TCD for assessment of stroke risk in SCD - Iron Health Alliance

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DIAGNOSTICS

SLIDE DECK

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TABLE OF CONTENTS


Use of MRI in evaluating liver iron loading

(and monitoring therapy)



Cardiac MRI



Cytogenetic

Assessment in MDS



Transcranial

Doppler
Ultrasonography

(TCD) for assessment
of stroke risk in Sickle Cell Disease



Glossary of terms

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USE OF MRI

IN EVALUATING

LIVER IRON LOADING

(AND MONITORING
THERAPY)

NOTE:

These slides are for use in educational oral presentations only. If any published figures/tables from these slides are to be
us
ed 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

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Outline


Introduction to iron and liver iron overload


Key methods for assessing liver iron


liver biopsy


SF


SQUID


liver MRI


SIR method


relaxometry

methods (R2 and R2*)


Clinical recommendations for measuring LIC


Summary

LIC = liver iron concentration; MRI = magnetic resonance imaging;

SF = serum ferritin; SIR = signal intensity ratio;

SQUID = superconducting quantum interface device.

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Introduction

to iron

and iron overload

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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 mortality
1



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 organs
2,3

1
Ladis V, et al.
Ann NY Acad Sci
. 2005;1054:445
-
50.
2
Gabutti V, Piga A.
Acta Haematol
. 1996;95:26
-
36.
3
Olivieri NF.

N Engl J Med
. 1999;341:99
-
100.

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Importance of analysing liver iron


A patient’s LIC is the best measure of total body iron stores



Knowing the liver iron concentration helps to predict the risk of hepatic
and extra
-
hepatic complications
1

4


1
Batts KP.
Mod Pathol
. 2007;20:S31
-
9.
2
Jensen PD, et al.
Blood
. 2003;101:91
-
6.
3
Angelucci E, et al.
Blood
.
2002;100:17
-
21.
4
Telfer PT, et al.
Br J Haematol
. 2000;110:971
-
7.

8

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LIC
threshold
of 7 mg
Fe/g dry wt

0

5

10

15

20

25

All

(n = 1,744)

TM

(n =
937)

TI

(n = 84)

SCD

(n = 80)

Mean LIC + SD over previous year prior
to enrolment in EPIC trial

(mg Fe/g dry wt)

Cappellini MD, et al.
Blood.

2008;112:[abstract 3880].

Importance of analysing liver iron (cont.)

All transfusion
-
dependent patients prior to study enrolment
had moderate
-
to
-
severe hepatic iron loading

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Overview of LIC correlations with other
measurements

DFS = disease
-
free survival.

1
Angelucci E, et al.
N Engl J Med
. 2000;343:327
-
31.
2
Jensen PD, et al.
Blood
. 2003;101:91
-
6.
3
Angelucci E,
et al.
Blood
. 2002;100:17
-
21.
4
Telfer PT, et al.
Br J Haematol
. 2000;110:971
-
7.
5
Noetzli LJ, et al.
Blood
.
2008;112:2973
-
8.

LIC

Hepatocellular

injury
2

and

fibrosis
3

Body iron

stores
1

Cardiac

iron
5

Cardiac

DFS
4

10

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LIC prediction of total body iron stores

BMT = bone marrow transplantation.

1
Olynyk JK, et al.
Am J Gastroenterol
. 1998;93:346
-
50.
2
Angelucci E, et al.
N Engl J Med
. 2000;343:327
-
31.

Sample > 1 mg dry wt (n = 25)

r = 0.98

0

5

10

15

20

25

300

250

200

150

100

50

0

Body iron stores (mg/kg)

LIC (mg Fe/g dry wt)

Hereditary haemochromatosis
1

Iron removed (g)

LIC (µg/g)

0

5

10

15

20

25

50,000

40,000

30,000

20,000

10,000

0

β
-
TM
2

LIC is a reliable measure of total body iron stores in

hereditary haemochromatosis and β
-
TM

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Serum
ferritin

measurement alone
underestimates the body iron load

Origa R, et al.
Haematologica
. 2007;92:583
-
8.

Taher A, et al.
Haematologica
. 2008;93:1584
-
6.


-
TI


-
TM

0

5

10

15

20

25

30

35

LIC (mg Fe/g dry wt)

SF (

g/L)

2,000

4,000

6,000

8,000

10,000

12,000

14,000

0

SF (

g/L)

0

5

10

15

20

25

30

35

40

45

50

LIC (mg Fe/g dry wt)

1,000

2,000

3,000

4,000

5,000

6,000

7,000

8,000

9,000

10,000

0


-
TI



-
TM

SF has almost no sensitivity or specificity for iron

stores in thalassaemia intermedia

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Assessing liver
iron overload

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Key methods for assessing liver iron


Liver biopsy


L䥃


advantages and disadvantages


correlation of LIC with other measurements



SF concentration over time


advantages and disadvantages


correlation of SF levels with other measurements


SQUID


advantages and disadvantages


Liver MRI


advantages and disadvantages


relaxometry

methods (T2 and T2*)


SIR method

Olivieri NF, Brittenham GM.
Blood.

1997;89:739
-
61.

Direct method

Indirect methods

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Liver biopsy

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Technique for taking a percutaneous

liver biopsy

Step 1.
The patient lies on his back, or his left side

Step 4.

The patient must hold breath for 5
-
10 seconds
when the needle is quickly pushed in and out. As the
needle comes out it brings with it a small sample of
liver tissue

Patient preparation:
Blood tests are done shortly
before the biopsy to check blood clotting time, to
exclude risk of bleeding following the biopsy. The
biopsy is commonly preceded by an ultrasound
examination of the liver to determine the best and
safest biopsy site

Step 3.
A special hollow needle is inserted into the
liver, usually between the 2 lower ribs on the right
hand side

Step 2.
The place for the biopsy is cleaned with
antiseptic and local anaesthesia is provided (s.c. on
the right hand side)

Liver biopsy

A tiny incision is made between the ribs, and a needle is
inserted to reach the area of the liver where a tissue sample

is taken. The procedure requires local anaesthesia

Area where a tissue
sample is taken from

Overall:
The procedure is carried out by a qualified
physician or surgeon in an outpatient care centre or
hospital. It is fast (not longer than 5 min) and the
patient is discharged shortly after

adam.com

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Processing the liver biopsy sample


Gross
histopathological

examination


reveals presence of abnormal cells

or liver tissue


used to determine presence and

degree of cirrhosis and fibrosis



LIC measurement


by iron staining


by atomic absorption spectroscopy:

the current gold standard!



