`doi:l0.l053/euhj.200].2822. available online at http:/lwwwjdealibrary.com on "IE #1,.
`
`Cardiovascular T2-star (T2*) magnetic resonance for
`the early diagnosis of myocardial iron overload
`
`L. J. Anderson‘. S. Holdenz, B. Davisz, E. Prescott”, C. C. Charrier‘,
`N. H. Bunce‘, D. N. Firmin‘, B. Wonke”, J. Porter’, J. M. Walker2 and
`D. J. Pennell1
`
`'Curdt'm'ascular MR Unit, Royal Brampton Hospital, London; 2Unt‘twrsiry College Hospital. London:
`3Wl'u‘rrirrgrorr Hospital. London. UK.
`
`Alms To develop and validate a non-invasive method for
`measuring myocardial iron in order to allow diagnosis and
`treatment before overt cardiomyopathy and failure develops.
`
`Methods and Results We have developed a new magnetic
`resonance Til-star (TZ‘) technique for the measurement of
`tissue iron, with validation to chemical estimation ofiron in
`patients undergoing liver biopsy. To assess the clinical value
`of this technique. we subsequently correlated myocardial
`iron measured by this T2‘
`technique with ventricular
`function in 106 patients with thalassaemia major. There
`was a significant. curvilinear, inverse correlation between
`iron concentration by biopsy and liver T2“ (r=0~93,
`P<0-000|). Inter-study cardiac reproducibility was 5~0":u.
`As myocardial
`iron increased.
`there was a progressive
`decline in ejection fraction (r=0-6l. P<0‘00l). All patients
`with ventricular dysfunction had a myocardial T2' of
`<20 ms. There was no significant correlation between
`myocardial T2‘ and the conventional parameters of iron
`status. scrum ferritin and liver iron. Multivariate analysis of
`clinical parameters to predict the requirement for cardiac
`
`medication identified myocardial ’1‘? as the most signifi-
`cant variable (odds ratio 0-79. P<0-002).
`
`iron deposition can be repro-
`Conclusions Myocardial
`ducibly quantified using myocardial T2“ and this is the
`most significant variable for predicting the need for ven~
`tn'cular dysfunction treatment. Myocardial
`iron content
`cannot be predicted from serum ferritin or liver iron. and
`conventional asseSSmcnts of cardiac function can only
`detect those with advanced disease. Early intensification of
`iron chelation therapy, guided by this technique. should
`reduce mortality from this reversible cardiomyopathy.
`(Eur Heart .1 20m; 22: 2171—2179, dol:lll.lll§3lctth].200l.
`2822)
`.t_:u 200] The European Society of Cardiology
`
`Key Words: Cardiomyopathy, magnetic
`imaging. heart failure and thalassaemia.
`
`resonance
`
`See page 2MB, dnirlDJ053leuhi.2000.295l for the Editorial
`comment on this article
`
`
`
`Introduction
`
`Cardiac failure secondary to transfusional iron overload
`remains the commonest cause of death in patients with
`thalassaemia major“ '2'. In the United Kingdom. approxi-
`mately 50'I-E. of patients die before reaching the age of
`35”]. The cardiomyopathy is reversible if intensive iron
`chclation treatment is instituted in time['1 ('i, but diagnosis
`is often delayed by the unpredictability of cardiac iron
`deposition and the late development of symptoms. and
`echocardiographic abnormalitiesl""'. Once heart failure
`
`Revision submitted ll June 200i. accepted 13 June 200], and
`published l9 October lefil.
`Correrpmnlmuc Professor D. J. Pcnncll. Cardiovascular MR Unit.
`Royal Brampton Hospital. Sydney Street. London SW3 6NP.
`U.K.
`
`0|95-668X1‘UII2221'II +09 535.001'0
`
`develops, the outlook is usually poorM with precipitous
`deterioration and death, despite intensive chclation.
`Direct measurement of myocardial
`iron would allow
`earlier diagnosis and treatment and help to reduce
`mortality from this reversible cardiomyopathy.
`The aim of this study was to develop a reproducible
`magnetic resonance (MR) method for quantifying
`myocardial
`iron concentration. For this purpose. we
`investigated myocardial TZ-star (T2*). a relaxation par-
`ameter arising principally from local magnetic field
`inhomogeneities that are increased with iron deposition.
