Highlights
Key points
– In 84,699 UK Biobank participants (3,979 G+P- carriers) with 1‑week accelerometer data and 8 years median follow-up, higher moderate‑to‑vigorous physical activity (MVPA) was associated with lower incidence of atrial fibrillation (AF), heart failure (HF), myocardial infarction (MI), and stroke, regardless of genotype.
– For G+P- carriers, MVPA of roughly 100–400 minutes per week associated with the lowest risk estimates for major cardiovascular outcomes; hazard ratios (HRs) vs zero activity included AF 0.68 (95% CI 0.58–0.79), HF 0.58 (0.47–0.71), MI 0.49 (0.24–1.00), and stroke 0.35 (0.12–0.99).
– CMR indices of cardiac remodeling (LV size and LV mass) showed similar relationships with MVPA in carriers and noncarriers. Higher MVPA was not associated with increased risk of malignant ventricular arrhythmias (VAs) in G+P- carriers.
Background and clinical context
Advances in genetics have made it increasingly common to identify individuals who carry pathogenic or likely pathogenic variants associated with inherited cardiomyopathies (eg, hypertrophic cardiomyopathy [HCM], dilated cardiomyopathy [DCM], arrhythmogenic right ventricular cardiomyopathy [ARVC]) before they develop overt disease. These genotype‑positive, phenotype‑negative (G+P-) individuals present a clinical dilemma: physical activity delivers broad cardiovascular and general health benefits, but high‑intensity exercise has been implicated in disease penetrance and arrhythmic risk in certain inherited cardiomyopathies, particularly ARVC. As a result, clinicians and patients must balance the known benefits of guideline‑recommended MVPA against uncertain risks of disease progression in G+P- carriers.
Observational data that directly compare the effects of routine MVPA on cardiovascular outcomes and cardiac structure in G+P- versus noncarrier populations have been limited. The study by Ajufo et al. (JAMA Cardiol, 2025) leverages accelerometer‑measured activity and genomic data in the UK Biobank to address this gap.
Study design and methods
This was a population‑based cohort analysis of UK Biobank participants who had whole‑genome sequencing data, 1 week of wrist accelerometer–measured physical activity, and no prevalent heart failure, atrial fibrillation, diagnosed cardiomyopathy, prior malignant ventricular arrhythmia, or ICD. Recruitment took place at 22 UK assessment centers from February 2013 to December 2015. Median follow‑up for clinical outcomes was 8.0 years (IQR 7.5–8.5). Data were analyzed March 2024 to June 2025.
Exposure: minutes per week of moderate‑to‑vigorous physical activity (MVPA) derived objectively from wrist accelerometry.
Outcomes: incident cardiovascular events (AF, HF, MI, stroke), cardiac magnetic resonance (CMR) measures of cardiac remodeling (eg, left ventricular volumes and mass), and surrogate clinical outcomes of cardiomyopathy onset and malignant ventricular arrhythmias. Analyses compared associations in G+P- carriers versus genotype noncarriers and examined dose–response relationships across MVPA volume.
Covariates included standard demographic and clinical risk factors. Subgroup analyses examined variant groups (DCM-, HCM-, and ARVC-associated variants).
Key findings
Population and exposure
– N = 84,699 participants; mean age 62 ± 8 years; 57% women.
– N = 3,979 G+P- carriers identified by whole‑genome sequencing.
– MVPA was derived objectively from a single week of accelerometer wear.
Primary clinical outcomes
– Greater MVPA was associated with lower incidence of major cardiovascular outcomes in the whole cohort and in G+P- carriers specifically.
– In multivariable models among G+P- carriers, the hazard ratios at the optimal MVPA level (vs zero) were:
– AF: HR 0.68 (95% CI 0.58–0.79)
– HF: HR 0.58 (95% CI 0.47–0.71)
– MI: HR 0.49 (95% CI 0.24–1.00)
– Stroke: HR 0.35 (95% CI 0.12–0.99)
– The lowest risk estimates for most outcomes among G+P- carriers clustered between 100 and 400 minutes of MVPA per week — a range that overlaps with commonly recommended physical activity targets (eg, 150–300 min/week moderate activity).
Cardiac structure and remodeling (CMR subcohort)
– Among participants with CMR imaging, higher MVPA associated with modest increases in LV volumes and LV mass — patterns consistent with physiologic remodeling.
– The magnitude and direction of MVPA‑related remodeling were similar between G+P- carriers and noncarriers, suggesting no disproportionate adverse structural remodeling among carriers within the MVPA range studied.
Cardiomyopathy onset and ventricular arrhythmias
– For G+P- carriers, higher MVPA was associated with lower observed risk of incident clinical cardiomyopathy (HR at optimal MVPA vs 0 = 0.03; 95% CI, 0.00–0.98). This estimate has wide CI and likely reflects small event counts.
– There was no evidence that higher MVPA increased the risk of malignant ventricular arrhythmias (eg, HR at 400 minutes MVPA vs 0 = 0.98; 95% CI, 0.83–1.14).
Variant subgroup analyses
– Overall patterns were broadly consistent across variants associated with DCM, HCM, and ARVC.
– Precision was limited for ARVC‑associated variants because of smaller numbers, so findings should be interpreted cautiously for that group.
