European Journal of Haematology ISSN 0902-4441
`
`R E V I E W A R T I C L E
`
`The heart in transfusion dependent homozygous
`thalassaemia today – prediction, prevention and
`management
`Athanassios Aessopos, Vasilios Berdoukas, Maria Tsironi
`
`First Department of Medicine, University of Athens, ‘Laiko’ Hospital, Goudi, Athens, Greece
`
`Abstract
`
`Cardiac disease remains the major cause of death in thalassaemia major. This review deals with the
`mechanisms involved in heart failure development, the peculiar clinical presentation of congestive heart
`failure and provides guidelines for diagnosis and management of the acute phase of cardiac failure. It
`emphasizes the need for intensive medical – cardiac care and aggressive iron chelating management as,
`with such approaches, today, the patients outcomes can be favourable in the long term.
`It covers
`advances in the assessment of cardiac iron overload with the use of magnetic resonance imaging and
`makes recommendations for preventing the onset of cardiac problems by tailoring iron chelation therapy
`appropriate to the degree of cardiac iron loading found.
`
`Key words thalassaemia major; cardiomyopathy; cardiac failure; transfusion therapy; iron chelation therapy
`
`Correspondence Athanassios Aessopos, MD, PhD, First Department of Medicine, University of Athens, ‘Laiko’ Hospital, Goudi,
`Athens TK: 11527, Greece. Tel: +30 (210) 7771161; Fax: +30 (210) 7788830; e-mail: aaisopos@cc.uoa.gr
`
`Accepted for publication 24 June 2007
`
`doi:10.1111/j.1600-0609.2007.01018.x
`
`In beta thalassaemia major transfusions and iron chela-
`tion therapy have significantly improved the survival and
`reduced the morbidity (1, 2). In the 1960’s 80% of
`patients had died by the age of 16 (3) and now at least
`80% survive beyond the age of 40 yrs (4). This improve-
`ment is unique, as no other formerly fatal genetic defect
`has shown such a benefit. However, heart complications
`still represent significant morbidity and remain the lead-
`ing cause of mortality in transfusion dependent thalas-
`saemia (TM) patients
`(2). Cardiac dysfunction with
`congestive cardiac failure (CCF), arrhythmias and ulti-
`mately, premature deaths continue to present. In some
`cases this was because of the difficulty in accepting the
`chelation treatment, which was cumbersome (5), but also
`occurred even in some patients who accepted the chela-
`tion therapy well (6, 7).
`In this review, we present some aspects of the existing
`knowledge including our view, acquired of our 30 yrs
`experience in following the cardiac course of the disease
`in more than 1000 thalassaemic patients. Pathophysiol-
`ogy of the heart injury, clinical findings, diagnosis of
`CCF and the global strategies regarding therapeutic
`
`interventions for CCF in TM patients, as well as for
`prevention of its onset are herein presented.
`
`Mechanisms of heart injury
`
`Cardiac structure and function in TM are mainly
`affected by two competing factors:
`iron load and
`increased cardiac output (CO). The cardiac iron deposi-
`tion results in a decrease of left ventricular function. The
`anaemia together with marrow expansion leads to vol-
`ume overload and increased CO that
`then demands
`increased contractility adding additional stress to the
`heart. (Starling’s Law).
`
`The cardiac iron load
`
`Direct iron related injury
`
`Iron overload results principally from the regular blood
`transfusions.
`Patients
`receive
`between
`0.3
`and
`0.5 mg ⁄ kg ⁄ d of iron through transfusions. The average
`daily losses are less than 1 mg in males and 2 mg in
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`females. There are no other physiological mechanisms
`for effecting body iron reduction. In addition to the
`transfused iron, TM patients absorb more iron than nor-
`mal individuals. The mechanism of increased absorption
`is thought to be related to paradoxical Hepcidin suppres-
`sion from the dyserythropoiesis (8–10). In the presence
`of excess iron Hepcidin should be elevated to inhibit iron
`absorption but
`the dyserythropoiesis overrides
`that
`effect. Among the different mechanisms in the cellular
`pathways of ferrous iron (Fe2+) membrane L-type cal-
`cium channels are significantly involved (11). L-type
`Ca2+ channels are high-capacity pathways for ferrous
`iron (Fe2+) uptake into cardiomyocytes in conditions of
`iron overload.
