil, Colombia, Mexico, and Venezuela to assess the prevalence of liver and cardiac iron overload using magnetic resonance imaging (MRI) in patients with chronic anemias except thalassemia.

Methods: Patients aged >10 years with transfusion-dependent anemias, except thalassemia, either with <20 units of red blood cell (RBC) transfusions with serum ferritin (SF) levels >2000?ng/mL or with ≥20 units of RBC transfusions regardless of SF level in their lifetime, were enrolled. Iron overload was assessed using MRI.

Results: Among 175 patients included, the majority had sickle cell disease (SCD; 52%), followed by aplastic anemia (AA; 17.7%), myelodysplastic syndrome (MDS; 8.6%), Diamond-Blackfan anemia (DBA; 4%), pure red cell aplasia (1.1%), and others (16.6%). Liver iron overload was observed in 76.4% of patients, while cardiac iron overload was seen in 19.2% when assessed by MRI. The prevalence of iron overload was 80.2% in patients with SCD, 73.3% in MDS, 77.4% in AA, 100% in pure red cell aplasia, 71.4% in DBA, and 68.9% in other transfusion-related disorders. A moderate correlation between liver iron concentration (LIC) and SF was observed in patients with SCD and MDS (r?=?0.47 and r?=?0.61, respectively). All adverse events reported were consistent with the published data for deferasirox or underlying disease.

Conclusion: A high prevalence of iron overload in this patient population in Latin American countries indicates that a better diagnosis and management of iron overload is required in these countries.     

Impact of cardiac magnetic resonance imaging in nonischemic cardiomyopathies

Non-ischemic cardiomyopathies include a wide spectrum of disease states afflicting the heart, whether a primary process or secondary to a systemic condition. Cardiac magnetic resonance imaging(CMR) has established itself as an important imaging modality in the evaluation of non-ischemic cardiomyopathies. CMR is useful in the diagnosis of cardiomyopathy, quantification of ventricular function, establishing etiology, determining prognosis and risk stratification. Technical advances and extensive research over the last decade have resulted in the accumulation of a tremendous amount of data with regards to the utility of CMR in these cardiomyopathies. In this article, we review CMR findings of various non-ischemic cardiomyopathies and focus on current literature investigating the clinical impact of CMR on risk stratification, treatment, and prognosis.     

Long Term Comparative Studies in Thalassemia Patients Treated with Deferoxamine or a Deferoxamine/Deferiprone Combination. Identification of Effective Chelation Therapy Protocols

For the past 2–6 years, two groups of thalassemia patients, one of 16 patients on deferoxamine (DFO) monotherapy (35–80 mg/kg, 2–5 days/week) and the other group comprising 19 patients on a deferiprone (L1) and DFO combination therapy (L1 75–100 mg/kg/day and DFO 30–60 mg/kg, 1–5 days/week), have been studied and compared before and after the introduction of the combination therapy. The patients on the combination therapy were mainly those not complying or experiencing toxicity with DFO. The effects of chelation therapy on iron load was monitored using regular serum ferritin measurements and also magnetic resonance imaging (MRI) T2* relaxation time measurements at the end of the study. In both groups, cardiac MRI T2* levels were within the normal range (>19 ms) in more than 75% of the patients. There was a substantial improvement in serum ferritin levels and normalization of the MRI T2* levels of the liver in many cases treated with the combination therapy at effective doses by comparison to the DFO group, where the serum ferritin and MRI T2* levels were largely unchanged. It would appear that the major overall determining factor in the rapid clearance of excess iron in thalassemia patients and the maintenance of normal iron stores is the selection and implementation of effective chelation dose protocols. The International Committee on Chelation (ICOC) combination protocol L1 (80–110 mg/kg/day)/DFO (40–60 mg/kg at least 3 days per week) and to a lesser extent, DFO monotherapy at about 50 mg/kg/day, 5 days/week, appears to achieve this goal.     

MRI用于肝多房棘球蚴病铁沉积评估的初步研究

目的　探索MRI联合血清铁蛋白用于肝多房棘球蚴病患者肝脏铁沉积评估的效果。方法　对96例肝多房棘球蚴病确诊患者和30例健康志愿者行常规1.5T 磁共振扫描,并采集相关实验室检查资料,分析肝脏/肌肉信号强度比、血清铁蛋白水平、肝功能指标及其相关性等。结果　肝多房棘球蚴病患者与健康志愿者肝脏/肌肉信号强度比分别为（1.95 ± 0.57）和（2.22 ± 0.28）,差异有统计学意义（t = 2.022,P < 0.05）,且肝多房棘球蚴病患者肝脏/肌肉信号强度比与血清铁蛋白水平呈中度负相关( rs = –0.446,P < 0.01)。 结论　肝多房棘球蚴病患者肝脏内多存在异常铁沉积,而血清铁蛋白检测可辅助判断肝多房棘球蚴病患者肝脏内异常铁沉积。MRI测量的肝脏/肌肉信号强度比可作为无创性评估肝多房棘球蚴病患者肝脏铁沉积的一种方法。     

Pro-oxidative/antioxidative imbalance: a key indicator of adverse outcome in hematopoietic stem cell transplantation

