评估血浆神经酰胺作为肾脏病与心血管事件之间关系的中介物。

Evaluation of plasma sphingolipids as mediators of the relationship between kidney disease and cardiovascular events.

机构信息

Department of Medicine, University of Washington, United States.

出版信息

EBioMedicine. 2023 Sep;95:104765. doi: 10.1016/j.ebiom.2023.104765. Epub 2023 Aug 25.

DOI:10.1016/j.ebiom.2023.104765

PMID:37634384

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10474367/

Abstract

BACKGROUND

Sphingolipids are a family of circulating lipids with regulatory and signaling roles that are strongly associated with both eGFR and cardiovascular disease. Patients with chronic kidney disease (CKD) are at high risk for cardiovascular events, and have different plasma concentrations of certain plasma sphingolipids compared to patients with normal kidney function. We hypothesize that circulating sphingolipids partially mediate the associations between eGFR and cardiovascular events.

METHODS

We measured the circulating concentrations of 8 sphingolipids, including 4 ceramides and 4 sphingomyelins with the fatty acids 16:0, 20:0, 22:0, and 24:0, in plasma from 3,463 participants in a population-based cohort (Cardiovascular Health Study) without prevalent cardiovascular disease. We tested the adjusted mediation effects by these sphingolipids of the associations between eGFR and incident cardiovascular disease via quasi-Bayesian Monte Carlo method with 2,000 simulations, using a Bonferroni correction for significance.

FINDINGS

The mean (±SD) eGFR was 70 (±16) mL/min/1.73 m; 62% of participants were women. Lower eGFR was associated with higher plasma ceramide-16:0 and sphingomyelin-16:0, and lower ceramides and sphingomyelins-20:0 and -22:0. Lower eGFR was associated with risk of incident heart failure and ischemic stroke, but not myocardial infarction. Five of eight sphingolipids partially mediated the association between eGFR and heart failure. The sphingolipids associated with the greatest proportion mediated were ceramide-16:0 (proportion mediated 13%, 95% CI 8-22%) and sphingomyelin-16:0 (proportion mediated 10%, 95% CI 5-17%). No sphingolipids mediated the association between eGFR and ischemic stroke.

INTERPRETATION

Plasma sphingolipids partially mediated the association between lower eGFR and incident heart failure. Altered sphingolipids metabolism may be a novel mechanism for heart failure in patients with CKD.

FUNDING

This study was supported by T32 DK007467 and a KidneyCure Ben J. Lipps Research Fellowship (Dr. Lidgard). Sphingolipid measurements were supported by R01 HL128575 (Dr. Lemaitre) and R01 HL111375 (Dr. Hoofnagle) from the National Heart, Lung, and Blood Institute (NHLBI).

摘要

背景

神经酰胺是一类具有调节和信号作用的循环脂质，与 eGFR 和心血管疾病密切相关。慢性肾脏病（CKD）患者发生心血管事件的风险较高，与肾功能正常的患者相比，其某些血浆神经酰胺的浓度存在差异。我们假设循环神经酰胺部分介导了 eGFR 与心血管事件之间的关联。

方法

我们在无明显心血管疾病的人群队列（心血管健康研究）中，对 3463 名参与者的血浆中 8 种神经酰胺的浓度进行了测量，其中包括 4 种神经酰胺和 4 种鞘磷脂，这些鞘磷脂的脂肪酸为 16:0、20:0、22:0 和 24:0。我们使用了贝叶斯蒙特卡罗法进行了 2000 次模拟，通过 quasi-Bayesian 方法对这些神经酰胺进行了调整，以检验 eGFR 与心血管疾病之间的关联，并通过 Bonferroni 校正进行了显著性检验。

结果

平均（±SD）eGFR 为 70（±16）mL/min/1.73 m；62%的参与者为女性。较低的 eGFR 与较高的血浆神经酰胺-16:0 和鞘磷脂-16:0 有关，与较低的神经酰胺和鞘磷脂-20:0 和 -22:0 有关。较低的 eGFR 与心力衰竭和缺血性卒中的发病风险有关，但与心肌梗死无关。8 种神经酰胺中有 5 种部分介导了 eGFR 与心力衰竭之间的关联。与 eGFR 相关性最强的神经酰胺是神经酰胺-16:0（介导比例为 13%，95%CI 8-22%）和鞘磷脂-16:0（介导比例为 10%，95%CI 5-17%）。没有神经酰胺介导 eGFR 与缺血性卒中之间的关联。

解释

血浆神经酰胺部分介导了较低的 eGFR 与心力衰竭之间的关联。改变的神经酰胺代谢可能是 CKD 患者心力衰竭的一种新机制。

资金

本研究得到了 T32 DK007467 和 KidneyCure Ben J. Lipps 研究奖学金（Lidgard 博士）的支持。鞘脂类物质的测量工作得到了 R01 HL128575（Lemaitre 博士）和 R01 HL111375（Hoofnagle 博士）的支持，这两个项目均来自于美国国立心肺血液研究所（NHLBI）。