**8. Management**

**6.5. Family history**

146 Cardiomyopathies - Types and Treatments

[119].

**7. Differential diagnosis**

is each considered as a major diagnostic criteria [119].

usually curative in idiopathic RVOT‐VT.

ARVC/D is a familial disease. Having a first‐degree family member with proven ARVC/D is considered an increased risk for other family members to be affected. ARVC/D confirmed in a first‐degree relative who meets current Task Force criteria; ARVC/D 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/D in the patient under evaluation

If a first‐degree relative is diagnosed with ARVC/D but does not fulfill the diagnostic criteria, only a minor criterion is counted. Sudden death of a family member under the age of 35 years, presumably but not proven to be due to ARVC/D related arrhythmias, and ARVC/D confirmed pathologically or by current Task Force criteria in a second‐degree relative is a minor criterion

It is crucial to differentiate ARVC/D from other diseases that primarily involve RV as the prognosis and management are very different. Differential diagnosis of ARVC/D includes: **1. Right ventricular outflow tract VT (RVOT‐VT):** RVOT‐VT is a benign disorder that may cause exercise‐induced left bundle branch block (LBBB) morphology VT with the inferior axis. In RVOT‐VT there is no family history of ARVC/D or SCD, the ECG shows no depolarization or repolarization abnormalities and no RV structural changes can be detected. There is usually no reproducibly inducible VT by premature extrastimuli at programmed stimulation during electrophysiologic studies [142]. Idiopathic RVOT VT may be inducible by regular burst pacing and isoproterenol infusion [143]. The prognosis of RVOT‐VT is usually good with very low risk of SCD. Furthermore, catheter ablation is

**2. Dilated cardiomyopathy:** Biventricular dilatation and congestive heart failure may mimic advanced ARVC/D with LV involvement. Characteristic ECG and cardiac MRI (CMRI)

**3. Myocarditis:** Myocarditis due to viral infection or other causes may mimic ARVC/D. In general, endomyocardial biopsy is required to distinguish ARVC/D from myocarditis.

**4. Cardiac sarcoidosis:** Sarcoidosis is a disease of unknown etiology, characterized by the presence of noncaseating granulomas. It may affect mainly lungs, but other tissues such as heart, skin, eyes, reticuloendothelial system, kidneys, and central nervous system can be affected. About 5% of sarcoidosis patients may have cardiac involvement, which may manifest as conduction abnormalities, ventricular arrhythmias, valvular dysfunction or congestive heart failure. Although sarcoid patients typically have myocardial sarcoid granulomas and scarring in the LV and interventricular septum, the RV can also be affected. Patients can present with clinical features similar to those of ARVC/D including

abnormalities in ARVC/D help to distinguish the two entities.

### **8.1. Risk stratification**

The clinical objectives in ARVC/D management are prevention of SCD and death from heart failure; minimizing disease progression to RV, LV, or biventricular heart failure; improvement of quality of life by controlling palpitations, and minimizing appropriate or inappropriate implantable cardioverter defibrillator (ICD) discharges as much as possible; and improving functional capacity by optimization of heart failure management [147].

Therapeutic options consist of lifestyle changes, pharmacological treatment (beta‐blockers, heart failure medications, antiarrhythmic medications), electrophysiological study (EPS) and catheter ablation, ICD implantation, and surgical intervention (e.g., RV isolation and heart transplantation).

### **8.2. Therapeutic options**

### *8.2.1. Lifestyle changes*

There is an established relationship between SCD and intense exertion in young individuals with ARVC/D. Competitive sports activity has been shown to increase the risk of SCD by fivefold in adolescent and young adults with ARVC/D [148]. Early identification of affected athletes by preparticipation screening and their disqualification from competitive sports activity may be "life‐saving" [149]. Also, physical exercise has been implicated as a factor promoting development and progression of the ARVC/D phenotype [147]. In the animal study, it was demonstrated that in heterozygous plakoglobin‐deficient mice, endurance training accelerated the development of RV dilatation, dysfunction, and ventricular ectopy, suggesting that chronically increased ventricular load might contribute to worsening of the ARVC/D phenotype [150].

Studies have shown that repetitive exercise and endurance sports increase age‐related penetrance, the risk of VT/VF, and occurrence of heart failure in ARVC/D desmosomal‐gene carriers [151, 152]. So, patients with a definite diagnosis of ARVC/D are encouraged not participate in endurance and/or competitive sports.

