Hypereosinophilic cardiomyopathy is a form of cardiac injury caused by infiltration, activation and degranulation of eosinophils within the myocardium and endocardium, with possible progression from acute eosinophilic myocarditis to intracardiac thrombosis, Loeffler endocarditis, endomyocardial fibrosis and restrictive cardiomyopathy. It does not represent a single disease, but rather the cardiac phenotype of different conditions unified by persistent eosinophilia, tissue eosinophilia or pathological eosinophilic activation. The heart may be involved in reactive, clonal, lymphocytic, idiopathic, vasculitic, parasitic, neoplastic or iatrogenic forms, and injury may occur even when peripheral eosinophilia is intermittent, already treated or not proportional to the intensity of the tissue infiltrate.
The term “hypereosinophilic” refers to HES (hypereosinophilic syndrome), defined by the presence of hypereosinophilia associated with organ damage attributable to eosinophils. In cardiological practice, however, the concept must be broader, because there are acute eosinophilic myocarditis forms due to medication reactions, eosinophilic granulomatosis with polyangiitis (EGPA), helminth infections, hematological neoplasms, myeloproliferative forms and organ-limited forms in which the heart is the main target. The clinical consequence is relevant: diagnosis cannot stop at the finding of elevated eosinophils, but must identify the mechanism sustaining them, because therapy, recurrence risk, hematological, immunological and infectious disease assessment, and prognosis change radically from one form to another.
Epidemiology is difficult to quantify. Hypereosinophilic syndromes are rare, eosinophilic myocarditis is underdiagnosed, acute forms may be mistaken for acute coronary syndrome, lymphocytic myocarditis or idiopathic heart failure, while chronic forms may reach clinical attention only after endomyocardial fibrosis has already developed. In patients with HES, cardiac involvement has historically been described as one of the main causes of morbidity and mortality, although its frequency varies according to diagnostic criteria, study period and earlier use of echocardiography, cardiac magnetic resonance (CMR), molecular testing and targeted therapies. The essential clinical point is that injury is potentially reversible in the early stages, but becomes progressively less recoverable when thrombosis, endocardial organization and restrictive fibrosis replace active inflammation.
Hypereosinophilic cardiomyopathy develops when eosinophils, cells normally involved in antiparasitic immunity, allergic responses and inflammatory regulation, become numerically and functionally harmful to the heart. The eosinophil is not merely a cell “present” in the tissue: when activated, it releases cationic proteins, oxidizing enzymes, lipid mediators, cytokines, chemokines, extracellular traps and procoagulant factors capable of damaging the endothelium, endocardium, cardiomyocytes and microcirculation. Cardiac injury therefore results from the combination of cellular infiltration, toxic degranulation, myocardial necrosis, platelet activation, thrombosis and fibrotic repair.
Etiological causes must be arranged rigorously, because the same cardiac picture may depend on very different diseases. Reactive forms or secondary forms are due to external or immunological stimuli that increase eosinophil production, survival and recruitment. They include helminth infections, especially Strongyloides stercoralis, Toxocara, Trichinella, Schistosoma, filariae and other parasites according to geographical area and exposure; severe allergic and atopic diseases; medication reactions; autoimmune diseases and vasculitides; solid neoplasms or lymphomas with production of eosinophilopoietic cytokines; inflammatory bowel diseases; immunodeficiencies and some endocrinopathies. In these forms the eosinophil is stimulated by an upstream process and the heart becomes a target of inflammatory excess.
Primary or clonal forms derive from hematological proliferation of myeloid cells with eosinophilic differentiation. The paradigm is the myeloid neoplasm with FIP1L1-PDGFRA rearrangement, historically classified among chronic eosinophilic leukemias and highly sensitive to imatinib. Other alterations include rearrangements of PDGFRB, FGFR1, PCM1-JAK2, BCR-ABL1, JAK2 V617F and variants associated with myeloproliferative or myelodysplastic neoplasms or systemic mastocytosis. These forms must be recognized because therapy is not simply anti-inflammatory: if the clone is controlled, eosinophilia may regress rapidly and organ damage may stabilize or improve, especially if fibrosis is not advanced.
The lymphocytic variant of HES is sustained by clones or aberrant populations of T lymphocytes that produce interleukin-5 (IL-5), interleukin-4, interleukin-13 and other mediators of type 2 polarization. In this condition the eosinophil is not clonal in the myeloid sense, but is kept alive and recruited by a pathological lymphocytic signal. The patient may present cutaneous, lymph node, respiratory, gastrointestinal or systemic manifestations and, in some cases, progression to T-cell lymphoma. The distinction is important because the diagnostic approach requires lymphocyte immunophenotyping, study of T-cell receptor clonality and longitudinal hematological monitoring.
