The American Journal of Medicine (2005) 118, 957-967

REVIEW

Heart failure in ␤-thalassemia syndromes:

A decade of progress
George Hahalis, MD,a Dimitrios Alexopoulos, MD,a Dimitrios T. Kremastinos, MD,b
Nicholas C. Zoumbos, MDc

a
Department of Cardiology, Patras University Medical School, Rio Patras, Greece;
b
Onassis Cardiac Surgery Center, Athens, Greece; and
c
Department of Hematology, Patras University Medical School, Rio Patras, Greece.

KEYWORDS: ABSTRACT: The thalassemias are common monogenic disorders of hemoglobin synthesis. ␤-thalas-
Thalassemia; semias are the most important among the thalassemia syndromes and have become a worldwide clinical
Heart failure; problem due to an increasing immigrant population. In ␤-thalassemia major, regular blood transfusions
Cardiomyopathy; are necessary early in life. Beta-thalassemia intermedia refers to a less severe phenotype, whereas
Iron overload; ␤-thalassemia/hemoglobin E disease encompasses a broad phenotypic spectrum. Blood transfusions
Chelation therapy and increased gastrointestinal iron absorption result in iron overload and tissue damage. Among patients
with ␤-thalassemia major, biventricular, dilated cardiomyopathy remains the leading cause of mortality.
In some patients, a restrictive type of left ventricular cardiomyopathy or pulmonary hypertension is
noted. The clinical course, although variable and occasionally fulminant, is more benign in recent than
in older series. Myocarditis has been described as a cause of left-sided heart failure in younger patients.
Pulmonary arterial hypertension is the principal cause of heart failure in ␤-thalassemia intermedia.
Chelation therapy has improved prognosis in ␤-thalassemia major both by reducing the incidence of
heart failure and by reversing cardiomyopathy. Estimation of the patient’s cardiac risk is mainly based
on clinical criteria and serial echocardiography. A new cardiovascular magnetic resonance technique will
probably fulfill the need for more precise risk stratification in ␤-thalassemia syndromes. By increasing the
proportion of patients on optimal chelation, survival in ␤-thalassemia major may further improve. Recent
advances in gene therapy are expected to result in the long-awaited cure of this disease.
© 2005 Elsevier Inc. All rights reserved.

The thalassemias are anemias of variable severity, which result
from mutations of the genes encoding the synthesis of ␣- and
␤-globin chains of hemoglobin.1-4 Serious thalassemia is as-
sociated with iron overload, tissue damage, and increased risk
of cardiovascular complications. Thalassemias are prevalent in
a belt ranging from the Mediterranean basin through the Mid-
dle East and Indian subcontinent up to Southeast Asia. Beta-
thalassemias are the most important among the thalassemia
syndromes with an average trait prevalence of 7% in Greece,
Requests for reprints should be addressed to George Hahalis, MD, 7
Larnakos Street, 26441 Patras, Greece.
E-mail address: ghahalis@otenet.gr.
15% among Cypriots, and 4.8% in Thailand.1,4 Furthermore,
the hemoglobin E gene, which can interact with ␤-thalassemic
alleles and cause a broad phenotypic spectrum, reaches a fre-
quency of up to 50% in Thailand.1
Within the first months of life, adult hemoglobin con-
taining 2 pairs of ␣ and ␤ chains (HbA:␣2␤2) physiologi-
cally replaces fetal hemoglobin (HbF:␣2␥2).2 In ␤-thalasse-
mia, deficient production of structurally normal ␤-chains
and the attending accumulation of unopposed ␣-chains lead
to anemia, largely as a consequence of ineffective hemo-
poiesis.2-4 In ␤-thalassemia major, severity of anemia re-
quires initiation of blood transfusions during infancy. Pa-
tients with a less severe phenotype, ie, ␤-thalassemia

0002-9343/$ -see front matter © 2005 Elsevier Inc. All rights reserved.
doi:10.1016/j.amjmed.2005.02.021
958 The American Journal of Medicine, Vol 118, No 9, September 2005

Figure 1 Beta-thalassemia syndromes: definition of terms, hematology, including genotype/phenotype relationships, and therapy (adapted
from 1,2,4,15,30,58).