#### *8.2.2. Pharmacological therapy*

### *8.2.2.1. Beta‐blockers*

VTs and cardiac arrest in ARVC/D are frequently triggered by adrenergic stimulation and occur during or immediately after physical exercise [153–157]. Autonomic dysfunction with in‐ creased sympathetic stimulation of ventricular myocardium and subsequent reduction of β‐ adrenoceptor density were demonstrated with the use of radionuclide imaging and quantitative positron emission tomography [158, 159]. Beta‐blockers are useful in the treatment of heart failure, preventing the effort‐related VT, and possibly minimizing disease progression by lowering RV wall stress.

Beta‐blocker therapy is recommended in ARVC/D patients with recurrent VT, as an adjunct to ICD therapy. It may also be a helpful addition to minimize inappropriate ICD shocks due to sinus tachycardia, supraventricular tachycardia, or atrial fibrillation/flutter with high‐ ventricular rate [147].

#### *8.2.2.2. Heart failure therapy*

For ARVC/D patients who developed right‐ and/or left‐sided heart failure standard pharma‐ cological treatment with angiotensin‐converting‐enzyme inhibitors, angiotensin II receptor blockers, β‐blockers, and diuretics are recommended [147].

ARVC/D patients with severe RV dilatation are at risk of thromboembolism. A 0.5% annual incidence rate of thromboembolic complications is reported during a mean follow‐up period of 99±64 months in a cohort of 126 ARVC/D patients [160]. Long‐term oral anticoagulation is indicated for secondary prevention in patients with documented intra‐cavitary thrombosis or venous/systemic thromboembolism [147].

#### *8.2.2.3. Antiarrhythmic drugs*

The aim of antiarrhythmic drug (AAD) therapy in patients with ARVC/D is to improve the quality of life by preventing symptomatic VT and ICD shocks. The data about AAD in ARVC/ D are limited due to the lack of randomized control studies, the change in medication regimes over time and the common need for other modalities of treatment like VT ablation or ICD implantation [147, 161–163].

Although initial studies suggest that sotalol, administered at a dosage of 320–640 mg/day, is the most effective therapy with approximately 68% of patients achieving complete or partial arrhythmia suppression [164, 165], more recent available data suggest that amiodarone (loading dose of 400–600 mg daily for 3 weeks and then maintenance dose of 200–400 mg daily), alone or in combination with β‐blockers, is the most effective drug for preventing symptomatic VTs and has relatively low proarrhythmic risk even in patients with ventricular dysfunction, although its ability to prevent SCD is unproven [166]. This variation in drugs effect may be partially a result of significant differences in design of the two studies, and the difference in sotalol doses, the difference in the amiodarone loading strategies and the method of medication selection [161]. There is relatively limited data about the combination of antiarrhythmic therapy. One recent report demonstrated the effective addition of flecainide to patients receiving sotalol with a resultant reduction in recurrent arrhythmias [167]. The addition of flecainide in this study was accomplished without significant adverse events. Several other studies have reported that the combination of amiodarone and beta‐blockers may be effective in patients unable to achieve arrhythmia suppression with amiodarone alone [168, 169].

### *8.2.3. Catheter ablation*

*8.2.2. Pharmacological therapy*

148 Cardiomyopathies - Types and Treatments

by lowering RV wall stress.

ventricular rate [147].

*8.2.2.2. Heart failure therapy*

*8.2.2.3. Antiarrhythmic drugs*

implantation [147, 161–163].

VTs and cardiac arrest in ARVC/D are frequently triggered by adrenergic stimulation and occur during or immediately after physical exercise [153–157]. Autonomic dysfunction with in‐ creased sympathetic stimulation of ventricular myocardium and subsequent reduction of β‐ adrenoceptor density were demonstrated with the use of radionuclide imaging and quantitative positron emission tomography [158, 159]. Beta‐blockers are useful in the treatment of heart failure, preventing the effort‐related VT, and possibly minimizing disease progression

Beta‐blocker therapy is recommended in ARVC/D patients with recurrent VT, as an adjunct to ICD therapy. It may also be a helpful addition to minimize inappropriate ICD shocks due to sinus tachycardia, supraventricular tachycardia, or atrial fibrillation/flutter with high‐

For ARVC/D patients who developed right‐ and/or left‐sided heart failure standard pharma‐ cological treatment with angiotensin‐converting‐enzyme inhibitors, angiotensin II receptor

ARVC/D patients with severe RV dilatation are at risk of thromboembolism. A 0.5% annual incidence rate of thromboembolic complications is reported during a mean follow‐up period of 99±64 months in a cohort of 126 ARVC/D patients [160]. Long‐term oral anticoagulation is indicated for secondary prevention in patients with documented intra‐cavitary thrombosis or

