Arrhythmogenic Cardiomyopathy: Etiology, Diagnosis, and Treatment

Imperial College, London, UK.
Annual review of medicine (Impact Factor: 12.93). 02/2010; 61(1):233-53. DOI: 10.1146/
Source: PubMed


Arrhythmogenic right ventricular cardiomyopathy (ARVC) has a prevalence of at least 1 in 1000, is a leading cause of sudden cardiac death in people aged < or =35 years, and accounts for up to 10% of deaths from undiagnosed cardiac disease in the <65 age group. The classic form of the disease has an early predilection for the right ventricle, but recognition of left-dominant and biventricular subtypes has prompted proposal of the broader term arrhythmogenic cardiomyopathy. The clinical profile of the disease bridges the gap between the cardiomyopathies and inherited arrhythmia syndromes. The early "concealed" phase is characterized by propensity toward ventricular tachyarrhythmia in the setting of well-preserved morphology, histology, and ventricular function. As the disease progresses, however, myocyte loss, inflammation, and fibroadiposis become evident. Up to 40% of cases harbor rare variants in genes encoding components of the desmosome, specialized intercellular junctions that confer mechanical strength to cardiac and epithelial tissue, and may also participate in signaling networks. Phenotypic heterogeneity and the nonspecific nature of associated features complicate clinical diagnosis, which requires multipronged cardiovascular investigation rather than a single test. Development of a prospectively validated risk-stratification algorithm for the full disease spectrum remains the foremost clinical challenge.

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    • "Over the years, it has become clear that ARVD/C is not a structural defect present at birth, explaining the original term dysplasia, and that the disease can also be biventricular or even left dominant [3]. The aforementioned cardiac arrhythmias tend to occur in the early, “concealed” phase of the disease, in the absence of the extensive structural damage that characterizes the later phases, and sudden cardiac death is often the first clinical manifestation of the disease [23]. The cardiac arrhythmias are probably related to remodeling of gap junctions and downregulation of the sodium current, which may occur because desmosomes, gap junctions, and the voltage-gated sodium channels form a “triad” of molecules that actually interact with each other [24]. "
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    ABSTRACT: Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an inherited cardiomyopathy associated with cardiac arrhythmias originating in the right ventricle, heart failure, and sudden cardiac death. Development of ARVD/C type 1 has been attributed to differential expression of transforming growth factor beta 3 (TGF β 3). Several mechanisms underlying the molecular basis of ARVD/C type 1 have been proposed. Evaluating previously described mechanisms might elucidate how TGF β 3 contributes to disease progression in ARVD/C type 1. Here we review how TGF β 3 can induce fibrogenesis through Smad and/or β -catenin signaling. Moreover, the role of apoptosis is addressed. Finally the extent to which the immune system has been demonstrated to be a modulating and amplifying agent in the onset and progression of ARVD/C in general is discussed.
    Full-text · Article · Dec 2013
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    • "Screening of desmosomal genes has identified mutations in 40-58 % of patients diagnosed with ARVC, but also in 5 % of patients in a DCM cohort from the United Kingdom [12–15]. The observed clinical and genetic overlap between ARVC and DCM has led to the postulation of arrhythmogenic cardiomyopathy as the encompassing entity [16]. "
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    ABSTRACT: Background Recently, we showed that the c.40_42delAGA (p.Arg14del) mutation in the phospholamban (PLN) gene can be identified in 10–15 % of Dutch patients with dilated cardiomyopathy or arrhythmogenic cardiomyopathy. The arrhythmogenic burden of the p.Arg14del mutation was illustrated by the high rate of appropriate ICD discharges and a positive family history for sudden cardiac death. Methods Our goal was to evaluate the geographical distribution and the origin of this specific mutation in the Netherlands and to get an estimation of the prevalence in a Dutch population cohort. Therefore, we investigated the postal codes of the places of residence of PLN p.Arg14del mutation carriers and places of birth of their ancestors. In addition, a large population-based cohort (PREVEND) was screened for the presence of this mutation. Results By April 2012, we had identified 101 probands carrying the PLN p.Arg14del mutation. A total of 358 family members were also found to carry this mutation, resulting in a total of 459 mutation carriers. The majority of mutation carriers live in the northern part of the Netherlands and analysing their grandparents’ places of birth indicated that the mutation likely originated in the eastern part of the province of Friesland. In the PREVEND cohort we identified six heterozygous PLN p.Arg14del mutation carriers out of 8,267 subjects (0.07 %). Conclusion The p.Arg14del mutation in the PLN gene is the most frequently identified mutation in Dutch cardiomyopathy patients. The mutation that arose 575–825 years ago is likely to have originated from the eastern part of the province of Friesland and is highly prevalent in the general population in the northern part of the Netherlands.
    Full-text · Article · Apr 2013 · Netherlands heart journal: monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation
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    • "These occur mostly in the early “concealed” phase of the disease, in the absence of the extensive structural damage, including the fibro-fatty replacement of the myocardium, that characterizes the later phases. These and other characteristics of ARVC have been reviewed in detail elsewhere (Thiene et al., 2007; Basso et al., 2009, 2012; Sen-Chowdhry et al., 2010; Sen-Chowdhry and McKenna, 2012). The disease does not only occur in humans, but has also been described for cats (Fox et al., 2000; Harvey et al., 2005), dogs (Basso et al., 2004; Oxford et al., 2011), and horses (Freel et al., 2010). "
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    ABSTRACT: Objective: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is associated with remodeling of gap junctions and also, although less well-defined, down-regulation of the fast sodium current. The gap junction remodeling and down-regulation of sodium current have been proposed as contributors to arrhythmogenesis in ARVC by slowing conduction. The objective of the present study was to assess the amount of conduction slowing due to the observed gap junction remodeling and down-regulation of sodium current. Methods: The effects of (changes in) gap junctional conductance, cell dimensions, and sodium current on both longitudinal and transversal conduction velocity were tested by simulating action potential propagation in linear strands of human ventricular cells that were either arranged end-to-end or side-by-side. Results: A 50% reduction in gap junction content, as commonly observed in ARVC, gives rise to an 11% decrease in longitudinal conduction velocity and a 29% decrease in transverse conduction velocity. A down-regulation of the sodium current through a 50% decrease in peak current density as well as a -15 mV shift in steady-state inactivation, as observed in an experimental model of ARVC, decreases conduction velocity in either direction by 32%. In combination, the gap junction remodeling and down-regulation of sodium current result in a 40% decrease in longitudinal conduction velocity and a 52% decrease in transverse conduction velocity. Conclusion: The gap junction remodeling and down-regulation of sodium current do result in conduction slowing, but heterogeneity of gap junction remodeling, in combination with down-regulation of sodium current, rather than gap junction remodeling per se may be a critical factor in arrhythmogenesis in ARVC.
    Preview · Article · May 2012 · Frontiers in Physiology
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