ARVD

 

Introduction

Arrhythmogenic right ventricular dysplasia or cardiomyopathy (ARVD/C) is a heart muscle disease, often familial, characterized by structural and functional abnormalities of the RV due to replacement of the myocardium by fatty and fibrofatty tissue. Clinical presentation of ARVD/C usually consists of arrhythmias of RV origin that range from isolated premature ventricular beats to sustained ventricular tachycardia or ventricular fibrillation that leads to sudden cardiac death. However the spectrum of presentation is very broad and includes global or regional dysfunction and structural alterations of the RV; ECG depolarization/repolarization changes, characteristically in right precordial leads; and evolution to right or biventricular heart failure that mimics dilated cardiomyopathy.

In the 22 years since ARVD/C was first described, previously reported as auricularization of the RV, considerable progress has been made in our understanding of the pathogenesis, morbid anatomy, and clinical presentation of this condition.

Hystopathology

The most striking morphological feature of ARVD/C is diffuse or segmental lack of myocardium in the RV free wall, which is replaced by fatty or fibrofatty tissue. Only subendocardial layers are preserved, in which some myocardium appears to be interspersed with fibrosis. Persistent strands of cardiomyocytes bordered by or embedded in a variable area of fibrosis are observed also in the epicardial and mediomural layers inside the fat. In two thirds of cases patchy acute myocarditis with myocyte death and focal round cell inflammatory infiltrates (mostly lymphocytes) is present. This disease is largely overlooked by routine autopsy, because the limit between normal and pathological fatty infiltration is unclear. The purely adipose form of ARVD/C is characterized by partial or almost total replacement of RV wall by fatty tissue, with predominant involvement of the apex and infundibulum, in absence of fibrosis and inflammatory infiltrates. In this variant, risk of sudden death in the absence of other concomitant heart disease is controversial.

ARVD 2

The fibrofatty form was the first described, characterized by fibrosis that borders or is embedded with cardiomyocytes, RV wall thinning with aneurysmal dilatation, and inflammatory infiltrates. Aneurysms that typically affect inflow, apical, and outflow portions of the RV (“triangle of dysplasia”) have been reported in 50% of the cases in the autopsy series. In this variant, the LV and, more rarely, the ventricular septum may be involved to a lesser extent. (inserire imagine di triangolo e imagine anatomia patologica del cuore)

Genetic

A familial history of ARVD/C is present in 30% to 50% of cases. The most common pattern of inheritance is autosomal-dominant with variable penetrance and polymorphic phenotypic expression, although an autosomal-recessive pattern has also been reported. Linkage analysis has located the genetic abnormality on chromosomes 1, 2, 3, 14 for the dominant form and on chromosome 17 for the recessive variant of the disease. This latter form is characteristically associated with Naxos disease. In this condition, signs of the disease are more severe and penetrance in family members is 90%. Some families are not linked to these loci, which suggests further genetic heterogeneity. A genetic test is not currently available. It’s very difficult to assess the real incidence and prevalence of ARVD/C: patients with a clinical diagnosis of ARVD/C based on symptoms, right precordial ECG changes, RV arrhythmias, and structural and functional RV abnormalities represent only one extreme of the disease spectrum. Beyond this in several cases the first presentation is sudden death and the causes often remain unknown.

Diagnosis

Patients with ARVD may present at any age but are usually young or middle-aged; the majority of patients are men (3:1 ratio). Because of the progressive nature of the disorder, patients may present with any number of symptoms. Palpitations, fatigue, and syncope appear to be the most common symptoms, but patients may have other nonspecific complaints such as abdominal pain and mental confusion. In some cases, cardiac arrest following physical exertion such as participation in sports may be the initial presenting problem.

Signs and Symptoms of ARVD


 

Symptoms
Abdominal pain
Decreased exercise tolerance
Dizziness
Dyspnea (especially with exertion)
Fatigue
Mental confusion
Palpitations
Syncope or fainting
Signs
Cardiac arrest
Peripheral edema
Sudden death
Tachycardia

 


Screening for ARVD 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.

 

The physical examination is normal in at least 50 percent of patients with ARVD. One important diagnostic clue, if present, is a widely split S2. An S3 or S4 heart sound may be noted. Rarely, a murmur may be appreciated. If the right ventricle is greatly dilated, asymmetry of the chest wall may be seen.

