Cardiac Iron Overload – Role of Cardiac Magnetic Resonance Imaging (MRI)

 

 

Article By

 

Alpa Bharati

 

Abstract

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[1].  Almost 10% of the world’s total thalassemics are born in India every year[2].

 

Introduction

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.

 

Pathophysiology

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[6]. 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%[7].

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[8]. It can help in monitoring and altering treatment options which would lead to improved life span.

 

Conclusion

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.

TC- Apr 2016 - 021 - Writers Art pg 34

 

References:

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  3. Online Mendelian Inheritance in Man (OMIM) Hemoglobin – Alpha locus 1; HBA1- 141800
  4. Online Mendelian Inheritance in Man (OMIM) Hemoglobin – Alpha locus 2; HBA2 – 141850
  5. Online Mendelian Inheritance in Man (OMIM) Hemoglobin – Beta Locus HBB -141900
  6. Mavrogeni S, Markussis  V, Kaklamanis L, et al. A comparison  of magnetic resonance  and cardiac biopsy in the evaluation of heart iron in patients with b-Thalassemia. Eur J Hematol 2005;75:241-7
  7. Kirk P, Roughton M, Porter JB et al. Cardiac T2* magnetic resonance  for  prediction  of cardiac complications in thalassemia major. Circulation 2009 Nov 17;120(20):1961-8
  8. Mark A Tanner, Renzo Galanello, Carlo Dessi et al. Combined chelation therapy in thalassemia major for the  treatment  of severe myocardial siderosis with left ventricular dysfunction. J Cardiovasc Magn Reson 2008 10:12