Introduction

Arrhythmogenic cardiomyopathy is a broad diagnosis that includes any ventricular dysfunction not caused by ischemic, hypertensive, or valvular heart disease in which arrhythmia (including atrial fibrillation, ventricular arrhythmia, and conduction disease) is part of the clinical presentation.¹ This includes the relatively well-defined arrhythmogenic right ventricular cardiomyopathy (ARVC), but also less well-known phenotypes such as arrhythmogenic left ventricular cardiomyopathy, which is also known as left-dominant arrhythmogenic cardiomyopathy and is very similar to arrhythmogenic dilated cardiomyopathy (DCM). It also includes systemic disorders that may affect the myocardium, such as sarcoidosis, amyloidosis, myocarditis, and Chagas disease, as well as genetic channelopathies. Increasing recognition of the widely variable presentations and etiologies of nonischemic heart disease substrates associated with arrhythmias led to the development of the 2019 Expert Consensus Statement on the topic, to guide the management and risk stratification of such patients, for whom such guidelines did not specifically exist outside of cardiac sarcoidosis, Chagas disease, and inherited channelopathies.^1-4

Discrepancies in Treatment

The dreaded complication that all arrhythmogenic cardiomyopathy have in common is sudden cardiac death (SCD) due to a malignant ventricular arrhythmia, and much effort is centered on identifying high-risk individuals and taking steps to minimize their risk. In patients with ischemic cardiomyopathy, plenty of data exist to guide and support the use of implantable cardioverter-defibrillator (ICD) for primary prevention of SCD in patients with reduced left ventricular ejection fraction (LVEF).⁵ In patients with nonischemic cardiomyopathy, which by definition includes all patients with arrhythmogenic cardiomyopathy, reduced (<35%) LVEF as a sole guideline for prophylactic ICD implantation has demonstrated less clear benefit compared to patients with ischemic cardiomyopathy.^6,7 Several reasons exist for this discrepancy. First, severely depressed LVEF is simply a surrogate for myocardial scarring (thought to be the main substrate for malignant ventricular arrhythmia), which also is presumed to be relatively fixed; this assumption is a more valid one for ischemic cardiomyopathy compared to nonischemic cardiomyopathy. In fact, in many patients with nonischemic cardiomyopathy, goal-directed medical therapy (including cardiac resynchronization therapy in those with left bundle branch block) may actually lead to reverse remodeling with improved LVEF and survival.^2,3 Conversely, in nonischemic cardiomyopathy, even a small amount of myocardial fibrosis may be arrhythmogenic and confer higher risk for malignant ventricular arrhythmia and SCD without significant impact on the LVEF. Multiple studies have linked presence of late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) imaging to increased risk of malignant ventricular arrhythmia independent of LVEF.⁷ Furthermore, when it comes to arrhythmogenic cardiomyopathy, certain genetic subgroups, particularly those with lamin A/C, filamin C, and desmosomal mutations, a higher propensity for malignant ventricular arrhythmia has been observed that is independent of LVEF.^8,9 Clearly some patients with arrhythmogenic cardiomyopathy will benefit from ICD implantation for primary prophylaxis against SCD, but it is still unclear who these patients are based on conventional cardiac assessments, and better risk stratification is needed.¹⁰

Highlights From the New Guidelines

One of the main takeaways from the 2019 Heart Rhythm Society (HRS) guidelines is the definition and classification of arrhythmogenic cardiomyopathy. Although previous guidelines exist for ARVC, heart failure, genetic cardiomyopathy, global SCD prevention, and channelopathies, this is the first major guideline to define and guide management of all arrhythmogenic cardiomyopathy. As noted in the introduction, the decision about and when and in whom to implant an ICD is critical for the management of arrhythmogenic cardiomyopathy, and these recommendations were updated:¹

