arrhythmogenic right ventricular dysplasia

Arrhythmogenic right ventricular

dysplasiaBy

Mohamed Zannoun, MDAssociated Professor of Pediatrics,

Al Azhar University, Damietta

05/03/23 dr. M. Abdel Salam zannoun

• Arrhythmogenic right ventricular cardiomyopathy (ARVC). • Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C).


• Arrhythmogenic right ventriculardysplasia (ARVD)

Why ARVD Is an important cause of

ventricular arrhythmias in children and young adults.

It is seen predominantly in males.

30-50% of cases have a familial distribution.05/03/23 dr. M. Abdel Salam zannoun

Incidence About 1/10,000 in the general population, although

some studies have suggested that it may be as common as 1/1,000.

The incidence is 40/10,000, It accounts for up to 17% of all sudden cardiac

deaths making it the most common cause of sudden cardiac death in children and young population. .



Inherited heart disease.

Genetic of AVRD

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


Genetic of AVRD It is usually inherited in an autosomal

dominant pattern, with variable expression.

The mutations in the desmin-gene could cause ARVD.

Desmin is a intermediate filament protein, which is linked to the desmosomes



Intercellular Mechanical Junction Basso et al. Lancet 2009; 373; 1289=1300

ARVD Genetic Mutations - 2010

PKP2 (plakophilin-2) - 25% of cases DSG2 (desmoglein-2) - 10% of cases DSP (desmoplakin) - 10% of cases JUP (plakoglobin) Naxos syndrome - rare RYR2 (ryanodine receptor) - atypical disease DSC2 (desmocollin-2) - 3% of cases TGFB3 (transforming growth factor) - rare Several other genetic loci have been identified

but genes not yet identified.


Comprehensive Desmosome Mutation Analysis in North Americans with ARVD

100 patients with ARVC/D (definate in 82, 18 probable) Among the 82 patients with definate ARVC/D

Desmosome gene mutation in 43 (52%) Single heterozygous desmosome gene mutation in 35 (81%) Two mutations in 6 patients (7%) Three mutations in two patients (4%) PKP2 mutation most common (n=37, 45%) DSG2 second most common (n=7, 9%) DSP third most common (n = 2, 2%) DSC2 and JUP least common (1 each)

Digenic heterozygosity (mutations in more than one gene) seen in 5% of patients den Haan, Calkins, Judge Circ Cardiovasc Genetics 2009; 2: 428 428-435



Take care of

AVRD is often found in association with diffuse palmoplantar keratoderma, and woolly hair, because their genes are nearby and often inherited together


Natural history and progression

1-Early clinically ‘’concealed ‘’ phase with or without minor arrhythmias (SCD may be the first manifestation, sport restriction is mandatory).

2-’’Overt electrical heart disorder’’, with severe arrhythmias and impending cardiac arrest

3-Final stage of ‘’ biventricular pump failure’’ mimicking dilated cardiomyopathy with cardiomegaly, CHF, and the risk of thromboembolic complication.


Presentation

Symptoms Up to 80% of individuals with ARVD

present with syncope sudden cardiac death palpitationsSymptoms are usually exercise-related


Other symptoms Abdominal pain Decreased exercise tolerance Dizziness Dyspnea (especially with exertion) Fatigue Mental confusion


Time of presentationThe first clinical signs of ARVD

are usually during late childhood and adolescence.

However, Signs of ARVD have been

demonstrated in infants.


signs Cardiac arrest Peripheral edema Sudden death Tachycardia (Ventricular arrhythmias ) The type of arrhythmia ranges from frequent

premature ventricular complexes (PVCs) to ventricular tachycardia (VT) to ventricular fibrillation (VF).


Pathogenesis

There are two pathological patterns seen in ARVD:-

1- Fatty infiltration 2- Fibro-fatty infiltration.


Fatty infiltration

Fatty infiltration, is confined to the right ventricle.

Partial or near-complete replacement of myocardium with fatty tissue

The apical and infundibular regions of the RV are mostly affected.

The left ventricle and ventricular septum are usually spared.



An illustration of fatty replacement of cardiac muscle within the right ventricular wall.

Fibro-fatty infiltration

Myocardial atrophy is due to injury and apoptosis.

