Arrhythmogenic right ventricular dysplasia (ARVD), an inherited arrhythmogenic disease of heart muscle that can lead to sudden cardiac death (SCD), has been variously named as arrhythmogenic right ventricular cardiomyopathy (ARVC), arrhythmogenic cardiomyopathy (AC), “left-dominant arrhythmogenic cardiomyopathy” (LDAC), “arrhythmogenic left ventricular dysplasia” (ALVD). The conflicting nomenclature associated with this disease entity is rather unparalleled [1] . After the discovery of the autosomal recessive pattern of transmission in the Greek island of Naxos, the first gene (plakoglobin) associated with the development of ARVD was identified. This was followed by the discovery of multiple other mutations affecting the desmosomal proteins. Defective desmosomal proteins may result in impaired mechanical coupling between individual myocardial cells, leading to myocyte uncoupling especially under conditions that increase myocardial strain [2] . The resulting non-specific inflammatory and fibrotic responses to injury, as well as adipocytosis may be similar to that seen in other forms of myocardial damage. Although it is widely agreed that the morphologic substrate of ARVD/C is the presence of fibro-fatty tissue predominantly involving predominantly involving the right ventricle (Figure 1), its pathogenic mechanisms are yet to be fully elucidated. The plethora of academic discourse about nomenclature of ARVD/C from its discovery to date is hardly reflected in any other disease entity in the medical literature. We discuss herein the rationale of this multiple nosology and its clinical impact. The broader term “arrhythmogenic ventricular dysplasia/cardiomyopathy” (AVD/C) will be used when appropriate to name ARVD, ARVC, AC, LDAC or ALVD.

During a surgical procedure to map and treat ventricular tachycardia (VT) at the Hôpital de La Salpêtrière [3] , arrhythmogenic right ventricular dysplasia was first recognized as a “trouble in development” (dysontogenetic mechanism) by Fontaine’s team (1977 in a book chapter). Fontaine et al. first described VT originating from the right ventricle (RV) rather than the usual scarred regions of the left ventricular (LV) serving as the substrate/ origin for VT. They identified an interesting, but unexpected, low amplitude signals during epicardial ventricular mapping that consistently occurred after the end of each QRS complex on the surface electrocardiogram [3] . Later, a similar signal was also observed as a notch at the end of right precordial QRS complexes (Figure 2), which is now recognised as an epsilon wave [4] . In 1982, the same French team first described the clinical entity of this arrhythmogenic disease of the RV in 24 young patients with resistant VT and preserved LV function [5] . Among these patients, 6 had 2-D echocardiograms confirming enlarged RV dimensions. Since then, compelling data regarding pathological, clinical, diagnostic, phenotype/genotype correlates, and outcomes of this disease entity have been published.

Eleven years after the original report by Fontaine et al., a group of pathologist at Padua reported in the Veneto region, similar right ventricular pathologies in 12 of 49 hearts of young adults who died suddenly, with most death occuring during exertion [6] . They observed a progressive loss of myocardium; lipomatous or fibro-lipomatous replacement; and foci of inflammation, degeneration, and necrosis predominantly in the RV. Because cardiac pathologies were not previously reported in these young adults, the findings described were attributed to an unknown mechanism, and they used the term “right ventricular cardiomyopathy” to describe this disease entity. In 1990, these authors reported 6 competitive athletes presenting with fatal arrhythmias arising from the RV [7] . The term arrhythmogenic right ventricular cardiomyopathy (ARVC) was first used by Nava and his colleagues (an Italian group) in 1992 when they described the clinical profile of a concealed form of this disease entity presenting with apparently idiopathic ventricular arrhythmias [8] . Interestingly, the Italian group first used the term “cardiomyopathy” in January 1988 [6] , and thereafter they reverted to the term “dysplasia” in November 1988 [9] . Both reports included patients from the same disease cohort with fatty and fibro-fatty replacement of RV free wall being the hallmark of the disease.

In 2007, Sen-Chowdhry et al. from a London school introduce the term “arrhythmogenic cardiomyopathy” as they found a left-dominant arrhythmogenic cardiomyopathy (LDAC) where LV involvement may precede the onset of significant right ventricular dysfunction [10] . Importantly, they also demonstrated desmosomal mutations and the presence of fibrosis and fat in LDAC to be similar in proportion as obtained in ARVD/C [11] .

In 2015, Lopez-Ayala et al. proposed the term “arrhythmogenic left ventricular dysplasia” (ALVD) [12] , affirming that contrary to previous knowledge, the left ventricle is involved not only in the later stages, but also to a great extent in the “concealed” course or, as a distinct entity of the same disease.

Whether naming the same disease entity differently by each school is based on scientific evidence will be discussed herein.

