Arrhythmogenic right ventricular cardiomyopathy/dysplasia
© Thiene et al; licensee BioMed Central Ltd. 2007
Received: 09 May 2007
Accepted: 14 November 2007
Published: 14 November 2007
Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a heart muscle disease clinically characterized by life-threatening ventricular arrhythmias. Its prevalence has been estimated to vary from 1:2,500 to 1:5,000. ARVC/D is a major cause of sudden death in the young and athletes. The pathology consists of a genetically determined dystrophy of the right ventricular myocardium with fibro-fatty replacement to such an extent that it leads to right ventricular aneurysms. The clinical picture may include: a subclinical phase without symptoms and with ventricular fibrillation being the first presentation; an electrical disorder with palpitations and syncope, due to tachyarrhythmias of right ventricular origin; right ventricular or biventricular pump failure, so severe as to require transplantation. The causative genes encode proteins of mechanical cell junctions (plakoglobin, plakophilin, desmoglein, desmocollin, desmoplakin) and account for intercalated disk remodeling. Familiar occurrence with an autosomal dominant pattern of inheritance and variable penetrance has been proven. Recessive variants associated with palmoplantar keratoderma and woolly hair have been also reported. Clinical diagnosis may be achieved by demonstrating functional and structural alterations of the right ventricle, depolarization and repolarization abnormalities, arrhythmias with the left bundle branch block morphology and fibro-fatty replacement through endomyocardial biopsy. Two dimensional echo, angiography and magnetic resonance are the imaging tools for visualizing structural-functional abnormalities. Electroanatomic mapping is able to detect areas of low voltage corresponding to myocardial atrophy with fibro-fatty replacement. The main differential diagnoses are idiopathic right ventricular outflow tract tachycardia, myocarditis, dialted cardiomyopathy and sarcoidosis. Only palliative therapy is available and consists of antiarrhythmic drugs, catheter ablation and implantable cardioverter defibrillator. Young age, family history of juvenile sudden death, QRS dispersion ≥ 40 ms, T-wave inversion, left ventricular involvement, ventricular tachycardia, syncope and previous cardiac arrest are the major risk factors for adverse prognosis. Preparticipation screening for sport eligibility has been proven to be effective in detecting asymptomatic patients and sport disqualification has been life-saving, substantially declining sudden death in young athletes.
Diseases name and synonyms
Arrhythmogenic right ventricular cardiomyopathy/dysplasia
Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a unique heart muscle disease, clinically characterized by non-ischemic ventricular arrhythmias originating from the right ventricle (RV), at risk of cardiac arrest. It is one of the major causes of sudden death in the young and in the athletes. The pathology consists of progressive dystrophy of the RV myocardium with fibro-fatty replacement.
In the last 25 years, it was possible to identify the disease , to realize its heredo-familiar character  and the risk of sudden death , to report the pathology , to put forward clinical diagnostic criteria , to find therapeutic measures  and, finally, to discover the genetic background .
The prevalence of approximately 1 in 5,000 people has been estimated . The exact prevalence of ARVC/D, however, is unknown and could be higher than the estimated because of the existence of many non-diagnosed or misdiagnosed cases.
In the Veneto Region, Italy, the prevalence of the disease has been estimated to vary from 1:2,000 to 1:5,000 .
The disease was first described by Giovanni Maria Lancisi in 1736, who in his book De Motu Cordis et Aneurysmatibus reported a family with disease recurrence in four generations: the affected members presented with palpitations, heart failure, dilation and aneurysms of the RV and sudden death .
Dalla Volta et al. in 1961 reported a patient with "auricularization" of the RV pressure curve, emphasizing the peculiar hemodynamic picture of this non-ischemic heart muscle disease with RV behaving like an atrium . However, we had to wait until the 80's to find the first clinical and pathologic series of patients with ARVC/D reported by Drs Marcus, Nava and Thiene [1–3].
