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

Aims: Low-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 results: We 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. Conclusion: Our results identify the susceptibility of LDL to aggregate as a novel measurable and modifiable factor in the progression of human ASCVD.

68Ga-DOTA-RGD peptide: biodistribution and binding into atherosclerotic plaques in mice.

PURPOSE: Increased expression of αvß3/αvß5 integrin is involved in angiogenesis and the inflammatory process in atherosclerotic plaques. The novel 68Ga-DOTA-RGD peptide binds with high affinity to αvß3/αvß5 integrin. The aim of this study was to investigate the uptake of the 68Ga-DOTA-RGD peptide in atherosclerotic plaques. METHODS: Uptake of intravenously administered 68Ga-DOTA-RGD peptide was studied ex vivo in excised tissue samples and aortic sections of LDLR-/-ApoB100/100 atherosclerotic mice. The uptake of the tracer in aortic cryosections was examined by using digital autoradiography. Subsequently, the autoradiographs were combined with histological and immunohistological analysis of the sections. RESULTS: DOTA-RGD peptide was successfully labelled with the generator-produced 68Ga. The tracer had reasonably good specific radioactivity (8.7 ± 1.1 GBq/µmol) and was quite stable in vivo. According to ex vivo biodistribution results, 68Ga-DOTA-RGD was cleared rapidly from the blood circulation and excreted through the kidneys to the urine with high radioactivity in the intestine, lungs, spleen and liver. Autoradiography results showed significantly higher uptake of 68Ga-DOTA-RGD peptide in the atherosclerotic plaques compared to healthy vessel wall (mean ratio ± SD 1.4 ± 0.1, p = 0.0004). Conclusion We observed that 68Ga-DOTA-RGD is accumulated into the plaques of atherosclerotic mice. However, this data only shows the feasibility of the approach, while the clinical significance still remains to be proven. Further studies are warranted to assess the uptake of this tracer into human atherosclerotic plaques.