EGPA deserves separate discussion because it is a vasculitis of small and medium-sized vessels associated with asthma, chronic rhinosinusitis, eosinophilia and possible positivity for anti-neutrophil cytoplasmic antibodies (ANCA). Cardiac involvement in EGPA may manifest as eosinophilic myocarditis, pericarditis, coronary vasculitis, heart failure, arrhythmias, endocavitary thrombosis or fibrosis. ANCA-negative forms tend to present more frequently with tissue and cardiac eosinophilic phenotypes, while ANCA-positive forms more often show classic vasculitic manifestations such as glomerulonephritis and neuropathy, although this distinction is not absolute. In a patient with asthma, nasal polyposis, eosinophilia and new cardiomyopathy, EGPA must be considered a priority.
Idiopathic forms are diagnosed when eosinophilia is persistent, organ damage is compatible with eosinophilic toxicity and no reactive, clonal, lymphocytic or syndromic cause is identified. This category must not be used prematurely for convenience, because it may conceal unrecognized parasitoses, myeloid neoplasms with untested alterations, vasculitides, medication reactions, lymphomas or autoimmune diseases. Idiopathy is an active diagnosis of exclusion, not a label to apply after a blood count.
Risk factors for cardiac involvement include duration and intensity of eosinophilia, very high eosinophil levels, myeloproliferative forms, EGPA with cardiac phenotype, diagnostic delay, failure to control eosinophilia, recurrences, previous endocardial damage, presence of thrombi, ventricular dysfunction, established fibrosis and cardiovascular comorbidities. However, the relationship between the number of eosinophils in the blood and cardiac damage is not linear. Some patients with high eosinophilia do not develop heart disease, whereas others present severe myocarditis with moderate or transient eosinophilia. What matters, therefore, is not only the quantity of eosinophils, but their activation state, the tissue in which they accumulate, the cause sustaining them and the speed of treatment.
The initial pathogenetic mechanism is eosinophilic recruitment into the myocardium and endocardium. Cytokines such as IL-5, interleukin-3 and granulocyte-macrophage colony-stimulating factor (GM-CSF) prolong eosinophil survival and activation. Chemokines such as eotaxins and endothelial signals promote adhesion and migration into tissue. Once in the heart, eosinophils release major basic protein (MBP), eosinophil cationic protein (ECP), eosinophil peroxidase (EPO) and eosinophil-derived neurotoxin (EDN). These proteins are cytotoxic to cardiomyocytes and endothelium, alter cell membranes, promote necrosis, increase vascular permeability and amplify the local inflammatory response.
Major basic protein is particularly important because it can damage the endocardium and endothelium, neutralize surface anticoagulant molecules and promote thrombosis. Eosinophil peroxidase generates oxidizing species capable of altering lipids, proteins and extracellular matrix. Eosinophil cationic protein increases cellular damage and inflammatory activation. These mediators transform the eosinophil from a defensive cell into a cardiotoxic cell. Damage does not necessarily require epicardial coronary ischemia: it may be microvascular, endocardial, interstitial and myocytic, with a clinical presentation similar to infarction, myocarditis or heart failure.
The classic pathophysiology evolves through three phases, which in reality may overlap. The necrotic phase is dominated by eosinophilic infiltration, edema, myocyte necrosis and acute myocarditis. It may be clinically silent or may manifest with chest pain, elevated troponin, arrhythmias, ventricular dysfunction and shock. The thrombotic phase derives from endocardial injury and activation of coagulation: the damaged endocardium exposes pro-adhesive surfaces, platelets are activated, apical recesses and hypokinetic areas promote stasis and mural thrombi form, often at the ventricular apices. The fibrotic phase corresponds to scar repair of the endocardium and subendocardial myocardium, with fibrous thickening, apical obliteration, entrapment of chordae tendineae, atrioventricular valve insufficiency and restrictive physiology.
This sequence explains why hypereosinophilic cardiomyopathy may present in apparently opposite ways. In the early phase it resembles myocarditis, with chest pain, fever, elevated troponin and acute dysfunction. In the intermediate phase it may present with systemic embolism or stroke from a ventricular thrombus. In the late phase it behaves as restrictive cardiomyopathy, with dyspnea, congestion, ascites, edema, dilated atria, elevated filling pressures, ventricles that are not necessarily markedly dilated and severe functional limitation. The diagnostic error consists in searching for a single phenotype instead of recognizing the evolutionary stage.