Marcus et al. in 1982 reported the disease in adults, first emphasizing the origin of arrhythmias from the RV and the histopathological substrate consisting of fibro-fatty replacement of the RV free wall, accounting for epsilon wave and ventricular arrhythmias of RV origin with left bundle branch block (LBBB) morphology .
In 1988, Thiene et al. observed an impressive series of sudden deaths in the young (≤ 35 years), with pathology consisting of ARVC/D, mostly occurring during effort, and all characterized by inverted T-waves in the right precordial leads at electrocardiogram (ECG) and apparently benign ventricular arrhythmias of LBBB morphology . They accounted for 20% of all sudden deaths in the young and for the first time it was acknowledged that ARVC/D is another important cause of sudden death in the young .
Signal averaged ECG proved to be a sensitive tool to detect delay in the electric impulse transmission in the RV myocardium . Improvements in the diagnostic procedures led the proposal of diagnostic criteria, whether major or minor, based upon RV dysfunction or structural alterations at imaging, tissue characterization at biopsy, repolarization or depolarization abnormalities and arrhythmias at the ECG, and family history of sudden death .
The first gene locus (ARVD1) was found by Rampazzo et al. in 1994 at chromosome 14q23 . The pathological profile was described in detail by Basso et al. in 1996, emphasizing the frequent left ventricular (LV) involvement and an inflammatory component .
The first gene defect was discovered in the recessive variant of the disease (identified since 1985) from the Naxos island and consisting of a cardiocutaneous syndrome (ARVC/D, palmoplantar keratosis and woolly hair) . A deletion was detected in the gene encoding plakoglobin, a cell junction protein .
Thereafter, other genes encoding cell junction proteins were found defective in the dominant, classical form of ARVC/D: desmoplakin , plakophilin-2 , desmoglein-2 , desmocollin-2 . These mutations were found to account for intercalated disk remodeling at the ultrastructural level . Other variants of the disease were explained by mutation of the ryanodyne 2 receptor  and transforming growth factor β 3 genes .
The implantable cardioverter defibrillator (ICD) represented a major advance in therapy .
Finally, electroanatomic mapping proved to be a sensitive tool for identifying areas of fibro-fatty replacement with low amplitude electrical activity .
Clinical features and natural history
The onset occurs usually after childhood, with palpitations and/or syncope.
The following clinical pictures of the disease have been observed :
3) RV failure. The progressive loss of the RV myocardium may impair the mechanical function of the RV and account for severe pump failure.
Pathology and pathogenesis
The myocardial atrophy is progressive with time and by no way is present at birth, as seen in Uhl's disease, a congenital heart defect in which the RV myocardium failed to develop during embryonic life . Instead, the myocardial loss is the consequence of cell death occurring after birth, usually during childhood . An apoptotic mechanisms of myocyte death has been proven, either at post-mortem  or in vivo in endomyocardial biopsy specimens .
More than half of the hearts studied at post-mortem disclosed LV involvement, usually limited to the subepicardium of the postero-lateral free wall . The involvement of the ventricular septum is rare, probably because it is not a subepicardial structure. In the most severe cases requiring transplantation, aneurysms may be seen also in the LV .
Histology of the RV myocardium discloses severe atrophy of the myocardium, replaced by fibro-fatty tissue, which should be regarded as an healing phenomenon following myocyte deaths . Fibrous tissue, present in variable amounts, is an essential part of the healing process and plays a fundamental role in the intraventricular conduction delay of the electrical impulse, which is at the basis of onset of the life-threatening arrhythmias.
Death of single or multiple myocytes may be seen at histology, as proof of the acquired nature of myocardial atrophy, and may be associated with inflammatory infiltrates .
Myocardial inflammation may be seen in up to 75% of hearts at autopsy, and probably it plays a role in triggering ventricular tachyarrhythmias . Nobody knows whether inflammation is a reactive phenomenon to cell death, or whether it is the consequence of an infection or immune mechanism. Viruses have been detected in the myocardium of some ARVC/D patients and have been claimed to support an infective etiology of the disease . Others say that the viruses are innocent bystanders or that spontaneous cell degeneration may serve as a milieu favoring viral settlement in the myocardium .
