Associations of chronic pain and genetic risks with incident atrial fibrillation: a prospective cohort study.

Against the backdrop of a continuously deepening global trend of population aging [], the spectrum of human chronic diseases has undergone a fundamental transformation []. The single-disease model is increasingly being replaced by a complex multimorbidity pattern driven by systemic aging, which spans across organs and systems, and has become the primary cause of health loss in the elderly population [–]. This state of multimorbidity not only significantly exacerbates individuals’ risks of falls, disability, and premature death but also brings an unbearable dual burden of disease and economic costs to healthcare systems []. Crucially, multimorbidity is far from a simple superposition of multiple disease phenotypes at the “phenomenon” level; it involves complex interactions and synergistic deterioration of pathophysiological processes across multiple systems, posing major challenges for precise prevention, diagnosis, and treatment []. Therefore, moving beyond traditional single-disease classification systems to uncover the common mechanisms driving multimorbidity from a systemic perspective has become a core scientific issue urgently needing resolution in the fields of aging and chronic disease research. In this context, cardiometabolic multimorbidity (CMM)—defined as the co-occurrence of two or more cardiovascular and metabolic diseases (such as hypertension, type 2 diabetes, coronary atherosclerotic heart disease, etc.) in an individual—has emerged as a growing public health challenge, associated with high disability burdens and healthcare costs [, ]. Unlike single disease traits, CMM not only represents dysfunction in cardiovascular metabolism but also reflects multisystem-interactive metabolic disorders [–]. Its pathophysiological mechanisms involve synergistic dysregulation of organs such as bone, muscle, and heart [–]. Recent evidence indicates that CMM can significantly influence the onset and prognosis of chronic diseases across multiple systems [], particularly in terms of changes in body composition (abdominal obesity) [], low grip strength [], and bone loss (fractures) []. These emerging findings reflect a systemic imbalance along the Musculoskeletal-Heart crosstalk in the context of metabolic aging. Deepening the understanding of the comorbid mechanisms along this axis is crucial for advancing the shift from a “single-disease-centered” to a “systemic-health-centered” medical paradigm, as well as for developing precision medical strategies based on this axis. Building on a systematic cognitive paradigm of disease traits, frailty, as a core geriatric syndrome, has garnered widespread attention due to its strong correlation with CMM [, ]. Frailty characterizes a state of multisystem homeostatic imbalance in the human body []; it is not only a key aspect of the aging process but has also been proven to be a powerful driver and susceptibility “soil” for the development of various chronic diseases, including CMM, sarcopenia (SP), osteoporosis (OP), and other metabolism-related conditions [, ]. Observational studies have repeatedly demonstrated significant bidirectional associations between frailty and components of CMM, together forming a complex, mutually exacerbating disease network [], with systemic inflammation previously identified as a central hub in this network [–]. However, current research paradigms often treat metabolic abnormalities (e.g., insulin resistance, atherosclerosis) and physical aging (e.g., sarcopenia, osteoporosis) as parallel, independent risk dimensions [–]. The dynamic interactions between these dimensions in driving the onset and progression of CMM, as well as their shared biological underpinnings, remain a scientific black box that has yet to be thoroughly explored. Therefore, from a “multimorbidity” perspective, identifying high-risk populations for frailty states centered on CMM and elucidating the common genetic pathological mechanisms are key pathways for developing precise prevention and clinical diagnosis and treatment strategies.