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Heart Online First, published on November 13, 2015 as 10.1136/heartjnl-2015-307959
Division of Cardiology, Mayo
Clinic, Rochester, Minnesota,
USA
Correspondence to
Dr Sunil Mankad, Division of
Cardiology, Mayo Clinic,
Rochester, MN 55905, USA;
Mankad.sunil@mayo.edu
Received 29 August 2015
Revised 5 October 2015
Accepted 6 October 2015
To cite: Mankad R,
Bonnichsen C, Mankad S.
Heart Published Online First:
[please include Day Month
Year] doi:10.1136/heartjnl-
2015-307959
Copyright Article author (or their employer) 2015. Produced by BMJ Publishing Group Ltd (& BCS) under licence.
Review
Hypereosinophilic syndrome: cardiac diagnosis
and management
Rekha Mankad, Crystal Bonnichsen, Sunil Mankad
ABSTRACT
Hypereosinophilic syndrome (HES) is a heterogeneous
group of conditions that is defined at its core by
hypereosinophilia (HE) (blood eosinophil count of
>1.5×109/L) and organ damage directly attributable to
the HE. Cardiac dysfunction occurs frequently in all forms
of HES and is a major cause of morbidity and mortality.
Once a significantly elevated eosinophil count is
identified, it must be confirmed on repeat testing and
the aetiology for the HE must be rigorously sought out
with a focus on identifying whether organ dysfunction is
occurring. Echocardiography is routinely performed to
assess for cardiac involvement, looking for evidence of
left ventricular and/or right ventricular apical obliteration
or thrombi or a restrictive cardiomyopathy. Cardiac
magnetic resonance imaging and CT are often useful
adjuncts to establish the diagnosis but endomyocardial
biopsy remains the gold standard. To decrease the
degree of eosinophilia, treatment can include
corticosteroids and/or imatinib based on the aetiology.
Anticoagulation, standard heart failure therapy for a
restrictive cardiomyopathy and finally cardiac
transplantation may be indicated in the treatment
algorithm.
INTRODUCTION
Hypereosinophilic syndrome (HES) is a group of
conditions in which there is an overproduction of
eosinophils that subsequently infiltrate and damage
multiple organs. Cardiac manifestations, particu-
larly eosinophilic myocarditis (EM) and endomyo-
cardial fibrosis (EMF), are a typical cause of
morbidity and mortality in HES. This review will
briefly discuss the definition and aetiology of HES
with an overview of the clinical cardiac presenta-
tions/diagnoses. In addition, a focused discussion of
cardiac management and treatment will be
reviewed.
DEFINITION
An eosinophil is a granulocyte whose function is
not clearly understood, but likely plays a role in
host immune response to infection and inflamma-
tion. Typically, eosinophils are not normally found
in all of the organs (they are seen in the thymus,
spleen, gastrointestinal tract, lymph nodes and
uterus). The production of eosinophils is controlled
by specific cytokines: IL-5, IL-3 and GM-CSF.1
These cytokines are typically produced by activated
T lymphocytes, mast cells and stromal cells, and are
usually responsible for reactive eosinophilia. Clonal
eosinophils are typically derived from mutated pro-
genitors (such as in tyrosine kinase receptors,
platelet-derived growth factor receptor β and fibro-
blast growth factor receptor 1).2 The Year 2011
Mankad R, et al. Heart 2015;0:1–7. doi:10.1136/heartjnl-2015-307959
Working Conference of Eosinophil Disorders and
Syndromes (Vienna, Austria; 27–28 May 2011)
was tasked with reviewing the criteria for establish-
ing the definition of various disorders related to
eosinophilic abnormalities. The goal was to sim-
plify the prior classifications into a contemporary
multidisciplinary scheme.2 Hypereosinophilia (HE)
is defined as an elevated eosinophil count
(>1.5×109/L) noted on two separate tests greater
than a month apart or the finding of tissue HE
(which includes >20% eosinophils on bone
marrow section, extensive tissue infiltration by eosi-
nophils validated by a pathologist or marked depos-
ition of eosinophilic granule proteins in tissue). HE
is further subdivided into a hereditary (familial)
variant, HE of undetermined significance, primary
(clonal/neoplastic) variant and a secondary (or
reactive) HE.2 The HESs are then those conditions
with peripheral HE for any reason, along with
organ damage directly attributed to tissue HE
(table 1). The organ damage must be due to HE
and not related to an alternative cause. HES can be
idiopathic, primary (neoplastic) or secondary
(reactive) based on the cause of the HE (table 2). In
prior classifications, HES was defined as HE in
which an aetiology was not found; the new pro-
posed classification has modified the diagnosis for
