Hemoglobin, 30 (2):219–227, (2006)

Copyright © Taylor & Francis Group, LLC

ISSN: 0363-0269 print/1532-432X online
DOI: 10.1080/03630260600642542

PROCEEDINGS 15TH ICOC

Hemoglobin, Vol. 30, No. 02, March 2006: pp. 0–0
1532-432X
0363-0269
LHEM
Hemoglobin

Taiwan, April 2005

LOW SERUM FERRITIN LEVELS ARE MISLEADING FOR DETECTING

CARDIAC IRON OVERLOAD AND INCREASE THE RISK OF
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CARDIOMYOPATHY IN THALASSEMIA PATIENTS. THE

IMPORTANCE OF CARDIAC IRON OVERLOAD MONITORING
USING MAGNETIC RESONANCE IMAGING T2 AND T2*

Annita Kolnagou, Charalambos Economides, Eleni Eracleous, and

Prevention
A. KolnagouofetCardiomyopathy
al. by Chelation and MRI

George J. Kontoghiorghes
Postgraduate Research Institute of Science, Technology, Environment and Medicine,
For personal use only.

Limassol, Cyprus

䡺 The incidence of cardiomyopathy was monitored in a 6-year follow-up study involving 56 trans-
fused thalassemia patients treated with deferoxamine (DFO), deferiprone (L1) or their combination.
During this period, five female patients on regular subcutaneous or intravenous DFO presented
with cardiac complications. Three patients suffered congestive heart failure and the other two
arrhythmias. Four of the five patients maintained serum ferritin levels of about 1 mg/L or below
and the fifth about 1.5 mg/L for several years prior to the cardiomyopathy. Cardiac magnetic reso-
nance imaging (MRI) T2* and T2 was performed in four patients after the cardiomyopathy, iden-
tifying the presence of moderate-to-heavy siderosis. The treatment of the five patients has since
changed, involving mainly the use of L1. Low serum ferritin levels appear to be misleading for
detecting cardiac iron overload and this may increase the risk of cardiomyopathy. The MRI T2 and
T2* relaxation time measurements are a more accurate method of detecting cardiac iron overload.
Chelation therapy using L1 or appropriate L1/DFO combinations can reduce cardiac iron overload
and the mortality rate in thalassemia patients.

Keywords Iron overload, Cardiomyopathy, Serum ferritin, Thalassemia, Deferoxamine

(DFO), Deferiprone (L1), Magnetic resonance imaging (MRI) T2 and T2*

Presented at the 15th ICOC, Taichung, Taiwan, 22–26 April 2005.

Address correspondence to Professor George J. Kontoghiorghes, Postgraduate Research Insti-
tute of Science, Technology, Environment and Medicine, 3, Ammochostou Street, Limassol 3021,
Cyprus; Fax: +357-25395926; E-mail: pri_gjk@cylink.com.cy

219
 220 A. Kolnagou et al.

INTRODUCTION
The transfusion of red blood cells (RBCs) in thalassemia and other
refractory anemia conditions causes an increase in total body iron load and
organ damage due to excess iron deposition and toxicity. Any form of
excess iron is potentially toxic, mainly because of the ability of iron to cata-
lyze the formation of toxic free radicals but also because of many other iron
overload toxicity mechanisms (1–4).
The first signs of organ damage usually appear when transfused thalas-
semia patients have received about 50–100 units of RBCs and no effective
chelation therapy. In thalassemia patients, excess iron deposition in the
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endocrine organs can cause reduced growth and absent puberty, whereas in
the pancreas it can cause diabetes (5). In the heart, any form of excess iron
may potentially be associated with irreversible heart damage, which is the
main cause of death in iron loaded thalassemia patients. Post mortem
examination of iron loaded thalassemia patients, who suffered congestive
heart failure, have indicated that excess iron in the heart is associated with
the loss of myofibers and the disruption of myocytes (6).
Serum ferritin level estimation has been the major diagnostic tool for
identifying iron deficiency and iron overload in the last 30 years. The estima-
For personal use only.