`Iron is stored in cells, including myocytes, in the form
`ferritin, haemosiderin and free iron. The latter is
`of
`referred as the labile cellular iron (LCI) (12). There is a
`significant flux between the three forms, with haemo-
`siderin being the least accessible. The LCI is thought to
`be the most accessible to chelation, but it is also the
`most toxic form as it stimulates the formation of free
`radicals. These result in peroxidative damage of mem-
`brane lipids and proteins provoking cellular injury. In
`the heart, this leads to impaired function of the mito-
`chondrial respiratory chain and is clinically manifested
`by reduction of cardiac muscular contractility and CCF
`development
`(13). Furthermore,
`in the presence of
`increased intracellular ferrous iron, the ryanodine sensi-
`tive calcium channels of sarcoplasmic reticulum (SR), are
`inhibited. This modulates SR calcium release, resulting in
`further reduction of cardiac function and arrhythmia
`development. The new knowledge on calcium channels
`may offer new potential therapeutic interventions for cel-
`lular iron reduction and treatment of arrhythmia and
`cardiac dysfunction (11, 14, 15).
`To date, at least 90 genes that control iron metabolism
`have been identified (16). Due to the possible gene varia-
`tions the handling of iron in each individual is expected
`to be different. Similarly the action of iron chelators
`could be affected and act differently in the individual
`patient. It has been shown that TM patients who express
`the apo-lipoprotein E4 allele were at greater risk for left
`ventricular (LV) dysfunction. Apo E4 is less efficient at
`handling oxidative stress (17, 18) when compared to Apo
`E2 and Apo E3. Additionally the genetic variations of
`the GSTM1 enzyme (Glutathione S-Transferase M1) are
`associated with increased cardiac iron deposition in
`patients with TM (19). These concepts fit in well with the
`wide range of reported different clinical cardiac courses
`seen in TM patients who have followed similar life-time,
`well accepted treatment (6).
`Knowledge derived by recent magnetic resonance
`imaging (MRI) studies which also assessed cardiac func-
`tion, showed that all patients with reduced LV function
`
`94
`
`had cardiac iron overload and in many cases this was
`severe (20–23). This strongly suggests that in addition to
`the damage caused by the accumulated iron, excessive
`iron in the myocytes results in greater amounts of LCI
`leading to free radical formation that overwhelms the
`antioxidant mechanisms and ultimately precipitates car-
`diac dysfunction. In the above MRI studies, despite
`heavy iron load, many TM patients maintained normal
`cardiac function, albeit perhaps temporarily, and this
`may be related to their different,
`intracellular
`iron
`metabolism, in particular their neutralisation of oxidants
`as discussed above.
`
`Indirect iron related injury
`
`Infections
`
`Any significant infection may precipitate cardiac failure
`particularly in the presence of other underlying cardiac
`pathology. Immune competence in beta-thalassemia is
`impaired (24–27) and patients are more vulnerable to
`infections. Furthermore, siderophore bacteria, such as
`yersinia and klebsiella, rely on iron for multiplication
`and grow well in the microenvironment of TM patients
`(26, 27).
`Iron overload is considered to be the main etiologic
`factor that can disturb the immune balance in favour of
`the growth of infectious organisms (25). This may also
`be affected by differences in the existing immunogenetic
`profile in TM (28) especially with respect to viral infec-
`tions. Two severe cardiac complications, pericarditis and
`myocarditis, are linked to iron load induced viral infec-
`tion susceptibility.