The diagnosis of ARVD often is made following a work-up for tachycardia in an otherwise healthy adult. Fifty to 90 percent of persons with ARVD will have characteristic findings on a resting electrocardiogram. These findings include T-wave inversion in the anterior precordial leads (V1 through V6), epsilon waves, or VT with a left bundle branch block pattern, although polymorphic and right bundle branch block patterns also have been reported. Epsilon waves are small deflections just beyond the QRS complex; they are best visualized on a signal averaged electrocardiogram in leads V1 through V3. Any potential in leads V1 through V3 that exceeds the QRS duration in lead V6 by more than 25 milliseconds should be considered an epsilon wave.

E wave

In 1994, a scoring system based on major and minor criteria was implemented to help establish the diagnosis of ARVD. Although these criteria are specific, they lack sensitivity and have never been validated, in part because there is no single definitive means of making the diagnosis. The preferred method for making the diagnosis is based on histologic evidence of fibrofatty myocardium. Unfortunately, biopsy lacks sufficient sensitivity because of the segmental nature of the disease process. Once ARVD is suspected, early consultation with a cardiologist is recommended so that further testing may be performed to exclude other diagnoses. These tests involve invasive and noninvasive modalities. Noninvasive testing includes Holter monitoring, exercise stress testing, chest radiography, and MRI of the heart. Invasive testing includes right ventricular angiography, contrast echocardiography, electrophysiologic studies, and endomyocardial biopsy.

Criteria for Diagnosis of ARVD/C

Diagnostic criteria would be fulfilled by the presence of:• 2 major criteria or
• 1 major plus 2 minor criteria or
• 4 minor criteria

1. Family history
Major
-Familial disease confirmed at necropsy or surgery.
Minor
-Family history of premature sudden death (<35 years of age) due to suspected ARVD/C.
-Family history (clinical diagnosis based on present criteria).
2. ECG depolarization/conduction abnormalities
Major
-Epsilon waves or localized prolongation (>110 ms) of QRS complex in right precordial leads (V1–V3).
Minor
-Late potentials on signal-averaged ECG.
3. ECG repolarization abnormalities
Minor
-Inverted T waves in right precordial leads (V2 and V3) in people >12 years of age and in absence of right bundle branch block.
4. Arrhythmias
Minor
-Sustained or nonsustained left bundle branch block–type ventricular tachycardia documented on ECG or Holter monitoring or during exercise testing.
-Frequent ventricular extrasystoles (>1000/24 h on Holter monitoring).
5. Global or regional dysfunction and structural alterations1
Major
-Severe dilatation and reduction of RV ejection fraction with no or mild LV involvement.
-Localized RV aneurysms (akinetic or dyskinetic areas with diastolic bulgings). Severe segmental dilatation of RV.
Minor
-Mild global RV dilatation or ejection fraction reduction with normal LV.
-Mild segmental dilatation of RV.
-Regional RV hypokinesia.
6. Tissue characteristics of walls
Major
-Fibrofatty replacement of myocardium on endomyocardial biopsy.

1 Detected by echocardiography, angiography, magnetic resonance imaging, or radionuclide scintigraphy.

Differential Diagnosis of ARVD


Anatomic
Atrial septal defect
Biventricular dysplasia
Isolated myocarditis
Naxos disease (ARVD associated with palmoplantar keratosis)
Right ventricular infarct
Right-sided valve insufficiency
Uhl’s anomaly (congenital absence of right ventricular myocardium)
Arrhythmias
Benign extrasystoles
Bundle branch reentry
Dilated cardiomyopathy VT
Idiopathic right ventricular arrhythmia
Ischemic heart disease VT
Right ventricular outflow tract VT
Supraventricular tachycardia

Results of Holter monitoring and exercise stress testing usually are normal. In more advanced cases of ARVD, stress testing may induce VT. Chest radiographs usually are normal unless extensive ventricular enlargement is present.

It is debatable which imaging modality is the best for diagnosing ARVD. Contrast echocardiography and right ventricular angiography are able to identify ventricular aneurysms and areas of dyskinesis in the triangle of dysplasia but require invasive techniques. Heart MRI is able to provide noninvasive localization of structural changes and regional dysfunction, although identification of intramyocardial fibrofatty change is difficult.