HE and HES. Primary or neoplastic HES indicate a
stem cell, myeloid or eosinophilic neoplasm and
are considered clonal. Secondary or reactive HES
has multiple potential causes. The HE in these
states is caused by an overproduction of eosinophi-
lopoietic cytokines (such as IL-5) and is polyclonal.
Parasitic infections are common cause of HE in
developing countries3 and can result in HES.
Certain solid tumours and T-cell lymphoma where
there is HE can also result in end organ dysfunc-
tion and damage. HE can occur in other conditions
but it is unknown if it is directly related to the
disease presentation and complications. These
include eosinophilic granulomatosis with polyangii-
tis (Churg–Strauss) and Hyper-IgE syndrome (an
autosomal dominant hyperimmunoglobulin E syn-
drome often accompanied by eczema and facial
abnormalities).2 In upto 75% of cases of HE, an
underlying cause is not found; thus, affected indivi-
duals are frequently labelled with idiopathic HES.4
EPIDEMIOLOGY
HESs are rare and the overall incidence and preva-
lence have not been well characterised. Identifying
patients with HES through the Surveillance,
Epidemiology and End Results (SEER) database,
the incidence was approximately 0.035 per
100 000.5 Over the 5 year period (2001–2005)
reported in SEER, the median age at diagnosis was
1
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Review
Table 1 Definition of eosinophil abnormalities based on
suggested revised classification
Eosinophilia Eosinophil count of >0.5 eosinophils×109/L blood
hypereosinophilia (HE) >1.5 eosinophils×109/L blood on two tests ≥1 month
apart and/or tissue HE (based on eosinophils on bone
marrow biopsy or presence of eosinophilic granule
proteins in tissue)
Hypereosinophilic Diagnosis of HE plus organ damage/dysfunction
syndrome directly due to HE (with the exclusion of other
conditions as the cause for the organ dysfunction)
52.5 with a male to female ratio of 1.47.5 Certain HES variants
appear to occur exclusively in males where others have an equal
distribution between the sexes.4 Until relatively recently, the
prognosis was quite poor, but with recent advances in the man-
agement of HES along with the earlier diagnosis and treatment
of organ involvement, an 80% survival at 5 years and a 42%
survival at 10–15 years has been reported.6
PATHOPHYSIOLOGY/CLINICAL PRESENTATION
The extensive infiltration of eosinophils into tissues can in and
of itself cause damage if the proliferation is significant enough,
but the organ damage may occur through an associated fibrosis.7
Activated eosinophils may cause tissue damage through the
release of toxic granules, release of cytokines or recruitment of
inflammatory cells.8
As HES can be a multisystem condition, patients may present
with signs and symptoms related to any organ system. Typically
symptom onset evolves slowly and can be very nonspecific.
Weakness, fatigue, cough, myalgias, shortness of breath, rash
and diarrhoea may be presenting complaints.2 There is signifi-
cant heterogeneity in the extent and degree of organ involve-
ment in a given individual.4 A rash and cough/dyspnoea are the
two most common symptoms followed by gastrointestinal dis-
turbances. Cardiac and neurologic signs and symptoms are rarer
but potentially life threatening due to rapid progression of com-
plications.4 Eosinophilic cardiac disease was first described in
1936 by Wilhelm Loffler who described a ‘fibroplastic parietal
endocarditis with blood eosinophilia’ that is consistent with the
EMF seen in HES at later stages. Historically, cardiac involve-
ment was felt to be present in up to 40%–50% of HES9 10 but
may be even higher.11 Cardiac disease is a major cause of mor-
bidity and mortality.6 12 13 A more recent retrospective review
over a 19-year period, identifies cardiac dysfunction as the
Table 2 Categories of HES
Category of HES Aetiology/Causes
Primary (neoplastic) HES Stem cell, myeloid, or eosinophilic neoplasm:
▸ PDGFRA
▸ PDGFRB
▸ FGFR1
Secondary (reactive) HES Overproduction of eosinophilopoietic cytokines:
▸ Parasitic infections
▸ T-cell lymphoma
▸ Certain solid tumours
▸ T-cell lymphocytic variant
Idiopathic HES Cause of HE unknown
FGFR1, fibroblast growth factor receptor 1; HE, hypereosinophilia; HES,
hypereosinophilic syndrome; PDGFRA, platelet-derived growth factor receptor α;
PDGFRB, platelet-derived growth factor receptor β.
2 Mankad R, et al. Heart 2015;0:1–7. doi:10.1136/heartjnl-2015-307959
major cause of death in 247 HES patients.11 The cardiac path-
ology of HES has been divided into three stages: (1) an acute
necrotic stage, (2) a thrombotic stage and (3) a fibrotic stage
