Arrhythmogenic right ventricular dysplasia

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Arrhythmogenic right ventricular dysplasia (ARVD, also known as arrhythmogenic right ventricular cardiomyopathy or ARVC) is a type of nonischemic cardiomyopathy that involves primarily the right ventricle. It is characterized by hypokinetic areas involving the free wall of the right ventricle, with fibrofatty replacement of the right ventricular myocardium, with associated arrhythmias originating in the right ventricle.

ARVD is an important cause of ventricular arrhythmias in children and young adults. It is seen predominantly in males, and 30-50% of cases have a familial distribution. It is usually inherited in an autosomal dominant pattern, with variable expression. The penetrance is 20-35% in general, but significantly higher in Italy. Seven gene loci have been implicated in ARVD. However, about 50% of families that express ARVD that undergo genetic screening do not show linkage with any of the known chromosomal loci. It is unclear whether the pathogenesis varies with the different loci involved. A standard genetic screening test is not available.

Naxos disease is an autosomal recessive variant of ARVD, described initially on the Greek island of Naxos. There, the penetrance is >90%. It involves the gene that codes for plakoglobin (a protein that is involved in cellular adhesion), on chromosome 17p. Naxos disease is described as a triad of ARVD, palmoplantar keratosis, and wooly hair. The signs of Naxos disease are more severe than with autosomal dominant ARVD.

Arrhythmogenic right ventricular dysplasia (ARVD), also called arrhythmogenic right ventricular cardiomyopathy (ARVC) or arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C), is an inherited heart disease.

ARVD is caused by genetic defects of the parts of heart muscle (also called myocardium or cardiac muscle) known as desmosomes, areas on the surface of heart muscle cells which link the cells together. The desmosomes are composed of several proteins, and many of those proteins can have harmful mutations.

The disease is a type of nonischemic cardiomyopathy that involves primarily the right ventricle. It is characterized by hypokinetic areas involving the free wall of the right ventricle, with fibrofatty replacement of the right ventricular myocardium, with associated arrhythmias originating in the right ventricle.

ARVD is often found in association with diffuse palmoplantar keratoderma, and woolly hair, because their genes are nearby and often inherited together ^[1]:513[2]

ARVC/D is an important cause of ventricular arrhythmias in children and young adults. It is seen predominantly in males, and 30-50% of cases have a familial distribution.

It is usually inherited in an autosomal dominant pattern, with variable expression. Novel studies showed that mutations (point mutations) in genes encoding for desmosomal proteins (see intercalated disc) are the main causatives for the development of this disease. Recently it could be shown, that mutations in the desmin gene could cause ARVC. Desmin is an intermediate filament protein, which is linked to the desmosomes. The penetrance is 20–35% in general, but significantly higher in Italy. Seven gene loci have been implicated in ARVD. However, about 50% of families that express ARVD that undergo genetic screening do not show linkage with any of the known chromosomal loci. It is unclear whether the pathogenesis varies with the different loci involved. Standard genetic screening test are currently tested and evaluated in different state of the art cardiovascular research centres and hospitals. Types include:

Type	OMIM	Gene	Locus
ARVD1	107970	TGFB3	14q23-q24
ARVD2	600996	RYR2	1q42-q43
ARVD3	602086	?	14q12-q22
ARVD4	602087	?	2q32.1-q32.3
ARVD5	604400	TMEM43	3p23
ARVD6	604401	?	10p14-p12
ARVD7	609160	?	10q22.3
ARVD8	607450	DSP	6p24
ARVD9	609040	PKP2	12p11
ARVD10	610193	DSG2	18q12.1-q12
ARVD11	610476	DSC2	18q12.1
ARVD12	611528	JUP	17q21

The incidence of ARVD is about 1/10,000 in the general population in the United States, although some studies have suggested that it may be as common as 1/1,000. Recently, 1/200 were found to be carriers of mutations that predispose to ARVC^[3] It accounts for up to 17% of all sudden cardiac deaths in the young. In Italy, the incidence is 40/10,000, making it the most common cause of sudden cardiac death in the young population.

Up to 80% of individuals with ARVD present with syncope or sudden cardiac death. The remainder frequently present with palpitations or other symptoms due to right ventricular outflow tract (RVOT) tachycardia (a type of monomorphic ventricular tachycardia).

Symptoms are usually exercise-related. In populations where hypertrophic cardiomyopathy is screened out prior to involvement in competitive athletics, it is a common cause of sudden cardiac death.