Statistical and clinical interpretation
– Associations were adjusted for multiple covariates; benefit was observed across outcomes with hazard ratios often in the 30–50% relative risk reduction range for active versus inactive participants.
– For MI and stroke, confidence intervals were wider reflecting fewer events and less precision for some outcomes.
Strengths
– Large sample size with genome sequencing to identify carriers, objective accelerometer data rather than self‑report, and CMR data in a substantial subcohort.
– Longitudinal follow‑up (median 8 years) with adjudicated clinical outcomes through linked health records.
– Direct comparison of MVPA associations in genotype carriers versus noncarriers addressing a clinically relevant question.
Limitations
– Observational design: residual confounding and reverse causation remain possible despite multivariable adjustment. Active participants may differ in unmeasured ways (health behaviors, healthcare access) that influence outcomes.
– Accelerometer data represent a 1‑week snapshot; activity patterns may change over long follow‑up.
– UK Biobank participants are a healthier, more socioeconomically advantaged sample than the general population, which may limit generalizability.
– Low event counts for some outcomes (incident cardiomyopathy, malignant VAs) and limited numbers of ARVC variant carriers resulted in wide confidence intervals and imprecise estimates for those endpoints.
– The study evaluated MVPA in the range typical for leisure and habitual activity; it did not test effects of repeated high‑intensity competitive training or long‑term extreme endurance exposure, which may carry different risks for some genetic cardiomyopathies.
Expert commentary and clinical implications
This study addresses an important clinical uncertainty: should genotype‑positive, phenotype‑negative individuals be discouraged from routine MVPA because of fear of provoking disease expression or arrhythmic events? The data provide reassuring evidence that, in this middle‑aged UK population, MVPA within and somewhat above guideline ranges was associated with cardiovascular benefit and not associated with excess adverse remodeling or arrhythmic events among G+P- carriers.
Implications for clinical practice
– For G+P- individuals, routine counseling can emphasize the cardiovascular and general health benefits of guideline‑recommended MVPA (typically 150–300 minutes per week of moderate intensity or equivalent).
– Clinical decisions should remain individualized. Phenotypic evaluation (ECG, imaging, symptoms, family history of sudden cardiac death), variant specifics (gene, variant pathogenicity), and patient goals (eg, recreational exercise vs elite competition) should guide counseling.
– The study does not provide evidence to support unqualified participation in sustained high‑intensity competitive sports for all G+P- carriers, particularly those with ARVC‑associated variants where prior evidence has suggested increased penetrance with endurance exercise.
Mechanistic considerations
– The similar pattern of physiologic remodeling (increased LV volume and mass) in carriers and noncarriers suggests that ordinary MVPA drives expected adaptive cardiac changes rather than pathological remodeling in G+P- individuals.
– Potential mechanisms by which MVPA reduces cardiometabolic events—improved blood pressure, lipid profile, insulin sensitivity, body weight, and endothelial function—apply equally to carriers and noncarriers and likely account for the observed risk reductions.
Research and practice gaps
– Prospective studies that track long‑term activity patterns and incident phenotypic conversion in younger G+P- cohorts, especially those engaging in high‑intensity training, are needed.
– Variant‑specific stratified studies (eg, PKP2 or desmosomal variants in ARVC vs sarcomeric variants in HCM) with larger numbers will help refine gene‑specific advice.
– Randomized trials of exercise (feasibility and safety) in genotype‑positive populations would be informative but may be difficult to conduct; pragmatic prospective registries are a feasible alternative.
Conclusion
In this large, well‑characterized cohort, objectively measured MVPA in the range of contemporary guideline recommendations was associated with lower risk of major cardiovascular outcomes and similar patterns of structural remodeling in genotype‑positive phenotype‑negative cardiomyopathy variant carriers compared with noncarriers. There was no signal of increased malignant arrhythmia risk associated with higher MVPA in carriers within the MVPA range studied. These findings support advising G+P- individuals that guideline‑recommended MVPA is likely beneficial and not clearly harmful, while emphasizing individualized counseling, phenotypic surveillance, and caution for exposure to extreme competitive training until more data are available.
Funding and clinicaltrials.gov
Funding and trial registration details are as reported in the original manuscript: Ajufo E, Kany S, Jurgens SJ, et al. Physical Activity and Cardiovascular Outcomes in Phenotype‑Negative Cardiomyopathy Variant Carriers. JAMA Cardiol. 2025. See the original article for detailed funding and disclosures. No clinicaltrials.gov registration applies to this observational analysis.
References
1. Ajufo E, Kany S, Jurgens SJ, Churchill TW, Guseh JS, Aragam KG, Nauffal V, Pirruccello JP, Choi SH, Lakdawala NK, Ho CY, Ellinor PT, Khurshid S. Physical Activity and Cardiovascular Outcomes in Phenotype‑Negative Cardiomyopathy Variant Carriers. JAMA Cardiol. 2025 Nov 8:e254466. doi:10.1001/jamacardio.2025.4466. PMID: 41205222; PMCID: PMC12596747.
2. Doherty A, Jackson D, Hammerla N, et al. Large scale population assessment of physical activity using wrist worn accelerometers: The UK Biobank study. Nat Commun. 2017;8:15012. doi:10.1038/ncomms15012.
3. World Health Organization. WHO Guidelines on physical activity and sedentary behaviour. 2020. Available at: https://www.who.int/publications/i/item/9789240015128 (accessed 2025).
