Diagnostic Backgrounder

Diagnostic Backgrounder
CARDIAC MRI Diagnostic Backgrounder NOTE: These slides are for use in educational oral presentations only. If any published figures/tables from these slides are to be used for another purpose (e.g. in printed materials), it is the individual’s responsibility to apply for the relevant permission. Specific local use requires local approval

Outline Introduction to iron overload Assessing cardiac iron loading
echocardiography cardiac MRI Cardiac MRI in practice preparation of the patient acquisition of the image analysis of the data Excel spreadsheet ThalassaemiaTools (CMRtools) cmr42 FerriScan MRmap MATLAB Summary MRI = magnetic resonance imaging.

Introduction to iron overload

Introduction to iron overload
Iron overload is common in patients who require intermittent or regular blood transfusions to treat anaemia and associated conditions it may be exacerbated in some conditions by excess gastrointestinal absorption of iron Iron overload can lead to considerable morbidity and mortality1 Excess iron is deposited in major organs, resulting in organ damage the organs that are at risk of damage due to iron overload include the liver, heart, pancreas, thyroid, pituitary gland, and other endocrine organs2,3 1Ladis V, et al. Ann NY Acad Sci. 2005;1054: Gabutti V, Piga A. Acta Haematol. 1996;95: Olivieri NF. N Engl J Med. 1999;341:

Importance of analysing cardiac iron
In β-thalassaemia major, cardiac failure and arrhythmia are risk factors for mortality1 signs of myocardial damage due to iron overload: arrhythmia, cardiomegaly, heart failure, and pericarditis2 heart failure has been a major cause of death in β-thalassaemia patients in the past (50–70%)1,3 In MDS, the results of studies are less comprehensible the reported proportion of MDS patients with cardiac iron overload is inconsistent; from high to only a small proportion of MDS patients4–7 cardiac iron overload occurs later than does liver iron overload4,7,8 however, cardiac iron overload can have serious clinical consequences in MDS patients 1Borgna-Pignatti C, et al. Haematologica. 2004;89: Gabutti V, Piga A. Acta Haematol. 1996;95: Modell B, et al. Lancet. 2000;355: Jensen PD, et al. Blood. 2003;101: 5Chacko J, et al. Br J Haematol. 2007;138: Konen E, et al. Am J Hematol. 2007;82: 7Di Tucci AA, et al. Haematologica. 2008;93: Buja LM, Roberts WC. Am J Med. 1971;51:

Importance of analysing cardiac iron (cont.)
In 2010, the overall mortality rate of β-thalassaemia major patients in the UK was substantially lower than a decade ago (1.65 vs 4.3 per 1,000 patient years)1,2 due to improved monitoring and management of iron overload over the last decade, 77% of patients have normal cardiac T2*1 cardiac iron overload is no longer the leading cause of death in this population1 60 17 23 7 10 20 30 40 50 70 Baseline Latest follow-up Patients (%) p < 0.001 p < 0.001 cT2* ≤ 20 ms cT2* < 10 ms cT2* = cardiac T2*. 1Thomas AS, et al. Blood. 2010;116:[abstract 1011]. 2Modell B, et al. Lancet. 2000;355:

Cardiac T2*: Overview of correlations with other measurements
Transfusion duration† ↑1 Ventricular dysfunction ↑1-3 Arrhythmia and heart failure ↑4 T2*↓ Need for cardiac medication↑1-2 APFR↓ EPFR:APFR↑5 SF and LIC1-3 Weak or no correlation †For thalassaemia, but not sickle cell. APFR = atrial peak filling rate; EPFR = early peak filling rate; LIC = liver iron concentration; SF = serum ferritin. 1Wood JC, et al. Blood. 2004;103: Anderson LJ, et al. Eur Heart J. 2001;22: Tanner MA, et al. J Cardiovasc Magn Reson. 2006;8: Kirk P, et al. Circulation. 2009;120: 5Westwood MA, et al. J Magn Reson Imaging. 2005;22:

Cardiac T2*: Relationship with LVEF
90 Normal T2* range 80 Normal LVEF range 70 60 Cardiac T2* value of 37 ms in a normal heart 50 LVEF (%) 40 30 20 10 Cardiac T2* value of 4 ms in a significantly iron-overloaded heart 10 20 30 40 50 60 70 80 90 100 Cardiac T2* (ms) Myocardial T2* values < 20 ms are associated with a progressive and significant decline in LVEF LVEF = left-ventricular ejection fraction. Anderson LJ, et al. Eur Heart J. 2001;22:

Cardiac T2*: Relationship with cardiac failure and arrhythmia
0.6 < 6 ms 0.15 0.10 0.05 0.20 0.25 0.30 0.5 < 10 ms 0.4 6–8 ms Proportion of patients developing cardiac failure Proportion of patients with arrhythmia 0.3 0.2 8–10 ms 10–20 ms 0.1 > 20 ms > 10 ms 60 120 180 240 300 360 60 120 180 240 300 360 Follow-up time (days) Follow-up time (days) T2* < 10 ms: relative risk 159 (p < 0.001) T2* < 6 ms: relative risk 268 (p < 0.001) T2* < 20 ms: relative risk 4.6 (p < 0.001) T2* < 6 ms: relative risk 8.65 (p < 0.001) Low myocardial T2* predicts a high risk of developing cardiac failure and arrhythmia Kirk P, et al. Circulation. 2009;120:

Assessing cardiac iron overload

Assessing cardiac iron loading: Agenda
Echocardiography Cardiac MRI advantages and disadvantages of cardiac MRI MRI: a non-invasive diagnostic tool T2* is the standard method for analysing cardiac iron

Echocardiography

Assessing cardiac iron loading: Echocardiography
Pros Cons Readily available1 Relatively inexpensive1 Does not detect early damage2 Echocardiographic diastolic function parameters correlate poorly with LVEF and T2*1 Cannot directly or indirectly quantify cardiac iron levels EF = ejection fraction. 1Leonardi B, et al. JACC Cardiovasc Imaging. 2008;1: Hoffbrand AV. Eur Heart J. 2001;22:

Cardiac MRI

MRI: A non-invasive diagnostic tool
Indirectly measures levels of iron in the heart MRI measures longitudinal (T1) and transverse (T2) relaxation times of the protons iron deposition disrupts the homogeneous magnetic field and shortens T1 and T2 times in a concentration-dependent manner Protons Magnetic field RF/spin echo/gradient echo Iron Echo signal → T1, T2 Signal processing RF = radio-frequency. 1Wood JC, Ghugre N. Hemoglobin. 2008;32: Wood JC, et al. Circulation. 2005;112: 3Wang ZJ, et al. Radiology. 2005;234: Ghugre NR, et al. Magn Reson Med. 2006;56:681-6.

MRI: A non-invasive diagnostic tool (cont.)
Protons If a spin-echo sequence is used, the relaxation time is T2 If a gradient-echo sequence is used, it is T2* Cardiac MRI methods gradient-echo T2* MRI: most used in clinical practice spin-echo T2 MRI: less useful (motion artefacts common due to characteristics of the heart) Magnetic field Most used in clinical practice: Gradient echo Spin echo Image acquired at different TEs Image acquired at different TEs Excel or software Excel or software If a spin-echo sequence is used, the relaxation time is T2 If a gradient-echo sequence is used, it is T2* T2* [ms} T2* [ms} R2* [Hz]= 1,000/T2* R2* [Hz]= 1,000/T2* TE = echo time. Adapted from Wood JC, Ghugre N. Hemoglobin. 2008;32:85-96.

Assessing cardiac iron loading: Cardiac MRI
Advantages of MRI Disadvantages of MRI Non- invasive Rapidly assesses iron content in the septum of the heart Relative iron burden can be reproducibly estimated Functional parameters can be examined concurrently (e.g. LVEF) Iron status of liver and heart can be assessed in parallel Allows longitudinal follow-up Good correlation with morbidity and mortality outcomes Indirect measurement of cardiac iron Requires MRI imager with dedicated imaging method Relatively expensive and varied availability .

