LDL aggregation susceptibility as a novel risk factor for atherosclerosis

Atherosclerotic cardiovascular disease (ASCVD) is the leading worldwide cause of mortality and morbidity, being both an economic burden for healthcare systems and a source of great individual suffering. The low density lipoprotein cholesterol (LDL-C) concentration in plasma is a causal and modifiable risk factor for ASCVD. Atherogenesis is initiated and then driven by retention, modification, and aggregation of low density lipoprotein (LDL) particles in the arterial intima. Experimental work by our group and others has demonstrated that aggregated LDL particles can induce lipid accumulation in macrophages and this can also activate intimal cells and thereby induce inflammation in the arterial wall. Here, it was hypothesized that it is not only the plasma concentration of LDL particles that influences atherogenesis, but also their characteristics. This thesis aims at testing whether subjects with aggregation-prone LDL have an increased risk for ASCVD and/or ASCVD death. For this purpose, a method to measure LDL aggregation susceptibility was developed, and it was further studied if LDL aggregation susceptibility is modifiable. In addition, it is studied here if LDL aggregates cause a heightened inflammatory response in cells present in the artery wall. The first publication was a hypothesis-generating study, where it was discovered that LDL particles from ASCVD patients are more prone to aggregate in comparison to those from healthy individuals, and importantly, that aggregation-prone LDL predicted future ASCVD death in a group of patients with established ASCVD. It was found that the aggregation-prone LDL particles are rich in sphingolipids but have less phosphatidylcholines than their aggregation-resistant LDL counterparts. Three interventions in animal models aimed at altering the LDL composition, were observed not only to lower the susceptibility LDL particles to aggregate but also to slow the development of atherosclerosis. Similar compositional changes induced in humans by proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition or adoption of a healthy Nordic diet also lowered the LDL aggregation susceptibility. In the second publication it was demonstrated that genetic background, here ethnicity, influenced LDL aggregation susceptibility. LDL particles from South Asians were more prone to aggregate compared to those from white Caucasians, a finding that may partly explain why South Asians are at higher risk for ASCVD. The third study was a dietary intervention to investigate if different macronutrients could alter LDL particles aggregation susceptibility. Saturated fats were found to increase LDL aggregation, while unsaturated fats or simple sugars had no effect. In addition, the consumption of plant stanol esters, that are known to reduce the LDL-C concentration, was found to decrease the LDL aggregation susceptibility. This thesis propose that the aggregation susceptibility of LDL particles is a novel modifiable risk factor of ASCVD; its assessment may add predictive power to the conventional ASCVD risk estimation. The evaluation of this biomarker may facilitate the identification of those patients who would benefit most from aggressive LDL-C-lowering therapies.