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Arrhythmogenic right ventricular cardiomyopathy: an overview and update.

Introduction

Arrhythmogenic right ventricular cardiomyopathy is a rare primary myocardial disease that is clinically characterized by life-threatening ventricular arrhythmias secondary to fibrofatty replacement of the right ventricular myocardium.

Although genetic factor plays a major role in disease determinism, the modifications are not manifested at birth.

The term "arrhythmogenic right ventricular cardiomyopathy" (ARVC) is mostly agreed, replacing the previous name of "arrhythmogenic right ventricular dysplasia" (ARVD), still in use. A special mention should be made regarding the possibility of process extension from the right ventricle to the interventricular septum or even to the left ventricle [1].

The current term of "arrhythmogenic right ventricular cardiomyopathy" is more appropriate than ARVD, considering that the disease is not manifested at birth but its onset is later, during adult life.

History

In 1905, Osler described a particular lesion characterized by thin ventricles ("parchmentlike"), as a necroptic finding in a young man, apparently healthy, deceased following a medium intensity physical activity [2].

In 1952, similar gross finding of the right ventricle was observed in a congenital disease named Uhl's anomaly [3].

In 1977, the term "arrhythmogenic right ventricular dysplasia" was introduced, being based on an abnormal development of the ventricular wall, similar to that seen in Uhl's anomaly [4, 5].

In 1986, Protonotarios Nikos, a cardiologist, reported a familial cardiac disease associated with a cutaneous syndrome [6], being named according to the Greek island of origin (Naxos disease) and later on another syndrome has been described, as Carvajal syndrome [7], both having a recessive transmission in descendants.

The term of "dysplasia" has been replaced by the designation of "cardiomyopathy" and the main diagnosis features have been set [8], as the task force criteria, with later modifications [9].

Brief update on myocardial fibers desmosomes

The myocardial cells are disposed in columns, being kept together by specialized junctions, named intercalated discs. These junctions comprise cell-to-cell adhesion junctions composed of fascia adherens, gap junctions, and maculae adherentes (desmosomes). Desmosomes reinforce the fascia adherens and are parts of both transverse and lateral components of the intercalated discs [10].

The desmosomes mediate direct cell-to-cell contact by providing anchoring sites for intermediate filaments, being necessary for electrical conduction, mechanical contraction [11], participating also in tissue morphogenesis and differentiation [12]. In the area of the macula adherens, desmogleins and desmocollins provide the linkage between the plasma membranes of adjacent cells.

Electron microscopy reveals on the cytoplasmic side of the plasma membrane of each of the adjoining cells a disc-shaped structure consisting of very dense material called the desmosomal attachment plaque. This structure measures about 400 nm x 250 nm x 10 nm and anchors intermediate filaments [13]. The filaments appear to loop through the attachment plaques and extend back out into the cytoplasm. They are thought to play a role in dissipating physical forces throughout the cell, by their attachment to the intermediate filaments. In myocardial fibers, each attachment plaque is composed of five constitutive proteins, junctional plakoglobin, plakophilin-2, desmoplakin, desmoglein-2, and desmocollin-2. Their encoding genes have been identified (Table 1) [11].

The intercellular space of the macula adherens is up to 30 nm and is occupied by a dense medial band, the intermediate line. This line represents extracellular portions of the transmembrane glycoproteins, the desmogleins and desmocollins, which are members of the cadherin family of [Ca.sup.2+]-dependent cell adhesion molecules. In the presence of [Ca.sup.2+], extracellular portions of desmogleins and desmocollins bind adjacent identical molecules of neighboring cells (homotypic binding), forming a "cadherin zipper", identified in X-ray crystallographic studies. The cytoplasmic portions of desmogleins and desmocollins are integral components of the desmosomal attachment plaque. They interact with plakoglobin, desmoplakin, and plakophilin that are involved in desmosome assembly and the anchoring of intermediate filaments of desmin [10].