Accumulating evidence suggests that gene mutation-related changes or distribution of desmosomal proteins give rise to altered expression and distribution of other intercalated disk proteins, including gap junction [35] and ion channel proteins, resulting in mechanical and electric uncoupling and slow conduction, and conduction block. These factors favor reentry in the early concealed stage of the disease. It is very likely that fibrofatty alteration responsible for altered tissue architecture follows in the later overt stage of the disease. This sequence of changes is strongly supported by identification of altered distribution of the desmosomal protein plakoglobin in histologically-unaffected left ventricular and septal tissue in patients with proven AC [34] . In addition, ventricular fibrillation and sudden death may occur in the early concealed stage of the disease even in the absence of identifiable fibrofatty changes [36] . In contrast, in the overt stage, the modified tissue architecture characterized by interconnecting vital myocardial bundles embedded in fibrotic tissue contributes importantly to further aggravation of activation delay by lengthening of conduction pathways and load mismatch at pivotal points [23] [37] - [39] . This highly arrhythmogenic substrate frequently is the cause of monomorphic ventricular tachycardia with left bundle branch block morphology.

The major metabolic differences between embryonic and adult cardiomyocytes are: 1) embryonic cardiomyocytes use mostly glycolysis for energy production, and 2) adult cardiomyocytes produce most energy via fatty acid oxidation (FAO) but retain capacity to readily switch to glucose or other substrate utilization when fatty acid is not available or FAO is compromised [40] [41] . Therefore, using a specific metabolic milieu, Kim et al. reproduced in vitro, exaggerated lipogenesis and apoptosis in mutant plakoglobin (PKP2) with induced pluripotent stem cells-derived cardiomyocytes (iPSC-CMs), thus revealing crucial pathogenic insights that metabolic derangement in adult-like metabolic milieu underlies ARVD/C pathologies [42] .

Arrhythmogenic ventricular dysplasia/cardiomyopathy (AVD/C) is characterize by the “malfunction” of des- mosomes which are cell-cell adhesion organelles. They are particularly abundant in heart and skin, tissues that normally experience mechanical stress. Patients with this arrhythmogenic ventricular disease often exhibit disease flares in response to stress or exercise, emphasizing the importance of biomechanical determinants of disease [43] . However, the relationship between changes in biomechanical properties of the myocardium produced by desmosomal mutations and heart rhythm abnormalities is poorly characterized. One of most recent and exciting avenue is the discovery of marked subcellular redistribution of plakoglobin, connexion 42, and Nav1.5 without changes in their total cellular content in a zebrafish model of AC [44] . These observations pinpoint aberrant trafficking of intercalated disc proteins as a central mechanism in AC myocyte injury and electrical abnormalities [44] . In general, membrane cellular abnormal trafficking is being recognised as a major arrhythmogenic mechanism of sudden cardiac death [45] .

Inflammation is a major factor in the pathogenesis of lethal arrhythmias in AVD/C. The deleterious effect of an inflammatory process has been originally suspected in 1995 from the study of pathological material of patients who experienced a worsening of AVD/C [46] . The presence of cardiotropic viruses has already been reported [47] , and a link between inflammation and ventricular arrhythmogenesis has been recently observed [48] . Pathologic myocardium displays a particular susceptibility to acute superimposed myocarditis [46] . Indeed, Lopez-Ayala et al. analysed the genetic basis of myocarditis in ARVD and ALVD affected patients and unaffected mutation-carrying relatives. Myocarditis clustered in families bearing certain mutations [12] .

Inhibition of abnormal peroxisome proliferator activated receptor gamma (PPARγ) activation can prevent all AVD/C pathologies, and the elimination of reactive oxygen species can reduce apoptosis of AVD/C cardiomyocytes [42] . Aberrant membrane cell trafficking of intercalated disc proteins is a central mechanism of cardiomyocyte injury and related arrhythmogenesis in AVD/C [44] . These two observations highlights potential new therapeutic targets (pharmacologic or gene therapy) to either prevent or forestall disease progression that can be exploited in future researches [46] .

Since the discovery of the disease in 1977 and its full clinical description in 1988, there are many advances in the understanding of the disease morphology, diagnostic criteria, phenotype/genotype correlates, and risk prediction for its catastrophic complication of SCD. Naming the disease as ARVD, ARVC, AC, LDAC or ALVD did not substantially change our current management approaches. However, the knowledge of early LV involvement with minimal structural changes together with overt arrhythmic manifestations will reinforce our diagnostic decision-making especially in teasing out the protean aetiologies for left ventricular arrhythmias.

AVD/C which is an inherited desmosomal and nondesmosomal pathology affecting both ventricles is characterized by life-threatening arrhythmias and premature death. The diagnosis remains challenging and requires a multifaceted approach for patient evaluation. The multiplicity of nomenclature for the disease entity might be confusing but also shows that our knowledge on the morphology and pathophysiology of this disease is far from being completely elucidated. However, compelling existing data which underlies introduction of new nosologies have advanced our understanding of the pathophysiology and molecular basis of the disease, yielding an avenue for developing new mechanism-based therapies that is yet to be exploited.

AiméBonny,Mohammed A.Talle,GuyFontaine,11, (2015) Arrhythmogenic Ventricular Dysplasia/Cardiomyopathy: Insights from the Rationale of Disease Nomenclature and Clinical Perspectives. World Journal of Cardiovascular Diseases,05,218-226. doi: 10.4236/wjcd.2015.58025