Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetic cardiomyopathy characterized by sudden death in the setting of recurrent ventricular arrhythmias and right ventricular (RV) dysfunction, although concomitant or isolated left ventricular dysfunction may also be present. With an estimated prevalence between 1 in 1000 to 1 in 5000,¹ our basic understanding of ARVC has relied on a series of longitudinal registries over the past three decades.^2-4 One of the earliest studies describing sudden death with ARVC found that 10 out of 12 subjects died during exercise.⁵ Since the description of nine families with a strong inheritance pattern in the Veneto region of Italy,⁶ ARVC has been associated with an autosomal dominant pattern with variable penetrance though an autosomal recessive form is also seen. With advancement in genetic testing, mutations involving the cardiac desmosome have been implicated in up to 60% of index cases.^7,8 The natural history of ARVC was well demonstrated in the Johns Hopkins registry where the clinical features of 100 affected individuals were carefully detailed.³ The majority of these patients were diagnosed between 20 to 40 years of age raising the concept of an initial "concealed phase," where asymptomatic young individuals at risk for the disease transition into an "electrical phase" with symptomatic ventricular arrhythmias. While RV dilation and dysfunction are common, progression to heart failure (HF) is rare, entailing less than 10% of the registry.³

The deleterious role of exercise in ARVC is related to both sudden death occurring during exercise and symptomatic progression of RV dysfunction. From an early multicenter series of 42 post-mortem cases attributed to ARVC, 34 deaths (81%) were sudden in nature with nearly half of these occurring during exercise.⁴ In the Veneto region of Italy, affected individuals were restricted from exercise activity and enrolled in a familial ARVC registry that began in 1980.² In addition, pre-participation screening including 12 lead electrocardiograms (ECG) for all competitive athletes was instituted in Italy in 1982. With this change in practice, the rate of sudden death among young athletes in 1979 decreased from 3.6 per 100,000 person-years to 0.43 per 100,000 person-years from 2001 to 2004.⁹ A major factor in this change was the identification of young individuals with ARVC and restriction of sports.⁹ Even with athletic ECG screening in Veneto from 1979-1999, sudden death still occurred, with a fivefold higher incidence of ARVC-related sudden death in athletes versus non-athletes.¹⁰

Since desmosomes provide intercellular integrity, endurance athletes with the genetic predisposition for ARVC are hypothesized to be most at risk for phenotypic expression. The hemodynamic impact of exercise was demonstrated in one study of athletes where RV shear stress increased 125% with prolonged strenuous exercise in comparison to 14% on the left.¹¹ With this increased stretch on the thin-walled right ventricle, the effect of exercise in individuals with ARVC is thought to promote breakdown of the desmosome that eventually triggers fibrofatty replacement of the RV walls.

To further strengthen the adverse role of exercise in ARVC, a heterozygous plakoglobin-deficient mouse model was exercised vigorously in comparison to wild-type control mice. With sustained exercise, the desmosomal mutant mice demonstrated a clear propensity for developing an ARVC phenotype in the form of RV enlargement, systolic dysfunction, and ventricular arrhythmias in comparison to a wild-type control.¹² Interestingly, load reducing therapy in the form of furosemide and nitrates was able to curtail this phenotypic transition in the same mouse model,¹³ though whether this regimen works in humans is not known.

More recently, these findings were evaluated in human cohorts. In the Johns Hopkins ARVC registry, the physical activity of 87 individuals with desmosomal mutations was evaluated.¹⁴ In comparison to non-athletes, the endurance athletes were more likely to develop ventricular arrhythmias and HF over a mean follow-up of 8.4 years. Furthermore, six of eight individuals in the top quartile of activity level who continued with significant exercise following their diagnosis experienced their first ventricular tachycardia/ventricular fibrillation event in follow-up in comparison to only one of eight individuals who reduced exercise after diagnosis.¹⁴

In conjunction, 108 index cases in the North American multidisciplinary study of ARVC were differentiated into sports participation as competitive, recreational, or inactive.¹⁵ Over three years of follow-up, competitive athletes were diagnosed with ARVC at a younger age while having twice the risk of the adverse events, mainly due to increased ventricular arrhythmias. Interestingly, there was no difference between the inactive and recreational sports groups. This was despite the fact that 93% of the recreational athletes participated in high dynamic sports such as running, biking, basketball and swimming.