`in TM patients
`Pericarditis,
`frequently seen (50%)
`with poor or no chelation in the past (3), is very rare
`today (5%), with the use of chelation therapy (6). Simi-
`larly,
`the reported myocarditis
`in TM patient with
`decreased LV function (29), seems most likely to be
`related to iron load. Even though there may be histo-
`logical evidence of infections, as demonstrated by lym-
`phocytic infiltration, recent evidence shows that LV
`failure only occurs in the presence of excessive iron
`(20–23). Viral myocarditis without
`iron in the heart
`may be rare and may follow similar outcomes to those
`of
`the normal population. Elevated plasma cardiac
`enzymes or troponine may be indicative of concomitant
`viral myocarditis.
`
`Vascular involvement (afterload)
`
`in TM, as observed
`involvement
`Systemic arterial
`recently through clinical, functional (30) and anatomical
`(31) studies, plays a role in the development of cardiac
`dysfunction by
`affecting heart
`afterload. Vascular
`involvement starts early in life and becomes obvious in
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`Journal compilation 80 (93–106) ª 2008 Blackwell Munksgaard
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`Aessopos et al.
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`Cardiac disease in thalassaemia major
`
`(32). The anatomical component
`the older patients
`including elastic tissue abnormalities is expressed in
`arteries by thickening and disruption of the elastic lami-
`nae and adventitia, followed by calcium deposition. The
`injury is suggested to be mediated by the chronic haemo-
`lytic state along with the increased labile plasma iron
`(LPI). Erythrocyte membrane fragments, haem and free
`haemoglobin in addition to free iron, provoke a strong
`oxidative stress on endothelium (32). A component of
`the vascular dysfunction is due to the reduction of nitric
`oxide (NO). There are at least three mechanisms respon-
`sible for that effect related to haemolysis; a) Red cell
`destruction releases arginase which reduces arginine
`levels and its supplementation to the endothelium. b)
`Oxyhaemoglobin is
`transformed to methhaemoglobin
`after reacting with NO and converts it to inactive NO3
`i.e. neutralising it and c) Oxidative stress inactivates
`endothelial cell enzymes and reduces formation of NO
`from the precursor arginine (33).
`Similar mechanisms apply also to the pulmonary
`artery bed, where vascular contribution together with
`coexisting hypercoaguability is considered to be responsi-
`ble for increased pulmonary artery resistance (34, 35).
`
`Arrhythmias
`
`The iron induced cardiac toxicity is often complicated
`by arrhythmias such as extra atrial and ventricular
`beats, paroxysmal atrial tachycardia, flutter or fibrilla-
`tion. Life threatening ventricular tachycardia is rare
`and often associated with reduced LV function. Short
`runs of non-specific ventricular tachycardia are quite
`common and are more common with elevated cardiac
`iron. Atrial arrhythmias occur more frequently. These
`are more clinically relevant and difficult to treat, but
`less specific for iron toxicity. Some of these arrhyth-
`mias can also be triggering factors for CCF or reduced
`cardiac
`function in TM patients without previous
`obvious LV dysfunction.
`
`Endocrine abnormalities
`
`Iron toxicity may also indirectly affect heart function by
`damaging other organs in varying degrees. The endocrine
`abnormalities hypothyroidism and diabetes mellitus can
`have a significant impact on cardiac function (36). Hypo-
`thyroidism can precipitate pericardial effusion, decreased
`LV function, bradycardia and increased peripheral vascu-
`lar resistance. The onset of diabetes is often associated
`with the presentation of cardiac dysfunction. Chronic
`hyperglycaemia is an oxidative stress on many organs,
`particularly the heart. Hypocalcaemia associated with
`occult or overt hypoparathyroidism can precipitate heart
`dysfunction.
`
`Medications
`
`Vitamin C has been given to patients in order to enhance
`their iron excretion when they are on chelation therapy.