Introduction: Pretransplantation iron overload (IO) is considered as a predictor of adverse outcome in hematopoietic stem cell transplantation (HSCT). Peroxidative tissue injury caused by IO leads to progressive organ dysfunction. Methods: This is a retro‐prospective study which explores the possible relationship between IO, oxidative stress and transplant outcome. Serum samples of 149 consecutive HSCT candidates were subjected to analysis of iron parameters, including nontransferrin bound iron (NTBI) and pro‐oxidant/antioxidant status. Results: Serum ferritin was found to be positively correlated with NTBI and negatively correlated with glutathione peroxidase (GPx) and superoxide dismutase (SOD). An inverse correlation of NTBI with SOD, total antioxidant potential (TAP) and malonyldialdehide (MDA) was also demonstrated. An adverse impact of serum ferritin level on early posttransplant complications including pulmonary toxicity, fungal infections and sinusoidal obstruction syndrome (SOS) was shown. A significant impact of NTBI on +30 day (P = 0.027) and +100 day survival (P = 0.028) was shown in auto‐transplanted patients. MDA levels had a significant impact on +30 day and +100 day survival in autologous (P = 0.047; P = 0.026) and allogeneic (P = 0.053; P = 0.059) groups. GPx (P = 0.016) and MDA (P = 0.021) were identified as independent prognostic parameters for overall survival in allo‐transplanted patients. Conclusion: Pretransplantation IO might be a major contributor to adverse outcome in HSCT recipients through an impaired pro‐oxidative/antioxidative homeostasis. The reversible nature of IO and oxidative stress suggests that early preventive strategies might have a potential to improve transplant outcome.     

Magnetic Resonance Imaging Assessment of Excess Iron in Thalassemia,Sickle Cell Disease and Other Iron Overload Diseases

Patients with transfusion-dependent anemia develop cardiac and endocrine toxicity from iron overload. Classically, serum ferritin and liver biopsy have been used to monitor patient response to chelation therapy. Recently, magnetic resonance imaging (MRI) has proven effective in detecting and quantifying iron in the heart and liver. Tissue iron is paramagnetic and increases the MRI relaxation rates R2 and R2* in a quantifiable manner. This review outlines the principles and validation of non invasive iron estimation by MRI, as well as discussing some of the technical considerations necessary for accurate measurements. Specifically, the use of R2 or R2* methods, choice of echo times, appropriate model for data fitting, the use of a pixel-wise or region-based measurement, and the choice of field strength are discussed.     

Standardized T2* Map of a Normal Human Heart to Correct T2* Segmental Artefacts; Myocardial Iron Overload and Fibrosis in Thalassemia Intermedia Versus Thalassemia Major Patients and Electrocardiogram Changes in Thalassemia Major Patients

Studies of the standardized, 3D, 16-segments map of the circumferential distribution of T2* values, of cardiovascular magnetic resonance (CMR) in thalassemia major (TM) and thalassemia intermedia (TI) patients and of electrocardiogram (ECG) changes associated with TM, have been carried out. Similarly, the segment-dependent correction map of the T2* values and the artifactual variations in normal subjects and the T2* correction map to correct segmental measurements in patients with different levels of myocardial iron burden have been evaluated.

Cardiovascular magnetic resonance can be a suitable guide to cardiac management in TI, as well as in TM; TI patients show lower myocardial iron burden and more pronounced high cardiac output findings than TM patients. Moreover, it is proposed that, due to its good positive predictive value (PPV) and low cost, ECG can be a suitable guide to orient towards CMR examination in TM cases.     

Myocyte Damage and Loss of Myofibers is the Potential Mechanism of Iron Overload Toxicity in Congestive Cardiac Failure in Thalassemia. Complete Reversal of the Cardiomyopathy and Normalization of Iron Load by Deferiprone

Cardiac damage caused by iron overload toxicity is the main cause of death in thalassemia patients. Biopsy samples of poorly chelated thalassemia patients who suffered congestive cardiac failure (CCF) show extensive iron deposition in the myocardium. In one patient who survived CCF, a cardiac biopsy was performed during the removal of a thrombus caused by a port-a-cath, which was used for the administration of intravenous (iv) deferoxamine (DFO). Ultrastructural pathology studies of the cardiac biopsy indicated extensive iron deposition in myocytes with accumulation of iron mainly in lysosomes, leading in some cases to their disruption. Damage to other intracellular components of the myocytes and loss of myofibers was also observed. The patient became intolerant to iv and subcutaneous (sc) DFO 2 years after the CCF, and was then treated with deferiprone (L1) for 7 years. Within 1 year of L1 treatment at 75–80 mg/kg/day, serum ferritin levels were reduced to <0.45 mg/L and she became asymptomatic, needing no further drugs for her cardiomyopathy. Lowering the L1 dose to 50–70 mg/kg/day caused an increase in serum ferritin levels. Maintenance of normal iron stores during the last 3 years as detected by cardiac and liver magnetic resonance imaging (MRI) T2 and T2* and normalization of serum ferritin levels (<0.15 mg/L) was observed following L1 therapy at 80–85 mg/kg/day. Deferiprone (>80 mg/kg/day) appears to be effective in the rapid clearance of cardiac iron, in the reversal of iron overload related cardiomyopathy, in the maintenance of normal iron stores and the overall long-term survival of thalassemia patients.     

Advances in treatment of ulcerative colitis with herbs: From bench to bedside

Ulcerative colitis (UC), an idiopathic inflammatory disorder in the colon, has become a clinical challenge, owing to the increasing incidence and poor prognosis. The conventional treatments for UC including aminosalicylates, corticosteroids, and immunosuppressants, induce remission in only half of patients. Meanwhile, the treatments often come with serious side effects which can be life-threatening. Herbal medicine, one of the most common traditional Chinese medicine modalities, has been introduced for centuries into clinical treatment of many human diseases such as infections and functional disorders. Recently, the potential effectiveness of herbs has been suggested as the treatment of UC, as shown by a variety of clinical trials and experimental studies. The herbs reported in the literature include aloe vera gel, butyrate, tormentil extracts, wheat grass juice, and curcumin. In the review, bioactivity of the herbs and their involvement in UC treatment are discussed.