`Although a rare disease in the UK. thalassaemia
`the commonest genetic disorder worldwide. with
`is
`approximately 94 million licterozygotes for beta thalas-
`sacmia and 60 000 homozygotes born each year'””. Iron
`overload cardiomyopathy is also a complication of
`hereditary haemocltromatosis. which predominantly
`
`t
`
`- 20ll| The European Society of Cardiology
`
`Apotex Tech.
`Ex. 2015
`
`
`
`2l72 L J. Anderson et al.
`
`
`affects those of northern European ancestry, where
`homozygous mutations of the HFE gene approximate
`06%”. Patients receiving multiple transfusions during
`chemotherapy and bone marrow transplant. or for other
`indications such as sickle cell anaemia. may also benefit
`from assessment with this technique.
`
`Methods
`
`Study populations
`
`Liver biopsy patients
`We prospectively studied 30 beta-thalassaemic patients
`(12 females and 18 males. aged 18 38, mean 27-l i 6-7
`years) undergoing liver biopsy for routine clinical man-
`agement. The biopsy iron concentrations were compared
`with the liver TZ“ measurements derived by MR. All
`scans were performed within 21 days of the liver biopsy
`(mean 10 :l: 7-0 days) and no adjustments to chclation
`treatment were made between investigations. in 27 cases,
`a section of the biopsy specimen was also examined
`histologically (cirrhosis 3 patients. periportal fibrosis
`l0 patients).
`
`Tlralnssaemia major coliort
`A total of
`i09 regularly transfused patients with
`thalassaemia major were scanned. Three patients were
`excluded from comparison analysis of ventricular func~
`tion due to cardiac anomalies (l corrected tetralogy of
`Fallot,
`l subaortic shelf and l peripheral pulmonary
`artery stenosis). The residual cohort of l06 patients
`included 50 males and 56 females. aged l3—4l, mean
`27*? years. All patients had received iron chelation
`therapy since the mid-to-late 19705. or from early child-
`hood in patients born after this time. with a broad
`range of compliance to treatment (serum ferritin 262
`7624 pg . l‘ 1, mean 2095 e. [559 pg .l' '). Seventeen
`patients required medication for ventricular dysfunc-
`tion (antiarrhythmics or angiotensin-convertEng-enzyme
`inhibitors).
`
`Normal subjects
`Normal ranges for T2‘ values in the liver. heart. spleen
`and skeletal muscle were established in
`IS healthy
`volunteers (9 males, 6 females, aged 26-39. mean
`3! i 3-? years).
`
`Liver biopsy iron assays
`
`All biopsy specimens were analysed at the Royal Free
`Hospital, London' '1'. The dry weights of all specimens in
`this study exceeded 05 mg (mean 1-33 :l- 0-59 mg).
`
`Serum ferritin measurements
`
`Measurements of serum ferritin were carried out by
`enzyme immunoassay (WHO Ferritin 80/602 First
`International Standard. nonnal range IS 300 pg .
`l ' ').
`
`Magnetic resonance
`
`Patients were scanned with a Picker l‘ST Edge Scanner
`(Marconi Medical Systems, Ohio, U.S.A.). Each scan
`lasted approximately 45 min and included the measure-
`ment of liver and heart T2“. and left and right ventricu—
`lar
`function. volumes
`and mass
`using standard
`techniquesl"‘l.
`The liver T3!“ was determined as follows: a single
`l0 mm slice through the centre of the liver was scanned
`at eight different echo times (TE 2-2-20-1 ms). Each
`image was acquired during a l0 l3 s breath-hold using
`a gradient-echo sequence (repetition time 200 ms, flip
`angle 20‘, matrix 96 x IZS pixels, field of view 35 cm,
`sampling bandwidth of l25 kHz). The signal intensity of
`the liver parenchyma and the background noise were
`measured in each of the eight images using in-housc
`software (CMRtools.
`('1 Imperial College). Background
`noise was subtracted from the liver signal intensity, and
`the net value was plotted against the echo time for each
`image. A trendline was fitted to the resulting exponential
`decay curve, with an equation of the form y= Kc m”?
`where K represents a constant, TE represents the echo
`time and y represents the image signal intensity.
`For the measurement of myocardial T2",
`at single
`short axis mid-ventricular slice was acquired at nine
`separate echo times (TE 5-6—17-6 ms). The repetition
`time between radiofrequency pulses was between [1-8
`23.8 ms. depending on the echo time used. A gradient
`echo sequence was used (flip angle 35', matrix IZS X 256
`pixels, phase encode group 8.