intermedia, will, if at all, become transfusion-dependent
later in life. In ␤-thalassemia/hemoglobin E disease, inter-
patient hemoglobin levels range between 3 and 13 g/dL,
blood transfusion requirements are variable and phenotype
varies between mild and serious anemia (Figure 1).4
Morbidity due to cardiovascular, endocrinological, and
hepatic disease is considerable in ␤-thalassemia syn-
dromes,5-14 whereas heart failure still constitutes the leading
cause of mortality in patients with ␤-thalassemia major.
Thus, ␤-thalassemias not only affect a large number of
people worldwide resulting in a tremendous health care and
social problem, but they also require a multidisciplinary
medical expertise.1,2,5,14 In particular, physicians should
become familiar with thalassemia-related problems in coun-
tries where a growing immigrant population resulted in an
increasing number of such patients, including the United
States and Canada, as well as many European countries.15
Research achievements in the last decade elucidated both
the natural history of ␤-thalassemia major, which is princi-
pally determined by the cardiac function, and the pleiomor-
Hahalis et al Heart failure in ␤-thalassemia syndromes
phic pathophysiology of heart failure in ␤-thalassemia syn-
dromes. This review focuses on recent advances in our
understanding of heart failure in ␤-thalassemia syndromes.
Iron cardiotoxicity and histopathology
The increase of plasma iron turnover in ␤-thalassemia re-
sults in saturation of the iron storage and transport proteins
and emergence of ␣ “free” plasma iron pool.16 Cardiomy-
ocytes are sensitive to redox-active iron and the accompa-
nying elaboration of hydroxyl radical (.OH). This iron-
mediated oxidative stress causes lipid peroxidation,
mitochondrial injury, membrane disruption, and contractile
dysfunction with myocyte death.16-19 In vivo, thalassemia is
linked with endothelial dysfunction and increased oxidati-
tive stress, whereas desferrioxamine administration and iron
deficiency confer beneficial biological effects.20-24
Histopathology in iron overload states lends further sup-
port toward a deleterious effect of iron on the cardiovascular
system.25-31 In advanced iron overload, a rust-brown myo-
cardial appearance due to iron deposition preferentially in
the subepicardial layers is a common autopsy finding. In-
volvement of the conduction system is less severe and
inhomogeneous.6,25,26 Cardiac hypertrophy, chamber dila-
tion, and pericardial effusion along with focal myocardial
degeneration are invariably present.6 In patients with
␤-thalassemia major and congestive heart failure, mild to
moderate fibrosis in the absence of inflammation was found,
whereas, on electron microscopy, disruption of the sarco-
meres together with iron-containing granules between myo-
fibrils were evident.27 Autopsy findings in less advanced
iron loading have been reported on ␤-thalassemia/hemoglo-
bin E patients with intermedia phenotype.28-31 The results of
these studies can probably be extrapolated to other ␤-thalas-
semia intermedia patients, by assuming qualitative similar-
ities between these 2 less severe phenotypes. Cardiac iron
deposition was reported to be usually slight despite severe
hepatic iron loading, to follow the same intramyocardial
distribution pattern and to spare the conduction system. At
least moderate myocardial hypertrophy and left ventricular
involvement were evident in most patients and attributed to
chronic anemia.28 In about half of unselected autopsies,
chronic pulmonary artery obstruction along with right ven-
tricular disease was found.29,31 Pulmonary vascular abnor-
malities resembled those in idiopathic pulmonary arterial
hypertension in many cases or may have resulted from
chronic embolic disease in other patients.29-32 Further au-
topsy findings included iron infiltration of the coronary
arterial walls, pericarditis, degenerative and rheumatic valve
disease.28,29 Of note, among Southeast Asian patients who
suffered from nonheavily transfused ␤-thalassemia “major,” a
mixed picture between less serious and advanced iron overload
was found.28,29 The aforementioned findings implicate a pos-
sible pathological continuum between cardiac alterations in
serious iron loading and iron-mediated, age-dependent28,29
cardiovascular disorders in less severe ␤-thalassemia.
959
The pathophysiological diversity
of heart failure
␤-thalassemia major
On the background of cardiac iron overload, multiple fac-
tors can detrimentally affect cardiac function, including
volume overload, high cardiac output, neurohumoral acti-
vation, eccentric left ventricular hypertrophy, genetic pre-
disposition, endocrinopathies, and increased elaboration of
pro-inflammatory cytokines, as well as additional or un-
known factors.10-12,20,33-41 Heart failure usually develops
among patients with nonoptimal chelation therapy and
multi-endocrinopathies.12 Dyspnea or fatigue is reliably re-
ported by the patients, and even mildly symptomatic pa-
tients demonstrate a substantial reduction in exercise capac-
ity. Right heart failure manifests either early or, more
frequently, evolves and predominates during the course of
left-sided heart failure. Occasionally, acute right-sided heart
failure may mimic acute abdomen and result in diagnostic
delay.42 Paroxysmal atrial fibrillation is common and almost
invariably associated with myocardial dysfunction. Resto-
ration of sinus rhythm per se usually does not reverse
cardiomyopathy. Due to longer survival of thalassemic pa-
tients, the incidence of this arrhythmia may increase in the
future and be rather age- and volume– overload- than
cardiomyopathy-dependent. The clinical picture of the dis-
ease varies between a long-lasting course and, sometimes,
complete remission to fulminant disease.6,10-12,43
Biventricular dilated cardiomyopathy
This is the most common underlying pathophysiological
abnormality among heart failure patients with ␤-thalassemia
major.10-12,43 Contractile dysfunction is accompanied by
low cardiac output and may demonstrate substantial long-
term variations (Figure 2). This is more likely explained by
the extent of cardiac iron deposition or the myocardial
responsiveness to the intensified chelation therapy. In ad-
vanced disease, a distinct hemodynamic pattern of severe
right ventricular cardiomyopathy is evident.12 Ischemic car-
diomyopathy is notably very uncommon, due to the rare
incidence of coronary artery disease both clinically44 and
angiographically (Kremastinos DT: unpublished data).
Myocarditis/pericarditis
In our series of 1048 patients, 4.5% of them with a mean age
of 15 years were diagnosed over a 9-year period to have left
heart failure as a consequence of biopsy-proven myocardi-
tis.34 Almost half of the cases had a complete recovery,
whereas 44% of the patients died. In a subsequent study, an
association of heart failure with the major histocompatibil-
ity in patients with ␤-thalassemia major was reported. This
960 The American Journal of Medicine, Vol 118, No 9, September 2005