Who does the test?


preparation of the samples might be by

a trained technician


the analysis requires a qualified pathologist

Angelucci E, et al.
Haematologica
. 2008;93:741
-
52.

Image from: www.pathguy.com/lectures/cirrhosis_trichrome.jpg

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Liver biopsy

Liver biopsy with iron measurement by atomic absorption
spectroscopy is the gold standard for measuring LIC
1

LIC threshold

(mg Fe/g dry wt)
2

LIC threshold

(

浯l F支g ry w)

Clini捡c r敬敶慮捥

1.8

32

Upper 95% of normal



15.0

269

Greatly increased risk of cardiac disease and
early death

1
Angelucci E, et al.
Haematologica
. 2008;93:741
-
52.
2
St Pierre TG, et al.
Blood
. 2005;105:855
-
61.

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Liver biopsy: pros and cons

Pros
1

Cons


Direct measurement of LIC


Validated reference standard


Quantitative, specific, and sensitive


Allows for measurement of

non
-
haem storage iron


Provides information on liver
histology/pathology


Correlates with morbidity and mortality


Invasive and painful procedure with risk of potentially serious
complications
1


May involve sampling errors, especially in patients with cirrhosis
1


Requires skilled physicians
1


Laboratory techniques not standardized
1



iron measurement by atomic absorption spectroscopy
2

or
chemical determination
3


wet or dry weight quoted


iron concentration varies throughout the liver,
4

sample size often
insufficient (requires ≥ 1 mg dry weight, or > 4 mg wet weight)

1
TIF.
Guidelines for the Clinical Management of Thalassemia
. 2nd rev. ed. Cyprus: TIF; 2008. Available from:

www.thalassaemia.org.cy/pdf/Guidelines_2nd_revised_edition_EN.pdf. Accessed December 2010.
2
Angelucci E,
et al.
Haematologica
. 2008;93:741
-
52.
3
Wood JC.
Blood Rev
. 2008;22 Suppl 2:S14
-
21.
4
Ambu R, et al.
J Hepatol
.

1995;23:544
-
9.

19

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Heterogeneity of iron concentration

throughout the liver

From autopsy of a patient with beta
-
zero
-
thalassaemia.

Ambu R, et al.
J Hepatol
. 1995;23:544
-
9.

0

20%

20

40%

40

60%

60

80%

80

100%

Iron is unevenly distributed in the liver; therefore, a small
sample may not give an absolutely representative mean LIC

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SF Concentration

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Ferritin and SF


Ferritin

is primarily an intracellular

protein that


stores iron in a form readily accessible to
cells


releases iron in a controlled fashion



The molecule is shaped like a hollow sphere
and it stores ferric (Fe
3+
) iron in its central
cavity


the storage capacity of
ferritin


is approximately 4,500 Fe
3+

ions

per molecule



Ferritin

is found in all tissues, though
primarily in the liver, spleen, and

bone marrow



A small amount is also found in

the blood as serum
ferritin

Harrison PM, Arosio P.
Biochim Biophys Acta
. 1996;1275:161
-
203.

SF > 1,000 µg/L is a marker of
excess body iron

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SF: pros and cons


SF levels from a blood sample are measured


Pros

Cons


Easy to assess


Inexpensive


Positive correlation with morbidity

and mortality


Allows longitudinal follow
-
up of patients


Indirect measurement of iron burden


Fluctuates in response to inflammation,
abnormal liver function, ascorbate
deficiencies

TIF.
Guidelines for the Clinical Management of Thalassaemia
. 2nd rev. ed. Cyprus: TIF; 2008. Available from:

www.thalassaemia.org.cy/pdf/Guidelines_2nd_revised_edition_EN.pdf. Accessed December 2010.

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SQUID

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SQUID: superconducting quantum

interference device

Carneiro AA, et al.
Reson Med
. 2005;43:122
-
8.

Magnetizing coil

Dewar

Liquid

helium

SQUID

Pick to coil

Water bag

Patient

Mattress

Bed

Piston

H
2
O

Patient preparation:
No special patient preparation is required.
U
ltrasound is used to evaluate the depth and size of the liver. The
p
atient lies on their back with their torso
surrounded by a 5
-
L water bag
to minimize contributions from other tissues

Step 2.
LIC corresponds to the variation of magnetization detected and
is calculated using custom
-
made Matlab 6.5 software

Principle of the technique:
Normal tissue is diamagnetic and has a
magnetic susceptibility similar to that of water. In the presence of iron,
tissue susceptibility is changed proportional to the amount of iron
present. This alteration is detected, allowing non
-
invasive
measurement of LIC

Step 1.
The susceptometer applies a low
-
power (114

T and 7.7 Hz)
homogeneous magnetizing field
in the hepatic region
. Sensitive
detectors measure the interference of tissue iron vs the water reference
medium within the field

Overall:
The procedure is carried out by a qualified radiologist in a
hospital. It is fast (not longer than 5 min) and the patient is discharged
immediately after. Processing could be done on the spot and is faster
then LIC histopathological examination

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SQUID: pros and cons

Pros

Cons


Non
-
invasive
1


Wide linear range
1


Good correlation with LIC by biopsy
2


Requires expensive, specialized
equipment and expertise
1


Not widely available
1


Each machine should be
individually calibrated
1


SQUID can underestimate LIC
3

1
TIF.
Guidelines for the Clinical Management of Thalassaemia
. 2nd rev. ed. Cyprus: TIF; 2008. Available from:

www.thalassaemia.org.cy/pdf/Guidelines_2nd_revised_edition_EN.pdf. Accessed December 2010.
2
Sheth S.
Pediatr Radiol
. 2003;33:373
-
7.
3
Piga A, et al.
Blood
. 2005;106:[abstract 2689].

250

200

150

100

50

0

0

50

100

150

200

250

Hepatic iron (magnetic) (

浯氠F支朠e整ew)

Hepatic iron (biopsy)

(

浯氠F支朠e整ew)

R = 0.99

p < 0.001

SQUID is a non
-
invasive method that has been calibrated,
validated, and used in clinical studies, but the complexity, cost
and technical demands limit its use

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Liver MRI

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MRI

ROI = region of interest; SI = signal intensity; TE = echo time.

Brittenham GM, Badman DG.

Blood
. 2003;101:15
-
9.

Ridgway JP.
J Cardiovasc Magn Reson
. 2010;12:71.