`field of view 35 cm,
`sampling bandwidth of 250 kHz). The repetition time
`was adjusted to the patient‘s heart rate. Each image was
`acquired during an 8 l3 s breath-hold. A gating delay
`time of Orns after the R-wave was chosen in order to
`obtain myocardial images in a consistent position in the
`cardiac cycle irrespective of the heart
`rate. A full-
`thickness region of interest was measured in the left
`ventricular myocardium, encompassing both epicardial
`and endocardial regions. This was located in the septum,
`distant from the cardiac veins. which can cause suscep-
`tibility artefactsl'". The myocardial T2!“ was calculated
`using the same method as that in the liver.
`
`Statistical analysis
`
`l standard
`Summary data are presented as mean :l:
`deviation. Pearson’s and Spearman‘s tests were used to
`assess the correlation between liver iron and liver T2“.
`For reproducibility data, the coellicient of variation was
`defined as the standard deviation of the differences
`between the two separate measurements, divided by
`their mean and expressed as a percentage. T2“ values
`measured in healthy volunteers showed a normal distri-
`bution and are expressed with 95% reference ranges.
`Pearson‘s coefficient ofcorrelation was used to assess the
`degree of association between myoeardial T2" and liver
`
`
`
`CMR for early diagnosis of cardiac iron overload 2173
`
`l-IHMtoo:o:DUrQtn0U!
`
`GI
`
`0
`
`2-5
`
`to
`
`0-5
`
`0
`
`15
`Liver T2“ (ms)
`
`0))
`
`o
`
` 1
`
`—0-5
`
`0
`
`0-5
`
`1
`
`1-5
`
`2
`
`2-5
`
`3
`
`35
`
`Log? liver 1‘2“
`
`(5!) Regression curve for the relationship between liver T2* and liver
`Figure l
`biopsy iron concentration. Black circles depict librotic biopsies, and squares depict
`non-llbrotic biopsies. The flbrotic samples show increased variability, compatible
`with previous reports. (b) There was a close linear relation between 1'2" and liver
`iron concentration in the non-flbrotie samples following log,
`transformation
`(r=ll'93, P<ll.0001), see text for details.
`
`T2‘ and myocardial T2* and serum fcrritin. Stata
`statistical software was used for computations (Stata
`Corporation, Texas, U.S.A.).
`
`Results
`
`Validation of T2* values as a measurement
`oftissue iron concentration
`
`There was a significant, curvilinear. inverse correlation
`between liver T2“ and the liver iron content for all
`samples (r=0v8|, Fig.
`l(a)). There was a better corre-
`
`the fibrotic samples (FD-68). as would be predicted
`from the known variability of iron measurements
`from fibrotic biopsics'” ”'1. Therefore we subsequently
`employed non-fibrotic samples to generate predictions
`of liver iron content from the measured T2“ values. As
`liver iron concentration and liver TI!" measurements
`were positively skewed. the values were logc transformed
`in order to analyse the correlation (Fig.
`|(b)). For the
`non-fibrotic samples, both Pearson’s and Spearman‘s
`tests gave a correlation coellicient of 0-93 which is highly
`significant (P<0'000l ). Regression analysis shows that a
`one unit increase in log. T2" is associated with a l-O'i
`unit increase in log iron concentration (95% confidence
`
`
`
`2l74 L. J. Anderson et al.
`
`
`Reproducibility
`
`Ten patients were scanned on two occasions to assess the
`inter-study reproducibility of the T2" teehniq uc (interval
`1 2i days. mean 7-1 days). The eoellieient of variation
`was 36% for the liver and 50% for the heart. This
`compared favourably with coefficients of variation for
`signal
`intensity ratio measurements from these same
`images (liver-to-muscle 79%. liver-to-noisc 8‘8'i’... heart-
`to-musclc I2'6%, and heart-to-noisc l4'l"-'=-). techniques
`that have previously been used.
`The images from l0 patients were studied indepen-
`dently by two observers to assess inter-observer varia-
`bility. The coelficient of variation was 4-59!" for the liver
`and 64% for the heart. This compared favourably with
`signal
`intensity ratio measurements (liver-to-musele
`54%,
`liver-to-noisc 6-l"u, heart-to-muscle [08's. and
`heart-to-noise 76%).
`
`Normal 71".?“ values
`
`The normal values for 1‘? using the technique described
`above Were: Heart 52 i l6ms. liver 33 :l: 7ms. skeletal
`muscle 30 :i: 5 ms. spleen 56 :l: 22 ms.
`
`Heart iron, liver iron, serum ferritin and the
`relationships between these variables
`
`In many patients we found a marked discordance
`between liver and heart iron concentration (Fig. 2) and
`no significant correlation could be found between liver
`and heart T2‘ in this large cohort (r=0-l5, P=0-ll).