Figure 2 Recurrent, long-lasting heart failure in a patient with ␤-thalassemia major. Symptoms (New York Heart Association functional
classification), myocardial function, serum ferritin levels and quality of chelation therapy are depicted. Symptoms of heart failure were
severe in 1996-1997 as well as in 2000 (class III to IV). Improvement of chelation treatment resulted in lowering of serum feritin over the
ensuing 8 years. Despite the rather unpredictable change of ejection fraction (LVEF) and end-diastolic dimensions (LVIDD) with regard
to serum ferritin levels, a complete normalization both of cardiac function and clinical status of the patient were finally noted. (Normal
values: serum ferritin, 20-250 ng/mL [desirable ferritin levels in ␤-thalassemias: less than 1000 ng/ml]; left ventricular ejection fraction,
higher than 55%; left ventricular diameter at end-diastole, lower than 55 mm 11,53).

suggests an autoimmune pathophysiology of left-sided heart
failure in these patients.45 Similar to iron-induced cardio-
myopathy, genetic factors may therefore modulate predis-
position of thalassemic patients to myocarditis.10,35,45 Fu-
ture studies on thalassemic inflammatory cardiomyopathy
should determine the prevalence of both immune-competent
infiltrates and viral genomic materials in the myocardium by
biopsy-ascertained immune-histochemistry as well as mod-
ern molecular techniques.
Although very frequent in the past, pericarditis seems to
have a decreasing incidence in the chelation era. The avail-
able data, however, are contradictory and do not unani-
mously support this common experience.6,10,12,43
semic patients with congestive heart failure demonstrate a
restrictive type of left ventricular cardiomyopathy, in that
almost all of the aforementioned criteria are met with the
exception of the left ventricular contractility, which is al-
ways impaired.10 Neither pure diastolic myocardial heart
failure in the presence of preserved ventricular systolic
function nor right ventricular restrictive cardiomyopathy
have, in our experience, been encountered in ␤-thalassemia
major. In some patients, an echo-Doppler pattern of “left
restrictive-right dilated” cardiomyopathy in association with
pulmonary hypertension has been observed.10 In other pa-
tients, this finding probably reflects a timely disparate myo-
cardial behavior of the 2 ventricles in the absence of pul-
monary hypertension (Figure 3).12

