Rizza S, Copetti M, Rossi C, Cianfarani M A, Zucchelli M, Luzi A, Pecchioli C, Porzio O, Di Cola G, Urbani A, Pellegrini F, Federici M
Department of Systems Medicine, University of Rome "Tor Vergata", 00133 Rome, Italy.
Unit of Biostatistics, IRCCS, "Casa Sollievo della Sofferenza" San Giovanni Rotondo, FG, Italy.
Atherosclerosis. 2014 Feb;232(2):260-4. doi: 10.1016/j.atherosclerosis.2013.10.029. Epub 2013 Nov 18.
Age is one of the most important determinants of cardiovascular health, therefore the management of cardiovascular diseases (CVD) in elderly people entails great challenge. A possible explanation of vascular senescence process is the mitochondrial damage and dysfunction. We hypothesized that metabolomic profiling would identify biomarkers predicting major cardiovascular events (MACEs) in elderly people, improving the clinical standard cardiovascular risk factors.
Targeted-mass-spectrometry-based profiling of 49 metabolites was performed in a group of very old participants (n = 67, mean age = 85 ± 3 years) with a high rate of previous CVD (68%). Principal Component Analysis, Random Survival Forest analysis and Cox proportional hazards regression modeling were used to evaluate the relation between the metabolite factors and recurring MACEs. We tested discrimination ability and reclassification of clinical and metabolomic models. At follow-up (median = 3.5 years), 17 MACEs occurred (5 cardiovascular deaths, 1 nonfatal myocardial infarction, 7 nonfatal strokes and 4 peripheral artery surgeries) (incidence = 7.3% person-years). Metabolite factor 1, composed by medium- and long-chain acylcarnitines, and factor 7 (alanine) were independently associated with MACEs, after adjustment for clinical CV covariates [HR = 1.77 (95%CI = 1.11-2.81, p = 0.016) and HR = 2.18 (95%CI = 1.17-4.07, p = 0.014), respectively]. However, only factor 1 significantly increases the prediction accuracy of the Framingham Recurring-Coronary-Heart-Disease-Score, with a significant improvement in discrimination (integrated discrimination improvement = 7%, p = 0.01) and correctly reclassifying 41% of events and 37% of non-events resulting in a cNRI = 0.79 (p = 0.005).
Aging mitochondrial dysfunction evaluated by metabolomic profiling is associated with MACEs, independently of standard predictors.
年龄是心血管健康的最重要决定因素之一，因此老年人心血管疾病（CVD）的管理面临巨大挑战。血管衰老过程的一种可能解释是线粒体损伤和功能障碍。我们假设代谢组学分析将识别出预测老年人主要心血管事件（MACE）的生物标志物，从而改善临床标准心血管危险因素。
对一组既往CVD发生率较高（68%）的高龄参与者（n = 67，平均年龄 = 85 ± 3岁）进行了基于靶向质谱的49种代谢物分析。采用主成分分析、随机生存森林分析和Cox比例风险回归模型来评估代谢物因素与复发性MACE之间的关系。我们测试了临床和代谢组学模型的辨别能力和重新分类情况。在随访（中位数 = 3.5年）期间，发生了17例MACE（5例心血管死亡、1例非致命性心肌梗死、7例非致命性中风和4例外周动脉手术）（发病率 = 7.3%人年）。在调整临床心血管协变量后，由中链和长链酰基肉碱组成的代谢物因子1和因子7（丙氨酸）与MACE独立相关[HR分别为1.77（95%CI = 1.11 - 2.81，p = 0.016）和HR = 2.18（95%CI = 1.17 - 4.07，p = 0.014）]。然而，只有因子1显著提高了弗明汉复发性冠心病评分的预测准确性，在辨别能力上有显著改善（综合辨别改善 = 7%，p = 0.01），并正确重新分类了41%的事件和37%的非事件，导致cNRI = 0.79（p = 0.005）。
通过代谢组学分析评估的衰老线粒体功能障碍与MACE相关，独立于标准预测指标。
