Physician's Version            Meet Our Physicians Arrhythmogenic right ventricular dysplasia (ARVD), also known as arrhythmogenic right ventricular cardiomyopathy (ARVC), is a genetic cause for sudden cardiac arrest (SCA), a condition in which the heart stops beating.  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 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 ARVD genes should be monitored aggressively for disease development.  Pathophysiology Regardless of the mode of inheritance, it appears that the mutant genes code for similar proteins. The mutant proteins are called desmosomes. Desmosomes help keep adjacent heart cells attached together and are crucial in maintaining the structural integrity if the heart. In ARVD, the defective desmosomes when placed under mechanical stress (exercise), detach from each other, leading to cell death. This cell death causes inflammation with scar formation and fat deposition. These fibrofatty islands predispose the individual to develop arrhythmias. Initially, the disease process is localized but gradually the disease spreads from discrete areas to involve the rest of the RV. The left ventricle (LV) is 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 an electrocardiogram, ECG. There seems to be an increased association of arrhythmia and SCA with exercise. in patients with ARVD. Anyone identified with ARVD should avoid competitive athletics or extremes of physical exertion because these activities predispose to SCA. Diagnosis The diagnosis of ARVD presents a difficult challenge. Even normal hearts have some degree of fat and fibrous tissue.  ARVD should be considered in patients who present with a specific type of arrhythmia called ventricular tachycardia (VT) arising from the RV (Figure 1) 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). Unfortunately, even with these criteria, patients with less severe forms of the disease can be missed. Figure 1 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 lack type ventricular tachycardia (sustained and nonsustained) (ECG, Holter, exersise testing) Frequent ventricular extrasystoles (more than 1,000/24 h) (Holter). 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). ICDs are devices placed under the patient’s skin that continuously monitor the heart’s electrical activity. If a life threatening arrhythmia is detected the device “shocks” the heart back in to normal rhythm. 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). Since medications are not 100% effective in aborting SCA, they are 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 certain medications i.e beta blocking agents, e.g. metoprolol. 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. As may be expected, patients with mild disease and short lasting 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.