Integral
radiofrequency
transmitter
(body) coil


Main
magnet
coils

Main
magnet
coils

x,y,z
gradient
coils

Patient table

Patient preparation:
All infusion and medication pumps should be
removed. The scan does not require contrast agent, and so no
peripheral vein access is needed

Step 2.
Post
-
processing:
As TE increases, the image’s SI decreases.
The relationship between TE and SI in a selected part of the image (i.e.
ROI) is analysed with specialized software or manually.
D
ata are
reported as relaxation times (T2 or T2*), depending on
the
acquisition
method

Principle of the technique:

A
strong
magnetic field is used to
organize the protons in the tissue in
1

direction. Then radiofrequency is
used to “knock” them off. The time for them to re
-
align with the
magnetic field and the energy they release during the process depend
on the interactions of the proton with other ions, notably iron ions.
These events could be measured at various TEs and then analysed to
reveal the iron content in the tissue

Step 1.
Image acquisition: Images are taken at various TEs

Overall:
The procedure is carried out by a qualified radiologist in a
hospital. Acquisition is fast (approx. 5 min)
,

and the patient is
discharged immediately after. Processing may require specialized
software and is done afterwards

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MRI is increasingly being used

as a non
-
invasive method to measure LIC

Pros

Cons


Non
-
invasive
1,2


Assesses iron content throughout the liver
2


Increasingly and widely available worldwide
2


Pathological status of liver and heart can be
assessed in parallel
2


Validated relationship with biopsy LIC
3‒6


Indirect measurement of LIC
2


Requires MRI with dedicated imaging method
2


Sensitivity depends on type of scanner, degree
of iron overload, presence of fibrosis, and

inflammation
7

1
Chavhan GB, et al.
Radiographics
. 2009;29:1433
-
49.
2
TIF.
Guidelines for the Clinical Management of Thalassaemia
.
2nd rev. ed. Cyprus: TIF; 2008. Available from: www.thalassaemia.org.cy/pdf/Guidelines_2nd_ revised_edition_EN.pdf.
Accessed December 2010.
3
Christoforidis A, et al.
Eur J Haematol
. 2009;82:388
-
92.

4
St Pierre TG, et al.
Blood
. 2005;105:855
-
61.
5
Wood JC, et al.
Blood
. 2005;106:1460
-
5.
6
Hankins JS, et al.
Blood
.
2009;113:4853
-
5.
7
Sirlin CB, Reeder SB.
Magn Reson Imaging Clin N Am
. 2010;18:359
-
81.

29

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MRI scanners


Manufacturers


Siemens Healthcare (
Erlangen
, Germany;
www.siemensmedical.com
)


GE Healthcare (Milwaukee, WI, USA;
www.gemedicalsystems.com
)


Philips Healthcare (Best, the Netherlands;
www.medical.philips.com
)



Magnetic field strength


most imaging is done on 1.5 T machines


3 T machines give


better
signal:noise

ratio
1


worse susceptibility artefacts
1


The upper detection limit is halved, therefore it is too low for many patients
1


lower T2 and T2* values than 1.5 T machines
2




Liver package
(including standard sequences and analysis of the data)

is included in the software provided together with the MRI machine


specialized LIC analysis software can be bought separately

1
Wood JC, Ghugre N.
Hemoglobin
. 2008;32:85
-
96.
2
Storey P, et al.
J Magn Reson Imaging
. 2007;25:540
-
7.

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Overview of MRI techniques used to

measure LIC

DATA
ACQUISITION

DATA ANALYSIS

MAJOR PROS

AND CONS

A combination of

gradient and spin

echos

Free website

+
Fast acquisition

Simple data analysis


Limited sensitivity
Reproducibility

Gradient echo (same
technique as cardiac
iron measurement)

(1 min)

Manually (free xls
sheet) or with
dedicated software
(e.g CMR tool 3,000
GBP per year)

+
Fast acquisition

Correlates well with LIC


Susceptible to artefacts
Training needs

Spin echo

(15min)

Done centrally by
Resonance Health
(300 USD per scan)

+
Gold Standard

Little training need


Longer data acquisition time
Cost of analysis

Signal Intensity

Ratio (SIR) method
(Gandon/Ernst)

Relaxometry
method

R2*(T2*)

R2(T2)

(Ferriscan
®
)

Liver MRI
Technique

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MRI measurement of LIC: techniques


There are 2 broad groups of techniques


SIR methods (
Gandon

et al. methods)


relaxometry

methods (
FerriScan
®

and T2* (R2*) methods)

Pros

Cons

SIR

method


Fast data acquisition


Relatively simple algorithms and

data analysis


Can be used in scanners with
different magnetic strengths

(0.5, 1.0, 1.5 T)


Limited range of sensitivity (u
pper limit
is 21 mg Fe/g dry wt [380

mol/L])


Assumptions on reference tissue


Not reliable in cirrhosis


Smaller reproducibility

Relaxometry
method


Greater range of sensitivity


Does not rely on reference tissue
assumptions


T2* (or R2*) is very quick

(requires a single breath
-
hold)


Has only been calibrated at 1.5 T


Takes longer to acquire data, when
done as T2 (or R2)

Argyropoulou MI, Astrakas L.
Pediatr Radiol
. 2007;37:1191
-
200. Gandon Y, et al.
Lancet
. 2004;363:357
-
62. St
Pierre TG, et al.
Ann N Y Acad Sci
. 2005;1054:379
-
85. Wood JC.
Curr Opin Hematol
. 2007;14:183
-
90. Wood JC,
et al.
Blood
. 2005;106:1460
-
5.

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SIR methods


Most common protocol includes


4
-
gradient echo sequences with different TEs


1 spin
-
echo sequence

0

100

300

400

200

0

100

200

400

300

Study group


Validation group

Biopsy LIC (
µ
mol Fe/g dry wt)

MRI LIC

(
µ
mol Fe/g dry wt)

Gandon Y, et al.
Lancet
. 2004;363:357
-
62.

1. Patient
preparation

(5 min)

2. Image
acquisition

(approx. 5
-
20 min)

3. Data analysis

(depends on
experience)

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SIR methods (cont.)


