Elsevier

Cardiovascular Pathology

Volume 57, March–April 2022, 107393
Cardiovascular Pathology

The spectrum of macrophage-predominant inflammatory myocardial disease presenting as fulminant heart failure

https://doi.org/10.1016/j.carpath.2021.107393Get rights and content

Highlights

  • Endomyocardial biopsy results are integral for diagnosis and management of myocarditis. Current diagnostic classifications of myocarditis are based on the microscopic and immunochemical characterization of inflammation do not include monocyte/macrophage-predominant (i.e. “histiocytic”) myocarditis as a histologic subtype. We describe 6 cases of patients with acute heart failure whose endomyocardial biopsies showed predominant inflammation with macrophages and monocytes identified by immunopositivity for CD68.

  • Our cases were both cardiac limited (i.e. primary) and associated with systemic disease, including autoimmune disease. Some biopsies showed coagulative necrosis, and some showed features resembling antibody mediated rejection of cardiac allografts. Clinical outcomes ranged from spontaneous resolution to persistent heart failure.

  • Histiocytic myocarditis appears to be a distinct histopathological subtype associated with heterogeneous clinical contexts and outcomes, and its presence may reflect antibody mediated myocardial injury.

Abstract

Background

Endomyocardial biopsy results are integral for diagnosis and management of myocarditis. Current diagnostic classifications of myocarditis are based on the microscopic and immunochemical characterization of inflammation do not include monocyte/macrophage-predominant (i.e. “histiocytic”) myocarditis as a histologic subtype.

Methods

Endomyocardial biopsies from 6 patients with sudden heart failure were reviewed by 3 cardiac pathologists. Routine stains and immunostains to identify T cells and monocytes/macrophages, complement C4d, and endothelium were applied. Electron microscopy was performed in 2 cases.

Results

The 6 patients included 2 with diagnoses of systemic lupus erythematosus (SLE) and 4 without known disease. Microscopy showed space-occupying inflammation in 2 cases and interstitial inflammation in 4. No giant cell myocarditis or eosinophilic myocarditis was found. Immunostains showed infiltration predominantly by macrophages and/or monocytes with markedly fewer T cells. In 4 of 6 cases necrotic cells were immunopositive for complement C4d. Monocytes we identified immunochemically within the microvasculature in 5 cases and by electron microscopy in 2. Patients with SLE had microvascular C4d positivity or interstitial/sarcolemmal staining. Clinical outcomes ranged from spontaneous resolution to persistent heart failure requiring an internal cardioverter/defibrillator.

Conclusions

(1) Heart failure with CD68 predominant inflammation (“histiocytic” myocardial inflammatory disease, HMID) occurs with variable clinical presentation and outcome; (2) HMID may be primary or secondary; (3) some cases of HMID show features suggestive of antibody and/or complement mediated myocardial injury, and (4) HMID is a diagnosis distinct from those in classification systems currently in use.

Introduction

Inflammatory myocardial disease has been defined by the World Health Organization (WHO) as myocarditis with cardiac dysfunction [1]. Etiologies of myocarditis are infectious, autoimmune, and idiopathic, and myocarditis may be primary, i.e. limited to the heart, or secondary, i.e., occurring as part of a multisystemic process. Myocarditis is an important consideration in the differential diagnosis of unexplained heart failure, and endomyocardial biopsy (EMB) results are integral both in directing treatment and in determining prognosis [[2], [3], [4]–5]. The diagnosis of myocarditis by endomyocardial biopsy is principally based on identifying and characterizing myocardial inflammatory infiltrates by light microscopic morphology and immunohistochemical characterization of the inflammatory infiltrate, sometimes in conjunction with molecular identification of infectious agents, including viruses [2] Current morphological classification of myocarditis based on endomyocardial biopsy findings includes lymphocytic, eosinophilic, giant cell, and granulomatous subtypes [6].

Since 2019 we have seen 6 cases of fulminant heart failure in which endomyocardial biopsy showed inflammation with an infiltrate composed predominantly of macrophages (histiocytes), identified by immunohistochemistry for CD68. Three cases showed coagulative myocyte necrosis, and in three cases, biopsy findings resembled those described in antibody mediated rejection of cardiac allografts, 2 of these in patients with systemic lupus erythematosus (SLE). The details of histopathology and immunohistochemistry varied among the 6 biopsies, and the responses to clinical management also were variable, ranging from spontaneous remission to progressive heart failure. The purpose of this report is to describe and discuss the heterogeneous clinical and pathological details of these cases in order to better characterize the clinicopathological significance of endomyocardial biopsies showing predominantly histiocytic infiltrates.

Section snippets

Patients

All 6 cases involve patients who presented to the Heart Failure and Transplant Unit of at University of Rochester Medical Center, Rochester New York. In the time interval in which these cases were received, a total of 48 endomyocardial biopsies for unexplained heart failure were performed at our institution. All patients presented in cardiogenic shock; patients 2, 3, 4, and 6 were referred from hospitals outside the URMC system. Cases were equally distributed among sexes. Cases 1 and 2 had no

Biopsy findings

Biopsy results are summarized in Table 2.

Discussion

Endomyocardial biopsies in all 6 of our cases showed myocardium with inflammation composed predominantly of CD68 positive macrophages and/or monocytes, and for this reason, we have classified them as representing histiocytic inflammatory myocardial disease or “histiocytic myocarditis.” This diagnostic designation conveys the essential pathoanatomical features of these biopsies and also reflects the acute clinical presentation of our 6 patients. However, histiocytic myocarditis per se is not

Conclusions

Macrophage predominant inflammation may be seen in endomyocardial biopsies of patients with acute heart failure, and we propose that HMID be recognized as one morphological subtype of acute myocarditis that may present in a variety of clinical contexts. The features of our cases that suggest antibody and/or complement mediated injury in patients with HMID could reflect a potential for therapeutic approaches analogous to those used for antibody-mediated allograft rejection, e.g. intravenous

Acknowledgments

The authors thank Sierra Kovar and Karen Vanderbilt for expert technical assistance.

References (19)

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Cited by (3)

Funding: This project was funded by the Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Disclosures: Nothing to disclose.

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