Exercise restriction is protective for genotype-positive family members of arrhythmogenic right ventricular cardiomyopathy patients

Abstract

Aims

In arrhythmogenic right ventricular cardiomyopathy (ARVC) patients, exercise worsens disease course, so exercise restriction is recommended. However, recommendations for genotype-positive ARVC family members is incompletely resolved. We aimed to provide evidence for exercise recommendations for genotype-positive ARVC family members.

Methods and results

Arrhythmogenic right ventricular cardiomyopathy family members inheriting a pathogenic desmosomal variant were interviewed about exercise history from age 10. Exercise was characterized by duration, intensity, and dose (duration*intensity). Associations between exercise and (i) diagnosis by 2010 Task Force Criteria and (ii) development of sustained ventricular arrhythmias were examined. The study included 101 family members (age: 40.5 ± 19.3 years, male: 41%, Plakophilin-2 variant: 81%). Forty-four individuals (44%) met diagnostic criteria and 16 (16%) experienced sustained ventricular arrhythmia. Individuals who met diagnostic criteria had significantly higher average exercise duration and dose, but not peak intensity than those who did not. Only one individual who exercised below the American Heart Association recommended minimum (650 metabolic equivalent of task-hours/year) met diagnostic criteria or experienced sustained ventricular arrhythmia as opposed to 50% of individuals who exceeded it (adjusted odds ratio = 0.03, 95% confidence interval 0.003–0.26). The difference in exercise exposure between affected and unaffected individuals was more striking in females than in males. Females who had done high-dose exercise in adolescence had the worst survival free from diagnosis (P < 0.01).

Conclusions

In phenotype-negative ARVC family members with a pathogenic desmosomal variant, athletic activities should be limited, particularly exercise dose. Exercise may play a greater role in promoting disease in female family members.

Introduction

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart muscle disease associated with ventricular tachyarrhythmia and sudden death.¹ Up to two-thirds of ARVC patients have pathogenic variants in desmosomal genes.² As exercise promotes ventricular arrhythmias and structural progression,^3–5 avoidance of frequent high intensity and competitive endurance exercise is recommended to patients with definite ARVC.⁶

Following identification of a pathogenic variant in probands, cascade genetic testing is indicated⁶ to identify at-risk family members. Retrospective studies have suggested that endurance exercise is associated with age-related penetrance in genotype positive relatives.^3,4,7 Unfortunately, the evidence to make quantifiable or personalized recommendations for exercise in these typically asymptomatic^2,8 individuals is limited.⁶ Only one study of 28 family members has focused on exercise in ARVC family members.⁷ Other studies quantifying exercise in ARVC were populated either solely⁵ or largely by probands.^3,4 Extrapolating results of probands to family members is problematic, as family members often have a milder course.²

Growing evidence suggests that sex may influence ARVC development and course. Among affected individuals, males are disproportionately probands, display earlier disease onset and worse arrhythmia.⁹ Recently, testosterone levels were shown to be independently associated with ventricular arrhythmias in males with ARVC.¹⁰ Furthermore, testosterone elevated but oestradiol attenuated cardiomyocyte apoptosis and lipogenesis in an induced pluripotent stem cell (iPSC)-derived cardiomyocyte in vitro model of ARVC from a patient with a Plakophilin-2 (PKP2) variant.¹⁰ Considering exercise triggers testosterone release,¹¹ we hypothesized that exercise exposure would have a disproportionate influence on outcomes in male family members.

Developing an evidence base to make exercise recommendations for genotype-positive family members is important. On one hand, ARVC represents a rare opportunity to reduce phenotypic expression of a genetic disease through lifestyle modification. On the other hand, the health benefits of exercise¹² are indisputable. It invites the questions: (i) which parameter(s) of exercise (intensity, duration, or both) best predicts outcomes, (ii) whether ARVC family members can participate in certain levels of exercise safely, and (iii) whether exercise recommendations can be personalized by sex. We addressed these questions by evaluating the exercise history and clinical outcomes of 101 family members with pathogenic desmosomal variants from the Johns Hopkins ARVC Registry.

