2026 ESC临床共识声明：嗜酸性粒细胞增多症心脏受累的流行病学、病因学、诊断和治疗现状

Current state of knowledge on the epidemiology, aetiology, diagnosis, and management of heart involvement in eosinophilia. A Clinical Consensus Statement of the ESC Working Group on Myocardial & Pericardial Diseases

Petr Kuchynka$^{1}$,*,†, Antonio Brucato i̇$^{2}$,†, Carsten Tschöpe i̇$^{3}$,4,5,6,7, Matteo Cameli i̇$^{8}$, Silvia Castelleti$^{9}$, Leslie T. Cooper$^{10}$, Marc R. Dweck$^{11}$, Andrea Frustaci i̇$^{12}$, Bettina Heidecker$^{3}$,$^{4}$,$^{5}$,$^{6}$, Karin Klingel i̇$^{13}$, Johanna Kuusisto$^{14}$, George Lazaros i̇$^{15}$, Marco Merlo$^{16}$,$^{17}$, Antonis Pantazis$^{18}$, Steffen E. Petersen$^{19}$,$^{20}$, Angelos G. Rigopoulos$^{21}$, Arsen D. Ristic$^{22}$, Frantisek Sedlak$^{23}$, Mary N. Sheppard$^{24}$, and Massimo Imazio$^{25}$,$^{26}$

$^{1}$2nd Department of Medicine, Department of Cardiovascular Medicine, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, 128 08, U Nemocnice 2, Prague 2, Czech Republic; $^{2}$Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy; $^{3}$German Heart Center at Charité (DHZC), Clinic for Cardiology, Angiology, and Intensive Medicine, Germany; $^{4}$Charité – Universitätsmedizin Berlin, Germany; $^{5}$Berlin Institute of Health at Charité (BIH), Germany; $^{6}$German Centre for Cardiovascular Research (DZHK), Partner Site Berlin, Germany; $^{7}$Center for Regenerative Therapies (BCRT) - Berlin, Germany; $^{8}$Department of Medical Biotechnologies, Division of Cardiology, University of Siena, Siena, Italy; $^{9}$IRCS, Instituto Auxologico Italiano, Department of Cardiology, San Luca Hospital, Cardiomyopathy Unit, Milan, Italy; $^{10}$Department of Cardiovascular Medicine, Mayo Clinic, Jacksonville, FL, USA; $^{11}$British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK; $^{12}$Cellular and Molecular Cardiology Lab, IRCCS L. Spallanzani, Rome, Italy; $^{13}$Cardiopathology, Institute for Pathology and Neuropathology, University Hospital Tuebingen, Tuebingen, Germany; $^{14}$Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio, Finland; $^{15}$1st Cardiology Department, Hippokration Hospital, National and Kapodistrian University of Athens, Greece; $^{16}$Center for Diagnosis and Treatment of Cardiomyopathies, Cardiovascular Department, Azienda Sanitaria Universitaria Giuliano-lsontina (ASUGI), University of Trieste, Trieste, Italy; $^{17}$Member of ERN-Guard HEART, Trieste, Italy; $^{18}$Royal Brompton and Harefield NHS Foundation Trust, London, UK; $^{19}$William Harvey Research Institute, NIHR Barts Biomedical Research Centre, Queen Mary University London, Charterhouse Square, London, UK; $^{20}$Barts Heart Centre, St Bartholomew's Hospital, London, UK; $^{21}$Department of Adult Cardiology, Mitera General Hospital, Hyelia Group, Athens, Greece; $^{22}$Department of Cardiology, University of Belgrade, Belgrade, Serbia; $^{23}$1st Department of Medicine, Department of Hematology, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic; $^{24}$Department of Cardiovascular Pathology, Cardiovascular and Genetics Research Institute, St Georges Medical School, London, UK; $^{25}$Department of Medicine, University of Udine, Udine, Italy; and $^{26}$Cardiothoracic Department, University Hospital Santa Maria della Misericordia, Udine, Italy

Received 3 June 2025; revised 5 October 2025; accepted 3 February 2026; online publish-ahead-of-print 21 May 2026

Abstract

Heart involvement in eosinophilia represents a rare entity with substantial cardiac morbidity and mortality. This disorder is often overlooked and diagnosed in its advanced stages. In a subgroup of patients with eosinophilic heart disease, peripheral blood eosinophilia may not be present, and the biopsy of the affected organ or tissue is essential to establish the correct diagnosis. In this clinical consensus statement, an expert consensus group reviews the epidemiology, aetiology, diagnosis,

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and management of eosinophilic heart disease. The aim of the document is to increase awareness about the cardiac involvement associated with eosinophilia in order to diagnose the disease in early phases and prevent deleterious heart damage and adverse outcomes of affected individuals. The spectrum of physiological and immunological derangements requires a multi-disciplinary approach for optimal management of affected individuals.

Graphical abstract

Current state of knowledge on the epidemiology, aetiology, diagnosis and management of heart involvement in eosinophilia


Keywords

Eosinophilia ● Endomyocardial fibrosis ● Myocarditis ● Cardiac magnetic resonance ● Endomyocardial biopsy ● Immunosuppression

Introduction

Eosinophilia is defined by the presence of an increased number of eosinophils in the peripheral blood exceeding the upper limit of normal, with a corresponding absolute eosinophil count (AEC) of 0.5 x 10$^{9}$/L$^{1}$. The severity of eosinophilia has been arbitrarily divided into mild (<1.5 x 10$^{9}$/L), moderate (1.5 x 10$^{9}$/L—5 x 10$^{9}$/L), and severe (>5 x 10$^{9}$/L).2 The term hypereosinophilia (HE) is used for persistent AEC >1.5 x 10$^{9}$/L and/or confirmation of tissue HE. The detection of tissue eosinophil infiltrates (TEO) is based on histopathological analysis of the affected organ or tissue gained by biopsy or autopsy. Hypereosinophilic syndrome (HES) is characterized by blood HE and organ damage or dysfunction caused by eosinophils. The entity 'tissue-restricted HES (organ-restricted HES)' describes cases with TEO associated with organ damage in which peripheral HE is absent.1 The association between blood eosinophilia and related cardiac pathology was first documented in 1936 by Löffler, who described two cases of endocarditis parietalis $fibroplastica^{3}$ Nowadays, three possible phases of heart involvement in eosinophilia can be distinguished.4 The first stage of the disease, characterized by eosinophilic infiltration of the heart with subsequent endomyocardial damage (necrosis and inflammation), corresponds to

eosinophilic myocarditis (EM). The second phase associated with the hypercoagulable state is known as the thrombotic stage. The third stage, characterized by scanning is called the fibrotic stage and can lead to the development of restrictive cardiomyopathy known as endomyocardial fibrosis. Heart involvement in eosinophilia is a rare but underdiagnosed disorder, in which early diagnosis and initiation of appropriate treatment are important to decrease mortality and morbidity. This clinical consensus statement of the European Society of Cardiology (ESC) Working Group on Myocardial & Pericardial Diseases aims to describe the epidemiology, aetiology, diagnostic approach, and treatment of heart involvement in eosinophilia.