• For those with prior cardiac arrest secondary to malignant ventricular arrhythmia or hemodynamically unstable ventricular tachycardia (VT), ICD implantation remains a Class I indication.
• For ARVC with hemodynamically stable VT, ICD implantation is a:
  • Class IIa indication. Interestingly, this is different from the 2015 ARVC management guidelines,11 which considered ICD a Class I indication for VT regardless of the hemodynamic effect. Although VT may be tolerated in ARVC and outcome data are limited and mostly retrospective, the available studies point to the negative prognostic effect of sustained VT, therefore supporting the recommendation of ICD implantation.
  • Class I indication for all other forms of arrhythmogenic cardiomyopathy.
• For those with syncope due to a suspected malignant ventricular arrhythmia, ICD implantation is a Class IIa recommendation.
• For those with an LVEF ≤35% and life expectancy of at least 1 year, ICD implantation is a:
  • Class I indication for those with New York Heart Association Class II-III symptoms.
  • Class IIa indication for those with New York Heart Association Class I symptoms.
• ICD implantation was also a Class IIa indication in those with the following specific genetic profiles:
  • Individuals with lamin A/C (LMNA) mutation and either an indication for pacing otherwise or at least 2 of the following: male, LVEF <45%, any nonsustained VT
  • Individuals with filamin C (FLNC) mutation and LVEF <45%
  • Individuals with phospholamban (PLN) mutation and LVEF <45% or nonsustained VT
• For patients with ARVC specifically who do not meet any of the above criteria, individuals with a combination of the following major and minor criteria may also be ICD candidates (Class II):
  • Major criteria
    • Any nonsustained VT
    • Ability to induce VT on electrophysiologic study
    • LVEF <50%
  • Minor criteria
    • Male
    • >1,000 premature ventricular contractions in a 24-hour period (cannot be used if nonsustained VT already used as a criterion)
    • Right ventricular dysfunction as defined by 2010 task force criteria
    • Proband
    • 2 or more desmosomal mutations
  • Those with any of the following combinations meet the Class IIa recommendation:
    • All 3 major
    • 2 major + 2 minor
    • 1 major + 4 minor
  • Those with the following combinations meet the Class IIb recommendation:
    • 2 major
    • 1 major + 2 minor
    • 4 minor

Many of these recommendations are not new. However, the incorporation of genetic data in recommendations for ICD implantation is a major new update and a step toward precision medicine, based on the growing evidence that certain genotypes do place individuals at higher risk for malignant ventricular arrhythmia and SCD.^7-9

From a medical management standpoint, there are also some new suggestions in the 2019 HRS consensus statement on arrhythmogenic cardiomyopathy. First, based on preclinical data that demonstrated benefit of preload reduction in slowing disease progression and early right ventricular remodelling,¹² an additional Class IIb recommendation is to use isosorbide dinitrate (in addition to diuretics, which is a Class IIa recommendation) to aggressively reduce preload in patients with arrhythmogenic cardiomyopathy with right ventricular dysfunction. Second, now a Class IIb recommendation for those with ICDs but refractory ventricular arrhythmias and with preserved LVEF and right ventricular ejection fraction, is the addition of flecainide to metoprolol when other therapies, including catheter ablation, have failed.¹ This recommendation is based primarily on limited data from a 2017 retrospective observational study that suggested that the addition of flecainide may be useful in this population.¹³

Lastly, these consensus guidelines update the recommendations for exercise in patients with arrhythmogenic cardiomyopathy. It has been well-established that individuals with ARVC should not participate in competitive sports or high-intensity endurance exercise because those can increase their risk of malignant ventricular arrhythmia and SCD as well as progression of right ventricular dysfunction in adults and children (Figure 1).^14-18 The 2019 HRSA guidelines provide a better definition of the level of exercise intensity recommended for ARVC, which should remain within "moderate intensity." They do acknowledge less data in other forms of arrhythmogenic cardiomyopathy to justify similar exercise restrictions, although preliminary findings suggest similar risks in LMNA variant carriers.¹⁹

