Digging through eosinophils to identify cases of myocardial involvement—an effort well spent

Hypereosinophilic syndromes (HES) represent a group of disorders marked by the sustained overproduction of eosinophils, in which eosinophilic infiltration and mediator release lead to multiple organ damage and dysfunction (1). Despite being well-defined nosological entities, comprehensive data regarding these rare conditions are limited.

Although the disease clinical presentation can be heterogeneous, the most common target organs include the skin, lung, and gastrointestinal tract; the cardiovascular system is involved in approximately 40–50% of patients, mainly in the form of eosinophilic myocarditis (EM), a potentially life-threatening inflammatory disease of the heart (1-3).

The clinical presentation of EM can be heterogeneous, and is traditionally described as evolving through three stages, although these stages may be overlapping and not clearly sequential (4-6): an acute necrotic stage, an intermediate phase characterized by thrombus formation along the damaged endocardium, and finally a fibrotic stage leading to cardiac dysfunction due to restrictive cardiomyopathy (also called Loeffler endocarditis).

EM should be considered in patients exhibiting hypereosinophilia, elevated serum troponin levels, and increased serum natriuretic peptides (5,6). Echocardiographic assessment may reveal indicative findings such as endocardial wall thickening, endoventricular thrombus, and features of restrictive cardiomyopathy; however, these findings are not specific to EM (7).

Endomyocardial biopsy typically provides conclusive evidence of eosinophil-mediated cardiac involvement but is generally reserved for selected cases where the diagnosis remains uncertain, due to the substantial procedural risks, particularly considering the high incidence of left ventricular thrombi in this patient population (8).

Several reports have shown that cardiac magnetic resonance imaging (CMR) reliably detects all stages and manifestations of eosinophil-mediated heart damage, including endocardial thickening, intracardiac thrombi and a subendocardial late gadolinium enhancement (LGE) pattern indicative of fibrosis (9,10). In a previous paper by Pöyhönen et al. (10), the authors also correlate the CMR findings with histology in 15 patients with EM, showing a good correlation within different stages of the disease as demonstrated by the presence of extensive myocardial LGE in patients with necrotizing EM. Nevertheless, robust evidence of CMR reliability in EM is still lacking, and descriptions of suggestive findings in this condition are still very limited.

In the recent issue published in Cardiovascular Diagnosis and Therapy, Reeder et al. (11) report on the experience of 11 patients diagnosed with EM over a span of 37 years at a quaternary referral center in the United States, representing one of the largest studies of EM patients who underwent CMR.

The first main finding of the study, is the low prevalence of HES among subjects exhibiting peripheral eosinophilia, leading to an even lower number of EM cases. Indeed, only 36 patients with a definite diagnosis of HES were identified from an initial cohort of 1,664 patients who underwent echocardiography with an associated the International Statistical Classification of Diseases and Related Health Problems, 10^th Revision (ICD-10) code for eosinophilia between September 1986 and April 2023, with just 11 patients (31% of HES patients) diagnosed with EM. These numbers do not seem to justify screening programs using advanced diagnostic investigations (i.e., echocardiogram or CMR) based solely on the presence of hypereosinophilia. The use of specific cardiac biomarkers, like high-sensitivity troponin, seems promising, but it should be validated in large-scale studies on patients with hypereosinophilia. The most prevalent symptom at presentation was cough, with asthma being the most common comorbidity. Among the 8 patients who underwent CMR, the most common finding was subendocardial pattern of LGE (6/7, 86%): one patient did not undergo delayed enhancement imaging because of severe kidney dysfunction, followed by endoventricular thrombosis in 63% (5/8) of patients. Although this represents a small cohort of patients, this study confirms the critical role of CMR in the diagnosis and follow-up of EM; suggested that it should be performed in all the subjects with HES. However, larger studies are required to establish validated diagnostic criteria for non-invasive diagnosis of EM, as is feasible for most other forms of myocarditis.

The authors also compared the differences between HES patients who had cardiac involvement in and those who did not. Interestingly, there were no significant differences in baseline characteristics between the two groups, highlighting how we miss robust predictors of worst cardiac prognosis in this setting. Nevertheless, the factors that may contribute to potential cardiac involvement in HES patients remain mostly unknown. Furthermore, although there were no significant differences in mortality, patients with cardiac involvement experienced a significantly higher incidence of thromboembolic events (64% vs. 24%, P=0.02), and 9% of them were hospitalized for heart failure during the follow-up. These differences indicate the necessity of an early diagnosis of myocardial involvement, which is critical given the often-reversible nature of this type of heart disease and the potential risk of short- to medium-term complications in the absence of specific therapy. This is supported by a few reports from our group as well (12,13). Finally, the high prevalence of thrombotic complications reported by the authors in the EM group is a key message and underscores the need for dedicated studies to assess the usefulness of prophylactic anticoagulant therapy in these patients, as well as its length during the follow-up.