(table 3). The development of the cardiac disease in HES can be
unpredictable and the stages may overlap.12 Sustained eosino-
philia does not necessarily always equate to the development of
EM and conversely, the degree of cardiac dysfunction does not
directly correlate with the degree of eosinophilia.
The first phase of acute necrosis is the result of EM.
Eosinophils and lymphocytes infiltrate cardiac tissue, releasing
toxic proteins from degranulating eosinophils.14 15 At this stage,
myocardial necrosis and apoptosis occurs. However, typically
no cardiac symptoms are endorsed by patients at this stage.
However, due to small microemboli that may form on the endo-
cardial surface, conjunctival or subungual splinter haemorrhages
may be identified.12 Rarely, a more fulminant course of EM may
occur that can be rapidly fatal without early diagnosis and
treatment.12
The second stage occurs when thrombus forms along the
damaged endocardium. Thrombus formation occurs due to mul-
tiple reasons but is likely directly the result of the disrupted
endothelium, exposing von Willebrand factor and collagen
which bind platelets and tissue factor (which are vital for the
development of fibrin thrombus).15 The thrombi most often
develop within both ventricles, typically at the apex but may
extend toward the base of the heart into the subvalvular regions
and less commonly the outflow tracts.16 These thrombi can
them embolise causing strokes and ischaemic extremities.17 18
Overall, it appears that up to 25% of patients with HES develop
thromboembolic complications and that 5%–10% die from
those complications.15
The final cardiac stage is one in which fibrosis replaces the
thrombi on the denuded endocardium. EMF leads to scarring.
A restrictive cardiomyopathy develops, with symptoms of dys-
pnoea and signs of left-sided or right-sided heart failure.18 19
Restriction of the valve leaflets from fibrosis results in valvular
regurgitation, with mitral regurgitation seen most commonly.16
The fibrosis is irreversible and may be the point at which the
patient is first diagnosed with HES.
The clinical presentation for cardiac involvement as noted
above can vary depending on the stage of myocardial damage.
Cardiac involvement correlates with the occurrence of embolisa-
tion, clinical heart failure and need for cardiac surgery and can
be confirmed with echocardiography.9 In an older review, more
Table 3 Stages of cardiac pathology in HES
Stages of cardiac
involvement in HES Characterisation of stage
Acute necrosis Eosinophilic myocarditis with eosinophilic and
lymphocytic infiltration. Myocardiac necrosis and
apoptosis with rare microembolic phenomena.
Typically no other cardiac symptoms. Rarely can
exhibit a fulminant course.
Thrombotic stage Thrombus along damaged endocardium. Thrombi
within apices of one of both ventricles, and can
encroach on base of the heart into the subvalvular
regions. Embolic phenomena can occur.
Fibrotic stage Thrombi are replaced by fibrosis. Scarring occurs.
Restrictive cardiomyopathy with signs and
symptoms of left or right sided heart failure.
Fibrosis that occurs at the base of the heart can
lead to valvular regurgitation.
HES, hypereosinophilic syndrome.
 Downloaded from http://heart.bmj.com/ on November 18, 2015 - Published by group.bmj.com
than half of the patients with HES and cardiac pathology, pre-
sented with dyspnoea; chest pain and cough were seen less
often. In that same review, 75% of patients who were evaluated
had signs and symptoms of heart failure.18 Arrhythmias may
occur as a result of fibrosis of the conduction system or due to
the scarring of the myocardium. Myocardial infarctions are rare
but can occur as the result of an embolic phenomenon from the
left ventricular (LV) apex or outflow tract. Cardiac symptoms
typically evolve over weeks to months but can be more pro-
longed than that.9
It is important to note that EM can occur separately for HES.
The aetiologies are varied and include malignancy, hypersensi-
tivity myocarditis (HSM), parasitic infections and eosinophilic
granulomatosis with polyangiitis (formerly referred to as
Churg–Strauss). Pathologically, EM is characterised by myocar-
dial inflammation with eosinophils, often with associated
eosinophilia, not necessarily HE, and is distinct in its presenta-
tion as it is often more acute than indolent.20 HSM is an auto-
immune reaction in the heart, typically related to a drug
reaction and can present as rapidly progressive heart failure or
sudden death. Multiple drugs have been implicated and patients
frequently have fever, rash, ECG abnormalities and peripheral
eosinophilia. On myocardial biopsy, the pattern is one of inter-