tion of iron concentration in liver biopsy samples has also been used for
monitoring iron overload and been found in many cases to be related to
serum ferritin levels. However, many unexplained deaths have occurred due
to congestive heart failure in the last 2–3 decades, despite the fact that the
affected thalassemia patients had low serum ferritin levels. This was a major
setback because not only could serum ferritin levels not predict cardiac iron
overloads but patients could have been at risk of a cardiomyopathy without
being aware of the presence of toxic iron levels in the heart. Similarly, not
only serum ferritin levels but also liver iron concentrations, estimated from
liver biopsies, also could not be used to identify the cause of the cardiomyo-
pathy or be correlated with cardiac iron overload and function.
In the past 10 years, a number of new, non invasive techniques have
been developed for assessing the concentration of iron in various organs,
especially the liver and the heart, and also for assessing the efficacy of chela-
tion therapy protocols. Superconducting quantum interference device
(SQUID)-biosusceptometry has been used mainly for liver iron estimation,
and in many cases, the results appear to be correlated with serum ferritin
levels and liver iron concentration from liver biopsies (7,8).
New non invasive magnetic resonance imaging (MRI) methods have
also recently been developed for examining cardiac iron overload in iron
loaded thalassemia patients. Increasing evidence suggests that MRI T2* and
T2 relaxation time measurements can detect the presence of excess iron in
the heart and other organs, including the liver (9–12). However, these MRI
 Prevention of Cardiomyopathy by Chelation and MRI 221

T2* and T2 methods of estimating cardiac iron overload do not appear to

correlate with serum ferritin levels or liver iron concentration in iron
loaded thalassemia patients (11,12). It is also apparent from MRI T2* and
T2 relaxation time measurements that the distribution of excess iron
between the liver and the heart is unrelated. It is also apparent that some
patients may have normal iron deposits in the liver but heavy iron deposits
in the heart, and vice versa (12). Further studies using MRI T2* and T2 and
histopathological examination of liver biopsies and post mortem heart
biopsies indicated that the distribution of iron in the liver and the heart,
and possibly in other organs, is not uniform. However, despite these and
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other limitations, MRI T2* and T2 relaxation time measurements remain,

at present, the only reliable diagnostic tools for the non invasive measure-
ments of cardiac iron overload.
Chelation therapy protocols using intensive intravenous (IV) deferox-
amine (DFO) or oral deferiprone (L1) have shown that excess cardiac iron,
which was monitored using MRI T2* and T2, can be progressively reduced
and cardiac function to be improved (13–15). Deferiprone is much more
effective than subcutaneous DFO in the mobilization of iron from the heart
because of the differences in the physicochemical and pharmacological
For personal use only.

properties between the two chelators, and also because of the mechanisms
involved in the removal of iron (2,16).

PATIENTS AND METHODS

The relationship between serum ferritin levels, cardiac iron overload
and the risk of cardiomyopathy has been evaluated in 56 thalassemia
patients over a period of 6 years. Prior to this period, all patients were
treated with subcutaneous or IV DFO. Serum ferritin levels were monitored
at about 3–5 month intervals in all the patients. The MRI T2 and T2* relax-
ation time measurements were introduced in Cyprus for cardiac and liver
iron estimations during the third year of the 6-year study period. Priority for
MRI assessment was initially given to patients with high serum ferritin levels
and those presenting cardiac complications. Monitoring of cardiac and
other organ iron overload by MRI T2 and T2* is currently carried out
mostly within a year in all thalassemia patients.
During the 6-year study period, five female patients have presented
cardiac complications at different times; three suffered congestive heart
failure and the other two arrhythmias. The DFO treatment in all five
patients was slightly different in each case. Two patients (1 and 2) received
subcutaneous DFO five or six times per week using a 24-hour elastomeric
infuser, another two patients (3 and 4) received subcutaneous DFO five
times per week using an 8–12-hour infusion with the aid of an electronic
pump, and the last patient received IV DFO via a port-a-cath device. More
 222 A. Kolnagou et al.

details of the chelation therapy and the age of the five patients with the car-
diomyopathy are given in Table 1. As indicated in Table 1, all five patients
complied well with the DFO treatment and had low serum ferritin levels
prior to the cardiomyopathy. Four of the five patients maintained serum
ferritin levels at about 1.0 mg/L or below, and one about 1.5 mg/L for sev-
eral years before the cardiomyopathy (Table 1).
The cardiac symptoms, echocardiographic findings and the diagnosis
for the cardiomyopathy in all five patients are given in Table 2. The ejection
fraction (EF), left-ventricular end-diastolic dimension (LVEDD), fraction
shortening (FS) and the ratio between the protodiastolic wave (E) and tele-
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diastolic wave (A) (E/A) have been measured in all patients. The cardiac
symptoms on presentation of the cardiomyopathy and the diagnosis are
also listed and appear to be different in each case (Table 2).