Restrictive type of left ventricular

cardiomyopathy Pulmonary arterial hypertension
True restrictive cardiomyopathy is characterized by restric- Recent studies clearly demonstrated the absence of pulmo-
tive hemodynamics, nondilated ventricles and, at least ini- nary arterial hypertension among asymptomatic patients as
tially, near normal or normal contractility.46 Some thalas- well as in the vast majority of those with heart failure.11,12
Hahalis et al Heart failure in ␤-thalassemia syndromes 961

Figure 3 “Dilated-right/restrictive-left” cardiomyopathy in ␤-thalassemia major. This patient initially developed “dilated-right/restrictive-
left” cardiomyopathy and succumbed to “dilated-right/dilated-left” cardiomyopathy. M-mode tracings (A) depict nondilated, hypokinetic
left ventricle (LV) and right ventricular dilatation (RV). Two-dimensional echocardiogram (B) shows right heart dilatation. Biventricular
systolic function was depressed (ejection fraction: left ventricular, 42%; right ventriclular on first-pass radionuclide ventriculography, 27%).
Doppler of both mitral inflow (C) and tricuspid inflow (D) (high E/A ratio and short E-deceleration time) as well as the exclusively diastolic,
forward flow in the hepatic vein (E) indicate biventricular restrictive physiology along with inferior vena cava congestion (F). Hemodynamic
pattern (G) indicates equalized and elevated left and right ventricular end-diastolic pressures (arrows) and, in addition, relatively low
pulmonary artery systolic pressures (asterisks). On the electrocardiogram (H), PR prolongation, nonspecific ST/T changes, and right axis
deviation are evident.