`There have been case reports of patients who developed
`sudden acute cardiac failure with a fatal outcome that
`had been precipitated by the administration of Vitamin
`C possibly by releasing free iron that is toxic (37).
`
`Increased CO effect (preload)
`
`Disease related increased CO, resulting in increased
`workload on the heart, contributes to the development
`of cardiac dysfunction in TM patients. In other chronic
`anemias, resting CO increases when Hb levels decline
`below 9 g ⁄ dL (38–41). TM patients, however, even those
`well transfused (mean pre transfusion Hb level > 9.5 g⁄ dL)
`with excellent suppression of marrow activity and with
`mean Hb level between transfusions of 11.3 g ⁄ dL, still
`demonstrate some degree of high CO (Cardiac Index
`4.3 ± 0.9 L ⁄ m2 in TM cf. 3.8 ± 0.8 P < .01 in normal
`individuals) (6). It is more obvious in cases were low Hb
`levels and tissue hypoxia stimulate compensatory reac-
`tions leading to development of peripheral shunts (42).
`Liver iron load or viral induced hepatic injury can also
`contribute, as cirrhosis can increase CO significantly
`(43). Furthermore, the presence of elastic fibre degenera-
`tion, affecting elastic lamina and adventitia, which render
`vessels more susceptible to dilatation by pulse pressure
`increase in the context of a hyperkinetic state also
`increases the total blood volume (31).
`
`Summary of the mechanisms of heart injury
`
`In TM, the impaired heart from iron overload, is obliged
`to maintain a high output through a rigid vascular bed
`that results from the abovementioned vascular damage
`and is therefore subjected to a continuous state of both
`volume and pressure overload rendering the LV more
`susceptible to decompensation. Similarly, in TM patients
`the coexistence of high CO state and gradually increasing
`pulmonary vascular resistance seems to lead to the devel-
`opment of pulmonary hypertension (PHT), which readily
`precipitates right ventricular (RV) failure (34). Infections,
`with a direct or indirect effect also have an impact on
`heart function. In well-treated TM patients, the inhibi-
`tion of the above mechanisms, result in a considerable
`reduction of LV dysfunction incidence, vascular damage,
`PHT development and RV failure (44, 45).
`
`Heart pathology
`
`Iron is thought to saturate liver firstly, and then to
`accumulate in other organs. In the heart, it accumulates
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`Cardiac disease in thalassaemia major
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`Aessopos et al.
`
`in all four chambers, papillary muscles and the electri-
`cal conduction system,
`including the sinoatrial and
`atrioventricular nodes (46). In the free wall of the left
`ventricle there is more iron concentrated in the epicar-
`dial
`layers than in the endocardial and middle third
`(47). From the epicardium, it encroaches upon the peri-
`cardium. Such iron deposition raises a possibility that
`pericarditis may also have an iron induced chemical
`inflammatory component and also may cause fibrosis of
`the pericardium with or without a history of viral peri-
`carditis (Fig. 1). Histology has shown individual myo-
`cyte hypertrophy with multiple deposits of brown
`granular material within the cytoplasm of the myocytes
`(Fig. 2). These granules stain positive with Prussian
`blue,
`confirming heavy myocardial
`iron deposition.
`Interstitial macrophages containing iron are also present
`(48). Moreover, the study of cardiac biopsies from TM
`patients with light and electron microscopy, as well as
`with X-ray microanalysis has revealed the presence of
`disrupted myocytes showing loss of myofibers, dense
`nuclei, and a variable number of pleomorphic electron
`dense granules. These cytoplasmic granules or sidero-
`somes consist of iron-containing particles as confirmed
`by X-ray microanalysis.
`
`Clinical presentation of cardiac involvement in TM
`
`Cardiac involvement includes heart failure, arrhythmias
`and pericarditis. The presentation of pericarditis is simi-
`lar to that which occurs in the general population. This
`is also the case with arrhythmias.
