Carotid endarterectomy plaques of patients with elevated levels of lipoprotein(a) demonstrate increased intraplaque angiogenesis

Abstract

Background and Aims : Elevated lipoprotein(a) [Lp(a)] levels have been demonstrated to be a causal risk factor for the development of cardiovascular disease. Previously, we described that patients with elevated Lp(a) levels have an increased risk of major adverse cardiovascular events (MACE), mostly stroke, 30 days after undergoing carotid endarterectomy (CEA). Aim: Unravelling the mechanism underlying this increase in MACE.Methods: We performed targeted plasma proteomics analysis using the proximity extension assay for 276 proteins on complete plasma from patients undergoing CEA with high levels (>195 mg/dl; N=39) and low levels (<7 mg/dl; N=73) of Lp(a).Results: Surprisingly, no differences were observed in the expression of systemic plasma proteins. Hence, we started to assess the local effects of Lp(a) on plaque morphology. Plaque phenotyping demonstrated that patients with high levels (>195 mg/dl; N=57) of Lp(a) had a 33% increase in mean vessel density compared to patients with low levels (<7 mg/dl; N=106), as attested by semi-quantitatively scoring of the plaques. This increase in neovascularization correlates with decreased plaque stability, as was indicated by increased intraplaque haemorrhage. In-vitro stimulation of Human Arterial Endothelial Cells with physiologically relevant levels of Lp(a) (100 mg/dl), results in enhanced collagen degradation capacity, hyper-sprouting in a 3D spheroid assay and increased blood vessel invasion using a 3D collagen-invasiveness assay. Currently, we are elucidating the signalling pathways underlying this Lp(a)-induced angiogenesis, which we strive to present at the EAS 2022.Conclusions: Lp(a)-induced intraplaque angiogenesis can contribute to the increased risk of major adverse cardiovascular events in patients with elevated levels of Lp(a). Background and Aims : Elevated lipoprotein(a) [Lp(a)] levels have been demonstrated to be a causal risk factor for the development of cardiovascular disease. Previously, we described that patients with elevated Lp(a) levels have an increased risk of major adverse cardiovascular events (MACE), mostly stroke, 30 days after undergoing carotid endarterectomy (CEA). Aim: Unravelling the mechanism underlying this increase in MACE. Methods: We performed targeted plasma proteomics analysis using the proximity extension assay for 276 proteins on complete plasma from patients undergoing CEA with high levels (>195 mg/dl; N=39) and low levels (<7 mg/dl; N=73) of Lp(a). Results: Surprisingly, no differences were observed in the expression of systemic plasma proteins. Hence, we started to assess the local effects of Lp(a) on plaque morphology. Plaque phenotyping demonstrated that patients with high levels (>195 mg/dl; N=57) of Lp(a) had a 33% increase in mean vessel density compared to patients with low levels (<7 mg/dl; N=106), as attested by semi-quantitatively scoring of the plaques. This increase in neovascularization correlates with decreased plaque stability, as was indicated by increased intraplaque haemorrhage. In-vitro stimulation of Human Arterial Endothelial Cells with physiologically relevant levels of Lp(a) (100 mg/dl), results in enhanced collagen degradation capacity, hyper-sprouting in a 3D spheroid assay and increased blood vessel invasion using a 3D collagen-invasiveness assay. Currently, we are elucidating the signalling pathways underlying this Lp(a)-induced angiogenesis, which we strive to present at the EAS 2022. Conclusions: Lp(a)-induced intraplaque angiogenesis can contribute to the increased risk of major adverse cardiovascular events in patients with elevated levels of Lp(a).