Methods

The data, analytic methods, and study materials will not be made available to other researchers for purposes of reproducing the results or replicating the procedure.

Population

Study participants were recruited from the Johns Hopkins ARVC Registry, which prospectively enrols ARVC patients and their family members. Participants over the age of 10 are routinely invited for a detailed exercise history interview. The inclusion criteria for the current study were: (i) family members of definite ARVC probands per the 2010 Task Force Criteria;¹³ (ii) who carried a pathogenic or likely pathogenic desmosomal variant (Class 4 or 5); (iii) had undergone an exercise interview; and (iv) had undergone clinical evaluation for ARVC. Pathogenicity of variants were adjudicated according to the joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association of Molecular Pathology.¹⁴ The Johns Hopkins School of Medicine Institutional Review Board approved the study and participants provided written informed consent.

Clinical phenotypes

Medical history was obtained by review of medical records, clinical evaluation, and patient interview as previously described.⁹ Genetic counsellors with expertise in ARVC evaluated family history and constructed three-generation pedigrees.

Endpoints included (i) diagnosis of definite ARVC by the 2010 Task Force Criteria and (ii) first sustained ventricular arrhythmia. A sustained ventricular arrhythmia was a composite of spontaneous sustained ventricular tachycardia, aborted sudden cardiac death, or appropriate implantable defibrillator firing for a ventricular arrhythmia as described before.⁷ Ventricular arrhythmias were adjudicated by electrocardiograms, medical records, and device-stored electrocardiograms. Device setting were at the discretion of the treating physician. Both endpoints were ascertained at the time of last clinical follow-up or exercise interview, whichever came first. We refer to this as the time of phenotyping throughout the manuscript.

Exercise interviews

Structured telephone interviews were conducted to capture regular exercise exposure in adolescence and adulthood.^3,7 Participants were prompted to list regular exercise done for leisure/recreation, work, and transportation since age 10. Intensity, frequency, and duration of each regularly performed activity were recorded. Participants rated the intensity of each activity as light, moderate, or vigorous using language and definitions from the Multi-Ethnic Study of Atherosclerosis Typical Week Physical Activity Survey.¹⁵ Frequency and duration of each activity were recorded as participants’ estimate of how many months of the year, days of the month, and hours per day spent on each activity at a given intensity.

Exercise analysis

We calculated annual exercise dose and duration from age 10 to the time of phenotyping. Each regularly performed activity was assigned a metabolic equivalent of task (MET) value according to the 2011 Compendium of Physical Activities (https://sites.google.com/site/compendiumofphysicalactivities/). Vigorous intensity activities are considered those ≥6 METs.¹⁶ We recorded the peak MET of regularly performed activities for each participant. Intensity and duration of aerobic physical activity was multiplied and integrated into the metabolic equivalent of task-hours (MET-Hour), a robust tool commonly used for measuring energy expenditure associated with physical activity. We refer to this as the exercise ‘dose’. Total exercise dose was calculated and subsequently annualized (MET-Hour/year). For all analyses, only exercise performed prior to the study endpoints was considered.

American Heart Association/American College of Sports Medicine (AHA/ACSM) recommendations suggest either moderate-intensity activity of at least 150 min per week or vigorous-intensity activity of at least 75 min per week to healthy adults for cardiovascular health.¹⁷ This is equivalent to a range from 390 to 650 MET-h/year. We chose the upper bound (650 MET-h/year) as the cut-off for the AHA/ACSM-recommended minimum in the analyses.

Statistical analysis

Baseline characteristics by the Task Force Criteria status were compared by the χ² test or Kruskal–Wallis test for categorical variables, and t-test or Wilcoxon Rank-Sum test for continuous variables.

Cumulative exercise dose was visualized in spaghetti plots. Five parameters of exercise (average MET-hours/year, peak MET-hours/year, average hours/year, peak hours/year, peak MET) by study endpoints were compared with the Wilcoxon Rank-Sum test.

