Abstract Body (Do not enter title and authors here): Background: Exercise may lead to disease progression and higher risk of sudden death in certain cardiomyopathies conferred by rare genetic variants. Whether general activity recommendations (i.e.,150-300 minutes/week of moderate-to-vigorous physical activity (MVPA)] are appropriate for individuals carrying a cardiomyopathy-associated variant without overt disease (G+P-) are unclear.

Research Question: Do the effects of MVPA on cardiovascular (CV) outcomes, cardiac structure and function, and risk of developing overt cardiomyopathy and arrhythmias vary according to G+P- status?

Methods: In UK Biobank participants undergoing 1-week of accelerometry, we assessed: i) associations between MVPA (as a spline term) and incident CV outcomes (i.e.,atrial fibrillation [AF], heart failure [HF], myocardial infarction [MI], and stroke) using Cox models adjusted for demographic and lifestyle factors, deriving optimal levels of MVPA from splines for each outcome; ii) effects of MVPA on derived indices of cardiac structure and function in a subset with cardiac magnetic resonance (CMR) imaging; iii) effects on progression to overt cardiomyopathy and malignant arrhythmia using analogous models estimating risk of incident non-ischemic cardiomyopathy (NICM) and ventricular arrhythmias (VA). The presence of varying effects on account of G+P- status was assessed by comparing model results with non-carriers.

Results: Among 84,733 individuals (age 62±8 years, 56.4% women, 3,986 G+P-) undergoing accelerometry, MVPA levels were nearly identical for G+P- individuals and non-carriers (both medians:230, quartile-1:115, quartile-3:403). In multivariable models, higher MVPA was broadly associated with lower risk of incident CV disease in the G+P- group (hazard ratio[HR] at optimal MVPA level vs zero, 95% CI, AF:0.80, 0.69–0.92; HF:0.57, 0.47–0.69; MI:0.44, 0.33–0.58; stroke:0.34,0.24–0.50]) (Figure 1). MVPA was also associated with similar degrees of cardiac remodeling (e.g., LV dilation) in G+P- vs non-carriers (Figure 2). No associations were observed between MVPA and risk of NICM or VA in G+P- individuals.

Conclusions and Relevance: MVPA generally within the range of guideline-based recommendations associates with lower risk of adverse CV outcomes and similar degrees of cardiac remodeling for G+P- individuals compared to non-carriers. Although individual-level risk stratification remains critical, G+P- individuals should be encouraged to adhere to guideline-based activity recommendations.