Baritello Omar, Sündermann Simon H, Espinosa-Garnica Kristian, Kempfert Jörg, Jähnert Markus, Beetz Nick L, Geisel Dominik, Gaugel Jasmin, Rominger Julia, Müller-Werdan Ursula, Herpich Catrin, Norman Kristina, Chadt Alexandra, Al-Hasani Hadi, Völler Heinz, Salzwedel Annett, Vogel Heike
Department of Rehabilitation Medicine, Faculty of Health Sciences Brandenburg, University of Potsdam, Potsdam, Germany.
Research Group Molecular and Clinical Life Science of Metabolic Diseases, Faculty of Health Sciences Brandenburg, University of Potsdam, Potsdam, Germany.
J Cachexia Sarcopenia Muscle. 2025 Jun;16(3):e13846. doi: 10.1002/jcsm.13846.
Deterioration of functional capacity mostly determinates frailty in older patients with cardiovascular disease (CVD). Elucidating the pathophysiological mechanisms of physical frailty is an important goal for improving functional health-related outcomes. Our objective was the determination of the transcriptomic signature of physical frailty phenotypes in older patients undergoing cardiac surgery.
Patients aged ≥ 70 years, referred for elective cardiac surgery (e.g., coronary artery bypass graft) or transcatheter aortic valve implantation (TAVI) were recruited. At hospital admission, frailty was assessed based on moderately/severely impaired mobility (Timed Up and Go; ≥ 10 and ≥ 20 s), low gait speed (5-m Walk Test; ≥ 6 s) or reduced handgrip strength (male ≤ 27, female ≤ 16 kg). Muscle specimens (M. quadriceps femoris) were collected during surgery/intervention and used for total RNA isolation and sequencing. Differential gene expression analysis was performed using DESeq2 and regression analyses investigated association between frailty and gene expression levels.
Sixty-three patients (77.6 ± 4.3 years; 74% male) referred to cardiac surgery (n = 34, 54%) or TAVI (n = 29, 46%) were included. Overall, 43 patients (70.2%) were characterized as frail by moderately/severely impaired mobility, 19 (30.6%) by low gait speed and 19 (30.2%) by low handgrip strength. In total, 37 patients (59%) experienced ≥ 1 complication (e.g., need of transfusion, atrial fibrillation and delirium); one patient died. Based on transcriptome data, 10 overlapping genes between all physical frailty phenotypes were identified, with S100A1 showing the strongest differences in expression level (e.g., handgrip R = 0.579; p = 0.001). Additional functional studies in C2C12 myoblasts demonstrated the impact of S100A1 on muscle function, and a second independent human cohort confirmed that higher S100A1 blood levels were correlated with increased handgrip strength.
Our data highlight the potential role of S100A1 in the pathophysiological mechanisms of skeletal muscle impairments in older CVD patients and warrants further consideration as a target gene for physical frailty. These findings also advance our understanding of the genetic and biological factors contributing to frailty, potentially guiding future therapeutic strategies to mitigate its impact on health outcomes.
功能能力下降在很大程度上决定了老年心血管疾病（CVD）患者的虚弱状态。阐明身体虚弱的病理生理机制是改善与功能健康相关结局的重要目标。我们的目的是确定接受心脏手术的老年患者身体虚弱表型的转录组特征。
招募年龄≥70岁、因择期心脏手术（如冠状动脉搭桥术）或经导管主动脉瓣植入术（TAVI）就诊的患者。入院时，根据中度/重度活动能力受损（计时起立行走试验；≥10秒和≥20秒）、低步速（5米步行试验；≥6秒）或握力降低（男性≤27千克，女性≤16千克）评估虚弱状态。在手术/干预期间采集股四头肌肌肉标本，用于总RNA提取和测序。使用DESeq2进行差异基因表达分析，并通过回归分析研究虚弱与基因表达水平之间的关联。
纳入63例患者（77.6±4.3岁；74%为男性），其中34例（54%）接受心脏手术，29例（46%）接受TAVI。总体而言，43例患者（70.2%）因中度/重度活动能力受损被判定为虚弱，19例（30.6%）因步速低被判定为虚弱，19例（30.2%）因握力低被判定为虚弱。共有37例患者（59%）发生≥1种并发症（如输血需求、心房颤动和谵妄）；1例患者死亡。基于转录组数据，在所有身体虚弱表型中鉴定出10个重叠基因，其中S100A1在表达水平上差异最为显著（例如，握力R=0.579；p=0.001）。在C2C12成肌细胞中进行的额外功能研究证明了S100A1对肌肉功能的影响，另一个独立的人类队列证实，较高的S100A1血药浓度与握力增加相关。
我们的数据突出了S100A1在老年CVD患者骨骼肌损伤病理生理机制中的潜在作用，值得进一步考虑将其作为身体虚弱的靶基因。这些发现也增进了我们对导致虚弱的遗传和生物学因素的理解，可能为未来减轻其对健康结局影响的治疗策略提供指导。