`Similarly. no significant correlation was found between
`heart T2‘ and serum ferritin level at the time of the scan
`(r=0‘l0, P=0-32). To confirm that this finding was not
`due to spurious individual ferritin readings.
`the mean
`ferritin for 12 months prior to the scan was also com-
`pared to heart T32“, and once again there was no
`significant correlation (r=0-09. P=O’35).
`
`Myocardial iron and parameters of
`ventricular function
`
`In the normal range of myocardial T2‘ (Iowa 95""
`confidence interval 20 ms), parameters of ventricular
`function (ejection fraction, volume and mass) fell within
`the normal rangel'" (Fig. 3). Below a myocardial T2" of
`20 ms. there was a progressive and significant decline in
`left ventricular ejection fraction (r=0v6l, P<D'000I) and
`an increase in the left ventricular end-systolic volume
`index (r=0-50. P<l)-000l), and left ventricular mass
`index (r=0‘40. P<0-00l).
`
`Myocordiol T2* and clinical outcome
`
`Logistic regression was performed to relate the require-
`ment for cardiac medication to seven clinical covariates.
`
`
`
`
`Figure 2 Discordance of liver and heart iron deposition.
`Short axis plane. including the adjacent liver (TE 5-6 ms).
`The top panel shows a patient with severe cardiac iron
`deposition but minimal liver iron deposition (heart darker
`than liver). The lower panel shows a patient with normal
`myocardial iron but severe liver iron overload (liver darker
`than heart).
`
`I? patients required medication for
`or [06 patients.
`ventricular dysfunction. and univariate analysis identi-
`fied myocardial T21",
`left ventricular ejection fraction
`and left ventricular end systolic volume as significant
`variables (Table 1). Using multivariate backward step-
`wise regression analysis. with a cut-oll' of P=0-l
`for
`removing variables and P=0-05 for including variables.
`only myocardial TZ‘ (odds ratio 0-79. 95"»1'. confidence
`interval 0-67 0-92, P=0-002) and serum ferritin (odds
`ratio 0-95. 95% confidence interval 0-9] 1-00, P=0-05)
`were significant. Depite the lack of correlation between
`
`
`
`CMR for eerily diagnosis of cardiac iron overload 2! 75
`
`
`..
`n
`.i!
`.
`(a)
`""‘="';'-“-}-s-;-'.‘;-‘"-‘ :;‘*.'*‘
`3%):
`c .
`g-
`
`0
`
`10
`
`20
`
`30
`
`60
`50
`40
`Heart T2" (m5)
`
`70
`
`80
`
`90
`
`100
`
`160
`
`140
`
`120
`
`100
`
`80
`
`60
`
`40
`
`—_..’---_-_-_..__————L-
`20
`(mlat
`end-systolicvolume
`Index
`
`0
`
`10
`
`21]
`
`30
`
`60
`50
`40
`Heart 1‘2" ([115)
`
`70
`
`80
`
`90
`
`100
`
`.2]
`
`0
`
`10
`
`20
`
`30
`
`60
`50
`40
`Heart 1'2" (ms)
`
`70
`
`80
`
`90
`
`100
`
`Figure 3 Relationships between myocardial T2* values and parameters at ventricular
`function: (a) left ventricular ejection fraction, (b) left ventricular mass index,
`to) left
`ventricular end-systolic volume index. The broken lines represent
`the normal reference
`ranges for myocardial T2* and parameters of cardiac function.
`
`
`
`2176 L J. Anderson et a].
`
`
`
`Figure 4 MR gradient echo images of dill'ercntial tissue iron clearance before and during
`intravenous chelation therapy: before treatment (top row), after 3 months (middle row) and
`after 6 months of treatment (bottom row). The left column shows the liver (transaxial view,
`TE 4.5 ms), and the right column shows the heart (horizontal long axis, TE [4 ms), which is
`dilated (RV — right ventricle 182 ml end-diastolic volume, LV — left ventricle I83 ml end
`diastolic volume). There is severe iron loading (dark tissue signal) in the liver (L), pancreas
`(P) and heart prior to treatment (liver T2*= [-2 ms, myocardial T2*= 10 ms). By 3 months,
`the liver iron is noticeably improved (liver T2*=5-l ms), but cardiac iron deposition has
`changed little ('l‘2*=10~l ms). Myocardial iron deposition only shows improvement at 6
`months (T2*=12°l ms) and even at
`this time the heart remains dilated (end-diastolic
`
`
`
`CMR firr early diagnosis of cardiac iron overload 2177
`—————-—-—-————-—-——___—_—_—
`
`for cardiac medication. This may be related to increased
`clinical vigilance in the treatment of patients with high
`serum ferritins. As cardiac medication had been initiated
`in all patients prior to CMR scanning. physicians were
`blinded to myocardial TI!" measurement. Myocardial
`TZ“ values were between 4-9 ms and 13 ms in this
`group.