Thrombosis is an integral part of pathogenesis, not an incidental complication. Activated eosinophils can increase tissue factor expression, damage the endothelium, interfere with thrombomodulin, stimulate platelets and contribute to procoagulant extracellular networks. Mural thrombus therefore arises from the combination of injured endocardial surface, inflammation, blood stasis, segmental dysfunction and local hypercoagulability. This explains the frequency of embolic events and the need to search for thrombi even when the main symptoms are inflammatory.
Endomyocardial fibrosis is the final consequence of chronic repair. Fibroblasts, myofibroblasts, transforming growth factor beta (TGF-beta), eosinophilic mediators and extracellular matrix produce progressive endocardial thickening. When fibrosis involves the ventricular apex, it may obliterate the cavity; when it involves chordae tendineae or papillary muscles, it causes mitral or tricuspid regurgitation; when it stiffens the ventricle, it causes restrictive physiology with a marked increase in filling pressures. At this point, reduction of eosinophilia may stop the biological aggression, but does not always remove already organized mechanical damage.
The cause-damage-disease sequence can therefore be described in a unified way: a reactive, clonal, lymphocytic, vasculitic or idiopathic condition increases eosinophil number and activation; eosinophils migrate into the heart and release cytotoxic mediators; the endocardium, microcirculation and cardiomyocytes are injured; inflammation produces necrosis and dysfunction; the damaged endocardium promotes mural thrombosis; the thrombus may embolize or organize; repair becomes endomyocardial fibrosis; fibrosis stiffens the ventricle, deforms the valve apparatuses and produces restrictive cardiomyopathy. The speed with which eosinophilic activity is interrupted determines how much of the damage remains reversible.
The clinical presentation depends on the cause of eosinophilia, speed of onset, stage of cardiac injury and extracardiac organs involved. History taking must start from the current symptom, but must immediately extend to exposures, travel, diet, contact with animals, parasitoses, asthma, rhinitis, nasal polyposis, dermatitis, urticaria, fever, weight loss, night sweats, lymphadenopathy, medications introduced in the preceding weeks, autoimmune diseases, neoplasms, neurological, gastrointestinal and cutaneous symptoms. The clinical question is not only “is the heart diseased?”, but “why are eosinophils damaging the heart?”.
In the phase of acute eosinophilic myocarditis, the patient may report chest pain, dyspnea, palpitations, fever, general malaise, myalgia, cough, syncope or presyncope. Chest pain may simulate an acute coronary syndrome, with elevated troponin and electrocardiographic abnormalities. Dyspnea may result from acute ventricular dysfunction, pulmonary edema, eosinophilic pulmonary involvement or asthma. Palpitations may reflect sinus tachycardia, atrial fibrillation, extrasystoles, ventricular tachycardia or conduction disturbances. In fulminant cases, hypotension, cardiogenic shock, elevated lactate, oliguria and need for intensive support appear.
In subacute forms, the picture may be less dramatic but more insidious. The patient reports progressive reduction in exercise tolerance, fatigability, dyspnea, chest heaviness, intermittent palpitations, low-grade fever, weight loss or systemic symptoms. Endocavitary thrombi may already form in this phase. An ischemic stroke, transient ischemic attack, peripheral embolism, splenic or renal infarction may be the first recognized manifestation. The appearance of an embolic event in a patient with eosinophilia must prompt active search for Loeffler endocarditis and mural thrombi, even if systolic function does not appear severely reduced.
In the late fibrotic phase, the restrictive picture predominates. The patient reports exertional dyspnea, orthopnea, dependent edema, abdominal tension, ascites, painful hepatomegaly, early satiety, asthenia and reduced functional capacity. Restrictive physiology produces increased atrial and venous pressures with ventricles that are often not very dilated. Right ventricular involvement causes prominent systemic congestion; left ventricular involvement causes pulmonary congestion and reduced output. When fibrosis involves the mitral or tricuspid apparatus, valve regurgitation worsens congestion and accelerates heart failure.
Extracardiac symptoms guide etiology. Adult-onset asthma, chronic rhinosinusitis, nasal polyposis, peripheral neuropathy, purpura, mononeuritis multiplex, migratory pulmonary infiltrates and ANCA positivity suggest EGPA. Pruritus, eczema, angioedema, lymphadenopathy and recurrent cutaneous manifestations may suggest the lymphocytic variant of HES. Splenomegaly, constitutional symptoms, anemia, thrombocytopenia or thrombocytosis, elevated vitamin B12, elevated tryptase or myeloproliferative signs suggest a clonal form. Abdominal pain, diarrhea, fever, eosinophilia after travel or rural exposure suggest parasitosis. Rash, fever, hepatic, renal or lymph node involvement after introduction of a medication suggest a systemic reaction with eosinophilia.