Epidemiology

Eosinophilic heart disease (EHD) is a rare but clinically significant condition. Among patients with HES or eosinophilic granulomatosis with polyangiitis (EGPA), EHD occurs in approximately 13%-50% of cases, depending on definition and diagnostic method.$^{5-11}$ The median age of onset is approximately 41 years, and the condition appears to affect both sexes equally.$^{6,7,12}$ Primary forms of eosinophilia, such as

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idiopathic HES and EGPA, are less common than secondary or reactive forms, including those triggered by drug reactions, parasitic infections, or malignancies. Geographical variation is notable. Parasitic causes are more frequent in tropical regions, while drug- and immune-related cases dominate in high-income countries.$^{8}$ Awareness of these epidemiological patterns is essential to guide clinical suspicion and diagnostic work-up. Prevalence and characteristics of heart involvement in eosinophilia vary and depend on the underlying aetiology. HES is itself a rare syndrome, and the prevalence fluctuates between 0.36 and 6.3 per 100 000.$^{5}$ HES may be associated with aberrations in the gene for platelet-derived growth factor receptor (PDGFR) that occurs almost exclusively in males, whereas other aetiologies appear to be equally distributed between the sexes.$^{6}$ EGPA has an estimated prevalence of 3.4 per 100 000 and does not exhibit sex predominance.$^{7}$ Geographic distribution and ethnic differences are largely related to exposure to the underlying causes, i.e. toxicariasis is more frequent in ethnic groups living in tropical areas.$^{8}$ Most patients diagnosed with HES are between 20 and 50 years old, although HES can also develop in children.$^{6.9}$ In a large systematic review of 179 patients with EM, median age was 41 years (interquartile range 27–53 years) with similar prevalence in both sexes; paediatric cases (≤16 years of age) accounted for 10%. In-hospital death was 22.3%, with the highest occurrence in patients with drug-associated hypersensitivity form (36%).$^{12}$

Aetiology

Although there are many valid classifications of HE,$^{13-15}$ from a practical clinical point of view, it is helpful to categorize patients with eosinophilia into two main groups according to aetiology: primary (neoplastic) eosinophilia and secondary (reactive) eosinophilia. When no identifiable cause is found, eosinophilia is referred to as idiopathic (Table 1). Finally, another rarer group is familial HE, a hereditary form with occurrence in relatives of affected individuals.$^{15}$ Primary neoplastic expansion of eosinophils is associated with a defective progenitor cell, leading to clonal expansion of eosinophils. Progenitor cell mutations such as fusions of tyrosine kinases, including PDGFRA, PDGFRB, JAK2, FLT3, or genetic rearrangements of ETV6:ABL1, can cause clonal expansion, defining the clinical entity of myeloid/lymphoid neoplasia with eosinophilia and fusions of tyrosine kinase genes.$^{16-18}$ Other causes may be underlying myeloproliferative disorders such as chronic myeloid leukaemia (CML), acute myeloid leukaemia (AML), myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN).$^{15}$ On the border between myeloid neoplasms and idiopathic HE is the clinical entity called chronic eosinophilic leukaemia not otherwise specified with evidence of blasts or clonal karyotypic rearrangement. Secondary HE is non-clonal and is caused by excessive levels of eosinophilopoietic cytokines such as interleukin (IL)-5. This secondary HE can be triggered by allergic diseases, parasitic infections, drugs, rheumatic diseases, vasculitis, some solid neoplasms, T-cell lymphomas and many others.$^{13}$ Moreover, some diseases are so closely associated with eosinophilila that they form defined syndromes, such as EGPA or Gleich syndrome, also known as episodic angioedema with eosinophilia.$^{15}$ A special variant of reactive HE is the lymphocytic variant of HES, which is caused by clonal aberrant T cells without the presence of an underlying lymphoproliferative disease.$^{13,15}$

Pathogenesis

Three phases of the EHD can be arbitrarily distinguished: necrotic, thrombotic, and fibrotic stages. The degree of EHD is influenced by the stimulus attracting the eosinophils, the duration of eosinophilia, and the level of eosinophil activation.$^{4}$ A common mechanism of damage has been hypothesized,$^{19-22}$ and this relates to the activation of eosinophils, degranulation of their crystalloids with subsequent release of cationic proteins, which are able to damage the myocardium,

# Table 1 Selected common causes of eosinophilia

|Neoplastic HE|Reactive HE| |---|---| |Myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions|Allergies| |Myeloproliferative hypereosinophilia (e.g. CML, AML, MDS/MPN)|Parasitic infection (e.g. Toxocariasis, Stronglyloidiasis)| |Chronic eosinophilic leukaemia, not otherwise specified|Drugs| ||Solid tumours| ||T-cell lymphomas| ||Lymphocytic variant HES| ||Idiopathic HE| ||Defined syndromes:| ||EGPA| ||Gleich syndrome| ||Familial HE|

AML, acute myeloid leukaemia; CML, chronic myeloid leukaemia; EGPA, eosinophilic granulomatosis with polyangiitis; HE, hypereosinophilia; HES, hypereosinophilic syndrome; MDS, myelodysplastic syndrome; MPN, myeloproliferative neoplasm.

endocardium, intramural coronary vessels, and induce the local thrombogenesis. The most important cationic proteins released in endomyocardial tissues are major basic protein, eosinophil cationic protein (ECP), eosinophil-derived neurotoxin, and eosinophil peroxidase. The cationic proteins released are highly cytotoxic through a variety of mechanisms, including the formation of pores in the cytoplasmic membranes and increased oxidative stress. This leads to tissue damage inflammation, and production of multiple cytokines and chemokines, including granulocyte colony-stimulating factor, IL-3, and IL-5, that attract other immune cells and eosinophils. ECP is also able to contribute to the release of histamine and tryptase by cardiac mast cells. The role of CCR3, IL-17A, and interferon-gamma in the pathophysiology of EM is still uncertain.$^{6,23,24}$

Moreover, tissue factors are subsequently released and promote a hypercoagulable state. Heart involvement by degranulated eosinophils may manifest as EM that is histologically depicted by necrosis of cardiomyocytes adjacent to eosinophil and lymphocytic infiltrates; endocardial thrombi may also be present, as in Loeffler disease,$^{25,26}$ eventually evolving into endomyocardial fibrosis.$^{27-29}$ An eosinophilic infiltration of the myocardium associated with a prominent angitis of intramural vessels and possible microaneurysm formation constitutes a specific variant of EGPA.$^{30}$ Recent genetic studies have identified susceptibility loci such as GPA33 and IRF1/IL5 in patients with ANCA-negative EGPA, suggesting distinct immunogenetic mechanisms in this subgroup. These findings may have implications for future diagnostic stratification and targeted therapy.$^{31}$ It is recognized that the evolutive steps from acute eosinophil inflammation to endomyocardial fibrosis are not strictly separated and that overlapping of single phases may occur, e.g. persisting eosinophilic myocardial inflammation in patients with endomycardial fibrosis if HE and eosinophil degranulation persist.$^{32}$ Recognition of the myocardial, endocardial, and vascular impact of eosinophilic damage is crucial to establish the most appropriate therapy and its duration.

Diagnostic approach

Considering the complexity of the EHD, a comprehensive evaluation of the affected patients is of great importance. A multidisciplinary

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approach, including various non-invasive and invasive diagnostic tools is key for an appropriate patient investigation.

