Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a genetic form of cardiomyopathy that primarily affects the right ventricle. It may also involve the left ventricle and culminate in life-threatening ventricular arrhythmias, prompting sudden cardiac death (SCD) and biventricular heart failure.
ARVC/D is characterized pathologically by myocardial atrophy, fibrofatty replacement, fibrosis and ultimate thinning of the wall with chamber dilation and aneurysm formation.9 These changes consequently produce electrical instability precipitating ventricular tachycardia (VT) and SCD.
Epidemiology
The estimated prevalence of ARVC/D in the general population is approximately 1:5000, affecting men more frequently than women with a ratio of 3:1. ARVC/D accounts for 11%–22% of cases of SCD in the young athlete patient population.
It has been difficult to determine the incidence of ARVC/D due to the different clinical manifestations of the disease. These manifestations vary greatly, especially in different ethnic groups.
Gemayel C, Pelliccia A, Thompson PD. Arrhythmogenic right ventricular cardiomyopathy. J Am Coll Cardiol. 2001
Dalal D, Nasir K, Bomma C, et al. Arrhythmogenic right ventricular dysplasia: a United States experience. Circulation. 2005
Symptoms
ARVC/D is a devastating disease given the fact that the first symptom is often SCD, which makes early detection and a family screening test the cornerstone in the diagnostic evaluation.
Other common presentations are palpitations (27%), syncope (26%), atypical chest pain, RV failure and 6% may remain asymptomatic. Early intervention with an Implantable Cardioverter-Defibrillator (ICD) decreases the risk of SCD, but ARVC/D is a progressive disease, which can progress to refractory/recalcitrant VT or a ventricular fibrillation storm despite ICD therapy.
The most common arrhythmia is sustained or nonsustained monomorphic VT that originates in the RV and therefore has a left bundle branch block morphology. Alternatively, in some cases where the LV is involved, VT could present with a right bundle branch block morphology.
These symptoms are usually exercise-related, mainly due to an activation of the sympathetic nervous system, which may lead to premature beats and re-entrant arrhythmogenic circuits. In a pathological myocardial substrate, this can perpetuate the incidence of life-threatening arrhythmias.
The advanced stage of ARVC/D is characterized by signs and symptoms of RV or LV failure depending on which ventricle is more affected (in the classic form, it is generally the RV more affected than the LV), and finally frank biventricular congestive heart failure, which may be difficult to distinguish clinically from dilated cardiomyopathy.
Dalal D, Nasir K, Bomma C, et al. Arrhythmogenic right ventricular dysplasia: a United States experience. Circulation. 2005
Diagnosis
ARVC/D should be suspected in a young patient with palpitations, syncope or aborted SCD. VT with LBBB morphology is the classic presentation. Other electrocardiographic abnormalities such as inverted T waves in right precordial leads (V1–V3) and frequent premature ventricular complex, even in asymptomatic patients, should arouse the suspicion for this cardiomyopathy.
Clinical diagnosis of ARVC/D is often difficult because of the non-specific nature of the disease and the broad spectrum of phenotypic variations. There is no definitive diagnostic standard. Endomyocardial biopsy of the RV is definitive (gold standard) when positive but it often yields a false-negative result and in most patients, assessment of transmural myocardium is not possible based on the fact that the disease spreads from epicardium to endocardium. Therefore, it is not practical in the clinical setting.
Several investigations contribute to the diagnosis of ARVC/D. Consensus diagnostic criteria have been developed, which include RV biopsy, non-invasive electrocardiography, family history and imaging evaluation with echocardiography, cardiovascular magnetic resonance imaging and angiography.
The advent of the molecular genetics era has made a tremendous diagnostic impact and contributed new insights to the understanding of its pathophysiology.
The 1994 Task Force criteria were based upon clinical experience, family history, and structural, functional and electrocardiographic abnormalities in patients with severe disease. Thus, these criteria have high specificity but lack sensitivity, increasing the risk of a false negative in the early stages of ARVC/D. A modification of these original criteria was made in order to include first degree relatives on early stage of the disease or incomplete expression. This increased the sensitivity, but not surprisingly also increased the risk of false positives cases. These diagnostic criteria were revised in 2010 and now incorporate the advances in both technology and genetics.
The diagnosis is based on the presence of major and minor criteria, which are classified into six categories (global or regional dysfunction and structural alterations, tissue characterization of wall, repolarization abnormalities, depolarization/conduction abnormalities, arrhythmias and family history). The diagnosis of ARVC/D is made in the presence of two major or one major plus two minor criteria or four minor criteria taken from different groups.
Corrado D, Thiene G. Arrhythmogenic right ventricular cardiomyopathy/dysplasia: clinical impact of molecular genetic studies. Circulation. 2006
Marcus FI, McKenna WJ, Sherrill D, et al. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the Task Force Criteria. Circulation. 2010
Pathogenesis
Different causes have been suggested such as congenital defects, genetics and acquired factors. The hypothesis of a congenital cause leads to the adoption of the term dysplasia, but ARVC/D has been differentiated and its natural history through adult life has been well documented. This hypothesis has evolved into the idea of genetically determined cardiomyopathy, which has been retained on genetic grounds. In approximately 30%–50% of cases it is transmitted with an autosomal dominant pattern of inheritance, with incomplete penetrance and variable expression.