Etiology and epidemiology

ARVC consists in partial or total progressive replacement of cardiac muscle fibers with a fibro-adipose tissue, beginning from the epicardial surface towards the endocardium. In the advanced stages of the disease, the right ventricular wall becomes extremely thin, with endocardium-epicardium apposition [12].

ARVC prevalence in general population is variable, with ranges from 1: 2 000 to 1: 5 000, with a special mention that some of these values may be even larger [13]. ARVC represents 2-5% of cases of young people sudden death, in Europe [14, 15].

According to the results of a retrospective study performed on 200 persons with sudden death, the cause has been microscopically detected as ARVC, in 10.4% of cases [16].

As confirmed by our experience [17], males are more frequently affected compared to females, the rate between men: women being approximately 3:1 [18]. The disease is usually manifested in the second-fifth decades of life, as palpitations, syncope, and sudden death [19]. The symptoms are extremely rare under 12 years old or more than 60 years old age [20], and cardiac failure is extremely rare, manifested during late progression of the disease. An exemplifying result has been provided by a study performed on 439 patients, 36 [+ or -] 14 years old age, revealing a specific symptomatology in 419 patients (95%), only 20 of them being asymptomatic [21].

Genetic syndromes and pathogeny

Genetic mutations have been identified in approximately 60% of patients [20]. The majority of cases have AD (autosomal dominant) transmission, with variable penetrance, although a minority of cases represents a manifestation of cardiocutaneous syndrome with AR (autosomal recessive) transmission, such as Naxos or Carvajal syndromes [22].

Naxos syndrome is correlated with a homozygous deletion of two base pairs found in the plakoglobin gene located in the 17q21.2 locus (Table 1) [11, 23].

ARVC in Carvajal syndrome is associated with woolly hair and palmoplantar keratodermia, as a consequence of homozygous DSP mutations in the desmoplakin gene located in the 6p24.3 locus (Table 1) [11, 24].

Although the literature considers ARVC as a genetic disease involving intercellular junctions of desmosomal-type [19, 25], there are other causative genes.

Currently, 16 mutations have been described in ARVC (Table 1), six of them being associated with desmosomal-type junctional complexes from the intercalated disks [11, 26, 27]. Relatively recent studies have revealed that approximately 50-60% of patients with ARVC have a mutated gene encoding a desmosomal protein [28-30]. Occasionally, multiple mutations have been identified in the same patient [31].

Other types of mutations characteristic for ARVC are seen in atypical types of disease, involving non-desmosomal proteins, such as desmin (DES), transmembrane protein 43 (TMEM43), lamin-A/C (LMNA), titin (TTN), phospholamban (PLN), and [alpha]-T-catenin (CTNNA3) [11, 20, 32].

A rare type of disease has been identified in 1994, involving only several families, named ARVC type 1, determined by transforming growth factor [beta]-3 (TGF[beta]3) mutations [33, 34], manifested as myocardial fibrosis, as a result of increased TGFB3 expression [11].

The pathogenic mechanism is not completely elucidated but two theories are currently under debate, namely the degeneration-inflammation model and the transdifferentiation model [1], as possible pathways of structural alterations of the right ventricular wall in ARVC.

According to the degeneration-inflammation model of pathogenesis, the alteration of myocardial intercellular adhesion results in a diminished stress resistance of cardiac muscle fibers and the most susceptible fibers are those located in the right ventricle. The necrosis and inflammation are followed by fibrosis and infiltration with adipose tissue, as a non-specific local response, analogous to the process taking place in other myocardial diseases [35].

The local inflammation, mainly expressed by accumulation of neutrophils and lymphocytes, has been described by Basso, in 1996, and has been also identified by other researchers, especially in severe types of ARVC [36, 37].

The pathogenic mechanism is not completely elucidated but two theories are currently under debate, namely the degeneration-inflammation model and the transdifferentiation model [1], as possible pathways of structural alterations of the right ventricular wall in ARVC.

