Abstract Aims As promising compounds to lower Lipoprotein(a) (Lp(a)) are emerging, the need for a precise characterization and comparability of the Lp(a)-associated cardiovascular risk is increasing. Therefore, we aimed to evaluate the distribution of Lp(a) concentrations across the European population, to characterize the association with cardiovascular outcomes and to provide high comparability of the Lp(a)-associated cardiovascular risk by use of centrally determined Lp(a) concentrations. Methods and results Based on the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE)-project, we analysed data of 56 804 participants from 7 prospective population-based cohorts across Europe with a maximum follow-up of 24 years. All Lp(a) measurements were performed in the central BiomarCaRE laboratory (Biokit Quantia Lp(a)-Test; Abbott Diagnostics). The three endpoints considered were incident major coronary events (MCE), incident cardiovascular disease (CVD) events, and total mortality. We found lower Lp(a) levels in Northern European cohorts (median 4.9 mg/dL) compared to central (median 7.9 mg/dL) and Southern European cohorts (10.9 mg/dL) (Jonckheere–Terpstra test P < 0.001). Kaplan–Meier curves showed the highest event rate of MCE and CVD events for Lp(a) levels ≥90th percentile (log-rank test: P < 0.001 for MCE and CVD). Cox regression models adjusted for age, sex, and cardiovascular risk factors revealed a significant association of Lp(a) levels with MCE and CVD with a hazard ratio (HR) of 1.30 for MCE [95% confidence interval (CI) 1.15‒1.46] and of 1.25 for CVD (95% CI 1.12‒1.39) for Lp(a) levels in the 67‒89th percentile and a HR of 1.49 for MCE (95% CI 1.29‒1.73) and of 1.44 for CVD (95% CI 1.25‒1.65) for Lp(a) levels ≥ 90th percentile vs. Lp(a) levels in the lowest third (P < 0.001 for all). There was no significant association between Lp(a) levels and total mortality. Subgroup analysis for a continuous version of cube root transformed Lp(a) identified the highest Lp(a)-associated risk in individuals with diabetes [HR for MCE 1.31 (95% CI 1.15‒1.50)] and for CVD 1.22 (95% CI 1.08‒1.38) compared to those without diabetes [HR for MCE 1.15 (95% CI 1.08‒1.21; HR for CVD 1.13 (1.07–1.19)] while no difference of the Lp(a)- associated risk were seen for other cardiovascular high risk states. The addition of Lp(a) levels to a prognostic model for MCE and CVD revealed only a marginal but significant C-index discrimination measure increase (0.001 for MCE and CVD; P < 0.05) and net reclassification improvement (0.010 for MCE and 0.011 for CVD). Conclusion In this large dataset on harmonized Lp(a) determination, we observed regional differences within the European population. Elevated Lp(a) was robustly associated with an increased risk for MCE and CVD in particular among individuals with diabetes. These results may lead to better identification of target populations who might benefit from future Lp(a)-lowering therapies.

中文翻译：

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欧洲人群中的脂蛋白（a）与心血管疾病风险：BiomarCaRE 联盟的结果

摘要 目标随着有希望的降低脂蛋白（a）（Lp（a））的化合物的出现，对 Lp（a）相关心血管风险的精确表征和可比性的需求正在增加。因此，我们旨在评估 Lp(a) 浓度在欧洲人群中的分布，表征与心血管结局的关联，并通过使用集中确定的 Lp(a) 来提供与 Lp(a) 相关的心血管风险的高度可比性浓度。方法和结果 基于欧洲心血管风险评估生物标志物 (BiomarCaRE) 项目，我们分析了来自欧洲 7 个前瞻性人群队列的 56 804 名参与者的数据，最长随访时间为 24 年。所有 Lp(a) 测量均在中央 BiomarCaRE 实验室 (Biokit Quantia Lp(a)-Test; 雅培诊断）。考虑的三个终点是主要冠状动脉事件（MCE）、心血管疾病（CVD）事件和总死亡率。我们发现北欧队列（中位数 4.9 mg/dL）的 L​​p(a) 水平低于中部（中位数 7.9 mg/dL）和南欧队列（10.9 mg/dL）（Jonckheere-Terpstra 检验 P < 0.001）。Kaplan-Meier 曲线显示 Lp(a) 水平≥90% 的 MCE 和 CVD 事件的最高事件发生率（对数秩检验：对于 MCE 和 CVD，P < 0.001）。调整年龄、性别和心血管危险因素的 Cox 回归模型显示 Lp(a) 水平与 MCE 和 CVD 显着相关，MCE 的风险比 (HR) 为 1.30 [95% 置信区间 (CI) 1.15-1.46] CVD 为 1.25 (95% CI 1.12-1.39) Lp(a) 水平在第 67-89 个百分位数中，而 MCE 的 HR 为 1.49 (95% CI 1. 29-1.73) 和 1.44 (95% CI 1.25-1.65) Lp(a) 水平 ≥ 90% 与 Lp(a) 水平处于最低三分之一（所有 P < 0.001）。Lp(a) 水平与总死亡率之间没有显着关联。对立方根转换 Lp(a) 的连续版本的亚组分析确定了糖尿病患者的最高 Lp(a) 相关风险 [MCE 1.31 (95% CI 1.15-1.50)] 和 CVD 1.22 (95% CI 1.08-1.38) 与没有糖尿病的患者相比 [MCE 的 HR 1.15 (95% CI 1.08-1.21; CVD 的 HR 1.13 (1.07-1.19)]，而其他心血管高风险的 Lp(a) 相关风险没有差异风险状态。将 Lp(a) 水平添加到 MCE 和 CVD 的预后模型中仅显示 C 指数歧视测量值略有增加（MCE 和 CVD 为 0.001；P < 0。05）和净重新分类改进（MCE 为 0.010，CVD 为 0.011）。结论 在这个关于统一 Lp(a) 测定的大型数据集中，我们观察到欧洲人口中的区域差异。Lp(a) 升高与 MCE 和 CVD 风险增加密切相关，尤其是在糖尿病患者中。这些结果可能会导致更好地识别可能受益于未来降低 Lp(a) 疗法的目标人群。