Due to the lack of linear association between diagnosis and exercise parameters, we dichotomized exercise parameters into bottom tertile vs. the rest. Below vs. above 650 MET-h/year was also examined. The associations between each exercise parameter and endpoints were estimated by logistic regression. The concordance statistics for logistic models were calculated.

To account for family membership, random-effects logistic regression clustering on family with a robust variance was used.

Average exercise dose in 10-year increments (age 11–20, 21–30, 31–40, 41–50, >50) was first stratified by sex and then compared between affected and unaffected family members by the Wilcoxon Rank-Sum test. Survival from study endpoints was estimated by the Kaplan–Meier method and compared using the log-rank test.

Statistical analyses were performed using Stata/IC 14.2. A two-sided P-value of <0.05 was considered statistically significant.

Results

Study population

The study included 101 ARVC family members from 60 families (56 individuals had been included in prior publications^3,7) All family members carried pathogenic/likely pathogenic variants in desmosomal genes. PKP2 variants were the most common (N = 82, 81%). A list of variants is included in Supplementary material online, Table S1.

As in Table 1, more than half were female (N = 60, 59%). Age at phenotyping was 40.5 ± 19.3 years (range 11–85 years). Less than half met the Task Force Criteria (N = 44, 44%). Importantly, females were more likely to be affected than males (31/60 females vs. 13/41 males; P = 0.047). Sixteen (16%) individuals experienced sustained ventricular arrhythmias (11 appropriate implantable cardioverter-defibrillator interventions for ventricular arrhythmia, 4 sustained ventricular tachycardia, and 1 ventricular fibrillation arrest).

Association of exercise parameters with phenotypes

Figure 1 shows the lifespan accumulated exercise dose from age 10 stratified by diagnosis. Each line represents an individual, starting at age 10 and ending at the age of meeting diagnostic criteria (in red) or phenotyping (in black). As expected, a larger proportion of unaffected family members had been relatively sedentary (flat lines) than those who had been diagnosed. However, it was common for an unaffected individual to have been physically active (near vertical slope) at some time in their history.

We next compared each exercise parameter between affected and unaffected family members. As in Table 2, family members who met the Task Force Criteria had significantly higher average annual exercise dose (MET-Hours) and duration than those who did not. In contrast, no significant difference was observed in the highest exercise intensity (peak MET). Only average exercise dose differed significantly between family members who developed a sustained ventricular arrhythmia and those who did not (P = 0.048) (Supplementary material online, Table S2).

Table 3 displays the associations between exercise parameters and outcomes. Model 1 adjusted for age and sex. Model 2 additionally controlled for family membership. Highest exercise intensity (peak MET) was again not associated with diagnosis or ventricular arrhythmia. In contrast, average exercise duration and dose were strongly associated with diagnosis. Comparing the concordance statistics of exercise parameters, peak intensity had the lowest concordance statistic (0.68). Average exercise duration and average exercise dose performed better (0.73 and 0.74, respectively). As exercise dose integrates both duration and intensity, we chose it as the metric in following analyses.

Desmoplakin carriers were significantly more likely to have left ventricular dysfunction defined by left ventricular ejection fraction < 55% compared to non-carriers [4 (36%) vs. 6 (7%), P = 0.002]. Among them, individuals with left ventricular dysfunction had more exercise dose (MET-hours/year) than those without (2574, interquartile interval: 1890–2676 vs. 1377, interquartile interval: 718–3820). However, it did not reach statistical significance (P = 0.45).

Safe exercise level for genotype-positive arrhythmogenic right ventricular cardiomyopathy family members

We next evaluated whether a safe level of exercise could be identified. In Figure 2, only one (5%) out of 19 family members with average exercise dose below 650 MET-hours/year met the Task Force Criteria as opposed to approximately half (44–63%) of the family members who exercised more. After adjusting for age and sex, family members who limited average exercise dose below 650 MET-hours/year were significantly less likely to be diagnosed (adjusted odds ratio = 0.03, 95% confidence interval: 0.003–0.26). The association to ventricular arrhythmia did not reach statistical significance (Table 3).

