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BACKGROUND: Despite current treatment strategies for atherosclerotic vascular disease focusing on lifestyle modification and lowering cholesterol, a significant residual risk of major atherosclerotic complication remains, prompting investigation into lipoprotein(a) (Lp(a)) as a potential predictive biomarker. The objective of this study was to determine the usefulness of Lp(a) in identifying patients at high risk of incident extracoronary atherosclerotic vascular disease and complications.METHODS: Data from 460 544 participants in the UK Biobank with prospectively measured Lp(a) concentrations were included in this analysis. Cox proportional hazards regressions modeled the associations of Lp(a) concentrations with incident peripheral artery disease (PAD) and incident carotid artery stenosis and progression to the first major adverse limb event and the first stroke, respectively.RESULTS: Of the study participants, the median [interquartile range] age at study enrollment was 58 [51-64] years, 54.2% were male, 94.4% were European, 5.5% had diabetes, and 10.5% were smokers. Over a median follow-up time of 13.6 [12.9-14.4] years, 6347 (1.4%) and 1972 (0.43%) developed the first incidence of PAD and carotid stenosis, respectively. Among participants with prevalent PAD and carotid stenosis at enrollment, 196 (2.7%) and 67 (1.9%) progressed to the first incidence of major adverse limb event and stroke, respectively. Median Lp(a) concentrations were significantly different in those without atherosclerotic vascular disease at 19.5 nmol/L [7.6-73.5] compared with incident PAD at 25.3 nmol/L [8.3-107.3], progression to major adverse limb event at 33.3 nmol/L [8.7-158.2], incident carotid stenosis at 29.5 nmol/L [8.5-116.3], and carotid stenosis progression to stroke at 37.8 nmol/L [11.1-158.3]. The risk estimate per 75 nmol/L Lp(a) for incident PAD (hazard ratio [HR], 1.18 [95% CI, 1.15-1.20]; <0.0001) was similar to that for incident carotid stenosis (HR, 1.17 [95% CI, 1.13-1.20]; <0.0001). Among participants with PAD, those with high Lp(a) concentrations had 1.57 times the risk of developing major adverse limb event than participants with normal Lp(a) concentrations (95% CI, 1.14-2.16; =0.006). Among participants with carotid stenosis, participants had 1.40 times the risk of developing an ischemic stroke with high Lp(a) concentrations, although this was not significant (95% CI, 0.81-2.40; =0.228).CONCLUSIONS: High concentrations of Lp(a) are associated with both incident extracoronary atherosclerotic vascular disease and progression to major complications.