Arrhythmogenic Right Ventricular Cardiomyopathy / Dysplasia (ARVC, ARVD)
Arrhythmogenic Right Ventricular Cardiomyopathy / Dysplasia (ARVC, ARVD)
Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is considered a genetic cardiomyopathy that predominantly affects the right ventricle. ARVC is defined by the gradual loss of myocardial cells, which are replaced by fat and fibrous tissue. This process begins in the epicardium and gradually moves towards the endocardium. As the fibrofatty replacement progresses, the ventricular wall becomes thinner and the ventricle begins to dilate. Approximately 50% of cases exhibit biventricular cardiomyopathy, although the disease is less pronounced in the left ventricle. Rarely the condition is confined to the left ventricle. ARVC causes ventricular tachycardia and sudden cardiac arrest; the disease is one of the most common causes of sudden cardiac arrest among adolescents and athletes (hypertrophic cardiomyopathy is the most common cause).
Genetic mutations in ARVC
At least 13 genes have been implicated in ARVC. The majority of these are genes encoding desmosomal proteins. The desmosome is a component of the intercalated disc that connects myocardial cells mechanically and electrically. Most mutations are inherited in an autosomal dominant manner, with variable penetrance and expressivity. Recessive forms exist, although they are rare (Naxos disease, Carvajal syndrome). The prevalence of ARVC is between 0.02 and 0.05% in Europe (Corrado et al). ARVC is more malignant in men, the reason for which remains elusive.
Gene mutations can be confirmed in roughly 60% of individuals with ARVC. Mutations in the desmosomal gene PKP2 is the most common. Mutations in non-desmosomal genes are less common. The following genes are associated with ARVC:
Clinical characteristics of ARVC
ARVC is typically concealed (asymptomatic) during childhood and adolescence and becomes symptomatic between the second and fourth decades of life. Likewise, the right ventricle may appear functionally and morphologically normal on echocardiography and cardiac MRI during the first two decades of life.
The most common initial presentation is palpitations or syncope. ARVC can, however, cause ventricular tachycardia, which may degenerate into ventricular fibrillation at any age. Exercise, or any other activity causing adrenergic stimulation, increase the risk of syncope, ventricular arrhythmias and sudden cardiac arrest.
ARVC can cause ventricular tachycardia, ventricular fibrillation and sudden cardiac arrest at any age. Palpitations, syncope or cardiac arrest–particularly during physical activity–in a young adult with T-wave inversions in V1–V4, or other ECG changes (see below) should lead to a suspicion of ARVC.
The gradual loss of myocardium leads to ventricular dilation and right heart failure. Biventricular heart failure is less common.
ECG in ARVC
- T-wave inversion in the lead V1 through V4.
- Epsilon wave, a late depolarization/potential occurring between the end of the QRS complex and the beginning of the T wave, in leads V1 and V2 (Figure 1).
- Terminal activation duration (TAD), defined as the interval between the nadir (lowest point) of the S-wave and the end of the depolarization, is prolonged (>55 ms in V1-V2). Refer to Figure 2.
- Epsilon wave and prolonged TAD strongly suggests ARVC.
- Low limb lead voltage.
- Patients with ARVC display frequent premature ventricular contractions (PVC), which may advance to monomorphic ventricular tachycardia (VT).
- Ventricular tachycardia in ARVC has LBBB morphology, with negative T-waves in V1 through V4.
- PVCs and ventricular tachycardia can be provoked by physical any adrenergic stimulation, e.g physical activity.
Echocardiography in ARVC
Echocardiography shows global right ventricular dilation. The left ventricle and the septum are generally spared. Regional wall-motion abnormalities–i.e hypokinesia, dyskinesia and kinesia–may also be seen. With pronounced fibrofatty replacement, ventricular aneurysm develops.
Since echocardiography is insufficient for visualization of the right ventricle, cardiac magnetic resonance imaging (MRI) is the preferred imaging technique. Estimation of the degree of fibrofatty replacement is possible using late gadolinium enhancement.
Differential diagnoses to ARVC
- Idiopathic RVOT-VT (ventricular tachycardia originating from RVOT).
- Congenital heart disease with right ventricular load.
Diagnostic criteria for ARVC
The diagnosis is based on clinical data, ECG, genetic analyzes and cardiac MRI. Current criteria (endorsed by ESC, AHA, ACC) use major and minor criteria, divided into 6 categories. Based on the findings, the likelihood of ARVC can be graded as possible, borderline or definitive:
- Definitive ARVC: 2 major, or 1 major and 2 minor, or 4 minor from different categories
- Borderline ARVC: 1 major and 1 minor, or 3 minor from different categories.
- Possible ARVC: 1 major, or 2 minor from different categories
Table 1. Criteria for ARVC
Categories are numbered from 1 to 6.
- CATEGORY 1: Global or regional dysfunction and structural alteration†
- 2D echocardiography
- Major criteria: Regional RV akinesia, dyskinesia, or aneurysm and one of the following (end-diastole): PLAX RVOT ≥32 mm (≥19 mm per square meter when corrected for body surface area), PSAX RVOT ≥36 mm (≥21 mm per square meter when corrected for body surface area), or fractional area change of ≤33%.
- Minor criteria: Regional RV akinesia or dyskinesia and one of the following (end-diastole): PLAX RVOT 29 to <32 mm (16 to <19 mm per square meter when corrected for body surface area), PSAX RVOT 32 to <36 mm (18 to <21 mm per square meter when corrected for body surface area), or fractional area change of 34 to 40%.
