About ARVC

The clinical picture of Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) was first described by Guy Fontaine in 1977. Although several decades of intensive research have past, many questions regarding this clinical entity remain unresolved.

What is ARVC?

ARVC is an autosomal-dominant hereditary disease and an important cause of sudden death, particularly in young people, although people from all age groups may be affected. The prevalence is between 1:2000 and 1:5000. With this website, we want to inform you about the diagnosis, treatment and genetic background of ARVC. Our website also gives us the possibility to introduce our Multicenter ARVC Program.
As often with rare diseases, pronounced and uncommon manifestations of ARVC are overrepresented in the medical literature. Unfortunately, there are only a few studies reporting data with large sample sizes over a long-term period. Hence, it may be difficult to answer certain questions of treating physicians, affected patients and their relatives.
We have established this Multicenter ARVC Registry to follow a large patient population over a long-term period. Our goal is to answer important questions regarding diagnosis, risk stratification and treatment. Our registry consist of >300 index patients and family members. We are working together with allSwiss University Hospitals and the largest Cantone-Hospitals, as well as with University Hospitals from Germany, the Netherlandsand Russia. Thus, we would appreciate participation of your ARVC patients in our registry and clinical studies.

Whom to screen for ARVC?

ARVC manifests through ventricular arrhythmias (VA) and ventricular tachycardias (VT) that mostly arise from the right ventricle (RV). Some VAs are asymptomatic and can only be detected by routine electrocardiography. Others, e.g. rapid sustained VT or ventricular fibrillation are diagnosed because of syncopes or survived sudden cardiac arrest. ARVC patients mainly develop their arrhythmias after adolescence, mosty before the age of 45. Men are more commonly affected than women. Increased physical activity is a common trigger for arrhythmias in ARVC. Idiopathic right ventricular outflow tract (RVOT) tachycardia constitutes an important differential diagnosis to ARVC and arises in the RVOT. However, in contrast to ARVC, patients with idiopathic RVOT tachycardia do not display macroscopic cardiac structural abnormalities. Importantly, all patients with RVOT tachycardia should be screened for ARVC. Patients with ARVC will attract attention by a dilated RV on echocardiography or x-ray. At later stages, the left ventricle may also be affected, which can resemble idiopathic dilative cardiomyopathy.

The following information shall help physicians to diagnose ARVC:

Symptoms

The most frequent symptoms in ARVC are palpitations, dizziness, syncope, chest pain and dyspnea. A minority of ARVC patients will develop atrial arrhythmias (mostly atrial fibrillation and atrial flutter). Ventricular tachycardias (VT) are usually caused by fibro-fatty infiltration and susceptibility for rotary electrical circuits (re-entry) mainly originating in the right ventricle (RV). Often, a single patient with ARVC may have several re-entry circuits. The three most commonly involved RV regions are the RVOT, the RV apex and the subtricuspid region, also called "the triangle of dysplasia". These regions typically display regional wall motion abnormalities and aneurysms that can be visualized by echocardiography, RV angiography and cardiac magnetic resonance tomography (CMR). According to current knowledge, no extracardiac manifestations of ARVC exist (exception: „Naxos disease“ featuring a dysplastic RV, palmoplantar hyperkeratosis and wooly hair, mainly prevalent on the greek island of Naxos).

Pathology
Macroscopic fibro-fatty remodelling Microscopic fibro-fatty remodelling

Autoptic examination demonstrates a regional or diffuse remodelling of the right ventricular myocardium into fibro-fatty tissue. These structural changes typically begin in the subepicardial region and by time expand through the whole myocardium (see images on the left and right). Not infrequently, the left ventricle may also be affected by this pathologic process.

Genetics

ARVC is a hereditary disease with an autosomal-dominant trait. Its penetrance and phenotypic expression are strongly variable. An affected person carries a 50% risk of passing the genetic mutation on to his offspring. Most frequently, genes encoding the desmosome, an important cardiac structure that stabilizes the myocardium, are involved. However, one has to assume that other, yet unknown genes might play a role in this pathologic process. Genetic counseling by specialists should be available for all ARVC patients and their families. As significant intra-family variations in phenotypic expression of ARVC exist, several non-genetic factors also play an important role in disease manifestation. Thus, cardiac screening of all first degree relatives of an ARVC index patient, namely by 12-lead surface electrocardiography (ECG), transthoracic echocardiography (TTE), stress testing and 24-h ECG should be performed according to the revised 2010 Task Force Criteria. Clinical follow-up in asymptomatic healthy relatives is recommended every 2-3 years until the age of 60. This is important, as ARVC can also manifest in the elderly. Genetic cascade screening of relatives is recommended, if a pathogenic mutation is found in the index patient. Genetic testing for all known desmosomal and non-desmosomal ARVC associated genes is now routinely available as well as cascade family screening for specific genetic mutations.