Figure 1: Impact of Type of Exercise on Arrhythmogenic Cardiomyopathy Outcome

Limitations

Although this new consensus statement is an important step forward toward personalizing care of patients with arrhythmogenic cardiomyopathy, there are some limitations that need to be addressed. One of the big areas with emerging data that is not addressed in the new 2019 HRS guidelines is how to incorporate advanced imaging into SCD risk stratification and recommendations for primary-prevention ICD implantation. As noted, multiple studies have linked the presence of LGE identified on CMR to increased risk for malignant ventricular arrhythmia and SCD.⁷ Interestingly, further research has suggested that there is interplay between a patient's genetics and their CMR findings (i.e., that the same LGE pattern may have a different risk profile in different genetic groups).²⁰ Clearly, more research is required on how to best use this imaging data to help stratify patients' risk of SCD and should be incorporated into future guidelines.

Another limitation in these guidelines is the relatively underrepresented role of desmosomal mutations. Although mutations in filamin C, lamin A/C, and phospholamban (with the other clinical criteria noted above) are all new Class IIa indications for an ICD, mutations in the desmosomal genes are limited to only "minor criteria" and, importantly, only in those with ARVC. Although the role of desmosomal mutations in ARVC is well-established, carriers also confer a higher risk of SCD or malignant ventricular arrhythmia in patients with an arrhythmogenic left ventricular cardiomyopathy or arrhythmogenic DCM phenotype,⁹ which is not addressed in the guidelines (Figure 2).

Figure 2: Genetically Determined Risk of SCD and Ventricular Arrhythmias in DCM Phenotype

Finally, although arrhythmogenic cardiomyopathy is typically a disease of adulthood, some studies suggest that as many as one-sixth of arrhythmogenic cardiomyopathy patients may show features of their illness during adolescence,²¹ and these guidelines do not address management of this growing pediatric population. Similar disease expression is seen between adult and pediatric groups,²¹ although the many links with genetic factors, environmental factors (particularly with relation to exercise), and immunologic factors are not well understood.²²

Conclusion

The recently published consensus statement on arrhythmogenic cardiomyopathy is a significant step forward toward implementing more standardized and evidence-based diagnosis and treatment of this heterogenous group of disease processes. That said, there is still much work to be done to use the ever-growing knowledge base on the genetics of these illnesses in combination with clinical features (including CMR) to establish thoughtful, evidence-based guidelines for risk assessment and management.

