Arrhythmogenic Right Ventricular Dysplasia

What is Arrhythmogenic Right Ventricular Dysplasia

Arrhythmogenic right ventricular dysplasia is a heart problem in which muscle tissue in the lower right chamber (ventricle) of the heart is replaced with fat and scar tissue. This condition is passed from parent to child (is inherited).

Over time, this condition can cause the right ventricle to weaken and to not pump blood well. Abnormal heart rhythms (arrhythmias) can also develop. Arrhythmias can be severe and life-threatening.

What are the causes?

This condition is caused by abnormal genes (gene mutations) that affect the structures that bind the heart muscles together.

What increases the risk?

This condition is more likely to develop in:

• People who have a parent or sibling who was diagnosed with the disease.
• People who have a close relative who had a sudden, unexplained death before the age of 40.
• Males.

What are the signs or symptoms?

This condition usually develops over a long period of time without causing problems. Children rarely have symptoms. The most common early symptoms are:

• An unexpected, life-threatening arrhythmia in a young person that happens during exercise.
• Rapid heartbeat or irregular, skipped heartbeats (palpitations).
• Dizziness.
• Fainting.
• Chest pain.
• Shortness of breath.

Signs and symptoms in the later stage of the disease may include:

• Increased difficulty breathing.
• Fatigue.
• Swelling in the legs.

How is this diagnosed?

This condition is diagnosed based on:

• Family history. Your health care provider may ask if you have a family history of the condition, or if a close family member has had an unexplained early death.
• Your symptoms.
• A physical exam.

You may also have other tests, including:

• Electrocardiogram (ECG). This test records the electrical activity of the heart and can help to detect arrhythmias.
  • You may have an ECG done while exercising (stress test).
  • You may also have an ECG done over a period of 24 hours while wearing a portable ECG machine (Holter monitor).
• Echocardiogram. This test uses sound waves to create an image of the heart. This may show an abnormal heart structure.
• An MRI of the heart.
• Genetic testing to check for the gene mutations that are linked to the disease.

How is this treated?

There is no cure for this condition. However, treatment can prevent arrhythmias and heart failure. Treatment may include:

• Having a small, lightweight, battery-powered device placed under the skin in the chest or abdomen (implantable cardioverter defibrillator). If your heart goes into a dangerous rhythm, this device can shock your heart back into a normal rhythm.
• Medicines to prevent arrhythmias, such as beta blockers.
• Medicines to open up blood vessels, reduce fluid in your body, and strengthen your heart’s ability to pump blood.
• Cardiac ablation. This is a procedure to disable (ablate) a small amount of heart tissue in very specific places.
• Heart transplant, in severe cases.

Follow these instructions at home:

• Take over-the-counter and prescription medicines only as told by your health care provider. Do nottake any other medicines, including over-the-counter medicines, unless you check with your health care provider first.
• Do notparticipate in competitive sports or do exercise that requires a lot of energy. Ask your health care provider what activities are safe for you.
• Do notuse any products that contain nicotine or tobacco, such as cigarettes and e-cigarettes. If you need help quitting, ask your health care provider.
• Do notabuse alcohol or drugs. Limit alcohol intake to no more than 1 drink a day for nonpregnant women and 2 drinks a day for men. One drink equals 12 oz of beer, 5 oz of wine, or 1½ oz of hard liquor.
• Do not use caffeine or other stimulants.
• Follow instructions from your health care provider about eating or drinking restrictions.

Keep all follow-up visits as told by your health care provider. This is important.

Contact a health care provider if:

• You feel fatigued.
• You have swelling in your legs.

Get help right away if:

• You have palpitations or a rapid heartbeat.
• You feel very light-headed.
• You faint.
• You have trouble breathing.
• You have chest pain.

These symptoms may represent a serious problem that is an emergency. Do not wait to see if the symptoms will go away. Get medical help right away. Call your local emergency services (911 in the U.S.).

Summary

• Arrhythmogenic right ventricular dysplasia is a heart problem in which muscle tissue in the lower right chamber (ventricle) of the heart is replaced with fat and scar tissue.
• Abnormal heart rhythms (arrhythmias) can develop in this condition. Arrhythmias can be severe and life-threatening.
• If you have a family history of the condition or an unexplained death in your family, talk with your health care provider about screening for the condition.
• An implantable cardioverter defibrillator placed under the skin in the chest or abdomen can treat life-threatening arrhythmias.

Additional Info on Arrhythmogenic Right Ventricular Dysplasia 

Arrhythmogenic right ventricular dysplasia (ARVD) is a cardiomyopathy characterized by replacement of the normal myocardium with fibrofatty tissue, mainly of the right ventricle but also occasionally with involvement of the left ventricle.

It is defined clinically by palpitations and syncope and potentially life-threatening ventricular arrhythmias.

Synonyms

• Arrhythmogenic right ventricular cardiomyopathy
• ARVC

Epidemiology & Demographics

Prevalence

1:2000 to 5000 persons. It is one of the leading causes of arrhythmic cardiac arrest in young people and athletes.