The ROI is selected in the liver

and the reference tissue

(muscle or fat), in each image



The SI of the liver region is

divided by that of the

reference tissue



A calculation algorithm to

assist has been developed

for 0.5, 1.0, and 1.5 T

MRI machines
1

1
Gandon Y. Available from: http://www.radio.univ
-
rennes1.fr/Sources/EN/HemoResult.html. Accessed December 2010.

1. Patient
preparation

(5 min)

2. Image
acquisition

(approx. 5
-
20 min)

3. Data analysis

(relatively fast)

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Relaxometry methods: T2, T2*, T2′, R2, and R2*


If a
spin
-
echo

sequence is used, the relaxation time is
T2



If a
gradient
-
echo

sequence is used, it is
T2*



These are related by the equation
1




1/T2* =
1/T2

+ 1/T2′



T2′ is the magnetic field
inhomogeneity

of the tissue


To attain a positive linear relationship with HIC


T2* can be transformed into reciprocal

R2*: R2* [Hz] = 1,000/T2* [ms]


T2 can be transformed into reciprocal

R2: R2 [Hz] = 1,000/T2 [ms]

1
Anderson LJ, et al.
Eur Heart J
. 2001;22:2171
-
9.
2
Wood JC, Ghugre N.
Hemoglobin
. 2008;32:85
-
96.

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Relaxometry methods: R2 and R2*


Several pulse sequences are included in the MRI software package

Parameters

R2 (for FerriScan
®
)

spin echo sequence

T2* (and R2*)
gradient

echo sequence

FOV (mm)

300 x 225

350 x 300

Matrix (lines)

256 x 176

128 x 80

Resolution (mm)

1.17 x 1.28 x 5.0

2.73 x 3.75 x 10.0

TR (ms)

2500

200

TE (ms)

6, 9, 12, 15, 18

Minimum possible (ideally < 2.0 ms)

NEX (n)

1

1

Flip angle (
°
)

90

20

BW (Hz/px)

300

1,950

Segments (n)



8

FatSat

On

On

Wood JC, Ghugre N.
Hemoglobin
. 2008;32:85
-
96.

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1
Wood JC, et al.
Blood
. 2005;106:1460
-
5.
2
St Pierre TG, et al.
Blood
. 2005;105:855
-
61.

Biopsy LIC (mg Fe/g dry wt)

Mean R2 (Hz)

300

250

200

150

100

50

0

Hepatitis

Hereditary haemochromatosis


-
thalassaemia/Hb E


-
thalassaemia

0

10

20

30

40

Biopsy LIC (mg Fe/g dry wt)

350

300

250

200

150

100

50

0

0

10

20

30

40

50

60

R2 (Hz)

LIC by biopsy, R = 0.98

Linear fit using biopsy data

Controls, LIC by norms alone

Correlation between R2
-
estimated LIC

and LIC by biopsy

R2
-
LIC calibration curve

by St Pierre et al. 2005
2

R2
-
LIC calibration curve

by Wood et al. 2005
1

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Correlation between R2*
-
estimated LIC and LIC
by biopsy

1
Wood JC, et al.
Blood
. 2005;106:1460
-
5.
2
Hankins JS, et al.
Blood
. 2009;113:4853
-
5.

R2* (Hz)

Biopsy LIC (mg Fe/g dry wt)

R = 0.97

Patients

Controls

Fit

0

200

400

600

800

1,000

1,200

1,400

1,600

1,800

2,000

0

10

20

30

40

50

60

30

25

20

15

10

5

0

0

200

400

600

800

1000

R2*MRI (Hz)

LIC (mg Fe/g dry wt)

Correlation coefficient = 0.98

p

< 0.001

R2*
-
LIC calibration curve

by Hankins et al.
2

R2*
-
LIC calibration curve

by Wood et al.
1

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LIC estimated with R2 and R2* MRI correlate
well with each other

Wood JC, et al.
Blood
. 2005;106:1460
-
5.

0

10

20

30

40

50

0

10

20

30

40

50

Estimated HIC (mg/dry) by R2
-
SP

Estimated HIC (mg/dry) by R2*

Patient data

Linear fit, R=0.94

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30

25

20

15

10

5

0

0

200

400

600

800

1000

Liver R2* (Hz)

HIC (mg Fe/g of dry weight liver)

Hankins, et al.

Wood, et al.

Anderson, et al.

[Fe] (mg/g dry wt)

Cardiac R2* (Hz)

0

2

4

6

8

10

12

14

0

100

200

300

400

R
2
= 0.82540

Liver MRI

Cardiac MRI

Gradient relaxometry (T2*, R2*) can
conveniently measure cardiac and liver iron

HIC = hepatic iron concentration


Carpenter JP, et al.
J Cardiovasc Magn Reson
. 2009;11 Suppl 1:P224.

Hankins et al
Blood
. 2009;113:4853
-
4855.

Cardiac and liver iron can be assessed together conveniently

by gradient echo during a single MRI measurement.

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Relaxometry methods: pros and cons

Pros

Cons

R2*


Correlate well to biopsy LIC
1

4


Greater sensitivity to iron deposits
5


Faster (images can be obtained in a single
breath
-
hold) and easier
6


Can perform cardiac and liver iron assessment
at the same time


More susceptible to artefacts


Requires expert training of a
technician/ radiologist for data
acquisition and data analysis

R2

(Ferriscan
®
)



Correlate well to biopsy LIC
1

4


Less affected by susceptibility artefacts
6


Highly sensitive and specific over a large range
of LIC, including patients with severe
haemosiderosis
7


The gold standard method in clinical trials


Requires no training for data analysis (done
centralized by Resonance Health)


Multiple breath
-
holds required which
increases MRI time


Cost of analysis (300 USD per scan)

1
Christoforidis A, et al.
Eur J Haematol
. 2009;82:388
-
92.
2
St Pierre TG, et al.
Blood
. 2005;105:855
-
61.
3
Wood JC,
et al.
Blood
. 2005;106:1460
-
5.
4
Hankins JS, et al.
Blood
. 2009;113:4853
-
5.
5
Anderson LJ, et al.
Eur Heart J
.
2001;22:2171
-
9.
6
Wood JC, Ghugre N.
Hemoglobin
. 2008;32:85
-
96.
7
Papakonstantinou, O, et al.
J

Magn Reson

Imaging
. 2009;29:853
-
9.

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Relaxometry methods: R2 and R2* (cont.)


Correct position is important so that the LIC across the whole liver
can be measured


Images are taken at various TEs


Red line indicates correct

position of the slice

1. Patient
preparation

(5 min)

2. Image
acquisition

(approx. 5
-
20 min)

3. Data analysis

(depends on
experience)

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Liver R2* MRI

Liver with normal iron levels

Liver with severe iron overload

Images courtesy of Dr J. de Lara Fernandes.

T2* = 15.7 ms or R2* = 63.7 Hz or LIC = 1.3mg/g

T2* = 1.1 ms or R2* = 909 Hz or LIC = 25.0 mg/g

TE=1.3ms

TE=3.6ms

TE=7.1ms

TE=1.3ms

TE=3.6ms

TE=7.1ms

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How can I avoid artefacts when assessing LIC by MRI?