`
`Discussion
`
`Iron overload pathophysioiogy
`
`Iron overload occurs either due to excess gastrointestinal
`absorption or secondary to repeated blood transfusions.
`The human body has no mechanism for excreting excess
`iron. which is stored as crystalline iron oxide within
`ferritin and haemosiderin in the body. The aetiology of
`the iron overload effects the tissue distribution of iron.
`In hereditary haemochromatosis, iron is carried from
`the intestine to the liver via the portal vein (as transfer-
`rin) and deposited in the periportal hepatocytes.
`In
`severe disease,
`iron is also deposited in the pancreas.
`heart and endocrine organs. In thalassaemia. iron over-
`load results from both excessive iron absorption and
`transfusional siderosis. Transfusional iron leads to iron
`deposition in the reticulo-endothelial system of the
`spleen, liver and bone marrow. In advanced cases iron
`also accumulates in parenchymal cells of the liver. heart,
`pancreas and endocrine organs, which are sensitive to
`the toxic effects of iron. When the iron-binding capacity
`of transferrin is exhausted. free iron appears as non-
`lransferrin bound iron (NTBI). The toxicity of NTBI is
`much higher than bound iron, and promotes hydroxyl
`radical formation resulting in peroxidative damage to
`membrane lipids and proteins. In the heart this results in
`impaired function of the mitochondrial
`respiratory
`chain and is manifested clinically as heart failurel'“.
`The presence of two types of iron explains the nature
`of the relationship between myocardial function and
`iron concentration (as shown in Fig. 3). As iron accu-
`mulates in the normal storage form in the heart, the TI!"
`falls, but there is little clfeet on cardiac function until a
`threshold is reached where the iron storage capacity is
`exhausted. At this point NTBI starts to appear, which
`profoundly affects cardiac function. Thus the relation-
`ship between the measured TI’.‘ and cardiac function is
`shallow until a critical level is reached. after which rapid
`deterioration occurs. This explains why identification of
`abnormal systolic function is a late sign of iron toxicity.
`Iron clears more slowly from the heart than the liver
`(Fig. 4), which may contribute to the high mortality of
`patients with established cardiomyopathy despite inten-
`sive chelation. Using this T2“ technique, it is possible to
`identify much earlier those patients who require inten-
`sive cltelation prior to the onset of systolic dysfunction
`and this should avoid the mortality associated with overt
`heart failure.
`
`Table l Univariate analysis of clinical variables to test
`the strength of their relationship to the need firr cardiac
`medication
`
`
`
`
`
` Variable Odds ratio (95% Cl) P value
`
`0003
`0-81 (0-7], 0-93)
`Myocardiul TZ‘ (ms)
`<0'00I
`0-88 (0-82. 0-94)
`LVEF ("o)
`0'00]
`l~05 (Mil. l-OS)
`LVESV (ml)
`0'17
`09? (0-93. l‘Dl)
`Serum ferritin (pg. I
`0'85
`l‘DI (0'91, l'l2)
`Liver Tl‘ (ml)
`039
`1-58 (0‘56. 4-5l)
`Diabetes mellitus
`
`
`HJI [0-94. 1'08)Age "~85
`
`')
`
`Cl=conlidenoc interval; LVEF=left ventricular ejection fraction:
`LVESV=lcft ventricular end systolic volume.
`
`MR T.” technique to measure myocardia!
`iron
`
`We chose a gradient-echo TZ" sequence rather than a
`spin-echo T2 sequence because of the greater sensitivity
`to iron deposition. T2“ is related to T2 by summation of
`tissue relaxation (T2), and magnetic inhomogeneity.
`known as T2 prime (T2‘). in the form:
`UTE“: llTl'l-IITZ‘
`
`loss in affected tissues
`Iron overload causes signal
`because iron deposits become magnetized in the scanner,
`inducing local irregularities in the magnetic field. which
`cause water protons around these deposits to lose phase
`coherencelw'. This effect is concentration dependent'm'.
