Supplementary Material for: Higher sRAGE Levels Predict Mortality in Frail Older Adults with Cardiovascular Disease

<b><i>Introduction:</i></b> The evidence that blood levels of the soluble receptor for advanced glycation end products (sRAGE) predict mortality in people with cardiovascular diseases (CVD) is inconsistent. To clarify this matter, we investigated if frailty status influences this association. <b><i>Methods:</i></b> We analysed data of 1,016 individuals (median age, 75 years) from 3 population-based European cohorts, enrolled in the FRAILOMIC project. Participants were stratified by history of CVD and frailty status. Mortality was recorded during 8 years of follow-up. <b><i>Results:</i></b> In adjusted Cox regression models, baseline serum sRAGE was positively associated with an increased risk of mortality in participants with CVD (HR 1.64, 95% CI 1.09–2.49, <i>p</i> = 0.019) but not in non-CVD. Within the CVD group, the risk of death was markedly enhanced in the frail subgroup (CVD-F, HR 1.97, 95% CI 1.18–3.29, <i>p</i> = 0.009), compared to the non-frail subgroup (CVD-NF, HR 1.50, 95% CI 0.71–3.15, <i>p</i> = 0.287). Kaplan-Meier analysis showed that the median survival time of CVD-F with high sRAGE (&gt;1,554 pg/mL) was 2.9 years shorter than that of CVD-F with low sRAGE, whereas no survival difference was seen for CVD-NF. Area under the ROC curve analysis demonstrated that for CVD-F, addition of sRAGE to the prediction model increased its prognostic value. <b><i>Conclusions:</i></b> Frailty status influences the relationship between sRAGE and mortality in older adults with CVD. sRAGE could be used as a prognostic marker of mortality for these individuals, particularly if they are also frail.

<b><i>研究背景：</i></b> 目前关于晚期糖基化终产物可溶性受体（soluble receptor for advanced glycation end products, sRAGE）的血液水平能否预测心血管疾病（cardiovascular diseases, CVD）患者死亡率的相关研究证据并不一致。为厘清这一学术问题，本研究旨在探讨衰弱状态是否会对该关联产生影响。<b><i>研究方法：</i></b> 本研究纳入了FRAILOMIC项目旗下3个欧洲人群队列的1016名个体（中位年龄75岁）的相关数据开展分析。研究对象根据心血管疾病病史与衰弱状态进行分层分组，并在为期8年的随访期间记录所有研究对象的死亡事件。<b><i>研究结果：</i></b> 在校正后的Cox回归模型中，心血管疾病患者的基线血清sRAGE水平与死亡率升高呈正相关（风险比HR=1.64，95%置信区间CI=1.09~2.49，<i>p</i>=0.019），而非心血管疾病人群未观察到此类关联。在心血管疾病组内，与非衰弱亚组（CVD-NF，HR=1.50，95%CI=0.71~3.15，<i>p</i>=0.287）相比，衰弱亚组（CVD-F，HR=1.97，95%CI=1.18~3.29，<i>p</i>=0.009）的死亡风险显著升高。Kaplan-Meier分析结果显示，血清sRAGE水平较高（>1554 pg/mL）的衰弱型心血管疾病（CVD-F）患者的中位生存时间，较同亚组内sRAGE水平较低的患者缩短2.9年；而非衰弱型心血管疾病（CVD-NF）患者则未观察到生存时间差异。受试者工作特征（Receiver Operating Characteristic, ROC）曲线下面积分析显示，针对CVD-F亚组，在预后预测模型中加入sRAGE可提升其预测效能。<b><i>研究结论：</i></b> 衰弱状态会影响心血管疾病老年人群中sRAGE水平与死亡率之间的关联。sRAGE可作为此类心血管疾病老年患者死亡率的预后标志物，尤其对于同时合并衰弱的患者而言。