Author + information
- Thomas Wichter, MD, FESC* ( and )
- Günter Breithardt, MD, FESC, FACC
- ↵*Reprint requests and correspondence to:
Priv.-Doz. Dr. med. Thomas Wichter, Medizinische Klinik und Poliklinik C, Universitätsklinikum Münster, D-48129 Münster, Germany
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a frequent cause of ventricular tachycardia (VT) and sudden death in apparently healthy adolescents and young adults. In this issue of the Journal, Hodgkinson et al. (1) report on the role of implantable cardioverter-defibrillators (ICDs) in an autosomal form of familial ARVC in which a 3p25 deoxyribonucleic acid haplotype (ARVD5) segregates with disease. Despite substantial efforts and extensive analyses in large families from Newfoundland, the responsible gene and gene product have not yet been identified so far (2). The authors studied 11 families and stratified 367 subjects to high-risk (n = 197), low-risk (n = 92), and indeterminate-risk (n = 78) groups. They compared the mortality in 48 high-risk subjects after ICD implantation with that in a matched historical control group of 58 high-risk subjects who were alive at the same age at which the ICD subjects received the device. In this high-risk group of subjects with ARVD5, male patients were at a significantly greater risk of death when compared with females (odds ratio 5.1). The five-year mortality rate for males with an ICD was 0% compared with 28% in matched controls. In the same five-year period, ICD therapies for any VT occurred in 70% and for VT >240 beats/min (potentially life-threatening) in 30% of patients, irrespective of the indication for ICD implantation (primary or secondary prevention). The authors conclude that the unknown mutation at the ARVD5 locus on chromosome 3p25 results in high mortality and that ICD therapy guided by risk stratification, including genetic haplotyping, results in a significant improvement of survival in male patients of this ARVC population (1).
Efficacy of ICD therapy in patients with ARVC
In the present study by Hodgkinson et al. (1), the 78% appropriate ICD discharge rate during follow-up is remarkably similar to that reported in previous studies. Table 1summarizes the main results of initial preliminary reports (3–5) and recent studies in larger patient populations (1,6–8) with ARVC after implantation of an ICD system. However, when compared with the study by Wichter et al. (7), the follow-up period after ICD implantation is much shorter (mean 80 vs. 31 months), thus explaining the differences in the rates of overall mortality and complications.
A unique and first-time feature of the present study is the comparison of an ICD-treated group of patients with a matched historical control group of similar risk profile within a genetically homogeneous ARVD5 population. Despite this advantage, there are several limitations to the study concept, which were addressed by the authors. Apart from a possible selection bias in the ICD group and the retrospective analysis of clinical data in the historical control group, the median follow-up periods in ICD patients and control subjects differed significantly in male (2.6 vs. 9.5 years) and female (0.7 vs. 28.8 years) patients, thus questioning some of the conclusions drawn from the follow-up analyses in the present study.
However, the reported 28% five-year total mortality reduction in male patients with an ICD compared with familial controls has excellent correlation with the estimated benefit of ICD therapy on survival reported in previous studies (5–7). Furthermore, the time to first ICD discharge for VT >240 beats/min was similar to the time of death in the control group. Therefore, the results from the present study confirm the concept of “hypothetical death,” which calculates the benefit of ICD therapy on survival by the difference between total mortality and the occurrence of potentially lethal VT >240 beats/min, terminated by the ICD (7). In contrast to the findings in males, the results for women were not statistically significant, thus supporting the clinical observation that disease expression and long-term prognosis in ARVC is less malignant in women.
Compared with previous series, most patients (73%) in the study by Hodgkinson et al. (1) received the ICD for primary prevention of sudden death. The decision for ICD implantation was made on the basis of clinical risk stratification and genetic haplotyping. Interestingly, the results indicate that the high rate of appropriate ICD discharges for VT is independent of the indication for ICD implantation (primary or secondary prevention), thus supporting previous preliminary information (6,8) on the potential benefit of ICD implantation for primary prevention of sudden death in ARVC patients considered to be at high risk. However, in the general ARVC population, the criteria for optimal selection of patients who benefit from ICD implantation for primary prevention remain to be defined.
Genetic background of ARVC
Approximately 30% to 50% of index patients with ARVC have a familial background indicating a genetic origin of the disease. However, because of incomplete diagnostic and genetic work-up of family members, the proportion of familial cases of ARVC is probably underestimated.