The pathogenic mechanism is not completely elucidated but two theories are currently under debate, namely the degeneration-inflammation model and the transdifferentiation model [1], as possible pathways of structural alterations of the right ventricular wall in ARVC.

According to the degeneration-inflammation model of pathogenesis, the alteration of myocardial intercellular adhesion results in a diminished stress resistance of cardiac muscle fibers and the most susceptible fibers are those located in the right ventricle. The necrosis and inflammation are followed by fibrosis and infiltration with adipose tissue, as a non-specific local response, analogous to the process taking place in other myocardial diseases [35].

The local inflammation, mainly expressed by accumulation of neutrophils and lymphocytes, has been described by Basso, in 1996, and has been also identified by other researchers, especially in severe types of ARVC [36, 37].

Mononuclear infiltration occurrence in myocardium may also be the result of a viral infection, but viral myocarditis is not considered as an etiologic factor of ARVC [38]. The involvement of viral infections in ARVC pathogeny cannot be completely excluded, as they induce variable degrees of myocardial cells apoptosis, facilitated by genetic predisposition [31, 39].

As a consequence, it is still debated if the inflammation associated or not with viral infections with myocardial tropism is a direct cause or only a secondary manifestation of myocytary lesions characteristic for ARVC. Another plausible hypothesis is that local proinflammatory mediators may interfere with the integrity and desmosomal activity of the intercalated disks, considering their ability of plakoglobin redistribution or TGF[beta]3 overexpression [36, 37]. In a transdifferentiation model, desmosomes are able to contribue to the mediation of some intercellular signals, via Wnt/ [beta]-catenin pathway, being negatively regulated by plakoglobin by nuclear competition with [beta]-catenin [40]. This perturbation of the intercellular signals induces cardiac cells apoptosis and their replacement with fibro-adipose tissue.

Arrhythmias are probably the result of gap junctions remodeling in intercalated disks and sodium flux downregulation, due to interrelationships between desmosomes, gap junctions, and voltage-gated sodium channels [41].

It is also plausible that the two mentioned mechanisms are intricated, as more as ARVC is currently considered a disease of the intercalated disk, as a carrefour of desmosomal and non-desmosomal close interactions [31, 41].

Gross findings and histopathology

The morphologic characteristic of ARVC is the progressive replacement of right ventricle myocytes with fibro-adipose tissue (Figures 1-3). This process is initiated in subepicardial layers and progresses toward endocardium, in a different manner when compared to ischemic cardiomyopathy, resulting in ventricular wall thinning [42]. The replacement of myocardium with fibro-adipose tissue may be parcelar or diffuse [17]. In evolution, apex, infundibulum or posterior-inferior ventricular wall saccular aneurysms may occur. In late stages, the ventricular wall is extremely thin, with epicardial apposition on endocardium, termed as "papyraceous right ventricle" [26].

Having this classic description as a start point, necropsic studies have revealed a fibro-adipose infiltration of the left ventricle wall or, exceptionally, of the ventricular septae in patients with ARVC [1]. In rare circumstances, there are parcelar gross findings and consequently the diagnosis is only microscopical [43], as confirmed in our practical experience.

Trichromic staining may evidentiate discrete areas of fibrosis and the remodeling of intercellular intercalated disks is evident in electron microscopy [1].

Immunohistochemical study of the desmosomal proteins is not a useful method in diagnosis as the same lesional feature may be also described in other myocardial lesions, such as sarcoidosis or giant cells myocarditis [36, 44].

Diagnosis and differentials

A scoring system is currently used to facilitate the diagnosis, namely the Task Force Criteria (TFC), a system proposed by McKenna and co-workers, in 1994, later revised by Marcus and co-workers, in 2010 (Table 2) [43, 45].

Using this score, a specific value is attributed to family history, clinical imaging, electrocardiography, and molecular genetic testing [43]. A patient having two major criteria, or one major criterion and two minor criteria, or four minor criteria is diagnosed with ARVC. Patients having either one major criterion and one minor criterion or three minor criteria are considered as suspicious for diagnosis. The diagnosis is excluded in patients having only one major or two minor criteria [1].

