Arrhythmogenic right ventricular cardiomyopathy: Treatment and prognosis

INTRODUCTION — The arrhythmogenic cardiomyopathies (ACM) are heart muscle disorders defined by the presence of specific myocardial abnormalities and arrhythmias that are not explained by ischemic, hypertensive, or valvular heart disease. Among the ACMs, arrhythmogenic right ventricular cardiomyopathy (ARVC) is the best characterized disease with regard to diagnosis, treatment, and outcomes.

The treatment and prognosis of definite ARVC and nondefinite forms of ARVC (eg, borderline, probable, asymptomatic gene carriers) will be reviewed here.

The pathogenesis, genetics, clinical manifestations, diagnostic criteria, and evaluation of ARVC are discussed separately. (See "Arrhythmogenic right ventricular cardiomyopathy: Pathogenesis and genetics" and "Arrhythmogenic right ventricular cardiomyopathy: Anatomy, histology, and clinical manifestations" and "Arrhythmogenic right ventricular cardiomyopathy: Diagnostic evaluation and diagnosis".)

MANAGEMENT OF DEFINITE ARVC — In patients with definite ARVC (table 1), the goals of therapy are to prevent sudden cardiac death (SCD) and to slow the rate of disease progression. For patients with symptomatic ventricular arrhythmias (VA) and/or repeated implantable cardioverter-defibrillator (ICD) therapies, an additional goal of treatment is to reduce the burden of VAs [1-3]. Our approach to management is largely consistent with major society guidelines [1,4]:

Overview

●Confirm the diagnosis – Patients with suspected ARVC should have the diagnosis confirmed with additional testing. The approach to confirming the diagnosis of ARVC and appropriate genetic testing is discussed in detail separately. (See "Arrhythmogenic right ventricular cardiomyopathy: Diagnostic evaluation and diagnosis".)

●Advise activity restriction – Patients with definite ARVC should be restricted from endurance and competitive sports because of the strong association between exercise and an increased risk of VAs and heart failure (HF). (See 'Activity restriction' below.)

●Treat most patients with beta blockers – Patients with definite ARVC and a prior history of sudden cardiac arrest (SCA) or documented ventricular tachyarrhythmias should receive a beta blocker. In addition, beta blocker therapy is used as prophylaxis for VAs in most patients with definite ARVC regardless of their history of VAs. (See 'Beta blockers' below.)

●Assess the need for an ICD – All patients with definite ARVC should be assessed for ICD placement. (See 'Patients with an indication for an ICD' below and 'Patients without a clear indication for an ICD' below.)

●Treat refractory ventricular arrhythmias – Patients with definite ARVC who receive repeated ICD shocks despite treatment with a beta blocker usually require either antiarrhythmic drug therapy or radiofrequency catheter ablation (RFA) to reduce the burden of arrhythmias and ICD shocks (algorithm 1). (See 'Treatment of recurrent or refractory ventricular arrhythmias' below.)

●Treatment to prevent heart failure and appropriate referral for cardiac transplantation – Patients with ARVC who progress to severe right ventricular or biventricular HF should receive standard pharmacologic therapy for HF. On rare occasions, cardiac transplantation may be indicated (algorithm 1). (See 'Management to prevent disease progression' below and 'Cardiac transplantation' below.)

Activity restriction — We counsel all patients with ARVC about the increased risks of exercise, which include life-threatening VAs and development of HF. Patients with definite ARVC should be advised to avoid (figure 1):

●Competitive sports that have a moderate or high-intensity component (eg, triathlon, cycling, downhill skiing).

●Noncompetitive sports with a high-intensity or moderate-intensity component (eg, basketball, ice hockey, sprinting, and singles tennis).

●Sports where loss of consciousness would pose a risk to themselves or others (eg, racing, diving, mountain climbing).

●Any activity, competitive or not, that causes palpitations, presyncope, or syncope.

Competitive or noncompetitive participation in sports with uniformly low metabolic demands (eg, riflery, bowling; (figure 1)) is typically considered safe [2,4-17].