Physical examination begins with assessment of hemodynamic stability. Tachycardia, hypotension, cold skin, confusion, oliguria and hypoxemia indicate possible fulminant myocarditis or cardiogenic shock. Pulmonary crackles, third heart sound and increased work of breathing indicate congestion. Jugular venous distension, hepatomegaly, ascites, dependent edema and hepatojugular reflux indicate right-sided congestion or restrictive physiology. Systolic murmurs due to mitral or tricuspid regurgitation may appear when fibrosis and thrombi deform the subvalvular apparatus. An irregular rhythm suggests atrial fibrillation; bradycardia or pauses may indicate conduction disturbances.
The skin must be examined carefully. Urticaria, eczema, nodules, palpable purpura, livedo, necrotic lesions, maculopapular rash or signs of systemic reaction may point toward allergic, vasculitic, lymphocytic or iatrogenic causes. The respiratory system must be assessed for wheezing, signs of asthma, infiltrates, pleural effusions or respiratory failure. Neurological examination searches for mononeuritis multiplex, focal deficits, sensory or motor neuropathy and signs of embolism. The abdomen may show hepatosplenomegaly, pain, ascites or signs of eosinophilic gastrointestinal involvement. Examination must be deliberately systemic because the heart is rarely the only organ involved.
A particularly dangerous presentation is apparent coronary syndrome with non-obstructive coronary arteries. The patient has chest pain, elevated troponin, ST-segment or T-wave abnormalities and coronary angiography without a culprit lesion. In this context, eosinophilia, even if moderate, must raise suspicion of eosinophilic myocarditis. CMR and, in selected cases, endomyocardial biopsy become decisive. Treating the picture as simple “infarction with unobstructed coronary arteries” without searching for active eosinophilia may delay corticosteroids, etiological therapy and prevention of the thrombotic phase.
Another critical presentation is restrictive heart failure in a patient with a remote history of eosinophilia. In the fibrotic phase, peripheral eosinophilia may be less evident or already intermittent, while mechanical damage persists. The patient may present with dilated atria, valve regurgitation, apical obliteration, organized thrombi and elevated filling pressures. If the history of eosinophilia is not reconstructed, the diagnosis may be confused with idiopathic restrictive cardiomyopathy, amyloidosis, constrictive pericarditis or primary valve disease.
The clinical sequence during a real visit must therefore proceed from the symptom to the timing of disease. Chest pain and troponin suggest the acute inflammatory phase. Embolic event or ventricular thrombus suggest the thrombotic phase. Chronic congestion, dilated atria and restrictive physiology suggest the fibrotic phase. In parallel, asthma, parasitosis, medications, myeloproliferative signs, skin, neuropathy and constitutional symptoms guide the cause. The clinical diagnosis is strong when the cardiac stage and eosinophilic context tell the same biological story.
The diagnostic pathway must proceed on two parallel tracks: confirming eosinophilic cardiac involvement and identifying the cause of eosinophilia. Stopping at only one of the two steps produces an incomplete diagnosis. A patient with compatible CMR and an apical thrombus also requires hematological, immunological and infectious disease assessment; a patient with elevated eosinophils requires cardiac imaging if symptoms, elevated troponin, increased natriuretic peptide or electrocardiographic abnormalities are present. Diagnosis is more effective the earlier it is made, before irreversible fibrosis develops.
First-line evaluation includes complete blood count with leukocyte differential and eosinophil count, repeated count if the picture is not urgent, cardiac troponin, B-type natriuretic peptide (BNP) or N-terminal pro-B-type natriuretic peptide (NT-proBNP), C-reactive protein, erythrocyte sedimentation rate, renal function, liver function, electrolytes, coagulation, immunoglobulin E (IgE), vitamin B12, tryptase, lactate dehydrogenase, urinalysis and assessment of organ damage. The electrocardiogram (ECG) may show sinus tachycardia, nonspecific repolarization abnormalities, ST-segment elevation or depression, T-wave inversion, blocks, supraventricular or ventricular arrhythmias. A normal ECG does not exclude the disease.
Transthoracic echocardiography is the most important initial cardiological examination. In the acute phase it may show global or regional ventricular dysfunction, apparent wall thickening due to edema, pericardial effusion, mitral or tricuspid regurgitation and increased filling pressures. In the thrombotic phase it may reveal apical or mural thrombi, sometimes better visualized with echocardiographic contrast. In the fibrotic phase it may show endocardial thickening, apical obliteration, dilated atria, small or normal ventricles, restrictive filling pattern, atrioventricular valve insufficiency and pulmonary hypertension. Echocardiography must always search for thrombi, because their identification immediately changes therapy.
