Header Graphic

====

                     Back to Patient's Version

Arrhythmogenic right ventricular dysplasia (ARVD), also known as arrhythmogenic right ventricular cardiomyopathy (ARVC), is a genetic cause for sudden cardiac arrest (SCA).  In ARVD, there is progressive replacement of normal tissue of the heart, the myocyte, with fat and fibrous tissue (scar tissue). This tends to occur predominantly in the right ventricle (RV) of the heart.  The replacement of the normal heart tissue predisposes the individual to arrhythmias (abnormal heart rhythm secondary to abnormal electrical activity of the heart), hence the name, arrhythmogenic [prone to arrhythmia] right ventricular dysplasia [abnormally formed] = ARVD.   This disease tends to affect any where from 1 in 1000 to 1 in 5000 individuals. The reason for this discrepancy is that the diagnosis of ARVD is difficult to make, and it can be mistaken for other disease states. ARVD has a higher prevalence in certain communities, the best well known in northeast Italy.  Clinically, ARVD is relevant because it is an important cause of sudden death in individuals <30 years of age and has been found in up to 20% of sudden deaths in young people.

Genetics

30 % cases of ARVD occur in families. This may be an underestimation as the genes responsible for this disease may or may not express themselves in affected patients, termed low penetrance. If these genes do express themselves, it may be with varying degrees, a condition known as variable expression. .  Low penetrance and variable expression make it difficult to trace the disease along a family line.

The genes responsible for ARVD may follow two forms of inheritance, autosomal dominant and autosomal recessive. The autosomal dominant (AD) form is the most common. In this form, anyone possessing the gene is at risk for having this syndrome. Furthermore, offspring of people with the mutant gene have a 50% chance of inheriting it from their affected parent. The autosomal recessive (AR) pattern of inheritance is far less common. An individual must receive mutant genes form both their parents, otherwise they will be silent carriers of the mutant genes with no physical manifestation. The AR form is mainly associated with a certain syndrome called Naxos (named for the Greek island where it was first noted) disease, in which there is ARVD along with disorders of the skin and hair. Other conditions similar to Naxos disease have also been linked to an AR inheritance of mutant genes.

Genetic counseling for families of patients who have a relative with ARVD is available at our Genetic Cardiac Program. Genotyping has two roles: first, it will allow confirmation of ARVD in index cases [first member of the family to present with disease] and, second, it will allow for efficient screening of extended family members. In patients affected with ARVD, comprehensive screening for gene mutations will yield a positive result in approximately 40 to 50% of cases. Armed with this knowledge, clinicians can employ focused specific genetic analysis to screen family members. Due to slowly progressive nature of this disease, asymptomatic family members found to have genes linked to ARVD should be monitored aggressively for development of this disease. 

Pathophysiology

Regardless of the mode of inheritance, it appears that the mutant genes code for proteins that make up desmosomes, which are intracellular adhesion complexes that provide mechanical connections between cardiac myocytes (heart cells). When placed under mechanical stress, the impaired desmosomes cause myocytes to detach from each other leading to cell death. This cell death causes inflammation with scar formation and fat deposition. Fatty replacement involves the whole thickness of the RV in 45%, the outer half of RV free wall in 27%, the outer two-thirds in 28% of cases. These fibrofatty islands act as areas of reentry giving rise to ventricular tachycardia, VT. Reentry may be thought of as short circuit in the heart in which electrical currents can cycle rapidly and then chaotically. Initially the disease process is localized, occurring in three discrete areas of the right ventricle known as the “triangle of dysplasia”. This triangle describes the areas involved: the posterior wall, the apex, and the outflow tract of the RV. Gradually the disease spreads from these discrete areas to involve the rest of the RV. The left ventricle (LV) and the intraventricular septum are usually spared.  If LV involvement occurs, it tends to occur as a late manifestation.