Clinical presentation

Cardiac involvement in cases of eosinophilia is a major contributor to morbidity and mortality.33 Cardiac manifestations at presentation are observed in ~5% of cases of HES, although the frequency of cardiac symptoms may increase to 19%~63% as the disease progresses.34 Cardiac symptoms have been more frequently reported in idiopathic rather than in other variants of the syndrome and symptoms severity does not correlate with eosinophil count or duration of disease.11.34 Notably, the presence of cardiac symptoms depends mainly on the stage of the disease.33 Overall, the most common symptom in patients with cardiac involvement at the time of diagnosis is dyspnoea occurring in ~60% of cases, while at the same time, three out of four patients de- pict symptoms or signs of heart failure.35 During the initial necrotic phase, cardiac manifestations range from a clinically silent condition to a life-threatening form due to acute necrotizing EM.11.33.36 In the latter instance, patients complain of symptoms typical of acute myocarditis, including chest pain, palpitations, dyspnoea, fatigue, and syncope or near-syncope due to complex arrhythmias or high-degree atrioven- tricular block.11.36.37 In the intermediate thrombotic phase, thrombi may be observed in the apical region of both ventricles with occasional extension to the basal segments and rarely to the outflow tracts.11.33.38 Peripheral thrombotic embolization may result in extremities ischa- mia, stroke, myocardial infarction, renal failure, loss of vision, etc.11.33 Overall, embolism complicates ~25% of cases, with fatal outcome being observed in up to 10% of them.6 Finally, in the last fibrotic stage, pro- gressive endocardial scarring can lead to a restrictive cardiomyopathy with left, right, or biventricular (congestive) heart failure.11.30 Extensive valvular leaflet fibrosis at this stage may affect valve function, with mitral regurgitation most commonly observed.11.33.35 Occasionally, eosinophilia with heart involvement may present with features of a dilated cardiomyopathy, asymmetric left ventricular septal hypertrophy, or pericardial involvement (such as constrictive pericarditis, eosinophilic pericarditis, or isolated pericardial effusion, overall in <10% of cases).11.39 Furthermore, other organs may be affected, with dermatological, pulmonary, and gastrointestinal manifestations being the most common.14

Laboratory tests

Laboratory tests are essential for establishing the diagnosis of EHD and are important for the differential diagnosis. Blood tests for initial diagnostic work-up should include a complete blood cell count with differential (this blood count analysis should be done serially to assess eosinophil level over time). Eosinophila is easily masked by concomitant corticosteroid therapies. Other parameters that should be analysed include serum calcium and phosphorus, renal and liver function tests, ESR, CRP, troponin, BNP or NT-proBNP, LDH, serum protein electrophoresis, ANA, ANCA, serum tryptase, vitamin B12, and total immunoglobulin $E.^{40,41}$ Eosinophilic cationic protein (ECP) testing may be useful.$^{23}$ Moreover, HIV and Toxocara serology are often routinely advised based on the French guidelines for the aetiological work-up of eosinophilia and the management of $HES.^{41}$ Other serology for parasitic infections, such as Stronglyoides, may be considered based on the clinical context.$^{41}$ It is also advised to test the stool for ova and parasites.$^{41}$ If these laboratory tests are unrevealing and eosinophilia persists, a blood smear should be obtained, and consultation with the haematology service should be considered for additional testing for FIP1L1-PDGFRA mutations, T-lymphocyte phenotyping with flow cytometry, and bone marrow aspiration and biopsy.$^{41}$ The bone marrow is to be examined for cellularity, expression of CD34, mast

cells, dysplasia, reticulin fibrosis, and karyotype.$^{41}$ If these are unrevealing, additional molecular studies are considered, including FGFR1 and PDGFRA and B, BCR-ABL1 and 2, JAK2, KIT D816 V, FLT3, ETV6, and clonal T-cell receptor rearrangements in the bone marrow.$^{41}$

Key points for laboratory tests

● Eosinophilia in peripheral blood might be transient, and so repeated blood count with differential is advised.

● In some patients with EHD, peripheral blood eosinophilia may be absent. In these cases, tissue eosinophilia can only be detected by thorough tissue analysis of the affected organ.

● ANCA are usually negative in EGPA with cardiac involvement.

● Elevated values of LDH, serum tryptase, vitamin B, or abnormalities in electrophoresis should raise suspicion of an underlying haematological disorder.

● An increase in troponin or natriuretic peptides in patients with HE is suggestive of myocardial involvement.

Electrocardiogram

While the ECG is often abnormal, there are no highly specific changes for the detection of the disease. ECG was shown to be abnormal in the vast majority (90.6%) of patients with histologically proven EM.$^{12}$. This constituted bundle branch blocks in 6.3%, ST segment elevations in 38.6%, and other ST-T changes in 45.7%.$^{12}$ In 68 patients with EGPA and heart involvement, an abnormal ECG was observed in 72%.$^{42}$ Repolarization changes were observed in 37%, pathological Q waves in 7%, conduction defects in 19%, and rhythm abnormalities in 28%.$^{42}$

Key points for ECG

● There are no highly indicative changes for the disease diagnosis.

● ST-T changes, including ST-segment elevation, are the most com-mon abnormalities.

● Other abnormalities include pathological Q waves, bundle branch blocks, and rhythm abnormalities.

Echocardiography

Echocardiography represents the first-line imaging method in the evaluation of patients with suspected EHD. This imaging modality also has a key role in follow-up. In the first (necrotic/inflammatory) stage of the disease corresponding to EM, there are no pathognomonic echocardiographic signs that can reliably distinguish EM from other types of myocardial inflammation.$^{4}$ The left ventricle is typically of normal size or usually only mildly dilated. As myocardial damage predominantly affects the subendocardial tissue, increased subendocardial echogenicity might be present already in the early phase of the disease.$^{43}$ Two recently published systematic reviews analysed 179 and 274 patients with EM, respectively. Left ventricular ejection fraction was decreased in the majority of patients; the median ejection fraction was 35% (IQR 25%–50%) in one study and 31% (IQR 23.0%–45.7%) in the other.$^{12,44}$ Left ventricular wall thickening was present in 42.9% of cases and right ventricular systolic dysfunction was recorded in 25.7%$^{44}$ The prevalence of pericardial effusion varied between 34.1% and 50.8%$^{12,44}$ Moreover, 5.7%–6.1% of the patients developed cardiac tamponade.$^{12,44}$ During the second (thrombotic) stage, it is common to observe endomycardial thickening and intracardiac thrombotomic masses.$^{45}$ The thrombi are typically located at the apex of the left or right ventricle, with both ventricles often affected. Contrast echocardiography

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can be useful in the detection of these pathological masses, especially in cases with limited image quality of unenhanced ultrasonography. The thrombotic process may extend from the apical part of the ventricle to the sub-valvular regions and even to the inflow tract of mitral or tricuspid valves, which can lead not only to valvular impairment but also to a reduction of the ventricular cavity size.$^{45}$ The detection of left or right ventricular thrombi (especially in the apex) in regions with preserved contractility should always raise suspicion of heart involvement associated with eosinophilia.$^{45}$ When HE is present, this type of cardiac involvement is considered diagnostic. In the third (fibrotic) stage, endomycardial fibrosis develops. Endomycardial fibrosis usually appears as an area of greater echogenicity than the surrounding myocardium, typically affecting the apical ventricular region.$^{45}$ Adjacent thrombus is typically present (Figure 1). This type of heart involvement typically manifests as a restrictive cardiomyopathy with diastolic dysfunction of a non-dilated left ventricle and the presence of biatrial enlargement.$^{46}$ Fibrotic or thrombotic involvement of the valve leaflets or more often of sub-valvular apparatus is also frequent, most commonly involving the mitral and tricuspid valve and causing regurgitation. Valve stenosis and aortic or pulmonary valve involvement are rare. In order to detect the very early stages of heart involvement, speckle tracking echocardiography has demonstrated promise. In a study published by Yamamoto comparing 32 patients with HES and normal conventional echocardiographic findings with 31 healthy volunteers, global longitudinal strain $\le 17\%$ predicted subclinical myocardial dysfunction in patients with HE with a sensitivity of 66% and specificity of 78%.$^{47}$

Key points for echocardiography

● In the early stages of the EHD, patients present with echocardiographic features of myocarditis.