When assessing LIC, one thing that is really important is to
use fat saturation (usually automatically included in all the
sequences). This is especially important if a patient has
steatosis (e.g. adults with haemochromatosis)

How frequent are artefacts in liver MRI?

In contrast to cardiac MRI, the risk for motion artefacts (e.g.
due to breathing) or susceptibility artefacts is much lower
when performing liver MRI. As in cardiac MRI, if artefacts are
present and too severe, scans may have to be repeated

FAQ: artefacts

Questions and answers were prepared under the review of Dr J. de Lara Fernandes, University of Campinas, Brazil.

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Relaxometry methods: R2 and R2* (cont.)


Determine ROI


entire liver boundary, excluding obvious

hilar

vessels
1



Slice thickness


varies, generally 5

15 mm
1

4



Number of slices


anything from about 1 to 20 slices

can be studied
1

4

Red outline shows position of ROI

1
Wood JC, et al.
Blood
. 2005;106:1460
-
5.
2
St Pierre TG, et al.
Blood
. 2005;105:855
-
61.

3
Papakonstantinou O, et al.
J Magn Reson Imaging
. 2009;29:853
-
9.
4
Hankins JS, et al.
Blood
. 2009;113:4853
-
5.

1. Patient
preparation

(5 min)

2. Image
acquisition

(approx. 5
-
20 min)

3. Data analysis

(depends on
experience)

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Relaxometry methods: R2 and R2* (cont.)


As TE increases, SI should decrease



When plotted on a graph


as iron load increases, the curve gets steeper


T2 or T2* can be calculated from the curve


R2 and R2* can also be calculated



Calculations are done


manually, or


by specific licensed software

(e.g.
CMRtools
®
), or


images could be directly sent to a validated

centre performing
FerriScan
®

for analysis

100

80

60

40

20

0

15

20

0

5

10

SI

TE (ms)

Typical non
-
iron
-
loaded tissue

1. Patient
preparation

(5 min)

2. Image
acquisition

(approx. 5
-
20 min)

3. Data analysis

(depends on
experience)

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Analysis of the data


The data can be analysed manually or using

post
-
processing software

Manually

Post
-
processing software


Excel spreadsheet



ThalassaemiaTools

(
CMRtools
)


cmr
42


FerriScan


MRmap


MATLAB

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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


cmr
42(3)

Easy to use

FDA approved
3

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.

1
www.cmrtools.com/cmrweb/ThalassaemiaToolsIntroduction.htm. Accessed Dec 2010.

2
Pennell DJ.
JACC Cardiovasc Imaging
. 2008;1:579
-
81.

3
www.circlecvi.com. Accessed Dec 2010.

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Method

Pros

Cons

FerriScan
1

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 300 per scan

Patients data are sent to reference
centre

MRmap
2

Uses IDL runtime, which is a commercial software
(less expensive than cmr
42
/CMRtools)

Can quantify T1 and T2 map with the same
software

Purely a research tool

Not intended for diagnostic or clinical
use


MATLAB
3

Low cost

Available only locally

Physicists or engineers need to write
a MATLAB program for display and
T2* measurement

1
www.resonancehealth.com/resonance/ferriscan. Accessed Dec 2010.

2
www.cmr
-
berlin.org/forschung/mrmapengl/index.html. Accessed Dec 2010.

3
Wood JC, Noetzli L.
Ann N Y Acad Sci
. 2010;1202:173
-
9.

Analysis of the data (cont.)

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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 (the plateau) are
subjectively discarded to obtain a curve with an R
2

> 0.995. A new single exponential curve is made by
fitting the remaining signals.

What is the most frequent mistake made
when interpreting the data from an MRI scan?

Interpreting a liver MRI is more challenging than for a
cardiac MRI, especially in patients with severe liver iron
overload. Correcting the data using truncation analysis is
very important (done automatically by some software).
The example (see following slide) clearly shows what
happens, if the truncation is not done correctly

FAQ: mistakes in manual analysis

of liver MRI data

Questions and answers were prepared under the review of Dr J. de Lara
Fernandes
, University of Campinas, Brazil.

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Non
-
truncated analysis with results with a poor R
2


(< 0.995). The apparent LIC of 4.65 suggests mild LICs.
Observe the flat plateau of the data points after a

TE of 3.62 ms

The same patient, but analysing the data with only the 3 first
data points results in a better (although not perfect) R
2
.

The LIC results in severe iron overload, reflecting the real
concentrations of iron

Analysis without
truncation of the data

Analysis with
truncation of the data

FAQ: mistakes in manual analysis

of liver MRI data (cont.)

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How to start measuring liver iron loading in a
hospital? What steps need to be taken?

To start assessing liver iron loading by MRI, these steps can be followed

1.
Check MRI machine requirements


0.5

1.5 T (1.5 T is highly recommended for T2* and T2
calculations; 0.5 T only for SIR)


calibrated


includes a liver package

2.
Optional: buy software for analysing the data (otherwise, Excel
spreadsheet can be used)

3.
Optional: training of personnel for acquiring MRI images

4.
Optional: training of personnel on how to analyse the data

FAQ: how to start measuring liver iron loading?

Questions and answers were prepared under the review of Dr J. de Lara Fernandes, University of Campinas, Brazil.

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LIC: interpretation of results


LIC threshold values for classification of iron overload

Iron levels

LIC (mg Fe per

g dry weight)

LIC (µmol Fe

per g dry wt)

R2 (s
−1
)


R2* (s
−1
)

T2* (ms)

Normal

< 2

< 35.6

< 50

< 88

> 11.4

Mild

overload

≥ 2−7

≥ 35.6 − 125.0

≥ 50


100

≥ 88


263

> 3.8


11.4

Moderate
overload

≥ 7−15

≥ 125 − 269

≥ 100


155

≥ 263


555

> 1.8


3.8

Severe
overload

≥ 15

≥ 269

≥ 155

≥ 555

≤ 1.8


Values estimated based on R2 LIC calibration curve;
R2, R2* and T2* values valid for MRI machines
with 1.5T only.


St Pierre TG, et al.
Blood

2005;105:855

861; Wood JC, et al.
Blood

2005;106:1460

1465.