The first clinical signs of ARVD are usually during adolescence. However, signs of ARVD have been demonstrated in infants.

The pathogenesis of ARVD is largely unknown. Apoptosis (programmed cell death) appears to play a large role. It is unclear why only the right ventricle is involved. The disease process starts in the subepicardial region and works its way towards the endocardial surface, leading to transmural involvement (possibly accounting for the aneurysmal dilatation of the RV). Residual myocardium is confined to the subendocardial region and the trabeculae of the RV. These trabeculae may become hypertrophied.

Aneurysmal dilatation is seen in 50% of cases at autopsy. It usually occurs in the diaphragmatic, apical, and infundibular regions (known as the triangle of dysplasia). The left ventricle is involved in 50-67% of individuals. If the left ventricle is involved, it is usually late in the course of disease, and confers a poor prognosis.

There are two pathological patterns seen in ARVD, Fatty infiltration and fibro-fatty infiltration.

The first, fatty infiltration, is confined to the right ventricle. This involves a partial or near-complete substitution of myocardium with fatty tissue without wall thinning. It involves predominantly the apical and infundibular regions of the RV. The left ventricle and ventricular septum are usually spared. No inflammatory infiltrates are seen in fatty infiltration. There is evidence of myocyte (myocardial cell) degeneration and death seen in 50% of cases of fatty infiltration.

The second, fibro-fatty infiltration, involves replacement of myocytes with fibrofatty tissue. A patchy myocarditis is involved in up to 2/3 of cases, with inflammatory infiltrates (mostly T cells) seen on microscopy. Myocardial atrophy is due to injury and apoptosis. This leads to thinning of the RV free wall (to < 3 mm thickness) Myocytes are replaced with fibrofatty tissue. The regions preferentially involved include the RV inflow tract, the RV outflow tract, and the RV apex. However, the LV free wall may be involved in some cases. Involvement of the ventricular septum is rare. The areas involved are prone to aneurysm formation.

Right ventricular outflow tract tachycardia

Monomorphic ventricular tachycardia originating from the right ventricular outflow tract.

Ventricular arrhythmias due to ARVD typically arise from the diseased right ventricle. The type of arrhythmia ranges from frequent premature ventricular complexes (PVCs) to ventricular tachycardia (VT) to ventricular fibrillation (VF).

While the initiating factor of the ventricular arrhythmias is unclear, it may be due to triggered activity or reentry.

Ventricular arrhythmias are usually exercise-related, suggesting that they are sensitive to catecholamines. The ventricular beats typically have a right axis deviation. Multiple morphologies of ventricular tachycardia may be present in the same individual, suggesting multiple arrhythmogenic foci or pathways.

Right ventricular outflow tract (RVOT) tachycardia is the most common VT seen in individuals with ARVD. In this case, the EKG shows a left bundle branch block (LBBB) morphology with an inferior axis.

The differential diagnosis for the ventricular tachycardia due to ARVD include:

• Congenital heart disease
  • Repaired tetralogy of Fallot
  • Ebstein’s anomaly
  • Uhl’s anomaly
  • Atrial septal defect
  • Partial anomalous venous return
• Acquired heart disease
  • Tricuspid valve disease
  • Pulmonary hypertension
  • Right ventricular infarction
  • Bundle-branch re-entrant tachycardia
• Miscellaneous
  • Pre-excited AV re-entry tachycardia
  • Idiopathic RVOT tachycardia
  • Sarcoidosis

In order to make the diagnosis of ARVD, a number of clinical tests are employed, including the electrocardiogram (EKG), echocardiography, right ventricular angiography, cardiac MRI, and genetic testing.

90% of individuals with ARVD have some EKG abnormality. The most common EKG abnormality seen in ARVD is T wave inversion in leads V₁ to V₃. However, this is a non-specific finding, and may be considered a normal variant in right bundle branch block (RBBB), women, and children under 12 years old.

RBBB itself is seen frequently in individuals with ARVD. This may be due to delayed activation of the right ventricle, rather than any intrinsic abnormality in the right bundle branch.

The epsilon wave

The epsilon wave (marked by red triangle), seen in ARVD.

The epsilon wave is found in about 50% of those with ARVD. This is described as a terminal notch in the QRS complex. It is due to slowed intraventricular conduction. The epsilon wave may be seen on a surface EKG; however, it is more commonly seen on signal averaged EKGs.