● Intraventricular thrombotic masses in regions without regional contractility impairment (e.g. aneurysms) should raise a suspicion of EHD.

● In patients with HE, biventricular apical pathological masses can be observed.

● Contrast echocardiography can be helpful in the detection of path-logical masses.

● In the later stages of the disease, patients can present with echocardiographic features of restrictive cardiomyopathy.

Cardiac magnetic resonance

Cardiac magnetic resonance (CMR) is pivotal in assessing cardiac involvement in patients with eosinophilia, although evidence is predominantly based on small case series. In particular, CMR is highly valuable for diagnosis and characterization of EHD, including the detection of endomyocardial fibrosis (Figure 1), myocardial oedema often associated with wall thickening, reductions in LV ejection fraction, intracardiac thrombi and pericardial effusion.$^{48-52}$ CMR provides important information about the extent and type of myocardial damage, such as fibrosis and inflammation, which are common in EHD.$^{8,48,51,53}$ Late gadolinium enhancement (LGE) is useful for diagnosing subendocardial and mid-wall fibrosis suggestive of eosinophilic myocardial involvement.$^{48}$ Diffuse (global) subendocardial LGE in patients with HE is considered a specific finding for heart involvement in eosinophilia. This feature of CMR can correlate with left ventricular remodelling and has prognostic implications, as the extent of LGE has been associated with adverse clinical outcomes.$^{48}$ Moreover, CMR can monitor the disease's response to treatment, as demonstrated by changes in LGE patterns following therapeutic interventions.$^{53}$ However, CMR is still unable to completely replace EMB in establishing the differential diagnosis related to the type of myocardial inflammation. Although there are some features suggestive of EM (especially useful in patients

with peripheral blood eosinophilia), only EMB has the capability to distinguish EM from lymphocytic, giant cell, or granulomatous myocarditis. Moreover, patients with fulminant myocarditis, who are haemodynamically unstable, are unable to undergo CMR examination.

In summary, CMR is an indispensable tool in the non-invasive diagnostic arsenal for EHD in haemodynamically stable patients. It offers a comprehensive evaluation that supports both the diagnosis and management of these patients.

Key points for CMR

● CMR is advised in all patients with HE and suspected heart involvement.

● CMR is useful for the evaluation of all three stages of EHD. Although there are some features suggestive of EM, CMR is unable to rule out other types of myocardial inflammation, such as lymphocytic, giant cell, or granulomatous myocarditis.

● In patients with suspected fulminant EM, EMB is strongly advised and subsequently, in haemodynamically stable patients, CMR examination can be performed.

Computed tomography and nuclear imaging methods

Patients with EHD can present with symptoms of breathlessness and chest pain that may trigger investigation with a CT coronary angiography (CTCA). It is therefore worth considering the features of this imaging investigation that may raise suspicion of EHD. CTCA provides a clear visualization of the apices of the left and right ventricles. It can, therefore, detect the characteristic thickening of both apices associated with EM, as well as hypoperfusion in the centre of these areas to suggest thrombus (Figure 1). In practice, further imaging with CMR is usually required to provide better tissue characterization and to differentiate EM from apical hypertrophic cardiomyopathy. CT may also be advised as a primary diagnostic test in patients with a contraindication to CMR, in whom the apices are not well visualized on echocardiography and where biopsy is felt to be high risk due to suspicion of thrombus. Chest CT scans may be very useful in evaluating pulmonary involvement, usually present in EGPA and possibly also in other disorders associated with HE.

18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) can provide useful information in patients with acute myocarditis. 18F-FDG is a glucose analogue that is taken up by cells with high glucose requirements, including inflammatory cells. It can, therefore, provide a useful readout of myocardial inflammation. Patients require dietary preparation to switch physiological myocardial metabolism from glucose to fatty acids and, therefore, to prevent false positive results due to physiological myocyte 18F-FDG uptake.$^{54}$ Finally, in patients with HE, PET-CT scans provide important data regarding the differential diagnosis of HE, especially in the exclusion of malignant tumours. 18-FDG PET requires further study in EM to assess whether it might provide a useful diagnostic tool and clinical readout of disease activity.

Selective coronary angiography and invasive haemodynamic evaluation

In patients with eosinophilia presenting as a possible acute coronary syndrome (chest pain, ST segment changes, increased troponin levels, left ventricular wall motion abnormalities), invasive coronary angiography or alternatively CT coronary angiography is advised to rule out an acute coronary syndrome. $^{23,44}$ A documented coronary occlusion may be the result of thrombotic occlusion or embolism, owing to fresh mural thrombus of the left ventricle. Histology in such cases does not

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Figure 1 (A-F) Examples of endomyocardial fibrosis on multimodality imaging (marked with asterisk): echocardiographic images in apical four-chamber views in end-diastole (A) and end-systole (B); contrast-enhanced computed tomography showing the endomyocardial fibrosis (C) and depicting normal coronary arteries (D); cardiac magnetic resonance scan showing pathological apical masses of both ventricles on a four chamber view (E) and depicting subendocardial late gadolinium enhancement with overlying thrombus at the apex (F). (G-H) cardiac magnetic resonance scan in a patient with eosinophilic myocarditis showing diffuse subendocardial oedema on a T2 weighted short axis view (G) and diffuse, global subendocardial left ventricular late gadolinium enhancement (note the papillary muscle involvement) (H)

reveal any evidence of plaque disruption or healing, hence intracoronary imaging is not expected to reveal any complicated plaque features.$^{55}$ In rare cases, coronary spasm,$^{56}$ spontaneous coronary artery dissection$^{57,58}$ or large coronary aneurysms$^{59-62}$ have been described in patients with acute coronary syndrome or sudden cardiac death, as an expression of eosinophilic coronary periarteritis.$^{63-65}$ Invasive haemodynamics may be unremarkable in early disease stages. In patients with right ventricular endomyocardial fibrosis, identical pressure tracings of the right ventricle and right atrium may be found, whilst the pulmonary artery pressure is not elevated. However, in cases of left ventricular and biventricular endomyocardial fibrosis, pulmonary hypertension, and elevation of the left ventricular end-diastolic pressure with the dip-and-plateau sign are common.$^{66,67}$ Although replaced nowadays by non-invasive imaging, invasive contrast ventriculography may show apical obliteration as well as outpouchings or a square shape of the left ventricle due to apical cavity obliteration.$^{66}$

