Lawler Patrick R, Akinkuolie Akintunde O, Chu Audrey Y, Shah Svati H, Kraus William E, Craig Damian, Padmanabhan Latha, Glynn Robert J, Ridker Paul M, Chasman Daniel I, Mora Samia
Center for Lipid Metabolomics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
J Am Heart Assoc. 2017 Jul 21;6(7):e005549. doi: 10.1161/JAHA.117.005549.
Levels of LDL (low-density lipoprotein) cholesterol in the population are declining, and increasing attention is being focused on residual lipid-related pathways of atherosclerotic cardiovascular disease risk beyond LDL cholesterol. Among individuals with low (<130 mg/dL) LDL cholesterol, we undertook detailed profiling of circulating atherogenic lipoproteins in relation to incident cardiovascular disease in 2 populations.
We performed proton nuclear magnetic resonance spectroscopy to quantify concentrations of LDL and VLDL (very low-density lipoprotein) particle subclasses in 11 984 JUPITER trial participants (NCT00239681). Adjusted Cox models examined cardiovascular disease risk associated with lipoprotein measures according to treatment allocation. Risk (adjusted hazard ratio [95%CI] per SD increment) among placebo-allocated participants was associated with total LDL particles (1.19 [1.02, 1.38]) and total VLDL particles (1.21 [1.04, 1.41]), as well as apolipoprotein B, non-high-density lipoprotein cholesterol, and triglycerides, but not LDL-c. Rosuvastatin reduced LDL measures but had variable effects on triglyceride and VLDL measures. On-statin levels of the smallest VLDL particle subclass were associated with a 68% per-SD (adjusted hazard ratio 1.68 [1.28, 2.22]) increase in residual risk-this risk was related to VLDL cholesterol and not triglyceride or larger VLDL particles. There was evidence that residual risk prediction during statin therapy could be significantly improved through the inclusion of key VLDL measures (Harrell C-index 0.780 versus 0.712; <0.0001). In an independent, prospective cohort of 4721 individuals referred for cardiac catheterization (CATHGEN), similar patterns of lipoprotein-related risk were observed.
Atherogenic lipoprotein particle concentrations were associated with cardiovascular disease risk when LDL cholesterol was low. VLDL lipoproteins, particularly the smallest remnant subclass, may represent unused targets for risk prediction and potential therapeutic intervention for reducing residual risk.
URL: http://www.clinicaltrials.gov. Unique identifier: NCT00239681.
人群中低密度脂蛋白（LDL）胆固醇水平正在下降，人们越来越关注除LDL胆固醇之外的动脉粥样硬化性心血管疾病风险的残留脂质相关途径。在LDL胆固醇水平较低（<130mg/dL）的个体中，我们对两个队列中循环中致动脉粥样硬化脂蛋白与心血管疾病发病情况进行了详细分析。
我们对11984名JUPITER试验参与者（NCT00239681）进行了质子核磁共振波谱分析，以量化LDL和极低密度脂蛋白（VLDL）颗粒亚类的浓度。根据治疗分配情况，调整后的Cox模型研究了与脂蛋白测量值相关的心血管疾病风险。在安慰剂组参与者中，风险（每标准差增加的调整后风险比[95%CI]）与总LDL颗粒（1.19[1.02,1.38]）、总VLDL颗粒（1.21[1.04,1.41]）以及载脂蛋白B、非高密度脂蛋白胆固醇和甘油三酯相关，但与LDL-c无关。瑞舒伐他汀降低了LDL测量值，但对甘油三酯和VLDL测量值有不同影响。他汀治疗时最小的VLDL颗粒亚类水平与残留风险每标准差增加68%相关（调整后风险比1.68[1.28,2.22]）——这种风险与VLDL胆固醇有关，而与甘油三酯或更大的VLDL颗粒无关。有证据表明，通过纳入关键的VLDL测量值，他汀治疗期间的残留风险预测可得到显著改善（Harrell C指数0.780对0.712；<0.0001）。在一个由4721名接受心脏导管检查的个体组成的独立前瞻性队列（CATHGEN）中，观察到了类似的脂蛋白相关风险模式。
当LDL胆固醇水平较低时，致动脉粥样硬化脂蛋白颗粒浓度与心血管疾病风险相关。VLDL脂蛋白，尤其是最小的残余亚类，可能是残留风险预测未被利用的靶点以及降低残留风险的潜在治疗干预靶点。
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