美洲印第安人心脏衰老和冠心病风险的纵向脂质组学标志物：强心家族研究

摘要(中文译文)

左心室舒张功能随年龄增长而下降是心脏衰老的标志性特征，也是心血管疾病的早期前兆。尽管血脂异常是冠心病的已知驱动因素，但将脂质代谢与心脏衰老及后续冠心病风险联系起来的分子通路仍知之甚少。此外，尚未在大型人群中系统开展心脏衰老的纵向脂质组学分析。我们采用非靶向液相色谱-质谱联用技术，在强心家族研究（SHFS）的两次临床检查中，对1801名美国印第安人的1542种空腹血浆脂质种类进行了重复测量（基线平均年龄：40.0岁；平均间隔：5.5年）。我们使用广义估计方程（GEE）检验了各脂质种类与心脏衰老指标（E/A比值、等容舒张时间和减速时间）之间的纵向关联，并校正了人口学、生活方式和临床因素。随后在博加卢萨心脏研究（BHS）中重复验证了显著关联（基线平均年龄：48.1岁）。采用脆弱Cox比例风险模型检验心脏衰老相关脂质是否可预测20年随访期间新发冠心病。我们发现，多种脂质种类（主要为甘油磷脂、甘油脂和鞘磷脂）与心脏衰老指标相关，其中大多数呈反向关联。部分关联在非洲裔美国人和白人参与者的双种族队列中得到证实。此外，与舒张功能（E/A比值和减速时间）相关的特定甘油磷脂和脂肪酸的基线水平与冠心病风险降低相关（HR范围：0.21-0.86）。相反，其他与E/A相关的甘油磷脂则与冠心病风险增加相关（HR范围：1.24-1.34）。总之，我们识别出与亚临床心脏衰老轨迹相关的独特脂质组学特征，其中若干特征还可预测晚年冠心病风险。这些发现凸显了从中年到老年阶段心脏衰老的分子相关物，并提示脂质组学通路或可作为未来冠心病的早期生物标志物。

Abstract

Age-related decline in left ventricular (LV) diastolic function is a hallmark of cardiac aging and an early precursor to cardiovascular disease. While dyslipidemia is a known driver of coronary heart disease (CHD), the molecular pathways linking lipid metabolism to cardiac aging and subsequent CHD risk remain poorly understood. Furthermore, longitudinal lipidomic profiling of cardiac aging in large human populations has not been systematically conducted. Using an untargeted LC-MS, we repeatedly measured 1542 fasting plasma lipid species in 1801 American Indians across two clinical exams in the Strong Heart Family Study (SHFS) (mean age at baseline: 40.0 years; mean interval: 5.5 years apart). We examined longitudinal associations between individual lipid species and measures of cardiac aging (E/A ratio, isovolumic relaxation time, and deceleration time) using generalized estimation equation (GEE), adjusted for demographic, lifestyle, and clinical factors. Significant associations were then replicated in the Bogalusa Heart Study (BHS) (mean age at baseline: 48.1 years). Frailty Cox proportional hazards models were used to examine whether cardiac aging-related lipids predicted incident CHD over a 20-year follow-up. We found that multiple lipid species, primarily glycerophospholipids, glycerolipids, and sphingomyelins, were associated with measures of cardiac aging, with the majority showing inverse associations. Some of these associations were confirmed in a biracial cohort of African American and White participants. Additionally, baseline levels of specific glycerophospholipids and fatty acids associated with diastolic function (E/A ratio and deceleration time) were linked to a reduced risk of CHD (HR range: 0.21-0.86). Conversely, other E/A-associated glycerophospholipids were linked to increased CHD risk (HR range: 1.24-1.34). In summary, we identified distinct lipidomic signatures associated with trajectories of subclinical cardiac aging, several of which also predict later-life CHD risk. These findings highlight molecular correlates of cardiac aging from midlife into older adulthood and suggest that lipidomic pathways may serve as early biomarkers for future: Keywords are required, The following are suggested: "Cardiac aging, Risk, Lipidomic markers". Please check if correct. CHD.

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