The aim of antiarrhythmic drug (AAD) therapy in patients with ARVC/D is to improve the quality of life by preventing symptomatic VT and ICD shocks. The data about AAD in ARVC/ D are limited due to the lack of randomized control studies, the change in medication regimes over time and the common need for other modalities of treatment like VT ablation or ICD

Although initial studies suggest that sotalol, administered at a dosage of 320–640 mg/day, is the most effective therapy with approximately 68% of patients achieving complete or partial arrhythmia suppression [164, 165], more recent available data suggest that amiodarone (loading dose of 400–600 mg daily for 3 weeks and then maintenance dose of 200–400 mg daily), alone or in combination with β‐blockers, is the most effective drug for preventing symptomatic VTs and has relatively low proarrhythmic risk even in patients with ventricular dysfunction, although its ability to prevent SCD is unproven [166]. This variation in drugs effect may be partially a result of significant differences in design of the two studies, and the difference in sotalol doses, the difference in the amiodarone loading strategies and the method of medication

blockers, β‐blockers, and diuretics are recommended [147].

venous/systemic thromboembolism [147].

*8.2.2.1. Beta‐blockers*

Fibrofatty replacement of RV myocardium creates scar regions that form a substrate for re‐ entry arrhythmias and VT.

Although VT catheter ablation is effective in the short term, the recurrence rate of VT after endocardial ablation procedures is about 50–75% in 3‐year follow‐up, which is likely secondary to the progressive nature of the disease [148, 170]. The discovery of the epicardial arrhythmo‐ genic substrate in RVC/D patients makes epicardial VT ablation an attractive approach. The combination of endocardial and epicardial ablation approaches resulted in a higher success rate (77–83%) and lower recurrence of VTs over 18 and 36 month follow‐up periods [171, 172]. However, this is at the expense of potential complications such as epicardial bleeding and coronary stenosis occurring in approximately 5% of cases [172]. Nevertheless, catheter ablation remains an important therapeutic modality for decreasing patient morbidity in conjunction with ICD implantation and antiarrhythmic medication especially in ARVC/D patients with incessant VT or frequent appropriate ICD interventions on VT despite maximal pharmaco‐ logical therapy, including amiodarone [147, 161].

#### *8.2.4. Implantable cardioverter defibrillator therapy*

High‐risk markers for mortality in ARVC/D include the history of syncope, sustained VT, severe RV dysfunction, and LV involvement [173–175]. ICD is the only treatment option that has been shown to reduce mortality. Over a 4‐year follow‐up period, the survival benefit of ICD implantation was about 25% in one study [176]. In a recent meta‐analysis, the estimated annual mortality rate of patients with ARVC/D, who underwent ICD implantation, was 0.9%, significantly lower than those without ICDs [177]. A similar finding was noted in a large cohort of ARVC/D patients and family members where SCD during follow‐up occurred more frequently among index‐patients without an ICD (16% vs. 0.6%) [178]. The American College of Cardiology, American Heart Association and the European Society of Cardiology recom‐ mend ICD implantation for ARCV/D patients with high‐risk features [179]. ICD Implantation is recommended in ARVC/D patients who have experienced hemodynamically unstable VT, sustained VT or VF (class I). Also, ICD implantation is recommended in ARVC/D patients with severe RV systolic dysfunction, LV systolic dysfunction or both (Class I). ICD implantation should be considered in ARVC/D patients who have experienced hemodynamically stable, sustained VT or who have "major" risk factors such as unexplained syncope, moderate ventricular dysfunction, or NSVT (Class IIa) [147] (**Figure 9**).

**Figure 9.** Indications for ICD in ARVC/D patients based on risk stratification. Modified with permission from Corrado et al. [147].

#### *8.2.5. Surgical interventions*

### *8.2.5.1. Heart transplantation*

Heart transplantation is recommended as a final therapeutic option in ARVC/D patients with either severe, unresponsive congestive heart failure or recurrent episodes of VT/VF, which are refractory to catheter (and surgical) ablation and/or ICD therapy in experienced centers [147].

The most common indication for heart transplantation in ARVC/D patients is the progression of heart failure followed by intractable VTs [180]. Survival rates after 1‐year post‐heart transplant after were 94% and at an average follow‐up of 6.2 ± 4.8 year it was 88%. In a recent study involving a large cohort of ARVC/D patients, the need for cardiac transplantation was 4% [178].

#### *8.2.5.2. Other surgical therapies*

There is currently no clinical role for surgical therapies such as beating heart cryoablation [181], RV disarticulation [182], RV cardiomyoplasty [183], and left cardiac sympathetic denervation [184] in the treatment of patients with ARVC/D.

