Arrhythmogenic right ventriculardysplasia

KumaresanDr. Kim Vaiphei

Introduction

• ARVD is an unusual, often familial, condition characterized by the replacement of myocardial tissue by fat and fibrous tissue.

• The name arrhythmogenic right ventricular dysplasia (ARVD) was coined by Frank and Fontaine in 1978.

• In 1996, WHO and the ISFC: decided that ARVD had to be considered as a manifestation of a cardiomyopathy(ARVD/C).

Incidence/prevalence

• ARVC/D is an important cause of ventricular arrhythmias in children and young adults.

• 80% of the disease is diagnosed in patients younger than 40 years.

• It is seen predominantly in males with M:F ratio 2-3:1.• It accounts for up to 17% of all sudden cardiac deaths in the

young. • Prevalence - 0.02% to 0.1% (average 1:5,000) but it is Prevalence - 0.02% to 0.1% (average 1:5,000) but it is

dependent on geographic circumstances.dependent on geographic circumstances.– In certain regions of Italy and Greece (Island of Naxos), an In certain regions of Italy and Greece (Island of Naxos), an

increased prevalence of 0.4% to 0.8%.increased prevalence of 0.4% to 0.8%.

Pathophysiology

• ARVD is characterized by progressive replacement of the right ventricular myocardium by fibrofatty tissue.

• The most common location for this tissue transformation is between the anterior infundibulum, right ventricular apex, and inferior or diaphragmatic aspect of the right ventricle, the so-called “triangle of dysplasia”.

• Dysplasia in this region usually leads to dilatations or aneurysms having paradoxical systolic motion (expansion with systole instead of contraction).

Triangle of dysplasia

Genetic factors

• ARVD is a genetic disease that have a strong familial association, with more than 30-50% of patients.

• The most common mode of inheritance is autosomal dominant.

• Several ARVD/C loci have been identified.• Mutations in plakoglobin (PKP 2) is the most common cause

of ARVD/C, accounting for approximately 20% of the cases.• Mutations in desmoglein (DSG 2) and desmoplakin (DSP) each

accounts for approximately 10 to 15 of the cases of ARVD/C.

Chromosomal loci and causal genes

Chromosome Symbol Protein Function

ARVD/C 1 14q24.3 TGF3 TGF3 Mitotic factor

ARVD/C 2 14q42.2 RYR 2 Ryanodine receptor 2 Ca channel

ARVD/C 3 1q12

ARVD/C 4 2q32.1

ARVD/C 5 3p23

ARVD/C 6 10p12

ARVD/C 7 10q22

ARVD/C 8 6p24 DSP Desmoplakin Desmosomes

ARVD/C 9 12p11 PKP 2 Plakoglobin 2 Desmosomes

18q12.1 DSG 2 Desmoglein 2 Desmosomes

Naxos disease 17q21 JUP Plakoglobin Desmosomes

• “Disease of desmosomal dysfunction”• Desmosomes bind myocardial cells to one another,

providing cellular contact necessary for electrical conduction and mechanical contraction

• Right ventricular wall and, in particular, “triangle of dysplasia”, is thin, making it prone to disruption

• Exercise causes increased inotropy. This may worsen disruption and accelerate disease process.

Autosomal recessive variant of ARVD/C

• Naxos disease is an autosomal recessive variant of ARVD, described initially on the Greek island of Naxos.

• 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.

Etiopathogenesis

• The exact pathogenesis of ARVD/C is unknown. • Basso et al proposed 4 theories that may potentially explain

the development and occurrence of the disease.DysontogenicDegenerativeInflammatory Apoptotic

• D’Amati et al proposed a transdifferentiation theory, which is based on the hypothesis that cells can change from muscle to adipose tissue.

• In the disontogenetic theory, the absence of myocardium is considered to be the consequence of a congenital aplasia or hypoplasia of the right ventricular wall, leading to a parchmentlike appearance.