Studies of patients who have definite ARVC or a pathologic gene variant report a strong association between exercise intensity and the occurrence of life-threatening VAs or worsening HF [9,18]. As an example:

●Among a cohort of 108 patients with definite ARVC that included 41 competitive athletes, 48 recreational athletes, and 19 inactive patients, the risk of ventricular tachycardia (VT) or SCD was significantly higher among competitive athletes compared with either recreational athletes (61 versus 33 percent; adjusted hazard ratio [HR] 2.0, 95% CI 1.2-3.3) or inactive patients (61 versus 22 percent; adjusted HR 2.1, 95% CI 1.1-3.9) [9].

Beta blockers — In patients with definite ARVC, we suggest beta blocker treatment for all patients. The goals of therapy are to reduce the risk of malignant arrhythmias and, in patients with an ICD, to reduce the risk of ICD shocks [1,2,4,6]. There are no data to guide which specific beta blocker is best or which dose is optimal; these decisions are generally guided by clinician preference. We typically start with a long-acting, cardioselective beta blocker, such as metoprolol succinate 50 mg daily.

The rationale for beta blocker treatment in ARVC patients includes the following observations [19,20]:

●Prior studies have shown that beta blockers lower the risk of SCD in a wide variety of patients with structural heart disease including those with a prior myocardial infarction and those with HF. (See "Acute myocardial infarction: Role of beta blocker therapy" and "Ventricular arrhythmias: Overview in patients with heart failure and cardiomyopathy", section on 'Heart failure therapy'.)

●It is well known that many patients with ARVC who experience a cardiac arrest do so during exercise [21].

●In patients with ARVC, infusion of high-dose isoproterenol can trigger nonsustained and sustained VAs.

Patients with an indication for an ICD — All patients with definite ARVC should be assessed for ICD placement.

Survivors of sudden cardiac arrest — For patients with resuscitated or spontaneously aborted SCA caused by documented or presumed VT or ventricular fibrillation (VF) that is spontaneous (ie, not caused by a reversible disorder such as hyperkalemia), we prefer an ICD rather than antiarrhythmic therapy or no treatment for the secondary prevention of SCD [4].

The evidence to support this approach includes observational studies specific to patients with definite ARVC and trials that enrolled patients with diseases other than ARVC.

●One study of patients with ARVC included patients who had ICDs for either primary (n = 135) or secondary prevention (n = 177) [22]. Among patients implanted for secondary prevention of SCD, 86 patients (60 percent) experienced an appropriate ICD therapy during an average follow-up of 8.8 years, including 58 patients (19 percent) with appropriate therapy for VF. Over the same period, 64 patients (21 percent) experienced an inappropriate ICD intervention that were primarily related to supraventricular tachycardia.

●Trials that compared ICDs with antiarrhythmic drug therapy predominantly enrolled patients with ischemic heart disease and did not include patients with ARVC. In aggregate, these trials generally showed a mortality benefit with ICDs, particularly in patients with low ejection fraction. These trials are discussed elsewhere. (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy", section on 'Evidence for use of ICD therapy'.)

Patients with symptomatic VT or VF — For patients with symptoms caused by documented VT or VF that is spontaneous (ie, not caused by a reversible disorder such as hyperkalemia), we prefer an ICD over antiarrhythmic drugs or no treatment for secondary prevention of malignant arrhythmias and SCD.

The rationale and evidence to support this approach is similar to survivors of SCA, as described immediately above. Notably, patients with symptomatic VT/VF comprised only a small proportion of the patients enrolled in trials of secondary prevention. (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy", section on 'Evidence for use of ICD therapy'.)

Patients with asymptomatic VT or VF — For patients with ARVC who have documented VT or VF but do not have symptoms, we suggest an ICD for primary prevention of sudden death over antiarrhythmic therapy or no treatment. This approach is consistent with the 2019 Heart Rhythm Society (HRS) guidelines for patients with ACM [4]. The efficacy of an ICD is less clear in this population due to the low rate of SCD in this population.

