In this longitudinal population-based study, we explored the 12-year trajectories of muscle mass and strength in older adults with and without AF, while considering the baseline levels of the inflammatory markers GDF-15 and IL-6. Our findings showed that AF was associated with a steeper decline in the chair stand test performance. Declines in muscle mass and lower-limb strength were also greater in the AF/high-biomarker profiles compared to the non-AF/low-biomarker profiles, suggesting that individuals with AF and elevated inflammatory markers exhibited the most pronounced deterioration over time.

Our study revealed that individuals with AF showed a significant increase in duration to complete the chair stand test over the 12-year follow-up period, even after adjusting for clinical and socio-demographic covariates. The chair stand test assesses lower limb functionality and neuromuscular coordination [24, 27], indicating a decline in functional capacity. This result aligns with previous studies indicating that AF is linked to impaired lower limb function and mobility limitations, including longer chair-stand test durations, after adjusting for comorbidities and demographic variables [4, 6, 28]. AF may impair functional mobility through multiple pathways, including reduced cardiac output and cerebral blood flow, and an increased risk of stroke, that can contribute to cognitive and motor deficits. Its association with frailty may further increases the energy cost of walking, while polypharmacy and low physical activity, both common in AF, can also negatively affect mobility [4, 6]. Although no consensus exists on a cut‑off defining clinically meaningful deterioration in chair‑stand performance, previous population‑based work [29] suggests that a decline of approximately one second per year is associated with increased disability risk. Thus, the average annual change observed in individuals with AF in our study falls within a range considered clinically relevant in older adults.

Although previous studies found a significant decline in handgrip strength among patients with AF [4, 28], our overall findings did not show statistically significant reductions in handgrip strength or calf circumference. This may suggest that the association between AF and muscle decline was not uniform across all participants, but rather more evident in specific subgroups of AF combined with higher inflammatory levels. Consistent with this interpretation, we observed that individuals with elevated circulating levels of GDF-15 and IL-6, particularly those with AF, experienced more substantial losses in muscle mass and both upper and lower limb strength over time. These findings suggest a possible concurrent effect of systemic inflammation and mitochondrial stress on musculoskeletal deterioration in the context of AF, a condition already characterized by altered hemodynamics and cellular stress. Notably, GDF-15, a cytokine induced by cellular stress, has emerged as a sensitive biomarker of mitochondrial dysfunction to the point of being classified as mitokine [30,31,32]. This latter is upregulated in response to mitochondrial damage, oxidative stress, and impaired mitochondrial protein synthesis, all of which are commonly observed in aging and chronic disease states, including AF [30, 33]. Elevated GDF-15 has been linked to impaired physical function, frailty and sarcopenia [18, 19, 32], and evidence from the Atherosclerosis Risk in Communities Study (ARIC) indicates that high GDF-15 levels also predict the long-term risk of incident AF [34], underscoring its position at the intersection of cardiovascular and functional decline. In our cohort, individuals with higher baseline GDF-15 levels, regardless of AF status, had significant declines in both muscle mass and lower limb strength, suggesting that GDF-15 may contribute to, rather than merely reflect, impaired muscle performance. Similarly, IL-6, a pleiotropic cytokine involved in immune regulation, has been associated to mitochondrial stress and fragmentation, reduced oxidative phosphorylation, and increased reactive oxygen species in skeletal muscle [18], all of which contributes to muscle wasting. Elevated IL-6 contributes to oxidative stress in skeletal muscle by impairing the nuclear factor erythroid 2-related factor 2 antioxidant response (Nrf2), thereby promoting muscle degradation and functional decline [35]. In our study, higher IL-6 levels were associated with were associated with poorer chair stand performance and reduced muscle mass regardless of AF. These findings corroborate prior studies showing that IL-6 is a pro-inflammatory cytokine linked to muscular decline and impaired physical performance, including poor performance at the chair stand test, and increased cardiovascular risk [17, 36]

