Cardiac Iron Overload – Role of Cardiac Magnetic Resonance Imaging (MRI)
Hemoglobinopathies are a major health concern in India with beta thalassemia being the most significant. Beta thalassemia (B-thalassemia) is the most common single-gene disorder in the Indian population. Almost 10% of the world’s total thalassemics are born in India every year.
Thalassemia is an inherited autosomal recessive disorder resulting in abnormality of adult haemoglobin (HbA). This results in poor oxygen carrying capacity of haemoglobin and reduced life of circulating red blood cells. These patients thus develop severe anaemia. B-thalassemia presents as major, intermediate or minor variants. B-thalassemia major results in severe anaemia and patients are usually symptomatic within the first two years of life. These patients present with extreme fatigue, failure to thrive, poor muscle growth, jaundice, hepatosplenomegaly and skeletal abnormalities due to expanding bone marrow. Patients with Beta thalassemia major need repeated blood transfusions for life usually starting from the first one or two years of age. There is an increase in the red blood cell (RBC) turnover due to the severe anaemia prompting the marrow to increase the RBC generation and due to rapid RBC loss due to defective haemoglobin. Regular, almost monthly, blood transfusions are needed to counter the anaemia in most thalassemia major cases. This results in accumulation of iron from the dying RBCs which accumulates in all body tissues, notably, the liver, spleen, heart and endocrine glands. Cardiac failure, rhythm disturbances and sudden cardiac death are some of the common causes of mortality resulting from cardiac iron deposition.
Cardiac MRI is a simple non-invasive method of detecting the iron content of liver and heart and thus guides in decision making for initiation of chelation therapy to prevent serious complication such as cardiac failure and death.
Adult haemoglobin comprises of four protein chains, two alpha globin and two beta globin chains. Thalassemia is classified as alpha or beta depending on which globin chain is affected. In alpha thalassemia, there is an abnormality in production of the alpha chains and in beta thalassemia there is an abnormality of the beta chains. The production of alpha globin is related to HbA1 and HbA2 genes on chromosome 16 and beta globin is encoded by a single HBB gene on chromosome 11[3-5]. B-thalassemia is further characterised as major when no beta chains are produced, intermediate when some beta globin is produced and minor (or trait) where the production is least compromised and patients may be just a silent carrier. Patients with beta thalassemia major need repeated, often monthly, blood transfusion usually from the first or second year of life. The chronic anaemia due to poor oxygen carrying capacity of the abnormal haemoglobin and reduced life span of the RBCs induces increased production of RBCs from the bone marrow. The bone marrow expands to produce higher amounts of red cells to counter the anaemia and the spleen enlarges as it removes the defective RBCs. To sustain life, repeated blood transfusions are needed. These repeated transfusions as well as increased turnover of the RBCs induced by the disease itself leads to iron accumulation in the body tissues, notably in the liver, spleen and endocrine glands. One of the major complications of this iron overload is cardiac iron deposition which can result in cardiac failure, rhythm disturbances and sudden cardiac death.
Iron deposited in the myocardium and liver is graded as mild, moderate or severe. Extent of iron in the tissues is measured as a T2* value in milliseconds (msec) which is correlated to actual tissue iron content in milligram of iron per gram of the tissue. In the presence of iron overload, chelation therapy is initiated to reduce the tissue iron content. Chelation therapy with its side-effects needs careful monitoring. The decision to start chelation also needs to be weighed by assessing the benefits of chelation to the risk of the therapy itself. Identifying cardiac iron overload by T2* imaging gives a definitive guidance in identifying patients at risk of serious iron overload and for follow up in those who have undergone chelation.
Calculating cardiac iron deposition by MRI
A non-contrast cardiac MRI (CMRI) is performed with ECG gating. Cine images are acquired for assessment of ventricular function followed by T2* imaging. The latter is done at the mid-part of the interventricular septum. T2* imaging calculates the signal from the myocardium by calculating the rate of myocardial signal loss with increasing the echo time. Multiple (usually 8 -12) images are acquired at the same level with increasing the echo times from approximately 2.5 msec to 15 msec. The signal obtained from the interventricular septum is calculated by placing a region of interest (ROI). This ROI is propagated through all the images obtained at the same level but having different echo times. The signal from the myocardium for each echo time is obtained and a graph is plotted depicting the myocardial signal versus the echo times and the rate of loss of signal is deduced. This rate is significantly increased with deposition of iron which is a strong ferromagnetic substance. The rate of loss of signal therefore corresponds to the amount of myocardial iron content. Correlation of myocardial T2 values with biopsy specimens of the myocardium was done by Mavrogeni et al. This shows that CMRI can non-invasively estimate the cardiac iron content. A formula for conversion of T2* value in milliseconds to actual iron content in milligram of iron per gram of tissue has been developed based on these studies on both 1.5 Tesla and 3 Tesla MRI scanners. CMRI can also accurately calculate the ventricular function in the same setting. This provides a huge advantage for patients who can now be evaluated non-invasively for iron overload, a condition that was only quantifiable earlier by biopsy. A regular follow up by CMRI every year of all patients on repeated blood transfusion and increased RBC turnover would reduce mortality in these patients.
In a multicentre study by Kirk et al, cardiac T2* value of < 20msec was associated with arrhythmia and cardiac T2* value of < 10msec on 1.5 Tesla MRI was a strong predictor of heart failure with sensitivity of 97% and specificity of 85%.
Regular screening of all patients on chronic blood transfusion is a vital tool for predicting serious cardiac complications. Tanner et al concluded that alterations in chelation therapy to clear the myocardial iron must be guided by repeated myocardial T2* scans. It can help in monitoring and altering treatment options which would lead to improved life span.
CMRI is a must in patients with chronic blood transfusion and has the potential of reducing instances of sudden cardiac arrest and improve outcomes. It is a simple non-invasive technique and can be used more frequently but greater awareness and increasing the availability of the scanning hardware and software is needed for the same.
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- Online Mendelian Inheritance in Man (OMIM) Hemoglobin – Alpha locus 1; HBA1- 141800
- Online Mendelian Inheritance in Man (OMIM) Hemoglobin – Alpha locus 2; HBA2 – 141850
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