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Implementation of liver and cardiac MRI

Slide presented at Global Iron Summit 2011
-

With the permission of Juliano de Lara Fernandes

1.5T MRI Scanner

Experienced radiologist

Cardiac acquisition package

Routine cardiac MR exams

Post
-
processing analysis

US$1.000.000

US$50.000

US$40.000 or US$4.000/y

or in
-
house or outsource

Yes

No

½ day training

1 day training

Yes

No

1
-
2 day training

4 day training

Liver

Analysis

Heart

Analysis

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Summary

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Summary


Iron overload is a serious problem among patients who require blood
transfusions to treat anaemia and associated conditions



Analysing liver iron overload is important


to predict risk of hepatic and extra
-
hepatic complications



The extent of iron accumulation in the liver is a key prognostic indicator
for morbidity and mortality



MRI has the added advantage that iron levels throughout the liver can
be analysed, rather than just the
biopsied

section (iron levels throughout
the liver can vary)


R2 is the most commonly used technique in clinical practice,
although R2* is a comparable alternative across most ranges

of iron overload and is faster

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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 p
erm
ission.

Specific local use requires local approval

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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
)


cmr4
2


FerriScan


MRmap


MATLAB


Summary

MRI = magnetic resonance imaging.

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Introduction to

iron overload

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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 mortality
1




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 organs
2,3

1
Ladis V, et al.
Ann NY Acad Sci
. 2005;1054:445
-
50.
2
Gabutti V, Piga A.
Acta Haematol
. 1996;95:26
-
36.

3
Olivieri NF.
N Engl J Med
. 1999;341:99
-
109.

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Importance of analysing cardiac iron


In β
-
thalassaemia

major, cardiac failure and arrhythmia are risk factors

for mortality
1



signs of myocardial damage due to iron overload: arrhythmia,
cardiomegaly
,
heart failure, and pericarditis
2


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 patients
4

7


cardiac iron overload occurs later than does liver iron overload
4,7,8



however, cardiac iron overload can have serious clinical

consequences in MDS patients

1
Borgna
-
Pignatti C, et al.
Haematologica
. 2004;89:1187
-
93.
2
Gabutti V, Piga A.
Acta Haematol
.
1996;95:26
-
36.

3
. Modell B, et al.
Lancet
. 2000;355:2051
-
2.
4
Jensen PD, et al.
Blood
. 2003;101:4632
-
9.

5
Chacko J, et al.
Br J Haematol
. 2007;138:587
-
93.
6
Konen E, et al.
Am J Hematol
. 2007;82:1013
-
6.

7
Di Tucci AA, et al.
Haematologica
. 2008;93:1385
-
8.

8
Buja LM, Roberts WC.
Am J Med
. 1971;51:209
-
21.

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Baseline

Latest follow
-
up

p < 0.001

p < 0.001

cT2* ≤ 20 ms

cT2* < 10 ms

Patients (%)

cT2* = cardiac T2*.


1
Thomas AS, et al.
Blood
. 2010;116:[abstract 1011].
2
Modell B, et al.
Lancet
. 2000;355:2051
-
2.

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
population
1

60

17

23

7

0

10

20

30

40

50

60

70

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Cardiac T2*: Overview of correlations with other
measurements

1
Wood JC, et al.
Blood
. 2004;103:1934
-
6.
2
Anderson LJ, et al.
Eur Heart J
. 2001;22:2171
-
9.
3
Tanner MA,
et al. J
Cardiovasc Magn Reson
. 2006;8:543
-
7.
4
Kirk P, et al.
Circulation
. 2009;120:1961
-
8.

5
Westwood MA, et al.
J Magn Reson Imaging
. 2005;22:229
-
33.


For thalassaemia, but not sickle cell.

APFR = atrial peak filling rate; EPFR = early peak filling rate; LIC = liver iron concentration;

SF = serum ferritin.

Weak or no correlation

Transfusion

duration



1

Ventricular

dysfunction


1
-
3

Arrhythmia and

heart failure


4

APFR



EPFR:APFR

5

Need for cardiac

medication

1
-
2

T2*


SF and
LIC
1
-
3

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LVEF (%)

0

50

70

40

30

20

10

60

80

90

0

20

40

60

90

80

100

10

30

50

70

Cardiac T2* (ms)

Cardiac T2* value of

37 ms in a normal heart

Cardiac T2* value of

4 ms in a significantly

iron
-
overloaded heart

LVEF = left
-
ventricular ejection fraction.

Anderson LJ, et al.
Eur Heart J.
2001;22:2171
-
9.

Normal T2* range

Normal

LVEF

range

Cardiac T2*: Relationship with LVEF

Myocardial T2* values < 20 ms are associated with a
progressive and significant decline in LVEF

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0.1

Cardiac T2*: Relationship with cardiac failure
and arrhythmia

Kirk P, et al.
Circulation
. 2009;120:1961
-
8.

T2* < 10 ms: relative risk 159 (p < 0.001)

T2* < 6 ms: relative risk 268 (p < 0.001)

Cardiac failure

Proportion of patients
developing cardiac failure

Follow
-
up time (days)

60

0

120

180

240

300

360

0.3

0.2

0

0.4

0.5

0.6

< 6 ms

6

8 ms

8

10 ms

> 10 ms

Arrhythmia

60

0

120

180

240

300

360

0.15

0.10

0.05

0

0.20

0.25

0.30

< 10 ms

10

20 ms

> 20 ms

T2* < 20 ms: relative risk 4.6 (p < 0.001)

T2* < 6 ms: relative risk 8.65 (p < 0.001)

Follow
-
up time (days)

Proportion of patients


with arrhythmia

Low myocardial T2* predicts a high risk of developing

cardiac failure and arrhythmia

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Assessing

cardiac iron
overload

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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


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Echocardiography

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Assessing cardiac iron loading
:
E
chocardiography

EF = ejection fraction.

1
Leonardi B, et al.
JACC Cardiovasc Imaging
. 2008;1:572
-
8.
2
Hoffbrand AV.
Eur Heart J
. 2001;22:2140
-
1.

Pros

Cons


Readily available
1


Relatively
inexpensive
1


Does not detect early damage
2


Echocardiographic

diastolic function
parameters correlate poorly with LVEF and T2*
1


Cannot directly or indirectly quantify cardiac
iron levels

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Cardiac MRI

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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


RF = radio
-
frequency
.

1
Wood JC, Ghugre N.
Hemoglobin
. 2008;32:85
-
96.
2
Wood JC, et al.
Circulation
. 2005;112:535
-
43.

3
Wang ZJ, et al.
Radiology
. 2005;234:749
-
55.
4
Ghugre NR, et al.
Magn Reson Med
. 2006;56:681
-
6.

Protons

Magnetic field

RF/spin echo/gradient echo

Echo signal → T1, T2

Signal processing

Iron

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MRI: A non
-
invasive diagnostic tool (cont.)