• In the degenerative theory, the loss of the myocardium is considered to be a consequence of progressive myocyte death due to some metabolic or ultrastructural defect.

• In the inflammatory theory, the fibrofatty replacement is viewed as a healing process in the setting of chronic myocarditis.

• The disappearance of the right ventricular myocardium might be the consequence of an inflammatory necrotic injury

followed by fibrofatty repair.• Thus, an infectious and/or immune myocardial reaction might

intervene in the etiology and pathogenesis of the disease

• Apoptosis plays a large role and detected in biopsy and autopsy specimens.

• Abnormal bouts of recurring or continued apoptosis lead to progressive myocardial muscle loss followed by fibrofatty replacement.

• These apoptotic bouts may enhance the electrical vulnerability of the right ventricle, leading to potentially life-threatening arrhythmias.

• The "transdifferentiation theory," suggests that cardiomyocytes transdifferentiate into adipocytes in response to stress.

Gross

• Anatomic malformations of RV consist of Mild-to-severe global RV dilation,Thinning of the RV free wall (0.3cm) RV aneurysms Intramural fat infiltration

• Left ventricle and septum usually spared.• In contrast, the trabeculae of the apex and the right side of

the ventricular septum are hypertrophied.

Histology

• The most striking feature of the disease is the diffuse or segmental loss of myocardium with replacement by fat and fibrous tissue.

• The disease process starts in the subepicardial region and works towards the endocardial surface, leading to transmural involvement (possibly accounting for the aneurysmal dilatation of the RV).

• Only the subendocardial layers are preserved.

• There are two pathological patterns seen in ARVD.

Fatty infiltration and Fibro-fatty infiltration.

Fatty infiltration• The first pattern, partial or near-complete

replacement of myocardium by fatty tissue without wall thinning.

• Fatty infiltration is confined to the right ventricle.• The left ventricle and ventricular septum are usually

spared. • No inflammatory infiltrates are seen in this stage. • There is evidence of myocyte degeneration

(intracytoplasmic vacuoles and myofibrillar Loss) and apoptosis..

Fibro-fatty infiltration

• Later stage involves the replacement of myocytes with fatty tissue and fibrosis.

• 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.

• A patchy myocarditis is seen in 1/3 of cases,with inflammatory infiltrates ( T cells).

• Prone to aneurysm formation.

• LV and IVS are also involved in the late stage of the disease.

• Fatty infiltration of RV per se probably is a different process that may not be considered synonymous with ARVD/C.

• Therefore, the diagnosis of ARVD/C should only be made in the presence of fibrosis, which probably is more arrhythmogenic than just fatty infiltration.

Phases of ARVD

• The concealed phase. This phase is characterized by RV changes with or without ventricular arrhythmias. It is mostly seen in young people involved in competitive sports. Sudden death is often the first manifestation.

• The second stage of ARVD is overt electrical disorder. The RV undergoes both functional and structural changes, leading to RV arrhythmias or cardiac arrest.

• The third phase of ARVD is RV failure. The progression of RV muscle disease leads to RV dysfunction. Left ventricular function is usually spared at this point.

• The final stage is biventricular pump failure. In this final stage, the LV and IVS is also involved.

• The progression leads to heart failure, as well as other complications such as atrial fibrillation and thromboembolic events.

Clinical presentation

• In as many as 80% of patients, the first manifestation of the disease is unexplained syncope or sudden cardiac death.

• The remainder frequently present with palpitations or other symptoms due to right ventricular outflow tract (RVOT) tachycardia .

• Symptoms are usually exercise-related. • The first clinical signs of ARVD are usually during adolescence.

Diagnosis

• Begins with a thorough personal and family history, ideally of first- and second-degree relatives.

• A personal history of palpitations, especially in a young person, or a family history of sudden cardiac death or death at an early age should raise the index of suspicion for ARVD.

