A new test for Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC)

The diagnosis and management of Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) can be problematic – the disease has a highly variable clinical presentation, and cardiac arrhythmias and sudden cardiac death occur frequently. Currently the diagnosis is usually made clinically using criteria that have been defined by an international task force -whilst these are specific they are not very sensitive. Furthermore, the structural changes in ARVC generally spare the sub-endocardium and do not tend to involve the inter-ventricular septum and therefore the pathological features of ARVC may not be identified on conventional endomyocardial biopsy. Additionally, the pathological features are more pronounced in patients with severe disease, but may not be observed in patients with early disease.

Genetic testing offers an alternative method of diagnosis, and mutations in desmosomal proteins including desmoplakin, plakoglobin, plakophilin 2, desmocollin 2 and desmoglein 2 have been identified in approximately 40% of patients with ARVC. The authors of this paper had previously observed that levels of plakoglobin (also known as γ-catenin) were greatly reduced at intercalated disks in patients with rare recessive forms of ARVC. They further studied commoner forms of ARVC related to a variety of desmosomal genes and observed a decreased plakoglobin (a protein which links adhesion molecules at the intercalated disk to the cytoskeleton) signal level. Following this they sought to identify whether a decreased plakoglobin signal-level, identified at the myocardial cell-cell junctions was a sensitive and specific marker of ARVC using immunohistochemical techniques on human myocardial samples.

Myocardial samples from 11 patients with ARVC were tested for desmosomal gene mutations and of these 8 had the mutation. Myocardial autopsy samples from 10 patients with no evidence of clinical or pathological heart disease were used as a control. All ARVC samples but no controls demonstrated a marked reduction in levels of plakoglobin. Other desmosomal proteins showed variable changes but levels of the non-desmosomal adhesion molecule N-cadherin were normal in all patients with ARVC. In order to ascertain whether a decreased plakoglobin level was specific for ARVC, myocardial samples from 15 subjects with either dilated, ischaemic or hypertrophic cardiomyopathy were analysed. In all of these, N-cadherin and plakoglobin levels were indistinguishable from controls. Additionally, blinded immunohistochemical analysis of cardiac biopsy samples from the Johns Hopkins ARVC registry was performed. The correct diagnosis was made in 10/11 subjects with a definite diagnosis of ARVC on clinical criteria. The authors also ruled out ARVC in 10/11 subjects without ARVC, overall sensitivity 91%, specificity 82%, positive predictive value 83%, negative predictive value 90%. The plakoglobin level was diffusely reduced in ARVC samples including in those obtained from the left ventricle and inter-ventricular septum.

The results from this study demonstrate that reduced plakoglobin at intercalated disks is a consistent feature of ARVC and is not seen in other forms of heart muscle disease. It also shows that levels of the non-desmosomal adhesion molecule N-cadherin is normal in patients with ARVC or other forms of heart disease. Further validation studies will be necessary before this new test can be used clinically. In addition, it is also unknown whether all causes of ARVC result in decreased levels of plakoglobin at the intercalated disks – viral infection causing myocarditis has been associated with ARVC in some patients. This would suggest that acquired causes may also lead to the disease. Finally, although in ARVC myocardial degeneration and fibro-fatty replacement occur preferentially in the right ventricle, a diffuse reduction in plakoglobin levels was observed. This might suggest that it is not necessary to biopsy the heart in areas showing structural change to make the diagnosis. Moreover, it could be possible to obtain comparable information from more accessible tissues containing desmosomes such as hair follicles and buccal mucosa

· Asimaki A, Tandri H, Huang H et al. A New Diagnostic Test for Arrhythmogenic Right Ventricular Cardiomyopathy. N Engl J Med 2009;360:1075-84

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