Clinical Presentation

When symptoms are present, they tend to occur around 30 yrs of age. However, patients’ age can range from 10 to 50 years.  Men and women appear to be equally affected. The most common symptoms of ARVD are due to an arrhythmia, or due to decreased blood supply to vital organs, such as the brain, caused by an arrhythmia. Symptoms include palpitations (awareness of ones heart beat), dizziness, shortness of breath, syncope (loss of conciseness), or near syncope. Unfortunately, SCA may also be the presenting symptom; patients with no prior symptoms may present with SCA. Some patients may be asymptomatic, and the diagnosis of ARVD is suspected due to a positive family history or findings on noninvasive tests such as an echocardiogram or ECG.  

As previously mentioned, the replacement of normal heart muscles with fat and fibrous tissue predispose to the development of arrhythmias. The most common type of arrhythmias initiate from the RV. These may range from premature ventricle contractions to sustained VT. The frequency of such arrhythmias in ARVD varies with the severity of the disease. Patients with severe forms of the disease tend to have arrhythmias more commonly.  

There seems to be an increased association of VT and SCA with exercise in patients with ARVD. It is presumed that genetically predisposed athletes have increased mechanical stress placed on the heart promoting a more severe and advanced form of the disease.  Also exercise leads to increased catecholamine levels that may predispose to development of VT.  Anyone identified with ARVD should avoid competitive athletics or extremes of physical exertion because these activities would predispose to SCA.

Diagnosis

The diagnosis of ARVD presents a difficult challenge. Even normal hearts have some degree of fat and fibrous tissue. Generally, there is an effort to document abnormal areas of right ventricular dilatation and function with echocardiography and MRI (Fig 1,2). However, echocardiography and MRI may be inaccurate at detecting abnormal motion of the RV, and changes that occur on an ECG in patients with ARVD can occur in different disease states. Thus, requiring just one specific finding might lead to a missed diagnosis in patients who truly have ARVD, or might label patients with healthy hearts as having ARVD.

Figure 1 Video of MRI Showing Dilatation and

Poor Right Ventricular Wall Motion

MRI images couresy of Dr. Steve Wolfe, Advanced Cardiac Imaging, New York City

Note severe hypokinesis of RV with preserved LV wall motion

 

Figure 2.  Gadolinium delayed enhancement cardiac MRI

Diffuse fibrosis of the RV wall with preservation of normal LV tissue (fibrous tissue appears white normal cardiac tissue appears black; see arrows)

MRI images courtesy of Dr. Steve Wolfe, Advanced Cardiac Imaging, New York City

 

ARVD should be considered in patients who present with VT arising from the RV (Figure 3) in the absence of overt heart disease, or in cases of SCA, occurring particularly during exercise. In order to improve the accuracy of diagnosis, a list of diagnostic criteria has been formulated (Table 1). These criteria consist of findings typically seen in ARVD and cover several different diagnostic modalities.  They include the patient’s family history, patients own history of arrhythmias, ECG findings (Figure 4), findings on imaging studies and on biopsy. Among these broad categories the criteria are divided into major and minor. A diagnosis of ARVD can be made when two major criteria, or one major plus two minor criteria, or four minor criteria alone are met. This combination of criteria helps detect patients who truly have the disease. Unfortunately, even with these criteria, patients with less severe forms of the disease can be missed.

Figure 3.  Electrocardiogram of VT Arising from RV

 

Table 1 Criteria for Diagnosis of ARVD

Diagnosis depends on 2 major and 2 minor criteria or 4 minor criteria

Criteria

  Major

Minor

Family History

Familial disease confirmed at necropsy or surgery

Family history of premature sudden death (<35 years) caused be suspected ARVD

Family history of ARVD

ECG depolarization/conduction abnormalities

Epsilon waves or prolongation of the QRS complex ( ≥ 110 msec) in the right precordial leads     ( V1 – V3)

Late potentials seen on signal averaged ECG

Repolarization abnormalities

 

Inverted T waves in the right precordial leads in patients > 12 in the absence of right bundle branch block

Tissue characterization of walls

Fibrofatty replacement of myocardium on endomyocardial biopsy.