Clinical and differential diagnosis
In vivo diagnosis may be achieved by demonstrating alterations of the RV function and structure, typical depolarization and repolarization abnormalities, arrhythmias of the LBBB morphology, fibro-fatty replacement of the myocardium and existence of a family history.
Criteria for diagnosis of ARVC/D
1. Family history
Familial disease confirmed at necropsy or surgery.
Family history of premature sudden death (<35 years of age) due to suspected ARVC/D.
Family history (clinical diagnosis based on present criteria).
2. ECG depolarization/conduction abnormalities
Epsilon waves or localized prolongation (>110 ms) of QRS complex in right precordial leads (V1-V3).
Late potentials on signal-averaged ECG.
3. ECG repolarization abnormalities
Inverted T waves in right precordial leads (V2 and V3) in people >12 years of age and in absence of right bundle branch block.
Sustained or nonsustained left bundle branch block-type ventricular tachycardia documented on ECG or Holter monitoring or during exercise testing.
Frequent ventricular extrasystoles (>1000/24 h on Holter monitoring).
5. Global or regional dysfunction and structural alterations*
Severe dilatation and reduction of RV ejection fraction with no or mild LV involvement.
Localized RV aneurysms (akinetic or dyskinetic areas with diastolic bulgings). Severe segmental dilatation of RV.
Mild global RV dilatation or ejection fraction reduction with normal LV.
Mild segmental dilatation of RV.
Regional RV hypokinesia.
6. Tissue characteristics of walls
Fibro-fatty replacement of myocardium on endomyocardial biopsy.
Morphologic changes accounting for global and/or regional dysfunction are detectable by echocardiography, angiography, cardiac magnetic resonance imaging (MRI), or radionuclide scintigraphy. Major criteria consist of severe dilatation and reduction in systolic function of the RV with no (or only mild) impairment of the LV; localized RV aneurysms (akinesia or diskinetic areas with diastolic bulgings); and severe segmental dilatation of the RV. Minor criteria are mild global RV dilatation and/or reduction in ejection fraction with normal LV, mild segmental dilatation of the RV free wall and regional RV hypokinesia.
Radionuclide angiography is also an accurate non-invasive imaging technique for detection of global RV dysfunction and regional wall motion abnormalities. Its diagnostic concordance with RV angiography is nearly 90% .
Tissue characterization of the RV free wall with fibro-fatty replacement of the myocardium, as demonstrated on endomyocardial biopsy (Fig. 8) or surgical resection, is considered a major criterion.
In contrast, repolarization abnormalities consisting of inverted T-waves in right precordial leads (V2 and V3) in the absence of RBBB, in individuals older than 12 years of age, are considered a minor criterion (Fig. 2).
As far as depolarization/conduction abnormalities, epsilon wave or localized prolongation of the QRS complex >110 ms in V1-V3 is a major criterion, whereas the presence of late potentials on signal averaged ECG has to be considered minor (Fig. 5).
Also arrhythmias, like sustained or non-sustained VT with LBBB morphology (Fig. 6), on basal ECG, Holter or exercise testing and frequent premature ventricular beats, >1000 over 24 hour Holter monitoring, are considered minor.
Finally, family history is a major criterion when familial disease is confirmed at necropsy or surgery, whereas it is minor in case of family history of premature sudden death (<35 years) or a family history of clinical diagnosis based on the present criteria.
Proposed modification of Task Force criteria for the diagnosis of familial ARVC/D
ARVC/D in First-Degree Relative Plus One of the Following:
T-wave inversion in right precordial leads (V2 and V3)
Late potentials seen on signal-averaged ECG
LBBB type VT on ECG, Holter monitoring or during exercise testing
Extrasystoles >200 over a 24-h period*
4. Structural or functional abnormality of the RV
Mild global RV dilatation and/or EF reduction with normal LV
Mild segmental dilatation of the RV
Regional RV hypokinesia
Of course, mutational analysis will help to establish with certainty who are the gene carriers, although asymptomatic. However, since these patients may not have the phenotypic expression of the disease, the Task Force criteria are critical to this assessment.