FAQ: Cardiac MRI What are sequences?
Sequences are a set of radio-frequency and gradient pulses (slight tilts in the magnetization curves of the scanner) generated repeatedly during the scan, which produce echoes with varied amplitudes and shapes that will define the MR image What is gradient echo? A gradient-echo sequence is obtained after 2 gradient impulses are applied to the body, resulting in a signal echo that is read by the coils. In these sequences, the spins are not refocused and, therefore, are subject to local inhomogeneities, with a more rapid decay curve. For gradient-echo pulse sequences, the T2* relaxation times (which reflect these inhomogeneities) on the signal are more significant 1Image from Ridgway JP. J Cardiovasc Magn Reson. 2010;12:71.

Gradient relaxometry (T2. , R2
Gradient relaxometry (T2*, R2*) is the method for analysing cardiac iron levels T2* (gradient echo) T2 (spin echo) Pros Greater sensitivity to iron deposition2 Shorter acquisition time1 Less affected by motion artefacts3 More readily available3 Easier to perform4 Good reproducibility5 Less affected by susceptibility artefacts1, due to metal implants, air–tissue interfaces, proximity to cardiac veins Cons More sensitive to static magnetic field inhomogeneity1 Noise, motion, and blood artefacts can complicate analysis (particularly in heavily iron-loaded hearts)7 Lack of sensitivity6 Motion artefacts6 Poor signal-to-background noise ratios at longer TEs6 Longer acquisition time1 1Guo H, et al. J Magn Reson Imaging. 2009;30: Anderson LJ, et al. Eur Heart J. 2001;22: Wood JC, Noetzli L. Ann N Y Acad Sci. 2010;1202: Wood JC, Ghugre N. Hemoglobin. 2008;32: Westwood M, et al. J Magn Reson Imaging. 2003;18:33-9. 6Hoffbrand AV. Eur Heart J. 2001;22: He T, et al. Magn Reson Med. 2008;60:

Gradient relaxometry (T2. , R2
Gradient relaxometry (T2*, R2*) can conveniently measure cardiac and liver iron Cardiac MRI Liver MRI 30 2 4 6 8 10 12 14 Hankins, et al. 25 20 Wood, et al. HIC (mg Fe/g of dry weight liver) 15 [Fe] (mg/g dry wt) 10 Anderson, et al. R2 = 5 100 200 300 400 200 400 600 800 1000 Cardiac R2* (Hz) Liver R2* (Hz) Cardiac and liver iron can be assessed together conveniently by gradient echo during the a single MRI measurement. HIC = hepatic iron concentration Carpenter JP, et al. J Cardiovasc Magn Reson. 2009;11 Suppl 1:P224. Hankins et al Blood. 2009;113:

Cardiac T2* MRI is usually measured in the septum of the heart
Heart with normal iron levels T2* = 22.8 ms or R2* = 43.9 Hz Heart with severe iron overload T2* = 5.2 ms or R2* = 192 Hz Images courtesy of Dr J. de Lara Fernandes.

What is R2*? Conversion from T2* to R2* is a simple mathematical calculation: R2* = 1,000/T2* Level of cardiac iron overload T2*, ms R2*, Hz Normal  201 < 50 Mild, moderate 10–201 50–100 Severe < 102 > 100 These values are only applicable to 1.5 T scanners1 1Anderson LJ, et al. Eur Heart J. 2001;22: Kirk P, et al. Circulation. 2009;120:

Why should the data be presented as R2* and not T2*?
Seven whole hearts from patients with transfusion-dependent anaemias were assessed by histology and cardiac MRI 2 4 6 8 10 12 14 2 4 6 8 10 12 14 [Fe] (mg/g dry wt) [Fe] (mg/g dry wt) R2 = 0.949 R2 = 10 20 30 40 50 60 70 100 200 300 400 Cardiac T2* (ms) Cardiac R2* (Hz) R2* has a linear relationship with tissue iron concentration, which simplifies the interpretation of data and allows comparison of changes over time Carpenter JP, et al. J Cardiovasc Magn Reson. 2009;11 Suppl 1:P224.