For example, a study of 30 asymptomatic patients with ARVC who had an ICD placed for documented and sustained VT/VF, the rate of appropriate ICD therapies was 1 percent per year and there were no deaths [23].

Low ejection fraction — In patients with ARVC who have a left ventricular ejection fraction less than 35 percent, New York Heart Association class II to III HF symptoms, and a reasonable expectation of one-year survival, we prefer an ICD placement for primary prevention of SCA over antiarrhythmic therapy or no treatment. This recommendation is based on the efficacy of primary prevention ICDs derived from studies of patients with HF due to ischemic and nonischemic cardiomyopathy, which are described elsewhere. (See "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF".)

Syncope — For patients with ARVC and syncope that is suspected to be of arrhythmic origin, we suggest an ICD for primary prevention of SCD over no treatment [4].

Syncope of suspected arrhythmic origin is defined as a loss of consciousness not caused by circumstances that eventually lead to the loss of reflex-mediated heart rate or vascular tone. Arrhythmic syncope is characterized by abrupt onset and a recovery that is rapid and complete. Given the multiple, non-life-threatening mechanisms that can cause syncope, we complete a comprehensive evaluation (eg, history, ambulatory electrocardiogram monitoring) to determine the cause of syncope before ICD placement. When other causes of syncope are reasonably excluded, syncope is presumed arrhythmic in origin (ie, "unexplained syncope," "arrhythmic syncope"). In patients with ARVC, syncope is strongly associated with eventual SCA and sustained VT [1,24]. For example:

In a study of 106 patients with definite ARVC and without a history of VT/VF, the presence of syncope was associated with a higher likelihood of ICD therapy for VT/VF (72 versus 30 percent in those without syncope; adjusted HR 3.16, 95% CI 1.39-5.63) [24].

Patients without a clear indication for an ICD — For patients with definite ARVC who do not have a clear indication for a secondary or primary prevention ICD, we assess the need for a primary prevention ICD by estimating the annual risk of malignant arrythmias or sudden death using a risk model. While individual risk factors and algorithms can be used to estimate the benefit of primary prevention ICDs, risk models capture the most important risk factors.

Assessment by risk model — In conjunction with other clinical information, we routinely use estimates from risk models to determine the risk of SCA or sustained VF/VT and, subsequently, the benefit of an ICD for primary prevention. We use the 2021 international registry risk model [25] or the 2019 international registry risk model (available at arvcrisk.com) to calculate the risk of SCA or sustained VT/VF, and we consider a five-year risk of SCA ≥5 percent or a five-year risk of sustained VT/VF ≥12.5 percent high enough to place a primary prevention ICD [26]. In the absence of prospective trials, our approach is based on clinical experience, our low threshold to place primary prevention ICDs in patients with definite ARVC, and the relatively high accuracy of ARVC risk models [25-27].

Studies that describe these risk models include:

●A cohort study of 864 patients aggregated from North America and Europe with definite ARVC with or without a history of sustained VAs was used to create a risk model for life-threatening ventricular arrhythmias (LTVA, defined as SCA, VF, or rapid VT [sustained or treated by an ICD]) [25]. During a median follow-up of 5.8 years, 11 percent of subjects had incident LTVA. The independent predictors of LTVA included in the final model were male sex, age, 24-hour premature ventricular complex (PVC) count, and the number of leads with T-wave inversions. The model was accurate in the overall cohort of patients and in the subgroup of patients without a history of VT/VF. The model tested but did not ultimately include desmoplakin gene status, syncope, right ventricular ejection fraction, and left ventricular ejection fraction.

●The 2019 international registry risk model was derived from a cohort of 528 patients from North America and Europe who had definite ARVC and no history of SCD or sustained VT/VF [26]. After a median of 4.8 years of observation, 28 percent of patients had either SCA, sustained VT, or appropriate ICD therapy. A multivariable model to predict the annual rate of these outcomes included the factors age, male sex, cardiac syncope in the last six months, nonsustained VT, 24-hour PVC count, number of leads with T-wave inversions, and right ventricular ejection fraction. Left ventricular ejection fraction was assessed but not included in the final model.