TABLE 1 Chelation Therapy, Serum Ferritin Levels and Other Clinical Data on the Thalassemia
Patients Before Cardiomyopathy

Patient Sex-Age (years) Deferoxamine Chelation Therapya Serum Ferritin (μg/L)

1 F-41 45 mg/kg/6 days/week (subcutaneous)* 1015.0

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2 F-30 50 mg/kg/5 days/week (subcutaneous)* 1117.0

3 F-32 45 mg/kg/5 days/week (subcutaneous) 727.0
4 F-37 50 mg/kg/5 days/week (subcutaneous) 1371.0
5 F-44 50 mg/kg/24 hours (IV) (via a port-a-cath) 687.0
a
Subcutaneous administration of 24-hours/day in patients 1* and 2* using an elastomeric pump
infuser and of 12-hours/day in patients 3 and 4 using an electronic pump.

TABLE 2 Cardiac Symptoms, Echocardiographic Findings and Diagnosis of the Cardiomyopathy in the
Thalassemia Patients

Echocardiographic
Patient Cardiac Symptoms Findingsa Diagnosis

1 SVE; dyspnea
2 AF; SVE
3 Tachycardia; SVE
4 SVE; bigeminy; couples
of ventricular extrasystols
5 Arrythmias
(SVE; AF; RBBB)
EF: 24%; FS: 9%; CCF; restrictive type of cardiomyopathy
LVEDD: 4.6; E/A: >2.0
EF: 27%; FS: 14%; CCF; restrictive type of cardiomyopa-
LVEDD: 5.1; E/A: >2.0 thy; diastolic dysfunction
EF: 59%; FS: 26%; Tachycardia due to iron overload
LVEDD: 3.9; E/A: 1.5
EF: 73%; FS: 36%; Restrictive type of cardiomyopathy
LVEDD: 3.9; E/A: >2.0
EF: 50%; FS: 37%; CCF; diastolic heart failure; diastolic
LVEDD: 4.7; E/A: >2.0 dysfunction of left ventricle;
restrictive type of trans mitral flow

SVE: supraventricular extrasystols; EF: ejection fraction; FS: fraction shortening; LVEDD: left-ventri-
cular end-diastolic dimension; E/A: ratio between the protodiastolic (E) wave and telediastolic (A)
wave; CCF: congestive cardiac failure; RBBB: right bandle branch block.
a
Normal values: EF = 50%; FS = >30%; LVEDD = 3.6–5.6 cm; E/A = 1–2.
 Prevention of Cardiomyopathy by Chelation and MRI 223

Cardiac MRI T2* and T2 relaxation time measurements were per-

formed in four of the five patients in order to identify the level of any excess
iron in the heart and exclude other possible causes for the cardiomyopathy.
Two MRI centers were available at the time of the cardiomyopathies for car-
diac iron estimation, one measuring T2 and T2* and the other only T2
relaxation times. Patient 2 used the MRI center assessing T2 and patient 3
the center measuring both T2 and T2* relaxation times (Table 3). Patient 5
had a port-a-cath device installed because of diastolic heart failure. She had
a cardiac biopsy during the surgical removal of a thrombus that was caused
by the port-a-cath device, which was used for the IV administration of DFO.
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The MRI methodology was not available at the time for a cardiac iron assess-
ment, but the cardiac biopsy sample obtained from the patient was evalu-
ated both histopathologically and by electron microscopy (6).
The MRI T2 and T2* methods for cardiac iron overload assessment
have been carried out as previously described (9,10). In all patients, the
level of iron overload at the interventricular septum of the heart was charac-
terized using the MRI T2* and T2 relaxation times, measured by a Philips
MRI scanner, 1.5 Tesla ACS NT Intera Master (Philips Medical Systems,
Eindhoven, The Netherlands). The T2 relaxation times were measured
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using a 16 echo Spin Echo sequence with a minimum time echo of 6 ms

(9). The T2* relaxation times were carried out using the breath holding
method at 11 different time echos with a minimum time echo of 2.5 ms and
maximum 14 ms (10). The level of cardiac iron overload as assessed by the
MRI relaxation time measurements was arbitrarily divided into four catego-
ries for both T2 and T2*, namely severe or heavy, moderate, mild and nor-
mal siderosis. The relaxation time measurements of both T2 and T2* for all
these categories are given in Table 3. Serum ferritin measurements were
also carried out in the four patients within 2 months during the period of