CMR is essential for characterizing inflammation, edema, necrosis, thrombosis and fibrosis. In eosinophilic myocarditis it may show myocardial edema, hyperemia, T1 and T2 abnormalities, subendocardial or intramyocardial late gadolinium enhancement (LGE) and ventricular dysfunction. In Loeffler endocarditis it may document endocavitary thrombi, endocardial thickening, apical obliteration and subendocardial fibrosis. The subendocardial pattern may simulate ischemia, but the distribution does not always respect a single coronary territory and must be interpreted together with coronary angiography or coronary computed tomography when indicated. CMR is also useful for monitoring response to therapy, regression of edema and persistence of fibrosis.
Coronary angiography or coronary computed tomography is indicated when the presentation simulates an acute coronary syndrome, when ischemic changes, typical chest pain, high risk factors or instability are present. Eosinophilic myocarditis cannot be diagnosed by approximate exclusion of infarction: it must be demonstrated that the picture is not explained by a culprit coronary lesion. In some patients, coronary artery disease and eosinophilic damage may coexist; in these cases, tissue imaging, damage distribution and hematological evaluation become essential.
Endomyocardial biopsy is the most specific examination for demonstrating eosinophilic myocarditis when it shows eosinophilic infiltrate, degranulation, myocyte necrosis, endocardial damage, organized thrombus or fibrosis. It is not necessary in all patients, but is particularly important in fulminant cases, in forms with shock, in uncertain diagnoses, in patients who do not respond to therapy, when it is necessary to distinguish from lymphocytic myocarditis, giant cell myocarditis, cardiac sarcoidosis, infectious myocarditis or infiltrative disease. The limitation is the focal distribution of injury: a negative sample does not completely exclude the disease if suspicion remains high. Procedural risk must be balanced against diagnostic benefit.
In the absence of univocal official international cardiological criteria for hypereosinophilic cardiomyopathy alone, according to the Valent-Klion-Roufosse classification of eosinophilic diseases and the ESC approach to cardiomyopathies, a clinically grounded diagnosis requires:
integrated diagnostic assessment
Etiological investigation is mandatory. For infectious forms, travel history, exposures, parasitological tests, targeted serology and, before systemic corticosteroids in at-risk patients, Strongyloides stercoralis must be excluded or treated empirically according to specialist assessment, because immunosuppression may precipitate potentially fatal hyperinfection. For allergic or iatrogenic forms, exposure to medications, supplements, herbal products and environmental substances must be reconstructed. For EGPA, asthma, rhinosinusitis, polyposis, neuropathy, pulmonary infiltrates, ANCA, renal function, urinalysis and vasculitic signs are assessed. For neoplasms and lymphomas, constitutional symptoms, lymphadenopathy, splenomegaly and hematological abnormalities are sought.
Hematological assessment must include peripheral smear, vitamin B12, tryptase, lactate dehydrogenase and, when appropriate, bone marrow evaluation with cytology, histology, cytogenetics, immunophenotyping and molecular tests. Alterations to search for include FIP1L1-PDGFRA, PDGFRB rearrangements, FGFR1, PCM1-JAK2, BCR-ABL1, JAK2 V617F, KIT D816V and other profiles according to the clinical picture. Signs such as splenomegaly, anemia, thrombocytopenia or thrombocytosis, circulating myeloid precursors, elevated tryptase and elevated vitamin B12 increase suspicion of a clonal form. Negative initial tests do not exclude all clonal forms, so the pathway must be guided by hematology.
The lymphocytic variant requires lymphocyte immunophenotyping and study of T-cell receptor clonality. Aberrant T-cell populations, IL-5 production and cutaneous or lymph node manifestations may guide suspicion. This diagnosis is important because the patient may require immunomodulatory therapy and surveillance for lymphoproliferative evolution. In this case as well, the heart cannot be managed separately from the immunohematological system that fuels eosinophils.
The cardiological differential diagnosis includes acute coronary syndrome, viral myocarditis, non-eosinophilic autoimmune myocarditis, giant cell myocarditis, cardiac sarcoidosis, idiopathic dilated cardiomyopathy, restrictive cardiomyopathy, amyloidosis, Fabry disease, constrictive pericarditis, infective endocarditis with emboli, ventricular thrombosis from another cause and radiation-induced heart disease. Constrictive pericarditis may simulate restriction, but shows pericardial signs and ventricular interdependence. Amyloidosis produces apparent hypertrophy, low voltages and a characteristic CMR pattern. Sarcoidosis may cause blocks and LGE, but is not sustained by eosinophilia. Distinction requires integration of imaging, laboratory findings and sometimes histology.