The endomyocardial biopsy may be performed in cases were non-invasive paraclinical investigations are not conclusive.

However, the endomyocardial biopsies are frequently fals negative, as ARVC is initiated in subepicardial areas and has a slow progression towards endocardium, so the subendocardial areas used to collect tissular fragment may not be yet involved. Moreover, the biopsies are usually done from the interventricular septum, an area which is frequently unaffected. Not the last, the disease may be focal, and the presence of fibro-adipose tissue in myocardium is not a specific marker of the disease, as it may also occur in ischemic cardiomyopathy [1, 18].

In order to increase biopsy accuracy, the collection should be achieved from the right ventricle free wall, but this would increase the risk of cardiac tamponade.

However, myocardial endobiopsy remains the diagnosis invasive method, the general indication being to collect the fragment from the "triangle of dysplasia", an area between the apex, infundibulum, and posteroinferior wall. The biopsies from septae or left ventricle are not useful for diagnosis [1, 20].

Nowadays, an important value in diagnosis and screening is attributed to genetic testing, though a negative result cannot exclude ARVC diagnosis [29].

A supplementary criterion to support the diagnosis is also the therapeutic response to isoproterenol, as intravenous administration of very high dose (45 mcg/min), for 3 min [46, 47]. ECG is continuously registered during the test and 10 minutes after the administration of this drug, the test being positive if polymorphic PVCs (>3 morphologies) and if at least one couplet is observed [46, 47].

The differentials in ARVC include a multitude of heart diseases, such as: conventional dilatative cardiomyopathy, right-sided sarcoidosis, myocarditis, and idiopathic arrhythmias. As a differential from dilatative cardiomyopathy, discordance between arrhythmias severity and ventricular disfunction is noticed in ARVC, a feature that facilitates the differential diagnosis.

Clinical manifestations are similar in right-sided sarcoidosis, but there is characteristic involvement of the interventricular septum and atrioventricular arrhythmias, while they are rare in ARVC. Furthermore, specific granulomatous inflammation evidentiated in microscopy settles the differential diagnosis.

Differential with viral myocarditis is difficult, mononuclears being evident in both microscopic specimens. Serological and genetic tests may be, in this case, useful for differential diagnosis.

Perspectives

As the causative genes for ARVC have been identified, the premises of populational screening are met. The Sanger method represents the gold standard of sequencing, with two times of PCR applied for target exons [11]. Due to long time and high costs, next generation sequencing (NGS) methods are currently developed, being usefull in whole genome, exon, or target gene sequencing [11]. With the currently available panels for genetic analysis, ARVC can be detected in a week [11].

Unfortunately, causative mutations are difficult to distinguish from other genetic noise [48]. In order to eliminate the genetic noise, data for ethnically matched controls is necessary, associated with special softwares for prediction of pathogenic mutations to evaluate the genetic result of a patient [49]. Furthermore, the compatibility with the phenotype of the disease is needed in order to validate the genetic result [11].

Conclusions

ARVC is a genetic disease with vital prognosis determined in a majority of cases by gene mutations. Patients have severe ventricular arrhythmias, syncope, and sudden death risk.

Light microscopy allows the observation of fibro-adipose tissue progressively replacing the right ventricular wall myocardium.

Due to the tremendous progress in elucidating the genetic determinism of ARVC, genetic testing may be used as a populational screening and premises of possible practical applications in therapy may prevent sudden cardiac death in young people.

DOI: 10.22551/2017.15.0402.10095

Conflict of interest

The authors declare that they have no competing interests.

References

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Adriana Grigoras (1, 2), Laura Adriana Knieling (1, 2), Cornelia Amalinei *, (1, 2)

(1) Department of Morphofunctional Sciences I, "Grigore T. Popa" University of Medicine and Pharmacy, Iasi, Romania, (1) Institute of Legal Medicine Iasi, Romania

Received: March 2017; Accepted after review: May 2017; Published: June 2017.