Thus, previous reports were not confirmed,47,48 despite the
attractive theoretical background.10,47-53 Exceptionally,
some older patients with high ferritin values do develop pul-
monary hypertension10 and figures will probably increase in
the future due to the growing population of aging patients.
Acute cor pulmonale, which is occasionally encountered, re-
flects the increased thromboembolic risk of these patients.11,52
Normal ventricular systolic function
among asymptomatic patients
In contrast to an older report,54 recent investigations11,53
indicate that left ventricular filling in asymptomatic patients
with ␤-thalassemia major is not restrictive but rather undis-
turbed and compatible with increased preload.55 Moreover,
the right-sided inflow features suggest impaired right ven-
tricular relaxation and carry prognostic information.11
␤-thalassemia intermedia
Aessopos et al recently reported on 110 Greek patients, half
of whom were splenectomized. In approximately 50% of the
patients, at least mild pulmonary hypertension and pericar-
dial thickening were evident on echocardiography. Pulmo-
nary pressures correlated with age and cardiac output,
whereas high-output pulmonary hypertension was found on
catheterization in all 6 patients with heart failure.5 A higher
962 The American Journal of Medicine, Vol 118, No 9, September 2005
susceptibility for pulmonary hypertension in ␤-thalassemia in-
termedia appears plausible, although both thalassemia phe-
notypes share common predisposing factors5,11,32,48-53,56 in-
cluding hemolysis-mediated pulmonary hypertension:57
Compared with ␤-thalassemia major patients, those with
less severe phenotype both are older5,12 and suffer from
more serious anemia. As a result of sporadic only transfu-
sion requirements, patients with ␤-thalassemia intermedia
retain, in addition, almost 100% of their own erythrocytes,
which are potentially more procoagulant and associated
with a higher incidence of splenectomy.49,52
␤-thalassemia/hemoglobin E disease
Heart disease is the leading cause of mortality among trans-
fusion-dependent patients.30,58,59 Therefore, the major phe-
notype probably carries a comparable, although poorly de-
fined, cardiac risk with that of the general ␤-thalassemia
major patients.
Patients with the intermedia phenotype may develop
biventricular failure.59 Acute pericarditis is frequent, and
chronic pericardial disease is found in some patients.29,30,59
Degenerative valve disturbances are analogous to those de-
scribed in Greek patients, whereas rheumatic valve disease
is the consequence of frequent streptococcal infections.5,28
Pulmonary hypertension is well documented, largely in
splenectomized patients with thrombocytosis and right heart
failure, whereas accompanying hypoxemia is partially re-
versed by aspirin administration.28,29,60-62 Pathophysiologi-
cally, the vascular perturbation in this disorder may reflect
qualitative, but probably not quantitative, similarities with
the general ␤-thalassemia intermedia patient, including he-
molysis, high output, hypoxia, postsplenectomy thrombocy-
tosis, activated endothelial cells, nucleated erythrocytes and
cytokine elevation, in the context of hypercoagulable state
and predisposition to thromboembolism.5,49,52,57-63
Normal ventricular systolic function
in asymptomatic patients
Chamber dilatation and eccentric hypertrophy follow the
degree of anemia, whereas myocardial function appears
normal61 similar to other ␤-thalasemia intermedia pa-
tients.5,64 Furthermore, paroxysmal atrial fibrillation is a
relatively common cause of morbidity in these patients.
Screening for cardiac disease and risk
stratification in heart failure
␤-thalassemia major
Myocardial dysfunction, which might have been obscured
by the altered loading conditions in anemia, could represent
Figure 4 Beta-thalassemia major: recommendations for patient
management in relation to the clinical cardiac risk category.
a preclinical, high cardiac risk equivalent and, if detected,
lead to timely intensified chelation therapy.65-76 However,
most investigated techniques suffer from lack of informa-
tion on their incremental prognostic value beyond that given
by simple clinical parameters. This is an important draw-
back, because prognosis is influenced not only by the pres-
ence and severity of cardiac involvement but also by the
extent of iron burden.10-12 We would therefore recommend
that clinicians initially integrate hematological and cardiac
information for screening and heart failure prognostication.
This simple approach helps broadly categorize the patient’s
cardiac risk. Hematological data include frequency and age
of onset of blood transfusions, ferritin levels, quality of
chelation therapy and extent of iron overload-induced co-
morbidities. The accuracy of several measurements of se-
rum ferritin, although limited by co-existing liver disease,
has been prognostically validated.9,77 Assessment of cardiac
status is accomplished by considering past history of heart
failure, functional class, rapidity of disease evolution and
severity of myocardial dysfunction. Echocardiography or
left ventricular rest/stress radionuclide ventriculography
should be used periodically for early detection of myocar-
dial dysfunction. Such findings are alarming in the context
of high iron loading.11,12 Liver biopsy is at present the
reference method for estimation of iron burden and cardiac
risk2 but is considered by many thalassemic patients as
cumbersome for serial examinations (Figure 4).
The need for noninvasive, precise risk determination in
thalassemia will probably be fulfilled by a new cardiovas-
cular T2-star magnetic resonance technique (T2*). Cardiac
T2* seems to accurately quantify cardiac iron-overload.76
Myocardial T2* correlated inversely with left ventricular
ejection fraction but not with liver iron or ferritin levels.