`An additional benefit of the shorter acquisition times
`of gradient-echo images is minimization of motion
`artefacts from myocardial contraction and respiratory
`movement, which greatly alTect
`the accuracy and
`reproducibility of T2 images.
`Previous work using spin-echo techniques with signal-
`intensity-ratios or T2 measurements. have shown an
`inverse relationship to liver iron eoncentrationlz'i‘“.
`However. in practice. the limited sensitivity of spin-echo
`techniques. motion artefacts and poor signal to noise
`at longer echo timesm‘n'z”, have made quantification
`of myocardial
`iron
`unsatisfactorylz‘“. Because of
`these problems, gradient-echo techniques using signal-
`intensity-ratios have recently been used to quantify liver
`ironm 39]. but no studies in the heart have been
`reported. We have used multiple echoes to generate T2*
`instead of relying on signal
`ratios between tissues,
`and for the first time have applied the technique to the
`heart. This range of echo times improves quantification
`of severe iron overload, provides high sensitivity at
`low and normal
`tissue iron levels, and gives greater
`reproducibility than signal intensity ratios.
`The normal value of myocardial 1‘2" in this study was
`52¢ [6 ms. There is limited literature with which to
`compare these results. Li et of. studied l3 normals and
`reported a T2“ of 33 i 65 ms, but only two echo times
`were usedl'm'. Wacker et nl. reported the normal myo-
`
`
`
`L. J. Anderson el al.
`2178
`——-—————-——.—_—_——___—,__
`
`(remote from ischaemia) as 48 £29 ms using a 10 echo
`time techniquela". Reeder reports normal T2‘ values of
`38 :t 6ms in the mid septum in five normal volunteers,
`and showed reduced values adjacent to the cardiac veins
`due to their local susceptibilityll‘”. The variation in these
`values may result from residual Tl effects associated
`with the short repetition times imposed in breath-hold
`acquisitions, and may lead to over-estimation of T2“.
`However.
`this effect
`is much less significant
`in the
`presence of short myocardial T? values
`in
`iron
`overload.
`
`Validation of T2* measurements. and
`variability between tissues
`
`We have shown a significant curvilinear correlation
`between liver T2‘ and biopsy iron concentration
`(r=0-93. P<0-000l. for non-fibrotic livers). Using the
`T2'
`technique in a large cohort of patients, we also
`found that
`there is no reliable relationship between
`myocardial 1'2" and serum ferritin or liver T2‘. This
`indicates that cardiological management based on these
`established parameters of iron status is unreliable.
`
`Heart failure and causality
`
`The poor predictive value of serum ferritin and liver iron
`measurements have made heart disease difficult to detect
`in thalassaemia. raising questions over the causal re-
`lationship between cardiac iron overload and cardiac
`l'ailurel32 3‘". Recently, myocarditis has been implicated
`in the development of heart failure in thalassaemiaw'w.
`This
`study demonstrates
`the
`relationship between
`deterioration in ventricular function and myocardial
`iron loading and illustrates clear evidence for the causal-
`ity of iron overload and heart failure in thalassaemia
`patients. Whilst our study supports the aetiological role
`of iron in thalassaemic cardiomyopathy. other factors
`such as antioxidant state'm may also be important.
`
`Study limitations
`
`It is not possible definitively to predict myocardial iron
`concentration from the myocardial TZ‘ value. because
`no validation has been performed with cardiac tissue.
`This requires myocardial biopsies and will be difficult
`because of inhomogenous myocardial depositionl3"""5'
`and small samples. Nonetheless. the data presented in
`this study, showing the strong relationship between
`declining myocardial 1‘2" and impaired ventricular func-
`tion. clearly indicates the empirical value of myocardial
`T2". and the validation data from the liver biopsies
`supports the relationship between tissue iron and T2*.
`The TI!" of iron-loaded tissue decreases with increas-
`ing field
`strength and therefore the
`threshold of
`
`addition, relaxation parameters such as T2‘ may be
`machine and sequence dependent, and further validation
`work is required before widespread use.
`
`Conclusions
`
`Gradient-echo T2"' MR provides a rapid, non-invasive.
`reproducible means
`for assessing myocardial
`iron.
`Myocardial
`iron content cannot be predicted from
`serum ferritin or liver iron. and conventional assess-
`ments of cardiac function can only detect
`those with
`advanced disease. Early diagnosis and treatment of
`myocardial
`iron overload is
`likely to prevent
`the
`mortality seen in patients with established ventricular
`dysfunction.