References

1. Towbin JA, McKenna WJ, Abrams DJ, et al. 2019 HRS expert consensus statement on evaluation, risk stratification, and management of arrhythmogenic cardiomyopathy. Heart Rhythm 2019;16:e301-e372.
2. Dias JC, Ramos AN Jr, Gontijo ED, et al. 2 nd Brazilian Consensus on Chagas Disease, 2015. Rev Soc Bras Med Trop 2016;49Suppl 1:3-60.
3. Birnie DH, Sauer WH, Bogun F, et al. HRS expert consensus statement on the diagnosis and management of arrhythmias associated with cardiac sarcoidosis. Heart Rhythm 2014;11:1305-23.
4. Priori SG, Wilde AA, Horie M, et al. HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes: document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013. Heart Rhythm 2013;10:1932-63.
5. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail 2016;18:891-975.
6. Køber L, Thune JJ, Nielsen JC, et al. Defibrillator Implantation in Patients with Nonischemic Systolic Heart Failure. N Engl J Med 2016;375:1221-30.
7. Zipse MM, Tzou WS. Sudden cardiac death in nonischemic cardiomyopathy: Refining risk assessment. J Cardiovasc Electrophysiol 2017;28:1361-6.
8. Begay RL, Graw SL, Sinagra G, et al. Filamin C Truncation Mutations Are Associated With Arrhythmogenic Dilated Cardiomyopathy and Changes in the Cell-Cell Adhesion Structures. JACC Clin Electrophysiol 2018;4:504-14.
9. Gigli M, Merlo M, Graw SL, et al. Genetic Risk of Arrhythmic Phenotypes in Patients With Dilated Cardiomyopathy. J Am Coll Cardiol 2019;74:1480-90.
10. Miles C, Finocchiaro G, Papadakis M, et al. Sudden Death and Left Ventricular Involvement in Arrhythmogenic Cardiomyopathy. Circulation 2019;139:1786-97.
11. Corrado D, Wichter T, Link MS, et al. Treatment of Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia: An International Task Force Consensus Statement. Circulation 2015;132:441-53.
12. Fabritz L, Hoogendijk MG, Scicluna BP, et al. Load-reducing therapy prevents development of arrhythmogenic right ventricular cardiomyopathy in plakoglobin-deficient mice. J Am Coll Cardiol 2011;57:740-50.
13. Ermakov S, Gerstenfeld EP, Svetlichnaya Y, Scheinman MM. Use of flecainide in combination antiarrhythmic therapy in patients with arrhythmogenic right ventricular cardiomyopathy. Heart Rhythm 2017;14:564-9.
14. Lie ØH, Dejgaard LA, Saberniak J, et al. Harmful Effects of Exercise Intensity and Exercise Duration in Patients With Arrhythmogenic Cardiomyopathy. JACC Clin Electrophysiol 2018;4:744-53.
15. Maupain C, Badenco N, Pousset F, et al. Risk Stratification in Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia Without an Implantable Cardioverter-Defibrillator. JACC Clin Electrophysiol 2018;4:757-68.
16. Te Riele ASJM, James CA, Sawant AC, et al. Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy in the Pediatric Population: Clinical Characterization and Comparison With Adult-Onset Disease. JACC Clin Electrophysiol 2015;1:551-60.
17. James CA, Bhonsale A, Tichnell C, et al. Exercise increases age-related penetrance and arrhythmic risk in arrhythmogenic right ventricular dysplasia/cardiomyopathy-associated desmosomal mutation carriers. J Am Coll Cardiol 2013;62:1290-7.
18. Sawant AC, Te Riele AS, Tichnell C, et al. Safety of American Heart Association-recommended minimum exercise for desmosomal mutation carriers. Heart Rhythm 2016;13:199-207.
19. Pasotti M, Klersy C, Pilotto A, et al. Long-term outcome and risk stratification in dilated cardiolaminopathies. J Am Coll Cardiol 2008;52:1250-60.
20. Augusto JB, Eiros R, Nakou E, et al. Dilated cardiomyopathy and arrhythmogenic left ventricular cardiomyopathy: a comprehensive genotype-imaging phenotype study. Eur Heart J Cardiovasc Imaging 2020;21:326-36.
21. DeWitt ES, Chandler SF, Hylind RJ, et al. Phenotypic Manifestations of Arrhythmogenic Cardiomyopathy in Children and Adolescents. J Am Coll Cardiol 2019;74:346-58.
22. Ackerman MJ, Giudicessi JR. Pediatric-Onset Arrhythmogenic Cardiomyopathy: Look Right, Look Left, Look Both Ways. J Am Coll Cardiol 2019;74:359-61.

Clinical Topics: Arrhythmias and Clinical EP, Heart Failure and Cardiomyopathies, Implantable Devices, EP Basic Science, Genetic Arrhythmic Conditions, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias

Keywords: Arrhythmias, Cardiac, Arrhythmogenic Right Ventricular Dysplasia, Cardiac Resynchronization Therapy, Lamin Type A, Ventricular Premature Complexes, Contrast Media, Defibrillators, Implantable, Bundle-Branch Block, Filamins, Cardiomyopathy, Dilated, Atrial Fibrillation, Channelopathies, Ventricular Dysfunction, Right, Stroke Volume, Flecainide, Retrospective Studies, Isosorbide Dinitrate, Metoprolol, Metabolic Equivalent, Prevalence, Ventricular Remodeling, Diuretics

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