`Heart failure can present at any time after the age of
`10 yrs but with optimal treatment, heart failure usually
`occurs in the third or fourth decade of life (6). The pre-
`sentation can be abrupt, sometimes associated with an
`infection or with a slow relentless onset.
`Although some patients can present with symptoms of
`left-sided heart
`failure including exertional dyspnoea,
`cough and fatigue, followed by raˆ les and gallop rhythm
`on chest auscultation, it is worth noting that the majority
`presents with symptoms and signs of right ventricular
`dysfunction. The patients often present to an outpatient
`clinic with severe fatigability and abdominal pain, the
`latter due to liver distention. The patient may be lying
`on the examination couch without dyspnoea. These signs
`can easily be misinterpreted as not being symptoms of
`cardiac origin (49, 50). The clinical course in this young
`population, has often been associated with a gradual
`reduction in physical activity, which obscures and delays
`the presentation.
`However, clinical examination with the patient in a
`correct position, will reveal a positive hepatojugular
`reflex with neck vein distention and a third and fourth
`heart sounds. In more severe cases, peripheral oedema
`
`96
`
`A
`
`B
`
`Figure 1 (A) Operative field in a 27 yr old male thalassaemia patient
`with a history of recurrent pericarditis and effusive constrictive peri-
`carditis at
`the time of surgery (B) with biopsy from the same
`patient demonstrating significant pericardial thickening with severe
`iron deposition and a small amount of muscle in the left hand corner
`which contains iron (Prussian Blue Stain).
`
`Figure 2 Histological features from an autopsy from a 29 yr old male
`thalassaemia patient who died of congestive cardiac failure. Histology
`shows individual myocyte hypertrophy with multiple deposits of
`brown granular material within the cytoplasm of the myocytes. These
`granules stain positive with Prussian blue, confirming heavy myo-
`cardial iron deposition.
`
`ª 2008 The Authors
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`Aessopos et al.
`
`Cardiac disease in thalassaemia major
`
`and ascites may be found. This peculiar clinical appear-
`ance in TM patients should be kept in mind. It results
`from the thin iron loaded right ventricle decompensating
`earlier (51). Raˆ les may be found in cases where there is
`also left sided heart failure.
`
`Investigation findings for CCF
`
`Chest X-ray, shows cardiomegaly but frequently there are
`no features of pulmonary congestion. Lung congestion
`and pleural effusion may be present as well as a prominent
`pulmonary artery in cases with coexisting PHT.
`It is unusual for the electrocardiogram (ECG) to be
`normal. Wide QRS complex with low voltage, inverted T
`waves, non-specific ST-T changes, Left Ventricular
`Hypertrophy, prolonged A-V conduction and arrhyth-
`mias are frequently seen.
`Doppler echocardiographic study usually shows biven-
`tricular dilatation and systolic and diastolic dysfunction.
`The variety, however, of the different abovementioned
`pathogenetic factors and their degree of contribution to
`the cardiac damage,
`including the different treatment
`regimes (lower transfusion schemes,
`inadequate chela-
`tion)
`lead TM patients, who present with CCF not
`always
`to show uniform cardiac injury. Restrictive
`cardiomyopathy-constrictive pericarditis or high cardiac
`state Doppler echocardiographic findings could present
`either alone or in combination. The development of
`significant PHT may accompany the CCF in almost all
`the above forms, contributing to the precipitation of
`right-sided heart failure. In cases with impaired LV func-
`tion, thrombus formation in the apex of the heart may
`be present and can lead to the development of stroke
`(52) (Fig. 3).
`
`Figure 3 A 30 yr old female thalassaemia patient 2-D four chamber
`view with the presence of an apical thrombus.
`
`Therapeutic approach to TM patients with CCF
`
`Thalassaemia patients with signs and symptoms of CCF
`should be hospitalised and closely monitored. Extensive
`laboratory tests should be performed and include:
`arterial blood gas,
`endocrine profile,
`liver and renal function tests,
`chest X-ray,
`ECG and
`Doppler echocardiographic study.
