Exercise and ARVCImplications for Diagnosis and Management

Yongkeun Cho, MD, PhDKyungpook National University Hospital

Daegu, Korea

Disclosure

• None.

ARVC: Gene mutation-related hereditary cardiomyopathy?

• Up to two-thirds of ARVC patients have mutations in genes encoding the cardiac desmosome.

However• Many patients with the same gene

mutations with the probands are asymptomatic and/or phenotype-negative.

• Sudden death was frequently exercise related and occurred in young competitive athletes during sporting activities.

• In the Veneto Region of Italy, ARVC was the most frequent cause of sport-related sudden cardiac arrest, being responsible for nearly 30% of death in young competitive athletes (Corrado, Am J

Med 1990;89:588-96).

Ohno, J Arrhythm 2016;32:398-403

Different effects of prolonged exercise on the RV and LVDouglas, JACC 1990;15:64-9

• 41 athletes before, at the finish and after recovery from the Hawaii Ironman Triathlon (3.9 km swim, 180.2 km bike ride, 42.2 km run). 2-D echocardiograms were analyzed.

• After exercise, LV and LA and RA sizes were reduced, whereas RV size increased (diastole: 21.4 to 24.2 cm2; systole: 15.8 to 18.2 cm2; p <0.01).

• Changes in all variables returned toward prerace values during recovery.

• Probably the RV is more susceptible to fatigue than the LV after prolonged exercise.

La Gerche, Card Electrophysiol Clin 2013;5:97-105

High prevalence of RV involvementin endurance athletes with ventricular arrhythmias

Heidbuchel, EHJ 2003;24:1473–80

• 46 high-level endurance athletes (performing 3 X 2 hrs sports/wk for >5 yrs; 80% competitive; 80% cyclists) diagnosed with sustained VT (37%) or NSVT (52%) or frequent PVC (11%).

• Most (86%) ventricular arrhythmias were of RV origin.• Only 1 (2%) athlete had a family history suggestive of ARVC.• After a medium follow-up of 4.7 years, 18 of 46 athletes had a major

rhythm disorders (6 appropriate ICD shocks, 3 sustained VT, 9 SD: all cyclists).

• Endurance athletes with arrhythmias have a high prevalence of RV structural and/or arrhythmic involvement.

• Endurance sports seems to be related to the development and/or progression of the underlying arrhythmogenic substrate.

Increase in RV dimensions in an elite cyclist with arrhythmias.La Gerche, Circulation 2014;130:992-1002

• Initially assessed during a period of relatively low training in June 2010 and then 18 months after a return to professional competition.

Exercise-induced RV dysfunction and structural remodeling in endurance athletes

La Gerche, EHJ 2012;33:998-1006

• 40 athletes at baseline, immediately after an endurance race (3–11 hr duration) and 1-wk postrace.

• Marathon, endurance triathlon, alpine cycling race, and an ultratriathlon.• Intense endurance exercise causes acute dysfunction of the RV, but not the LV.

Although short-term recovery appears complete, chronic structural changes and reduced RV function are evident in some of the most practiced athletes.

Delayed gadolinium enhancement in 5 athletes. Images of 5 athletes in whom focal delayed gadolinium enhancement (DGE) was identified in the interventricular septum (indicated with arrows)

RV fatigue developing during endurance exerciseClaessen, Med Sci Sports Exerc 2014;46:1717-26

• 14 male endurance athletes (age = 36±6 yr, BMI = 23.1±1.94 kg/m2)• Completed 150 km of cycling, including 11 climbs with a total elevation gain of 1,088 m. • Although LV function is unchanged, intense endurance exercise results in RV dilation

and reduced RVEF, which is appreciable at rest but is even greater during exercise.

Lower than expected desmosomal gene mutation prevalence in endurance athletes with complex ventricular arrhythmias of RV origin

La Gerche, Heart 2010;96:1268-74

Pathologicalgenotype

(n=6)

Normal genotype (n=41)

P value

Sports dymanic componentClass B (40-70% of Max O2)Class C (>70% of Max O2)

06 (100%)

1 (3%)39 (97%)

1.0

Sports static componentI (<20% of MVC)II (20-50% of MVC)III (>50% of MVC)

3 (50%)0

3 (50%)

8 (20%)1 (2%)

32 (78%)

0.25

Level of exerciseProfessional/eliteAmateur competitionRecreational

2 (33%)2 (33%)2 (33%)

27 (66%)7 (17%)7 (17%)

0.31

Amount of sports practicedHours per weekTotal hours (X 1,000)

9.2 (9)10.0 (5.6)

14.3 (8.9)11.6 (8.6)

0.0050.69

Family history of ARVC 1 (17%) 1 (2%) 0.24

MVC: Maximal voluntary contraction

• 42 consecutive athletes (42±11 yrs) excluding idiopathic RVOT VT.

• Performed 14±9 hr/wk of moderate to intense sport practice for 19±9 yrs.

• Found lower rates of desmosomal gene mutations, particularly among those performing the most exercise.