Furthermore, presence of severe cardiac iron overload in
some patients despite moderate only hepatic iron loading76
challenge the concept that cardiac iron overload is an un-
avoidably “late” phenomenon.75 Although promising, this
technique is costly and cannot be available in poor coun-
tries, where the disease is very prevalent.
Hahalis et al Heart failure in ␤-thalassemia syndromes
␤-thalassemia intermedia and ␤-thalassemia/
hemoglobin E disease
Age, high ferritin levels, severity of anemia, need of
blood transfusions, and splenectomy pose even asymp-
tomatic patients at increased, although as yet ill-defined,
cardiovascular risk. Surveillance for heart disease is im-
perative, given the interpatient heterogeneity of iron
loading, particularly in association with the splenectomy
status.78 Clinical information and regular echocardio-
graphic monitoring, including investigation of pulmonary
artery pressures, are therefore important tools for cardiac
risk stratification, whereas the role of magnetic resonance
techniques has yet to be determined.79 Moreover, heart
failure patients should undergo a thorough diagnostic
workup for precise determination of the cause and sever-
ity of the underlying cardiopulmonary disease.
The role of chelation therapy in prevention
and course of cardiac disease—therapeutic
implications
␤-thalassemia major
In recent series, the prevalence of heart failure has been
more than halved but is still 2.5% among well-treated pa-
tients.6,10,12,80,81 Even more, the age of onset of heart failure
could only modestly, by 1 decade, be prolonged, due to sub-
optimal chelation of many adolescents14 and possibly to other,
as yet poorly characterized causes (eg, genetic susceptibility).
Pump failure is the principal cause of mortality,6,8-14 while
sudden death in ␤-thalassemia major is notably uncom-
mon10,12 despite data revealing a proarrhythmic substrate.82
Primary prevention
In the last 2 decades, nonrandomized studies assessed prog-
nosis in ␤-thalassemia major.8,9,23,83,84 These investigations
demonstrated a survival improvement, which was almost
entirely due to cardiac disease prevention among patients on
optimal chelation therapy.
Zurlo et al13 reported that the 5-year survival probability
after the first decade of life was 81% for subjects born in
1960-1964 versus 97% for those born in 1970-1974. Modell
et al14 showed that about 50% of patients with ␤-thalasse-
mia died before the age of 35 years. The survival probability
of both the 1955-1964 and 1965-1974 birth cohorts was
50% at the age of 40 years and better than in older series.
Such outcome improvement, albeit modest, confirmed ob-
servations made by the same investigators 2 decades earlier
on the survival benefit conferred by desferrioxamine. Ehlers
et al84 reported almost a doubling of survival for patients
placed on chelation therapy. Brittenham et al8 demonstrated
963
that for each unit increase in the natural logarithm of the
ratio of transfused iron to total desferrioxamine use (equiv-
alent to a quadrupling of serum ferritin), the relative risk for
cardiac disease was 9.9 and for death 12.6. Probability of
survival to at least the age of 25 years was 32% for patients
on ineffective chelation versus 100% for those on good
chelation therapy. Olivieri et al9 reported a survival proba-
bility without cardiac disease of 91% at 15 years among
appropriately chelated patients. Even in high-risk patients,
intensive intravenous chelation treatment resulted in an ac-
tuarial survival of 63% at 13 years.85
Thus, the long-term outlook of patients on optimal che-
lation therapy is good. Furthermore, the dogma “it is never
too late” seems to apply to every patient with ␤-thalassemia
major, because prognosis is largely determined by the cur-
rent quality of chelation treatment.8,9,85
Course of heart failure
In advanced cardiac iron overload states, outcome of heart
failure is dismal,6,43,86 with a reported 3-month mortality
rate of 58% in the prechelation era.6,43 Recent findings from
Kremastinos et al indicate an improved prognosis over older
series. Five-year survival was 48% and positively associ-
ated with left ventricular systolic function. All deaths oc-
curred among patients with biventricular cardiomyopathy,
shortly after involvement of the nonfailing ventricle.10 Such
improved survival is explained by the widespread use of
chelation treatment and possibly also by better management
of anemia and use of angiotensin-converting enzyme inhib-
itors.10,87 Thus, heart failure seems to have a milder course
among patients on adequate chelation, similar to that of the
general population of heart failure patients.10,87 Further-
more, a substantial minority of these patients experience
reversal of cardiomyopathy after intensification of chela-
tion.11,12,85,88 In contrast, insufficient chelation therapy may
be associated with a fulminant course.12
Therapeutic implications
Intensification of chelation therapy is of paramount impor-
tance in asymptomatic high-risk patients as well as in pa-
tients with heart failure, because of its additional and pos-
sibly also greater benefit as compared with current
therapeutic modalities for systolic heart failure (Figure 1).
By extrapolating current guidelines, such established treat-
ment options should also be recommended for thalassemic
patients.89
In face of the altered loading conditions in thalassemia,
initiation of therapy with angiotensin-converting enzyme
inhibitors should be implemented early, for example when
the left ventricular ejection fraction approaches a value of
50%.12,90,91 Angiotensin II receptor blockers can alterna-
tively or additionally be used. Diuretics, including spirono-
lactone antagonists and digitalis glycosides, are necessary in
964 The American Journal of Medicine, Vol 118, No 9, September 2005