Predominant Sex and Age

Mean age, 31 yr (range, 12 to 50 yr), predominantly male

Risk Factors

Family history of ARVD (present in nearly 50% of affected patients)

Genetics

• •Autosomal dominant (most common) with variable penetrance and polymorphic phenotypic expression
• •Autosomal recessive (rarely, e.g., Naxos disease)
• •Several different gene mutations in desmosomal proteins
• •Gene mutations can be identified in 50% of affected individuals

Physical Findings & Clinical Presentation

• •ARVD can present with palpitations, syncope, and chest discomfort and less commonly sudden cardiac arrest and signs of right ventricular failure such as dyspnea, edema, and fatigue. Patients may be clinically asymptomatic for many yr.
• •Cardiac arrest after physical exertion may be the initial presentation.
• •Physical examination will be normal in most patients. Widely split S2 is an important diagnostic clue.

Etiology

ARVD is characterized by progressive replacement of mainly the right ventricular myocardium with fibrofatty tissue after apoptotic myocardial cell death caused by mutations of desmosomal protein.

Diagnosis

A major criterion equals 2 points; a minor criterion equals 1 point. The diagnosis of ARVD is considered definite if the patient has 4 points and probable with 3 points.

Here is the table for diagnostic criteria.

Global or Regional Dysfunction and Structural Alterations

From Marcus IM: Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia proposed modification of the Task Force criteria, Circulation 121:1533-1541, 2010.

Major

2D echo criteria

Regional RV akinesia, dyskinesia, or aneurysm and one of the following measured at end diastole:

PLAX RVOT ≥32 mm or

PSAX RVOT ≥36

Fractional area change ≤33%

MRI criteria

Regional RV akinesia or dyskinesia or dyssynchronous RV contraction and one of the following:

Ratio of RV end-diastolic volume to BSA >100, <110 ml/m2 (male) or >100 ml/m2

RV ejection fraction >40% ≤45%

RV angiography criteria

Regional RV akinesia, dyskinesia, or aneurysm

Minor

2D echo criteria

Regional RV akinesia or dyskinesia or dyssynchronous RV contraction and one of the following measured at end diastole:

PLAX RVOT ≥29 <32 mm or

PSAX RVOT ≥32 <36

Fractional area change >33% ≤40%

MRI criteria

Regional RV akinesia or dyskinesia or dyssynchronous RV contraction and one of the following:

Ratio of RV end-diastolic volume to BSA ≥110 ml/m2 (male) or ≥100 ml/m2

RV ejection fraction ≤40%

Tissue characterization of wall

Major

Residual myocytes <60% by morphometric analysis (or <50% if estimated) with fibrous replacement of the RV free wall myocardium in >1 sample, with or without fatty replacement of tissue on endomyocardial biopsy

Minor

Residual myocytes 60%-75% by morphometric analysis (or 50%-65% if estimated), with fibrous replacement of the RV free wall myocardium in >1 sample with or without fatty replacement of tissue on endomyocardial biopsy

Repolarization abnormalities

Major

Inverted T waves in right precordial leads (V1, V2, and V3) or beyond in individuals >14 yr of age (in the absence of complete RBBB QRS ≥120 ms)

Minor

Inverted T waves in V1 and V2 in individuals >14 yr of age (in the absence of complete RBBB) or in V4, V5, and V6

Inverted T waves in leads V1, V2, V3, and V4 in individuals >14 yr of age in the presence of a complete RBBB

Depolarization or conduction abnormalities

Major

Epsilon wave (reproducible low-amplitude signals between end of QRS complex to onset of T wave) in the right precordial leads (V1-V3)

Minor

Late potentials by SAECG in ≥1 of 3 parameters in the absence of a QRSd of ≥110 ms on standard ECG

Filtered QRS ≥114 ms

Duration of terminal QRS <40 mV ≥38 ms

Root-mean-square voltage of terminal 40 ms ≤20 μV

Terminal activation duration ≥55 ms measured from the nadir of the end of the QRS, including R’, in V1, V2, or V3 in absence of complete RBBB

Arrhythmias

Major

Nonsustained or sustained VT of LBBB morph with superior axis

Minor

Nonsustained or sustained VT of RVOT configuration, LBBB morph with inferior axis or of unknown axis

>500 PVCs per 24 hr (Holter)

Family history

Major

ARVD/C in first-degree relative who meets Task Force criteria

ARVD/C confirmed pathologically at autopsy or surgery in first-degree relative

Identification of pathogenic mutation categorized as associated or probably associated with ARVD/C in the patient under evaluation

Minor

History of ARVD/C in first-degree relative in whom it is not possible to determine whether the family member meets Task Force criteria

Premature sudden death (<35 yr of age) caused by suspected ARVD/C in a first-degree relative

ARVD/C confirmed pathologically or by current Task Force criteria in second-degree relative

A major criterion equals 2 points, a minor criterion 1 point. The diagnosis of arrhythmogenic right ventricular dysplasia (ARVD) is considered definite if the patient has 4 points and probable with 3 points. BSA, Body surface area; ECG, electrocardiogram; MRI, magnetic resonance imaging; PLAX, parasternal long axis; PSAX, parasternal short axis; PVCs, premature ventricular contractions; RBBB, right bundle branch block; RV, right ventricle; RVOT, right ventricular outflow tract; SAECG, signal-averaged electrocardiogram; 2D, two dimensional; VT, ventricular tachycardia.