Ventricular ectopy seen on a surface EKG in the setting of ARVD is typically of left bundle branch block (LBBB) morphology, with a QRS axis of -90 to +110 degrees. The origin of the ectopic beats is usually from one of the three regions of fatty degeneration (the “triangle of dysplasia”): the RV outflow tract, the RV inflow tract, and the RV apex.

Signal averaged ECG (SAECG) is used to detect late potentials and epsilon waves in individuals with ARVD.

Echocardiography may reveal an enlarged, hypokinetic right ventricle with a paper-thin RV free wall. The dilatation of the RV will cause dilatation of the tricuspid valve annulus, with subsequent tricuspid regurgitation. Paradoxical septal motion may also be present.

Fatty infiltration of the RV free wall can be visible on cardiac MRI. Fat has increased intensity in T1-weighted images. However, it may be difficult to differentiate intramyocardial fat and the epicardial fat that is commonly seen adjacent to the normal heart. Also, the sub-tricuspid region may be difficult to distinguish from the atrioventricular sulcus, which is rich in fat.

Cardiac MRI can visualize the extreme thinning and akinesis of the RV free wall. However, the normal RV free wall may be about 3 mm thick, making the test less sensitive.

Right ventricular angiography is considered the gold standard for the diagnosis of ARVD. Findings consistent with ARVD are an akinetic or dyskinetic bulging localized to the infundibular, apical, and subtricuspid regions of the RV. The specificity is 90%; however, the test is observer dependent.

Transvenous biopsy of the right ventricle can be highly specific for ARVD, but it has low sensitivity. False positives include other conditions with fatty infiltration of the ventricle, such as chronic alcohol abuse and Duchenne/Becker muscular dystrophy.

False negatives are common, however, because the disease progresses typically from the epicardium to the endocardium (with the biopsy sample coming from the endocardium), and the segmental nature of the disease. Also, due to the paper-thin right ventricular free wall that is common in this disease process, most biopsy samples are taken from the ventricular septum, which is commonly not involved in the disease process.

A biopsy sample that is consistent with ARVD would have > 3% fat, >40% fibrous tissue, and <45% myocytes.

A post mortem histological demonstration of full thickness substitution of the RV myocardium by fatty or fibro-fatty tissue is consistent with ARVD.

ARVD is an autosomal dominant trait with reduced penetrance. Approximately 40-50% of ARVD patients have a mutation identified in one of several genes encoding components of the desmosome, which can help confirm a diagnosis of ARVD.^[4] Since ARVD is an autosomal dominant trait, children of an ARVD patient have a 50% chance of inheriting the disease causing mutation. Whenever a mutation is identified by genetic testing, family-specific genetic testing can be used to differentiate between relatives who are at-risk for the disease and those who are not. ARVD genetic testing is clinically available.^[5]

There is no pathognomonic feature of ARVD. The diagnosis of ARVD is based on a combination of major and minor criteria. To make a diagnosis of ARVD requires either 2 major criteria or 1 major and 2 minor criteria or 4 minor criteria.

Major Criteria

• Right ventricular dysfunction
  • Severe dilatation and reduction of RV ejection fraction with little or no LV impairment
  • Localized RV aneurysms
  • Severe segmental dilatation of the RV
• Tissue characterization
  • Fibrofatty replacement of myocardium on endomyocardial biopsy
• Conduction abnormalities
  • Epsilon waves in V₁ – V₃.
  • Localized prolongation (>110 ms) of QRS in V₁ – V₃
• Family history
  • Familial disease confirmed on autopsy or surgery

Minor Criteria

• Right ventricular dysfunction
  • Mild global RV dilatation and/or reduced ejection fraction with normal LV.
  • Mild segmental dilatation of the RV
  • Regional RV hypokinesis
• Tissue characterization
• Conduction abnormalities
  • Inverted T waves in V₂ and V₃ in an individual over 12 years old, in the absence of a right bundle branch block (RBBB)
  • Late potentials on signal averaged EKG.
  • Ventricular tachycardia with a left bundle branch block (LBBB) morphology
  • Frequent PVCs (> 1000 PVCs / 24 hours)
• Family history
  • Family history of sudden cardiac death before age 35
  • Family history of ARVD

There is a long asymptomatic lead-time in individuals with ARVD. While this is a genetically transmitted disease, individuals in their teens may not have any characteristics of ARVD on screening tests.

Many individuals have symptoms associated with ventricular tachycardia, such as palpitations, light-headedness, or syncope. Others may have symptoms and signs related to right ventricular failure, such as lower extremity edema, or liver congestion with elevated hepatic enzymes. Unfortunately, sudden death may be the first manifestation of disease.

