The clinicopathology report by Roberts et al of 4 cases of arrhythmogenic right ventricular (RV) cardiomyopathy (ARVC; including 2 previously neglected examples reported by Waller et al in 1980 under the name of “parchment heart syndrome”), has provided the opportunity to summarize the major steps made in the knowledge of the pathobiology and pathophysiology of this rare cardiomyopathy in the past 3 decades. At the time of the publication by Waller et al, as elegantly illustrated by their original illustrations, the disease was still considered a congenital heart defect, consisting of the underdevelopment of portions of both the RV and the left ventricular (LV) walls. Confusion in the published data regarding this entity has been created by the misuse of the term “Uhl’s anomaly.” The latter condition was described as “an almost total absence of the myocardium of the right ventricle” in a 7-month-old infant, with the epicardium applied directly to the endocardium in the absence of intervening fat. This was most probably the substrate of the parchment hearts reviewed in patients aged <5 years listed in the first table in the report by Roberts et al. In contrast, in ARVC, fat and fibrous tissue with residual myocytes is always present between the epicardial and endocardial layers. Additional features in the differential diagnosis include the lack of a family history, heart failure as the clinical picture, the infrequency of arrhythmias, and a significantly earlier age of presentation, usually in childhood, for Uhl’s anomaly. Thus, the distinction made by the authors between those patients aged <5 years and >15 years is likely not arbitrary but reflects 2 different entities. However, it is not clear whether Roberts et al, by republishing reports of these cases, still maintain the view that the parchment heart is a congenital heart disease.

Several etiopathogenetic theories have been put forward, in addition to the maldevelopmental hypothesis (i.e., congenital dysplasia, aplasia, or hypoplasia), such as inflammatory (myocarditis) and that of programmed cell death (apoptosis). However, the most attractive one has been the dystrophic theory (myocardial dystrophy), because the histopathologic features of ARVC are quite similar to those observed in Duchenne’s or Becker’s skeletal muscle dystrophies, which are characterized by progressively acquired muscular atrophy replaced by exuberant fatty and fibrous tissue. The dystrophic theory was supported by the recognition in the late 1980s of the hereditary familial background of ARVC, which eventually led to the identification of the first disease gene in the recessive variant. The recessive variant is characterized by a cardiocutaneous phenotype (Naxos disease). The discovery of the plakoglobin gene opened the door to the identification of additional disease-causing genes in the autosomal dominant variants of ARVC (i.e., desmoplakin, plakophillin-2, desmoglein-2, and desmocollin-2 ). All these genes encode for proteins of the mechanical intercellular junctions, thus explaining why the disease is now considered a disease of the desmosome, just as hypertrophic cardiomyopathy is considered a disease of the sarcomere. Genetic screening of probands affected by ARVC has been able to detect pathogenetic mutations in ≤50% of cases. These major advances have evolved into the current clinical view of ARVC as a genetically determined myocardial disease that is now listed among the cardiomyopathies.

The morphologic features of ARVC have been systematically assessed only from the late 1980s. Since the original description by Thiene et al, who investigated a series of juvenile sudden deaths that occurred in the northeast of Italy and thus recognized that the disease is a major cause of sudden death in the young, the pathologic diagnosis of ARVC (see the series listed in the third table of the report by Roberts et al ) has been traditionally based on gross and histologic evidence of transmural myocardial loss with fibrofatty replacement of the RV free wall, extending from the epicardium toward the endocardium. RV aneurysms, whether single or multiple, located in the so-called triangle of dysplasia (i.e., inflow, apex, and outflow) are considered a pathognomonic feature of ARVC, although not necessarily present in all cases. Hearts with end-stage disease and congestive heart failure have consistently showed a greater prevalence of biventricular involvement, usually with multiple aneurysms and a parchment-like appearance of the free wall.

All these morphologic features refer to the classic ARVC picture, as evidenced by the 4 cases reported by Roberts et al and the “parchment heart” cases in those aged >15 years reviewed by Roberts et al in their Table 1. However, recently, it has been demonstrated that the disease has a pathology phenotypic spectrum much wider than previously thought, with grossly normal hearts at one end, in which only a careful histopathologic investigation can reveal ARVC features in one or both ventricles, and hearts with massive RV with or without LV involvement at the opposite end. Moreover, it has been clarified that ARVC should be kept distinct from pure fatty infiltration of the RV and adipositas cordis, thus emphasizing the need to adopt strict diagnostic criteria, not only in the clinical setting, but also in forensic and general pathology.

That the “transmural fibro-fatty myocardial replacement of the RV free wall” has been always considered in the past the conditio sine qua non for the pathologic diagnosis of ARVC, might explain why several cases with early segmental RV involvement (i.e., not yet full thickness deepening from the epicardium to endocardium) or those with predominant or isolated LV disease, usually without wall thinning and aneurysm formation, escaped diagnosis. This should clarify why the term “parchment heart syndrome” cannot be adopted as a synonym of ARVC but should only be used to address the peculiar subgroup of ARVC, characterized by RV and/or LV free wall thinning with aneurysms. Regardless, the existence of cases with biventricular involvement or predominantly either LV or RV involvement should, as proved in the transgenic animal models of ARVC, suggest the use of the more comprehensive term “arrhythmogenic cardiomyopathy.”

The clinical presentation of the disease is also more complex than previously thought. Since the beginning, ARVC has been recognized as a disease of the myocardium with electrical, more than mechanical, dysfunction. It has been characterized by life-threatening ventricular arrhythmias and the risk of sudden death at any point during the disease course, including as the first manifestation of the disease and, in particular, during effort. In contrast, heart failure has been reported as a clinical feature in only a few cases. The 4 patients reported by Roberts et al all had ventricular arrhythmias and/or sudden death, and the 2 patients who required heart transplantation had previous undergone implantable cardioverter defibrillator placement. However, we must recognize that the wide variability in the reported clinical symptoms and signs has mostly depended on selection bias (i.e., whether the cases were coming from arrhythmias/sudden death or from heart failure/cardiac transplantation referral centers).

Only the prospective long-term evaluation of families of ARVC probands would be able to provide an unbiased clinical and morphologic profile of the disease. The preliminary data have demonstrated that congestive heart failure and overt ventricular arrhythmias represent only the tip of the iceberg and that most mutation carriers are patients with only mild symptoms and signs of the disease, if any.

To increase the diagnostic sensitivity and specificity, in particular of the concealed forms of ARVC, updated diagnostic criteria have recently been proposed by an international task force. New cardiac imaging tools, such as magnetic resonance imaging and electroanatomic mapping, together with cascade genetic screening of family members, could play an additional role in the early diagnosis of ARVC. When treating patients with an ARVC diagnosis, risk stratification remains the main clinical challenge for timely preventive strategies, including not only lifestyle modification, but also drug therapy and implantable cardioverter defibrillator.