Costacou Tina, Vaisar Tomas, Miller Rachel G, Davidson W Sean, Heinecke Jay W, Orchard Trevor J, Bornfeldt Karin E
Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA 15261.
Department of Medicine, University of Washington, Seattle, WA 98109.
medRxiv. 2023 Nov 7:2023.11.06.23298165. doi: 10.1101/2023.11.06.23298165.
Cholesterol efflux capacity (CEC) negatively correlates with cardiovascular disease risk. Small HDL particles account almost quantitively for CEC, perhaps mediated through efflux of outer leaflet plasma membrane phospholipids by ABCA1. People with type 1 diabetes (T1D) are at increased risk of coronary artery disease (CAD) despite normal levels of HDL-cholesterol (HDL-C). We therefore tested the hypotheses that small HDL particles (HDL-P)-rather than HDL-C levels-predict incident CAD in T1D.
Incident CAD (CAD death, myocardial infarction, and/or coronary revascularization) was determined in a cohort of 550 participants with childhood-onset T1D. HDL-P was quantified by calibrated ion mobility analysis. CEC and phospholipid efflux were quantified with validated assays.
During a median follow-up of 26 years, 36.5% of the participants developed incident CAD. In multivariable Cox models, levels of HDL-C and apolipoprotein A-I (APOA1) did not predict CAD risk. In contrast, extra-small HDL particle levels strongly and negatively predicted risk (hazard ratio [HR]=0.25, 95% confidence interval [CI]=0.13-0.49). An increased concentration of total HDL particles (T-HDL-P) (HR=0.87, CI=0.82-0.92) and three other HDL sizes were weaker predictors of risk: small HDL (HR=0.80, 0.65-0.98), medium HDL (HR=0.78, CI=0.70-0.87) and large HDL (HR=0.72, CI=0.59-0.89). Although CEC negatively associated with incident CAD, that association disappeared after the model was adjusted for T-HDL-P. Isolated small HDLs strongly promoted ABCA1-dependent efflux of membrane outer leaflet phospholipids.
Low concentrations of T-HDL-P and all four sizes of HDL subpopulations predicted incident CAD independently of HDL-C, APOA1, and other common CVD risk factors. Extra-small HDL was a much stronger predictor of risk than the other HDLs. Our data are consistent with the proposal that small HDLs play a critical role in cardioprotection in T1D, which might be mediated by macrophage plasma membrane outer leaflet phospholipid export and cholesterol efflux by the ABCA1 pathway.
胆固醇流出能力（CEC）与心血管疾病风险呈负相关。小HDL颗粒几乎定量地决定了CEC，这可能是通过ABCA1介导的质膜外层小叶磷脂流出实现的。1型糖尿病（T1D）患者尽管HDL胆固醇（HDL-C）水平正常，但患冠状动脉疾病（CAD）的风险增加。因此，我们检验了以下假设：在T1D中，是小HDL颗粒（HDL-P）而非HDL-C水平预测CAD的发生。
在一个550名儿童期发病的T1D参与者队列中确定CAD的发生情况（CAD死亡、心肌梗死和/或冠状动脉血运重建）。通过校准离子迁移率分析对HDL-P进行定量。用经过验证的检测方法对CEC和磷脂流出进行定量。
在中位随访26年期间，36.5%的参与者发生了CAD。在多变量Cox模型中，HDL-C和载脂蛋白A-I（APOA1）水平不能预测CAD风险。相比之下，超小HDL颗粒水平强烈且负向预测风险（风险比[HR]=0.25，95%置信区间[CI]=0.13 - 0.49）。总HDL颗粒（T-HDL-P）浓度增加（HR=0.87，CI=0.82 - 0.92）以及其他三种HDL大小是较弱的风险预测指标：小HDL（HR=0.80，0.65 - 0.98）、中HDL（HR=0.78，CI=0.70 - 0.87）和大HDL（HR=0.72，CI=0.59 - 0.89）。尽管CEC与CAD的发生呈负相关，但在模型校正T-HDL-P后，这种关联消失了。分离出的小HDL强烈促进ABCA1依赖的膜外层小叶磷脂流出。
低浓度的T-HDL-P以及所有四种大小的HDL亚群独立于HDL-C、APOA1和其他常见的心血管疾病风险因素预测CAD的发生。超小HDL是比其他HDL更强的风险预测指标。我们的数据与以下观点一致，即小HDL在T1D的心脏保护中起关键作用，这可能是由巨噬细胞质膜外层小叶磷脂输出和通过ABCA1途径的胆固醇流出介导的。