Diagnosis

• The physical examination is normal in at least 50 percent of patients with ARVD.

• A definite diagnosis of ARVD/C is based on histologic demonstration of transmural fibrofatty replacement of RV myocardium at autopsy or surgery.

• Myocardial biopsy lacks sufficient sensitivity because, the biopsy is performed mostly in the IVS, whereas the typical pathologic changes of ARVD/C are more pronounced in the RVFW.

Diagnostic Criteria

• In 1994, the European Society of Cardiology and International Society and Federation of Cardiology

• scoring system based on major and minor criteria was introduced– Structural changes– Histologic tissue changes– EKG changes– Arrythmias– Family History

ECG

• 10-50% have normal ECG on presentation• 50 to 90 % of pts with ARVD will have characteristic

findings on ECG.• T-wave inversion in the anterior precordial leads (V1

through V6).• Prolonged QRS• Epsilon waves (30%)- best in leads V1-V3 • VT with Complete/incomplete RBBB.

Epsilon wave

RV contrast angiography• Angiographic evidence of ARVD/C consists of

akinesis/ dyskinetic bulgings localized in the anatomic triangle of dysplasia and the presence of hypertrophic trabeculae .

• However, – the invasive nature of the angiographic technique, – x-ray exposure, – common occurrence of extrasystoles during contrast

injection, – and considerable interobserver variability

• preclude the use of RV angiography as a primary diagnostic technique.

Echocardiography• The most widely used noninvasive technique for

assessing cardiac performance in ARVD/C. • The most conspicuous findings:

RV dilation, enlargement of the RA.Isolated dilatation of the RVOT, localized aneurysms and akinesis/ dyskinesis of the inferior wall and the RV apex.

• Computed Tomographyabundant epicardial adipose tissueprominent trabeculations

scalloped appearance of the RV free wallintramyocardial fat deposits

• Magnetic Resonance ImagingIt can distinguish fat from muscleIt provides information about RV wall

motion and function.

Uhl’s anomaly

• Uhl anomaly was first described in 1952 by Hendry Uhl.

• Also k/a “parchment right ventricle”• It is a very rare congenital heart disease charactrized

by absence of the myocardial layer in the right ventricle, with apposition of the endocardium and epicardium.

• Uhl’s anomaly is rarely familial.• CCF is the usual mode of presentation.• Arrythmias or heart blocks are rare in this condition.

• Both sexes are equally affected.• Pts age at death ranged from one day to 84 yrs with

median of 15 yrs. (In ARVD, males are commonly affected with median age at death of 33yrs).

Pathology

• Complete absence of myocardium in the right ventricle with apposing endocardium and epicardium.

• No interposed adipose tissue or fibrosis.• No evidence of inflammation

Exercise and ventricular arrhythmias

• ARVD/C usually is characterized by the occurrence of symptomatic RV arrhythmias during exercise.

• These arrhythmias that typically are induced by adrenergic stimulation.

• During exercise testing, 50% to 60% of patients with ARVD/C show ventricular arrhythmias

• The occurrence of arrhythmic cardiac arrest due to ARVD/C is significantly increased in athletes.

• Particularly in certain regions in Italy, ARVD/C has been shown to be the most frequent disease (22%) leading to exercise-induced cardiac death in athletes.

Natural history

• Natural history of ARVD/C: cardiac electrical instability and progressive RV dysfunction.

• Mortality rates ranged from 4% to 20%.• May account for up to 5% of SDs in young adults in the US and

25% of exercise-related deaths. • In most patients, the mechanism of SD in ARVD/C is

acceleration of VT with ultimate degeneration into VF. • Generally, RV failure and LV dysfunction were independently

associated with cardiovascular mortality.

Treatment

• There are five therapeutic options in patients with ARVD/C: – (1) antiarrhythmic agents– (2) radiofrequency ablation– (4) Heart failure treatment – (5) surgical treatment.