. 2021 May 7;23(6):57. doi: 10.1007/s11886-021-01489-0

Table 1.

Main human studies addressing the role of sports activity as a modifying factor in arrhythmogenic cardiomyopathy

Reference	Aim and design of the study	Study population and definitions	Main results	Conclusions
James CA et al. J Am Coll Cardiol. 2013 [16••]	Aim: to test the hypothesis that exercise influences age-related penetrance, arrhythmic risk, and progression to heart failure in ACM Study type: Observational, retrospective.	Study population: 87 patients with pathogenic ACM associated desmosomal mutation (76 PKP2, 7 DSG2, 3 DSP, 1 DSC2) Definitions: “Endurance athletics” were sports with a high dynamic demand (>70% Max O₂), done for at least 50 h/year at vigorous intensity.	The 56 ACM endurance athletes: 1. Developed symptoms at a younger age 2. Had a lower lifetime event free survival from VT/VF 3. Had a lower lifetime event free survival from HF	The amount and intensity of exercise increases the likelihood of diagnosis, of VT/VF, and of developing HF among ACM desmosomal mutation carriers
Sawant ACM et al., J Am Heart Assoc. 2014 [17]	Aim: To investigate whether exercise is associated with onset of gene-elusive ACM and has a differential impact in desmosomal and gene-elusive patients. Study type: Observational, retrospective.	Study populations: ACM patients who met revised 2010 ACM Task Force Criteria. Definitions: “Endurance athletics” were sports with a high dynamic demand (>70% Max O₂), done for at least 50 h/year at vigorous intensity.	1. ACM patients without desmosomal mutations did significantly more intense exercise prior to presentation than desmosomal mutation carriers 2. Patients without desmosomal mutations were significantly less likely to have a family history of ACM 3. Exercise history influences disease course more in gene-elusive ACM patients. Top intensity exercise was associated with significantly earlier age of onset, worse structural disease at clinical presentation, and shorter freedom from ventricular arrhythmia in follow-up	Gene-elusive, non-familial ACM is associated with very high intensity exercise, suggesting exercise has a disproportionate role in the pathogenesis of these cases
Saberniak J et al. Eur J Heart Fail 2014 [18]	Aim: To investigate the impact of vigorous exercise on myocardial function in patients with ACM and in their mutation positive family members. Study type: Observational, cross-sectional.	Study populations: 110 patients, 65 ACM index patients and 45 mutation-positive family members. Definitions: Intensity of physical activity was graded as vigorous if ≥6 METs. The duration of regularly performed exercise was expressed in years. Subjects with a history of physical activity with intensity ≥6 METs for ≥4 h/week (≥1440 METs × min/week) for ≥6 years were defined as athletes.	ACM patients with a history of athletic activity, compared with ACM non-athletes, had: 1. Reduced RV and LV function 2. Worse outcome, with a higher frequency and earlier onset of VA 3. Need of cardiac transplantation	ACM subjects with a history of athletic activity showed reduced RV and LV function compared with non-athletes by echocardiography and by MRI. Higher levels of physical activity correlated with reduced LV and RV function, and only athletes had cardiac transplantation. Diagnosis of ACM and onset of VA occurred at younger age in athletes compared with non-athletes
Ruwald ACM et al., Eur Heart J 2015 [19]	Aim: To assess the effects of competitive and recreational sport participation on age at first onset of symptoms, and risk of VT/death in ACM probands. To investigate whether a change in exercise level after ACM diagnosis is associated with a reduction in the risk of subsequent VT/death. Study type: Observational, prospective	Study population: 322 ACM probands or family members Definitions: Patients were asked what type of exercise level they performed both before and after diagnosis, with the following pre-specified fixed options: (i) inactive; (ii) recreational; (iii) competitive /professional; or (iv) unknown. Based on the recommendations for sports participation in patients with cardiovascular disease they differentiate between high dynamic sports (basketball, soccer, hockey, skiing, running, biking, and tennis) and low to moderately dynamic sports (bowling, golf, weight lifting, wrestling, baseball, or softball)	ACM patients engaged in competitive sport had: 1. Significantly higher risk of VT/death 2. Symptoms developed at an earlier age	In ACM patients, competitive sport was associated with a twofold increased risk of VT/death, and earlier presentation of symptoms, when compared with inactive patients, and to patients who participated in recreational sport