Assessment by risk factors — While some risk factors are strongly associated with SCA risk across numerous studies, other risk factors have an unclear association with SCA. Risk models, by their nature, generally include the most important individual risk factors, as noted above. Individual risk factors include:

•Age – Younger age is consistently associated with a higher risk of SCA.

•Sex – Male sex is consistently associated with a higher risk of SCD and sustained VT/VF.

•Frequency of premature ventricular contractions – A higher burden of premature ventricular contractions (PVCs) or nonsustained VT episodes is consistently associated with a higher risk of SCA and sustained VT/VF.

•T-wave inversions on surface electrocardiogram – The risk of SCA and sustained VT/VF increases as the number of leads with T-wave inversions increase.

•Proband status – The index case in a family may have a higher risk of SCA than other family members. However, this effect may be biased by early identification and treatment of relatives [11,28,29].

•High-risk genotypes – We do not routinely use genotype to determine SCA risk [30]. However, there are some rare and well-described ACMs associated with an elevated risk of SCD. These groups include:

-Patients with multiple pathologic gene variants.

-Patients with Naxos disease (characterized by palmoplantar keratosis and woolly hair) [31].

-Patients with recessive forms of ARVC (eg, desmoplakin, Carvajal syndrome [32], or TMEM43 mutation).

-Patients with ARVD5-locus gene variants [33-36].

In patients with these characteristics, a well-described family history and data from case-series may help guide management.

For example, in a retrospective case-control study that included 197 patients identified as at-risk for SCD based upon clinical history, DNA haplotyping (ARVD5-locus mutation), and/or pedigree position, 48 patients with an ICD (13 for secondary prevention) were compared with an age-matched control group of 58 other high-risk patients [33]. The five-year mortality for males in the control group was 28 percent, compared with 0 percent in the patients treated with an ICD. (See "Arrhythmogenic right ventricular cardiomyopathy: Pathogenesis and genetics", section on 'Genetics'.)

Infrequently used assessments — We do not routinely use risk stratification algorithms (eg, 2019 HRS criteria) or programmed electrical stimulation to determine the need for an ICD.

●Risk stratification algorithms – Risk stratification algorithms (ie, criteria) may overestimate the risk of SCD. The 2015 Task Force criteria were assessed in a cohort of 365 patients with confirmed ARVC (50 percent with a primary prevention indication for ICD) [1,37]. During a median of 4.2 years of observation, 190 patients (52 percent) experienced a sustained VA. Among patients who received a primary prevention ICD based on "major" criteria, the observed event rates were higher than expected event rates (observed rate of 15.5 percent per year versus expected rate of 1 to 10 percent per year). The observed event rates for patients with primary prevention ICDs based on "minor" criteria were similar to expected event rates (observed rate less than 2.4 percent per year versus expected rate of 1 to 10 percent). The accuracy of the 2019 HRS criteria has not been assessed.

●Inducibility of VT/VF with programmed electrical stimulation – We use programmed electrical stimulation in patients with ARVC and intermediate risk for malignant arrhythmias only if the results of programmed stimulation would influence the decision to place an ICD. One example would be a patient with ARVC with syncope that is not clearly "cardiac" in origin. (See "Invasive diagnostic cardiac electrophysiology studies".)

Choice of device and programming — The clinical factors that influence the decision to place a transvenous or subcutaneous ICD (S-ICD) in patients with ARVC are similar to the factors used in the broader group of patients undergoing ICD placement (algorithm 2). (See "Subcutaneous implantable cardioverter defibrillators", section on 'Comparison with TV-ICD'.)

In patients with ARVC, studies suggest that malignant arrythmias can be effectively treated by antitachycardia pacing (ATP) delivered by a transvenous ICD or by cardioversion-defibrillation delivered by an S-ICD. As examples:

●In a prospective study of 108 patients with ARVC whose transvenous ICDs were programmed to deliver ATP, sustained VT was successfully treated with ATP in 92 percent of patients and there were no sudden deaths [12].