Endomyocardial biopsy

EM can occur in association with a wide spectrum of diseases, including allergic reactions as well as haematological diseases or neoplastic disorders. In the majority of patients, eosinophilia in peripheral blood is present, which is suggestive of the diagnosis, but in the absence of peripheral eosinophilia, the diagnosis of EM is challenging and may lead to a delay in therapy. 68,69 Therefore, early performed EMB is strongly advised in unstable patients, as CMR imaging cannot differentiate among acute lymphocytic, giant cell, granulomatous, and eosinophilic

myocarditis. $^{70,71}$ The possible utility of early performance of EMB in patients with suspected fulminant myocarditis was observed in a retrospective multicentric FULLMOON study. Early (within 2 days after intensive care unit admission) performed EMB was associated with significantly better survival in comparison with delayed EMB (survival free of heart transplantation or left ventricular assist device implantation at 1 year was 70% vs 49%). $^{72}$ While the FULLMOON provides useful, albeit low-level, evidence supporting a strategy of early biopsy in fulminant myocarditis, it poses a risk of selection bias and residual confounding.

At least 3–4 EMB samples should be taken as the eosinophilic infiltrates may be focal. In EMB, the presence of eosinophils with myocyte necrosis is diagnostic (Figure 2).$^{73,74}$ In necrotizing EM, which is the most aggressive form, EMB reveals extensive myocyte necrosis with foci consisting of eosinophils, macrophages, lymphocytes, some plasma cells, and occasionally scattered giant cells. $^{75,76}$ The differential diagnosis is giant cell myocarditis, but the clinical picture is different, with no peripheral eosinophilia and more giant cells on biopsy. Well-formed giant cell granulomas, as in sarcoid, are not seen. Degranulation of eosinophils with release of granule cytotoxic proteins, including major basic protein, ECP, eosinophil-derived neurotoxin, and eosinophil peroxidase, induces necrosis/apoptosis of myocytes and inflammation, $^{77}$ and damages endothelial cells and activates platelets. $^{78}$ The most common forms of EM comprise Loeffler endomyocarditis with subendocardial fibrosis and thrombosis, drug-related hypersensitivity myocarditis, and EGPA-myocarditis. $^{12,79}$ The patterns of inflammation may be diffuse, as seen in patients treated with mesalamine or may consist of poorly formed macrophage-granulomas and no or very focal myocyte necrosis in patients on multiple drug therapy before transplantation. $^{75}$

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In the active phase of EGPA, eosinophilic vasculitis is usually associated with myocardial eosinophilic inflammation.

Key points for EMB

● EMB is advised at an early stage in all patients with suspected EM to direct the therapy.

● In case of suspected fulminant EM, EMB is strongly advised to be done as soon as possible.

● Eosinophils are present (sometimes with extensive myocyte necrosis) in EMB.

• Eosinophilic vasculitis may be seen with EGPA.

● EMB should be performed before immunosuppressive treatment initiation.

Differential diagnosis

Differential diagnosis comprises searching for specific HE aetiology (Table 2) and differentiation from other cardiac disorders presenting with similar symptomatology or clinical findings (e.g. findings on imaging methods).

In a systematic revision of 179 histologically proven cases of EM, hypersensitivity accounted for 34.1% of cases (drugs more frequently associated with EM were antibiotics such as β-lactam or minocycline, central nervous system drugs such as clozapine or carbamazepine, vaccines and antitubercular agents), EGPA for 12.8%, HES for 8.4%, infection 5% (most commonly Toxocara canis), malignancy 1.1%; while the aetiology remained idiopathic or undefined in 35.7%.$^{12}$ Establishing the correct diagnosis may be challenging, but it is of great importance as the subsequent therapy may be substantially different (e.g. antiparasitic drugs in some infectious forms, imatinib in patients with the FIP1L1-PDGFRA or the FIP1L1-PDGFRB fusion transcript, corticosteroids, or combined immunosuppressive therapies in other forms of HE). Unfortunately, diagnosis of EGPA is often delayed,$^{80}$ since ANCA are mostly negative (present only in approximately 30%) in EGPA with cardiac involvement, and glucocorticoid treatment for asthma or dyspnoea may rapidly normalize peripheral blood eosinophilil counts.$^{41}$ Considering the complexity of the heart's involvement in eosinophilia, multidisciplinary cooperation is very important. The multidisciplinary team would optimally include cardiologists, radiologists, nuclear medicine specialists, haematologists, rheumatologists, and specialists in infectious diseases. Particularly in patients with suspected EGPA, pulmonary, nephrology, neurology, and gastroenterology input is often required.

The differential diagnosis of HE with heart involvement includes mainly excluding other forms of myocarditis and restrictive cardiomyopathy, acute or chronic coronary syndromes, and valvular diseases.

Key points for differential diagnosis

● Hypersensitivity to drugs or other agents is very common and targeted patient's history is required to reveal this possible aetiology.

● In patients without a clear association between hypersensitivity and HE infectious (parasitic) aetiology, haematological disorder, rheumatological disease, and malignancy have to be excluded.

Treatment

Suggested treatment algorithm is shown in Figure 3.

Figure 3 depicts the stepwise treatment algorithm for EHD, while Table 3 focuses on immunosuppressive therapy and provides recommended drug administration with detailed dosing for patients with HES and EGPA.

Conventional pharmacological treatment

There are no specific recommendations for the management of heart failure and arrhythmias in patients with EHD and so the treatment of heart failure and arrhythmias should follow current ESC guidelines. 81-83

Anticoagulation

Eosinophilia can lead to endothelial damage and create a hypercoagulable state, increasing the risk of intracardiac thrombosis even in sinus rhythm and without regional ventricular contractility abnormalities. Anticoagulation is clearly advised in the presence of intracardiac thrombosis, typically observed in the thrombotic or fibrotic stage of the EHD. According to the scientific statement from the American Heart Association focused on management of patients at risk for and with left ventricular thrombus, anticoagulation for the prevention of left ventricular thrombus is advised in patients with EM and a prior embolic episode.$^{84}$ Based on published systematic reviews on EM, intracardiac thrombosis prevalence varies between 13.7% and 17.1%.$^{12,44}$ It therefore seems reasonable to consider anticoagulation in most cases of EM and especially in subgroups with the persistent eosinophilia often observed in HES or EGPA.$^{85}$ Based on recent ESC guidelines for cardiomyopathies, anticoagulation to reduce the risk of stroke and thrombo-embolic events should be considered in restrictive cardiomyopathies in general (including the one associated with HE) with atrial fibrillation (AF) or atrial flutter.$^{46}$ There is a lack of randomized prospective trials comparing vitamin K antagonist warfarin with direct oral anticoagulants (DOACs), specifically in heart involvement associated with eosinophilia. There is increasing evidence that DOACs have non-inferior efficacy and similar or superior safety in patients with non-valvular AF, atrial flutter, or subjects with left ventricular thrombosis.$^{86}$ However, evidence for DOACs in HE comes only from case reports, and thus, these drugs, representing alternatives to warfarin, should be used with caution and considering the risk/benefit ratio on an individual basis.$^{43,87}$

Key points for anticoagulation

● Anticoagulation is advised in all patients with EHD and intracardiac thrombosis.