ARVD is a progressive disease. Over time, the right ventricle becomes more involved, leading to right ventricular failure. The right ventricle will fail before there is left ventricular dysfunction. However, by the time the individual has signs of overt right ventricular failure, there will be histological involvement of the left ventricle. Eventually, the left ventricle will also become involved, leading to bi-ventricular failure. Signs and symptoms of left ventricular failure may become evident, including congestive heart failure, atrial fibrillation, and an increased incidence of thromboembolic events.

The goal of management of ARVD is to decrease the incidence of sudden cardiac death. This raises a clinical dilemma: How to prophylactically treat the asymptomatic patient who was diagnosed during family screening.

A certain subgroup of individuals with ARVD are considered at high risk for sudden cardiac death. Characteristics associated with high risk of sudden cardiac death include:

• Young age
• Competitive sports activity
• Malignant familial history
• Extensive RV disease with decreased right ventricular ejection fraction.
• Left ventricular involvement
• Syncope
• Episode of ventricular arrhythmia

Management options include pharmacological, surgical, catheter ablation, and placement of an implantable cardioverter-defibrillator.

Prior to the decision of the treatment option, programmed electrical stimulation in the electrophysiology laboratory may be performed for additional prognostic information. Goals of programmed stimulation include:

• Assessment of the disease’s arrhythmogenic potential
• Evaluate the hemodynamic consequences of sustained VT
• Determine whether the VT can be interrupted via antitachycardia pacing.

Regardless of the management option chosen, the individual is typically suggested to undergo lifestyle modification, including avoidance of strenuous exercise, cardiac stimulants (i.e.: caffeine, nicotine, pseudoephedrine) and alcohol. If the individual wishes to begin an exercise regimen, an exercise stress test may have added benefit.

Pharmacologic management of ARVD involves arrhythmia suppression and prevention of thrombus formation.

Sotalol, a beta blocker and a class III antiarrhythmic agent, is the most effective antiarrhythmic agent in ARVD. Other antiarrhythmic agents used include amiodarone and conventional beta blockers (i.e.: metoprolol). If antiarrhythmic agents are used, their efficacy should be guided by series ambulatory holter monitoring, to show a reduction in arrhythmic events.

While angiotensin converting enzyme inhibitors (ACE Inhibitors) are well known for slowing progression in other cardiomyopathies, they have not been proven to be helpful in ARVD.

Individuals with decreased RV ejection fraction with dyskinetic portions of the right ventricle may benefit from long term anticoagulation with warfarin to prevent thrombus formation and subsequent pulmonary embolism.

Catheter ablation may be used to treat intractable ventricular tachycardia. It has a 60-90% success rate.^[6] Unfortunately, due to the progressive nature of the disease, recurrence is common (60% recurrence rate), with the creation of new arrhythmogenic foci. Indications for catheter ablation include drug-refractory VT and frequent recurrence of VT after ICD placement, causing frequent discharges of the ICD.

An ICD is the most effective prevention against sudden cardiac death. Due to the prohibitive cost of ICDs, they are not routinely placed in all individuals with ARVD.

Indications for ICD placement in the setting of ARVD include:

• Cardiac arrest due to VT or VF
• Symptomatic VT that is not inducible during programmed stimulation
• Failed programmed stimulation-guided drug therapy
• Severe RV involvement with poor tolerance of VT
• Sudden death of immediate family member

Since ICDs are typically placed via a transvenous approach into the right ventricle, there are complications associated with ICD placement and follow-up.

Due to the extreme thinning of the RV free wall, it is possible to perforate the RV during implantation, potentially causing pericardial tamponade. Because of this, every attempt is made at placing the defibrillator lead on the ventricular septum.

After a successful implantation, the progressive nature of the disease may lead to fibro-fatty replacement of the myocardium at the site of lead placement. This may lead to undersensing of the individual’s electrical activity (potentially causing inability to sense VT or VF), and inability to pace the ventricle.

Cardiac transplant surgery may be performed in ARVD. It may be indicated if the arrhythmias associated with the disease are uncontrollable or if there is severe bi-ventricular heart failure that is not manageable with pharmacological therapy.

