Biological and Clinical Complexity in Atrial Fibrillation and Sarcopenia: Insights from Early-Life Exposures, Multimorbidity and Polymedication Patterns, and Longitudinal Muscle Outcomes

Background The aging population has raised attention to sarcopenia and atrial fibrillation (AF) are two common conditions that are highly prevalent and associated with adverse clinical outcomes. However, the biological pathway contributing to impaired muscle health and functional decline in older adults remains to be elucidated. This thesis investigated the impact of early-life factors, multimorbidity, polymedication, and inflammation on vulnerability to sarcopenia and adverse outcomes in AF patients. Aim This thesis adopted a life-course aspect to investigate: (1) the developmental origins of sarcopenia; (2) the identification of comorbidity and polymedication patterns in AF patients and their link with adverse outcomes; and (3) longitudinal trajectories in muscle mass and strength among AF patients, considering the impact of baseline inflammatory markers. Method The first study was a narrative review bringing together findings regarding low birth weight, the developmental origins of health and disease theory, epigenetic alterations, chronic inflammation, and their associations with sarcopenia onset in later life. The second study involved 633 AF patients under direct oral anticoagulant therapy, and applied latent class analysis to identify patterns of comorbidity and polymedication, and assessed the risk of thromboembolism, bleeding, falls, and mortality using Cox models. The third study used 12 years of longitudinal Swedish cohort data to compare trajectories of muscle mass and strength between patients with AF and those without AF, while assessing the role of inflammatory biomarkers (IL-6 and GDF-15). Results The first study emphasized the role of early-life determinants, including intrauterine growth restrictions, low birth weight, on the onset of sarcopenia in later life. The second study identified four distinct comorbidity and polymedication patterns in AF patients. Between those, neurocognitive-psychiatric and musculoskeletal-immunological patterns exhibited significantly increased risk of adverse clinical events. The third study revealed that patients with AF experienced accelerated decrease in muscular strength compared to non-AF individuals, with increased levels of IL-6 and GDF-15 amplified this association. Conclusions This thesis presents a comprehensive understanding of aging-related vulnerability demonstrating that the sarcopenia onset has association with the early life developmental programming. Moreover, distinct comorbidity-polymedication patterns were highlighted the heterogeneity of AF patients affecting their experience in adverse clinical outcomes. Additionally, muscle deterioration and functional decline among AF patients was amplified with increased levels of inflammatory markers. These findings promote the implementation of life-course approach to prevention, the integration of multimorbidity-polymedication profiles into AF management, and the investigation of inflammatory marker-targeted interventions to facilitate healthy aging.