Diagnosis of ARVC

ARVC is diagnosed according to the 2010 revised Task Force Criteria.

Non-invasive tests
ECG: Pathognomonic Epsilon Wave in V1 Signal-averaged ECG: Typical late potentials

Patients with suspected ARVC should be evaluated by a thorough history, clinical examination, ECG, signal-averaged ECG (SAECG), 24h-ECG, stress testing and TTE. 12-lead ECG may show depolarization abnormalities such as pathognomonic epsilon waves (see image on the upper left) and repolarization abnormalities (T-wave inversions in the precordial and inferior leads, particularly V1-V3) (see image on the lower left). SAECG reveals late potentials in about 50% of patients that are caused by delayed de-and repolarization (see image on the right). Although TTE is easily available (see video on the lower right), complete assessment of the RV is often difficult.

T-Wave Inversions and a typical slurred S-upstroke in V1-V3 (arrow)

Evaluation of all RV regions regarding segmental wall motion abnormalities is difficult and needs expertise. We have established a specific TTE protocol for ARVC at the University Hospital Zurich to validate the echocardiographic revised 2010 Task Force Criteria. For long, cardiac magnetic resonance tomography (CMR) has been regarded as the best method for ARVC diagnosis. Today, its role is controversial. There is general agreement that a diagnosis of ARVC should not be solely made on the basis of CMR findings.

Invasive tests
Right Ventricle Angiography

If non-invasive tests do not provide clear results, invasive tests are recommended: (1) RV angiography (2) electrophysiologic study (EPS), and endomyocardial biopsy (3). Besides CMR, RV angiography is considered as an important tool for diagnosis of regional wall motion abnormalities (see image on the left and video on the right). However, interpretation of the images needs expertise and quantification of RV volumes is not well validated. In our center we routinely perform an EPS right after RV angiography to test for inducibility of ventricular arrhythmias. VTs with multiple morphologies (pleomorphic), particularly with left bundle branch block morphology and a superior axis (QRS negative in leads II, III, aVF, and positive in lead aVL) are characteristic of ARVC. Routine endomycardial biopsies taken from the septal RV are often not diagnostic, as the septum is not involved in the disease process or only involved at a very late stage. A negative biopsy finding thus cannot exclude ARVC. Regions containing fibro-fatty tissue can also be detected with three-dimensional electroanatomical mapping during an EPS, occasionally in combination with voltage-guided biopsy (see image on the lower left).

3-D Electroanatomical Mapping
Therapy

Management of patients with ARVC should be individualized and depend on patients‘ symptoms, results of cardiac testing and ventricular arrhythmias. Therapeutic options include (1) restriction from strenuous physical activity (2) antiarrhythmics (betablocker, sotalol or amiodarone), (3) implantation of an ICD and in case of refractory VT (4) catheter-ablation therapy. Implantation of an ICD is recommended, if there is a high risk for sudden cardiac death. (1) A survived sudden cardiac arrest (2) syncopes (3) significant RV dilatation (4) LV involvement; (5) documented sustained VT (6) inducibility of VT/VF during EPS are generally excepted as risk factors conferring an increased risk for sudden cardiac death. Yet, risk stratification is not perfect and future studies will improve our understanding of risk.

Follow-Up

Disease progression may be very variable in ARVC and depends on many, yet unknown factors. We recommend that a clinical follow-up visit including ECG, Holter ECG, stress testing and TTE or CMR is performed once yearly. Other imaging modalities such as SPECT-scintigraphy, PET-CT or RV angiography may be helpful, if TTE or CMR do not yield clear results. An ICD-patient should be seen every 3-6 months and the device should be interrogated within this time period.

Prognosis

The long-term prognosis of ARVC patients is generally good, if the disease is diagnosed early and treated appropriately. This treatment includes restriction from strenuous physical activity. Only in rare cases an irreversible severe contractile dysfunction of one or both ventricles and/or incessant ventricular arrhythmias may occur necessitating cardiac replacement therapy.