●In a study of 29 patients with ARVC who underwent S-ICD placement, all patients who had inducible VF at the time of S-ICD placement were successfully converted to sinus rhythm, and, during long-term observation, all episodes of sustained VAs were successfully terminated by the S-ICD [38].

Further information on the approach to ICD programming and the relative advantages of transvenous ICDs and S-ICDs can be found elsewhere. (See "Implantable cardioverter-defibrillators: Optimal programming", section on 'Tachycardia therapies' and "Implantable cardioverter-defibrillators: Overview of indications, components, and functions" and "Subcutaneous implantable cardioverter defibrillators", section on 'Comparison with TV-ICD'.)

Treatment of recurrent or refractory ventricular arrhythmias — Patients who continue to experience ICD shocks despite beta blocker therapy usually require additional therapy aimed at reducing or eliminating VT. Repeated appropriate ICD therapies (particularly ICD shocks) for recurrent VAs, while life-saving, can be debilitating and significantly reduce the patient's quality of life. In this situation, antiarrhythmic drug therapy is often attempted. If antiarrhythmic drug therapy is ineffective or poorly tolerated, RFA (if available) is a reasonable next option. In rare instances and at experienced centers, bilateral cardiac sympathetic denervation or heart transplantation may be helpful for patients who have recurrent VT following ablation.

Antiarrhythmic drugs — In patients with definite ARVC who have frequent appropriate ICD discharges or symptomatic VT despite optimal beta blocker therapy, we suggest treatment with antiarrhythmic drug therapy to reduce the risk of recurrent VAs [1,2,4,39]. Antiarrhythmic drugs have not been shown to reduce the risk of SCD in ARVC.

In patients with definite ARVC and frequent VAs despite optimal beta blocker therapy, we suggest initial treatment with sotalol over other antiarrhythmics. In patients who will start sotalol who are already taking beta blockers, the existing beta blocker (eg, metoprolol, carvedilol) can be continued for certain indications (eg, HF with reduced ejection fraction) or discontinued to avoid beta blockade from two separate agents.

The rationale for initial use of sotalol is based on clinical experience and observational studies. As an example:

●In a nonrandomized study of 81 ARVC patients that compared the efficacy of several antiarrhythmic drugs, sotalol suppressed inducible VAs at invasive electrophysiology study or spontaneous VAs on ambulatory monitors more than class I drugs, beta blockers, calcium channel blockers, and amiodarone (table 2) [39].

If sotalol is ineffective or poorly tolerated, we may use flecainide or amiodarone after a careful discussion of the risks, benefits, and alternative therapies [40]. As an example:

●In a series of eight patients treated with sotalol or metoprolol who experienced breakthrough VT, the addition of flecainide resulted in the suppression of VT in six of the eight patients over an average follow-up of 36 months [40].

Radiofrequency catheter ablation — We use RFA as an adjunct therapy for ARVC patients with frequent and appropriate ICD discharges despite a trial of an antiarrhythmic medication such as sotalol or flecainide [4]. In patients with ARVC, RFA is not adequate as the sole therapy for the treatment of VAs and is not recommended as an alternative to ICD for SCD prevention [1]. RFA can successfully treat some arrhythmogenic foci that are refractory to medical therapy in ARVC, but due to the patchy and progressive nature of this disease, RFA is rarely a definitive therapy; there is a high rate of VT recurrence despite RFA [41-44]. As an example:

●In one study of patients with ARVC who had at least three prior episodes of VT and who underwent RFA, only 56 percent of patients were free of VT at three years after ablation [45].

Further details on RFA can be found elsewhere. (See "Sustained monomorphic ventricular tachycardia in patients with structural heart disease: Treatment and prognosis", section on 'Radiofrequency catheter ablation'.)