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)

TE = echo time.

Adapted from Wood JC, Ghugre N.
Hemoglobin
. 2008;32:85
-
96.

Protons

Magnetic field

Most used in
clinical practice:

Gradient echo

Image acquired
at different TEs

Excel or
software

T2* [ms}

R2* [Hz]=

1,000/T2*

Spin echo

Image acquired
at different TEs

Excel or
software

T2* [ms}

R2* [Hz]=

1,000/T2*

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Assessing cardiac iron loading
:

C
ardiac 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

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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

1
Image from Ridgway JP.
J Cardiovasc Magn Reson
. 2010;12:71.

FAQ: Cardiac MRI

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Gradient relaxometry (T2*, R2*) is the method
for analysing cardiac iron levels

1
Guo H, et al.
J Magn Reson Imaging
. 2009;30:394
-
400.
2
Anderson LJ, et al.
Eur Heart J
.
2001;22:2171
-
9.
3
Wood JC, Noetzli L.
Ann N Y Acad Sci
. 2010;1202:173
-
9.
4
Wood JC, Ghugre N.
Hemoglobi
n. 2008;32:85
-
96.
5
Westwood M, et al.
J Magn Reson Imaging
. 2003;18:33
-
9.

6
Hoffbrand AV.
Eur Heart J
. 2001;22:2140
-
1.
7
He T, et al.
Magn Reson Med
. 2008;60:1082
-
9.

T2* (gradient echo)

T2 (spin echo)

Pros


Greater sensitivity to iron deposition
2


Shorter acquisition time
1


Less affected by motion artefacts
3


More readily available
3


Easier to perform
4


Good reproducibility
5


Less affected by susceptibility
artefacts
1
, due to metal implants,
air

tissue interfaces, proximity to
cardiac veins

Cons


More sensitive to static magnetic field
inhomogeneity
1


Noise, motion, and blood artefacts can
complicate analysis (particularly in
heavily iron
-
loaded hearts)
7


Lack of sensitivity
6


Motion artefacts
6


Poor signal
-
to
-
background noise
ratios at longer TEs
6


Longer acquisition time
1

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HIC = hepatic iron concentration

Carpenter JP, et al.
J Cardiovasc Magn Reson
. 2009;11 Suppl 1:P224.

Hankins et al
Blood
. 2009;113:4853
-
4855.

30

25

20

15

10

5

0

0

200

400

600

800

1000

Liver R2* (Hz)

HIC (mg Fe/g of dry weight liver)

Hankins, et al.

Wood, et al.

Anderson, et al.

[Fe] (mg/g dry wt)

Cardiac R2* (Hz)

0

2

4

6

8

10

12

14

0

100

200

300

400

R
2
= 0.82540

Liver MRI

Cardiac MRI

Gradient relaxometry (T2*, R2*) can
conveniently measure cardiac and liver iron

Cardiac and liver iron can be assessed together conveniently

by gradient echo during the a single MRI measurement.

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Cardiac T2* MRI is usually measured in the
septum of the heart

Heart with normal iron levels

Heart with severe iron overload

Images courtesy of Dr J. de Lara Fernandes.

T2* = 22.8 ms or R2* = 43.9 Hz

T2* = 5.2 ms or R2* = 192 Hz

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Conversion from T2* to R2* is a simple mathematical calculation:

R2* = 1
,
000/T2*

Level of cardiac iron overload

T2*, ms

R2*, Hz

Normal




1

< 50

Mild, moderate

10

20
1

50

100

Severe

< 10
2

> 100

1
Anderson LJ, et al.
Eur Heart J
. 2001;22:2171
-
9.
2
Kirk P, et al.
Circulation
. 2009;120:1961
-
8.

These values are only applicable to 1.5 T scanners
1


What is R2*?

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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

[Fe] (mg/g dry wt)

Cardiac T2* (ms)

[Fe] (mg/g dry wt)

0

2

4

6

8

10

12

14

0

10

20

30

40

50

60

70

R
2

= 0.949

Cardiac R2* (Hz)

0

2

4

6

8

10

12

14

0

100

200

300

400

R
2
= 0.82540

Carpenter JP, et al.
J Cardiovasc Magn Reson
. 2009;11 Suppl 1:P224.

R2* has a linear relationship with tissue iron

concentration, which simplifies the interpretation of data

and allows comparison of changes over time

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Anderson LJ, et al.
Eur Heart J
. 2001;22:2171
-
9.

Hockey stick effect?

Or a more gradual relationship?

The relationship between cardiac T2*/R2* and LVEF

Heart T2* (ms)

LVEF (%)

R2* (s

1
)

LVEF (%)

90

80

70

60

50

40

30

20

10

0

10

20

30

40

50

60

70

80

90

100

0

100

80

60

40

20

0

0

50

100

150

200

250

Why should the data be presented as R2* and
not T2*? (cont.)

R2* allows demonstration of cardiac risk in a more gradual way

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Transform to R2*

Standard errors on a single measurement are approximately
constant with R2*, but are non
-
uniform with T2*

Westwood M, et al.
J Magn Reson Imaging
. 2003;18:33
-
9.

60

50

40

30

20

10

0

0

10

20

30

40

50

60

T2* second measurement (ms)

T2* first measurement (ms)

120

100

80

60

40

20

0

0

20

40

60

80

100

120

R2* second measurement (s

1
)

R2* first measurement (s

1
)

Why should the data be presented as R2* and
not T2*? (cont.)

R2* has a constant standard error that makes

assessment of the significance of changes easier

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Cardiac T2*

MRI in practice

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MRI scanners


Manufacturers


Siemens Healthcare (
Erlangen
, Germany;
www.siemensmedical.com
)


GE Healthcare (Milwaukee, WI, USA;
www.gemedicalsystems.com
)


Philips Healthcare (Best, the Netherlands;
www.medical.philips.com
)



Magnetic field


T2* varies with magnetic field strength
1


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)

1
Anderson LJ, et al.
Eur Heart J.
2001;22:2171
-
9.
2
Kirk P, et al.
Circulation.

2009;120:1961
-
8.