Electrophysiologic studies are used to detect delayed potentials that can lead to tachycardic events. With these studies, it is possible to determine the number of arrhythmic morphologies, the ease of tachycardia induction, tolerance to tachycardic events, and the capacity for the tachycardia to develop into lethal arrhythmias. Electrophysiologic studies also can be used to distinguish between idiopathic right ventricular arrhythmias, which tend to have a relatively benign course, and ARVD.

Natural History

Natural history of ARVD/C depends of both cardiac electrical instability and progressive ventricular dysfunction. Ventricular arrhythmias range from isolated premature ventricular beats (with LBBB morphology) to nonsustained or sustained ventricular tachycardia, which may lead to ventricular fibrillation and sudden death at any time during the disease. An imbalance of adrenergic innervation has been documented and may contribute to arrhythmogenesis in ARVD/C because it increases propensity for ventricular tachyarrhythmias by dispersion of refractoriness and generation of delayed afterdepolarizations, particularly during exercise and catecholamine exposure. Later in the disease evolution, progressive impairment of ventricular contractility may result in right or biventricular heart failure. Infact  Macroscopic or histologic involvement of the LV is founded in 76% of hearts with ARVD/C. This involvement seems to be age dependent, more common in patients with long-standing clinical history, and progressive, as evaluated by serial echocardiographic examinations. In the natural history however, the following clinicopathological phases should be considered: (1) the concealed phase, characterized by subtle RV structural changes, with or without minor ventricular arrhythmias, during which sudden death may occasionally be the first manifestation of the disease (mostly in young people during competitive sports or intense physical exercise) ; (2) an overt electrical disorder, in which symptomatic RV arrhythmias that may cause cardiac arrest are associated with overt RV functional and structural abnormalities; (3) RV failure due to progression and extension of RV muscle disease that provokes global RV dysfunction with relatively preserved LV function ; (4) the final stage of biventricular pump failure due to significant LV involvement. At this stage, ARVD/C mimics biventricular dilated cardiomyopathy of other causes that leads to congestive heart failure and such related complications as atrial fibrillation and thromboembolic events.

Therapy

One of the major goals when treating ARVD is to prevent sudden cardiac death. Treatment decisions should be made in conjunction with a cardiologist or cardiac electrophysiologist. Although there is no way to cure ARVD, the arrhythmias can be managed. Available therapies include lifestyle modifications, antiarrhythmic medications, radiofrequency ablation, defibrillator implantation, and other surgery. The first step in management is to educate patients about the disease. Although no definitive evidence exists regarding lifestyle modifications, patients should avoid activities that may trigger a tachycardic event, such as excessive physical exertion. Once effective control of arrhythmias is achieved, physical activities may be increased under close medical supervision.

Antiarrhythmic medications are the initial and most commonly used therapy in ARVD. No single drug has been shown to be completely effective in controlling or abolishing the arrhythmias, although intravenous amiodarone reportedly has been effective in terminating acute VT in patients with ARVD. Sotalol and amiodarone are class III drugs. Other drug regimens include class II antiarrhythmics (beta blockers such as propranolol), alone or in combination with class Ia drugs (procainamide [Pronestyl]) or class Ic drugs (flecainide, propafenone), class Ic drugs alone, and amiodarone with class Ic or class II drugs. For chronic management of ARVD, treatment with sotalol, beta blockers, propafenone, and amiodarone alone or in combination is used most often with variable success.  Radiofrequency ablation is used in cases of drug refractory or incessant VT, frequent tachycardia following internal defibrillator placement, and localized arrhythmia sites. The goal of radiofrequency ablation is to eliminate conduction pathways that are critical to the perpetuation of arrhythmias. Because radiofrequency ablation is completely successful in only 30 to 65 percent of cases, many patients will require more than one ablation session. These so-called relapses are often the result of disease progression that creates a new reentrant circuit.

The AICD works by providing antitachycardia pacing and defibrillation shocks as needed when arrhythmias occur. As with optimal antiarrhythmic treatment, the timing of AICD placement is debatable because no reliable risk stratification exists for patients with ARVD. In general, placement of an AICD should be considered strongly in patients with drug-refractory arrhythmias., Other indications for an AICD include younger age at onset, cardiac arrest, and left ventricular involvement . The most significant relative contraindication to AICD placement is incessant VT.