Differential Diagnosis

• •Cardiomyopathy with involvement of the right ventricle
• •Uhl anomaly: Rare anomaly that presents mainly in childhood with signs and symptoms of right heart failure and characterized by a paper-thin right ventricle resulting from death of the myocytes throughout the right ventricle
• •Idiopathic RV tachycardia
• •Sarcoidosis
• •Right ventricular infarction

Workup

• •Initial workup includes history with focus on sudden death in the family, resting ECG, 24-Holter ECG, signal-averaged ECG, and imaging studies with echocardiography and cardiac MRI.
• •ECG will have diagnostic findings in 50%-90% of patients with ARVD, including T-wave inversions in anterior precordial leads V₁ to V₆, epsilon waves, and a QRS duration longer than 110 ms in V1 or >40 ms longer in V1 than V6.

• This 12-lead electrocardiogram tracing with lead Vfn¹¹ rhythm strip shows sinus rhythm with T-wave inversion over the right precordial leads. In addition, there is an epsilon wave (small deflection at the end of the QRS complex), evident in lead V¹, which is characteristic of arrhythmogenic right ventricular cardiomyopathy.From Olshansky B et al: Arrhythmia essentials, ed 2, Philadelphia, 2017, Elsevier.
• •Ventricular tachycardia (VT) with left bundle branch block pattern and frequent PVCs (>500 in 24 hr) might be detected by 24-hr Holter monitoring.
• •An abnormal signal-averaged ECG is a minor diagnostic criteria.
• •Echocardiography will show right ventricular dilation with regional wall motion abnormalities, aneurysms, and depressed RV function that varies with the severity of the disease.
• •MRI is a noninvasive method to detect structural abnormalities (fibrofatty changes) and regional dysfunction. Cardiac MRI (CMR) is the most sensitive method to detect ARVD, but it has high false-positive rates. Cardiac CT angiogram will reveal thinning and aneurysmal dilation of the RV anterior wall and outflow tract.

If the routine tests are not conclusive, endomyocardial biopsy and electrophysiologic testing can be considered. However, biopsies and radionuclide ventriculography are rarely performed in the U.S.

Treatment

No curative treatment is available. The treatment goal is focused on preventing sudden cardiac death, symptomatic treatment of right heart failure, and pharmacologic and invasive treatment of arrhythmias. Therapy with cardio-selective beta-blockers is recommended. Family members with a negative phenotype (either healthy gene carriers or those with an unknown genotype) do not need any specific treatment other than sports restriction; however, lifelong clinical assessment with the use of noninvasive tests at least every 2 yr is warranted. 

Corrado D et al: Arrhythmogenic right ventricular cardiomyopathy, N Engl J Med 376:61-72, 2017.

Nonpharmacologic Therapy

• •Avoidance of activity that may trigger ventricular tachycardia and may lead to disease progression.
• •ICD implantation needs to be considered in patients who have the definite diagnosis of ARVD. Patients with unexplained syncope, advanced disease, documented ventricular arrhythmias, or a family history of sudden cardiac death or who have been resuscitated from cardiac arrest are at high risk. A subcutaneous ICD might be an alternative option instead of transvenous implantation.
• •Radiofrequency catheter ablation is used in cases of refractory VT or frequent tachycardia after defibrillator placement.
• •Cardiac transplantation.

Pharmacologic Treatment

Antiarrhythmic therapy with sotalol (first-line treatment) or amiodarone, often in combination with beta-blockers, is used for tachycardia suppression.

Referral

• •Early cardiology and electrophysiology referral
• •Consider referring for genetic counseling

Pearls & Considerations

Prevention

All first-degree relatives should be tested if ARVD is confirmed. Sports activity increases the risk of sudden cardiac death among adolescents and young adults with ARVC. The estimated overall mortality ranges from 0.08% to 3.6% per yr.

Suggested Readings

• Bhonsale A., et al.: Incidence and predictors of implantable cardioverter-defibrillator therapy in patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy undergoing implantable cardioverter-defibrillator implantation for primary prevention. J Am Coll Cardiol 2011; 58: pp. 1485-1496.
• Calkins H.: Arrhythmogenic right ventricular dysplasia. Curr Probl Cardiol 2013; 38: pp. 103-123.
• Kim C., et al.: Studying arrhythmogenic right ventricular dysplasia with patient-specific iPSCs. Nature 2013; 6 (494): pp. 105-110.
• Peters S.: QRS fragmentation and epsilon waves in Fontaine leads in arrhythmogenic right ventricular cardiomyopathy. Int J Cardiol 2014;
• Schinkel A.F.: Implantable cardioverter defibrillators in arrhythmogenic right ventricular dysplasia/cardiomyopathy: patient outcomes, incidence of appropriate and inappropriate interventions, and complications. Circ Arrhythm Electrophysiol 2013; pp. 562-568.