`As stated above recent MRI studies have confirmed
`that almost all patients with decreased left ventricular
`function have severe iron load (20–23). In the acute fail-
`ure patients the values of MRI measurements are only
`important to determine the degree of iron overload for
`future follow-up and can be postponed till after the
`patient has improved clinically.
`such as
`Triggering factors
`for CCF development
`arrhythmias, blood volume overload after transfusion,
`infections,
`severe anaemia,
`should be identified and
`treated. In cases where Yersinia enterocolitica or Klebsiel-
`la pneumoniae infection is suspected (53), patients should
`be treated even before immunological or bacterial culture
`test results are available. If arrhythmias are present, the
`least negative inotropic antiarrhythmic agent, amioda-
`rone should be infused intravenously (54). In general,
`implantable defibrillators are not recommended for the
`management of ventricular arrhythmias in TM and the
`essential intervention is intensification of chelation ther-
`apy. However,
`in rare case of sustained ventricular
`tachycardia, later in the clinical progress, an implantable
`defibrillator may be necessary.
`Daily measurements of body weight, blood pressure
`and 24-hrs urine secretion are of paramount importance
`in these patients. Frequent monitoring of Hct, Hb, blood
`electrolytes, urea, creatinine, glucose, AST, ALT, uric
`acid, is also mandatory.
`
`Chelation therapy
`
`Combination of the two iron chelators (deferrioxamine
`and deferiprone) seems to maximise the efficacy produc-
`ing additive and synergistic effects in iron excretion (55,
`56). It seems that each of those two agents chelates iron
`from different pools and there is at least an additive
`effect when combined treatment is administered (57).
`Available evidence now suggests that combined therapy
`should be the treatment of choice for patients with estab-
`lished cardiac failure. We have reported two cases with
`severe CCF who reversed with intensive combination
`therapy (58, 59) and we have at least eight more patients
`with similar outcome. Two other studies show similar
`responses (56, 60). In a recent study with combined
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`treatment, apart from significant reduction in ferritin,
`cardiac and liver iron and improvement in cardiac func-
`tion, the absolute endothelial function was also improved
`(45). Furthermore, improvement with glucose tolerance
`with the use of combination therapy has been reported
`(61, 62) as well as anecdotal reports of improvement in
`other endocrine functions. Desferrioxamine should be
`administrated at a dose of 60–80 mg ⁄ kg ⁄ d intravenously
`and deferiprone at a dose of 75–100 mg ⁄ kg ⁄ d in three
`divided doses.
`If deferiprone is contraindicated,
`the
`patient should be managed with continuous desferrriox-
`amine infusions which usually requires the placement of
`an indwelling catheter (63). Continuous desferrioxamine
`infusions alone have been shown to improve cardiac
`function and salvage patients (64). It seems however, that
`the rate of removal of iron with such therapy is much
`slower than with combination therapy (45, 63).
`Caution should be taken with the 24 h desferrioxamine
`infusion to avoid fluid overload especially when intra-
`venous antibiotics and antiarrthymic agents are also
`indicated.
`
`Transfusions
`
`is
`As CO may be close to normal when Hb level
`‡10 g ⁄ dL, patients’ Hb concentration should be kept
`above 10 g ⁄ dL by regular blood transfusions. The
`patients should only be transfused with one packed red
`cell unit no greater than 250 mL with diuretic treatment
`as well.
`
`Endocrinopathies
`
`If hypothyroidism is present, a titrated dose of hormone
`replacement should be carefully initiated. Diabetes mell-
`itus should be regulated with caution. Although hypo-
`parathyroidism is generally rare in the thalassaemic
`population, it is more often seen in patients with CCF
`and shows the typical ECG abnormalities of prolonged
`QT interval (36). Calcium is necessary for heart muscle
`cell contractility. CCF with the coexistence of low serum
`calcium levels is extremely resistant to conventional treat-
`ment (65). Serum calcium level should be corrected by
`intravenous calcium administration accompanied by oral
`vitamin D.