### **9. Family screening**

ARVC/D is a familial disease and screening the family of affected individuals is important. All first‐degree family members of the affected individual should be screened for ARVC/D. Screening should begin during the teenage years unless otherwise indicated. Screening tests include ECG, signal‐averaged ECG, Holter monitoring, echocardiogram, exercise stress test, and cardiac MRI. If a pathogenic mutation is identified in an ARVC/D patient, parents, siblings, and children of this patient can be tested for the mutation via the cascade method. In a recent study that looked at this matter it was found that one‐third of family members fulfill conven‐ tional diagnostic Task Force criteria. Siblings are at the highest risk of disease even after correcting for age and sex, and an accurate prediction of ARVC/D diagnosis among relatives can be obtained using a model including symptoms, being a sibling, the presence of a patho‐ genic mutation, and female gender [185]. Meeting Task Force criteria independent of family history had a higher prognostic value for arrhythmic events than conventional Task Force criteria, which include family history. It was also noted that arrhythmic risk prediction is improved by applying modified Task Force criteria that exclude family history. This provides the physician with a reliable risk stratification tool, which does not require a difficult man‐ agement scheme or additional testing [185].

### **10. Conclusions**

**Figure 9.** Indications for ICD in ARVC/D patients based on risk stratification. Modified with permission from Corrado

Heart transplantation is recommended as a final therapeutic option in ARVC/D patients with either severe, unresponsive congestive heart failure or recurrent episodes of VT/VF, which are refractory to catheter (and surgical) ablation and/or ICD therapy in experienced centers [147]. The most common indication for heart transplantation in ARVC/D patients is the progression of heart failure followed by intractable VTs [180]. Survival rates after 1‐year post‐heart transplant after were 94% and at an average follow‐up of 6.2 ± 4.8 year it was 88%. In a recent study involving a large cohort of ARVC/D patients, the need for cardiac transplantation was

There is currently no clinical role for surgical therapies such as beating heart cryoablation [181], RV disarticulation [182], RV cardiomyoplasty [183], and left cardiac sympathetic denervation

ARVC/D is a familial disease and screening the family of affected individuals is important. All first‐degree family members of the affected individual should be screened for ARVC/D. Screening should begin during the teenage years unless otherwise indicated. Screening tests

et al. [147].

4% [178].

*8.2.5. Surgical interventions*

150 Cardiomyopathies - Types and Treatments

*8.2.5.1. Heart transplantation*

*8.2.5.2. Other surgical therapies*

**9. Family screening**

[184] in the treatment of patients with ARVC/D.

ARVC/D is a rare cardiac disease characterized by fibrofatty replacement of myocardial tissue. It affects the RV primarily, but an extension to the LV in more advanced stages of the disease may occur. At the molecular level, both ventricles are affected, presumably in all stages of the disease. Its prevalence has been estimated to vary from 1:2000 to 1:5000. Patients typically present between the second and the fourth decade of life with VT episodes originating from the RV. It is also a major cause of SCD in the young patients and athletes.

The ARVC/D is an inherited cardiomyopathy and the causative genes encode proteins of mechanical cell junctions (e.g., plakoglobin, plakophilin‐2, desmoglein‐2, desmocollin‐2, and desmoplakin) accounting for intercalated disk remodeling. The mode of inherence is mostly an autosomal dominant trait with variable penetrance. The rare recessively inherited variants are often associated with palmoplantar keratoderma and wooly hair. The diagnosis is made according to the modified Task Force criteria, based on functional and structural alterations of the RV, depolarization and repolarization abnormalities, fibrofatty replacement in the endo‐ myocardial biopsy, VT with LBBB morphology, and family history. The use of the Task Force criteria helps to avoid under an overdiagnosis of the disease. Echocardiography and cardiac magnetic resonance imaging (MRI) are the main imaging tools to visualize structural and functional abnormalities. The ARVC/D should be differentiated from other cardiac diseases such as idiopathic RVOT‐VT and myocarditis. ARVC/D therapy consists of lifestyle changes, antiarrhythmic drugs, and catheter ablation. Young age at diagnosis, family history of juvenile SCD, LV involvement, VT, syncope, and previous cardiac arrest are the major risk factors for adverse prognosis. Implantable cardioverter defibrillator (ICD) therapy has been demonstrat‐ ed to affect positively patients' mortality, and it should be considered in all high‐risk patients. Heart transplantation may be required in about 4% of the ARVC/D patients. Ongoing research is focused on the understanding of disease pathophysiology and providing a curative therapy that may be able to stop disease progression.
