Author + information
- †Sarver Heart Center, University of Arizona Health Sciences Hospital, Tucson, Arizona
- ‡Cardiovascular Institute, University of Colorado Anschutz Medical Campus, Aurora, Colorado
- ↵∗Reprint requests and correspondence:
Dr. Frank I. Marcus, The University of Arizona, Sarver Heart, 1501 North Campbell, Tucson, Arizona 85724-5037.
- arrhythmogenic right ventricular dysplasia/cardiomyopathy
- magnetic resonance imaging
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is being recognized with increasing frequency as physicians have become more aware of this entity. Some estimate that ARVC may be present in 1 in 5,000 people. The disease is primarily caused by an autosomal dominant genetic defect. Therefore, a person with ARVC has a 50% chance of transmitting this disease to his or her offspring, which can cause marked anxiety because it is well known that ARVC can cause arrhythmic death. However, it is also clear that there is no close relation between an individual who has the genetic abnormality and the clinical manifestations of the disease. This is known as a lack of association of genotype with the phenotypic expression of the disease.
The obvious question that arises when a patient is diagnosed with ARVC is whether the first-degree relatives should have genetic testing for the genes responsible for ARVC. Of the 11 genes currently described in ARVC, the majority of cases are caused by mutations in 5 desmosomal genes. Desmosomes are specialized intercellular junctions that provide myocyte-to-myocyte adhesion. Also, the question arises as to the age at which a clinical evaluation should be conducted in relatives and how the information gained from a genetic and clinical evaluation should be used.
It is now known that 30% to 50% of patients with ARVC have mutations in at least 1 of the genes responsible for the disease. The remainder of patients with ARVC have undiscovered genetic abnormalities or have the disease de novo. If a pathogenic mutation is found in the affected individual (proband), genetic testing is indicated in first-degree relatives. However, if the proband does not have a pathological ARVC gene mutation, genetic testing in the related family members is not indicated, because the identification of a rare variant will have unknown significance. Thus, the genetics of this disease are complex, and consultation with a genetic counselor can be most helpful.
Another important question is at what age family members of a proband who has a pathological gene and is suspected of having the disease should be evaluated. Genetic testing can be performed at any age; however, clinical evaluation should be guided by the consistent observation that sudden cardiac death (SCD) caused by ARVC is extremely rare at <10 years of age. In a recently published study of the causes of SCD in children (1), there was a single 10-year-old child who had ARVC and SCD. No deaths occurred below the age of 10 years. There were 7 others with ARVC who died between the ages of 14 and 19 years. This information was based on a study conducted in Ontario, Canada, during a 5-year period from 2005 to 2009 that involved individuals 1 to 19 years of age and included 116 cases of adjudicated SCD. Because electrical abnormalities such as premature ventricular beats occur before structural abnormalities in the right or left ventricle, it is of questionable value to attempt to assess morphological abnormalities in family members by magnetic resonance imaging before 10 years of age. Knowledge of the relation of the structural and electrical abnormalities of the disease and the rate of progression of these abnormalities in ARVC would assist in determining at what age and how frequently a practitioner should repeat evaluation of electrical and structural abnormalities of family members with ARVC who do not meet the 2010 modified Task Force Criteria (TFC) at baseline.
The study by te Riele et al. (2) in this issue of the Journal addresses this question. They analyzed the data of 37 relatives who had complete baseline evaluation and follow-up evaluation with a mean of 4.1 ± 2.3 years. These 37 family members had a risk of developing ARVC. Of these, 28 (76%) were mutation carriers but did not meet TFC. Over this duration of time, electrical progression by electrocardiographic Holter monitoring or signal-averaged electrocardiography occurred in 27%, whereas structural progression was found in only 1 of the 37 patients. This finding has clinical relevance, because it is well documented that structural lesions of the right ventricle by imaging are subject to considerable error and must be interpreted with caution. Misinterpretation of structural abnormalities by magnetic resonance imaging has been noted to be common (3), and a false interpretation of the right ventricle as enlarged may cause anxiety and could lead to unwarranted insertion of an implantable cardioverter-defibrillator (ICD).
In the report by te Riele et al. (2), 8 of the 43 family members with definite criteria for ARVC at the first evaluation had an arrhythmic event during 3.2 ± 2.4 years of follow-up; however, none of the subjects who did not meet modified TFC at first evaluation developed sustained ventricular arrhythmias. These data suggest that family members who do not meet the 2010 TFC for the diagnosis of ARVC have an excellent prognosis over a 4-year period and are unlikely to have structural progression during this time. An important contribution of the paper by te Riele et al. (2) is that evaluation of family members who do not meet the TFC should be focused on electrical abnormalities and not on structural changes; however, those family members who meet the TFC should be observed closely for electrical progression. It is not clear how best to treat arrhythmic events in these patients to prevent recurrent ventricular arrhythmias or SCD—whether by antiarrhythmic drugs or ICD insertion. ICDs are associated with significant device or lead malfunction. Another treatment option that is being evaluated is the use of both endocardial and epicardial ablation to eliminate ventricular arrhythmias.
In this study (2), the investigators did not use the criteria of Hamid et al. (4) to classify the disease status in first-degree family members, although the data using the Hamid et al. criteria to classify family members are shown in Online Tables 3 and 4. These criteria take into account the higher probability of having ARVC in relatives than in the general population and provide higher sensitivity in detecting the disease.
Despite this limitation and the need for further investigation, the paper by te Riele et al. (2) provides important insights for the clinical practitioner, indicating that the evaluation of disease progression in family members who do not meet the TFC for ARVC should focus on evaluation of the electrical aspects of ARVC with simple and available methods (electrocardiography, Holter monitoring) rather than with costly and often unreliable information from cardiac magnetic resonance imaging.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
This paper was funded in part by a grant from the National Institutes of Healthhttp://dx.doi.org/10.13039/100000002 (NIH 1R01HL116906-01A1). Both authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- American College of Cardiology Foundation