Acquired factors have also been suggested as the cause of ARVC/D. The strongest association has been made with viral myocarditis inducing arrhythmogenic cardiomyopathy. On histopathology, a lymphocytic infiltrate with disappearance of myocytes and fibrofatty replacement is often found, which can also be seen in viral myocarditis. It is possible that the wide variation in presentation of ARVC/D patients could be explained by its genetic heterogeneity and modifying factors such as exercise and/or viral myocarditis.
McKenna WJ, Thiene G, Nava A, et al. Diagnosis of arrhythmogenic right ventricular dysplasia/cardiomyopathy. Task Force of the Working Group Myocardial and Pericardial Disease of the European Society of Cardiology and of the Scientific Council on Cardiomyopathies of the International Society and Federation of Cardiology. Br Heart J. 1994
Risk factor: Physical activity
Exercise has been related to an increased incidence of ventricular conduction disorders, SCD, worsening symptoms and progression of the fibro-fatty atrophy, particularly in young patients and competitive athletes. For that reason, high risk patients with suspected or confirmed ARVC/D diagnosis should avoid vigorous physical activity including competitive sports, regular training and strenuous exertion involving abrupt physical effort, as well as any recreational activity associated with symptoms.
Complications
ARVC/D is a progressive disease with life-threatening complications, which constitute a clinical diagnostic challenge for physicians, given the different genotypic and phenotypic variations and the wide ranges of clinical manifestations.
The main challenge is to improve the risk stratification for better identification of high risk patients of SCD and heart failure, who most benefit from early intervention with lifestyle changes, restriction of physical activity, antiarrhythmic drugs, ICD placement, new ablation approaches with simultaneous endocardial and epicardial ablation and, if necessary, heart transplantation. These interventions are available and life saving, with the potential to change the natural history of the disease by offering a good quality and better life expectancy.
Late complications of the disease, who develop heart failure symptoms or life threatening and untreatable VT, heart transplantation could be an option with good short and long term survival. Heart transplantation is essentially the final therapeutic option for these patients.
Therapy
Patients with ARVC/D may remain asymptomatic or may present with a wide variety of symptoms. Therefore, the therapeutic strategy has to be individualized, based on clinical presentation, risk stratification and patient/physician preference. The main goal of therapy is to prevent serious events, which requires identifying high-risk patients for malignant arrhythmias and SCD.
Pharmacological therapy:
Antiarrhythmic medications have been used for symptomatic control in patients who are not candidates for an implantable cardioverter-defibrillator (ICD) or as an adjunct therapy to reduce frequent ICD discharges due to recurrent VT. Antiarrhythmic medications have been mostly recommended in patients with severe LV dysfunction and severe symptoms of ventricular arrhythmias. Beta-adrenergic blocking agents have shown effectiveness in reducing adrenergically-stimulated arrhythmias.
The combination of beta-blockers and amiodarone have had a beneficial effect in suppression of non-sustained VT, reduction in the frequency of sustained ventricular arrhythmias,91 and reduction of VT rate preventing syncope and favoring antitachycardia pacing termination rather than shock therapy. Furthermore, they favor the suppression of other arrhythmias, especially supraventricular tachycardia and atrial fibrillation which may cause symptoms or interfere with ICD function, resulting in inappropriate discharges.
Sotalol and amiodarone have been proposed as effective treatment of sustained VT or ventricular fibrillation as adjunctive therapy to ICD or in patients with ARVC/D that are not candidates for ICD implantation.
Non Pharmacologic Therapy:
Implantable cardioverter-defibrillator (ICD)
It represents prophylactic implantation based on a clinical profile with one or more identifiable risk factors for SCD. There is a consensus that high-risk patients should be considered as ICD placement candidates. Consequently, patients with episodes of sustained VT or VF, unexplained syncope, non-sustained VT on noninvasive monitoring, familial history of sudden death, extensive disease including those with LV involvement and good functional status are potential candidates for ICD implantation even in the absence of ventricular arrhythmias. Additionally, patients with genotypes of ARVC/D associated with a high risk for SCD should be considered as possible candidates for ICD therapy. It is currently recommended that asymptomatic patients have to be managed in a case by case basis.
Radiofrequency ablation
Radiofrequency ablation has been reserved for patients with recurrent ventricular arrhythmias despite treatment with antiarrhythmic drugs. Ablation is considered a complementary therapy to ICD, useful for management of symptoms but may not be sufficient to prevent SCD.
Surgical treatment
Surgical isolation of the RV free wall prevents the propagation of malignant arrhythmias from the RV to the LV; by performing this surgical procedure there would be less substrate for the electrical disturbance. This therapeutic approach was once an option for patients with VT refractory to antiarrhythmic medications. However, patients were at risk of postoperative RV failure. Over the last decades, this procedure has been replaced by ICD placement, which has achieved widespread acceptance as a preventive treatment for SCD.
Epstein AE, DiMarco JP, Ellenbogen KA, et al. ACC/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the American Association for Thoracic Surgery and Society of Thoracic Surgeons. Circulation. 2008
Zipes DP, Camm AJ, Borggrefe M, et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines . J Am Coll Cardiol. 2006
Wichter T, Borggrefe M, Haverkamp W, Chen X, Breithardt G. Efficacy of antiarrhythmic drugs in patients with arrhythmogenic right ventricular disease. Results in patients with inducible and noninducible ventricular tachycardia. Circulation. 1992
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