Update on RV Cardiomyopathy/Dysplasia or Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia (ARVC/D): Review of Consensus Guidelines

Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is an inherited cardiomyopathy. The disease affects mainly the right ventricle, though recent MRI imaging has shown that the left ventricle becomes involved as well. The disease process is a thinning of the ventricular wall and muscle replacement with fatty and fibrous tissue. This leads to ventricular arrhythmias and possible sudden cardiac death (SCD), plus the development of heart failure, affecting first the right and then the left ventricle. Symptoms at patient presentation seem to correlate with the amount of ventricular arrhythmias present.^1,2

Between 5-12 causative desmosomal genes have been identified for ARVC/D.^3,4 However, only 30-50% of patients have one of these, suggesting there are more types that have not been identified.

The disease incidence is 1 per 5000.¹ Patients present with symptoms between the second to fifth decades of life, with 11-22% of cases of SCD seen in the young athletic population.⁵

Intensive study of the disorder has taken place at a number of medical centers. An example is the Johns Hopkins ARVC/D Program founded in 1999. This center, as is true of others, has goals of seeking further understanding of the disease, educating the medical and patient community, and serving as a referral center.¹ Professionals from such centers participate in task force groups, present their accumulated knowledge, and come to a consensus opinion on diagnostic criteria and treatment directions. For a disorder such as ARVC/D, the data is nonrandomized and observational, due to the low disease prevalence and lack of controlled studies.² Most of the data presented is from registries and/or expert opinion. This article will review the information from these task groups that currently guides ARVC/D patient care.

Initial Evaluation 

The suspicion of ARVC/D as a diagnosis leads to an evaluative process that includes a physical examination, family history, ECG, possibly a signal-averaged ECG (SAECG), a 24-hour Holter, and comprehensive noninvasive imaging. An MRI can be helpful, but sometimes leads to misdiagnosis. Electrophysiologic testing may also be included. Endomyocardial biopsy was performed more frequently in the past, but is not done as much due to the detailed tissue imaging of the noninvasive MRI. An additional test that may be performed is the administration of high-dose isoproterenol. This test is considered positive for ARVC/D if polymorphic PVCs and at least couplets are observed, or sustained, non-sustained, or polymorphic VT is produced with administration of the drug.⁶

Risk Stratification 

The testing results seen in ARVC/D patients leads to assignment into different classifications of diagnostic certainty and risk stratification. There may be a history of prolonged strenuous exertion leading to increased myocardial strain and increased risk. Ventricular electrical instability manifests with cardiac arrest, sustained VT or VF, unstable sustained VT, syncope, or non-sustained VT. Left and right heart failure can occur. Those affected are most often of a young age and male. Electrophysiologic testing may reveal inducible VT/VF, presence of scar, and a fragmented electrogram in the right ventricle. The ECG may show T wave inversion, QRS fragmentation, and the presence of Epsilon waves.² The number of PVCs on a 24-hour Holter can also help in assessing sudden death risk.¹

Diagnosis

The 2010 Task Force Criteria for the diagnosis of ARVC/D sorted the clusters of findings and assigned levels of importance.⁷ The categories that emerged included global or regional dysfunction and structural alterations, tissue characterization of the ventricular wall, repolarization abnormalities, depolarization/conduction abnormalities, arrhythmias, and family history. Certain findings were considered ‘major’ and others were considered ‘minor.’ Probability of diagnosis was then defined in the following way:

Definite diagnosis: 2 major or 1 major and 2 minor criterion, or 4 minor from different categories. 

Borderline: 1 major and 1 minor, or 3 minor from different categories. 

Possible: 1 major or 2 minor criterion from different categories.

Major

Global or regional dysfunction and structural alterations: 

2D echo: regional RV akinesis, dyskinesia, or aneurysm and one of the following at end diastole: parasternal long-axis view RVOT ≥32 mm, parasternal short-axis view RVOT ≥36 mm, or fractional area change ≤33%.

MRI: regional RV akinesis 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 (female) or RV ejection fraction ≤40%.