All first degree family members of the affected individual should be screened for ARVD. This is used to establish the pattern of inheritance. Screening should begin during the teenage years unless otherwise indicated. Screening tests include:

• Echocardiogram
• EKG
• Signal averaged EKG
• Holter monitoring
• Cardiac MRI
• Exercise stress test

• Sevilla FC and Spanish international left wing-back Antonio Puerta died from the condition, at the age of 22, on 28 August 2007, three days after suffering several cardiac arrests, while disputing a La Liga game against Getafe CF.^[7][8]
• Englishman Matt Gadsby also died from the condition after collapsing on the pitch on 9 September 2006, while playing with his team Hinckley United in a Conference North game against Harrogate Town.^[9][10]
• Model Krissy Taylor, sister of Niki Taylor, died from the disease at age 17 in 1995.

• Woolly hair nevus

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

• In 1977, the concept of a specific RV cardiomyopathy was first suggested in a report of six patients with sustained ventricular tachycardia (VT) and enlarged right ventricles
• Arrhythmogenic right ventricular cardiomyopathy (ARVC) was described for the first time by Frank and Fontaine in 1978^[1]
• It was first described in patients undergoing surgical ablation for right ventricular outflow tract (RVOT) tachycardia
• In 1982, the term “arrhythmogenic right ventricular dysplasia” was first used in a case series of 24 patients with left bundle branch block (LBBB) pattern VT, RV wall motion abnormalities and replacement of the RV myocardium by adipose and fibrous tissue^[2]
• The term arrhythmogenic right ventricular dysplasia was not formally recognized as a distinct entity until 1994, following the publication of diagnostic criteria by the World Health Organization/International Society and Federation of Cardiology Task Force^[3]
• In 1994, diagnostic criteria were published by the Working Group on Myocardial and Pericardial Diseases of the European Society of Cardiology and the Scientific Council on Cardiomyopathies of the International Society and Federation of Cardiology
• In 2010, these criteria were modified
• The first gene mutations linked to the disease were identified in a recessive, syndromic variant of ARVC known as Naxos disease.
• The cause of this particularly malignant form of the condition was found to be a two-base pair deletion in the gene encoding plakoglobin, a major component of cell-to-cell junctions^[4]
• Disease-causing mutations in other genes encoding desmosomal proteins in the more common autosomal dominant forms of ARVC were then identified^[5][6][7]
• Latter on, very similar clinical and histological phenotypes have been identified in patients with mutations in non-desmosomal genes, including titin, desmin and lamin A/C^[8][9][10]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Variants of arrythmogenic right ventricular dysplasia can be classified based on the the genetic abnormality involved; So far, 12 variants have been identified. Another classification was based on the clinical manifestation which was first developed by Fontaine et al. and lead to the identification of 3 clinical forms (based on a 9-year observation of 4 patients with different clinical course of ARVC). Later on, another variant of the ARVC classification was proposed, in which the RV and left ventricular forms were distinguished and a total of eleven different clinical forms were identified. However, these classifications did not define prognosis and approaches to treatment and hence, none was widely used in clinical practice. So, The development of clinical classification is considered an important task and an ultimate challenge.

Arhythmogenic right ventricular dysplasia can be classified based upon the genetic abnormality involved into 12 variants:☂^{[1][2][3][4][5][6][7][8][9][10][11][12]}

Variant	Associated mutation
ARVD1	This variant is due to a heterozygous mutation in the TGFB3 gene on chromosome 14q24 190230
ARVD2	Associated with a mutation in the RYR2 gene on chromosome 1q42-q43 180902
ARVD3	Associated with a mutation in the chromosome 14q12-q22 region 602086
ARVD4	Associated with a mutation in the chromosome 2q32.1-q32.3 region 602087
ARVD5	Associated with a mutation in the TMEM43 gene on chromosome 3p23 region 604400
ARVD6	Associated with a mutation in the chromosome 10p14-p12 region 604401
ARVD7	Associated with a mutation in the chromosome 10q22.3 region 609160
ARVD8	Associated with a mutation in the DSP gene on chromosome 6p24 607450, 125647
ARVD9	Associated with a mutation in the PKP2 gene on chromosome 12p11 609040, 125647
ARVD10	Associated with a mutation in the DSG2 gene on chromosome 18q12.1-q12 610193, 125671
ARVD11	Associated with a mutation in the DSC2 gene on chromosome 18q12.1 610476, 125645
ARVD12	Associated with a mutation in the JUP gene on chromosome 17q21 611528, 173325

Another classification is based on the clinical manifestations and course of the disease, six clinical forms of ARVC have been identified:^{[13][14][15][16]}