- MRI (Magnetic Resonance Imaging)
- Major criteria: Regional RV akinesia or dyskinesia or dyssynchronous RV contraction and one of the following: ratio of RV end-diastolic volume to body surface area ≥110 ml per square meter (male patients) or ≥100 ml per square meter (female patients), or RV ejection fraction ≤40%.
- Minor criteria: Regional RV akinesia or dyskinesia or dyssynchronous RV contraction and one of the following: ratio of RV end-diastolic volume to body-surface area 100 to <110 ml per square meter (male patients) or 90 to <100 ml per square meter (female patients), or RV ejection fraction 41 to 45%.
- Right ventricular angiography
- Major criteria: Regional RV akinesia, dyskinesia, or aneurysm.
- 2D echocardiography
- CATEGORY 2: Tissue characterization
- Major criteria: <60% residual myocytes on morphometric analysis (or <50%, if estimated) and fibrous replacement of the RV free-wall myocardium, with or without fatty replacement of tissue, in at least one endomyocardial- biopsy sample.
- Minor criteria: 60 to 75% residual myocytes, on morphometric analysis (or 50 to 65%, if estimated) and fibrous replacement of the RV free-wall myocardium, with or without fatty replacement of tissue, in at least one endomyocardial-biopsy sample.
- CATEGORY 3: Repolarization abnormalities
- Major criteria: Inverted T waves in right precordial leads (V1, V2, and V3) or beyond in patients older than 14 yr of age (in the absence of complete right bundle-branch block, QRS ≥120 msec).
- Minor criteria: Inverted T waves in leads V1 and V2 in patients older than 14 yr of age (in the absence of complete right bundle-branch block) or in V4, V5, or V6; inverted T waves in leads V1, V2, V3, and V4 in patients older than 14 yr of age (in the presence of complete right bundle-branch block).
- CATEGORY 4: Depolarization & conduction abnormalities
- Major criteria: Epsilon wave (reproducible low-amplitude signals from end of QRS complex to onset of the T wave) in the right precordial leads (V1, V2, and V3).
- Minor criteria: Late potentials on signal-averaged ECG in at least one of three parameters in the absence of a QRS complex duration of ≥110 msec on the standard ECG; filtered QRS complex duration, ≥114 msec; duration of terminal QRS complex <40 μV (low-amplitude signal duration), ≥38 msec; root-mean-square voltage of terminal 40 msec, ≤20 μV; terminal activation duration of QRS complex, ≥55 msec, measured from the nadir of the S wave to the end of the QRS complex, including R′, in V1, V2, or V3, in the absence of complete right bundle-branch block.
- CATEGORY 5: Arrhythmias
- Major criteria: Nonsustained or sustained ventricular tachycardia with a left bundle branch block and superior axis pattern (negative or indeterminate QRS complex in leads II, III, and aVF and positive QRS complex in lead aVL).
- Minor criteria: Nonsustained or sustained ventricular tachycardia of RV outflow configuration with a left bundle-branch block and inferior axis pattern (positive QRS complex in leads II, III, and aVF and negative QRS complex in lead aVL) or unknown axis, or >500 ventricular extrasystoles per 24 hr (on Holter monitoring).
- CATEGORY 6: Family history
- Major criteria: ARVC confirmed in a first-degree relative who meets current taskforce criteria, ARVC confirmed pathologically at autopsy or surgery in a first-degree relative, or identification of a pathogenic mutation categorized as associated or probably associated with ARVC in the patient under evaluation‡.
- Minor criteria: History of ARVC in a first-degree relative in whom it is not possible or practical to determine whether current task-force criteria are met, premature sudden death (at <35 yr of age) due to suspected ARVC in a first-degree relative, or ARVC confirmed pathologically or by current task-force criteria in a second-degree relative.
Table adapted from Marcus et al.
The diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC) is considered to be definite if the patient meets two major criteria, one major and two minor criteria, or four minor criteria from different categories; the diagnosis is considered to be borderline if the patient meets one major and one minor criteria or three minor criteria from different categories, and the diagnosis is classified as possible if the patient meets one major or two minor criteria from different categories. ECG denotes electrocardiogram, PLAX parasternal long-axis view, PSAX parasternal short-axis view, RV right ventricular, and RVOT RV outflow tract.
† Hypokinesia is not included in this or subsequent definitions of RV regional wall-motion abnormalities for the proposed modified criteria.
‡ A pathogenic mutation is a DNA alteration associated with ARVC that alters or is expected to alter the encoded protein, is unobserved or rare in a large, non-ARVC control population, and either alters or is predicted to alter the structure or function of the protein or has shown linkage to the disease phenotype in a conclusive pedigree (i.e., a pedigree providing conclusive evidence of a mendelian inheritance of the disease phenotype).
Treatment of ARVC
Treatment of ARVC is primarily focused on preventing sudden cardiac arrest. There are no randomized controlled clinical trials to support the use of antiarrhythmic drugs. Beta-blockers lack antiarrhythmic effects but are still prescribed to most patients with ARVC due to their ability to reduce the effect of adrenergic stimulation in the heart. An ICD should be considered in patients who have experienced syncope, left ventricular dysfunction or risk factors for sudden cardiac arrest. Right heart failure is managed as HFREF (heart failure with reduced ejection fraction).