Background and Aims

Elevated Lp(a) serum levels are associated with increased risk for atherosclerotic coronary artery disease and stroke. Here, we analyzed the effect of plasma Lp(a) levels on caspase-1 and the pro-inflammatory cytokines it processes. We further directly compare the molecular composition of Lp(a) and LDL isolated from the same donors as well as their pro-atherogenic and pro-inflammatory potential.

Methods

Human plasmas with varying Lp(a) levels and isolated Lp(a) and LDL were incubated with THP-1 macrophages for three hours and caspase-1 activation and the release of pro-inflammatory cytokines IL-1β, IL-1α, and IL-18 was measured. Molecular composition of Lp(a) and LDL isolated from the same donors was determined by lipidomics and proteomics approaches.

Results

Plasma Lp(a) levels ranging from 1.7 to 165.3 mg/dL correlated significantly with caspase-1 activity (r = 0.496), IL-18 (r = 0.496), and IL-1α (r = 0.447) in macrophages. IL-1β secretion correlated significantly with plasma triglycerides, and not with Lp(a) levels.

Lipidomics comparison of LDL and Lp(a) indicated that Lp(a) was significantly depleted of poly-unsaturated fatty acids in all lipid classes. Proteomics analyses revealed that Lp(a) is enriched in inflammation-associated proteins. Lp(a) from induced robust and dose-dependent caspase-1 activation and release of IL-1β and IL-18 compared to a mild induction upon incubation with LDL from the same donors.

Conclusions

Our data show that plasma Lp(a) levels directly correlate with inflammasome activation in macrophages, isolated Lp(a) induces stronger dose-dependent caspase-1 activation than LDL, and LDL and Lp(a) have clear structural differences additionally to apo(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. While previous studies have shown the atherogenicity of Lp(a) on monocyte activation and migration as well by activation of the vessel wall, the atherosclerotic plaque phenotype of individuals with elevated Lp(a) levels have not been studied up till now.

Methods

Therefore, we measured Lp(a) levels in 1506 subjects of the Athero-Express Biobank located at the University Medical Centre Utrecht, The Netherlands. Athero-Express started in 2002 and is a prospective ongoing biobank study that includes all patients undergoing carotid or iliofemoral endarterectomy in two referral hospitals in the Netherlands. From these 1506 subjects we compared the plaques from patients with extremely high (>195 mg/dl; N=57) and low (<7 mg/dl; N=106) Lp(a) levels.

Results

Analysis showed that plaques from patients with elevated Lp(a) levels demonstrated a 33% increase in blood vessel area per plaque, indicating an increased plaque angiogenesis. Intraplaque neovascularization has been shown to drive the progression of atherosclerosis and enhance plaque instability leading to increased cardiovascular risk.

Conclusions

So far, we have shown that human arterial endothelial cells stimulated with Lp(a) show enhanced collagen degradation capacity, probably due to increased migratory capacity and matrix metalloproteinase (MMP) activity. By using whole plaque RNA sequencing, combined with immunohistochemistry and ex-vivo validation studies (data available at the EAS 2021), we aim to further characterise the plaque phenotype in patients with elevated levels of Lp(a) and thereby provide more insight in the atherogenic potential of Lp(a).

Background and Aims

We tested the hypotheses (i) that elevated lipoprotein(a) is causally associated with both mitral and aortic valve calcification, and (ii) that aortic valve calcification mediates the effect of elevated lipoprotein(a) on aortic valve stenosis.

Methods

From the Copenhagen General Population study, we included 12,006 individuals who underwent cardiac computed tomography to measure mitral and aortic valve calcification. Participants had information on plasma lipoprotein(a), LPA kringle IV type 2 number of repeats; and two single nucleotide polymorphisms (LPA rs10455872 and rs3798220); genetic instruments known to be associated with plasma lipoprotein(a). These instruments were used to investigate the genetic association of lipoprotein(a) with mitral and aortic valve calcification to indicate causality.

Results

At age 70-79, 29% and 54% had mitral and aortic valve calcification. For 10-fold higher lipoprotein(a) levels, multifactorially adjusted odds ratios for mitral and aortic valve calcification were 1.26 (95% CI: 1.13-1.41) and 1.65 (1.50-1.81). Correspondingly, for ≤23 versus ≥36 kringle IV type 2 number of repeats the age and sex adjusted odds ratios for mitral and aortic valve calcification were 1.53 (1.18-1.99) and 2.23 (1.81-2.76). For carriers versus non-carriers of LPA rs10455872, odds ratios for mitral and aortic valve calcification were 1.33 (1.13-1.57) and 1.86 (1.64-2.13). For aortic valve stenosis, 20% (95% CI: 12%-28%) of the effect of lipoprotein(a) was mediated through calcification.