Type	Characterestics
Sudden arrhythmic death	Presents as the only clinical manifestation
Latent arrhythmic form	Frequent PVCs and/or nonsustained VT in the absence of sustained VT and syncope Isolated RV PVCs; RV PVCs with episodes of nonsustained VT
The manifested arrhythmic form	Sustained VT/ventricular fibrillation (VF)
ARVC with a progressive CHF	The main manifestation of the disease is CHF: Predominantly right heart failure Biventricular heart failure
ARVC in combination with LVNC	Arrhythmic form without CHF Biventricular heart failure
Nonarrhythmic form of ARVC	Asymptomatic ARVC

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

The pathogenesis of ARVD involves apoptosis with fatty and fibro-fatty infiltration of the right ventricular free wall leading to heart failure and ventricular arrhythmias. Arrhythmogenic right ventricular cardiomyopathy is considered as a disease of the desmosome. Desmosomes are abundant in the skin and myocardium and their function is to contribute mechanical attachment between cells and work as an important mediator of the intracellular and intercellular signal transduction. Desmosomes are composed of plakoglobin, plakophilins, desmoplakin, desmogleins, and desmocollins. ARVC is usually caused by mutations in genes encoding for desmosomal proteins such as Plakoglobin (JUP), desmoplakin (DSP), plakophilin‐2 (PKP2), desmoglein‐2 (DSG2), and desmocollin‐2 (DSC2). A minority of cases is caused by mutations in nondesmosomal genes. Mode of transmission of Arrhythmogenic right ventricular cardiomyopathy is mostly an autosomal‐dominant trait. Autosomal‐recessive forms are rare, mostly in the cardiocutaneous syndromes such as Carvajal syndrome and Naxos disease. Studied have shown that multiple mutations with digenic heterozygosity are associated with earlier manifestation and more malignant phenotype.

There are two pathological patterns seen in ARVD, fatty infiltration and fibro-fatty infiltration.

Apoptosis (programmed cell death) appears to play a role in the pathogenesis of ARVD and high levels of apopain have been observed.^[1] It is unclear why only the right ventricle is involved. The disease process starts in the subepicardial region and works its way towards the endocardial surface, leading to transmural involvement (possibly accounting for the aneurysmal dilatation of the RV). The presence of residual myocardium is confined to the subendocardial region and the trabeculae of the RV. These trabeculae may become hypertrophied.

Aneurysmal dilatation of the right ventricle is observed in 50% of cases at autopsy. It usually occurs in the diaphragmatic, apical, and infundibular regions (known as the triangle of dysplasia).

The left ventricle is involved in 50-67% of individuals. If the left ventricle is involved, it is usually late in the course of disease, and confers a poor prognosis.

The first, fatty infiltration, is confined to the right ventricle. This involves a partial or near-complete substitution of myocardium with fatty tissue without wall thinning. It involves predominantly the apical and infundibular regions of the RV. The left ventricle and ventricular septum are usually spared. No inflammatory infiltrates are seen in fatty infiltration. There is evidence of myocyte (myocardial cell) degeneration and death seen in 50% of cases of fatty infiltration.

The second, fibro-fatty infiltration, involves replacement of myocytes with fibro-fatty tissue. A patchy myocarditis is observed in up to 2/3 of cases, with inflammatory infiltrates (mostly T cells) seen on microscopy. Myocardial atrophy is due to injury and apoptosis. This leads to thinning of the RV free wall (to < 3 mm thickness). The regions preferentially involved include the RV inflow tract, the RV outflow tract, and the RV apex. However, the LV free wall may be involved in some cases. Involvement of the ventricular septum is rare. The areas involved are prone to aneurysm formation.

• Arrhythmogenic right ventricular cardiomyopathy is considered as a disease of the desmosome
• Desmosomes are abundant in the skin and myocardium and their function is:
  • Contribute mechanical attachment between cells
  • Works as an important mediator of the intracellular and intercellular signal transduction
• Desmosomes are composed of plakoglobin, plakophilins, desmoplakin, desmogleins, and desmocollins^[2]
• ARVC is usually caused by mutations in genes encoding for desmosomal proteins:
  • Plakoglobin (JUP), desmoplakin (DSP), plakophilin‐2 (PKP2), desmoglein‐2 (DSG2), and desmocollin‐2 (DSC2)^[3][4]
• A minority of cases is caused by mutations in nondesmosomal genes
• Mode of transmission of Arrhythmogenic right ventricular cardiomyopathy is mostly an autosomal‐dominant trait
• Autosomal‐recessive forms are rare, mostly in the cardiocutaneous syndromes such as:^[4]
  • Carvajal syndrome
  • Naxos disease
• Many studies have shown that multiple mutations with compound and digenic heterozygosity were common and were associated with earlier manifestation and more malignant phenotype^[5][6][7]
• Recently published animal study demonstrated that loss of PKP2 only in adult myocyte was sufficient for the development of an arrhythmia without overt structural disease, that later gives way to an ARVC and finally, a biventricular dilated cardiomyopathy (DCM)