* Corresponding author: Cornelia Amalinei, MD, PhD, Department of Morphofunctional Sciences I, "Grigore T. Popa" University of Medicine and Pharmacy, 16, Universitatii Street, 700115, Iasi, Romania. E-mail: cornelia.amalinei@umfiasi.ro

Caption: Fig. 1. Myocardium appearance in ARVC with important decrease in cardiomyocytes number (HE, 40x)

Caption: Fig. 2. Myocardium appearance in ARVC with progressive fibro-adipose replacement of myocardium initiated from epicardium (Masson's trichrome, 40x)

Caption: Fig. 3. Fibro-adipose replacement of myocardium (HE, 40x)
Table 1. Genetic syndromes manifested by ARVC

           Genetic
           syndrome or       Genetic               Mutated
Genotype   other diseases    mutation   Location   proteins

ARVC12     Naxos             JUP        17q21.2    plakoglobin

ARVC8      Carvajal          DSP        6p24.3     desmoplakin
           (DCM with wooly
           hair and
           keratoderma)

ARVC1      --                TGFB3      14q24.3    transforming
                                                   growth factor
                                                   [beta]-3

ARVC2      DCM               RYR2       1q43       cardiac
           CPVT                                    ryanodine
                                                   receptor

ARVC3      --                unknown    14q12-     NA
                                        q22

ARVC4      HCM               TTN        2q32.1-    titin
           DCM                          q32.3

ARVC5      EDMD              TMEM43     3p25.1     transmembrane
           RV aneurysm                             protein 43

ARVC6      --                unknown    10p14-     NA
                                        p12

ARVC7      Myopathy          DES        2q35       desmin
           Cardiomyopathy

ARVC9      --                PKP2       12p11      plakophilin-2

ARVC10     --                DSG2       18q12.1    cadherin-like

ARVC11     -                 DSC2       18q12.1    transmembrane
                                                   glycoproteins

           DCM               PLN        6q22.1     phospholamban

           EDMD

           Premature aging
           syndrome          LMNA       1q22       lamin A/C
           DCM with sinus
           bradycardia and
Others     conduction
           disturbance

           Long QT           SCN5A      3p21       cardiac sodium
           syndrome type 3                         channel
           Brugada
           syndrome
           Progressive
           cardiac
           conduction
           disease
           DCM
           --
                             CTNNA3     10q22.2    alpha-T catenin

                          Mutated
                          proteins
           Transmission   location or
Genotype   type           function

ARVC12     AR             Desmosome

ARVC8      AR             Desmosome

ARVC1      AD             Myocardial
                          fibrosis

ARVC2      AD             Sarcoplasmic
                          reticulum;
                          cardiac
                          contraction

ARVC3      AD             Desmosome

ARVC4      AD             Passive
                          restoring
                          force of the
                          sarcomere

ARVC5      AD             Nuclear
                          membrane
                          organizer

ARVC6      AD             NA

ARVC7      AD             Intermediate
                          filament

ARVC9      AD             Desmosome

ARVC10     AD             Desmosome

ARVC11     AD             Desmosome
                          Calcium
                          handling in
           AD             myocardium
                          contractions

                          Lining of the
           AD             nuclear
                          membrane;
                          cells
Others                    stabilization

           AD             Rapid structural
                          changes as
                          response to
                          myocardium
                          electrical field

                          Binds to
           AD             plakophilin;
                          intercellular
                          adhesion

Dilated cardiomyopathy (DCM); Catecholaminergic polymorphic
ventricular tachycardia (CPVT); Hypertrophic cardiomyopathy
(HCM); Emery-Dreifuss muscle dystrophy (EDMD), Not available (NA)

