Corresponding Author
Key words: arrhythmogenic cardiomyopathy, cardiac sarcoidosis, genetic, granulomas, inflammation
Cardiac sarcoidosis (CS) is an idiopathic disease which can result in conduction abnormalities, ventricular arrhythmias, and/or heart failure. For over a century, the hallmark of CS has been the presence of noncaseating granulomatous inflammation and fibrosis in the absence of a specific cause such as infection. Although murine models and some clinical case series suggest CS likely results from an interplay between genetic (including the mammalian target of rapamycin [mTOR]) and environmental factors, genetic testing is not part of the standard management of CS in 2024, and current diagnostic algorithms recommend genetic testing to exclude other diagnoses.1 However, with the increased use of genetic testing in the evaluation of cardiomyopathies, gene mutations typical of arrhythmogenic cardiomyopathy (ACM) have been identified in some patients with a diagnosis of presumed “isolated CS” (ie, sarcoidosis with involvement limited to the heart).2,3 To further complicate matters, the inflammatory phase of ACM is detectable by cardiac fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging that is traditionally used to diagnose CS.4 Collectively, these data suggest that the clinical, genetic, imaging, and histological overlap between ACM gene mutations and inflammatory cardiomyopathies are blurring the diagnostic boundaries between ACM, myocarditis, and CS.
The occurrence of “hot phases,” or inflammatory phases, of ACM characterized by lymphocytic myocarditis is well described.5 However, to further obscure the distinction with CS, ACM can also be associated with granulomatous inflammation typical of CS. Of particular interest, our group and others have described a “sarcoid”-like pattern consisting of noncaseating granulomatous inflammation in patients with ACM (Figure 1).6,7 Because noncaseating granulomas are just one pattern of chronic inflammation shared by many diseases, investigators have sought a more comprehensive genetic testing linked to a deep mechanistic understanding of the disease microenvironment at a cellular and molecular level.
Figure 1.
Granulomatous Inflammation in a Patient With Arrhythmogenic Cardiomyopathy
In this example, a patient with clinically diagnosed arrhythmogenic cardiomyopathy and concurrent desmoplakin (DSP) gene mutation (c.2998-1G>C; likely pathogenic) was found to have (A) abundant subepicardial and mid-mural fibrofatty replacement of the myocardium with (B) multifocal non-necrotizing granulomas (hematoxylin and eosin stain; A, 100× original magnification and B, 400× original magnification).
In an elegant study of the tissue microenvironment, Liu et al described the immunologic phenotype and distinct molecular signatures of the cardiac sarcoid granuloma using spatial transcriptomics and single-nucleus RNA sequencing.8 A distinct organization of GPNMB (transmembrane glycoprotein NMB)+ multinucleated giant cells cuffed by HLA-DR (human leukocyte antigen-DR isotype)+ epithelioid macrophages in addition to involvement of MITF (microphthalmia-associated transcription factor), and mTOR pathways can distinguish CS from other forms of inflammatory cardiac diseases.8 While the role of autoimmunity and the inflammatory phase of ACMs is now well recognized, we are only beginning to understand its implications.9 The findings of noncaseating granulomatous inflammation in certain genetic ACMs beg further inquiry into the overlap between the pathophysiologic mechanisms of the 2 conditions, with potential diagnostic, prognostic, and therapeutic ramifications.
Personalized management strategies in suspected cardiac sarcoidosis (CS) could benefit from an assessment of cardiomyopathy-related and mTOR genes10 as well as the histological patterns of injury that could influence both family screening and therapy. The frequency of arrhythmogenic cardiomyopathy (ACM) or mTOR gene variants in “isolated CS” remains unknown.10 Noncaseating granulomas in the context of a pathogenic ACM gene variant may have a different clinical trajectory than granulomas resulting from a pathogenic mTOR variant.
Therefore, it is time to rethink the traditional histopathological framework as the foundation for distinctions between ACM, myocarditis, and CS. New classifications of cardiomyopathies that integrate genotype and clinical phenotype with histology in a modern iteration of the MOGE(s) classification11 are needed to generate more accurate risk estimates of clinical outcomes, including heart failure and ventricular arrhythmias. Clinical implementation of advanced histopathologic tools and pathway-specific, cardiac imaging tracers hold the promise of a more personalized cardiomyopathy classification with refined prognosis and more effective treatments.
Funding support and author disclosures
The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Footnotes
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References
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