Severity assessment must be contextual to the diagnosis. Rhythm, blood pressure, oxygen saturation, diuresis, lactate in unstable patients, renal function, liver function and signs of embolism must be monitored. Holter ECG or continuous monitoring searches for supraventricular arrhythmias, ventricular tachycardias, blocks and pauses. Serial imaging assesses regression of edema, changes in ventricular function, appearance or resolution of thrombi and progression of fibrosis. In patients with advanced fibrotic disease, right and left heart catheterization may be needed to distinguish restriction, constriction, pulmonary hypertension and hemodynamic severity.
Treatment must pursue three simultaneous objectives: rapidly suppress eosinophilic activity, treat the cause sustaining it and manage the cardiac consequences. Heart failure therapy alone is not sufficient if eosinophils remain active; reduction of eosinophils alone is not sufficient if the patient has thrombi, arrhythmias, shock or restrictive fibrosis. The strategy depends on cardiac stage, clinical severity, cause of eosinophilia, infectious risk and presence of extracardiac damage.
In severe acute eosinophilic myocarditis, especially with elevated troponin, ventricular dysfunction, arrhythmias, shock, pulmonary edema or rapid worsening, systemic corticosteroids are the most commonly used initial anti-inflammatory treatment, after rapid assessment of infectious causes and Strongyloides risk. In fulminant cases, high-dose intravenous methylprednisolone and cardiac intensive care may be needed. Response may be rapid if damage is mainly inflammatory, but diagnostic delays increase the risk of thrombosis and fibrosis. When the etiology is a medication reaction, definitive discontinuation of the suspected agent is an essential part of therapy.
If parasitosis is suspected, anthelmintic treatment must target the responsible agent. Strongyloides stercoralis is particularly important because corticosteroids and immunosuppression may trigger hyperinfection. In patients with epidemiological risk, positive serology or inability to wait in a severe cardiac picture, ivermectin use must be discussed promptly with infectious disease specialists. Infections such as schistosomiasis, toxocariasis, trichinellosis or filariasis require specific treatments and must not be confused with idiopathic HES.
In myeloid forms with FIP1L1-PDGFRA or PDGFRB rearrangement, imatinib is the cornerstone treatment because it acts on the tyrosine kinase signal sustaining the eosinophilic clone. Hematological and molecular response may be marked even with relatively low doses in PDGFRA-positive forms. When active cardiac involvement exists, many experts combine corticosteroids with the start of targeted therapy or use them immediately beforehand, to reduce the risk of acute inflammatory worsening related to rapid lysis or modulation of eosinophils. Forms with FGFR1 or PCM1-JAK2 have different behavior and require specialist hematological management, sometimes with intensive strategies or hematopoietic stem cell transplantation.
In idiopathic HES or the lymphocytic variant, corticosteroids are often the first choice, especially if organ damage is active. In corticosteroid-dependent, refractory or relapsing patients, corticosteroid-sparing treatments such as mepolizumab, an antibody against IL-5, may be considered and has demonstrated reduction of flares in FIP1L1-PDGFRA-negative HES. In selected settings, interferon alfa, hydroxyurea, other anti-eosinophil biologics or targeted immunomodulation are also used. The choice depends on biological variant, organs involved, required speed of action, toxicity, accessibility and previous response.
In EGPA with cardiac involvement, the picture is considered severe and therapy must be aggressive. International recommendations indicate systemic glucocorticoids associated with cyclophosphamide or rituximab for remission induction in severe forms, while mepolizumab has an established role in relapsing, refractory or non-severe forms and in reducing corticosteroid exposure. Cardiac involvement must not be treated as simple eosinophilic asthma: myocarditis, heart failure, elevated troponin, positive CMR or arrhythmias define a higher prognostic risk and require coordination between cardiology, rheumatology and immunology.
Cardiological therapy follows the stage. In heart failure with reduced left ventricular ejection fraction, standard heart failure therapies are used, adapted to blood pressure, renal function, congestion and stability. Diuretics are useful for congestion, but in advanced restrictive physiology the margin between decongestion and excessive preload reduction is narrow. Beta-blockers, inhibition of the renin-angiotensin-aldosterone system, mineralocorticoid receptor antagonists and type 2 sodium-glucose cotransporter inhibitors may be used when the phenotype allows it, but they do not replace control of eosinophilia.