Bilateral cardiac sympathetic denervation — Bilateral cardiac sympathectomy, which has been used in other patient populations with recurrent VT (eg, long QT syndrome, catecholaminergic polymorphic VT, etc), may be an option for select patients with ARVC and recurrent VT refractory to antiarrhythmic therapy and RFA [46]. Bilateral cardiac sympathectomy is an option for arrhythmia reduction/cure in patients who otherwise may require cardiac transplantation. (See "Electrical storm and incessant ventricular tachycardia", section on 'Management of refractory cases'.)

The effect of sympathectomy is limited to single center experiences. In one series of eight patients with refractory VT who underwent bilateral cardiac sympathetic denervation, there was a significant reduction in sustained VT/ICD shocks compared with one year preprocedure, and five of the eight patients had no recurrent VT over mean follow-up of two years [46].

Management to prevent disease progression — Once a decision has been made as to whether ICD implantation is warranted, and any symptomatic arrhythmias have been addressed, the next step in management is to prevent or slow the progression of arrhythmias and HF [47,48].

●Limit physical activity – We counsel all patients with ARVC to avoid endurance and competitive sports. Optimal activities for patients with ARVC include activities with both a low static and low dynamic component (figure 1), such as yoga, golfing, and walking. (See 'Activity restriction' above.)

●Medical therapy – If the patient develops HF from right ventricular systolic dysfunction, the approach to management in patients with ARVC is similar to that used in other patients with HF with reduced ejection fraction [4]. In addition to treatment with beta blockers for arrhythmias and diuretics for volume overload, we typically use an angiotensin converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB) and a mineralocorticoid receptor antagonist (MRA).

In patients with ARVC, the efficacy of these medications is unknown, and the use of these agents is based on expert opinion, indirect evidence of the effect of these medications in other cardiomyopathies, and limited data from animal models of ARVC [4]. Professional society guidelines suggest treating patients with ARVC and right ventricular dysfunction with isosorbide dinitrate for preload reduction; however, our experts have rarely used isosorbide in patients with ARVC and prefer to optimize other medical therapies first.

In patients with ARVC who develop HF symptoms due to left ventricular systolic dysfunction, the management of HF is similar to patients with other diseases causing left ventricular systolic dysfunction. A full discussion of therapy for patients with symptomatic HF and reduced ejection fraction is presented separately. (See "Overview of the management of heart failure with reduced ejection fraction in adults", section on 'Pharmacologic therapy'.)

Cardiac transplantation — Patients with ARVC who develop HF symptoms or VAs that are progressive and debilitating despite the optimal use of medications, ICDs, and other adjunctive therapies may be candidates for cardiac transplantation (see "Heart transplantation in adults: Indications and contraindications"). Examples of studies that describe the indications for and efficacy of heart transplantation in patients with ARVC include the following:

●Eighteen patients with ARVC followed at a single center from 1995 to 2009 underwent successful cardiac transplantation (11 males, average age 40 years at time of transplant) [49]. Thirteen of the 18 patients who underwent transplantation did so to treat HF symptoms, while five had a transplant primarily for VT. Both short-term and long-term survival following transplantation (94 and 88 percent survival at one and six years, respectively) were at or above the national average.

●In a separate analysis of data from the UNOS database, which identified 73 patients with ARVC who underwent cardiac transplantation, survival at 1 and 10 years (87 and 77 percent, respectively) was not significantly different from the patients without ARVC who underwent transplantation [50].

MANAGEMENT OF PATIENTS WITHOUT DEFINITE ARVC — The management of patients with nondefinite ARVC (eg, borderline, probable, asymptomatic gene carriers) depends on the certainty of the ARVC diagnosis, presence or absence of a pathogenic gene variant, characteristics of the patient’s family, and the type of treatment. Among patients with nondefinite ARVC, common clinical decisions include the following:

●Activity restriction – In patients with nondefinite ARVC or who are pathogenic gene variant carriers, we advise against participation in strenuous or competitive sports (figure 1). This approach to activity restriction is similar to patients with definite ARVC and is consistent with the 2019 Heart Rhythm Society guidelines [4]. Studies in this population are limited and are predominantly composed of patients with PKP2 mutations. In one study of exercise intensity that included 87 pathogenic gene variant carriers (87 percent had a PKP2 mutation, 41 percent were probands), endurance athletes (50 or more hours per year of exercise above 70 percent of predicted peak oxygen consumption [VO₂]) had a higher risk of life-threatening arrhythmias (55 versus 26 percent in nonendurance athletes) and were more likely to have HF (18 percent versus none) [8].