In the autosomal-recessive Naxos disease, a syndromic form of ARVC with palmoplantar keratoderma and woolly hair, mutations in the JUPgene on chromosome 17q21, encoding the desmosomal protein plakoglobin, were identified. In the more frequent nonsyndromic autosomal-dominant forms of ARVC, disease-causing mutations have been identified in only three of nine chromosomal loci detected (9,10). In ARVD2, mutations in the RYR2gene on chromosome 1q42-43, encoding for the human cardiac ryanodine receptor (calcium release channel protein), were reported in the Veneto region of Italy. In ARVC8, mutations in the DSPgene on chromosome 6p24, encoding for the desmosomal protein desmoplakin, were identified. Very recently, mutations in the PKP2gene on chromosome 12p11 (ARVC9) encoding for the desmosomal armrepeat protein plakophilin-2 were identified (10).
According to these findings, familial ARVC currently is considered a disease of the desmosome, whereas familial hypertrophic cardiomyopathy is regarded a disease of the sarcomere, and familial dilative cardiomyopathy is considered a disease of the cytoskeleton.
Genotype-phenotype correlations in patients with ARVC
Familial ARVC is a genetically heterogeneous disorder with incomplete penetrance and variable phenotypic expression. This variable expression results in significant difficulties in the correct phenotyping of family members of index patients. Given the sometimes subtle and borderline clinical findings in early stages or mild forms of the disease, these diagnostic limitations have hampered the identification of chromosomal loci and affected genes by methods using linkage analysis and the candidate gene approach. As a result, the number of genotyped subjects with ARVC reported in previous studies is very small.
However, it has become clear that in familial ARVC, there is not only genetic (within chromosomal loci) but also allelic (within affected genes) heterogeneity. Gerull et al. (10) recently reported 25 different heterozygous mutations (mostly stop signals) in the PKP2gene on chromosome 12p11 (ARVD9) in 32 of 120 (27%) unrelated index patients with ARVC. The gene encodes plakophilin-2, an essential armrepeat protein of the cardiac desmosome. The authors found a significant variability in disease penetrance and phenotypic expression, indicating that not only different genes and gene products (proteins) but also different mutations within an affected gene may be important. Moreover, even within families, in which all affected members carry the same genetic mutation, the clinical manifestation, disease expression, and long-term prognosis may differ significantly, thus emphasizing the role of confounding environmental factors and gene-gene interrelations (modifier genes). This results in a complex genetic situation similar to hypertrophic cardiomyopathy, in which many of the mutations are private, thus only present in a given family.
For these reasons, the findings of Hodgkinson et al. (1) in an apparently genetically homogeneous population haplotyped to ARVD5 may not be transferable to the overall ARVC population with different genetic backgrounds (between or within genetic loci). In addition, because the gene responsible for ARVD5 has not yet been identified, the extent and the consequences of genetic heterogeneity within the 11 families reported in the present study remain unknown.
Therefore, the clinical usefulness of genetic screening in ARVC for the purpose of risk stratification, assessment of prognosis, and clinical decision making, also with regard to ICD implantation, remains questionable. At the present time, apart from the insights to disease mechanisms and pathophysiology, the main advantage of genotyping patients with ARVC is the potential to identify genetically affected relatives of a diagnosed index patient at a subclinical and/or asymptomatic stage. An early identification of asymptomatic mutation carriers would offer the opportunity to provide more detailed recommendations with regard to family planning and diagnostic as well as therapeutic management during long-term follow-up.
In the future, a more detailed knowledge and understanding of genotype-phenotype relationships in large populations of patients with ARVC may ultimately result in the development of genotype-specific treatment strategies (or even gene therapy), based either on the pathophysiologic background or on the prognostic implications of the underlying genetic mutation. Initial steps toward such a goal have been reported in the long QT syndrome and other diseases. In ARVC, however, there is still a long way to go.
This work was supported by grants from the European Commission (QLG-CT-2000-01091), Brussels, Belgium, and the Deutsche Forschungsgemeinschaft (SFB 556, project C4), Bonn, Germany.
↵* Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
- American College of Cardiology Foundation
- ↵Hodgkinson KA, Parfrey PS, Bassett AS, et al. The impact of implantable cardioverter-defibrillator therapy on survival in autosomal-dominant arrhythmogenic right ventricular cardiomyopathy (ARVD5). J Am Coll Cardiol 2005;45:400–8.
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