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It is known that immunoreactive signal for the desmosomal protein plakoglobin is reduced at cardiac intercalated disks in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC), which seems to be a constant finding regardless the mutated desmosomal gene. Furthermore, this reduction in plakoglobin signal affects broadly all myocardium, from fibro-fatty infiltrated areas to apparently healthy myocardium at both right and left ventricle. After Prof. Saffitz´s group presented the results of this important finding in 2009, a number of samples were studied and the technique became an interesting tool for a disease with not always easy diagnosis. The sensitivity of the test in this first series was up to 91% for ARVC. The specificity, positive and negative predictive value were 82%, 83% and 90% respectively. In that paper, plaklogobin signal was tested in a cohort of 15 patients that had undergone cardiac transplantation. The study comprised samples from patients with hypertrophic cardiomyopathy, dilated cardiomyopathy and ischemic cardiomyopathy (5 patients were included in each category). In all cases plakogobin signal was preserved.
In this recent collaborative paper from Asimaki, Saffitz and collaborators, the plakoglobin signal from two groups of patients with the diagnosis of myocarditis (granulomatous and lymphocytic) were compared to an ARVC cohort. The study started after the incidental finding of reduced plakoglobin signal in a patient with sarcoidosis who initially was thought to have ARVC. This led to collection of cases from 10 centres from USA, UK and Italy (18 ARVC, 26 sarcoidosis, 16 giant cell myocarditis, 25 lymphocytic myocarditis and 28 control group). Plakogolobin signal, Cx43, and subsequently inflammatory markers in tissue and sera were evaluated.
The authors observed a 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. This is the first study to report desmosomal disruption in sarcoidosis and giant cell myocarditis. Connexin43 signal was reduced in half of the granulomatous myocarditis samples.
This common feature of ARVC and granulomatous myocarditis led to the investigation of disease mechanisms. To determine whether cytokines might promote dislocation of plakoglobin from desmosomes, authors incubated cultures of neonatal rat ventricular myocytes with selected inflammatory mediators. Brief exposure to low concentrations of interleukin (IL)-17, tumor necrosis factor-a (TNF-a), 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.
Investigation on the samples from patients with ARVC demonstrated myocardial expression of IL-17 and TNF-a and elevated levels of serum inflammatory mediators, including IL-6R, IL-8, monocyte chemoattractant protein 1, and macrophage inflammatory protein 1b, compared with controls (all p<0.0001).
Authors concluded that the results suggest novel disease mechanisms involving desmosomal proteins in granulomatous myocarditis and implicate cytokines in disruption of desmosome and arrhythmogenesis in ARVC.
The paper includes robust and extensive information to support the association between inflammatory markers in the pathogenesis of ARVC. Future studies will elucidate the role of inflammation in disease progression and prognosis in ARVC. The study opens a new way to the investigation of future therapeutic targets.
From this paper we know that immunoreactive plakoglobin signal is constantly depressed not only in ARVC but also in apparently normal myocardium from patients with diagnosis of sarcoidosis (17/19, 89%) and giant cell myocarditis (14/16, 87%), but not in the lymphocytic myocarditis samples (3/25, 12%). This finding can be of enormous value in the clinical scenario when differentiating types of myocarditis with different therapeutic approach and prognosis, in which a significant number of biopsies are required to increase the likelihood of identification of the granuloma.
Presented by: Dr Jose María López-Ayala and Dr Juan Gimeno, Department of Cardiology, Hospital Universitario Virgen Arrixaca, Murcia, Spain.
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