Why should the data be presented as R2* and not T2*? (cont.)
The relationship between cardiac T2*/R2* and LVEF Hockey stick effect? Or a more gradual relationship? 100 80 60 40 20 90 80 70 60 50 LVEF (%) LVEF (%) 40 30 20 10 10 20 30 40 50 60 70 80 90 100 50 100 150 200 250 Heart T2* (ms) R2* (s–1) R2* allows demonstration of cardiac risk in a more gradual way Anderson LJ, et al. Eur Heart J. 2001;22:

Why should the data be presented as R2* and not T2*? (cont.)
Standard errors on a single measurement are approximately constant with R2*, but are non-uniform with T2* Transform to R2* 60 120 50 100 40 80 T2* first measurement (ms) 30 R2* first measurement (s–1) 60 20 40 10 20 10 20 30 40 50 60 20 40 60 80 100 120 T2* second measurement (ms) R2* second measurement (s–1) R2* has a constant standard error that makes assessment of the significance of changes easier Westwood M, et al. J Magn Reson Imaging. 2003;18:33-9.

Cardiac T2* MRI in practice

MRI scanners Manufacturers
Siemens Healthcare (Erlangen, Germany; GE Healthcare (Milwaukee, WI, USA; Philips Healthcare (Best, the Netherlands; Magnetic field T2* varies with magnetic field strength1 need 1.5 T for cutoff levels of 20 ms (iron overload) and 10 ms (severe iron overload)1,2 Cardiac package needs to be acquired separately from the manufacturers. The cost is about USD 40,000. However, in most centres, this is available since MRI is frequently used in non-iron-related cardiovascular imaging includes all necessary for acquisition of the image sequences are included in Siemens and Philips Healthcare cardiac packages, but for GE Healthcare they need to be acquired separately (note: variations may exist between countries) 1Anderson LJ, et al. Eur Heart J. 2001;22: Kirk P, et al. Circulation. 2009;120:

Cardiac T2* MRI in practice: The process
3. Analysis of MRI data (time depends on experience*) 1. Patient preparation (5 min) 2. Acquisition of the MRI image (approx min) Doctor with patient at the MRI scanner, Stock photo, File #: Man in Scanner, Stock photo , File #: T2*, R2* *Time to manually calculate T2*/R2* values in an Excel spreadsheet depends on the experience of the physician.

Cardiac T2* MRI in practice: The process (cont.)
Preparation of the patient Acquisition of the image Analysis of the data (post-processing) Excel spreadsheet ThalassaemiaTools, CMRtools cmr42 FerriScan MRmap MATLAB

Preparation of the patient

Preparation of the patient
Standard precautions need to be taken There is no need for peripheral vein access since no contrast agent is required Special care remove all infusion/medication pumps (e.g. with insulin, pain-relieving drugs) stop continuous i.v. application of ICT during the measurement ECG signal should be positioned according to scanner specifications ECG = electrocardiography.

Acquisition of the image

Acquisition of the image: MRI pulse sequences
are a preselected set of defined radio-frequency and gradient pulses are computer programs that control all hardware aspects of the scan determine the order, spacing, and type of radio-frequency pulses that produce magnetic resonance images according to changes in the gradients of the magnetic field Several different pulse sequences exist1 a gradient-echo sequence generates T2* 1Wood JC, Ghugre N. Hemoglobin. 2008;32:85-96.