• ARVC like phenotype may be acquired through intense exercise without an gene mutation.

Exercise increases age-related penetrance and arrhythmic risk in ARVC–associated desmosomal mutation carriers

James, JACC 2013;62:1290-7

• 87 carriers (46 male; 44±18 yrs) were interviewed about physical activity from age 10.

• Prolonged endurance exercise >1 hr/d may accelerate the disease in ARVC and increase the risk of ventricular arrhythmias.

Exercise has a disproportionate role in the pathogenesis ofARVC in patients without desmosomal mutations

Sawant, J Am Heart Assoc 2014;3:e001471

Model of the relative influence of exercise and genetics in the pathogenesis of ARVC

Exercise intensity among 82 index patients stratified by genotype and 2010 family history TFC

18.4 Met-H/d

• 82 patients (39 desmosomal, all probands) were interviewed about regular physical activity from age 10.

• Participation in endurance athletics, duration, and intensity of exercise prior to clinical presentation were compared between patients with desmosomal and gene-elusive ARVC.

Excessive exercise and heartHeidbuchel, Br J Sports Med 2012;46(Suppl I):i44-i50, Sharma, EHJ 2012;33:939-40

• Healthy training with balanced exercise and recovery results in physiological remodeling in which enhanced cardiac structure and function enable greater cardiac performance during exercise.

• Excessive exercise (training too intense and/or recovery too short) may cause cardiac injury and proarrhythmic remodeling which predominantly affects the RV.

Cardiac arrest in a 30-years old female badminton player

Exercise-related palpitation in a 42-years old male cyclist

ARVC: Clinical course and predictors of arrhythmic riskMazzanti, JACC 2016;68:2540-50

• Predictors of life-threatening arrhythmic events were determined in 301 consecutive ARVC patient.

• AF, syncope, participation in strenuous exercise after the diagnosis of ARVC, sustained monomorphic VT, and male sex predicted lethal arrhythmias at follow-up.

Safety of AHA-recommended minimum exercisefor desmosomal mutation carriers

Sawant, HR 2016;13:199-207

• 28 family members with PKP2 mutation were interviewed about exercise from age 10.

• Both participation in endurance athletics and higher-intensity exercise were associated with diagnosis.

• Endurance athletes were also significantly more likely to develop VT/VF.

• Those who restricted exercise ≤AHA goal ( 650 MET-hr/yr) were significantly less likely to be diagnosed and had no VT/VF.

• At diagnosis and first VT/VF, family members had accumulated 2.8-fold and 3.5-fold, respectively, greater MET-Hr exercise than the AHA-recommended minimum.

• Those who developed VT/VF had performed particularly high-intensity exercise in adolescence compared to unaffected family members.

Animal studies also showed……

• Age- and training-dependent development of ARVC in heterozygous plakoglobin-deficient mice. Kirchhof, Circulation 2006;114:1799-806.

• Swimming up to 90 min/d, 6 d/wk for 8-wk training period.

• Mice heterozygous for plakoglobin (plakoglobin+/−) subjected to strenuous exercise were compared with inactive plakoglobin+/− mice.

• Exercised mice displayed worsened RV function and a higher incidence of spontaneous arrhythmias compared with inactive mice.

• Cardiac arrhythmogenic remodeling in a rat model of long-term intensive exercise training. Benito, Circulation 2011;123:13-22.

• Running up to 60 cm/s for 60 min, 5 d/wk for 16-wk (≒10 human yrs).

• Exercised rats had pronounced LVH, diastolic dysfunction, and marked fibrosis in the RV and both atria.

• VT was inducible in 42% of exercised rats compared with only 6% of sedentary rats.

• The fibrotic changes caused by 16 wks of intensive exercise were reversed after an 8-wk exercise cessation.

The concept of exercise-induced ARVCZaidi, EHJ 2015;36:1955-7, Corrado, NEJM 2017;376:61-72

• Ventricular arrhythmias frequently arise from the RV and are associated with structural and functional changes of the RV among endurance athletes.

• Strenuous exercise may accelerate disease progression. There is a dose-dependent relationship between exercise intensity and duration and disease severity.

AHA/ACC scientific statementRecommendations for competitive athletes with ARVC

Maron, JACC 2015;66:2362-71

1. Athletes with a definite/borderline/possiblediagnosis of ARVC should not participate in most competitive sports, with the possible exception of low-intensity class 1A sports (Class III; Level of Evidence C).

2. Prophylactic ICD placement in athlete-patients with ARVC for the sole or primary purpose of permitting participation in high-intensity sports competition is not recommended because of the possibility of device-related complications (Class III; Level of Evidence C).

Mitchell, JACC 2005;45:1364-7

ConclusionHaugaa, Scandanavian Cardiovascular J 2015;49:299-307

• There is an important link between exercise and outcomes in ARVC.

• Vigorous athletic activity is associated with earlier onset of disease and higher incidence of ventricular arrhythmias.

• Recommend ARVC patients to restrict from competitive sports, but patients with less severe disease and asymptomatic mutation-positive family members may continue recreational sports.