There is an autosomal dominant pattern of inheritance.^{[8][9][10][11][12][13][14][15][16][17][18][19]}

Variant	Associated mutation
ARVD1	This variant is due to a heterozygous mutation in the TGFB3 gene on chromosome 14q24 190230
ARVD2	Associated with a mutation in the RYR2 gene on chromosome 1q42-q43 180902
ARVD3	Associated with a mutation in the chromosome 14q12-q22 region 602086
ARVD4	Associated with a mutation in the chromosome 2q32.1-q32.3 region 602087
ARVD5	Associated with a mutation in the TMEM43 gene on chromosome 3p23 region 604400
ARVD6	Associated with a mutation in the chromosome 10p14-p12 region 604401
ARVD7	Associated with a mutation in the chromosome 10q22.3 region 609160
ARVD8	Associated with a mutation in the DSP gene on chromosome 6p24 607450, 125647
ARVD9	Associated with a mutation in the PKP2 gene on chromosome 12p11 609040, 125647
ARVD10	Associated with a mutation in the DSG2 gene on chromosome 18q12.1-q12 610193, 125671
ARVD11	Associated with a mutation in the DSC2 gene on chromosome 18q12.1 610476, 125645
ARVD12	Associated with a mutation in the JUP gene on chromosome 17q21 611528, 173325

Right ventricular outflow tract tachycardia

Monomorphic ventricular tachycardia originating from the right ventricular outflow tract.

Ventricular arrhythmias due to ARVD typically arise from the diseased right ventricle. The type of arrhythmia ranges from frequent premature ventricular complexes (PVCs) to ventricular tachycardia (VT) to ventricular fibrillation (VF).

While the initiating factor of the ventricular arrhythmias is unclear, it may be due to triggered activity or reentry.

Ventricular arrhythmias are usually exercise-related, suggesting that they are sensitive to catecholamines. The ventricular beats typically have a right axis deviation. Multiple morphologies of ventricular tachycardia may be present in the same individual, suggesting multiple arrhythmogenic foci or pathways.

Right ventricular outflow tract (RVOT) tachycardia is the most common VT seen in individuals with ARVD. In this case, the EKG shows a left bundle branch block (LBBB) morphology with an inferior axis.

Template:WH Template:WS CME Category::Cardiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Arrhythmogenic right ventricular cardiomyopathy is typically inherited as an autosomal dominant pattern with variable penetrance and incomplete expression. Approximately 40% to 50% of ARVC/D patients have a mutation in genes encoding a desmosome protein. The gene is on the chromosome 14q23-q24.There is an autosomal recessive trait variant associated with palmoplantar keratosis and wooly hair named Naxos disease.

Arrhythmogenic right ventricular cardiomyopathy is cause by genetic inheritance as:^[1][2]

• An autosomal dominant pattern with variable penetrance and incomplete expression.
• A mutation in genes encoding a desmosome protein ( 40% to 50% of ARVC/D patients)
• The gene is on the chromosome 14q23-q24
• There is an autosomal recessive trait variant associated with palmoplantar keratosis and wooly hair named Naxos disease

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

The differential diagnosis of ARVC from other diseases can be challenging. It must be differentiated form RV outflow tract (RVOT) tachycardia or ectopy, Brugada syndrome, sarcoidosis, myocarditis, congenital abnormalities, pulmonary hypertension, RV infarct, DCM, Athlete heart, and Uhl’s anomaly. At autopsy, one has to differentiate between normal fat deposition in the right ventricle and the presence of scars in the subepicardium due to ischemia

The differential diagnosis for the ventricular tachycardia due to ARVD include:^{[1][2][3][4][5]}