● Anticoagulation is advised in all patients with EHD and atrial fibrillation or atrial flutter.

● Anticoagulation is advised in all patients with EM and a history of embolic event and might also be appropriate in most patients without a history of thrombo-embolic episode during the acute phase of the disease.

● In case of left ventricular thrombosis and no other reasons for anticoagulation, the duration of anticoagulation is advised for at least 3–6 months and the prolongation of the therapy needs to be considered when ongoing myocardial inflammation or eosinophilia is present.

● DOACs as an alternative to warfarin are reasonable in patients in whom a therapeutic INR range is difficult to achieve consistently.

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 Figure 2 Endomyocardial biopsy findings in patients with different forms of eosinophilic myocarditis. Left column demonstrates eosinophilic granulocytes (Giemsa stain) whilst the right column shows the detection of CD3+ T lymphocytes on immunohistochemistry. Eosinophilic granulomatosis with polyangiitis (A), hypereosinophilic syndrome (B), Löffler endomyocarditis (C), and chronic hypersensitivity myocarditis (D). A ×200, B–D ×400

Immunosuppressive therapy and monoclonal antibodies

Guideline-directed treatment for heart failure, ventricular arrhythmias, and thromboembolism forms the foundation of therapy for all forms of EM.$^{81-83}$ Case series reports that in addition to guideline-directed

therapy, immunosuppression tailored to specific causes of EM, may accelerate recovery and decrease adverse outcomes. Early initiation of immunosuppressive therapy is recommended in EGPA. However, prospective clinical trials to guide management have not been performed in any form of EHD.

The initial evaluation of eosinophilia in the setting of new cardiac symptoms should focus on distinguishing secondary from primary (i.e. clonal or

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Table 2 Proposed approach to differential diagnosis in clinical practice

|Condition|Clues|| |---|---|---| |EGPA|EGPA is suspected in patients with bronchial asthma, chronic rhinosinusitis with nasal polyps and eosinophilia developing multi-organ involvement, particularly peripheral neuropathy, lung infiltrates, cardiomyopathy or other complications such as skin, gastrointestinal, or kidney involvement.ANCA are usually negative in patients with heart involvementBiopsy of involved tissue is very helpfulHypersensitivity/drug-induced Parasitic infections|Skin rash, history of drug exposureTargeted serology and stool examination (namely Toxocara canis, strongyloides)| |Primary HES|FIP1L1-PDGFRA, -PDGFRB, -FGFR1 rearrangement|| |Other myeloid or lymphoid malignancies, including systemic mastocytosis|Serum Vitamin B12 and tryptase Haematological consultation and bone marrow examination|| |Solid tumours|Imaging methods: PET-CT or alternatively contrast-enhanced CT of the chest, abdomen, and pelvisBased on the clinical context lung or gastrointestinal endoscopy||

ANCA, antineutrophil cytoplasmic antibodies; EGPA, eosinophilic granulomatosis with polyangiitis; CT, computed tomography; FGR1, fibroblast growth factor receptor 1; FIP1L1, factor interacting with PAPOLA and CPSF1; HES, hypereosinophilic syndrome; PDGFRA, Platelet Derived Growth Factor Receptor A; PDGFRB, Platelet Derived Growth Factor Receptor B; PET, positron emission tomography.

idiopathic) causes as noted above. It is especially important to identify secondary causes of eosinophilia, such as parasitic infections, atopic disorders, and drug reactions from malignancies, such as myeloid and lymphoid malignancies, using appropriate genetic tests, and bone marrow biopsy where appropriate. The diagnosis and treatment of myeloproliferative neoplasms, such as CML, is beyond the scope of this manuscript.$^{88}$

Tailored immunosuppression is based upon the specific cause. In cases of fulminant EM pulse doses of methylprednisolone 7–14 mg/kg/day with a maximal daily dose 1000 mg intravenously for 3 days, followed by 1 mg/kg/day with subsequent tapering is $advised^{52}$ (Table 3).

Hypersensitivity myocarditis, often a drug-specific response occurring within 1–2 months of initial exposure, may be associated with skin rash and elevated liver function studies (including eosinophilia and systemic symptoms or DRESS syndrome). Cardiac involvement may be initially treated with drug withdrawal and systemic glucocorticoids. Regimens include oral prednisone, often with intravenous methylprednisolone for the first several days. In cases of steroid non-or incomplete response, cyclosporine, tofacitinib and intravenous immunoglobulins have been used.

EGPA with cardiac involvement should be promptly treated with corticosteroids combined either with cyclophosphamide or rituximab.$^{91,92}$ The 2021 American College of Rheumatology and Vasculitis Foundation guideline recommends cyclophosphamide as the preferred agent for patients with cardiac involvement because experience with cyclophosphamide is more robust in these patients. The initial recommended dose is 1.5–2 mg/kg orally daily for 3–6 months or 15 mg/kg, respectively 600 mg/m$^{2}$, intravenously every 2 weeks for 3 doses, then every 3 weeks for at least 3 doses with dose adjustments for kidney function and age.$^{93}$ Rituximab, which is monoclonal antibody targeted against CD 20 (a surface antigen presented on B lymphocytes), represents an alternative to cyclophosphamide. This biologic drug is usually preferred in younger patients in the context of disease manifestation in order to avoid gonodotoxicity as a possible side effect of cyclophosphamide treatment. Rituximab can be administered weekly in lower doses (375 mg/m$^{2}$ intravenously) for four subsequent weeks. More common is its application in two higher doses (1000 mg intravenously) on Days 1 and 15.$^{91}$

In idiopathic HES, glucocorticoids are commonly used as initial therapy, given their ability to decrease the eosinophil count rapidly.$^{6}$ Peg IFN-alpha treatment has been associated with recovery as well, but side effects, including myalgias and transaminitis, may limit long-term use.$^{94}$ Mepolizumab is a humanized anti-IL-5 monoclonal antibody that has also been reported to be effective and well-tolerated for long-term management.$^{95}$ Finally, the anti-CD-52 monoclonal antibody alemtuzumab has been used successfully in a series of refractory cases of EHD.$^{96,97}$

Key points for immunosuppressive treatment

● This therapy should be tailored based on the underlying aetiology,type, severity, and duration of heart involvement.

● An individualized approach led by multidisciplinary approach is advised.

● For EGPA with cardiac involvement, we advise cyclophosphamide on top of corticosteroids for induction therapy, with rituximab on top of corticosteroids as an alternative, particularly in younger patients to avoid gonadotoxicity.

Specific treatment of underlying disease

Treatment of EM requires therapy of the underlying primary cause of eosinophilia in addition to suppression of eosinophilic inflammation. Particularly in the case of reactive eosinophilia, it is important to treat any parasitic infection, e.g. with ivermectin or albendazole, to treat the underlying tumour or lymphoma, and to withdraw potentially toxic drugs and avoid allergens.