stitial infiltrate with eosinophils but with minimal cell necrosis.21
EMF can be a separate syndrome in which fibrosis typically at
the apices of the left and/or right ventricles (RV), presents with
symptoms related to a restrictive cardiomyopathy (with left-
sided and right-sided heart failure).22 Although EMF resembles
the late stages of the cardiac involvement in HES, there is not a
consistently identified serum or myocardial eosinophilia.23
Whether transient eosinophilia is the culprit is unclear.
Infectious and/or environmental aetiologies have been
implicated.24
DIAGNOSIS
Per the definition for HES, there must a peripheral eosinophilia
(eosinophil count >1.5×109/L) or tissue HE (figure 1). This
elevation in eosinophils must be present on two separate labora-
tory tests at least 1 month apart. A careful review of the indivi-
dual’s history for travel to determine parasitic exposure,
complete review of medication usage along with a thorough
history and exam are important to determine causes for HE.
Even if asymptomatic, the patient with HE requires a
Figure 1 Shown are focal intact eosinophils in myocardium, and focal
intact and degranulated eosinophils within fresh ( probably
biopsy-related) thrombus, suggestive of eosinophilic heart disease.
Mankad R, et al. Heart 2015;0:1–7. doi:10.1136/heartjnl-2015-307959
Review
comprehensive evaluation to assess for presence and degree of
organ involvement. This may dictate the urgency of other
testing as well as potential aetiologies. Initial testing could
include some of the following: a complete blood count, serum
vitamin B12 levels, serum immunoglobulins, peripheral blood
smear, serum chemistries, creatinine, liver function tests, chest
X-ray, ECG, troponin level (which has been shown to correlate
with the presence of cardiomyopathy25) and stool samples or
serology for parasites (for those from endemic areas or with a
travel history). Assessing for organ involvement is important to
establish the diagnosis of HES over HE alone. This evaluation
would include further testing with pulmonary function testing,
echocardiography, abdominal imaging (CT most commonly)
and tissue biopsies as appropriate. As part of the haematological
assessment, peripheral blood screening would be undertaken
and possibly bone marrow biopsy with tissue typing for the
characterisation of the aetiology of the HE. There are many var-
iants that would be screened for to assess for clonal aetiologies.
One myeloproliferative variant (Fip1-like1-platelet-derived
growth factor receptor α (FIP1L1-PDGFRA) fusion), which has
a poor prognosis, is characterised by elevated serum tryptase
which is of importance from a treatment standpoint.25 This par-
ticular cause of HES has an increased incidence of more pro-
found cardiac disturbances with greater mortality without
treatment.26
Cardiac diagnosis is typically initially suspected based on signs
and symptoms of cardiac dysfunction. ECG is typically non-
specific and can consist of T-wave inversions, left atrial enlarge-
ment, LV hypertrophy, premature ventricular complexes or first
degree atrioventricular block.18 These changes indicate some
potential underlying cardiac abnormality but are not specific for
HES. Echocardiography is a critical diagnostic tool in the evalu-
ation of cardiac disease in HES. During the initial stage of
cardiac involvement (necrotic stage of EM), echocardiography is
typically normal, although wall thickening may be identified if
there is significant oedema within the myocardium due to the
inflammatory process. In the thrombotic stage, thrombi can be
identified within the apices of either the LV or RV or both
(figure 2). The appearance can be mistaken for LV noncompac-
tion, apical hypertrophic cardiomyopathy (HCM) or even
typical LV apical thrombus due to an apical wall motion abnor-
mality. The use of contrast agents, to better define the apex, can
help differentiate thrombi from apical HCM and noncompac-
tion and can also reveal the preserved systolic function at the
apex in HES that distinguishes it from an apical infarction with
Figure 2 Transthoracic echo imaging: apical four-chamber view
demonstrates a large thrombus filling the left ventricular cavity.
3
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Figure 3 Transthoracic echo imaging: (A) (left) demonstrates an apical four-chamber view. Contrast echocardiography clear delineates thrombus
present at the left ventricular apex (white arrow points to black defect of thrombus). (B) Shows the corresponding parasternal short-axis view and
also highlights the benefit of contrast echocardiography at identifying thrombus (white arrow).