The most common commercially available T2* acquisition techniques
Sequence Group Number of echoes per breath-hold Heart regions Pre-pulse RR intervals TR Bright blood (Anderson et al.)1 London (Pennell) 1 (but multiple breath-holds) 1 (septum) No 1 Variable Novel bright blood (Westwood et al)2 Multiple Fixed Black blood (He et al)3-4 Yes 2 Multi-slice (Pepe et al)5 Pisa (Pepe) Multi-region The various techniques give clinically comparable results.2-3, 5 1Anderson LJ, et al. Eur Heart J. 2001;22: Westwood M, et al. J Magn Reson Imaging. 2003;18: He T, et al. J Magn Reson Imaging. 2007;25: He T, et al. Magn Reson Med. 2008;60: Pepe A, et al. J Magn Reson Imaging. 2006;23:662-8.

Acquisition of the image: TEs
Images are taken at a minimum of 5 different TEs, normally 8‒121 The choice of minimum TE determines the smallest measurable T21 ideally, min TE  2 ms, max TE 17‒20 ms Different T2* acquisition techniques according to TE multiple breath-hold: acquire an image for each TE in separate breath-holds2 single breath-hold multi-echo acquisition: acquire images for all TE during 1 breath-hold3 Mean R2* compared with true value in the case of synthetic images for different minimum TEs, but same echo duration (18 ms)4 500 450 400 350 300 250 200 150 100 50 True R2* (Hz) Mean R2*: ramp, dualtone, & uniform (Hz) Shortest TE = 2 ms Shortest TE = 1 ms Shortest TE = 4 ms Shortest TE = 5.5 ms True 1Wood JC, Noetzli L. Ann N Y Acad Sci. 2010;1202: Anderson LJ, et al. Eur Heart J. 2001;22: Westwood M, et al. J Magn Reson Imaging. 2003;18: Ghugre NR, et al. J Magn Reson Imaging. 2006;23:9-16.

How does the MRI data output looks like?
Data visualization Frame TE (ms) Mean ST 1.9 89.5 1 3.6 83.6 2 5.3 76.8 3 7.0 70.6 4 8.7 64.5 5 10.4 59.2 6 12.2 54.9 7 13.9 50.2 8 15.6 45.8 9 17.3 42.4 During a single breath hold the pulse sequence run several times at increasing echo time (TE), generating data points corresponding to decreased signal intensity1 1Wood JC, Ghugre N. Hemoglobin. 2008;32:85-96.

FAQ: Acquisition technique
Which is recommended: single or multiple breath-hold technique? Comparison of the 2 methods, single and multiple breath-hold, showed no significant skewing between T2* values in all patients with -thalassaemia major, regardless of their T2* value (see Bland-Altman plots)1 However, in cardiac MRI the most recommended technique is single breath-hold, because it allows quick acquisition of the information. This is especially important to avoid movement artefacts (heart beating, breathing) and assure the good quality of the MRI image Patients with T2* < 20 ms1 Patients with T2*  20 ms 1 1Westwood M, et al. J Magn Reson Imaging. 2003;18:33-9.

Acquisition of the image
Single breath-hold multi-echo acquisition take a short-axis slice of the ventricle (halfway between the base and the apex): orange line image acquisition should occur immediately after the R wave do not alter any settings that could alter TE (e.g. FOV) Image courtesy of Dr J. de Lara Fernandes.

Analysis of the data (post-processing)

How T2* is calculated from the MRI output?
Data visualization Curve Fitting T2* Noise level T2* calculation is fitting a curve on the data points and calculating at what echo time no signal is left from iron (only noise)1 1Wood JC, Ghugre N. Hemoglobin. 2008;32:85-96.

Analysis of the data The data can be analysed manually or using post-processing software Manually Post-processing software Excel spreadsheet ThalassaemiaTools (CMRtools) cmr42 FerriScan MRmap MATLAB

Analysis of the data (cont.)
Method Pros Cons Excel spreadsheet Low cost Time-consuming Tedious ThalassaemiaTools (CMRtools)1 Fast (1 min)2 Easy to use FDA approved GBP 3,000 per year cmr42(3) FDA approved3 Can generate T2*/R2* and T2/R2 maps with same software Allows different forms of analysis Generates pixel-wise fitting with colour maps 40,000 USD first year costs 12,000 USD per year after FDA = Food and Drug Administration. 1www.cmrtools.com/cmrweb/ThalassaemiaToolsIntroduction.htm. Accessed Dec Pennell DJ. JACC Cardiovasc Imaging. 2008;1: www.circlecvi.com. Accessed Dec 2010.