Average exercise dose increased by 513 (95% confidence interval: 162–865) MET-hours/year per point of Task Force Criteria adjusting for gender and age).

When we examined PKP2 carriers only, the findings were similar.

The role of sex

Survival free from diagnosis was worse in female family members (P = 0.006), but survival free from ventricular arrhythmias was similar by sex (Supplementary material online, Figures S1 and S2).

Figure 3 examines the association of exercise across the lifespan and diagnosis by comparing the average exercise dose in 10-year increments between affected and unaffected family members stratified by sex. Female family members who developed disease exercised significantly more than those unaffected in each age group. Among males, unaffected family members were generally more active. The difference in exercise dose between affected and unaffected male family members, while present, was not statistically significant (also in Supplementary material online, Tables S3 and S4).

Finally, we examined the association of exercise dose in adolescence (age 11–20) with survival free from diagnosis stratified by sex (Figure 4). Among the four groups, females who had done high-dose adolescent exercise [top quartile: ≥7155 (interquartile interval: 3906–22 917) MET-Hours/year] had the worst lifetime survival from diagnosis (P < 0.01). Four of these 14 females who had been most active in adolescence developed an arrhythmia (two sustained ventricular tachycardia and two defibrillator firing for ventricular arrhythmia).

Discussion

Main findings

This is the largest study focusing on exercise in genotype-positive ARVC family members. It has three main findings. (i) Higher average exercise duration and dose (duration*intensity) were associated with developing ARVC, while peak intensity alone was not. It was common for unaffected family members to have had periods of high-intensity exercise. (ii) When family members exercised below the upper bound of the AHA/ACSM-recommended minimum range, the risk of developing ARVC and sustained ventricular arrhythmias was much lower, albeit not zero (5%). (iii) There was no evidence that exercise has a lesser influence on pathogenesis of disease in women. Instead, women who had participated in high levels of exercise during adolescence had a high likelihood of developing ARVC.

Prior literature

The data on which to derive exercise recommendations for genotype positive, phenotype-negative family members is limited. We previously reported higher exercise duration was associated with increased penetrance and ventricular arrhythmias in 87 patients with desmosomal variants, of whom 51 were family members.³ Later, Saberniak et al.⁴ showed exercise in the 3 years before first clinical presentation was associated with reduced biventricular function in 65 probands and 45 genotype-positive family members. Recently, this group presented data suggesting exercise intensity prior to a first clinical visit was a strong marker of life-threatening ventricular arrhythmia independent of exercise duration in a mixed family member/proband cohort.¹⁸ However, in all these studies, probands contributed most of the events.

Family members are different from probands, displaying fewer symptoms and a less severe disease course.² The extent and benefit of limiting exercise in family members may therefore differ. To fill this evidence gap, Sawant et al. examined 28 PKP2-positive family members.⁷ The study suggested exercise below the upper bound of the AHA/ACSM-recommended minimum range may be safe for PKP2-positive family members. The sample size was small. This manuscript confirms and extends these prior findings.

Implications for exercise guidance for arrhythmogenic right ventricular cardiomyopathy family members

The 2019 Heart Rhythm Society expert consensus statement⁶ on ARVC management recommended that physicians counsel genotype positive, phenotype-negative patients that frequent high-intensity or competitive endurance exercise is associated with increased penetrance. However, it is silent on which parameters (duration, intensity, or both) to use to guide exercise participation.

With a larger sample size, our study has strengthened the evidence base and provided nuance to these recommendations. Our data show peak intensity was not associated with outcomes. Instead, the best predictors of outcome were high average exercise dose and duration. Therefore, in addition to considering avoidance of competitive and high-intensity exercise, it may be reasonable for individuals to consider limiting very long durations of exercise. On the other hand, it appears that the long-term risk of occasional high-intensity exercise is modest.