 

Global or regional dysfunction and structural alterations

Severe dilation and reduction of RV ejection fraction with minimal LV involvement

 

Mild global RV dilation or ejection fraction reduction with normal LV

Localized RV aneurysms

Mild segmental dilation of the RV

Severe segmental dilation of the RV

Regional RV hypokinesia

Arrhythmia

 

Left bundle branch block type ventricular tachycardia (sustained and nonsustained)                                                                                                  (ECG, Holter, exercise testing)

Frequent ventricular extrasystoles (more than 1,000/24 h) (Holter).

 

Figure 4

Epsilon Wave

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.

Treatment

Currently, no definitive treatment is present which cures the disease. The goal of therapy is to prevent death from VT and SCA. This is effectively accomplished by using implanted cardioverter-defibrillator (ICD). ICD implantation is generally recommended for patients who have had a documented episode of sustained VT, SCA or in patients who are thought to be at high risk for SCA (Table 2). Use of antiarrhythmic drugs (AADs), i.e. sotalol, is reserved for patients who are not candidates for ICD or after ICD implantation to prevent frequent ICD discharges. Milder forms of the disease with no symptoms suggestive of arrhythmia may be treated with beta blocking agents, e.g. metoprolol.  Radiofrequency ablation (RFA) targeted to the site of the arrhythmia may be occasionally be recommend for high risk patients who are not candidates for an ICD, or those who have arrhythmias refractory to treatment post ICD. In this context indications for RFA are similar to those of AAD.  As mentioned previously, increased physical activity may advance disease and lead to arrhythmias. Thus, patients with ARVD should not participate in competitive sports or in activities in which loss of conciseness may lead to harm e.g. scuba diving. Low intensity activities such as golf are considered safe.

Table 2 High Risk Features in Patients with ARVD

 

  • Younger patients
  • Patients who present with recurrent syncope
  • Patients with history of cardiac arrest or sustained VT
  • Patients with clinical signs of RV failure
  • Patients with LV involvement
  • Patients with or having a family member with the high risk ARVD gene (ARVD2)
  • Patients with an increase in QRS dispersion ≥ 40 msec                                              (maximum measured QRS duration minus minimum measured QRS duration)

 

  • Patients with Naxos disease

 

Prognosis

The overall prognosis in ARVD is not clear. Small retrospective analysis of patients with ARVD has quantified an annual mortality of 2.3%.   As may be expected, patients with mild disease and nonsustained episodes of VT tend to have a relatively better prognosis than patients with severe disease, a history of sustained VT, or evidence of right or left sided heart failure. Family members of affected patients also need to be screened periodically using a modified diagnostic criteria, which takes into account minor abnormalities of the ECG, Holter, or echocardiographic criteria.(Table 3), as with time they may develop ARVD.  

Table 3 Proposed Modification of Task Force Criteria for the Diagnosis of Familial ARVC

ARVC in First-Degree Relative Plus One of the Following:


1. ECG

T-wave inversion in right precordial leads (V2 and V3)

2. SAECG

Late potentials seen on signal-averaged ECG

3. Arrhythmia

LBBB type VT on ECG, Holter monitoring or during exercise testing

 

Extrasystoles >200 over a 24-h period*

4. Structural or functional abnormality of the RV

Mild global RV dilatation and/or EF reduction with normal LV

 

Mild segmental dilatation of the RV

 

Regional RV hypokinesia

ARVC = arrythmogenic right ventricular cardiomyopathy; ECG = electrocardiogram; EF = ejection fraction; LBBB = left bundle branch block; RV = right ventricle; SAECG = signal-averaged electrocardiography; VT = ventricular tachycardia.
* Previously >1,000/24-h period in task force criteria.

Modified from Hamid M.S., Norman M., Quraishi A., Firoozi S. et al. Prospective evaluation of relatives for familial arrhythmogenic right ventricular cardiomyopathy/dysplasia reveals a need to broaden diagnostic criteria, J Am Coll Cardiol 16 (2002) (40), pp. 1445–1450.