ARVC/D is heredo-familial in nearly 50% of cases, thus the ongoing myocardial atrophy may be genetically determined. The classical form is an autosomal dominant disease with variable penetrance [2, 11]. In the 90's, gene loci have been mapped to various chromosomes, the first (ARVD1) by Rampazzo et al. to chromosome 14q23 . The candidate genes were first searched for in those coding cytoskeleton or sarcomeric proteins, however ARVC/D revealed to be neither a cytoskeleton disease, like dilated cardiomyopathy, nor a sarcomeric disease, like hypertrophic cardiomyopathy. The key for interpretation came from a recessive form of ARVC/D, the so-called Naxos disease, a cardiocutaneous syndrome featured by palmoplantar keratosis, woolly hair and heart muscle disease [25, 62]. Noteworthy, epidermic cells and myocytes share similar mechanical junctional apparatus, i.e. desmosomes and fascia adherens, which provides continuous cell-to-cell connection. This explains why genes coding proteins of the intercellular junction became candidate genes. Intercalated discs contain three types of cell-cell connection: gap junction (or nexus), adherens junction, and desmosome. Gap junctions mediate ion transfer between cells and each gap junction channel is a composite of two hemi-channels, or connexons, located within the cytoplasmic membrane of adjacent cells. The connexon, in turn, is formed by an assembly of six connexin subunits, of which connexin 43 (Cx 43) is the principal subtype in the human heart, but also connexins 40 and 45 are expressed at lower levels.
Synchronous contraction requires transmission of force between cells, which is accomplished via adheren junctions. The transmembrane component of an adherens junction, which establishes intercellular contact, is a cadherin, i.e. Ca2+-dependent glycoprotein. N-cadherin is the predominant isoform expressed in the human heart. Attached to the cytoplasmic tail of N-cadherin are β-catenin and plakoglobin (γ-catenin), both of which bind to α-catenin, which in turn, interacts directly with actin filaments within the sarcomere.
The genes encoding the desmosomal cadherins are clustered on chromosome 18q12.1 and four desmogleins (DSG1-4) and three desmocollins (DSC1-3) are recognized. The desmosomal cadherins comprise the transmembrane component of the desmosomal complex. Their extracellular domains interface directly with their counterparts on neighboring cells. Besides their role in cell adhesion, the desmosomal cadherins may function as regulators of morphogenesis. The intracellular portions of the desmosomal cadherins interact with proteins of the armadillo family, i.e. plakoglobin and plakophilin. Noteworthy, plakoglobin is also found in adhering junctions together with its homologue β-catenin. β-catenin, conversely, is not a constituent of desmosomes as it binds specifically to the classical cadherins. However, β-catenin has an additional nonadhesive function as a regulator of transcription, and a similar role has been postulated for plakoglobin. The plakophilins are found in the nucleus as well as the desmosome, although their function therein remains speculative. Binding sites for both plakoglobin and plakophilin are situated in the N-terminal domain of desmoplakin. At its C-terminal, desmoplakin anchors desmin intermediate filaments to the cardiomocyte surface .
Genes involved in ARVC
Mode of transmission
Author, year [References]
McKoy et al., 2000 
Cardiac Ryanodine receptor
Tiso et al., 2001 
Rampazzo et al., 2002 
Gerull et al., 2004 
Transforming Growth Factor Beta-3
Beffagna et al., 2004 
Pilichou et al., 2006 
Syrris et al., 2006 
Cell junction protein mutations may account for a final common pathway, namely disruption of intercellular junction, myocyte death and structural changes, which are the substrate of life-threatening ventricular arrhythmias .
A recessive mutation of desmoplakin has been proven to explain another cardiocutaneous syndrome, i.e. Carvajal disease , characterized by keratoderma, woolly hair and a biventricular form of ARVC/D , with distinct ultrastructural abnormalities of intercalated discs and decreased immunoreactive signals for desmoplakin, plakoglobin and Cx 43.