Lie OH et al. JACMC EP 2018 [20]	Aim: to explore the impact of exercise intensity, exercise duration, and exercise dose on outcome in ACM patients Study type: Observational, retrospective	Study population: 173 patients diagnosed with ACM Definitions: Patients were classified as regularly engaging in high intensity exercise (>6 METs), for example, running, aerobics, fast swimming, or competitive sports, or low-intensity exercise (3 to 6 METs), for example, walking, dancing, or weight lifting. Regular physical activity <3 METs was not recorded as exercise. On the basis of exercise intensity and duration, they categorized patients into 4 groups: 1. Low-intensity and short-duration exercise (low/short); 2. Low-intensity and long-duration exercise (low/long); 3. High-intensity and short-duration exercise (high/short); 4. High-intensity and long-duration exercise (high/long)	1. VA were more prevalent in patients with high-intensity exercise than low-intensity exercise, and more prevalent in long-duration than short-duration exercise 2. High-intensity exercise was a strong and independent marker of VA, even when adjusted for the interaction with long-duration exercise, whereas long-duration exercise was not	High-intensity exercise and long-duration exercise were both associated with unfavorable outcome in ACM patients, but high-intensity exercise was a strong marker of VA independently from exercise duration. Low intensity exercise, even for long durations, was associated with a milder phenotype and can be advised for patients with ACM
Salas AR et al. J Cardiovasc Electrophysiol. 2018 [21]	Aim: To discover the impact of dynamic physical activity on 36 patients with high-risk definite ACM. Study type: Observational retrospective cohort study	Study population: 36 high-risk ACM Definitions: According to the guidelines on sports participation for patients with cardiovascular disease the following were considered high dynamic sports: badminton, long or middle-distance running (marathon), cross-country skiing, squash, basketball, ice hockey, hockey, rugby, football, swimming, singles tennis, handball, boxing, kayaking, cycling, decathlon, rowing, speed skating, and triathlon. The intensity of dynamic activity was classified in accordance with the mean frequency of weekly physical exercise sessions in the 10 years before diagnosis: high/competitive (>3 h/wk), moderate (1 to 3 h/wk), and minimal/inactive (<1 h/wk)	The major arrhythmic event-free survival was shorter and the occurrence of severe RV dysfunction was more probable in the high-intensity exercise group, followed by the moderate intensity group and by the low-intensity/inactive group	A dose-dependent relationship between a history of dynamic physical activity and phenotypic severity based on the early onset of major arrhythmic events and deterioration of RV contractility was observed.
Müssingrbrodt Int J Sports Med 2019 [22]	Aim: To assess the role of exercise on long-term results of radiofrequency CA therapy of VT in patients with ACM Study type: Observational	Study population: 38 patients with definite ACM and previous CA for VT. Before CA, 30 were involved in sports activities (recreational and competitive) and 8 had sedentary lifestyle Definitions: According to the recommendations for competitive athletes with cardiovascular abnormalities, highly dynamic sports such as running or cycling were distinguished from low to moderately dynamic sports such as walking, golf or yoga	After CA: 1. No patient continued competitive sport 2. Patients practicing recreational exercise activities were not exposed to a greater risk for VT than patients with a sedentary lifestyle 3. Patients with a sedentary lifestyle or low to moderately dynamic sports activities had the same risk for VT recurrence as patients with highly dynamic sports activities	Recreational sports do not impair long-term results after CA therapy compared with a sedentary lifestyle and are not associated with an increased risk for VT recurrences after CA
Paulin heart rhythm 2020 [23]	Aim: To evaluate the impact of exercise on arrhythmic risk and cardiac death in TMEM43 p.S358L ACM. Study type: Observational	Study population: 80 individuals with the TMEM43 p.S358L mutation enrolled in a prospective registry who had received a primary prevention ICD. Definitions: The modified Paffenbarger Physical Activity Questionnaire was used. Subjects were asked questions pertaining to daily walking distances; number of flights of stairs climbed; frequency, duration, and type of sports played; and leisure and recreational activity. MET/h per day were calculated.	Exercise ≥9.0 MET-h/day (high level) in the year before ICD implantation was associated with an adjusted 9.1-fold increased hazard of first appropriate ICD discharge.	Exercise ≥9.0 MET-h/day is associated with an increased risk of malignant ventricular arrhythmias in the TMEM43 p.S358L subtype of ACM.

