Susceptibility of low-density lipoprotein particles to aggregate depends on particle lipidome, is modifiable, and associates with future cardiovascular deaths

Abstract

AimsLow-density lipoprotein (LDL) particles cause atherosclerotic cardiovascular disease (ASCVD) through their retention, modification, and accumulation within the arterial intima. High plasma concentrations of LDL drive this disease, but LDL quality may also contribute. Here, we focused on the intrinsic propensity of LDL to aggregate upon modification. We examined whether inter-individual differences in this quality are linked with LDL lipid composition and coronary artery disease (CAD) death, and basic mechanisms for plaque growth and destabilization.Methods and resultsWe developed a novel, reproducible method to assess the susceptibility of LDL particles to aggregate during lipolysis induced ex vivo by human recombinant secretory sphingomyelinase. Among patients with an established CAD, we found that the presence of aggregation-prone LDL was predictive of future cardiovascular deaths, independently of conventional risk factors. Aggregation-prone LDL contained more sphingolipids and less phosphatidylcholines than did aggregation-resistant LDL. Three interventions in animal models to rationally alter LDL composition lowered its susceptibility to aggregate and slowed atherosclerosis. Similar compositional changes induced in humans by PCSK9 inhibition or healthy diet also lowered LDL aggregation susceptibility. Aggregated LDL in vitro activated macrophages and T cells, two key cell types involved in plaque progression and rupture.ConclusionOur results identify the susceptibility of LDL to aggregate as a novel measurable and modifiable factor in the progression of human ASCVD.

The effect of intakes of fish and Camelina sativa oil on atherogenic and anti-atherogenic functions of LDL and HDL particles: A randomized controlled trial

“…We have previously shown that 277 intake of CSO decreases serum LDL cholesterol compared with the fatty fish and lean fish 278 groups and IDL particle concentration compared with the lean fish group [25,32]. Taken [8]. Here, we found no change in the LDL aggregation among 287 the groups, but it should be noted that the individual differences in LDL aggregation were 288 large, as also reported earlier [8].…”

“…The susceptibility of LDL to aggregation has recently been shown to differ significantly 232 among human donors and to be associated with cardiovascular deaths [8]. Here, we again 233 found significant individual differences in LDL aggregation, but found no statistically…”

“…Modified lipoproteins may further aggregate or fuse 31 [4], which increases their binding strength to proteoglycans [5,6] and prevents their exit back 32 to the bloodstream [7]. The aggregation susceptibility of LDL varies among individuals and 33 was recently shown to associate with cardiovascular deaths [8]. LDL, particularly when 34 modified, also stimulate several atherogenic processes, such as interleukin-8 (IL-8) secretion 35 of endothelial cells, which induce the chemotactic recruitment of monocytes to the arterial 36 intima [1,9,10].…”

“…Physical activity, alcohol intake, smoking, body weight and use of 116 medications known to affect the measures of lipid metabolism were to be kept constant 117 during the study. As an objective measure of compliance, the proportions of plasma fatty 118 acids in phospholipids were measured using gas chromatography as previously described [28] 119 with an exception of using C19:0 as an internal standard instead of C17:0. aggregation by human recombinant sphingomyelinase as previously described [8]. LDL 139 aggregation was followed by measuring the particle size using dynamic light scattering.…”

High-Risk Atherosclerosis and Metabolic Phenotype: The Roles of Ectopic Adiposity, Atherogenic Dyslipidemia, and Inflammation

“…30,55 This concept is supported by the notion that a common underlying trait connecting lipoprotein metabolism to heart disease risk is the extent to which the condition influences the duration of exposure to arterial tissue, due to either the properties of the LDL-P (e.g., small LDL) or to reduced hepatic LDL receptor expression (e.g., in familial hypercholesterolemia). Further traits that have been associated with potentially higher atherogenicity of small LDL-P include compositional and conformational changes that render them more prone to retention, 64 aggregation, 65,66 and oxidation 64 in the arterial wall. Overall, there is not incontrovertible evidence supporting the concept that particle for particle, a small LDL-P (<25 nm) is more atherogenic than a large LDL-P.…”