• Congenital heart disease
  • Repaired tetralogy of Fallot
  • Ebstein’s anomaly
  • Uhl anomaly
  • Atrial septal defect
  • Partial anomalous pulmonary venous return
• Acquired heart disease
  • Tricuspid valve disease
  • Pulmonary hypertension
  • Right ventricular infarction
  • Bundle branch reentrant ventricular tachycardia
• Miscellaneous
  • Pre-excited AV re-entry tachycardia
  • Idiopathic RVOT ventricular tachycardia

Disease	Characteristics	Signs and Symptoms	Associated Conditions	Histopathology	Lab finding & Other evaluation	Prognosis
ARVC
RVOT
Sarcoidosis

Ventricular tachycardia associated with ARVD/C may be difficult to differentiate from RVOT VT. Electrocardiographic clues that support the diagnosis of ARVD/C include multifocal and/or polymorphic ventricular tachycardia (VT) originating from the right ventricle, T wave inversions in the right precordial leads, slurred upstroke (≥55 ms) of the S wave in V₁ to V₃ leads, and the presence of an epsilon wave.

ARVD is distinguished from dilated cardiomyopathy by the greater degree of arrhythmogenicity. In dilated cardiomyopathy, although ventricular arrhythmia commonly occurs, it is rare in the absence of significant ventricular dysfunction. In contrast, ARVD is significantly associated with ventricular arrhythmia even in the absence of ventricular dysfunction. Furthermore, sudden cardiac death is the first clinical manifestation of the disease in more than 50% of probands with ARVD. Additionally, regional ventricular involvement and the presence of ventricular aneurysm, which are hallmarks of ARVD/C, argue against the diagnosis of dilated cardiomyopathy.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

ARVD is a rare disease. It is observed more commonly in males, and accounts for 17% of all sudden cardiac deaths in the young.

Incidence

The incidence of ARVC/D is difficult to be determined due the different clinical manifestations of the disease which vary greatly, especially in different ethnic groups. This could be secondary to the genetic heterogeneity and variable phenotype expression, diverse disease progression. All this make the diagnosis difficult and decreases the real evaluation of the incidence.

• The incidence of ARVD is about 1/10,000 in the general population in the United States, although some studies have suggested that it may be as common as 1/1,000.
• In Italy, the incidence is 40/10,000, making it the most common cause of sudden cardiac death in the young population. It is more common in Northern Italy ^[1][2]

• The estimated prevalence of ARVC/D in the general population is approximately 1:5000
• ARVC/D accounts for 11%–22% of cases of SCD in the young athlete patient population^[3][4]
• It accounts for approximately 22% of cases in athletes in northern Italy and about 17% of SCD in young people in the United States

• Men are more frequently affected than women, with a male to female ratio of 3:1

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Once hypertrophic cardiomyopathy is excluded, arrhythmogenic right ventricular dysplasia is a common cause of sudden cardiac death among competitive athletes.

Family screening

All first degree family members of the affected individual should be screened for ARVD. This is used to establish the pattern of inheritance. Screening should begin during the teenage years unless otherwise indicated. Screening tests include:

• Echocardiogram
• EKG
• Signal averaged EKG
• Holter monitoring
• Cardiac MRI
• Exercise stress test

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

• The first clinical signs of ARVD are usually during adolescence. However, signs of ARVD have been demonstrated in infants.
• There may be a long asymptomatic lead-time in individuals with ARVD. While this is a genetically transmitted disease, individuals in their teens may not have any characteristics of ARVD on screening tests.

Many individuals have symptoms associated with ventricular tachycardia, such as palpitations, light-headedness, or syncope. Others may have symptoms and signs related to right ventricular failure, such as lower extremity edema, liver congestion with elevated hepatic enzymes. Unfortunately, sudden death may be the first manifestation of disease.

ARVD is a progressive disease. Over time, the right ventricle becomes more involved, leading to right ventricular failure. The right ventricle will fail before there is left ventricular dysfunction. However, by the time the individual has signs of overt right ventricular failure, there will be histological involvement of the left ventricle. Eventually, the left ventricle will also become involved, leading to bi-ventricular failure. Signs and symptoms of left ventricular failure may become evident, including congestive heart failure, atrial fibrillation, and an increased incidence of thromboembolic events.

It accounts for up to 17% of all sudden cardiac deaths in the young. In Italy, the incidence is 40/10,000, making it the most common cause of sudden cardiac death in the young population. The left ventricle is involved in 50-67% of individuals. If the left ventricle is involved, it is usually late in the course of disease, and confers a poor prognosis. Once hypertrophic cardiomyopathy is excluded, it is a common cause of sudden cardiac death in competitive athletes.

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