Analysis of the data (cont.)
Method Pros Cons FerriScan1 Centralized analysis of locally acquired data (206 active sites across 25 countries) Easy set-up on most MRI machines EU approved Validated on GE, Philips, and Siemens scanners USD 100 per scan Patients data are sent to reference centre MRmap2 Uses IDL runtime, which is a commercial software (less expensive than cmr42/CMRtools) Can quantify T1 and T2 map with the same software Purely a research tool Not intended for diagnostic or clinical use MATLAB3 Low cost Available only locally Physicists or engineers need to write a MATLAB program for display and T2* measurement 1www.resonancehealth.com/resonance/ferriscan. Accessed Dec www.cmr-berlin.org/forschung/ mrmapengl/index.html. Accessed Dec Wood JC, Noetzli L. Ann N Y Acad Sci. 2010;1202:173-9.

FAQ: Mistakes in analysing the data
What are the most common mistakes in analysing the data that could lead to a wrong interpretation of the T2* value? Interpreting the data from cardiac MRI is usually quite straightforward; problems may arise when analysing data from patients with severe cardiac iron overload. In this case, the signal from heavily iron-loaded muscle will decay quickly and a single exponential decay curve does not fit the data well.1 Models exist that can help to solve this issue (see next slide): the offset model (Prof Wood and colleagues) truncation of the data (Prof Pennell and colleagues) Both models should give comparable results; the differences should not be clinically relevant Signal decay curve from a patient with T2* ≈ 5 ms, showing that the data do not fit well2 1Wood JC, Noetzli L. Ann N Y Acad Sci. 2010;1202: Ghugre NR, et al. J Magn Reson Imaging. 2006;23:9-16.

FAQ: Mistakes in analysing the data (cont.)
What is truncation? After the selection of the ROI, the signal decay can be fitted using different models. In the truncation model, the late points in the curve that form a plateau are subjectively discarded; the objective is to have a curve with an R2 > A new single exponential curve is made by fitting the remaining signals.1 Generally, a truncation model should be used with the bright-blood technique to obtain more reproducible and more accurate T2* measurements1 What is an offset model? The offset model consists of a single exponential with a constant offset. Using only the exponential model can underestimate the real T2* values (at quick signal loss at short TE, there is a plateau), while inclusion of the offset model into the fitting equation can improve this.2 Generally, the offset model is recommended to be used with the black-blood technique 1He T, et al. Magn Reson Med. 2008;60: Ghugre NR, et al. J Magn Reson Imaging. 2006;23:9-16.

FAQ: How to start measuring cardiac iron loading?
How to start measuring cardiac iron loading in a hospital? What steps need to be taken? To start assessing cardiac iron loading by MRI, these steps can be followed: Check MRI machine requirements 1.5 T calibrated Buy cardiac package from the manufacturer. It must include all that is necessary for acquisition of the data (the sequences are included with Siemens and Philips Healthcare cardiac packages, but for GE Healthcare they need to be acquired separately) Optional: buy software for analysing the data (if not, Excel spreadsheet can be used) Highly recommended: training of personnel for acquisition of cardiac MR images (e.g. functional analyses) Highly recommended: training of personnel on how to analyse the data with the chosen software

Implementation of liver and cardiac MRI
1.5T MRI Scanner US$ Yes ½ day training Liver Analysis Experienced radiologist No 1 day training Post-processing analysis US$ or US$4.000/y or in-house or outsource Cardiac acquisition package US$50.000 Yes 1-2 day training Heart Analysis Routine cardiac MR exams No 4 day training Slide presented at Global Iron Summit With the permission of Juliano de Lara Fernandes