`
`Melissa Wright of the Hammersmith Hospital. London gave
`valuable statistical advice. This work was supported by a British
`Heart Foundation Junior Fellowship Grant
`(FSI9806-l).
`the
`Wellcomc Trust. and CORDA. the heart charity.
`
`References
`
`[I] Zurlo MG. De Stefano P. Borgna-Pignatti C at at. Survival
`and causes of death in thalassaemic major. Lancet
`l9li9; 2:
`27 30.
`{2] Olivicri NF. Nathan DG. MncMillan ll! et of. Survival
`in medically
`treated patients with homozygous
`bela-
`thalassacmia. N Engll Med 1994; 33f: 574 R.
`[3] Modcll B. Khan M. Darlison M. Survival in beta thalassaemia
`major in the UK: Data from the UK Thalassacmiu Register.
`Lancet 2000; 355 (9220): 205] 2.
`[4] Aldouri MAWB. Hoffbrand AV. Flynn DM. Ward SE.
`Agnew .IE.
`lIilson A]. High incidence of cardiomyopathy
`in beta-thttlassacmitt patients receiving regular transfusion
`and iron ehclntion:
`reversal by intensified chelution. Acta
`Haematol I990; 84: ll] 1.
`l. Wyss M.
`[S] Wuckcr PHD. Balmcr-Rucdin D. Obcrhansli
`Regression of cardiac insufficiency after ambulatory intm-
`venous dcferoxaminc in thalassaemia major. Chest l993; [03:
`1276 8.
`[6] Davis BA. Porter 18. Long-ten-n outcome of continuous
`24-hour dcf‘eroxaminc infusion via indwelling intravenous
`catheters in high-risk beta-thalassaemia. Blood 2000; 95:
`1229 -36.
`[7] Henry WLNA. Wiener M. Miller DR. Canalc VC. Piomelli S
`Echocardiographie abnormalities
`in patients with trans-
`fusion-dependent anaemia and secondary myocardial
`iron
`deposition. Am J Med 1978; 64: 547 55.
`[8] Nienhuis AW. Griffith l". Strawczynski H et al. Evaluation
`of cardiac function in patients with lhalussacmia major. Ann
`NY Acad Sci 1980:344: 384 96.
`[9} Fclkcr GM. Thompson RE. Hare JM et ui. Underlying causes
`and long-term survival in patients with initially unexplained
`cardiomyopathy. N Eng] J Med 2000; 342'
`IO'J'? 84.
`:ltl] Weathcrall DJ. Anaemia as a World Health Problem. Oxford
`Textbook of Medicine. Oxford University Press I996. 22:
`3463 82.
`[3. Summervillc L.
`[ill Olynyk JK. Cullen DJ. Aquiliu S. Rossi
`Powell LW. A population-based study of the clinical expres-
`sion of the hemochromatosis gene. N Engl J Med [999. 34]:
`Till 24
`liver-iron
`of
`5 Measurement
`Sherlock
`[III Barry M.
`concentration in needle-biopsy specimens Lancet Hill;
`1:
`"NJ.
`13E. Van
`[13] Pattynama PM. Dc R005 A. Van dcr Wall
`Voorthutsen AE. Evaluation of cardiac
`function with
`
`
`
`CMR jin- eurly diagnosis of cardiac iron overload 2179
`—-———.—_.—___——________—______
`
`In
`[l4] Reader SB. Fantnesh AZ. Boxerman JL. McVeigh ER.
`vivo measurement of T2" and field inhomogeneity maps in the
`human heart at LST. Magn Reson Med I998: 39: 988 98.
`[IS] Villeneuve JP. Bilodeau M. Lepage R. Cote J. Lefebvrc M.
`Variability in hepatic iron concentration measurement from
`needle-biopsy specimens. J llepatol 1996:25: 172-7.
`[16] Emond MJ. Bronncr MP. Carlson TI-l. Lin M. Labbe RF.
`Kowdley KV. Quantitative study of the variability of hepatic
`iron concentrations. Clin Chem I999: 45: 340—6.
`[l7] Lorenz CH. Walker ES. Morgan VL. Klein 55. Graham TP.
`Normal human right and left ventricular mass. systolic
`function. and gender differences by cine magnetic resonance
`imaging. J Cardiovasc Magn Reson I999: I: 'l 2!.
`[I8] Hershko C. Link G. Cabantchik l. Pathophysiology of iron
`overload. Ann NY Acad Sci 1998; 850: I9! 20L
`[[9] Stark DD.
`l-Iepatie iron overload: paramagnetic pathology.