Despite the progress in the understanding and treatment of these rare forms of myocarditis, many uncertainties remain regarding their management. For example, considering that this condition ranges from paucisymptomatic forms to fulminant cases that can lead to cardiogenic shock and death or urgent heart transplantation, are there specific characteristics that can help identify patients who are likely to worsen? Or in the many patients who, if well-treated, experience a favorable outcome in terms of reverse remodeling and clinical recovery, is it justified to continue medical therapy (both in terms of immunomodulatory therapy and heart failure support)? And if so, for how long? Drawing from the experience of many potentially reversible forms of cardiomyopathy (e.g., alcoholic or peripartum cardiomyopathy), is there a role for genetic testing in determining how many of these cases are linked to individual susceptibility? Clinical trials and international registries are clearly needed to enhance knowledge about this condition, improving the acute and long-term prognosis.

In conclusion, HES represent a class of disorders with distinctive clinical and instrumental characteristics. When accompanied by cardiac involvement, they can be associated with prognostically relevant complications that necessitate early recognition. Given the diagnostic and therapeutic complexity of these diseases, a truly multidisciplinary approach is essential (Figure 1). This should involve the clinical cardiologist, the cardiovascular radiologist with CMR expertise, the interventional cardiologist capable of performing endomyocardial biopsy, the anatomic pathologist, and, of course, the internist. Even in this little corner of the vast world of cardiomyopathies, only through close team collaboration can we achieve meaningful results for our patients.

Figure 1 The “heart side” of the HES team. The HES management, due to the heterogeneity and the complexity of the disease, always need a multidisciplinary approach, especially when a cardiac involvement is suspected or confirmed. HES, hypereosinophilic syndromes; CMR, cardiac magnetic resonance; EMB, endomyocardial biopsy.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Cardiovascular Diagnosis and Therapy. The article did not undergo external peer review.

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cdt.amegroups.com/article/view/10.21037/cdt-24-514/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Ogbogu PU, Rosing DR, Horne MK 3rd. Cardiovascular manifestations of hypereosinophilic syndromes. Immunol Allergy Clin North Am 2007;27:457-75. [Crossref] [PubMed]
2. Piccirillo F, Mastroberardino S, Nafisio V, et al. Eosinophilic Myocarditis: From Bench to Bedside. Biomedicines 2024;12:656. [Crossref] [PubMed]
3. Brambatti M, Matassini MV, Adler ED, et al. Eosinophilic Myocarditis: Characteristics, Treatment, and Outcomes. J Am Coll Cardiol 2017;70:2363-75. [Crossref] [PubMed]
4. Weller PF, Bubley GJ. The idiopathic hypereosinophilic syndrome. Blood 1994;83:2759-79. [Crossref] [PubMed]
5. Zhong Z, Yang Z, Peng Y, et al. Diagnosis and treatment of eosinophilic myocarditis. J Transl Autoimmun 2021;4:100118. [Crossref] [PubMed]
6. Russo M, Ismibayli Z, Antonaci S, et al. Eosinophilic myocarditis: from etiology to diagnostics and therapy. Minerva Cardiol Angiol 2024;72:656-73. [Crossref] [PubMed]
7. Davies J, Gibson DG, Foale R, et al. Echocardiographic features of eosinophilic endomyocardial disease. Br Heart J 1982;48:434-40. [Crossref] [PubMed]
8. Wright BL, Leiferman KM, Gleich GJ. Eosinophil granule protein localization in eosinophilic endomyocardial disease. N Engl J Med 2011;365:187-8. [Crossref] [PubMed]
9. Plastiras SC, Economopoulos N, Kelekis NL, et al. Magnetic resonance imaging of the heart in a patient with hypereosinophilic syndrome. Am J Med 2006;119:130-2. [Crossref] [PubMed]
10. Pöyhönen P, Rågback J, Mäyränpää MI, et al. Cardiac magnetic resonance in histologically proven eosinophilic myocarditis. J Cardiovasc Magn Reson 2023;25:79. [Crossref] [PubMed]
11. Reeder M, Okushi Y, Lo Presti Vega S, et al. The Cleveland Clinic experience of eosinophilic myocarditis in the setting of hypereosinophilic syndrome: demographics, cardiac imaging, and outcomes. Cardiovasc Diagn Ther 2024;14:1122-33. [Crossref] [PubMed]
12. Amelotti N, Mapelli M, Guglielmo M, et al. What's behind your eosinophilic myocarditis? A case of Churg-Strauss syndrome diagnosed during acute heart failure. ESC Heart Fail 2023;10:709-15. [Crossref] [PubMed]
13. Mapelli M, Cefalù C, Zaffalon D, et al. Hypereosinophilic syndrome onset with Loeffler's endocarditis after COVID-19 infection. Eur Heart J Cardiovasc Imaging 2022;23:e472. [Crossref] [PubMed]