TABLE 3 Comparison of Magnetic Resonance Imaging (MRI) T2* and T2 Relaxation Time
Measurements of Cardiac Iron Overload and Serum Ferritin Levels in Thalassemia Patients With
Cardiomyopathy

Patient MRI T2* (ms) MRI T2 (ms) Serum Ferritin (μg/L)a

1 6.20 30.0 581.0

2 Not done 36.8 934.0
3 9.35 23.3 539.0
4 4.50 25.0 710.0
5 Heart biopsy; heavy iron deposition Not done 740.0

Cardiac iron overload range level categories of MRI T2* and T2 relaxation time measurements. MRI
T2*: <9 ms = heavy or severe siderosis; 9-14 ms = moderate siderosis; 14-20 ms = light siderosis; >20 ms =
normal. MRI T2: <35 ms = heavy or severe siderosis; 35-42 ms = moderate siderosis; 45-50 ms = light
siderosis; >50 ms = normal.
a
Measured within 2 months during the MRI study period.
 224 A. Kolnagou et al.

the MRI assessment, confirming the presence of low serum ferritin levels
despite the cardiomyopathy (Table 3).

RESULTS AND DISCUSSION

Serum ferritin levels are continuously monitored in iron loaded thalas-
semia patients and regarded as the most convenient diagnostic method for
determining the level of iron overload. However, recent evidence suggests
that serum ferritin levels are not related to the level of cardiac iron over-
load. This may put patients at risk of cardiomyopathy, which is the main
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cause of death in thalassemia patients (10,11,17).

Five patients, who complied well with the subcutaneous and IV DFO
regimen and had low serum ferritin levels for several years before the study
period, unexpectedly presented cardiomyopathies (Tables 1and 2). The
serum ferritin levels of the five patients were 0.7–1.4 mg/L before, and 0.5–
0.9 mg/L after, the cardiomyopathy was diagnosed (Tables 1 and 3).
The clinical symptoms and echocardiographic findings supported the
diagnosis for the cardiomyopathy in all five patients (Table 2). Three of the
patients (1, 2 and 5) suffered a congestive heart failure, and the other two
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patients (3 and 4) arrhythmias. The echocardiographic parameters were

different in each patient. The EF findings were abnormal in three patients,
two with congestive heart failure (1 and 2) and one with an arrhythmia
(patient 3). In one patient with congestive heart failure (patients 5) the EF
was on the borderline of normal, and in patient 4 with the arrhythmia, it
was within the normal range. However, the FS findings were abnormal in
three patients (1, 2 and 3) and normal in patients 4 and 5. Similarly, the
ratio between the E/A wave was abnormal only in patients 4 and 5, while
the LVEDD was normal in all patients (Table 2).
Cardiac MRI T2* and T2 relaxation time measurements were per-
formed in four of the five patients after the cardiomyopathy was diagnosed,
identifying moderate to heavy siderosis (Table 3). In most cases, the MRI
T2 and T2* relaxation time measurements were within the same heavy sid-
erosis range categories, but in patients 2 and 3, the MRI T2* and T2 relax-
ation time measurements suggested the presence of moderate to heavy
siderosis. Despite that the number of patients identified to have cardiomy-
opathy is small, it is significant that iron overload cardiomyopathy has been
observed both in patients with heavy and also moderate cardiac siderosis.
Similarly, heavy siderosis was identified in the cardiac biopsy sample of
patient 5, despite the fact that she had a low serum ferritin level at the time
of the biopsy (Table 3) (6).
Future studies correlating MRI T2 and T2* with cardiac iron concen-
tration and the incidence of cardiomyopathy will provide more precise evi-
dence for the diagnosis, prophylaxis and appropriate chelation therapy
 Prevention of Cardiomyopathy by Chelation and MRI 225

protocols required for each affected patient. Although cardiac iron

overload is related to cardiomyopathy and increased mortality in thalas-
semia, so far, there has been no evidence to suggest what the level of
iron deposition is and in which part of the heart it is particularly toxic,
or what the toxic forms of iron are, and the toxicity mechanisms impli-
cated in the cardiomyopathy. It is also not clear whether all the tissues of
the heart, or specifically the myocardium, are susceptible to the same
level of damage from iron overload toxicity. However, it was clearly
shown in at least one study that the loss of myofibers and the disruption
of myocytes appeared to be a major form of iron overload toxicity in
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congestive heart failure in iron loaded thalassemia patients (6). In gen-

