European Heart Journal Advance Access originally published online on February 15, 2007
European Heart Journal 2007 28(5):529-530; doi:10.1093/eurheartj/ehl530
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Arrhythmogenic right ventricular cardiomyopathy: a ‘final common pathway’ that defines clinical phenotype
1 Department of Pediatrics, Section of Pediatric Cardiology, Baylor College of Medicine, Texas Children's Hospital, 6621 Fannin Street, MC 19345-C, Houston, TX 77030, USA
2 Department of Medicine, University of Arizona, Tucson, AZ, USA
* Corresponding author. Tel: +1 832 826 5651; fax: +1 832 825 5921. E-mail address: jtowbin{at}bcm.tmc.edu
This editorial refers to ‘Desmoglein-2 mutations in arrhythmogenic right ventricular cardiomyopathy: a genotype-phenotype characterization of familial disease’
by P. Syrris et al., on page 581
Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a primary heart muscle disease with distinct characteristics. ARVD/C predominantly affects the right ventricle (RV), with RV dilation and thinning due to fibrofatty infiltration of the ventricular myocardium, and ultimately depressed systolic function leading to right heart failure or biventricular failure.1 Early in its clinical course, ARVD/C typically presents with ventricular arrhythmias (usually with a left bundle branch pattern), syncope, or sudden cardiac death.2 Tragically, this clinical scenario commonly occurs in young, healthy, athletic individuals. A set of clinical criteria, known as the ‘Task Force Criteria’, first described by McKenna et al.3 in 1994 and later modified for inclusion of family members,4 utilizes electrical, myocardial and clinical features to clinically diagnose patients with this disorder.3,4
The familial nature of ARVD/C has been recognized for many years but the underlying genetic and mechanistic basis of the disease has only recently come to light. The disease is transmitted with an autosomal dominant trait, although autosomal recessive disease with complex phenotype including associated skin and hair abnormalities is also well described.5 In the majority of cases, penetrance appears to be low, usually well below 50%. In the early 1990s, we proposed that similar clinical phenotypes occur based on disruption in ‘final common pathways’ by direct mutation in genes encoding proteins in a defined pathway or by a cascade of events in which there is secondary disturbance via disruption in binding partners or acquired disruptions (medications, infections, metabolic derangements).6 Over the past decade, many examples supporting this concept have been published; for instance, it is clear that disruption of sarcomere function leads to hypertrophic cardiomyopathy. Similarly, ion channel function abnormalities can cause primary arrhythmic disorders. Dilated cardiomyopathy occurs due to disruption of the sarcolemma and cytoskeletal linkage to the sarcomere. The newest ‘kid on the block’, ARVD/C, is a disease of the desmosome that is responsible for intercellular binding. Six genes have been identified that are associated with ARVD/C including plakophilin-2 (PKP2), desmoplakin (DSP), desmocollin-2 (DSC-2), plakoglobin (JUP), and transforming growth factor beta-3 (TGFB3), as well as desmoglein-2 (DSG2).7
Genotype–phenotype correlations, the ‘holy grail’ of translational ‘bedside-to-bench-to-bedside’ research, have been difficult to achieve in most of the cardiovascular genetic disorders, and ARVD/C is no exception. However, the publication by Syrris et al.,8 provides compelling evidence that mutations in DSG2 display a high degree of penetrance and that LV involvement is prominent. In addition, they demonstrate that the Task Force Criteria and its modification are only fair at identifying family members who carry the genetic basis of ARVD/C, 58 and 75%, respectively. There was an exceedingly low prevalence of classical electrocardiographic findings, only 8% had sustained ventricular arrhythmias, but a family history of sudden death was present or aborted sudden death in 66% of gene carriers.
Among the most intriguing, and possibly the most lasting impact of this work, is the clear demonstration that the left ventricle (LV) is significantly affected and that ARVD/C is not exclusively a disease of the RV. Suggestions that this is the case in ARVD/C have been previously provided in the case of DSP mutations, with both heterozygous and homozygous carriers developing left-sided disease.9 This has also been borne out by animal models of desmosome-encoding gene mutations that cause ARVD/C in humans. Our group recently showed that the mechanism of disease in DSP mutant mice includes disruption of the cell–cell junctions, loss of desmosomes at the intercalated disks, and fibrous replacement associated with lipid infiltration in both the RV and LV of these animals.10 Non-invasive imaging using both echocardiography and cardiac magnetic resonance imaging clearly demonstrated biventricular dilation and systolic dysfunction in these animals. It is likely that mechanical stress placed on the cell–cell junctions over time ultimately leads to classic clinical features, with mechanical stress magnified by the load placed on both the RV and LV during exercise. We predict that animal models with the mutations identified by Syrris et al. would produce a similar phenotype as that found in our DSP model. In addition, we showed that the position of the mutation in DSP determines the clinical features due to disruption of binding partners and the roles played in normal function by those partners. The mutations and the differences in clinical phenotype described in DSG2 in the publication herein are likely due to similar mechanisms.
In summary, the publication by Syrris et al.8 substantially adds to our growing understanding of this paradigm disorder. It supports the notion of ‘final common pathways’ of cardiovascular disease and also places into perspective another important new concept that cardiovascular phenotypes are not simple and do not follow the ‘classic’ descriptions initially outlined but instead are complex and commonly demonstrate ‘overlapping phenotypes’, features of more than one clinical disease. In the case of ARVD/C, the overlap between RV dysfunction, LV dysfunction, and arrhythmias will broaden our view of the clinical profile of this disease. The predominance of LV involvement in some patients affected with this genetic abnormality poses a challenge in differentiating ARVD/C with major LV involvement from idiopathic dilated cardiomyopathy. It is of interest that patient III-4 of family B had markedly impaired LV function with an LVEF of 25%, yet the non-sustained VT was predominantly of RV origin. It is not clear if this is a consistent pattern in patients affected with this chromosomal abnormality. The diagnostic question remains to be answered. In the other genetic forms of ARVD/C, LV involvement is predominantly epicardial. Is this also true for this variant? Is the septum usually not affected as with the other genetic forms?
The presence of LV involvement and the demonstration by Syrris et al. of the less than ideal criteria for the diagnosis of ARVD/C will be addressed in an upcoming meeting to consider modification of the Task Force Criteria. We suggest that differences in clinical phenotypes occur due to disruptions in overlapping and interacting pathways. In the case of ARVD/C, mutations in any of the desmosome-encoding genes will lead to disruption of cell–cell contacts. As the sarcolemma of cells freely interact with these contacts, we speculate that disturbance of membrane-bound ion channels are involved in the generation of arrhythmias and the disturbance of LV function, as predicted by the ‘final common pathway hypothesis’. Perhaps, the name of the disease should be changed to ‘arrhythmogenic desmosomal cardiomyopathy’ to reflect this broader spectrum of the disease. We believe that Syrris et al. has provided excellent insight to the diverse clinical manifestations of ARVD/C.
Conflict of interest: none declared.
Footnotes
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
doi:10.1093/eurheartj/ehl380 
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[Abstract/Free Full Text]
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