`
`Conventional cardiac disease management
`
`Diuretics, including loop diuretics (e.g. furosemide) and
`potassium-sparing agents (e.g. spironolactone), as well as
`angiotensin-converting enzyme (ACE)-inhibitors should
`be prescribed based on arterial blood pressure. In cases
`of persistent normal sinus tachycardia, small doses of
`Carvedilol may be given. Digoxin must be prescribed to
`
`patients with atrial fibrillation resistant to conversion.
`Diuretics must be prescribed with care for reasons stated
`in the following section.
`
`Pulmonary hypertension
`
`If PHT is present, then based on the recent observation
`of reduction of NO availability in haemolytic anaemia,
`sildenafil should be given in titrated dose, as a first
`choice. It has been shown to be effective in reducing pul-
`monary pressure by NO release (35).
`
`Management of low CO state
`
`Hypoalbuminemia is often present. The combination of
`excessive hepatic iron, hepatic viral infections and other
`recent infections with the stress of congestion leads to
`liver dysfunction, which, in turn, results in reduced albu-
`min production. The low serum albumin level could be
`masked by diuretic administration. It is important to
`note that TM patients with CCF, after strong diuresis, in
`combination with hypoalbuminemia are at significant
`risk of developing reduced renal function or acute renal
`failure caused by further reduction in CO due to signifi-
`cant preload reduction in the presence of ventricular
`dysfunction. Thus, careful albumin administration with
`a gradual negative fluid balance by diuretics is necessary.
`In case of reduction of renal output, treatment with
`intravenous positive inotropic agents (e.g. dopamine-
`in a titrated dose alone and ⁄ or with
`dobutamine)
`haemodialysis should be considered. Though adrenal
`insufficiency seems to be rare in TM it is possible that
`the adrenal reserves are diminished. It may therefore be
`valuable in such cases in the ICU setting to give the
`patients stress dose steroids empirically. It can also pro-
`foundly improve their responses to inotropes.
`The above treatment can yield very positive results,
`often within a short period of time – even before any sig-
`nificant reduction in the cardiac iron load would be
`expected. If the patient survives the acute phases of CCF,
`treatment should be continued. Patients’ general clinical
`condition, echocardiographic studies and MRI T2* mea-
`surements could guide subsequent treatment modifica-
`tions. Until
`the ejection fraction approaches normal,
`transfusions should be given at 7–10 daily intervals with
`reduced amounts of packed cells avoiding volume over-
`load. In particular, changing the intravenous desferriox-
`amine to daily subcutaneous infusions once the patient is
`stabilized, is the first step. This allows the patient to be
`discharged from hospital. It is essential to note that with
`appropriate intervention, particularly intensive chelation
`therapy the cardiac function can improve significantly
`within 6 months. In our own experience, we have seen
`that within 2–3 yrs of intensive chelation the heart iron
`
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`Journal compilation 80 (93–106) ª 2008 Blackwell Munksgaard
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`Apotex. Tech.
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`

`Aessopos et al.
`
`Cardiac disease in thalassaemia major
`
`can be significantly reduced and in some case rendered
`completely free of iron. Ultimately, heart function may
`revert to normal class I (NYHA) and eventually the
`patients can cease their cardiac medications.
`
`Conclusions on CCF in TM
`
`Treatment of iron induced cardiomyopathy requires close
`follow-up and significant effort until the patient is stabi-
`lised. If the patient survives the acute phase, the potential
`reversibility of heart injury by heart iron removal prom-
`ises an outcome better than that seen in the past in such
`situations and may be better than that seen with other
`causes of cardiomyopathy with equivalent clinical sever-
`ity in the general population (29). However as Hippo-
`crates stated, it is better to prevent than to cure. Today
`the great challenge in TM patients is to achieve even
`better results in preventing heart injury.