Cardiogenic shock requires intensive care, hemodynamic monitoring and, in refractory cases, mechanical circulatory support. The choice among inotropes, vasopressors, intra-aortic balloon pump, percutaneous devices, venoarterial extracorporeal membrane oxygenation (VA-ECMO) or ventricular assistance depends on ventricular dysfunction, arrhythmias, oxygenation, intracardiac thrombi, embolic risk and expected reversibility. In fulminant eosinophilic myocarditis, temporary support may allow recovery if inflammation is rapidly controlled.
Anticoagulation is indicated in the presence of intracardiac thrombus, systemic embolism, atrial fibrillation according to thromboembolic risk, severe ventricular dysfunction with marked stasis or Loeffler endocarditis in the thrombotic phase according to individual assessment. Thrombi must be monitored with echocardiography, CMR or contrast echocardiography until resolution or stable organization. The choice of anticoagulant depends on renal function, bleeding risk, interactions, need for procedures and presence of large or mobile thrombi. Anticoagulation does not correct the cause of thrombosis if the endocardium remains actively damaged by eosinophils.
Arrhythmias require specific treatment. Atrial fibrillation worsens restrictive physiology because it eliminates the atrial contribution to filling and increases embolic risk. Ventricular tachycardias may occur in the inflammatory or fibrotic phase; therapy includes correction of electrolytes, control of inflammation, selected antiarrhythmic agents, ablation in appropriate cases and implantable cardioverter-defibrillator (ICD) when risk persists according to cardiomyopathy and ventricular arrhythmia indications. Early implantation during reversible acute myocarditis must be assessed cautiously, but residual fibrosis and major events may make permanent protection necessary.
In the advanced fibrotic phase, anti-eosinophilic therapy may stop biological activity, but mechanical restriction may persist. Treatment becomes treatment of restrictive heart failure, right-sided congestion, arrhythmias, thrombi and valve diseases. In selected cases with endomyocardial fibrosis, apical obliteration and severe valve regurgitation, endocardiectomy with valve repair or replacement may be considered, but operative risk is high and benefit depends on patient selection, center experience and control of eosinophilia. Heart transplantation is rare and reserved for selected end-stage heart failure, with careful assessment of systemic disease and recurrence risk.
Follow-up must monitor eosinophils, underlying cause, cardiac function, thrombi, fibrosis, arrhythmias and extracardiac damage. Serial blood counts, cardiac markers when indicated, ECG, Holter, echocardiography and CMR are necessary when residual activity or fibrosis must be characterized. Reduction of eosinophil count alone does not demonstrate cardiac healing: a patient may have normalized eosinophils and persistent thrombus, or non-reversible restrictive fibrosis. Conversely, new cardiac symptoms in a patient with controlled HES must prompt search for recurrence, thrombosis, arrhythmias or another concomitant heart disease.
Prognosis depends on the stage at diagnosis. Forms recognized in the necrotic-inflammatory phase may improve markedly with rapid therapy, especially if there are no extensive thrombi or fibrosis. Thrombotic forms have a prognosis related to emboli, thrombus resolution and control of eosinophilic endocarditis. Fibrotic forms have a worse prognosis because restriction, cavity obliteration and valve damage are often poorly reversible. Unfavorable factors include diagnostic delay, untreated clonal form, EGPA with severe myocarditis, shock, reduced left ventricular ejection fraction (LVEF), fibrosis on CMR, mobile thrombi, ventricular arrhythmias, multiorgan involvement and inability to stably control eosinophilia.
The complications of hypereosinophilic cardiomyopathy reflect progression from inflammation to thrombosis and fibrosis. The first complication is acute myocarditis with myocyte necrosis. It may be mild and paucisymptomatic, but it may also present as fulminant myocarditis with cardiogenic shock, multiorgan failure and need for mechanical support. Damage is mediated by eosinophilic infiltration and degranulation, not by persistent coronary occlusion, although the picture may simulate infarction. The main risk is therapeutic delay, because the inflammatory phase is the one in which treatment can most significantly change the natural history.
Acute heart failure appears when inflammation reduces contractility, increases myocardial edema, alters relaxation or produces functional valve regurgitation. It manifests with dyspnea, pulmonary edema, hypoxemia, hypotension and congestion. In severe cases it progresses to cardiogenic shock. The reversible component depends on how much damage is edema and limited necrosis and how much is already fibrosis. Control of eosinophilia is therefore a form of heart failure therapy, because it removes the biological aggression that fuels dysfunction.