Reference

Aim and design of the study

Study population and definitions

Main results

Conclusions

James CA et al. J Am Coll Cardiol. 2013 [16••]

Aim:

to test the hypothesis that exercise influences age-related penetrance, arrhythmic risk, and progression to heart failure in ACM

Study type:

Observational, retrospective.

Study population:

87 patients with pathogenic ACM associated desmosomal mutation (76 PKP2, 7 DSG2, 3 DSP, 1 DSC2)

Definitions:

“Endurance athletics” were sports with a high dynamic demand (>70% Max O₂), done for at least 50 h/year at vigorous intensity.

The 56 ACM endurance athletes:

1. Developed symptoms at a younger age

2. Had a lower lifetime event free survival from VT/VF

3. Had a lower lifetime event free survival from HF

The amount and intensity of exercise increases the likelihood of diagnosis, of VT/VF, and of developing

HF among ACM desmosomal mutation carriers

Sawant ACM et al., J Am Heart Assoc. 2014 [17]

Aim:

To investigate whether exercise is associated with onset of gene-elusive ACM and has a differential impact in desmosomal and gene-elusive patients.

Study type:

Observational, retrospective.

Study populations:

ACM patients who met revised 2010 ACM Task Force Criteria.

Definitions:

“Endurance athletics” were sports with a high dynamic demand (>70% Max O₂), done for at least 50 h/year at vigorous intensity.

1. ACM patients without desmosomal mutations did significantly more intense exercise prior to presentation than desmosomal mutation carriers

2. Patients without desmosomal

mutations were significantly less likely to have a family

history of ACM

3. Exercise history influences disease course more in gene-elusive ACM patients. Top intensity exercise was associated with significantly earlier age of onset, worse structural disease at clinical presentation, and shorter freedom from ventricular arrhythmia in follow-up

Gene-elusive, non-familial ACM is associated with very high intensity exercise, suggesting exercise has a disproportionate role in the pathogenesis of these cases

Saberniak J et al.

Eur J Heart Fail 2014 [18]

Aim:

To investigate the impact of vigorous exercise on myocardial function in patients with ACM and in their mutation positive family members.

Study type:

Observational, cross-sectional.

Study populations:

110 patients, 65 ACM index patients and 45 mutation-positive family members.

Definitions:

Intensity of physical activity was graded as vigorous if ≥6

METs. The duration of regularly performed exercise was expressed in years. Subjects with a history of physical activity with intensity ≥6 METs for ≥4 h/week (≥1440 METs × min/week) for ≥6 years were defined as athletes.

ACM patients with a history of athletic activity, compared with ACM non-athletes, had:

1. Reduced RV and LV function

2. Worse outcome, with a higher frequency and earlier onset of VA

3. Need of cardiac transplantation

ACM subjects with a history of athletic activity showed reduced RV and LV function compared with non-athletes by echocardiography and by MRI.

Higher levels of physical activity correlated with reduced LV and RV function, and only athletes had cardiac transplantation.

Diagnosis of ACM and onset of VA occurred at younger age in athletes compared with non-athletes

Ruwald ACM et al.,

Eur Heart J 2015 [19]

Aim:

To assess the effects of competitive and recreational sport participation on age at first onset of symptoms, and risk of VT/death in ACM probands.

To investigate whether a change in exercise level after ACM diagnosis is associated with a reduction in the risk of subsequent VT/death.

Study type:

Observational, prospective

Study population:

322 ACM probands or family members

Definitions:

Patients were asked what type of exercise level they performed both before and after diagnosis, with the following pre-specified fixed options: (i) inactive; (ii) recreational; (iii) competitive /professional; or (iv) unknown.

Based on the recommendations for sports participation in patients with cardiovascular disease they differentiate between high dynamic sports (basketball, soccer, hockey, skiing, running, biking, and tennis) and low to moderately dynamic sports (bowling, golf, weight lifting, wrestling, baseball, or softball)

ACM patients engaged in competitive sport had:

1. Significantly higher risk of VT/death

2. Symptoms developed at an earlier age

In ACM patients, competitive sport was associated with a twofold increased risk of VT/death, and earlier presentation of symptoms, when compared with inactive patients, and to patients who participated in recreational sport

Lie OH et al.

JACMC EP 2018 [20]

Aim:

to explore the impact of exercise intensity, exercise duration, and exercise dose on outcome in ACM patients

Study type:

Observational, retrospective

Study population:

173 patients diagnosed with ACM

Definitions:

Patients were classified as regularly engaging in high intensity exercise (>6 METs), for example, running, aerobics, fast swimming, or competitive sports, or low-intensity exercise (3 to 6 METs), for example, walking, dancing, or weight lifting. Regular physical activity <3 METs was not recorded as exercise.