thrombus27 (figure 3). Three-dimensional echocardiography
may improve visualisation of the apices and identify thrombus
in lieu of a contrast agent. The progression from thrombus to
fibrosis is not well identified specifically on echocardiography but
does have change in the clinical presentation (more heart failure
symptoms vs embolic phenomena). The apices remain obliterated
but now with fibrosis and less so with thrombus. It is at this stage
that valvular regurgitation may be better identified. The posterior
leaflet of the mitral valve can become thickened and adherent to
the underlying endocardium of the posterobasal wall, restricting
its motion. The mural thombofibrotic material between the pos-
terior mitral leaflet and posterobasal LV wall limit the excursion
of that leaflet and ultimately tether it (figure 4 Significant mitral
regurgitation can be seen and is typically posteriorly directly due
to the restricted motion of the posterior leaflet. In addition, a
restrictive cardiomyopathic picture emerges with characteristic
mitral valve Doppler indices of poor LV compliance and elevated
filling pressures (figure 5). This restrictive physiology is typically
related to the endocardial/myocardial fibrosis that occurs;
however these hemodynamics may be seen due to the small LV
cavity caused by a large noncompliant apical ‘mass’.28 There is
limited data on the use of myocardial strain imaging to assess sys-
tolic function in patients with EM but it may be helpful to differ-
entiate a true restrictive cardiomyopathy from merely restrictive
filling.28
Cardiac magnetic resonance (CMR) imaging has emerged as a
newer modality for the diagnosis of cardiac disease in HES.29–31
CMR can detect ventricular thrombi with a higher degree of
sensitivity and specificity than echocardiography and in addition
contrast-enhanced CMR can identify inflammation and fibrosis
(figures 6 and 7).31 32 Thus, CMR may be able to detect myo-
cardial abnormalities in the early stages of the cardiac involve-
ment in HES (the acute myocarditis/necrotic stage) prior to
echocardiographic abnormalities. CMR can be an important
adjuvant imaging tool that may be useful in following the
cardiac disease course.33 CT imaging has been described as a
potential tool as well to identify LV thrombus and concomi-
tantly assess for coronary artery disease as a potential culprit for
the presence of apical thrombus.34
However, despite the importance of the noninvasive imaging
tools, endomyocardial biopsy (EMB) remains the gold standard
for the diagnosis of cardiac involvement in HES, particularly