Intracardiac thrombosis is a characteristic complication. Thrombi often form at the ventricular apices or on damaged endocardial surfaces, but may also involve other areas of stasis or fibrosis. The cause is the combination of toxically injured endocardium, procoagulant eosinophils, activated platelets, contractile dysfunction and slowed flow. Thrombi may be bulky, layered, mobile or organized. Their presence increases embolic risk and may contribute to subsequent cavity obliteration and fibrosis.
Systemic emboli derive from fragmentation or mobilization of mural thrombi. They may cause ischemic stroke, transient ischemic attack, acute limb ischemia, renal infarctions, splenic infarctions, mesenteric emboli and multiorgan damage. A neurological event in a patient with eosinophilia must not be automatically attributed to vasculitis or atherosclerosis: endocavitary thrombi and Loeffler endocarditis must be sought. Prevention requires early identification, anticoagulation when indicated and control of eosinophilic activity.
Endomyocardial fibrosis is the most disabling late complication. The endocardium thickens, the ventricular cavity may be partially obliterated, the apices become rigid and the ventricle loses compliance. The result is restrictive cardiomyopathy with elevated filling pressures, dilated atria, pulmonary or systemic congestion, reduced functional capacity and poor exercise tolerance. Unlike edema and inflammation, fibrosis is poorly reversible; this is why prevention of the fibrotic phase is one of the main objectives of early diagnosis.
Atrioventricular valve diseases are frequent in advanced fibrotic forms. Fibrosis may entrap chordae tendineae, papillary muscles and valve leaflets, causing mitral or tricuspid regurgitation. Regurgitation increases volume overload, dilates the atria, worsens congestion and promotes atrial fibrillation. In severe cases, valve damage becomes a main determinant of symptoms, even if eosinophilia is controlled. Surgical correction may be complex because the valve is part of a fibrotic endomyocardial apparatus.
Advanced restrictive cardiomyopathy causes chronic congestion. The patient develops ascites, edema, hepatomegaly, venous hypertension, pleural effusions, reduced output and malnutrition. Diuretic therapy improves symptoms but may excessively reduce preload, because the rigid ventricle depends on elevated filling pressures to maintain output. This balance makes clinical management difficult and explains why late forms have a worse prognosis than initial myocarditis.
Arrhythmias may appear in any phase. Acute inflammation promotes extrasystoles, ventricular tachycardia, ventricular fibrillation and repolarization disturbances. Fibrosis creates a substrate for reentry and chronic ventricular tachycardias. Atrial dilation and elevated filling pressure promote atrial fibrillation. Arrhythmias worsen heart failure because they reduce filling, increase myocardial oxygen demand and may produce emboli. Sudden death may result from ventricular tachyarrhythmias, blocks or rapid hemodynamic deterioration.
Pericardial involvement may manifest as pericarditis, pericardial effusion or pleuritic chest pain, especially in systemic inflammatory forms and EGPA. Effusion is often secondary to inflammation, but in severe cases it may contribute to dyspnea and instability. The presence of pericarditis together with eosinophilia, elevated troponin and ventricular dysfunction must suggest eosinophilic myopericarditis, not isolated pericarditis.
Extracardiac complications modify cardiac prognosis. Neuropathy, glomerulonephritis, pulmonary infiltrates, severe asthma, eosinophilic enteritis, liver disease, systemic thromboses, lymphomas or myeloid neoplasms may sustain inflammation, limit therapies and increase mortality. In patients with EGPA, the heart is a major prognostic factor; in myeloid forms, risk depends on control of the clone; in parasitic forms, unprotected immunosuppression may produce severe infectious complications. Management of the heart is inseparable from management of the entire eosinophilic disease.
Recurrences are a relevant complication. They may occur when therapy is tapered too rapidly, when the cause has not been identified, when the hematological clone persists, when EGPA reactivates or when an idiopathic form is not truly controlled. Each recurrence may add new endocardial damage, a new thrombus or new fibrosis. Follow-up must therefore distinguish hematological remission, clinical remission and cardiac remission, because they do not always coincide.
The most serious complication in practical terms is late diagnosis. When the patient is recognized in the inflammatory phase, treatment can prevent thrombosis and fibrosis. When the patient presents in the restrictive phase, many lesions are already structured. For this reason, every significant eosinophilia with chest pain, dyspnea, elevated troponin, increased BNP or NT-proBNP, ECG abnormalities, embolism or signs of heart failure must be considered a possible cardiological emergency. The therapeutic window exists, but it progressively closes as the inflamed endocardium becomes scar tissue.