From the Cardiovascular Science Institute - ICCC; IIB-Sant Pau, Hospital de Sant Pau, Barcelona, Spain (G.C.-B., T.P., J.C., L.B.).
CiberCV, Institute Carlos III, Madrid, Spain (T.P., L.B.).
Arterioscler Thromb Vasc Biol. 2019 May;39(5):945-955. doi: 10.1161/ATVBAHA.118.312414.
Objective- Heterozygous familial hypercholesterolemia (FH) is the most common genetic disorder associated with premature atherosclerotic cardiovascular disease. Circulating microvesicles (cMV) are released when cells are activated. We investigated whether cMV could provide information on coronary calcification and atherosclerosis in FH patients. Approach and Results- Eighty-two patients (mean of 44±9 years old) with molecular diagnosis of heterozygous FH and asymptomatic cardiovascular disease were investigated. Atherosclerotic plaque characterization was performed by computed tomography angiography, and Agatston coronary calcium score and plaque composition sum were calculated. cMV were quantified by flow cytometry using AV (annexin V) and cell surface-specific antibodies. Of the 82 FH patients, 48 presented atherosclerotic plaque. Patients with atherosclerosis were men and older in a higher percentage than patients without atherosclerotic plaque. FH patients with atherosclerotic plaque showed higher levels of total AV cMV, cMV AV from platelet origin, from granulocytes and neutrophils, and cMV AV from endothelial cells than FH-patients without atherosclerotic plaque. Plaque composition sum correlated with platelet- and endothelial-derived cMV, and Agatston coronary calcium score correlated with granulocyte-, platelet-, and endothelial-derived cMV. Receiver operating characteristic curve analyses indicated that the cluster of platelet-, granulocyte-, neutrophil, and endothelial-derived cMV considered together, added significant predictive value to the specific SAFEHEART (Spanish Familial Hypercholesterolaemia Cohort Study) risk equation for plaque presence (area under the curve=0.866, 95% CI, 0.775-0.958; P<0.0001, P=0.030 for the increment of the area under the curve). Conclusions- Endothelial-, granulocyte-, neutrophil- and platelet-derived cMV discriminate and map coronary atherosclerotic plaque and calcification in asymptomatic patients with FH. Liquid biopsy of cMV may be a surrogate biomarker of coronary atherosclerotic plaque burden in FH patients.
目的-杂合子家族性高胆固醇血症（FH）是与早发动脉粥样硬化性心血管疾病相关的最常见遗传疾病。当细胞被激活时，会释放出循环微泡（cMV）。我们研究了 cMV 是否可以提供 FH 患者冠状动脉钙化和动脉粥样硬化的信息。
方法和结果- 对 82 名经分子诊断患有杂合子 FH 和无症状心血管疾病的患者进行了研究。通过计算机断层血管造影术进行动脉粥样硬化斑块特征分析，并计算出 Agatston 冠状动脉钙评分和斑块组成总和。通过流式细胞术使用 AV（膜联蛋白 V）和细胞表面特异性抗体对 cMV 进行定量。在 82 名 FH 患者中，有 48 名患者存在动脉粥样硬化斑块。患有动脉粥样硬化的患者中男性和年龄较大的比例高于没有动脉粥样硬化斑块的患者。与无动脉粥样硬化斑块的 FH 患者相比，有动脉粥样硬化斑块的 FH 患者的总 AV cMV、血小板来源的 cMV AV、来自粒细胞和中性粒细胞的 cMV AV 以及内皮细胞来源的 cMV AV 水平更高。斑块组成总和与血小板和内皮细胞衍生的 cMV 相关，Agatston 冠状动脉钙评分与粒细胞、血小板和内皮细胞衍生的 cMV 相关。受试者工作特征曲线分析表明，血小板、粒细胞、中性粒细胞和内皮细胞衍生的 cMV 簇一起考虑，对斑块存在的特定 SAFEHEART（西班牙家族性高胆固醇血症队列研究）风险方程具有显著的预测价值（曲线下面积=0.866，95%CI，0.775-0.958；P<0.0001，P=0.030 用于曲线下面积的增加）。
结论- 内皮细胞、粒细胞、中性粒细胞和血小板衍生的 cMV 可区分和描绘无症状 FH 患者的冠状动脉粥样硬化斑块和钙化。cMV 的液体活检可能是 FH 患者冠状动脉粥样硬化斑块负担的替代生物标志物。
