Physical Activity and Cardiovascular Outcomes in Phenotype-Negative Cardiomyopathy Variant Carriers

IMPORTANCE Exercise may lead to disease progression and higher risk of sudden death in individuals with genetic cardiomyopathies, but the effects of exercise among individuals carrying a cardiomyopathy-associated variant without clinical manifestations (G+P−) are unclear. OBJECTIVE To examine whether the effects of moderate to vigorous physical activity (MVPA) on cardiovascular (CV) outcomes, cardiac structure and function, and risk of developing overt cardiomyopathy and malignant ventricular arrhythmias (VAs) vary by G+P− status. DESIGN, SETTING, AND PARTICIPANTS UK Biobank participants with whole-genome sequencing providing 1 week of accelerometer-based physical activity data and without prevalent heart failure (HF), atrial fibrillation (AF), cardiomyopathy, VAs, or implantable cardioverter-defibrillators were included in this cohort study. The study was conducted at 22 assessment centers throughout the UK from February 2013 to December 2015 with a median follow-up of 8 years. Data were analyzed from March 2024 to June 2025. EXPOSURE Accelerometer-measured MVPA (minutes/week). MAIN OUTCOMES AND MEASURES Associations were analyzed between MVPA volume and future incidence of adverse CV outcomes (AF, HF, myocardial infarction [MI], and stroke), cardiac magnetic resonance (CMR)–based measures of cardiac remodeling, and surrogates for clinical cardiomyopathy onset (cardiomyopathy and VA). Associations were compared between G+P− carriers and noncarriers. RESULTS Among 84 699 individuals (mean [SD] age, 62 [8] years; 48 353 [57%] women; 3979 G+P− carriers), greater MVPA was associated with a lower risk of adverse CV outcomes over a median (IQR) 8.0 (7.5-8.5) years, irrespective of genotype. In multivariable models, higher MVPA was broadly associated with lower risk of incident CV disease in G+P− carriers (hazard ratio [HR] at optimal MVPA level vs zero [95%CI], AF: 0.68 [0.58–0.79]; HF: 0.58 [0.47-0.71]; MI: 0.49, [0.24-1.00]; stroke: 0.35 [0.12-0.99]). For G+P− carriers, MVPA in the range of 100 to 400 minutes per week was generally associated with lowest risk. Among individuals with CMR imaging, MVPA was associated with a similar pattern and extent of cardiac remodeling (eg, left ventricular dilation and left ventricular hypertrophy) in G+P− carriers vs noncarriers. Among G+P− carriers, higher MVPA was associated with lower risk of incident cardiomyopathy (HR at optimal MVPA vs 0, 0.03; 95% CI, 0.00-0.98) with no increase in risk of VA (eg, HR at 400 minutes of MVPA vs 0, 0.98; [95%CI], 0.83-1.14). Findings were generally consistent across variants associated with dilated cardiomyopathy, hypertrophic cardiomyopathy, or arrhythmogenic right ventricular cardiomyopathy, although precision of estimates for arrhythmogenic right ventricular cardiomyopathy were limited. CONCLUSIONS AND RELEVANCE In this cohort study, MVPA within the general range of guideline-based recommendations was associated with lower risk of adverse CV outcomes and similar degrees of cardiac remodeling for G+P− carriers compared to noncarriers. Findings support the appropriateness of guideline-based MVPA recommendations for G+P− carriers.