Stroes, Erik S.G.

Abstract Aims Lipoprotein(a) [Lp(a)] is a causal risk factor for cardiovascular events. However, the effect of Lp(a) on coronary plaque composition and high-risk plaque features has not been fully characterized. This study aimed to investigate the association between Lp(a) and coronary atherosclerotic plaque phenotype at the plaque level. Methods and results This study included 710 patients who underwent coronary computed tomography angiography (CCTA) and had Lp(a) measured between 2008 and 2024. CCTA scans were analysed with a previously validated artificial intelligence-based algorithm (AI-QCT, Cleerly Inc.). The association of Lp(a) with non-calcified and calcified plaque volumes and HRP features was evaluated at the plaque level using generalized estimating equation models adjusted for traditional cardiovascular risk factors. Among the 710 patients, the mean age was 56 ± 10 years and 379 (53%) were male. In total, 3642 plaques were identified. In the adjusted plaque-level analysis, elevated Lp(a) (≥150 nmol/L) was associated with an increase in non-calcified plaque volume per plaque (P = 0.009), but not with an increase in calcified plaque volume (P = 0.81). Furthermore, elevated Lp(a) (≥150 nmol/L) was strongly associated with the presence of high-risk plaque at the plaque level (adjusted odds ratio: 1.78, 95% CI: 1.25–2.54, P = 0.001), whereas low-density lipoprotein-cholesterol and high-sensitivity C-reactive protein were not (P > 0.05). Conclusion In this plaque-level CCTA study of 3642 individual plaques, elevated Lp(a) levels were independently associated with increased non-calcified plaque volume and with the presence of high-risk plaque, but not with calcified plaque volume. These findings elucidate the impact of Lp(a) on unstable plaque phenotypes, even in patients without prior cardiovascular events.

Background: The importance of protein glycosylation in regulating lipid metabolism is becoming increasingly apparent. We set out to further investigate this by studying patients with type I congenital disorders of glycosylation (CDGs) with defective N-glycosylation. Methods: We studied 29 patients with the 2 most prevalent types of type I CDG, ALG6 (asparagine-linked glycosylation protein 6)–deficiency CDG and PMM2 (phosphomannomutase 2)–deficiency CDG, and 23 first- and second-degree relatives with a heterozygous mutation and measured plasma cholesterol levels. Low-density lipoprotein (LDL) metabolism was studied in 3 cell models—gene silencing in HepG2 cells, patient fibroblasts, and patient hepatocyte-like cells derived from induced pluripotent stem cells—by measuring apolipoprotein B production and secretion, LDL receptor expression and membrane abundance, and LDL particle uptake. Furthermore, SREBP2 (sterol regulatory element-binding protein 2) protein expression and activation and endoplasmic reticulum stress markers were studied. Results: We report hypobetalipoproteinemia (LDL cholesterol [LDL-C] and apolipoprotein B below the fifth percentile) in a large cohort of patients with type I CDG (mean age, 9 years), together with reduced LDL-C and apolipoprotein B in clinically unaffected heterozygous relatives (mean age, 46 years), compared with 2 separate sets of age- and sex-matched control subjects. ALG6 and PMM2 deficiency led to markedly increased LDL uptake as a result of increased cell surface LDL receptor abundance. Mechanistically, this outcome was driven by increased SREBP2 protein expression accompanied by amplified target gene expression, resulting in higher LDL receptor protein levels. Endoplasmic reticulum stress was not found to be a major mediator. Conclusions: Our study establishes N-glycosylation as an important regulator of LDL metabolism. Given that LDL-C was also reduced in a group of clinically unaffected heterozygotes, we propose that increasing LDL receptor–mediated cholesterol clearance by targeting N-glycosylation in the LDL pathway may represent a novel therapeutic strategy to reduce LDL-C and cardiovascular disease.