`
`Prevention of heart disease
`
`two main
`accepted treatment has
`The nowadays
`components:
`transfusion and chelation therapy. Until
`recently the latter was only available as parenteral
`desferrioxamine.
`
`Hb levels
`
`increased CO is low Hb levels,
`The main cause of
`marrow expansion and their consequences. Transfusion
`therapy should reduce the CO, however many patients
`on the recommended transfusion regimes (between 9.5
`and 10 g ⁄ dL) still have an increased CO (6). In general
`high CO states are well tolerated even with low Hb levels
`and in older patients (41). However coupled with other
`factors, especially that of transfusion iron overload,
`it
`increases the risk of cardiac impairment.
`It is uncertain how the situation in which there are
`good transfusion levels but there is still increased CO,
`could or should be rectified. Even though an older study
`showed that after 5 months at higher pretransfusion Hb
`levels an increased red cell consumption (66) did not
`result, higher transfusion levels did not necessarily convey
`any particular patient benefit on bone marrow expansion
`and increased blood volume (67). Thus, higher pretransfu-
`sion Hb levels (mean approx. 10.5 g ⁄ dL) may be desirable
`and long term may reduce the CO and marrow expansion.
`However, the target should be to reduce iron rather than
`to be too concerned about the marginally elevated CO. In
`contrast,
`in patients who have low pretransfusion Hb
`levels, their transfusions should be increased in either
`frequency or volume. If the low Hb levels persist despite
`adequate transfusions and the red cell consumption is
`elevated, splenectomy should be considered (68).
`
`Iron load
`The suggested iron chelation regimes available till recently
`i.e. with desferrioxamine at 30–40 mg ⁄ kg body weight per
`infusion, 8–10 hrs per
`infusion 5–7 days per week,
`improved survival and reduced morbidity (69). However,
`careful iron balance studies have shown that only 52% of
`patients on the most commonly used 5 day per week
`regime will be in negative iron balance (55). Although des-
`ferrioxamine enters the liver rapidly, it enters all other cells
`very slowly. These, accompanied by varying compliance
`and other factors mentioned in the section on mechanisms
`of iron induced heart injury, result in continuing presenta-
`tion of cardiac dysfunction and premature cardiac deaths.
`
`Predictive factors of heart injury from iron
`
`For many years, prediction of potential heart iron injury
`in TM patient was considered necessary in order to
`assess the efficacy of the treatment regimes, particularly
`the chelation therapy and to propose any modification.
`
`Ferritin levels
`
`The traditional biochemical parameter, serum ferritin,
`was relied on universally.
`Ferritin levels seen in iron load states mainly represent
`a component that has leaked out of cells. It was shown
`that ferritin levels had an increasing linear relationship
`to the number of transfusions that patients received (70).
`With chelation therapy, ferritin levels most often showed
`significant reduction. Analysed as single measurements
`or as mean measurements, they had been regarded as
`reasonable indicators of iron load and prognosis. There
`have been a number of studies that relate the risk of
`death from cardiac disease to ferritin levels that have
`been maintained by patients (71). In general, it was con-
`sidered that once chelation was commenced, ferritin lev-
`els should be maintained below 1500 ng ⁄ L. Even in a
`recent Italian study, deaths in TM were related to higher
`ferritin levels at the time of death (2). Overall, persis-
`tently high levels of ferritin are associated with poor out-
`comes and efforts
`should be consistently made to
`maintain them low. However
`cardiac deaths
`still
`occurred in patients with satisfactory ferritin levels. In
`two recent studies, one which assessed most recent (23)
`and one of which assessed highest, lowest, mean 5 yr and
`most recent ferritin (22), there was a statistically signifi-
`cant relationship of ferritin to MRI assessed cardiac iron
`but no predictive value between the two indices.
`The limitations of ferritin levels in predicting iron load
`and toxicity, includ