Department of Vascular Medicine, Academic Medical Center, Amsterdam UMC, Amsterdam, the Netherlands. Electronic address: https://twitter.com/Zheng_KH.
Division of Cardiovascular Medicine, Sulpizio Cardiovascular Center, University of California, San Diego, La Jolla, California.
J Am Coll Cardiol. 2019 May 7;73(17):2150-2162. doi: 10.1016/j.jacc.2019.01.070.
Lipoprotein(a) [Lp(a)], a major carrier of oxidized phospholipids (OxPL), is associated with an increased incidence of aortic stenosis (AS). However, it remains unclear whether elevated Lp(a) and OxPL drive disease progression and are therefore targets for therapeutic intervention.
This study investigated whether Lp(a) and OxPL on apolipoprotein B-100 (OxPL-apoB) levels are associated with disease activity, disease progression, and clinical events in AS patients, along with the mechanisms underlying any associations.
This study combined 2 prospective cohorts and measured Lp(a) and OxPL-apoB levels in patients with AS (V >2.0 m/s), who underwent baseline F-sodium fluoride (F-NaF) positron emission tomography (PET), repeat computed tomography calcium scoring, and repeat echocardiography. In vitro studies investigated the effects of Lp(a) and OxPL on valvular interstitial cells.
Overall, 145 patients were studied (68% men; age 70.3 ± 9.9 years). On baseline positron emission tomography, patients in the top Lp(a) tertile had increased valve calcification activity compared with those in lower tertiles (n = 79; F-NaF tissue-to-background ratio of the most diseased segment: 2.16 vs. 1.97; p = 0.043). During follow-up, patients in the top Lp(a) tertile had increased progression of valvular computed tomography calcium score (n = 51; 309 AU/year [interquartile range: 142 to 483 AU/year] vs. 93 AU/year [interquartile range: 56 to 296 AU/year; p = 0.015), faster hemodynamic progression on echocardiography (n = 129; 0.23 ± 0.20 m/s/year vs. 0.14 ± 0.20 m/s/year] p = 0.019), and increased risk for aortic valve replacement and death (n = 145; hazard ratio: 1.87; 95% CI: 1.13 to 3.08; p = 0.014), compared with lower tertiles. Similar results were noted with OxPL-apoB. In vitro, Lp(a) induced osteogenic differentiation of valvular interstitial cells, mediated by OxPL and inhibited with the E06 monoclonal antibody against OxPL.
In patients with AS, Lp(a) and OxPL drive valve calcification and disease progression. These findings suggest lowering Lp(a) or inactivating OxPL may slow AS progression and provide a rationale for clinical trials to test this hypothesis.
脂蛋白(a)[Lp(a)]是氧化磷脂（OxPL）的主要载体，与主动脉瓣狭窄（AS）的发生率增加有关。然而，目前尚不清楚升高的 Lp(a)和 OxPL 是否会导致疾病进展，因此是否是治疗干预的靶点。
本研究旨在探讨 Lp(a)和载脂蛋白 B-100 上的 OxPL（OxPL-apoB）水平是否与 AS 患者的疾病活动度、疾病进展和临床事件相关，并探讨其潜在机制。
本研究结合了 2 项前瞻性队列研究，对 AS 患者（V>2.0 m/s）进行基线 F-氟化钠（F-NaF）正电子发射断层扫描（PET）、重复计算机断层扫描钙评分和重复超声心动图检查。体外研究探讨了 Lp(a)和 OxPL 对瓣状间充质细胞的影响。
共有 145 例患者入组（68%为男性；年龄 70.3±9.9 岁）。在基线正电子发射断层扫描中，最高 Lp(a)三分位组患者与较低三分位组患者相比，瓣环钙化活性增加（n=79；病变最严重节段的 F-NaF 组织与背景比值：2.16 比 1.97；p=0.043）。在随访期间，最高 Lp(a)三分位组患者的瓣环计算机断层扫描钙评分进展更快（n=51；309 AU/年[四分位距：142 至 483 AU/年]比 93 AU/年[四分位距：56 至 296 AU/年；p=0.015]），超声心动图上的血流动力学进展更快（n=129；0.23±0.20 m/s/年比 0.14±0.20 m/s/年；p=0.019），主动脉瓣置换和死亡风险增加（n=145；风险比：1.87；95%置信区间：1.13 至 3.08；p=0.014），与较低三分位组相比。OxPL-apoB 也有类似的结果。体外实验中，Lp(a)通过 OxPL 诱导瓣状间充质细胞的成骨分化，并通过针对 OxPL 的 E06 单克隆抗体抑制该作用。
在 AS 患者中，Lp(a)和 OxPL 驱动瓣环钙化和疾病进展。这些发现表明降低 Lp(a)或使 OxPL 失活可能会减缓 AS 的进展，并为临床试验提供了检验这一假设的依据。