Summary

Summary Iron overload is common in patients who require intermittent or regular blood transfusions to treat anaemia and associated conditions Analysing cardiac iron levels is important in β-thalassaemia major, cardiac failure and arrhythmia are risk factors for mortality in MDS, cardiac iron overload can have serious clinical consequences due to improved monitoring and management of iron overload over the last decade, 77% of patients have normal cardiac T2*1 MRI: the method to rapidly and effectively assess cardiac iron loading T2* allows specific assessment of cardiac iron levels. The use of this convenient, non-invasive procedure has had a significant impact on outcomes in patients with cardiac iron overload1 R2* is a simple calculation from T2* and has a linear relationship with cardiac iron concentration 1Thomas AS, et al. Blood. 2010;116:[abstract 1011]. 2Modell B, et al. J Cardiovasc Magn Reson. 2008;10:42-9.

GLOSSARY OF TERMS

GLOSSARY AML = acute myeloid leukemia APFR = Atrialp peak filling rate
BA = basilar artery ß-TM = Beta Thalassemia Major ß-TI = Beta Thalassemia Intermedia BM = bone marrow BTM = bone marrow transplantation BW = bandwidth CFU = colony-forming unit CMML = chronic myelomonocytic leukemia CT2 = cardiac T2*. DAPI = 4',6-diamidino-2-phenylindole References Kassab MY et al. J Am Board Fam Med 2007;20:65–71. Krejza J et al. AJR Am J Roentgenol 2000;174:1297–1303.

GLOSSARY DFS = = disease-free survival. DysE = dyserythropoiesis
ECG = electrocardiography EDV = end-diastolic velocity EF = ejection fraction EPFR = early peak filling rate FatSat = fat saturation FAQ = frequently asked questions FDA = Food and Drug Administration FISH = fluorescence in situ hybridization. FOV = field of view GBP = Currency, pound sterling (£)

GLOSSARY Hb = hemoglobin HbE = hemoglobin E HbF = fetal hemoglobin
HbS = sickle cell hemoglobin. HbSS = sickle cell anemia. HIC = hepatic iron concentration HU = hydroxyurea ICA = internal carotid artery. ICT = iron chelation therapy IDL = interface description language IPSS = International Prognostic Scoring System iso = isochromosome

GLOSSARY LIC = liver iron concentration
LVEF = left-ventricular ejection fraction MCA = middle cerebral artery MDS = Myelodysplastic syndromes MDS-U = myelodysplastic syndrome, unclassified MRA = magnetic resonance angiography MRI = magnetic resonance imaging MV = mean velocity. N = neutropenia NEX = number of excitations NIH = National Institute of Health OS = overall survival

GLOSSARY pB = peripheral blood PI = pulsatility index
PSV = peak systolic Velocity RA =refractory anemia RAEB = refractory anemia with excess blasts RAEB -T = refractory anemia with excess blasts in transformation RARS = refractory anemia with ringed sideroblasts RBC = red blood cells RF = radio-frequency RCMD = refractory cytopenia with multilineage dysplasia RCMD-RS = refractory cytopenia with multilineage dysplasia with ringed sideroblasts RCUD = refractory cytopenia with unilineage dysplasia

GLOSSARY RN = refractory neutropenia ROI = region of interest
RT = refractory thrombocytopenia SCD = sickle cell disease SD = standard deviation SI = signal intensity SIR = signal intensity ratio SF = serum ferritin SNP-a = single-nucleotide polymorphism SQUID = superconducting quantum interface device. STOP = = Stroke Prevention Trial in Sickle Cell Anemia STOP II = Optimizing Primary Stroke Prevention in Sickle Cell Anemia

GLOSSARY T = thrombocytopenia
TAMMV = time-averaged mean of the maximum velocity. TCCS = transcranial colour-coded sonography TCD = transcranial doppler ultrasonography TCDI = duplex (imaging TCD) TE = echo time TR = repetition time WHO = World Health Organization WPSS = WHO classification-based Prognostic Scoring System

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