In families with ARVC that do not have an identifiable pathogenic gene mutation, we do not restrict asymptomatic family members from exercise. This approach is based on our experience. Exercise restriction in symptomatic persons is discussed elsewhere. (See 'Activity restriction' above.)

●Beta blockers – In patients suspected of having ARVC who have a nondefinite diagnosis, we typically use beta blockers for prophylaxis against VAs if the following characteristics are present:

•"Borderline" ARVC (table 1)

•Pathogenic gene carriers with evidence of ventricular arrhythmias (VAs) but who do not have an ICD

For these patients, we typically initiate therapy with metoprolol succinate 50 mg daily. If the patient has intolerance to beta blockers, we typically discontinue beta blockers and only resume therapy if the patient develops signs or symptoms of VAs or if the patient’s diagnosis of ARVC becomes definite. This approach is largely based on our experience managing such patients and the pathophysiology of ARVC. (See 'Beta blockers' above.)

In patients who are members of gene-elusive families (ie, families with cases of definite ARVC but without a pathogenic gene variant) beta blocker prophylaxis is based on whether the individual has clinical evidence of ARVC. In patients who have no evidence of ARVC, we do not advise beta blocker therapy for SCD prophylaxis.

●Implantable cardioverter-defibrillators – In patients with nondefinite ARVC who do not have a clear indication for an ICD, we generally do not assess the need for ICD placement using the risk assessment methods described above, which are most accurate for patients with definite ARVC (see 'Patients without a clear indication for an ICD' above). Instead, we follow the patient clinically for signs or symptoms of ARVC that support a definite diagnosis of ARVC and reevaluate the need for an ICD if the diagnosis of ARVC is confirmed.

PROGNOSIS

The clinical course of ARVC may be impacted by the number and type of mutations. ARVC is most commonly caused by mutations in desmosomal genes and is inherited in an autosomal dominant pattern with variable penetrance and expressivity. In a study of 577 patients that included 22 patients (4 percent) with multiple mutations, patients with multiple mutations had significantly earlier occurrence (mean age 28 years compared with 35 years for the entire cohort) of sustained VT/ventricular fibrillation (VF), lower VT-/VF-free survival, and more frequent LV dysfunction (29 percent), HF (19 percent), and cardiac transplantation (9 percent) compared with those with only one mutation [51]. DSP mutation carriers had a more than fourfold increased occurrence of LV dysfunction (40 percent) and HF (13 percent) compared with PKP2 carriers. Missense mutation carriers had similar transplant-free survival and rates of clinical VT/VF episodes when compared with those with truncating or splice site mutations [51]. (See "Arrhythmogenic right ventricular cardiomyopathy: Pathogenesis and genetics".)

The clinical course of ARVC is affected by participation in endurance and competitive sports [8,9,13,52,53]. Several studies from throughout the world have reported that participation in endurance and competitive sports increases the chance of developing HF, requiring a cardiac transplant, or experiencing a sustained ventricular arrhythmia. (See 'Activity restriction' above and "Athletes: Overview of sudden cardiac death risk and sport participation", section on 'Arrhythmogenic (right and/or left) ventricular cardiomyopathy'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Arrhythmias in adults" and "Society guideline links: Cardiomyopathy".)

SUMMARY AND RECOMMENDATIONS

●Activity restriction – We counsel all patients with definite arrhythmogenic right ventricular cardiomyopathy (ARVC) about the increased risks of exercise, which include life-threatening ventricular arrhythmias (VAs) and development of heart failure (HF). We counsel patients with definite ARVC to avoid rigorous and competitive sports (figure 1). (See 'Activity restriction' above.)