Figure 5 Causes of heart failure in ␤-thalassemia intermedia
and ␤-thalassemia major. Top: pulmonary arterial hypertension
with severe right chamber dilatation in a patient with ␤-thalasse-
mia intermedia. Pulmonary angiogram revealed chronic thrombo-
embolic disease. Bottom: Severe biventricular dilated cardiomy-
opathy with large thrombus in the left ventricular apex (arrows) in
a patient with ␤-thalassemia major and fatal outcome.
symptomatic patients, whereas beta-blocker therapy has to
be considered in compensated patients.89
Patients with ␤-thalassemia major have a higher-than-
average possibility of developing malignancies.13 Chelation
therapy should be intensified in patients undergoing chemo-
therapy with drugs known to exert an iron-mediated toxic-
ity, such as anthracyclines,92 in order to minimize the risk of
fulminant cardiomyopathy.12
Right ventricular involvement and the attending asyn-
chronous left ventricular contraction are frequent findings in
end-stage, thalassemic heart failure. Resynchronization of
contractility by means of atrial-synchronized biventricular
pacing both improves contractility and alleviates symptoms
in refractory systolic heart failure93 and should therefore be
considered in selected thalassemic patients. Anticoagulation
is indicated in patients with atrial fibrillation, in the occa-
sional patient with ventricular thrombus, and in those with
pulmonary hypertension (Figure 5). Due to coexisting he-
patic disease, a lower-than-average anticoagulant dose is
required. Restoration of sinus rhythm usually should be
undertaken in appropriately prepared patients. Prophylactic
antithrombotic treatment is additionally recommended in
patients exposed to transient thromboembolic risk, includ-
ing surgery and prolonged immobilization.52
Advanced or complete atrioventricular block will neces-
sitate the implantation of a pacemaker device. Interestingly,
malignant ventricular tachyarrhythmias occur rarely.10-12
This may be partly related to recovery of myocardial func-
tion in some patients or rapid decline of pump function in
others.12 Implantation of a cardioverter-defibrillator is
thereby rarely necessary. In exceptional cases, and when the
fate of dysfunctional myocardium has not been clarified,
automatic wearable defibrillators may be a therapeutic op-
tion. Finally, in carefully selected patients with end-stage
disease, heart transplantation has been recommended.94 In
fact, we are aware of one patient who is still alive 17 years
after heart transplantation.
␤-thalassemia intermedia
Primary prevention— course of heart failure—
therapeutic implications
Both the natural history and the optimal management of the
disease and its cardiac complications, as well as the etiology
of death, remain poorly understood.1,95 In our experience,
some patients who become transfusion dependent succumb
to dilated cardiomyopathy with or without concomitant pul-
monary hypertension and appear to have a worse outcome
than those with isolated pulmonary hypertension. Clearly,
future studies should clarify these issues and help establish
stricter transfusion and chelation criteria.1 At present, initi-
ation of treatment follows anemia severity, clinical infor-
mation regarding iron loading as well as cardiac complica-
tions, including atrial fibrillation, pulmonary hypertension,5
or cardiomyopathy. Antithrombotic prophylaxis has been
suggested for splenectomized patients at high transient
thromboembolic risk (Figure 5).5,52 Anticoagulation should
adhere to the same guidelines as in patients with the major
phenotype, whereas oxygen administration as well as di-
uretic and digitalis treatment should be individualized. In
documented pulmonary hypertension, a life-long therapy
with vasodilators32 will be necessary.
␤-thalassemia/hemoglobin E disease
Primary prevention— course of heart failure—
therapeutic implications
Patients with the major phenotype are probably indistin-
guishable from other ␤-thalassemia major patients31 regard-
ing iron loading and salutary effects of chelation treatment.
Hahalis et al Heart failure in ␤-thalassemia syndromes
Patients with less severe disease may attain old age, but the
main cause of mortality among older patients is cardiac.29
Guidance of transfusion and chelation therapy has to
follow the same principles applied for the general ␤-thalas-
semia patient.95,96 It is recommended that chelation treat-
ment be initiated at hepatic iron concentrations of higher
than 4 mg iron/g liver, dry weight.95 Unnecessary blood
transfusions should be avoided, if possible.1 Splenecto-
mized patients suffering from the intermedia phenotype
who are free from cardiac disease should receive a life-long
antiplatelet therapy, because they may exhibit a higher
thromboembolic risk than other ␤-thalassemia intermedia
patients. In addition, anticoagulation, vasodilators, and
probably also initiation of blood transfusions will be re-
quired in patients with pulmonary hypertension.97
Future perspective
Oral chelators such as deferiprone (“L1”) will improve
adherence to chelation therapy and probably also prognosis
in thalassemia. In nonrandomized trials, deferiprone alone
or in combination with desferrioxamine seems to be at least
as effective as desferrioxamine in reducing the incidence of
cardiac disease and removing myocardial iron.95,98,99
Hemoglobinopathies are desirable targets for genetic
therapies. Successful allogenic bone marrow transplantation
reverses the ␤-thalassemia phenotype through stem cell
replacement but is associated with toxicity and problems
with donor availability. It is expected that both the discovery
of the ␤-globin locus control region and progress in vector
construction, as well as efficiency of gene transfer will result in
the long-awaited eradication of ␤-thalassemia.100
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