Arrhythmogenic right ventricular dysplasia pathophysiology

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

Overview

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.

Pathophysiology

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

Apoptosis

Apoptosis (programmed cell death) appears to play a role in the pathogenesis of ARVD and high levels of apopain have been observed. 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 Dilation of the Right Ventricle

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).

Left Ventricular Involvement

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.

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.

Fibro-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.

Genetics

There is an autosomal dominant pattern of inheritance..

ARVD1

This variant is due to a heterozygous mutation in the TGFB3 gene (190230) on chromosome 14q24.

ARVD2

This variant (600996) is associated with a mutation in the RYR2 gene (180902) on chromosome 1q42-q43.

ARVD3

This variant (602086) is associated with a mutation in the chromosome 14q12-q22 region.

ARVD4

This variant (602087) is associated with a mutation in the chromosome 2q32.1-q32.3 region.

ARVD5

This variant (604400) is associated with a mutation in the TMEM43 gene (612048) on chromosome 3p23 region.

ARVD6

This variant (604401), is associated with a mutation in the chromosome 10p14-p12 region.

ARVD7

This variant 609160) is associated with a mutation in the chromosome 10q22.3 region.

ARVD8

This variant 607450) is associated with a mutation in the DSP gene (125647) on chromosome 6p24.<ref.Rampazzo A, Nava A, Malacrida S et-al. Mutation in human desmoplakin domain binding to plakoglobin causes a dominant form of arrhythmogenic right ventricular cardiomyopathy. Am. J. Hum. Genet. 2002;71 (5): 1200-6. doi:10.1086/344208 - Free text at pubmed - Pubmed citation</ref>

ARVD9

This variant (609040) is associated with a mutation in the PKP2 gene (602861) on chromosome 12p11.

ARVD10

This variant (610193) is associated with a mutation in the DSG2 gene (125671) on chromosome 18q12.1-q12.

ARVD11

This variant (610476) is associated with a mutation in the DSC2 gene (125645) on chromosome 18q12.1.

ARVD12

This variant (611528) is associated with a mutation in the JUP gene (173325) on chromosome 17q21.

Ventricular arrhythmias

Monomorphic ventricular tachycardia 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.