●Beta blockers – We treat nearly all patients with definite ARVC with a long-acting, cardioselective beta blocker, such as metoprolol succinate. (See 'Beta blockers' above.)

●Implantable cardioverter-defibrillators (ICDs)

•Patients with an indication for an ICD

-Survivors of sudden cardiac arrest – For patients with resuscitated or spontaneously aborted sudden cardiac arrest (SCA) caused by documented or presumed ventricular tachycardia (VT) or ventricular fibrillation (VF) that is spontaneous (ie, not caused by a reversible disorder such as hyperkalemia), we prefer an ICD rather than antiarrhythmic therapy or no treatment for the secondary prevention of sudden cardiac death (SCD). (See 'Survivors of sudden cardiac arrest' above and "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy".)

-Symptoms caused by documented VT or VF – For patients with symptoms caused by documented VT or VF that is spontaneous (ie, not caused by a reversible disorder such as hyperkalemia), we prefer ICD over antiarrhythmic drug use or no treatment for secondary prevention of malignant arrhythmias and SCD. (See 'Patients with symptomatic VT or VF' above and "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy".)

-Documented VT/VF without symptoms – For patients with ARVC who have documented VT or VF but do not have symptoms, we suggest an ICD for primary prevention of SCD over antiarrhythmic therapy or no treatment (Grade 2C). (See 'Patients with asymptomatic VT or VF' above.)

-Low left ventricular ejection fraction – In patients with ARVC who have a left ventricular ejection fraction less than 35 percent, New York Heart Association class II to III HF symptoms, and a reasonable expectation of one-year survival, we prefer ICD placement for primary prevention of SCA over antiarrhythmic therapy or no treatment. (See 'Low ejection fraction' above and "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF".)

-Syncope likely caused by VT/VF – For patients with definite ARVC who have syncope that is likely caused by VT or VF, we suggest an ICD for secondary prevention of SCD (Grade 2C). (See 'Syncope' above.)

•Patients without a clear indication for an ICD – For patients with definite ARVC who do not have a clear indication for a secondary or primary prevention ICD, we assess the need for a primary prevention ICD by estimating the annual risk of malignant arrythmias or SCD. We favor the use a risk model to estimate the benefit of an ICD for primary prevention. (See 'Patients without a clear indication for an ICD' above and 'Assessment by risk model' above.)

●Treatment of recurrent or refractory arrhythmias

•In patients with definite ARVC who have frequent appropriate ICD discharges or symptomatic VT despite optimal beta blocker therapy, we suggest initial treatment with sotalol (Grade 2C) (algorithm 1). If sotalol is ineffective or poorly tolerated, flecainide or amiodarone are alternative therapies [40]. (See 'Antiarrhythmic drugs' above.)

•If antiarrhythmic drug therapy is ineffective or poorly tolerated, radiofrequency catheter ablation (if available) is a reasonable next option. In rare instances and at experienced centers, bilateral cardiac sympathetic denervation or heart transplantation may be helpful for patients who have recurrent VT following ablation (algorithm 1). (See 'Antiarrhythmic drugs' above and 'Radiofrequency catheter ablation' above.)

●Management to slow the progression of disease – For patients with ARVC and symptomatic right or left ventricular dysfunction, in particular patients with symptoms of HF, the medical management is similar to the general management of patients with HF with reduced ejection fraction (algorithm 1). (See 'Management to prevent disease progression' above.)

●Cardiac transplantation – Patients with ARVC who develop HF symptoms or VAs that are progressive and debilitating despite the optimal use of medications, ICDs, and other adjunctive therapies may be candidates for cardiac transplantation (algorithm 1). (See 'Cardiac transplantation' above.)

●Management of patients without definite ARVC – The management of patients with nondefinite ARVC depends on the certainty of the ARVC diagnosis, presence of a pathogenic gene variant, characteristics of the patient’s family, and the type of treatment. (See 'Management of patients without definite ARVC' above.)

●Prognosis – The prognosis in ARVC is related to the rate of SCD and progression to HF. (See 'Prognosis' above.)