While ARVC has become closely associated with multiple desmosomal mutations, a subset of patients that fulfill the task force criteria for ARVC without these typical mutations has been described.¹⁶ By targeting athletes with ventricular arrhythmias, definite or suspected ARVC was identified in 41 of 47 athletes with only six of these athletes having pathogenic mutations. Similarly, 43 "gene-elusive" patients were identified in the John Hopkins registry and compared to a group with desmosomal mutations.¹⁷ This distinct subset was found to have performed significantly more intense exercise prior to their diagnosis, particularly in those less than 25 years of age. There was also a significantly reduced incidence of ARVC within the family (10% versus 40%). These observations suggest two issues. While a minority of the gene-elusive individuals exhibits a familial influence indicating undiscovered genotypes, the significant levels of physical activity in this group suggest the possibility that intense exercise alone without a genetic mutation may lead to the ARVC phenotype.

An updated consensus statement regarding competitive sports participation from the American Heart Association and American College of Cardiology was released in 2005.¹⁸ Given the increased prevalence of ventricular arrhythmias and HF with high level athletics, it is a class III indication for anyone with a definite, borderline, or possible diagnosis of ARVC to participate in competitive sports except for low-intensity class 1A sports, such as billiards, bowling, and golf.¹⁸ In addition, the 2015 International Task Force Consensus Statement on Treatment of ARVC gave a class IIa recommendation that individuals with definite ARVC restrain from athletic activities beyond recreational low-intensity sports.¹⁹ A class IIa recommendation was also made for asymptomatic genotype carriers (possible ARVC) to consider avoiding competitive sports. Importantly, an implantable cardioverter-defibrillator should not be placed simply to allow sports participation without otherwise meeting clinical criteria for the device.

Research in the field will continue to solidify our exercise advice for individuals and families affected by ARVC. Compound and digenic heterozygosity for desmosomal mutations, male gender, biventricular dysfunction, and non-sustained ventricular tachycardia are just some of the identified risk factors for adverse events that may better stratify whom to restrict from activity.¹⁹ A recent study illustrated that an exercise treadmill test was able to elicit an abnormal electrical substrate in asymptomatic gene carriers when compared to healthy controls in the form of inducible epsilon waves, premature ventricular contractions and prolonged QRS terminal activation duration.²⁰ Similarly, athletes with a normal resting echocardiogram but ventricular arrhythmias from the right ventricle were compared to healthy endurance athletes and non-athletes after exercise.²¹ This group with ventricular arrhythmias had significantly attenuated RV function in response to exercise suggestive of subclinical disease. It remains to be seen whether these findings can be predictive of progression towards RV dysfunction. With further data, risk stratification may be enhanced to help guide our exercise recommendations and follow-up in a more personalized fashion, whether it be individuals with symptomatic ARVC or asymptomatic genetic carriers.

For now, it is clear that competitive sports should be avoided in patients with ARVC. Participation in moderate- to high-intensity recreational sports is also discouraged. The recommendations for activity restrictions in asymptomatic gene carriers (genotype positive/phenotype negative) have less data. If these individuals were to continue with significant physical activity, close clinical follow-up with particular attention towards new symptoms and repeat testing with ECG evaluation and cardiac imaging is mandated. The choice between a magnetic resonance imaging versus echocardiogram as well as the utility of exercise testing and signal averaged ECG should be determined on a case-by-case basis. With further research, improved risk stratification may help delineate the optimal exercise prescription and restriction for these individuals.

Table 1: Summary of Available Consensus Statements Regarding ARVC and Exercise Participation

Demographic	Recommendation	Classification
AHA/ACC Scientific Statement: Eligibility for Competitive Athletes with ARVC18
Athletes with possible, borderline, or definite ARVC	Participation in most competitive sports is not recommended with possible exception of low-intensity class 1A sports	Class III
Athletes with ARVC	Prophylactic ICD placement to permit sports participation is not recommended	Class III
International Task Force Consensus Statement on the Treatment of ARVC19
Definite ARVC	Should not participate in competitive and/or endurance sports	Class I
Definite ARVC	Restrict athletic activities; possible exception: recreational low-intensity sports	Class IIa
ARVC family members (gene carriers, negative phenotype)	Consider competitive sports activity restriction	Class IIa
ARVC family members (negative genotype/phenotype)	Consider competitive sports activity restriction	Class IIb

References

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Keywords: American Heart Association, Arrhythmogenic Right Ventricular Dysplasia, Athletes, Death, Sudden, Defibrillators, Implantable, Desmosomes, Electrocardiography, Exercise Test, Follow-Up Studies, Furosemide, Genetic Predisposition to Disease, Genetic Testing, Heart Failure, Heart Ventricles, Hemodynamics, Heterozygote, Magnetic Resonance Imaging, Mutation, Nitrates, Penetrance, Prevalence, Risk Factors, Tachycardia, Ventricular, Ventricular Dysfunction, Right, Ventricular Dysfunction, Left, Ventricular Function, Right, Ventricular Fibrillation, Ventricular Premature Complexes, gamma Catenin, Sports

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