Table 2. The Task Force Criteria in ARVC/D--2010

Categories         Major criteria

Global or          By 2D echo:
regional           Regional RV akinesia,
dysfunction        dyskinesia or aneurysm
and structural     By MRI:
alterations        Regional RV akinesia,
                   dyskinesia or dyssynchronous
                   RV contraction and 1 of the
                   following:
                     --Ratio of RV end-diastolic
                       volume to BSA [greater
                       than or equal to]110 mL/
                       [m.sup.2] (male) or
                       [greater than or equal to]
                       100 mL/[m.sup.2] (female)
                     --RV ejection fraction
                       [less than or equal to]40%

                   By RV angiography:
                   Regional RV akinesia,
                   dyskinesia or aneurysm

Tissue             Residual myocytes <60% by
characterization   morphometric analysis (or <50%
of the wall        if estimated) with fibrous
                   replacement of the RV free wall
                   myocardium in [greater than or
                   equal to] 1 sample, with or
                   without fatty replacement of
                   tissue on endomyocardial
                   biopsy

Repolarization     Inverted T waves in right
abnormalities      precordial leads (V1, V2, and
                   V3) or beyond in individuals
                   >14 years of age (in the
                   absence of complete right
                   bundle-branch block QRS
                   [greater than or equal to]
                   120 ms)

Depolarization/    Epsilon wave (reproducible
conduction         low-amplitude signals between
abnormalities      end of QRS complex to onset
                   of the T wave) in the right
                   precordial leads (V1 to V3)

Arrhythmias        Nonsustained or sustained
                   ventricular tachycardia of
                   left bundle-branch morphology
                   with superior axis (negative
                   or indeterminate QRS in leads
                   II, III, and aVF and positive
                   in lead aVL)

Family             ARVC confirmed pathologically
history            at autopsy or surgery
                   Identification of a pathogenic
                   mutation categorized as
                   associated or probably
                   associated with ARVC in the
                   patient under evaluation

Categories         Minor criteria

Global or          By 2D echo:
regional           Regional RV
dysfunction        akinesia or dyskinesia
and structural     By MRI:
alterations        Regional RV akinesia,
                   dyskinesia or dyssynchronous
                   RV contraction and 1 of the
                   following:
                     --Ratio of RV end-diastolic
                       volume to BSA
                       [greater than or equal to]
                       100 to <110 mL/[m.sup.2]
                       (male) or [greater than or
                        equal to] 90 to <100
                        mL/[m.sup.2] (female)
                     --RV ejection fraction >40%
                       to [less than or equal to]
                       45%

Tissue             Residual myocytes 60% to 75%
characterization   by morphometric analysis (or
of the wall        50% to 65% if estimated) with
                   fibrous replacement of the RV
                   free wall myocardium in
                   [greater than or equal to] 1
                   sample, with or without fatty
                   replacement of tissue on
                   endomyocardial biopsy

Repolarization     Inverted T waves in leads V1
abnormalities      and V2 in individuals >14 years
                   of age (in the absence of
                   complete right bundle-branch
                   block) or in V4, V5, or V6
                   Inverted T waves in leads V1,
                   V2, V3, and V4 in individuals
                   >14 years of age in the
                   presence of complete right
                   bundle-branch block

Depolarization/    Late potentials by SAECG in
conduction         [greater than or equal to] 1
abnormalities      of 3 parameters in the absence
                   of a QRS duration of
                   [greater than or equal to]
                   110 ms on the standard ECG

Arrhythmias        Nonsustained or sustained
                   ventricular tachycardia of RV
                   outflow configuration, left
                   bundle-branch block morphology
                   with inferior axis (positive
                   QRS in leads II, III, and aVF
                   and negative in lead aVL) or
                   of unknown axis >500
                   ventricular extrasystoles per
                   24 hours (Holter)

Family             Premature sudden death (<35
history            years of age) due to suspected
                   ARVC in a first-degree
                   relative

Right ventricle (RV), Electrocardiography (ECG),
Signal-averaged electrocardiography (SAECG)
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Author:Grigoras, Adriana; Knieling, Laura Adriana; Amalinei, Cornelia
Publication:Archive of Clinical Cases
Article Type:Disease/Disorder overview
Date:Jun 1, 2017
Words:4799
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