RV angiography: regional RV akinesia, dyskinesia, or aneurysm.⁷

Tissue characterization of wall: residual myocytes <60% by morphometric analysis, plus fibrous replacement of the RV free wall in ≥1 sample.⁷

Repolarization abnormalities: inverted T waves in right precordial leads (V1, V2, and V3) or beyond for those above 14 years (if RBBB not present).⁷ (Figure 1)

Depolarization/conduction abnormalities: Epsilon waves in the right precordial leads.⁷ (Figure 1)

Arrhythmias: non-sustained or sustained ventricular tachycardia of left bundle-branch morphology with superior axis.⁷

Family history: confirmation in a first-degree relative; pathologic confirmation at autopsy or surgery of a first-degree relative; identification of a pathogenic mutation in the patient.⁷

Minor

Global or regional dysfunction and structural alterations: 

2D echo: regional RV akinesia or dyskinesia and one of the following at end diastole: parasternal long-axis view RVOT ≥29 to <32 mm, parasternal short-axis view RVOT ≥32 to <36 mm, or fractional area change >33% to ≤40%.

MRI: regional RV akinesia or dyskinesia or dyssynchronous RV contraction and one of the following: ratio of RV end-diastolic volume to BSA ≥100 to <110 mL/m2 (male) or ≥90 to <100 mL/m2 (female) or RV ejection fraction >40% to ≤45%.⁷

Tissue characterization of wall: residual myocytes 60% to 75% by morphometric analysis.⁷

Repolarization abnormalities: inverted T waves in V1 and V2, and V3 or beyond for those above 14 years (if RBBB not present) or in V4-V6. Inverted T waves in right precordial leads (V1, V2, V3, and V4) for those above 14 years in presence of RBBB.⁷ (Figure 1)

Depolarization/conduction abnormalities: Abnormal signal-averaged ECG; terminal activation duration of QRS ≥55 ms (nadir of S wave to end of QRS) (delayed upstroke of S waves).⁷ (Figure 1)

Arrhythmias: nonsustained or sustained ventricular tachycardia of RV outflow configuration; greater than 500 PVCs per 24 hours.⁷

Family history: history of ARVC/D in first-degree relative who cannot be tested; SCD ≤35 years in first-degree relative with suspected ARVC/D; confirmed ARVC/D in second-degree relative.⁷

A 2015 International Task Force Consensus Statement reviewed the role for electrophysiologic testing and therapy directions for ARVC/D patients.² Once again, because the population is so small, there were no randomized trials from which to draw. The recommendations of the group were developed from the experience of the clinicians and from databases. Each area considered in the consensus statement will be briefly discussed and the recommendations will follow. It should be noted that a recommendation with “I” assigned to it is one which all agree should be done. A Class IIa recommendation “should be considered,” Class IIb “may be considered,” and Class III should not be done.

Electrophysiologic Study for ARVC/D 

Electrophysiologic testing can be helpful to differentiate between ARVC/D and idiopathic RVOT. For the question of whether an arrhythmia is inducible, for ARVC/D this would be induction of either VF or sustained VT (>30 sec or requiring termination). 

Electrophysiologic testing may be used for determination of detection/discrimination algorithms and for antitachycardia pacing protocols (although there is some conflicting data on the helpfulness of this). However, the predictive value of inducibility did not predict arrhythmic outcome in most studies cited in the consensus.

The summary of recommendations follows:

IIa: An electrophysiologic study should be considered for diagnosis and/or evaluation of suspected patients.
IIb: Programmed electrical stimulation may be considered for arrhythmic risk stratification of asymptomatic ARVC/D patients. This should include a minimum of 2 drive-cycle lengths and 3 ventricular extrastimuli while pacing from 2 RV sites (apex and RVOT).
IIb: Endocardial voltage mapping may be considered for diagnosis and prognostic evaluation of ARVC/D.²

Therapy

Therapy objectives for the ARVC/D patient include: finding the correct diagnosis; accurately quantifying risk stratification for the determination of need for an ICD; reducing mortality from sudden cardiac death or heart failure; prevention of disease progression; reduction or abolishment of palpitations, ventricular tachycardia recurrences, or ICD discharges in order to improve symptoms and quality of life; limitation of heart failure symptoms; and increasing functional capacity.^1,2 There are five important treatment modalities that were discussed in the consensus statement. They include: lifestyle changes, pharmacology, catheter ablation, ICD, and heart transplantation.²

Lifestyle changes

Data over the last few years has shown that there is a link between intense exertion and sudden cardiac death. A five-fold increase in risk for ARVC/D has been found in young, active adults.8 Physical exercise seems to promote development and progression of the disease. There is a great need for early identification so that those at risk can be cautioned to curtail activity.