Conclusions

Elevated lipoprotein(a) was causally from human genetics and observationally associated with both mitral and aortic valve calcification. Aortic valve calcification mediated 20% of the effect of elevated lipoprotein(a) on aortic valve stenosis.

Background and Aims

Aortic stenosis is most common valvular heart disease in the Western world. Lipoprotein(a) [Lp(a)] is an independent risk factor of atherosclerotic cardiovascular diseases (ASCVD) and calcific aortic valve stenosis (CAVS).

To assess the role of Lp(a) as well as autoantibodies to Lp(a) in CAVS in patients with and without ASCVD.

Methods

The study included 250 patients (mean age 69±3, males 42%) that were divided into 3 groups. There were 2 groups of patients with CAVS depending on presence (group 1) or absence of ASCVD (group 2). Control group included the patients without ASCVD or CAVS. Lipids, Lp(a), autoantibodies to Lp(a) and Cu²⁺oxidized Lp(a) [autoAbs to oxLp(a)] were measured in serum for all the patients.

Results

Indicators of aortic stenosis severity in group 2 were significant higher than in group 1: median [25;75%] of maximum jet velocity 4.65 [3.77;5.28] vs 3.85 [2.6;4.5] m/s (p<0.05), mean gradient of pressure 52.9 [40.25;69.50] vs 41.0 [24.0;55.0] mmHg (p<0.05). Lp(a) level in group 1 was 22.6 [6.5;51.1] vs group 2 (14.0 [5.9;48.3]) and group 3 (12.1[4.9;25.1]) mg/dl, (p<0.05 for both). Level of IgM autoAbs to oxLp(a) in group 1 was (8.6 [7.3;10.5]) vs group 2 (9.4 [7.7;11.2]) and group 3 (11.6 [9.4;14.6] lab.units), p<0.001. According to multifactors logistic regression analysis concentration of Lp(a), level of IgM autoAbs to oxLp(a) (p<0.05 for both) and age (p<0.001) were independent predictors of CAVS.

Conclusions

Concentration of Lp(a) associated with CAVS in patients with ASCVD. The level of IgM autoAbs to oxLp(a) are associated with CAVS regardless ASCVD.

Background and Aims

Background:Lipoprotein(a) [Lp(a)] is a recognized cardiovascular risk factor. Lp(a) concentration in heterozygous familial hypercholesterolemia (heFH) is not well established. Whether the genetic defect responsible for heFH plays a role in determining Lp(a) concentration is unknown.

Aims:To study Lp(a) concentration in subjects genetically diagnosed with heFH and to assess the influence of the genetic defect responsible for heFH on its concentration.

Methods

Methods: Cross-sectional study, performed in a lipid clinic in Spain. We studied 511 heFH adults according to the responsible gene (LDLR, APOB, APOE and PCSK9). We selected 443 subjects LDLR, 27 subjects APOB, 37 subjects carriers of the p.(Leu167del) mutation in APOE, and 4 subjects PCSK9.

Results

Results:

Lipid levels differed across gene groups after adjusting for age, sex, and BMI.Lp(a) concentration differed among subjects with LDLR, APOB, and APOE mutation(p <0.001).Median Lp(a) concentration was greatest in APOB-dependent FH 36.5 mg/dL(IQR 22.0,60.8),intermediate in LDLR-dependent FH,21.7 mg/dL (IQR 17.9, 26.4)(and independent on the affected LDL receptor protein domain) and lowest in carriers of the p.(Leu167del) mutation in APOE, 7.9 mg/dL (IQR 4.9,12.7).Lp(a) geometric means, adjusted for age, sex, and BMI differed significantly. The geometric mean of LPA KIV-2 repeats did not differ among the FH gene subgroups and the estimations and differences for Lp(a) remained unchanged after adjustment for the number of KIV-2 repeats.

Conclusions

Conclusions: The concentration of Lp(a) in heFH is depending on the responsible gene. Lp(a) concentration was gratest in APOB- dependent FH. In LDLR-dependent, FH Lp(a) levels are not different depending on the affected protein domain.