Since the mainstay of anti-inflammatory (and also anti-eosinophilic) empirical treatment of life-threatening EM is immunosuppression with high-dose corticosteroids, it is necessary to exclude parasitic infections (especially Strongyloides infection) because of the risk of hyperinfection syndrome.$^{97}$ If a Strongyloides infection cannot be excluded, it is advisable to treat the patient with antiparasitic drugs, e.g. ivermectin.$^{97,98}$

Other specific treatments of eosinophilia are closely related to its aetiology. In primary eosinophilia, suppression of the pathological eosinophil-producing clone is necessary. In case of positive PDGFRA/PDGFRB rearrangement, treatment with the tyrosine kinase inhibitor imatinib is usually advised.$^{14,99,100}$ Kinase inhibitors are also being tested

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 Figure 3 Suggested treatment algorithm

in other genetic alterations, with promising results from the FIGHT-203 trial of pemigatinib for FGFR1 rearrangement.$^{101}$ Ruxolitinib for JAK2 genetic rearrangement is now being evaluated and seems promising in case reports.$^{102}$ Among other approaches for aggressive diseases, allogeneic stem cell transplantation could be a potentially curative method.$^{103}$

In lymphocytic and idiopathic variants of HE resistant to corticosteroids and chronic eosinophilic leukaemia, cytoreduction therapy with hydroxyurea or treatment with interferon alpha can be used.$^{14}$ Recently, monoclonal antibodies blocking the signalling of the eosinopoietic cytokine IL-5 have become a major advance in the treatment of HE. The anti-IL-5 antibodies mepolizumab and reslizumab and the anti-IL-5 receptor antibody benralizumab were originally approved for the treatment of eosinophilic asthma.$^{14}$ Mepolizumab was subsequently successfully evaluated and approved for the treatment of idiopathic HES and EGPA.$^{95,104-106}$ As demonstrated in a very recent systematic review assessing 25 studies with 1131 patients suffering from EGPA and treated with IL-5 and IL-5 receptor inhibitors utility not only of mepolizumab but also of reslizumab and benralizumab was shown. All these drugs proved their efficacy in remission control and corticosteroid tapering.$^{107}$

Key points for specific treatment of underlying disease

● Treatment of parasitic infections, such as Strongyloides, should be consulted with specialists in infectious diseases.

● In case of positive PDGFRA/PDGFRB rearrangement, treatment with the tyrosine kinase inhibitor imatinib is usually advised.

● The anti-IL-5 antibodies, such as mepolizumab might be advised as corticoid-sparing agents for treatment of HES and EGPA.

Non-pharmacological treatment

Management of arrhythmias and prevention of sudden cardiac death should be in concordance with current guidelines. $^{81,82}$ Indications for mechanical circulatory support in patients with advanced heart failure

Table 3 Select immunosuppressive regimens for HES and EGPA

|Corticosteroids|Initially methylprednisolone 7–14 mg/kg i.v. pulses for three consecutive days, then 1 mg/kg/day i.v./ per os with slow tapering based on clinical status (e.g. 10 mg/ every 2 weeks)| |---|---| |Additional immunosuppressive agents used for steroid-refractory eosinophilic heart disease|| |Cyclophosphamide|600 mg/m$^{2}$ on Days 0, 15, and 30 (other doses based on the underlying aetiology and clinical course)$^{a}$| |Rituximab|375 mg/m$^{2}$ once per week for four consecutive weeks or two infusions of 1000 mg 2 weeks apart$^{a}$ (other doses based on the underlying aetiology and clinical course)$^{a}$| |Mepolizumab|300 mg s.c. once per month as a corticosteroid-sparing agent in selected $cases^{a,b}$|

Clinically assess for other organ involvement and exclude neoplastic and infectious (parasitic) forms that have specific treatment algorithms.

$^{a}$Together with corticosteroids; after consultation within multidisciplinary team.

$^{b}$Not validated by randomized trials in EGPA organ or life-threatening manifestation as induction therapy.

should be in line with current guidelines for acute and chronic heart failure.$^{83,108}$ Based on a recent systematic review describing 274 cases with EM, intra-arterial balloon pumping or Impella were used in 9.5% of patients and extracorporeal membrane oxygenation (ECMO) in 4.4% of individuals.$^{44}$ In patients with severe forms of fulminant EM, a combination of ECMO and Impella (ECPELLA) may be needed.

Indications for valvular surgery should follow guidelines for the management of valvular heart disease.$^{109}$ In patients with valvular involvement associated with HE, our effort is to try to influence the valvular impairment by pharmacological treatment. The therapy is mainly focused on eliminating valvular thrombosis by adequate anticoagulation

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and controlling the underlying disease causing HE by targeted immuno-suppressive or other therapy. In patients with HES needing cardiac surgery and unsuitable for valve repair, the choice between mechanical and biological valves can be challenging. However, current evidence favours the use of biological valves. Mechanical valves in patients with HE carry a high risk of recurrent thrombosis, while biological valves are likely to have shorter longevity.$^{43}$ In a series of 28 patients with HES and significant valvular involvement, 12 patients underwent cardiac surgery and mechanical prosthesis implantation. All these patients suffered from valvular dysfunction due to thrombosis or endocardial proliferation despite anticoagulation therapy.$^{110}$ Nine of them had to undergo an-other mitral valve replacement (four of them died postoperatively and one of them 8 months after the first operation).$^{110}$ In 13 patients with HES, when bioprosthesis was implanted, one patient had recurren-th thrombosis (one patient died postoperatively, and three died dur-ing the follow-up).$^{110}$ When technically feasible, valvular repair is preferred, as this procedure is associated with fewer thrombotic events than valvular replacement and prosthesis implantation.

In patients with advanced stages of EHD and endomyocardial fibrosis who develop symptoms of heart failure or embolic cardiac event, surgery with endocardial decortication and/or resection of ventricular pathological mass is advised.$^{111-113}$

Proposed management of patients with suspected EHD is shown in Figure 4.

Key points for non-pharmacological treatment

● Patients with fulminant EM may need mechanical circulatory support and is advised to refer them to expert centres.

Heart transplantation

Heart transplantation as an ultimate type of treatment for advanced stages of EHD is reported rarely. In a systematic review of 122 patients with histologically proven EM published by Brambatti et al., heart transplantation was reported only in one patient (0.8%) with idiopathic aetiology of the disease. 12 In a recent systematic review of EM published by Techasatian, 6 out of 220 (2.7%) with histologically proven EM and none out of 54 patients with CMR imaging-based myocarditis underwent heart transplantation. 44 Based on the data from 190 consecutive patients undergoing heart transplantation for various reasons, 14 (7.4%) suffered from EM based on the analysis of explained hearts. 114 In two of these patients receiving dobutamine (one also receiving dopamine), tapering or discontinuation of the inotropic infusion resulted in a significant decrease of the peripheral eosinophilia in one case and normalization in the other case. These changes in blood eosinophilia were accompanied by only mild residual eosinophilic infiltration in cardiac myocardial samples. 114 Posttransplant 8-year survival for patients with EM was 50%, which was similar to that of other heart transplant recipients without this type of myocardial inflammation. 114 In international study, nine patients with EGPA undergoing heart transplantation were identified 80: all were ANCA negative; the vasculitis and cardiomyopathy diagnoses were concomitant for five patients, suggesting a delay in the diagnosis. Despite ongoing immunosuppression, histologic examination of 7 (78%) patients' explained hearts showed histologic patterns suggestive of active vasculitis, indicating that most patients were undertaken. The overall 5-year survival rate was low (57%) but rose to 80% when considering only the six patients transplanted during the last decade.