The following recommendations were developed:
Class I: Patients with the diagnosis are not to participate in competitive and/or endurance sports.
Class IIa: Patients with the diagnosis should be restricted from athletic participation, with possible exception of recreational low-intensity sports.
Class IIb: Restriction may be considered in family members with a negative phenotype, either healthy gene carriers (IIa) or with unknown genotypes (IIb).²

Pharmacology

Pharmacological agents that are recommended for use with the ARVC/D population include antiarrhythmics, beta-blockers, and heart failure drugs.

Antiarrhythmic Drugs: Anti-arrhythmic drugs are prescribed with the goal of preventing symptomatic ventricular arrhythmias and decreasing ICD discharges. The most commonly used drug is amiodarone alone or with beta-blockers.² Other drugs that have been found useful include sotalol, and in rare cases, flecainide, propafenone, and dofetilide.¹ Antiarrhythmic drug recommendations:

Class I: Antiarrhythmics should be used as an adjunct to ICD therapy.
Class IIa: Antiarrhythmics should be considered to improve symptoms from frequent ventricular ectopy.
Class IIb: Antiarrhythmic may be considered as an adjunct to catheter ablation in patients without an ICD and with hemodynamically stable VT.
Class III: Antiarrhythmics are not recommended for asymptomatic ARVC/D without ventricular arrhythmias or for healthy gene carriers.²

Beta-blockers: Beta-blocking agents have been shown to reduce the risk of SCD. Beta-blockers decrease heart rate with exercise and when adrenergic stimulation is a trigger. They have been proven effective for arrhythmia prevention, for heart failure management, for lowering RV wall stress, and thus slowing down disease progression. The drugs recommended for use are the non-vasodilating beta-blockers.²

The following are the consensus recommendations:
Class I: Beta-blockers should be used for patients with recurrent VT, with appropriate or inappropriate ICD therapies.
Class IIa: Beta-blockers should be considered in all.
Class III: Prophylactic use of beta-blockers in healthy gene carriers is not recommended.²

Heart Failure and Antithrombotic Drug Therapy: Heart failure in both the right and left ventricles occurs in some of these patients. In addition, thrombus formation can occur because of tissue pockets in the diseased ventricles. Treatment recommendations for this group include the following:

Class I: If failure is present, use of angiotensin-converting-enzyme inhibitors, angiotensin II receptor blockers, beta-blockers, and diuretics is recommended.
Class I: Long-term oral anticoagulation should be prescribed for prevention if there is a history of documented thrombosis or thromboembolism.
Class IIb: For those with asymptomatic failure, angiotensin-converting-enzyme inhibitors or angiotensin II receptor blockers may be considered.
Class III: Prophylactic anticoagulation for prevention of thromboembolism is not recommended.²

Ablation

The replacement of RV myocardium with fibro-fatty tissue in the ARVC/D process leads to scars that are responsible for macroreentrant circuits supporting VT.

Ablation of VTs in ARVC/D is useful for minimizing symptoms and preventing ICD therapies. It must be kept in mind that such ablations are not curative and are being performed primarily for improving the quality of life and reducing the quantity of ICD shocks. An epicardial ablation approach has also been found effective for some patients, as often the epicardial tissue is found to be involved in the arrhythmia circuit.

The consensus group’s recommendations related to ablation include the following:

Class I: Ablation is recommended with incessant VT or frequent appropriate shocks in spite of antiarrhythmic therapy.
Class I: An epicardial ablation approach is recommended for those that fail endocardial ablation.
Class IIa: Ablation should be considered for those with incessant VT or frequent appropriate ICD discharges who have failed pharmacological therapy.
Class IIa: Combined endocardial/epicardial ablation should be considered as an initial strategy if the operator and lab are experienced in epicardial VT ablation in ARVC/D patients.
Class IIb: Ablation may be considered in those with incessant VT or frequent appropriate ICD discharges who have not failed a drug and do not wish to be treated with a drug.
Class IIb: Ablation may be indicated for those without an ICD with drug-refractory, hemodynamically stable, single morphology VT.
Class III: Ablation is not recommended as an alternative to an ICD for SCD prevention.²

ICD Implantation

Implantable defibrillators are indicated for those with an increased risk of SCD.

