Altered Desmosomal Proteins in Granulomatous Myocarditis and Potential Pathogenic Links to Arrhythmogenic Right Ventricular Cardiomyopathy

• Published in: Circulation. Arrhythmia and electrophysiology Vol. 4; no. 5; pp. 743 - 752
• Main Authors: Asimaki, Angeliki, Tandri, Harikrishna, Duffy, Elizabeth R, Winterfield, Jeffrey R, Mackey-Bojack, Shannon, Picken, Maria M, Cooper, Leslie T, Wilber, David J, Marcus, Frank I, Basso, Cristina, Thiene, Gaetano, Tsatsopoulou, Adalena, Protonotarios, Nikos, Stevenson, William G, McKenna, William J, Gautam, Shiva, Remick, Daniel G, Calkins, Hugh, Saffitz, Jeffrey E
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 01.10.2011; Lippincott Williams & Wilkins
• Subjects: Adolescent; Adult; Aged; Animals; Arrhythmias, Cardiac - blood; Arrhythmias, Cardiac - etiology; Arrhythmias, Cardiac - physiopathology; Autopsy; Biological and medical sciences; Biopsy; Cardiac dysrhythmias; Cardiology. Vascular system; Cardiomyopathies - blood; Cardiomyopathies - etiology; Cardiomyopathies - physiopathology; Case-Control Studies; Cells, Cultured; Chemokine CCL2 - blood; Chemokine CCL4 - blood; Child; Desmosomes - metabolism; Female; gamma Catenin - metabolism; Heart; Humans; Intercellular Junctions - drug effects; Intercellular Junctions - metabolism; Interleukin-17 - metabolism; Interleukin-17 - pharmacology; Interleukin-6 - metabolism; Interleukin-6 - pharmacology; Interleukin-8 - blood; Male; Medical sciences; Middle Aged; Models, Animal; Myocarditis - metabolism; Myocarditis - pathology; Myocarditis - physiopathology; Myocarditis. Cardiomyopathies; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Rats; Rats, Wistar; Sarcoidosis - metabolism; Sarcoidosis - physiopathology; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Signal Transduction - physiology; Tumor Necrosis Factor-alpha - metabolism; Tumor Necrosis Factor-alpha - pharmacology; Ventricular Dysfunction, Right - blood; Ventricular Dysfunction, Right - etiology; Ventricular Dysfunction, Right - physiopathology; Young Adult; Heart; ARVC; Neonatal; Giant cell myocarditis; Arrhythmia; Intercalated disk; Cell junction; Cardiovascular disease; gamma catenin; Desmosome; Potential; Myocardial disease; Myocyte; Result; Prevention; Reduction; Signal; Gene; Arrhythmogenic right ventricular dysplasia; giant cells; Heart disease; Systemic disease; cytokines; desmosomes; Catenin; Culture; WHO; Human; False positive; Sarcoidosis; myocarditis; Cytokine; Patient; Inflammation; Method; Contrast; Case study; Newborn; Animal; Mutation; Technique; Monocyte chemoattractant protein 1
• ISSN: 1941-3149; 1941-3084
• DOI: 10.1161/CIRCEP.111.964890

BACKGROUND—Immunoreactive signal for the desmosomal protein plakoglobin (γ-catenin) is reduced at cardiac intercalated disks in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC), a highly arrhythmogenic condition caused by mutations in genes encoding desmosomal proteins. Previously, we observed a false-positive case in which plakoglobin signal was reduced in a patient initially believed to have ARVC but who actually had cardiac sarcoidosis. Sarcoidosis can masquerade clinically as ARVC but has not been previously associated with altered desmosomal proteins. METHODS AND RESULTS—We observed marked reduction in immunoreactive signal for plakoglobin at cardiac myocyte junctions in patients with sarcoidosis and giant cell myocarditis, both highly arrhythmogenic forms of myocarditis associated with granulomatous inflammation. In contrast, plakoglobin signal was not depressed in lymphocytic (nongranulomatous) myocarditis. To determine whether cytokines might promote dislocation of plakoglobin from desmosomes, we incubated cultures of neonatal rat ventricular myocytes with selected inflammatory mediators. Brief exposure to low concentrations of interleukin (IL)-17, tumor necrosis factor-α (TNF-α), and IL-6 (cytokines implicated in granulomatous myocarditis) caused translocation of plakoglobin from cell-cell junctions to intracellular sites, whereas other potent cytokines implicated in nongranulomatous myocarditis had no effect, even at much higher concentrations. We also observed myocardial expression of IL-17 and TNF-α and elevated levels of serum inflammatory mediators, including IL-6R, IL-8, monocyte chemoattractant protein 1, and macrophage inflammatory protein 1β, in patients with ARVC (all P<0.0001 compared with controls). CONCLUSIONS—The results suggest novel disease mechanisms involving desmosomal proteins in granulomatous myocarditis and implicate cytokines, perhaps derived in part from the myocardium, in disruption of desmosomal proteins and arrhythmogenesis in ARVC.