Taken together, these findings emphasize the relevance of assessing inflammatory and mitochondrial stress markers such as GDF-15 and IL-6 when evaluating muscle health in older adults with AF. These biomarkers may provide insight into the underlying cellular dysfunction that possibly leads to progressive muscle impairment and may represent interconnected manifestation of underlying aging processes. The convergence of systemic inflammation and AF-related physiological stressors, including endothelial dysfunction, heightened oxidative stress, reduced nitric oxide bioavailability, mitochondrial energy deficits, and compromised skeletal muscle perfusion, provides a possible framework for understanding why AF often co-occur with accelerated functional decline [6]. Rather than implying a causal pathway, these patterns may reflect a shared vulnerability state in which AF, chronic systemic inflammation, and declining muscle function emerge as interconnected features of biological aging. Nevertheless, it should be noted that, although aging is frequently accompanied by low-grade inflammation [37], circulating inflammatory marker levels are dynamic and may fluctuate in response to transient stressors, acute illnesses, or short-term physiological changes. As a result, a single time-point biomarker measurement may be subject to regression dilution bias [38], potentially attenuating the underlying association between inflammation, AF and longitudinal muscle decline. Additionally, AF status was only assessed at baseline, which prevents us from determining how AF and systemic inflammation relate both at the onset and over time. Future studies incorporating repeated assessments of inflammatory markers and AF status will be essential to clarify the temporal dynamics and to better understand the underlying pathophysiological mechanisms.

Results from our investigation underscore the importance of incorporating functional and muscular assessments in longitudinal studies of AF-related aging populations. The observed decline in chair stand performance among individuals with AF may reflect progressive impairments in the interplay between the musculoskeletal and cardiovascular systems. Regular evaluations of lower limb function may therefore be a practical and cost-effective approach for monitoring functional decline in clinical settings. Although inflammatory biomarkers were measured only at baseline, their associations with long-term muscle trajectories support their role in risk stratification for older adults with AF. Circulating GDF-15 and IL-6, rather than serving solely as diagnostic markers, could be integrated into a multidimensional geriatric assessment to complement clinical and functional evaluation with information on systemic inflammation and mitochondrial stress. Such combined assessment could help identify older individuals with AF who are at heightened risk of accelerated functional decline and who may benefit from timely preventive strategies. The interplay between systemic inflammation and AF-related muscle deterioration highlights the potential benefits of inflammation-targeted interventions to preserve physical function. In individuals with AF and elevated inflammatory markers, integrated management approaches, including targeted physical training (e.g., lower limb strengthening and endurance training), nutritional interventions and lifestyle modifications may help mitigate future physical decline. Early interventions may reduce the risk associated with AF, including falls, cognitive impairment, bleeding, and other cardiovascular complications [6]. Future longitudinal and interventional studies are needed to evaluate concurrent changes in inflammatory biomarkers and muscle performance, and to determine whether biomarker-guided preventive strategies can attenuate muscle decline and improve long-term functional outcomes in older adults with AF.

Key strengths of this study include the longitudinal population-based design, the application of two different muscle strength measurements, and the repeated assessments over 12 years within the SNAC-K cohort. In addition, results were adjusted for several confounders, and the robustness of the findings was confirmed with sensitivity analysis. However, several limitations warrant discussion. First, SNAC-K participants are healthier and of higher socioeconomic status compared with the general Swedish population, potentially affecting the generalizability of our results. In addition, 39% of the original cohort was excluded due to missing data on key variables and exclusion criteria. Comparison of included and excluded participants showed that excluded participants were older and had higher burden of comorbidities. Therefore, the association between AF, inflammation, and muscle decline may be underestimated or potentially distorted due to healthy participant bias. Calf circumference was used as a proxy for muscle mass, in line with the EWGSOP2 recommendations [21] indicating that it may be used when more precise methods (e.g., bioelectrical impedance analysis) are unavailable. However, it is an indirect measure and may be influenced by adiposity or peripheral edema, particularly relevant in AF, where fluid retention is common. However, edema would be expected to inflate calf circumference and thereby bias results toward underestimating true muscle loss. The fact that the association persisted despite this potential attenuation suggests that the underlying relationship between inflammation, AF, and muscle mass decline is unlikely to be explained by measurement limitations alone.

Moreover, biomarker assessments were restricted to baseline values, without the possibility of evaluating changes over time in inflammatory levels. AF status was defined at baseline, and we did not model incident AF during follow-up. Consequently, some participants classified as non-AF at baseline may have developed AF later, and we cannot fully disentangle whether muscle decline preceded or followed AF onset in these individuals. This temporal ambiguity raises the possibility of reverse causation or shared underlying pathology rather than a strictly causal effect of AF on muscle decline. Accordingly, our findings should be interpreted as reflecting long-term associations and differential trajectories rather than definitive causal relationships. Finally, although we accounted for several key confounders, residual confounding from unmeasured factors such as subclinical cardiac conditions, or nutritional status and protein intake, may still be present.