It is of vital importance that risk stratification is assessed, taking into consideration prior sustained ventricular arrhythmias, syncope, and the extent of structural disease.¹ The placement of an ICD imparts a lifetime of prevention.

Three categories of risk have been proposed for SCD. Those with high risk have experienced a cardiac arrest due to a ventricular arrhythmia. Those considered low risk are probands and relatives without risk factors, and healthy gene carriers. Intermediate risk is decided on an individual basis. Taking this stratification into account, the following has been recommended:

Class I: ICD implantation is recommended in those who have experienced ≥1 episodes of unstable sustained VT or VF.
Class I: ICD implantation is recommended in those with severe systolic dysfunction of the RV, LV, or both.
Class IIa: Implantation should be considered in those with ≥1 episodes of hemodynamically stable sustained VT.
Class IIa: ICD implantation should be considered in those who have major risk factors (unexplained syncope, moderate ventricular dysfunction, NSVT).
Class IIb: ICD may be considered in patients with minor risk factors after careful consideration of risks and benefits.
Class III: ICDs implanted prophylactically are not recommended for those with no risk factors or in healthy gene carriers.2

The type of device generally recommended is a single-chamber system so that lead complications can be minimized. Since the population is younger, there may be many device and lead changes in the future, so a single-lead system minimizes potential lead complications. Antitachycardia pacing has often been effective for this group and should be considered when programming the device. For those with ejection fractions below 35% and a wide QRS, resynchronization would be reasonable.

Heart Transplantation

Heart transplantation is considered a final option for those with severe congestive heart failure or episodes of VT/VF that are refractory to ablation and/or ICD therapy.

Follow-Up

The follow-up care of the ARVC/D patient will be a lifelong endeavor. The progress of the disease must be evaluated at regular intervals, and this will probably include ECGs, echocardiography, Holter monitoring, and exercise testing. Follow-up should probably occur every 1-2 years depending on age, symptoms, and severity. For healthy gene carriers and family members, follow-up every 2-3 years is recommended (adolescence to young adulthood).²

Summary

ARVC/D is a complex, life-threatening disorder. Having caregivers who are knowledgeable and skilled in care of the disease is of vital importance. There is a continuous need for data collection and discovery of the genetic patterns associated with the disease. Awareness of the criteria for diagnosis and treatment by providers helps to ensure that patients receive appropriate care.

References

1. Calkins H. Arrhythmogenic right ventricular dysplasia/cardiomyopathy: three decades of progress. Circ J. 2015;79:901-913.
2. Corrado D, Wichter T, Link M, et al. Treatment of arrhythmogenic right ventricular cardiomyopathy/dysplasia: An International Task Force Consensus Statement. Circulation. 2015;132:441-453.
3. Marcus FI, Edson S, Towbin JA. Genetics of arrhythmogenic right ventricular cardiomyopathy. J Am Coll Cardiol. 2013;61:1945-1948.
4. Romero J, Mejia-Lopez E, Manrique C, Lucariello R. Arrhythmogenic right ventricular cardiomyopathy (ARVC/D): a systematic literature review. Clin Med Insights Cardiol. 2013;7:97-114.
5. Dalal D, Nasir K, Bomma C, et al. Arrhythmogenic right ventricular dysplasia: a United States experience. Circulation. 2005;112:3823-3832.
6. Denis A, Sacher F, Derval N, et al. Diagnostic value of isoproterenol testing in arrhythmogenic right ventricular cardiomyopathy. Circ Arrhythm Electrophysiol. 2014;7:590-597.
7. Marcus FI, McKenna WJ, Sherrill D, et al. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the Task Force Criteria. Circulation. 2010;31:1533-1541.
8. Corrado D, Basso C, Rizzoli G, Sciavon M, Thiene G. Does sports activity enhance the risk of sudden death in adolescents and young adults? J Am Coll Cardiol. 2003;42:1959-1963.