`Radiology I99]; 179: 333 5.
`[20] Hardy PA.
`licnltelman RM. Transverse relaxation rate
`enhancement caused by magnetic particulates. Magn Reson
`Imaging I989; 7: 265 75.
`[2|] Kallwasser JPGR. Schallt KP. Hartl W. Non-invasive
`quantitation of liver iron-overload by magnetic resonance
`imaging. Br! Haematol 1990; 74: 360 -3.
`22] Gomori JMHG. Tamary H. Zandbaek .l at al. Hepatic iron
`overload: quantitative MR imaging. Radiology l99l: £79:
`361-9.
`[23] Jensen PDJF. Christensen T. Ellegaard .l. Non-invasive
`assessment of tissue iron overload in the liver by magnetic
`resonance imaging. Br] l-lacmatol I994; 87: I'll-84.
`[24] Liu PP. I'lenkelman M. Joshi J er a1. Quantification ofcarcliae
`and tissue iron by nuclear magnetic resonance rclaxometry in
`a novel marine thalassaemia
`cardiac iron overload model.
`Can J Cardiol I996; 12: l55-64.
`l-ledrick TD. Roitcy R.
`[25] Johnston DL. Rice L. Vick W.
`Assessment of tissue iron overload by nuclear magnetic
`resonance imaging. Am J Med 1989; 8?: 40 7.
`[26] Mavrogcni SI. Gotsis ED. Markussis V or a]. T2 relaxation
`time study ofiron overload in b-thalassemia. MAGMA l998;
`6: 7 l2.
`[2?] Gandon Y. Guyadcr D. l'leautot JF er al. l-lemochromatosis:
`diagnosis and quantification of liver iron with gmdient-eeho
`MR imaging. Radiology I994; 193: 533 8.
`
`[28] Ernst OSG. Bonvarlct P. Canva-Deleambre V. Paris JC.
`L'llcrminc C. Hepatic iron overload: diagnosis and quantili-
`cation with MR imaging. AJR Am J Rocntgenol 1997: 168:
`l205 -8.
`
`[29] Bonkovslty HLRR. Cable EE. Davidoll' A. Rijcltcn TH. Stark
`DD. Hepatic iron concentration: noninvasive estimation by
`means of MR imaging techniques. Radiology I999: 212:
`227 34.
`
`I-laacke EM. Gropler RJ.
`[30] Li D. Dhawale P. Rubin PJ.
`Myocardial signal response to dipyridamole and dobutamine:
`Demonstration of the BOLD elfect using a double echo
`gradient echo sequence. Magn Reson Med I996; 36: 1640.
`[SI] Wackcr CM. Bock M. l-lartlep AW et al. BOLD-MRI in it)
`patients with coronary artery disease: Evidence for imaging of
`capillary recruitment in myocardium supplied by the slenotie
`artery. MAGMA 1999: 8: 4B 54.
`and
`{32] MacDonald RA. Mallory GK. Hemoehromatosis
`hemosiderosis; study onII autopsied cases. Arch Intern Med
`(Chicago) l960; 105: 686- 700.
`[33] Buja LM. Rubens WC. Iron in the heart. Etiology and clinical
`significance. Am J Med l9l‘l: 5|: 209 -2l.
`[34] Jessup M. Manno CS. Diagnosis and management of iron-
`induced hcan disease in Cooley's anemia Ann NY Acad Sci
`l998: 850: 242- 50.
`[35] Kremastinos DT. Tiniakos G. Theodoraltis GN. Katritsis
`DG. Toutouzas PK. Myocarditis in beta-thalassaemia major.
`A cause of heart failure. Circulation I995; 9!: 66-1].
`[36] Kremastinos DT. Flcvari
`l'. Spyropoulou M. Vrettou H.
`Tsiapras D. Stavropoulos-Giokas CG. Association of heart
`failure in homozygous bcta-thalassacmia with the major
`histocompatibility complex. Circulation 1999;
`IOO: 2074-8.
`{37] Economou-Petersen E. Aessopos A. Kladi A er al. Apolipo-
`protein E epsilon4 allele as a genetic risk factor for left
`ventricular failure in homozygous beta-thalassemia. Blood
`I998; 92: 3455 9.
`[38] Barosi G. Arhustini E. Gavazzi A. Grasso M. Pucci A.
`Myocardial
`iron grading by endomyocardial biopsy. A
`clinico-pathologic study on iron overloaded patients. Eur J
`Haematol I989; 42‘ 382 8.
`
`