This leads to thinning of the RV wall. Myocytes are replaced with fibrofatty tissue. The LV wall may be involved in some cases. Involvement of the ventricular septum is rare. The areas involved are prone to aneurysm

formation



The myocardium of the right ventricle is partially replaced by fat and fibrous tissue. Strands of myocardium are visible within the fibrous-fatty tissue.These findings are consistent with ARVC/D


Histologic specimen showing combination of fatty deposits (white) and interstitial fibrosis (blue) incorporating atrophic myocytes (red

ventricular tachycardia


http://en.wikipedia.org/wiki/Ventricular_tachycardia

http://en.wikipedia.org/wiki/File:RVOT_Tachycardia.png


Differential diagnosis

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


Uhl's Anomaly Definition Partial/total absence of the RV myocardiumPartial/total absence of the RV myocardium,

termed parchment heartparchment heart since the parietal myocardium is paper thin and translucent since the endocardium is in apposite with the epicardium without intervening muscle.

Uhl's Anomaly Presentation -Cyanosis, dyspnea and right-sided right-sided

failurefailure, usually in infancy or early childhood.

-No genetic basis


Diagnosis

In order to make the diagnosis of ARVD,a number of clinical tests are needed, including Electrocardiogram (EKG). Echocardiography. Right ventricular angiography. Cardiac MRI. genetic testing.


Electrocardiogram

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.


Electrocardiogram

Localized prolongation (>110 ms) of QRS in V1 - V3

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.


Epsilon wave The epsilon wave 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.05/03/23 dr. M. Abdel Salam zannoun

epsilon wave


http://en.wikipedia.org/wiki/File:ARVD-Epsilon_wave.png


Precordial leads of an ECG f recorded during regular sinus rhythm, with an epsilon wave (arrow) in leads V1–V. The ECG shows a right bundle branch block pattern.


12 - lead surface electrocardiogram demonstrating sinus rhythm with prolonged QRS duration, T wave inversion, and epsilon waves (arrows) in the right recordial leads ARVD - arrhythmogenic right ventricular dysplasia

Signal averaged ECG

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


Echocardiography

Echocardiography may reveal an enlarged, hypokinetic right ventricle with a paper-thin RV wall.

The dilatation of the RV will cause dilatation of the tricuspid valve, with subsequent tricuspid regurgitation.

Paradoxical septal motion may also be present.


Cardiac MRI

Fatty infiltration of the RV free wall can be visible on cardiac MRI.

Cardiac MRI can visualize the extreme thinning and akinesis of the RV wall.


Right ventricular angiography

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.


RV angiogram of a patient with ARVD/C: prominent trabeculations and akinetic aneurysmatic bulges of the RVOT (arrow).

Right ventricular biopsy

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.


Right ventricular biopsy

False negatives are common, Because the disease progresses typically from

the epicardium to the endocardium (with the biopsy sample coming from the endocardium).

Segmental nature of the disease. Paper-thin right ventricular 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.


Genetic Testing

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.

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.


Diagnostic Criteria 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 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


Management

The goal of management of ARVD is to decrease the incidence of 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


ManagementManagement options include:- Pharmacological Surgical Catheter ablation Placement of an implantable cardioverter-

defibrillator


Pharmacologic management

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).


http://en.wikipedia.org/wiki/Antiarrhythmic_agent

Pharmacologic management

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 Catheter ablation may be used

to treat intractable ventricular tachycardia. It has a 60-90% success rate.

Indications for catheter ablation include drug-refractory VT and frequent recurrence of VT after ICD placement.


Implantable cardioverter-defibrillator

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.


Cardiac transplant surgery Cardiac transplant surgery may be

performed in ARVD. Indicated if the arrhythmias

associated with the disease are uncontrollable

If there is severe bi-ventricular heart failure that is not manageable with pharmacological therapy.


Family screening

All first degree family members of the affected individual should be screened for ARVD.

Screening tests include: Echocardiogram EKG Signal averaged EKG Holter monitoring Cardiac MRI Exercise stress test



Home message

ARVD is a rare but important cause of sudden cardiac death

Diagnosis of ARVD is difficult. Because of the lifelong implications of a diagnosis of

ARVD on the patient and their family members physicians should be slow to diagnose ARVD.

The New Diagnostic Criteria represent a major step forward


Home message

It appears that the new criteria will result in an earlier diagnosis of ARVD in family members.

We recommend to place an ICD in all patients who meet full diagnostic criteria.

Identification of genetic and clinical risk factors for sudden death remains an active area of investigation.


Home message

Final home message


arrhythmogenic right ventricular dysplasia

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