On the basis of exercise intensity and duration, they categorized patients into 4 groups:

1. Low-intensity and short-duration exercise (low/short);

2. Low-intensity and long-duration exercise (low/long);

3. High-intensity and short-duration exercise (high/short);

4. High-intensity and long-duration exercise (high/long)

1. VA were more prevalent in patients with high-intensity exercise than low-intensity exercise, and more prevalent in long-duration than short-duration exercise

2. High-intensity exercise was a strong and independent marker of VA, even when adjusted for the interaction with long-duration exercise, whereas long-duration exercise was not

High-intensity exercise and long-duration exercise were both associated with unfavorable outcome in ACM patients, but high-intensity exercise was a strong marker of VA independently from exercise duration. Low intensity exercise, even for long durations, was associated with a milder phenotype and can be advised for patients with ACM

Salas AR et al. J Cardiovasc Electrophysiol. 2018 [21]

Aim:

To discover the impact of dynamic physical activity on 36 patients with high-risk definite ACM.

Study type:

Observational retrospective cohort study

Study population:

36 high-risk ACM

Definitions:

According to the guidelines on sports participation for patients with cardiovascular disease the following were considered high dynamic sports: badminton, long or middle-distance running (marathon), cross-country skiing, squash, basketball, ice hockey, hockey, rugby, football, swimming, singles tennis, handball, boxing, kayaking, cycling, decathlon, rowing, speed skating, and triathlon.

The intensity of dynamic activity was classified in accordance with the mean frequency of weekly physical exercise sessions in the 10 years before diagnosis: high/competitive (>3 h/wk), moderate (1 to 3 h/wk), and minimal/inactive (<1 h/wk)

The major arrhythmic event-free survival was shorter and the occurrence of severe RV dysfunction was more probable in the high-intensity exercise group, followed by the moderate intensity group and by the low-intensity/inactive group

A dose-dependent relationship between a history of dynamic physical activity and phenotypic severity based on the early onset of major arrhythmic events and deterioration of RV contractility was observed.

Müssingrbrodt Int J Sports Med

2019 [22]

Aim:

To assess the role of exercise on long-term results of radiofrequency CA therapy of VT in patients with ACM

Study type:

Observational

Study population:

38 patients with definite ACM and previous CA for VT.

Before CA, 30 were involved in sports activities (recreational and competitive) and 8 had sedentary lifestyle

Definitions:

According to the recommendations for competitive athletes with cardiovascular abnormalities, highly dynamic sports such as running or cycling were distinguished from low to moderately dynamic sports such as walking, golf or yoga

After CA:

1. No patient continued competitive sport

2. Patients practicing recreational exercise activities were not exposed to a greater risk for VT than patients with a sedentary lifestyle

3. Patients with a sedentary lifestyle or low to moderately dynamic sports activities had the same risk for VT recurrence as patients with highly dynamic sports activities

Recreational sports do not impair long-term results after CA therapy compared with a sedentary lifestyle and are not associated with an increased risk for VT recurrences after CA

Paulin heart rhythm 2020 [23]

Aim:

To evaluate the impact of exercise on arrhythmic risk and cardiac death in TMEM43 p.S358L ACM.

Study type:

Observational

Study population:

80 individuals with the TMEM43 p.S358L mutation enrolled in a prospective registry who had received a primary prevention ICD.

Definitions:

The modified Paffenbarger Physical Activity Questionnaire was used. Subjects were asked questions pertaining to daily walking distances; number of flights of stairs climbed; frequency, duration, and type of sports played; and leisure and recreational activity.

MET/h per day were calculated.

Exercise ≥9.0 MET-h/day (high level) in the year before ICD implantation was associated with an adjusted 9.1-fold increased hazard of first appropriate ICD discharge.

Exercise ≥9.0 MET-h/day is associated with an increased risk of malignant ventricular arrhythmias in the TMEM43 p.S358L subtype of ACM.

ACM arrhythmogenic right ventricular cardiomyopathy, CA catheter ablation, HF heart failure, ICD implantable cardioverter-defibrillator, LV left ventricle, MET metabolic equivalent of task, MRI magnetic resonance imaging, RV right ventricle, VA ventricular arrhythmias, VF ventricular fibrillation, VT ventricular tachycardia