Figure 4 Shown in (A) to the left, is

an apical four-chamber view
demonstrating the endomyocardial
fibrosis extending along lateral wall of
the ventricle (yellow arrows) all the
way down to the posterior mitral
leaflet (red arrow). The posterior mitral
valve leaflet has suffered direct tissue
injury and now demonstrates reduced
leaflet excursion leading to severe
eccentric mitral regurgitation shown in
(B) to the right (RA, right atrium; LA,
left atrium; LV, left ventricle). Image
courtesy of Dr Natesa G Pandian.

4 Mankad R, et al. Heart 2015;0:1–7. doi:10.1136/heartjnl-2015-307959

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Review

Figure 5 Shown is the characteristic mitral Doppler inflow pattern of a restrictive cardiomyopathy pattern (A, left). The mitral valve deceleration
time is 105 ms, with a peak early inflow velocity of 1.1 m/s. The mitral annular tissue Doppler (B, right) also demonstrates classic findings of a
restrictive cardiomyopathy with a markedly reduced early diastolic longitudinal relaxation velocity (0.04 m/s).

early in the course to differentiate EM from other forms of
myocarditis. Serial EMB can be used to assess course and treat-
ment response. Infiltration of eosinophils into the myocardium
may be detected; however, more often fibrosis, mural throm-
bus and inflammation of intramural coronary vessels are
detected.35 However, it must be recognised that EMB may be
negative if the process primarily involves the LV rather than
the RV.9
MANAGEMENT OF HES CARDIAC DISEASE
HE has multiple potential treatment options, based on the aeti-
ology. The management of cardiac disease in HES is to normal-
ise the damaging HE. Corticosteroids are one of the
cornerstones of therapy for HES to reduce eosinophil count and
counteract inflammation.36 Patients with the FIP1L1-PDGFRA
mutation should be treated with a tyrosine kinase inhibitor (ima-
tinib) given its possible effectiveness37 along with steroids (with

Figure 6 Selected short-axis images

from cardiac MRI study in a patient
with eosinophilic myocarditis. (A)
Steady state free precession (SSFP)
imaging demonstrates marked
thickening of the anterior, lateral and
inferior walls of the left ventricle. (B)
Marked increase in T2 signal involving
the same walls that were thickened on
SSFP imaging, suggesting oedema. (C)
First pass perfusion imaging
demonstrates an inner rim of
non-enhancing thrombus. (D) Delayed
enhancement imaging demonstrates
hyperenhancement involving the
subendocardial region with associated
nonenhancing rind of thrombus along
the subendocardial surface.

Mankad R, et al. Heart 2015;0:1–7. doi:10.1136/heartjnl-2015-307959 5

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Figure 7 Delayed enhancement images demonstrating intense
hyperenhancement of the subendocardial surface with a large,
nonenhancing thrombus filling the left ventricular cavity.
cardiac involvement, steroids should be used along with the
imatinib to prevent the occurrence of acute heart failure from
necrotising myocarditis).38 The haematological abnormalities
can remiss with this treatment but advanced cardiac disease may
not be affected. Other second line treatment options are avail-
able for refractory cases.
Echocardiography should be used to follow documented
cardiac disease at relatively frequent intervals (<6 months).15 If
no cardiac abnormalities are seen initially in the evaluation of
HES, repeat evaluation and imaging should take place at least
every 6 months.11 LV or RV thrombi or embolic phenomena
would indicate the need for anticoagulation therapy. The dur-
ation of the therapy is best determined by the ongoing presence
of ventricular thrombi along with the status of the endomyocar-
dial disease activity. There is no data to suggest that prophylactic
use of anticoagulation can alter the progression of the disease.15
Congestive heart failure should be managed by current heart
failure guidelines, which include diuretic therapy, β blockade,
ACE inhibitors to name a few.
Valvular disease that is significant and contributing to ongoing
heart failure symptoms may require surgical intervention. Given
the rarity of HES, there is limited data in regard to valve
surgery in these patients. However, both valve repair and valve
replacement have been described.39–41 Replacement appears to
be more common than repair. The type of valve used, mechan-
ical versus bioprosthetic, is an important consideration in this
group of patients. There appears to be a high risk of valve
thrombosis in the mechanical valve group despite anticoagula-
tion.42 Thus, bioprosthetic valves may be the better option;
however, this may require a repeat procedure due to valve
deterioration, particularly in a relatively young patient. It is
important that the eosinophilia be controlled prior to valve
surgery. In the setting of a restrictive cardiomyopathy with
refractory symptoms, heart transplantation may be considered.
Limited data are available but has been reported.43
CONCLUSION
HES is a rare condition that may have several aetiologies.
Cardiac involvement is frequent and carries with it a high rate
of morbidity and mortality. Identifying cardiac dysfunction early
6 Mankad R, et al. Heart 2015;0:1–7. doi:10.1136/heartjnl-2015-307959
and following it serially can help determine treatment
approaches in a timely fashion. Echocardiography is an integral
part of the diagnosis of cardiac involvement but CMR appears
to have an important role. Overall prognosis has improved for
HES, but limited data exist on the best course for cardiac
disease.
Twitter Follow Rekha Mankad at @RMankadMD and Sunil Mankad at
@MDMankad
Contributors All authors contributed in a significant manner to the writing of this
manuscript.
Competing interests None declared.
Provenance and peer review Commissioned; externally peer reviewed.
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Hypereosinophilic syndrome: cardiac

diagnosis and management
Rekha Mankad, Crystal Bonnichsen and Sunil Mankad

Heart published online November 13, 2015

Updated information and services can be found at:

http://heart.bmj.com/content/early/2015/11/13/heartjnl-2015-307959

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