eral, it is reasonable to assume that the higher the level of cardiac iron,
the higher the level of damage to the heart and the prospect of conges-
tive heart failure. It remains to be seen whether, in addition to thalas-
semia patients with heavy or moderate siderosis, which has been
observed in this study, other patients with light or normal range sidero-
sis, as detected by MRI T2 and T2* cardiac iron relaxation time measure-
ments, will also develop cardiomyopathy.
The chelation therapy protocol has changed for all five patients follow-
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ing the cardiomyopathy diagnosis. Three of the patients (1, 3 and 4) started
receiving combination therapy of DFO (40–50 mg/kg at least 3 days/week)
with L1 (75–90 mg/kg/day), patient 2 has increased the DFO dose from 50
to 80 mg/kg, 5 days/week, and patient 5 was switched to L1 monotherapy
of 80 mg/kg/day. Similarly, as a result of these findings, L1 was introduced
either as a monotherapy or as a combination therapy with DFO in 31 of the
56 patients. Patients 2 and 5, who were using either DFO or L1 monother-
apy, became asymptomatic within 1 year, needing no further treatment with
anti arrhythmic and anticoagulant drugs.
There is increasing evidence that the use of L1 at doses >80 mg/kg/
day can reduce the incidence of cardiomyopathy and mortality in iron
loaded thalassemia patients (12,13,15). The mechanisms of the removal
of iron by L1 from the heart of iron loaded thalassemia patients have
been previously described (2,16). Among these mechanisms is the ability
of L1 to enter heart cells at effective high concentrations, remove iron
from intracellular iron pools and its iron complex to be rapidly cleared
out of the cells. Deferiprone is also effective at minimizing iron uptake
and deposition in heart cells because of its ability to mobilize iron from
non-transferrin-bound-iron (NTBI) and transferrin, both of which are
implicated in the transfer of excess iron into heart and other cells.
The use of subcutaneous DFO is less effective in the clearance of excess
iron from the heart unless higher doses are used, e.g., 80 mg/kg 5 days/week,
as in patient 2 in this study. Similar effects have also been observed when
effective IV DFO dose protocols have been used (14). It should be noted
 226 A. Kolnagou et al.

however, that in patient 2, auditory toxicity resulting in partial deafness

occurred within 7 months of using the high dose of DFO (80 mg/kg/day, 5
days/week). Such DFO therapies should be considered with caution and
regular monitoring for toxic side effects should be used.
Progressive rapid reduction of cardiac iron overload, as assessed by MRI
T2* and T2 relaxation time measurements, which was associated with
improved cardiac function, has also been observed in iron loaded thalas-
semia patients receiving subcutaneous DFO and oral L1 combination ther-
apy (18). Unpublished information suggests that there is a reduction of
cardiomyopathy incidences and related mortalities in thalassemia patients
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receiving L1 as a monotherapy or in combination with DFO. It remains to

be seen whether the risk of cardiomyopathy and mortality will also be
reduced when new oral and IV chelating drugs are introduced in the near
future (12). Preliminary findings using ICL670 in thalassemia patients do
not suggest that this new chelating drug will be effective as a monotherapy
for cardiac iron mobilization, and it is more likely that it will be used in
combination therapies, especially synergistically with L1, which appears to
have a cardio-specific iron removal effect (19,20).
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CONCLUSIONS
Serum ferritin levels are misleading with regards to estimating cardiac
iron overload. A large number of patients are at risk of cardiomyopathy if
they are diagnosed late for the presence of excess iron in the heart by MRI
T2* and T2 relaxation time measurements. In these cases, the introduction
of new, more effective chelation therapy protocols for the clearance of
excess cardiac iron is needed for the prevention of cardiomyopathy. Mag-
netic resonance imaging T2 and T2* relaxation time measurements and
the administration of L1 can be used prophylactically for the reduction and
prevention of cardiac iron overload, the incidence of cardiomyopathy, and
overall mortality rate in thalassemia patients. High doses of subcutaneous
or IV DFO may also reduce cardiac iron overload in thalassemia patients
but toxic side effects are common at such effective doses. So far, ICL670
and other new iron chelating drugs have not been shown to be effective in
the mobilization of excess iron from the heart. Combination therapy proto-
cols of these new iron chelating drugs and L1 are likely to achieve this goal
in the future.

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