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Cardiac T2* MRI in practice: The process

LIVER
TE
ROI
1.3
134
2.46
114
3.62
99
4.78
81
5.94
70
7.1
59
8.26
49
9.42
40
10.58
35
11.74
28
E
0.14925
T2*
2.1
ms
R2*
476.1905
Hz
LIC
12.88801
mg/g
LIC calculation according to: Hankins JS, et al. Blood. 2009;113:4853-5.
Normal
>11.4
Light
3.8 - 11.4
Moderate
1.8-3.8
Severe
<1.8
T2*
Normal
<88
Light
88-263
Moderate
263-555
Severe
>555
R2*
Normal
<2
Light
2-7
Moderate
7-15
Severe
>15
mg/g
y = 166.48552e
-
0.14925x
R² = 0.99845
0
20
40
60
80
100
120
140
160
0
2
4
6
8
10
12
14
Please insert the values of TE and
ROI from an individual patient.
Please insert the value from the
graph, encircled green.
T2*, R2*

*Time to manually calculate T2*/R2* values in an Excel spreadsheet depends on the experience

of the physician.

1. Patient

preparation

(5 min)

2. Acquisition of

the MRI image

(approx. 5
-
20 min)

3. Analysis of

MRI data

(time depends

on experience*)

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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


cmr
42


FerriScan


MRmap


MATLAB

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Preparation

of the patient

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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.

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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


cmr
42


FerriScan


MRmap


MATLAB

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Acquisition

of the image

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Acquisition of the image: MRI pulse sequences


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 exist
1


a gradient
-
echo sequence generates T2*

1
Wood JC, Ghugre N.
Hemoglobin.

2008;32:85
-
96.

90

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1
Anderson LJ, et al.
Eur Heart J
. 2001;22:2171
-
9.
2
Westwood M, et al.
J Magn Reson Imaging
.
2003;18:33
-
9.
3
He T, et al.
J Magn Reson Imaging
. 2007;25:1205
-
9.
4
He T, et al.
Magn Reson Med
.
2008;60:1082
-
9.
5
Pepe A, et al.
J
Magn Reson Imaging
. 2006;23:662
-
8.

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

London

(Pennell)

Multiple

1 (septum)

No

1

Fixed

Black blood

(He et al)
3
-
4

London

(Pennell)

Multiple

1 (septum)

Yes

2

Fixed

Multi
-
slice

(Pepe et al)
5

Pisa

(Pepe)

Multiple

Multi
-
region

No

1

Fixed

The most common commercially available T2*
acquisition techniques

The various techniques give clinically comparable results.
2
-
3, 5

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Acquisition of the image: TEs


Images are taken at a minimum

of 5 different
TEs
, normally 8‒12
1



The choice of minimum TE determines
the smallest

measurable T2
1


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
-
holds
2


single breath
-
hold multi
-
echo
acquisition: acquire images for

all TE during 1 breath
-
hold
3

Mean R2* compared with true value in the case of
synthetic images for different minimum TEs,

but same echo duration (18 ms)
4

1
Wood JC,
Noetzli

L.
Ann N Y
Acad

Sci
. 2010;1202:173
-
9.
2
Anderson LJ, et al.
Eur

Heart J
.
2001;22:2171
-
9.
3
Westwood M, et al.
J
Magn

Reson

Imaging
. 2003;18:33
-
9.
4
Ghugre NR, et al.

J
Magn

Reson

Imaging
. 2006;23:9
-
16.

500

450

400

350

300

250

200

150

100

50

0

0

100

200

300

400

500

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

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How does the MRI data output looks like?

Data visualization

MRI data output

1
Wood JC, Ghugre N.
Hemoglobin
. 2008;32:85
-
96.

During a single breath hold the pulse sequence run several

times at increasing echo time (TE), generating data points
corresponding to decreased signal intensity
1

Frame

TE (ms)

Mean ST

0

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

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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

-
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 ee 䉬B湤
-
A汴浡渠灬p瑳
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

1
Westwood M, et al.
J Magn Reson Imaging
. 2003;18:33
-
9.

Patients with T2* < 20 ms
1

Patients with T2*


20 ms

1

FAQ: Acquisition technique

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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.

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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


cmr
42


FerriScan


MRmap


MATLAB

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Analysis

of the data

(post
-
processing)

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How T2* is calculated from the MRI output?

Data visualization

1
Wood JC, Ghugre N.
Hemoglobin
. 2008;32:85
-
96.

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


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Analysis of the data


The data can be analysed manually or using

post
-
processing software

Manually

Post
-
processing software


Excel spreadsheet



ThalassaemiaTools

(
CMRtools
)


cmr
42


FerriScan


MRmap


MATLAB


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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


cmr
42(3)


Easy to use


FDA approved
3


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.

1
www.cmrtools.com/
cmrweb
/ThalassaemiaToolsIntroduction.htm. Accessed Dec 2010.
2
Pennell DJ.
JACC
Cardiovasc

Imaging.
2008;1:579
-
81.
3
www.circlecvi.com. Accessed Dec 2010.

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Method

Pros

Cons

FerriScan
1


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

MRmap
2


Uses IDL runtime, which is a commercial software
(less expensive than cmr
42
/CMRtools)


Can quantify T1 and T2 map with the same
software


Purely a research tool


Not intended for diagnostic or
clinical use


MATLAB
3


Low cost


Available only locally


Physicists or engineers need to
write a MATLAB program for
display and T2* measurement

1
www.resonancehealth.com/resonance/ferriscan. Accessed Dec 2010.
2
www.cmr
-
berlin.org/forschung/
mrmapengl/index.html. Accessed Dec 2010.
3
Wood JC, Noetzli L.
Ann N Y Acad Sci.
2010;1202:173
-
9.

Analysis of the data (cont.)

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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):

1.

the offset model (Prof Wood and colleagues)

2.

truncation of the data (Prof Pennell and colleagues)


Both models should give comparable results; the differences should
not be clinically relevant

1
Wood JC, Noetzli L.
Ann N Y Acad Sci
. 2010;1202:173
-
9.
2
Ghugre NR, et al.

J Magn Reson Imaging
.
2006;23:9
-
16.

Signal decay curve from a patient with
T2* ≈ 5 ms, showing that the data do
not fit well
2

FAQ: Mistakes in analysing the data

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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 R
2

> 0.995. 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* measurements
1

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

1
He T, et al.
Magn Reson Med.
2008;60:1082
-
9.
2
Ghugre NR, et al
. J Magn Reson Imaging
.
2006;23:9
-
16.

FAQ: Mistakes in analysing the data (cont.)

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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:

1.
Check MRI machine requirements


1.5 T


calibrated

2.
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)

3.
Optional: buy software for analysing the data (if not, Excel spreadsheet can
be used)

4.
Highly recommended: training of personnel for acquisition of cardiac MR
images (e.g. functional analyses)

5.
Highly recommended: training of personnel on how to analyse the data
with the chosen software

FAQ: How to start measuring cardiac