Moreover, remodeling of intercalated disc may lead to widening of myocyte gap junction, which may also contribute to the arrhythmogenicity of the disease and enhance the risk of sudden death .
Two other gene defects have been reported to explain the disease so far. One is the gene encoding for the cardiac ryanodine receptor 2, which is located in the smooth sarcoplasmic reticulum and mediates calcium release for electroanatomical coupling (ARVD2 with polymorphic ventricular arrhythmias) . Similar mutations have been shown to account for cathecolaminergic VT, a peculiar malignant arrhythmic disease in normal hearts . Mild pathologic substrates have been described in ARVD2 , but clearly this disease is different from the classical form of ARVC/D and most probably we are dealing with the same nosographic entity as cathecolaminergic VT.
Another form of ARVC/D was found to be associated with regulatory mutations in the TGFβ gene . The gene defect may account for increased propensity for extracellular matrix production and adipogenesis. However, the report has been anedoctical and needs to be confirmed.
Risk stratification and therapy
Young age, "malignant" family history, QRS dispersion ≥ 40 ms, T-wave inversion beyond V1, LV involvement, VT, syncope or previous cardiac arrest are considered the major determinants for adverse prognosis and impending sudden death .
In refractory congestive heart failure, cardiac transplantation is the only therapeutic option .
In asymptomatic patients without a family history and a mild form of ARVC/D, β-blockers are recommended with follow-up control. If the form of ARVC/D is severe, electrophysiology-intracavitary testing is recommended. If negative, β-blockers and serial follow-up should be undertaken. If positive, ICD should be considered, as well as β-blockers and other antiarrhythmic drugs.
In the absence of symptoms and a family history, it is controversial whether electrophysiologic testing should be carried out even in patients at low risk. Finally, it should be underlined that, at present, no curative therapy has been postulated and clearly the aforementioned treatments are palliative. Gene therapy is still far from being established  and no treatment to limit disease progression has been conceived so far. Some drug interventions targeting the cascade of events leading to apoptosis and cell death, such as anticaspase agents, might be hypothesized. Corticosteroid treatment may be considered for myocardial inflammation, which is so frequently observed and probably aggravates the arrhythmogenicity: it is a hypothesis that needs to be investigated.
Prevention of sudden death
ICD aims to convert ventricular flutter/fibrillation into sinus rhythm for resuscitation from cardiac arrest. The device may be implanted in selected patients at risk or may be external, used on the spot in case of sudden cardiac arrest occurring in public sites, like sports courts, airports, schools, etc. The availability of this tool even at home for families at risk, should be considered, provided it is accompanied by a life-support training.
Drug therapy and ablation plays a fundamental role in the arrhythmic mechanism to prevent onset of life-threatening arrhythmias. The efficacy is, however, limited and the recurrence of arrhythmias quite high.
A different life style may be safe "per se", regardless of the need of antiarrhythmic/ablation therapy or ICD. These are palliative, empiric treatments.
Curative therapy of the disease, the radical form of prevention of sudden death, may be accomplished in various ways:
a) Heart replacement, in case of refractory congestive heart failure and/or arrhythmias, with cardiac transplantation.
b) Some therapy to prevent myocyte death and inflammation, to block onset and progression of the disease at the pathobiological level. Nothing is available so far and transgenic animal models are ideal to investigate the pathogenesis of the diseases and to figure out curative therapies [40, 41].
c) Repair of the defective genes at somatic level (gene therapy), a controversial and yet inconclusive approach.
d) Genetic counseling and birth control.
It must be underscored that the phenotypic expression of the gene defect, with the exception of cardiocutaneous syndromes, is only at the cardiac level and nowadays a series of effective measures are available to ensure normal life, with very low risk of premature death in affected patients.
This work has been supported by the European Commission – 5th Framework Program ARVC/D Contract QLG1-CT-2000-01091
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