Exercise is irrefutably beneficial in the prevention and treatment of chronic diseases (e.g. cardiovascular diseases, cancer, diabetes, and depression).¹² Whether genotype-positive ARVC family members can exercise regularly at a certain level without increasing the risk of developing ARVC is relevant because they are often young when identified.² In our study, only 1 (5%) family member who exercised at or below the upper bound of the AHA/ACSM-recommended minimum range (650 MET-hours/year) met Task Force Criteria. Previously, when this level was suggested as safe,³ 7 family members exercised a median of 310 MET-hours/year and only 1 met diagnostic criteria.

Surprisingly, a substantial number of genotype-positive family members had thus far escaped ARVC despite high-dose exercise. For instance, among those doing >3300 MET-Hours/year, only 63% met Task Force Criteria. This is a reminder that ARVC is likely an oligogenic disease. Other genetic and environmental modifiers are also likely important.¹⁹ Further studies are required to elucidate the role of other aetiologic factors.

Exercise and sex in arrhythmogenic right ventricular cardiomyopathy

Sex differences have been long observed in ARVC. Male patients develop the disease earlier and have more ventricular arrhythmias.^9,20 However, our findings remind us that among individuals ascertained through family screening, women are not necessarily at low risk. This is perhaps not surprising as males who are highly susceptible to disease are often the proband.

We had hypothesized that exercise would play a lesser role in the pathogenesis of ARVC among females. In contrast, we found no evidence for this. The difference in exercise between affected and unaffected individuals was higher in females than in males. This suggests that exercise may be a more prominent etiologic factor in female than in male family members. The data convincingly show that among genotype-positive relatives, female athletes have a considerable risk for developing ARVC and that limiting exercise is as important, if not more so, than for their male relatives.

Limitations

Exercise history was collected retrospectively. Family members diagnosed with ARVC may be more likely to report exercise, which leads to recall bias. Furthermore, it is challenging to recall peak exercise intensity accuray, which may lead to understatement of the level of exertion practiced by some individuals. Also, exercise histories could not be obtained from deceased family members. While this is the largest study of exercise in family members of ARVC patients, we were nonetheless constrained by limited power, particularly in analyses stratified by sex and for the ventricular arrhythmia outcome. Last, as 80% of individuals in this study carried a pathogenic variant in PKP2, we were unable to address whether the effect of exercise varies by the genotype.

Conclusions and clinical implications

Our findings inform shared decision-making regarding exercise for genotype-positive ARVC family members. In addition to avoiding competitive or frequent high-intensity activities, limiting very long hours spent on more moderate exercise may also reduce risk. Exercising at moderate dose within the minimum range recommended for healthy adults may be a reasonable choice. There was no evidence that female relatives were at lower risk of developing ARVC than their male counterparts and indeed exercise seemed to play a particularly prominent role in promoting disease penetrance in females. Nonetheless, as some genotype-positive family members did not develop ARVC despite participating in high-dose exercise, patients’ values and preferences are a critical part of discussions about exercise.

Funding

The 2017 Clinical Research Award in Honour of Mark Josephson and Hein Wellens Scholarship from the Heart Rhythm Society (to W.W.) and by a grant from the Fondation Leducq’ (to H.C.). The Johns Hopkins ARVD/C Program is supported by the Leonie-Wild Foundation, Dr Francis P. Chiaramonte Private Foundation, the Leyla Erkan Family Fund for ARVD Research, the Dr Satish, Rupal, and Robin Shah ARVD Fund at Johns Hopkins, the Bogle Foundation, the Healing Hearts Foundation, the Campanella family, the Patrick J. Harrison Family, the Peter French Memorial Foundation, and the Wilmerding Endowments.

Conflict of interest: Dr H.C. is a consultant for Medtronic Inc. and Abbott, Inc. Dr H.C. receives research support from Boston Scientific Corp and Ms C.T. and Dr C.A.J. receive salary support from this grant. Dr H.T. receives research support from Abbott. All remaining authors have declared no conflicts of interest.

References