Prognosis and outcome

The outcome of EHD, including EM, is difficult to assess, mainly due to the wide spectrum of disease presentation and the influence of underlying aetiology. In fact, the clinical onset of EM may range from mildly symptomatic to fulminant forms, $^{12,33,44,115,116}$ but most of the epidemiologic data derive from autopsies or transplanted hearts. $^{117}$. Therefore, an underestimation of the disease is probable and, in addition, we may have an overestimation of fulminant cases, which are most likely recognized in clinical practice and subsequently published.

Furthermore, the natural history of the EM is not unique and hardly predictable. The spectrum of possible evolutions includes important complications. The development of systolic or diastolic left ventricular dysfunction is the worst scenario, possibly associated with malignant arrhythmias and a possible restrictive pattern with the presence of endomyocardial fibrosis. These complicated forms can lead to cardiovascular death, heart transplant, or left ventricular assist device implantation. Other relevant complications are intravenousricular thrombi, valvular dysfunctions, and coronary vasospasm. Oppositely, some patients can show a significant improvement or recovery of the left ventricular dysfunction. Techasatian et al. reported that 10% of patients die during hospitalization and 30% of patients survive less than three years. ㊹However, Brambatti et al. demonstrate that, despite the frequent fulminant presentation, the recovery after mechanical support and steroid-based therapy was common: among 30 patients, 86.7% survived, and 73.3% normalized left ventricular ejection fraction before discharge. 12 The prognostic stratification (especially regarding the arrhythmias) and the identification of responders to the immunosuppressive therapy remain important unmet needs (Figure 5). In this perspective, the aetiological classification, through a cardiomyopathy-oriented approach, ㊻appears crucial so far. For instance, hypersensitivity myocarditis carries a particularly high ventricular arrhythmic risk (i.e. cardiac arrest was reported up to 44.6% in some series, independent of the degree of myocardial infiltration). 12,23,24,44,46,115-118 The building of international large registries in the future is pivotal for overcoming those demanding issues. Finally, immunosuppressive therapy may prevent recurrence of EM. 74 However, the data on recurrence are scarce and the possibility of relapsing EM during the corticosteroid tapering, the benefits of long-term steroid-sparing agents and the possible role of biologic drugs in non-EGPA-related EM should also be a focus of future research. ㊹

Current evidence gaps

In the last few years, the awareness of heart involvement in eosinophilia has increased, but its relative rarity, the heterogeneity of clinical features and the inconstant presence of peripheral eosinophilia within the aetiological variety still hinder having large case series and knowledge of the real prevalence of this condition.$^{12,44,7,119}$ There are no randomized controlled trials in patients with EM, respectively, focusing on any aspect of EHD. There are a few, relatively small-sized randomized trials in the field of HES and EGPA (Supplementary Table S1). However, the description of cardiac involvement is very limited in these studies and sub-analyses of the cohorts with heart involvement are missing. Thus, the main limitation of this consensus statement relies on the fact that the majority of advice is based on expert opinions and the evidence from systematic reviews of case series and small observational studies.$^{44}$ Furthermore, the published observational studies were not only of limited size but also included heterogeneous series with substantial risk of bias.$^{44}$ The data from the international registry of acute eosinophilic myocarditis (NCT06447935), which are expected to be published in the following months, could increase our knowledge on the topic of EHD.$^{120}$ Furthermore, the detailed pathways at the cellular level by which myocardial damage is induced are not fully

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Hypereosinophilia and management of haemodynamically stable patients

 Figure 4 Diagnostic pathway of patients with suspected eosinophilic heart disease. *An intracardiac mass is suspicious of eosinophilic heart disease when observed in the left or right ventricle without underlying regional systolic dysfunction, particularly when observed in the apices of both ventricles. **Chest pain, dyspnoea, palpitations, syncope unexplained by coronary artery disease or other cardiac diseases (valvular or congenital heart disease, pre-existing cardiomyopathy or pericardial disease). ***In autoimmune screening RF, ANA, ANCA, ENA blot, anti-ds DNA, immunoglobulins including subclasses, complement and potentially other examinations based on clinical scenario are advised. *****Immunosuppressive therapy

Heart involvement in eosinophilia

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 Figure 5 Complications associated with eosinophilic heart disease. HT heart transplantation, LV left ventricular, MCS mechanical circulatory support, VAD ventricular assist device

understood. This represents an obstacle in providing reliable and specific biomarkers, beyond eosinophilic cationic protein, useful in the diagnostic and follow-up phases. $^{121,122}$ Moreover, the limitations of EMB as the gold standard in the clinical assessment account for the need for novel multi-modality imaging parameters in a non-invasive path: PET-CT, CMR T1, and T2-mapping, CMR feature-tracking, and machine learning algorithms may all improve diagnosis and prognostication in this clinical setting, but are often expensive and not widely available. Further clinical studies are required in this area.$^{123-127}$ Finally, evidence-based treat-to-target regimens still remain uncertain due to the lack of randomized trials; these trials would help standardize care, establishing appropriate types of treatment (including newer biological and targeted therapies) and their long-term efficacy and safety, in order to improve outcomes. $^{12,44,128,129}$ Unfortunately, to the best of our knowledge, no randomized trial focusing primarily on EHD is ongoing. Nevertheless, there are several ongoing randomized, controlled trials with mepolizumab, benralizumab, depemokimab, and NS-229 in EGPA and mepolizumab, depemokimab, dupilumab, and ruxolitinib in HES$^{130-137}$ that may indirectly inform cardiac care in the future.

In summary, there is currently the lack of: (1) randomized trials specifically targeting EM or predefined cardiac endpoints in HES or EGPA; (2) data to guide the optimal duration and intensity of immunosuppression in patients with cardiac involvement; (3) prospective studies on imaging- and biomarker-based monitoring strategies; and (4) robust evidence for the choice and duration of anticoagulation in patients with mural thrombi.

Conclusions

Heart involvement in eosinophilia represents a rare disease associated with a wide range of clinical manifestations and a broad spectrum of underlying aetiologies. Early detection of heart involvement associated with HE and identifying the cause of eosinophilia is of utmost

importance to initiate appropriate treatment and prevent deleterious heart damage leading to poor outcomes. A multidisciplinary approach for the management of affected individuals with EHD is needed.

Acknowledgements

We are grateful to Martin Masek, M.D., Ph.D., Department of Radiology, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Czech Republic, for providing us with some of the figures used in this publication (Figure 1).

Bettina Heidecker is funded by the German Heart Center Foundation.

Supplementary Data

Supplementary data are available at European Journal of Heart Failure online.

Declarations

Disclosure of Interest

BH: is an inventor on patents that use RNA for the diagnosis of myocarditis. Patent protection is in process for MCG for the diagnosis and measurement of therapy response in inflammatory cardiomyopathy and for cytokines for targeted therapy in inflammatory cardiomyopathy and heart failure. BH has received speaker fees from Pfizer and AstraZeneca unrelated to this work.

LC has equity ownership and serves on the board of directors of Stromal Therapeutics.

SP: Consultancy, Circle Cardiovascular Imaging, Inc., Calgary, Alberta, Canada (SEP).

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Data Availability

No new data were generated or analysed in support of this clinical consensus statement.

Funding

All authors declare no funding for this contribution.

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